U.S. patent application number 11/020391 was filed with the patent office on 2005-05-26 for compounds that modulate ppar activity and methods of preparation.
Invention is credited to Cheng, Xue-Min, Filzen, Gary F., Geyer, Andrew G., Lee, Chitase, Trivedi, Bharat K..
Application Number | 20050113422 11/020391 |
Document ID | / |
Family ID | 27789158 |
Filed Date | 2005-05-26 |
United States Patent
Application |
20050113422 |
Kind Code |
A1 |
Cheng, Xue-Min ; et
al. |
May 26, 2005 |
Compounds that modulate PPAR activity and methods of
preparation
Abstract
This invention discloses compounds that alter PPAR activity. The
invention also discloses pharmaceutically acceptable salts of the
compounds, pharmaceutically acceptable compositions comprising the
compounds or their salts, and methods of using them as therapeutic
agents for treating or preventing hyperlipidemia and
hypercholesteremia in a mammal. The present invention also
discloses method for making the disclosed compounds.
Inventors: |
Cheng, Xue-Min; (Ann Arbor,
MI) ; Filzen, Gary F.; (Ann Arbor, MI) ;
Geyer, Andrew G.; (Novi, MI) ; Lee, Chitase;
(Ann Arbor, MI) ; Trivedi, Bharat K.; (Farmington
Hills, MI) |
Correspondence
Address: |
WARNER-LAMBERT COMPANY
2800 PLYMOUTH RD
ANN ARBOR
MI
48105
US
|
Family ID: |
27789158 |
Appl. No.: |
11/020391 |
Filed: |
December 22, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11020391 |
Dec 22, 2004 |
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10324266 |
Dec 19, 2002 |
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6867224 |
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60362411 |
Mar 7, 2002 |
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Current U.S.
Class: |
514/340 ;
514/365; 514/374; 546/270.4; 546/271.4; 548/200; 548/215 |
Current CPC
Class: |
A61P 9/10 20180101; C07D
417/12 20130101; C07D 277/26 20130101; A61P 3/00 20180101; A61P
3/10 20180101; A61P 3/06 20180101 |
Class at
Publication: |
514/340 ;
514/374; 514/365; 548/200; 548/215; 546/270.4; 546/271.4 |
International
Class: |
A61K 031/4439; A61K
031/421; A61K 031/426; C07D 413/04; C07D 417/04 |
Claims
What is claimed is:
1. A compound having formula 1: 163or a pharmaceutically acceptable
salt thereof, wherein: V.sup.1 is a saturated or unsaturated,
substituted or unsubstituted hydrocarbon chain or
hydrocarbon-heteroatom chain having from 3 to 6 atoms wherein the
carbon atom of position 1 is connected to the carbon atom of
position 2 to form a five to eight member r ing wherein the 164is
attached to a substitutionally available position of said ring;
X.sup.0 and X.sup.1 are independently O or S; X.sup.2 is absent, O,
S, or NR.sup.4; Ar.sup.1 is substituted or unsubstituted aryl or
heteroaryl; R.sup.1, R.sup.2, and R.sup.3 are independently
hydrogen, lower alkyl, lower alkoxy, lower thioalkoxy,
--O(CH.sub.2).sub.pCF.sub.3, halogen, nitro, cyano, --OH, --SH,
--CF.sub.3, S(O).sub.pAlkyl, S(O).sub.pAryl,
--(CH.sub.2).sub.mOR.sup.4, or --(CH.sub.2).sub.mNR.sup.5- R.sup.6,
COR.sup.4, --CO.sub.2H, --CO.sub.2R.sup.4, or --NR.sup.5R.sup.6 or
R.sup.1 and R.sup.2 are joined together to form a substituted or
unsubstituted, saturated or unsaturated cyloalkyl or
heterocycloalkyl ring; R.sup.4 is hydrogen, alkyl, alkenyl,
alkynyl, or aryl; R.sup.5 and R.sup.6 are independently hydrogen,
alkyl, alkenyl, alkynyl, cycloalkyl, SO.sub.2Alkyl or,
SO.sub.2Aryl, or joined together to form a 4 to 7 member ring
having 0 to 3 heteroatoms; m is 0 to 5; n is 0 to 5; and p is 0 to
2.
2. (canceled)
3. (canceled)
4. (canceled)
5. (canceled)
6. (canceled)
7. (canceled)
8. (canceled)
9. (canceled)
10. (canceled)
11. (canceled)
12. (canceled)
13. (canceled)
14. (canceled)
15. A method of treating, preventing or controlling non-insulin
dependent diabetes mellitus in a mammal comprising administering to
the mammal in need thereof a therapeutically effective amount of a
compound of claim 1.
16. A method of treating, preventing or controlling obesity in a
mammal comprising administering to the mammal in need thereof a
therapeutically effective amount of a compound of claim 1.
17. A method of treating, preventing or controlling hyperglycemia
in a mammal comprising administering to the mammal in need thereof
a therapeutically effective amount of a compound of claim 1.
18. A method of treating, preventing or controlling hyperlipidemia
in a mammal comprising administering to the mammal in need thereof
a therapeutically effective amount of a compound of claim 1.
19. A method of treating, preventing or controlling
hypercholesteremia in a mammal comprising administering to the
mammal in need thereof a therapeutically effective amount of a
compound of claim 1.
20. A method of treating, preventing or controlling atherosclerosis
in a mammal comprising administering to the mammal in need thereof
a therapeutically effective amount of a compound of claim 1.
21. A method of treating, preventing or controlling
hypertriglyceridemia in a mammal comprising administering to the
mammal in need thereof a therapeutically effective amount of a
compound of claim 1.
22. A method of treating, preventing or controlling
hyperinsulinemia in a mammal comprising administering to the mammal
in need thereof a therapeutically effective amount of a compound of
claim 1.
23. A method of treating a patient exhibiting glucose disorders
associated with circulating glucocorticoids, growth hormone,
catecholamines, glucagon, or parathyroid hormone, comprising
administering to the patient a therapeutically effective amount of
a compound of claim 1.
24. A method of making the compound having Formula 1: 165or a
pharmaceutically acceptable salt thereof, the method comprising
reacting: 166in a solvent in the presence of a base with:
167wherein: R.sup.10 is a lower alkyl V.sup.1 is a saturated or
unsaturated, substituted or unsubstituted hydrocarbon chain or
hydrocarbon-heteroatom chain having from 3 to 6 atoms wherein the
carbon atom of position 1 is connected to the carbon atom of
position 2 to form a five to eight member ring wherein the 168is
attached to a substitutionally available position of said ring;
X.sup.0 and X.sup.1 are independently O or S; X.sup.2 is absent, O,
S, or NR.sup.4; X is a halogen; Ar.sup.1 is substituted or
unsubstituted aryl or heteroaryl; R.sup.1, R.sup.2, and R.sup.3 are
independently hydrogen, lower alkyl, lower alkoxy, lower
thioalkoxy, --O(CH.sub.2).sub.pCF.sub.3, halogen, nitro, cyano,
--OH, --SH, --CF.sub.3, S(O).sub.pAlkyl, S(O).sub.pAryl,
--(CH.sub.2).sub.mOR.sup.4, or --(CH.sub.2).sub.mNR.sup.5R.sup.6,
COR.sup.4, --CO.sub.2H, --CO.sub.2R.sup.4, --NR.sup.5R.sup.6; or
--NR.sup.5R.sup.6 or R.sup.1 and R2 are joined together to form a
substituted or unsubstituted, saturated or unsaturated cyloalkyl or
heterocycloalkyl ring; R.sup.4 is hydrogen, alkyl, alkenyl,
alkynyl, or aryl; R.sup.5and R.sup.6 are independently hydrogen,
alkyl, alkenyl, alkynyl, cycloalkyl, SO.sub.2Alkyl or,
SO.sub.2Aryl, or joined together to form a 4 to 7 member ring
having 1 to 3 heteroatoms; m is 0 to 5; n is 0 to 5; and p is 0 to
2.
25. (canceled)
26. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention relates to compounds and
pharmaceutical formulations that can be used to treat conditions
mediated by nuclear receptors, more specifically, to compounds and
pharmaceutical formulations that modulate PPAR activity.
BACKGROUND OF THE INVENTION
[0002] Hypercholesterolemia, hyperlipidemia, and diabetes are well
recognized risk factors in the onset of atherosclerosis and
coronary heart disease. Hypercholesterolemia and hyperlipidemia are
characterized by excessively high levels of blood cholesterol and
lipids. The blood cholesterol pool is generally dependent on
dietary uptake of cholesterol from the intestine and biosynthesis
of cholesterol throughout the body, especially the liver. The
majority of cholesterol in plasma is carried on apolipoprotein
B-containing lipoproteins, such as low-density lipoproteins (LDL)
and very-low-density lipoproteins (VLDL). The risk of coronary
artery disease in man increases when LDL and VLDL levels increase.
Conversely, high levels of cholesterol carried in high-density
lipoproteins (HDL) is protective against coronary artery disease
(Am. J. Med., 1977; 62:707-714).
[0003] The statins represent perhaps the most important class of
lipid-lowering drugs. These compounds inhibit HMG-CoA reductase
which is implicated in the rate-limiting step in cellular
cholesterol biosynthesis. Representative statins include
atorvastatin, lovastatin, pravastatin, and simvastatin. The
effectiveness of these compounds depends on LDL receptor
regulation. Other important antilipidemia drugs include fibrates
such as gemfibril and clofibrate, bile acid sequestrants such as
cholestyramine and colestipol, probucol, and nicotinic acid
analogs.
[0004] To date, a number of oral antidiabetic agents have been
developed. The most commonly used hypoglygemic drugs are the
sulfonylureas. Sulfonylureas are generally used to stimulate
insulin. The biguanide metformin is generally used to improve
insulin sensitivity and to decrease hepatic glucose output.
Acarbose is used to limit postprandial hyperglycemia. Thiazolidine
2,4 diones are used to enhance insulin action without increasing
insulin secretion.
[0005] Peroxisome Proliferator Activation Receptors (PPAR) are
implicated in a number of biological processes and disease states
including hypercholesterolemia, hyperlipidemia, and diabetes. PPARs
are members of the nuclear receptor superfamily of transcription
factors that includes steroid, thyroid, and vitamin D receptors.
They play a role in controlling expression of proteins that
regulate lipid metabolism. Furthermore, the PPARs are activated by
fatty acids and fatty acid metabolites. There are three PPAR
subtypes PPAR .alpha., PPAR .beta. (also referred to as PPAR
.delta.), and PPAR .gamma.. Each receptor shows a different pattern
of tissue expression, and differences in activation by structurally
diverse compounds. PPAR .gamma., for instance, is expressed most
abundantly in adipose tissue and at lower levels in skeletal
muscle, heart, liver, intestine, kidney, vascular endothelial and
smooth muscle cells as well as macrophages. PPAR receptors are
associated with regulation of insulin sensitivity and blood glucose
levels, macrophage differentiation, inflammatory response, and cell
differentiation. Accordingly, PPARs have been associated with
obesity, diabetes, carcinogenesis, hyperplasia, atherosclerosis,
hyperlipidemia, and hypercholesterolemia.
[0006] In addition, PPAR.alpha. agonists lower plasma triglycerides
and LDL cholesterol and are therefore useful in treating
hypertriglyceridemia, hyperlipidemia and obesity. PPAR .gamma. is
associated with the development of non-insulin-dependent diabetes
mellitus (NIDDM), hypertension, coronary artery disease,
hyperlipidemia and certain malignancies. Finally, activation of
PPAR .beta. has been demonstrated to increase HDL levels.
(Leibowitz, WO97/28149, Aug. 1997.) More recently, a PPAR .beta.
selective agonist was reported to have shown a dose-related
increase in serum HDL-C and decrease in LDL-C and VLDL-TG in
insulin-resistant middle aged rhesus monkeys. (W. R. Oliver et al.,
PNAS, v. 98, pp. 5306-5311, 2001).
[0007] Antilipidemic and antidiabetic agents are still considered
to have non-uniform effectiveness. The effectivieness of
antidiabetic and antilipidemic therapies is limited, in part
because of poor patient compliance due to unacceptable side
effects. These side effects include diarrhea and gastrointestinal
discomfort, and in the case of antidiabetics, edema, hypoglycemia
and hepatoxicity. Furthermore, each type of drug does not work
equally well in all patients.
[0008] For the reasons set forth above, there is a need for novel
antilipidemic and antidiabetic agents that can be used alone or in
combination. Furthermore, 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
hyperlipidemia in which HDL is increased and LDL lowered.
SUMMARY OF THE INVENTION
[0009] The present invention provides compounds capable of
modulating PPAR activity. Compounds of the present invention are
described by Formula 1: 1
[0010] or a pharmaceutically acceptable salt thereof,
[0011] where:
[0012] V.sup.1 is a saturated or unsaturated, substituted or
unsubstituted hydrocarbon chain or hydrocarbon-heteroatom chain
having from 3 to 6 atoms wherein the carbon atom of position 1 is
connected to the carbon atom of position 2 to form a five to eight
member ring where the 2
[0013] is attached to a substitutionally available position of said
ring;
[0014] X.sup.0 and X.sup.1 are independently O or S;
[0015] X is absent, O, S, or NR.sup.4;
[0016] Ar.sup.1 is substituted or unsubstituted aryl or
heteroaryl;
[0017] R.sup.1, R.sup.2, and R.sup.3 are independently hydrogen,
lower alkyl, lower alkoxy, lower thioalkoxy,
--O(CH.sub.2).sub.pCF.sub.3, halogen, nitro, cyano, --OH, --SH,
--CF.sub.3, S(O).sub.pAlkyl, S(O).sub.pAryl,
--(CH.sub.2).sub.mOR.sup.4, or --(CH.sub.2).sub.mNR.sup.5- R.sup.6,
COR.sup.4, --CO.sub.2H, --CO.sub.2R.sup.4, or --NR.sup.5R.sup.6 or
R.sup.1 and R.sup.2 are joined together to form a substituted or
unsubstituted, saturated or unsaturated cyloalkyl or
heterocycloalkyl ring;
[0018] R.sup.4 is hydrogen, alkyl, alkenyl, alkynyl, or aryl;
[0019] R.sup.5 and R.sup.6 are independently hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, SO.sub.2Alkyl or, SO.sub.2Aryl, or
joined together to form a 4 to 7 member ring having 0 to 3
heteroatoms;
[0020] m is 0 to 5;
[0021] n is 0 to 5; and
[0022] p is 0 to 2.
[0023] In another embodiment or the present invention, compounds of
Formula 2 are provided: 3
[0024] or a pharmaceutically acceptable salt thereof,
[0025] where:
[0026] V.sup.1 is a saturated or unsaturated, substituted or
unsubstituted hydrocarbon chain or hydrocarbon-heteroatom chain
having from 3 to 6 atoms wherein the carbon atom of position 1 is
connected to the carbon atom of position 2 to form a five to eight
member ring where the 4
[0027] is attached to a substitutionally available position of said
ring;
[0028] X.sup.0 and X.sup.1 are independently O or S;
[0029] X.sup.2 is absent, O, S, or NR.sup.4;
[0030] Ar.sup.1 is substituted or unsubstituted aryl or
heteroaryl;
[0031] R.sup.1, R.sup.2, and R.sup.3 are independently hydrogen,
lower alkyl, lower alkoxy, lower thioalkoxy,
--O(CH.sub.2).sub.pCF.sub.3, halogen, nitro, cyano, --OH, --SH,
--CF.sub.3, S(O).sub.pAlkyl, S(O).sub.pAryl,
--(CH.sub.2).sub.mOR.sup.4 or --(CH.sub.2).sub.mNR.sup.5R- .sup.6,
COR.sup.4, --CO.sub.2H, --CO.sub.2R.sup.4, or --NR.sup.5R.sup.6 or
R.sup.1 and R.sup.2 are joined together to form a substituted or
unsubstituted, saturated or unsaturated cyloalkyl or
heterocycloalkyl ring;
[0032] R.sup.4 is hydrogen, alkyl, alkenyl, alkynyl, or aryl;
[0033] R.sup.5 and R.sup.6 are independently hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, SO.sub.2Alkyl or, SO.sub.2Aryl, or
joined together to form a 4 to 7 member ring having 0 to 3
heteroatoms;
[0034] m is 0 to 5;
[0035] n is 0 to 5;
[0036] p is 0 to 2; and
[0037] where T is a saturated or unsaturated, substituted or
unsubstituted hydrocarbon chain or hydrocarbon-heteroatom chain
having from 2 to 6 atoms wherein the carbon atom of position 3 is
connected to the carbon atom of position 4 to form a four to eight
member ring.
[0038] In another embodiment of the present invention a
pharmaceutical composition comprising a compound of Formula 1 and
one or more pharmaceutically acceptable carriers, diluents, or
excipients is provided.
[0039] In one embodiment of the present invention a method of
treating, preventing or controlling hypercholesteremia in a mammal
is provided. The method comprises administering to the mammal in
need thereof a therapeutically effective amount of the compounds of
the present invention.
[0040] In another embodiment of the present invention a method for
treating, preventing, or controlling obesity is provided.
[0041] In another embodiment of the present invention a method for
treating, preventing, or controlling hyperglycemia is provided.
[0042] In another embodiment of the present invention a method for
treating, preventing, or controlling hyperlipidemia is
provided.
[0043] In another embodiment of the present invention a method for
treating, preventing, or controlling atherosclerosis is
provided.
[0044] In another embodiment of the present invention a method for
treating, preventing, or controlling hypertriglyceridemia is
provided.
[0045] In another embodiment of the present invention a method for
treating, preventing, or controlling hyperinsulinemia is
provided.
[0046] In another embodiment of the present invention a method for
treating, preventing, or controlling non-insulin dependent diabetes
mellitus is provided.
[0047] In another embodiment of the present invention a method for
treating a patient exhibiting glucose disorders associated with
circulating glucocorticoids, growth hormone, catecholamines,
glucagon, or parathyroid hormone is provided.
[0048] For each disease state treatable, preventable, or
controllable by the method of the present invention, a
therapeutically effective amount of the compounds of the present
invention are administered to the mammal in need thereof.
[0049] In yet another embodiment of the present invention, a method
of preparing the compounds of the present invention is
provided.
DETAILED DESCRIPTION OF THE INVENTION
[0050] The following definitions are used, unless otherwise
described: alkyl, alkoxy, alkenyl, alkynyl, etc. denote both
straight and branched groups; but reference to an individual
radical such as "propyl" embraces only the straight chain radical,
a branched chain isomer such as "isopropyl" being specifically
referred to.
[0051] The term "alkyl" as used herein refers to a straight or
branched hydrocarbon of from 1 to 11 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 can also be substituted with one or more of the substituents
selected from 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, --NH.sub.2, --NHC.sub.1-C.sub.6
alkyl, --CONR'R", or --N(C.sub.1-C.sub.6alkyl).sub.2 where R' and
R" are independently alkyl, akenyl, alkynyl, aryl, or joined
together to form a 4 to 7 member ring. Useful alkyl groups have
from 1 to 6 carbon atoms (C.sub.1-C.sub.6 alkyl).
[0052] The term "lower alkyl" as used herein refers to a subset of
alkyl which means a straight or branched hydrocarbon radical having
from 1 to 6 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. Optionally, lower alkyl is
referred to as "C.sub.1-C.sub.6alkyl."
[0053] The term "alkenyl" means a straight or branched unsaturated
hydrocarbon radical having from 2 to 12 carbon atoms 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.
[0054] The term "alkynyl" means a straight or branched hydrocarbon
radical having 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.
[0055] The term "alkylene" as used herein refers to a 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
groups of this invention can be optionally substituted. The
alkylene group can also be 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, nitro, cyano,
.dbd.O, .dbd.S, --OH, --SH, --CF.sub.3, --CO.sub.2H,
--CO.sub.2C.sub.1-C.sub.6 alkyl, --NH.sub.2, --NHC.sub.1-C.sub.6
alkyl, --CONR'R", or --N(C.sub.1-C.sub.6alkyl).sub.2 where R' and
R" are independently alkyl, akenyl, alkynyl, aryl, or joined
together to form a 4 to 7 member ring. Useful alkylene groups have
from 1 to 6 carbon atoms (C.sub.1-C.sub.6 alkylene).
[0056] The term "halogen" includes chlorine, fluorine, bromine, and
iodine.
[0057] 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.
[0058] The term "hydrocarbon chain" as used herein refers to a
straight hydrocarbon of from 2 to 6 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, --NH.sub.2, --NHC.sub.1-C.sub.6
alkyl, --CONR'R", or --N(C.sub.1-C.sub.6alkyl).sub.2 where R' and
R" are independently alkyl, akenyl, alkynyl, aryl, or joined
together to form a 4 to 7 member ring.
[0059] The term "hydrocarbon-heteroatom chain" as used herein
refers to a hydrocarbon chain wherein one or more carbon atoms are
replaced with a heteroatom. The hydrocarbon-heteroatom 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, --NH.sub.2, --NH(C.sub.1-C.sub.6
alkyl), --CONR'R", or --N(C.sub.1-C.sub.6alkyl).sub.2 where R' and
R" are independently alkyl, akenyl, alkynyl, aryl, or joined
together to form a 4 to 7 member ring.
[0060] The term "heteroalkylene" as used herein, refers to an
alkylene radical as defined above that includes one or more
heteroatoms such as oxygen, sulfur, or nitrogen (with valence
completed by hydrogen or oxygen) in the carbon chain or terminating
the carbon chain.
[0061] The terms "lower alkoxy" and "lower thioalkoxy" as used
herein refers to O-alkyl or S-alkyl of from 1 to 6 carbon atoms as
defined above for "lower alkyl."
[0062] The term "aryl" as used herein refers to an aromatic ring
which is unsubstituted or optionally substituted by 1 to 4
substituents selected from lower alkyl, lower alkoxy, lower
thioalkoxy, --O(CH.sub.2).sub.pCF.s- ub.3, halogen, nitro, cyano
--OH, --SH, --CF.sub.3, --CO.sub.2H, --CO.sub.2C.sub.1-C.sub.6
alkyl, --NH.sub.2, --NHC.sub.1-C.sub.6 alkyl, --SO.sub.2alkyl,
--SO.sub.2NH.sub.2, --CONR'R", or --N(C.sub.1-C.sub.6alkyl).sub.2
where R' and R" are independently alkyl, akenyl, alkynyl, aryl, or
joined together to form a 4 to 7 member ring. 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, or the like.
[0063] The term "heteroaryl" means an aromatic ring containing one
or more heteroatoms. The heteroaryl is optionally substituted with
one or more groups enumerated 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, and
quinazolinyl, and the like.
[0064] The term "heterocycle" means a saturated or unsaturated
mono- or polycyclic (i.e. bicyclic) ring incorporating one or more
(i.e. 1-4) heteroatoms selected from N, O, and S. It is understood
that a heterocycle is optionally substituted with --OH, --O(alkyl),
SH, S(alkyl), amine, halogen, acid, ester, amide, amidine, alkyl
ketone, aldehyde, nitrile, fluoroalkyl, nitro, sulphone, sulfoxide
or C1-6 alkyl. Examples of suitable monocyclic heterocycles
include, but are not limited to substituted or unsubstituted
thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,
isothiazolyl, oxazolyl, isoxazolyl, triazoiyl, tetrazolyl,
pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, pyrrolidinyl,
piperazinyl, azetidinyl, aziridinyl, morpholinyl, thietanyl,
oxetaryl. Examples of monocyclic diheterocycles include, but are
not limited to, 1-, 2-, 4-, or 5-imidazolyl, 1-, 3-, 4-, or
5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-,
4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 1,3-, or 5-triazolyl,
1-, 2-, or 3-tetrazolyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 1-
or 2-piperazinyl, 2-, 3-, or 4-morpholinyl. Examples of suitable
bicyclic heterocycles include, but are not limited to indolizinyl,
isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl,
benzimidazolyl, quinolinyl, isoquinolinyl, quinazolinyl, 1-, 2-,
3-, 4-, 5-, 6-, or 7-indolyl, 1-, 2-, 3-, 5-, 6-, 7-, or
8-indolizinyl, 1-, 2-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-,
5-, 6-, or 7-benzothienyl, 2-, 4-, 5-, 6-, or 7-benzoxazolyl, 1-,
2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 3-, 4-, 5-, 6-, 7-, or
8-quinolinyl, and 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl.
[0065] The term "heterocycloalkyl" means a nonaromatic ring with
from 4 to 8 members, with up to 4 heteroatoms for example, N, O,
and S. Examples of heterocycloalkyl, include, but are not limited
to, 2- or 3-tetrahydrothieno, 2- or 3-tetrahydrofurano, 2- or
3-pyrrolidino, 2-, 4-, or 5-thiazolidino, 2-, 4-, or 5-oxazolidino,
2-, 3-, or 4-piperidino, N-morpholinyl or N-thiamorpholinyl or
tetrahydropyrano.
[0066] The term "cycloalkyl" means a saturated hydrocarbon ring,
and includes for example, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl, and the like. The
cycloalkyl group can be substituted with 1 to 3 substituents from
the group of substituents described above for aryl. Preferrably the
cycloalkyl will have from 3 to 8 carbon atoms.
[0067] The term "patient" means all mammals including humans.
Examples of patients include humans, cows, dogs, cats, goats,
sheep, pigs, and rabbits.
[0068] A "therapeutically effective amount" is an amount of a
compound of the present invention that when administered to a
patient ameliorates a symptom of dyslipidemia, non-insulin
dependent diabetes mellitus, obesity, hyperglycemia,
hypercholesteremia, hyperlipidemia, atherosclerosis,
hypertriglyceridemia, or hyperinsulinemia.
[0069] The term "a pharmaceutically acceptable salt" refers to the
relatively non-toxic, inorganic and organic acid or base addition
salts of compounds of the present 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.
[0070] The present invention provides compounds capable of
modulating PPAR activity having Formula 1: 5
[0071] or a pharmaceutically acceptable salt thereof,
[0072] where:
[0073] V.sup.1 is a saturated or unsaturated, substituted or
unsubstituted hydrocarbon chain or hydrocarbon-heteroatom chain
having from 3 to 6 atoms wherein the carbon atom of position 1 is
connected to the carbon atom of position 2 to form a five to eight
member ring where the 6
[0074] is attached to a substitutionally available position of said
ring;
[0075] X.sup.0 and X.sup.1 are independently O or S;
[0076] X.sup.2 is absent, O, S, or NR.sup.4;
[0077] Ar.sup.1 is substituted or unsubstituted aryl or
heteroaryl;
[0078] R.sup.1, R.sup.2, and R.sup.3 are independently hydrogen,
lower alkyl, lower alkoxy, lower thioalkoxy,
--O(CH.sub.2).sub.pCF.sub.3, halogen, nitro, cyano, --OH, --SH,
--CF.sub.3, S(O).sub.pAlkyl, S(O).sub.pAryl, --(CH.sub.2).sub.mOR,
or --(CH.sub.2).sub.mNR.sup.5R.sup.- 6, COR.sup.4, --CO.sub.2H,
--CO.sub.2R.sup.4, or --NR.sup.5R.sup.6 or R.sup.1 and R.sup.2 are
joined together to form a substituted or unsubstituted, saturated
or unsaturated cyloalkyl or heterocycloalkyl ring;
[0079] R.sup.4 is hydrogen, alkyl, alkenyl, alkynyl, or aryl;
[0080] R.sup.5 and R.sup.6 are independently hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, SO.sub.2Alkyl or, SO.sub.2Aryl, or
joined together to form a 4 to 7 member ring having 0 to 3
heteroatoms;
[0081] m is 0 to 5;
[0082] n is 0 to 5; and
[0083] p is 0 to 2.
[0084] Additional Examples of compounds of Formula 1 include those
where R.sup.1, R.sup.2, and R.sup.3 are independently hydrogen,
alkyl, or alkoxy. Examples of compounds of Formula 1 where R.sup.1,
R.sup.2, and R.sup.3 are independently alkyl include, but are not
limited to, those where R.sup.1, R.sup.2, and R.sup.3 are
independently methyl, ethyl, isopropyl, n-propyl, t-butyl, n-butyl,
or isobutyl. Examples of compounds of Formula 1 where R.sup.1,
R.sup.2, and R.sup.3 are independently alkoxy include, but are not
limited to, those where R.sup.1, R.sup.2, and R.sup.3 are
independently methoxy, ethoxy, isopropoxy, n-propoxy, t-butoxy,
n-butoxy, or isobutoxy.
[0085] Additional Examples of compounds of Formula 1 include those
where R.sup.1 and R.sup.3 are hydrogen and R.sup.2 is alkyl, or
alkoxy. Examples of compounds of Formula 1 where R.sup.1 and
R.sup.3 are hydrogen and R.sup.2 is alkyl or alkoxy include, but
are not limited to, those where R.sup.2 is methoxy, ethoxy,
isopropoxy, n-propoxy, t-butoxy, n-butoxy, isobutoxy, methyl,
ethyl, isopropyl, n-propyl, t-butyl, n-butyl, or isobutyl.
[0086] Examples of compounds of Formula 1 include those where
V.sup.1 is --CH.sub.2CH.sub.2CO--O--,
--CH.sub.2--CH.sub.2--O--CO--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
--HC.dbd.CH--HC.dbd.CH--, --N.dbd.CH--HC.dbd.CH--,
--HC.dbd.N--HC.dbd.CH--, --HC.dbd.CH--N.dbd.CH--- ,
--HC.dbd.CH--HC.dbd.N--, --CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--O--CH.sub.2--, --CH.sub.2--HC.dbd.CH--,
--CH.sub.2CH.sub.2--NH--CH.sub.2--, --COCH.dbd.CH--O--,
--O--CH.dbd.CH--CO--, --O--CH.dbd.CH--, --CH.dbd.CH--O--,
--O--CH.sub.2--CH.dbd.CH--, --CH.dbd.CH--CH.sub.2--O--,
--CH.sub.2--CH.sub.2--CO--NR.sup.4,
--CH.sub.2--CH.sub.2--CO--CH.sub.2--,
--CH.sub.2--CH.sub.2--NR.sup.4--CH.sub.2--,
--CH.sub.2--NR.sup.4--CH.sub.- 2--CH.sub.2--,
--CH.dbd.CH--NR.sup.4--, --NR.sup.4--CH.dbd.CH--,
--CH.dbd.CH--CH.sub.2--, --CH.sub.2--CH.sub.2--NR.sup.4--,
--NR.sup.4--CH.sub.2--CH.sub.2--, --O--CH.sub.2--CH.sub.2--,
--O--CH.sub.2--CH.sub.2--CH.sub.2--, --CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.sub.2--CH.sub.2--O--,
--O--CH(CH.sub.3)--CH.sub.2--CH.sub.- 2--,
--CH.sub.2--CH.sub.2--CH(CH.sub.3)--O--,
--CH.sub.2--CH.sub.2--CH.sub- .2--NR.sup.4--,
--NR.sup.4--CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CO--NR.sup.4--,
--NR.sup.4--CO--CH.sub.2--CH.sub.2-- -, --O--NR.sup.4--CO--,
--CO--NR.sup.4--O--, --O--CH.sub.2--CH.sub.2--CH.s- ub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--O--, --CH.sub.2--CH.sub.2--NR.sup.-
4--CO--, --CH.sub.2--CH.sub.2--CH.sub.2--CO--,
--CO--CH.sub.2--CH.sub.2--C- H.sub.2--,
--NR.sup.4--CO--CH.sub.2--CH.sub.2--, --CO--NR.sup.4--CH.sub.2--
-CH.sub.2--, --CH.sub.2--CH.sub.2--CO--,
--CH.sub.2--CO--CH.sub.2--, --CH.sub.2.dbd.CH.sub.2--S--,
--S--CH.sub.2.dbd.CH.sub.2--, or --CO--CH.sub.2--CH.sub.2--. It
will be understood that the left-most atom of these groups in
attached to the atom labeled "1" in Formula 1 and the right-most
atom of these groups is attached to the atom label "1" in Formula
1.
[0087] Furthermore, examples of compounds of Formula 1 include
those where V.sup.1 is optionally substituted with 1 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, --NH.sub.2, --NHC.sub.1-C.sub.6
alkyl, --CONR'R", or --N(C.sub.1-C.sub.6alkyl).sub.2 where R' and
R" are independently alkyl, akenyl, alkynyl, aryl, or joined
together to form a 4 to 7 member ring. and
--N(C.sub.1-C.sub.6alkyl).sub.- 2.
[0088] Additional examples of compounds of Formula 1, include but
are not limited to, compounds of Formulae 1a-1h: 789
[0089] or a pharmaceutically acceptable salt thereof,
[0090] where:
[0091] X.sup.0 and X.sup.1 are independently O or S;
[0092] X.sup.2 is absent, O, S, or NR.sup.4;
[0093] Ar.sup.1 is substituted or unsubstituted aryl or
heteroaryl;
[0094] R.sup.1, R.sup.2, and R.sup.3 are independently hydrogen,
lower alkyl, lower alkoxy, lower thioalkoxy,
--O(CH.sub.2).sub.pCF.sub.3, halogen, nitro, cyano, --OH, --SH,
--CF.sub.3, S(O).sub.pAlkyl, S(O).sub.pAryl,
--(CH.sub.2).sub.mOR.sup.4, or --(CH.sub.2).sub.mNR.sup.5- R.sup.6,
COR.sup.4, --CO.sub.2H, --CO.sub.2R.sup.4, or --NR.sup.5R.sup.6 or
R.sup.1 and R.sup.2 are joined together to form a substituted or
unsubstituted, saturated or unsaturated cyloalkyl or
heterocycloalkyl ring;
[0095] R.sup.4 is hydrogen, alkyl, alkenyl, alkynyl, or aryl;
[0096] R.sup.5 and R.sup.6 are independently hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, SO.sub.2Alkyl or, SO.sub.2Aryl, or
joined together to form a 4 to 7 member ring having 0 to 3
heteroatoms;
[0097] m is 0 to 5;
[0098] n is 0 to 5; and
[0099] p is 0 to 2.
[0100] Z.sup.1, Z.sup.2, Z.sup.3, and Z.sup.4 are independently O,
S, CR.sup.5R.sup.6, NR.sup.4, or N; and
[0101] Z.sup.1, Z.sup.2, Z.sup.3, and Z.sup.4 are bonded to a
sufficient number of hydrogen atoms or substituents to complete the
valency of each atom with the proviso that Z.sup.1, Z.sup.2,
Z.sup.3, and Z.sup.4 are not all heteroatoms and that not more than
two adjacent atoms in Z.sup.1, Z.sup.2, Z.sup.3, and Z.sup.4 are
heteroatoms and that in Formulae 1b, 1c, 1d, 1f, and 1g, Z.sup.1,
Z.sup.2, Z.sup.3, and Z.sup.4 are not all carbon atoms.
[0102] Additional examples of compound of Formula 1 include, but
are not limited to, those compounds of Formula 2: 10
[0103] or a pharmaceutically acceptable salt thereof,
[0104] where:
[0105] V.sup.1 is a saturated or unsaturated, substituted or
unsubstituted hydrocarbon chain or hydrocarbon-heteroatom chain
having from 3 to 6 atoms wherein the carbon atom of position 1 is
connected to the carbon atom of position 2 to form a five to eight
member ring where the 11
[0106] is attached to a substitutionally available position of said
ring;
[0107] X.sup.0 and X.sup.1 are independently O or S;
[0108] X.sup.2 is absent, O, S, or NR.sup.4;
[0109] Ar.sup.1 is substituted or unsubstituted aryl or
heteroaryl;
[0110] R.sup.1, R.sup.2, and R.sup.3 are independently hydrogen,
lower alkyl, lower alkoxy, lower thioalkoxy,
--O(CH.sub.2).sub.pCF.sub.3, halogen, nitro, cyano, --OH, --SH,
--CF.sub.3, S(O).sub.pAlkyl, S(O).sub.pAryl,
--(CH.sub.2).sub.mOR.sup.4, or --(CH.sub.2).sub.mNR.sup.5- R.sup.6,
COR.sup.4, --CO.sub.2H, --CO.sub.2R.sup.4, or --NR.sup.5R.sup.6 or
R.sup.1 and R.sup.2 are joined together to form a substituted or
unsubstituted, saturated or unsaturated cyloalkyl or
heterocycloalkyl ring;
[0111] R.sup.4 is hydrogen, alkyl, alkenyl, alkynyl, or aryl;
[0112] R.sup.5 and R.sup.6 are independently hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, SO.sub.2Alkyl or, SO.sub.2Aryl, or
joined together to form a 4 to 7 member ring having 0 to 3
heteroatoms;
[0113] m is 0 to 5;
[0114] n is 0 to 5;
[0115] p is 0 to 2; and
[0116] where T is a saturated or unsaturated, substituted or
unsubstituted hydrocarbon chain or hydrocarbon-heteroatom chain
having from 2 to 6 atoms wherein the carbon atom of position 3 is
connected to the carbon atom of position 4 to form a four to eight
member ring.
[0117] Examples of compounds of Formula 1 include those where T is
--CH.sub.2CH.sub.2CO--O--, --CH.sub.2--CH.sub.2--O--CO--,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--,
--HC.dbd.CH--HC.dbd.CH--, --N.dbd.CH--HC.dbd.CH--,
--HC.dbd.N--HC.dbd.CH--, --HC.dbd.CH--N.dbd.CH--- ,
--HC.dbd.CH--HC.dbd.N--, --CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--O--CH.sub.2--, --CH.sub.2--HC.dbd.CH--,
--CH.sub.2CH.sub.2--NH--CH.sub.2--, --COCH.dbd.CH--O--,
--O--CH.dbd.CH--CO--, --CH.dbd.CH--NR.sup.4--,
--NR.sup.4--CH.dbd.CH--, --CH.dbd.CH--CH.sub.2--,
--CH.sub.2--CH.sub.2--NR.sup.4--, --NR.sup.4--CH.sub.2--CH.sub.2--,
--O--CH.sub.2--CH.sub.2--, --CH.sub.2--CH.sub.2--O--,
--CH.sub.2--CH.sub.2--CO--, --CH.sub.2--CO--CH.sub.2--,
--CO--CH.sub.2--CH.sub.2--, --CH.sub.2--CH.sub.2--CH.sub.2--CO--,
--CO--CH.sub.2--CH.sub.2--CH.sub.2-- -,
--CH.sub.2--CO--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CO--CH.sub.- 2--,
--CH.sub.2--CH.sub.2--CH.sub.2--NR.sup.4--,
--NR.sup.4--CH.sub.2--CH.- sub.2--CH.sub.2--,
--O--CH.sub.2--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--CH.sub.2--O--,
--CO--NR.sup.4--CH.sub.2--CH.sub.2--- ,
NR.sup.4CO--CH.sub.2--CH.sub.2--,
--CH.sub.2--CH.sub.2--NR.sup.4--CO--, or
--CH.sub.2--CH.sub.2--CO--NR.sup.4--. It will be understood that
the left-most atom of these groups in attached to the atom labeled
"4" in Formula 2 and the right-most atom of these groups is
attached to the atom label "3" in Formula 2.
[0118] Furthermore, examples of compounds of Formula 1 include
those where T is optionally substituted with 1 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, --NH.sub.2, --NHC.sub.1-C.sub.6
alkyl, --CONR'R", or --N(C.sub.1-C.sub.6alkyl).sub.2 where R' and
R" are independently alkyl, akenyl, alkynyl, aryl, or joined
together to form a 4 to 7 member ring.
[0119] Other examples of compounds of Formula 2 include, but are
not limited to, those where V.sup.1 is: 12
[0120] where:
[0121] Z.sup.1, Z.sup.2, Z.sup.3, and Z.sup.4 are independently O,
S, CR.sup.5R.sup.6, NR.sup.4, or N; and
[0122] Z.sup.1, Z.sup.2, Z.sup.3, and Z.sup.4 are bonded to a
sufficient number of hydrogen atoms or substituents (as defined
above for V.sup.1) to complete the valency of each atom with the
proviso that Z.sup.1, Z.sup.2, Z.sup.3, and Z.sup.4 are not all
heteroatoms and that not more than two adjacent atoms in Z.sup.1,
Z.sup.2, Z.sup.3, and Z are heteroatoms and that in Formulae 2a,
2b, 2c, 2d, 2g and 2h, Z.sup.1, Z.sup.2, Z.sup.3, and Z.sup.4 are
not all carbon atoms. Accordingly, such examples include those of
Formulae 2a-2h: 131415
[0123] or a pharmaceutically acceptable salt thereof,
[0124] where:
[0125] X.sup.0 and X.sup.1 are independently 0 or S;
[0126] X.sup.2 is absent, O, S, or NR.sup.4;
[0127] Ar.sup.1 is substituted or unsubstituted aryl or
heteroaryl;
[0128] R.sup.1, R.sup.2, and R.sup.3 are independently hydrogen,
lower alkyl, lower alkoxy, lower thioalkoxy,
--O(CH.sub.2).sub.pCF.sub.3, halogen, nitro, cyano, --OH, --SH,
--CF.sub.3, S(O).sub.pAlkyl, S(O).sub.pAryl,
--(CH.sub.2).sub.mOR.sup.4, or --(CH.sub.2).sub.mNR.sup.5- R.sup.6,
COR.sup.4, --CO.sub.2H, --CO.sub.2R.sup.4, or --NR.sup.5R.sup.6 or
R.sup.1 and R.sup.2 are joined together to form a substituted or
unsubstituted, saturated or unsaturated cyloalkyl or
heterocycloalkyl ring;
[0129] R.sup.4 is hydrogen, alkyl, alkenyl, alkynyl, or aryl;
[0130] R.sup.5 and R.sup.6 are independently hydrogen, alkyl,
alkenyl, alkynyl, cycloalkyl, SO.sub.2Alkyl or, SO.sub.2Aryl, or
joined together to form a 4 to 7 member ring having 0 to 3
heteroatoms;
[0131] m is 0 to 5;
[0132] n is 0 to 5;
[0133] p is 0 to 2;
[0134] T is a saturated or unsaturated, substituted or
unsubstituted hydrocarbon chain or hydrocarbon-heteroatom chain
having from 2 to 6 atoms wherein the carbon atom of position 3 is
connected to the carbon atom of position 4 to form a four to eight
member ring;
[0135] Z.sup.1, Z.sup.2, Z.sup.3, and Z.sup.4 are independently O,
S, CR.sup.5R.sup.6, NR.sup.4, or N; and
[0136] Z.sup.1, Z.sup.2, Z.sup.3, and Z.sup.4 are bonded to a
sufficient number of hydrogen atoms or substituents (as defined
above for V.sup.1) to complete the valency of each atom with the
proviso that Z.sup.1, Z.sup.2, Z.sup.3, and Z.sup.4 are not all
heteroatoms and that not more than two adjacent atoms in Z.sup.1,
Z.sup.2, Z.sup.3, and Z.sup.4 are heteroatoms and that in Formulae
2a, 2b, 2c, 2d, 2g and 2h, Z.sup.1, Z.sup.2, Z.sup.3, and Z.sup.4
are not all carbon atoms.
[0137] Further examples of compounds of Formulae 1 and 2 include,
but are not limited to, those where the heteroatom of the
hydrocarbon-heteroatom chain is is N, O, or S.
[0138] Furthermore, examples of compounds of Formula 2 include
those where T is optionally substituted with 1 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, --NH.sub.2, --NHC.sub.1-C.sub.6
alkyl, --CONR'R", or --N(C.sub.1-C.sub.6alkyl).sub.2 where R' and
R" are independently alkyl, akenyl, alkynyl, aryl, or joined
together to form a 4 to 7 member ring.
[0139] Examples of compounds of Formula 1 include
[0140]
5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl-
]-indan-2-carboxylic acid;
[0141]
{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfany-
l]-indan-2-yl}-acetic acid;
[0142]
6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl-
]-1-benzopyran-2-carboxylic acid;
[0143]
{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfany-
l]-2,3-dihydro-benzofuran-2-yl}-acetic acid;
[0144]
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfany-
l]-1-benzopyran-2-yl}-acetic acid;
[0145]
5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl-
]-benzofuran-2-carboxylic acid;
[0146]
{6-[4-Methyl-2-(4-trifluoromethylphenyl)thiazol-5-ylmethylsulfanyl]-
-1-oxo-3,4-dihydro-1H-naphthalen-2-yl}-acetic acid;
[0147]
{2-Methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmeth-
ylsulfanyl]-chroman-2-yl}-acetic acid;
[0148]
{2,8-Dimethyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl-
methylsulfanyl]-chroman-2-yl}-acetic acid;
[0149]
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfany-
l]-3,4-dihydro-1H-isoquinolin-2-yl}-acetic acid;
[0150]
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfany-
l]-3,4-dihydro-2H-quinolin-1-yl}-acetic acid;
[0151]
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfany-
l]-2-oxo-3,4-dihydro-2H-isoquinolin-1-yl}-acetic acid;
[0152]
7-Methoxy-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmeth-
ylsulfanyl]-1,2,3,4-tetrahydro-naphthalen-2-yl}-acetic acid;
[0153]
7-Methoxy-6-[4-methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethy-
lsulfanyl]-chroman-2-yl-acetic acid;
[0154]
7-Methyl-6-[4-methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethyl-
sulfanyl]-chroman-2-yl-acetic acid;
[0155]
6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-
-2H-chromene-3-carboxylic acid;
[0156]
6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-
-chroman-3-carboxylic acid;
[0157]
6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-
-chroman-3-yl-acetic acid;
[0158]
{6-Methoxy-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmet-
hylsulfanyl]-indan-1-yl}-acetic acid;
[0159]
6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-
-4-oxo-chroman-3-ylidene-acetic acid;
[0160]
3-{5-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfan-
yl]-2,3-dihydro-indol-1-yl}-propionic acid;
[0161]
6-Methoxy-5-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethy-
lsulfanyl]-3-oxo-3H-benzo[d]isoxazo-2-yl-acetic acid;
[0162]
{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfany-
l]-indol-1-yl}-acetic acid; and
[0163] pharmaceutically acceptable salts thereof.
[0164] Further examples of compounds of Formula 1 include
[0165]
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfany-
l]-chroman-2-yl}-acetic acid, (2S);
[0166]
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfany-
l]-chroman-2-yl}-acetic acid, (2R);
[0167]
{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfany-
l]-2,3-dihydro-benzofuran-2-yl}-acetic acid, (2R);
[0168]
{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfany-
l]-2,3-dihydro-benzofuran-2-yl}-acetic acid, (2S);
[0169]
6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl-
]-chroman-2-carboxylic acid, (2S);
[0170]
6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfanyl-
]-chroman-2-carboxylic acid, (2R);
[0171]
2-Methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethy-
lsulfanyl]-chroman-2-carboxylic acid, (2R);
[0172]
2-Methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethy-
lsulfanyl]-chroman-2-carboxylic acid, (2S);
[0173]
{7-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfany-
l]-2,3,4,5-tetrahydro-benzo[b]oxepin-2-yl}-acetic acid, (2S);
[0174]
{7-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsulfany-
l]-2,3,4,5-tetrahydro-benzo[b]oxepin-2-yl}-acetic acid, (2R); and
pharmaceutically acceptable salts thereof.
[0175] Yet further examples of compounds of Formula 1 include
[0176]
{4-Methyl-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmeth-
oxy]-indol-1-yl}-acetic acid;
[0177]
{2-Methyl-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmeth-
oxy]-indol-1-yl}-acetic acid;
[0178]
{3-Methyl-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmeth-
oxy]-indol-1-yl}-acetic acid;
[0179]
{6-Methoxy-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmet-
hoxy]-indol-1-yl}-acetic acid;
[0180]
1-Carboxymethyl-2-methyl-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-t-
hiazol-5-ylmethoxy]-1H-indole-3-carboxylic acid ethyl ester;
[0181]
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-1H-i-
ndol-3-yl}-acetic acid;
[0182]
{1-Methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmeth-
oxy]-1H-indol-3-yl}-acetic acid;
[0183]
{5-Methoxy-1-methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-th
iazol-5-ylmethylsulfanyl]-1H-indol-3-yl}-acetic acid;
[0184]
{5-Methoxy-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmet-
hylsulfanyl]-1H-indol-3-yl}-acetic acid; and
[0185] pharmaceutically acceptable salts thereof.
[0186] Yet further examples of compounds of Formula 1 include
[0187]
{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indo-
l-1-yl}-acetic acid;
[0188]
{6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benz-
o[b]thiophen-3-yl}-acetic acid; and
[0189] pharmaceutically acceptable salts thereof.
[0190] 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. The present invention includes all diastereomeric,
enantiomeric, and epimeric forms as well as the appropriate
mixtures thereof. Stereoisomers may be obtained, if desired, by
methods known in the art as, for example, the separation of
stereoisomers by chiral chromatographic columns. 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.
[0191] In some situations, compounds may exist as tautomers. All
tautomers are included within Formula I and are provided by this
invention.
[0192] In addition, the compounds of the present invention can
exist in unsolvated as well as solvated forms with pharmaceutically
acceptable solvents such as water, ethanol, and the like. In
general, the solvated forms are considered equivalent to the
unsolvated forms for the purposes of the present invention.
[0193] The present invention includes all pharmaceutically
acceptable, non-toxic esters of the compounds of Formula I. Such
esters 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 arylalkyl 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.
[0194] The compounds of the present invention are suitable to be
administered to a patient for the treatment, control, or prevention
of non-insulin dependent diabetes mellitus, hypercholesteremia,
hyperlipidemia, obesity, hyperglycemia, hyperlipidemia,
atherosclerosis, hypertriglyceridemia, and hyperinsulinemia.
Accordingly, the compounds of the present invention can be
administered to a patient alone or as part of a composition that
contains other components such as excipients, diluents, and
carriers, all of which are well-known in the art. The compositions
can be administered to humans and animals either orally, rectally,
parenterally (intravenously, intramuscularly, or subcutaneously),
intracisternally, intravaginally, intraperitoneally,
intravesically, locally (powders, ointments, or drops), or as a
buccal or nasal spray.
[0195] 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.
[0196] These compositions may also contain adjuvants 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.
[0197] 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 inert customary
excipient (or carrier) such as sodium citrate or dicalcium
phosphate or (a) fillers or extenders, as for example, starches,
lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders,
as for example, carboxymethylcellulose, alignates, gelatin,
polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for
example, glycerol; (d) disintegrating agents, as for example,
agar-agar, calcium carbonate, potato or tapioca starch, alginic
acid, certain complex silicates, and sodium carbonate; (e) solution
retarders, as for example paraffin; (f) absorption accelerators, as
for example, quaternary ammonium compounds; (g) wetting agents, as
for example, cetyl alcohol and glycerol monostearate; (h)
adsorbents, as for example, kaolin and bentonite; and (i)
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.
[0198] 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.
[0199] 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.
[0200] 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.
[0201] Besides such inert diluents, the composition can also
include adjuvants, such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0202] 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.
[0203] 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.
[0204] 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.
[0205] 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. 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.
Preparation of Compounds of the Invention
[0206] The present invention contains compounds that can be
synthesized in a number of ways familiar to one skilled in organic
synthesis. The compounds outlined herein can be synthesized
according to the methods described below, along with methods
typically utilized by a synthetic chemist, and combinations or
variations of those methods which are generally known to one
skilled in the art of synthetic chemistry. The synthetic route of
compounds in the present invention is not limited to the methods
outlined below. It is assumed one skilled in the art will be able
to use the schemes outlined below to synthesize compounds claimed
in this invention. Individual compounds may require manipulation of
the conditions in order to accommodate various functional groups. A
variety of protecting groups generally known to one skilled in the
art may be required. Purification, if necessary, can be
accomplished on a silica gel column eluted with the appropriate
organic solvent system. Also, reverse phase HPLC or
recrystallization may be employed as needed.
[0207] In still another embodiment of the present invention, a
method of preparing the compounds of the present invention is
provided. The method of the present invention comprises reaction of
a compound having Formula: 16
[0208] in a solvent in the presence of a base such as cesium
carbonate with: 17
[0209] wherein
[0210] V.sup.1, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, X.sup.0, X.sup.1, X.sup.2, Ar.sup.1, m, n, and p are the
same as described above;
[0211] X is a halogen; and
[0212] R.sup.10 is a lower alkyl.
[0213] The resulting ester is then converted to the compounds of
Formulae 1 and 2 by various methods know in the art for the
conversion of esters to acids, such as via hydrolysis for example.
A useful aryl halide, for example, is
5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole- .
Compounds 1, 1a-e, 2, 2a-e, and 3-53 will be provided when T and
V.sup.1 are defined as given above.
[0214] The compounds of the present invention can be prepared using
the synthetic route outlined in Scheme 1. With reference to Scheme
1, compound A is converted to the ester B. Although any compatible
method for esterification may be used, a useful method is to react
compound A with an alcohol, such as methanol, in the presence of an
acid such as hydrochloric acid. Ester B is then reacted with
cholorsulfonic acid to form compound C. Compound C is then reduced
to form compound D. Compound D is then alkylated with the halide
compound E to form compound F. A useful halide compound E is
5-chloromethyl-4-methyl-2-(4-trifluoromethyl-- phenyl)-thiazole,
for example. Compound F is then saponified with aqueous LiOH in the
THF to give the final compound G. Ar.sup.1, X.sup.0, X.sup.1,
R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are the same as defined
above for Formulas 1-2 above; X is a halogen. Compound G
corresponds to the compounds described by Formula 1-2 above when
X.sup.0 is S. Specifically, compound G corresponds to Formula 2
when R.sup.1 and R.sup.2 are joined together to form a ring.
1819
[0215] Alternatively, the compounds of the present invention can be
prepared using the synthetic route outlined in Scheme 2. With
reference to Scheme 2, compound H is reacted with a reducing agent
such a Dibal to form compounds with formula I. Compound I is then
reacted with dimethyl malonate to form compounds with formula J.
Compounds with formula J is then reacted with cholorsulfonic acid
followed by a reduction to form compound K. Compound K is then
alkylated with the halide compound E. The resulting compound is
then reacted with acid to form compound L. A useful halide compound
E is 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-
-thiazole, for example. Compound L corresponds to the compounds
described by Formula 1-2 above when V.sup.1 is --CH2--CH2--CH--O--,
X.sup.0 is S, and n is 1. Specifically, compound L corresponds to
Formula 2 when R.sup.1 and R.sup.2 are joined together to form a
ring, V.sup.1 is --CH2--CH2-CH--O--, and n is 1. 20
[0216] Scheme 3 provide yet another synthetic route to the
compounds of the present invention. Compound H is reacted with
cholorsulfonic acid followed by reduction to form compound M.
Compound M is then alkylated with the halide compound E to form
compound N. A useful halide compound E is
5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole, for
example. Compound N is reacted with a reducing agent such as Dibal
to form compounds with formula O. Compound O is reacted with Wittig
reagent P to form compound Q. Compound Q is then saponified with
aqueous LiOH to form compound L. W, Y, Ar.sup.1, X.sup.0, X.sup.1,
R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are the same as defined
above for Formulas 1-2 above; X is a halogen. Compound L
corresponds to the compounds described by Formula 1-2 above when
X.sup.0 is S. Specifically, compound L corresponds to Formula 2
when R.sup.1 and R.sup.2 are joined together to form a ring. 21
[0217] Another alternative synthetic route to the compounds of the
present invention is provided in Scheme 4. Compound R may be
prepared by de-methylation of the corresponding methyl ether with
boron tribromide. Compound S is prepared by thiocarbamoylation of
compound R. Compound T is then prepared by a Newman-Karnes
rearrangement of compound S in refluxing diphenyl ether.
Saponification and re-esterification of compound S then gives
compound D. Compound D is then alkylated with the halide compound E
to form compound F. A useful halide compound E is
5-chloromethyl-4-methyl- -2-(4-trifluoromethyl-phenyl)-thiazole,
for example. Compound F is then saponified with aqueous LiOH in the
THF to give the final compound G. R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 are the same as defined above for Formulas I-IV above; X is
a halogen. Compound G corresponds to the compounds described by
Formula 1-2 above. Specifically, compound G corresponds to Formula
2 when R.sup.1 and R.sup.2 are joined together to form a ring.
2223
[0218] The following non-limiting descriptions also demonstrate
methods for the synthesis of compounds of Formula I.
EXAMPLE 1
Synthesis of
5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsu-
lfanyl]-indan-2-carboxylic Acid (Compound 1)
[0219] 24
Preparation of Indan-2-carboxylic Acid Methyl Ester (Compound
1A)
[0220] 25
[0221] Indan-2-carboxylic acid (2.0 g, 12.34 mmol) was dissolved in
MeOH (50 mL) and was then treated with H.sub.2SO.sub.4 (1 mL). The
reaction mixture was refluxed overnight. MeOH was evaporated and
the residue was diluted with water and ether. Layers were separated
and the aqueous layer was extracted with ether (2.times.30 mL). The
combined organics were dried with MgSO.sub.4 and condensed to
afford the product (2.01 g, 95%) as white crystals.
[0222] MS: 177 (M+1).sup.+
Preparation of 5-Methyl-indan-2-carboxylic Acid Methyl Ester
(Compound 1B)
[0223] 26
[0224] Chlorosulfonic acid (5 mL) was cooled to 0.degree. C. Then
compound 1A (1.0 g, 5.68 mmol) was added over 30 min. The mixture
was stirred at RT for 3 h and was poured into ice (100 g). The
cloudy solution was extracted with ether (2.times.50 mL). The
extracts were dried with magnesium sulfate and concentrated to give
a brown oil which was passed through a short pad of silica gel to
afford the desired product (1.17 g, 75%) as white plates.
[0225] MS: 259 (M-Me).sup.+
Preparation of 5-Mercapto-indan-2-carboxylic Acid Methyl Ester
(Compound 1C)
[0226] 27
[0227] The above product (1.0 g, 3.64 mmol) was refluxed with tin
powder (2.2 g, 18.5 mmol) in MeOH (10 mL) and 4M HCl/dioxane (10
mL). After 3 h, the reaction mixture was poured into ice with
CH.sub.2Cl.sub.2 (50 mL). The phases were separated and the aqueous
layer was extracted with CH.sub.2Cl.sub.2 (2.times.50 mL). The
combined organic layers were dried with magnesium sulfate, filtered
and evaporated to give the crude thiol compound as a yellow oil
(total mass: 830 mg). It was used for the next step without further
purification.
[0228] MS: 207 (M-1).sup.+
Preparation of
5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-lmethyls-
ulfanyl]-indan-2-carboxylic Acid Methyl Ester (Compound 1D)
[0229] 28
[0230] Compound 1C (crude mixture from above, 830 mg) was dissolved
in acetonitrile (80 mL) with the chloride
5-chloromethyl-4-methyl-2-(4-trifl- uoromethyl-phenyl)-thiazole
(0.50 g, 1.71 mmol) and Cs.sub.2CO.sub.3 (2.37 g, 7.27 mmol) The
reaction mixture was stirred at RT overnight. Ether (50 mL) and
H.sub.2O were added and stirring was continued for another 5 min.
The layers were separated and the aqueous layer was extracted with
ether (2.times.100 mL). The combined organics was dried over
MgSO.sub.4 and concentrated to an oil. The crude product was
purified by column chromatography eluted with EtOAc and hexanes to
give the desired product as a thick yellow oil (0.48 g, 28% for 2
steps).
[0231] MS: 464 (M+1).sup.+
Preparation of
5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl-
sulfanyl]-indan-2-Carboxylic Acid (Compound 1)
[0232] To the solution of the above methyl ester (0.46 g, 0.99
mmol) in MeOH (7 mL) and THF (7 mL) was added LiOH.H.sub.2O (83 mg,
1.98 mmol). After refluxing overnight, the solution was cooled to
RT and solvents were removed by rotavap. The residue was dissolved
in water and neutralized with 1N HCl. The cloudy solution was
extracted with EtOAc (3.times.50 mL) and the extracts were dried
with MgSO.sub.4 and concentrated. The crude product was purified by
chromatography to afford a yellow solid, which was further washed
with ether to yield the desired product as yellowish crystals (213
mg, 48%).
[0233] MS: 450 (M+1).sup.+
[0234] CHN: Calc'd: C, 58.78; H, 4.04; N, 3.12. Found: C, 58.45; H,
3.96; N, 2.96.
EXAMPLE 2
Synthesis of
{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyls-
ulfanyl]-indan-2-yl}-acetic Acid (Compound 2)
[0235] 29
Preparation of indan-2-yl-acetic Acid Methyl Ester (Compound
2A)
[0236] 30
[0237] Compound 2A was made following the procedure in Example 1,
by replacing Indan-2-carboxylic acid with indan-2-yl-acetic acid.
Compound 2A was prepared in 94% yield.
[0238] NMR (.sup.1H, CDCl.sub.3): .delta. 7.15 (5H, m), 3.69 (3H,
s), 3.13 (2H, m), 2.88 (1H, m), 2.64 (2H, m), 2.49 (2H, d, j=1.97
hz):
Preparation of (5-Chlorosulfonyl-indan-2-yl)-acetic Acid Methyl
Ester (Compound 2B)
[0239] 31
[0240] Compound 2B was prepared according to the method of Example
1 utilizing compound 2A. Compound 2B was prepared in 63% yield. MS:
253 (M-Cl).sup.+.
Preparation of (5-Mercapto-indan-2-yl)-acetic Acid Methyl Ester
(Compound 2C)
[0241] 32
[0242] Compound 2C was prepared according to the method of Example
1 utilizing compound 2B. The crude product was used
immediately.
Preparation of
{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethy-
lsulfanyl]-indan-2-yl}-acetic Acid Methyl Ester (Compound 2D)
[0243] 33
[0244] Compound 2D was prepared according to the method of Example
1 utilizing compound 2C. Compound 2D was prepared in 27% yield. MS:
478 (M+1).sup.+.
Preparation of
{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethy-
lsulfanyl]-indan-2-yl}-acetic Acid (Compound 2)
[0245] Compound 2 was prepared according to the method of example 1
utilizing compound 2D. Compound 2 was prepared in 48% yield. MS:
462 (M-1).sup.+.
EXAMPLE 3
Synthesis of
6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsu-
lfanyl]-1-benzopyran-2-carboxylic Acid (Compound 3)
[0246] 34
Preparation of Chroman-2-carboxylic Acid Methyl Ester (Compound
3A)
[0247] 35
[0248] Compound 3A was prepared by hydrogenation of the methyl
4-oxo-4H-chromene-2-carboxylate catalyzed by 10% Pd/C in 93% yield.
MS: MS: 193 (M+1).sup.+.
Preparation of 6-Chlorosulfonyl-chroman-2-carboxylic Acid Methyl
Ester (Compound 3B)
[0249] 36
[0250] Compound 3B was prepared according to the method of Example
1 utilizing compound 3A. The crude product was used
immediately.
Preparation of 6-Mercapto-chroman-2-carboxylic Acid Methyl Ester
(Compound 3C)
[0251] 37
[0252] Compound 3C was prepared according to the method of Example
1 utilizing compound 3B. Compound 3C was prepared in 67% yield. MS:
223 (M-1).sup.+.
Preparation of
6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl-
sulfanyl]-1-benzopyran-2-carboxylic Acid Methyl Ester (Compound
3D)
[0253] 38
[0254] Compound 3D was prepared according to the method of Example
1 utilizing compound 3C. Compound 3D was prepared in 49% yield. MS:
480 (M+1).sup.+.
Preparation of
6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl-
sulfanyl]-1-benzopyran-2-carboxylic Acid (Compound 3)
[0255] Compound 3 was prepared according to the method of Example 1
utilizing compound 3D. Compound 3 was prepared in 58% yield. MS:
466 (M+1).sup.+.
EXAMPLE 4
Synthesis of
{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyls-
ulfanyl]-2,3-dihydro-benzofuran-2-yl}-acetic Acid (Compound 4)
[0256] 39
Preparation of (2,3-Dihydro-benzofuran-2-yl)-acetic Acid Methyl
Ester (Compound 4B)
[0257] 40
[0258] Compound 4B was prepared by hydrogenation of the
corresponding tetrahydrofuran derivative catalyzed by 10% Pd/C in
99% yield. MS: MS: 193 (M+1).sup.+.
Preparation of
(5-Chlorosulfonyl-2,3-dihydro-benzofuran-2-yl)-acetic Acid Methyl
Ester(Compound 4C)
[0259] 41
[0260] Compound 4C was prepared according to the method of Example
1 utilizing compound 4B. The crude product was used
immediately.
Preparation of (5-Mercapto-2,3-dihydro-benzofuran-2-yl)-acetic Acid
Methyl Ester (Compound 4D)
[0261] 42
[0262] Compound 4D was prepared according to the method of Example
1 utilizing compound 4C. Compound 4D was prepared in 44% yield for
2 steps. MS: 223 (M-1).sup.+.
Preparation of
{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethy-
lsulfanyl]-2,3-dihydro-benzofuran-2-yl}-acetic Acid Methyl Ester
(Compound 4E)
[0263] 43
[0264] Compound 4E was prepared according to the method of Example
1 utilizing compound 4D in 10% yield. MS: 480 (M+1).sup.+.
Preparation of
{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethy-
lsulfanyl]-2,3-dihydro-benzofuran-2-yl}-acetic Acid Methyl Ester
(Compound 4)
[0265] Compound 4 was prepared according to the method of Example 1
utilizing compound 4D in 32% yield. MS: 466 (M+1).sup.+.
EXAMPLE 5
Synthesis of
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyls-
ulfanyl]-1-benzopyran-2-yl}-acetic Acid (Compound 5)
[0266] 44
Preparation of Chroman-2-ol (compound 5 A)
[0267] 45
[0268] Dihydrocoumarin (5 g, 33.74 mmol) was dissolved in 50 mL of
toluene and cooled to -78.degree. C. Dibal (1 M solution in
toluene, 38 mL, 38 mmol) was added to the reaction flask over a 45
minutes period. The reaction mixture was stirred at this
temperature for 2 h. Water (50 mL) was added slowly along with some
toluene to ensure a smooth stirring of the reaction mixture. The
slurry was warmed to room temperature and stirring was continued
overnight. The organic layer was decanted and dried with magnesium
sulfate. Solvent was removed via rotatory evaporator to give
compound 5A as a clear oil (4.5 g, 89%). MS: 149 (M-1).sup.+.
Preparation of 2-Chroman-2-yl-malonic Acid Dimethyl Ester (Compound
5B)
[0269] 46
[0270] A mixture of 5A (6.77 g, 45 mmol), methyl malonate (16.8 g,
127 mmol), and piperidine (0.8 g, 9.4 mmol) was stirred at
50.degree. C. for 3 h. The reaction was worked up by adding water
(150 mL), 1 N HCl (10 mL), and ether (250 mL). Layers were
separated and the ether layer was dried with magnesium sulfate.
Solvent was concentrated to give compound 5B (5.6 g, 47%) as a
clear oil. MS: 265 (M+1).sup.+.
Preparation of 2-(6-Mercapto-chroman-2-yl)-malonic Acid Dimethyl
Ester(Compound 5C)
[0271] 47
[0272] 1). Chlorosulfonic acid (15 mL) was cooled to 0.degree. C.
Then compound 5B (5.5 g, 20.8 mmol) was added over 30 min. The
mixture was stirred at RT for 3 h and was poured into ice (100 g).
The cloudy solution was extracted with ether (2.times.100 mL). The
extracts were dried with magnesium sulfate and concentrated to give
the desired product (4.0 g, 53%) as a yellow oil. The crude product
was used immediately for the next step without purification.
[0273] 2). The above product was refluxed with tin powder (10 g, 84
mmol) in MeOH (20 mL) and 4M HCl/dioxane (20 mL). After 3 h, the
reaction mixture was poured into ice with CH.sub.2Cl.sub.2 (200
mL). The phases were separated and the aqueous layer was extracted
with CH.sub.2Cl.sub.2 (2.times.50 mL). The combined organic layers
were dried with magnesium sulfate, filtered and evaporated to give
the thiol compound 5C as a yellow oil (2.3 g, 37%, 2 steps). MS:
297 (M+1).sup.+.
Preparation of
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethy-
lsulfanyl]-1-benzopyran-2-yl}-acetic Acid (Compound 5)
[0274] 1). Compound 5C (200 mg, 0.67 mmol) was dissolved in
acetonitrile (10 mL) with
5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol- e
(200 mg, 0.68 mmol) and Cs.sub.2CO.sub.3 (425 mg, 1.3 mmol). The
reaction mixture was stirred at RT overnight. Ether (10 mL) was
added and stirring was continued for another 5 min. The mixture was
filtered and washed with more ether. The filtrate was concentrated
and the residue was purified by column chromatography eluted with
ether and hexanes to give the desired product as a thick oil (85
mg, 23%). MS: 552 (M+1).sup.+.
[0275] 2). The above methyl ester was heated to reflux with HBr
(48%, 10 mL) for 30 min. The mixture was cooled to RT and HBr was
removed by rotatory evaporator. Residue was dissolved in ether (20
mL) and ethyl acetate (5 mL) and treated with 10 drops of saturated
NaHCO.sub.3. The mixture was stirred at RT overnight and was then
filtered through a pad of silica gel. The product, compound 5
crystallized in ether/hexanes (1:1) to give 12 mg white solid. MS:
480 (M+1).sup.+.
Alternate Synthesis of
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-
-ylmethylsulfanyl]-1-benzopyran-2-yl}-acetic Acid (Compound 5)
Preparation of 6-Mercapto-chroman-2-one (Compound 5D)
[0276] 48
[0277] 1. To chlorosulfonic acid (15 g, 0.13 mmol) cooled at
0.degree. C. was added dihydrocoumarin (4.5 g, 30 mmol) dropwise.
The ice bath was removed and the reaction was continued for another
2 h. The reaction was quenched by pouring the mixture into iced
water (150 mL). Layers were separated and the aqueous layer was
extract with EtOAc (3.times.50 mL). Combined organics were dried
with MgSO.sub.4 and filtered. Solvent was evaporated to afford the
sulfonyl cloride derivative as an off-white solid (4.6 g, 61%)
[0278] 2. Product from above (3.9 g, 15.8 mmol) was refluxed in HCl
in dioxane (4 M) with tin powder (12 g, 101 mmol) for 2 h. The
reaction mixture was poured into ice-CH.sub.2Cl.sub.2 bath. Layers
were separated and the aqueous layer was extracted with
CH.sub.2Cl.sub.2. After drying, solvent was removed to afford the
thio product 5D as a white solid (1.56 g, 55%). MS: 179
(M-1).sup.+.
Preparation of
6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl-
sulfanyl]-chroman-2-one(compound 5E)
[0279] 49
[0280] Compound 5D (1.05 g, 5.8 mmol) was dissolved in THF (80 mL)
with the
5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (1.40
g, 5.0 mmol) and Cs.sub.2CO.sub.3 (3.0 g, 9.2 mmol). The reaction
mixture was stirred at RT overnight. Ether (50 mL) and H.sub.2O
were added and stirring was continued for another 5 min. The layers
were separated and the aqueous layer was extracted with ether
(2.times.100 mL). The combined organics was dried over MgSO.sub.4
and concentrated to an oil. The crude product was purified by
column chromatography eluted with EtOAc and hexanes to give the
desired product 5E as an off-white solid (1.1 g, 53%). MS: 436
(M+1).sup.+.
Preparation of
6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl-
sulfanyl]-chroman-2-ol (compound 5F)
[0281] 50
[0282] The above compound 5E (200 mg, 0.46 mmol) was dissolved in
toluene (25 mL) and was cooled to -78.degree. C. Dibal-H (1 mL, 1 M
solution in toluene) was added dropwise and the reaction mixture
was stirred at this temperature for 2 h. The reaction was quenched
with slow addition of water (0.5 mL) and stirring was continued for
another 30 min. After it was warmed to room temperature, the
mixture was passed through a short pad of MgSO.sub.4. Solvent was
removed to afford the product 5F (125 mg, 62%)
[0283] MS: 438 (M+1).sup.+
Preparation of
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethy-
lsulfanyl]-1-benzopyran-2-yl}-acetic Acid Methyl Ester(Compound
5G)
[0284] 51
[0285] Mixture of compound 5F (130 mg, 0.3 mmol) and
methyl(triphenylphosphoranylidene) acetate (110 mg, 0.33 mmol) in
CDCl.sub.3 (15 mL) was heated to 60.degree. C. for 2 h. After the
reaction mixture was cooled to RT, ether (100 mL) was added and the
mixture was passed through a short silica gel column eluted with
ether. Solvent was removed to afford compound 5G as an off-white
solid (95 mg, 65%). MS: 494 (M+1).sup.+.
Preparation of
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethy-
lsulfanyl]-1-benzopyran-2-yl}-acetic Acid (Compound 5)
[0286] The above ester 5G (1.6 g, 3.2 mmol) was dissolved in THF (5
mL), MeOH (10 mL), and water (5 mL). It was treated with LiOH.H2O
(200 mg, 4.9 mmol) followed by refluxing for 30 min. Solvent was
removed and the residue was diluted with EtOAc (75 mL) and ether
(15 mL) followed by addition of concentrated HCl. Stirring was
continued for 30 min and the solution was passed through a short
pad of MgSO.sub.4. Solvent was removed and the product was
recrystallized with ether to afford the product compound 5 as a
white solid (1.2 g, 77%). MS: 494 (M+1).sup.+. CHN: Calc'd: C,
57.6; H, 4.20; N, 2.90. Found: C 57.6, H 3.92, N 2.85.
EXAMPLE 6
Synthesis of
5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethylsu-
lfanyl]-benzofuran-2-carboxylic Acid (Compound 6)
[0287] 52
Preparation of 5-Hydroxy-benzofuran-2-carboxylic Acid Methyl Ester
(Compound 6A)
[0288] 53
[0289] A solution of 5-methoxy-benzofuran-2-carboxylic acid methyl
ester (5.0 g, 24 mmol) in 50 mL DCM at 0.degree. C. was treated
portionwise with boron tribromide (4.4 mL of a 1 M solution in
DCM). After 3 hours, the reaction mixture was carefully quenched
with 50% NH.sub.4OH. The organic layer was separated and washed
1.times.50 mL brine, dried (Na.sub.2SO.sub.4), and concentrated in
vacuo to give 2 g (43%) of the title compound pure enough for
subsequent use. 400 MHz .sup.1H NMR (DMSO-d.sub.6) .delta. 9.47 (s,
1H), 7.56 (s, 1H), 7.45 (d, 1H, J=8.8 Hz), 7.00 (s, 1H), 6.91 (d,
1H, J=8.8 Hz), 3.81 (s, 3H).
Preparation of 5-Dimethylthiocarbamoyloxy-benzofuran-2-carboxylic
Acid Methyl Ester (Compound 6B)
[0290] 54
[0291] A solution of 5-hydroxy-benzofuran-2-carboxylic acid methyl
ester (2 g, 10 mmol) in 50 mL dry DMF was treated portionwise with
NaH (252 mg of a 95% dispersion in mineral oil, 10 mmol). After 30
min, dimethylthiocarbamoyl chloride (1.9 g, 15 mmol) was added and
the reaction stirred at 40.degree. C. for 1.5 hours. The reaction
mixture was then concentrated in vacuo, and the residue taken up in
EtOAc. The organic layer was then washed 1.times. water,
1.times.brine, dried (Na.sub.2SO.sub.4) and the solvent removed in
vacuo to give 3.5 g of the crude title compound. Recrystallization
from CHCl.sub.3/hexanes, gave 1.3 g (45%) of the title compound.
400 MHz .sup.1H NMR (DMSO-d.sub.6) .delta. 7.72 (s, 1H), 7.68 (d,
1H, J=9.8 Hz), 7.43 (s, 1H), 7.17 (d, 1H, J=9.8 Hz), 3.85 (s, 3H),
3.32 (s, 3H), 3.29 (s, 3H).
Preparation of 5-Dimethylcarbamoylsulfanyl-benzofuran-2-carboxylic
Acid Methyl Ester (Compound 6C)
[0292] 55
[0293] A solution of
5-dimethylthiocarbamoyloxy-benzofuran-2-carboxylic acid methyl
ester (1.3 g, 4.7 mmol) in 25 mL diphenyl ether was heated at
reflux for 2.5 hours. The reaction mixture was then cooled and the
resulting precipitate collected. Purification by flash column
chromatography (gradient elution: 100% hexanes to 45%
EtOAc/hexanes), gave the title compound (0.58 g, 45%) as a brown
solid.
[0294] 400 MHz .sup.1H NMR (DMSO-d.sub.6) .delta. 7.86 (s, 1H),
7.74 (s, 1H), 7.72 (d, 1H, J=9.0 Hz), 7.48 (d, 1H, J=9.0 Hz), 3.85
(s, 3H), 3.36 (s(br), 6H); MS nz/z 280 (M+1).
Preparation of 5-Mercapto-benzofuran-2-carboxylic Acid Methyl Ester
(Compound 6D)
[0295] 56
[0296] A solution of
5-dimethylcarbamoylsulfanyl-benzofuran-2-carboxylic acid methyl
ester (0.5 g, 1.8 mmol) and potassium hydroxide (0.5 g, 12.5 mmol)
in 25 ml 2:1 ethanol/water was heated at reflux for 18 hours. The
reaction was then cooled, acidified with 2 M HCl, extracted
2.times.25 mL EtOAc, dried (Na.sub.2SO.sub.4) and the solvent
removed in vacuo to give 350 mg of the crude product. The crude
mixture was then refluxed overnight in 25 mL MeOH and catalytic
H.sub.2SO.sub.4. The reaction was then cooled, concentrated in
vacuo, taken up in EtOAc and washed with brine. The organic layer
was then dried (Na.sub.2SO.sub.4) and concentrated in vacuo to give
330 mg (95%) of the title compound pure enough for subsequent use.
400 MHz .sup.1H NMR (DMSO-d.sub.6) .delta. 7.66 (s, 1H), 7.62 (s,
1H), 7.57(d, 1H, J=9.0 Hz), 7.37 (d, 1H, J=9.0 Hz), 5.49 (s(br),
1H), 3.85 (s, 3H).
Preparation of
5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl-
sulfanyl]-benzofuran-2-carboxylic Acid Methyl Ester (Compound
6E)
[0297] 57
[0298] A mixture of 5-mercapto-benzofuran-2-carboxylic acid methyl
ester (300 mg, 1.4 mmol) and
5-chloromethyl-4-methyl-2-(4-trifluoromethyl-pheny- l)-thiazole
(550 mg, 1.9 mmol) was dissolved in 5 ml anhydrous acetonitrile
followed by addition of cesium carbonate (700 mg, 2.1 mmol). The
reaction was then stirred at 60.degree. C. for 2 hours, filtered
and concentrated in vacuo. Purification by flash column
chromatography (gradient elution: 5% EtOAc/hexanes to 45%
EtOAc/hexanes), gave the title compound (410 mg, 61%) as a pale
yellow solid. M.p. 132-133.degree. C.; IR (thin film) cm.sup.-1:
1731; 400 MHz .sup.1H NMR (DMSO-d.sub.6) .delta. 7.95 (d, 2H, J=8.1
Hz), 7.79 (s, 1H), 7.74 (d, 2H, J=8.1 Hz), 7.65 (m, 2H), 7.51 (d,
1H, J=9.0 Hz), 4.44 (s, 2H), 3.82 (s, 3H); MS m/z 464 (M+1); Anal.
Calc'd for C.sub.22H.sub.16F.sub.3N.sub.1O.sub.3S.sub.2 C, 57.01;
H, 3.48; N, 3.02; found: C, 56.94; H, 3.44; N, 2.84.
Preparation of
5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl-
sulfanyl]-benzofuran-2-carboxylic Acid (Compound 6)
[0299] The product from example 6E (350 mg, 0.75 mmol), dissolved
in 5 ml THF and 1 ml water, was treated with lithium hydroxide
monohydrate (159 mg, 3.75 mmol); stirring at room temperature for 1
hour. The reaction mixture was then acidified to about pH 3 with 2
N HCl. The reaction was then extracted into ethyl acetate
(2.times.20 ml). The organic extracts were washed with brine, dried
over anhydrous sodium sulfate, decanted, and concentrated.
Recrystallization from CHCl.sub.3/hexanes, gave 232 mg (68%) of the
title compound. M.p. 207-209.degree. C.; IR (thin film) cm.sup.-1:
1684; 400 MHz .sup.1H NMR (DMSO-d.sub.6) .delta. 7.95 (d, 2H, J=8.1
Hz), 7.77 (s, 1H), 7.74 (d, 2H, J=8.1 Hz), 7.62 (d, 1H, J=8.8 Hz),
7.55 (s, H), 7.48 (d, 1H, J=8.8 Hz), 4.43 (s, 2H); MS m/z 448
(M-1); Anal. Calc'd for
C.sub.21H.sub.14F.sub.3N.sub.1O.sub.3S.sub.2 C, 56.12; H, 3.14; N,
3.12; found: C, 55.68; H, 3.16; N, 2.98.
EXAMPLE 7
Synthesis of
{6-[4-Methyl-2-(4-trifluoromethylphenyl)thiazol-5-ylmethylsul-
fanyl]-1-oxo-3,4-dihydro-1H-naphthalen-2-yl}acetic Acid (Compound
7)
[0300] 58
Preparation of Dimethylthiocarbamic Acid
O-(5-oxo-5,6,7,8,-tetrahydronapht- halen-2-yl)ester (compound
7A)
[0301] 59
[0302] To a solution of 4-hydroxy-1-tetralone (6.5 g, 40 mmol) in
Dioxane (75 mL), under nitrogen atmosphere, was added
dimethylthiocarbonyl chloride (4.9 g, 40 mmol), triethylamine (5.6
mL, 40 mmol), and DMAP (0.48 g, 3.9 mmol) successively. The
resulting mixture was warmed to reflux and refluxed 16 h, then
diluted with water (150 mL) and extracted with EtOAc. The combined
extracts were washed with water and brine, and the organic phase
dried over sodium sulfate then concentrated by roto-vap. The
residue was purified by recrystallization in EtOAc/Hexane to give
5.08 g (51%) of brown solid. (mp 126-127.degree. C.) Analyzed for
C.sub.13H.sub.15NO.sub.2: Calcd: C, 62.62%; H, 6.06%; N, 5.62%;
Found: C, 62.38%; H, 6.02%; N, 5.65%.
[0303] To solution of
{6-[4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-yl-
methylsufanyl]-1-oxo-3,4-dihydro-1H-naphthalen-2-yldene}acetic acid
(0.50 g, 1.0 mmol) in chilled glacial acetic acid (3 mL) was added
zinc powder (0.30 g, 4.5 mmol). The resulting mixture was stirred 1
h, diluted with water, and extracted with EtOAc. The combined
extracts were washed with water and brine, and the organic phase
dried over magnesium sulfate and concentrated under vacuum. The
residue was purified by recrystallization in methanol to give 0.273
g (54%) of white crystals. (158-159.degree. C.) Analyzed for
C.sub.24H.sub.22NO.sub.3S.sub.2: Calcd: 58.64%; H, 4.10%; N, 2.85%;
Found: C, 58.94%; H, 3.97%; N, 2.69%.
Preparation of 6-Mecapto-3,4-dihydro-2H-naphthalen-1-one (Compound
7B)
[0304] 60
[0305] Neat dimethylthiocarbamic acid
O-(5-oxo-5,6,7,8,-tetrahydronaphthal- en-2-yl)ester (5.7 g, 23
mmol) was heated to 230-240.degree. C. under nitrogen atmosphere
for 1 h, then cooled to room temperature. The residue was dissolved
in methanol (100 mL), placed under nitrogen atmosphere, and
solution of 50% aqueous sodium hydroxide in water (20 mL) added.
The resulting mixture was refluxed for 16 h, cooled to room
temperature, acidified with 2N HCL and extracted with EtOAc. The
combined extracts were washed with saturated aqueous sodium
bicarbonate and brine. The organic phase was dried over sodium
sulfate and concentrated under vacuum. The residue was purified by
flash chromatography (silica gel, 10% EtOAc/Hexane) to give 3.59 g
(89%) of a yellow oil. NMR (400 Mhz, CDCl.sub.3) .delta. 2.08-2.12
(m, 2H), 2.58-2.62 (m, 2H), 2.87 (t, J=6 Hz, 2H), 7.10-7.15 (m,
2H), 7.88 (d, J=8 Hz, 1H). MS: (m+1) 179.
Preparation of
6-[4-Methyl-2-(4-trifluoromethylpheyl)thiazol-5-ylmethylsul-
fanyl]-3,4-dihydro-2H-naphthalen-1-one (compound 7C)
[0306] 61
[0307] To a solution of 6-mercapto-3,4-dihydro-2H-naphthalen-1-one
(3.5 g, 20 mmol) in acetonitrile (100 mL), under nitrogen
atmosphere, was added
%-chloromethyl-4-methyl-2-(4-trifluoromethylphenyl)thiazole (5.7 g,
20 mmol) followed by cesium carbonate (6.4 g, 20 mmol). The
resulting mixture was stirred 16 h, diluted with water (100 mL).
The precipitate was collected by filtration, dried, dissolved in
EtOAc, and filtered through a plug of silica gel. The filtrate was
concentrated under vacuum and the residue purified by
recrystallization in iso-propanol to give 5.21 g (61%) of cream
colored crystals. (mp 123-124.degree. C.) Analyzed for
C.sub.22H.sub.18F.sub.3NOS.sub.2: Calcd: C, 60.95%; H, 4.19%; N,
3.23%; Found: C, 60.79%; H, 4.09%; N, 3.09%.
Preparation of
{6-[4-Methyl-2-(4-trifluoromethylphenyl)thiazol-5-ylmethyls-
ulfanyl]-1-oxo-3,4-dihydro-1H-naphthalen-2-ylidene}acetic Acid
(Compound 7D)
[0308] 62
[0309] A slurry of
6-[4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-ylmeth-
ylsulfanyl]-3,4-dihydro-2H-naphthalen-1-one (2.0 g, 4.6 mmol) in
glyoxylic acid monohydrate (2.0 g, 22 mmol), under nitrogen
atmosphere, was warmed to 160.degree. C. and stirred for 1 h. The
reaction mixture was cooled to room temperature, dissolved in EtOAc
(100 mL) and filtered. The filtrate was washed with water (50
mL.times.3) and brine. The organic phase was dried over magnesium
sulfate, concentrated under vacuum, and purified by
recrystallization in ethanol to give 1.02 g (45%) of yellow solid.
Analyzed for C.sub.24H.sub.18NO.sub.3S.sub.2: Calcd: C, 58.89%; H,
3.71%; N, 2.86%; Found: C, 58.715; H, 3.56%; N, 2.77.
Preparation of
{6-[4-Methyl-2-(4-trifluoromethylphenyl)thiazol-5-ylmethyls-
ulfanyl]-1-oxo-3,4-dihydro-1H-naphthalen-2-yl}acetic Acid (Compound
7)
[0310] To solution of
{6-[4-methyl-2-(4-trifluoromethylphenyl)thiazol-5-yl-
methylsufanyl]-1-oxo-3,4-dihydro-1H-naphthalen-2-yldene}acetic acid
(0.50 g, 1.0 mmol) in chilled glacial acetic acid (3 mL) was added
zinc powder (0.30 g, 4.5 mmol). The resulting mixture was stirred 1
h, diluted with water, and extracted with EtOAc. The combined
extracts were washed with water and brine, and the organic phase
dried over magnesium sulfate and concentrated under vacuum. The
residue was purified by recrystallization in methanol to give 0.273
g (54%) of white crystals. (158-159.degree. C.) Analyzed for
C.sub.24H.sub.22NO.sub.3S.sub.2: Calcd: 58.64%; H, 4.10%; N, 2.85%;
Found: C, 58.94%; H, 3.97%; N, 2.69%.
EXAMPLE 8
Synthesis of
{2-Methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5--
ylmethylsulfanyl]-chroman-2-yl}-acetic Acid (Compound 8)
[0311] 63
Preparation of (2-Methyl-2H-chromen-2-yl)-acetic Acid Ethyl Ester
(Compound 8A)
[0312] 64
[0313] A suspension of 2-hydroxy-3-methylbenzylaldehyde (5.0 g,
40.9 mmol) and diethyl isopropylidenemalonate (8.2 g, 40.9 mmol) in
DMF (200 mL) was heated to 135.degree. C. for over night. DMF was
removed by rotovap and the residue was treated with water and
EtOAc. Layers were separated and the aqueous layer was extracted
with EtOAc (100 mL.times.3). The combined organics were dried over
MgSO.sub.4 and filtered. Solvent was removed and the crude product
was purified through silica gel column to give the desired product
as a white solid (5.98 g, 63%). MS 233 (M+1).sup.+.
Preparation of (2-Methyl-chroman-2-yl)-acetic Acid Ethyl Ester
(Compound 8B)
[0314] 65
[0315] Compound 8A was hydrogenated in MeOH using 10% Pd/C as
catalyst. The mixture was then filtered and washed with EtOAc.
Solvent was dried to give the product as a thick oil (3.7 g, 100%).
MS 235 (M+1).sup.+.
Preparation of (6-Chlorosulfonyl-2-methyl-chroman-2-yl)-acetic Acid
Ethyl Ester (Compound 8C)
[0316] 66
[0317] Compound 8B (4.94 g, 21 mmol) was dissolved in CHCl.sub.3
(100 mL) and the solution was cooled to 0.degree. C. Chlorosulfonic
acid (4.92 g, 42 mmol) was added dropwise. The reaction mixture was
stirred at 0.degree. C. for 30 min. followed by RT for 3 h. Quench
the reaction with ice. Extractive work up followed by column
chromatography gave the product as a yellowish oil (300 mg, 4%). MS
331 (M-1).sup.+.
Preparation of (6-Mercapto-2-methyl-chroman-2-yl)-acetic Acid Ethyl
Ester (Compound 8D)
[0318] 67
[0319] Compound 8D was made the same way as 1C 92% yield as a
mixture of the methyl (major) and ethyl esters (minor). MS 265
(M+1, Et ester).sup.+, MS 251 (M+1, Me ester).sup.+.
Preparation of
{2-Methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol--
5-ylmethylsulfanyl]-chroman-2-yl}-acetic Acid Methyl/Ethyl Esters
(Compound 8E)
[0320] 68
[0321] Compound 8E was made the same way as 1D in 41% yield. The
mixture was mainly methyl ester with trace of the ethyl ester. MS
508 (M+1, Me ester).sup.+, MS 5221 (M+1, Et ester).sup.+.
Preparation of
{2-Methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol--
5-ylmethylsulfanyl]-chroman-2-yl}-acetic acid (Compound 8)
[0322] Compound 8 was made from Compound 8E the same way as 1E in
58% yield. MS 494 (M+1).sup.+.
EXAMPLE 9
Synthesis of
{2,8-Dimethyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazo-
l-5-ylmethylsulfanyl]-chroman-2-yl}-acetic Acid (Compound 9)
[0323] 69
Preparation of (2,8-Dimethyl-chromen-2-yl)-acetic Acid Ethyl Ester
(Compound 9A)
[0324] 70
[0325] Compound 9A was made similar to 1A in 73% yield. MS 247
(M+1).sup.+.
Preparation of (2,8-Dimethyl-chroman-2-yl)-acetic Acid Ethyl Ester
(Compound 9B)
[0326] 71
[0327] Compound 9B was made similar to 1B in 83% yield. MS 249
(M+1).sup.+.
Preparation of (6-Chlorosulfonyl-2,8-dimethyl-chroman-2-yl)-acetic
Acid Ethyl Ester (Compound 9C)
[0328] 72
[0329] Compound 9C was made similar to 1C in 96% yield. MS 311
(M-Cl).sup.+.
Preparation of (6-Mercapto-2,8-dimethyl-chroman-2-yl)-acetic Acid
Methyl Ester (Compound 9D)
[0330] 73
[0331] Compound 9D was made the same way as 1C using MeOH as
solvent in 90% yield. The ethyl ester was completely
transesterified to the methyl ester. MS 266, M.sup.+.
Preparation of
{2,8-Dimethyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thia-
zol-5-ylmethylsulfanyl]-chroman-2-yl}-acetic Acid Methyl Ester
(Compound 9E)
[0332] 74
[0333] Compound 9E was made the same way as 1D in 75% yield. MS 522
(M+1).sup.+.
Preparation of
{2,8-Dimethyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thia-
zol-5-ylmethylsulfanyl]-chroman-2-yl}-acetic Acid (Compound 9)
[0334] Compound 9 was made the same way as 1E in 50% yield. MS 508
(M+1).sup.+.
EXAMPLE 10
Synthesis of
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyls-
ulfanyl]-3,4-dihydro-1H-isoguinolin-2-yl}-acetic Acid (Compound
10)
[0335] 75
Preparation of (3,4-Dihydro-1H-isoquinolin-2-yl)-acetic Acid Methyl
Ester (Compound 10A)
[0336] 76
[0337] Methyl bromoacetate (6.32 g, 41.3 mmol) was slowly added to
a stirred solution of sodium hydride (1.65 g, 41.3 mmol) and
1,2,3,4-tetrahydroisoquinoline (5.0 g, 37.5 mmol). The mixture was
stirred at RT for 3 hr. After removing the solvent, the residue was
diluted with water and ether. Layers were separated and the aqueous
layer was extracted with ether (3.times.50 ml). The combined
organics were dried with MgSO.sub.4 and condensed to afford the
desired product 10A (5.29 g, 69%) as a yellow oil. MS: 206
(M+1).sup.+.
Preparation of
(6-Chlorosulfonyl-3,4-dihydro-1H-isoquinolin-2-yl)-acetic Acid
Methyl Ester (Compound 10B)
[0338] 77
[0339] 10B was prepared analogously to compound 1B. 24% yield. MS:
304 (M+1).sup.+.
Preparation of (6-Mercapto-3,4-dihydro-1H-isoquinolin-2-yl)-acetic
Acid Methyl Ester (Compound 10C)
[0340] 78
[0341] 10C was prepared analogously to compound 1C. 74% yield. MS:
238 (M+1).sup.+.
Preparation of
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethy-
lsulfanyl]-3,4-dihydro-1H-isoquinolin-2-yl}-acetic Acid Methyl
Ester (Compound 10D)
[0342] 79
[0343] Compound 10D was prepared analogously to compound 1D. Yield
was 6% after flash column purification. MS: 493 (M+1).sup.+.
Preparation of
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethy-
lsulfanyl]-3,4-dihydro-1H-isoquinolin-2-yl}-acetic Acid(Compound
10)
[0344] Compound 10 was prepared analogously to compound 1. Compound
10 was prepared in 4% yield. MS: 479 (M+1).sup.+.
EXAMPLE 11
Synthesis of
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyls-
ulfanyl]-3,4-dihydro-2H-quinolin-1-yl}-acetic Acid (Compound
11)
[0345] 80
Preparation of (3,4-Dihydro-2H-quinolin-1-yl)-acetic Acid Methyl
Ester (Compound 11A)
[0346] 81
[0347] 11A was prepared analogously to compound 1A. 99% yield. MS:
206 (M+1).sup.+.
Preparation of
(6-Chlorosulfonyl-3,4-dihydro-2H-quinolin-1-yl)-acetic Acid Methyl
Ester (Compound 11B)
[0348] 82
[0349] 11B was prepared analogously to compound 1B. 12% yield. MS:
304 (M+1).sup.+.
Preparation of (6-Mercapto-3,4-dihydro-2H-quinolin-1-yl)-acetic
Acid Methyl Ester (Compound 11C)
[0350] 83
[0351] 11C was prepared analogously to compound 1C. Used as
unpurified oil. MS: 238 (M+1).sup.+.
Preparation of
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethy-
lsulfanyl]-3,4-dihydro-2H-quinolin-1-yl}-acetic Acid Methyl Ester
(Compound 11D)
[0352] 84
[0353] Compound 11D was prepared analogously to compound 1D. Yield
was 40% after flash column purification. MS: 493 (M+1).sup.+.
Preparation of
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethy-
lsulfanyl]-3,4-dihydro-2H-isoquinolin-1-yl}-acetic Acid (Compound
11)
[0354] Compound 11 was prepared analogously to compound 1. Compound
11 was prepared in 4% yield. MS: 479 (M+1).sup.+.
EXAMPLE 12
Synthesis of
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyls-
ulfanyl]-2-oxo-3,4-dihydro-2H-isoquinolin-1-yl}-acetic Acid
(Compound 12)
[0355] 85
Preparation of (2-Oxo-3,4-Dihydro-2H-quinolin-1-yl)-acetic Acid
Methyl Ester (Compound 12A)
[0356] 86
[0357] 12A was prepared analogously to compound 1A. 95% yield. MS:
220 (M+1).sup.+.
Preparation of
(6-Chlorosulfonyl-2-oxo-3,4-dihydro-2H-quinolin-1-yl)-aceti- c Acid
Methyl Ester (Compound 12B)
[0358] 87
[0359] 12B was prepared analogously to compound 1B. 11% yield. MS:
318 (M+1).sup.+.
Preparation of
(6-Mercapto-2-oxo-3,4-dihydro-2H-quinolin-1-yl)-acetic Acid Methyl
Ester (Compound 12C)
[0360] 88
[0361] 12C was prepared analogously to compound 1C. 92% yield. MS:
252 (M+1).sup.+.
Preparation of
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethy-
lsulfanyl]-2-oxo-3,4-dihydro-2H-quinolin-1-yl}-acetic Acid Methyl
Ester (Compound 12D)
[0362] 89
[0363] Compound 12D was prepared analogously to compound 1D. Yield
was 36%. MS: 507 (M+1).sup.+.
Preparation of
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethy-
lsulfanyl]-2-oxo-3,4-dihydro-2H-isoquinolin-1-yl}-acetic Acid
(Compound 12)
[0364] Compound 12 was prepared analogously to compound 1. Compound
12 was prepared in 70% yield. MS: 493 (M+1).sup.+.
EXAMPLE 13
Synthesis of
{7-Methoxy-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-
-ylmethylsulfanyl]-1,2,3,4-tetrahydro-naphthalen-2-yl}-acetic Acid
(Compound 13)
[0365] 90
Preparation of
(7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-acetic Acid Ethyl
Ester (Compound 13A)
[0366] 91
[0367] 7-Methoxy-2-tetralone (4.5 g, 25.5 mmol) in 25 ml THF was
added to a stirred solution of 1.6 M n-butyl lithium (24 ml) and
triethyl phosphonoacetate (8.59 g, 38.3 mmol) in 100 ml THF. The
mixture was stirred at RT overnight. Water (100 ml) was then added
and the layers were separated. The aqueous layer was extracted with
ether (2.times.50 ml). The combined organics was dried with
MgSO.sub.4 and evaporated to give a dark oil. It was purified by
silica gel chromatography eluted with 20% EtOAc/Hexanes to afford
the pure product as a yellow oil (5.5 g, 88%).
[0368] Compound 13A was then prepared by hydrogenation of the
unsaturated oil catalyzed by Pd/C (20%) in 90% yield. MS: 249
(M+1).sup.+.
Preparation of
(6-Chlorosulfonly-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2- -yl)
acetic Acid Ethyl Ester (Compound 13B)
[0369] 92
[0370] 13B was prepared analogously to compound 1B. 59% yield. MS:
311 (M-Cl).sup.+.
Preparation of
(6-Mercapto-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-a- cetic
Acid Methyl Ester (Compound 13C)
[0371] 93
[0372] 13C was prepared analogously to compound 1C. Yield was 34%
after flash column purification. MS: 265 (M-1).sup.+.
Preparation of
{7-Methoxy-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-
-5-ylmethylsulfanyl]-1,2,3,4-tetrahydro-naphthalen-2-yl}-acetic
Acid Methyl Ester (Compound 13D)
[0373] 94
[0374] Compound 13D was prepared analogously to compound 1D. Yield
was 23% after flash column purification. MS: 522 (M+1).sup.+.
Preparation of
{7-Methoxy-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-
-5-ylmethylsulfanyl]-1,2,3,4-tetrahydro-naphthalen-2-yl}-acetic
Acid (Compound 13)
[0375] Compound 13 was prepared analogously to compound 1. Compound
13 was prepared in 81% yield. MS: 508 (M+1).sup.+.
EXAMPLE 14
Synthesis of
7-Methoxy-6-[4-methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-y-
lmethylsulfanyl]-chroman-2-yl-acetic Acid (Compound 14)
[0376] 95
Preparation of 7-Methoxy-chroman-2-one (Compound 14A)
[0377] 96
[0378] Compound 14A was prepared by hydrogenation of
7-methoxy-chromen-2-one catalyzed by 10% Pd/C in 96% yield. MS: 179
(M+1).sup.+.
Preparation of
3-(2-Hydroxy-4-methoxy-5-thiocyanato-phenyl)-propionic Acid Methyl
Ester (Compound 14B)
[0379] 97
[0380] Compound 14A (3 g), KSCN (4.9 g) were dissolved in MeOH (125
mL) at 0.degree. C., Br.sub.2 (3 g) was added, then stirred for 2
h. The reaction mixture was quenched with water (200 mL) and ethyl
acetate (200 mL). The ethyl acetate was separated and washed with
water, brine, dried (MgSO.sub.4), concentrated, to afford compound
14B (3.5 g). mp 105-016.degree. C.;
[0381] MS: 268 (M+1).sup.+.
Preparation of 6-Mercapto-7-methoxy-chroman-2-ol (Compound 14C)
[0382] 98
[0383] Compound 14B (3.5 g) was dissolved in 500 mL of toluene and
cooled to -78.degree. C. Dibal (1M solution in toluene, 40 mL) was
added to the reaction over 30 minutes period. The reaction mixture
was stirred at this temperature for 2 h. Water (10 mL) was added
slowly, the slurry was warmed to room temperature, and stirring was
continued overnight. The organic layer was decanted and dried
(MgSO.sub.4). Solvent was removed to give compound 14C as a oil
(2.2 g). MS: 211(M-1).sup.+.
Preparation of 6-Mercapto-7-methoxy-chroman-2-yl-acetic Acid Methyl
Ester (Compound 14D)
[0384] 99
[0385] Mixture of compound 14C (2.2 g) and
methyl-triphenyphosphoranyliden- e-acetate (2.2 g) in CDCl.sub.3
(25 mL) was heated to 60.degree. C. for 3 h. After cooled to RT,
ether was added and the mixture was passed through a short silical
gel column, eluted with ether. Solvent was removed to afford
compound 14D, as a oil (150 mg). MS: 267 (M-1).sup.+.
Preparation of
7-Methoxy-6-[4-methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-
-ylmethylsulfanyl]-chroman-2-yl-acetic Acid Methyl Ester (Compound
14E)
[0386] 100
[0387] Compound 14E was prepared according to the method of example
1D utilizing compound 14D. Compound 14E was prepared in 20% yield.
MS: 524 (M+1).sup.+.
Preparation of
7-Methoxy-6-[4-methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-
-ylmethylsulfanyl]-chroman-2-yl-acetic Acid (Compound 14)
[0388] Compound 14 was prepared according to the method of example
1 utilizing compound 14E. MS: 510 (M+1).sup.+.
EXAMPLE 15
Synthesis of
7-Methyl-6-[4-methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-yl-
methylsulfanyl]-chroman-2-yl-acetic Acid (Compound 15)
[0389] 101
Preparation of 7-Methyl-chroman-2-one (Compound 15A)
[0390] 102
[0391] Compound 15A was prepared according to the method of example
1A utilizing compound 7-methyl-chromen-2-one. MS: 163
(M+1).sup.+.
Preparation of
3-(2-Hydroxy-4-methyl-5-thiocyanato-phenyl)-propionic Acid Methyl
Ester (Compound 15B)
[0392] 103
[0393] Compound 15B was prepared according to the method of example
1B utilizing compound 15A. MS: 252 (M+1).sup.+.
Preparation of 6-Mercapto-7-methyl-chroman-2-ol (Compound 15C)
[0394] 104
[0395] Compound 15C was prepared according to the method of example
1C utilizing compound 15B. MS: 195 (M-1).sup.+.
Preparation of 6-Mercapto-7-methyl-chroman-2-yl-acetic Acid Methyl
Ester (Compound 15D)
[0396] 105
[0397] Compound 15D was prepared according to the method of example
1D utilizing compound 15C. MS: 251 (M-1).sup.+.
Preparation of
7-Methyl-6-[4-methyl-2-(4-trifluoromethyl-pheny)-thiazol-5--
ylmethylsulfanyl]-chroman-2-yl-acetic acid methyl ester (Compound
15E)
[0398] 106
[0399] Compound 15E was prepared according to the method of example
1D utilizing compound 15D. Compound 15E was prepared in 45% yield.
MS: 508 (M+1).sup.+.
Preparation of
7-Methyl-6-[4-methyl-2-(4-trifluoromethyl-pheny)-thiazol-5--
ylmethylsulfanyl]-chroman-2-yl-acetic Acid (Compound 15A)
[0400] Compound 15 was prepared according to the method of example
1 utilizing compound 15E. Compound 15 was prepared in 30% yield.
MS: 494 (M+1).sup.+.
EXAMPLE 16
Synthesis of
6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsul-
fanyl]-2H-chromene-3-carboxylic Acid (Compound 16)
[0401] 107
Preparation of 2H-Chromene-3-carbonitrile (Compound 16A)
[0402] 108
[0403] 2-Hydroxy-benzaldehyde (14 g), acrylate nitrile (30.5 g) and
DABCO (5.1 g) were heated to reflux for 24 h. The reaction mixture
was cooled, concentrated. The crude oil was mixed with ether (300
mL) and 2N HCl (200 mL), stirred for 30 minutes. The ether layer
was washed with water, brine, dried (MgSO.sub.4), concentrated to
afford a oil compound 16A (16.8 g). MS: 158 (M+1).sup.+.
Preparation of 2H-Chromene-3-carboxylic Acid (Compound 16B)
[0404] 109
[0405] Compound 16A (16.8 g), 10% NaOH (500 mL) were heated to
reflux for 12 h. The reaction mixture was cooled to 0.degree. C.,
acidified with concentrated HCl till pH 2. The product was
precipitated, filtered, dried under vacuum, to afford compound 16B,
an off-white solid (13.3 g). MS: 177 (M+1).sup.+.
Preparation of 2H-Chromene-3-carboxylic Acid Methyl Ester (Compound
16C)
[0406] 110
[0407] Compound 16B (5 g) and concentrated HCl (2 mL) in MeOH (200
mL) were heated to reflux for 30 h. The reaction mixture was
quenched with water (200 mL) and ether (200 mL). Separated the
organic layer, washed with water, brine, dried (MgSO.sub.4),
concentrated to give an off-white solid, compound 16C (4.2 g). mp
56-57.degree. C.; MS: 191 (M+1).sup.+.
Preparation of 6-Chlorosulfonyl-2H-chromene-3-carboxylic Acid
Methyl Ester (Compound 16D)
[0408] 111
[0409] Compound 16D was prepared according to the method of example
1B utilizing compound 16C. The crude product was used
immediately.
Preparation of 6-Mercapto-2H-chromene-3-carboxylic Acid Methyl
Ester (Compound 16E)
[0410] 112
[0411] Compound 16E was prepared according to the method of example
1C utilizing compound 16D. Compound 16E was prepared in 20% yield.
MS: 221 (M-1).sup.+.
Preparation of
6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethyls-
ulfanyl]-2H-chromene-3-carboxylic Acid Methyl Ester (Compound
16F)
[0412] 113
[0413] Compound 16F was prepared according to the method of example
1D utilizing compound 16E. Compound 16F was prepared in 45% yield.
MS: 478 (M+1).sup.+.
Preparation of
6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethyls-
ulfanyl]-2H-chromene-3-carboxylic Acid (Compound 16)
[0414] Compound 16 was prepared according to the method of example
1 utilizing compound 16F. Compound 16 was prepared in 30% yield.
MS: 464 (M+1).sup.+.
EXAMPLE 17
Synthesis of
6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsul-
fanyl]-chroman-3-carboxylic Acid (Compound 17)
[0415] 114
Preparation of Chroman-3-carboxylic Acid Methyl Ester (Compound
17A)
[0416] 115
[0417] Compound 17A was prepared according to the method of example
3A utilizing compound 16C. Compound 17A was prepared in 95% yield.
MS: 193 (M-1).sup.+.
Preparation of 6-Chlorosulfonyl-chroman-3-carboxylic Acid Methyl
Ester (Compound 17B)
[0418] 116
[0419] Compound 17B was prepared according to the method of example
1B utilizing compound 17A. The crude product was used
immediately.
Preparation of 6-Mercapto-chroman-3-carboxylic Acid Methyl Ester
(Compound 17C)
[0420] 117
[0421] Compound 17C was prepared according to the method of example
1C utilizing compound 17B. Compound PPC was prepared in 85% yield.
mp 83-84.degree. C.; MS: 223 (M-1).sup.+.
Preparation of
6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethyls-
ulfanyl]-chroman-3-carboxylic Acid Methyl Ester (Compound 17D)
[0422] 118
[0423] Compound 17D was prepared according to the method of example
1D utilizing compound 17C. Compound 17D was prepared in 45% yield.
MS: 480 (M+1).sup.+.
Preparation of
6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethyls-
ulfanyl]-chroman-3-carboxylic Acid (Compound 17)
[0424] Compound 17 was prepared according to the method of example
1 utilizing compound 17D. Compound 17was prepared in 65% yield. mp
139-140.degree. C.; MS: 466 (M+1).sup.+.
EXAMPLE 18
Synthesis of
6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsul-
fanyl]-chroman-3-yl-acetic Acid (Compound 18)
[0425] 119
Preparation of Chroman-3-yl-methanol (Compound 18A)
[0426] 120
[0427] Compound 17A (3 g) was dissolved in 300 mL of toluene at
-78.degree. C. DibalH (1M solution in toluene, 32 mL) was added to
the reaction over 30 minutes period. The reaction mixture was
stirred at this temperature for 2 h. 2N NaOH (5 mL) was added
slowly, the slurry was warmed to room temperature, and stirring was
continued overnight. The organic layer was decanted and dried
(MgSO.sub.4). Solvent was removed to afford an off-white solid,
compound 18A (2.5 g). MS: 165 (M+1).sup.+.
Preparation of Toluene-4-sulfonic acid Chroman-3-ylmethyl Ester
(Compound 18B)
[0428] 121
[0429] Compound 18A (3.6 g) was dissolved in pyridine (11 mL) at
RT. Toluene sulfonyl chloride (4.5 g) was added, stirred for 6 h.
The reaction mixture was quenched with 2N HCl (500 .mu.L), ether
extraction (2.times.200 .mu.L). The combined ether was washed with
water, brine, dried (MgSO.sub.4), concentrated, to afford an orange
color solid, compound 18B (4.2 g). mp 83-84.degree. C.; MS: 319
(M+1).sup.+.
Preparation of Chroman-3-yl-acetonitrile (Compound 18C)
[0430] 122
[0431] Compound 18B (1.25 g), NaCN (0.15 g) in 25 mL of DMF, were
heated to 60.degree. C. for 12 h. The solvent was removed, the
reaction mixture was mixed with water (125 mL) and ether (125 mL).
The ether layer was separated, washed with water, brine, dried
(MgSO.sub.4), concentrated to afford compound 18C (0.67 g). mp
54-55.5.degree. C.; MS: 174 (M+1).sup.+.
Preparation of 3-Cyanomethyl-chroman-6-sulfonyl Chloride (Compound
18D)
[0432] 123
[0433] Compound 18D was prepared according to the method of example
1B utilizing compound 18C. The crude product was used
immediately.
Preparation of 6-Mercapto-chroman-3-yl-acetonitrile (Compound
18E)
[0434] 124
[0435] Compound 18E was prepared according to the method of example
1C utilizing compound 18D. Compound 18E was prepared in 35% yield.
MS: 204 (M-1).sup.+.
Preparation of
6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethyls-
ulfanyl]-chroman-3-yl-acetonitrile (Compound 18F)
[0436] 125
[0437] Compound 18F was prepared according to the method of example
1D utilizing compound 18E. Compound 18F was prepared in 80% yield.
MS: 461 (M+1).sup.+.
Preparation of
6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethyls-
ulfanyl]-chroman-3-yl-acetic Acid (Compound 18)
[0438] Compound 18F (1.5 g), MeOH (5 mL), THF (25 mL), 50% NaOH (5
mL), water (5 mL), were heated to reflux overnight. The solvent was
removed. The crude reside was mixed with water (200 mL) and ether
(200 mL). The mixture was acidified with 2N HCl to pH 2. The ether
layer was separated, washed with water, brine, dried (MgSO.sub.4),
concentrated to give a oil product. The oil material was mixed with
20 mL of MeOH, stirred at RT till a white precipitate form. The
solid was filtered to afford compound 18 (0.75 g). mp
149-149.5.degree. C.; MS: 480 (M+1).sup.+.
EXAMPLE 19
Synthesis of
{6-Methoxy-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-
-ylmethylsulfanyl]-indan-1-yl}-acetic Acid (Compound 19)
[0439] 126
Preparation of (6-Methoxy-indan-1yl)-acetic Acid Ethyl Ester
(Compound 19A)
[0440] 127
[0441] 6-Methoxy-1-indanone (5.0 g, 30.8 mmol) and triethyl
phosphonoacetate (13.82 g, 61.6 mmol) in THF (15 ml) was added to a
stirred solution of sodium hydride (2.46 g, 61.6 mmol) and ethanol
(1.06 g, 23.1 mmol). The mixture was heated at 80.degree. C.
overnight. After removing the solvent in vacuo, the residue was
diluted with water (50 ml) and layered with ether (50 ml). The
layers were separated and the aqueous layer extracted with ether
(2.times.25 ml). The combined organics were dried with MgSO.sub.4
and condensed to give a crude dark oil. It was purified bysilica
gel chromatography eluted with 10% EtOAc/Hexanes to afford the
yellow solids in 39% yield.
[0442] Compound 19A was then prepared by hydrogenation of the
unsaturated solid catalyzed by Pd/C (10%) in quantitative yield.
MS: 235 (M+1).sup.+.
Preparation of (5-Chlorosulfonyl-6-methoxy-indan-1-yl)-acetic Acid
Ethyl Ester (Compound 19B)
[0443] 128
[0444] 19B was prepared analogously to compound 1B. 39% yield. MS:
333 (M+1).sup.+.
Preparation of (5-Mercapto-6-methoxy-indan-1-yl)-acetic Acid Ethyl
Ester (Compound 19C)
[0445] 129
[0446] 19C was prepared analogously to compound 1C. Used as
unpurified oil. MS: 267 (M+1).sup.+.
Preparation of
{6-Methoxy-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-
-5-ylmethylsulfanyl]-indan-1-yl}-acetic Acid Methyl Ester (Compound
19D)
[0447] 130
[0448] Compound 19D was prepared analogously to compound 1D. Yield
was 51% after flash column purification. MS: 522 (M+1).sup.+.
Preparation of
{6-Methoxy-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-
-5-ylmethylsulfanyl]-indan-1-yl}-acetic Acid (Compound 19)
[0449] Compound 19 was prepared analogously to compound 1. Compound
19 was prepared in 14% yield. MS: 494 (M+1).sup.+.
EXAMPLE 20
Synthesis of
6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsul-
fanyl]-4-oxo-chroman-3-ylidene-acetic Acid (Compound 20)
[0450] 131
Preparation of 4-Oxo-chroman-3-ylidene-acetic Acid (Compound
20A)
[0451] 132
[0452] A solution of 4-chromanone (1.2 g), glyoxylic acid
monohydrate (3 g), NaOH (1.6 g) in 5 mL of MeOH and 5 mL of water
was heated to reflux for 2 h. The reaction mixture was
concentrated, mixed with 25 mL of water, acidified with HCl till pH
2. The product was precipitated, filtered, washed with water, dried
under vacuum to afford an off-white solid compound 20A (0.38 g). mp
134-136.degree. C.; MS: 205(M+1).sup.+.
Preparation of 4-Oxo-chroman-3-yl-acetic Acid Methyl Ester
(Compound 20B)
[0453] 133
[0454] A solution of compound 20A (0.38 g), Tin powder (0.5 g), 1
mL of MeOH, 5 mL of 4N HCl in dioxane was heated to reflux for 2 h.
The reaction mixture was cooled to 0.degree. C., filtered the
solid. The filtrate was mixed with 50 mL of ethyl acetate and 50 ml
of water. The organic layer was separated, washed with water,
brine, dried (MgSO.sub.4). Concentrated to afford compound 20B (0.4
g). MS: 221 (M+1).sup.+.
Preparation of 6-Chlorosulfonyl-4-oxo-chroman-3-yl-acetic Acid
Methyl Ester (Compound 20C)
[0455] 134
[0456] Compound 20C was prepared according to the method of example
1B utilizing compound 20B. The crude product was used
immediately.
Preparation of 6-Mercapto-4-oxo-chroman-3-yl-acetic Acid Methyl
Ester (Compound 20D)
[0457] 135
[0458] Compound 20D was prepared according to the method of example
1C utilizing compound 20C. Compound 20D was prepared in 75% yield.
MS: 251 (M-1).sup.+.
Preparation of
6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethyls-
ulfanyl]-4-oxo-chroman-3-ylidene-acetic Acid Methyl Ester (Compound
20E)
[0459] 136
[0460] Compound 20E was prepared according to the method of example
1D utilizing compound 20D. Compound 20E was prepared in 65% yield.
mp 93-94.degree. C.; MS: 508 (M+1).sup.+.
Preparation of
6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethyls-
ulfanyl]-4-oxo-chroman-3-ylidene-acetic Acid (Compound 20)
[0461] Compound 20 was prepared according to the method of example
1 utilizing compound 20E. Compound 20 was prepared in 10% yield.
MS: 494 (M+1).sup.+.
EXAMPLE 21
Synthesis of
3-{5-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethyl-
sulfanyl]-2,3-dihydro-indol-1-yl}-propionic Acid (Compound 21)
[0462] 137
Preparation of 3-(2,3-Dihydro-indol-1-yl)-propionic Acid Methyl
Ester (Compound 21A)
[0463] 138
[0464] A solution of indoline (6.15 g), methyl 3-bromopropionate
(13 g), potassium carbonate (21 g) in 150 mL of acetonitrile was
refluxed fro 16 h. The reaction mixture was concentrated, mixed
with 300 nL of ether. The mixed reaction solution was filtered,
concentrated down to afford compound UUA (8 g). MS: 206
(M+1).sup.+.
Preparation of 3-(5-Thiocyanato-2,3-dihydro-indol-1-yl)-propionic
Acid Methyl Ester (Compound 21B)
[0465] 139
[0466] Compound 21B was prepared according to the method of example
14B utilizing compound 21A. Compound 21B was prepared in 80% yield.
MS: 263 (M-1).sup.+.
Preparation of 3-(5-Mercapto-2,3-dihydro-indol-1-yl)-propionic Acid
Methyl Ester (Compound 21C)
[0467] 140
[0468] Sodium borohydride (0.6 g) was added to a solution of
compound 21B (0.65 g) in 20 mL of MeOH at 0.degree. C. by portion
in 15 minutes period. The mixture was stirred for another 30
minutes at RT, quenched with 50 mL of water and 50 mL of ether. The
organic layer was separated, washed with water, brine, dried
(MgSO.sub.4), concentrated to afford compound 21C (0.42 g). MS: 236
(M-1).sup.+.
Preparation of
3-{5-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmeth-
ylsulfanyl]-2,3-dihydro-indol-1-yl}-propionic Acid Methyl Ester
(Compound 21D)
[0469] 141
[0470] Compound 21D was prepared according to the method of example
1D utilizing compound 21C. Compound 21D was prepared in 20% yield.
MS: 493 (M+1).sup.+.
Preparation of
3-{5-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmeth-
ylsulfanyl]-2,3-dihydro-indol-1-yl}-propionic Acid (Compound
21)
[0471] Compound 21 was prepared according to the method of example
1 utilizing compound 21D. Compound 21 was prepared in 60% yield. Mp
78-80.degree. C.; MS: 479 (M+1).sup.+.
EXAMPLE 22
Synthesis of
6-Methoxy-5-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-y-
lmethylsulfanyl]-3-oxo-3H-benzo[d]isoxazo-2-yl-acetic Acid
(Compound 22)
[0472] 142
Preparation of 2, N-Dihydroxy-4-methoxy-benzamide (Compound
22A)
[0473] 143
[0474] The 50%(w/w) NaOH (28 mL) was added to a solution of
NH.sub.2OH hydrochloride salt (13.9 g, 0.2 mole) in water (65 mL)
by portion at RT. The 2-hydroxy-4-methoxy-benzoic acid methyl ester
(18.2 g, 0.1 mole) in dioxane (50 mL) was added dropwise, another 6
h stirred at RT. The reaction mixture was concentrated, mixed with
300 mL of water, acidified with concentrated HCl till pH 5. The
product was precipitated, filtered, washed with water and dried
under vacuum, to afford an off-white solid compound 22A (17.3 g).
MS: 184 (M+1).sup.+.
Preparation of 6-Methoxy-benzo[d]isoxazol-3-one (Compound 22B)
[0475] 144
[0476] The 1,1'-carbonyldiimidazole (30.5 g) in 200 mL of THF was
added dropwise to a refluxing solution of RRA (17.3 g) in 300 mL of
THF, another 1.5 h at refluxing condition. The reaction mixture was
concentrated, mixed with 400 mL of water, acidified with
concentrated HCl till PH 2. The product was precipitated, filtered,
washed with water, dried under vacuum, to afford an off-white solid
compound RRB (6.1 g). MS: 166
[0477] (M+1).sup.+.
Preparation of 6-Methoxy-3-oxo-3H-benzo[d]isoxazol-2-yl-acetic Acid
Methyl Ester (Compound 22C)
[0478] 145
[0479] The KN(TMS).sub.2 (7.2 g) was added to a solution of
compound 22B (4 g) in 150 mL of THF at 0.degree. C. by portion,
another one hour at 0.degree. C. with stirring. Methyl bromoacetate
(7 g) was added, stirred at RT overnight. The reaction mixture was
quenched with 150 mL of ethyl acetate and 100 mL of 2N HCl. The
organic layer was separated, washed with water, brine, dried
(MgSO.sub.4), concentrated to afford an off-white solid compound
22C (2.5 g). mp 185-188.degree. C.; MS: 238 (M+1).sup.+.
Preparation of
5-Chlorosulfonyl-6-methoxy-3-oxo-3H-benzo[d]isoxazol-2-yl-a- cetic
Acid Methyl Ester (Compound 22D)
[0480] 146
[0481] Compound 22D was prepared according to the method of example
1B utilizing compound 22C. The crude product was used
immediately.
Preparation of
5-Mercapto-6-methoxy-3-oxo-3H-benzo[d]isoxazol-2-yl-acetic Acid
Methyl Ester (Compound 22E)
[0482] 147
[0483] Compound 22E was prepared according to the method of example
1C utilizing compound 22D. Compound 22E was prepared in 10% yield.
MS: 268 (M-1).sup.+.
Preparation of
6-Methoxy-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol--
5-ylmethylsulfanyl]-3-oxo-3H-benzo[d]isoxazol-2-yl-acetic Acid
Methyl Ester (Compound 22F)
[0484] 148
[0485] Compound 22F was prepared according to the method of example
1D utilizing compound 22E. Compound 22F was prepared in 10% yield.
MS: 525 (M+1).sup.+.
Preparation of
6-Methoxy-5-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-
-ylmethylsulfanyl]-3-oxo-3H-benzo[d]isoxazo-2-yl-acetic Acid
(compound 22)
[0486] Compound 22 was prepared according to the method of example
1 utilizing compound 22F. Compound 22was prepared in 50% yield. mp
245-247.degree. C.; MS: 511 (M+1).sup.+.
EXAMPLE 23
Synthesis of
{6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy-
]-benzo[b]thiophen-3-yl}-acetic Acid (compound 23)
[0487] 149
Preparation of 4-(3-Methoxy-phenylsulfanyl)-3-oxo-butyric Acid
Methyl Ester (compound 23A)
[0488] 150
[0489] A solution of methyl 2-chloroacetoacetate (15.0 g, 0.10 mol)
in 20 ml of acetonitrile was added dropwise to a mixture of
3-methoxythiophenol (14.0 g, 0.10 mol) and cesium carbonate (65.2
g, 0.20 mol) in 400 ml of acetonitrile over 30 min. The mixture was
stirred at room temperature for 2 hours, then filtered through
Celite.RTM.. The filtrate was concentrated and purified using
normal phase chromatography. 400 MHz .sup.1H NMR (CDCl.sub.3)
.delta. 7.21 (dt, 1H), 6.95-6.85 (m, 2H), 6.78 (dd, 1H), 3.82 (s,
2H), 3.80 (s, 3H), 3.74 (s, 3H), 3.65 (s, 2H), MS (ES
(M-1)=253).
Preparation of (6-methoxybenzo[b]thiophen-3-yl)acetic Acid Methyl
Ester (compound 23B)
[0490] 151
[0491] The product from example 23A (2.54 g, 0.01 mol) was added
dropwise to 25 ml of methanesulfonic acid at room temperature, and
the solution was stirred at the same temperature for 15 minutes,
then the reaction mixture was added to 250 ml of ice-water. The
aqueous mixture was extracted with ethyl acetate. The organic phase
was washed with brine, sodium bicarbonate, dried over sodium
sulfate, and concentrated to give 23B in good purity. 400 MHz
.sup.1H NMR (CDCl.sub.3) .delta. 7.64 (d, 1H), 7.32 (d, 1H), 7.18
(s, 1H), 7.04 (dd, 1H), 3.88 (s, 3H), 3.82 (s, 2H), 3.71 (s, 3H),
MS (ES (M+1)=236).
Preparation of (6-hydroxy-benzo[b]thiophen-3-yl)acetic Acid Methyl
Ester (Compound 23C)
[0492] 152
[0493] To a stirred solution of the product from example 23B (2.20
g, 9.32 mmol) in 50 ml of dichloromethane at -78.degree. C. was
added dropwise a solution of boron tribromide (11.68 g, 46.6 mmol)
in 50 ml of dichloromethane. After the completion of the addition
of boron tribromide, the reaction mixture was maintained at
-78.degree. C. for 1 h, then allowed to reach room temperature and
stirred at the same temperature overnight. The mixture was cooled
to 0.degree. C., carefully quenched with 100 ml of water, extracted
with ethyl acetate, washed with brine, dried over sodium sulfate,
concentrated, and purified using normal phase chromatography to
afford the title product. 400 MHz .sup.1H NMR (CDCl.sub.3) .delta.
7.59 (d, 1H), 7.25 (d, 1H), 7.16 (s, 1H), 6.92 (dd, 1H), 5.20 (brs,
1H), 3.82 (s, 2H), 3.71 (s, 3H), MS (ES (M+1)=223).
Preparation of
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmetho-
xy]-benzo[b]thiophen-3-yl}-acetic Acid Methyl Ester (Compound
23D)
[0494] 153
[0495] The title compound was prepared from compound 23C in a
manner analogous to compound 6E. MS m/z 478 (M+1).
Preparation of
{6-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmetho-
xy]-benzo[b]thiophen-3-yl}-acetic Acid (Compound 23)
[0496] The title compound was prepared from compound 23D in a
manner analogous to compound 6. MS m/z 464 (M+1).
EXAMPLE 24
Synthesis of
{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy-
]-indol-1-yl}-acetic Acid (Compound 24)
[0497] 154
Preparation of
5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethox-
y]-1H-indole (compound 24A)
[0498] 155
[0499] 5-Hydroxyindole (200 mg, 1.5 mmol) was dissolved in
acetonitrile (10 mL) with the chloride
5-chloromethyl-4-methyl-2-(4-trifluoromethyl-ph- enyl)-thiazole
(0.50 g, 1.7 mmol) and Cs.sub.2CO.sub.3 (2.37 g, 7.27 mmol) The
reaction mixture was stirred at RT overnight. Ether (50 mL) and
H.sub.2O were added and stirring was continued for another 5 min.
The layers were separated and the aqueous layer was extracted with
ether (2.times.100 mL). The combined organics was dried over
MgSO.sub.4 and concentrated. The crude product was purified by
column chromatography eluted with EtOAc and hexanes to give the
desired product as a white solid (0.3 g, 51% yield).
[0500] MS m/z 389 (M+1).sup.+.
Preparation of
{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmetho-
xy]-indol-1-yl}-acetic Acid Methyl Ester (Compound 24B)
[0501] 156
[0502] Compound 24B was made from Compound 24A in the same way as
10A in 56% yield.
[0503] MS m/z 461 (M+1).sup.+.
Preparation of
{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmetho-
xy]-indol-1-yl}-acetic Acid (Compound 24)
[0504] Compound 24 was prepared according to the method of example
1 utilizing compound 24B. Compound X was prepared in 72% yield. MS
m/z 447 (M-1).sup.+.
EXAMPLE 25
Synthesis of
{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyls-
ulfanyl]-indol-1-yl}-acetic Acid (Compound 25)
[0505] 157
Preparation of (2,3-Dihydro-indol-1-yl)-acetic Acid Methyl Ester
(Compound 25A)
[0506] 158
[0507] Compound 25A was prepared analogously to compound 10A in 66%
yield.
[0508] MS m/z 192 (M+1).sup.+.
Preparation of (5-Thiocyanato-2,3-dihydro-indol-1-yl)-acetic Acid
Methyl Ester (Compound 25B)
[0509] 159
[0510] Compound 25B was prepared analogously to compound 14B in 40%
yield.
[0511] MS m/z 249 (M+1).sup.+.
Preparation of (5-Mercapto-2,3-dihydro-indol-1-yl)-acetic Acid
Methyl Ester (Compound 25C)
[0512] 160
[0513] Compound 25B (1.05 g, 4.2 mmol) was refluxed in a solution
of water (2 ml), methanol (20 ml) and mercaptoacetic acid (1.2 g,
13 mmol) for 3 h. The solvent was removed under the vacuo, and the
crude product was passed a short silica gel chromatography to give
25C in 95% yield.
[0514] MS m/z 224 (M+1).sup.+.
Preparation of
{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethy-
lsulfanyl]-2,3-dihydro-indol-1-yl}-acetic Acid Methyl Ester
(Compound 25D)
[0515] 161
[0516] Compound 25D was made from compound 25C the same way as
compound 1D in 31% yield. MS m/z 479 (M+1).sup.+.
Preparation of
{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethy-
lsulfanyl]-indol-1-yl}-acetic Acid Methyl Ester (Compound 25E)
[0517] 162
[0518] Compound 25D (600 mg, 1.3 mmol), and
tetrachloro-1,2-benzoquinone (300 mg, 1.3 mmol) were stirred in 10
ml anhydrous ether at RT for 1 h. The compound 25E was purified
using normal phase chromatography in 15% yield.
[0519] MS m/z 447 (M-1).sup.+.
Preparation of
{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethy-
lsulfanyl]-indol-1-yl}-acetic Acid (Compound 25)
[0520] Compound 25 was prepared according to the method of example
1 utilizing compound 25E. Compound 25 was prepared in 97% yield. MS
m/z 463 (M-1).sup.+.
Biological Assays
[0521] The compounds of the present invention have demonstrated
PPAR modulating activity in the standard assays commonly employed
by those skilled in the art. Accordingly, such compounds and
formulations comprising such compounds are useful for treating,
preventing or controlling dyslipidemia in a mammal.
[0522] A. Selectivity Measurements
[0523] 1. Test A. Transient Transfections Assay Using the HepG2
Hepatoma Cell Line.
[0524] HepG2 cells were transiently transfected with an expression
plasmids encoding hPPAR.alpha., hPPAR.beta. or mPPAR.gamma.
chimeric receptors and a reporter containing the yeast upstream
activating sequence (UAS) upstream of the viral E1B promoter
controlling a luciferase reporter gene. In addition, the plasmid
pRSV9.beta.-gal was used to control for transfection efficiency.
HepG2 cells were grown in DMEM supplemented with 10% FBS and 1
.mu.M non-essential amino acid. On the first day, cells were split
into 100 mm dishes at 2.5.times.10.sup.6/dish and incubated
overnight at 37C.degree./5% CO.sub.2. On the second day the cells
were transiently transfected with plasmid DNA encoding a chimeric
receptor, the luciferase reporter gene; and .beta.-gal. For each
100 mm dish, 15 .mu.g of lucifease reporter (PG5E1b) DNA, 15 .mu.g
of Gal4-PPARchimeric receptor DNA, and 1.5 .mu.g of .beta.-gal
plasmid DNA were mixed with 1.4 ml of opti-MEM in the tube. 28
.mu.l of LipoFectamine-2000 reagent was added to 1.4 ml of opti-MEM
in the tube, and incubate for 5 min at RT. The diluted
Lipofectamine-2000 reagent was combined with the DNA mixture, and
incubate for 20 min at RT. After fresh medium was added to each 100
mm dish of cells, 2.8 ml of Lipofectamine2000-DNA mixture was added
dropwise to the 100 mm dish containing 14 ml of medium, and
incubate 37.degree. C. overnight. On day three cells were
trypsinized off the 100 mm dishes and re-plated on 96 well plates.
Cells were plated at 2.5.times.10.sup.4cells per well in 150 .mu.l
of media and 50 .mu.l of compound diluted by media was added. The
concentrations of reference agents and test compound added were in
the range from 50 .mu.M to 50 pM. After addition of compounds, the
plates were incubated at 37.degree. C. for 24 hours. Subsequently
cells were washed once with 100 .mu.l of PBS, lysed, and processed
for measuring luciferase and .beta.-gal activity using Dual-Light
luciferase kit from Tropix.RTM., according to the manufacturer's
recommendations, on an EG&G Bethold MicroLumat LB96P
luminometer. EC.sub.50 values were obtained using the GraphPad
Prism.TM. program. Surprisingly, the compounds of the present
invention exhibit activity for both PPAR.alpha. and PPAR.beta..
Accordingly, the compounds of the present invention should find
considerable therapeutic applications for hypercholesterolemia and
hyperlipidemia. The Hep G2-hBeta EC.sub.50 ("EC.sub.50.beta.") data
as well as the Hep G2-hAlpha IEC.sub.50 ("EC.sub.50.alpha.") data
of the compounds of the invention are presented in Table 1
below.
1TABLE 1 Example Hep G2-h.beta. EC.sub.50 nM Hep G2-h.alpha.
EC.sub.50 nM 1 177.7 384 2 267.4 1957 3 762.0 917 4 1542 899 5 8.3
3737.75 6 2000000 2044 7 614.0 -- 8 3470.0 -- 9 2000000 -- 10 111.1
-- 11 286.0 1928 12 896.1 2000000 13 24.1 1190 14 19.0 2000000 15
252.2 1301 16 2210.0 -- 17 2130.0 2185 18 394.0 1002254.5 19 113.0
42 20 -- -- 21 -- -- 22 2000000 -- 23 1.7 572.0 24 -- -- 25 --
--
Formulations
[0525] The compounds of the present invention can be administered
alone or in combination with one or more therapeutic agents. These
include, for example, other agents for treating, preventing or
controlling dyslipidemia, non-insulin dependent diabetes mellitus,
obesity, hyperglycemia, hypercholesteremia, hyperlipidemia,
atherosclerosis, hypertriglyceridemia, or hyperinsulinemia.
[0526] The compounds are thus well suited to formulation for
convenient administration to mammals for the prevention and
treatment of such disorders.
[0527] The following examples further illustrate typical
formulations provided by the invention.
2 Formulation 1 Ingredient Amount compound of Formulas 1-50 0.5 to
800 mg sodium benzoate 5 mg isotonic saline 1000 mL
[0528] The above ingredients are mixed and dissolved in the saline
for IV administration to a patient.
3 Formulation 2 Ingredient Amount compound of Formulas 1-50 0.5 to
800 mg cellulose, microcrystalline 400 mg stearic acid 5 mg silicon
dioxide 10 mg sugar, confectionery 50 mg
[0529] The ingredients are blended to uniformity and pressed into a
tablet that is well suited for oral administration to a
patient.
4 Formulation 3 Ingredient Amount compound of Formulas 1-50 0.5 to
800 mg starch, dried 250 mg magnesium stearate 10 mg
[0530] The ingredients are combined and milled to afford material
suitable for filling hard gelatin capsules administered to a
patient.
5 Formulation 4 Ingredient Amount % wt./(total wt.) compound of
Formulas 1-50 1 to 50 Polyethylene glycol 1000 32 to 75
Polyethylene glycol 4000 16 to 25
[0531] The ingredients are combined via melting and then poured
into molds containing 2.5 g total weight.
[0532] While embodiments of the invention have been illustrated and
described, it is not intended that these embodiments illustrate and
describe all possible forms of the invention. Rather, the words
used in the specification are words of description rather than
limitation, and it is understood that various changes may be made
without departing from the spirit and scope of the invention.
* * * * *