U.S. patent application number 10/324948 was filed with the patent office on 2003-06-19 for oxamic acids and derivatives as thyroid receptor ligands.
Invention is credited to Chiang, Yuan-Ching Phoebe, Dow, Robert L..
Application Number | 20030114521 10/324948 |
Document ID | / |
Family ID | 22401838 |
Filed Date | 2003-06-19 |
United States Patent
Application |
20030114521 |
Kind Code |
A1 |
Chiang, Yuan-Ching Phoebe ;
et al. |
June 19, 2003 |
Oxamic acids and derivatives as thyroid receptor ligands
Abstract
The present invention provides novel compounds of the Formula 1
and prodrugs thereof, geometric and optical isomers thereof, and
pharmaceutically acceptable salts of such compounds, prodrugs and
isomers, wherein R.sup.1--R.sup.8 and W are as described herein.
Pharmaceutical compositions containing such compounds, prodrugs,
isomers or pharmaceutically acceptable salts thereof, and methods,
pharmaceutical compositions and kits for treating obesity,
hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders,
thyroid disease, hypothyroidism and related disorders and diseases
such as diabetes mellitus, atherosclerosis, hypertension, coronary
heart disease, hypercholesteremia, depression and osteoporosis are
also provided.
Inventors: |
Chiang, Yuan-Ching Phoebe;
(East Lyme, CT) ; Dow, Robert L.; (Waterford,
CT) |
Correspondence
Address: |
PFIZER INC.
PATENT DEPARTMENT, MS8260-1611
EASTERN POINT ROAD
GROTON
CT
06340
US
|
Family ID: |
22401838 |
Appl. No.: |
10/324948 |
Filed: |
December 20, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10324948 |
Dec 20, 2002 |
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09966647 |
Oct 1, 2001 |
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6533456 |
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Current U.S.
Class: |
514/535 |
Current CPC
Class: |
A61P 19/00 20180101;
C07C 2601/02 20170501; C07D 211/14 20130101; C07D 217/08 20130101;
C07D 317/58 20130101; A61P 3/04 20180101; C07D 211/16 20130101;
C07D 217/04 20130101; C07D 295/096 20130101; C07D 209/08 20130101;
A61P 3/10 20180101; A61P 9/12 20180101; C07D 215/20 20130101; C07D
215/08 20130101; C07C 311/29 20130101; C07C 2601/14 20170501; C07C
2602/08 20170501; A61P 5/14 20180101; C07D 217/06 20130101; C07D
295/26 20130101; A61P 19/10 20180101; A61P 17/00 20180101; A61P
25/24 20180101; A61P 3/06 20180101; A61P 9/06 20180101; C07C
2602/42 20170501; C07D 333/20 20130101; C07C 2601/08 20170501; C07D
295/192 20130101; A61P 43/00 20180101; C07C 317/22 20130101; C07C
2602/10 20170501; A61P 9/00 20180101; A61P 27/06 20180101; A61P
5/48 20180101; C07C 2601/04 20170501; A61P 5/16 20180101; A61P 9/10
20180101; C07C 235/74 20130101 |
Class at
Publication: |
514/535 |
International
Class: |
A61K 031/24 |
Claims
What is claimed is:
1. A compound of the Formula 26a prodrug thereof; a geometric or
optical isomer thereof, or a pharmaceutically acceptable salt of
said compound, said prodrug, or said isomer, wherein: R.sup.1,
R.sup.2 and R.sup.3 are each independently hydrogen, halogen,
C.sub.1-6 alkyl, trifluoromethyl, --CN, --OCF.sub.3 or --OC.sub.1-6
alkyl; R.sup.4 is hydrogen, C.sub.1-12 alkyl optionally substituted
with one to three substitutents independently selected from Group
Z, C.sub.2-12 alkenyl, halogen, --CN, aryl, heteroaryl, C.sub.3-10
cycloalkyl, heterocycloalkyl, --S(O).sub.2NR.sup.9R.sup.10,
--C(O)NR.sup.9R.sup.10, --(C.sub.1-6 alkyl)-NR.sup.9R.sup.10,
--NR.sup.9C(O)R.sup.10, --NR.sup.9C(O)NR.sup.9R.- sup.10,
--NR.sup.9S(O).sub.2R.sup.10, --(C.sub.1-6 alkyl)--OR.sup.11,
--OR.sup.11 or --S(O).sub.aR.sup.12, provided that, where R.sup.5
is not fluoro, R.sup.4 is --S(O).sub.2NR.sup.9R.sup.10,
--C(O)NR.sup.9R.sup.10, --(C.sub.1-6 alkyl)-NR.sup.9R.sup.10,
--NR.sup.9C(O)R.sup.10, --NR.sup.9C(O)NR.sup.9R.sup.10,
--NR.sup.9S(O).sub.2R.sup.10, --(C.sub.1-6alkyl)-OR.sup.11,
--OR.sup.11 or --S(O).sub.aR.sup.12; or R.sup.3 and R.sup.4 may be
taken together to form a carbocyclic ring A of the formula
--(CH.sub.2).sub.b-- or a heterocyclic ring A selected from the
group consisting of --Q--(CH.sub.2).sub.c-- and
--(CH.sub.2).sub.j--Q--(CH.sub.2).sub.k-- wherein Q is O, S or
NR.sup.17, wherein said carbocyclic ring A and said heterocyclic
ring A are each independently optionally substituted with one or
more substituents independently selected from C.sub.1-4 alkyl,
halide or oxo; R.sup.5 is fluoro, hydroxy, C.sub.1-4 alkoxy or
OC(O)R.sup.9; or R.sup.4 and R.sup.5 may be taken together to form
a heterocyclic ring B selected from the group consisting of
--CR.sup.9.dbd.CR.sup.10--NH--, --N.dbd.CR.sup.9--NH--,
--CR.sup.9.dbd.CH--O-- and --CR.sup.9.dbd.CH--S--; R.sup.6 is
hydrogen, halogen, C.sub.1-4 alkyl or trifluoromethyl; R.sup.7 is
hydrogen or C.sub.1-6 alkyl; R.sup.8 is --OR.sup.9 or
--NR.sup.19R.sup.20; R.sup.9 and R.sup.10 for each occurrence are
independently (A) hydrogen, (B) C.sub.1-12 alkyl optionally
substituted with one or more substituents independently selected
from Group V, (C) C.sub.2-12 alkenyl, (D) C.sub.3-10 cycloalkyl
optionally substituted with one or more substituents independently
selected from C.sub.1-6 alkyl, C.sub.2-5 alkynyl, C.sub.3-10
cycloalkyl, --CN, --NR.sup.13R.sup.14, oxo, --OR.sup.18,
--COOR.sup.18 or aryl optionally substituted with X and Y, (E) aryl
optionally substituted with X and Y, or (F) het optionally
substituted with X and Y; or R.sup.9 and R.sup.10 for any
occurrence may be taken together to form a heterocyclic ring C
optionally further containing a second heterogroup selected from
the group consisting of --O--, --NR.sup.13-- and --S--, and
optionally further substituted with one or more substituents
independently selected from C.sub.1-5 alkyl, oxo,
--NR.sup.13R.sup.14, --OR.sup.18, --C(O).sub.2R.sup.18, --CN,
--C(O) R.sup.9, aryl optionally substituted with X and Y, het
optionally substituted with X and Y, C.sub.5-6 spirocycloalkyl, and
a carbocyclic ring B selected from the group consisting of 5-, 6-,
7- and 8-membered partially and fully saturated, and unsaturated
carbocyclic rings, and including any bicyclic group in which said
carbocyclic ring B is fused to a carbocyclic ring C selected from
the group consisting of 5-, 6-, 7-and 8-membered partially and
fully saturated, and unsaturated carbocyclic rings; R.sup.11 is
C.sub.1-12 alkyl optionally substituted with one or more
substituents independently selected from Group V, C.sub.2-12
alkenyl, C.sub.3-10 cycloalkyl, trifluoromethyl, difluoromethyl,
monofluoromethyl, aryl optionally substituted with X and Y, het
optionally substituted with X and Y, --C(O)NR.sup.9R.sup.10 or
--C(O)R.sup.9; R.sup.12 is C.sub.1-12 alkyl optionally substituted
with one or more substituents independently selected from Group V,
C.sub.2-12 alkenyl, C.sub.3-10 cycloalkyl, aryl optionally
substituted with X and Y, or het optionally substituted with X and
Y; R.sup.13 and R.sup.14 for each occurrence are independently
hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, --(C.sub.1-6
alkyl)-C.sub.1-6 alkoxy, aryl optionally substituted with X and Y,
het optionally substituted with X and Y, --(C.sub.1-4 alkyl)-aryl
optionally substituted with X and Y, --(C.sub.1-4
alkyl)-heterocycle optionally substituted with X and Y,
--(C.sub.1-4 alkyl)-hydroxy, --(C.sub.1-4 alkyl)-halo, --(C.sub.1-4
alkyl)-poly-halo, --(C.sub.1-4 alkyl)-CONR.sup.15R.sup.16 or
C.sub.3-10 cycloalkyl; R.sup.15 and R.sup.16 for each occurrence
are independently hydrogen, C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl
or aryl optionally substituted with X and Y; R.sup.17 is hydrogen,
C.sub.1-6 alkyl, --COR.sup.9 or --SO.sub.2R.sup.9; R.sup.18 is
hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, --(C.sub.1-6
alkyl)-C.sub.1-6 alkoxy, aryl optionally substituted with X and Y,
het optionally substituted with X and Y, --(C.sub.1-4 alkyl)-aryl
optionally substituted with X and Y, --(C.sub.1-4
alkyl)-heterocycle optionally substituted with X and Y,
--(C.sub.1-4 alkyl)-hydroxy, --(C.sub.1-4 alkyl)-halo, --(C.sub.1-4
alkyl)-poly-halo, --(C.sub.1-4 alkyl)-CONR.sup.15R.sup.16,
--(C.sub.1-4 alkyl)-(C.sub.1-4 alkoxy) or C.sub.3-10 cycloalkyl;
R.sup.19 is hydrogen or C.sub.1-6 alkyl; R.sup.20 is hydrogen or
C.sub.1-6 alkyl; W is O, S(O).sub.d, CH.sub.2 or NR.sup.9; Group Z
is C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen, --CF.sub.3,
--OCF.sub.3, hydroxy, oxo, --CN, aryl, heteroaryl, C.sub.3-10
cycloalkyl, hetercycloalkyl, --S(O).sub.aR.sup.12,
--S(O).sub.2NR.sup.9R.sup.10, --C(O)R.sup.9R.sup.10, and
--NR.sup.9R.sup.10; Group V is halogen, --NR.sup.13R.sup.14,
--OCF.sub.3, --OR.sup.9, oxo, trifluoromethyl, --CN, C.sub.3-10
cycloalkyl, aryl optionally substituted with X and Y, and het
optionally substituted with X and Y; het for each occurrence is a
heterocyclic ring D selected from the group consisting of 4-, 5-,
6-, 7- and 8-membered partially and fully saturated, and
unsaturated, heterocyclic rings containing from one to four
heteroatoms independently selected from the group consisting of N,
O and S, and including any bicyclic group in which said
heterocyclic ring D is fused to a benzene ring or a heterocyclic
ring E selected from the group consisting of 4-, 5-, 6-, 7- and
8-membered partially and fully saturated, and unsaturated,
heterocyclic rings containing from one to four heteroatoms
independently selected from the group consisting of N, O and S; X
and Y for each occurrence are independently (A) hydrogen, (B)
halogen, (C) trifluoromethyl, (D) --OCF.sub.3, (E) --CN, (F)
C.sub.1-6 alkyl optionally substituted with one or more
substituents independently selected from the group consisting of
halogen, --OCF.sub.3, --CF.sub.3 and phenyl, (G) C.sub.1-6 alkoxy,
(H) aryl optionally substituted with one or more substituents
independently selected from the group consisting of halogen,
--OCF.sub.3, --CF.sub.3, C.sub.1-4 alkyl and C.sub.1-4 alkoxy, (I)
--C(O).sub.2R.sup.13, (J) --C(O)NR.sup.13R.sup.14, (K)
--C(O)R.sup.13, (L) --NR.sup.13C(O)NR.sup.13R.sup.14 and (M)
--NR.sup.13C(O)R.sup.14; or X and Y for any occurrence in the same
variable may be taken together to form (a) a carbocyclic ring D of
the formula --(CH.sub.2).sub.e-- or (b) a heterocyclic ring F
selected from the group consisting of --O(CH.sub.2).sub.fO--,
(CH.sub.2).sub.gNH-- and --CH.dbd.CHNH--; a and d are each
independently 0, 1 or 2; b is 3, 4, 5, 6 or 7; c, f, g, j and k are
each independently 2, 3, 4, 5 or 6; and e is 3, 4, 5, 6 or 7.
2. A compound or pharmaceutically acceptable salt as defined in
claim 1 wherein W is oxygen.
3. A compound or pharmaceutically acceptable salt as defined in
claim 2 wherein R.sup.1 is located at the 3 position, R.sup.2 is
located at the 5 position, R.sup.3 is located at the 2' position,
R.sup.4 is located at the 3' position, R.sup.5 is located at the 4'
position, and R.sup.6 is located at the 5' position.
4. A compound or pharmaceutically acceptable salt as defined in
claim 3 wherein R.sup.3 is hydrogen, or R.sup.3 and R.sup.4 are
taken together to form a carbocyclic ring A of the formula
--(CH.sub.2).sub.b-- or a heterocyclic ring A selected from the
group consisting of --Q--(CH.sub.2).sub.c and
--(CH.sub.2).sub.j--Q--(CH.sub.2).sub.k-- wherein Q is O, S or
NR.sup.17, wherein said carbocyclic ring A and said heterocyclic
ring A are each independently optionally substituted with one or
more substituents independently selected from C.sub.1-4 alkyl,
halide or oxo, R.sup.5 is hydroxy, R.sup.6 is hydrogen and R.sup.7
is hydrogen.
5. A compound or pharmaceutically acceptable salt as defined in
claim 4 wherein R.sup.1 and R.sup.2 are each independently methyl,
bromo or chloro, and R.sup.8 is hydroxy, methoxy, ethoxy,
isopropoxy, NH.sub.2 or NH(CH.sub.3).
6. A compound or pharmaceutically acceptable salt as defined in
claim 5 wherein R.sup.4 is S(O).sub.2NR.sup.9R.sup.10, and R.sup.10
is hydrogen or methyl.
7. A compound or pharmaceutically acceptable salt as defined in
claim 6 wherein R.sup.1 is chloro, R.sup.2 is methyl, R.sup.8 is
ethoxy, R.sup.9 is ethyl and R.sup.10 is hydrogen.
8. A compound or pharmaceutically acceptable salt as defined in
claim 6 wherein R.sup.1 is chloro, R.sup.2 is methyl, R.sup.8 is
hydroxy, R.sup.9 is ethyl and R.sup.10 is hydrogen.
9. A compound or pharmaceutically acceptable salt as defined in
claim 6 wherein R.sup.1 is chloro, R.sup.2 is methyl, R.sup.8 is
ethoxy, R.sup.9 is n-butyl and R.sup.10 is hydrogen.
10. A compound or pharmaceutically acceptable salt as defined in
claim 6 wherein R.sup.1 is chloro, R.sup.2 is methyl, R.sup.8 is
hydroxy, R.sup.9 is n-butyl and R.sup.10 is hydrogen.
11. A compound or pharmaceutically acceptable salt as defined in
claim 6 wherein R.sup.1 is chloro, R.sup.2 is methyl, R.sup.8 is
ethoxy, R.sup.9 is --CH.sub.2-cyclopropyl and R.sup.10 is
hydrogen.
12. A compound or pharmaceutically acceptable salt as defined in
claim 6 wherein R.sup.1 is chloro, R.sup.2 is methyl, R.sup.8 is
hydroxy, R.sup.9 is --CH.sub.2-cyclopropyl and R.sup.10 is
hydrogen.
13. A compound or pharmaceutically acceptable salt as defined in
claim 6 wherein R.sup.1 is chloro, R.sup.2 is methyl, R.sup.8 is
isopropoxy, R.sup.9 is cyclopropyl and R.sup.10 is hydrogen.
14. A compound or pharmaceutically acceptable salt as defined in
claim 6 wherein R.sup.1 is chloro, R.sup.2 is methyl, R.sup.8 is
hydroxy, R.sup.9 is cyclopropyl and R.sup.10 is hydrogen.
15. A compound or pharmaceutically acceptable salt as defined in
claim 5 wherein R.sup.4 is S(O).sub.2NR.sup.9R.sup.10, and R.sup.9
and R.sup.10 are taken together with the nitrogen atom to which
they are attached to form N(CH.sub.2).sub.4, N(CH.sub.2).sub.5,
morpholine or 27
16. A compound or pharmaceutically acceptable salt as defined in
claim 15 wherein R.sup.9 and R.sup.10 are taken together with the
nitrogen atom to which they are attached to form
N(CH.sub.2).sub.4.
17. A compound or pharmaceutically acceptable salt as defined in
claim 15 wherein R.sup.9 and R.sup.10 are taken together with the
nitrogen atom to which they are attached to form 28
18. A compound or pharmaceutically acceptable salt as defined in
claim 6 wherein R.sup.9 is hydrogen, isopropyl,
--CH.sub.2-2-thienyl, --CH.sub.2-cyclopropyl, cyclopropyl,
--(CH.sub.2).sub.2OH, exo-2-norbornyl, methyl, ethyl,
4-fluorophenyl, cyclobutyl, cyclopentyl, cyclohexyl, n-propyl,
n-butyl, n-pentyl, n-hexyl, n-octyl or n-decyl.
19. A compound or pharmaceutically acceptable salt as defined in
claim 18 wherein R.sup.1 is chloro, R.sup.2 is methyl, R.sup.8 is
hydroxy, R.sup.9 is cyclopropyl and R.sup.10 is hydrogen.
20. A compound or pharmaceutically acceptable salt as defined in
claim 18 wherein R.sup.1 is chloro, R.sup.2 is methyl, R.sup.8 is
ethoxy, R.sup.9 is cyclopropyl and R.sup.10 is hydrogen.
21. A compound or pharmaceutically acceptable salt as defined in
claim 18 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
hydroxy, R.sup.9 is cyclopropyl and R.sup.10 is methyl.
22. A compound or pharmaceutically acceptable salt as defined in
claim 18 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
ethoxy, R.sup.9 is cyclopropyl and R.sup.10 is methyl.
23. A compound or pharmaceutically acceptable salt as defined in
claim 18 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
hydroxy, R.sup.9 is cyclobutyl and R.sup.10 is methyl.
24. A compound or pharmaceutically acceptable salt as defined in
claim 18 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
ethoxy, R.sup.9 is cyclobutyl and R.sup.10 is methyl.
25. A compound or pharmaceutically acceptable salt as defined in
claim 18 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
hydroxy, R.sup.9 is cyclopropyl and R.sup.10 is hydrogen.
26. A compound or pharmaceutically acceptable salt as defined in
claim 18 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
ethoxy, R.sup.9 is cyclopropyl and R.sup.10 is hydrogen.
27. A compound or pharmaceutically acceptable salt as defined in
claim 18 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
hydroxy, R.sup.9 is cyclobutyl and R.sup.10 is hydrogen.
28. A compound or pharmaceutically acceptable salt as defined in
claim 18 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
ethoxy, R.sup.9 is cyclobutyl and R.sup.10 is hydrogen.
29. A compound or pharmaceutically acceptable salt as defined in
claim 5 wherein R.sup.4 is --C(O)NR.sup.9R.sup.10, and R.sup.10 is
hydrogen, methyl or ethyl.
30. A compound or pharmaceutically acceptable salt as defined in
claim 29 wherein R.sup.9 is methyl, ethyl, isopropyl, n-propyl,
isobutyl, n-butyl, n-pentyl, n-hexyl, 4-fluorophenyl,
--CH.sub.2-2-thienyl, cyclopropyl, --CH.sub.2-cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, --CH.sub.2-cyclohexyl,
endo-2-norbornyl, exo-2-norbornyl, (S)-1-phenylethyl,
(R)-1-phenylethyl, --CH.sub.2-2-chlorophenyl,
--CH.sub.2-4-chlorophenyl, --CH.sub.2-4-fluorophenyl,
--CH.sub.2-3-chloro-4-fluorophenyl,
--CH.sub.2-2-chloro-4-fluorophenyl,
--CH.sub.2-2-fluoro-4-chlorophenyl, --CH.sub.2-3,4-difluorophenyl,
--CH.sub.2-4-isopropylphenyl, --CH.sub.2-2,3-dichlorophenyl,
--CH.sub.2-2,4-dichlorophenyl, --CH.sub.2-3,4-dichlorophenyl,
--CH.sub.2-3-trifluoromethyl-4-chlorophenyl, 4-phenylphenyl,
3-(2,4-dimethyl)pentyl, (R)-1-(1-naphthyl)ethyl,
1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl,
(R)-1-(2-naphthyl)ethyl, (R)-2-(1-naphthyl)ethyl,
--CH.sub.2-(1-naphthyl), (R)-1-cyclohexylethyl,
(S)-1-cyclohexylethyl, --CH.sub.2-3,4-methylenedioxyphenyl,
--CH.sub.2-4-t-butylphenyl, --CH.sub.2-2,3-dichlorophenyl,
1-indanyl, (R)-1-indanyl, (S)-1-indanyl, 5-indanyl,
1-(1,2,3,4-tetrahydronaphthyl) or (R)-1-cyclohexylethyl.
31. A compound or pharmaceutically acceptable salt as defined in
claim 30 wherein R.sup.1 is chloro, R.sup.2 is chloro, R.sup.8 is
ethoxy, R.sup.9 is 3-(2,4-dimethyl)pentyl and R.sup.10 is
hydrogen.
32. A compound or pharmaceutically acceptable salt as defined in
claim 30 wherein R.sup.1 is chloro, R.sup.2 is chloro, R.sup.8 is
hydroxy, R.sup.9 is 3-(2,4-dimethyl)pentyl and R.sup.10 is
hydrogen.
33. A compound or pharmaceutically acceptable salt as defined in
claim 30 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
hydroxy, R.sup.9 is cyclopropyl and R.sup.10 is methyl.
34. A compound or pharmaceutically acceptable salt as defined in
claim 30 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
ethoxy, R.sup.9 is cyclopropyl and R.sup.10 is methyl.
35. A compound or pharmaceutically acceptable salt as defined in
claim 30 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
hydroxy, R.sup.9 is cyclobutyl and R.sup.10 is methyl.
36. A compound or pharmaceutically acceptable salt as defined in
claim 30 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
ethoxy, R.sup.9 is cyclobutyl and R.sup.10 is methyl.
37. A compound or pharmaceutically acceptable salt as defined in
claim 30 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
hydroxy, R.sup.9 is 3-(2,4-dimethyl)pentyl and R.sup.10 is
hydrogen.
38. A compound or pharmaceutically acceptable salt as defined in
claim 30 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
ethoxy, R.sup.9 is 3-(2,4-dimethyl)pentyl and R.sup.10 is
hydrogen.
39. A compound or pharmaceutically acceptable salt as defined in
claim 30 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
hydroxy, R.sup.9 is n-pentyl and R.sup.10 is methyl.
40. A compound or pharmaceutically acceptable salt as defined in
claim 30 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
ethoxy, R.sup.9 is n-pentyl and R.sup.10 is methyl.
41. A compound or pharmaceutically acceptable salt as defined in
claim 30 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
hydroxy, R.sup.9 is isopropyl and R.sup.10 is methyl.
42. A compound or pharmaceutically acceptable salt as defined in
claim 30 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
ethoxy, R.sup.9 is isopropyl and R.sup.10 is methyl.
43. A compound or pharmaceutically acceptable salt as defined in
claim 30 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
hydroxy, R.sup.9 is cyclobutyl and R.sup.10 is methyl.
44. A compound or pharmaceutically acceptable salt as defined in
claim 30 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
ethoxy, R.sup.9 is cyclobutyl and R.sup.10 is methyl.
45. A compound or pharmaceutically acceptable salt as defined in
claim 30 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
NH.sub.2, R.sup.9 is cyclobutyl and R.sup.10 is methyl.
46. A compound or pharmaceutically acceptable salt as defined in
claim 30 wherein R.sup.1 is chloro, R.sup.2 is chloro, R.sup.8 is
hydroxy, R.sup.9 is cyclobutyl and R.sup.10 is methyl.
47. A compound or pharmaceutically acceptable salt as defined in
claim 30 wherein R.sup.1 is chloro, R.sup.2 is chloro, R.sup.8 is
ethoxy, R.sup.9 is cyclobutyl and R.sup.10 is methyl.
48. A compound or pharmaceutically acceptable salt as defined in
claim 1 wherein R.sup.4 is --C(O)NR.sup.9R.sup.10, and R.sup.9 and
R.sup.10 are taken together with the nitrogen atom to which they
are attached to form N(CH.sub.2).sub.7, N(CH.sub.2).sub.6,
N(CH.sub.2).sub.5, N(CH.sub.2).sub.4, morpholine, 29
49. A compound or pharmaceutically acceptable salt as defined in
claim 5 wherein R.sup.4 is --CH.sub.2NR.sup.9R.sup.10, and R.sup.10
is hydrogen, methyl or --COCH.sub.3.
50. A compound or pharmaceutically acceptable salt as defined in
claim 49 wherein R.sup.9 is methyl, n-propyl, isopropyl,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, exo-2-norbornyl,
--CH.sub.2-4-fluorophenyl, --CH.sub.2-4-chlorophenyl,
--CH.sub.2-4-isopropylphenyl, --CH.sub.2-3,4-methylenedioxyphenyl,
(R)-1-(1-naphthyl)ethyl, (R)-1-phenylethyl, (S)-1-phenylethyl,
(R)-1-cyclohexylethyl, 1-(1,2,3,4-tetrahydronaphthyl), 1-indanyl or
--CH.sub.2-(1-naphthyl).
51. A compound or pharmaceutically acceptable salt as defined in
claim 5 wherein R.sup.4 is --CH.sub.2NR.sup.9R.sup.10 wherein
R.sup.9 and R.sup.10 are taken together with the nitrogen atom to
which they are attached to form N(CH.sub.2).sub.6, morpholine,
30
52. A compound or pharmaceutically acceptable salt as defined in
claim 5 wherein R.sup.4 is --NHCOR.sup.9.
53. A compound or pharmaceutically acceptable salt as defined in
claim 52 wherein R.sup.9 is cyclopropyl or cyclobutyl.
54. A compound or pharmaceutically acceptable salt as defined in
claim 5 wherein R.sup.4 is --S(O).sub.2R.sup.12.
55. A compound or pharmaceutically acceptable salt as defined in
claim 54 wherein R.sup.12 is 4-chlorophenyl, phenyl, 1-naphthyl,
2-naphthyl, CH.sub.2-cyclopropyl, isopropyl, CH.sub.2-cyclobutyl,
CH.sub.2-cyclohexyl, cyclopentyl, CH.sub.2-4-fluorophenyl, 4-tolyl,
methyl, ethyl, n-butyl, CH.sub.2-phenyl or n-propyl.
56. A compound or pharmaceutically acceptable salt as defined in
claim 55 wherein R.sup.1 is chloro, R.sup.2 is chloro, R.sup.8 is
hydroxy and R.sup.12 is ethyl.
57. A compound or pharmaceutically acceptable salt as defined in
claim 55 wherein R.sup.1 is chloro, R.sup.2 is chloro, R.sup.8 is
ethoxy and R.sup.12 is ethyl.
58. A compound or pharmaceutically acceptable salt as defined in
claim 55 wherein R.sup.1 is chloro, R.sup.2 is chloro, R.sup.8 is
hydroxy and R.sup.12 is --CH.sub.2-cyclobutyl.
59. A compound or pharmaceutically acceptable salt as defined in
claim 55 wherein R.sup.1 is chloro, R.sup.2 is chloro, R.sup.8 is
hydroxy and R.sup.12 is --CH.sub.2-cyclobutyl.
60. A compound or pharmaceutically acceptable salt as defined in
claim 55 wherein R.sup.1 is chloro, R.sup.2 is chloro, R.sup.8 is
hydroxy and R.sup.12 is --CH.sub.2-cyclohexyl.
61. A compound or pharmaceutically acceptable salt as defined in
claim 55 wherein R.sup.1 is chloro, R.sup.2 is chloro, R.sup.8 is
ethoxy and R.sup.12 is --CH.sub.2-cyclohexyl.
62. A compound or pharmaceutically acceptable salt as defined in
claim 55 wherein R.sup.1 is chloro, R.sup.2 is chloro, R.sup.8 is
hydroxy and R.sup.12 is cyclopentyl.
63. A compound or pharmaceutically acceptable salt as defined in
claim 55 wherein R.sup.1 is chloro, R.sup.2 is chloro, R.sup.8 is
ethoxy and R.sup.12 is cyclopentyl.
64. A compound or pharmaceutically acceptable salt as defined in
claim 55 wherein R.sup.1 is chloro, R.sup.2 is chloro, R.sup.8 is
hydroxy, and R.sup.12 is --CH.sub.2-cyclopropyl.
65. A compound or pharmaceutically acceptable salt as defined in
claim 55 wherein R.sup.1 is chloro, R.sup.2 is chloro, R.sup.8 is
ethoxy, and R.sup.12 is --CH.sub.2-cyclopropyl.
66. A compound or pharmaceutically acceptable salt as defined in
claim 55 wherein R.sup.1 is chloro, R.sup.2 is chloro, R.sup.8 is
hydroxy, and R.sup.12 is --CH.sub.2-cyclobutyl.
67. A compound or pharmaceutically acceptable salt as defined in
claim 55 wherein R.sup.1 is chloro, R.sup.2 is chloro, R.sup.8 is
ethoxy, and R.sup.12 is --CH.sub.2-cyclobutyl.
68. A compound or pharmaceutically acceptable salt as defined in
claim 55 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
hydroxy, and R.sup.12 is --CH.sub.2-cyclopropyl.
69. A compound or pharmaceutically acceptable salt as defined in
claim 55 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
ethoxy, and R.sup.12 is --CH.sub.2-cyclopropyl.
70. A compound or pharmaceutically acceptable salt as defined in
claim 3 wherein R.sup.1 and R.sup.2 are each independently methyl,
bromo or chloro, R.sup.3 is hydrogen, R.sup.4 and R.sup.5 are taken
together to form 31R.sup.6 is hydrogen, R.sup.7 is hydrogen,
R.sup.8 is ethoxy, hydroxy or NH.sub.2, and R.sup.10 is hydrogen or
methyl.
71. A compound or pharmaceutically acceptable salt as defined in
claim 5 wherein R.sup.3 is hydrogen, and R.sup.4 is
--OR.sup.11.
72. A compound or pharmaceutically acceptable salt as defined in
claim 71 wherein R.sup.11 is phenyl, 4-chlorophenyl or
4-fluorophenyl.
73. A compound or pharmaceutically acceptable salt as defined in
claim 5 wherein R.sup.3 is hydrogen, and R.sup.4 is --(C.sub.1-6
alkyl)-OR.sup.11.
74. A compound or pharmaceutically acceptable salt as defined in
claim 73 wherein R.sup.4 is --CH.sub.2--OR.sup.11.
75. A compound or pharmaceutically acceptable salt as defined in
claim 74 wherein R.sup.11 is phenyl or 4-fluorophenyl.
76. A compound or pharmaceutically acceptable salt as defined in
claim 5 wherein R.sup.3 and R.sup.4 are taken together to form said
carbocyclic ring A or said heterocyclic ring A.
77. A compound or pharmaceutically acceptable salt as defined in
claim 76 wherein R.sup.3 and R.sup.4 are taken together to form
said carbocyclic ring A.
78. A compound or pharmaceutically acceptable group as defined in
claim 77 wherein R.sup.3 and R.sup.4 are taken together to form
--(CH.sub.2).sub.3--, --CH.sub.2--C(CH.sub.3).sub.2--CH.sub.2--or
--(CH.sub.2).sub.4--.
79. A compound or pharmaceutically acceptable salt as defined in
claim 78 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
hydroxy, and R.sup.3 and R.sup.4 are taken together to form
--(CH.sub.2).sub.3--.
80. A compound or pharmaceutically acceptable salt as defined in
claim 78 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
ethoxy, and R.sup.3 and R.sup.4 are taken together to form
--(CH.sub.2).sub.3--.
81. A compound or pharmaceutically acceptable salt as defined in
claim 78 wherein R.sup.1 is chloro, R.sup.2 is methyl, R.sup.8 is
hydroxy, and R.sup.3 and R.sup.4 are taken together to form
--(CH.sub.2).sub.3--.
82. A compound or pharmaceutically acceptable salt as defined in
claim 78 wherein R.sup.1 is chloro, R.sup.2 is methyl, R.sup.8 is
ethoxy, and R.sup.3 and R.sup.4 are taken together to form
--(CH.sub.2).sub.3--.
83. A compound or pharmaceutically acceptable salt as defined in
claim 78 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
hydroxy, and R.sup.3 and R.sup.4 are taken together to form
--(CH.sub.2).sub.4--.
84. A compound or pharmaceutically acceptable salt as defined in
claim 78 wherein R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
ethoxy, and R.sup.3 and R.sup.4 are taken together to form
--(CH.sub.2).sub.4--.
85. A compound or pharmaceutically acceptable salt as defined in
claim 76 wherein R.sup.3 and R.sup.4 are taken together to form
said heterocyclic ring A.
86. A compound or pharmaceutically acceptable salt as defined in
claim 85 wherein said heterocyclic ring A is
--Q--(CH.sub.2).sub.c--.
87. A compound or pharmaceutically acceptable salt as defined in
claim 1 wherein R.sup.8 is --OR.sup.9.
88. A compound or pharmaceutically acceptable salt as defined in
claim 87 wherein R.sup.9 is C.sub.1-12 alkyl.
89. A compound or pharmaceutically acceptable salt as defined in
claim 88 wherein R.sup.9 is methyl.
90. A compound or pharmaceutically acceptable salt as defined in
claim 88 wherein R.sup.9 is ethyl.
91. A compound or pharmaceutically acceptable salt as defined in
claim 88 wherein R.sup.9 is isopropyl.
92. A pharmaceutically acceptable salt as defined in claim 1
wherein said salt is a potassium salt.
93. A pharmaceutically acceptable salt as defined in claim 1
wherein said salt is a sodium salt.
94. A compound as defined in claim 1 selected from the group
consisting of:
N-[3-chloro-4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-phe-
nyl]-oxamic acid,
N-[4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-3,5-dime-
thyl-phenyl]-oxamic acid,
N-{4-[3-(cyclobutyl-methyl-carbamoyl)-4-hydroxy--
phenoxy]-3,5-dimethyl-phenyl}-oxamic acid,
N-{3-chloro-4-[3-(cyclobutyl-me-
thyl-carbamoyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-oxamic acid,
N-[4-(7-hydroxy-indan-4-yloxy)-3,5-dimethyl-phenyl]-oxamic acid,
N-{3,5-dichloro-4-[3-(cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-phe-
nyl}-oxamic acid,
N-[3,5-dichloro-4-(3-cyclopentanesulfonyl-4-hydroxy-phen-
oxy)-phenyl]-oxamic acid,
N-[3,5-dichloro-4-(3-cyclopropylmethanesulfonyl--
4-hydroxy-phenoxy)-phenyl]-oxamic acid,
N-[3,5-dichloro-4-(3-cyclobutylmet-
hanesulfonyl-4-hydroxy-phenoxy)-phenyl]-oxamic acid,
N-[4-(3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl-
]-oxamic acid,
N-[3-chloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenox-
y)-5-methyl-phenyl]-oxamic acid,
N-[4-(3-cyclobutylmethanesulfonyl-4-hydro-
xy-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid,
N-[4-(3-cyclopentylmethanesu-
lfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid,
N-[3-chloro-4-(3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-p-
henyl]-oxamic acid,
N-[3,5-dichloro-4-(3-cyclopentylmethanesulfonyl-4-hydr-
oxy-phenoxy)-phenyl]-oxamic acid,
N-[4-(3-cyclohexylmethanesulfonyl-4-hydr-
oxy-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid,
N-[3-chloro-4-(3-cyclohexyl-
methanesulfonyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-oxamic acid,
N-[3,5-dichloro-4-(3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy)-phenyl]-
-oxamic acid,
N-[3,5-dichloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-ph-
enoxy)-phenyl]-oxamic acid,
N-{4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-p-
henoxy]-3,5-dimethyl-phenyl}-oxamic acid and
N-{3-chloro-4-[3-(4-fluoro-be-
nzenesulfonyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-oxamic acid.
95. A pharmaceutically acceptable salt of each of said compounds as
defined in claim 94 wherein said salt is a potassium salt.
96. A pharmaceutically acceptable salt of each of said compounds as
defined in claim 94 wherein said salt is a sodium salt.
97. A compound as defined in claim 1 selected from the group
consisting of
N-[3-chloro-4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-
-oxamic acid methyl ester,
N-[4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-
-3,5-dimethyl-phenyl]-oxamic acid methyl ester,
N-{4-[3-(cyclobutyl-methyl-
-carbamoyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-oxamic acid
methyl ester,
N-{3-chloro-4-[3-(cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenoxy]--
5-methyl-phenyl}-oxamic acid methyl ester,
N-[4-(7-hydroxy-indan-4-yloxy)-- 3,5-dimethyl-phenyl]-oxamic acid
methyl ester, N-{3,5-dichloro-4-[3-(cyclo-
butyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-phenyl}-oxamic acid
methyl ester,
N-[3,5-dichloro-4-(3-cyclopentanesulfonyl-4-hydroxy-phenoxy)-pheny-
l]-oxamic acid methyl ester,
N-[3,5-dichloro-4-(3-cyclopropylmethanesulfon-
yl-4-hydroxy-phenoxy)-phenyl]-oxamic acid methyl ester,
N-[3,5-dichloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-phenyl]-
-oxamic acid methyl ester,
N-[4-(3-cyclopropylmethanesulfonyl-4-hydroxy-ph-
enoxy)-3,5-dimethyl-phenyl]-oxamic acid methyl ester,
N-[3-chloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-ph-
enyl]-oxamic acid methyl ester,
N-[4-(3-cyclobutylmethanesulfonyl-4-hydrox-
y-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid methyl ester,
N-[4-(3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl-
]-oxamic acid methyl ester,
N-[3-chloro-4-(3-cyclopentylmethanesulfonyl-4--
hydroxy-phenoxy)-5-methyl-phenyl]-oxamic acid methyl ester,
N-[3,5-dichloro-4-(3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy)-phenyl-
]-oxamic acid methyl ester,
N-[4-(3-cyclohexylmethanesulfonyl-4-hydroxy-ph-
enoxy)-3,5-dimethyl-phenyl]-oxamic acid methyl ester,
N-[3-chloro-4-(3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-ph-
enyl]-oxamic acid methyl ester,
N-[3,5-dichloro-4-(3-cyclohexylmethanesulf-
onyl-4-hydroxy-phenoxy)-phenyl]-oxamic acid methyl ester,
N-[3,5-dichloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy)-phenyl-
]-oxamic acid methyl ester,
N-{4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-p-
henoxy]-3,5-dimethyl-phenyl}-oxamic acid methyl ester and
N-{3-chloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-5-methyl-p-
henyl}-oxamic acid methyl ester.
98. A compound as defined in claim 1 selected from the group
consisting of
N-[3-chloro-4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-
-oxamic acid ethyl ester,
N-[4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)--
3,5-dimethyl-phenyl]-oxamic acid ethyl ester,
N-{4-[3-(cyclobutyl-methyl-c-
arbamoyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-oxamic acid ethyl
ester,
N-{3-chloro-4-[3-(cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-5-methy-
l-phenyl}-oxamic acid ethyl ester,
N-[4-(7-hydroxy-indan-4-yloxy)-3,5-dime- thyl-phenyl]-oxamic acid
ethyl ester, N-{3,5-dichloro-4-[3-(cyclobutyl-met-
hyl-carbamoyl)-4-hydroxy-phenoxy]-phenyl}-oxamic acid ethyl ester,
N-[3,5-dichloro-4-(3-cyclopentanesulfonyl-4-hydroxy-phenoxy)-phenyl]-oxam-
ic acid ethyl ester,
N-[3,5-dichloro-4-(3-cyclopropylmethanesulfonyl-4-hyd-
roxy-phenoxy)-phenyl]-oxamic acid ethyl ester,
N-[3,5-dichloro-4-(3-cyclob-
utylmethanesulfonyl-4-hydroxy-phenoxy)-phenyl]-oxamic acid ethyl
ester,
N-[4-(3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl-
]-oxamic acid ethyl ester,
N-[3-chloro-4-(3-cyclobutylmethanesulfonyl-4-hy-
droxy-phenoxy)-5-methyl-phenyl]-oxamic acid ethyl ester,
N-[4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-
-oxamic acid ethyl ester,
N-[4-(3-cyclopentylmethanesulfonyl-4-hydroxy-phe-
noxy)-3,5-dimethyl-phenyl]-oxamic acid ethyl ester,
N-[3-chloro-4-(3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-p-
henyl]-oxamic acid ethyl ester,
N-[3,5-dichloro-4-(3-cyclopentylmethanesul-
fonyl-4-hydroxy-phenoxy)-phenyl]-oxamic acid ethyl ester,
N-[4-(3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-
-oxamic acid ethyl ester,
N-[3-chloro-4-(3-cyclohexylmethanesulfonyl-4-hyd-
roxy-phenoxy)-5-methyl-phenyl]-oxamic acid ethyl ester,
N-[3,5-dichloro-4-(3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy)-phenyl]-
-oxamic acid ethyl ester,
N-[3,5-dichloro-4-[3-(4-fluoro-benzenesulfonyl)--
4-hydroxy-phenoxy)-phenyl]-oxamic acid ethyl ester,
N-{4-[3-(4-fluoro-benzenesulfonyl)-4-hyd
roxy-phenoxy]-3,5-dimethyl-pheny- l}-oxamic acid ethyl ester and
N-{3-chloro-4-[3-(4-fluoro-benzenesulfonyl)-
-4-hydroxy-phenoxy]-5-methyl-phenyl}-oxamic acid ethyl ester.
99. A compound as defined in claim 1 selected from the group
consisting of
N-[3-chloro-4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-
-oxamic acid isopropyl ester,
N-[4-(3-cyclopropylsulfamoyl-4-hydroxy-pheno-
xy)-3,5-dimethyl-phenyl]-oxamic acid isopropyl ester,
N-{4-[3-(cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phe-
nyl}-oxamic acid isopropyl ester,
N-{3-chloro-4-[3-(cyclobutyl-methyl-carb-
amoyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-oxamic acid isopropyl
ester, N-[4-(7-hydroxy-indan-4-yloxy)-3,5-dimethyl-phenyl]-oxamic
acid isopropyl ester,
N-{3,5-dichloro-4-[3-(cyclobutyl-methyl-carbamoyl)-4-hydroxy-pheno-
xy]-phenyl}-oxamic acid isopropyl ester,
N-[3,5-dichloro-4-(3-cyclopentane-
sulfonyl-4-hydroxy-phenoxy)-phenyl]-oxamic acid isopropyl ester,
N-[3,5-dichloro-4-(3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)-phenyl-
]-oxamic acid isopropyl ester,
N-[3,5-dichloro-4-(3-cyclobutylmethanesulfo-
nyl-4-hydroxy-phenoxy)-phenyl]-oxamic acid isopropyl ester,
N-[4-(3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl-
]-oxamic acid isopropyl ester,
N-[3-chloro-4-(3-cyclobutylmethanesulfonyl--
4-hydroxy-phenoxy)-5-methyl-phenyl]-oxamic acid isopropyl ester,
N-[4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-
-oxamic acid isopropyl ester,
N-[4-(3-cyclopentylmethanesulfonyl-4-hydroxy-
-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid isopropyl ester,
N-[3-chloro-4-(3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy)-5-methyl-p-
henyl]-oxamic acid isopropyl ester,
N-[3,5-dichloro-4-(3-cyclopentylmethan-
esulfonyl-4-hydroxy-phenoxy)-phenyl]-oxamic acid isopropyl ester,
N-[4-(3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-
-oxamic acid isopropyl ester,
N-[3-chloro-4-(3-cyclohexylmethanesulfonyl-4-
-hydroxy-phenoxy)-5-methyl-phenyl]-oxamic acid isopropyl ester,
N-[3,5-dichloro-4-(3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy)-phenyl]-
-oxamic acid isopropyl ester,
N-[3,5-dichloro-4-[3-(4-fluoro-benzenesulfon-
yl)-4-hydroxy-phenoxy)-phenyl]-oxamic acid isopropyl ester,
N-{4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl-
}-oxamic acid isopropyl ester and
N-{3-chloro-4-[3-(4-fluoro-benzenesulfon-
yl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-oxamic acid isopropyl
ester.
100. A compound as defined in claim 1 selected from the group
consisting of
N-{3,5-dichloro-4-[4-hydroxy-3-(pyrrolidine-1-sulfonyl)-phenoxy]-pheny-
l}-oxamic acid,
N-[4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimeth-
yl-phenyl]-oxamic acid ethyl ester,
N-[4-(4-hydroxy-3-methylsulfamoyl-phen-
oxy)-3,5-dimethyl-phenyl]-oxamic acid ethyl ester,
N-{4-[3-(4-fluoro-pheny-
lsulfamoyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-oxamic acid
ethyl ester,
N-[4-(3-dimethylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]--
oxamic acid ethyl ester,
N-{4-[3-(cyclopropyl-methyl-sulfamoyl)-4-hydroxy--
phenoxy]-3,5-dimethyl-phenyl}-oxamic acid ethyl ester,
N-{4-[3-(cyclobutyl-methyl-sulfamoyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phe-
nyl}-oxamic acid ethyl ester,
N-[4-(3-cyclobutylsulfamoyl-4-hydroxy-phenox-
y)-3,5-dimethyl-phenyl]-oxamic acid ethyl ester,
N-[4-(3-cyclopentylsulfam-
oyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid ethyl
ester,
N-{4-[4-hydroxy-3-(pyrrolidine-1-sulfonyl)-phenoxy]-3,5-dimethyl-phenyl}--
oxamic acid ethyl ester,
N-{4-[4-hydroxy-3-(piperidine-1-sulfonyl)-phenoxy-
]-3,5-dimethyl-phenyl}-oxamic acid ethyl ester,
N-[4-(3-cyclohexylsulfamoy-
l-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid ethyl ester,
N-[4-(4-hydroxy-3-propylsulfamoyl-phenoxy)-3,5-dimethyl-phenyl]-oxamic
acid ethyl ester,
N-[4-(3-butylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimethyl--
phenyl]-oxamic acid ethyl ester,
N-{4-[3-(cyclopropyl-methyl-sulfamoyl)-4--
hydroxy-phenoxy]-3,5-dimethyl-phenyl}-oxamic acid,
N-{4-[3-(cyclobutyl-met-
hyl-sulfamoyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-oxamic acid,
N-[4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-oxam-
ic acid,
N-[4-(3-cyclobutylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-pheny-
l]-oxamic acid,
N-[3-chloro-4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-5-
-methyl-phenyl]-oxamic acid ethyl ester,
N-[3-chloro-4-(3-cyclobutylsulfam-
oyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-oxamic acid ethyl ester,
N-[3-chloro-4-(3-cyclopentylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-
-oxamic acid ethyl ester,
N-[3-chloro-4-(3-cyclohexylsulfamoyl-4-hydroxy-p-
henoxy)-5-methyl-phenyl]-oxamic acid ethyl ester,
N-[3-chloro-4-(4-hydroxy-
-3-sulfamoyl-phenoxy)-5-methyl-phenyl]-oxamic acid ethyl ester,
N-{3-chloro-4-[4-hydroxy-3-(piperidine-1-sulfonyl)-phenoxy]-5-methyl-phen-
yl}-oxamic acid ethyl ester,
N-{3-chloro-4-[3-(4-fluoro-phenylsulfamoyl)-4-
-hydroxy-phenoxy]-5-methyl-phenyl}-oxamic acid ethyl ester,
N-[3-chloro-4-(3-dimethysulfamoyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-oxa-
mic acid ethyl ester,
N-[3-chloro-4-(4-hydroxy-3-methylsulfamoyl-phenoxy)--
5-methyl-phenyl]-oxamic acid ethyl ester,
N-[3-chloro-4-(4-hydroxy-3-propy-
lsulfamoyl-phenoxy)-5-methyl-phenyl]-oxamic acid ethyl ester,
N-[3-chloro-4-(4-hydroxy-3-pentylsulfamoyl-phenoxy)-5-methyl-phenyl]-oxam-
ic acid ethyl ester,
N-[3-chloro-4-(3-hexylsulfamoyl-4-hydroxy-phenoxy)-5--
methyl-phenyl]-oxamic acid ethyl ester,
N-[3-chloro-4-(4-hydroxy-3-octylsu-
lfamoyl-phenoxy)-5-methyl-phenyl]-oxamic acid ethyl ester,
N-[3-chloro-4-(3-decylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-oxami-
c acid ethyl ester,
N-[4-(3-butylsulfamoyl-4-hydroxy-phenoxy)-3-chloro-5-m-
ethyl-phenyl]-oxamic acid ethyl ester,
N-{3-chloro-4-[3-(ethyl-methyl-sulf-
amoyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-oxamic acid ethyl ester,
N-{3-chloro-4-[4-hydroxy-3-(methyl-propyl-sulfamoyl)-phenoxy]-5-methyl-ph-
enyl}-oxamic acid ethyl ester,
N-{4-[3-(butyl-methyl-sulfamoyl)-4-hydroxy--
phenoxy]-3-chloro-5-methyl-phenyl}-oxamic acid ethyl ester,
N-{3-chloro-4-[4-hydroxy-3-(morpholine-4-sulfonyl)-phenoxy]-5-methyl-phen-
yl}-oxamic acid ethyl ester,
N-{3-chloro-4-[3-(cyclopropylmethyl-sulfamoyl-
)-4-hydroxy-phenoxy]-5-methyl-phenyl}-oxamic acid ethyl ester,
N-{3-chloro-4-[4-hydroxy-3-(2-hydroxy-ethylsulfamoyl)-phenoxy]-5-methyl-p-
henyl}-oxamic acid ethyl ester,
N-[3-chloro-4-(3-cyclopropylsulfamoyl-4-hy-
droxy-phenoxy)-5-methyl-phenyl]-oxamic acid isopropyl ester,
N-[3-chloro-4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-
-oxamic acid,
N-[3-chloro-4-(3-cyclobutylsulfamoyl-4-hydroxy-phenoxy)-5-me-
thyl-phenyl]-oxamic acid,
N-[3-chloro-4-(3-cyclopentylsulfamoyl-4-hydroxy--
phenoxy)-5-methyl-phenyl]-oxamic acid,
N-[3-chloro-4-(3-cyclohexylsulfamoy-
l-4-hydroxy-phenoxy)-5-methyl-phenyl]-oxamic acid,
N-[3-chloro-4-(4-hydrox-
y-3-sulfamoyl-phenoxy)-5-methyl-phenyl]-oxamic acid,
N-{3-chloro-4-[3-(4-fluoro-phenylsulfamoyl)-4-hydroxy-phenoxy]-5-methyl-p-
henyl}-oxamic acid,
N-[3-chloro-4-(4-hydroxy-3-propylsulfamoyl-phenoxy)-5--
methyl-phenyl]-oxamic acid,
N-[4-(3-butylsulfamoyl-4-hydroxy-phenoxy)-3-ch-
loro-5-methyl-phenyl]-oxamic acid,
N-{3-chloro-4-[4-hydroxy-3-(morpholine--
4-sulfonyl)-phenoxy]-5-methyl-phenyl}-oxamic acid,
N-{3,5-dichloro-4-[4-hy-
droxy-3-(pyrrolidine-1-sulfonyl)-phenoxy]-phenyl}-oxamic acid ethyl
ester,
N-{3,5-dichloro-4-[3-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-4-hydroxy-p-
henoxy]-phenyl}-oxamic acid ethyl ester,
N-[3,5-dichloro-4-(3-cyclobutylsu-
lfamoyl-4-hydroxy-phenoxy)-phenyl]-oxamic acid ethyl ester,
N-{4-[3-(bicyclo[2.2.1]hept-2-ylsulfamoyl)-4-hydroxy-phenoxy]-3,5-dichlor-
o-phenyl}-oxamic acid ethyl ester,
N-(3,5-dichloro-4-{4-hydroxy-3-[(thioph-
en-2-ylmethyl)-sulfamoyl]-phenoxy}-phenyl)-oxamic acid ethyl ester,
N-[3,5-dichloro-4-(4-hydroxy-3-isopropylsulfamoyl-phenoxy)-phenyl]-oxamic
acid ethyl ester,
N-[3,5-dichloro-4-(3-dimethylsulfamoyl-4-hydroxy-phenox-
y)-phenyl]-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[4-hydroxy-3-(pyrrol-
idine-1-sulfonyl)-phenoxy]-phenyl}-oxamic acid and
N-[3,5-dichloro-4-(4-hy-
droxy-3-isopropylsulfamoyl-phenoxy)-phenyl]-oxamic acid.
101. A compound as defined in claim 1 selected from the group
consisting of
N-{3,5-dichloro-4-[3-(3,3-dimethyl-piperidine-1-carbonyl)-4-hydroxy-ph-
enoxy]-phenyl}-oxamic acid ethyl ester,
N-{4-[3-(3,4-dihydro-1H-isoquinoli-
ne-2-carbonyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-oxamic acid
ethyl ester,
N-{4-[3-(3,4-dihydro-2H-quinoline-1-carbonyl)-4-hydroxy-phenoxy]-3-
,5-dimethyl-phenyl}-oxamic acid ethyl ester,
N-{4-[3-(2,3-dihydro-indole-1-
-carbonyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-oxamic acid
ethyl ester,
N-{4-[3-(3,3-dimethyl-piperidine-1-carbonyl)-4-hydroxy-phenoxy]-3,-
5-dimethyl-phenyl}-oxamic acid ethyl ester,
N-{4-[4-hydroxy-3-(3-methyl-3--
phenyl-piperidine-1-carbonyl)-phenoxy]-3,5-dimethyl-phenyl}-oxamic
acid ethyl ester,
N-{4-[3-(azepane-1-carbonyl)-4-hydroxy-phenoxy]-3,5-dimethyl-
-phenyl}-oxamic acid ethyl ester,
N-{4-[4-hydroxy-3-(1-naphthalen-1-yl-(1R-
)-ethylcarbamoyl)-phenoxy]-3,5-dimethyl-phenyl}-oxamic acid ethyl
ester,
N-{4-[4-hydroxy-3-(1-phenyl-(1R)-ethylcarbamoyl)-phenoxy]-3,5-dimethyl-ph-
enyl}-oxamic acid ethyl ester,
N-{4-[3-(bicyclo[2.2.1]hept-2-ylcarbamoyl)--
4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-oxamic acid ethyl ester,
N-{4-[3-(4-chloro-benzylcarbamoyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl-
}-oxamic acid ethyl ester,
N-{4-[3-(1-cyclohexyl-(1R)-ethylcarbamoyl)-4-hy-
droxy-phenoxy]-3,5-dimethyl-phenyl}-oxamic acid ethyl ester,
N-{4-[4-hydroxy-3-(1-naphthalen-2-yl-(1R)-ethylcarbamoyl)-phenoxy]-3,5-di-
methyl-phenyl}-oxamic acid ethyl ester,
N-[4-(3-cyclobutylcarbamoyl-4-hydr-
oxy-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid ethyl ester,
N-[4-(3-cyclopentylcarbamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-oxam-
ic acid ethyl ester,
N-{4-[4-hydroxy-3-(1-isopropyl-2-methyl-propylcarbamo-
yl)-phenoxy]-3,5-dimethyl-phenyl}-oxamic acid ethyl ester,
N-{4-[4-hydroxy-3-(pyrrolidine-1-carbonyl)-phenoxy]-3,5-dimethyl-phenyl}--
oxamic acid ethyl ester,
N-{4-[4-hydroxy-3-(morpholine-4-carbonyl)-phenoxy-
]-3,5-dimethyl-phenyl}-oxamic acid ethyl ester,
N-{4-[4-hydroxy-3-(1-napht-
halen-1-yl-(1R)ethylcarbamoyl)-phenoxy]-3,5-dimethyl-phenyl}-oxamic
acid,
N-{4-[4-hydroxy-3-(1-phenyl-(1R)ethylcarbamoyl)-phenoxy]-3,5-dimethyl-phe-
nyl}-oxamic acid,
N-{4-[3-(cyclopropyl-methyl-carbamoyl)-4-hydroxy-phenoxy-
]-3,5-dimethyl-pentyl}-oxamic acid,
N-{4-[3-(cyclobutyl-methyl-carbamoyl)--
4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-oxamic acid,
N-{4-[4-hydroxy-3-(1-isopropyl-2-methyl-propylcarbamoyl)-phenoxy]-3,5-dim-
ethyl-phenyl}-oxamic acid,
N-{4-[3-(cyclopentyl-methyl-carbamoyl)-4-hydrox-
y-phenoxy]-3,5-dimethyl-phenyl}-oxamic acid,
N-{4-[3-(cyclohexyl-methyl-ca-
rbamoyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-oxamic acid,
N-{3-chloro-4-[4-hydroxy-3-(3-methyl-3-phenyl-piperidine-1-carbonyl)-phen-
oxy]-5-methyl-phenyl}-oxamic acid ethyl ester,
N-{4-[3-(azepane-1-carbonyl-
)-4-hydroxy-phenoxy]-3-chloro-5-methyl-phenyl}-oxamic acid ethyl
ester,
N-{3-chloro-4-[3-(3,3-dimethyl-piperidine-1-carbonyl)-4-hydroxy-phenoxy]--
5-methyl-phenyl}-oxamic acid ethyl ester,
N-(3-chloro-4-{4-hydroxy-3-[(thi-
ophen-2-ylmethyl)-carbamoyl]-phenoxy}-5-methyl-phenyl)-oxamic acid
ethyl ester,
N-{3-chloro-4-[3-(2,3-dichloro-benzylcarbamoyl)-4-hydroxy-phenoxy]-
-5-methyl-phenyl}-oxamic acid ethyl ester,
N-[3-chloro-4-(3-cyclopropylcar-
bamoyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-oxamic acid ethyl ester,
N-{3-chloro-4-[3-(2,3-dihydro-indole-1-carbonyl)-4-hydroxy-phenoxy]-methy-
l-phenyl}-oxamic acid ethyl ester,
N-{3-chloro-4-[3-(3,4-dihydro-2H-quinol-
ine-1-carbonyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-oxamic acid
ethyl ester,
N-{3-chloro-4-[3-(3,4-dihydro-1H-isoquinoline-2-carbonyl)-4-hydrox-
y-phenoxy]-5-methyl-phenyl}-oxamic acid ethyl ester,
N-{3-chloro-4-[4-hydroxy-3-(indan-1-ylcarbamoyl)-phenoxy]-5-methyl-phenyl-
}-oxamic acid ethyl ester,
N-{3-chloro-4-[4-hydroxy-3-(indan-5-ylcarbamoyl-
)-phenoxy]-5-methyl-phenyl}-oxamic acid ethyl ester,
N-{4-[3-(bicyclo[2.2.1]hept-2-ylcarbamoyl)-4-hydroxy-phenoxy]-3-chloro-5--
methyl-phenyl}-oxamic acid ethyl ester,
N-{3-chloro-4-[3-(cyclohexylmethyl-
-carbamoyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-oxamic acid ethyl
ester,
N-{3-chloro-4-[3-(1-cyclohexyl-(1R)ethylcarbamoyl)-4-hydroxy-phenoxy]-5-m-
ethyl-phenyl}-oxamic acid ethyl ester,
N-{3-chloro-4-[3-(1-cyclohexyl-(1S)-
ethylcarbamoyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-oxamic acid
ethyl ester,
N-{3-chloro-4-[4-hydroxy-3-(piperidine-1-carbonyl)-phenoxy]-5-meth-
yl-phenyl}-oxamic acid ethyl ester,
N-{4-[3-(azocane-1-carbonyl)-4-hydroxy-
-phenoxy]-3-chloro-5-methyl-phenyl}-oxamic acid ethyl ester,
N-[3-chloro-4-(3-cyclohexylcarbamoyl-4-hydroxy-phenoxy)-5-methyl-phenyl]--
oxamic acid ethyl ester,
N-{3-chloro-4-[4-hydroxy-3-(1-phenyl-(1R)ethylcar-
bamoyl)-phenoxy]-5-methyl-phenyl}-oxamic acid ethyl ester,
N-[3-chloro-4-(4-hydroxy-3-propylcarbamoyl-phenoxy)-5-methyl-phenyl]-oxam-
ic acid ethyl ester,
N-[4-(3-butylcarbamoyl-4-hydroxy-phenoxy)-3-chloro-5--
methyl-phenyl]-oxamic acid ethyl ester,
N-[3-chloro-4-(4-hydroxy-3-pentylc-
arbamoyl-phenoxy)-5-methyl-phenyl]-oxamic acid ethyl ester,
N-[3-chloro-4-(3-hexylcarbamoyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-oxami-
c acid ethyl ester,
N-{3-chloro-4-[3-(1,1-dimethyl-propylcarbamoyl)-4-hydr-
oxy-phenoxy]-5-methyl-phenyl}-oxamic acid ethyl ester,
N-[3-chloro-4-(3-diisopropylcarbamoyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-
-oxamic acid ethyl ester,
N-{3-chloro-4-[3-(2,2-dimethyl-propylcarbamoyl)--
4-hydroxy-phenoxy]-5-methyl-phenyl}-oxamic acid ethyl ester,
N-{3-chloro-4-[3-(1,2-dimethyl-propylcarbamoyl)-4-hydroxy-phenoxy]-5-meth-
yl-phenyl}-oxamic acid ethyl ester,
N-{3-chloro-4-[4-hydroxy-3-(1-phenyl-(-
1S)ethylcarbamoyl)-phenoxy]-5-methyl-phenyl}-oxamic acid ethyl
ester,
N-{3-chloro-4-[3-(ethyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-5-methyl-phe-
nyl}-oxamic acid ethyl ester,
N-{3-chloro-4-[4-hydroxy-3-(methyl-propyl-ca-
rbamoyl)-phenoxy]-5-methyl-phenyl}-oxamic acid ethyl ester,
N-{3-chloro-4-[3-(ethyl-isopropyl-carbamoyl)-4-hydroxy-phenoxy]-5-methyl--
phenyl}-oxamic acid ethyl ester,
N-{3-chloro-4-[3-(cyclobutyl-methyl-carba-
moyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-oxamic acid ethyl ester,
N-{4-[3-(azepane-1-carbonyl)-4-hydroxy-phenoxy]-3-chloro-5-methyl-phenyl}-
-oxamic acid,
N-{3-chloro-4-[3-(1-cyclohexyl-(1S)ethylcarbamoyl)-4-hydroxy-
-phenoxy]-5-methyl-phenyl}-oxamic acid,
N-{3-chloro-4-[3-(cyclobutyl-methy-
l-carbamoyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-oxamic acid,
N-{4-[3-(bicyclo[2.2.1]hept-2-ylcarbamoyl)-4-hydroxy-phenoxy]-3,5-dichlor-
o-phenyl}-oxamic acid ethyl ester,
N-{4-[3-(bicyclo[2.2.1]hept-2-ylcarbamo-
yl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}-oxamic acid ethyl
ester,
N-(3,5-dichloro-4-{4-hydroxy-3-[(thiophen-2-ylmethyl)-carbamoyl]-phenoxy}-
-phenyl)-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[3-(2-chloro-benzylcar-
bamoyl)-4-hydroxy-phenoxy]-phenyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[4-hydroxy-3-(3-methyl-3-phenyl-piperidine-1-carbonyl)--
phenoxy]-phenyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[3-(3,4-dihydr-
o-1H-isoquinoline-2-carbonyl)-4-hydroxy-phenoxy]-phenyl}-oxamic
acid ethyl ester,
N-{3,5-dichloro-4-[4-hydroxy-3-(indan-1-ylcarbamoyl)-phenoxy]-phen-
yl}-oxamic acid ethyl ester,
N-(4-{3-[(benzo[1,3]dioxol-5-ylmethyl)-carbam-
oyl]-4-hydroxy-phenoxy}-3,5-dichloro-phenyl)-oxamic acid ethyl
ester,
N-{4-[3-(azepane-1-carbonyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}-oxam-
ic acid ethyl ester,
N-{3,5-dichloro-4-[4-hydroxy-3-(4-methyl-piperidine-1-
-carbonyl)-phenoxy]-phenyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[3-(4-fluoro-phenylcarbamoyl)-4-hydroxy-phenoxy]-phenyl-
}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[3-(cyclohexylmethyl-carbamoy-
l)-4-hydroxy-phenoxy]-phenyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[3-(1-cyclohexyl-(1R)ethylcarbamoyl)-4-hydroxy-phenoxy]-
-phenyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[3-(1-cyclohexyl-(1S)e-
thylcarbamoyl)-4-hydroxy-phenoxy]-phenyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[4-hydroxy-3-(piperidine-1-carbonyl)-phenoxy]-phenyl}-o-
xamic acid ethyl ester,
N-{3,5-dichloro-4-[4-hydroxy-3-(3-methyl-piperidin-
e-1-carbonyl)-phenoxy]-phenyl}-oxamic acid ethyl ester,
N-{4-[3-(biphenyl-3-ylcarbamoyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}--
oxamic acid ethyl ester,
N-[3,5-dichloro-4-(3-cyclopropylcarbamoyl-4-hydro-
xy-phenoxy)-phenyl]-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[3-(2,3-dic-
hloro-benzylcarbamoyl)-4-hydroxy-phenoxy]-phenyl}-oxamic acid ethyl
ester,
N-[3,5-dichloro-4-(3-cyclobutylcarbamoyl-4-hydroxy-phenoxy)-phenyl]-oxami-
c acid ethyl ester,
N-[3,5-dichloro-4-(3-cyclopentylcarbamoyl-4-hydroxy-ph-
enoxy)-phenyl]-oxamic acid ethyl ester,
N-(3,5-dichloro-4-{4-hydroxy-3-[(n-
aphthalen-1-ylmethyl)-carbamoyl]-phenoxy}-phenyl)-oxamic acid ethyl
ester,
N-{3,5-dichloro-4-[3-(4-fluoro-benzylcarbamoyl)-4-hydroxy-phenoxy]-phenyl-
}-oxamic acid ethyl ester,
N-{4-[3-(azocane-1-carbonyl)-4-hydroxy-phenoxy]-
-3,5-dichloro-phenyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[4-hydrox-
y-3-(1,2,3,4-tetrahydro-naphthalen-1-ylcarbamoyl)-phenoxy]-phenyl}-oxamic
acid ethyl ester,
N-{3,5-dichloro-4-[4-hydroxy-3-(1-isopropyl-2-methyl-pr-
opylcarbamoyl)-phenoxy]-phenyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[4-hydroxy-3-(6-methoxy-3,4-dihydro-2H-quinoline-1-carb-
onyl)-phenoxy]-phenyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[4-hydro-
xy-3-(6-methyl-3,4-dihydro-2H-quinoline-1-carbonyl)-phenoxy]-phenyl}-oxami-
c acid ethyl ester,
N-{3,5-dichloro-4-[4-hydroxy-3-(4-isopropyl-benzylcarb-
amoyl)-phenoxy]-phenyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[3-(4-c-
hloro-benzylcarbamoyl)-4-hydroxy-phenoxy]-phenyl}-oxamic acid ethyl
ester,
N-{3,5-dichloro-4-[4-hydroxy-3-((1R)indan-1-ylcarbamoyl)-phenoxy]-phenyl}-
-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[4-hydroxy-3-((1S)indan-1-ylca-
rbamoyl)-phenoxy]-phenyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[4-hy-
droxy-3-(1-phenyl-(1R)ethylcarbamoyl)-phenoxy]-phenyl}-oxamic acid
ethyl ester,
N-{3,5-dichloro-4-[4-hydroxy-3-(1-naphthalen-1-yl-(1S)ethylcarbamo-
yl)-phenoxy]-phenyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[3-(3,4-di-
fluoro-benzylcarbamoyl)-4-hydroxy-phenoxy]-phenyl}-oxamic acid
ethyl ester,
N-{3,5-dichloro-4-[3-(3-chloro-4-fluoro-benzylcarbamoyl)-4-hydroxy-
-phenoxy]-phenyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[3-(2-chloro--
4-fluoro-benzylcarbamoyl)-4-hydroxy-phenoxy]-phenyl}-oxamic acid
ethyl ester,
N-{3,5-dichloro-4-[4-hydroxy-3-(1-naphthalen-2-yl-(1R)ethylcarbamo-
yl)-phenoxy]-phenyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[3-(2,4-di-
chloro-benzylcarbamoyl)-4-hydroxy-phenoxy]-phenyl}-oxamic acid
ethyl ester,
N-{3,5-dichloro-4-[3-(3,4-dichloro-benzylcarbamoyl)-4-hydroxy-phen-
oxy]-phenyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[3-(4-chloro-3-tri-
fluoromethyl-benzylcarbamoyl)-4-hydroxy-phenoxy]-phenyl}-oxamic
acid ethyl ester,
N-{3,5-dichloro-4-[3-(4-chloro-2-fluoro-benzylcarbamoyl)-4-hydroxy-
-phenoxy]-phenyl}-oxamic acid ethyl ester,
N-{4-[3-(4-tert-butyl-benzylcar-
bamoyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}-oxamic acid ethyl
ester,
N-[3,5-dichloro-4-(3-cyclohexylcarbamoyl-4-hydroxy-phenoxy)-phenyl]-oxami-
c acid ethyl ester,
N-[3,5-dichloro-4-(4-hydroxy-3-isopropylcarbamoyl-phen-
oxy)-phenyl]-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[4-hydroxy-3-(isop-
ropyl-methyl-carbamoyl)-phenoxy]-phenyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[3-(cyclopropylmethyl-carbamoyl)-4-hydroxy-phenoxy]-phe-
nyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[3-(4-fluoro-benzylcarbamo-
yl)-4-hydroxy-phenoxy]-phenyl}-oxamic acid,
N-[3,5-dichloro-4-(3-dimethylc-
arbamoyl-4-hydroxy-phenoxy)-phenyl]-oxamic acid and
N-{3,5-dichloro-4-[4-hydroxy-3-(1-isopropyl-2-methyl-propylamino-carbonyl-
)-phenoxy]-phenyl}-oxamic acid.
102. A compound as defined in claim 1 selected from the group
consisting of
N-{3,5-dichloro-4-[4-hydroxy-3-(indan-1-ylaminomethyl)-phenoxy]-phenyl-
}-oxamic acid ethyl ester,
N-{4-[3-(2,3-dihydro-indol-1-ylmethyl)-4-hydrox-
y-phenoxy]-3,5-dimethyl-phenyl}-oxamic acid ethyl ester,
N-{4-[3-(3,3-dimethyl-piperidin-1-ylmethyl)-4-hydroxy-phenoxy]-3,5-dimeth-
yl-phenyl}-oxamic acid ethyl ester,
N-{4-[4-hydroxy-3-(3-methyl-3-phenyl-p-
iperidin-1-ylmethyl)-phenoxy]-3,5-dimethyl-phenyl}-oxamic acid
ethyl ester,
N-{4-[3-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-4-hydroxy-phenoxy]-
-3,5-dimethyl-phenyl}-oxamic acid ethyl ester,
N-(4-{3-[(4-fluoro-benzylam-
ino)-methyl]-4-hydroxy-phenoxy}-3,5-dimethyl-phenyl)-oxamic acid
ethyl ester,
N-(4-{3-[(4-chloro-benzylamino)-methyl]-4-hydroxy-phenoxy}-3,5-dim-
ethyl-phenyl)-oxamic acid ethyl ester,
N-(4-{4-hydroxy-3-[(4-isopropyl-ben-
zylamino)-methyl]-phenoxy}-3,5-dimethyl-phenyl)-oxamic acid ethyl
ester,
N-[4-(3-azepan-1-ylmethyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-oxamic
acid ethyl ester,
N-[4-(3-{[(benzo[1,3]dioxol-5-ylmethyl)-amino]-methyl}--
4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid ethyl ester,
N-(4-{4-hydroxy-3-[(1,2,3,4-tetrahydro-naphthalen-1-ylamino)-methyl]-phen-
oxy}-3,5-dimethyl-phenyl)-oxamic acid ethyl ester,
N-[4-(3-dimethylaminome-
thyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid ethyl
ester,
N-(4-{4-hydroxy-3-[(methyl-propyl-amino)-methyl]-phenoxy}-3,5-dimethyl-ph-
enyl)-oxamic acid ethyl ester,
N-[4-(3-cyclopropylaminomethyl-4-hydroxy-ph-
enoxy)-3,5-dimethyl-phenyl]-oxamic acid ethyl ester,
N-[4-(4-hydroxy-3-morpholin-4-ylmethyl-phenoxy)-3,5-dimethyl-phenyl]-oxam-
ic acid ethyl ester,
N-(4-{4-hydroxy-3-[(isopropyl-methyl-amino)-methyl]-p-
henoxy}-3,5-dimethyl-phenyl)-oxamic acid ethyl ester,
N-{4-[4-hydroxy-3-(isopropylamino-methyl)-phenoxy]-3,5-dimethyl-phenyl}-o-
xamic acid ethyl ester,
N-[4-(3-cyclobutylaminomethyl-4-hydroxy-phenoxy)-3-
,5-dimethyl-phenyl]-oxamic acid ethyl ester,
N-[4-(3-cyclopentylaminomethy-
l-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid ethyl ester,
N-{3-chloro-4-[3-(3,3-dimethyl-piperidin-1-ylmethyl)-4-hydroxy-phenoxy]-5-
-methyl-phenyl}-oxamic acid methyl ester,
N-{3-chloro-4-[3-(2,3-dihydro-in-
dol-1-ylmethyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-oxamic acid
methyl ester,
N-(3-chloro-4-{3-[(4-fluoro-benzylamino)-methyl]-4-hydroxy-phenoxy-
}-5-methyl-phenyl)-oxamic acid ethyl ester,
N-{3-chloro-4-[4-hydroxy-3-(3--
methyl-3-phenyl-piperidin-1-ylmethyl)-phenoxy]-5-methyl-phenyl}-oxamic
acid ethyl ester,
N-(3-chloro-4-{3-[(4-chloro-benzylamino)-methyl]-4-hydr-
oxy-phenoxy}-5-methyl-phenyl)-oxamic acid ethyl ester,
N-(3-chloro-4-{4-hydroxy-3-[(4-isopropyl-benzylamino)-methyl]-phenoxy}-5--
methyl-phenyl)-oxamic acid ethyl ester,
N-{3-chloro-4-[3-(3,4-dihydro-1H-i-
soquinolin-2-ylmethyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-oxamic
acid ethyl ester,
N-[4-(3-azepan-1-ylmethyl-4-hydroxy-phenoxy)-3-chloro-5-meth-
yl-phenyl]-oxamic acid ethyl ester,
N-[4-(3-{[(benzo[1,3]dioxol-5-ylmethyl-
)-amino]-methyl}-4-hydroxy-phenoxy)-3-chloro-5-methyl-phenyl]-oxamic
acid ethyl ester,
N-(3-chloro-4-{4-hydroxy-3-[(1,2,3,4-tetrahydro-naphthalen-1-
-ylamino)-methyl]-phenoxy}-5-methyl-phenyl)-oxamic acid ethyl
ester,
N-[3-chloro-4-(3-dimethylaminomethyl-4-hydroxy-phenoxy)-5-methyl-phenyl]--
oxamic acid ethyl ester,
N-(3-chloro-4-{4-hydroxy-3-[(methyl-propyl-amino)-
-methyl]-phenoxy}-5-methyl-phenyl)-oxamic acid ethyl ester,
N-[3-chloro-4-(3-cyclopropylaminomethyl-4-hydroxy-phenoxy)-5-methyl-pheny-
l]-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[3-(2,3-dihydro-indol-1-ylme-
thyl)-4-hydroxy-phenoxy]-phenyl}-oxamic acid methyl ester,
N-{3,5-dichloro-4-[3-(3,3-dimethyl-piperidin-1-ylmethyl)-4-hydroxy-phenox-
y]-phenyl}-oxamic acid methyl ester,
N-{3,5-dichloro-4-[4-hydroxy-3-(indan-
-1-ylaminomethyl)-phenoxy]-phenyl}-oxamic acid methyl ester,
N-{3,5-dichloro-4-[3-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-4-hydroxy-ph-
enoxy]-phenyl}-oxamic acid methyl ester,
N-[4-(3-azepan-1-ylmethyl-4-hydro-
xy-phenoxy)-3,5-dichloro-phenyl]-oxamic acid methyl ester,
N-(3,5-dichloro-4-{3-[(1-cyclohexyl-(1R)ethylamino)-methyl]-4-hydroxy-phe-
noxy}-phenyl)-oxamic acid ethyl ester,
N-{4-[3-(bicyclo[2.2.1]hept-2-ylami-
nomethyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}-oxamic acid ethyl
ester,
N-{3,5-dichloro-4-[4-hydroxy-3-(3-methyl-3-phenyl-piperidin-1-ylmethyl)-p-
henoxy]-phenyl}-oxamic acid ethyl ester,
N-(3,5-dichloro-4-{3-[(4-fluoro-b-
enzylamino)-methyl]-4-hydroxy-phenoxy}-phenyl)-oxamic acid ethyl
ester,
N-(3,5-dichloro-4-{4-hydroxy-3-[(1-phenyl-(1R)ethylamino)-methyl]-phenoxy-
}-phenyl)-oxamic acid ethyl ester,
N-(3,5-dichloro-4-{4-hydroxy-3-[(1-phen-
yl-(1S)ethylamino)-methyl]-phenoxy}-phenyl)-oxamic acid ethyl
ester,
N-[3,5-dichloro-4-(4-hydroxy-3-{[(naphthalen-1-ylmethyl)-amino]-methyl}-p-
henoxy)-phenyl]-oxamic acid ethyl ester,
N-(3,5-dichloro-4-{4-hydroxy-3-[(-
1-naphthalen-1-yl-(1R)ethylamino)-methyl]-phenoxy}-phenyl)-oxamic
acid ethyl ester,
N-(3,5-dichloro-4-{4-hydroxy-3-[(1,2,3,4-tetrahydro-naphthal-
en-1-ylamino)-methyl]-phenoxy}-phenyl)-oxamic acid ethyl ester,
N-[3,5-dichloro-4-(3-cyclohexylaminomethyl-4-hydroxy-phenoxy)-phenyl]-oxa-
mic acid ethyl ester,
N-[3,5-dichloro-4-(3-cyclopentylaminomethyl-4-hydrox-
y-phenoxy)-phenyl]-oxamic acid ethyl ester,
N-[4-(3-{[(benzo[1,3]dioxol-5--
ylmethyl)-amino]-methyl}-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-oxamic
acid ethyl ester,
N-(3,5-dichloro-4-{3-[(4-chloro-benzylamino)-methyl]-4--
hydroxy-phenoxy}-phenyl)-oxamic acid ethyl ester,
N-(3,5-dichloro-4-{4-hyd-
roxy-3-[(4-isopropyl-benzylamino)-methyl]-phenoxy}-phenyl)-oxamic
acid ethyl ester,
N-[3,5-dichloro-4-(4-hydroxy-3-methylaminomethyl-phenoxy)-ph-
enyl]-oxamic acid ethyl ester,
N-[3,5-dichloro-4-(3-cyclopropylaminomethyl-
-4-hydroxy-phenoxy)-phenyl]-oxamic acid ethyl ester,
N-[3,5-dichloro-4-(4-hydroxy-3-morpholin-4-ylmethyl-phenoxy)-phenyl]-oxam-
ic acid ethyl ester and
N-[3,5-dichloro-4-(3-cyclobutylaminomethyl-4-hydro-
xy-phenoxy)-phenyl]-oxamic acid ethyl ester.
103. A compound as defined in claim 1 selected from the group
consisting of
N-{4-[4-hydroxy-3-(isopropylmethylcarbamoyl)-phenoxy]-3,5-dimethyl-phe-
nyl}-oxamide,
N-{4-[4-hydroxy-3-(1-isopropyl-2-methyl-propylcarbamoyl)-phe-
noxy]-3,5-dimethyl-phenyl}-oxamide,
N-[3,5-dichloro-4-(3-cyclohexylcarbamo-
yl-4-hydroxy-phenoxy)-phenyl]-oxamide,
N-{3-chloro-4-[4-hydroxy-3-(morphol-
ine-4-sulfonyl)-phenoxy]-5-methyl-phenyl}-oxamide,
N-[4-(3-benzenesulfonyl-
-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-oxamide,
N-{3-chloro-4-[3-(cyclob-
utylmethylcarbamoyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-oxamide,
N-{3-chloro-4-[3-(cyclopropylmethyl-amino-sulfonyl)-4-hydroxy-phenoxy]-5--
methyl-phenyl}-oxamide,
N-{3-chloro-4-[4-hydroxy-3-(methylpropylsulfamoyl)-
-phenoxy]-5-methyl-phenyl}-oxamide,
N-{4-[4-hydroxy-3-(pyrrolidine-1-carbo-
nyl)-phenoxy]-3,5-dimethyl-phenyl}-oxamide,
N-[3-chloro-4-(3-cyclopropylsu-
lfamoyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-oxamide and
N-{4-[3-(cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phe-
nyl}-oxamide,
104. A compound as defined in claim 1 selected from the group
consisting of
N-{3,5-dichloro-4-[3-(4-chloro-benzenesulfonyl)-4-hydroxy-phenoxy]-phe-
nyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[3-(4-chloro-benzenesulfon-
yl)-4-hydroxy-phenoxy]-phenyl}-oxamic acid,
N-{3-chloro-4-[3-(4-chloro-ben-
zenesulfonyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-oxamic acid,
N-{3-chloro-4-[3-(4-chloro-benzenesulfonyl)-4-hydroxy-phenoxy]-5-methyl-p-
henyl}-oxamide,
N-[4-(3-benzenesulfonyl-4-hydroxy-phenoxy)-3,5-dichloro-ph-
enyl]-oxamic acid ethyl ester,
N-[4-(3-benzenesulfonyl-4-hydroxy-phenoxy)--
3,5-dichloro-phenyl]-oxamic acid,
N-[4-(3-benzenesulfonyl-4-hydroxy-phenox-
y)-3,5-dichloro-phenyl]-oxamide,
N-{3,5-dichloro-4-[4-hydroxy-3-(naphthale-
ne-1-sulfonyl)-phenoxy]-phenyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[4-hydroxy-3-(naphthalene-1-sulfonyl)-phenoxy]-phenyl}--
oxamic acid,
N-{3,5-dichloro-4-[4-hydroxy-3-(naphthalene-2-sulfonyl)-pheno-
xy]-phenyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[4-hydroxy-3-(napht-
halene-2-sulfonyl)-phenoxy]-phenyl}-oxamic acid,
N-{3,5-dichloro-4-[4-hydr-
oxy-3-(toluene-4-sulfonyl)-phenoxy]-phenyl}-oxamic acid and
N-{3,5-dichloro-4-[4-hydroxy-3-(toluene-4-sulfonyl)-phenoxy]-phenyl}-oxam-
ide.
105. A compound as defined in claim I selected from the group
consisting of
N-[3,5-dichloro-4-(3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)-phe-
nyl]-oxamic acid ethyl ester,
N-[4-(4-hydroxy-3-methanesulfonyl-phenoxy)-3-
,5-dimethyl-phenyl]-oxamic acid,
N-[3,5-dichloro-4-(3-ethanesulfonyl-4-hyd-
roxy-phenoxy)-phenyl]-oxamic acid,
N-{3,5-dichloro-4-[4-hydroxy-3-(propane-
-2-sulfonyl)-phenoxy]-phenyl}-oxamic acid ethyl ester,
N-[3,5-dichloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-phenyl]-
-oxamic acid ethyl ester,
N-[3,5-dichloro-4-(3-cyclohexylmethanesulfonyl-4-
-hydroxy-phenoxy)-phenyl]-oxamic acid ethyl ester,
N-[3,5-dichloro-4-(3-cy-
clopentanesulfonyl-4-hydroxy-phenoxy)-phenyl]-oxamic acid ethyl
ester,
N-{4-[3-(butane-1-sulfonyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}-oxami-
c acid,
N-[3,5-dichloro-4-(4-hydroxy-3-phenylmethanesulfonyl-phenoxy)-phen-
yl]-oxamic acid,
N-{3,5-dichloro-4-[4-hydroxy-3-(propane-1-sulfonyl)-pheno-
xy]-phenyl}-oxamic acid,
N-{3,5-dichloro-4-[3-(4-fluoro-phenylmethanesulfo-
nyl)-4-hydroxy-phenoxy]-phenyl}-oxamic acid,
N-[3,5-dichloro-4-(3-cyclopro-
pylmethanesulfonyl-4-hydroxy-phenoxy)-phenyl]-oxamic acid,
N-[3,5-dichloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-phenyl]-
-oxamic acid and
N-[4-(3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-
-dimethyl-phenyl]-oxamic acid.
106. A compound as defined in claim 1 selected from the group
consisting of
N-[3,5-dichloro-4-(4-hydroxy-3-phenoxy-phenoxy)-phenyl-oxamic acid
ethyl ester,
N-{3,5-dichloro-4-[3-(4-chloro-phenoxy)-4-hydroxy-phenoxy]-p-
henyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[3-(4-chloro-phenoxy)-4--
hydroxy-phenoxy]-phenyl}-oxamic acid,
N-[3,5-dichloro-4-(4-hydroxy-3-pheno- xy-phenoxy)-phenyl]-oxamic
acid, N-{3,5-dichloro-4-[3-(4-fluoro-phenoxy)-4-
-hydroxy-phenoxy]-phenyl}-oxamic acid ethyl ester,
N-{3,5-dichloro-4-[3-(4-
-fluoro-phenoxy)-4-hydroxy-phenoxy]-phenyl}-oxamic acid,
N-{4-[3-(4-fluoro-phenoxy)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-oxamic
acid,
N-[4-(4-hydroxy-3-phenoxy-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid
and
N-{4-[3-(4-chloro-phenoxy)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-ox-
amic acid.
107. A compound as defined in claim 1 selected from the group
consisting of
N-[3-chloro-4-(7-hydroxy-2,2-dimethyl-indan-4-yloxy)-5-methyl-phenyl]--
oxamic acid,
N-[4-(7-hydroxy-indan-4-yloxy)-3,5-dimethyl-phenyl]-oxamic acid,
N-[3-chloro-4-(7-hydroxy-indan-4-yloxy)-5-methyl-phenyl]-oxamic
acid, N-[4-(7-hydroxy-indan-4-yloxy)-3,5-dimethyl-phenyl]-oxamic
acid ethyl ester,
N-[4-(7-hydroxy-indan-4-yloxy)-3,5-dimethyl-phenyl]-oxamide,
N-[3-chloro-4-(7-hydroxy-indan-4-yloxy)-5-methyl-phenyl]-oxamide,
N-[3-chloro-4-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-5-methyl--
phenyl]-oxamic acid and
N-[3-chloro-4-(4-hydroxy-5,6,7,8-tetrahydro-naphth-
alen-1-yloxy)-5-methyl-phenyl]-oxamide.
108. A compound as defined in claim 1 selected from the group
consisting of
N-{3-chloro-4-[3-(4-fluoro-phenoxymethyl)-4-hydroxy-phenoxy]-5-methyl--
phenyl}-oxamic acid ethyl ester and
N-[3-chloro-4-(4-hydroxy-3-phenoxymeth-
yl-phenoxy)-5-methyl-phenyl]-oxamic acid ethyl ester.
109. A compound as defined in claim 1 selected from the group
consisting of N-[3,5-dichloro-4-(1H-indol-5-yloxy)-phenyl]-oxamic
acid ethyl ester,
N-[3,5-dichloro-4-(1H-indol-5-yloxy)-phenyl]-oxamic acid ethyl
ester, N-[3,5-dichloro-4-(1H-indol-5-yloxy)-phenyl]-oxamic acid,
N-[3,5-dichloro-4-(1H-indol-5-yloxy)-phenyl]-oxamide,
N-[3-chloro-4-(1H-indol-5-yloxy)-5-methyl-phenyl]-oxamic acid,
N-[3-chloro-4-(1H-indol-5-yloxy)-5-methyl-phenyl]-oxamide,
N-[3,5-dichloro-4-(2-methyl-1H-indol-5-yloxy)-phenyl]-oxamic acid
ethyl ester and
N-[3,5-dichloro-4-(2-methyl-1H-indol-5-yloxy)-phenyl]-oxamic
acid.
110. A compound as defined in claim 1 selected from the group
consisting of
N-[3,5-dichloro-4-(4-fluoro-3-methyl-phenoxy)-phenyl]-oxamic acid,
N-[4-(4-fluoro-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid,
N-[3,5-dichloro-4-(4-fluoro-phenoxy)-phenyl]-oxamic acid ethyl
ester, N-[3,5-dichloro-4-(3,4-difluoro-phenoxy)-phenyl]-oxamic acid
ethyl ester,
N-[3,5-dichloro-4-(3-chloro-4-fluoro-phenoxy)-phenyl]-oxamic acid
ethyl ester,
N-[4-(3,4-difluoro-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid,
N-[4-(3-chloro-4-fluoro-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid,
N-[4-(4-fluoro-3-methyl-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid,
N-[3,5-dichloro-4-(4-fluoro-phenoxy)-phenyl]-oxamic acid,
N-[3,5-dichloro-4-(3,4-difluoro-phenoxy)-phenyl]-oxamic acid,
N-[3,5-dichloro-4-(3-chloro-4-fluoro-phenoxy)-phenyl]-oxalamic
acid,
N-{4-[3-(cyclobutyl-methyl-carbamoyl)-4-fluoro-phenoxy]-3,5-dimethyl-phen-
yl}-oxalamic acid ethyl ester,
N-{4-[3-(cyclobutyl-methyl-carbamoyl)-4-flu-
oro-phenoxy]-3,5-dimethyl-phenyl}-oxalamic acid and
N-[4-(4-fluoro-phenoxy)-3,5-dimethyl-phenyl]-oxalamic acid ethyl
ester.
111. A compound or pharmaceutically acceptable salt as defined in
claim 3 wherein R.sup.5 is fluoro.
112. A compound or pharmaceutically acceptable salt as defined in
claim 111 wherein R.sup.4 is hydrogen, fluoro, chloro, methyl or
cyclobutyl-methyl-carbamoyl.
113. A compound or pharmaceutically acceptable salt as defined in
claim 112 wherein R.sup.1 and R.sup.2 are each independently methyl
or chloro.
114. A compound or pharmaceutically acceptable salt as defined in
claim 113 wherein R.sup.1 and R.sup.2 are each methyl.
115. A compound or pharmaceutically acceptable salt as defined in
claim 113 wherein R.sup.1 and R.sup.2 are each chloro.
116. A compound or pharmaceutically acceptable salt as defined in
claim 113 wherein R.sup.7 is hydrogen, and R.sup.8 is hydrogen or
--OR.sup.9.
117. A compound or pharmaceutically acceptable salt as defined in
claim 116 wherein R.sup.9 is methyl or ethyl.
118. A compound as defined in claim 1 selected from the group
consisting of: N-[4-(4-fluoro-phenoxy)-3,5-dimethyl-phenyl]-oxamic
acid, N-[3,5-dichloro-4-(4-fluoro-phenoxy)-phenyl]-oxamic acid,
N-[3,5-dichloro-4-(3,4-difluoro-phenoxy)-phenyl]-oxamic acid,
N-[4-(3-methyl-4-Fluoro-phenoxy)-3,5-dichloro-phenyl]-oxamic acid,
N-[3,5-dichloro-4-(3-chloro-4-fluoro-phenoxy)-phenyl]-oxamic acid,
N-[4-(3,4-difluoro-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid,
N-[4-(3-chloro-4-fluoro-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid,
N-[4-(3-methyl-4-fluoro-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid,
N-[3,5-dichloro-4-(4-fluoro-phenoxy)-phenyl]-oxamic acid,
N-[3,5-dichloro-4-(3,4-difluoro-phenoxy)-phenyl]-oxamic acid,
N-{4-[3-(cyclobutyl-methyl-carbamoyl)-4-fluoro-phenoxy)-3,5-dimethyl-phen-
yl]-oxamic acid and
N-[4-(4-fluoro-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid.
119. A pharmaceutically acceptable salt of each of said compounds
as defined in claim 118 where said salt is independently a
potassium salt or a sodium salt.
120. An ester of each of said compounds as defined in claim 118
where said ester is independently a methyl ester, an ethyl ester or
an isopropyl ester.
121. A method of treating a condition selected from the group
consisting of obesity, hyperlipidemia, glaucoma, cardiac
arrhythmia, skin disorders, thyroid disease, hypothyroidism,
diabetes mellitus, atherosclerosis, hypertension, coronary heart
disease, hypercholesteremia, depression and osteoporosis, in a
mammal which comprises administering to said mammal an effective
treating amount of a compound, prodrug, isomer or pharmaceutically
acceptable salt as defined in claim 1.
122. A method as defined in claim 121 further including
administering an anorectic agent.
123. A method as defined in claim 121 further including
administering a lipase inhibitor.
124. A method as defined in claim 122 further including
administering a lipase inhibitor.
125. A method as defined in claim 121 wherein said condition is
obesity.
126. A method as defined in claim 122 wherein said condition is
obesity.
127. A method as defined in claim 123 wherein said condition is
obesity.
128. A method as defined in claim 124 wherein said condition is
obesity.
129. A pharmaceutical composition comprising a compound, prodrug,
isomer or pharmaceutically acceptable salt as defined in claim 1,
and a pharmaceutically acceptable vehicle, diluent or carrier.
130. A pharmaceutical composition as defined in claim 129 further
including an anorectic agent.
131. A pharmaceutical composition as defined in claim 129 further
including a lipase inhibitor.
132. A pharmaceutical composition as defined in claim 130 further
including a lipase inhibitor.
133. A pharmaceutical composition for treating a condition selected
from the group consisting of obesity, hyperlipidemia, glaucoma,
cardiac arrhythmia, skin disorders, thyroid disease,
hypothyroidism, diabetes mellitus, atherosclerosis, hypertension,
coronary heart disease, hypercholesteremia, depression and
osteoporosis, in a mammal comprising a compound, prodrug, isomer or
pharmaceutically acceptable salt as defined in claim 1, and a
pharmaceutically acceptable vehicle, diluent or carrier.
134. A pharmaceutical composition as defined in claim 133 further
including an anorectic agent.
135. A pharmaceutical composition as defined in claim 133 further
including a lipase inhibitor.
136. A pharmaceutical composition as defined in claim 134 further
including a lipase inhibitor.
137. A pharmaceutical composition as defined in claim 133 wherein
said condition is obesity.
138. A pharmaceutical composition as defined in claim 134 wherein
said condition is obesity.
139. A pharmaceutical composition as defined in claim 135 wherein
said condition is obesity.
148. A pharmaceutical composition as defined in claim 136 wherein
said condition is obesity.
149. A kit for the treatment of a condition selected from the group
consisting of obesity, hyperlipidemia, glaucoma, cardiac
arrhythmia, skin disorders, thyroid disease, hypothyroidism,
diabetes mellitus, atherosclerosis, hypertension, coronary heart
disease, hypercholesteremia, depression and osteoporosis which
comprises: a first compound, said first compound being a compound,
prodrug, isomer, or pharmaceutically acceptable salt as defined in
claim 1, and a pharmaceutically acceptable vehicle, carrier or
diluent, in a first unit dosage form; a second compound, said
second compound being an anorectic agent or a lipase inhibitor, and
a pharmaceutically acceptable vehicle, carrier or diluent, in a
second unit dosage form; and a container.
150. A kit as defined in claim 149 wherein said condition is
obesity.
Description
CROSSREFERENCE TO RELATED APPLICATION
[0001] This application is a divisional of U.S. non-provisional
application Ser. No. 09/966,647, filed Sep. 27, 2001, now allowed,
which claims benefit of U.S. non-provisional application Ser. No.
09/514,862, filed Feb. 28, 2000, now issued as U.S. Pat. No.
6,326,398, and provisional application No. 60/122,292, filed Mar.
1, 1999.
FIELD OF THE INVENTION
[0002] The present invention relates to novel thyroid receptor
ligands and, more particularly, relates to novel oxamic acids, and
derivatives thereof, which are useful in the treatment of obesity,
hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders,
thyroid disease, hypothyroidism and related disorders and diseases
such as diabetes mellitus, atherosclerosis, hypertension, coronary
heart disease, hypercholesteremia, depression and osteoporosis.
Also provided are methods, pharmaceutical compositions and kits for
treating such diseases and disorders.
BACKGROUND OF THE INVENTION
[0003] It is generally accepted that thyroid hormones,
specifically, biologically active iodothyronines, are critical to
normal development and to maintaining metabolic homeostasis.
Thyroid hormones stimulate the metabolism of cholesterol to bile
acids and enhance the lipolytic responses of fat cells to other
hormones.
[0004] Thyroid hormones also affect cardiac function both directly
and indirectly, e.g., by increasing the metabolic rate. For
example, tachycardia, increased stroke volume, increased cardiac
index, cardiac hypertrophy, decreased peripheral vascular
resistance and increased pulse pressure are observed in patients
with hyperthyroidism.
[0005] Disorders of the thyroid are generally treated with hormone
replacement by administering either naturally occurring thyroid
hormones or thyromimetic analogues thereof which mimic the effects
of thyroid hormones.
[0006] Two naturally occurring thyroid hormones, namely, thyroxine
or 3,5,3',5'-tetraiodo-L-thyronine (commonly referred to as
"T.sub.4") and 3,5,3'-triiodo-L-thyronine (commonly referred to as
"T.sub.3"), are shown below: 2
[0007] T.sub.3 is the more biologically active of the two and, as
will be appreciated from the structural formulae provided above,
differs from T.sub.4 by the absence of the 5' iodine.
[0008] T.sub.3 may be produced directly from the thyroid gland, or,
in peripheral tissues, by the removal of the 5' iodine by
deiodinase enzymes. Thyromimetic analogs are often designed to be
structurally similar to T.sub.3. In addition, naturally occurring
metabolites of T.sub.3 are known.
[0009] As discussed above, thyroid hormones affect cardiac
functioning, for example, by causing an increase in the heart rate
and, accordingly, an increase in oxygen consumption. While the
increase in oxygen consumption may result in certain desired
metabolic effects, nonetheless, it does place an extra burden on
the heart, which in some situations, may give rise to damaging side
effects. Therefore, as is known in the art, such as described by A.
H. Underwood et al. in an article published in Nature, Vol. 324:
pp. 425-429 (1986), efforts have been made to synthesize thyroid
hormone analogs which function to lower lipids and serum
cholesterol without generating the adverse cardiac effects referred
to above.
[0010] U.S. Pat. Nos. 4,766,121; 4,826,876; 4,910,305; and
5,061,798 disclose certain thyroid hormone mimetics, namely,
3,5-dibromo-3'-[6-oxo-3(1 H)-pyridazinylmethyl]-thyronines.
[0011] U.S. Pat. No. 5,284,971 discloses certain thyromimetic
cholesterol lowering agents, namely, 4-(3-cyclohexyl-4-hydroxy or
-methoxy phenylsulfonyl)-3,5 dibromo-phenylacetic compounds.
[0012] U.S. Pat. Nos. 5,401,772; 5,654,468; and 5,569,674 disclose
certain lipid lowering agents, namely, heteroacetic acid
derivatives, which compete with radiolabeled T.sub.3 in binding
assays using rat liver nuclei and plasma membrane preparations.
[0013] Certain oxamic acids and derivatives thereof are known in
the art, e.g., U.S. Pat. No. 4,069,343 describes the use of certain
oxamic acids to prevent immediate type hypersensitivity reactions;
U.S. Pat. No. 4,554,290 describes the use of certain oxamic acids
to control pests on animals and plants; U.S. Pat. No. 5,401,772
discloses certain oxamic acids as lipid lowering agents; U.S. Pat.
No. 5,232,947 describes the use of certain oxamic acids to improve
damaged cerebral functions of the brain; and European Patent
Specification published as EP 580,550 discloses certain oxamic acid
derivatives as hypocholesteremic agents.
[0014] In addition, certain oxamic acid derivatives of thyroid
hormones are known in the art. For example, N. Yokoyama et al. in
an article published in the Journal of Medicinal Chemistry, 38 (4):
695-707 (1995) describe replacing a --CH.sub.2 group in a naturally
occurring metabolite of T.sub.3 with an --NH group resulting in
--HNCOCO.sub.2H. Likewise, R. E. Steele et al. in an article
published in International Congressional Service (Atherosclerosis
X) 1066: 321-324 (1995) and Z. F. Stephan et al. in an article
published in Atherosclerosis, 126: 53-63 (1996), describe certain
oxamic acid derivatives useful as lipid-lowering thyromimetic
agents yet devoid of undesirable cardiac activities.
[0015] All of the documents cited herein, including the foregoing,
are incorporated by reference herein in their entireties.
SUMMARY OF THE INVENTION
[0016] The present invention provides compounds of Formula I: 3
[0017] prodrugs thereof, geometric and optical isomers thereof, and
pharmaceutically acceptable salts of said compounds, said prodrugs,
and said isomers, wherein:
[0018] R.sup.1, R.sup.2 and R.sup.3 are each independently
hydrogen, halogen, C.sub.1-6 alkyl, trifluoromethyl, --CN,
--OCF.sub.3 or --OC.sub.1-6 alkyl;
[0019] R.sup.4 is hydrogen, C.sub.1-12 alkyl optionally substituted
with one to three substitutents independently selected from Group
Z, C.sub.2-12 alkenyl, halogen, --CN, aryl, heteroaryl, C.sub.3-10
cycloalkyl, heterocycloalkyl, --S(O).sub.2NR.sup.9R.sup.10,
--C(O)NR.sup.9R.sup.10, --(C.sub.1-6 alkyl)-NR.sup.9R.sup.10,
--NR.sup.9C(O)R.sup.10, --NR.sup.9C(O)NR.sup.9R.sup.10,
--NR.sup.9S(O).sub.2R.sup.10, --(C.sub.1-6 aldyl)-OR.sup.11,
--OR.sup.11 or --S(O).sub.aR.sup.12, provided that, where R.sup.5
is not fluoro, R.sup.4 is --S(O).sub.2NR.sup.9R.sup.10,
--C(O)NR.sup.9R.sup.10, --(C.sub.1-6 alkyl)-NR.sup.9R.sup.10,
--NR.sup.9C(O)R.sup.10, --NR.sup.9C(O)NR.sup.9R.sup.10,
--NR.sup.9S(O).sub.2R.sup.10, --(C.sub.1-6alkyl)-OR.sup.11,
--OR.sup.11 or --S(O).sub.aR.sup.12;
[0020] or R.sup.3 and R.sup.4 may be taken together to form a
carbocyclic ring A of the formula --(CH.sub.2).sub.b-- or a
heterocyclic ring A selected from the group consisting of
--Q--(CH.sub.2).sub.c-- and
--(CH.sub.2).sub.j--Q--(CH.sub.2).sub.k-- wherein Q is O, S or
NR.sup.17, wherein said carbocyclic ring A and said heterocyclic
ring A are each independently optionally substituted with one or
more substituents independently selected from C.sub.1-4 alkyl,
halide or oxo;
[0021] R.sup.5 is fluoro, hydroxy, C.sub.1-4 alkoxy or
OC(O)R.sup.9;
[0022] or R.sup.4 and R.sup.5 may be taken together to form a
heterocyclic ring B selected from the group consisting of
--CR.sup.9.dbd.CR.sup.10--NH- --, --N.dbd.CR.sup.9--NH--,
--CR.sup.9.dbd.CH-- and --CR.sup.9.dbd.CH--S--;
[0023] R.sup.6 is hydrogen, halogen, C.sub.1-4 alkyl or
trifluoromethyl;
[0024] R.sup.7 is hydrogen or C.sub.1-6 alkyl;
[0025] R.sup.8 is --OR.sup.9 or --NR.sup.19R.sup.20;
[0026] R.sup.9 and R.sup.10 for each occurrence are independently
(A) hydrogen, (B) C.sub.1-12 alkyl optionally substituted with one
or more substituents independently selected from Group V, (C)
C.sub.2-12 alkenyl, (D) C.sub.3-10 cycloalkyl optionally
substituted with one or more substituents independently selected
from C.sub.1-6 alkyl, C.sub.2-5 alkynyl, C.sub.3-10 cycloalkyl,
--CN, --NR.sup.13R.sup.14, oxo, --OR.sup.18, --COOR.sup.18 or aryl
optionally substituted with X and Y, (E) aryl optionally
substituted with X and Y, or (F) het optionally substituted with X
and Y;
[0027] or R.sup.9 and R.sup.10 for any occurrence may be taken
together to form a heterocyclic ring C optionally further
containing a second heterogroup selected from the group consisting
of --O--, --NR.sup.13-- and --S--, and optionally further
substituted with one or more substituents independently selected
from C.sub.1-5 alkyl, oxo, --NR.sup.13R.sup.14, --OR.sup.18,
--C(O).sub.2R.sup.18, --CN, --C(O) R.sup.9, aryl optionally
substituted with X and Y, het optionally substituted with X and Y,
C.sub.5-6 spirocycloalkyl, and a carbocyclic ring B selected from
the group consisting of 5-, 6-, 7- and 8-membered partially and
fully saturated, and unsaturated carbocyclic rings, and including
any bicyclic group in which said carbocyclic ring B is fused to a
carbocyclic ring C selected from the group consisting of 5-, 6-,
7-and 8-membered partially and fully saturated, and unsaturated
carbocyclic rings;
[0028] R.sup.11 is C.sub.1-12 alkyl optionally substituted with one
or more substituents independently selected from Group V,
C.sub.2-12 alkenyl, C.sub.3-10 cycloalkyl, trifluoromethyl,
difluoromethyl, monofluoromethyl, aryl optionally substituted with
X and Y, het optionally substituted with X and Y,
--C(O)NR.sup.9R.sup.10 or --C(O)R.sup.9;
[0029] R.sup.12 is C.sub.1-12 alkyl optionally substituted with one
or more substituents independently selected from Group V,
C.sub.2-12 alkenyl, C.sub.3-10 cycloalkyl, aryl optionally
substituted with X and Y, or het optionally substituted with X and
Y;
[0030] R.sup.13 and R.sup.14 for each occurrence are independently
hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, --(C.sub.1-6
alkyl)--C.sub.1-6 alkoxy, aryl optionally substituted with X and Y,
het optionally substituted with X and Y, --(C.sub.1-4 alkyl)-aryl
optionally substituted with X and Y, --(C.sub.1-4
alkyl)-heterocycle optionally substituted with X and Y,
--(C.sub.1-4 alkyl)-hydroxy, --(C.sub.1-4 alkyl)-halo, --(C.sub.1-4
alkyl)-poly-halo, --(C.sub.1-4 alkyl)--CONR.sup.15R.sup.16 or
C.sub.3-10 cycloalkyl;
[0031] R.sup.15 and R.sup.16 for each occurrence are independently
hydrogen, C.sub.1-6 alkyl, C.sub.3-10 cycloalkyl or aryl optionally
substituted with X and Y;
[0032] R.sup.17 is hydrogen, C.sub.1-6 alkyl, --COR.sup.9 or
--SO.sub.2R.sup.9;
[0033] R.sup.18 is hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
--(C.sub.1-6 alkyl)-C.sub.1-6 alkoxy, aryl optionally substituted
with X and Y, het optionally substituted with X and Y, --(C.sub.1-4
alkyl)-aryl optionally substituted with X and Y, --(C.sub.1-4
alkyl)-heterocycle optionally substituted with X and Y,
--(C.sub.1-4 alkyl)-hydroxy, --(C.sub.1-4 alkyl)-halo, --(C.sub.1-4
alkyl)-poly-halo, --(C.sub.1-4 alkyl)-CONR.sup.15R.sup.16,
--(C.sub.1-4 alkyl)-(C.sub.1-4 alkoxy) or C.sub.3-10
cycloalkyl;
[0034] R.sup.19 is hydrogen or C.sub.1-6 alkyl;
[0035] R.sup.20 is hydrogen or C.sub.1-6 alkyl;
[0036] W is O, S(O).sub.d, CH.sub.2 or NR.sup.9;
[0037] Group Z is C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, halogen,
--CF.sub.3, --OCF.sub.3, hydroxy, oxo, --CN, aryl, heteroaryl,
C.sub.3-10 cycloalkyl, hetercycloalkyl, --S(O).sub.aR.sup.12,
--S(O).sub.2NR.sup.9R.sup.10, --C(O)R.sup.9R.sup.10, and
--NR.sup.9R.sup.10;
[0038] Group V is halogen, --NR.sup.13R.sup.14, --OCF.sub.3,
--OR.sup.9, oxo, trifluoromethyl, --CN, C.sub.3-10 cycloalkyl, aryl
optionally substituted with X and Y, and het optionally substituted
with X and Y;
[0039] het for each occurrence is a heterocyclic ring D selected
from the group consisting of 4-, 5-, 6-, 7- and 8-membered
partially and fully saturated, and unsaturated, heterocyclic rings
containing from one to four heteroatoms independently selected from
the group consisting of N, O and S, and including any bicyclic
group in which said heterocyclic ring D is fused to a benzene ring
or a heterocyclic ring E selected from the group consisting of 4-,
5-, 6-, 7- and 8-membered partially and fully saturated, and
unsaturated, heterocyclic rings containing from one to four
heteroatoms independently selected from the group consisting of N,
O and S;
[0040] X and Y for each occurrence are independently (A) hydrogen,
(B) halogen, (C) trifluoromethyl, (D) --OCF.sub.3, (E) --CN, (F)
C.sub.1-6 alkyl optionally substituted with one or more
substituents independently selected from the group consisting of
halogen, --OCF.sub.3, --CF.sub.3 and phenyl, (G) C.sub.1-6 alkoxy,
(H) aryl optionally substituted with one or more substituents
independently selected from the group consisting of halogen,
--OCF.sub.3, --CF.sub.3, C.sub.1-4 alkyl and C.sub.1-4 alkoxy, (I)
--C(O).sub.2R.sup.13, (J) --C(O)NR.sup.13R.sup.14, (K)
--C(O)R.sup.13, (L) --NR.sup.13C(O)NR.sup.13R.sup.14 and (M)
--NR.sup.13C(O)R.sup.14; or X and Y for any occurrence in the same
variable may be taken together to form (a) a carbocyclic ring D of
the formula --(CH.sub.2).sub.e-- or (b) a heterocyclic ring F
selected from the group consisting of --O(CH.sub.2).sub.fO--,
(CH.sub.2).sub.gNH-- and --CH.dbd.CHNH--;
[0041] a and d are each independently 0, 1 or 2;
[0042] bis 3, 4, 5, 6 or 7;
[0043] c, f, g, j and k are each independently 2, 3, 4, 5 or 6;
and
[0044] e is 3, 4, 5, 6 or 7.
[0045] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, designated the A Group,
contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein W is
O.
[0046] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the A Group, designated the
B Group, contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein R.sup.1
is located at the 3 position, R.sup.2 is located at the 5 position,
R.sup.3 is located at the 2' position, R.sup.4 is located at the 3'
position, R.sup.5 is located at the 4' position, and R.sup.6 is
located at the 5' position.
[0047] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the B Group, designated the
C Group, contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein R.sup.3
is hydrogen, or R.sup.3 and R.sup.4 are taken together to form a
carbocyclic ring A of the formula --(CH.sub.2).sub.b-- or a
heterocyclic ring A selected from the group consisting of
--Q--(CH.sub.2).sub.c and --(CH.sub.2).sub.j--Q--(CH.-
sub.2).sub.k-- wherein Q is O, S or NR.sup.17, wherein said
carbocyclic ring A and said heterocyclic ring A are each
independently optionally substituted with one or more substituents
independently selected from C.sub.1-4 alkyl, halide or oxo, R.sup.5
is hydroxy, R.sup.6 is hydrogen and R.sup.7 is hydrogen.
[0048] A preferred group of compounds pharmaceutically acceptable
salts of such compounds, of the C Group, designated the D Group,
contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein R.sup.1
and R.sup.2 are each independently methyl, bromo or chloro, and
R.sup.8 is hydroxy, methoxy, ethoxy, isopropoxy, NH.sub.2 or
NH(CH.sub.3).
[0049] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the D Group, designated the
E Group, contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein R.sup.4
is S(O).sub.2NR.sup.9R.sup.10, and R.sup.10 is hydrogen or
methyl.
[0050] Particularly preferred compounds of the E Group are
compounds wherein (a) R.sup.1 is chloro, R.sup.2 is methyl, R.sup.8
is ethoxy or hydroxy, R.sup.9 is ethyl and R.sup.10 is hydrogen,
(b) R.sup.1 is chloro, R.sup.2 is methyl, R.sup.8 is ethoxy or
hydroxy, R.sup.9 is n-butyl and R.sup.10 is hydrogen, (c) R.sup.1
is chloro, R.sup.2 is methyl, R.sup.8 is ethoxy or hydroxy, R.sup.9
is --CH.sub.2-cyclopropyl and R.sup.10 is hydrogen and (d) R.sup.1
is chloro, R.sup.2 is methyl, R.sup.8 is isopropoxy or hydroxy,
R.sup.9 is cyclopropyl and R.sup.10 is hydrogen; and
pharmaceutically acceptable salts of said compounds.
[0051] Another preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the D Group, designated the
F Group, contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein R.sup.4
is S(O).sub.2NR.sup.9R.sup.10, and R.sup.9 and R.sup.10 are taken
together with the nitrogen atom to which they are attached to form
N(CH.sub.2).sub.4, N(CH.sub.2).sub.5, morpholine or 4
[0052] Particularly preferred compounds of the F Group are those
wherein R.sup.9 and R.sup.10 are taken together with the nitrogen
atom to which they are attached to form N(CH.sub.2).sub.4.
[0053] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the E Group, designated the
G Group, contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein R.sup.9
is hydrogen, isopropyl, --CH.sub.2-2-thienyl,
--CH.sub.2-cyclopropyl, cyclopropyl, --(CH.sub.2).sub.2OH,
exo-2-norbornyl, methyl, ethyl, 4-fluorophenyl, cyclobutyl,
cyclopentyl, cyclohexyl, n-propyl, n-butyl, n-pentyl, n-hexyl,
n-octyl or n-decyl.
[0054] Particularly preferred compounds of the G Group are
compounds wherein (a) R.sup.1 is chloro, R.sup.2 is methyl, R.sup.8
is hydroxy or ethoxy, R.sup.9 is cyclopropyl and R.sup.10 is
hydrogen, (b) R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
hydroxy or ethoxy, R.sup.9 is cyclopropyl and R.sup.10 is methyl,
(c) R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is hydroxy or
ethoxy, R.sup.9 is cyclobutyl and R.sup.10 is methyl, (d) R.sup.1
is methyl, R.sup.2 is methyl, R.sup.8 is hydroxy or ethoxy, R.sup.9
is cyclopropyl and R.sup.10 is hydrogen and (e) R.sup.1 is methyl,
R.sup.2 is methyl, R.sup.8 is hydroxy or ethoxy, R.sup.9 is
cyclobutyl and R.sup.10 is hydrogen; and pharmaceutically
acceptable salts of said compounds.
[0055] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the D Group, designated the
J Group, contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein R.sup.4
is --C(O)NR.sup.9R.sup.10, and R.sup.10 is hydrogen, methyl or
ethyl.
[0056] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the J Group, designated the
K group, contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein R.sup.9
is methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl, n-pentyl,
n-hexyl, 4-fluorophenyl, --CH.sub.2-2-thienyl, cyclopropyl,
--CH.sub.2-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
--CH.sub.2-cyclohexyl, endo-2-norbornyl, exo-2-norbornyl,
(S)-1-phenylethyl, (R)-1-phenylethyl, --CH.sub.2-2-chlorophenyl,
--CH.sub.2-4-chlorophenyl, --CH.sub.2-4-fluorophenyl,
--CH.sub.2-3-chloro-4-fluorophenyl,
--CH.sub.2-2-chloro-4-fluorophenyl,
--CH.sub.2-2-fluoro-4-chlorophenyl, --CH.sub.2-3,4-difluorophenyl,
--CH.sub.2-4-isopropylphenyl, --CH.sub.2-2,3-dichlorophenyl,
--CH.sub.2-2,4-dichlorophenyl, --CH.sub.2-3,4-dichlorophenyl,
--CH.sub.2-3-trifluoromethyl-4-chlorophenyl, 4-phenylphenyl,
3-(2,4-dimethyl)pentyl, (R)-1-(1-naphthyl)ethyl,
1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl,
(R)-1-(2-naphthyl)ethyl, (R)-2-(1-naphthyl)ethyl,
--CH.sub.2-(1-naphthyl), (R)-1-cyclohexylethyl,
(S)-1-cyclohexylethyl, --CH.sub.2-3,4-methylenedioxyphenyl,
--CH.sub.2-4-t-butylphenyl, --CH.sub.2-2,3-dichlorophenyl,
1-indanyl, (R)-1-indanyl, (S)-1-indanyl, 5-indanyl,
1-(1,2,3,4-tetrahydronaphthyl) or (R)-1-cyclohexylethyl.
[0057] Particularly preferred compounds of the K Group are
compounds wherein (a) R.sup.1 is chloro, R.sup.2 is chloro, R.sup.8
is hydroxy or ethoxy, R.sup.9 is 3-(2,4-dimethyl)pentyl and
R.sup.10 is hydrogen, (b) R.sup.1 is methyl, R.sup.2 is methyl,
R.sup.8 is hydroxy or ethoxy, R.sup.9 is cyclopropyl and R.sup.10
is methyl, (c) R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is
hydroxy or ethoxy, R.sup.9 is cyclobutyl and R.sup.10 is methyl,
(d) R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8 is hydroxy or
ethoxy, R.sup.9 is 3-(2,4-dimethyl)pentyl and R.sup.10 is hydrogen,
(e) R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8is hydroxy or
ethoxy, R.sup.9 is n-pentyl and R.sup.10 is methyl, (g) R.sup.1 is
methyl, R.sup.2 is methyl, R.sup.8 is hydroxy or ethoxy, R.sup.9 is
isopropyl and R.sup.10 is methyl, (h) R.sup.1 is methyl, R.sup.2 is
methyl, R.sup.8 is hydroxy, ethoxy or NH.sub.2, R.sup.9 is
cyclobutyl and R.sup.10 is methyl and (i) R.sup.2 is chloro,
R.sup.2 is chloro, R.sup.8 is hydroxy or ethoxy, R.sup.9 is
cyclobutyl and R.sup.10 is methyl; and pharmaceutically acceptable
salts of said compounds.
[0058] Another preferred group of compounds and pharmaceutically
acceptable salts of such compounds, designated the L Group,
contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein R.sup.4
is --C(O)NR.sup.9R.sup.10, and R.sup.9 and R.sup.10 are taken
together with the nitrogen atom to which they are attached to form
N(CH.sub.2).sub.7, N(CH.sub.2).sub.6, N(CH.sub.2).sub.5,
N(CH.sub.2).sub.4, morpholine, 5
[0059] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the D Group, designated the
M Group, contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein R.sup.4
is --CH.sub.2NR.sup.9R.sup.10, and R.sup.10 is hydrogen, methyl or
--COCH.sub.3.
[0060] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the M Group, designated the
N group, contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein R.sup.9
is methyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, exo-2-norbornyl,
--CH.sub.2-4-fluorophenyl, --CH.sub.2-4-chlorophenyl,
--CH.sub.2-4-isopropylphenyl, --CH.sub.2-3,4-methylenedioxyphenyl,
(R)-1-(1-naphthyl)ethyl, (R)-1-phenylethyl, (S)-1-phenylethyl,
(R)-1-cyclohexylethyl, 1-(1,2,3,4-tetrahydronaphthyl), 1-indanyl or
--CH.sub.2-(1-naphthyl).
[0061] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the D Group, designated the
O group, contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein R.sup.4
is --CH.sub.2NR.sup.9R.sup.10 and R.sup.9 and R.sup.10 are taken
together with the nitrogen atom to which they are attached to form
N(CH.sub.2).sub.6, morpholine, 6
[0062] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the D Group, designated the
P Group, contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein
R.sup.4is --NHCOR.sup.9.
[0063] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the P Group, designated the
Q Group, contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein R.sup.9
is cyclopropyl or cyclobutyl.
[0064] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the D Group, designated the
R Group, contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein R.sup.4
is --S(O).sub.2R.sup.12, and R.sup.12 is 4-chlorophenyl, phenyl,
1-naphthyl, 2-naphthyl, CH.sub.2-cyclopropyl, isopropyl,
CH.sub.2-cyclobutyl, CH.sub.2-cyclohexyl, cyclopentyl,
CH.sub.2-4-fluorophenyl, 4-tolyl, methyl, ethyl, n-butyl,
CH.sub.2-phenyl or n-propyl.
[0065] Particularly preferred compounds of the R Group are
compounds wherein (a) R.sup.1 is chloro, R.sup.2 is chloro, R.sup.8
is hydroxy or ethoxy, and R.sup.12 is ethyl, (b) R.sup.1 is chloro,
R.sup.2 is chloro, R.sup.8 is hydroxy or ethoxy and R.sup.12 is
--CH.sub.2-cyclobutyl, (c) R.sup.1 is chloro, R.sup.2 is chloro,
R.sup.8 is hydroxy or ethoxy and R.sup.12 is --CH.sub.2-cyclohexyl,
(d) R.sup.1 is chloro, R.sup.2 is chloro, R.sup.8 is hydroxy or
ethoxy and R.sup.12 is cyclopentyl, (e) R.sup.1 is chloro, R.sup.2
is chloro, R.sup.8 is hydroxy or ethoxy, and R.sup.12 is
--CH.sub.2-cyclopropyl, (f) R.sup.1 is chloro, R.sup.2 is chloro,
R.sup.8 is hydroxy or ethoxy, and R.sup.12 is
--CH.sub.2-cyclobutyl, and (g) R.sup.1 is methyl, R.sup.2 is
methyl, R.sup.8 is hydroxy or ethoxy, and R.sup.12 is
--CH.sub.2-cyclopropyl; and pharmaceutically acceptable salts of
said compounds.
[0066] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the B Group, designated the
S Group, contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein R.sup.1
and R.sup.2 are each independently methyl, bromo or chloro, R.sup.3
is hydrogen, R.sup.4 and R.sup.5 are taken together to form 7
[0067] R.sup.6 is hydrogen, R.sup.7 is hydrogen, R.sup.8 is ethoxy,
hydroxy or NH.sub.2, and R.sup.10 is hydrogen or methyl.
[0068] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the D Group, designated the
T Group, contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein R.sup.3
is hydrogen, and R.sup.4 is --O.sup.11.
[0069] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the T Group, designated the
U Group, contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein
R.sup.11 is phenyl, 4-chlorophenyl or 4-fluorophenyl.
[0070] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the D Group, designated the
V Group, contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein R.sup.3
is hydrogen, and R.sup.4 is --(C.sub.1-6 alkyl)-OR.sup.11.
Particularly preferred compounds of the V Group are compounds
wherein R.sup.4 is --CH.sub.2--OR.sup.11.
[0071] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the V Group, designated the
W Group, contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein
R.sup.11 is phenyl or 4-fluorophenyl.
[0072] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the D Group, designated the
X Group, contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein R.sup.3
and R.sup.4 are taken together to form a carbocyclic ring A of the
formula --(CH.sub.2).sub.b-- or a heterocyclic ring A selected from
the group consisting of --Q--(CH.sub.2).sub.c and
--(CH.sub.2).sub.j--Q--(CH.sub.2).sub.k-- wherein Q is O, S or
NR.sup.17, wherein said carbocyclic ring A and said heterocyclic
ring A are each independently optionally substituted with one or
more substituents independently selected from C.sub.1-4 alkyl,
halide or oxo.
[0073] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the X Group, designated the
Y Group, contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein R.sup.3
and R.sup.4 are taken together to form said carbocyclic ring A.
[0074] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the Y Group, designated the
Z Group, contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein R.sup.3
and R.sup.4 are taken together to form --(CH.sub.2).sub.3--,
--CH.sub.2--C(CH.sub.3).sub.2--CH.- sub.2-- or
--(CH.sub.2).sub.4--.
[0075] Particularly preferred compounds of the Z Group are
compounds wherein (a) R.sup.1 is methyl, R.sup.2 is methyl, R.sup.8
is hydroxy or ethoxy, and R.sup.3 and R.sup.4 are taken together to
form --(CH.sub.2).sub.3--, (b) R.sup.1 is chloro, R.sup.2 is
methyl, R.sup.8 is hydroxy or ethoxy, and R.sup.3 and R.sup.4 are
taken together to form --(CH.sub.2).sub.3-- and (c) R.sup.1 is
methyl, R.sup.2 is methyl, R.sup.8 is hydroxy or ethoxy, and
R.sup.3 and R.sup.4 are taken together to form
--(CH.sub.2).sub.4--; and pharmaceutically acceptable salts of said
compounds.
[0076] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, designated the AA Group,
contains those compounds of Formula I and pharmaceutically
acceptable salts of such compounds, as shown above, wherein R.sup.8
is --OR.sup.9.
[0077] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the AA Group, designated the
AB Group, contains those compounds of Formula I and
pharmaceutically acceptable salts of such compounds, as shown
above, wherein R.sup.9 is C.sub.1-12 alkyl.
[0078] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the AB Group, designated the
AC Group, contains those compounds of Formula I and
pharmaceutically acceptable salts of such compounds, as shown
above, wherein R.sup.9 is methyl, isopropyl or ethyl.
[0079] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the AC Group, designated the
AD Group, contains those compounds of Formula I and
pharmaceutically acceptable salts of such compounds, as shown
above, wherein R.sup.9 is ethyl.
[0080] A preferred group of the pharmaceutically acceptable salts
of the compounds of Formula I, and the prodrugs, geometric and
optical isomers thereof, contains those pharmaceutically acceptable
salts of the compounds, prodrugs, and geometric and optical isomers
wherein the salt is a potassium or a sodium salt.
[0081] A preferred group of compounds of Formula I, designated the
AE Group, includes the specific compounds:
[0082]
N-[3-chloro-4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-p-
henyl]-oxamic acid,
[0083]
N-[4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl-
]-oxamic acid,
[0084]
N-{4-[3-(cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-3,5-dimeth-
yl-phenyl}-oxamic acid,
[0085]
N-{3-chloro-4-[3-(cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-5-
-methyl-phenyl}-oxamic acid,
[0086] N-[4-(7-hydroxy-indan-4-yloxy)-3,5-dimethyl-phenyl]-oxamic
acid,
[0087]
N-{3,5-dichloro-4-[3-(cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenox-
y]-phenyl}-oxamic acid,
[0088]
N-[3,5-dichloro-4-(3-cyclopentanesulfonyl-4-hydroxy-phenoxy)-phenyl-
]-oxamic acid,
[0089]
N-[3,5-dichloro-4-(3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)--
phenyl]-oxamic acid,
[0090]
N-[3,5-dichloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-p-
henyl]-oxamic acid,
[0091]
N-[4-(3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl--
phenyl]-oxamic acid,
[0092]
N-[3-chloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-5-met-
hyl-phenyl]-oxamic acid,
[0093]
N-[4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-p-
henyl]-oxamic acid,
[0094]
N-[4-(3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl--
phenyl]-oxamic acid,
[0095]
N-[3-chloro-4-(3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy)-5-me-
thyl-phenyl]-oxamic acid,
[0096]
N-[3,5-dichloro-4-(3-cyclopentylmethanesulfonyl-4-hydroxy-phenoxy)--
phenyl]-oxamic acid,
[0097]
N-[4-(3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-p-
henyl]-oxamic acid,
[0098]
N-[3-chloro-4-(3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy)-5-met-
hyl-phenyl]-oxamic acid,
[0099]
N-[3,5-dichloro-4-(3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy)-p-
henyl]-oxamic acid,
[0100]
N-[3,5-dichloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy)--
phenyl]-oxamic acid,
[0101]
N-{4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-3,5-dimethyl--
phenyl}-oxamic acid,
[0102]
N-{3-chloro-4-[3-(4-fluoro-benzenesulfonyl)-4-hydroxy-phenoxy]-5-me-
thyl-phenyl}-oxamic acid, and the prodrugs and geometric and
optical isomers thereof, and the pharmaceutically acceptable salts
of the compounds, prodrugs and isomers.
[0103] A preferred group of the pharmaceutically acceptable salts
of the compounds, prodrugs, and geometric and optical isomers of
the AE Group, designated the AF Group, contains those
pharmaceutically acceptable salts of the compounds, prodrugs, and
geometric and optical isomers wherein the salt is a potassium or a
sodium salt.
[0104] A preferred group of the compounds, and geometric and
optical isomers thereof, of the compounds of the AE group,
designated the AG Group, contains the ethyl esters of those
compounds.
[0105] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the B Group, designated the
AH Group, contains those compounds of Formula I and
pharmaceutically acceptable salts of such compounds, as shown
above, wherein R.sup.5 is fluoro.
[0106] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the AH Group, designated the
AI Group, contains those compounds of Formula I and
pharmaceutically acceptable salts of such compounds, as shown
above, wherein R.sup.4 is hydrogen, fluoro, chloro, methyl or
cyclobutyl-methyl-carbamoyl.
[0107] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the AI Group, designated the
AJ Group, contains those compounds of Formula I and
pharmaceutically acceptable salts of such compounds, as shown
above, wherein R.sup.1 and R.sup.2 are each independently methyl or
chloro.
[0108] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the AJ Group, designated the
AK Group, contains those compounds of Formula I and
pharmaceutically acceptable salts of such compounds, as shown
above, wherein R.sup.1 and R.sup.2 are each methyl.
[0109] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the AJ Group, designated the
AL Group, contains those compounds of Formula I and
pharmaceutically acceptable salts of such compounds, as shown
above, wherein R.sup.1 and R.sup.2 are each chloro.
[0110] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the AJ Group, designated the
AM Group, contains those compounds of Formula I and
pharmaceutically acceptable salts of such compounds, as shown
above, wherein R.sup.7 is hydrogen, and R.sup.8 is hydrogen or
--OR.sup.9.
[0111] A preferred group of compounds and pharmaceutically
acceptable salts of such compounds, of the AM Group, designated the
AN Group, contains those compounds of Formula I and
pharmaceutically acceptable salts of such compounds, as shown
above, wherein R.sup.9 is methyl or ethyl.
[0112] A preferred group of compounds of Formula I, designated the
AO Group, includes the specific compounds:
[0113] N-[4-(4-Fluoro-phenoxy)-3,5-dimethyl-phenyl]-oxamic
acid,
[0114] N-[3,5-Dichloro-4-(4-fluoro-phenoxy)-phenyl]-oxamic
acid,
[0115] N-[3,5-Dichloro-4-(3,4-difluoro-phenoxy)-phenyl]-oxamic
acid,
[0116] N-[4-(3-Methyl-4-Fluoro-phenoxy)-3,5-dichloro-phenyl]-oxamic
acid,
[0117] N-[3,5-Dichloro-4-(3-chloro-4-fluoro-phenoxy)-phenyl]-oxamic
acid,
[0118] N-[4-(3,4-Difluoro-phenoxy)-3,5-dimethyl-phenyl]-oxamic
acid,
[0119]
N-[4-(3--Chloro-4-fluoro-phenoxy)-3,5-dimethyl-phenyl]-oxamic
acid,
[0120] N-[4-(3-Methyl-4-fluoro-phenoxy)-3,5-dimethyl-phenyl]-oxamic
acid,
[0121] N-[3,5-Dichloro-4-(4-fluoro-phenoxy)-phenyl]-oxamic
acid,
[0122] N-[3,5-Dichloro-4-(3,4-difluoro-phenoxy)-phenyl]-oxamic
acid,
[0123]
N-{4-[3-(Cyclobutyl-methyl-carbamoyl)-4-fluoro-phenoxy)-3,5-dimethy-
l-phenyl]-oxamic acid,
[0124] N-[4-(4-Fluoro-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid,
and the prodrugs and geometric and optical isomers thereof, and the
pharmaceutically acceptable salts of the compounds, prodrugs and
isomers.
[0125] A preferred group of the pharmaceutically acceptable salts
of the compounds, prodrugs, and geometric and optical isomers of
the AO Group, designated the AP Group, contains those
pharmaceutically acceptable salts of the compounds, prodrugs, and
geometric and optical isomers wherein the salt is a potassium or a
sodium salt.
[0126] A preferred group of the compounds, and geometric and
optical isomers thereof, of the compounds of the AO group,
designated the AQ Group, contains the ethyl esters of those
compounds.
[0127] This invention provides methods of treating a condition
selected from obesity, hyperlipidemia, glaucoma, cardiac
arrhythmia, skin disorders, thyroid disease, hypothyroidism,
diabetes mellitus, atherosclerosis, hypertension, coronary heart
disease, hypercholesteremia, depression and osteoporosis, in a
mammal (including a human being) which comprise administering to
said mammal an effective treating amount of a compound of Formula
I, or a prodrug thereof, or a geometric or an optical isomer
thereof, or a pharmaceutically acceptable salt of such compound,
such prodrug, or such isomer, as described above.
[0128] In another aspect, this invention provides methods of
treating a condition selected from obesity, hyperlipidemia,
glaucoma, cardiac arrhythmia, skin disorders, thyroid disease,
hypothyroidism, diabetes mellitus, atherosclerosis, hypertension,
coronary heart disease, hypercholesteremia, depression and
osteoporosis, in a mammal (including a human being) which comprise
administering to said mammal effective treating amounts of a
compound of Formula I, or a prodrug thereof, or a geometric or an
optical isomer thereof, or a pharmaceutically acceptable salt of
such compound, such prodrug, or such isomer, as described above,
and an anorectic agent.
[0129] In another aspect, this invention provides methods of
treating a condition selected from obesity, hyperlipidemia,
glaucoma, cardiac arrhythmia, skin disorders, thyroid disease,
hypothyroidism, diabetes mellitus, atherosclerosis, hypertension,
coronary heart disease, hypercholesteremia, depression and
osteoporosis, in a mammal (including a human being) which comprise
administering to said mammal effective treating amounts of a
compound of Formula I, or a prodrug thereof, or a geometric or an
optical isomer thereof, or a pharmaceutically acceptable salt of
such compound, such prodrug, or such isomer, as described above,
and a lipase inhibitor.
[0130] In a preferred aspect, this invention provides methods of
treating obesity in mammals (including a human being) which
comprise administering to said mammal an obesity treating effective
amount of compound of Formula I, or a prodrug thereof, or a
geometric or an optical isomer thereof, or a pharmaceutically
acceptable salt of such compound, prodrug, or isomer, as described
above.
[0131] In another aspect, this invention provides methods of
treating obesity in mammals (including a human being) which
comprise administering to said mammal obesity treating effective
amounts of a compound of Formula I, or a prodrug thereof, or a
geometric or an optical isomer thereof, or a pharmaceutically
acceptable salt of such compound, prodrug, or isomer, as described
above, and an anorectic agent.
[0132] In another aspect, this invention provides methods of
treating obesity, in a mammal (including a human being) which
comprise administering to said mammal obesity treating effective
amounts of a compound of Formula I, or a prodrug thereof, or a
geometric or an optical isomer thereof, or a pharmaceutically
acceptable salt of such compound, such prodrug, or such isomer, as
described above, and a lipase inhibitor.
[0133] In another aspect, this invention provides pharmaceutical
compositions comprising a compound of Formula I, or a prodrug
thereof, or a geometric or an optical isomer thereof, or a
pharmaceutically acceptable salt of such compound, prodrug, or
isomer, as described above, and a pharmaceutically acceptable
vehicle, diluent or carrier.
[0134] In another aspect, this invention provides pharmaceutical
compositions comprising a compound of Formula I, or a prodrug
thereof, or a geometric or an optical isomer thereof, or a
pharmaceutically acceptable salt of such compound, prodrug, or
isomer, as described above, an anorectic agent and a
pharmaceutically acceptable vehicle, diluent or carrier.
[0135] In another aspect, this invention provides pharmaceutical
compositions comprising a compound of Formula I, or a prodrug
thereof, or a geometric or an optical isomer thereof, or a
pharmaceutically acceptable salt of such compound, prodrug, or
isomer, as described above, a lipase inhibitor and a
pharmaceutically acceptable vehicle, diluent or carrier.
[0136] In another aspect, this invention provides pharmaceutical
compositions for treating a condition selected from obesity,
hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders,
thyroid disease, hypothyroidism, diabetes mellitus,
atherosclerosis, hypertension, coronary heart disease,
hypercholesteremia, depression and osteoporosis, in a mammal
(including a human being) comprising a compound of Formula I, or a
prodrug thereof, or a geometric or an optical isomer thereof, or a
pharmaceutically acceptable salt of such compound, prodrug, or
isomer, as described above, and a pharmaceutically acceptable
vehicle, diluent or carrier.
[0137] In another aspect, this invention provides pharmaceutical
compositions for treating a condition selected from obesity,
hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders,
thyroid disease, hypothyroidism, diabetes mellitus,
atherosclerosis, hypertension, coronary heart disease,
hypercholesteremia, depression and osteoporosis, in a mammal
(including a human being) comprising a compound of Formula I, or a
prodrug thereof, or a geometric or an optical isomer thereof, or a
pharmaceutically acceptable salt of such compound, prodrug, or
isomer, as described above, an anorectic agent, and a
pharmaceutically acceptable vehicle, diluent or carrier.
[0138] In another aspect, this invention provides pharmaceutical
compositions for treating a condition selected from obesity,
hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders,
thyroid disease, hypothyroidism, diabetes mellitus,
atherosclerosis, hypertension, coronary heart disease,
hypercholesteremia, depression and osteoporosis, in a mammal
(including a human being) comprising a compound of Formula I, or a
prodrug thereof, or a geometric or an optical isomer thereof, or a
pharmaceutically acceptable salt of such compound, prodrug, or
isomer, as described above, a lipase inhibitor, and a
pharmaceutically acceptable vehicle, diluent or carrier.
[0139] In another preferred aspect, this invention provides
pharmaceutical compositions for treating obesity in a mammal
(including a human being) comprising a compound of Formula I, or a
prodrug thereof, or a geometric or an optical isomer thereof, or a
pharmaceutically acceptable salt of such compound, prodrug, or
isomer, as described above, and a pharmaceutically acceptable
vehicle, diluent or carrier.
[0140] In yet another aspect, this invention provides
pharmaceutical compositions for treating obesity in a mammal
(including a human being) comprising a compound of Formula I, or a
prodrug thereof, or a geometric or an optical isomer thereof, or a
pharmaceutically acceptable salt of such compound, prodrug, or
isomer, as described above, an anorectic agent, and a
pharmaceutically acceptable vehicle, diluent or carrier.
[0141] In yet another aspect, this invention provides
pharmaceutical compositions for treating obesity in a mammal
(including a human being) comprising a compound of Formula I, or a
prodrug thereof, or a geometric or an optical isomer thereof, or a
pharmaceutically acceptable salt of such compound, prodrug, or
isomer, as described above, a lipase inhibitor, and a
pharmaceutically acceptable vehicle, diluent or carrier.
[0142] In another aspect, this invention provides kits for the
treatment of a condition selected from obesity, hyperlipidemia,
glaucoma, cardiac arrhythmia, skin disorders, thyroid disease,
hypothyroidism, diabetes mellitus, atherosclerosis, hypertension,
coronary heart disease, hypercholesteremia, depression and
osteoporosis which comprise: a first compound, said first compound
being a compound of Formula I, or a prodrug thereof, or a geometric
or an optical isomer thereof, or a pharmaceutically acceptable salt
of such compound, prodrug, or isomer, as described above, and a
pharmaceutically acceptable vehicle, carrier or diluent, in a first
unit dosage form; a second compound, said second compound being an
anorectic agent or a lipase inhibitor, and a pharmaceutically
acceptable vehicle, carrier or diluent, in a second unit dosage
form; and a container.
[0143] In another preferred aspect, this invention provides kits
for the treatment of a obesity which comprise: a first compound,
said first compound being a compound of Formula I, or a prodrug
thereof, or a geometric or an optical isomer thereof, or a
pharmaceutically acceptable salt of such compound, prodrug, or
isomer, as described above, and a pharmaceutically acceptable
vehicle, carrier or diluent, in a first unit dosage form; a second
compound, said second compound being an anorectic agent or a lipase
inhibitor, and a pharmaceutically acceptable vehicle, carrier or
diluent, in a second unit dosage form; and a container.
[0144] Unless otherwise provided herein:
[0145] "alkyl" means a straight or branched hydrocarbon chain
radical, including as the case may be, for example, methyl, ethyl,
n-propyl, isopropyl, n-butyl and the like;
[0146] "alkenyl" means a straight or branched unsaturated,
univalent aliphatic radical;
[0147] "alkoxy" means an alkyl radical which is attached to the
remainder of the molecule by oxygen, including as the case may be,
for example, methoxy;
[0148] "alkynyl" means a straight or branched acyclic hydrocarbon
radical with one triple bond, including as the case may be, for
example, acetylene;
[0149] "carbocyclic" (carbocycle) means an unsaturated, or a
partially or fully saturated, ring having only carbon atoms in its
nucleus, including as the case may be an aryl (an organic radical
derived from an aromatic hydrocarbon by the removal of one atom,
e.g., phenyl from benzene, also including, for example,
naphthyl);
[0150] "cycloalkane" means a saturated, monocyclic hydrocarbon,
including as the case may be, for example, cyclohexane;
[0151] "cycloalkyl" means a monocyclic or polycyclic radical
derived from a cycloalkane, including as the case may be, for
example, cyclohexyl;
[0152] "halo" or "halogen" means a radical derived from the
elements fluorine, chlorine, bromine or iodine;
[0153] "heterocyclic" ("heterocycle") means a radical derived from
an unsaturated, or a partially or fully saturated, monocyclic or
polycyclic ring of different types of atoms, and includes aromatic
and non-aromatic heterocyclic groups containing one or more
heteroatoms each selected from O, S and N; examples of heterocyclic
groups include, e.g., benzimidazolyl, benzofuranyl,
benzothiophenyl, benzoxazolyl, furyl, imidazolyl, indolyl,
isoquinolyl, isothiazolyl, isoxazolyl, morpholinyl, oxadiazolyl,
oxazolyl, piperazinyl, piperidyl, pyranyl, pyrazinyl, pyrazolyl,
pyridyl, pyrimidyl, pyrrolyl, quinolyl, tetrahydroisoquinoly,
tetrahydroquinolyl, tetrahydrothienyl, tetrazolyl, thiadiazolyl,
thiazolyl, thienyl, thiomorpholinyl, thiophenyl and triazolyl;
where heterocyclic groups are specifically recited or covered as
substituents for the compounds of Formula I, it is understood that,
unless specifically noted otherwise, all suitable isomers of such
heterocyclic groups are intended;
[0154] a "hydrate" is a crystalline substance containing one or
more molecules of water of crystallization, i.e., a substance
containing water combined in the molecular form;
[0155] "pharmaceutically acceptable" means that the carrier,
diluent, vehicle excipients, and/or salt must be compatible with
the other ingredients of the formulation, and not deleterious to
the recipient thereof;
[0156] "pharmaceutically acceptable salts" of the compounds of this
invention may be formed of the compound itself, prodrugs, e.g.
esters, isomers and the like, and include all of the
pharmaceutically acceptable salts which are most often used in
pharmaceutical chemistry; for example, salts may be formed with
inorganic or organic acids such as hydrochloric acid, hydrobromic
acid, hydroiodic acid, carboxylic acids, sulfonic acids including
such agents as naphthalenesulfonic, ethanesulfonic,
hydroxyethanesulfonic, methanesulfonic ("mesylate"),
benzenesulfonic ("besylate") and toluenesulfonic acids, e.g.,
p-toluenesulfonic ("tosylate"), sulfuric acid, nitric acid,
phosphoric acid, tartaric acid, pyrosulfuric acid, metaphosphoric
acid, succinic acid, formic acid, phthalic acid, malic acid, maleic
acid, lactic acid, ascorbic acid, glycollic acid, gluconic acid,
mandelic acid, glutamic acid, aspartic acid, fumaric acid, pyruvic
acid, phenylacetic acid, pamoic acid, nicotinic acid, and the like;
suitable pharmaceutically acceptable salts also include alkali
metal salts (e.g. sodium, potassium salts), alkaline earth metal
salts (e.g. magnesium, calcium salts), amine salts (e.g. ammonium,
alkylammonium, dialkylammonium, trialkylammonium,
tetraalkylammonium, diethanolaminium, tri-ethanolaminium and
guanidinium salts); preferred salts include salts of organic acids
selected from formic, acetic, trifluoroacetic, propionic, benzoic,
citric, maleic, tartaric, methanesulfonic, benzenesulfonic or
toluenesulfonic, salts of inorganic acids selected from
hydrochloric, hydrobromic, sulfuric or phosphoric, amino acids
selected from aspartic and glutamic, and salts of sodium and
potassium;
[0157] a "polymorph" is a substance that occurs in two or more
forms;
[0158] a "prodrug" is a drug precursor which, following
administration, releases the drug in vivo via some chemical or
physiological process (e.g., a prodrug on being brought to the
physiological pH or through enzyme action is converted to the
desired drug form); exemplary prodrugs upon cleavage release the
corresponding free acid, and such hydrolyzable ester-forming
residues of the compounds of Formula I include but are not limited
to those having a carboxyl moiety wherein the free hydrogen is
replaced by (C.sub.1-C.sub.4)alkyl,
(C.sub.2-C.sub.7)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having
from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having
from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to
6 carbon atoms, 1-(alkoxy-carbonyloxy)ethyl having from 4 to 7
carbon atoms, 1-methyl-1-(alkoxy-carbonyloxy)ethyl having from 5 to
8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9
carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10
carbon atoms, 3-phthalidyl, 4-crotonolactonyl,
gamma-butyrolacton-4-yl,
di-N,N-(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
b-dimethylaminoethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di(C.sub.1-C.sub.2)alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-C.sub.3)alkyl;
[0159] a "radical" is a group of atoms that behaves as a single
atom in a chemical reaction, e.g., an organic radical is a group of
atoms which confers characteristic properties on a compound
containing it, or which remains unchanged during a series of
reactions;
[0160] a "solvate" is a molecular or ionic complex of molecules or
ions of a solvent with those of a solute; a "solvate" wherein the
solvent is water, forms "hydrates" or hydrated ions;
[0161] "spirocycloalkyl" means cycloalkyl having a spiro union (the
union formed by a single atom which is the only common member of
the rings); and
[0162] "treating," "treat" or "treatment" includes, inter alia,
preventative (e.g., prophylactic), palliative and curative
treatment.
DETAILED DESCRIPTION OF THE INVENTION
[0163] Unless otherwise noted, throughout this document: .degree.C.
is degrees Centigrade, % is percent, Calc. is calculated data, cm
is centimeter, DEE is diethyl ether, DME is dimethyl ether, DMF is
dimethylformamide, DMSO is dimethylsulfoxide, DTT is
dithiothreitol, EtOAc is ethyl acetate, EtOH is ethanol, Found is
found data, g is gram or grams, h is hour or hours, kg is kilogram
or kilograms, KOH is potassium hydroxide, L is liter or liters, M
is molar (concentration), MeOH is methanol, mg is milligram or
milligrams, min is minute or minutes, mL is milliliter or
milliliters, mm is millimole or millimoles, mM is millimolar
(concentration), MS is mass spectrum, N is normal (concentration),
NaOH is sodium hydroxide, nM is nanomolar (concentration), NMR is
proton nuclear magentic resonance spectrum, psi is pounds per
square inch, RT is room temperature, TEA is triethylamine, TFA is
trifluoroacetic acid, THF is tetrahydrofuran, .mu.g is microgram or
micrograms, and .mu.L is microliter or microliters.
[0164] As disclosed herein, a compound within the scope of Formula
I shall at all times be understood to include all active forms of
such compounds, including, for example, the free form thereof,
e.g., the free acid or base form and also, all prodrugs,
polymorphs, hydrates, solvates, stereoisomers, e.g., diastereomers
and enantiomers, and the like, and all pharmaceutically acceptable
salts as described above. It will also be appreciated that suitable
active metabolites of compounds within the scope of Formula I, in
any suitable form, are also included herein.
[0165] More specifically, certain compounds suitable for use in the
present invention such as, for example, certain compounds of
Formula I may have asymmetric centers and therefore exist in
different enantiomeric forms. All suitable optical isomers and
stereoisomers of such compounds, and mixtures thereof, are
considered to be within the scope of the invention. With respect to
such compounds, the present invention includes the use of a
racemate, a single enantiomeric form, a single diastereomeric form,
or mixtures thereof, as suitable. Moreover, such compounds may also
exist as tautomers. Accordingly, the present invention relates to
the use of all such suitable tautomers and mixtures thereof.
[0166] In addition, those skilled in the art will easily recognize
that physiologically active compounds which have accessible hydroxy
groups are frequently administered in the form of pharmaceutically
acceptable esters. The compounds of this invention can be
administered as esters, formed on the hydroxy groups. While the
mechanism has not yet been investigated and not wishing to be bound
by theory, it is believed that such esters are metabolically
cleaved in the body, and that the actual drug is the hydroxy
compound itself. It is possible, as has long been known in
pharmaceutical chemistry, to adjust the rate or duration of action
of the compound by suitable choices of ester groups.
[0167] Those skilled in the art will understand from this
disclosure how to prepare the compounds of the present invention
using any suitable known method. Moreover, the reaction SCHEMES of
the present description illustrate the preparation of the compounds
of the present invention and, unless otherwise indicated, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.9, R.sup.10, X
and Y in the reaction SCHEMES are as described above, Q of compound
14 of SCHEME A is preferably sodium or potassium, X.sup.1 of
SCHEMES D, I and L is preferably halide or sulfonate, T of SCHEMES
K and L is as described below. In addition, the Examples provided
herein further illustrate the preparation of the compounds of the
present invention.
[0168] The subject invention also includes isotopically-labelled
compounds, which are identical to those recited in Formula I, but
for the fact that one or more atoms are replaced by an atom having
an atomic mass or mass number different from the atomic mass or
mass number usually found in nature. Examples of isotopes that can
be incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and
chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, and
.sup.36Cl, respectively. Compounds of the present invention,
prodrugs thereof, and pharmaceutically acceptable salts of said
compounds or of said prodrugs which contain the aforementioned
isotopes and/or other isotopes of other atoms are within the scope
of this invention. Certain isotopically-labelled compounds of the
present invention, for example those into which radioactive
isotopes such as .sup.3H and .sup.14C are incorporated, are useful
in drug and/or substrate tissue distribution assays. Tritiated,
i.e., .sup.3H, and carbon-14, i.e., .sup.14C, isotopes are
particularly preferred for their ease of preparation and
detectability. Further, substitution with heavier isotopes such as
deuterium, i.e., .sup.2H, can afford certain therapeutic advantages
resulting from greater metabolic stability, for example increased
in vivo half-life or reduced dosage requirements and, hence, may be
preferred in some circumstances. Isotopically-labelled compounds of
Formula I of this invention and prodrugs thereof can generally be
prepared by carrying out the procedures disclosed in the SCHEME
and/or in the EXAMPLES below, by substituting a readily available
isotopically-labelled reagent for a non-isotopically labelled
reagent.
[0169] The starting materials for each synthetic SCHEME and EXAMPLE
provided by this description are either commercially available or
can be prepared according to methods known to those skilled in the
art such as described, for example, in the aforementioned U.S. Pat.
Nos. 5,401,772; 5,569,674; and 5,654,468, and European Patent
Specification published as EP 580,550.
[0170] The compounds of the present invention can be prepared from
a common intermediate I as described below 8
[0171] which itself may be synthesized according to any suitable
method known in the art. More specifically, those skilled in the
art will understand based upon the present disclosure how to
prepare the common intermediate 1 wherein W is oxygen,
(SO.sub.2).sub.d, CH.sub.2 or NR.sup.9 where d and R.sup.9 are as
described above. It is particularly preferred that W is oxygen.
[0172] For example, common intermediate 1 wherein W is oxygen
("1(a)") can be prepared by either
[0173] (a) 9
[0174] coupling a 4-nitrophenol (or a corresponding thiophenol) 2
with a bis-aryl iodonium tetrafluoroborate 3 at about RT in a
suitable organic solvent such as, for example, dichloromethane,
chloroform, DMF or DMSO, in the presence of a suitable copper
catalyst such as, for example, copper bronze and a suitable base
such as, for example, TEA, potassium-t-butoxide or sodium hydride
(J. Med. Chem, 38: 695-707 (1995));
[0175] (b) 10
[0176] coupling a 4-halonitrobenzene 4 (M is halogen), such as, for
example, a 4-iodonitrobenzene, a 4-bromonitrobenzene, or a
4-chloronitrobenzene, with a phenol (or a thiophenol) 5 such as,
for example, a 4-fluorophenol, at a suitable elevated temperature
(greater than about 120.degree. C., e.g., about 130.degree. C.) in
the presence of a suitable base such as, for example, potassium
carbonate, potassium hydroxide, or potassium-t-butoxide, in a polar
inert solvent such as, for example, DMSO or N-methylpyrrolidone
(NMP); or
[0177] (c) 11
[0178] coupling (at RT in dichloromethane) a phenylboronic acid 6
with a 4-nitrophenol 2 in the presence of copper (II) acetate and a
suitable base such as, for example, TEA, pyridine or a mixture of
TEA and pyridine. (Tetrahedron. Lett., 39:2933-2936, 2937-2940
(1998)).
[0179] Embodiments of the present invention wherein R.sup.4 of a
compound of Formula I is located at the 3' position and is
sulfonamide, amide, e.g., carboxamide, methylamino, carbamoyl or
sulfamoyl, aryloxy, e.g., phenyloxy or benzyloxy, phenylsulfone or
alkylsulfone, can be prepared, e.g., according to SCHEMES A and B,
C and D, E, F, G and J, H , and I, respectively, provided by the
present description hereinbelow.
[0180] In addition, a compound of Formula I wherein R.sup.4 is
located at the 3' position and R.sup.3 is located at the 2'
position and taken together are indanyl or tetrahydronaphthalyl can
be prepared according to SCHEMES K and L, also provided by the
present description hereinbelow.
[0181] Further, a compound of Formula I wherein R.sup.4 is located
at the 3' position and R.sup.5 is located at the 4' position and
R.sup.4 and R.sup.5 are taken together to form an indolyl can be
prepared according to SCHEME M, provided hereinbelow.
[0182] Further yet, a compound of Formula I wherein R.sup.5 is
located at the 4' position and is fluoro can be prepared according
to SCHEME N, provided hereinbelow.
[0183] In SCHEMES A and C described hereinbelow, the starting
material ("A") is the common intermediate 1 wherein R.sup.5 is
located at the 4' position and is methoxy or ("MeO"). In SCHEMES E,
H and I described hereinbelow, the starting material ("B") is the
common intermediate 1 wherein R.sup.5 is located at the 4' position
and is MeO and R.sup.4 is located at the 3' position and is
hydrogen. In SCHEME N, the starting material ("C") is compound 5
wherein R.sup.5 is at the 4' position and is fluoro.
[0184] It should be understood that the following SCHEMES are
provided solely for the purposes of illustration and do not limit
the invention which is defined by the claims. 12 13 14 15 16 17 18
19 20 21 22 23 24 25
[0185] By Scheme A:
[0186] The nitro intermediate A can be converted to the
3'-sulfonamide 7 or 8 by reaction of a 3'-chlorosulfonylated
intermediate of A and a primary or secondary amine in a suitable
solvent such as, for example, dichloromethane, THF, MeOH, EtOH or
acetonitrile, in the presence of a suitable base such as, for
example, TEA or diisopropylethylamine. Chlorosulfonylation of A can
be performed by stirring a solution of A in a neat chlorosulfonic
acid at from about 0.degree. C. to about 25.degree. C.
[0187] The sulfonamide 7 can be converted to the sulfonamide 8 by
alkylation. A preferred alkylation method uses a suitable alkylated
agent such as, for example, an alkyl halide, in the presence of a
suitable base such as, for example, potassium carbonate, sodium
hydride, potassium t-butoxide, NaOH or KOH, in a suitable organic
solvent such as, for example, acetone, THF, DMSO, 2-propanol or an
aqueous MeOH solution.
[0188] Demethylation of 8 to the phenol 9 can be accomplished by
reaction of 8 with a suitable boron trihalide such as, for example,
boron tribromide or boron trichloride, in a suitable organic
solvent such as, for example, dichloromethane or chloroform. Nitro
reduction of 9 to the aniline 10 can be effected using methods well
known in the art such as, for example, hydrogenation or reduction
with zinc dust or tin (II) chloride.
[0189] The aniline 10 can be converted to the oxamate 11 by
reaction of 10 with diethyl oxalate at about 120.degree. C. for
from about 5 to about 24 h, or with ethyl oxalyl chloride at about
RT in a suitable anhydrous aprotic solvent such as, for example,
DEE, dichloromethane, chloroform or THF.
[0190] The oxamate 11 may be converted to the oxamic acid 12 and
the oxamide 13 using conventional methods well known in the
relevant art. For example, the ester 11 may be hydrolyzed to the
acid 12 using suitable aqueous alkalides such as, for example,
alkali metal carbonates or hydroxides in an aqueous MeOH solution.
The oxamide 13 can be synthesized by reacting the ester 11 with an
amine in a suitable solvent such as, for example, dichloromethane,
chloroform, THF or MeOH.
[0191] The acid 12 can be converted to salts 14 such as, for
example, metal or ammonium salts by treatment of 12 with an
equivalent amount of the corresponding base such as, for example,
alkali or ammonium hydroxides, or by exchange with carboxylic acid
salts or alkali siloxides, or, by ion exchange methods known in the
art.
[0192] By Scheme B:
[0193] The primary aniline 10 can be converted to the secondary
aniline 15 according to methods well known in the art for
conversion of a primary to a secondary amine such as, for example,
by reductive alkylation. A preferred reductive alkylation method
employs an aldehyde, or a ketone, and a reducing agent in a
suitable solvent and is best performed in the presence of about
3.quadrature. molecular sieves. Preferred reducing agents are
sodium cyanoborohydride, sodium triacetoxy-borohydride and sodium
borohydride. Preferred organic solvents are EtOH and MeOH.
[0194] The resultant aniline 15 can be converted to the oxamate 16
and then the acid 17 by, e.g., methods analogous to those that have
been previously described in SCHEME A discussed above.
[0195] By Scheme C:
[0196] The nitro intermediate A can be converted to the aldehyde 18
by formylation. A preferred formylation method can be accomplished
by reaction of A with hexamethylenetetramine at about 65.degree. C.
in a suitable solvent such as, for example, TFA.
[0197] The aldehyde 18 can be oxidized to the carboxylic acid 19 by
methods well known in the art, e.g., Jones oxidation. Preferred
oxidation methods include Jones oxidation and those employing
sodium hypochlorite. Reaction of the aldehyde 18 with Jones reagent
(chromic acid/aqueous sulfuric acid) in acetone affords the
carboxylic acid 19.
[0198] The nitro containing carboxylic acid compound 19 can be
converted to the oxamate 20 in three steps (demethylation, nitro
reduction and oxamate formation) by, e.g., procedures analogous to
those described in SCHEME A provided hereinabove.
[0199] The oxamate 20 can be converted to the 3'-carboxamide
derivative 21 according to methods known in the art. For example,
employment of an acid chloride or anhydride (symmetrical or mixed)
of 20 with an amine in a suitable dried aprotic solvent such as,
for example, dichloromethane, THF, DME or DEE, in the presence of a
base such as TEA, dimethylaminopyridine or pyridine, are two
commonly used methods. Another method utilizes the reaction of 20
and the requisite amine in an aprotic solvent with any of the
standard carbodiimide coupling reagents such as, for example,
dicyclohexylcarbodiimide, 2-ethoxy-1-ethoxycarbonyl-1,2-dihy-
droquinolone and benzotriazol-1-yloxytris
(dimethylamino)-phosphonium-hexa- fluorophosphate.
[0200] The ester 21 can be hydrolyzed to the oxamic acid 22 by,
e.g., the procedure analogous to that described in SCHEME A
discussed above.
[0201] By Scheme D:
[0202] The amide 23 can be prepared by reaction of an acid chloride
or anhydride (symmetrical or mixed) of 19 with a primary amine in a
suitable solvent such as, for example, dichloromethane, THF, DME,
DEE in the presence of a base such as, for example, TEA, DMAP or
pyridine.
[0203] The amide 23 can be alkylated to the amide 24 by reaction of
carboxamide anion of 23 with a suitable alkylation agent such as,
for example, an alkyl halide. The carboxamide anion of 23 can be
generated in DMF with a suitable base such as, for example, sodium
hydride or potassium hydride. The alkylation of 23 can also be
performed by phase transfer catalysis without solvent or with a
suitable solvent such as, for example, DMF or DMSO. The phase
transfer reaction uses tetrabutylammonium bromide ("TBAB") as the
phase transfer agent and potassium carbonate, KOH or NaOH as the
base.
[0204] The amide 24 can be converted to the corresponding compound
21, e.g., in three steps by procedures analogous to those described
in SCHEME A discussed above.
[0205] By Scheme E:
[0206] The compound B can be converted to the oxamate 25, e.g., in
three steps by procedures analogous to those described in SCHEME A
provided hereinabove.
[0207] Formylation of 25 can be accomplished by a formylation
procedure analogous to that described in SCHEME C provided
hereinabove.
[0208] The aldehyde 26 can be converted to the, e.g., methylamino,
derivative 27 by methods known in the art. A preferred method
utilizes reductive amination. For example, the reductive amination
can be accomplished by the reaction of the aldehyde 26 with an
amine and a reducing agent in a suitable solvent and is best
performed in the presence of 3 molecular sieves. Preferred reducing
agents are sodium cyanoborohydride, sodium triacetoxyborohydride
and sodium borohydride. Preferred organic solvents include EtOH,
MeOH and 1,2-dichloroethane.
[0209] By Scheme F:
[0210] The oxamate 25 can be converted to the nitro compound 28 by
nitration. The nitro compound 28 can be reduced to the
corresponding aniline 29 by, e.g., catalytic hydrogenation or
chemical reduction with zinc dust or tin (II) chloride. Acylation
of 29 with carbonyl chloride in the presence of a suitable base
such as, for example, TEA or N,N-diisopropylethylamine, affords
diacylated compound 30. The diacylated oxamate 30 can be converted
to the oxamic acid 32 by hydrolysis with a suitable base such as,
for example, NaOH or KOH in an aqueous MeOH solution. Sulfonylation
of 29 with sulfonyl chloride in the presence of a suitable base
such as, for example, TEA or N,N-diisopropylethyl amine, yields
disulfonylated compound 31. Hydrolysis of 31 with a suitable base
such as, for example, NaOH or KOH, in an aqueous MeOH solution at
about 50.degree. C. produces the oxamic acid 33.
[0211] By Scheme G:
[0212] The benzyl ether 37 can be converted to the phenol 38 by
debenzylation. Treatment of 37 with thioanisole in TFA at ambient
temperature affords 38. Conversion of 38 to the phenyl ether 39 can
be accomplished by coupling 38 with aryliodonium tetrafluoroborate
and copper bronze in the presence of triethyl amine in
dichloromethane or coupling 38 with arylboronic acid and copper
(II) acetate in the presence of a suitable base such as, for
example, TEA, pyridine, or a mixture of TEA and pyridine.
Conversion of 39 to the oxamate 40 can be accomplished, e.g., in
three steps (demethylation, nitro reduction and oxamate formation)
according to procedures analogous to those described in Scheme A
discussed above. The oxamic acid 41 is prepared by alkaline
hydrolysis of ester 40.
[0213] By Scheme H:
[0214] Treatment of B with an arylsulfonic acid in the presence of
Eaton's Reagent at elevated temperature provides a 3'-aryl sulfone
42. Demethylation of 42 followed by hydrogenation and then reaction
with ethyl oxalyl chloride provides the oxamate 43. The oxamate 43
may be hydrolysed to the oxamic acid 44 using a base, such as, for
example, NaOH or KOH.
[0215] By Scheme I:
[0216] The nitro compound B can be converted to the 3'-sulfinic
acid 45 by treatment with chlorosulfonic acid followed by reduction
with sodium sulfite in the presence of a base such as, for example,
sodium bicarbonate or NaOH. Treatment of the sulfinic acid 45 with
alkyl halide in the presence of a base such as, for example, NaOH,
KOH, potassium t-butoxide, sodium hydride or sodium methoxide,
provides the alkyl sulfone 46. The nitro compound 46 can be
converted to the oxamate 47 via demethylation, hydrogenation and
oxamate formation. Hydrolysis of the oxamate 47 under basic
conditions provides the oxamic acid 48.
[0217] By Scheme J:
[0218] The methyl ether 18 can be converted to the phenol 49 using
procedures analogous to those described in SCHEME A. The phenol 49
can be protected as the trimethylsilylethoxymethyl ether 50 by
treatment with a strong base such as, for example, sodium hydride
or potassium t-butoxide in an aprotic solvent, e.g., THF, followed
by treatment with trimethylsilylethoxymethyl chloride
("SEMCL").
[0219] Treatment of the aldehyde 50 with a reducing agent such as,
for example, diisobutylaluminum hydride ("DIBALH") in an aprotic
solvent, e.g., dichloromethane or THF affords 51. Reaction of
alcohol 51 with a suitable phenol utilizing an azodicarbonyl
compound, e.g., 1,1 '-(azodicarbonyl)dipiperidine or
diethylazo-dicarboxylate and a phosphine such as, for example,
triphenyl- or tributylphosphine in an aprotic solvent, e.g., THF or
toluene, provides the ether 52.
[0220] Removal of the "SEM" protecting group present in 52 under
acidic conditions such as, for example, sulfuric or mineral acid in
an alcoholic solvent, e.g., MeOH or EtOH, or alternatively,
fluoride-mediated conditions (tetrabutylammonium fluoride/THF,
hydrogen fluoride/acetonitrile) affords phenol 53. Reduction of the
nitro group present in 53 by refluxing in acetic acid with a
powdered metal, e.g., zinc or iron, provides the amine 54.
Conversion to the oxamate 55 and the associated oxamic acids and
oxamides is accomplished utilizing procedures analogous to those
detailed in SCHEME A.
[0221] By Scheme K:
[0222] Compounds 56-62 can be prepared according to procedures
analogous to those described above in accordance with well known
methods in the art. Those skilled in the art would understand from
the present disclosure and, in particular, from SCHEME A, how to
convert compound 62 to the oxamate derivatives detailed in SCHEME
K. T completes, as discussed above where R.sup.3 and R.sup.4 are
taken together, a carbocyclic ring A of the formula
--(CH.sub.2).sub.b-- or a heterocyclic ring A selected from the
group consisting of --Q--(CH.sub.2).sub.c-- and
--(CH.sub.2).sub.j--Q--(CH.sub.2).sub.k-- wherein b, Q, c, j and k
are as described above, and wherein said carbocyclic ring A and
said heterocyclic ring A are each independently optionally
substituted with one or more substituents (e.g., R.sup.21,
R.sup.22) independently selected from C.sub.1-4 alkyl, halide or
oxo, as also described above.
[0223] By Scheme L:
[0224] Exhaustive treatment of 63 with a strong base such as, for
example, lithium hexamethyidisilizane, lithium diisopropylamide or
potassium t-butoxide and a suitable alkyl halide in an aprotic
solvent, e.g., THF, affords the bis-alkylated intermediate 65. This
process is carried out in a stepwise manner where R.sup.21 and
R.sup.22 are different, and in a single reaction flask where
R.sup.21 and R.sup.22 are the same.
[0225] One of the methyl ethers present in 65 can be selectively
deprotected by utilizing boron trichloride or aluminum chloride in
an aprotic solvent, e.g., dichloromethane or toluene.
[0226] Reduction of the ketone functionality present in 66 can be
accomplished by treatment with a hydrosilane, preferably,
triethylsilane, in the presence of an acid, e.g., methanesulfonic
acid or TFA, with or without a solvent present. Solvents can be
either protic or aprotic, with dichloromethane being preferred.
Those skilled in the art will understand from the present
disclosure how to convert the resultant reduced compounds to target
oxamate derivatives.
[0227] T is as described for SCHEME K.
[0228] By Scheme M:
[0229] The indole 69 can be prepared by coupling the commercially
available 5-hydroxy indole 67 with the 4-iodonitrobenzene 68 at
about 125.degree. C. in the presence of potassium carbonate for
about 3 h. The nitro compound 69 is converted to the target
compound 70 via hydrogenation and oxamate formation.
[0230] By Scheme N:
[0231] The diaryl ether 72 is prepared by coupling of the
commercially available fluorophenol 71 with the 4-halonitrobenzene
4 at 130.degree. C. in NMP in the presence of KOH. The oxamic acid
73 is synthesized from the nitro compound 72 via hydrogenation,
acylation, and hydrolysis.
[0232] In the preparation of the compounds of Formula I it is noted
that, as would be appreciated by those skilled in the art, some of
the methods useful for the preparation of such compounds, e.g., as
exemplified by SCHEMES J and L discussed above, may require
protection of a particular functionality, e.g., to prevent
interference by such functionality in reactions at other sites
within the molecule or to preserve the integrity of such
functionality. The need for, and type of, such protection is
readily determined by one skilled in the art, and will vary
depending on, for example, the nature of the functionality and the
conditions of the selected preparation method. See, e.g., T. W.
Greene, Protective Groups in Organic Synthesis, John Wiley &
Sons, New York, 1991. Suitable protecting groups for any particular
functionality would include those which are not substantially
chemically reactive under the reaction conditions described and
which can be removed without substantially chemically altering
other functionalities of any given intermediate of the compound of
Formula I, or of the compound of Formula I itself. The protecting
group can be removed as so desired in any given preparation method,
e.g., in a subsequent step.
[0233] Some of the Formula I compounds of this invention are acidic
and they form a salt with a pharmaceutically acceptable cation.
Some of the Formula I compounds of this invention are basic and
they form a salt with a pharmaceutically acceptable anion. All such
salts are within the scope of this invention and they can be
prepared by conventional methods such as combining the acidic and
basic entities, usually in a stoichiometric ratio, in either an
aqueous, non-aqueous or partially aqueous medium, as appropriate.
The salts are recovered either by filtration, by precipitation with
a non-solvent followed by filtration, by evaporation of the
solvent, or, in the case of aqueous solutions, by lyophilization,
as appropriate. The compounds can be obtained in crystalline form
by dissolution in an appropriate solvent(s) such as ethanol,
hexanes or water/ethanol mixtures.
[0234] Preferred anorectic agents in the compositions, methods and
kits of this invention include phenylpropanolamine, ephedrine,
pseudoephedrine, phentermine, a neuropeptide Y antagonist, a
cholecystokinin-A agonist, a monoamine reuptake inhibitor, a
sympathiomimetic agent, a serotoninergic agent, a dopamine agonist,
a melanocyte-stimulating hormone receptor agonist or mimetic, a
cannabinoid receptor antagonist, a melanocyte-stimulating hormone
analog, a melanin concentrating hormone antagonist, the OB protein,
a leptin analog, a galanin antagonist and an orexin receptor
antagonist.
[0235] A preferred monoamine reuptake inhibitor is sibutramine.
[0236] Preferred serotoninergic agents include dexfenfluramine and
fenfluramine.
[0237] A preferred dopamine agonist is bromocriptine.
[0238] A preferred lipase inhibitor is tetrahydrolipstatin.
[0239] Suitable anorectic agents for the compositions, methods and
kits of this invention can be prepared using methods known to those
skilled in the art, for example, phentermine can be prepared as
described in U.S. Pat. No. 2,408,345; sibutramine can be prepared
as described in U.S. Pat. No. 4,929,629; fenfluramine and
dexfenfluramine can be prepared as described in U.S. Pat. No.
3,198,834; and bromocriptine can be prepared as described in U.S.
Pat. Nos. 3,752,814 and 3,752,888.
[0240] Suitable lipase inhibitors can be prepared using methods
known to those skilled in the art, for example, tetrahydrolipstatin
{(2S,3S,5S)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydroxy-hex-
adecanoic 1,3 acid lactone} can be prepared as described in, e.g.,
U.S. Pat. Nos. 5,274,143; 5,420,305; 5,540,917; and 5,643,874.
[0241] The administration of a compound, prodrug, isomer or
pharmaceutically acceptable salt of the present invention and an
anorectic agent or a lipase inhibitor, as the case may be,
according to this invention can be sequential in time or
simultaneous with the simultaneous method being generally
preferred. For sequential administration, a compound, a prodrug, an
isomer or a pharmaceutically acceptable salt of the present
invention and an anorectic agent or a lipase inhibitor, as the case
may be, can be administered in any order. In addition, for
sequential administration, the compound, prodrug, isomer or
pharmaceutically acceptable salt of the present invention and the
anorectic agent (or the lipase inhibitor as the case may be), can
be administered in any order. It is generally preferred that such
administration be oral. It is even more preferred that the
administration be oral and simultaneous. However, for example, if
the subject being treated is unable to swallow, or oral absorption
is otherwise impaired or undesirable, parenteral or transdermal
administration will be appropriate. Where the administration is
sequential, the administration of a compound, prodrug, isomer or
pharmaceutically acceptable salt of the present invention and an
anorectic agent or a lipase inhibitor, as the case may be, can be
by the same method or by different methods.
[0242] The dose of a compound, prodrug, isomer or pharmaceutically
acceptable salt of this invention to be administered to a human or
animal is rather widely variable and subject to the judgment of the
attending physician or veterinarian. As would be understood by
those skilled in the art, it may be necessary to adjust the dose of
a compound, prodrug or isomer of this invention when it is
administered in the form of a salt, e.g., where the salt forming
moiety of which has an appreciable molecular weight. The general
range of effective administration rates of the compounds, prodrugs,
isomers or pharmaceutically acceptable salts of this invention is
from about 0.001 mg/kg body weight to about 100 mg/kg body,weight
of the subject per day. A preferred range of effective
administration rates of the compounds, prodrugs, isomers or
pharmaceutically acceptable salts of this invention is from about
0.01 mg/kg body weight to about 50 mg/kg body weight of the subject
per day. While it may be practical to administer the daily dose of
a compound, prodrug, isomer or pharmaceutically acceptable salt of
this invention, in portions, at various hours of the day, in any
given case, the amount of compound, prodrug, isomer or
pharmaceutically acceptable salt administered will depend on such
factors as the solubility of the compound, prodrug, isomer or
pharmaceutically acceptable salt of this invention, the formulation
used and the route of administration (e.g., orally, transdermally,
parenterally or topically).
[0243] Dosages of the compounds, prodrugs, isomers and
pharmaceutically acceptable salts of the present invention can be
administered to humans by any suitable route, with oral
administration being preferable. Individual tablets or capsules
should generally contain from about 0.1 mg to about 100 mg of
compound, prodrug, isomer or pharmaceutically acceptable salt of
this invention, in a suitable pharmaceutically acceptable vehicle,
diluent or carrier. Dosages for intravenous administration are
generally within the range of from about 0.1 mg to about 10 mg per
single dose as required. For intranasal or inhaler administration,
the dosage is generally formulated as from about a 0.1% to about a
1% (w/v) solution. In practice, the physician will determine the
actual dosage which will be most suitable for an individual patient
and it will vary with, e.g., age, weight and response of the
particular patient. The above dosages are exemplary of the average
case but there can, of course, be individual instances where higher
or lower dosage ranges are merited, and all such dosages of
compounds, prodrugs, isomers and pharmaceutically acceptable salts
of this invention, are within the scope of the present
invention.
[0244] Any suitable dosage of an anorectic agent can be used in
aspects of the present invention comprising such agents. The dosage
of the anorectic agent is generally in the range of from about 0.01
to about 50 mg/kg body weight of the subject per day, preferably
from about 0.1 to about 10 mg/kg body weight of the subject per
day, administered singly or as a divided dose. For example, where
the anorectic agent is phentermine, the dosage of phentermine is
from about 0.01 to 50 mg/kg body weight of the subject per day,
preferably from about 0.1 to about 1 mg/kg body weight of the
subject per day. In addition, where the anorectic agent is
sibutramine, the dosage range is from about 0.01 to about 50 mg/kg
body weight of the subject per day, preferably from about 0.1 to
about 1 mg/kg body weight of the subject per day; where the
anorectic agent is dexfenfluramine or fenfluramine, the dosage
range is from about 0.01 to about 50 mg/kg body weight of the
subject per day, preferably from about 0.1 to about 1 mg/kg body
weight of the subject per day; and where the anorectic agent is
bromocriptine, the dosage range is from about 0.01 to about 10
mg/kg body weight of the subject per day, preferably from about 0.1
to about 10 mg/kg body weight of the subject per day. In practice,
the physician will determine the actual dosage of anorectic agent
which will be most suitable for an individual patient and it will
vary with, e.g., age, weight and response of the particular
patient. The above dosages of anorectic agents are exemplary but
there can, of course, be individual instances where higher or lower
dosage ranges of such anorectic agents are merited, and all such
dosages are within the scope of the present invention.
[0245] Any suitable dosage of a lipase inhibitor can be used in
aspects of the present invention comprising such inhibitors. The
dosage of the lipase inhibitor is generally in the range of from
about 0.01 to about 50 mg/kg body weight of the subject per day,
preferably from about 0.05 to about 10 mg/kg body weight of the
subject per day, administered singly or as a divided dose. For
example, where the lipase inhibitor is tetrahydrolipstatin, the
dosage of tetrahydrolipstatin is preferably from about 0.05 to 2
mg/kg body weight of the subject per day. In practice, the
physician will determine the actual dosage of lipase inhibitor
which will be most suitable for an individual patient and it will
vary with, e.g., age, weight and response of the particular
patient. The above dosages of lipase inhibitors are exemplary but
there can, of course, be individual instances where higher or lower
dosage ranges of such lipase inhibitors are merited, and all such
dosages are within the scope of the present invention.
[0246] Any suitable route of administration may be used in the
present invention. It is usually preferred to administer the
compounds, prodrugs, isomers and pharmaceutically acceptable salts
of this invention orally for reasons of convenience; however, they
may be administered, for example, percutaneously, or as
suppositories for absorption by the rectum, as desired in a given
instance. As described above, the administration may be carried out
in single or multiple doses, as appropriate.
[0247] The compounds, prodrugs, isomers and pharmaceutically
acceptable salts of this invention may be administered alone, and
are preferably administered as pharmaceutical compositions
comprising a pharmaceutically acceptable vehicle, carrier or
diluent. The pharmaceutical compositions of the invention will
comprise a suitable amount of a compound, prodrug, isomer or
pharmaceutically acceptable salt of this invention, i.e., an amount
sufficient to provide the desired dosage.
[0248] The compounds, prodrugs, isomers and pharmaceutically
acceptable salts of this invention can be administered in a wide
variety of different dosage forms, i.e., they may be combined with
various pharmaceutically acceptable inert carriers in any suitable
form. Such carriers include solid diluents or fillers, sterile
aqueous media and various non-toxic organic solvents. The
pharmaceutical compositions can be formulated to contain a daily
dose, or a convenient fraction of a daily dose, in a dosage unit,
which may be a single tablet or a capsule or a convenient volume of
a liquid.
[0249] All of the usual types of pharmaceutical compositions may be
used in the present invention, including tablets, lozenges, hard
candies, chewable tablets, granules, powders, sprays, capsules,
pills, microcapsules, solutions, parenteral solutions, troches,
injections (e.g., intravenous, intraperitoneal, intramuscular or
subcutaneous), suppositories, elixirs, syrups and suspensions.
[0250] For parenteral administration, the compounds, prodrugs,
isomers and pharmaceutically acceptable salts of this invention may
be used as solutions in sesame or peanut oil, or as aqueous
solutions (e.g., aqueous propyleneglycol), as the case may be, and
they are best used in the form of a sterile aqueous solution which
may contain other substances; for example, enough salts or glucose
to make the solution isotonic, the pH of the solution being
suitably adjusted and buffered, where necessary, and surfactants
such as, for example, hydroxypropylcellulose. Such oily solutions
are suitable for intra-articular, intramuscular and subcutaneous
injection purposes. Such aqueous solutions are suitable for
intravenous injection purposes.
[0251] The compounds, prodrugs, isomers and pharmaceutically
acceptable salts of this invention may also be administered
topically and this may be done by way of, e.g., creams, jellies,
salves, lotions, gels, pastes, ointments, and the like, in
accordance with standard pharmaceutical practice. The compounds,
prodrugs, isomers and pharmaceutically acceptable salts of this
invention of the present invention may also be administered
transdermally (e.g., through the use of a patch). Any suitable
formulation for transdermal application comprising a compound of
the present invention may be employed and such formulations would
generally also contain a suitable transdermal carrier, e.g., an
absorbable pharmacologically acceptable solvent to promote and
assist passage of the compounds through the subject's skin. For
example, suitable transdermal devices may comprise the form of a
bandage having a backing member and a reservoir containing the
subject compound. Such bandage-type transdermal devices may further
include suitable carriers, rate-controlling barriers, and means for
securing the transdermal device to the subject's skin.
[0252] As will be described in detail hereinbelow, the
pharmaceutical compositions can be prepared by methods commonly
employed using conventional, organic or inorganic additives, such
as an excipient (e.g., sucrose, starch, mannitol, sorbitol,
lactose, glucose, cellulose, talc, calcium phosphate or calcium
carbonate), a binder (e.g., cellulose, methylcellulose,
hydroxymethylcellulose, polypropylpyrrolidone,
polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol,
sucrose or starch), a disintegrator (e.g., starch,
carboxymethylcellulose, hydroxypropylstarch, low substituted
hydroxypropylcellulose, sodium bicarbonate, calcium phosphate, or
calcium citrate), a lubricant (e.g., magnesium stearate, light
anhydrous silicic acid, talc or sodium lauryl sulfate), a flavoring
agent (e.g., citric acid, menthol, glycine or orange powder), a
preservative (e.g., sodium benzoate, sodium bisulfite,
methylparaben or propylparaben), a stabilizer (e.g., citric acid,
sodium citrate or acetic acid), a suspending agent (e.g.,
methylcellulose, polyvinylpyrrolidone, or aluminum stearate), a
dispersing agent (e.g., hydroxypropylmethylcellulose), a diluent
(e.g., water), a coloring agent, an emulsifying agent, and a base
wax (e.g., cocoa butter, white petrolatum or polyethylene
glycol).
[0253] Any of the compounds, prodrugs, isomers or pharmaceutically
acceptable salts of this invention may be readily formulated as
tablets, capsules, and the like. It is preferable to prepare
solutions from water-soluble salts, such as the hydrochloride
salt.
[0254] In general, all of the pharmaceutical compositions are
prepared according to methods usual in pharmaceutical
chemistry.
[0255] Capsules can be prepared by mixing a compound, prodrug,
isomer or pharmaceutically acceptable salt of the invention with a
suitable diluent and filling the proper amount of the mixture in
capsules. The usual diluents include inert powdered substances such
as starch of many different kinds, powdered cellulose, especially
crystalline and microcrystalline cellulose, sugars such as
fructose, mannitol and sucrose, grain flours and similar edible
powders.
[0256] Tablets can be prepared by direct compression, by wet
granulation, or by dry granulation. Their formulations usually
incorporate diluents, binders, lubricants and disintegrators as
well as a compound, prodrug, isomer or pharmaceutically acceptable
salt of this invention. Common diluents include, for example,
various types of starch, lactose, mannitol, kaolin, calcium
phosphate or sulfate, inorganic salts such as sodium chloride and
powdered sugar. Powdered cellulose derivatives may also be used.
Common tablet binders include substances such as starch, gelatin
and sugars such as lactose, fructose, glucose and the like. Natural
and synthetic gums are also convenient, including acacia,
alginates, methylcellulose, polyvinylpyrrolidine and the like.
Polyethylene glycol, ethylcellulose and waxes can also serve as
binders.
[0257] A lubricant is generally necessary in a tablet formulation
to prevent the tablet and punches from sticking in the die. The
lubricant is chosen from such slippery solids as talc, magnesium
and calcium stearate, stearic acid and hydrogenated vegetable
oils.
[0258] Tablet disintegrators include substances which swell when
wetted to break up the tablet and release a compound, prodrug,
isomer or pharmaceutically acceptable salt of this invention. They
include starches, clays, celluloses, algins and gums. More
particularly, corn and potato starches, methylcellulose, agar,
bentonite, wood cellulose, powdered natural sponge, cation-exchange
resins, alginic acid, guar gum, citrus pulp and
carboxymethylcellulose, for example, may be used as well as sodium
lauryl sulfate.
[0259] Tablets are often coated with sugar as a flavor and sealant,
or with film-forming protecting agents to modify the dissolution
properties of the tablet. The compounds, prodrugs, isomers and
pharmaceutically acceptable salts of this invention may also be
formulated as chewable tablets, by using large amounts of
pleasant-tasting substances such as mannitol in the formulation, as
is now well-established in the art.
[0260] Where it is desired to administer a compound, prodrug,
isomer or pharmaceutically acceptable salt of this invention as a
suppository, any suitable base can be used. Cocoa butter is a
traditional suppository base, which may be modified by the addition
of waxes to raise its melting point. Water-miscible suppository
bases comprising, particularly, polyethylene glycols of various
molecular weights are in wide use.
[0261] As discussed above, the effect of a compound, prodrug,
isomer or pharmaceutically acceptable salt of this invention may be
delayed or prolonged by proper formulation. For example, a slowly
soluble pellet of a compound, prodrug, isomer or pharmaceutically
acceptable salt of this invention may be prepared and incorporated
in a tablet or capsule. The technique may be improved by making
pellets of several different dissolution rates and filling capsules
with a mixture of the pellets. Tablets or capsules may be coated
with a film which resists dissolution for a predictable period of
time. The parenteral preparations may also be made long-acting by
dissolving or suspending a compound, prodrug, isomer or
pharmaceutically acceptable salt of this invention, as the case may
be, in oily or emulsified vehicles which allow it to disperse only
slowly in the serum.
[0262] The compounds, prodrugs, isomers and pharmaceutically
acceptable salts of this invention may also be administered to a
mammal other than a human. The method of administration and the
dosage to be administered to such a mammal will depend, for
example, on the animal species and the disease or disorder being
treated. The compounds, prodrugs, isomers and pharmaceutically
acceptable salts of this invention may be administered to animals
in any suitable manner, e.g., orally, parenterally or
transdermally, in any suitable form such as, for example, a
capsule, bolus, tablet, pellet, e.g., prepared by admixing a
compound, prodrug, isomer or pharmaceutically acceptable salt of
this invention with a suitable diluent such as carbowax or carnuba
wax together with a lubricant, liquid drench or paste, e.g.,
prepared by dispersing a compound, prodrug, isomer or
pharmaceutically acceptable salt of this invention in a
pharmaceutically acceptable oil such as peanut oil, sesame oil or
corn oil. The compounds, prodrugs, isomers and pharmaceutically
acceptable salts of this invention may also be administered to
animals as an implant. Such formulations are prepared in a
conventional manner in accordance with standard veterinary
practice. As an alternative, the compounds, prodrugs, isomers and
pharmaceutically acceptable salts of this invention may be
administered with the water supply, e.g., in the form of a liquid
or water-soluble concentrate. In addition, the compounds, prodrugs,
isomers and pharmaceutically acceptable salts of this invention,
e.g., within the pharmaceutical compositions of the invention, may
be administered in the animal feedstuff, e.g., a concentrated feed
additive or premix may be prepared for mixing with the normal
animal feed, commonly along with a suitable carrier therefor. The
carrier facilitates uniform distribution of a compound, prodrug,
isomer or pharmaceutically acceptable salt of this invention in
the, e.g., finished feed with which the premix is blended. Suitable
carriers include, but are not limited to, liquids, e.g., water,
oils such as soybean, corn, cottonseed, or volatile organic
solvents, and solids, e.g., a small portion of the feed or various
suitable meals including alfalfa, soybean, cottonseed oil, linseed
oil, corncob, corn, molasses, urea and bone, and mineral mixes.
[0263] Since the present invention has an aspect that relates to
the treatment of the disease/conditions described herein with a
combination of active ingredients which may be administered
separately, the invention also relates to combining separate
pharmaceutical compositions in kit form. The kit comprises two
separate pharmaceutical compositions: a compound of Formula I, or a
prodrug thereof, or a geometric or optical isomer thereof, or a
pharmaceutically acceptable salt of such compound, prodrug, or
isomer, and a second compound as described above. The kit comprises
a container for containing the separate compositions such as a
divided bottle or a divided foil packet. Typically the kit
comprises directions for the administration of the separate
components. The kit form is particularly advantageous when the
separate components are preferably administered in different dosage
forms (e.g., oral and parenteral), are administered at different
dosage intervals, or when titration of the individual components of
the combination is desired by the prescribing physician.
[0264] An example of such a kit is a so-called blister pack.
Blister packs are well known in the packaging industry and are
being widely used for the packaging of pharmaceutical unit dosage
forms (tablets, capsules, and the like). Blister packs generally
consist of a sheet of relatively stiff material covered with a foil
of a preferably transparent plastic material. During the packaging
process, recesses are formed in the plastic foil. The recesses have
the size and shape of the tablets or capsules to be packed. Next,
the tablets or capsules are placed in the recesses and the sheet of
relatively stiff material is sealed against the plastic foil at the
face of the foil which is opposite from the direction in which the
recesses were formed. As a result, the tablets or capsules are
sealed in the recesses between the plastic foil and the sheet.
Preferably the strength of the sheet is such that the tablets or
capsules can be removed from the blister pack by manually applying
pressure on the recesses whereby an opening is formed in the sheet
at the place of the recess. The tablet or capsule can then be
removed via said opening.
[0265] It may be desirable to provide a memory aid on the kit,
e.g., in the form of numbers next to the tablets or capsules
whereby the numbers correspond with the days of the regimen which
the tablets or capsules so specified should be ingested. Another
example of such a memory aid is a calendar printed on the card,
e.g., as follows "First Week, Monday, Tuesday, . . . etc . . .
Second Week, Monday, Tuesday, . . . " etc. Other variations of
memory aids will be readily apparent. A "daily dose" can be a
single tablet or capsule or several tablets or capsules to be taken
on a given day. Also, a daily dose of a compound of Formula I, or a
prodrug thereof, or a geometric or optical isomer thereof, or a
pharmaceutically acceptable salt of such compound, prodrug or
isomer, can consist of one tablet or capsule while a daily dose of
the second compound can consist of several tablets or capsules and
vice versa. The memory aid should reflect this.
[0266] In another specific embodiment of the invention, a dispenser
designed to dispense the daily doses one at a time in the order of
their intended use is provided. Preferably, the dispenser is
equipped with a memory-aid, so as to further facilitate compliance
with the regimen. An example of such a memory-aid is a mechanical
counter which indicates the number of daily doses that has been
dispensed. Another example of such a memory-aid is a
battery-powered micro-chip memory coupled with a liquid crystal
readout, or audible reminder signal which, for example, reads out
the date that the last daily dose has been taken and/or reminds one
when the next dose is to be taken.
[0267] Utility of the compounds of Formula I, or the isomers
thereof, or the pharmaceutically acceptable salts of such
compounds, or isomers thereof, can be evidenced by activity in at
least one of the two assays described below.
Assay 1
Oxygen Consumption
[0268] As would be appreciated by those skilled in the relevant
art, during increased energy expenditure, animals generally consume
more oxygen. In addition, metabolic fuels such as, for example,
glucose and fatty acids, are oxidized to CO.sub.2 and H.sub.2O with
the concomitant evolution of heat, commonly referred to in the art
as thermogenesis. Thus, the measurement of oxygen consumption in
animals, including humans and companion animals, is an indirect
measure of thermogenesis. Indirect calorimetry is commonly used in
animals, e.g., humans, by those skilled in the relevant art to
measure such energy expenditures.
[0269] Those skilled in the art understand that increased energy
expenditure and the concomitant burning of metabolic fuels
resulting in the production of heat may be efficacious with respect
to the treatment of, e.g., obesity. As is well known by those
skilled in the art, thyroid hormones affect cardiac functioning,
for example, by causing an increase in the heart rate and,
accordingly, an increase in oxygen consumption with concomitant
heat production.
[0270] The ability of the compounds, isomers thereof, and
pharmaceutically acceptable salts of said compounds and isomers of
this invention to generate a thermogenic response may be
demonstrated according to the following protocol.
[0271] A. Experimental.
[0272] This in vivo screen is designed to evaluate the efficacy and
cardiac effects of compounds that are tissue-selective thyroid
hormone agonists. The efficacy endpoints measured are whole body
oxygen consumption and the activity of liver mitochondrial
alpha-glycerophosphate dehydrogenase ("mGPDH"). The cardiac
endpoints that are measured are heart weight and heart mGPDH
activity. The protocol involves: (a) dosing fatty Zucker rats for
about 6 days, (b) measuring oxygen consumption and (c) harvesting
tissue for preparation of mitochondria and subsequent assaying of
enzyme activity thereby.
[0273] B. Preparation of Rats.
[0274] Male fatty Zucker rats having a body weight range of from
about 400 g to about 500 g are housed for from about 3 to about 7
days in individual cages under standard laboratory conditions prior
to the initiation of the study.
[0275] A compound of Formula I, or an isomer thereof, or a
pharmaceutically acceptable salt of such compound or isomer,
vehicle or T.sub.3 sodium salt, is administered by oral gavage as a
single daily dose given between about 3 p.m. to about 6 p.m. for
about 6 days. A compound of Formula I, or an isomer thereof, or a
pharmaceutically acceptable salt of such compound or isomer, or
T.sub.3 sodium salt is dissolved in a suitably small volume of
about 1N NaOH and then brought up to a suitable volume with about
0.01N NaOH containing about 0.25% of methyl cellulose (10:1, 0.01N
NaOH/MC:1N NaOH). The dosing volume is about 1 ml.
[0276] C. Oxygen Consumption.
[0277] About 1 day after the last dose of the compound is
administered, oxygen consumption is measured using an open circuit,
indirect calorimeter (Oxymax, Columbus Instruments, Columbus, Ohio
43204). The Oxymax gas sensors are calibrated with N.sub.2 gas and
a gas mixture (about 0.5% of CO.sub.2, about 20.5% of O.sub.2,
about 79% of N.sub.2) before each experiment.
[0278] The subject rats are removed from their home cages and their
body weights recorded. The rats are placed into the sealed chambers
(43.times.43.times.10 cm) of the Oxymax, the chambers are placed in
the activity monitors, and the air flow rate through the chambers
is then set at from about 1.6 L/min to about 1.7 L/min.
[0279] The Oxymax software then calculates the oxygen consumption
(mL/kg/h) by the rats based on the flow rate of air through the
chambers and the difference in oxygen content at the inlet and
output ports. The activity monitors have 15 infrared light beams
spaced about one inch apart on each axis, and ambulatory activity
is recorded when two consecutive beams are broken, and the results
are recorded as counts.
[0280] Oxygen consumption and ambulatory activity are measured
about every 10 min for from about 5 h to about 6.5 h. Resting
oxygen consumption is calculated on individual rats by averaging
the values excluding the first 5 values and the values obtained
during time periods where ambulatory activity exceeds about 100
counts.
Assay 2
Binding to Thyroid Hormone Receptors
[0281] The ability of a compound of Formula I, or an isomer
thereof, or a pharmaceutically acceptable salt of such compound or
isomer, ("the test thyromimetic compounds"), to bind to thyroid
hormone receptors can be demonstrated in the following
protocol.
[0282] A. Preparation of Insect Cell Nuclear Extracts
[0283] High Five cell pellets (BTI-TN-5B1-4, catalogue number
B855-02, Invitrogen.RTM., Carlsbad, Calif.) obtained about 48 h
after infection with baculovirus (GibcoBRL.RTM., Gaithersburg, Md.)
expressing either human TR.alpha. or TR.beta. were suspended in ice
cold Sample Buffer (10 mM Tris, pH 8.0; 1 mM MgCl.sub.2; 1 mM DTT;
0.05% Tween 20; 1 mM 4-(2-aminoethyl)-benzenesulfonylfluoride; 25
.mu.g/mL leupeptin). After about 10 min incubation on ice, the
suspension was homogenized by 20 strokes with a Dounce homogenizer
(VWR.RTM. Scientific Products, West Chester, Pa.) and centrifuged
at 800.times.g for about 15 min at 4.degree. C. The pellet (nuclei)
was suspended in a hypertonic buffer (0.4 M KCl; 10 mM Tris, pH
8.0; 1 mM MgCl.sub.2; 1 mM DTT; 0.05% Tween 20) and incubated for
about 30 min on ice. The suspension was centrifuged at
100,000.times.g for about 30 min at 4.degree. C. The supernatant
(nuclear extract) was stored in 0.5 mL aliquots at -80.degree.
C.
[0284] B. Binding Assay
[0285] Competition binding assays to measure the interaction of the
test thyromimetic compounds with thyroid hormone receptor .alpha.1
and .beta.1 (TR.alpha. and TR.beta.) are carried out according to
the following protocol.
[0286] Solutions of test thyromimetic compounds (final compound
concentration of 20 mM) are prepared using 100% DMSO as a solvent.
Each compound is serially diluted in an assay buffer (5 mM
Tris-HCI, pH 8.0; 50 mM NaCl; 2 mM EDTA; 10% (v/v) glycerol; 1 mM
DTT, "assay buffer") containing 0.4 nM .sup.125I-T.sub.3 (specific
activity of about 220 Ci/mmol) to yield solutions that varied in
compound concentration from about 10 .mu.M to about 0.1 nM.
[0287] High Five insect cell nuclear extract containing either
TR.alpha. or TR.beta. is diluted to a total protein concentration
of 0.0075 mg/mL using the assay buffer as diluent.
[0288] One volume (100 .mu.L) of each thyromimetic compound
dilution (containing 0.4 nM .sup.1251-T3) is combined with an equal
volume (100 .mu.L) of diluted nuclear extract containing TR.alpha.1
or TR.beta.1, and incubated at RT for about 90 min. 150 .mu.L
sample of the binding reaction is removed and placed into a 96-well
filter plate (Millipore.RTM., Bedford, Mass.) that had been
pre-washed with ice-cold assay buffer. The plate is subjected to
vacuum filtration using a filtration manifold (Millipore.RTM.).
Each well is washed five times by the addition of 200 .mu.L of
ice-cold assay buffer and subsequent vacuum filtration. The plate
is removed from the vacuum filtration manifold, the bottom of the
plate is briefly dried on paper towels, then 25 82 L of Wallac.RTM.
(EG&G Wallac.RTM., Gaithersburg, Md.) Optiphase Supermix
scintillation cocktail is added to each well and the top of the
plate is covered with plastic sealing tape (Microplate Press-on
Adhesive Sealing Film, Packard.RTM. Instrument Co., Inc., Downers
Grove, Ill.) and the radioactivity is quantitated using a
Wallac.RTM. Microbeta 96-Well plate scintillation counter.
[0289] The following EXAMPLES are provided solely for the purposes
of illustration and do not limit the invention which is defined by
the claims.
EXAMPLE 1
N-{3,5-Dichloro-4-[4-hydroxy-3-(pyrrolidine-1-sulfonyl)-phenoxy]-phenyl}-o-
xamic acid
Step A
[0290] 2',6'-Dichloro-4-methoxy-4'-nitrodiphenyl ether was prepared
by coupling of 2,6-dichloro-4-nitrophenol with
(4,4'-dimethoxydiphenyl)iodon- ium tetrafluoroborate in the
presence of copper powder and TEA according to the procedure
described in the J. Med. Chem., 38: 695-707(1995).
Step B
[0291] A solution of neat 2',6'-dichloro-4-methoxy-4'-nitrodiphenyl
ether (500 mg, 1.6 mmol) at 0.degree. C. was treated with
chlorosulfonic acid (877 mL, 7.5 mmol) and the reaction mixture
became immediately dark brown. The mixture was stirred for 5 min at
0.degree. C. and allowed to warm to RT. After stirring for 30 min
at RT, the reaction mixture was slowly dropped into 100 mL of ice
water with stirring. The brown precipitate was extracted with ethyl
acetate (3.times.75 mL). The combined organic extracts were washed
with sodium bicarbonate (1.times.100 mL), water (1.times.100 mL),
dried and concentrated to give a brown solid. The crude product was
used in the next step without further purification. NMR (400 MHz,
CDCl.sub.3) d 8.32 (s, 2H), 7.40 (d, 1H), 7.20-7.25 (dd, 1H), 7.09
(d, 1H), 4.04 (s, 3H). MS Calc.: 410.9, Found: 392.1 [M-1 for
5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-benzenes- ulfonic
acid].
Step C
[0292] To a solution of
5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-benzene- sulfonyl
chloride (200 mg, 0.48 mmol) in 5 mL of CH.sub.2Cl.sub.2 at RT was
added pyrrolidine (85 mL, 1.0 mmol). After stirring for 2 h at RT,
the reaction mixture was quenched with 1N HCl (5 mL) and extracted
with CH.sub.2Cl.sub.2 (3.times.10 mL). The combined extracts were
washed with 1N HCl (3.times.5 mL), saturated aqueous NaHCO.sub.3
(2.times.5 mL), dried and concentrated. The residue was purified by
preparative TLC (Hexane:EtOAC=2:1) to afford a white solid. NMR
(400 MHz, CDCl.sub.3) d 8.30 (s, 2H), 7.39 (d, 1H), 7.02-7.05 (dd,
1H), 6.95-6.98 (d, 1H), 3.91 (s, 3H), 3.35-3.38 (m, 4H), 1.82-1.87
(m, 4H). MS Calc.: 446.0, Found: 447.0 (M+1).
Step D
[0293] To a solution of
1-[5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-benz-
ene-sulfonyl]-pyrrolidine (178.5 mg, 0.4 mmol) in 8 mL of
chloroform at RT was added dropwise boron tribromide (1N in
CH.sub.2Cl.sub.2, 2.4 mL, 2.4 mmol). After stirring for 16 h at RT,
the reaction mixture was quenched with 10 mL of water. The mixture
was stirred for 1 h at RT, extracted with CH.sub.2Cl.sub.2
(1.times.5 mL) and EtOAc (2.times.10 mL). The combined organic
extracts were dried and concentrated. The product was used in the
next step without further purification. NMR (400 MHz, CD.sub.3OD) d
8.31 (s, 2H), 7.09 (d, 1H), 6.96-7.02 (m, 2H), 3.28-3.31(m, 4H),
1.79-1.82 (m, 4H). MS Calc.: 432.0, Found: 431.1 (M-1).
Step E
[0294] A mixture of
4-(2,6-dichloro-4-nitro-phenoxy)-2-(pyrrolidine-1-sulf-
onyl)-phenol (166 mg, 0.38 mmol) and catalyst about 10% Pd/C (17
mg) in a mixture of EtOAc (5 mL) and MeOH (10 mL) was hydrogenated
under 40 psi at RT for 1 h. The solution was filtered through
Celite.RTM. and concentrated to give a brown solid. The product was
used in the next step without further purification. NMR (400 MHz,
CDCl.sub.3) d 8.34 (s, 2H), 6.96-7.22 (broad S +m, 5H), 3.19 (m,
4H), 1.73 (m, 4H), Calc.: 402, Found: 401.1 (M-1).
Step F
[0295] A mixture of
4-(4-amino-2,6-dichloro-phenoxy)-2-(pyrrolidine-1-sulf-
onyl)-phenol (154 mg, 0.38 mmol) and diethyl oxalate (1.49 g, 10.2
mmol) was stirred at 120.degree. C. for 4 h. The excess diethyl
oxalate was distilled off in vacuo. The residue was purified by
preparative TLC (0.5% MeOH in CH.sub.2Cl.sub.2) to give an
off-white solid. NMR (400 MHz, CDCl.sub.3) d 9.06 (s, 1H), 8.60 (s,
1H), 7.76 (s, 2H), 7.03-7.06 (dd, 1H), 6.96-6.98 (d, 1H), 6.90 (d,
1H), 4.36-4.40 (q, 2H), 3.18-3.21 (m, 4H), 1.74-1.78 (m, 4H), 1.39
(t, 3H). MS Calc.: 502, Found: 501.1 (M-1).
Step G
[0296] A solution of
N-{3,5-dichloro-4-[4-hydroxy-3-(pyrrolidine-1-sulfony-
l)-phenoxy]-phenyl}-oxamic acid ethyl ester (10 mg, 0.02 mmol) in a
mixture of H.sub.2O (0.5 mL) and MeOH (0.5 mL) was added 2 drops of
3N KOH. The reaction mixture was stirred at RT for 2 h, acidified
with 1N HCl and extracted with EtOAc (4.times.5 mL). The combined
organic extracts were dried and concentrated to afford the title
compound as an off-white solid. NMR (400 MHz, CD.sub.3OD) d 7.96
(s, 2H), 7.02-7.06 (m, 2H), 6.95-6.98 (d, 1H), 3.28-3.31 (m, 4H),
1.78-1.81 (m, 4H). MS Calc.: 474.3 Found: 473.1 (M-1).
[0297] Using the appropriate starting materials, EXAMPLES 1-1 to
1-57 were prepared in an analogous manner to that described in
EXAMPLE 1.
EXAMPLE 1-1
[0298]
N-[4-(3-Cyclopropylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl-
]-oxamic acid ethyl ester, MS Calc.: 448.5 Found: 447.3 (M-1).
EXAMPLE 1-2
[0299]
N-[4-(4-Hydroxy-3-methylsulfamoyl-phenoxy)-3,5-dimethyl-phenyl]-oxa-
mic acid ethyl ester, MS Calc.: 422.5 Found: 421.3 (M-1).
EXAMPLE 1-3
[0300]
N-{4-[3-(4-Fluoro-phenylsulfamoyl)-4-hydroxy-phenoxy]-3,5-dimethyl--
phenyl}-oxamic acid ethyl ester, MS Calc.: 502.5 Found: 501.1
(M-1).
EXAMPLE 1-4
[0301]
N-[4-(3-Dimethylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-o-
xamic acid ethyl ester, MS Calc.: 436.5 Found: 435.3 (M-1).
EXAMPLE 1-5
[0302]
N-{4-[3-(Cyclopropyl-methyl-sulfamoyl)-4-hydroxy-phenoxy]-3,5-dimet-
hyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 462.5 Found: 461.2
(M-1).
EXAMPLE 1-6
[0303]
N-{4-[3-(Cyclobutyl-methyl-sulfamoyl)-4-hydroxy-phenoxy]-3,5-dimeth-
yl-phenyl}-oxamic acid ethyl ester, MS Calc.: 476.6 Found: 475.3
(M-1).
EXAMPLE 1-7
[0304]
N-[4-(3-Cyclobutylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-
-oxamic acid ethyl ester, MS Calc.: 462.5 Found: 461.2 (M-1).
EXAMPLE 1-8
[0305]
N-[4-(3-Cyclopentylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl-
]-oxamic acid ethyl ester, MS Calc.: 476.6 Found: 475.3 (M-1).
EXAMPLE 1-9
[0306]
N-{4-[4-Hydroxy-3-(pyrrolidine-1-sulfonyl)-phenoxy]-3,5-dimethyl-ph-
enyl}-oxamic acid ethyl ester, MS Calc.: 462.5 Found: 461.3
(M-1).
EXAMPLE 1-10
[0307]
N-{4-[4-Hydroxy-3-(piperidine-1-sulfonyl)-phenoxy]-3,5-dimethyl-phe-
nyl}-oxamic acid ethyl ester, MS Calc.: 476.6 Found: 475.2
(M-1).
EXAMPLE 1-11
[0308]
N-[4-(3-Cyclohexylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-
-oxamic acid ethyl ester, MS Calc.: 490.6 Found: 489.3 (M-1).
EXAMPLE 1-12
[0309]
N-[4-(4-Hydroxy-3-propylsulfamoyl-phenoxy)-3,5-dimethyl-phenyl]-oxa-
mic acid ethyl ester, MS Calc.: 450.5 Found: 449.3 (M-1).
EXAMPLE 1-13
[0310] N-[4-(3-Butylsulfamoyl-4-hydroxy-phenoxy)-3,5-d
imethyl-phenyl]-oxamic acid ethyl ester, MS Calc.: 464.5 Found:
463.3 (M-1).
EXAMPLE 1-14
[0311]
N-{4-[3-(Cyclopropyl-methyl-sulfamoyl)-4-hydroxy-phenoxy]-3,5-dimet-
hyl-phenyl}-oxamic acid, MS Calc.: 434.5 Found: 433.3 (M-1).
EXAMPLE 1-15
[0312]
N-{4-[3-(Cyclobutyl-methyl-sulfamoyl)-4-hydroxy-phenoxy]-3,5-dimeth-
yl-phenyl}-oxamic acid, MS Calc.: 448.5 Found: 447.3 (M-1).
EXAMPLE 1-16
[0313]
N-[4-(3-Cyclopropylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl-
]-oxamic acid, MS Calc.: 420.4 Found: 419.3 (M-1).
EXAMPLE 1-17
[0314]
N-[4-(3-Cyclobutylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-
-oxamic acid, MS Calc.: 434.5 Found: 433.2 (M-1).
EXAMPLE 1-18
[0315]
N-[3--Chloro-4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-5-methyl--
phenyl]-oxamic acid ethyl ester, MS Calc.: 468.1 Found: 466.5
(M-1).
EXAMPLE 1-19
[0316]
N-[3--Chloro-4-(3-cyclobutylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-p-
henyl]-oxamic acid ethyl ester, MS Calc.: 482.1 Found: 480.4
(M-1).
EXAMPLE 1-20
[0317]
N-[3--Chloro-4-(3-cyclopentylsulfamoyl-4-hydroxy-phenoxy)-5-methyl--
phenyl]-oxamic acid ethyl ester, MS Calc.: 496.2 Found: 494.9
(M-1).
EXAMPLE 1-21
[0318]
N-[3--Chloro-4-(3-cyclohexylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-p-
henyl]-oxamic acid ethyl ester, MS Calc.: 510.2 Found: 508.8
(M-1).
EXAMPLE 1-22
[0319]
N-[3--Chloro-4-(4-hydroxy-3-sulfamoyl-phenoxy)-5-methyl-phenyl]-oxa-
mic acid ethyl ester, MS Calc.: 428.1 Found: 426.7 (M-1).
EXAMPLE 1-23
[0320]
N-{3--Chloro-4-[4-hydroxy-3-(piperidine-1-sulfonyl)-phenoxy]-5-meth-
yl-phenyl}-oxamic acid ethyl ester, MS Calc.: 496.1 Found: 495.1
(M-1).
EXAMPLE 1-24
[0321]
N-{3--Chloro-4-[3-(4-fluoro-phenylsulfamoyl)-4-hydroxy-phenoxy]-5-m-
ethyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 522.1 Found: 520.4
(M-1).
EXAMPLE 1-25
[0322]
N-[3--Chloro-4-(3-dimethylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-phe-
nyl]-oxamic acid ethyl ester, MS Calc.: 456.1 Found: 457.3
(M+1).
EXAMPLE 1-26
[0323]
N-[3--Chloro-4-(4-hydroxy-3-methylsulfamoyl-phenoxy)-5-methyl-pheny-
l]-oxamic acid ethyl ester, MS Calc.: 442.1 Found: 441.2 (M-1).
EXAMPLE 1-27
[0324]
N-[3--Chloro-4-(4-hydroxy-3-propylsulfamoyl-phenoxy)-5-methyl-pheny-
l]-oxamic acid ethyl ester, MS Calc.: 470.1 Found: 469.2 (M-1).
EXAMPLE 1-28
[0325]
N-[3--Chloro-4-(4-hydroxy-3-pentylsulfamoyl-phenoxy)-5-methyl-pheny-
l]-oxamic acid ethyl ester, MS Calc.: 498.2 Found: 497.2 (M-1).
EXAMPLE 1-29
[0326]
N-[3--Chloro-4-(3-hexylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-phenyl-
]-oxamic acid ethyl ester, MS Calc.: 512.2 Found: 511.2 (M-1).
EXAMPLE 1-30
[0327]
N-[3--Chloro-4-(4-hydroxy-3-octylsulfamoyl-phenoxy)-5-methyl-phenyl-
]-oxamic acid ethyl ester, MS Calc.: 540.3 Found: 539.2 (M-1).
EXAMPLE 1-31
[0328]
N-[3--Chloro-4-(3-decylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-phenyl-
]-oxamic acid ethyl ester, MS Calc.: 568.3 Found: 567.3 (M-1).
EXAMPLE 1-32
[0329]
N-[4-(3-Butylsulfamoyl-4-hydroxy-phenoxy)-3-chloro-5-methyl-phenyl]-
-oxamic acid ethyl ester, MS Calc.: 484.2 Found: 483.2 (M-1).
EXAMPLE 1-33
[0330]
N-{3-Chloro-4-[3-(ethyl-methyl-sulfamoyl)-4-hydroxy-phenoxy]-5-meth-
yl-phenyl}-oxamic acid ethyl ester, MS Calc.: 470.1 Found: 469.2
(M-1).
EXAMPLE 1-34
[0331]
N-{3-Chloro-4-[4-hydroxy-3-(methyl-propyl-sulfamoyl)-phenoxy]-5-met-
hyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 484.2 Found: 483.2
(M-1).
EXAMPLE 1-35
[0332]
N-{4-[3-(Butyl-methyl-sulfamoyl)-4-hydroxy-phenoxy]-3-chloro-5-meth-
yl-phenyl}-oxamic acid ethyl ester, MS Calc.: 498.2 Found: 497.2
(M-1).
EXAMPLE 1-36
[0333]
N-{3-Chloro-4-[4-hydroxy-3-(morpholine-4-sulfonyl)-phenoxy]-5-methy-
l-phenyl}-oxamic acid ethyl ester, MS Calc.: 498.1 Found: 497.2
(M-1).
EXAMPLE 1-37
[0334]
N-{3-Chloro-4-[3-(cyclopropylmethyl-sulfamoyl)-4-hydroxy-phenoxy]-5-
-methyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 482.1 Found:
481.2 (M-1).
EXAMPLE 1-38
[0335]
N-{3-Chloro-4-[4-hydroxy-3-(2-hydroxy-ethylsulfamoyl)-phenoxy]-5-me-
thyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 472.1 Found: 471.2
(M-1).
EXAMPLE 1-39
[0336]
N-[3-Chloro-4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-p-
henyl]-oxamic acid isopropyl ester, MS Calc.: 482.1 Found: 481.2
(M-1).
EXAMPLE 1-40
[0337]
N-[3-Chloro-4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-p-
henyl]-oxamic acid, MS Calc.: 440.1 Found: 439.2 (M-1).
EXAMPLE 1-41
[0338]
N-[3-Chloro-4-(3-cyclobutylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-ph-
eny]-oxamic acid, MS Calc.: 454.1 Found: 452.8 (M-1).
EXAMPLE 1-42
[0339]
N-[3-Chloro-4-(3-cyclopentylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-p-
henyl]-oxamic acid, MS Calc.: 468.1 Found: 466.9 (M-1).
EXAMPLE 1-43
[0340]
N-[3-Chloro-4-(3-cyclohexylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-ph-
enyl]-oxamic acid, MS Calc.: 482.1 Found: 481.0 (M-1).
EXAMPLE 1-44
[0341]
N-[3-Chloro-4-(4-hydroxy-3-sulfamoyl-phenoxy)-5-methyl-phenyl]-oxam-
ic acid, MS Calc.: 400.0 Found: 398.9 (M-1).
EXAMPLE 1-45
[0342]
N-{3-Chloro-4-[3-(4-fluoro-phenylsulfamoyl)-4-hydroxy-phenoxy]-5-me-
thyl-phenyl}-oxamic acid, MS Calc.: 494.1 Found: 493.1 (M-1).
EXAMPLE 1-46
[0343]
N-[3-Chloro-4-(4-hydroxy-3-propylsulfamoyl-phenoxy)-5-methyl-phenyl-
]-oxamic acid, MS Calc.: 442.1 Found: 441.2 (M-1).
EXAMPLE 1-47
[0344]
N-[4-(3-Butylsulfamoyl-4-hydroxy-phenoxy)-3-chloro-5-methyl-phenyl]-
-oxamic acid, MS Calc.: 456.1 Found: 455.1 (M-1).
EXAMPLE 1-48
[0345]
N-{3-Chloro-4-[4-hydroxy-3-(morpholine-4-sulfonyl)-phenoxy]-5-methy-
l-phenyl}-oxamic acid, MS Calc.: 470.1 Found: 469.2 (M-1).
EXAMPLE 1-49
[0346]
N-{3,5-Dichloro-4-[4-hydroxy-3-(pyrrolidine-1-sulfonyl)-phenoxy]-ph-
enyl}-oxamic acid ethyl ester, MS Calc.: 502.0 Found: 501.1
(M-1).
EXAMPLE 1-50
[0347]
N-{3,5-Dichloro-4-[3-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)-4-hyd-
roxy-phenoxy]-phenyl}-oxamic acid ethyl ester, MS Calc.: 564.1
Found: 562.8 (M-1).
EXAMPLE 1-51
[0348]
N-[3,5-Dichloro-4-(3-cyclobutylsulfamoyl-4-hydroxy-phenoxy)-phenyl]-
-oxamic acid ethyl ester, MS Calc.: 502.0 Found: 500.3 (M-1).
EXAMPLE 1-52
[0349]
N-{4-[3-(Bicyclo[2.2.1]hept-2-ylsulfamoyl)-4-hydroxy-phenoxy]-3,5-d-
ichloro-phenyl}-oxamic acid ethyl ester, MS Calc.: 542.0 Found:
540.6 (M-1).
EXAMPLE 1-53
[0350]
N-(3,5-Dichloro-4-{4-hydroxy-3-[(thiophen-2-ylmethyl)-sulfamoyl]-ph-
enoxy}-phenyl)-oxamic acid ethyl ester, MS Calc.: 544.0 Found:
542.3 (M-1).
EXAMPLE 1-54
[0351]
N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylsulfamoyl-phenoxy)-phenyl]--
oxamic acid ethyl ester, MS Calc.: 490.0 Found: 488.9 (M-1).
EXAMPLE 1-55
[0352]
N-[3,5-Dichloro-4-(3-dimethylsulfamoyl-4-hydroxy-phenoxy)-phenyl]-o-
xamic acid ethyl ester, MS Calc.: 476.1 Found: 475.1 (M-1).
EXAMPLE 1-56
[0353]
N-{3,5-Dichloro-4-[4-hydroxy-3-(pyrrolidine-1-sulfonyl)-phenoxy]-ph-
enyl}-oxamic acid, MS Calc.: 474.1 Found: 473.1 (M-1).
EXAMPLE 1-57
[0354]
N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylsulfamoyl-phenoxy)-phenyl]--
oxamic acid, MS Calc.: 462.0 Found: 461.1 (M-1).
EXAMPLE 2
N-{3,5-Dichloro-4-[3-(3,3-dimethyl-piperidine-1-carbonyl)-4-hydroxy-phenox-
y]-phenyl}-oxamic acid ethyl ester
Step A
[0355] A mixture of 2',6'-dichloro-4-methoxy-4'-nitrodiphenyl ether
(5.0 g, 16 mmol), TFA (50 mL) and hexamethylenetetramine (3.35 g,
24 mmol) was stirred at 70.degree. C. for 3 h to give a yellow
solution. TFA was removed by rotavap to give a viscous yellow oil
which was diluted with H.sub.2O (100 mL) and stirred at RT for 0.5
h. Saturated aqueous NaHCO.sub.3 (300 mL) was added and the mixture
was extracted with EtOAc (3.times.100 mL). The combined organic
extracts are washed with brine (200 mL), dried and concentrated to
give a yellow solid. MS Calc.: 341.0 Found: 340.4 (M-1).
Step B
[0356] To a solution of
5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-benzald- ehyde (1.0 g,
2.9 mmol) in acetone (30 mL) was added slowly Jones reagent (3.0
mL). The resulting solution was stirred at RT for 1 h and quenched
with isopropanol (4 mL). The solid was removed by filtration
through Celite.RTM.. The bluish solution was concentrated to give
yellow solid with blue supernatant. The solid was dissolved in
EtOAc and dried over Na.sub.2SO.sub.4, filtered and concentrated.
The resulting yellow oily solid was partially dissolved in EtOAc
(25 mL) and extracted with saturated aqueous NaHCO.sub.3
(5.times.75 mL). The combined aqueous extracts were acidified with
2N HCl, extracted with EtOAc (4.times.100 mL), dried and
concentrated to give a yellow solid. MS Calc.: 356.9 Found: 357.8
(M-1).
Step C
[0357] To a solution of
5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-benzoic acid (0.81 g,
2.3 mmol) in chloroform (20 mL) at RT was added dropwise tribromide
(1 N in CH.sub.2Cl.sub.2, 4.5 mL, 4.5 mmol). The resulting mixture
was stirred at RT for 1 h and quenched with H.sub.2O (20 mL). After
stirring at RT for 0.5 h, the aqueous phase was basified with
saturated aqueous NaHCO.sub.3 (30 mL). The organic phase was
extracted with saturated aqueous NaHCO.sub.3 (4.times.50 mL). The
combined aqueous extracts were acidified with concentrated HCl to
give a white precipitate which was extracted with EtOAc
(4.times.100 mL). The combined organic extracts were dried and
concentrated to give a yellow-white solid. MS Calc.: 342.9 Found:
341.8 (M-1).
Step D
[0358] To a solution of
5-(2,6-dichloro-4-nitro-phenoxy)-2-hydroxybenzoic acid (0.69 g, 2
mmol) in a mixture of EtOAc (4 mL) and MeOH (12 mL) was added 10%
Pd/C (70 mg). The solution was hydrogenated under 40 psi of
pressure at RT for 2 h then filtered through Celite.RTM.. The
filtrate was concentrated. The product was used in the next step
without further purification. MS Calc.: 312.9 Found: 311.9
(M-1).
Step E
[0359] A mixture of
5-(2,6-dichloro-4-amino-phenoxy)-2-hydroxybenzoic acid (0.63 g, 2
mmol) and diethyl oxalate (4.4 g, 30 mmol) was stirred at
140.degree. C. for 3 h. The excess diethyl oxalate was removed
under vacuum to give a brown oily solid which was triturated with
hexanes to remove the remaining diethyl oxalate. The tan solid was
collected by filtration and washed with CH.sub.2Cl.sub.2/hexanes
(5% CH.sub.2Cl.sub.2 in hexanes). The product was used in the next
step without further purification. MS Calc.: 413.0 Found: 411.8
(M-1).
Step F
[0360] To a solution of
5-[2,6-dichloro-4-(ethoxyoxalyl-amino)-phenoxy]-2-- hydroxy-benzoic
acid (29 mg, 0.07 mmol) in THF at RT was added thionyl chloride (25
mg, 0.21 mmol). The resulting mixture was stirred at 60.degree. C.
for 1 h and concentrated in vacuum to give the acid chloride as a
tan solid. The acid chloride was dissolved in chloroform (0.5 mL)
and to which was added diisopropylethylamine (18 mg, about 0.14
mmol) and 3,3-dimethylpiperidine (9.4 mg, 0.083 mmol). The
resulting mixture was stirred at RT for 17 h and concentrated. The
crude product was purified by preparative TLC (6% acetone in
CH.sub.2Cl.sub.2) to give the title compound as a white solid. MS
Calc.: 509.4 Found: 507.2 (M-1).
[0361] Using the appropriate starting materials, EXAMPLES 2-1 to
2-109 were prepared in an analogous manner to that described in
EXAMPLE 2.
EXAMPLE 2-1
[0362]
N-{4-[3-(3,4-Dihydro-1H-isoquinoline-2-carbonyl)-4-hydroxy-phenoxy]-
-3,5-dimethyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 488.6
Found: 486.6 (M-1).
EXAMPLE 2-2
[0363]
N-{4-[3-(3,4-Dihydro-2H-quinoline-1-carbonyl)-4-hydroxy-phenoxy]-3,-
5-dimethyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 488.6 Found:
486.5 (M-1).
EXAMPLE 2-3
[0364]
N-{4-[3-(2,3-Dihydro-indole-1-carbonyl)-4-hydroxy-phenoxy]-3,5-dime-
thyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 474.5 Found: 473.3
(M-1).
EXAMPLE 2-4
[0365]
N-{4-[3-(3,3-Dimethyl-piperidine-1-carbonyl)-4-hydroxy-phenoxy]-3,5-
-dimethyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 468.6 Found:
466.7 (M-1).
EXAMPLE 2-5
[0366]
N-{4-[4-Hydroxy-3-(3-methyl-3-phenyI-piperidine-1-carbonyl)-phenoxy-
]-3,5-dimethyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 530.6
Found: 528.7 (M-1).
EXAMPLE 2-6
[0367]
N-{4-[3-(Azepane-1-carbonyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl-
}-oxamic acid ethyl ester, MS Calc.: 454.5 Found: 453.2 (M-1).
EXAMPLE 2-7
[0368]
N-{4-[4-Hydroxy-3-(1-naphthalen-1-yl-(1R)-ethylcarbamoyl)-phenoxy]--
3,5-dimethyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 526.6
Found: 525.2 (M-1).
EXAMPLE 2-8
[0369]
N-{4-[4-Hydroxy-3-(1-phenyl-(1R)-ethylcarbamoyl)-phenoxy]-3,5-dimet-
hyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 476.5 Found: 475.2
(M-1).
EXAMPLE 2-9
[0370]
N-{4-[3-(Bicyclo[2.2.1]hept-2-ylcarbamoyl)-4-hydroxy-phenoxy]-3,5-d-
imethyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 466.5 Found:
465.2 (M-1).
EXAMPLE 2-10
[0371]
N-{4-[3-(4-Chloro-benzylcarbamoyl)-4-hydroxy-phenoxy]-3,5-dimethyl--
phenyl}-oxamic acid ethyl ester, MS Calc.: 497.0 Found: 495.2
(M-1).
EXAMPLE 2-11
[0372]
N-{4-[3-(1-Cyclohexyl-(1R)-ethylcarbamoyl)-4-hydroxy-phenoxy]-3,5-d-
imethyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 482.6 Found:
483.3 (M+1).
EXAMPLE 2-12
[0373]
N-{4-[4-Hydroxy-3-(1-naphthalen-2-yl-(1R)-ethylcarbamoyl)-phenoxy]--
3,5-dimethyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 526.6
Found: 525.4 (M-1).
EXAMPLE 2-13
[0374]
N-[4-(3-Cyclobutylcarbamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-
-oxamic acid ethyl ester, MS Calc.: 426.5 Found: 425.3 (M-1).
EXAMPLE 2-14
[0375]
N-[4-(3-Cyclopentylcarbamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl-
]-oxamic acid ethyl ester, MS Calc.: 440.5 Found: 439.3 (M-1).
EXAMPLE 2-15
[0376]
N-{4-[4-Hydroxy-3-(1-isopropyl-2-methyl-propylcarbamoyl)-phenoxy]-3-
,5-dimethyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 470.6 Found:
469.2 (M-1).
EXAMPLE 2-16
[0377]
N-{4-[4-Hydroxy-3-(pyrrolidine-1-carbonyl)-phenoxy]-3,5-dimethyl-ph-
enyl}-oxamic acid ethyl ester, MS Calc.: 426.5 Found: 425.3
(M-1).
EXAMPLE 2-17
[0378]
N-{4-[4-Hydroxy-3-(morpholine-4-carbonyl)-phenoxy]-3,5-dimethyl-phe-
nyl}-oxamic acid ethyl ester, MS Calc.: 442.5 Found: 441.3
(M-1).
EXAMPLE 2-18
[0379]
N-{4-[4-Hydroxy-3-(1-naphthalen-1-yl-(1R)ethylcarbamoyl)-phenoxy]-3-
,5-dimethyl-phenyl}-oxamic acid, MS Calc.: 498.5 Found: 497.2
(M-1).
EXAMPLE 2-19
[0380]
N-{4-[4-Hydroxy-3-(1-phenyl-(1R)ethylcarbamoyl)-phenoxy]-3,5-dimeth-
yl-phenyl}-oxamic acid, MS Calc.: 448.5 Found: 447.3 (M-1).
EXAMPLE 2-20
[0381]
N-{4-[3-(Cyclopropyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-3,5-dimet-
hyl-pentyl}-oxamic acid, MS Calc.: 398.4 Found: 397.3 (M-1).
EXAMPLE 2-21
[0382]
N-{4-[3-(Cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-3,5-dimeth-
yl-phenyl}-oxamic acid, MS Calc.: 412.5 Found: 411.3 (M-1).
EXAMPLE 2-22
[0383]
N-{4-[4-Hydroxy-3-(1-isopropyl-2-methyl-propylcarbamoyl)-phenoxy]-3-
,5-dimethyl-phenyl}-oxamic acid, MS Calc.: 442.5 Found: 441.3
(M-1).
EXAMPLE 2-23
[0384]
N-{4-[3-(Cyclopentyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-3,5-dimet-
hyl-phenyl}-oxamic acid, MS Calc.: 426.5 Found: 425.3 (M-1).
EXAMPLE 2-24
[0385]
N-{4-[3-(Cyclohexyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-3,5-dimeth-
yl-phenyl}-oxamic acid, MS Calc.: 440.5 Found: 439.3 (M-1).
EXAMPLE 2-25
[0386]
N-{3-Chloro-4-[4-hydroxy-3-(3-methyl-3-phenyl-piperidine-1-carbonyl-
)-phenoxy]-5-methyl-phenyl}-oxamic acid ethyl ester, MS Calc.:
551.0 Found: 549.2 (M-1).
EXAMPLE 2-26
[0387]
N-{4-[3-(Azepane-1-carbonyl)-4-hydroxy-phenoxy]-3-chloro-5-methyl-p-
henyl}-oxamic acid ethyl ester, MS Calc.: 475.0 Found: 473.3
(M-1).
EXAMPLE 2-27
[0388]
N-{3-Chloro-4-[3-(3,3-dimethyl-piperidine-1-carbonyl)-4-hydroxy-phe-
noxy]-5-methyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 489.0
Found: 487.3 (M-1).
EXAMPLE 2-28
[0389]
N-(3-Chloro-4-{4-hydroxy-3-[(thiophen-2-ylmethyl)-carbamoyl]-phenox-
y}-5-methyl-phenyl)-oxamic acid ethyl ester, MS Calc.: 489.0 Found:
487.2 (M-1).
EXAMPLE 2-29
[0390]
N-{3-Chloro-4-[3-(2,3-dichloro-benzylcarbamoyl)-4-hydroxy-phenoxy]--
5-methyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 551.8 Found:
549.1 (M-1).
EXAMPLE 2-30
[0391]
N-[3-Chloro-4-(3-cyclopropylcarbamoyl-4-hydroxy-phenoxy)-5-methyl-p-
henyl]-oxamic acid ethyl ester, MS Calc.: 432.9 Found: 431.2
(M-1).
EXAMPLE 2-31
[0392]
N-{3-Chloro-4-[3-(2,3-dihydro-indole-1-carbonyl)-4-hydroxy-phenoxy]-
-methyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 494.9 Found:
492.2 (M-1).
EXAMPLE 2-32
[0393]
N-{3-Chloro-4-[3-(3,4-dihydro-2H-quinoline-1-carbonyl)-4-hydroxy-ph-
enoxy]-5-methyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 509.0
Found: 507.2 (M-1).
EXAMPLE 2-33
[0394]
N-{3-Chloro-4-[3-(3,4-dihydro-1H-isoquinoline-2-carbonyl)-4-hydroxy-
-phenoxy]-5-methyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 509.0
Found: 507.3 (M-1).
EXAMPLE 2-34
[0395]
N-{3-Chloro-4-[4-hydroxy-3-(indan-1-ylcarbamoyl)-phenoxy]-5-methyl--
phenyl}-oxamic acid ethyl ester, MS Calc.: 509.0 Found: 507.3
(M-1).
EXAMPLE 2-35
[0396]
N-{3-Chloro-4-[4-hydroxy-3-(indan-5-ylcarbamoyl)-phenoxy]-5-methyl--
phenyl}-oxamic acid ethyl ester, MS Calc.: 509.0 Found: 507.2
(M-1).
EXAMPLE 2-36
[0397]
N-{4-[3-(Bicyclo[2.2.1]hept-2-ylcarbamoyl)-4-hydroxy-phenoxy]-3-chl-
oro-5-methyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 487.0
Found: 485.1 (M-1).
EXAMPLE 2-37
[0398]
N-{3-Chloro-4-[3-(cyclohexylmethyl-carbamoyl)-4-hydroxy-phenoxy]-5--
methyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 489.0 Found:
487.3 (M-1).
EXAMPLE 2-38
[0399]
N-{3-Chloro-4-[3-(1-cyclohexyl-(1R)ethylcarbamoyl)-4-hydroxy-phenox-
y]-5-methyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 503.0 Found:
501.3 (M-1).
EXAMPLE 2-39
[0400] N-{3-Chloro-4-[3-(1-cyclohexyl-(1
S)ethylcarbamoyl)-4-hydroxy-pheno- xy]-5-methyl-phenyl}-oxamic acid
ethyl ester, MS Calc.: 503.0 Found: 501.4 (M-1).
EXAMPLE 2-40
[0401]
N-{3-Chloro-4-[4-hydroxy-3-(piperidine-1-carbonyl)-phenoxy]-5-methy-
l-phenyl}-oxamic acid ethyl ester, MS Calc.: 460.9 Found: 459.3
(M-1).
EXAMPLE 2-41
[0402]
N-{4-[3-(Azocane-1-carbonyl)-4-hydroxy-phenoxy]-3-chloro-5-methyl-p-
henyl}-oxamic acid ethyl ester, MS Calc.: 489.0 Found: 487.3
(M-1).
EXAMPLE 2-42
[0403]
N-[3-Chloro-4-(3-cyclohexylcarbamoyl-4-hydroxy-phenoxy)-5-methyl-ph-
enyl]-oxamic acid ethyl ester, MS Calc.: 475.0 Found: 473.3
(M-1).
EXAMPLE 2-43
[0404]
N-{3-Chloro-4-[4-hydroxy-3-(1-phenyl-(1R)ethylcarbamoyl)-phenoxy]-5-
-methyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 497.0 Found:
495.2 (M-1).
EXAMPLE 2-44
[0405]
N-[3-Chloro-4-(4-hydroxy-3-propylcarbamoyl-phenoxy)-5-methyl-phenyl-
]-oxamic acid ethyl ester, MS Calc.: 434.9 Found: 433.2 (M-1).
EXAMPLE 2-45
[0406]
N-[4-(3-Butylcarbamoyl-4-hydroxy-phenoxy)-3-chloro-5-methyl-phenyl]-
-oxamic acid ethyl ester, MS Calc.: 448.9 Found: 447.3 (M-1).
EXAMPLE 2-46
[0407]
N-[3-Chloro-4-(4-hydroxy-3-pentylcarbamoyl-phenoxy)-5-methyl-phenyl-
]-oxamic acid ethyl ester, MS Calc.: 462.9 Found: 461.2 (M-1).
EXAMPLE 2-47
[0408]
N-[3-Chloro-4-(3-hexylcarbamoyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-
-oxamic acid ethyl ester, MS Calc.: 477.0 Found: 475.2 (M-1).
EXAMPLE 2-48
[0409]
N-{3-Chloro-4-[3-(1,1-dimethyl-propylcarbamoyl)-4-hydroxy-phenoxy]--
5-methyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 462.9 Found:
461.2 (M-1).
EXAMPLE 2-49
[0410]
N-[3-Chloro-4-(3-diisopropylcarbamoyl-4-hydroxy-phenoxy)-5-methyl-p-
henyl]-oxamic acid ethyl ester, MS Calc.: 477.0 Found: 475.3
(M-1).
EXAMPLE 2-50
[0411]
N-{3-Chloro-4-[3-(2,2-dimethyl-propylcarbamoyl)-4-hydroxy-phenoxy]--
5-methyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 462.9 Found:
461.2 (M-1).
EXAMPLE 2-51
[0412]
N-{3-Chloro-4-[3-(1,2-dimethyl-propylcarbamoyl)-4-hydroxy-phenoxy]--
5-methyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 462.9 Found:
461.2 (M-1).
EXAMPLE 2-52
[0413]
N-{3-Chloro-4-[4-hydroxy-3-(1-phenyl-(1S)ethylcarbamoyl)-phenoxy]-5-
-methyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 497.0 Found:
495.3 (M-1).
EXAMPLE 2-53
[0414]
N-{3-Chloro-4-[3-(ethyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-5-meth-
yl-phenyl}-oxamic acid ethyl ester, MS Calc.: 434.9 Found: 433.3
(M-1).
EXAMPLE 2-54
[0415]
N-{3-Chloro-4-[4-hydroxy-3-(methyl-propyl-carbamoyl)-phenoxy]-5-met-
hyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 448.9 Found: 447.2
(M-1).
EXAMPLE 2-55
[0416]
N-{3-Chloro-4-[3-(ethyl-isopropyl-carbamoyl)-4-hydroxy-phenoxy]-5-m-
ethyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 462.2 Found: 461.2
(M-1).
EXAMPLE 2-56
[0417]
N-{3-Chloro-4-[3-(cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-5-
-methyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 460.9 Found:
459.3 (M-1).
EXAMPLE 2-57
[0418]
N-{4-[3-(Azepane-1-carbonyl)-4-hydroxy-phenoxy]-3-chloro-5-methyl-p-
henyl}-oxamic acid, MS Calc.: 446.9 Found: 445.3 (M-1).
EXAMPLE 2-58
[0419] N-{3-Chloro-4-[3-(1-cyclohexyl-(1
S)ethylcarbamoyl)-4-hydroxy-pheno- xy]-5-methyl-phenyl}-oxamic
acid, MS Calc.: 475.0 Found: 473.2 (M-1).
EXAMPLE 2-59
[0420]
N-{3-Chloro-4-[3-(cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-5-
-methyl-phenyl}-oxamic acid, MS Calc.: 432.9 Found: 431.3
(M-1).
EXAMPLE 2-60
[0421]
N-{4-[3-(Bicyclo[2.2.1]hept-2-ylcarbamoyl)-4-hydroxy-phenoxy]-3,5-d-
ichloro-phenyl}-oxamic acid ethyl ester, MS Calc.: 507.4 Found:
505.0 (M-1).
EXAMPLE 2-61
[0422]
N-{4-[3-(Bicyclo[2.2.1]hept-2-ylcarbamoyl)-4-hydroxy-phenoxy]-3,5-d-
ichloro-phenyl}-oxamic acid ethyl ester, MS Calc.: 507.4 Found:
505.1 (M-1).
EXAMPLE 2-62
[0423]
N-(3,5-Dichloro-4-{4-hydroxy-3-[(thiophen-2-ylmethyl)-carbamoyl]-ph-
enoxy}-phenyl)-oxamic acid ethyl ester, MS Calc.: 509.4 Found:
507.1 (M-1).
EXAMPLE 2-63
[0424]
N-{3,5-Dichloro-4-[3-(2-chloro-benzylcarbamoyl)-4-hydroxy-phenoxy]--
phenyl}-oxamic acid ethyl ester, MS Calc.: 537.8 Found: 535.0
(M-1).
EXAMPLE 2-64
[0425]
N-{3,5-Dichloro-4-[4-hydroxy-3-(3-methyl-3-phenyl-piperidine-1-carb-
onyl)-phenoxy]-phenyl}-oxamic acid ethyl ester, MS Calc.: 571.5
Found: 569.2 (M-1).
EXAMPLE 2-65
[0426]
N-{3,5-Dichloro-4-[3-(3,4-dihydro-1H-isoquinoline-2-carbonyl)-4-hyd-
roxy-phenoxy]-phenyl}-oxamic acid ethyl ester, MS Calc.: 529.4
Found: 527.2 (M-1).
EXAMPLE 2-66
[0427]
N-{3,5-Dichloro-4-[4-hydroxy-3-(indan-1-ylcarbamoyl)-phenoxy]-pheny-
l}-oxamic acid ethyl ester, MS Calc.: 529.4 Found: 527.2 (M-1).
EXAMPLE 2-67
[0428]
N-(4-{3-[(Benzo[1,3]dioxol-5-ylmethyl)-carbamoyl]-4-hydroxy-phenoxy-
}-3,5-dichloro-phenyl)-oxamic acid ethyl ester, MS Calc.: 547.4
Found: 545.2 (M-1).
EXAMPLE 2-68
[0429]
N-{4-[3-(Azepane-1-carbonyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl-
}-oxamic acid ethyl ester, MS Calc.: 495.4 Found: 493.3 (M-1).
EXAMPLE 2-69
[0430]
N-{3,5-Dichloro-4-[4-hydroxy-3-(4-methyl-piperidine-1-carbonyl)-phe-
noxy]-phenyl}-oxamic acid ethyl ester, MS Calc.: 495.4 Found: 493.2
(M-1).
EXAMPLE 2-70
[0431]
N-{3,5-Dichloro-4-[3-(4-fluoro-phenylcarbamoyl)-4-hydroxy-phenoxy]--
phenyl}-oxamic acid ethyl ester, MS Calc.: 507.3 Found: 505.1
(M-1).
EXAMPLE 2-71
[0432]
N-{3,5-Dichloro-4-[3-(cyclohexylmethyl-carbamoyl)-4-hydroxy-phenoxy-
]-phenyl}-oxamic acid ethyl ester, MS Calc.: 509.4 Found: 507.2
(M-1).
EXAMPLE 2-72
[0433]
N-{3,5-Dichloro-4-[3-(1-cyclohexyl-(1R)ethylcarbamoyl)-4-hydroxy-ph-
enoxy]-phenyl}-oxamic acid ethyl ester, MS Calc.: 523.4 Found:
521.2 (M-1).
EXAMPLE 2-73
[0434]
N-{3,5-Dichloro-4-[3-(1-cyclohexyl-(1S)ethylcarbamoyl)-4-hydroxy-ph-
enoxy]-phenyl}-oxamic acid ethyl ester, MS Calc.: 523.4 Found:
521.2 (M-1).
EXAMPLE 2-74
[0435]
N-{3,5-Dichloro-4-[4-hydroxy-3-(piperidine-1-carbonyl)-phenoxy]-phe-
nyl}-oxamic acid ethyl ester, MS Calc.: 481.3 Found: 481.2
(M-1).
EXAMPLE 2-75
[0436]
N-{3,5-Dichloro-4-[4-hydroxy-3-(3-methyl-piperidine-1-carbonyl)-phe-
noxy]-phenyl}-oxamic acid ethyl ester, MS Calc.: 495.3 Found: 493.1
(M-1).
EXAMPLE 2-76
[0437]
N-{4-[3-(Biphenyl-3-ylcarbamoyl)-4-hydroxy-phenoxy]-3,5-dichloro-ph-
enyl}-oxamic acid ethyl ester, MS Calc.: 565.4 Found: 563.2
(M-1).
EXAMPLE 2-77
[0438]
N-[3,5-Dichloro-4-(3-cyclopropylcarbamoyl-4-hydroxy-phenoxy)-phenyl-
]-oxamic acid ethyl ester, MS Calc.: 453.3 Found: 453.2 (M-1).
EXAMPLE 2-78
[0439]
N-{3,5-Dichloro-4-[3-(2,3-dichloro-benzylcarbamoyl)-4-hydroxy-pheno-
xy]-phenyl}-oxamic acid ethyl ester, MS Calc.: 572.2 Found: 571.0
(M-1).
EXAMPLE 2-79
[0440]
N-[3,5-Dichloro-4-(3-cyclobutylcarbamoyl-4-hydroxy-phenoxy)-phenyl]-
-oxamic acid ethyl ester, MS Calc.: 467.3 Found: 465.2 (M-1).
EXAMPLE 2-80
[0441]
N-[3,5-Dichloro-4-(3-cyclopentylcarbamoyl-4-hydroxy-phenoxy)-phenyl-
]-oxamic acid ethyl ester, MS Calc.: 481.3 Found: 479.2 (M-1).
EXAMPLE 2-81
[0442]
N-(3,5-Dichloro-4-{4-hydroxy-3-[(naphthalen-1-ylmethyl)-carbamoyl]--
phenoxy}-phenyl)-oxamic acid ethyl ester, MS Calc.: 533.4 Found:
551.1 (M-1).
EXAMPLE 2-82
[0443]
N-{3,5-Dichloro-4-[3-(4-fluoro-benzylcarbamoyl)-4-hydroxy-phenoxy]--
phenyl}-oxamic acid ethyl ester, MS Calc.: 521.3 Found: 519.2
(M-1).
EXAMPLE 2-83
[0444]
N-{4-[3-(Azocane-1-carbonyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl-
}-oxamic acid ethyl ester, MS Calc.: 509.4 Found: 507.2 (M-1).
EXAMPLE 2-84
[0445]
N-{3,5-Dichloro-4-[4-hydroxy-3-(1,2,3,4-tetrahydro-naphthalen-1-ylc-
arbamoyl)-phenoxy]-phenyl}-oxamic acid ethyl ester, MS Calc.: 543.4
Found: 541.2 (M-1).
EXAMPLE 2-85
[0446]
N-{3,5-Dichloro-4-[4-hydroxy-3-(1-isopropyl-2-methyl-propylcarbamoy-
l)-phenoxy]-phenyl}-oxamic acid ethyl ester, MS Calc.: 511.4 Found:
509.2 (M-1).
EXAMPLE 2-86
[0447]
N-{3,5-Dichloro-4-[4-hydroxy-3-(6-methoxy-3,4-dihydro-2H-quinoline--
1-carbonyl)-phenoxy]-phenyl}-oxamic acid ethyl ester, MS Calc.:
559.4 Found: 556.4 (M-1).
EXAMPLE 2-87
[0448]
N-{3,5-Dichloro-4-[4-hydroxy-3-(6-methyl-3,4-dihydro-2H-quinoline-1-
-carbonyl)-phenoxy]-phenyl}-oxamic acid ethyl ester, MS Calc.:
543.4 Found: 541.1 (M-1).
EXAMPLE 2-88
[0449]
N-{3,5-Dichloro-4-[4-hydroxy-3-(4-isopropyl-benzylcarbamoyl)-phenox-
y]-phenyl}-oxamic acid ethyl ester, MS Calc.: 545.4 Found: 545.0
(M-1).
EXAMPLE 2-89
[0450]
N-{3,5-Dichloro-4-[3-(4-chloro-benzylcarbamoyl)-4-hydroxy-phenoxy]--
phenyl}-oxamic acid ethyl ester, MS Calc.: 537.8 Found: 535.0
(M-1).
EXAMPLE 2-90
[0451]
N-{3,5-Dichloro-4-[4-hydroxy-3-((1R)indan-1-ylcarbamoyl)-phenoxy]-p-
henyl}-oxamic acid ethyl ester, MS Calc.: 529.4 Found: 527.1
(M-1).
EXAMPLE 2-91
[0452]
N-{3,5-Dichloro-4-[4-hydroxy-3-((1S)indan-1-ylcarbamoyl)-phenoxy]-p-
henyl}-oxamic acid ethyl ester, MS Calc.: 529.4 Found: 527.1
(M-1).
EXAMPLE 2-92
[0453]
N-{3,5-Dichloro-4-[4-hydroxy-3-(1-phenyl-(1R)ethylcarbamoyl)-phenox-
y]-phenyl}-oxamic acid ethyl ester, MS Calc.: 517.4 Found: 514.8
(M-1).
EXAMPLE 2-93
[0454]
N-{3,5-Dichloro-4-[4-hydroxy-3-(1-naphthalen-1-yl-(1S)ethylcarbamoy-
l)-phenoxy]-phenyl}-oxamic acid ethyl ester, MS Calc.: 567.4 Found:
564.8 (M-1).
EXAMPLE 2-94
[0455]
N-{3,5-Dichloro-4-[3-(3,4-difluoro-benzylcarbamoyl)-4-hydroxy-pheno-
xy]-phenyl}-oxamic acid ethyl ester, MS Calc.: 539.3 Found: 536.7
(M-1).
EXAMPLE 2-95
[0456]
N-{3,5-Dichloro-4-[3-(3-chloro-4-fluoro-benzylcarbamoyl)-4-hydroxy--
phenoxy]-phenyl}-oxamic acid ethyl ester, MS Calc.: 555.8 Found:
555.1 (M-1).
EXAMPLE 2-96
[0457]
N-{3,5-Dichloro-4-[3-(2-chloro-4-fluoro-benzylcarbamoyl)-4-hydroxy--
phenoxy]-phenyl}-oxamic acid ethyl ester, MS Calc.: 555.8 Found:
553.0 (M-1).
EXAMPLE 2-97
[0458]
N-{3,5-Dichloro-4-[4-hydroxy-3-(1-naphthalen-2-yl-(1R)ethylcarbamoy-
l)-phenoxy]-phenyl}-oxamic acid ethyl ester, MS Calc.: 567.4 Found:
565.1 (M-1).
EXAMPLE 2-98
[0459]
N-{3,5-Dichloro-4-[3-(2,4-dichloro-benzylcarbamoyl)-4-hydroxy-pheno-
xy]-phenyl}-oxamic acid ethyl ester, MS Calc.: 572.2 Found: 572.9
(M+1).
EXAMPLE 2-99
[0460]
N-{3,5-Dichloro-4-[3-(3,4-dichloro-benzylcarbamoyl)-4-hydroxy-pheno-
xy]-phenyl}-oxamic acid ethyl ester, MS Calc.: 572.2 Found: 571.1
(M-1).
EXAMPLE 2-100
[0461]
N-{3,5-Dichloro-4-[3-(4-chloro-3-trifluoromethyl-benzylcarbamoyl)-4-
-hydroxy-phenoxy]-phenyl}-oxamic acid ethyl ester, MS Calc.: 605.8
Found: 606.9 (M+1).
EXAMPLE 2-101
[0462]
N-{3,5-Dichloro-4-[3-(4-chloro-2-fluoro-benzylcarbamoyl)-4-hydroxy--
phenoxy]-phenyl}-oxamic acid ethyl ester, MS Calc.: 555.8 Found:
553.1 (M-1).
EXAMPLE 2-102
[0463]
N-{4-[3-(4-tert-Butyl-benzylcarbamoyl)-4-hydroxy-phenoxy]-3,5-dichl-
oro-phenyl}-oxamic acid ethyl ester, MS Calc.: 559.5 Found: 557.2
(M-1).
EXAMPLE 2-103
[0464]
N-[3,5-Dichloro-4-(3-cyclohexylcarbamoyl-4-hydroxy-phenoxy)-phenyl]-
-oxamic acid ethyl ester, MS Calc.: 495.4 Found: 493.2 (M-1).
EXAMPLE 2-104
[0465]
N-[3,5-Dichloro-4-(4-hydroxy-3-isopropylcarbamoyl-phenoxy)-phenyl]--
oxamic acid ethyl ester, MS Calc.: 455.3 Found: 453.1 (M-1).
EXAMPLE 2-105
[0466]
N-{3,5-Dichloro-4-[4-hydroxy-3-(isopropyl-methyl-carbamoyl)-phenoxy-
]-phenyl}-oxamic acid ethyl ester, MS Calc.: 469.3 Found: 467.2
(M-1).
EXAMPLE 2-106
[0467]
N-{3,5-Dichloro-4-[3-(cyclopropylmethyl-carbamoyl)-4-hydroxy-phenox-
y]-phenyl}-oxamic acid ethyl ester, MS Calc.: 467.3 Found: 465.2
(M-1).
EXAMPLE 2-107
[0468]
N-{3,5-Dichloro-4-[3-(4-fluoro-benzylcarbamoyl)-4-hydroxy-phenoxy]--
phenyl}-oxamic acid, MS Calc.: 493.3 Found: 491.1 (M-1).
EXAMPLE 2-108
[0469]
N-[3,5-Dichloro-4-(3-dimethylcarbamoyl-4-hydroxy-phenoxy)-phenyl]-o-
xamic acid, MS Calc.: 413.2 Found: 413.2 (M-1).
EXAMPLE 2-109
[0470]
N-{3,5-Dichloro-4-[4-hydroxy-3-(1-isopropyl-2-methyl-propylamino-ca-
rbonyl)-phenoxy]-phenyl}-oxamic acid, MS Calc.: 483.4 Found: 481.2
(M-1).
EXAMPLE 3
N-{3,5-Dichloro-4-[4-hydroxy-3-(indan-1-ylaminomethyl)-phenoxy]-phenyl}-ox-
amic acid ethyl ester
Step A
[0471] To a solution of 2',6'-dichloro-4-methoxy-4'-nitrodiphenyl
ether (10 g, 31.8 mmol) in chloroform (200 mL) at 0.degree. C. was
added dropwise borontribromide (1N in CH.sub.2Cl.sub.2, 63.7 mL,
63.7 mmol). After stirring at RT for 3 h, the reaction was quenched
with H.sub.2O (200 mL). The mixture was stirred at RT for 1 h, and
the phases were separated. The aqueous phase was extracted with
chloroform (2.times.150 mL). The combined organic phases were
washed with H.sub.2O (1.times.200 mL), saturated aqueous
NaHCO.sub.3 (1.times.200 mL), brine (1.times.200 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford a brown
solid. The crude product was used in the next step without further
purification. NMR (400 MHz, CD.sub.3OD) d 8.28 (s, 2H), 6.67-6.70
(m, 2H), 6.61-6.64 (m, 2H). MS Calc.: 299.0, Found: 298.2
(M-1).
Step B
[0472] To a solution of 2',6'-dichloro-4-hydroxy-4'-nitrodiphenyl
ether (9.5 g, 32 mmol) in a mixture of EtOAC (50 mL) and MeOH (150
mL) was added 0.48 g of 10% Pd/C. The mixture was hydrogenated
under 40 psi of pressure at RT for 5 h. The solution was filtered
through Celite.RTM. and concentrated to give a brown solid. NMR
(400 MHz, CD.sub.3OD) d 6.71 (s, 2H), 6.66-6.68 (m, 2H), 6.59-6.61
(m, 2H). MS Calc.: 269.0, Found: 268.2 (M-1).
Step C
[0473] A mixture of 2',6'-dichloro-4-hydroxy-4'-aminodiphenyl ether
(8.6 g, 31.8 mmol) and diethyl oxalate (69.8 g, 47.8 mmol) was
stirred at 140.degree. C. for 2 h to give a brown solution. The
excess diethyl oxalate was removed under reduced pressure and the
resulting oily brown solid was triturated with a mixture of
CH.sub.2Cl.sub.2/hexane (1/9, 200 mL) for 1 h. The solid was
collected by filtration, washed with CH.sub.2Cl.sub.2/hexane and
dried under vacuum to give a tan solid. The product was used in the
next step without further purification. NMR (400 MHz, CDCl.sub.3) d
7.68 (s, 2H), 6.59-6.61 (m, 2H), 6.53-6.55 (m, 2H), 4.25-4.30 (q,
2H), 1.27-1.31 (t, 3H). MS Calc.: 369.0, Found: 367.5 (M-1).
Step D
[0474] A mixture of
N-[3,5-dichloro-4-(4-hydroxy-phenoxy)-phenyl]-oxamic acid ethyl
ester (500 mg, 1.35 mmol), TFA (5.0 mL) and hexamethylenetetramine
(284 mg, 2.03 mmol) was stirred at 75.degree. C. for 1 h to give a
red-brown solution. The solution was cooled to RT. TFA was removed
under reduced pressure and 20 mL of H.sub.2O was added to the
remaining brown oil. After stirring for 20 min at RT, the mixture
was extracted with EtOAc (2.times.20 mL). The aqueous phase was
basified with saturated aqueous NaHCO.sub.3 and extracted with an
additional EtOAc (2.times.20 mL). The combined EtOAc extracts were
washed with saturated aqueous NaHCO.sub.3 (2.times.30 mL), H.sub.2O
(50 mL), 1 N HCl (2.times.50 mL), brine (50 mL), dried over
Na.sub.2SO.sub.4, filtered and concentrated to give a brown solid.
The crude product was purified by flash column chromatography to
afford a white solid. NMR (400 MHz, CDCl.sub.3) d 10.72 (s, 1H),
9.77 (s, 1H), 8.90 (s, 1H), 7.71 (s, 2H), 7.14-7.17 (dd, 1H),
6.96-6.98 (d, 1H), 6.89-6.90 (d, 1H), 4.42-4.47 (q, 2H), 1.23-1.27
(t, 3H). MS Calc.: 397.0, Found: 395.7 (M-1).
Step E
[0475] To a mixture of
N-[3,5-dichloro-4-(3-formyl-4-hydroxy-phenoxy)-phen- yl]-oxamic
acid ethyl ester (30 mg, 0.08 mmol) and aminoindan (10 mg, 0.08
mmol) in dichloroethane (1.0 mL) was added sodium
triacetoxyborohydride (22.4 mg, 0.11 mmol) and acetic acid (4.5 mg,
0.08 mmol) in single portions. After stirring at RT for 3 h, the
solution became clear and yellow. The solution was quenched with
saturated aqueous NaHCO.sub.3 (5 mL) and extracted with Et.sub.2O
(3.times.10 mL). The combined extracts were dried over
Na.sub.2SO.sub.4, filtered and concentrated to give the crude
product as a yellow glass. The crude product was purified by
preparative TLC (5% Et.sub.2O in CH.sub.2Cl.sub.2) to afford the
title compound as an off-white solid. NMR (400 MHz, CDCl.sub.3) d
8.94 (s, 1H), 7.74 (s, 2H), 7.36-7.37 (d, 1H), 7.19-7.25 (m, 4H),
6.75-6.77 (d, 1H), 6.61-6.64 (dd, 1H), 6.54-6.55 (d, 1H), 4.40-4.46
(q, 2H), 4.30-4.33 (t, 1H), 4.05-4.08 (d, 1H), 3.95-3.98 (d, 1H),
2.98-3.06 (m, 1H), 2.81-2.88 (m, 1H), 2.42-2.51 (m, 1H), 1.88-1.96
(m, 1H), 1.41-1.45 (t, 3H). MS Calc.: 514.20, Found: 513.1
(M-1).
[0476] Using the appropriate starting materials, EXAMPLES 3-1 to
3-54 were prepared in an analogous manner to that described in
EXAMPLE 3.
EXAMPLE 3-1
[0477]
N-{4-[3-(2,3-Dihydro-indol-1-ylmethyl)-4-hydroxy-phenoxy]-3,5-dimet-
hyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 460.5 Found: 459.3
(M-1).
EXAMPLE 3-2
[0478]
N-{4-[3-(3,3-Dimethyl-piperidin-1-ylmethyl)-4-hydroxy-phenoxy]-3,5--
dimethyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 454.6 Found:
453.3 (M-1).
EXAMPLE 3-3
[0479]
N-{4-[4-Hydroxy-3-(3-methyl-3-phenyl-piperidin-1-ylmethyl)-phenoxy]-
-3,5-dimethyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 516.6
Found: 515.3 (M-1).
EXAMPLE 3-4
[0480]
N-{4-[3-(3,4-Dihydro-1H-isoquiholin-2-ylmethyl)-4-hydroxy-phenoxy]--
3,5-dimethyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 474.6
Found: 473.3 (M-1).
EXAMPLE 3-5
[0481]
N-(4-{3-[(4-Fluoro-benzylamino)-methyl]-4-hydroxy-phenoxy}-3,5-dime-
thyl-phenyl)-oxamic acid ethyl ester, MS Calc.: 466.5 Found: 465.2
(M-1).
EXAMPLE 3-6
[0482]
N-(4-{3-[(4-Chloro-benzylamino)-methyl]-4-hydroxy-phenoxy}-3,5-dime-
thyl-phenyl)-oxamic acid ethyl ester, MS Calc.: 483.0 Found: 481.3
(M-1).
EXAMPLE 3-7
[0483]
N-(4-{4-Hydroxy-3-[(4-isopropyl-benzylamino)-methyl]-phenoxy}-3,5-d-
imethyl-phenyl)-oxamic acid ethyl ester, MS Calc.: 490.6 Found:
489.2 (M-1).
EXAMPLE 3-8
[0484]
N-[4-(3-Azepan-1-ylmethyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-o-
xamic acid ethyl ester, MS Calc.: 440.5 Found: 439.3 (M-1).
EXAMPLE 3-9
[0485]
N-[4-(3-{[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-methyl}-4-hydroxy-ph-
enoxy)-3,5-dimethyl-phenyl]-oxamic acid ethyl ester, MS Calc.:
492.5 Found: 491.3 (M-1).
EXAMPLE 3-10
[0486]
N-(4-{4-Hydroxy-3-[(1,2,3,4-tetrahydro-naphthalen-1-ylamino)-methyl-
]-phenoxy}-3,5-dimethyl-phenyl)-oxamic acid ethyl ester, MS Calc.:
488.6 Found: 487.4 (M-1).
EXAMPLE 3-11
[0487]
N-[4-(3-Dimethylaminomethyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-
-oxamic acid ethyl ester, MS Calc.: 386.5 Found: 385.3 (M-1).
EXAMPLE 3-12
[0488]
N-(4-{4-Hydroxy-3-[(methyl-propyl-amino)-methyl]-phenoxy}-3,5-dimet-
hyl-phenyl)-oxamic acid ethyl ester, MS Calc.: 414.9 Found: 413.4
(M-1).
EXAMPLE 3-13
[0489]
N-[4-(3-Cyclopropylaminomethyl-4-hydroxy-phenoxy)-3,5-dimethyl-phen-
yl]-oxamic acid ethyl ester, MS Calc.: 398.5 Found: 397.4
(M-1).
EXAMPLE 3-14
[0490]
N-[4-(4-Hydroxy-3-morpholin-4-ylmethyl-phenoxy)-3,5-dimethyl-phenyl-
]-oxamic acid ethyl ester, MS Calc.: 428.5 Found: 427.3 (M-1).
EXAMPLE 3-15
[0491]
N-(4-{4-Hydroxy-3-[(isopropyl-methyl-amino)-methyl]-phenoxy}-3,5-di-
methyl-phenyl)-oxamic acid ethyl ester, MS Calc.: 414.5 Found:
413.5 (M-1).
EXAMPLE 3-16
[0492]
N-{4-[4-Hydroxy-3-(isopropylamino-methyl)-phenoxy]-3,5-dimethyl-phe-
nyl}-oxamic acid ethyl ester, MS Calc.: 400.5 Found: 399.4
(M-1).
EXAMPLE 3-17
[0493]
N-[4-(3-Cyclobutylaminomethyl-4-hydroxy-phenoxy)-3,5-dimethyl-pheny-
l]-oxamic acid ethyl ester, MS Calc.: 412.5 Found: 411.4 (M-1).
EXAMPLE 3-18
[0494]
N-[4-(3-Cyclopentylaminomethyl-4-hydroxy-phenoxy)-3,5-dimethyl-phen-
yl]-oxamic acid ethyl ester, MS Calc.: 426.5 Found: 425.4
(M-1).
EXAMPLE 3-19
[0495]
N-{3-Chloro-4-[3-(3,3-dimethyl-piperidin-1-ylmethyl)-4-hydroxy-phen-
oxy]-5-methyl-phenyl}-oxamic acid methyl ester, MS Calc.: 461.0
Found: 461.1 (M+1).
EXAMPLE 3-20
[0496]
N-{3-Chloro-4-[3-(2,3-dihydro-indol-1-ylmethyl)-4-hydroxy-phenoxy]--
5-methyl-phenyl}-oxamic acid methyl ester, MS Calc.: 467.0 Found:
467.2 (M+1).
EXAMPLE 3-21
[0497]
N-(3-Chloro-4-{3-[(4-fluoro-benzylamino)-methyl]-4-hydroxy-phenoxy}-
-5-methyl-phenyl)-oxamic acid ethyl ester, MS Calc.: 486.9 Found:
485.2 (M-1).
EXAMPLE 3-22
[0498]
N-{3-Chloro-4-[4-hydroxy-3-(3-methyl-3-phenyl-piperidin-1-ylmethyl)-
-phenoxy]-5-methyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 537.1
Found: 535.2 (M-1).
EXAMPLE 3-23
[0499]
N-(3-Chloro-4-{3-[(4-chloro-benzylamino)-methyl]-4-hydroxy-phenoxy}-
-5-methyl-phenyl)-oxamic acid ethyl ester, MS Calc.: 503.4 Found:
501.1 (M-1).
EXAMPLE 3-24
[0500]
N-(3-Chloro-4-{4-hydroxy-3-[(4-isopropyl-benzylamino)-methyl]-pheno-
xy}-5-methyl-phenyl)-oxamic acid ethyl ester, MS Calc.: 511.2
Found: 509.2 (M-1).
EXAMPLE 3-25
[0501]
N-{3-Chloro-4-[3-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-4-hydroxy--
phenoxy]-5-methyl-phenyl}-oxamic acid ethyl ester, MS Calc.: 495.0
Found: 493.2 (M-1).
EXAMPLE 3-26
[0502]
N-[4-(3-Azepan-1-ylmethyl-4-hydroxy-phenoxy)-3-chloro-5-methyl-phen-
yl]-oxamic acid ethyl ester, MS Calc.: 461.0 Found: 459.2
(M-1).
EXAMPLE 3-27
[0503]
N-[4-(3-{[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-methyl}-4-hydroxy-ph-
enoxy)-3-chloro-5-methyl-phenyl]-oxamic acid ethyl ester, MS Calc.:
513.0 Found: 511.2 (M-1).
EXAMPLE 3-28
[0504]
N-(3-Chloro-4-{4-hydroxy-3-[(1,2,3,4-tetrahydro-naphthalen-1-ylamin-
o)-methyl]-phenoxy}-5-methyl-phenyl)-oxamic acid ethyl ester, MS
Calc.: 509.0 Found: 507.3 (M-1).
EXAMPLE 3-29
[0505]
N-[3-Chloro-4-(3-dimethylaminomethyl-4-hydroxy-phenoxy)-5-methyl-ph-
enyl]-oxamic acid ethyl ester, MS Calc.: 406.9 Found: 405.3
(M-1).
EXAMPLE 3-30
[0506]
N-(3-Chloro-4-{4-hydroxy-3-[(methyl-propyl-amino)-methyl]-phenoxy}--
5-methyl-phenyl)-oxamic acid ethyl ester, MS Calc.: 434.9 Found:
433.3 (M-1).
EXAMPLE 3-31
[0507]
N-[3-Chloro-4-(3-cyclopropylaminomethyl-4-hydroxy-phenoxy)-5-methyl-
-phenyl]-oxamic acid ethyl ester, MS Calc.: 418.9 Found: 417.3
(M-1).
EXAMPLE 3-32
[0508]
N-{3,5-Dichloro-4-[3-(2,3-dihydro-indol-1-ylmethyl)-4-hydroxy-pheno-
xy]-phenyl}-oxamic acid methyl ester, MS Calc.: 487.3 Found: 487.2
(M+1).
EXAMPLE 3-33
[0509]
N-{3,5-Dichloro-4-[3-(3,3-dimethyl-piperidin-1-ylmethyl)-4-hydroxy--
phenoxy]-phenyl}-oxamic acid methyl ester, MS Calc.: 481.4 Found:
481.2 (M+1).
EXAMPLE 3-34
[0510]
N-{3,5-Dichloro-4-[4-hydroxy-3-(indan-1-ylaminomethyl)-phenoxy]-phe-
nyl}-oxamic acid methyl ester, MS Calc.: 501.4 Found: 499.1
(M-1).
EXAMPLE 3-35
[0511]
N-{3,5-Dichloro-4-[3-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-4-hydr-
oxy-phenoxy]-phenyl}-oxamic acid methyl ester, MS Calc.: 501.4
Found: 501.1 (M+1).
EXAMPLE 3-36
[0512]
N-[4-(3-Azepan-1-ylmethyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-o-
xamic acid methyl ester, MS Calc.: 467.4 Found: 465.1 (M-1).
EXAMPLE 3-37
[0513]
N-(3,5-Dichloro-4-{3-[(1-cyclohexyl-(1R)ethylamino)-methyl]-4-hydro-
xy-phenoxy}-phenyl)-oxamic acid ethyl ester, MS Calc.: 509.4 Found:
507.2 (M-1).
EXAMPLE 3-38
[0514]
N-{4-[3-(Bicyclo[2.2.1]hept-2-ylaminomethyl)-4-hydroxy-phenoxy]-3,5-
-dichloro-phenyl}-oxamic acid ethyl ester, MS Calc.: 493.4 Found:
491.2 (M-1).
EXAMPLE 3-39
[0515]
N-{3,5-Dichloro-4-[4-hydroxy-3-(3-methyl-3-phenyl-piperidin-1-ylmet-
hyl)-phenoxy]-phenyl}-oxamic acid ethyl ester, MS Calc.: 557.5
Found: 555.1 (M-1).
EXAMPLE 3-40
[0516]
N-(3,5-Dichloro-4-{3-[(4-fluoro-benzylamino)-methyl]-4-hydroxy-phen-
oxy}-phenyl)-oxamic acid ethyl ester, MS Calc.: 507.35 Found: 505.0
(M-1).
EXAMPLE 3-41
[0517]
N-(3,5-Dichloro-4-{4-hydroxy-3-[(1-phenyl-(1R)ethylamino)-methyl]-p-
henoxy}-phenyl)-oxamic acid ethyl ester, MS Calc.: 503.4 Found:
501.0 (M-1).
EXAMPLE 3-42
[0518]
N-(3,5-Dichloro-4-{4-hydroxy-3-[(1-phenyl-(1S)ethylamino)-methyl]-p-
henoxy}-phenyl)-oxamic acid ethyl ester, MS Calc.: 503.4 Found:
501.0 (M-1).
EXAMPLE 3-43
[0519]
N-[3,5-Dichloro-4-(4-hydroxy-3-{[(naphthalen-1-ylmethyl)-amino]-met-
hyl}-phenoxy)-phenyl]-oxamic acid ethyl ester, MS Calc.: 539.4
Found: 536.7 (M-1).
EXAMPLE 3-44
[0520]
N-(3,5-Dichloro-4-{4-hydroxy-3-[(1-naphthalen-1-yl-(1R)ethylamino)--
methyl]-phenoxy}-phenyl)-oxamic acid ethyl ester, MS Calc.: 553.5
Found: 550.8 (M-1).
EXAMPLE 3-45
[0521]
N-(3,5-Dichloro-4-{4-hydroxy-3-[(1,2,3,4-tetrahydro-naphthalen-1-yl-
amino)-methyl]-phenoxy}-phenyl)-oxamic acid ethyl ester, MS Calc.:
529.4 Found: 526.8 (M-1).
EXAMPLE 3-46
[0522]
N-[3,5-Dichloro-4-(3-cyclohexylaminomethyl-4-hydroxy-phenoxy)-pheny-
l]-oxamic acid ethyl ester, MS Calc.: 481.4 Found: 478.8 (M-1).
EXAMPLE 3-47
[0523]
N-[3,5-Dichloro-4-(3-cyclopentylaminomethyl-4-hydroxy-phenoxy)-phen-
yl]-oxamic acid ethyl ester, MS Calc.: 467.4 Found: 465.1
(M-1).
EXAMPLE 3-48
[0524]
N-[4-(3-{[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-methyl}-4-hydroxy-ph-
enoxy)-3,5-dichloro-phenyl]-oxamic acid ethyl ester, MS Calc.:
533.4 Found: 531.0 (M-1).
EXAMPLE 3-49
[0525]
N-(3,5-Dichloro-4-{3-[(4-chloro-benzylamino)-methyl]-4-hydroxy-phen-
oxy}-phenyl)-oxamic acid ethyl ester, MS Calc.: 523.8 Found: 521.1
(M-1).
EXAMPLE 3-50
[0526]
N-(3,5-Dichloro-4-{4-hydroxy-3-[(4-isopropyl-benzylamino)-methyl]-p-
henoxy}-phenyl)-oxamic acid ethyl ester, MS Calc.: 531.4 Found:
529.2 (M-1).
EXAMPLE 3-51
[0527]
N-[3,5-Dichloro-4-(4-hydroxy-3-methylaminomethyl-phenoxy)-phenyl]-o-
xamic acid ethyl ester, MS Calc.: 413.3 Found: 411.2 (M-1).
EXAMPLE 3-52
[0528]
N-[3,5-Dichloro-4-(3-cyclopropylaminomethyl-4-hydroxy-phenoxy)-phen-
yl]-oxamic acid ethyl ester, MS Calc.: 439.3 Found: 437.3
(M-1).
EXAMPLE 3-53
[0529]
N-[3,5-Dichloro-4-(4-hydroxy-3-morpholin-4-ylmethyl-phenoxy)-phenyl-
]-oxamic acid ethyl ester, MS Calc.: 469.3 Found: 467.3 (M-1).
EXAMPLE 3-54
[0530]
N-[3,5-Dichloro-4-(3-cyclobutylaminomethyl-4-hydroxy-phenoxy)-pheny-
l]-oxamic acid ethyl ester, MS Calc.: 453.3 Found: 451.3 (M-1).
EXAMPLE 4
N-{4-[4-Hydroxy-3-(isopropylmethylcarbamoyl)-phenoxy]-3,5-dimethyl-phenyl}-
-oxamide
[0531] A solution of
N-{4-[4-hydroxy-3-(isopropylmethylcarbamoyl)-phenoxy]-
-3,5-dimethyl-phenyl}-oxamic acid ethyl ester (7.1 mg, 0.017 mmol)
in 1 mL of EtOH in the presence of magnesium sulfate (10 mg) at
0.degree. C. was bubbled in NH.sub.3 gas for 10 min. The solution
was allowed to warm to RT. After stirring at RT for 0.5 h, the
solution was diluted with 2 mL of CH.sub.2Cl.sub.2 and filtered.
The filtrate was concentrated to give the title compound as a white
solid. MS Calc.: 399.5 Found: 398.4 (M-1).
[0532] Using the appropriate starting materials, EXAMPLES 4-1 to
4-10 were prepared in an analogous manner to that described in
EXAMPLE 4.
EXAMPLE 4-1
[0533]
N-{4-[4-Hydroxy-3-(1-isopropyl-2-methyl-propylcarbamoyl)-phenoxy]-3-
,5-dimethyl-phenyl}-oxamide, MS Calc.: 441.5 Found: 440.5
(M-1).
EXAMPLE 4-2
[0534]
N-[3,5-Dichloro-4-(3-cyclohexylcarbamoyl-4-hydroxy-phenoxy)-phenyl]-
-oxamide, MS Calc.: 465.1 Found: 464.2 (M-1).
EXAMPLE 4-3
[0535]
N-{3-Chloro-4-[4-hydroxy-3-(morpholine-4-sulfonyl)-phenoxy]-5-methy-
l-phenyl}-oxamide, MS Calc.: 469.1 Found: 468.2 (M-1).
EXAMPLE 4-4
[0536]
N-[4-(3-Benzenesulfonyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-oxa-
mide, MS Calc.: 480.0 Found: 479.2 (M-1).
EXAMPLE 4-5
[0537]
N-{3-Chloro-4-[3-(cyclobutylmethylcarbamoyl)-4-hydroxy-phenoxy]-5-m-
ethyl-phenyl}-oxamide, MS Calc.: 431.1 Found: 430.3 (M-1).
EXAMPLE 4-6
[0538]
N-{3-Chloro-4-[3-(cyclopropylmethyl-amino-sulfonyl)-4-hydroxy-pheno-
xy]-5-methyl-phenyl}-oxamide, MS Calc.: 453.1 Found: 452.3
(M-1).
EXAMPLE 4-7
[0539]
N-{3-Chloro-4-[4-hydroxy-3-(methylpropylsulfamoyl)-phenoxy]-5-methy-
l-phenyl}-oxamide, MS Calc.: 455.1 Found: 454.2 (M-1).
EXAMPLE 4-8
[0540]
N-{4-[4-Hydroxy-3-(pyrrolidine-1-carbonyl)-phenoxy]-3,5-dimethyl-ph-
enyl}-oxamide, MS Calc.: 397.4 Found: 396.3 (M-1).
EXAMPLE 4-9
[0541]
N-[3-Chloro-4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-p-
henyl]-oxamide, MS Calc.: 439.1 Found: 438.2 (M-1).
EXAMPLE 4-10
[0542]
N-{4-[3-(Cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-3,5-dimeth-
yl-phenyl}-oxamide, MS Calc.: 411.5 Found: 410.3 (M-1).
EXAMPLE 5
N-{3,5-Dichloro-4-[3-(4-chloro-benzenesulfonyl)-4-hydroxy-phenoxy]-phenyl}-
-oxamic acid ethyl ester
Step A
[0543] A mixture of 2',6'-dichloro-4-methoxy-4'-nitrodiphenyl ether
(250 mg, 0.80 mmol), p-chlorobenzene sulfonic acid (90%, 290 mg,
1.4 mmol) and Eaton's reagent was stirred at 80.degree. C. for 5 h
and cooled to RT. The reaction mixture was quenched by adding
dropwise into 30 mL of ice water. A white precipitate formed. The
precipitate was collected by filtration and taken up in
CH.sub.2Cl.sub.2, dried and concentrated. The product was purified
by preparative TLC (25% EtOAc in Hex). NMR (400 MHz, CDCl.sub.3) d
8.29-8.30 (s, 2H), 7.83-7.86 (d, 2H), 7.53-754 (d, 1H), 7.42-7.46
(d, 2H), 7.04-7.07 (dd, 1H), 6.82-6.87 (d, 1H), 3.73 (s, 3H). MS
Calc.: 486.9, Found: 486.0 (M-1).
Step B
[0544] The title compound of this EXAMPLE 5 can be prepared from
the product of Step A via demethylation, hydrogenation, and oxamate
formation according to the methods analogous to those described in
the present disclosure and known procedures. NMR (400 MHz,
CDCl.sub.3) d 8.95 (s, 1H), 8.68 (broad s, 1H), 7.80-7.82 (d, 2H),
7.76 (s, 2H), 7.49-7.51 (d, 2H), 7.06 (d, 1H), 7.00-7.02 (dd, 1H),
6.93-6.95 (d, 1H), 4.43 (q, 2H), 1.44 (t, 3H). MS Calc.: 543.0
Found: 542.1 (M-1).
[0545] Using the appropriate starting materials, EXAMPLES 5-1 to
5-12 were prepared in an analogous manner to that described in
EXAMPLE 5.
EXAMPLE 5-1
[0546]
N-{3,5-Dichloro-4-[3-(4-chloro-benzenesulfonyl)-4-hydroxy-phenoxy]--
phenyl}-oxamic acid, MS Calc.: 514.9 Found: 513.0 (M-1).
EXAMPLE 5-2
[0547]
N-{3-Chloro-4-[3-(4-chloro-benzenesulfonyl)-4-hydroxy-phenoxy]-5-me-
thyl-phenyl}-oxamic acid, MS Calc.: 495.0 Found: 494.1 (M-1).
EXAMPLE 5-3
[0548]
N-{3-Chloro-4-[3-(4-chloro-benzenesulfonyl)-4-hydroxy-phenoxy]-5-me-
thyl-phenyl}-oxamide, MS Calc.: 494.0 Found: 493.2 (M-1).
EXAMPLE 5-4
[0549]
N-[4-(3-Benzenesulfonyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-oxa-
mic acid ethyl ester, MS Calc.: 509.0 Found: 508.2 (M-1).
EXAMPLE 5-5
[0550]
N-[4-(3-Benzenesulfonyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-oxa-
mic acid, MS Calc.: 481.0 Found: 480.2 (M-1).
EXAMPLE 5-6
[0551]
N-[4-(3-Benzenesulfonyl-4-hydroxy-phenoxy)-3,5-dichloro-phenyl]-oxa-
mide, MS Calc.: 480.0 Found: 479.2 (M-1).
EXAMPLE 5-7
[0552]
N-{3,5-Dichloro-4-[4-hydroxy-3-(naphthalene-1-sulfonyl)-phenoxy]-ph-
enyl}-oxamic acid ethyl ester, MS Calc.: 559.0 Found: 558.2
(M-1).
EXAMPLE 5-8
[0553]
N-{3,5-Dichloro-4-[4-hydroxy-3-(naphthalene-1-sulfonyl)-phenoxy]-ph-
enyl}-oxamic acid, MS Calc.: 531.0 Found: 530.1 (M-1).
EXAMPLE 5-9
[0554]
N-{3,5-Dichloro-4-[4-hydroxy-3-(naphthalene-2-sulfonyl)-phenoxy]-ph-
enyl}-oxamic acid ethyl ester, MS Calc.: 559.0 Found: 558.2
(M-1).
EXAMPLE 5-10
[0555]
N-{3,5-Dichloro-4-[4-hydroxy-3-(naphthalene-2-sulfonyl)-phenoxy]-ph-
enyl}-oxamic acid, MS Calc.: 559.0 Found: 558.2 (M-1).
EXAMPLE 5-11
[0556]
N-{3,5-Dichloro-4-[4-hydroxy-3-(toluene-4-sulfonyl)-phenoxy]-phenyl-
}-oxamic acid, MS Calc.: 495.0 Found: 494.1 (M-1).
EXAMPLE 5-12
[0557]
N-{3,5-Dichloro-4-[4-hydroxy-3-(toluene-4-sulfonyl)-phenoxy]-phenyl-
}-oxamide, MS Calc.: 494.0 Found: 493.0 (M-1).
EXAMPLE 6
N-[3,5-Dichloro-4-(3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)-phenyl]-
-oxamic acid ethyl ester
Step A
[0558] On cooling with an ice bath,
2',6'-dichloro-4-methoxy-4'-nitrodiphe- nyl ether (5 g, 16 mmol)
was added portionwise to chlorosulfonic acid (14 g, 120 mmol). The
resulting reddish-brown solution was allowed to warm to RT and
stirred at RT for 1 h. The reaction mixture was added dropwise into
ice water (200 mL), extracted with EtOAc (3.times.200 mL), dried
and concentrated to give a tan solid. The solid was added in
portions to a solution of Na.sub.2SO.sub.3 (6 g, 48 mmol) in
H.sub.2O (12 mL). The solution was made basic by addition of 32%
aqueous NaOH and the pH was adjusted to 9.0. After stirring at
65.degree. C. for 2 h then at 25.degree. C. for 19 h, the solution
was acidified with 1N HCl and a precipitate formed. The precipitate
was collected by filtration, washed with water and dried to afford
the product. MS Calc.: 377.0 Found: 376.1 (M-1).
Step B
[0559] To a solution of sodium ethoxide (0.29 mmol) in EtOH at RT
was added
2-methoxy-4-(2',6'-dichloro-4'-nitro-phenoxy)-benzenesulfinic acid
(100 mg, 0.26 mmol), the product of Step A, and cyclopropylmethyl
bromide (143 mg, 1.1 mmol). The resulting mixture was stirred at
reflux for 18 h and cooled to RT. To the solution was added 1N HCl
(5 mL), followed by extraction with EtOAc (3.times.10 mL). The
combined extracts were dried and concentrated. The crude product
was purified by preparative TLC (EtOAc:Hex, 1:1) to give a solid.
MS Calc.: 431.0, Found: 431.0 (M).
Step C
[0560] The title compound of this EXAMPLE 6 can be prepared from
the product of Step B via demethylation, hydrogenation, and oxamate
formation according to procedures analogous to those described in
EXAMPLE 1. NMR (400 MHz, CDCl.sub.3) d 8.93(s, 1H), 8.68 (s, 1H),
7.75 (s, 2H), 7.10-7.13 (m, 1H), 6.96-6.99 (m, 2H), 4.41 (q, 2H),
3.01 (d, 2H), 1.41 (t, 3H), 0.95-0.99 (m, 1H), 0.54-0.58 (m, 2H),
0.11-0.14 (m, 2H). MS Calc.: 487.0 Found: 485.9 (M-1).
[0561] Using the appropriate starting materials, EXAMPLES 6-1 to
6-13 were prepared in an analogous manner to that described in
EXAMPLE 6.
EXAMPLE 6-1
[0562]
N-[4-(4-Hydroxy-3-methanesulfonyl-phenoxy)-3,5-dimethyl-phenyl]-oxa-
mic acid, MS Calc.: 379.1 Found: 378.2 (M-1).
EXAMPLE 6-2
[0563]
N-[3,5-Dichloro-4-(3-ethanesulfonyl-4-hydroxy-phenoxy)-phenyl]-oxam-
ic acid, MS Calc.: 433.0 Found: 432.0 (M-1).
EXAMPLE 6-3
[0564]
N-{3,5-Dichloro-4-[4-hydroxy-3-(propane-2-sulfonyl)-phenoxy]-phenyl-
}-oxamic acid ethyl ester, MS Calc.: 475.0 Found: 474.0 (M-1).
EXAMPLE 6-4
[0565]
N-[3,5-Dichloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-p-
henyl]-oxamic acid ethyl ester, MS Calc.: 501.0 Found: 499.9
(M-1).
EXAMPLE 6-5
[0566]
N-[3,5-Dichloro-4-(3-cyclohexylmethanesulfonyl-4-hydroxy-phenoxy)-p-
henyl]-oxamic acid ethyl ester, MS Calc.: 529.1 Found: 528.0
(M-1).
EXAMPLE 6-6
[0567]
N-[3,5-Dichloro-4-(3-cyclopentanesulfonyl-4-hydroxy-phenoxy)-phenyl-
]-oxamic acid ethyl ester, MS Calc.: 501.0 Found: 499.9 (M-1).
EXAMPLE 6-7
[0568]
N-{4-[3-(Butane-1-sulfonyl)-4-hydroxy-phenoxy]-3,5-dichloro-phenyl}-
-oxamic acid, MS Calc.: 461.0 Found: 460.2 (M-1).
EXAMPLE 6-8
[0569]
N-[3,5-Dichloro-4-(4-hydroxy-3-phenylmethanesulfonyl-phenoxy)-pheny-
l]-oxamic acid, MS Calc.: 495.0 Found: 493.9 (M-1).
EXAMPLE 6-9
[0570]
N-{3,5-Dichloro-4-[4-hydroxy-3-(propane-1-sulfonyl)-phenoxy]-phenyl-
}-oxamic acid, MS Calc.: 447.0 Found: 446.0 (M-1).
EXAMPLE 6-10
[0571]
N-{3,5-Dichloro-4-[3-(4-fluoro-phenylmethanesulfonyl)-4-hydroxy-phe-
noxy]-phenyl}-oxamic acid, MS Calc.: 513.0 Found: 512.0 (M-1).
EXAMPLE 6-11
[0572]
N-[3,5-Dichloro-4-(3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)--
phenyl]-oxamic acid, MS Calc.: 459.0 Found: 458.2 (M-1).
EXAMPLE 6-12
[0573]
N-[3,5-Dichloro-4-(3-cyclobutylmethanesulfonyl-4-hydroxy-phenoxy)-p-
henyl]-oxamic acid, MS Calc.: 473.0 Found: 472.2 (M-1).
EXAMPLE 6-13
[0574]
N-[4-(3-Cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl--
phenyl]-oxamic acid, MS Calc.: 419.1 Found: 418.0 (M-1).
EXAMPLE 7
4-(3-Phenoxy-4-methoxyphenoxy)-3,5-dimethylnitrobenzene
Step A
[0575] To a cooled (0.degree. C.), stirred solution of
3-benzyloxy-4-methoxybenzaldehyde (10 g) in MeOH (100 mL) was added
hydrogen peroxide (5.5 mL of 30% aqueous) dropwise. After having
been warmed to RT, concentrated sulfuric acid (1 mL) was added and
the resulting solution was allowed to stir for 1.5 h. The reaction
mixture was partitioned between ethyl ether/saturated aqueous
sodium bicarbonate, another organic layer was dried over sodium
sulfate and concentrated in vacuo to afford an oil. Flash
chromatography (20% ethyl acetate/hexanes) afforded
3-benzyloxy-4-methoxyphenol (5.8 g).
Step B
[0576] To a solution of 3-benzyloxy-4-methoxyphenol (3 g) in DMSO
(2 mL) was added potassium t-butoxide (1.6 g). After 30 min,
4-chloro-3,5-dimethyl-nitrobenzene (2 g) was added and the
resulting solution was heated at 80.degree. C. for 2 h. The
reaction mixture was partitioned between ethyl acetate and 1N
aqueous NaOH, and the organic layer was washed with water, brine,
dried over sodium sulfate and concentrated in vacuo to afford
4-(3-benzyloxy-4-methoxyphenoxy)-3,5-dime- thylnitrobenzene (1.9 g)
as an orange solid.
Step C
[0577] A solution of
4-(3-benzyloxy-4-methoxyphenoxy)-3,5-dimethyinitroben- zene (1.65
g), TFA (3.5 mL) and thioanisole (2.2 mL) were stirred for 4 h. The
reaction was partitioned between ethyl acetate and water, the
organic layer dried over sodium sulfate and concentrated in vacuo.
Flash chromatography afforded
4-(3-hydroxy-4-methoxyphenoxy)-3,5-dimethylnitrob- enzene (1.2 g)
as a yellow oil.
Step D
[0578] A solution of
4-(3-hydroxy-4-methoxyphenoxy)-3,5-dimethylnitrobenze- ne (150 mg),
phenylboronic acid (190 mg), copper (II) acetate (189 mg) and TEA
(0.22 mL) in dichloromethane (4 mL) was stirred for 6 h. The
reaction was diluted into ethyl acetate, washed with 1N
hydrochloric acid, dried over sodium sulfate and concentrated in
vacuo. The resulting oil was flash chromatographed (10%
DEE/petroleum ether) to afford
4-(3-phenoxy-4-methoxyphenoxy)-3,5-dimethyl-nitrobenzene (130 mg)
as a colorless solid.
[0579] Using the appropriate starting materials, EXAMPLES 7-1 to
7-9 were prepared in an analogous manner to that described in
EXAMPLE 7.
EXAMPLE 7-1
[0580]
N-[3,5-Dichloro-4-(4-hydroxy-3-phenoxy-phenoxy)-phenyl-oxamic acid
ethyl ester, MS found: 460.
EXAMPLE 7-2
[0581]
N-{3,5-Dichloro-4-[3-(4-chloro-phenoxy)-4-hydroxy-phenoxy]-phenyl}--
oxamic acid ethyl ester, MS found: 495.
EXAMPLE 7-3
[0582]
N-{3,5-Dichloro-4-[3-(4-chloro-phenoxy)-4-hydroxy-phenoxy]-phenyl}--
oxamic acid, MS found: 467.
EXAMPLE 7-4
[0583]
N-[3,5-Dichloro-4-(4-hydroxy-3-phenoxy-phenoxy)-phenyl]-oxamic
acid, MS found: 432.
EXAMPLE 7-5
[0584]
N-{3,5-Dichloro-4-[3-(4-fluoro-phenoxy)-4-hydroxy-phenoxy]-phenyl}--
oxamic acid ethyl ester, MS found: 478.
EXAMPLE 7-6
[0585]
N-{3,5-Dichloro-4-[3-(4-fluoro-phenoxy)-4-hydroxy-phenoxy]-phenyl}--
oxamic acid, MS found: 450.
EXAMPLE 7-7
[0586]
N-{4-[3-(4-Fluoro-phenoxy)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}--
oxamic acid, MS found: 410.
EXAMPLE 7-8
[0587]
N-[4-(4-Hydroxy-3-phenoxy-phenoxy)-3,5-dimethyl-phenyl]-oxamic
acid, MS found: 392.
EXAMPLE 7-9
[0588]
N-{4-[3-(4-Chloro-phenoxy)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}--
oxamic acid, MS found: 426.
EXAMPLE 8
2,2-Dimethyl-7-hydroxy-4-methoxyindane
Step A
[0589] To a cooled (0.degree. C.), stirred solution of
4,7-dimethoxyindan-1-one (1 g) in THF (20 mL) was added lithium
hexamethyldisilizane (6.2 mL of a 1M solution in THF). After 45
min, methyl iodide (0.4 mL) was added and the resulting mixture was
allowed to stir at RT for 3 h.
Step B
[0590] After stirring at RT, following the addition of the first
equivalent of methyl iodide, the reaction mixture was recooled to
0.degree. C. and an additional portion of lithium
hexamethyldisilizane (6.2 mL) was added. After 45 min, methyl
iodide (0.4 mL) was added and the resulting mixture was allowed to
stir at RT for 3 h. The reaction was quenched with saturated
aqueous ammonium chloride, extracted with ethyl acetate, the
organic layer dried over sodium sulfate and concentrated to a dark
oil. Flash chromatography (hexanes:chloroform) afforded
2,2-dimethyl-4,7-dimethoxyindan-1-one (1.0 g) as a brown oil.
Step C
[0591] To a cooled (-78.degree. C.), stirred solution of
2,2-dimethyl-4,7-dimethoxy-indan-1-one (1 g) in dichloromethane (20
mL) was added boron trichloride (9 mL of a 1M solution in
dichloromethane) over a 5 min period. The reaction was allowed to
warm to RT, stirred for 3 h, then recooled to -78.degree. C.,
quenched with ice, allowed to warm to RT and stirred for 1 h. The
reaction was extracted with dichloromethane, the organic layers
dried over sodium sulfate, concentrated in vacuo and flash
chromatographed to afford
2,2-dimethyl-7-hydroxy-4-methoxyindan-1-one (0.85 g) as a tan
oil.
Step D
[0592] To a stirred solution of
2,2-dimethyl-7-hydroxy-4-methoxyindan-1-on- e (500 mg) and
methanesulfonic acid (466 mg) in dichloromethane (12 mL) was added
triethylsilane (564 mg). Every 0.5 h, over a 3 h period, additional
portions of methanesulfonic acid and triethylsilane were added. The
reaction was partitioned between water and dichloromethane, the
organic layer dried over sodium sulfate, concentrated in vacuo and
the resulting oil flash chromatographed (1:1, chloroform:hexanes)
to afford 2,2-dimethyl-7-hydroxy-4-methoxyindane (230 mg) as a
colorless waxy solid.
[0593] Using the appropriate starting materials, EXAMPLES 8-1 to
8-8 were prepared using methods analogous to those described in
EXAMPLE 8 and by SCHEMES K and L.
EXAMPLE 8-1
[0594]
N-[3-Chloro-4-(7-hydroxy-2,2-dimethyl-indan-4-yloxy)-5-methyl-pheny-
l]-oxamic acid, melting point found: 226-229.degree. C. (dec).
EXAMPLE 8-2
[0595] N-[4-(7-Hydroxy-indan-4-yloxy)-3,5-dimethyl-phenyl]-oxamic
acid, MS Found: 340.
EXAMPLE 8-3
[0596]
N-[3-Chloro-4-(7-hydroxy-indan-4-yloxy)-5-methyl-phenyl]-oxamic
acid, MS Found: 360.
EXAMPLE 8-4
[0597] N-[4-(7-Hydroxy-indan-4-yloxy)-3,5-dimethyl-phenyl]-oxamic
acid ethyl ester, MS Found: 368.
EXAMPLE 8-5
[0598] N-[4-(7-Hydroxy-indan-4-yloxy)-3,5-dimethyl-phenyl]-oxamide,
MS Found: 339.
EXAMPLE 8-6
[0599]
N-[3-Chloro-4-(7-hydroxy-indan-4-yloxy)-5-methyl-phenyl]-oxamide,
MS Found: 360.
EXAMPLE 8-7
[0600]
N-[3-Chloro-4-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-5-m-
ethyl-phenyl]-oxamic acid, MS Found: 374.
EXAMPLE 8-8
[0601]
N-[3-Chloro-4-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-5-m-
ethyl-phenyl]-oxamide, MS Found: 373.
EXAMPLE 9
N-{3-Chloro-4-[3-(4-fluoro-phenoxymethyl)-4-hydroxy-phenoxy]-5-methyl-phen-
yl}-oxamic acid ethyl ester
Step A
[0602] To a cooled (-78.degree. C.), stirred solution of
5-(2-chloro-6-methyl-4-nitro-phenoxy)-2-methoxy-benzaldehyde (10 g)
in dichloromethane (300 mL) was added boron tribromide (23.3 g)
dropwise. The reaction was allowed to warm to ambient temperature,
stirred for 1.5 h, ice was added to quench the reaction and work up
was done with ethyl acetate/water. The organic layer was dried over
sodium sulfate, concentrated in vacuo and the resulting oil
filtered through a plug of silica gel (eluting with chloroform) to
afford 5-(2-chloro-6-methyl-4-nit-
ro-phenoxy)-2-hydroxy-benzaldehyde (8.65 g) as an off-white
solid.
Step B
[0603] To a cooled (0.degree. C.), stirred solution of
5-(2-chloro-6-methyl-4-nitro-phenoxy)-2-hydroxy-benzaldehyde (8.6
g) in DMF (130 mL) was added sodium hydride (1.3 g of 60% in oil),
the cooling bath was removed after 5 min and the thick mixture
allowed to stir at RT for 45 min. Trimethylsiloxyethoxymethyl
chloride (5.59 g) was added and stirring was continued for 16 h.
The reaction was quenched with half-saturated ammonium chloride,
extracted with ethyl acetate, the combined organic layers dried
over sodium sulfate and concentrated in vacuo to afford a brown
oil. Flash chromatography (10-20% ethyl acetate:hexanes) afforded
5-(2-chloro-6-methyl-4-nitro-phenoxy)-2-(2-trim-
ethylsilanyl-ethoxymethoxy)-benzaldehyde (12.1 g) as an off-white
solid.
Step C
[0604] To a cooled (-78.degree. C.), stirred solution of
5-(2-chloro-6-methyl-4-nitro-phenoxy)-2-(2-trimethylsilanyl-ethoxymethoxy-
)-benzaldehyde (10 g) in THF (200 mL) was added diisobutylaluminum
hydride (46 mL of a 1M solution in THF). After 30 min, 0.5M sodium
potassium tartrate (100 mL) was added and the resulting mixture was
allowed to warm to RT. Extraction with ethyl acetate, drying over
sodium sulfate and concentration in vacuo afforded
[5-(2-chloro-6-methyl-4-nitro-phenoxy)-2--
(2-trimethylsilanyl-ethoxymethoxy)-phenyl ]-MeOH (10.6 g), which
was taken on to Step D without further purification.
Step D
[0605] To a solution of
[5-(2-chloro-6-methyl-4-nitro-phenoxy)-2-(2-trimet-
hylsilanyl-ethoxymethoxy)-phenyl]-MeOH (250 mg),
triphenyl-phosphine (300 mg) and p-fluorophenol (95 mg) was added
1,1'-(azodicarbonyl)dipiperdine (214 mg). After 18 h, hexanes were
added, solids filtered, washed with further portions of hexanes and
the filtrate was concentrated in vacuo. Residue was flash
chromatographed (hexanes-2% ethyl acetate/hexanes) to afford
{2-[4-(2-chloro-6-methyl-4-nitro-phenoxy)-2-(4-fluoro-phenoxymethy-
l)-phenoxymethoxy]-ethyl}-trimethylsilane (300 mg) as an oil.
Step E
[0606] To a stirred solution of
{2-[4-(2-chloro-6-methyl-4-nitro-phenoxy)--
2-(4-fluoro-phenoxymethyl)-phenoxymethoxy]-ethyl}-trimethylsilane
(280 mg) in MeOH (2.5 mL)/THF (0.2 mL) was added 6% sulfuric acid
in MeOH (2.5 mL) and the resulting solution was stirred for 1 h.
The reaction was quenched with 1 N aqueous sodium bicarbonate,
extracted with ethyl acetate, the organic layer dried over sodium
sulfate and concentrated in vacuo. Flash chromatography (15% ethyl
acetate/hexanes) afforded
4-(2-chloro-6-methyl-4-nitro-phenoxy)-2-(4-fluorophen-oxymethyl)-phenol
(170 mg) as a yellow semi-solid.
Step F
[0607] To a warm (100.degree. C.) solution of
4-(2-chloro-6-methyl-4-nitro-
-phenoxy)-2-(4-fluorophenoxymethyl)-phenol (100 mg) in glacial
acetic acid (2.5 mL) was added zinc dust (243 mg) and heating was
continued for 30 min. The reaction mixture was cooled, diluted with
ethyl acetate and filtered through Celite.RTM.. The filtrate was
washed with 1M aqueous sodium bicarbonate, dried over sodium
sulfate, concentrated in vacuo and flashed chromatographed (30%
ethyl acetate/hexanes) to afford
4-(4-amino-2-chloro-6-methyl-phenoxy)-2-(4-fluoro-phenoxymethyl)-phenol
(90 mg) as a tan solid.
Step G
[0608] A solution of
4-(4-amino-2-chloro-6-methyl-phenoxy)-2-(4-fluoro-phe-
noxy-methyl)-phenol (90 mg) in diethyloxylate (1 mL) was heated at
125.degree. C. for 18 h. The resulting solution was flash
chromatographed (30% ethyl acetate/hexanes) to afford
N-{3-chloro-4-[3-(4-fluoro-phenoxym-
ethyl)-4-hydroxy-phenoxy]-5-methyl-phenyl}-oxamic acid ethyl ester
(70 mg).
[0609] Using the appropriate starting materials, EXAMPLE 9-1 was
prepared in an analogous manner to that described in EXAMPLE 9.
EXAMPLE 9-1
[0610]
N-[3-Chloro-4-(4-hydroxy-3-phenoxymethyl-phenoxy)-5-methyl-phenyl]--
oxamic acid ethyl ester, MS Found: 454.
EXAMPLE 10
N-[3,5-Dichloro-4-(1H-indol-5-yloxy)-phenyl]-oxamic acid ethyl
ester
Step A
[0611] Potassium carbonate (0.71 g, 5.12 mmol) was added to a
solution of 5-hydroxyindole (0.62 g, 4.66 mmol) and
3,5-dichloro-4-iodonitrobenzene (1.48 g, 4.66 mmol) in
N-methylpyrrolidone (10 mL). The resulting mixture was stirred at
125.degree. C. for 3 h and cooled to RT. The mixture was poured
into 1N HCl (100 mL) and extracted with CH.sub.2Cl.sub.2
(3.times.25 mL). The combined organic extracts were washed with 1N
HCl (2.times.50 mL), H.sub.2O (3.times.100 mL), brine (1.times.100
mL), and then dried and concentrated. The residue was purified by
preparative TLC (35% CH.sub.2Cl.sub.2 in hexanes) to give a yellow
solid. MS Calc.: 322 Found: 321.2. (M-1).
Step B
[0612] The title compound of EXAMPLE 10 was prepared from the
product of Step A via hydrogenation and oxamate formation. MS
Calc.: 392.0 Found: 391.2. (M-1).
[0613] Using the appropriate starting materials, EXAMPLES 10-1 to
10-7 were prepared in an analogous manner to that described in
EXAMPLE 10.
EXAMPLE 10-1
[0614] N-[3,5-Dichloro-4-(1H-indol-5-yloxy)-phenyl]-oxamic acid
ethyl ester, MS Calc.: 392.0 Found: 391.2. (M-1).
EXAMPLE 10-2
[0615] N-[3,5-Dichloro-4-(1H-indol-5-yloxy)-phenyl]-oxamic acid, MS
Calc.: 364.0 Found: 363.1 (M-1).
EXAMPLE 10-3
[0616] N-[3,5-Dichloro-4-(1H-indol-5-yloxy)-phenyl]-oxamide, MS
Calc.: 372.1 Found: 371.2 (M-1).
EXAMPLE 10-4
[0617] N-[3-Chloro-4-(1H-indol-5-yloxy)-5-methyl-phenyl]-oxamic
acid, MS Calc.: 344.1 Found: 343.2 (M-1).
EXAMPLE 10-5
[0618] N-[3-Chloro-4-(1H-indol-5-yloxy)-5-methyl-phenyl]-oxamide,
MS Calc.: 343.1 Found: 342.2 (M-1).
EXAMPLE 10-6
[0619] N-[3,5-Dichloro-4-(2-methyl-1H-indol-5-yloxy)-phenyl]-oxamic
acid ethyl ester, MS Calc.: 406.0 Found: 405.2 (M-1).
EXAMPLE 10-7
[0620] N-[3,5-Dichloro-4-(2-methyl-1H-indol-5-yloxy)-phenyl]-oxamic
acid, MS Calc.: 378.0 Found: 377.1 (M-1).
EXAMPLE 11
N-[3,5-Dichloro-4-(4-fluoro-3-methyl-phenoxy)-phenyl]-oxamic
acid
Step A
[0621] A mixture of 3-methyl-4-fluorophenol (99 mg, 0.79 mmol),
potassium hydroxide (53 mg, 0.94 mmol),
4-iodo-3,5-dichloro-nitrobenzene (250 mg, 0.79 mmol) and 4A.degree.
molecular sieves (75 mg) in N-methylpyrolidinone (3 mL) was stirred
at 130.degree. C. for 2 h. The reaction mixture was poured into ice
cold 1 N HCl (20 mL) and EtOAc (25 mL) was added. The EtOAc phase
was separated and washed with 1N HCl (3.times.25 mL) and brine (25
mL). The EtOAc solution was dried over Na.sub.2SO.sub.4, filtered
and concentrated. The residue was purified by preparative TLC
(Hexanes: CH.sub.2Cl.sub.2=7:3) to afford
3,5-dichloro-4-(4-fluoro-3-methyl-phenoxy)-nitrobenzene (207 mg).
MS Calc.: 315.0 Found: 315.0 (M).
Step B
[0622] N-[3,5-Dichloro-4-(4-fluoro-3-methyl-phenoxy)-phenyl]-oxamic
acid ethyl ester was prepared from
3,5-dichloro-4-(4-fluoro-3-methyl-phenoxy)-- nitrobenzene via
hydrogenation and acylation. MS Calc.: 385.0 Found: 384.0
(M-1).
Step C
[0623] N-[3,5-Dichloro-4-(4-fluoro-3-methyl-phenoxy)-phenyl]-oxamic
acid was prepared from
N-[3,5-dichloro-4-(4-fluoro-3-methyl-phenoxy)-phenyl]-o- xamic acid
ethyl ester via hydrolysis. MS Calc.: 357.0 Found: 356.2 (M-1).
[0624] Using the appropriate starting materials, EXAMPLES 11-1 to
11-13 were prepared in an analogous manner to that described in
EXAMPLE 11.
EXAMPLE 11-1
[0625] N-[4-(4-Fluoro-phenoxy)-3,5-dimethyl-phenyl]-oxamic acid, MS
Calc.: 303.1 Found: 302.2 (M-1).
EXAMPLE 11-2
[0626] N-[3,5-Dichloro-4-(4-fluoro-phenoxy)-phenyl]-oxamic acid
ethyl ester, MS Calc.: 371.0 Found: 369.9 (M-1).
EXAMPLE 11-3
[0627] N-[3,5-Dichloro-4-(3,4-difluoro-phenoxy)-phenyl]-oxamic acid
ethyl ester, MS Calc.: 389.0 Found: 387.9 (M-1).
EXAMPLE 11-4
[0628] N-[3,5-Dichloro-4-(3-chloro-4-fluoro-phenoxy)-phenyl]-oxamic
acid ethyl ester, MS Calc.: 405.0 Found: 403.9 (M-1).
EXAMPLE 11-5
[0629] N-[4-(3,4-Difluoro-phenoxy)-3,5-dimethyl-phenyl]-oxamic
acid, MS Calc.: 321.1 Found: 320.1 (M-1).
EXAMPLE 11-6
[0630] N-[4-(3-Chloro-4-fluoro-phenoxy)-3,5-dimethyl-phenyl]-oxamic
acid, MS Calc.: 337.1 Found: 335.9 (M-1).
EXAMPLE 11-7
[0631] N-[4-(4-Fluoro-3-methyl-phenoxy)-3,5-dimethyl-phenyl]-oxamic
acid, MS Calc.: 317.1 Found: 316.1 (M-1).
EXAMPLE 11-8
[0632] N-[3,5-Dichloro-4-(4-fluoro-phenoxy)-phenyl]-oxamic acid, MS
Calc.: 343.0 Found: 342.1 (M-1).
EXAMPLE11-9
[0633] N-[3,5-Dichloro-4-(3,4-difluoro-phenoxy)-phenyl]-oxamic
acid, MS Calc.: 361.0 Found: 360.1 (M-1).
EXAMPLE 11-10
[0634]
N-[3,5-Dichloro-4-(3-chloro-4-fluoro-phenoxy)-phenyl]-oxalamic
acid, MS Calc.: 376.9 Found: 376.1 (M-1).
EXAMPLE 11-11
[0635]
N-{4-[3-(Cyclobutyl-methyl-carbamoyl)-4-fluoro-phenoxy]-3,5-dimethy-
l-phenyl}-oxalamic acid ethyl ester, MS Calc.: 442.2 Found: 441.1
(M-1).
EXAMPLE 11-12
[0636]
N-{4-[3-(Cyclobutyl-methyl-carbamoyl)-4-fluoro-phenoxy]-3,5-dimethy-
l-phenyl}-oxalamic acid, MS Calc.: 414.2 Found: 413.3 (M-1).
EXAMPLE 11-13
[0637] N-[4-(4-Fluoro-phenoxy)-3,5-dimethyl-phenyl]-oxalamic acid
ethyl ester, MS Calc.: 331.1 Found: 330.2 (M-1).
* * * * *