U.S. patent application number 12/247434 was filed with the patent office on 2009-07-02 for novel pyrazole-based hmg coa reductase inhibitors.
This patent application is currently assigned to Pfizer Inc.. Invention is credited to Daniel Merritt Bowles, Chulho Choi, Richard H. Hutchings, William K.C. Park, Jeffrey A. Pfefferkorn.
Application Number | 20090170852 12/247434 |
Document ID | / |
Family ID | 35708411 |
Filed Date | 2009-07-02 |
United States Patent
Application |
20090170852 |
Kind Code |
A1 |
Choi; Chulho ; et
al. |
July 2, 2009 |
NOVEL PYRAZOLE-BASED HMG CoA REDUCTASE INHIBITORS
Abstract
Novel compounds and pharmaceutical compositions useful as
hypocholesterolemic and hypolipidemic agents are described. More
specifically, potent inhibitors of the enzyme
3-hydroxy-3-methylglutaryl-coenzyme A reductase ("HMG CoA
reductase") are described. Methods of using such compounds and
compositions to treat subjects, including humans, suffering from
hyperlipidemia, hypercholesterolemia, hypertriglyceridemia,
atherosclerosis, Alzheimer's Disease, benign prostatic hypertrophy
(BPH), diabetes and osteoporosis are also described.
Inventors: |
Choi; Chulho; (Dexter,
MI) ; Bowles; Daniel Merritt; (Howell, MI) ;
Hutchings; Richard H.; (Ann Arbor, MI) ; Park;
William K.C.; (Ann Arbor, MI) ; Pfefferkorn; Jeffrey
A.; (Dexter, MI) |
Correspondence
Address: |
PFIZER INC.
PATENT DEPARTMENT, MS8260-1611, EASTERN POINT ROAD
GROTON
CT
06340
US
|
Assignee: |
Pfizer Inc.
|
Family ID: |
35708411 |
Appl. No.: |
12/247434 |
Filed: |
October 8, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11283264 |
Nov 18, 2005 |
7446121 |
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12247434 |
|
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60630481 |
Nov 23, 2004 |
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Current U.S.
Class: |
514/236.5 ;
514/406; 544/140; 548/365.7; 548/374.1 |
Current CPC
Class: |
C07D 401/06 20130101;
A61P 25/28 20180101; A61P 9/00 20180101; A61P 13/08 20180101; C07D
231/12 20130101; A61P 3/06 20180101; A61P 9/10 20180101; A61P 43/00
20180101; A61P 3/10 20180101; A61P 35/00 20180101; C07D 401/12
20130101; C07D 231/14 20130101; C07D 405/06 20130101; A61P 19/10
20180101 |
Class at
Publication: |
514/236.5 ;
548/374.1; 514/406; 544/140; 548/365.7 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 231/14 20060101 C07D231/14; C07D 413/06 20060101
C07D413/06; C07D 405/06 20060101 C07D405/06; A61K 31/415 20060101
A61K031/415 |
Claims
1. A compound of the formula (I): ##STR00176## or a
pharmaceutically acceptable salt thereof, wherein: R.sub.1 is
hydrogen, halogen, C.sub.1-C.sub.7alkyl, C.sub.3-C.sub.8cycloalkyl,
aryl, aralkyl, heteroaryl, or heteroaralkyl; where alkyl,
cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R.sub.1
is optionally substituted; R.sub.2 is
R.sub.2bR.sub.2aNCO(CH.sub.2).sub.n-- or
R.sub.2b-J-C(O)NR.sub.2a(CH.sub.2).sub.n--; J is a direct bond, O,
or N; R.sub.2a and R.sub.2b are each independently hydrogen,
C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.8 cycloalkyl, aryl, aralkyl,
heteroaryl or heteroaralkyl; where alkyl, cycloalkyl, aryl,
aralkyl, heteroaryl, or heteroaralkyl of R.sub.2a and R.sub.2b is
optionally substituted; or R.sub.2a and R.sub.2b taken together
with the nitrogen to which they are attached form a 4-11 member
ring optionally containing at least one additional heteroatom
selected from O, N and S, said ring being optionally substituted
with at least one of aryl, aralkyl, heteroaryl, heteroaralkyl,
C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 haloalkyl, C.sub.3-C.sub.8
cycloalkyl, halogen, R.sup.7O--, R.sup.7OOC(CH.sub.2).sub.n--,
R.sup.7R.sup.8NCO(CH.sub.2).sub.n--,
R.sup.7O.sub.2S(CH.sub.2).sub.n--, R.sup.8R.sup.7NSO.sub.2-- or
NC--; R.sup.7 and R.sup.8 are each independently hydrogen,
C.sub.1-C.sub.12 alkyl, aryl or aralkyl; where alkyl, aryl or
aralkyl of R.sup.7 and R.sup.8 is optionally substituted; n is 0, 1
or 2; R.sub.3 is hydrogen, C.sub.1-6 alkyl, C.sub.3-8cycloalkyl,
aryl, aralkyl, heteroaryl, or heteroaralkyl; where alkyl,
cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R.sub.3
is optionally substituted; and --- is a bond or is absent.
2. A compound according to claim 1 having the following (3R,5R)
stereospecific formula (Ia): ##STR00177##
3. A compound according to claim 1 having the structural formula
(II): ##STR00178## or a pharmaceutically acceptable salt thereof,
wherein: R.sub.2a and R.sub.2b are each independently hydrogen,
C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.8 cycloalkyl, aryl, aralkyl,
heteroaryl or heteroaralkyl; where alkyl, cycloalkyl, aryl,
aralkyl, heteroaryl, or heteroaralkyl of R.sub.2a and R.sub.2b is
optionally substituted; or R.sub.2a and R.sub.2b taken together
with the nitrogen to which they are attached form a 4-11 member
ring optionally containing at least one additional heteroatom
selected from O, N and S, said ring being optionally substituted
with at least one of aryl, aralkyl, heteroaryl, heteroaralkyl,
C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.8 cycloalkyl, halogen,
R.sup.7O--, R.sup.7OOC(CH.sub.2).sub.n--,
R.sup.7R.sup.8NCO(CH.sub.2).sub.n--,
R.sup.7O.sub.2S(CH.sub.2).sub.n--, R.sup.8R.sup.7NSO.sub.2-- or
NC--; R.sup.7 and R.sup.8 are each independently hydrogen,
C.sub.1-C.sub.12 alkyl, aryl or aralkyl; where alkyl, aryl or
aralkyl of R.sup.7 and R.sup.8 is optionally substituted; n is 0,
1, or 2; and --- is a bond or is absent.
4. A compound according to claim 3, wherein R.sub.2a is:
##STR00179## Where R.sub.4 and R.sub.5 are each independently
hydrogen or lower alkyl; q is 0, 1 or 2; each R.sub.6 is
independently hydrogen, halogen, alkyl, haloalkyl, alkoxy, or
cyano; and p is 0, 1, 2, 3, 4, or 5.
5. A compound according to claim 4 having the following (3R,5R)
stereospecific formula (IIa): ##STR00180##
6. A compound according to claim 1 having the structure of formula
(III): ##STR00181## or a pharmaceutically acceptable salt
thereof.
7. A compound according to claim 6 having the following (3R,5R)
stereospecific formula (IIIa): ##STR00182##
8. A compound of formula (IV): ##STR00183## or a pharmaceutically
acceptable salt thereof, wherein: R.sub.1 is hydrogen, halogen,
C.sub.1-C.sub.7alkyl, C.sub.3-C.sub.8cycloalkyl, aryl, aralkyl,
heteroaryl, or heteroaralkyl; where alkyl, cycloalkyl, aryl,
aralkyl, heteroaryl, or heteroaralkyl of R.sub.1 is optionally
substituted; R.sub.2 is R.sub.2bR.sub.2aN(CH.sub.2).sub.n-- or
R.sub.2b-J-C(O)NR.sub.2a(CH.sub.2).sub.n--; J is a direct bond, O,
or N; R.sub.2a and R.sub.2b are each independently hydrogen,
C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.8 cycloalkyl, aryl, aralkyl,
heteroaryl or heteroaralkyl; where alkyl, cycloalkyl, aryl,
aralkyl, heteroaryl, or heteroaralkyl of R.sub.2a and R.sub.2b is
optionally substituted; or R.sub.2a and R.sub.2b taken together
with the nitrogen to which they are attached form a 4-11 member
ring optionally containing at least one additional heteroatom
selected from O, N and S, said ring being optionally substituted
with at least one of aryl, aralkyl, heteroaryl, heteroaralkyl,
C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.8 cycloalkyl, halogen,
R.sup.7O--, R.sup.7OOC(CH.sub.2).sub.n--,
R.sup.7R.sup.8NCO(CH.sub.2).sub.n--,
R.sup.7O.sub.2S(CH.sub.2).sub.n--, R.sup.8R.sup.7NSO.sub.2-- or
NC--; R.sup.7 and R.sup.8 are each independently hydrogen,
C.sub.1-C.sub.12 alkyl, aryl or aralkyl; where alkyl, aryl or
aralkyl of R.sup.7 and R.sup.8 is optionally substituted; n is 0, 1
or 2; R.sub.3 is hydrogen, C.sub.1-6 alkyl, C.sub.3-8cycloalkyl,
aryl, aralkyl, heteroaryl, or heteroaralkyl; where alkyl,
cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R.sub.3
is optionally substituted; and --- is a bond or is absent.
9. A compound according to claim 8 having the following
stereospecific formula (IVa): ##STR00184##
10. A compound of formula (V): ##STR00185## or a pharmaceutically
acceptable salt thereof, wherein: R.sub.1 is hydrogen, halogen,
C.sub.1-C.sub.7alkyl, C.sub.3-C.sub.8cycloalkyl, aryl, aralkyl,
heteroaryl, or heteroaralkyl; where alkyl, cycloalkyl, aryl,
aralkyl, heteroaryl, or heteroaralkyl of R.sub.1 is optionally
substituted; R.sub.2 is R.sub.2bR.sub.2aNCO(CH.sub.2).sub.n-- or
R.sub.2b-J-C(O)NR.sub.2a(CH.sub.2).sub.n--; J is a direct bond, O,
or N; R.sub.2a and R.sub.2b are each independently hydrogen,
C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.8 cycloalkyl, aryl, aralkyl,
heteroaryl or heteroaralkyl; where alkyl, cycloalkyl, aryl,
aralkyl, heteroaryl, or heteroaralkyl of R.sub.2a and R.sub.2b is
optionally substituted; or R.sub.2a and R.sub.2b taken together
with the nitrogen to which they are attached form a 4-11 member
ring optionally containing at least one additional heteroatom
selected from O, N and S, said ring being optionally substituted
with at least one of aryl, aralkyl, heteroaryl, heteroaralkyl,
C.sub.1-C.sub.10 alkyl, C.sub.3-C.sub.8 cycloalkyl, halogen,
R.sup.7O--, R.sup.7OOC(CH.sub.2).sub.n--,
R.sup.7R.sup.8NCO(CH.sub.2).sub.n--,
R.sup.7O.sub.2S(CH.sub.2).sub.n--, R.sup.8R.sup.7NSO.sub.2-- or
NC--; R.sup.7 and R.sup.8 are each independently hydrogen,
C.sub.1-C.sub.12 alkyl, aryl or aralkyl; where alkyl, aryl or
aralkyl of R.sup.7 and R.sup.8 is optionally substituted; n is 0, 1
or 2; R.sub.3 is hydrogen, C.sub.1-6 alkyl, C.sub.3-8cycloalkyl,
aryl, aralkyl, heteroaryl, or heteroaralkyl; where alkyl,
cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R.sub.3
is optionally substituted; and --- is a bond or is absent.
11. A compound according to claim 1 selected from the group
consisting of:
(3R,5R)-7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyraz-
ol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-methyl-benzylcarbamoyl)-2-
H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-benzylcarbamoyl)-2-
H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-methyl-benzylcarbamoyl)-2-
H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2-
H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxy-benzylcarbamoyl)--
2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxy-benzylcarbamoyl)--
2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxy-benzylcarbamoyl)--
2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxy-benzylcarbamoyl)--
2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-[5-(benzyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-
-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-[(3-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-i-
sopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-[(4-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-i-
sopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-(R)-.alpha.-methyl-
-benzylcarbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(R)-.alpha.-methyl-benzylca-
rbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(S)-.alpha.-methyl-benzylca-
rbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-(benzyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-
-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(R)-.alpha.-methyl-benzylca-
rbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(S)-.alpha.-methyl-benzylca-
rbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenethylcarbamoyl-2H-pyrazo-
l-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-methylcarbamoyl-2H-pyrazol-3-
-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-ethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3--
yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-dimethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-
-3-yl]-3,5-dihydroxy-heptanoic acid;
7-(5-Benzylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,-
5R-dihydroxy-heptanoic acid;
7-(5-Benzylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,-
5R-dihydroxy-heptanoic acid;
3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methyl-benzylcarbamoyl)-2-(4-fluoro-p-
henyl)-2H-pyrazol-3-yl]-heptanoic acid;
3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2-(4-fluoro-p-
henyl)-2H-pyrazol-3-yl]-heptanoic acid;
3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2-(4-fluoro--
phenyl)-2H-pyrazol-3-yl]-heptanoic acid;
3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2-(4-fluoro--
phenyl)-2H-pyrazol-3-yl]-heptanoic acid;
7-{5-(Benzyl-methyl-carbamoyl)-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-
-3-yl}-3R,5R-dihydroxy-heptanoic acid;
7-{5-[(3-Fluoro-benzyl)-methyl-carbamoyl]-4-isopropyl-2-(4-fluoro-phenyl)-
-2H-pyrazol-3-yl}-3R,5R-dihydroxy-heptanoic acid;
7-{5-[(4-Fluoro-benzyl)-methyl-carbamoyl]-4-isopropyl-2-(4-fluoro-phenyl)-
-2H-pyrazol-3-yl}-3R,5R-dihydroxy-heptanoic acid;
3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(R)-.alpha.-methyl--
benzylcarbamoyl]-2H-pyrazol-3-yl]-heptanoic acid;
3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(S)-.alpha.-methyl--
benzylcarbamoyl]-2H-pyrazol-3-yl]-heptanoic acid;
3R,5R-Dihydroxy-7-{4-isopropyl-5-[N-methyl-(R)-.alpha.-methyl-benzylcarba-
moyl]-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-heptanoic acid;
3R,5R-Dihydroxy-7-{4-isopropyl-5-[N-methyl-(R)-.alpha.-methyl-benzylcarba-
moyl]-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-heptanoic acid;
3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2-(4-fluoro-p-
henyl)-2H-pyrazol-3-yl]-hept-6-enoic acid;
3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2-(4-fluoro--
phenyl)-2H-pyrazol-3-yl]-hept-6-enoic acid;
3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2-(4-fluoro--
phenyl)-2H-pyrazol-3-yl]-hept-6-enoic acid;
3R,5R-Dihydroxy-7-(4-isopropyl-5-methylcarbamoyl-2-(4-fluoro-phenyl)-2H-p-
yrazol-3-yl)-heptanoic acid;
7-(5-Ethylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,5-
R-dihydroxy-heptanoic acid;
7-(5-Dimethylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3-
R,5R-dihydroxy-heptanoic acid;
7-[5-(Benzyl-methyl-carbamoyl)-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-
-3-yl]-3R,5R-dihydroxy-hept-6-enoic acid;
3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(R)-.alpha.-methyl--
benzylcarbamoyl]-2H-pyrazol-3-yl]-hept-6-enoic acid;
3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(S)-.alpha.-methyl--
benzylcarbamoyl]-2H-pyrazol-3-yl]-hept-6-enoic acid;
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-methyl-benzyl)-ca-
rbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenylcarbamoyl-2H-pyrazol-3-
-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2-
H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-(4-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2-
H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(1-methyl-1-phenyl-ethylcarb-
amoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxymethyl-benzylcarba-
moyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(4-methoxy-benzyl)-methyl-c-
arbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-methyl-benzyl)-ca-
rbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(3-methoxy-benzyl)-methyl-c-
arbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-(benzyl-ethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H--
pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-(benzyl-isopropyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-
-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(1-phenyl-ethyl)-car-
bamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-(cyclohexylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-
-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(1-p-tolyl-ethylcarbamoyl)-2-
H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxymethyl-benzylcarba-
moyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[1-(3-methoxy-phenyl)-ethylc-
arbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[1-(4-methoxy-phenyl)-ethylc-
arbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethyl-b-
enzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-trifluoromethyl-b-
enzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-propylcarbamoyl-2H-pyrazol-3-
-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-(4-dimethylcarbamoyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4--
isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(pyridin-2-ylmethyl)-carbam-
oyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-5-(2-hydroxy-1-phenyl-ethylcarbamoyl)-4-is-
opropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(morpholine-4-carbonyl)-2H-p-
yrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-isopropylcarbamoyl-2H-pyrazo-
l-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-(cyclohexylmethyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-is-
opropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-(cyclopentylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropy-
l-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-5-isobutylcarbamoyl-4-isopropyl-2H-pyrazol-
-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-butylcarbamoyl)-2H-
-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-cyclopentylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyra-
zol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-phenyl-pyrrolidine-1-carb-
onyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-(cyclobutylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-
-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-[(2,3-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-
-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-(cyclopropylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropy-
l-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-[(2,4-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-
-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-trifluoromethoxy--
benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-butylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3--
yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(piperidine-1-carbonyl)-2H-p-
yrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethoxy--
benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-cyclohexylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyraz-
ol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-(4-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-
-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-(3-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-
-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-(cyclopentylmethyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-i-
sopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-ca-
rbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-[(2-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-i-
sopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-[(3,4-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-
-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-(3-ethoxymethyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopr-
opyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-(4-ethyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-
-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(5-trifluoromethyl-pyridin--
2-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic
acid;
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-trifluoromethyl-pyridin--
3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic
acid;
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-trifluoromethyl-piperidi-
n-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic
acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-isopropyl-benzylcarbamoyl-
)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-phenyl-piperidine-1-carbo-
nyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-phenyl-piperidine-1-carbo-
nyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-methyl-pyridin-3-ylmethy-
l)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[5-ethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3--
yl]-3,5-dihydroxy-heptanoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenylcarbamoyl-2H-pyrazol-3-
-yl]-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-[5-(cyclohexylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-
-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-propylcarbamoyl-2H-pyrazol-3-
-yl]-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-isopropylcarbamoyl-2H-pyrazo-
l-3-yl]-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-5-isobutylcarbamoyl-4-isopropyl-2H-pyrazol-
-3-yl]-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-[5-cyclopentylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyra-
zol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-butylcarbamoyl)-2H-
-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-[5-(cyclopropylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropy-
l-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-[5-butylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3--
yl]-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethoxy--
benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoic
acid;
(3R,5R)-7-[5-cyclohexylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyraz-
ol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-[5-(4-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-
-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-[5-(3-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-
-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-methylcarbamoyl-2H-pyrazol-3-
-yl]-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-ca-
rbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoic acid;
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-methyl-pyridin-3-ylmethy-
l)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoic acid;
7-[5-[(2,6-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopr-
opyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
7-[5-[(4-fluoro-2-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-
-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,4-trifluoro-benzyl)-car-
bamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
7-[5-[(3-fluoro-4-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-
-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,6-trifluoro-benzyl)-car-
bamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
7-[5-[(2,3-difluoro-4-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl-
)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
7-[5-[(2,3-difluoro-6-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-pheny-
l)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
7-[5-[(3-fluoro-4-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4--
isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
7-[5-[(4-fluoro-3-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4--
isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
7-[5-[(2,3-difluoro-4-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-pheny-
l)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
7-[5-[(2-fluoro-3-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4--
isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,5-trifluoro-benzyl)-car-
bamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
7-[5-[(3-fluoro-2-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-
-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
7-[5-[(2-fluoro-3-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-
-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
7-[5-[(3-fluoro-2-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4--
isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; and
(3R,5R)-7-[2-(4-Fluoro-phenyl)-4-isopropyl-5-(2-phenyl-piperidine-1-carbo-
nyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; or a
pharmaceutically acceptable salt thereof.
12. A compound of claim 11, wherein said pharmaceutically
acceptable salt is a sodium salt.
13. A compound according to claim 8 selected from the group
consisting of:
1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethy-
l]-4-isopropyl-1H-pyrazole-3-carboxylic acid
(3-fluoro-benzyl)-methyl-amide;
1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4-
-isopropyl-1H-pyrazole-3-carboxylic acid benzyl-methyl-amide; and
1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4-
-isopropyl-1H-pyrazole-3-carboxylic acid 4-methyl-benzylamide; or a
pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a compound of claim 1,
or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier, diluent, solvent or
vehicle.
15. A method of treating a subject suffering from hyperlipidemia,
hypercholesterolemia, hypertriglyceridemia, atherosclerosis,
Alzheimer's Disease, benign prostatic hypertrophy (BPH), diabetes
and osteoporosis comprising administering a therapeutically
effective amount of at least one compound of claim 1, or a
pharmaceutically acceptable salt thereof.
16. A combination comprising a compound of claim 1, or a
pharmaceutically acceptable salt thereof, and a second
pharmaceutically active agent.
17. The combination of claim 16, wherein said second
pharmaceutically active agent is a CETP inhibitor, a
PPAR-activator, an MTP/Apo B secretion inhibitor, a cholesterol
absorption inhibitor, HDL-cholesterol raising agent, triglyceride
lowering agent, a cholesterol synthesis inhibitor, a cholesterol
modulating agent, a fibrate, niacin, an ion-exchange resin, an
antioxidant, an ACAT inhibitor, bile acid sequestrant, an
anti-hypertensive agent, or an acetylcholine esterase
inhibitor.
18. The combination of claim 16 further comprising a
pharmaceutically acceptable carrier, diluent, solvent or
vehicle.
19. (canceled)
20. (canceled)
Description
RELATED APPLICATIONS
[0001] This application is a continuing application of U.S.
application Ser. No. 11/283,264, filed on Nov. 18, 2005, which
claims benefit of priority under 35 U.S.C 119(e) to U.S.
Provisional Application No. 60/630,481 filed on Nov. 23, 2004, the
contents of which are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] High levels of blood cholesterol and blood lipids are
conditions involved in the onset of atherosclerosis. The conversion
of HMG-CoA to mevalonate is an early and rate-limiting step in the
cholesterol biosynthetic pathway. This step is catalyzed by the
enzyme HMG-CoA reductase. It is known that inhibitors of HMG-CoA
reductase are effective in lowering the blood plasma level of low
density lipoprotein cholesterol (LDL-C), in man. (cf. M. S. Brown
and J. L. Goldstein, New England Journal of Medicine, 305, No. 9,
515-517 (1981)). It has been established that lowering LDL-C levels
affords protection from coronary heart disease (cf. Journal of the
American Medical Association, 251, No. 3, 351-374 (1984)).
[0003] To varying degrees, statins interfere with and/or inhibit
HMG-CoA reductase from catalyzing the conversion of HMG-CoA to
mevalonate. As such, statins are collectively potent lipid lowering
agents. Thus, statins are the drugs of first choice for management
of many lipid disorders. One representative statin is
atorvastatin.
[0004] Atorvastatin and pharmaceutically acceptable salts thereof
are selective, competitive inhibitors of HMG-CoA reductase. As
such, atorvastatin calcium is a potent lipid lowering compound and
is thus useful as a hypolipidemic and/or hypocholesterolemic agent,
as well as in the treatment of osteoporosis, BPH, diabetes and
Alzheimer's disease. A number of patents have issued disclosing
atorvastatin including U.S. Pat. Nos. 4,681,893; 5,273,995 and
5,969,156. Other representative statins include lovastatin,
pravastatin, simvastatin and rosuvastatin.
[0005] Statin drugs share many features, but also exhibit
differences in pharmacologic attributes that may contribute to
differences in clinical utility and effectiveness in modifying
lipid risk factors for coronary heart disease. (Clin. Cardiol. Bol.
26 (Suppl. III), III-32-III-38 (2003)). Accordingly, it would be
most beneficial to provide a statin having a combination of
desirable properties including (i) potent reversible inhibition of
HMG-CoA reductase, (ii) the ability to produce large reductions in
LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C),
(iii) the ability to increase HDL cholesterol (HDL-C), (iv)
relative hydrophilicity, (v) tissue selectivity (e.g., selectivity
of effect or uptake in hepatic cells through selective organic ion
transport), (vi) optimal pharmacokinetics or systemic
bioavailability so as to minimize any potential risk of systemic
adverse effects, while at the same time having enough systemic
availability so that any pleiotropic effects can be observed in the
vasculature with statin treatment, (vii) availability of once a day
dosing, (viii) a low potential for drug-drug interactions, (ix) the
ability to lower circulating very-low-density-lipoprotein (VLDL) as
well as the ability to lower triglyceride levels, (x) prolonged
elimination half-life to maximize effectiveness for lowering LDL-C,
(xi) absence or minimal metabolism via the cytochrome P450 (CYP)
enzyme system (e.g., the CYP3A4 system) so as to minimize any
potential risk of drug-drug interactions when statins are given in
combination with other drugs, and (xii) reduce levels of C-reactive
protein (CRP).
[0006] As described below, the present invention relates to
compounds and pharmaceutical compositions useful as
hypocholesterolemic and hypolipidemic agents. More specifically,
the present invention concerns certain potent inhibitors of the
enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase ("HMG CoA
reductase"). The invention further relates to methods of using such
compounds and compositions to treat subjects, including humans,
suffering from hyperlipidemia, hypercholesterolemia,
hypertriglyceridemia, atherosclerosis, Alzheimer's Disease, benign
prostatic hypertrophy (BPH), diabetes and osteoporosis.
SUMMARY OF THE INVENTION
[0007] The present invention provides a compound of the formula
(I):
##STR00001##
or a pharmaceutically acceptable salt, ester, amide, hydrate,
stereoisomer or prodrug thereof, or a pharmaceutically acceptable
salt of the prodrug, wherein: R.sub.1 is hydrogen, halogen,
C.sub.1-C.sub.7alkyl, C.sub.3-C.sub.8cycloalkyl, aryl, aralkyl,
heteroaryl, or heteroaralkyl; more specifically, R.sub.1 is
C.sub.1-C.sub.7alkyl or C.sub.3-C.sub.8cycloalkyl; even more
specifically, R.sub.1 is isopropyl; where alkyl, cycloalkyl, aryl,
aralkyl, heteroaryl, or heteroaralkyl of R.sub.1 is optionally
substituted as defined for each of these groups below; R.sub.2 is
hydrogen, halogen, C.sub.1-C.sub.7 alkyl, C.sub.3-C.sub.8
cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, NC--,
R.sub.2bR.sub.2aNCO(CH.sub.2).sub.n--,
R.sub.2bR.sub.2aNS(O).sub.n--, R.sub.2cS(O).sub.n--,
R.sub.2bR.sub.2aN(CH.sub.2).sub.n--,
R.sub.2b-J-C(O)NR.sub.2a(CH.sub.2).sub.n--,
R.sub.2b-J-SO.sub.2NR.sub.2a(CH.sub.2).sub.n--,
R.sub.2b-J-SONR.sub.2a(CH.sub.2).sub.n,
R.sup.7OOC(CH.sub.2).sub.n--, or R.sup.7CO(CH.sub.2).sub.n--; more
specifically, R.sub.2 is R.sub.2bR.sub.2a NCO(CH.sub.2).sub.n--;
even more specifically, R.sub.2 is R.sub.2bR.sub.2aNCO--; where
alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of
R.sub.2 is optionally substituted as defined for each of these
groups below; J is a direct bond, O, or N; R.sub.2a and R.sub.2b
are each independently hydrogen, C.sub.1-C.sub.10 alkyl,
C.sub.3-C.sub.8 cycloalkyl, aryl, aralkyl, heteroaryl or
heteroaralkyl; more specifically, R.sub.2a and R.sub.2b are each
independently hydrogen, C.sub.1-C.sub.7alkyl, aryl or aralkyl; even
more specifically, R.sub.2a and R.sub.2b are each independently
hydrogen, methyl or benzyl; where alkyl, cycloalkyl, aryl, aralkyl,
heteroaryl, or heteroaralkyl of R.sub.2a and R.sub.2b is optionally
substituted as defined for each of these groups below;
[0008] or R.sub.2a and R.sub.2b taken together with the nitrogen to
which they are attached form a 4-11 member ring optionally
containing at least one additional heteroatom selected from O, N
and S, said ring being optionally substituted with at least one of
aryl, aralkyl, heteroaryl, heteroaralkyl, C.sub.1-C.sub.10 alkyl,
C.sub.3-C.sub.8 cycloalkyl, halogen, R.sup.7O--,
R.sup.7OOC(CH.sub.2).sub.n--, R.sup.7R.sup.8NCO(CH.sub.2).sub.n--,
R.sup.7O.sub.2S(CH.sub.2).sub.n--, R.sup.8R.sup.7NSO.sub.2-- or
NC--;
R.sub.2c is aryl, aralkyl, alkyl, heteroaryl, or heteroaralkyl;
where aryl, aralkyl, alkyl, heteroaryl, or heteroaralkyl of
R.sub.2c is optionally substituted as defined for each of these
groups below; R.sup.7 and R.sup.8 are each independently hydrogen,
C.sub.1-C.sub.12 alkyl, aryl or aralkyl; where alkyl, aryl or
aralkyl of R.sup.7 and R.sup.8 is optionally substituted as defined
for each of these groups below; n is 0, 1 or 2; more specifically,
n is 0 or 1; even more specifically, n is 0; R.sub.3 is hydrogen,
C.sub.1-6 alkyl, C.sub.3-8cycloalkyl, aryl, aralkyl, heteroaryl, or
heteroaralkyl; more specifically, R.sub.3 is aryl; even more
specifically, R.sub.3 is phenyl or p-fluorophenyl; where alkyl,
cycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl of R.sub.3
is optionally substituted as defined for each of these groups
below; and --- is a bond or is absent.
[0009] The present invention provides a compound of the following
(3R,5R) stereospecific formula (Ia):
##STR00002##
or a pharmaceutically acceptable salt, ester, amide, hydrate,
stereoisomer or prodrug thereof, or a pharmaceutically acceptable
salt of the prodrug, wherein R.sub.1, R.sub.2, R.sub.3, and ----
are each as set forth above.
[0010] The invention further provides a compound of formula
(II):
##STR00003##
or a pharmaceutically acceptable salt, ester, amide, hydrate,
stereoisomer or prodrug thereof, or a pharmaceutically acceptable
salt of the prodrug, wherein R.sub.2a, R.sub.2b, n and ---- are
each as set forth above.
[0011] The invention further provides a compound of formula (II),
as set forth above, wherein R.sub.2a is:
##STR00004##
where R.sub.4 and R.sub.5 are each independently hydrogen or lower
alkyl;
[0012] q is 0, 1 or 2;
[0013] each R.sub.6 is independently hydrogen, halogen, alkyl,
haloalkyl, alkoxy, or cyano; and
[0014] p is 0, 1, 2, 3, 4, or 5;
or a pharmaceutically acceptable salt, ester, amide, hydrate,
stereoisomer or prodrug thereof, or a pharmaceutically acceptable
salt of the prodrug.
[0015] The invention further provides a (3R,5R) stereospecific
compound of formula (IIIa):
##STR00005##
or a pharmaceutically acceptable salt, ester, amide, hydrate,
stereoisomer or prodrug thereof, or a pharmaceutically acceptable
salt of the prodrug, wherein R.sub.2a, R.sub.2b, n and ---- are
each as defined above.
[0016] The invention further provides a compound of formula
(III):
##STR00006##
or a pharmaceutically acceptable salt, ester, amide, hydrate,
stereoisomer or prodrug thereof, or a pharmaceutically acceptable
salt of the prodrug, wherein R.sub.2a, R.sub.2b, n and ---- are
each as defined above.
[0017] The invention further provides a (3R,5R) stereospecific
compound of formula (IIIa):
##STR00007##
or a pharmaceutically acceptable salt, ester, amide, hydrate,
stereoisomer or prodrug thereof, or a pharmaceutically acceptable
salt of the prodrug, wherein R.sub.2a, R.sub.2b, n and ---- are
each as defined above.
[0018] The invention further provides a compound of formula
(IV):
##STR00008##
or a pharmaceutically acceptable salt, ester, amide, hydrate,
stereoisomer or prodrug thereof, or a pharmaceutically acceptable
salt of the prodrug, wherein R.sub.1, R.sub.2, R.sub.3 and ---- are
each as defined above.
[0019] The invention further provides a stereospecific compound of
formula (IVa):
##STR00009##
or a pharmaceutically acceptable salt, ester, amide, hydrate,
stereoisomer or prodrug thereof, or a pharmaceutically acceptable
salt of the prodrug, wherein R.sub.1, R.sub.2, R.sub.3 and ---- are
each as defined above.
[0020] The invention further provides a compound of formula
(V):
##STR00010##
or a pharmaceutically acceptable salt, ester, amide, hydrate,
stereoisomer or prodrug thereof, or a pharmaceutically acceptable
salt of the prodrug, wherein R.sub.1, R.sub.2, R.sub.3 and ---- are
each as defined above.
[0021] The invention further provides a compound of formula
(VI):
##STR00011##
wherein R.sub.1, R.sub.2a, R.sub.2b, and R.sub.3 are each as
defined above.
[0022] The invention further provides a compound of formula
(VII):
##STR00012##
wherein R.sub.1, R.sub.2a, R.sub.2b, R.sub.3 are each as defined
above, and X is a suitable counteranion; more specifically, X is F,
Cl, Br, or I anion; even more specifically, X is Br anion.
[0023] The invention further provides a compound selected from the
group consisting of: [0024]
(3R,5R)-7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-
-yl]-3,5-dihydroxy-heptanoic acid; [0025]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-methyl-benzylcarbamoyl)-2-
H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0026]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-benzylcarbamoyl)-2-
H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0027]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2-
H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0028]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-methyl-benzylcarbamoyl)-2-
H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; [0029]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2-
H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; [0030]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxy-benzylcarbamoyl)--
2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0031]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxy-benzylcarbamoyl)--
2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0032]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxy-benzylcarbamoyl)--
2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; [0033]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxy-benzylcarbamoyl)--
2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; [0034]
(3R,5R)-7-[5-(benzyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-
-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0035]
(3R,5R)-7-[5-[(3-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-i-
sopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0036]
(3R,5R)-7-[5-[(4-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-i-
sopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; [0037]
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[N-methyl-(R)-.alpha.-methyl-
-benzylcarbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
[0038]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(R)-.alpha.-methyl-benzylca-
rbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0039]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(S)-.alpha.-methyl-benzylca-
rbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0040]
(3R,5R)-7-[5-(benzyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-
-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; [0041]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(R)-.alpha.-methyl-benzylca-
rbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; [0042]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(S)-.alpha.-methyl-benzylca-
rbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; [0043]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenethylcarbamoyl-2H-pyrazo-
l-3-yl]-3,5-dihydroxy-heptanoic acid; [0044]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-methylcarbamoyl-2H-pyrazol-3-
-yl]-3,5-dihydroxy-heptanoic acid; [0045]
(3R,5R)-7-[5-ethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3--
yl]-3,5-dihydroxy-heptanoic acid; [0046]
(3R,5R)-7-[5-dimethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-
-3-yl]-3,5-dihydroxy-heptanoic acid; [0047]
7-(5-Benzylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,-
5R-dihydroxy-heptanoic acid; [0048]
7-(5-Benzylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,-
5R-dihydroxy-heptanoic acid; [0049]
3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methyl-benzylcarbamoyl)-2-(4-fluoro-p-
henyl)-2H-pyrazol-3-yl]-heptanoic acid; [0050]
3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2-(4-fluoro-p-
henyl)-2H-pyrazol-3-yl]-heptanoic acid; [0051]
3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2-(4-fluoro--
phenyl)-2H-pyrazol-3-yl]-heptanoic acid; [0052]
3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2-(4-fluoro--
phenyl)-2H-pyrazol-3-yl]-heptanoic acid; [0053]
7-[5-(Benzyl-methyl-carbamoyl)-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-
-3-yl]-3R,5R-dihydroxy-heptanoic acid; [0054]
7-{5-[(3-Fluoro-benzyl)-methyl-carbamoyl]-4-isopropyl-2-(4-fluoro-phenyl)-
-2H-pyrazol-3-yl}-3R,5R-dihydroxy-heptanoic acid; [0055]
7-{5-[(4-Fluoro-benzyl)-methyl-carbamoyl]-4-isopropyl-2-(4-fluoro-phenyl)-
-2H-pyrazol-3-yl}-3R,5R-dihydroxy-heptanoic acid; [0056]
3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(R)-.alpha.-methyl--
benzylcarbamoyl]-2H-pyrazol-3-yl]-heptanoic acid; [0057]
3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(S)-.alpha.-methyl--
benzylcarbamoyl]-2H-pyrazol-3-yl]-heptanoic acid; [0058]
3R,5R-Dihydroxy-7-{4-isopropyl-5-[N-methyl-(R)-.alpha.-methyl-benzylcarba-
moyl]-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-heptanoic acid; [0059]
3R,5R-Dihydroxy-7-{4-isopropyl-5-[N-methyl-(R)-.alpha.-methyl-benzylcarba-
moyl]-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-heptanoic acid; [0060]
3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2-(4-fluoro-p-
henyl)-2H-pyrazol-3-yl]-hept-6-enoic acid; [0061]
3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2-(4-fluoro--
phenyl)-2H-pyrazol-3-yl]-hept-6-enoic acid; [0062]
3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2-(4-fluoro--
phenyl)-2H-pyrazol-3-yl]-hept-6-enoic acid; [0063]
3R,5R-Dihydroxy-7-(4-isopropyl-5-methylcarbamoyl-2-(4-fluoro-phenyl)-2H-p-
yrazol-3-yl)-heptanoic acid; [0064]
7-(5-Ethylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3R,5-
R-dihydroxy-heptanoic acid; [0065]
7-(5-Dimethylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl)-3-
R,5R-dihydroxy-heptanoic acid; [0066]
7-[5-(Benzyl-methyl-carbamoyl)-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-
-3-yl]-3R,5R-dihydroxy-hept-6-enoic acid; [0067]
3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(R)-.alpha.-methyl--
benzylcarbamoyl]-2H-pyrazol-3-yl]-hept-6-enoic acid; [0068]
3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(S)-.alpha.-methyl--
benzylcarbamoyl]-2H-pyrazol-3-yl]-hept-6-enoic acid; [0069]
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-methyl-benzyl)-ca-
rbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; [0070]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenylcarbamoyl-2H-pyrazol-3-
-yl]-3,5-dihydroxy-heptanoic acid; [0071]
(3R,5R)-7-[5-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2-
H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0072]
(3R,5R)-7-[5-(4-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2-
H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0073]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(1-methyl-1-phenyl-ethylcarb-
amoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0074]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxymethyl-benzylcarba-
moyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0075]
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(4-methoxy-benzyl)-methyl-c-
arbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; [0076]
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-methyl-benzyl)-ca-
rbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; [0077]
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(3-methoxy-benzyl)-methyl-c-
arbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; [0078]
(3R,5R)-7-[5-(benzyl-ethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H--
pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0079]
(3R,5R)-7-[5-(benzyl-isopropyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-
-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0080] 35
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(1-phenyl-ethyl)-car-
bamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; [0081]
(3R,5R)-7-[5-(cyclohexylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-
-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0082]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(1-p-tolyl-ethylcarbamoyl)-2-
H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0083]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxymethyl-benzylcarba-
moyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0084]
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[1-(3-methoxy-phenyl)-ethylc-
arbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; [0085]
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[1-(4-methoxy-phenyl)-ethylc-
arbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; [0086]
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethyl-b-
enzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
[0087]
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-trifluoromethyl-b-
enzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
[0088]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-propylcarbamoyl-2H-pyrazol-3-
-yl]-3,5-dihydroxy-heptanoic acid; [0089]
(3R,5R)-7-[5-(4-dimethylcarbamoyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4--
isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0090]
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(pyridin-2-ylmethyl)-carbam-
oyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; [0091]
(3R,5R)-7-[2-(4-fluoro-phenyl)-5-(2-hydroxy-1-phenyl-ethylcarbamoyl)-4-is-
opropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0092]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(morpholine-4-carbonyl)-2H-p-
yrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0093]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-isopropylcarbamoyl-2H-pyrazo-
l-3-yl]-3,5-dihydroxy-heptanoic acid; [0094]
(3R,5R)-7-[5-(cyclohexylmethyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-is-
opropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0095]
(3R,5R)-7-[5-(cyclopentylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropy-
l-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0096]
(3R,5R)-7-[2-(4-fluoro-phenyl)-5-isobutylcarbamoyl-4-isopropyl-2H-pyrazol-
-3-yl]-3,5-dihydroxy-heptanoic acid; [0097]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-butylcarbamoyl)-2H-
-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0098]
(3R,5R)-7-[5-cyclopentylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyra-
zol-3-yl]-3,5-dihydroxy-heptanoic acid; [0099]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-phenyl-pyrrolidine-1-carb-
onyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0100]
(3R,5R)-7-[5-(cyclobutyl
methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-di-
hydroxy-heptanoic acid; [0101]
(3R,5R)-7-[5-[(2,3-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-
-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0102]
(3R,5R)-7-[5-(cyclopropylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropy-
l-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0103]
(3R,5R)-7-[5-[(2,4-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-
-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0104]
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-trifluoromethoxy--
benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
[0105]
(3R,5R)-7-[5-butylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3--
yl]-3,5-dihydroxy-heptanoic acid; [0106]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(piperidine-1-carbonyl)-2H-p-
yrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0107]
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethoxy--
benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid;
[0108]
(3R,5R)-7-[5-cyclohexylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyraz-
ol-3-yl]-3,5-dihydroxy-heptanoic acid; [0109]
(3R,5R)-7-[5-(4-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-
-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0110]
(3R,5R)-7-[5-(3-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-
-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0111]
(3R,5R)-7-[5-(cyclopentylmethyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-i-
sopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0112]
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-ca-
rbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; [0113]
(3R,5R)-7-[5-[(2-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-i-
sopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0114]
(3R,5R)-7-[5-[(3,4-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-
-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0115]
(3R,5R)-7-[5-(3-ethoxymethyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopr-
opyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0116]
(3R,5R)-7-[5-(4-ethyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-
-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0117]
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(5-trifluoromethyl-pyridin--
2-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic
acid; [0118]
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-trifluoromethyl-p-
yridin-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic
acid; [0119]
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-trifluoromethyl-piperidi-
n-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic
acid; [0120]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-isopropyl-benzylca-
rbamoyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0121]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-phenyl-piperidine-1-carbo-
nyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0122]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-phenyl-piperidine-1-carbo-
nyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0123]
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-methyl-pyridin-3-ylmethy-
l)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid; [0124]
(3R,5R)-7-[5-ethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3--
yl]-3,5-dihydroxy-heptanoic acid; [0125]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenylcarbamoyl-2H-pyrazol-3-
-yl]-3,5-dihydroxy-hept-6-enoic acid; [0126]
(3R,5R)-7-[5-(cyclohexylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-
-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; [0127]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-propylcarbamoyl-2H-pyrazol-3-
-yl]-3,5-dihydroxy-hept-6-enoic acid; [0128]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-isopropylcarbamoyl-2H-pyrazo-
l-3-yl]-3,5-dihydroxy-hept-6-enoic acid; [0129]
(3R,5R)-7-[2-(4-fluoro-phenyl)-5-isobutylcarbamoyl-4-isopropyl-2H-pyrazol-
-3-yl]-3,5-dihydroxy-hept-6-enoic acid; [0130]
(3R,5R)-7-[5-cyclopentylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyra-
zol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; [0131]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-butylcarbamoyl)-2H-
-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; [0132]
(3R,5R)-7-[5-(cyclopropylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropy-
l-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; [0133]
(3R,5R)-7-[5-butylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3--
yl]-3,5-dihydroxy-hept-6-enoic acid; [0134]
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethoxy--
benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoic
acid; [0135]
(3R,5R)-7-[5-cyclohexylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2-
H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; [0136]
(3R,5R)-7-[5-(4-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-
-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; [0137]
(3R,5R)-7-[5-(3-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-
-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid; [0138]
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-methylcarbamoyl-2H-pyrazol-3-
-yl]-3,5-dihydroxy-hept-6-enoic acid; [0139]
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-ca-
rbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoic acid;
[0140]
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-methyl-pyridin-3--
ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoic
acid; [0141]
7-[5-[(2,6-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)--
4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0142]
7-[5-[(4-fluoro-2-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-
-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0143]
7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,4-trifluoro-benzyl)-car-
bamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0144]
7-[5-[(3-fluoro-4-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-
-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0145]
7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,6-trifluoro-benzyl)-car-
bamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0146]
7-[5-[(2,3-difluoro-4-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl-
)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0147]
7-[5-[(2,3-difluoro-6-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-pheny-
l)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
[0148]
7-[5-[(3-fluoro-4-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4--
isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0149]
7-[5-[(4-fluoro-3-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4--
isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0150]
7-[5-[(2,3-difluoro-4-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-pheny-
l)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid;
[0151]
7-[5-[(2-fluoro-3-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4--
isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0152]
7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,5-trifluoro-benzyl)-car-
bamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0153]
7-[5-[(3-fluoro-2-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-
-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0154]
7-[5-[(2-fluoro-3-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-
-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; [0155]
7-[5-[(3-fluoro-2-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4--
isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; and [0156]
(3R,5R)-7-[2-(4-Fluoro-phenyl)-4-isopropyl-5-(2-phenyl-piperidine-1-carbo-
nyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid; or
[0157] a pharmaceutically acceptable salt, ester, amide or prodrug
thereof, or a pharmaceutically acceptable salt of the prodrug.
[0158] The invention further provides a compound selected from the
group consisting of: [0159]
1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4-
-isopropyl-1H-pyrazole-3-carboxylic acid
(3-fluoro-benzyl)-methyl-amide; [0160]
1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-e-
thyl]-4-isopropyl-1H-pyrazole-3-carboxylic acid
benzyl-methyl-amide; and [0161]
1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-e-
thyl]-4-isopropyl-1H-pyrazole-3-carboxylic acid
4-methyl-benzylamide; or
[0162] a pharmaceutically acceptable salt, ester, amide or prodrug
thereof, or a pharmaceutically acceptable salt of the prodrug.
[0163] The invention further provides a pharmaceutical composition
comprising a compound of the invention and a pharmaceutically
acceptable carrier, diluent, solvent or vehicle.
[0164] The invention further provides a combination of a compound
of the invention and another pharmaceutically active agent, each as
described herein. A pharmaceutical composition comprising the
aforementioned combination and a pharmaceutically acceptable
carrier, diluent, solvent or vehicle, each as described herein, is
also provided by the invention.
[0165] The invention further provides a method of preparation of a
compound, pharmaceutical composition or combination of the
invention, each as described herein.
[0166] The invention still further provides a method of treating a
subject suffering from hyperlipidemia, hypercholesterolemia,
hypertriglyceridemia, atherosclerosis, Alzheimer's Disease, benign
prostatic hypertrophy (BPH), diabetes and osteoporosis comprising
administering a therapeutically effective amount of at least one
compound, pharmaceutical composition or combination of the
invention, each as described herein, to the subject in need
thereof.
[0167] The invention still further provides the use of a compound,
pharmaceutical composition, or combination of the invention for
treating a subject suffering from hyperlipidemia,
hypercholesterolemia, hypertriglyceridemia, atherosclerosis,
Alzheimer's Disease, benign prostatic hypertrophy (BPH), diabetes
and osteoporosis.
[0168] The invention still further provides the use of a compound,
pharmaceutical composition, or combination of the invention in the
preparation of a medicament for the treatment of a subject
suffering from hyperlipidemia, hypercholesterolemia,
hypertriglyceridemia, atherosclerosis, Alzheimer's Disease, benign
prostatic hypertrophy (BPH), diabetes and osteoporosis.
[0169] The invention also provides a process comprising the steps
of:
[0170] (a) reacting a hydroxyl compound VIII:
##STR00013##
under conditions sufficient to form a compound IX:
##STR00014##
[0171] (b) reacting a compound IX under conditions sufficient to
form a compound X:
##STR00015##
[0172] (c) reacting a compound X under conditions sufficient to
form a compound XI:
##STR00016##
[0173] (d) reacting a compound XI under conditions sufficient to
form a compound XII:
##STR00017##
[0174] (e) reacting a compound XII under conditions sufficient to
form a compound XIII:
##STR00018##
wherein for steps (a)-(e), R.sub.1, R.sub.3, n, R.sup.7 are each as
defined herein, and
[0175] LG-O-- together is a leaving group; and
[0176] Z is R''' or R''''CX'=CX''Y where
[0177] R''' is alkenyl;
[0178] R'''', X' and X'' are each hydrogen, alkyl, alkenyl, aryl,
heteroaryl, or alkenyl substituent;
[0179] Y is either a direct bond or a linker group; and wherein the
non-hydrogen groups of R''', R'''', X', X'', or Y are optionally
substituted as defined herein.
[0180] The invention further provides a process comprising the
steps of:
[0181] (a) reacting a compound XIV:
##STR00019##
under conditions sufficient to form a compound XV:
##STR00020##
[0182] (b) reacting a compound XV under conditions sufficient to
form a compound XVI:
##STR00021##
[0183] (c) reacting a compound XVI under conditions sufficient to
form a compound XVII:
##STR00022##
wherein for steps (a)-(c), R.sub.1, R.sub.3, R.sub.2a, R.sub.2b,
and n are each as defined herein and LG-O-- together is a leaving
group; and
[0184] Z is R''' or R''''CX'=CX''Y where R''' is alkenyl;
[0185] R'''', X' and X'' are each hydrogen, alkyl, alkenyl, aryl,
heteroaryl, or alkenyl substituent;
[0186] Y is either a direct bond or a linker group; and wherein the
non-hydrogen groups of R''', R'''', X', X'', or Y are optionally
substituted as defined herein.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0187] Unless indicated otherwise, the following terms are defined
as follows:
[0188] The article "a" or "an" as used herein refers to both the
singular and plural form of the object to which it refers.
[0189] The term "alkyl" as used herein refers to an optionally
substituted a straight or branched hydrocarbon of from 1 to 12
carbon atoms and includes, for example, methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl,
n-hexyl, and the like. The alkyl group may also be optionally
substituted with one or more of the substituents selected from
cycloalkyl, lower alkoxy, lower thioalkoxy,
--O(CH.sub.2).sub.0-2CF.sub.3, --O-aryl, aryl, heteroaryl, halogen,
haloalkyl, nitro, cyano, .dbd.O, .dbd.S, --OH, --SH, --CF.sub.3,
--CO.sub.2H, --CO.sub.2C.sub.1-C.sub.6 alkyl, --NR'R'',
--NR'SO.sub.2R'', --NR'CONR'R'', or --CONR'R'' where R' and R'' are
independently H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,
aralkyl, heteroaryl, heteroaralkyl, or joined together to form a
4-7 member ring optionally containing at least one additional
heteroatom selected from N, O and S; or N, R' and R'' taken
together form a 4-7 member ring optionally containing at least one
additional heteroatom selected from N, O and S.
[0190] The term "lower alkyl" as used herein refers to a subset of
alkyl which means an optionally substituted straight or branched
hydrocarbon radical having from 1 to 7 carbon atoms and includes,
for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,
sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl and
the like. Alternatively, lower alkyl is referred to as
"C.sub.1-C.sub.7 alkyl." The lower alkyl group may also be
optionally substituted with at least one of the substituents
recited for the term "alkyl".
[0191] The term "alkenyl" as used herein means an optionally
substituted straight or branched hydrocarbon radical from 2 to 12
carbon atoms having at least one double bond and includes, for
example, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl,
1-pentenyl, 2-pentenyl, 3-methyl-3-butenyl, 1-hexenyl, 2-hexenyl,
3-hexenyl, 3-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl,
1-undecenyl, 1-dodecenyl, and the like. The alkenyl group may be
optionally substituted with at least one of the substituents
recited for the term "alkyl".
[0192] The term "alkynyl" as used herein means an optionally
substituted straight or branched hydrocarbon radical of 2 to 12
carbon atoms having at least one triple bond and includes, for
example, 3-propynyl, 1-butynyl, 3-butynyl, 1-pentynyl, 3-pentynyl,
3-methyl-3-butynyl, 1-hexynyl, 3-hexynyl, 3-hexynyl, 3-heptynyl,
1-octynyl, 1-nonynyl, 1-decynyl, 1-undecynyl, 1-dodecynyl, and the
like. The alkynyl group may be optionally substituted with at least
one of the substituents recited for the term "alkyl".
[0193] The term "alkylene" as used herein refers to an optionally
substituted divalent group derived from a straight or branched
chain saturated hydrocarbon having from 1 to 10 carbon atoms by the
removal of two hydrogen atoms, for example methylene, 1,2-ethylene,
1,1-ethylene, 1,3-propylene, 2,2-dimethylpropylene, and the like.
The alkylene group may be optionally substituted with one or more
of the substituents selected from lower alkyl, lower alkoxy, lower
thioalkoxy, --O(CH.sub.2).sub.0-2CF.sub.3, halogen, haloalkyl,
nitro, cyano, .dbd.O, .dbd.S, --OH, --SH, --CF.sub.3, --CO.sub.2H,
--CO.sub.2C.sub.1-C.sub.6 alkyl, --NR'R'', or --CONR'R'', where R'
and R'' are independently H, alkyl, cycloalkyl, alkenyl, alkynyl,
aryl, aralkyl, heteroaryl, or heteroaralkyl; or N, R' and R'' taken
together form a 4-7 member ring optionally containing at least one
additional heteroatom selected from N, O and S. Useful alkylene
groups have from 1 to 6 carbon atoms (C.sub.1-C.sub.6 alkylene).
Examples include, but are not limited to, methylene (--CH.sub.2--),
ethylene (--CH.sub.2CH.sub.2--), propylene (--(CH.sub.2).sub.3--),
and the like.
[0194] The term "halogen" or "halo" as used herein refers to
fluorine or fluoro, chlorine or chloro, bromine or bromo and iodine
or iodo.
[0195] The term "haloalkyl" as used herein refers to an alkyl group
where one or more of the hydrogens has been replaced by a halogen
or halo group each as defined herein.
[0196] The term "heteroatom" as used herein represents oxygen,
nitrogen, or sulfur (O, N, or S) as well as sulfoxyl or sulfonyl
(SO or SO.sub.2) unless otherwise indicated.
[0197] The term "hydrocarbon chain" as used herein refers to an
optionally substituted straight hydrocarbon of from 2 to 12 carbon
atoms. The hydrocarbon chain is optionally substituted with one or
more substituents selected from lower alkyl, lower alkoxy, lower
thioalkoxy, --O(CH.sub.2).sub.0-2CF.sub.3, halogen, nitro, cyano,
.dbd.O, .dbd.S, --OH, --SH, --CF.sub.3, --CO.sub.2H,
--CO.sub.2C.sub.1-C.sub.6 alkyl, --NR'R'' or --CONR'R'', where R'
and R'' are independently H, alkyl, cycloalkyl, alkenyl, alkynyl,
aryl, aralkyl, heteroaryl, or heteroaralkyl; or N, R' and R'' taken
together form a 4-7 member ring optionally containing at least one
additional heteroatom selected from N, O and S.
[0198] The terms "lower alkoxy" and "lower thioalkoxy" as used
herein refers to --O-alkyl or --S-alkyl of from 1 to 7 carbon atoms
as defined above for "lower alkyl."
[0199] The term "aryl" as used herein refers to a C.sub.5-C.sub.14
mono-, bi- or polycarbocyclic aromatic ring system which is
optionally substituted by at least one substituent selected from
lower alkyl, lower alkoxy, lower thioalkoxy, halogen,
--O(CH.sub.2).sub.0-2CF.sub.3, --Oaryl, --OSO.sub.2R', nitro, cyano
--OH, --SH, --CF.sub.3, --CO.sub.2H,
--CO.sub.2(C.sub.1-C.sub.6)alkyl, --NR'R'', --NR'SO.sub.2R'',
--NR'CONR'R'', --SO.sub.1-2alkyl, SO.sub.1-2aryl, --SO.sub.2NR'R'',
or --CONR'R'', where R' and R'' are independently H, alkyl,
cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl,
heteroaralkyl or joined together to form a 4-7 member ring
optionally containing at least one additional heteroatom selected
from N, O and S; or N, R' and R'' taken together form a 4-7 member
ring optionally containing at least one additional heteroatom
selected from N, O and S. Examples include, but are not limited to,
phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,
2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl,
3-methoxyphenyl, 4-methoxyphenyl, 2-chloro-3-methylphenyl,
2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl,
3-chloro-2-methylphenyl, 3-chloro-4-methylphenyl,
4-chloro-2-methylphenyl, 4-chloro-3-methylphenyl,
5-chloro-2-methylphenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl,
3,4-dichlorophenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, and the
like.
[0200] The term "aralkyl" as used herein means aryl, as defined
above, attached to an alkyl group, as defined above. Linkage to the
rest of the molecule may be through either the aryl or alkyl
portion of the aralkyl moiety. The aralkyl group may be optionally
substituted by at least one of the substituents recited above for
"alkyl" and "aryl". Examples of aralkyl include, but are not
limited to, benzyl, tolyl, and the like.
[0201] The term "heteroaryl" as used herein refers to an aryl
group, as defined above, containing one or more heteroatoms, as
defined above. The heteroaryl may be optionally substituted with at
least one of the substituents recited above for "aryl". Examples of
heteroaryl include, but are not limited to thienyl, furanyl,
pyrrolyl, pyridyl, pyrimidyl, imidazoyl, pyrazinyl, oxazolyl,
thiazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl,
isoquinolinyl, quinazolinyl, I-imidazolyl, 2-imidazolyl,
4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl,
5-pyrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl,
4-isothiazolyl, 5-isothiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,
3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 1-triazolyl, 3-triazolyl,
5-triazolyl, I-tetrazolyl, 2-tetrazolyl, 3-tetrazolyl, 2-pyrazinyl,
2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, indolizinyl,
isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl,
benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, 1-indolyl,
2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl,
1-indolizinyl, 2-indolizinyl, 3-indolizinyl, 5-indolizinyl,
6-indolizinyl, 7-indolizinyl, 8-indolizinyl, 1-isoindolyl,
2-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl,
6-isoindolyl, 7-isoindolyl, 2-benzothienyl, 3-benzothienyl,
4-benzothienyl, 5-benzothienyl, 6-benzothienyl, 7-benzothienyl,
2-benzoxazolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl,
7-benzoxazolyl, 1-benzimidazolyl, 2-benzimidazolyl,
4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl,
7-benzimidazolyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl,
5-quinolinyl, 6-quinolinyl, 7-quinolinyl, 8-quinolinyl,
1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl,
6-isoquinolinyl, 7-isoquinolinyl, 8-isoquinolinyl, and the
like.
[0202] The term heteroaralkyl, as used herein refers to heteroaryl,
as defined above, attached to an alkyl group, as defined above.
Linkage to the rest of the molecule can be either through the
heteroaryl or the alkyl portion of the heteroaralkyl moiety. The
heteroaralkyl may be optionally substituted with at least one of
those substituents recited above for "alkyl" and "heteroaryl".
[0203] The term "heterocycle" as used herein refers to an
optionally substituted saturated mono-, bi- or polycyclic ring
containing one or more heteroatoms selected from N, O, and S. The
heterocycle may be optionally substituted with at least one of
those substituents recited above for "alkylene". Examples of
suitable heterocycles include, but are not limited to, piperidinyl,
pyrrolidinyl, I-piperazinyl, 2-piperazinyl, 2-morpholinyl,
3-morpholinyl, 4-morpholinyl, piperazinyl, azetidinyl, aziridinyl,
thietanyl, oxetaryl, and the like.
[0204] The term "ring" as used herein includes heteroaryl,
heterocycle, cycloalkyl or aryl, each as defined above, and further
includes fused, monocyclic, bicyclic, and polycyclic permutations
thereof.
[0205] The term "cycloalkyl" as used herein refers to an optionally
substituted saturated cyclic C.sub.3-C.sub.12 alkyl group, where
alkyl is as defined above. Examples of suitable cycloalkyl groups
include, but are not limited to, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, decalinyl,
norpinanyl, or adamantyl. The cycloalkyl ring may be optionally
substituted by with at least one of those substituents recited
above for "alkyl" or "alkylene". Examples of substituted cycloalkyl
groups include, but are not limited to, fluorocyclopropyl,
2-iodocyclobutyl, 2,3-dimethylcyclopentyl, 2,2-dimethoxycyclohexyl,
3-phenylcyclopentyl, and the like.
[0206] The term "treating" or "treatment" refers to curative,
palliative and prophylactic treatment, including reversing,
ameliorating, alleviating, inhibiting the progress of, or
preventing the disorder or condition to which such term applies, or
one or more symptoms of such disorder or condition.
[0207] The term "stereoisomer" as used herein refers to both
geometric (e.g., cis and trans isomers) and/or optical isomers
(e.g., R and S enantiomers) of a compound of the invention.
Racemic, enantiomeric, diastereomeric and epimeric mixtures of such
isomers are contemplated by the present invention.
[0208] When a bond to a substituent is shown to cross the bond(s)
connecting 2 atoms in a ring, then such substituent may be bonded
to any atom in the ring, provided the atom will accept the
substituent without violating its valency. When there appears to be
several atoms of the substituent that may bond to the ring atom,
then it is the first atom of the listed substituent that is
attached to the ring, unless indicated otherwise.
[0209] When a bond is represented by a line such as "---" this is
meant to represent that the bond may be absent or present provided
that the resultant compound is stable and of satisfactory valency.
If an asymmetric carbon is created by such a bond, a particular
stereochemistry is not to be implied.
[0210] Unless indicated otherwise, "compound of the invention" or
"compounds of the invention" includes the compound itself as well
as its pharmaceutically acceptable salt, ester, amide, hydrate,
stereoisomer or prodrug thereof, or a pharmaceutically acceptable
salt of the prodrug, as well as other embodiments described
herein.
[0211] As used herein, the following terms have the meanings given:
RT or rt means room temperature. MP means melting point. MS means
mass spectroscopy. TLC means thin layer chromatography. [S]at.
means saturated. [C]one. means concentrated. TBIA means
[(4R,6R)-6-(2-Amino-ethyl)-2,2-dimethyl-[1,3]dioxan-4-yl]-acetic
acid tert-butyl ester. DCM means dichloromethane, which is used
interchangeably with methylene chloride. NBS means
N-Bromosuccinimide. "h" means hour. "v/v" means volume ratio or
"volume per volume". "R.sub.f" means retention factor. "Tf.sub.2O"
or "TfO" means triflic anhydride or
C(F).sub.3S(O).sub.2OS(O).sub.2C(F).sub.3. Ac.sub.2O means acetic
anhydride. "[T]rifluorotol." Or "TFT" means trifluorotoluene. "DMF"
means dimethylformamide. "DCE" means dichloroethane. "Bu" means
butyl. "Me" means methyl. "Et" means ethyl. "DBU" means
1,8-Diazabicyclo-[5.4.0]undec-7-ene. "TBS" means "TBDMS" or
tert-Butyldimethylsilyl. "DMSO" means dimethyl sulfoxide. "TBAF"
means tetrabutylammonium fluoride. THF means tetrahydrofuran. NBuli
or Buli means n-butyl lithium. TFA means trifluoroacetic acid. i-Pr
means isopropyl. [M].sub.n means minutes. ml or mL means
milliliter. "M" or "m" means molar. "Bn" means benzyl. "PyBOP"
means bromo-tris-pyrrolidino-phosphonium hexafluorophosphate.
"OtBu" means t-butoxy. "Ts" or "Tosyl" means p-toluenesulfonyl.
"PS-DIEA" means polystyrene-bound diisopropylethylamine. "PS-NCO"
means polystyrene-bound isocyanate resin. "Ph" means phenyl. As
used herein, "hydrogenolysis" means the cleaving of a chemical bond
by hydrogen. "EDCI" or "EDC" means
1-(3-dimethylaminopropyl)-3-ethylcarbondiimide hydrochloride. "NMP"
means 1-methyl-2-pyrrolidinone.
[0212] The term "patient" or "subject" means all mammals including
humans. Examples of patients or subjects include humans, cows,
dogs, cats, goats, sheep, pigs, and rabbits.
[0213] A "therapeutically effective amount" is an amount of a
compound of the present invention that when administered to a
patient treats a symptom of hyperlipidemia, hypercholesterolemia,
hypertriglyceridemia, atherosclerosis, Alzheimer's Disease, benign
prostatic hypertrophy (BPH), diabetes and osteoporosis. As would be
understood by one of skill in the art, a "therapeutically effective
amount" will vary from subject to subject and will be determined on
a case by case basis. Factors to consider include, but are not
limited to, the subject being treated, weight, health, compound
administered, etc.
[0214] The term "under conditions sufficient" as used herein refers
to those reaction conditions know in the art that would enable the
transformation of one compound to the next.
[0215] The term "a pharmaceutically acceptable salt, ester, amide,
hydrate, stereoisomer or prodrug" as used herein refers to those
acid addition salts, base addition salts, esters, amides, hydrates,
stereoisomers, and prodrugs of the compounds of the present
invention which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of patients without
undue toxicity, irritation, allergic response, and the like,
commensurate with a reasonable benefit/risk ratio, and effective
for their intended use, as well as the zwitterionic forms, where
possible, of the compounds of the invention.
[0216] The term "a pharmaceutically acceptable salt" refers to the
relatively non-toxic, inorganic and organic acid or base addition
salts of compounds of the invention. These salts can be prepared in
situ during the final isolation and purification of the compounds
or by separately reacting the purified compound in its free form
with a suitable organic or inorganic acid or base and isolating the
salt thus formed. Representative salts include the hydrobromide,
hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate,
valerate, oleate, palmitate, stearate, laurate, borate, benzoate,
lactate, phosphate, tosylate, citrate, maleate, fumarate,
succinate, tartrate, naphthylate mesylate, glucoheptonate,
lactobionate, and laurylsulphonate salts, and the like. These may
include cations based on the alkali and alkaline earth metals, such
as sodium, lithium, potassium, calcium, magnesium, and the like, as
well as non-toxic ammonium, quaternary ammonium, and amine cations
including, but not limited to, ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, ethylamine, and the like. (See, for example, Berge
S. M., et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;
66:1-19, which is incorporated herein by reference.) The free base
form may be regenerated by contacting the salt form with a base.
While the free base may differ from the salt form in terms of
physical properties, such as solubility, the salts are equivalent
to their respective free bases for the purposes of the present
invention.
[0217] Examples of pharmaceutically acceptable, non-toxic esters of
the compounds of the invention include C.sub.1-C.sub.6 alkyl esters
wherein the alkyl group is a straight or branched chain. Acceptable
esters also include C.sub.5-C.sub.7 cycloalkyl esters as well as
aralkyl esters such as, but not limited to, benzyl. C.sub.1-C.sub.4
alkyl esters are preferred. Esters of the compounds of the present
invention may be prepared according to conventional methods.
[0218] Examples of pharmaceutically acceptable, non-toxic amides of
the compounds of the invention include amides derived from ammonia,
primary (C.sub.1-C.sub.6)alkyl amines and secondary
di-(C.sub.1-C.sub.6)alkyl amines wherein the alkyl groups are
straight or branched chain. In the case of secondary amines, the
amine may also be in the form of a 5- or 6-membered heterocycle
containing one nitrogen atom. Amides derived from ammonia,
C.sub.1-C.sub.3 alkyl primary amines and C.sub.1-C.sub.2 dialkyl
secondary amines are preferred. Amides of the compounds of the
invention may be prepared according to conventional methods.
[0219] "Prodrugs" are intended to include any covalently bonded
carrier which releases the active parent drug according to Formulae
I, Ia, II, IIa, III, IIIa, IV, and V in vivo. Further, the term
"prodrug" refers to compounds that are transformed in vivo to yield
the parent compound of the above formulae, for example, by
hydrolysis in blood. A thorough discussion is provided in T.
Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol.
14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in
Drug Design, ed. Edward B. Roche, American Pharmaceutical
Association and Pergamon Press, 1987, both of which are hereby
incorporated by reference. Examples of prodrugs include, but are
not limited to, acetates, formates, benzoate derivatives of
alcohols, and amines present in compounds of the invention.
[0220] In some situations, compounds may exist as tautomers. All
tautomers of a compound of the invention are encompassed by the
present invention.
[0221] Certain compounds of the present invention can exist in
unsolvated form as well as solvated form including hydrated form.
In general, the solvated form including hydrated form is equivalent
to the unsolvated form and is intended to be encompassed within the
scope of the present invention.
[0222] Certain of the compounds of the present invention possess
one or more chiral centers and each center may exist in the R or S
configuration. For example, compounds of formulae (Ia), (IIa), and
(IIIa) are shown with a (3R,5R) configuration. Also envisioned are
compounds having a (3S,5S), (3S,5R) or (3R,5S). If a compound of
the invention further contains another chiral center(s), then that
center(s) could independently have either an R or S configuration.
The present invention includes all diastereomeric, enantiomeric,
and epimeric forms as well as the appropriate mixtures thereof.
Such stereoisomers may be obtained, if desired, by methods known in
the art including, for example, the separation of stereoisomers by
chiral chromatographic columns and by chiral synthesis.
Additionally, the compounds of the present invention may exist as
geometric isomers. The present invention includes all cis, trans,
syn, anti, entgegen (E), and zusammen (Z) isomers as well as the
appropriate mixtures thereof.
[0223] The compounds of the present invention are suitable to be
administered to a patient or subject for the treatment of
hyperlipidemia, hypercholesterolemia, hypertriglyceridemia,
atherosclerosis, Alzheimer's Disease, benign prostatic hypertrophy
(BPH), diabetes and osteoporosis. The compounds of the present
invention can be administered to a patient/subject alone, or
another compound of the invention, or as part of a pharmaceutical
composition.
[0224] A pharmaceutical composition of the invention contains at
least one compound of the invention and at least one
pharmaceutically acceptable carrier, diluent, solvent or vehicle.
The pharmaceutically acceptable carrier, diluent, solvent or
vehicle may be any such carrier known in the art including those
described in, for example, Remington's Pharmaceutical Sciences,
Mack Publishing Co., (A. R. Gennaro edit. 1985). A pharmaceutical
composition of the invention may be prepared by conventional means
known in the art including, for example, mixing at least one
compound of the invention with a pharmaceutically acceptable
carrier.
[0225] A composition of the invention can be administered to a
patient/subject either orally, rectally, parenterally
(intravenously, intramuscularly, or subcutaneously),
intracisternally, intravaginally, intraperitoneally,
intravesically, locally (powders, ointments, or drops), or as a
buccal or nasal spray.
[0226] Compositions suitable for parenteral injection may comprise
physiologically acceptable sterile aqueous or nonaqueous solutions,
dispersions, suspensions or emulsions, and sterile powders for
reconstitution into sterile injectable solutions or dispersions.
Examples of suitable aqueous and nonaqueous carriers, diluents,
solvents or vehicles include water, ethanol, polyols
(propyleneglycol, polyethyleneglycol, glycerol, and the like),
suitable mixtures thereof, vegetable oils (such as olive oil), and
injectable organic esters such as ethyl oleate. Proper fluidity can
be maintained, for example, by the use of a coating such as
lecithin, by the maintenance of the required particle size in the
case of dispersions and by the use of surfactants.
[0227] These compositions may also contain additives such as
preserving, wetting, emulsifying, and dispensing agents. Prevention
of the action of microorganisms can be ensured by various
antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, and the like. It may also be
desirable to include isotonic agents, for example sugars, sodium
chloride, and the like. Prolonged absorption of the injectable
pharmaceutical form can be brought about by the use of agents
delaying absorption, for example, aluminum monostearate and
gelatin.
[0228] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is admixed with at least one (a) inert
customary excipient (or carrier) such as sodium citrate or
dicalcium phosphate; (b) fillers or extenders, as for example,
starches, lactose, sucrose, glucose, mannitol, and silicic acid;
(c) binders, as for example, carboxymethylcellulose, alignates,
gelatin, polyvinylpyrrolidone, sucrose, and acacia; (d) humectants,
as for example, glycerol; (e) disintegrating agents, as for
example, agar-agar, calcium carbonate, potato or tapioca starch,
alginic acid, certain complex silicates, and sodium carbonate; (f)
solution retarders, as for example paraffin; (g) absorption
accelerators, as for example, quaternary ammonium compounds; (h)
wetting agents, as for example, cetyl alcohol and glycerol
monostearate; (i) adsorbents, as for example, kaolin and bentonite;
and (j) lubricants, as for example, talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, or mixtures thereof. In the case of capsules, tablets, and
pills, the dosage forms may also comprise buffering agents.
[0229] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethyleneglycols, and the like.
[0230] Solid dosage forms such as tablets, dragees, capsules,
pills, and granules can be prepared with coatings and shells, such
as enteric coatings and others well-known in the art. They may
contain opacifying agents, and can also be of such composition that
they release the active compound or compounds in a certain part of
the intestinal tract in a delayed manner. Examples of embedding
compositions which can be used are polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if
appropriate, with one or more of the above-mentioned
excipients.
[0231] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and elixirs. In addition to the active compounds, the
liquid dosage forms may contain inert diluents commonly used in the
art, such as water or other solvents, solubilizing agents and
emulsifiers, as for example, ethyl alcohol, isopropyl alcohol,
ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in
particular, cottonseed oil, groundnut oil, corn germ oil, olive
oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl
alcohol, polyethyleneglycols and fatty acid esters of sorbitan or
mixtures of these substances, and the like.
[0232] Besides such inert diluents, the composition can also
include additives, such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0233] Suspensions, in addition to the active compounds, may
contain suspending agents, as for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, or mixtures of these substances, and the
like.
[0234] Compositions for rectal administrations are preferably
suppositories which can be prepared by mixing the compounds of the
present invention with suitable non-irritating excipients or
carriers such as cocoa butter, polyethyleneglycol, or a suppository
wax, which are solid at ordinary temperatures but liquid at body
temperature and therefore, melt in the rectum or vaginal cavity and
release the active component.
[0235] Dosage forms for topical administration of a compound of
this invention include ointments, powders, sprays, and inhalants.
The active component is admixed under sterile conditions with a
physiologically acceptable carrier and any preservatives, buffers,
or propellants as may be required. Ophthalmic formulations, eye
ointments, powders, and solutions are also contemplated as being
within the scope of this invention.
[0236] The compounds of the present invention can be administered
to a patient at dosage levels in the range of about 0.1 to about
2,000 mg per day. For a normal human adult having a body weight of
about 70 kilograms, a dosage in the range of about 0.01 to about
100 mg per kilogram of body weight per day is preferable. The
specific dosage used, however, can vary from patient to patient.
For example, the dosage can depend on a numbers of factors
including the requirements of the patient, the severity of the
condition being treated, and the pharmacological activity of the
compound being used. The determination of optimum dosages for a
particular patient is well known to those skilled in the art.
[0237] The compounds of the invention, as described herein, may be
used either alone or in combination with another pharmaceutical
agent described herein, in the treatment of the following
diseases/conditions: dyslipidemia, hypercholesterolemia,
hypertriglyceridemia, atherosclerosis, peripheral vascular disease,
cardiovascular disorders, angina, ischemia, cardiac ischemia,
stroke, myocardial infarction, reperfusion injury, angioplastic
restenosis, hypertension, diabetes and vascular complications of
diabetes, obesity, unstable angina pectoris, Alzheimer's Disease,
BPH, osteoporosis, cerebrovascular disease, coronary artery
disease, ventricular dysfunction, cardiac arrhythmia, pulmonary
vascular disease, renal-vascular disease, renal disease, vascular
hemostatic disease, autoimmune disorders, pulmonary disease, sexual
dysfunction, cognitive dysfunction, cancer, organ transplant
rejection, psoriasis, endometriosis, and macular degeneration. A
combination of the invention may be part of a pharmaceutical
composition further containing a pharmaceutically active carrier,
diluent, solvent or vehicle, each as described herein.
[0238] Examples of a suitable pharmaceutically active agent include
a CETP inhibitor, a PPAR-activator, an MTP/Apo B secretion
inhibitor, a cholesterol absorption inhibitor, HDL-cholesterol
raising agent, triglyceride lowering agent, a cholesterol synthesis
inhibitor, a cholesterol modulating agent, a fibrate, niacin, an
ion-exchange resin, an antioxidant, an ACAT inhibitor, or bile acid
sequestrant; an anti-hypertensive agent; an acetylcholine esterase
inhibitor, an anti-diabetic compound, an anti-obesity compound, a
thyromimetic agent, an anti-resorptive agent, an anti-osteoporosis
agent, an antihypertensive agent, or a drug for the treatment of
Alzheimer's disease. Specific examples of each of these agents
include those known in the art as well as those specified
below.
[0239] In combination therapy treatment, both the compounds of the
invention and the other drug therapies are administered to mammals
by conventional methods. The following discussion more specifically
describes the various combination aspects of this invention.
[0240] Any cholesterol absorption inhibitor known in the art with
the ability of a compound to prevent cholesterol contained within
the lumen of the intestine from entering into the intestinal cells
and/or passing from within the intestinal cells into the blood
stream may be used. Such cholesterol absorption inhibition activity
is readily determined according to standard assays (e.g., J. Lipid
Res. (1993) 34: 377-395). Examples include, but are not limited to,
ZETIA.TM. as well as the cholesterol absorption inhibitors
described in WO 94/00480.
[0241] Any cholesterol ester transfer protein ("CETP") inhibitor
known in the art that inhibits the transfer of cholesteryl ester
and triglyceride between lipoprotein particles, including high
density lipoproteins (HDL), low density lipoproteins (LDL), very
low density lipoproteins (VLDL), and chylomicrons may be used. The
effect of a CETP inhibitor on lipoprotein profile is believed to be
anti-atherogenic. Such inhibition may be determined by means known
in the art (e.g., Crook et al. Arteriosclerosis 10, 625, 1990; U.S.
Pat. No. 6,140,343). Examples of suitable CETP inhibitors include,
but are not limited to, those described in U.S. Pat. Nos.
6,197,786, 6,723,752 and 6,723,753. Additional examples of useful
CETP inhibitors include the following compounds:
[2R,4S]-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethy-
l-6-trifluoromethyl-3,4-dihydroxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-
-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester
(Torcetrapib.TM.), and
3-{[3-(4-Chloro-3-ethyl-phenoxy)-phenyl]-[3-(1,1,2,2-tetrafluoro-etho-
xy)-benzyl]-amino}-1,1,1-trifluoro-propan-2-ol. To address the poor
solubility of many of the CETP inhibitors, an appropriate dosage
form such as one comprising (1) a solid amorphous dispersion
comprising a cholesteryl ester transfer protein (CETP) inhibitor
and an acidic concentration-enhancing polymer; and (2) an
acid-sensitive HMG-CoA reductase inhibitor, may be necessary. This
dosage form is more fully described in U.S. Ser. No.
10/739,567.
[0242] Any peroxisome proliferator activated receptor ("PPAR")
activator known in the art that activates or otherwise interacts
with a human PPAR may be used. Three mammalian PPARs have been
isolated and termed PPAR-alpha, PPAR-gamma, and PPAR-beta (also
known as NUC1 or PPAR-delta). These PPARs regulate expression of
target genes by binding to DNA sequence elements, termed PPAR
response elements. These elements have been identified in the
enhancers of a number of genes encoding proteins that regulate
lipid metabolism suggesting that PPARs play a pivotal role in the
adipogenic signaling cascade and lipid homeostasis. PPAR-gamma
receptors are associated with regulation of insulin sensitivity and
blood glucose levels. PPAR-.alpha. activators are associated with
lowering plasma triglycerides and LDL cholesterol. PPAR-.beta.
activators have been reported to both increase HDL-C levels and to
decrease LDL-C levels. Thus, activation of PPAR-.beta. alone, or in
combination with the simultaneous activation of PPAR-.alpha. and/or
PPAR-gamma may be desirable in formulating a treatment for
dyslipidemia in which HDL is increased and LDL lowered.
PPAR-activation is readily determined by those skilled in the art
by the standard assays (e.g. US 2003/0225158 and US 2004/0157885).
Examples of suitable PPAR-activator compounds include, but are not
limited to, those described in US 2003/0171377, US 2003/0225158, US
2004/0157885, and U.S. Pat. No. 6,710,063. Additional examples of
useful PPAR-activator compounds include the following compounds:
[5-Methoxy-2-methyl-4-(4'-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-ph-
enoxy]-acetic acid;
[5-Methoxy-2-methyl-4-(3'-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-ph-
enoxy]-acetic acid;
[4-(4'Fluoro-biphenyl-4-ylmethylsulfanyl)-5-methoxy-2methyl-phenoxy]-acet-
ic acid;
{5-Methoxy-2methyl-4-[4-(4-trifluoromethyl-benzyloxy)-benzylsulfa-
nyl]-phenoxy}-acetic acid;
{5-Methoxy-2-methyl-4-[4-(5-trifluoromethyl-pryidin-2-yl)-benzylsulfanyl]-
-phenoxy}-acetic acid;
(4-{4-[2-(3-Fluoro-phenyl)-vinyl]-benzylsulfanyl}-5-methoxy-2-methyl-phen-
oxy)-acetic acid;
[5-Methoxy-2-methyl-4-(3-methyl-4'-trifluoromethyl-biphenyl-4-ylmethylsul-
fanyl)-phenoxy]-acetic acid;
[5-Methoxy-2-methyl-4-(4'-trifluoromethyl-biphenyl-3-ylmethylsulfanyl)-ph-
enoxy]-acetic acid;
{5-Methoxy-2-methyl-4-[2-(4-trifluoromethyl-benzyloxy)-benzylsulfanyl]-ph-
enoxy}acetic acid; 3-{5-[2-(-5-Methyl-2
phenyl-oxazol-4-yl-ethoxy]-indol-1-yl}-propionic acid;
3-{4[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy-1H-indazol-1yl}propanoic
acid;
2-Methyl-2-{3-[({2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]carbon-
yl}amino)methyl]phenoxy}propionic acid;
1-{3'-[2-5-Methyl-2-phenyl-1,3-oxazol-4-y]-1,1'-biphenyl-3-yl}oxy)cyclobu-
tanecarboxylic acid;
3-[3-(1-Carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic
acid 3-trifluoromethyl-benzyl ester;
2-{2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}-
methyl)sulfanyl]phenoxy}acetic acid;
2-{2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-oxazol-5-yl}m-
ethyl)sulfanyl]phenoxy}acetic acid; methyl
2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)su-
lfanyl]phenoxy}acetate;
2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)su-
lfanyl]phenoxy}acetic acid;
(E)-3-[2-methyl-4-({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5--
yl}methoxy)phenyl]-2-propenoic acid;
2-{3-chloro-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}-
methyl)sulfanyl]phenyl}acetic acid;
2-{2-methyl-4-[({4-methyl-2-[3-fluoro-4-(trifluoromethyl)phenyl]-1,3-thia-
zol-5-yl}methyl)sulfanyl]phenoxy}acetic acid; and pharmaceutically
acceptable salts thereof.
[0243] Any MTP/Apo B secretion (microsomal triglyceride transfer
protein and/or apolipoprotein B secretion) inhibitor known in the
art which inhibits the secretion of triglycerides, cholesteryl
ester and phospholipids may be used. Such inhibition may be readily
determined according to standard assays (e.g., Wetterau, J. R.
1992; Science 258:999). Examples of suitable a MTP/Apo B secretion
inhibitor include, but are not limited to, imputapride (Bayer) as
well as those described in WO 96/40640 and WO 98/23593.
[0244] Any ACAT inhibitor known in the art that inhibits the
intracellular esterification of dietary cholesterol by the enzyme
acyl CoA: cholesterol acyltransferase may be used. Such inhibition
may be determined readily according to standard assays, such as the
method of Heider et al. described in Journal of Lipid Research.
24:1127 (1983). Examples of suitable ACAT inhibitors include, but
are not limited to, those described in U.S. Pat. No. 5,510,379
(carboxysulfonates), WO 96/26948 and WO 96/10559 (urea
derivatives). Additional examples include Avasimibe (Pfizer),
CS-505 (Sankyo) and Eflucimibe (Eli Lilly and Pierre Fabre).
[0245] Any lipase inhibitor (e.g., pancreatic lipase inhibitor, a
gastric lipase inhibitor) known in the art that inhibits the
metabolic cleavage of dietary triglycerides into free fatty acids
and monoglycerides may be used. Such lipase inhibition activity may
be readily determined according to standard assays (e.g., Methods
Enzymol. 286: 190-231). Examples of a suitable lipase inhibitor
include, but are not limited to, lipstatin,
(2S,3S,5S,7Z,10Z)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydro-
xy-7,10-hexadecanoic acid lactone, and tetrahydrolipstatin
(orlistat),
(2S,3S,5S)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydroxy-hexa-
decanoic 1,3 acid lactone, and the variously substituted
N-formylleucine derivatives and stereoisomers thereof (U.S. Pat.
No. 4,598,089); tetrahydrolipstatin U.S. Pat. Nos. 5,274,143;
5,420,305; 5,540,917; and 5,643,874; FL-386,
1-[4-(2-methylpropyl)cyclohexyl]-2-[-(phenylsulfonyl)oxy]-ethanone,
and the variously substituted sulfonate derivatives related thereto
(U.S. Pat. No. 4,452,813); WAY-121898,
4-phenoxyphenyl-4-methylpiperidin-1-yl-carboxylate, and the various
carbamate esters and pharmaceutically acceptable salts related
thereto (U.S. Pat. Nos. 5,512,565; 5,391,571 and 5,602,151);
valilactone, and a process for the preparation thereof by the
microbial cultivation of Actinomycetes strain MG147-CF2 (Kitahara,
et al., J. Antibiotics, 40 (11), 1647-1650 (1987)); esterastin;
ebelactone A and ebelactone B, and a process for the preparation
thereof by the microbial cultivation of Actinomycetes strain MG7-G1
(Umezawa, et al., J. Antibiotics, 33, 1594-1596 (1980); Japanese
Kokai 08-143457, published Jun. 4, 1996). The compound
tetrahydrolipstatin is especially preferred. Additional examples
include
N-3-trifluoromethylphenyl-N'-3-chloro-4'-trifluoromethylphenylure-
a, and the various urea derivatives related thereto, U.S. Pat. No.
4,405,644; esteracin (U.S. Pat. Nos. 4,189,438 and 4,242,453); and
cyclo-O,O'-[(1,6-hexanediyl)-bis-(iminocarbonyl)]dioxime, and the
various bis(iminocarbonyl)dioximes related thereto (Petersen et
al., Liebig's Annalen, 562, 205-229 (1949).
[0246] Any bile acid sequestrant known in the art may be used.
Examples of suitable bile acid sequestrants include, but are not
limited to, WELCHOL.RTM., COLESTID.RTM., LoCHOLEST.RTM.,
QUESTRAN.RTM. and fibric acid derivatives, such as ATROMID.RTM.,
LOPID.RTM. and TRICOR.RTM..
[0247] A compound of the invention can be used in combination with
an anti-diabetic compound, i.e. any compound (e.g. insulin) used in
the treating diabetes (especially Type II), insulin resistance,
impaired glucose tolerance, or the like, or any of the diabetic
complications such as neuropathy, nephropathy, retinopathy or
cataracts. Additional examples of an anti-diabetic compound
include, but are not limited to, a glycogen phosphorylase
inhibitor, an aldose reductase inhibitor, a sorbitol dehydrogenase
inhibitor, a glucosidase inhibitor, and an amylase inhibitor.
[0248] Any glycogen phosphorylase inhibitor known in the art that
inhibits the bioconversion of glycogen to glucose-1-phosphate which
is catalyzed by the enzyme glycogen phosphorylase may be used. Such
glycogen phosphorylase inhibition activity may be readily
determined according to standard assays (e.g., J. Med. Chem. 41
(1998) 2934-2938). A variety of glycogen phosphorylase inhibitors
are known to those skilled in the art including those described in
WO 96/39384 and WO 96/39385.
[0249] Any aldose reductase inhibitor known in the art that
inhibits the bioconversion of glucose to sorbitol catalyzed by the
enzyme aldose reductase. Aldose reductase inhibition may be readily
determined according to standard assays (e.g., J. Malone, Diabetes,
29:861-864 (1980). "Red Cell Sorbitol, an Indicator of Diabetic
Control").
[0250] Any sorbitol dehydrogenase inhibitor known in the art that
inhibits the bioconversion of sorbitol to fructose catalyzed by the
enzyme sorbitol dehydrogenase may be used. Such sorbitol
dehydrogenase inhibitor activity may be readily determined
according to standard assays (e.g., Analyt. Biochem (2000) 280:
329-331). Examples of a suitable sorbitol dehydrogenase inhibitor
include, but are not limited to, those described in U.S. Pat. Nos.
5,728,704 and 5,866,578.
[0251] Any glucosidase inhibitor known in the art that inhibits the
enzymatic hydrolysis of complex carbohydrates by glycoside
hydrolases, for example amylase or maltase, into bioavailable
simple sugars, for example, glucose. Such glucosidase inhibition
activity may be readily determined by those skilled in the art
according to standard assays (e.g., Biochemistry (1969) 8:
4214).
[0252] A generally preferred glucosidase inhibitor includes an
amylase inhibitor. Any amylase inhibitor known in the art that
inhibits the enzymatic degradation of starch or glycogen into
maltose may be used. Such amylase inhibition activity may be
readily determined by those skilled in the art according to
standard assays (e.g., Methods Enzymol. (1955) 1: 149).
[0253] Other preferred glucosidase inhibitors include, but are not
limited to, acarbose and the various amino sugar derivatives
related thereto (U.S. Pat. Nos. 4,062,950 and 4,174,439); adiposine
(U.S. Pat. No. 4,254,256); voglibose,
3,4-dideoxy-4-[[2-hydroxy-1-(hydroxymethyl)ethyl]amino]-2-C-(hydroxymethy-
l)-D-epi-inositol, and the various N-substituted pseudo-aminosugars
related thereto (U.S. Pat. No. 4,701,559); miglitol,
(2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydro-oxymethyl)-3,4,5-piperidinetrio-
l, and the various 3,4,5-trihydroxypiperidines related thereto
(U.S. Pat. No. 4,639,436); emiglitate, ethyl
p-[2-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidino]ethoxy]--
benzoate, the various derivatives related thereto and
pharmaceutically acceptable acid addition salts thereof (U.S. Pat.
No. 5,192,772); MDL-25637,
2,6-dideoxy-7-O-.beta.-D-glucopyranosyl-2,6-imino-D-glycero-L-gluco-hepti-
tol, the various homodisaccharides related thereto and the
pharmaceutically acceptable acid addition salts thereof (U.S. Pat.
No. 4,634,765); camiglibose, methyl
6-deoxy-6-[(2R,3R,4R,5S)-3,4,5-trihydroxy-2-(hydroxymethyl)piperidino]-.a-
lpha.-D-glucopyranoside sesquihydrate, the deoxy-nojirimycin
derivatives related thereto, the various pharmaceutically
acceptable salts thereof and synthetic methods for the preparation
thereof (U.S. Pat. Nos. 5,157,116 and 5,504,078); pradimicin-Q; and
salbostatin and the various pseudosaccharides related thereto (U.S.
Pat. No. 5,091,524).
[0254] Any amylase inhibitor known in the art may be used. Examples
include, but are not limited to, tendamistat and the various cyclic
peptides related thereto (U.S. Pat. No. 4,451,455); AI-3688 and the
various cyclic polypeptides related thereto (U.S. Pat. No.
4,623,714); and trestatin, consisting of a mixture of trestatin A,
trestatin B and trestatin C and the various trehalose-containing
aminosugars related thereto, (U.S. Pat. No. 4,273,765).
[0255] Additional examples of an anti-diabetic compound for use in
a combination of the invention include: biguanides (e.g.,
metformin), insulin secretagogues (e.g., sulfonylureas and
glinides), glitazones, non-glitazone PPAR.gamma. agonists,
PPAR.beta. agonists, inhibitors of DPP-IV, inhibitors of PDE5,
inhibitors of GSK-3, glucagon antagonists, inhibitors of
f-1,6-BPase (Metabasis/Sankyo), GLP-1/analogs (AC 2993, also known
as exendin-4), insulin and insulin mimetics (Merck natural
products), PKC-beta inhibitors, and AGE breakers.
[0256] A compound of the invention can be used in combination with
any anti-obesity agent known in the art. Anti-obesity activity may
be readily determined according to standard assays known in the
art. Examples of suitable anti-obesity agents include, but are not
limited to, phenylpropanolamine, ephedrine, pseudoephedrine,
phentermine, .beta.sub.3 adrenergic receptor agonists,
apolipoprotein-B secretion/microsomal triglyceride transfer protein
(apo-B/MTP) inhibitors, MCR-4 agonists, cholecystokinin-A (CCK-A)
agonists, monoamine reuptake inhibitors (e.g., sibutramine--U.S.
Pat. No. 4,929,629), sympathomimetic agents, serotoninergic agents,
cannabinoid receptor antagonists (e.g., rimonabant (SR-141,716A)),
dopamine agonists (e.g., bromocriptine--U.S. Pat. Nos. 3,752,814
and 3,752,888), melanocyte-stimulating hormone receptor analogs,
5HT2c agonists, melanin concentrating hormone antagonists, leptin
(the OB protein), leptin analogs, leptin receptor agonists, galanin
antagonists, lipase inhibitors (e.g., tetrahydrolipstatin, i.e.
orlistat), bombesin agonists, anorectic agents (e.g., a bombesin
agonist), Neuropeptide-Y antagonists, thyroxine, thyromimetic
agents, dehydroepiandrosterones or analogs thereof, glucocorticoid
receptor agonists or antagonists, orexin receptor antagonists,
urocortin binding protein antagonists, glucagon-like peptide-1
receptor agonists, ciliary neurotrophic factors (e.g.,
Axokine.TM.), human agouti-related proteins (AGRP), ghrelin
receptor antagonists, histamine 3 receptor antagonists or inverse
agonists, neuromedin U receptor agonists, and the like.
[0257] Any thyromimetic agent known in the art may also be used in
combination with a compound of the invention. Thyromimetic activity
may be readily determined according to standard assays (e.g.,
Atherosclerosis (1996) 126: 53-63). Examples of suitable
thyromimetic agents include, but are not limited to, those
described in U.S. Pat. Nos. 4,766,121; 4,826,876; 4,910,305;
5,061,798; 5,284,971; 5,401,772; 5,654,468; and 5,569,674.
[0258] A compound of the invention may further be used in
combination with an anti-resorptive agent (e.g., progestins,
polyphosphonates, bisphosphonate(s), estrogen agonists/antagonists,
estrogen, estrogen/progestin combinations, Premarin.TM., estrone,
estriol or 17.alpha.- or 17.beta.-ethynyl estradiol). Exemplary
progestins are available from commercial sources and include, but
are not limited to: algestone acetophenide, altrenogest, amadinone
acetate, anagestone acetate, chlormadinone acetate, cingestol,
clogestone acetate, clomegestone acetate, delmadinone acetate,
desogestrel, dimethisterone, dydrogesterone, ethynerone, ethynodiol
diacetate, etonogestrel, fluorogestone acetate, gestaclone,
gestodene, gestonorone caproate, gestrinone, haloprogesterone,
hydroxyprogesterone caproate, levonorgestrel, lynestrenol,
medrogestone, medroxyprogesterone acetate, melengestrol acetate,
methynodiol diacetate, norethindrone, norethindrone acetate,
norethynodrel, norgestimate, norgestomet, norgestrel, oxogestone
phenpropionate, progesterone, quingestanol acetate, quingestrone,
and tigestol. Preferred progestins are medroxyprogestrone,
norethindrone and norethynodrel.
[0259] Exemplary bone resorption inhibiting polyphosphonates
include polyphosphonates of the type described in U.S. Pat. No.
3,683,080. Preferred polyphosphonates are geminal diphosphonates
(also referred to as bis-phosphonates),
6-amino-1-hydroxy-hexylidene-bisphosphonic acid and
1-hydroxy-3(methylpentylamino)-propylidene-bisphosphonic acid.
Tiludronate disodium, ibandronic acid, alendronate, resindronate,
and zoledronic acid are each especially preferred polyphosphonates.
The polyphosphonates may be administered in the form of the acid,
or of a soluble alkali metal salt or alkaline earth metal salt.
Hydrolyzable esters of the polyphosphonates are likewise included.
Specific examples include, but are not limited to, ethane-1-hydroxy
1,1-diphosphonic acid, methane diphosphonic acid,
pentane-1-hydroxy-1,1-diphosphonic acid, methane dichloro
diphosphonic acid, methane hydroxy diphosphonic acid,
ethane-1-amino-1,1-diphosphonic acid,
ethane-2-amino-1,1-diphosphonic acid,
propane-3-amino-1-hydroxy-1,1-diphosphonic acid,
propane-N,N-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid,
propane-3,3-dimethyl-3-amino-1-hydroxy-1,1-diphosphonic acid,
phenyl amino methane diphosphonic acid, N,N-dimethylamino methane
diphosphonic acid, N(2-hydroxyethyl)amino methane diphosphonic
acid, butane-4-amino-1-hydroxy-1,1-diphosphonic acid,
pentane-5-amino-1-hydroxy-1-1,1-diphosphonic acid,
hexane-6-amino-1-hydroxy-1,1-diphosphonic acid and pharmaceutically
acceptable esters and salts thereof.
[0260] Any estrogen agonist/antagonist known in the art which bind
with the estrogen receptor, inhibit bone turnover and/or prevent
bone loss may be used in a combination of the invention. More
specifically, an estrogen agonist may be any chemical compound
capable of binding to the estrogen receptor sites in mammalian
tissue, and mimicking the actions of estrogen in one or more
tissue. An estrogen antagonist may be any chemical compound capable
of binding to the estrogen receptor sites in mammalian tissue, and
blocking the actions of estrogen in one or more tissues. Such
activities may be readily determined according to standard assays,
including estrogen receptor binding assays, and standard bone
histomorphometric and densitometer methods (Eriksen E. F. et al.,
Bone Histomorphometry, Raven Press, New York, 1994, pages 1-74;
Grier S. J. et. al., "The Use of Dual-Energy X-Ray Absorptiometry
In Animals", Inv. Radiol., 1996, 31(1):50-62; Wahner H. W. and
Fogelman I., The Evaluation of Osteoporosis: Dual Energy X-Ray
Absorptiometry in Clinical Practice, Martin Dunitz Ltd., London
1994, pages 1-296). Examples of a suitable estrogen
agonist/antagonist is
3-(4-(1,2-diphenyl-but-1-enyl)-phenyl)-acrylic acid (see Willson et
al., Endocrinology, 1997, 138, 3901-3911); tamoxifen (ethanamine,
2-(-4-(1,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl, (Z)-2-,
2-hydroxy-1,2,3-propanetricarboxylate (1:1)) and related compounds
(U.S. Pat. No. 4,536,516); 4-hydroxy tamoxifen (U.S. Pat. No.
4,623,660); raloxifene (methanone,
(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl)(4-(2-(1-piperidinyl)eth-
oxy)phenyl)-hydrochloride) (U.S. Pat. No. 4,418,068); toremifene
(ethanamine,
2-(4-(4-chloro-1,2-diphenyl-1-butenyl)phenoxy)-N,N-dimethyl-, (Z)-,
2-hydroxy-1,2,3-propanetricarboxylate (1:1) (U.S. Pat. No.
4,996,225); centchroman (1-(2-((4-(-methoxy-2,2,
dimethyl-3-phenyl-chroman-4-yl)-phenoxy)-ethyl)-p-pyrrolidine)
(U.S. Pat. No. 3,822,287); levormeloxifene; idoxifene
((E)-1-(2-(4-(1-(4-iodo-phenyl)-2-phenyl-but-1-enyl)-phenoxy)-ethyl)-pyrr-
olidinone (U.S. Pat. No. 4,839,155);
2-(4-methoxy-phenyl)-3-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-benzo[b]thio-
phen-6-ol (U.S. Pat. No. 5,488,058);
6-(4-hydroxy-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-benzyl)-naphthalen-2--
ol (U.S. Pat. No. 5,484,795);
(4-(2-(2-aza-bicyclo[2.2.1]hept-2-yl)-ethoxy)-phenyl)-(6-hydroxy-2-(4-hyd-
roxy-phenyl)-benzo[b]thiophen-3-yl)-methanone (WO 95/10513 assigned
to Pfizer Inc.); TSE-424 (Wyeth-Ayerst Laboratories); arazoxifene;
derivatives of 2-phenyl-3-aroyl-benzothiophene and
2-phenyl-3-aroylbenzothiophene-1-oxide (U.S. Pat. No. 4,133,814);
estrogen agonist/antagonists described in U.S. Pat. No. 4,133,814;
and estrogen agonist/antagonists described in commonly assigned
U.S. Pat. No. 5,552,412.
[0261] Especially preferred estrogen agonist/antagonists described
in U.S. Pat. No. 5,552,412 are:
cis-6-(4-fluoro-phenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,-7,8-t-
etrahydro-naphthalene-2-ol;
(-)-cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahyd-
ro-naphthalene-2-ol (also known as lasofoxifene);
cis-6-phenyl-5-(4-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-5,6,7,8-tetrahydro-n-
aphthalene-2-ol;
cis-1-(6'-pyrrolodinoethoxy-3'-pyridyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrah-
ydronaphthalene;
1-(4'-pyrrolidinoethoxyphenyl)-2-(4''-fluorophenyl)-6-hydroxy-1,2,3,-4-te-
trahydroisoquinoline;
cis-6-(4-hydroxyphenyl)-5-(4-(2-piperidin-1-yl-ethoxy)-phenyl)-5,6,-7,8-t-
etrahydro-naphthalene-2-ol; and
1-(4'-pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahydroisoq-
uinoline.
[0262] Any anti-osteoporosis agent known in the art may be used in
a combination of the invention. Examples include, but are not
limited to, parathyroid hormone (PTH) (a bone anabolic agent);
parathyroid hormone (PTH) secretagogues (see, e.g., U.S. Pat. No.
6,132,774), particularly calcium receptor antagonists; calcitonin;
and vitamin D and vitamin D analogs.
[0263] Any antihypertensive agent known in the art may be used in a
combination of the invention. Antihypertensive activity may be
determined according to standard tests (e.g. blood pressure
measurements). Examples of suitable antihypertensive agents
include, but are not limited to, (a) amlodipine and related
dihydropyridine compounds (U.S. Pat. Nos. 4,572,909 and 5,155,120)
such as, but not limited to, amlodipine benzenesulfonate salt (also
termed amlodipine besylate (NORVASC.RTM.)) (U.S. Pat. No.
4,879,303) and other pharmaceutically acceptable acid addition
salts of amlodipine (U.S. Pat. No. 5,155,120); (b) calcium channel
blockers such as, but not limited to, bepridil (U.S. Pat. No.
3,962,238 or U.S. Reissue No. 30,577), clentiazem (U.S. Pat. No.
4,567,175), diltiazem (U.S. Pat. No. 3,562), fendiline (U.S. Pat.
No. 3,262,977), gallopamil (U.S. Pat. No. 3,261,859); mibefradil,
prenylamine, semotiadil, terodiline, verapamil, aranipine,
barnidipine, benidipine, cilnidipine, efonidipine, elgodipine,
felodipine, isradipine, lacidipine, lercanidipine, manidipine,
nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine,
nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine,
bencyclane, etafenone, and perhexyline; (c) angiotensin converting
enzyme inhibitors ("ACE-inhibitors") such as, but not limited to,
alacepril (U.S. Pat. No. 4,248,883), benazepril (U.S. Pat. No.
4,410,520), captopril, ceronapril, delapril, enalapril, fosinopril,
imadapril, lisinopril, moveltopril, perindopril, quinapril,
ramipril, spirapril, temocapril, and trandolapril; (d)
angiotensin-II receptor antagonists such as, but not limited to,
candesartan (U.S. Pat. No. 5,196,444), eprosartan (U.S. Pat. No.
5,185,351), irbesartan, losartan, and valsartan; (e)
beta-adrenergic receptor blockers (beta- or -blockers) such as, but
not limited to, acebutolol (U.S. Pat. No. 3,857,952), alprenolol,
amosulalol (U.S. Pat. No. 4,217,305), arotinolol, atenolol,
befunolol, betaxolol; and (f) alpha-adrenergic receptor blockers
(alpha- or .alpha.-blockers) such as, but not limited to,
amosulalol (U.S. Pat. No. 4,217,307), arotinolol (U.S. Pat. No.
3,932,400), dapiprazole, doxazosin, fenspiride, indoramin,
labetolol, naftopidil, nicergoline, prazosin, tamsulosin,
tolazoline, trimazosin, and yohimbine, which may be isolated from
natural sources according to methods well known to those skilled in
the art.
[0264] Any compound that is known to be useful in the treatment of
Alzheimer's disease may be used in a combination of the invention.
Such compounds include acetylcholine esterase inhibitors. Examples
of known acetylcholine esterase inhibitors include, but not limited
to donepezil (ARICEPT.RTM.; U.S. Pat. Nos. 4,895,841, 5,985,864,
6,140,321, 6,245,911 and 6,372,760), tacrine (COGNEX.RTM.; U.S.
Pat. Nos. 4,631,286 and 4,816,456), rivastigmine (EXELON.RTM.; U.S.
Pat. Nos. 4,948,807 and 5,602,17) and galantamine (REMINYL; U.S.
Pat. Nos. 4,663,318 and 6,099,863).
[0265] The present invention contains compounds that can be
synthesized in a number of ways familiar to one skilled in organic
synthesis. The following non-limiting reaction schemes illustrate
the preparation of the compounds of the present invention. Unless
otherwise indicated, all variables in the reaction schemes and the
discussion that follow are defined above. Also unless indicated
otherwise, all starting materials and/or reagents are commercially
available. As would be understood by one of skill in the art,
individual compounds may require manipulation of the conditions in
order to accommodate various functional groups. A variety of
protecting groups known to one skilled in the art may be required.
Purification, if necessary, may be accomplished on a silica gel
column eluted with the appropriate organic solvent system. Also,
reverse phase HPLC or recrystallization may be employed.
##STR00023##
[0266] Scheme 1 describes a general synthetic scheme for the
preparation of a compound (12) from an amine (1). As would be
understood by one of skill in the art, elimination of the
hydrogenation step from the conversion of compound (10) to compound
(11) provides the corresponding olefin derivative.
##STR00024##
[0267] Scheme 1a highlights the preparation of compounds of this
invention using compound (24) as a representative, non-limiting
example. As shown, 4-fluoroaniline (13) (commercially available
from Sigma-Aldrich, Milwaukee, Wis.) was initially converted to a
diazonium salt and reacted with methyl 2-chloroacetoacetate to give
hydrazonoyl chloride (14). Treatment of hydrazonoyl chloride (14)
with Ag.sub.2CO.sub.3 resulted in in-situ generation of a
nitrilimine that was engaged in a 1,3-dipolar cycloaddition with
enone (16) to provide dihydropyrazole (17) as the major
regioisomer. Ceric ammonium nitrate (CAN) oxidation converted
dihydropyrazole (17) to pyrazole (18). Through a subsequent series
of routine manipulations pyrazole (18) was converted to amide (20).
The mevalonate side chain was installed by initial reduction of the
aldehyde functionality of intermediate (20) to the corresponding
alcohol which was converted to phosphonium salt (21) by treatment
with triphenylphosphine hydrobromide. Wittig olefination of
phosphonium salt (21) afforded olefin (22). Removal of the
acetonide protecting group with HCl followed by hydrogenation gave
intermediate (23). Elimination of the hydrogenation step in this
last step provides the corresponding olefin derivative. Finally,
the ester of compound (23) was hydrolyzed by treatment with NaOH to
give compound (24) which was isolated as a carboxylate salt.
##STR00025##
[0268] Scheme 1b illustrates another method for the preparation of
amide (20). Hydroxy-pyrazole (25) was prepared according to
procedures described in attorney docket number PC32787, U.S.
Provisional Application No. 60/653,469 filed on Feb. 15, 2005 and
was then converted to triflate (26). A palladium-mediated coupling
of triflate (26) with 2-styreneboronic acid afforded compound (27)
which was subsequently subjected to ozonolysis conditions to
provide aldehyde (28). Hydrolysis of the ester of intermediate (28)
provided carboxylic acid (29) which was finally converted to amide
(20) via an N-(3-dimethylaminopropyl)-N-ethylcarbodiimide
hydrochloride (EDCI) mediated coupling reaction.
##STR00026##
[0269] Scheme 2 describes an additional method for the preparation
of compounds of this invention. As illustrated, intermediate (10,
from Scheme 1) is hydrogenated over Pd--C to provide compound (30).
Treatment of compound (30) with 20% TFA/CH.sub.2Cl.sub.2 provides
lactone (32) via carboxylic acid (31). Lactone (32) can be utilized
as is or converted to the corresponding carboxylate sodium salt
(12) by treatment with NaOH.
##STR00027##
[0270] Scheme 2a describes an alternative method for the
preparation of compound (24) utilizing compound (22) as a
representative, non-limiting example of the invention. As
illustrated, intermediate (22, from Scheme 1a) is hydrogenated over
Pd--C to provide compound (33). Treatment of compound (28) with 20%
TFA/CH.sub.2Cl.sub.2 provides lactone (35) via the intermediacy of
carboxylic acid (34). Lactone (35) can be utilized as is or
converted to the corresponding carboxylate sodium salt (24) by
treatment with NaOH.
##STR00028##
[0271] Scheme 3 illustrates a method for preparing compound (12).
Aldehyde (8) was prepared as set forth in Scheme 1 and was then
condensed with the known phosphonium ylide (36) [for preparation,
see: Konoike, T.; Araki, Y. J. Org. Chem. 1994, 59, 7849-7854] to
afford olefin (37). Treatment of compound (37) with hydrofluoric
acid afforded keto-alcohol (38) which was subsequently reduced with
sodium borohydride to give diol (39). The olefin of compound (39)
was then hydrogenated giving (40) which was treated with aqueous
sodium hydroxide to provide compound (12).
##STR00029##
[0272] Scheme 3a illustrates a method for preparing compound (46)
as a representative, non-limiting example of the invention.
Aldehyde (41) was prepared according to the method of Scheme 1 for
the preparation of compound (8) and was then condensed with the
known phosphonium ylide (36) [for preparation, see: Konoike, T.;
Araki, Y. J. Org. Chem. 1994, 59, 7849-7854] to afford olefin (42).
Treatment of compound (42) with hydrofluoric acid afforded
keto-alcohol (43) which was subsequently reduced with sodium
borohydride to give diol (44). The olefin of compound (44) was then
hydrogenated giving (45) which was treated with aqueous sodium
hydroxide to provide compound (46).
##STR00030##
[0273] Scheme 4 highlights the preparation of compounds of this
invention using compound (58) as a representative, non-limiting
example. As shown, amine (47) is converted to a diazonium salt and
reacted with 2-chloro-3-oxo-butyronitrile (J. Org. Chem. 1978, 43,
3821-3824) to give hydrazonoyl chloride (48). Treatment of
hydrazonoyl chloride (48) with Ag.sub.2CO.sub.3 results in in-situ
generation of a nitrilimine that is engaged in a 1,3-dipolar
cycloaddition with enone (50) to provide dihydropyrazole (51).
Ceric ammonium nitrate (CAN) oxidation converts dihydropyrazole
(51) to pyrazole (52). Hydrogenation of pyrazole (52) over either
Pd--C or Raney-Ni followed by treatment with R.sub.2bC(O)Cl and
base provides amide (53). Reduction of (53) followed by oxidation
provides intermediate (54). Intermediate (54) can be optionally
N-alkylated by treatment with R.sub.2a--Cl and base. The mevalonate
side chain is installed by initial reduction of the aldehyde
functionality of intermediate (54) to the corresponding to alcohol
which is converted to phosphonium salt (55) by treatment with
triphenylphosphine hydrobromide. Wittig olefination of phosphonium
salt (55) affords olefin (56). Removal of the acetonide protecting
group with HCl followed by hydrogenation gives intermediate (57).
Elimination of the hydrogenation step in this last step provides
the corresponding olefin derivative. Finally, the ester of compound
(57) is hydrolyzed by treatment with NaOH to give compound (58)
which is isolated as a carboxylate salt. Notably, substitution of
R.sub.2bC(O)Cl with R.sub.2bSOCl or R.sub.2bSO.sub.2Cl in the
conversion of (52) to (53) allows for preparation of the
corresponding sulfinamide and sulfonamide derivatives of compound
(58), respectively.
##STR00031##
[0274] Scheme 5 highlights the preparation of compounds of this
invention using compound (72) as a representative, non-limiting
example. As shown, amine (59) is converted to a diazonium salt and
reacted with methyl 2-chloroacetoacetate to give hydrazonoyl
chloride (60). Treatment of hydrazonoyl chloride (60) with
Ag.sub.2CO.sub.3 results in in-situ generation of a nitrilimine
that is engaged in a 1,3-dipolar cycloaddition with enone (62) to
provide dihydropyrazole (63). Ceric ammonium nitrate (CAN)
oxidation converts dihydropyrazole (63) to pyrazole (64).
Hydrogenation of pyrazole (64) over Pd--C followed by reduction and
protection provides compound (65). Hydrolysis of (65) gives a
carboxylic acid that is treated with diphenylphosphoryl azide in
t-BuOH at elevated temperature to provide compound (66). Acidic
deprotection and acylation with R.sub.2bC(O)Cl provides
intermediate (67) which can be optionally N-alkylated by treatment
with R.sub.2a--Cl and base. The mevalonate side chain is installed
by initial deprotection of the alcohol functionality of
intermediate (67) and conversion to phosphonium salt (69) by
treatment with triphenylphosphine hydrobromide. Wittig olefination
of phosphonium salt (69) affords olefin (70). Removal of the
acetonide protecting group with HCl followed by hydrogenation gives
intermediate (71). Elimination of the hydrogenation step in this
last step provides the corresponding olefin derivative. Finally,
the ester of compound (71) is hydrolyzed by treatment with NaOH to
give compound (72) which is isolated as a carboxylate salt.
Notably, substitution of R.sub.2bC(O)Cl with R.sub.2bSOCl or
R.sub.2bSO.sub.2Cl in the conversion of (66) to (67) allows for
preparation of the corresponding sulfinamide and sulfonamide
derivatives of compound (72). Notably, substitution of
R.sub.2bC(O)Cl with R.sub.2bSOCl or R.sub.2bSO.sub.2Cl in the
conversion of (66) to (67) allows for preparation of the
corresponding sulfinamide and sulfonamide derivatives of compound
(72), respectively.
##STR00032##
[0275] Scheme 6a illustrates the preparation of compound (78).
Hydroxyl compound (73) is reacted under suitable conditions to form
compound (74). The "LG-O" of compound (74) together represents any
suitable leaving group such as, for example,
trifluoromethanesulfonate (CF.sub.3SO.sub.3), mesylate
(CH.sub.3SO.sub.3), tosylate (CH.sub.3C.sub.6H.sub.4SO.sub.3), such
that upon reaction with a suitable boronic acid or ester affords
compound (75). Examples of suitable boronic acids and esters
include any boronic acid or boronic ester that would convert
compound (74) to compound (75) including those of formula
Z-B(OR.sup.9)(OR.sup.10) where Z is R''' or R''''CX'=CX''Y where
R''' can be alkenyl; R.sup.9, R.sup.10, R'''', X' and X'' can each
be hydrogen, alkyl, alkenyl, aryl, heteroaryl, or alkenyl
substituent and where R.sup.9 and R.sup.10 can be taken together
with the oxygens to which they are attached to form a mono-, bi- or
polycyclic ring optionally containing one or more degrees of
unsaturation and optionally further substituted; Y is either a
direct bond or a linker group (e.g. alkylene group); and wherein
the non-hydrogen groups of R.sup.9, R.sup.10, R''', R'''', X', X'',
and Y are optionally substituted as defined herein.
[0276] Compound (75) can then be subjected to ozonolysis conditions
to afford aldehyde (76). Hydrolysis of the ester moiety of (76)
will provide carboxylic acid (77) which in turn can then be
converted to amide (78) via an EDCI mediated coupling reaction.
Compound (78) can then be converted to a compound of the invention
in a manner analogous to the conversion of compound (8) to compound
(12) illustrated in Scheme 1.
[0277] Alternatively, the conversion of compound (74) to compound
(75) can be achieved using a compound of formula
(R.sup.10O)(R.sup.90)B-Z-B(OR.sup.9)(OR.sup.10), wherein Z, R.sup.9
and R.sup.10 are each independently as defined herein.
[0278] Alternatively, the conversion of compound (74) to compound
(75) can be achieved using a compound of formula Z-BF.sub.3K,
wherein Z is as defined herein.
##STR00033##
[0279] Scheme 6b illustrates the preparation of compound (82).
Hydroxyl compound (79) is reacted under suitable conditions to form
compound (80). The "LG-O" of compound (80) together represents any
suitable leaving group such as, for example,
trifluoromethanesulfonate (CF.sub.3SO.sub.3), mesylate
(CH.sub.3SO.sub.3), tosylate (CH.sub.3C.sub.6H.sub.4SO.sub.3), such
that upon reaction with a suitable boronic acid or ester affords
compound (81). Examples of suitable boronic acids and esters
include any boronic acid or ester that would convert compound (80)
to compound (81) including those of formula
Z-B(OR.sup.9)(OR.sup.10) where Z is R''' or R''''CX'=CX''Y where
R''' can be alkenyl; R.sup.9, R.sup.10, R'''', X' and X'' can each
be hydrogen, alkyl, alkenyl, aryl, heteroaryl, or alkenyl
substituent and where R.sup.9 and R.sup.10 can be taken together
with the oxygens to which they are attached to form a mono-, bi- or
polycyclic ring optionally containing one or more degrees of
unsaturation and optionally further substituted; Y is either a
direct bond or a linker group (e.g. alkylene linker group); and
wherein the non-hydrogen groups of R.sup.9, R.sup.10, R''', R'''',
X', X'', and Y are optionally substituted as defined herein.
[0280] Compound (81) can then be subjected to ozonolysis conditions
to afford aldehyde (82). Compound (82) can then be converted to a
compound of the invention in a manner analogous to the conversion
of compound (8) to compound (12) illustrated in Scheme 1.
[0281] Examples of suitable compounds for the conversion of
compound (74) or (80) to, respectively, compound (75) and (81), as
illustrated in Schemes 6a and 6b, include but are not limited
to:
##STR00034##
Biological Activity
[0282] The compounds of the invention have demonstrated HMG Co-A
reductase inhibition in standard assays commonly employed by those
skilled in the art. (See, e.g., J. of Lipid Research 1998;
39:75-84; Analytical Biochemistry, 1991; 196:211-214; RR 740-01077
Pharmacology 8 Nov. 82). Accordingly, such compounds as well as
their pharmaceutical compositions and formulations are useful for
treating, controlling or preventing inter alia
hypercholesterolemia, hyperlipidemia, hypercholesterolemia,
hypertriglyceridemia, atherosclerosis, Alzheimer's Disease, benign
prostatic hypertrophy (BPH), diabetes and osteoporosis.
[0283] A.) In Vitro Assay
[0284] Rat Liver Microsomal Isolation Procedure:
[0285] Male Charles River Sprague-Dawley rats were fed with 2.5%
cholestyramine in rat chow diets for 5 days before sacrificing.
Livers were minced and homogenized in a sucrose homogenizing
solution in an ice bath 10 times. Homogenates were diluted into a
final volume of 200 mL, and centrifuged 15 min. with a Sorvall
Centrifuge at 5.degree. C., 10,000 rpm (12,000.times.G). The upper
fat layer was removed and the supernatant decanted into fresh
tubes. This step was repeated one more time before transferring the
supernatant into ultracentrifuge tubes and centrifuged at 36,000
rpm (105,000.times.G) for an hour at 5.degree. C. The resulting
supernatant was discarded and the pellet was added to total of 15
mL 0.2 M KH.sub.2PO.sub.4. Pellets were homogenized gently by hand
about 10 times. Samples were pooled and diluted into total of 60 mL
buffer. The protein concentration of the homogenate was determined
by the Lowry Method using a BCA (Bicinchoninic acid), kit from
Pierce Chemical Company. 1 mL aliquots of microsomes were kept
frozen in liquid nitrogen.
[0286] HMGCoA (3-Hydroxy-3-methylglutaryl CoA) Reductase Assay:
[0287] Materials and Methods:
[0288] [3-.sup.14C]-HMGCoA (57.0 mCi/mmol) was purchased from
Amersham Biosciences, UK. HMGCoA, mevalonolactone, .beta.-NADPH
(.beta.-Nicotinamide Adenine Dinucleotide Phosphate, Reduced form)
were purchased from Sigma Chemical Co. AG 1-8.times. resin was
purchased from Bio-Rad Laboratory.
[0289] One .mu.L of dimethyl sulfoxide (DMSO) or 1 .mu.L of DMSO
containing a test compound at a concentration sufficient to give a
final assay concentration of between 0.1 nM to 1 mM was placed into
each well of a Corning 96 well plate. A Volume of 34 .mu.L of
buffer (100 mM NaH.sub.2PO.sub.4, 10 mM Imidazole and 10 mM EDTA),
(Ethylenediaminetetraacetic acid) containing with 50 .mu.g/mL rat
liver microsomes was added into each well. After incubation for 30
min. on ice, 15 .mu.L of .sup.14C-HMGCoA (0.024 .mu.Ci) with 15 mM
NADPH, 25 mM DTT, (Dithiothreitol) was added and incubated at
37.degree. C. for an additional 45 min. The reaction was terminated
by the addition of 10 .mu.L of HCl followed by 5 .mu.L of
mevalonolactone. Plates were incubated at room temperature
overnight to allow lactonization of mevalonate to mevalonolactone.
The incubated samples were applied to columns containing 300 .mu.L
of AG1-X8 anion exchange resin in a Corning filter plate. The
eluates were collected into Corning 96 well capture plates.
Scintillation cocktail (Ultima-Flo-M) was added into each well and
plates counted on a Trilux Microbeta Counter. The IC.sub.50 values
were calculated with GraphPad software (Prism).
[0290] Procedure:
[0291] 1. Add 1 .mu.L DMSO or compounds into the wells according to
the protocol
[0292] 2. Add 35 .mu.L incubation buffer with the rat microsomes
into each well. Incubate 30 min. at 4.degree. C.
[0293] 3. Add 15 .mu.L .sup.14C-HMGCoA. Incubate 45 min. at
37.degree. C.
[0294] 4. Add 10 .mu.L HCl stop reagent
[0295] 5. Add 5 .mu.L mevelonolactone. Incubate overnight at room
temperature
[0296] 6. Apply the containing into the AG 1-X8 anion exchange
resin in Corning filter plate
[0297] 7. Collect the eluate into Corning capture plate
[0298] 8. Add scintillation cocktail Ultima-Flo-M
[0299] 9. Count on a Trilux Microbeta Counter
[0300] 10. Calculate IC.sub.50 values
[0301] Compounds of the invention exhibit a range of IC.sub.50
values of less than about 500 nM in the aforementioned in vitro
assay. Preferably, compounds of the invention exhibit a range of
IC.sub.50 values of less than about 100 nM. More preferably,
compounds of the invention exhibit a range of IC.sub.50 values of
less than about 20 nM.
[0302] B.) Cell Assay
[0303] Protocol for Sterol Biosynthesis in Rat Hepatocytes:
[0304] Cell Culture, Compounds Treatment and Cell Labeling:
[0305] Frozen rat hepatocytes purchased from XenoTech (cat#
N400572) were seeded on 6-well collagen I coated plates at a
density of 10.sup.5 cells/per well. The cells were grown in DMEM,
(Dulbecco's Modified Eagle Medium) (Gibco, #11054-020) containing
10% FBS (Fetal Bovine Serum) and 10 mM HEPES,
(N-2-hydroxyethyl-piperazine-N'-2-ethane sulfonic acid) (Gibco #
15630-080) for 24 hrs. The cells were pre-incubated with compounds
for 4 hrs and then labeled by incubating in medium containing 1
uCi/per mL of .sup.14C acetic acid for an additional 4 hrs. After
labeling, the cells were washed twice with 5 mM MOPS,
(3-[N-morpholino]propane sulfonic acid) solution containing 150 mM
NaCl and 1 mM EDTA and collected in the lysis buffer containing 10%
KOH and 80% (vol.) ethanol.
[0306] Cholesterol Extraction and Data Analysis:
[0307] In order to separate labeled cholesterol from labeled
non-cholesterol lipids, the cells lysates were subject to
saponification at 60.degree. C. for 2 hrs. The lysates were then
combined with 0.5 volume of H.sub.2O and 2 volumes of hexane,
followed by 30 minutes of vigorous shaking. After the separation of
two phases, the upper-phase solution was collected and combined
with 5 volumes of scintillation cocktail. The amount of .sup.14C
cholesterol was quantified by liquid scintillation counting. The
IC.sub.50 values were calculated with GraphPad software (Prism
3.03).
[0308] Compounds of the invention exhibit a range of IC.sub.50
values of less than about 1000 nM in the aforementioned cell assay.
Preferably, compounds of the invention exhibit a range of IC.sub.50
values of less than about 100 nM.
[0309] C.) Protocol for Sterol Biosynthesis in L6 Rat Myoblast:
[0310] Cell Culture, Compounds Treatment and Cell Labeling:
[0311] L6 rat myoblast purchased from ATCC(CRL-1458) were grown in
T-150 vented culture flasks and seeded on 12-well culture plates at
a density of 60,000 cells per well. The cells were grown in DMEM,
(Dulbecco's Modified Eagle Medium) (Gibco, #10567-014) containing
10% heat inactivated FBS (Fetal Bovine Serum) (Gibco # 10082-139)
for 72 hours until reaching confluence. The cells were
pre-incubated in media with compound and 0.2% DMSO (dimethyl
sulfoxide) for 3 hours and then labeled by incubating in medium
containing compound, 0.2% DMSO and 1 .mu.Ci/per mL of .sup.14C
acetic acid for an additional 3 hours. After labeling, the cells
were washed once with 1.times.PBS (Gibco #14190-144) then lysed
overnight at 4.degree. C. in buffer containing 10% KOH and 78%
(vol.) ethanol.
[0312] Cholesterol Extraction and Data Analysis:
[0313] Lipid ester bonds were hydrolyzed by saponification of the
lysates at 60.degree. C. for 2 hours. Sterols (including
cholesterol) were extracted from saponified lysates by combining
with 3 volumes of hexane and mixing by pipette 6 times. The upper
organic phase solution was collected and combined with an equal
volume of 1N KOH in 50% methanol and mixed by pipette 6 times. The
upper organic phase was collected in a scintillant-coated plate
(Wallac #1450-501) and hexanes removed by evaporation at room
temperature for 3 hours. The amount of .sup.14C cholesterol was
quantified by scintillation counting in a Trilux 1450 plate reader
(Wallac). The IC.sub.50 values were calculated from % inhibitions
relative to negative controls vs. compound concentration on
Microsoft excel 2000 data analysis wizard using a sigmoid
inhibition curve model with formula:
y=Bmax(1-(x.sup.n/K.sup.n+x.sup.n))+y2
[0314] Where K is the IC.sub.50 for the inhibition curve, X is
inhibitor concentration, Y is the response being inhibited and
Bmax+Y2 is the limiting response as X approaches zero.
[0315] Compounds of the invention have a L6 IC.sub.50 value greater
than about 100 nM in the aforementioned L6 Rat Myoblast.
Preferably, compounds of the invention exhibit a hepatocyte
selectivity greater than about ((L6 IC.sub.50/Rat hepatocyte
IC.sub.50)>1000), and have a L6 IC.sub.50 value greater than
about 1000 nM.
EXAMPLES
Example 1
(3R,5R)-7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3--
yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00035##
[0316] (a) Step A. Preparation of
[(4-Fluoro-phenyl)-hydrazono]-chloroacetic acid methyl ester
##STR00036##
[0317] (Reference: Tetrahedron Asymmetry 1999, 4447-4454): To a
solution of 4-fluoroaniline (10.0 g, 90.0 mmol; commercially
available from Sigma Aldrich) in MeOH (80 mL) was added 6 N HCl (80
mL) and the solution was cooled to 0.degree. C. NaNO.sub.2 (12.4 g,
180 mmol) was then slowly added as a solid. The reaction was
stirred for 15 min at 0.degree. C. after which time NaOAc was added
as a solid to adjust the reaction to pH 5. Subsequently, a solution
of methyl 2-chloroacetoacetate (10.96 mL, 90.0 mmol; commercially
available from Sigma Aldrich) in MeOH (40 mL) was slowly added at
0.degree. C. The reaction was then allowed to warm to 25.degree. C.
and stirred for 12 hr after which time the MeOH was removed under
reduced pressure and ether (300 mL) was added. The organic layer
was separated and washed with saturated NaHCO.sub.3 and water prior
to drying over Na.sub.2SO.sub.4. The organic layer was concentrated
to afford [(4-fluoro-phenyl)-hydrazono]-chloroacetic acid methyl
ester (19.42 g, 94%) that was utilized without further
purification: H-NMR (CDCl.sub.3) .delta. 8.37 (bs, 1H), 7.22-7.12
(m, 2H), 7.00-6.96 (m, 2H), 3.87 (s, 3H).
(b) Step B. Preparation of 4-Methyl-pent-2-enoic acid benzyl
ester
##STR00037##
[0319] To a solution of 4-methyl-2-pentenoic acid (24.0 g, 210
mmol; commercially available from TCI America) in acetone (300 mL)
was added K.sub.2CO.sub.3 (55.8 g, 404 mmol) and the reaction was
stirred at 25.degree. C. for 30 min. A solution of benzyl bromide
(25.2 mL, 212 mmol; commercially available from Sigma Aldrich) in
acetone (100 mL) was then added drop-wise. The reaction mixture was
subsequently heated to reflux for 16 hrs. After cooling to
25.degree. C., the acetone was removed under reduced pressure and
ether (300 mL) and water (300 mL) were added and the organic layer
was separated, washed with brine and dried over Na.sub.2SO.sub.4.
After concentration, the crude product was subjected to silica gel
chromatography (1-5% Ether/Hex) to afford 4-methyl-pent-2-enoic
acid benzyl ester (40.5 g, 98%): H-NMR (CDCl.sub.3) .delta.
7.36-7.28 (m, 5H), 6.96 (dd, 1H), 5.79 (d, 1H), 5.14 (s, 2H),
2.45-2.40 (m, 1H), 1.01 (d, 6H).
(c) Step C. Preparation of
1-(4-fluoro-phenyl)-4-isopropyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylic
acid 5-benzyl ester 3-methyl ester
##STR00038##
[0321] To a solution of [(4-fluoro-phenyl)-hydrazono]-chloroacetic
acid methyl ester (20.93 g, 90.8 mmol) and 4-methyl-pent-2-enoic
acid benzyl ester (18.54 g, 90.8 mmol) in dioxane (400 mL) at
25.degree. C. was added Ag.sub.2CO.sub.3 (63.0 g, 227 mmol;
commercially available from Sigma Aldrich). The reaction was
protected from light and stirred at 25.degree. C. for 48 hr.
Subsequently, the reaction mixture was filtered through a pad of
celite and the filtrate was concentrated. The crude product mixture
was subjected to silica gel chromatography (5-20% EtOAc/Hex) to
afford
1-(4-fluoro-phenyl)-4-isopropyl-4,5-dihydro-1H-pyrazole-3,5-dicarb-
oxylic acid 5-benzyl ester 3-methyl ester in approximately 90%
purity (29.3 g, 73%): H-NMR (CDCl.sub.3) .delta. 7.30-7.24 (m, 3H),
7.15-7.12 (m, 2H), 7.01-6.96 (m, 2H), 6.93-6.88 (m, 2H), 5.14 (d,
1H), 5.04 (d, 1H), 4.58 (d, 1H), 3.83 (s, 3H), 3.51-3.49 (m, 1H),
2.40-2.36 (m, 1H), 1.00 (d, 3H), 0.69 (d, 3H).
(d) Step D. Preparation of
1-(4-fluoro-phenyl)-4-isopropyl-1H-pyrazole-3,5-dicarboxylic acid
5-benzyl ester 3-methyl ester
##STR00039##
[0323] To a solution of
1-(4-fluoro-phenyl)-4-isopropyl-4,5-dihydro-1H-pyrazole-3,5-dicarboxylic
acid 5-benzyl ester 3-methyl ester (29.3, 73.5 mmol) in THF:Water
(1:1, 500 mL) at 0.degree. C. was slowly added ceric ammonium
nitrate (80.5 g, 147 mmol; commercially available from Sigma
Aldrich). The reaction was stirred at 0.degree. C. for 1 hr after
which time the THF was removed under reduced pressure and DCM (500
mL) was added. The organic layer was separated and washed with
water and brine. The organic layer was dried over Na.sub.2SO.sub.4
and concentrated, and the product was purified by silica gel
chromatography (5-15% EtOAc/Hex) to provide
1-(4-fluoro-phenyl)-4-isopropyl-1H-pyrazole-3,5-dicarboxylic acid
5-benzyl ester 3-methyl ester (18.95 g, 65%): H-NMR (CDCl.sub.3)
.delta. 7.29-7.21 (m, 5H), 7.07 (d, 2H), 6.94 (t, 2H), 5.12 (s,
2H), 3.89 (s, 3H), 3.88-3.80 (m, 1H), 1.31 (d, 6H).
(e) Step E. Preparation of
1-(4-fluoro-phenyl)-4-isopropyl-1H-pyrazole-3,5-dicarboxylic acid
3-methyl ester
##STR00040##
[0325] To a solution of
1-(4-fluoro-phenyl)-4-isopropyl-1H-pyrazole-3,5-dicarboxylic acid
5-benzyl ester 3-methyl ester (18.95 g, 47.8 mmol) in MeOH (300 mL)
at 25.degree. C. under N.sub.2 was added 10% Pd--C (700 mg;
commercially available from Sigma Aldrich). The reaction vessel was
evacuated and filled with H.sub.2 and then stirred at 25.degree. C.
for 3 hrs. Subsequently, the reaction vessel was flushed with
N.sub.2 and filtered through a pad of celite. The filtrate was
concentrated to afford
1-(4-fluoro-phenyl)-4-isopropyl-1H-pyrazole-3,5-dicarboxylic acid
3-methyl ester (14.6 g, 99%) in sufficient purity for use in the
next step: H-NMR (CDCl.sub.3) .delta. 7.36-7.31 (m, 2H), 7.11-7.06
(m, 2H), 3.90 (s, 3H), 3.86-3.82 (m, 1H), 1.43 (d, 6H).
(f) Step F. Preparation of
1-(4-fluoro-phenyl)-5-hydroxymethyl-4-isopropyl-1H-pyrazole-3-carboxylic
acid methyl ester
##STR00041##
[0326] (Reference: J. Med. Chem. 1996, 549-555) To a solution of
1-(4-fluoro-phenyl)-4-isopropyl-1H-pyrazole-3,5-dicarboxylic acid
3-methyl ester (15.9 g, 51.8 mmol) in THF (300 mL) at 0.degree. C.
was slowly added BH.sub.3.THF (1.0 M solution in THF, 104 mL, 104
mmol; commercially available from Sigma Aldrich). The reaction was
allowed to warm to 25.degree. C. for 30 min and then heated to
65.degree. C. for 3 hr. After cooling to 25.degree. C., MeOH (50
mL) was slowly added. Subsequently, the solvent was removed under
reduced pressure and a second portion of MeOH (100 mL) was slowly
added and the solution was stirred at 25.degree. C. for an
additional 20 min. The MeOH was then evaporated and EtOAc was added
and the organic layer was washed with 1N NaOH and brine prior to
drying over Na.sub.2SO.sub.4. The organic layer was concentrated
and purified by silica gel chromatography (15-35% EtOAc/Hex) to
provide
1-(4-fluoro-phenyl)-5-hydroxymethyl-4-isopropyl-1H-pyrazole-3-carboxylic
acid methyl ester (13.6 g, 90%): H-NMR (CDCl.sub.3) .delta.
7.59-7.56 (m, 2H), 7.15-7.11 (m, 2H), 4.57 (s, 2H), 3.89 (s, 3H),
3.66-3.62 (m, 1H), 1.36 (d, 6H).
(g) Step G. Preparation of
1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic
acid methyl ester
##STR00042##
[0328] To a solution of
1-(4-fluoro-phenyl)-5-hydroxymethyl-4-isopropyl-1H-pyrazole-3-carboxylic
acid methyl ester (13.6 g, 46.7 mmol) in CH.sub.2Cl.sub.2 (300 mL)
at 25.degree. C. was added solid NaHCO.sub.3 (19.6 g, 233 mmol)
followed by Dess Martin reagent (20.8 g, 49.0 mmol; commercially
available from Lancaster). The reaction was stirred at 25.degree.
C. for 4 hr after which time saturated sodium bisulfite (50 mL) was
added and the organic layer was separated and washed with water and
brine. The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated to an oil that was purified by silica gel
chromatography (15% EtOAc/Hex) to afford
1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic
acid methyl ester (11.3 g, 84%): H-NMR (CDCl.sub.3) .delta. 9.95
(s, 1H), 7.42-7.38 (m, 2H), 7.17-7.13 (m, 2H), 4.01-3.96 (m, 1H),
3.92 (s, 3H), 1.38 (d, 6H).
(h) Step H. Preparation of
1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic
acid
##STR00043##
[0330] To a solution of
1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic
acid methyl ester (11.34 g, 39.1 mmol) in MeOH (150 mL) was added
NaOH (156 mL of 1N solution, 156 mmol). The reaction was heated to
60.degree. C. for 4 hr. The solvent was then removed under reduced
pressure and water (150 mL) and Et.sub.2O (100 mL) were added. The
organic layer was discarded and the aqueous layer was acidified
with 10% HCl to pH 1 and then extracted with EtOAc (200
mL.times.2). The combined organic extracts were dried over
Na.sub.2SO.sub.4 and concentrated to give
1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic
acid (8.55 g, 79%) as a white solid that required no purification:
MS (APCI.sup.+): m/z 277.0 (M+H).
(i) Step I. Preparation of
1-(4-Fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic
acid benzylamide
##STR00044##
[0332] To a solution of
1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic
acid (1.25 g, 4.52 mmol) in CH.sub.2Cl.sub.2 (50 mL) at 25.degree.
C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (1.30 g, 6.79 mmol; commercially available from Sigma
Aldrich) followed by 1-hydroxybenzotriazole hydrate (1.04 g, 6.79
mmol; commercially available from Sigma Aldrich) and the reaction
was stirred for 5 min at 25.degree. C. Subsequently, benzyl amine
(0.533 g, 4.98 mmol; commercially available from Sigma Aldrich) was
added and the reaction was stirred for an additional 4 hrs as a
fine white precipitate developed. The organic layer was washed with
1 N HCl, saturated NaHCO.sub.3 and brine. After drying and
concentration, the product was purified by silica gel
chromatography (20% EtOAc/Hex) to provide
1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic
acid benzylamide (0.65 g, 39%): MS (APCI.sup.+): m/z 366.1
(M+H).
(j) Step J. Preparation of
1-(4-Fluoro-phenyl)-5-hydroxymethyl-4-isopropyl-1H-pyrazole-3-carboxylic
acid benzylamide
##STR00045##
[0334] To a solution of
1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic
acid benzylamide (0.620 g, 1.70 mmol) in THF:MeOH (40 mL) at
0.degree. C. was added sodium borohydride (96.3 mg, 2.55 mmol;
commercially available from Sigma Aldrich). The reaction was
stirred for 30 min at 0.degree. C. at which point TLC analysis
indicated the reaction was complete and the solvent was removed
under reduced pressure. To the reaction residue was added ethyl
acetate (50 mL) and saturated NaHCO.sub.3 (15 mL), and the organic
layer was separated, dried (Na.sub.2SO.sub.4) and concentrated. The
resulting oil was purified by silica gel chromatography (40%
EtOAc/Hex) to afford
1-(4-fluoro-phenyl)-5-hydroxymethyl-4-isopropyl-1H-pyrazole-3-carboxylic
acid benzylamide (0.540 g, 87%): MS (APCI.sup.+): m/z 368.1
(M+H).
(k) Step K. Preparation of
[5-Benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethyl]-
-triphenyl-phosphonium bromide
##STR00046##
[0336] To a solution of
1-(4-fluoro-phenyl)-5-hydroxymethyl-4-isopropyl-1H-pyrazole-3-carboxylic
acid benzylamide (0.525 g, 1.43 mmol) in acetonitrile (50 mL) was
added triphenylphosphine hydrobromide (0.49 g, 1.43 mmol;
commercially available from Sigma Aldrich). The reaction was heated
to 80.degree. C. for 24 hr after which time all starting material
was consumed as determined by TLC. The reaction solvent was removed
under reduced pressure and the resulting white solid was dried
under high vacuum for 12 hr to provide
[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethyl]-
-triphenyl-phosphonium bromide (0.977 g, 98%) in sufficient purity
for use in the next step.
(l) Step L. Preparation of
(6-{2-[5-Benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-
-vinyl}-2,2-dimethyl-[1R,3R]dioxan-4-yl)-acetic acid tert-butyl
ester
##STR00047##
[0338] To a solution of
[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethyl]-
-triphenyl-phosphonium bromide (0.562 g, 0.811 mmol) in THF:DMSO
(50:1, 50 mL) at -78.degree. C. was added 1.0 M LiHMDS (Lithium
Hexamethyldisilazide; 1.055 mL, 1.055 mmol; commercially available
from Sigma Aldrich). An orange color was noted as the base was
added. The reaction mixture was stirred at -78.degree. C. for 5 min
after which time a solution of
(6-formyl-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid tert-butyl
ester (0.252 g, 0.974 mmol; Tetrahedron Lett., 1990, 31, 2545-2548)
in THF (10 mL) was slowly added. After the addition, the reaction
mixture was stirred at -78.degree. C. for 30 min then allowed to
warm to 25.degree. C. and stirred at that temperature for 5 hr. The
reaction was quenched by drop-wise addition of saturated
NH.sub.4Cl. Ethyl acetate (50 mL) was then added and organic layer
was separated, washed with water, dried (Na.sub.2SO.sub.4),
concentrated. The crude product was purified by silica gel
chromatography (15-20% EtOAc/Hex) to afford
(6-{2-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazo-
l-3-yl]-vinyl}-2,2-dimethyl-[1R,3R]dioxan-4-yl)-acetic acid
tert-butyl ester (0.24 g, 50%) as an inseparable 1:4 mixture of
cis/trans olefin isomers: MS (APCI.sup.+): m/z 592.3 (M+H).
(m) Step M. Preparation of
(3R,5R)-7-[5-Benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-
-yl]-3,5-dihydroxy-heptanoic acid tert-butyl ester
##STR00048##
[0340] To a solution of
(6-{2-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-
-vinyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid tert-butyl ester
(0.360 g, 0.61 mmol) in MeOH (20 mL) was added 1N HCl (2 mL) and
the solution was stirred for 3 hrs at 25.degree. C. Subsequently,
the reaction solvent was removed under reduced pressure and ethyl
acetate (50 mL) and saturated NaHCO.sub.3 (10 mL) were added. The
organic layer was separated, washed with brine, dried
(Na.sub.2SO.sub.4) and concentrated to afford, after silica gel
chromatography (35% EtOAc/Hex),
7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-
-dihydroxy-hept-6-enoic acid tert-butyl ester (0.231 g, 69%).
Subsequently, to a solution of
7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-
-dihydroxy-hept-6-enoic acid tert-butyl ester (0.241 g, 0.437 mmol)
in MeOH (20 mL) was added 10% Pd--C (50 mg; commercially available
from Sigma Aldrich), and the reaction vessel was evacuated and
filled with hydrogen gas (via balloon) for 3 hours. The reaction
mixture was then filtered through a pad of celite and to the
filtrate was added The crude product was purified by silica gel
chromatography (30-50% EtOAc/Hex) to provide
(3R,5R)-7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-p-
yrazol-3-yl]-3,5-dihydroxy-heptanoic acid tert-butyl ester (0.143
g, 59%): MS (APCI.sup.+): m/z 554.3 (M+H).
(n) Step N. Preparation of
(3R,5R)-7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-
-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00049##
[0342] To a solution of
7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-
-dihydroxy-heptanoic acid tert-butyl ester (0.103 g, 0.186 mmol) in
MeOH (5 mL) was added 1.0 N NaOH (0.190 mL, 0.195 mmol;
commercially available from Sigma Aldrich) and the reaction was
stirred at 25.degree. C. for 48 hr after which time the reaction
was solvent was removed under reduced pressure. The resulting solid
was then azeotroped toluene (3.times.100 mL) and triturated with
diethyl ether to provide a light yellow solid that was dried under
vacuum at 60.degree. C. to afford
(3R,5R)-7-[5-benzylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-
-yl]-3,5-dihydroxy-heptanoic acid sodium salt (0.091 g, 94%): MS
(APCI.sup.+): m/z 498.2 (M+H); H-NMR (DMSO-d.sub.6) .delta. 8.55
(t, 1H), 7.53-7.49 (m, 2H), 7.33-7.13 (m, 7H), 4.70 (bs, 1H), 4.34
(d, 2H), 3.63-3.57 (m, 1H), 3.45-3.42 (m, 1H), 2.74-2.66 (m, 1H),
2.58-2.50 (m, 1H), 1.95-1.90 (m, 1H), 1.75-1.69 (m, 1H), 1.40-1.10
(m, 10H).
Example 2
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-methyl-benzylcarbamoyl)-2H-
-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00050##
[0344] The title compound was prepared in a manner analogous to the
method of Example 1. MS (APCI.sup.+): m/z 510.2 (M-H); H-NMR
(DMSO-d.sub.6) .delta. 7.53-7.50 (m, 2H), 7.30 (t, 2H), 7.20-7.17
(m, 1H), 7.08-7.05 (m, 3H), 4.33 (s, 3H), 3.61-3.59 (m, 1H),
3.45-3.44 (m, 1H), 3.25 (bs, 1H), 2.73-2.67 (m, 1H), 2.58-2.51 (m,
1H), 2.24 (s, 3H), 1.94-1.89 (m, 1H), 1.75-1.69 (m, 1H), 1.37-1.10
(m, 10H).
Example 3
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-benzylcarbamoyl)-2H-
-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00051##
[0346] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+): m/z 512.2 (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.53-7.49 (m, 2H), 7.30 (t, 2H), 7.14-6.95
(m, 4H), 4.30 (s, 2H), 3.62-3.55 (m, 1H), 3.46-3.42 (m, 1H),
3.26-3.19 (m, 1H), 2.69-2.61 (m, 1H), 2.58-2.51 (m, 1H), 2.21 (s,
3H), 1.91-1.88 (m, 1H), 1.72-1.66 (m, 1H), 1.34-1.10 (m, 10H).
Example 4
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-
-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00052##
[0348] The title compound was prepared in a manner analogous to the
method of Example 1. MS (APCI.sup.+): m/z 512.2 (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.52-7.48 (m, 2H), 7.29 (t, 2H), 7.10 (d,
2H), 7.02 (d, 2H), 4.29 (s, 2H), 3.62-3.56 (m, 1H), 3.45-3.42 (m,
1H), 3.28 (bs, 1H), 2.73-2.66 (m, 1H), 2.57-2.51 (m, 1H), 2.20 (s,
3H), 1.92-1.88 (m, 1H), 1.73-1.67 (m, 1H), 1.53-1.11 (m, 10H).
Example 5
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-methyl-benzylcarbamoyl)-2H-
-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid sodium salt
##STR00053##
[0350] The title compound was prepared in a manner analogous to the
method of Example 1. MS (APCI.sup.+): m/z 510.3 (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.50 (t, 1H), 7.53-7.46 (m, 3H), 7.31 (t,
2H), 7.20-7.18 (m, 1H), 7.08-7.06 (m, 3H), 6.28 (d, 1H), 5.69 (dd,
1H), 4.35 (d, 2H), 4.19-4.17 (m, 1H), 3.62-3.60 (m, 1H), 2.26 (s,
3H), 1.98-1.93 (m, 1H), 1.78-1.72 (m, 1H), 1.44-1.18 (m, 8H).
Example 6
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2H-
-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid sodium salt
##STR00054##
[0352] The title compound was prepared in a manner analogous to the
method of Example 1. MS (APCI.sup.+): m/z 510.2 (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.57 (t, 1H), 7.54-7.48 (m, 3H), 7.32-7.28
(m, 2H), 7.15-7.13 (m, 2H), 7.06-7.04 (m, 2H), 6.27 (d, 1H), 5.68
(dd, 1H), 5.17 (bs, 1H), 4.32 (d, 2H), 4.18-4.17 (m, 1H), 3.62-3.58
(m, 1H), 2.21 (s, 3H), 1.96-1.91 (m, 1H), 1.77-1.71 (m, 1H),
1.48-1.41 (m, 1H), 1.29-1.23 (m, 7H).
Example 7
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2-
H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00055##
[0354] The title compound was prepared in a manner analogous to the
method of Example 1. MS (APCI.sup.+): m/z 528.2 (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.52-7.49 (m, 2H), 7.30 (t, 2H), 7.16-7.12
(m, 1H), 6.84-6.81 (m, 2H), 6.72-6.70 (m, 1H), 4.31 (s, 2H), 3.66
(s, 3H), 3.62-3.57 (m, 1H), 3.47-3.43 (m, 1H), 3.29-3.18 (m, 2H),
2.70-2.66 (m, 1H), 2.56-2.54 (m, 1H), 1.92-1.88 (m, 1H), 1.72-1.67
(m, 1H), 1.36-1.10 (m, 10H).
Example 8
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2-
H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00056##
[0356] The title compound was prepared in a manner analogous to the
method of Example 1. MS (APCI.sup.+): m/z 528.2 (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.51-7.48 (m, 2H), 7.32-7.28 (m, 2H),
7.21-7.16 (m, 3H), 6.80 (d, 2H), 4.27 (s, 2H), 3.65 (s, 3H),
3.64-3.49 (m, 3H), 2.73-2.69 (m, 1H), 2.57-2.49 (m, 1H), 1.96-1.92
(m, 1H), 1.77-1.71 (m, 1H), 1.37-1.10 (m, 10H).
Example 9
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxy-benzylcarbamoyl)-2-
H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid sodium salt
##STR00057##
[0358] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+): m/z 526.3 (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.63 (t, 1H), 7.52-7.49 (m, 2H), 7.34-7.28
(m, 3H), 7.19-7.10 (m, 2H), 6.83-6.82 (m, 2H), 6.73 (d, 1H), 6.28
(dd, 1H), 5.73-5.69 (m, 1), 5.15-5.14 (m, 1H), 4.34 (d, 2H),
4.19-4.15 (m, 1H), 3.66 (s, 3H), 3.62-3.61 (m, 1H), 1.99-1.94 (m,
1H), 1.78-1.74 (m, 1H), 1.49-1.42 (m, 1H), 1.25-1.19 (m, 7H).
Example 10
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxy-benzylcarbamoyl)-2-
H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid sodium salt
##STR00058##
[0360] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+): m/z 524.1 (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.55 (t, 1H), 7.52-7.48 (m, 2H), 7.37 (s,
1H), 7.30 (t, 2H), 7.18 (d, 2H), 6.80 (d, 1H), 5.68 (dd, 1H), 5.15
(bs, 1H), 4.29 (d, 2H), 4.17-4.15 (m, 1H), 3.66 (s, 3H), 3.62-3.58
(m, 1H), 1.98-1.93 (m, 1H), 1.79-1.73 (m, 1H), 1.49-1.42 (m, 1H),
1.30-1.23 (m, 7H).
Example 11
(3R,5R)-7-[5-(benzyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H--
pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00059##
[0362] The title compound was prepared in a manner analogous to the
method of Example 1 MS (APCI.sup.+): m/z 512.1 (M-H); H-NMR
(DMSO-d.sub.6) .delta. 7.42-7.06 (m, 9H), 4.61 (s, 1H), 4.49 (s,
1H), 3.87-3.71 (m, 4H), 3.47-3.42 (m, 1H), 2.80-2.69 (m, 3H),
1.97-1.94 (m, 1H), 1.79-1.75 (m, 1H), 1.57-1.21 (m, 10H).
Example 12
(3R,5R)-7-[5-[(3-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-is-
opropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00060##
[0364] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+): m/z 530.3 (M-H); H-NMR
(DMSO-d.sub.6) .delta. 7.48-7.01 (m, 8H), 4.63 (s, 1H), 4.52 (s,
1H), 3.62-3.58 (m, 1H), 3.46-3.44 (m, 1H), 2.89-2.85 (m, 1H), 2.83
(s, 3H), 2.74-2.66 (m, 1H), 2.54-2.45 (m, 1H), 1.93-1.88 (m, 1H),
1.73-1.67 (m, 1H), 1.53-1.10 (m, 10H).
Example 13
(3R,5R)-7-[5-[(4-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-is-
opropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid sodium
salt
##STR00061##
[0366] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+): m/z 530.2 (M-H); H-NMR
(DMSO-d.sub.6) .delta. 7.52-7.08 (m, 8H), 4.71 (bs, 1H), 4.60 (s,
1H), 4.48 (s, 1H), 3.60-3.58 (m, 1H), 3.47-3.42 (m, 1H), 2.89-2.84
(m, 1H), 2.80 (s, 3H), 2.73-2.70 (m, 1H), 2.67-2.58 (m, 1H),
1.92-1.88 (m, 1H), 1.72-1.66 (m, 1H), 1.36-1.26 (m, 3H), 1.16-1.11
(m, 7H).
Example 14
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[N-methyl-(R)-.alpha.-methyl--
benzylcarbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid
sodium salt
##STR00062##
[0368] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+): m/z 526.22 (M+H).
Example 15
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(R)-.alpha.-methyl-benzylcar-
bamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00063##
[0370] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 512.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.27 (d, 1H), 7.54-7.50 (m, 2H), 7.46-7.07
(m, 8H), 5.11-5.03 (m, 1H), 4.70 (d, 1H), 3.65-3.52 (m, 1H),
3.49-3.38 (m, 1H), 3.22-3.12 (m, 1H), 2.73-2.65 (m, 1H), 2.57-2.49
(m, 1H), 1.94-1.89 (m, 1H), 1.74-1.68 (m, 1H), 1.40-1.06 (m,
13H).
Example 16
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(S)-.alpha.-methyl-benzylcar-
bamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00064##
[0372] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 512.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.27 (d, 1H), 7.54-7.50 (m, 2H), 7.44 (s,
1H), 7.34-7.07 (m, 7H), 5.11-5.03 (m, 1H), 4.70 (d, 1H), 3.65-3.52
(m, 1H), 3.49-3.38 (m, 1H), 3.22-3.12 (m, 1H), 2.73-2.65 (m, 1H),
2.57-2.49 (m, 1H), 1.94-1.89 (m, 1H), 1.74-1.68 (m, 1H), 1.40-1.06
(m, 13H).
Example 17
(3R,5R)-7-[5-(benzyl-methyl-carbamoyl)-2-(4-fluoro-Phenyl)-4-isopropyl-2H--
pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid sodium salt
##STR00065##
[0374] The title compound was prepared in a manner analogous to the
method of Example 1: H-NMR (DMSO-d.sub.6) .delta. 7.50-7.17 (m,
9H), 6.24 (d, 1H), 5.82 (dd, 1H), 4.53 (s, 1H), 4.19-4.18 (m, 1H),
3.63-3.59 (m, 1H), 2.97-2.94 (m, 1H), 2.83 (d, 2H), 1.96-1.92 (m,
1H), 1.78-1.72 (m, 1H), 1.47-1.43 (m, 1H), 1.35-1.29 (m, 1H),
1.19-1.10 (m, 6H).
Example 18
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(R)-.alpha.-methyl-benzylcar-
bamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid sodium
salt
##STR00066##
[0376] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) m/z 510.3 (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.38 (d, 1H), 7.53-7.50 (m, 2H), 7.35-7.09
(m, 8H), 6.27 (d, 1H), 5.69 (dd, 1H), 5.15 (s, 1H), 5.09 (t, 1H),
4.18-4.17 (m, 1H), 3.63-3.57 (m, 1H), 3.24-3.17 (m, 1H), 1.96 (dd,
1H), 1.77 (dd, 1H), 1.54-1.18 (m, 13H).
Example 19
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(S)-.alpha.-methyl-benzylcar-
bamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid sodium
salt
##STR00067##
[0378] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 510.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.38 (d, 1H), 7.54-7.50 (m, 2H), 7.35-7.09
(m, 8H), 6.28 (d, 1H), 5.69 (dd, 1H), 5.21-5.07 (m, 2H), 4.17 (q,
1H), 3.63-3.57 (m, 1H), 3.24-3.17 (m, 1H), 1.96 (dd, 1H), 1.77 (dd,
1H), 1.54-1.18 (m, 13H).
Example 20
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenethylcarbamoyl-2H-pyrazol-
-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00068##
[0380] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 512.6 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.19-7.95 (m, 1H), 7.55-7.01 (m, 10H),
4.78-4.63 (m, 1H), 3.66-3.51 (m, 1H), 3.42-3.35 (m, 1H), 3.26-3.08
(m, 1H), 2.78-2.60 (m, 2H), 2.58-2.40 (m, 2H), 1.98-1.83 (m, 1H),
1.76-1.63 (m, 1H), 1.43-1.05 (m, 13H).
Example 21
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-methylcarbamoyl-2H-pyrazol-3--
yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00069##
[0382] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+): m/z 422.2 (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.96-7.95 (m, 1H), 7.64 (s, 1H), 7.51-7.47
(m, 2H), 7.34-7.28 (m, 2H), 4.72 (bs, 1H), 3.59-3.51 (m, 1H),
3.47-3.42 (m, 1H), 2.72-2.43 (m, 5H), 1.91-1.86 (m, 1H), 1.70-1.64
(m, 1H), 1.47-1.11 (m, 10H).
Example 22
(3R,5R)-7-[5-ethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-y-
l]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00070##
[0384] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 436.6 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.09-7.97 (m, 1H), 7.55-7.45 (m, 2H),
7.35-7.03 (m, 4H), 4.78-4.63 (m, 1H), 3.66-3.55 (m, 1H), 3.51-3.39
(m, 1H), 3.26-3.08 (m, 3H), 2.78-2.60 (m, 1H), 2.58-2.40 (m, 1H),
1.98-1.83 (m, 1H), 1.76-1.63 (m, 1H), 1.43-1.05 (m, 13H).
Example 23
(3R,5R)-7-[5-dimethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol--
3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00071##
[0386] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 436.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.55-7.45 (m, 2H), 7.35-7.03 (m, 4H),
4.78-4.55 (m, 1H), 3.66-3.55 (m, 1H), 3.51-3.39 (m, 1H), 2.98-2.77
(d, 6H), 2.78-2.60 (m, 1H), 2.58-2.40 (m, 1H), 1.98-1.83 (m, 1H),
1.76-1.63 (m, 1H), 1.43-1.05 (m, 10H).
Examples 24-29
[0387] Examples 24-29 can be prepared in a manner analogous to the
method of Scheme 2:
TABLE-US-00001 ##STR00072## Ex Compound R.sub.6.sup.'
R.sub.6.sup.'' R.sub.6.sup.''' 24
7-(5-Benzylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H- H H H
pyrazol-3-yl)-3R,5R-dihydroxy-heptanoic acid 25
3R,5R-Dihydroxy-7-[4-isopropyl-5-(2-methyl- Me H H
benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]- heptanoic
acid 26 3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methyl- H Me H
benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]- heptanoic
acid 27 3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methyl- H H Me
benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]- heptanoic
acid 28 3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methoxy- H OMe H
benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]- heptanoic
acid 29 3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methoxy- H H OMe
benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]- heptanoic
acid
Examples 30-32
[0388] Examples 30-32 can be prepared in a manner analogous to the
method of Scheme 2
TABLE-US-00002 ##STR00073## Ex. Compound R.sub.6.sup.'
R.sub.6.sup.'' 30
7-[5-(Benzyl-methyl-carbamoyl)-4-isopropyl-2-(4-fluoro-phenyl)-2H-
H H pyrazol-3-yl]-3R,5R-dihydroxy-heptanoic acid 31
7-{5-[(3-Fluoro-benzyl)-methyl-carbamoyl]-4-isopropyl-2-(4-fluoro-
F H phenyl)-2H-pyrazol-3-yl}-3R,5R-dihydroxy-heptanoic acid 32
7-{5-[(4-Fluoro-benzyl)-methyl-carbamoyl]-4-isopropyl-2-(4-fluoro-
H F phenyl)-2H-pyrazol-3-yl}-3R,5R-dihydroxy-heptanoic acid
Examples 33-35
[0389] Examples 33-35 can be prepared in a manner analogous to the
method of Scheme 2
TABLE-US-00003 ##STR00074## Ex Example R.sub.2b R.sub.4 R.sub.5 33
3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(R)- H Me H
.alpha.-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-heptanoic acid 34
3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(S)- H H Me
.alpha.-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-heptanoic acid 35
3R,5R-Dihydroxy-7-{4-isopropyl-5-[N-methyl-(R)-.alpha.-methyl- Me
Me H benzylcarbamoyl]-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl}-
heptanoic acid
Examples 36-39
[0390] Examples 36-39 can be prepared in a manner analogous to the
method of Scheme 2
TABLE-US-00004 ##STR00075## Ex Compound R.sub.6.sup.'
R.sub.6.sup.'' R.sub.6.sup.''' 36
3R,5R-Dihydroxy-7-{4-isopropyl-5-(2-methyl- Me H H
benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]- hept-6-enoic
acid 37 3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methyl- H H Me
benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]- hept-6-enoic
acid 38 3R,5R-Dihydroxy-7-[4-isopropyl-5-(3-methoxy- H OMe H
benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]- hept-6-enoic
acid 39 3R,5R-Dihydroxy-7-[4-isopropyl-5-(4-methoxy- H H OMe
benzylcarbamoyl)-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]- hept-6-enoic
acid
Examples 40-42
[0391] Examples 40-42 can be prepared in a manner analogous to the
method of Scheme 2
TABLE-US-00005 ##STR00076## Ex. Compound R.sub.2a R.sub.2b 40
3R,5R-Dihydroxy-7-(4-isopropyl-5-methylcarbamoyl-2-(4-fluoro- Me H
phenyl)-2H-pyrazol-3-yl)-heptanoic acid 41
7-(5-Ethylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-
Ethyl H yl)-3R,5R-dihydroxy-heptanoic acid 42
7-(5-Dimethylcarbamoyl-4-isopropyl-2-(4-fluoro-phenyl)-2H-pyrazol-
Me Me 3-yl)-3R,5R-dihydroxy-heptanoic acid
Examples 43-45
[0392] Examples 43-45 can be prepared in a manner analogous to the
method of Scheme 2
TABLE-US-00006 ##STR00077## Ex Compound R.sub.2b R.sub.4 R.sub.5 43
7-[5-(Benzyl-methyl-carbamoyl)-4-isopropyl-2-(4-fluoro- Me H H
phenyl)-2H-pyrazol-3-yl]-3R,5R-dihydroxy-hept-6-enoic acid 44
3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(R)- H Me H
.alpha.-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]hept-6-enoic acid
45 3R,5R-Dihydroxy-7-[4-isopropyl-2-(4-fluoro-phenyl)-5-[(S)- H H
Me .alpha.-methyl-benzylcarbamoyl]-2H-pyrazol-3-yl]-hept-6-enoic
acid
Example 46
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-methyl-benzyl)-car-
bamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00078##
[0394] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 526.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.51-7.40, 7.35-7.22, 7.20-7.06, 5.70, 4.71, 4.57, 4.44, 3.65-3.55,
3.47-3.41, 3.11, 2.93-2.83, 2.78, 2.77, 2.68-2.63, 2.60-2.48,
2.46-2.44, 1.93-1.86, 1.75-1.64, 1.42-1.23, 1.05-1.10.
Example 47
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenylcarbamoyl-2H-pyrazol-3--
yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00079##
[0396] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 484.2 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 9.93 (s, 1H), 7.75-7.50 (m, 4H), 7.45-7.23
(m, 5H), 7.05 (t, 1H), 5.72 (s, 1H), 3.68-3.54 (m, 1H), 3.51-3.41
(m, 1H), 3.25-3.18 (m, 1H), 2.80-2.67 (m, 1H), 2.63-2.51 (m, 1H),
1.97-1.84 (m, 1H), 1.76-1.63 (m, 1H), 1.43-1.13 (m, 10H).
Example 48
(3R,5R)-7-[5-(3-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-
-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00080##
[0398] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 516.2 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.53-7.50 (m, 2H), 7.33-7.26 (m, 3H),
7.09-6.96 (m, 3H), 4.35 (s, 2H), 3.60-3.58 (m, 1H), 3.46-3.43 (m,
1H), 2.70-2.65 (m, 1H), 2.55-2.45 (m, 1H), 1.94 (dd, 1H), 1.74-1.68
(m, 1H), 1.37-1.10 (m, 10H).
Example 49
(3R,5R)-7-[5-(4-fluoro-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-
-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00081##
[0400] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 516.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.52-7.48 (m, 2H), 7.32-7.26 (m, 4H),
7.08-7.04 (m, 2H), 4.31 (s, 2H), 3.61-3.55 (m, 1H), 3.45-3.42 (m,
1H), 2.73-2.66 (m, 1H), 2.57-2.53 (m, 1H), 1.91-1.87 (m, 1H),
1.71-1.65 (m, 1H), 1.35-1.05 (m, 10H).
Example 50
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(1-methyl-1-phenyl-ethylcarba-
moyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00082##
[0402] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 526.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.55-7.51 (m, 2H), 7.35-7.10 (m, 7H),
3.61-3.58 (m, 1H), 3.45-3.43 (m, 1H), 3.10 (bs, 1H), 2.57-2.50 (m,
1H), 2.49-2.44 (m, 1H), 1.92-1.87 (m, 1H), 1.72-1.66 (m, 1H), 1.58
(s, 6H), 1.34-1.08 (m, 10H).
Example 51
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methoxymethyl-benzylcarbam-
oyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00083##
[0404] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 542.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.52-7.49 (m, 2H), 7.32-7.28 (t, 2H),
7.23-7.17 (m, 4H), 4.33 (s, 2H), 4.31 (s, 2H), 3.59-3.57 (m, 1H),
3.45-3.43 (m, 1H), 3.20 (s, 3H), 2.57-2.49 (m, 1H), 2.48-2.42 (m,
1H), 1.92-1.87 (m, 1H), 1.71-1.66 (m, 1H), 1.29-1.09 (m, 10H).
Example 52
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(4-methoxy-benzyl)-methyl-ca-
rbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00084##
[0406] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 542.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.53-7.40, 7.38-7.24, 7.23-7.03, 6.90-6.80, 4.75, 4.54, 4.41, 3.69,
3.67, 3.63-3.53, 3.49-3.40, 2.94-2.81, 2.78, 2.76, 2.74-2.63,
2.61-2.48, 2.24, 1.94-1.83, 1.72-1.66, 1.53, 1.42-1.20,
1.18-1.05.
Example 53
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-methyl-benzyl)-car-
bamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00085##
[0408] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 526.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.48-7.40, 7.31-7.21, 7.19-7.00, 5.70, 4.71, 4.58, 4.47, 3.65-3.55,
3.47-3.41, 3.11, 2.93-2.83, 2.78, 2.77, 2.68-2.63, 2.60-2.48,
2.46-2.44, 1.93-1.86, 1.75-1.64, 1.42-1.23, 1.05-1.10.
Example 54
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(3-methoxy-benzyl)-methyl-ca-
rbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00086##
[0410] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 542.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.48-7.44, 7.40-7.11, 6.88-6.76, 4.71, 4.59, 4.50, 3.68, 3.59,
3.45, 2.89-2.86, 2.81, 2.80, 2.76-2.63, 2.58-2.52, 1.94-1.89,
1.74-1.68, 1.42-1.23, 1.17-1.12.
Example 55
(3R,5R)-7-[5-(benzyl-ethyl-carbamoyl)-2-(4-fluoro-Phenyl)-4-isopropyl-2H-p-
yrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00087##
[0412] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 526.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.48-7.44, 7.39-7.32, 7.31-7.08, 4.71, 4.62, 4.47, 3.64-3.53,
3.51-3.39, 3.24-3.18, 2.95-2.80, 2.78-2.63, 2.62-2.49, 1.93-1.89,
1.73-1.67, 1.41-1.23, 1.22-1.08, 1.07-1.02.
Example 56
(3R,5R)-7-[5-(benzyl-isopropyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl--
2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00088##
[0414] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 540.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.49-7.41, 7.38-7.07, 4.71, 4.57, 4.44, 4.38-4.24, 4.09-4.03,
3.64-3.50, 3.47-3.28, 2.95-2.80, 2.77-2.63, 2.61-2.45, 2.24,
1.94-1.90, 1.74-1.65, 1.43-1.02.
Example 57
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(1S-phenyl-ethyl)-car-
bamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00089##
[0416] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 526.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.46-7.42, 7.35-7.12, 5.94-5.91, 5.25-5.21, 3.60-3.52, 3.46-3.41,
2.92-2.83, 2.71-2.65, 2.60, 2.54, 1.92-1.88, 1.72-1.66,
1.49-1.11.
Example 58
(3R,5R)-7-[5-(cyclohexylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl--
2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00090##
[0418] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 504.2 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.51-7.48 (m, 2H), 7.33-7.28 (m, 2H),
3.60-3.56 (m, 1H), 3.44-3.40 (m, 1H), 3.29-3.15 (m, 3H), 2.98 (d,
2H), 2.68-2.61 (m, 1H), 2.52-2.46 (m, 1H), 1.92-1.87 (m, 1H),
1.72-1.66 (m, 2H), 1.62-1.11 (m, 18H)-.
Example 59
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(1S-p-tolyl-ethylcarbamoyl)-2-
H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00091##
[0420] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 526.1 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.51-7.48 (m, 2H), 7.32-7.27 (m, 2H),
7.22-7.17 (m, 2H), 7.03-7.01 (m, 2H), 5.03-5.01 (m, 1H), 3.60-3.56
(m, 1H), 3.46-3.41 (m, 1H), 2.68-2.46 (m, 1H), 2.56-2.52 (m, 1H),
2.19 (s, 3H), 1.92-1.87 (m, 1H), 1.72-1.67 (m, 1H), 1.37-1.08 (m,
13H).
Example 60
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methoxymethyl-benzylcarbam-
oyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00092##
[0422] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 542.2 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.56 (t, 1H), 7.55-7.52 (m, 2H), 7.35-7.11
(m, 6H), 4.73 (bs, 1H), 4.37-4.33 (m, 4H), 3.64-3.62 (m, 1H),
3.48-3.46 (m, 1H), 3.23 (s, 3H), 2.72-2.69 (m, 1H), 2.59-2.45 (m,
1H), 1.95 (dd, 1H), 1.78-1.73 (m, 1H), 1.40-1.13 (m, 10H).
Example 61
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[1S-(3-methoxy-phenyl)-ethylc-
arbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00093##
[0424] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 542.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.26 (bs, 1H), 7.53-7.50 (m, 2H), 7.33-7.29
(m, 2H), 7.17-7.10 (m, 1H), 6.91-6.88 (m, 2H), 6.73-6.70 (m, 1H),
5.05-5.01 (m, 1H), 3.66 (s, 3H), 3.61-3.57 (m, 1H), 3.45-3.41 (m,
1H), 2.71-2.65 (m, 1H), 2.57-2.50 (m, 1H), 1.93-1.88 (m, 1H),
1.73-1.67 (m, 1H), 1.37-1.11 (m, 13H).
Example 62
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[1S-(4-methoxy-phenyl)-ethylc-
arbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00094##
[0426] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 542.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.35-8.08 (m, 1H), 7.65-7.40 (m, 2H),
7.38-7.15 (m, 4H), 6.93-6.70 (m, 2H), 5.17-4.95 (m, 1H), 4.80-4.60
(m, 1H), 3.80-3.50 (s, 3H), 2.80-2.58 (m, 1H), 2.56-2.50 (m, 1H),
2.40-2.18 (m, 1H), 1.98-1.82 (m, 1H), 1.79-1.63 (m, 1H), 1.54-0.78
(m, 14H).
Example 63
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethyl-be-
nzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid
sodium salt
##STR00095##
[0428] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 580.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.66-7.23, 4.71, 4.61, 3.58, 3.44, 3.27, 3.26, 2.61-2.44,
1.91-1.86, 1.71-1.65, 1.29-1.05.
Example 64
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-trifluoromethyl-be-
nzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid
sodium salt
##STR00096##
[0430] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 580.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.70-7.64, 7.5-7.44, 7.36-7.12, 4.71, 4.61, 3.59-3.56, 3.45-3.41,
2.86, 2.85, 2.73-2.43, 1.91-1.87, 1.71-1.66, 1.36-1.09.
Example 65
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-propylcarbamoyl-2H-pyrazol-3--
yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00097##
[0432] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 450.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.51-7.48 (m, 2H), 7.33-7.28 (m, 2H),
3.60-3.57 (m, 1H), 3.46-3.41 (m, 1H), 3.09 (t, 2H), 2.68-2.64 (m,
1H), 2.57-2.50 (m, 1H), 1.93-1.88 (m, 1H), 1.73-1.67 (m, 1H),
1.43-1.10 (m, 12H), 0.79 (t, 3H).
Example 66
(3R,5R)-7-[5-(4-dimethylcarbamoyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-i-
sopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00098##
[0434] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 567.2 m/z (M-H); H-NMR
(DMSO-d.sub.6) .delta. 8.64-8.59 (m, 1H), 7.67-7.35 (m, 4H),
7.30-7.05 (m, 4H), 4.72 (s, 1H), 4.36 (d, 2H), 3.65-3.35 (m, 2H),
2.90 (s, 3H), 2.82 (s, 3H), 1.91-1.83 (m, 1H), 1.75-1.62 (m, 1H),
1.40-1.05 (m, 13H).
Example 67
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(pyridin-2-ylmethyl)-carbamo-
yl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid sodium salt
##STR00099##
[0436] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 499.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.62-8.51 (m, 1H), 8.45-8.37 (m, 1H), 7.70
(t, 1H), 7.62-7.40 (m, 2H), 7.39-7.12 (m, 4H), 4.73 (s, 1H), 4.45
(d, 2H), 3.63-3.55 (m, 1H), 3.48-3.39 (m, 1H), 2.80-2.62 (m, 1H),
2.60-2.43 (m, 1H), 1.92-1.88 (m, 1H), 1.72-1.63 (m, 1H), 1.50-1.02
(m, 12H).
Example 68
(3R,5R)-7-[2-(4-fluoro-phenyl)-5-(2-hydroxy-1R-phenyl-ethylcarbamoyl)-4-is-
opropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00100##
[0438] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 528.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.26 (d, 1H), 7.54 (t, 1H), 7.50-7.16 (m,
9H), 5.12-5.00 (m, 1H), 4.97-4.92 (m, 1H), 4.71 (m, 1H), 3.70-3.50
(m, 2H), 3.48-3.38 (m, 1H), 3.22-3.05 (m, 1H), 2.78-2.60 (m, 1H),
2.58-2.48 (m, 1H), 1.91-1.86 (m, 1H), 1.73-1.67 (m, 1H), 1.40-1.00
(m, 13H).
Example 69
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(morpholine-4-carbonyl)-2H-py-
razol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00101##
[0440] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 478.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.59-7.38, 7.36-7.11, 4.78-4.64, 3.64-3.44, 3.42-3.30, 2.98-2.80,
2.78-2.63, 2.60-2.38, 1.93-1.87, 1.72-1.66, 1.40-1.10.
Example 70
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-isopropylcarbamoyl-2H-pyrazol-
-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00102##
[0442] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 450.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.65 (d, 1H), 7.52-7.45 (m, 2H), 7.35-7.23
(m, 1H), 4.70 (s 1H), 4.03-4.93 (m, 1H), 3.64-3.56 (m, 1H),
3.42-3.38 (m, 1H), 3.22-3.15 (m, 1H), 2.73-2.60 (m, 1H), 2.57-2.43
(m, 1H), 1.94-1.89 (m, 1H), 1.74-1.65 (m, 1H), 1.40-1.17 (m, 9H),
1.15-1.03 (m, 9H).
Example 71
(3R,5R)-7-[5-(cyclohexylmethyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-iso-
propyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00103##
[0444] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 518.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.46-7.39, 7.32-7.26, 3.61-3.57, 3.44-3.41, 3.16-3.12, 2.85, 2.83,
2.68-2.60, 2.58-2.51, 1.92-1.87, 1.72-1.45, 1.39-1.23, 1.15-1.03,
0.94-0.91, 0.76-0.71.
Example 72
(3R,5R)-7-[5-(cyclopentylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-
-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00104##
[0446] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 490.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.51-7.48 (m, 2H), 7.32-7.28 (m, 2H),
3.58-3.56 (m, 1H), 3.48-3.43 (m, 1H), 3.10 (d, 2H), 2.68-2.61 (m,
1H), 2.56-2.50 (m, 1H), 2.08-2.03 (m, 1H), 1.90-1.85 (m, 1H),
1.69-1.64 (m, 1H), 1.66-1.09 (m, 18H).
Example 73
(3R,5R)-7-[2-(4-fluoro-phenyl)-5-isobutylcarbamoyl-4-isopropyl-2H-pyrazol--
3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00105##
[0448] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 464.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.95 (bs, 1H), 7.51-7.48 (m, 2H), 7.32-7.28
(m, 2H), 3.60-3.56 (m, 1H), 3.45-3.43 (m, 1H), 3.18-3.13 (m, 1H),
2.96 (d, 2H), 2.71-2.65 (m, 1H), 2.56-2.52 (m, 1H), 1.92-1.87 (m,
1H), 1.88-1.74 (m, 2H), 1.39-1.05 (m, 10H), 0.79 (d, 6H).
Example 74
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-butylcarbamoyl)-2H--
pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00106##
[0450] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 487.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.51-7.47 (m, 2H), 7.32-7.28 (m, 2H),
3.59-3.56 (m, 1H), 3.44-3.24 (m, 1H), 3.18-3.12 (m, 2H), 2.67-2.61
(m, 1H), 2.46-2.43 (m, 1H), 1.90-1.86 (m, 1H), 1.68-1.46 (m, 1H),
1.55-1.51 (m, 1H), 1.39-1.05 (m, 12H), 0.82 (d, 6H).
Example 75
(3R,5R)-7-[5-cyclopentylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyraz-
ol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00107##
[0452] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 476.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.75 (d, 1H), 7.51-7.47 (m, 2H), 7.33-7.28
(m, 2H), 4.70 (d, 1H), 4.14-4.09 (m, 1H), 3.59-3.51 (m, 1H),
3.46-3.41 (m, 1H), 3.18-3.13 (m, 1H), 2.71-2.66 (m, 1H), 2.56-2.50
(m, 1H), 1.92-1.88 (m, 1H), 1.81-1.70 (m, 3H), 1.61-1.52 (m, 2H),
1.43-1.39 (m, 2H), 1.38-1.15 (m, 10H).
Example 76
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(2-phenyl-pyrrolidine-1-carbo-
nyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00108##
[0454] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 538.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of diastereomers] .delta. 7.51-7.47,
7.33-7.06, 6.93-6.92, 5.37-5.32, 5.14-5.11, 3.79-3.28, 2.96-2.89,
2.78-2.19, 1.92-1.56, 1.24-0.87.
Example 77
(3R,5R)-7-[5-(cyclobutylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl--
2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00109##
[0456] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 476.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.51-7.47 (m, 2H), 7.32-7.27 (m, 2H),
3.61-3.57 (m, 1H), 3.44-3.41 (m, 1H), 3.20-3.16 (m, 1H), 2.67-2.63
(m, 1H), 2.54-2.51 (m, 1H), 1.92-1.84 (m, 3H), 1.78-1.57 (m, 5H),
1.41-1.06 (m, 1.06).
Example 78
(3R,5R)-7-[5-[(2,3-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-Phenyl)--
4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00110##
[0458] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 548.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.48-7.01, 4.71-4.69, 3.59-3.57, 3.44, 2.88, 2.84-2.81, 2.72-2.68,
2.56-2.61, 1.92-1.88, 1.72-1.69, 1.40-1.24, 1.14-1.08.
Example 79
(3R,5R)-7-[5-(cyclopropyl
methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-di-
hydroxy-heptanoic acid sodium salt
##STR00111##
[0460] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 462.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.51-7.48 (m, 2H), 7.32-7.28 (m, 2H),
3.61-3.59 (m, 1H), 3.43-3.41 (m, 1H), 3.18-3.17 (m, 1H), 3.01 (d,
2H), 2.68-2.64 (m, 1H), 2.56-2.49 (m, 1H), 1.93-1.88 (m, 1H),
1.73-1.67 (m, 1H), 1.39-1.01 (m, 10H), 0.33-0.29 (m, 2H), 0.16-0.12
(m, 2H).
Example 80
(3R,5R)-7-[5-[(2,4-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)--
4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00112##
[0462] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 548.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.53-7.00, 4.71, 4.64, 4.60, 3.61-3.57, 3.44-3.42, 2.84, 2.81,
2.72-2.66, 2.56-2.53, 1.92-1.87, 1.72-1.66, 1.36-1.09.
Example 81
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(4-trifluoromethoxy-b-
enzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid
sodium salt
##STR00113##
[0464] The title compound was prepared in a manner analogous to the
method of Example 1: H-NMR [Mixture of rotamers at 25.degree. C.]
(DMSO-d.sub.6) .delta. 7.51-7.25, 4.72, 4.67, 4.57, 3.66-3.61,
3.51-3.42, 2.90, 2.87, 2.76-2.71, 2.52-2.44, 1.96-1.91, 1.76-1.72,
1.39-1.08.
Example 82
(3R,5R)-7-[5-butylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-y-
l]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00114##
[0466] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 464.2 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.97 (t, 3H), 7.56-7.51 (m, 3H), 7.35-7.31
(m, 2H), 4.74-4.73 (m, 1H), 3.69-3.59 (m, 1H), 3.56-3.40 (m, 1H),
3.21-3.12 (m, 3H), 2.78-2.63 (m, 1H), 2.60-2.43 (m, 1H), 1.95-1.90
(m, 1H), 1.75-1.69 (m, 1H), 1.47-1.33 (m, 2H), 1.31-1.21 (m, 12H),
1.20-1.10 (m, 1H), 0.85 (t, 3H).
Example 83
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(piperidine-1-carbonyl)-2H-py-
razol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00115##
[0468] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 476.2 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.66-7.60, 7.50-7.41, 7.34-7.27, 4.75-4.68, 3.63-3.60, 3.59-3.55,
3.52-3.43, 2.95-2.82, 2.80-2.63, 2.61-2.45, 1.95-1.90, 1.74-1.68,
1.60-1.51, 1.46-1.43, 1.42-1.38, 1.36-1.25, 1.24-1.13.
Example 84
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethoxy-b-
enzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid
sodium salt
##STR00116##
[0470] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) H-NMR (DMSO-d.sub.6) [Mixture
of rotamers at 25.degree. C.] .delta. 7.66-7.25, 4.73, 4.69, 4.59,
3.66-3.59, 3.52-3.43, 2.87, 2.86, 2.76-2.71, 2.58-2.52, 1.94-1.89,
1.74-1.68, 1.34-1.08.
Example 85
(3R,5R)-7-[5-cyclohexylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazo-
l-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00117##
[0472] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 490.1 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.82-7.76 (m, 1H), 7.59-7.43 (m, 2H),
7.39-7.25 (m, 2H), 4.78-4.64 (m, 1H), 3.80-3.58 (m, 2H), 3.56-3.40
(m, 1H), 3.23-3.08 (m, 1H), 2.78-2.60 (m, 1H), 2.59-2.43 (m, 1H),
1.96-1.86 (m, 1H), 1.80-1.62 (m, 4H), 1.60-1.43 (m, 1H), 1.41-1.04
(m, 18H).
Example 86
(3R,5R)-7-[5-(4-cyano-benzylcarbamoyl)-2-(4-fluoro-Phenyl)-4-isopropyl-2H--
pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00118##
[0474] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 523.1 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.78-8.75 (m, 1H), 7.78-7.74 (m, 2H),
7.61-7.51 (m, 2H), 7.49-7.40 (m, 2H), 7.39-7.29 (m, 2H), 4.76-4.71
(m, 1H), 4.43-4.38 (m, 2H), 3.68-3.58 (m, 1H), 3.57-3.42 (m, 1H),
3.23-3.16 (m, 2H), 2.80-2.62 (m, 1H), 2.61-2.50 (m, 1H), 1.95-1.91
(m, 1H), 1.75-1.68 (m, 1H), 1.43-1.08 (m, 12H).
Example 87
(3R,5R)-7-[5-(3-cyano-benzylcarbamoyl)-2-(4-fluoro-Phenyl)-4-isopropyl-2H--
pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00119##
[0476] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 523.1 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.78-8.75 (m, 1H), 7.77-7.60 (m, 2H),
7.59-7.40 (m, 4H), 7.38-7.23 (m, 2H), 4.76-4.72 (m, 1H), 4.43-4.38
(m, 2H), 3.68-3.58 (m, 1H), 3.57-3.42 (m, 1H), 3.23-3.16 (m, 2H),
2.80-2.62 (m, 1H), 2.61-2.50 (m, 1H), 1.95-1.91 (m, 1H), 1.75-1.68
(m, 1H), 1.43-1.08 (m, 12H).
Example 88
(3R,5R)-7-[5-(cyclopentylmethyl-methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-is-
opropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00120##
[0478] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 504 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.49-7.31, 3.65-3.61, 3.49-3.46, 3.36, 3.23, 2.89, 2.87, 2.74-2.72,
2.68-2.46, 2.28-2.21, 1.95-1.91, 1.76-1.16.
Example 89
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-car-
bamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00121##
[0479] Step A. Preparation of Methyl-(2-methyl-benzyl)-amine
##STR00122##
[0481] To a solution of 2-methylbenzaldehyde (10.0 g, 83.23 mmol)
in MeOH at 25.degree. C. was added methylamine (40% in H.sub.2O,
25.85 g, 332.9 mmol). The reaction mixture was stirred at
25.degree. C. for 30 min after which time it was cooled to
0.degree. C. and NaBH.sub.4 (6.30 g, 166.5 mmol) was added
portion-wise. The reaction mixture was then warmed to 25.degree. C.
and stirred for an additional 1 hr. The solvent was removed under
reduced pressure and water and CH.sub.2Cl.sub.2 were added. The
organic layer was separated and washed with saturated NaHCO.sub.3
and brine. After drying over Na.sub.2SO.sub.4, organic phase was
concentrated to afford desired methyl-(2-methyl-benzyl)-amine
(10.49 g, 93.2%) as an oil of sufficient purity for use in the next
reaction: MS (APCI.sup.+) 136.3 m/z (M+H); H-NMR (CDCl.sub.3)
.delta. 7.35-7.08 (m, 3H), 3.73 (s, 2H), 2.49 (s, 3H), 2.34 (s,
3H).
Step B. Preparation of
1-(4-Fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic
acid methyl-(2-methyl-benzyl)-amide
##STR00123##
[0483] To a solution of
1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic
acid (1.50 g, 5.43 mmol) in CH.sub.2Cl.sub.2 (100 mL) at 25.degree.
C. was added EDCI (1.56 g, 8.14 mmol) followed by HOBt.H.sub.2O
(1.25 g, 8.14 mmol) and the reaction was stirred for 10 min at
25.degree. C. Subsequently, methyl-(2-methyl-benzyl)-amine (1.10 g,
8.14 mmol) was added and the reaction was stirred for an additional
6 hrs at 25.degree. C. The organic layer was then washed with HCl,
saturated NaHCO.sub.3 and brine. After drying over Na.sub.2SO.sub.4
and concentration, the product was purified by column
chromatography (10-25% EtOAc/Hex) to afford desired
1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic
acid methyl-(2-methyl-benzyl)-amide as an oil (1.53 g, 71.6%). MS
(APCI.sup.+) 394.2 m/z (M+H).
Step C. Preparation of
5-(tert-Butyl-dimethyl-silanyloxy)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[-
methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3-oxo-hept-6-enoic
acid methyl ester
##STR00124##
[0485] To a solution of
1-(4-fluoro-phenyl)-5-formyl-4-isopropyl-1H-pyrazole-3-carboxylic
acid methyl-(2-methyl-benzyl)-amide (1.53 g, 3.89 mmol) in toluene
(80 mL) was added
3-(tert-butyl-dimethyl-silanyloxy)-5-oxo-6-(triphenyl-15-phosphanyl-
idene)-hexanoic acid methyl ester [prepared according to the
published method: Konoike, T.; Araki, Y. J. Org. Chem. 1994, 59,
7849-7854] (2.70 g, 5.06 mmol) and the reaction was heated to
95.degree. C. for 16 hrs. After cooling to 25.degree. C., the
solvent was removed under reduced pressure and product was run
through pad of silica gel (20-30% EtOAc/Hex) to afford
5-(tert-butyl-dimethyl-silanyloxy)-7-{2-(4-fluoro-phenyl)-4-iso-
propyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3-oxo-hept--
6-enoic acid methyl ester (2.48 g, 98.1%): MS (APCI.sup.+) 650.4
m/z (M+H).
Step D. Preparation of
7-[2-(4-Fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-
-2H-Pyrazol-3-yl]-5-hydroxy-3-oxo-hept-6-enoic acid methyl
ester
##STR00125##
[0487] To a solution of
5-(tert-butyl-dimethyl-silanyloxy)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[-
methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3-oxo-hept-6-enoic
acid methyl ester (2.48 g, 3.82 mmol) in MeCN (40 mL) at 25.degree.
C. was added HF (2.5 mL of 48% in water). Reaction was stirred at
25.degree. C. for 16 hrs. Subsequently, EtOAc (100 mL) and water
(100 mL) were added and the organic layer was separated, dried and
concentrated. Product was purified by column chromatography
(30%-50% EtOAc-Hex) to afford
7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-
-2H-pyrazol-3-yl}-5-hydroxy-3-oxo-hept-6-enoic acid methyl ester
(2.03 g, 98.0%): MS (APCI.sup.+) 536.4 m/z (M+H).
Step E.
7-{2-(4-Fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-car-
bamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoic acid methyl
ester
##STR00126##
[0489] To a solution of
7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-
-2H-pyrazol-3-yl}-5-hydroxy-3-oxo-hept-6-enoic acid methyl ester
(2.04 g, 3.81 mmol) in THF (100 mL) and MeOH (30 mL) at -78.degree.
C. was added diethylmethoxyborane (4.95 mL of 1.0 M solution, 4.95
mmol). Reaction was stirred at -78.degree. C. for 1 hrs after which
time NaBH.sub.4 (166 mg, 4.38 mmol) was added. Reaction mixture was
stirred at -78.degree. C. for 2 hr and then warmed to 0.degree. C.
after which time glacial acetic acid (0.5 mL) was added. Reaction
was diluted with EtOAc and water and organic layer was separated
and washed with sat. NaHCO.sub.3 and brine prior to concentration.
The resulting crude oil was then dissolved in MeOH (50 mL) and
evaporated again. Subsequently a second amount of MeOH (50 mL) was
added and the solution was stirred at 25.degree. C. for 12 hrs
after which time it was concentrated and purified by column
chromatography (40-60% EtOAc/Hex) to afford
7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-
-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoic acid methyl ester
(1.66 g, 81.1%): MS (APCI.sup.+) 538.4 m/z (M+H).
Step F.
7-{2-(4-Fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-car-
bamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid methyl
ester
##STR00127##
[0491] To a solution of
7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-
-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoic acid methyl ester
(1.190 g, 2.21 mmol) in MeOH (50 ml) was added Pd--C (0.1 g). The
reaction vessel was evacuated, flushed with nitrogen and then
filled with hydrogen (via balloon). Reaction was stirred at
25.degree. C. for 4 hrs. Reaction was then flushed with nitrogen
and filtered through a pad of celite. The filtrate was concentrated
and purified by column chromatography (30-40% EtOAc/Hex) to afford
7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-
-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid methyl ester (0.792
g, 66%): MS (APCI.sup.+) 540.2 m/z (M+H).
Step G.
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-ben-
zyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid
sodium salt
##STR00128##
[0493] To a solution of
7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-
-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid methyl ester (0.7920
g, 1.47 mmol) in MeOH (5 ml), NaOH solution (1.028N, 1.50 ml, 1.54
mmol) was added. The reaction mixture was stirred at 25.degree. C.
for 12 hrs. After solvent was evaporated, the crude product was
dried azeotropically with toluene (.times.3). It was dissolved in
MeOH/CH.sub.2Cl.sub.2 mixture (1:9, 10 ml) and diluted with
CH.sub.2Cl.sub.2 (15 ml). It was filtered through cotton and the
filtrate was concentrated, triturated with Et.sub.2O for 12 hrs.
The product was isolated by filtration and dried under vacuum at
60.degree. C. for 12 hrs to afford
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-ca-
rbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid sodium salt
(798 mg, 99%): MS (APCI.sup.+) 526.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.79-7.65, 7.58-7.46, 7.41-7.24, 7.22-7.07, 4.85-4.60, 3.62-3.58,
3.46-3.44, 2.89-2.85, 2.84, 2.74-2.66, 2.54-2.45, 2.29, 1.93-1.88,
1.73-1.67, 1.53-1.10.
Example 90
(3R,5R)-7-[5-[(2-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-is-
opropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00129##
[0495] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 530.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.55-7.10, 4.74, 4.70, 4.67, 3.67-3.62, 3.51-3.44, 2.92, 2.88,
2.75-2.69, 2.59-2.53, 1.95-1.90, 1.75-1.69, 1.39-1.11.
Example 91
(3R,5R)-7-[5-[(3,4-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)--
4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00130##
[0497] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 548.2 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.50-7.21, 4.62, 4.50, 3.56-3.61, 3.51-3.45, 2.86, 2.84, 2.76-2.69,
2.54-2.50, 1.94-1.90, 1.75-1.71, 1.41-1.07.
Example 92
(3R,5R)-7-[5-(3-ethoxymethyl-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopro-
pyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00131##
[0499] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 556.2 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.55-7.51 (m, 2H), 7.34-7.30 (m, 2H),
7.25-7.10 (m, 4H), 4.37 (s, 2H), 4.36 (s, 2H), 3.66-3.61 (m, 1H),
3.49-3.43 (m, 1H), 3.41 (q, 2H), 2.76-2.71 (m, 1H), 2.57-2.51 (m,
1H), 1.97-1.92 (m, 1H), 1.77-1.71 (m, 1H), 1.39-1.12 (m, 10H), 1.09
(t, 3H).
Example 93
(3R,5R)-7-[5-(4-ethyl-benzylcarbamoyl)-2-(4-fluoro-Phenyl)-4-isopropyl-2H--
pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00132##
[0501] The title compound was prepared in a manner analogous to the
method of Example 89: H-NMR (DMSO-d.sub.6) .delta. 7.55-7.51 (m,
2H), 7.35-7.30 (m, 2H), 7.23-7.10 (m, 4H), 4.32 (s, 2H), 3.65-3.60
(m, 1H), 3.49-3.44 (m, 1H), 3.23-3.21 (m, 1H), 2.75-2.71 (m, 1H),
2.69-2.61 (m, 1H), 2.51 (q, 2H), 1.97-1.92 (m, 1H), 1.77-1.71 (m,
1H), 1.39-1.14 (m, 10H), 1.11 (t, 3H).
Example 94
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(5-trifluoromethyl-pyridin-2-
-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid
sodium salt
##STR00133##
[0503] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 567.1 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.86 (s, 1H), 8.78 (t, 1H), 8.15 (d, 1H),
7.58-7.54 (m, 2H), 7.48 (d, 1H), 7.37-7.33 (m, 2H), 4.80-4.73 (m,
1H), 4.55 (d, 2H), 3.70-3.58 (m, 1H), 3.55-3.42 (m, 1H), 3.24-3.20
(m, 1H), 2.80-2.63 (m, 1H), 2.61-2.42 (m, 1H), 1.95-1.90 (m, 1H),
1.75-1.69 (m, 1H), 1.42-1.30 (m, 1H), 1.29-1.20 (m, 10H), 1.17-1.12
(m, 1H).
Example 95
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-trifluoromethyl-pyridin-3-
-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid
sodium salt
##STR00134##
[0505] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 567.1 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.85 (t, 1H), 8.70 (s, 1H), 7.96 (d, 1H),
7.86 (d, 1H), 7.58-7.56 (m, 2H), 7.39-7.34 (m, 2H), 4.73-4.78 (m,
1H), 4.51 (d, 2H), 3.67-3.55 (m, 1H), 3.45-3.45 (m, 1H), 3.26-3.18
(m, 1H), 2.80-2.68 (m, 1H), 2.64-2.55 (m, 1H), 1.97-1.92 (m, 1H),
1.77-1.65 (m, 1H), 1.42-1.21 (m, 10H), 1.20-1.10 (m, 2H).
Example 96
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-trifluoromethyl-piperidin-
-3-ylmethyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic
acid sodium salt
##STR00135##
[0507] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 573.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [A mixture of diastereomers] .delta. 8.11-8.08,
7.54-7.40, 7.36-7.28, 4.76-4.63, 3.64-3.58, 3.51-3.40, 3.22-3.11,
3.03-2.96, 2.80-2.60, 2.59-2.47, 2.40-2.35, 1.95-1.90, 1.82-1.62,
1.60-1.40, 1.39-1.02.
Example 97
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-isopropyl-benzylcarbamoyl)-
-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00136##
[0509] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 540.1 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.50 (t, 1H), 7.54-7.50 (m, 3H), 7.49-7.34
(m, 2H), 7.32-7.11 (m, 3H), 4.76-4.70 (m, 1H), 4.31 (d, 1H),
3.68-3.59 (m, 1H), 3.50-3.41 (m, 1H), 3.36-3.29 (m, 1H), 3.24-3.16
(m, 1H), 2.84-2.76 (m, 1H), 2.75-2.63 (m, 1H), 2.60-2.43 (m, 1H),
1.95-1.90 (m, 1H), 1.75-1.69 (m, 1H), 1.42-1.30 (m, 1H), 1.29-1.16
(m, 10H), 1.13 (d, 6H).
Example 98
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3R-phenyl-piperidine-1-carbo-
nyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00137##
[0511] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 552.1 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.52-7.43. 7.42-7.38, 7.36-7.03, 4.80-4.63, 4.60-4.50, 3.80-3.53,
3.50-3.33, 3.26-3.24, 3.20-3.02, 2.98-2.78, 2.76-2.44, 1.98-1.87,
1.84-1.61, 1.59-1.15.
Example 99
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3S-phenyl-piperidine-1-carbo-
nyl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00138##
[0513] The title compound was prepared in a manner analogous to the
method of Example 89: H-NMR (DMSO-d.sub.6) [Mixture of rotamers at
25.degree. C.] .delta. 7.54-7.09, 4.74-4.72, 4.62-4.51, 3.78-3.57,
3.51-3.45, 3.08-3.02, 2.89-2.80, 2.79-2.49, 1.97-1.85, 1.83-1.61,
1.58-1.11.
Example 100
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-methyl-pyridin-3-ylmethyl-
)-carbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00139##
[0515] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+). 513.1 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.64 (t, 1H), 8.34 (d, 1H), 7.59-7.51 (m,
3H), 7.49-7.38 (m, 1H), 7.35-7.31 (m, 2H), 7.15 (d, 1H), 4.77-4.68
(m, 1H), 4.32 (d, 2H), 3.63-3.59 (m, 1H), 3.49-3.40 (m, 1H),
3.24-3.19 (m, 1H), 2.76-2.62 (m, 1H), 2.60-2.44 (m, 1H), 2.38 (s,
3H), 1.95-1.91 (m, 1H), 1.75-1.70 (m, 1H), 1.40-1.19 (m, 10H),
1.19-1.11 (m, 1H).
Example 101
(3R,5R)-7-[5-ethylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-y-
l]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00140##
[0517] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 434.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.09-8.04 (m, 1H), 7.50-7.46 (m, 2H),
7.32-7.27 (m, 2H), 7.22-7.12 (m, 1H), 6.26 (d, 1H), 5.66 (dd, 1H),
5.13 (s, 1H), 4.21-4.14 (m, 1H), 3.65-3.55 (m, 1H), 3.41-3.27 (m,
1H), 3.23-3.15 (m, 2H), 2.00-1.94 (m, 1H), 1.80-1.75 (m, 1H),
1.49-1.40 (m, 1H), 1.38-1.07 (m, 8H), 1.02 (t, 3H).
Example 102
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-phenylcarbamoyl-2H-pyrazol-3--
yl]-3,5-dihydroxy-hept-6-enoic acid sodium salt
##STR00141##
[0519] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 482.2 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.82-7.58 (m, 5H), 7.43-7.23 (m, 4H), 7.02
(t, 1H), 6.17 (d, 1H), 5.76 (t, 1H), 4.95-4.71 (m, 1H), 3.97-3.81
(m, 1H), 3.58-3.41 (m, 1H), 3.21-3.05 (m, 1H), 2.55-2.39 (m, 1H),
1.84-1.71 (m, 1H), 1.62 (m, 1H), 1.40-1.08 (m, 8H), 0.83-0.65 (m,
1H).
Example 103
(3R,5R)-7-[5-(cyclohexylmethyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl--
2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid sodium salt
##STR00142##
[0521] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 502.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.51-7.47 (m, 2H), 7.33-7.28 (m, 2H), 6.26
(d, 1H), 5.68 (dd, 1H), 4.19-4.16 (m, 1H), 3.61-3.59 (m, 1H),
3.42-3.39 (m, 1H), 3.00 (d, 2H), 1.97-1.92 (m, 2H), 1.78-1.72 (m,
1H), 1.63-0.88 (m, 19H).
Example 104
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-propylcarbamoyl-2H-pyrazol-3--
yl]-3,5-dihydroxy-hept-6-enoic acid sodium salt
##STR00143##
[0523] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 448.3 m/z (M+H).
Example 105
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-isopropylcarbamoyl-2H-pyrazol-
-3-yl]-3,5-dihydroxy-hept-6-enoic acid sodium salt
##STR00144##
[0525] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 448.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.83-7.77 (m, 1H), 7.60-7.41 (m, 2H),
7.40-7.22, (m, 2H), 6.27 (d, 1H), 5.71-5.14 (m, 1H), 5.22-5.04 (m,
1H), 4.26-4.10 (m, 1H), 4.08-4.00 (m, 1H), 3.67-3.51 (m, 1H),
2.01-1.89 (m, 1H), 1.82-1.70 (m, 1H), 1.50-1.40 (m, 1H), 1.37-1.05
(m, 15H).
Example 106
(3R,5R)-7-[2-(4-fluoro-phenyl)-5-isobutylcarbamoyl-4-isopropyl-2H-pyrazol--
3-yl]-3,5-dihydroxy-hept-6-enoic acid sodium salt
##STR00145##
[0527] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 462.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.05 (bs, 1H), 7.51-7.48 (m, 2H), 7.32-7.28
(m, 2H), 6.26 (d, 1H), 5.69 (dd, 1H), 4.19-4.16 (m, 1H), 3.62-3.58
(m, 1H), 3.18 (d, 2H), 1.96-1.92 (m, 1H), 1.79-1.72 (m, 2H),
1.48-1.41 (m, 1H), 1.29-1.23 (m 7H), 0.80 (d, 6H).
Example 107
(3R,5R)-7-[5-cyclopentylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyraz-
ol-3-yl]-3,5-dihydroxy-hept-6-enoic acid sodium salt
##STR00146##
[0529] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 474.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.52-7.47 (m, 2H), 7.31-7.27 (m, 2H), 6.26
(d, 1H), 5.68 (dd, 1H), 4.16-4.10 (m, 2H), 3.63-3.60 (m, 1H),
3.21-3.15 (m, 1H), 1.97-1.93 (m, 1H), 1.79-1.73 (m, 4H), 1.60-1.53
(m, 2H), 1.47-1.40 (m, 4H), 1.36-1.17 (m, 7H).
Example 108
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(3-methyl-butylcarbamoyl)-2H--
pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid sodium salt
##STR00147##
[0531] The title compound was prepared in a manner analogous to the
method of Example 1: (M+H); H-NMR (DMSO-d.sub.6) .delta. 8.01 (bs,
1H), 7.50-7.47 (m, 2H), 7.32-7.28 (m, 2H), 6.26 (d, 1H), 5.67 (dd,
1H), 4.17-4.16 (m, 1H), 3.16-3.59 (m, 1H), 3.19-3.17 (m, 2H),
1.97-1.92 (m, 1H), 1.78-1.72 (m, 1H), 1.56-1.49 (m, 3H), 1.39-1.19
(m, 8H), 0.82 (d, 6H).
Example 109
(3R,5R)-7-[5-(cyclopropyl
methyl-carbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-yl]-3,5-di-
hydroxy-hept-6-enoic acid sodium salt
##STR00148##
[0533] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 460.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.50-7.46 (m, 2H), 7.31-7.27 (m, 2H), 6.26
(d, 1H), 5.56 (dd, 1H), 4.19-4.16 (m, 1H), 3.63-3.59 (m, 1H),
3.30-3.26 (m, 1H), 3.04 (d, 2H), 1.95-1.90 (m, 1H), 1.77-1.71 (m,
1H), 1.39-1.10 (m, 8H), 0.98-0.94 (m, 1H), 0.34-0.31 (m, 2H),
0.17-0.14 (m, 2H).
Example 110
(3R,5R)-7-[5-butylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazol-3-y-
l]-3,5-dihydroxy-hept-6-enoic acid sodium salt
##STR00149##
[0535] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 462.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.10-8.05 (m, 1H), 7.52-7.47 (m, 2H),
7.35-7.28 (m, 2H), 7.01 (s, 1H), 6.31-6.27 (m, 1H), 6.73-5.67 (m,
1H), 5.16 (s, 1H), 4.23-4.16 (m, 1H), 3.65-3.58 (m, 1H), 3.36-3.18
(m, 3H), 2.03-1.95 (m, 1H), 1.85-1.79 (m, 1H), 1.53-1.33 (m, 3H),
1.31-1.21 (m, 10H), 0.85 (t, 3H).
Example 111
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(3-trifluoromethoxy-b-
enzyl)-carbamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoic acid
sodium salt
##STR00150##
[0537] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 594.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.52-7.46, 7.36-7.25, 6.29-6.24, 5.86-5.73, 5.17, 4.71, 4.61,
4.24-4.21, 3.68-3.65, 2.91, 2.88, 1.99-1.95, 1.83-1.79,
1.49-1.12.
Example 112
(3R,5R)-7-[5-cyclohexylcarbamoyl-2-(4-fluoro-phenyl)-4-isopropyl-2H-pyrazo-
l-3-yl]-3,5-dihydroxy-hept-6-enoic acid sodium salt
##STR00151##
[0539] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 488.2 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 7.82-7.76 (m, 1H), 7.58-7.43 (m, 1H), 7.41
(s, 1H), 7.35-7.27 (m, 2H), 6.29 (d, 1H), 5.71 (dd, 1H), 5.21-5.18
(m, 1H), 4.21-4.18 (m, 1H), 3.78-3.66 (m, 1H), 3.65-3.60 (m, 1H),
3.22-3.17 (m, 1H), 2.00-1.96 (m, 1H), 1.82-1.60 (m, 4H), 1.39-1.40
(m, 2H), 1.38-1.02 (m, 15H).
Example 113
(3R,5R)-7-[5-(4-cyano-benzylcarbamoyl)-2-(4-fluoro-Phenyl)-4-isopropyl-2H--
pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid sodium salt
##STR00152##
[0541] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 521.0 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.91-8.78 (m, 1H), 7.95-7.70 (m, 2H),
7.63-7.41 (m, 4H), 7.40-7.23 (m, 2H), 6.33-6.23 (m, 1H), 5.80-5.64
(m, 1H), 5.23-5.18 (m, 1H), 4.45-4.35 (m, 2H), 4.23-4.18 (m, 1H),
3.64-3.58 (m, 1H), 2.10-1.95 (m, 1H), 1.82-1.71 (m, 1H), 1.56-1.42
(m, 1H), 1.40-1.05 (m, 10H).
Example 114
(3R,5R)-7-[5-(3-cyano-benzylcarbamoyl)-2-(4-fluoro-phenyl)-4-isopropyl-2H--
pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid sodium salt
##STR00153##
[0543] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 521.0 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.91-8.80 (m, 1H), 7.70-7.62 (m, 2H),
7.60-7.43 (m, 4H), 7.37-7.32 (m, 2H), 6.33-6.28 (m, 1H), 5.78-5.72
(m, 1H), 5.23-5.18 (m, 1H), 4.45-4.35 (m, 2H), 4.23-4.18 (m, 1H),
3.64-3.59 (m, 1H), 2.01-1.95 (m, 1H), 1.81-1.71 (m, 1H), 1.56-1.42
(m, 1H), 1.40-1.05 (m, 10H).
Example 115
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-methylcarbamoyl-2H-pyrazol-3--
yl]-3,5-dihydroxy-hept-6-enoic acid sodium salt
##STR00154##
[0545] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 420.1 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.10-8.05 (m, 1H), 7.53-7.50 (m, 2H),
7.36-7.30, (m, 3H), 6.33-6.28 (m, 1H), 5.74-5.69 (m, 1H), 5.22-5.15
(m, 1H), 4.23-4.17 (m, 1H), 3.70-3.60 (m, 1H), 3.26-3.22 (m, 1H),
2.71 (d, 3H), 2.01-1.97 (m, 1H), 1.83-1.77 (m, 1H), 1.56-1.45 (m,
1H), 1.33-1.06 (m, 9H).
Example 116
(3R,5R)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-car-
bamoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-hept-6-enoic acid sodium
salt
##STR00155##
[0547] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 524.1 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.50-7.43, 7.42-7.40, 7.37-7.24, 7.21-7.11, 6.30-6.23, 5.86-5.75,
5.21-5.15, 4.68, 4.62, 4.24-4.18, 3.73-3.61, 3.07-2.97, 2.89, 2.86,
2.28, 2.15, 2.02-1.96, 1.83-1.76, 1.53-1.45, 1.41-1.26,
1.24-1.18.
Example 117
(3R,5R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-[(6-methyl-pyridin-3-ylmethyl-
)-carbamoyl]-2H-pyrazol-3-yl]-3,5-dihydroxy-hept-6-enoic acid
sodium salt
##STR00156##
[0549] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 511.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. 8.72 (t, 1H), 8.35 (d, 1H), 7.57-7.50 (m,
3H), 7.35-7.33 (m, 3H), 7.15 (d, 1H), 6.29 (d, 1H), 5.74-5.69 (m,
1H), 5.21-5.15 (m, 1H), 4.35 (d, 1H), 4.22-4.18 (d, 1H), 3.64-3.58
(m, 1H), 2.39 (s, 3H), 2.00-1.96 (m, 1H), 1.82-1.76 (m, 1H),
1.50-1.44 (m, 1H), 1.32-1.24 (m, 8H).
Example 118
7-[5-[(2,6-difluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopro-
pyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00157##
[0551] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 548.2 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.51-7.26, 7.12-7.03, 7.02-6.98, 4.82, 4.80-4.70, 3.63-3.58,
3.50-3.39, 2.93, 2.89-2.81, 2.80, 2.78-2.63, 2.60-2.45, 1.96-1.91,
1.76-1.70, 1.42-1.20, 1.19-1.04.
Example 119
7-{5-[(4-fluoro-2-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4--
isopropyl-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00158##
[0553] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 560.2 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.50-7.42, 7.35-7.20, 7.18-7.09, 6.88-6.81, 4.73, 4.61, 4.44, 3.78,
3.63-3.60, 3.50-3.42, 3.35-3.20, 2.95-2.85, 2.82, 2.80-2.63,
2.62-2.50, 1.96-1.92, 1.76-1.70, 1.33-1.22, 1.20-1.13.
Example 120
7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,4-trifluoro-benzyl)-carb-
amoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00159##
[0555] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 566.2 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.50-7.42, 7.34-7.12, 4.70, 4.68, 3.63-3.61, 3.47-3.42, 2.91, 2.89,
2.76-2.72, 2.69-2.65, 1.97-1.92, 1.77-1.72, 1.42-1.27,
1.18-1.13.
Example 121
7-{5-[(3-fluoro-4-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4--
isopropyl-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00160##
[0557] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 560.1 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.50-7.42, 7.33-7.25, 7.18-7.04, 4.72, 4.56, 4.43, 3.79, 3.77,
3.71-3.60, 3.51-3.40, 3.38-3.33, 2.95-2.83, 2.81, 2.78-2.63,
2.60-2.43, 1.96-1.92, 1.76-1.71, 1.42-1.21, 1.19-1.14.
Example 122
7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,6-trifluoro-benzyl)-carb-
amoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00161##
[0559] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 566.2 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.50-7.40, 7.37-7.25, 7.18-7.08, 7.06-7.00, 4.86, 4.76, 4.72,
3.64-3.57, 3.52-3.40, 3.24-3.21, 2.97, 2.93-2.76, 2.75-2.60,
2.58-2.48, 1.96-1.91, 1.76-1.70, 1.42-1.20, 1.18-1.00.
Example 123
7-[5-[(2,3-difluoro-4-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-Phenyl)-
-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00162##
[0561] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 562.2 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.55-6.93, 4.73, 4.69, 4.66, 3.65-3.61, 3.49-3.45, 2.90, 2.87,
2.74-2.71, 2.69-2.67, 2.26, 2.23, 2.20, 1.95-1.90, 1.74-1.69,
1.45-1.12.
Example 124
7-[5-[(2,3-difluoro-6-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-Phenyl-
)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00163##
[0563] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 578.2 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.50-7.09, 6.84-6.76, 4.75, 4.70, 3.77, 3.68, 3.65-3.61, 3.51-3.47,
2.88, 2.74, 2.73-2.68, 2.59-2.56, 2.26, 1.97-1.91, 1.77-1.07.
Example 125
7-[5-[(3-fluoro-4-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-i-
sopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00164##
[0565] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 544.2 m/z (M+H); H-NMR
(DMSO-d.sub.6) .delta. [Mixture of rotamers at 25.degree. C.]
.delta. 7.75-7.40, 7.33-7.08, 7.06-6.98, 4.60, 4.48, 3.64-3.58,
3.45-3.38, 2.95-2.84, 2.82, 2.77-2.45, 2.18, 2.15, 1.96-1.91,
1.76-1.70, 1.43-1.22, 1.18-1.14.
Example 126
7-[5-[(4-fluoro-3-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-i-
sopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00165##
[0567] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 544.2 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.65-7.40, 7.33-7.22, 7.18-7.02, 4.74, 4.58, 4.45, 3.64-3.58,
3.45-3.38, 2.95-2.84, 2.82, 2.77-2.45, 2.18, 2.15, 1.96-1.91,
1.76-1.70, 1.43-1.22, 1.18-1.14.
Example 127
7-[5-[(2,3-difluoro-4-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl-
)-4-isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00166##
[0569] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 578.2 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.58-7.57, 7.49-7.44, 7.33-7.29, 7.14-7.10, 7.03-6.95, 4.75, 4.66,
4.62, 3.83, 3.80, 3.64-3.60, 3.49-3.46, 2.89, 2.85, 2.74-2.67,
2.59-2.52, 1.94-1.90, 1.74-1.68, 1.42-1.11.
Example 128
7-[5-[(2-fluoro-3-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-i-
sopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00167##
[0571] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 544.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.50-7.48, 7.47-7.40, 7.33-7.27, 7.19-7.13, 7.07-6.97, 4.72, 4.68,
4.64, 3.64-3.62, 3.49-3.45, 2.91, 2.87, 2.76-2.72, 2.68-2.60, 2.21,
2.15, 1.96-1.92, 1.77-1.71, 1.57-1.29, 1.17-1.11.
Example 129
7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2,3,5-trifluoro-benzyl)-carb-
amoyl]-2H-pyrazol-3-yl}-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00168##
[0573] The title compound was prepared in a manner analogous to the
method of Example 89: H-NMR (DMSO-d.sub.6) [Mixture of rotamers at
25.degree. C.] .delta. 7.59, 7.51-7.40, 7.34-7.28, 6.97, 4.73-4.71,
3.62-3.60, 3.49-3.45, 2.93, 2.87, 2.76-2.72, 2.71-2.636, 1.94-1.90,
1.74-1.68, 1.43-1.26, 1.17-1.12.
Example 130
7-[5-[(3-fluoro-2-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4--
isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00169##
[0575] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 560.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.50-7.26, 7.18-6.96, 4.73, 4.68, 4.63, 3.85, 3.70, 3.63-3.59,
3.49-3.42, 2.90, 2.87, 2.75-2.70, 2.61-2.57, 1.96-1.91, 1.76-1.70,
1.56-1.13.
Example 131
7-[5-[(2-fluoro-3-methoxy-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4--
isopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00170##
[0577] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 560.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta.
7.55-7.39, 7.33-7.29, 7.09-7.01, 4.68, 4.65, 3.80, 3.76, 3.63-3.61,
4.47-3.45, 2.90, 2.86, 2.72-2.68, 2.52-2.49, 2.47, 2.46, 1.96-1.91,
1.76-1.70, 1.47-1.12.
Example 132
7-[5-[(3-fluoro-2-methyl-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-i-
sopropyl-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium
salt
##STR00171##
[0579] The title compound was prepared in a manner analogous to the
method of Example 89: MS (APCI.sup.+) 544.3 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of rotamers at 25.degree. C.] .delta. 7.63,
7.51-7.47, 7.38-7.32, 7.29-7.14, 7.07-6.99, 4.74, 4.69, 4.63,
3.62-3.60, 3.48-3.45, 2.93-2.89, 2.87, 2.83, 2.73-2.70, 2.63-2.57,
2.18, 2.03, 1.93-1.89, 1.73-1.68, 1.37-1.12.
Example 133
1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4--
isopropyl-1H-pyrazole-3-carboxylic acid
(3-fluoro-benzyl)-methyl-amide
##STR00172##
[0581] To a
7-[5-[(3-fluoro-benzyl)-methyl-carbamoyl]-2-(4-fluoro-phenyl)-4-isopropyl-
-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt (270 mg,
0.49 mmol) in MeCN (50 ml) was slowly added TFA (1.0 mL, 1.23
mmol). The reaction mixture was stirred at 25.degree. C. and
monitored by HPLC. After 2 hrs, the reaction was completed. The
reaction mixture was diluted with EtOAc (150 ml) and washed with
H.sub.2O, saturated NaHCO.sub.3, and brine. The organic layer was
dried over Na.sub.2SO.sub.4 and concentrated. The crude product was
purified by silica gel column chromatography (70% EtOAc/Hex) to
afford
1-(4-fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4-
-isopropyl-1H-pyrazole-3-carboxylic acid
(3-fluoro-benzyl)-methyl-amide (210 mg, 84%): MS (APCI.sup.+) 512.2
m/z (M+H); H-NMR (CDCl.sub.3) [Mixture of rotamers at 25.degree.
C.] .delta. 7.40-7.21, 7.18-6.88, 4.72, 4.611, 4.58-4.48,
4.33-4.24, 2.98-2.93, 2.80-2.68, 2.63, 2.63 2.62, 2.61, 2.57, 2.56,
2.55, 2.17-2.14, 1.80-1.63, 1.61-1.58, 1.31-1.29.
Example 134
1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4--
isopropyl-1H-pyrazole-3-carboxylic acid benzyl-methyl-amide
##STR00173##
[0583] The title compound was prepared in a manner analogous to the
method of Example 133: MS (APCI.sup.+) 494.2 m/z (M+H); H-NMR
(CDCl.sub.3) [Mixture of rotamers at 25.degree. C.] .delta.
7.38-7.24, 7.17-7.10, 4.74, 4.61, 4.58-4.51, 4.33-4.28, 3.00-2.90,
2.80-2.70, 2.64-2.63, 2.62-2.57, 2.08-2.03, 1.75-1.63, 1.61-1.57,
1.32-1.28, 1.25-1.22.
Example 135
1-(4-Fluoro-phenyl)-5-[2-(4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-ethyl]-4--
isopropyl-1H-pyrazole-3-carboxylic acid 4-methyl-benzylamide
##STR00174##
[0585] The title compound was prepared in a manner analogous to the
method of Example 133: MS (APCI.sup.+) 494.1 m/z (M+H); H-NMR
(CDCl.sub.3) .delta. 7.35-7.32 (m, 2H), 7.24-7.10 (m, 6H),
4.56-4.51 (m, 3H), 4.32-4.30 (m, 1H), 2.95-2.89 (m, 1H), 2.79-2.72
(m, 1H), 2.68-2.67 (m, 1H), 2.59-2.54 (m, 1H), 2.30 (s, 3H),
1.83-1.56 (m, 3H), 1.38 (d, 6H).
Example 136
(3R,5R)-7-[2-(4-Fluoro-phenyl)-4-isopropyl-5-(2-phenyl-piperidine-1-carbon-
yl)-2H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic acid sodium salt
##STR00175##
[0587] The title compound was prepared in a manner analogous to the
method of Example 1: MS (APCI.sup.+) 552.2 m/z (M+H); H-NMR
(DMSO-d.sub.6) [Mixture of diastereomers] .delta. 7.68-7.43,
7.41-7.19, 5.93-5.83, 5.23-5.15, 4.78-4.69, 4.55-4.42, 3.70-3.58,
3.56-3.42, 2.99-2.83, 2.80-2.63, 2.62-2.51, 1.97-1.88, 1.86-1.63,
1.62-1.53, 1.49-1.12.
[0588] All publications, including but not limited to, issued
patents, patent applications, and journal articles, cited in this
application are each herein incorporated by reference in their
entirety.
[0589] Although the invention has been described above with
reference to the disclosed embodiments, those skilled in the art
will readily appreciate that the specific experiments detailed are
only illustrative of the invention. Accordingly, the invention is
limited only by the following claims.
* * * * *