U.S. patent number RE40,558 [Application Number 11/254,215] was granted by the patent office on 2008-10-28 for therapeutic uses of di-aryl acid derivatives.
This patent grant is currently assigned to Sanofi-Aventis Deutschland GmbH. Invention is credited to Mark Bobko, Thomas J. Caulfield, Robert D. Groneberg, Zaid Jayyosi, Michael F. Kelley, Richard F. Labaudiniere, Daniel G. McGarry, Gerard M. McGeehan, Anne Minnich, Litao Zhang.
United States Patent |
RE40,558 |
Jayyosi , et al. |
October 28, 2008 |
**Please see images for:
( Certificate of Correction ) ** |
Therapeutic uses of di-aryl acid derivatives
Abstract
The use of diaryl acid derivatives of formula (I) ##STR00001##
or pharmaceutically acceptable salts, N-oxides, hydrates or
solvates thereof, wherein the variables shown are defined in the
disclosure, and their pharmaceutical compositions as PPAR ligand
receptor binders. The PPAR ligand receptor binders of this
invention are useful as agonists or antagonists of the PPAR
receptor.
Inventors: |
Jayyosi; Zaid (Flemington,
NJ), McGeehan; Gerard M. (Wilmington, DE), Kelley;
Michael F. (West Chester, PA), Labaudiniere; Richard F.
(Sherborn, MA), Zhang; Litao (Churchville, PA),
Groneberg; Robert D. (Boulder, CO), McGarry; Daniel G.
(Branchburg, NJ), Caulfield; Thomas J. (Lebanon, NJ),
Minnich; Anne (Flemington, NJ), Bobko; Mark (Exton,
PA) |
Assignee: |
Sanofi-Aventis Deutschland GmbH
(Frankfurt am Main, DE)
|
Family
ID: |
22449544 |
Appl.
No.: |
11/254,215 |
Filed: |
October 20, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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PCT/US00/11833 |
Apr 28, 2000 |
|
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60131455 |
Apr 28, 1999 |
|
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Reissue of: |
09662649 |
Sep 14, 2000 |
06635655 |
Oct 21, 2003 |
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Current U.S.
Class: |
514/311; 514/362;
514/364; 514/365; 514/367; 514/372; 514/373; 514/374; 514/375;
514/378; 514/383; 514/396; 514/406; 514/410; 514/438; 514/439;
544/224; 544/283; 548/206; 548/215; 548/235; 548/240; 548/262.2;
548/304.4; 548/341.1; 548/452; 544/335; 544/336; 546/139; 546/152;
546/266; 548/128; 548/131; 548/136; 548/146; 514/363; 514/266.1;
514/256; 514/308; 514/247 |
Current CPC
Class: |
A61P
43/00 (20180101); C07C 233/11 (20130101); C07D
215/38 (20130101); C07D 409/12 (20130101); A61P
3/04 (20180101); C07C 323/12 (20130101); C07D
405/12 (20130101); C07C 235/06 (20130101); C07C
323/52 (20130101); C07C 235/34 (20130101); C07C
59/66 (20130101); C07C 311/51 (20130101); C07C
65/24 (20130101); A61P 9/02 (20180101); A61P
9/10 (20180101); C07D 217/04 (20130101); C07D
215/18 (20130101); C07D 333/28 (20130101); C07D
209/34 (20130101); A61P 9/00 (20180101); C07C
59/68 (20130101); C07D 215/233 (20130101); A61P
9/12 (20180101); C07D 215/12 (20130101); C07D
239/90 (20130101); A61P 5/48 (20180101); C07D
215/14 (20130101); C07D 213/643 (20130101); C07D
257/04 (20130101); C07D 263/32 (20130101); C07C
69/94 (20130101); C07D 307/81 (20130101); A61P
3/06 (20180101); C07D 209/18 (20130101); C07D
231/56 (20130101); C07D 403/12 (20130101); A61P
3/10 (20180101); C07D 241/44 (20130101); C07D
417/12 (20130101); A61P 3/00 (20180101); C07D
401/12 (20130101); C07D 215/60 (20130101) |
Current International
Class: |
C07D
215/14 (20060101); A61P 9/02 (20060101); A61K
31/421 (20060101); A61K 31/47 (20060101); A61P
3/04 (20060101); A61P 3/10 (20060101); C07D
263/32 (20060101) |
Field of
Search: |
;546/152 ;548/235
;514/311,374 |
References Cited
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|
Primary Examiner: Balasubram; Venkataraman
Attorney, Agent or Firm: Finnegan, Henderson, Farabow,
Garrett & Dunner, L.L.P.
Parent Case Text
This application .Iadd.is a Reissue of application Ser. No.
09/662,649, filed Sep. 14, 2000, now U.S. Pat. No. 6,635,655, which
.Iaddend.is .Iadd.a .Iaddend.continuation of international
application no. PCT/US00/11833, filed on Apr. 28, 2000, the
contents of which are incorporated by reference herein. This
application also claims the benefit of priority under 35 U.S.C.
.sctn.119(e) to U.S. Provisional Application No. 60/131,455, filed
on Apr. 28, 1999.
Claims
What is claimed is:
1. A compound of formula (I) ##STR00198## wherein: ##STR00199## is
oxazolyl or quinolinyl, which are optionally substituted by one or
more ring system substituents; ##STR00200## is phenyl, which is
optionally substituted by one or more ring system substituents, in
addition to being substituted by group Z; A is ##STR00201## .[.B
and E are a chemical bond;.]. a is 1; b is 0 or 1; .[.c is 0;.].
.[.d is 0;.]. g is 1-5; R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are,
independently, hydrogen, halogen or alkyl, wherein alkyl is
optionally substituted by one or more alkyl group substituents; Z
is R.sub.21O.sub.2C--, R.sub.21OC--, --CN, R.sub.21O.sub.2SHNCO--,
R.sub.21O.sub.2SHN--, (R.sub.21).sub.2NCO-- or R.sub.21O--;
R.sub.21 is independently hydrogen, alkyl, which is optionally
substituted by one or more alkyl group substituents, aryl, which is
optionally substituted by one or more ring system substituents,
cycloalkyl, which is optionally substituted by one or more ring
system substituents, or aralkyl, wherein the aryl portion is
optionally substituted by one or more ring system substituents and
the alkyl portion is optionally substituted by one or more alkyl
group substituents; R.sub.15, R.sub.16 are independently hydrogen,
alkyl, which is optionally substituted by one or more alkyl group
substituents, aralkyl, wherein the aryl portion is optionally
substituted by one or more ring system substituents and the alkyl
portion is optionally substituted by one or more alkyl group
substituents, or alkoxycarbonyl, wherein the alkyl portion is
optionally substituted by one or more alkyl group substituents; or
a pharmaceutically acceptable salt thereof, .Iadd.or .Iaddend.an
N-oxide thereof, .[.a hydrate thereof or a solvate thereof,.].
wherein alkyl is an aliphatic hydrocarbon group which is straight
or branched having 1 to about 20 carbon atoms; aryl is an aromatic
monocyclic or multicyclic ring system of about 6 to about 14 carbon
atoms; a ring system substituent is halo, unsubstituted lower alkyl
of 1 to about 4 carbon atoms, unsubstituted alkoxy, unsubstituted
aryloxy, unsubstituted aralkyloxy or unsubstituted
cycloalkylalkyloxy; and an alkyl group substituent is unsubstituted
acyl, carboxyl, unsubstituted carboxymethyl, unsubstituted
methoxycarbonylethyl, unsubstituted benzyloxycarbonylmethyl,
unsubstituted pyridylmethyloxycarbonylmethyl or unsubstituted
alkoxycarbonyl.
2. A compound according to claim 1 wherein .[.a=0;.]. R.sub.15 and
R.sub.16 are hydrogen; g is 1, 2, 3 or 4; and b=0.
3. A compound according to claim 1 wherein Z is
R.sub.21O.sub.2SHNCO--, and R.sub.21 is phenyl, wherein phenyl is
optionally substituted by one or more ring system substituents.
4. A compound according to claim 1 wherein Z is --CO.sub.2H or
--CN.
5. A compound according to claim 1 wherein ##STR00202## is
unsubstituted quinolin-2-yl, 3-substituted quinolin-2-yl,
4-substituted quinolin-2-yl, 6-substituted quinolin-2-yl or 7
substituted quinolin-2-yl; or 2-substituted-oxazol4-yl or 2,5
disubstituted-oxazol4-yl; 4-substituted oxazol-2-yl or
4,5-disubstituted-oxazol-2-yl; wherein an indicated substituent is
a ring system substituent.
6. A compound as claimed in claim 1, wherein the compound is
2-methyl-6-[3-(quinolin-2-ylmethoxy)-propoxymethyl]-benzoic
acid.
7. A compound as claimed in claim 1, which is of formula
##STR00203## wherein b=0; R.sub.1, R.sub.2, R.sub.3, R.sub.4 are
hydrogen R.sub.15, R.sub.16 are hydrogen; g=2, 3, 4 or 5; Z is
R.sub.21O.sub.2C--, R.sub.21OC--, or R.sub.21O--; R' is hydrogen,
halo, unsubstituted lower alkyl of 1 to about 4 carbon atoms,
unsubstituted alkoxy, unsubstituted aryloxy or unsubstituted
aralkyloxy; and R'' is hydrogen, halo, unsubstituted lower alkyl of
1 to about 4 carbon atoms, unsubstituted alkoxy, unsubstituted
aralkyloxy or unsubstituted cycloalkylalkyloxy, or a
pharmaceutically acceptable salt thereof, .Iadd.or .Iaddend.an
N-oxide thereof.[., a hydrate thereof or a solvate thereof.]. .
8. A compound according to claim 7, wherein Z is --CO.sub.2H.
9. A compound according to claim 7, wherein R' is hydrogen; and R''
is lower alkyl of 1 to about 4 carbon atoms.
10. A compound according to claim 7, wherein ##STR00204## is
2-substituted-oxazol-4-yl, wherein the substituent is a ring system
substituent.
11. A compound according to claim 1, wherein the compound is
##STR00205## ##STR00206##
12. A compound according to claim 1, wherein the compound is
##STR00207##
13. A compound .[.according to claim 1.]. , wherein the compound is
##STR00208##
14. A pharmaceutical composition comprising a pharmaceutically
acceptable amount of the compound according to claim 1 and a
pharmaceutically acceptable carrier.
.[.15. A method of treating a patient suffering from a
physiological disorder capable of being modulated by a compound
according to claim 1 having PPAR ligand binding activity,
comprising administering to the patient a pharmaceutically
effective amount of the compound wherein the disorder is associated
with a physiological detrimental blood level of insulin, glucose,
free fatty acids, or triglycerides..].
.[.16. A method of treating a patient suffering from a
physiological disorder capable of being modulated by a compound
according to claim 1 having PPAR ligand binding activity,
comprising administering to the patient a pharmaceutically
effective amount of the compound, wherein the physiological
disorder is hyperglycemia..].
.[.17. The method according to claim 16, wherein the hyperglycemia
is diabetes..].
18. .[.The method according to claim 16, wherein the hyperglycemia
is.]. .Iadd.A method of treating a patient suffering from a
physiological disorder capable of being modulated by a compound
according to claim 1 having PPAR ligand binding activity,
comprising administering to the patient a pharmaceutically
effective amount of the compound, wherein the disorder is
.Iaddend.Type II diabetes.
.[.19. A method of treating a patient suffering from a
physiological disorder capable of being modulated by a compound
according to claim 1 having PPAR ligand binding activity,
comprising administering to the patient a pharmaceutically
effective amount of the compound, wherein the physiological
disorder is hyperinsulinism..].
.[.20. A method of treating a patient suffering from a
physiological disorder capable of being modulated by a compound
according to claim 1 having PPAR ligand binding activity,
comprising administering to the patient a pharmaceutically
effective amount of the compound, wherein the physiological
disorder is insulin resistance..].
.[.21. A method of treating a patient suffering from a
physiological disorder capable of being modulated by a compound
according to claim 1 having PPAR ligand binding activity,
comprising administering to the patient a pharmaceutically
effective amount of the compound, wherein the physiological
disorder is a cardiovascular condition..].
.[.22. The method according to claim 21, wherein the cardiovascular
condition is atherosclerosis..].
.[.23. A method of treating a patient suffering from a
physiological disorder capable of being modulated by a compound
according to claim 1 having PPAR ligand binding activity,
comprising administering to the patient a pharmaceutically
effective amount of the compound, wherein the physiological
disorder is hyperlipidemia..].
24. A method of treating a patient suffering from a physiological
disorder capable of being modulated by a compound according to
claim 1 having PPAR ligand binding activity, comprising
administering to the patient a pharmaceutically effective amount of
the compound, wherein the physiological disorder is
hypertension.
25. A method of treating a patient suffering from a physiological
disorder capable of being modulated by a compound according to
claim 1 having PPAR ligand binding activity, comprising
administering to the patient a pharmaceutically effective amount of
the compound, wherein the physiological disorder is an eating
disorder.
.Iadd.26. A compound of formula (I) ##STR00209## wherein:
##STR00210## is a oxazolyl or quinolinyl, which are optionally
substituted by one or more substituents selected from phenyl
optionally substituted by one or more ring system substituents,
thienyl optionally substituted by one or more ring system
substituents, cycloalkyl optionally substituted by one or more ring
system substituents, lower alkyl optionally substituted by one or
more alkyl group substituents, branched alkyl optionally
substituted by one or more alkyl group substituents, fluoro,
chloro, alkoxy wherein the alkyl portion is optionally substituted
by one or more alkyl group substituents, aralkyloxy wherein the
aryl portion is optionally substituted with one or more ring system
substituents and the alkyl portion is optionally substituted with
one or more alkyl group substituents, trifluoromethyl, and
trifluoromethyloxy; ##STR00211## is phenyl, which is optionally
substituted by one or more ring system substituents, in addition to
being substituted by group Z; ##STR00212## a is 1; b is 0 or 1; g
is 1-5; R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are, independently,
hydrogen, halogen or alkyl, wherein alkyl is optionally substituted
by one or more alkyl group substituents; Z is R.sub.21O.sub.2C--,
R.sub.21OC--, --CN, R.sub.21O.sub.2SHNCO--, R.sub.21O.sub.2SHN--,
(R.sub.21).sub.2NCO-- or R.sub.21O--; R.sub.21 is independently
hydrogen, alkyl, which is optionally substituted by one or more
alkyl group substituents, aryl, which is optionally substituted by
one or more ring system substituents, cycloalkyl, which is
optionally substituted by one or more ring system substituents, or
aralkyl, wherein the aryl portion is optionally substituted by one
or more ring system substituents and the alkyl portion is
optionally substituted by one or more alkyl group substituents;
R.sub.15, R.sub.16 are independently hydrogen, alkyl, which is
optionally substituted by one or more alkyl group substituents,
aralkyl, wherein the aryl portion is optionally substituted by one
or more ring system substituents and the alkyl portion is
optionally substituted by one or more alkyl group substituents, or
alkoxycarbonyl, wherein the alkyl portion is optionally substituted
by one or more alkyl group substituents; or a pharmaceutically
acceptable salt thereof, or an N-oxide thereof, wherein alkyl is an
aliphatic hydrocarbon group which is straight or branched having 1
to about 20 carbon atoms; aryl is an aromatic monocyclic or
multicyclic ring system of about 6 to about 14 carbon atoms; a ring
system substituent is halo, unsubstituted lower alkyl of 1 to about
4 carbon atoms, unsubstituted alkoxy, unsubstituted aryloxy,
unsubstituted aralkyloxy or unsubstituted cycloalkylalkyloxy; and
an alkyl group substituent is unsubstituted acyl, carboxyl,
unsubstituted carboxymethyl, unsubstituted methoxycarbonylethyl,
unsubstituted benzyloxycarbonylmethyl, unsubstituted
pyridylmethyloxycarbonylmethyl or unsubstituted
alkoxycarbonyl..Iaddend.
.Iadd.27. A compound according to claim 26 wherein R.sub.15 and
R.sub.16 are hydrogen; and g is 1, 2, 3 or 4..Iaddend.
.Iadd.28. A compound according to claim 26 wherein Z is
R.sub.21O.sub.2SHNCO--, and R.sub.21 is phenyl, wherein phenyl is
optionally substituted by one or more ring system
substituents..Iaddend.
.Iadd.29. A compound according to claim 26 wherein Z is --CO.sub.2H
or --CN..Iaddend.
.Iadd.30. A compound according to claim 26 wherein ##STR00213## is
unsubstituted quinolin-2-yl, 3-substituted quinolin-2-yl,
4-substituted quinolin-2-yl, 6-substituted quinolin-2-yl or 7
substituted quinolin-2-yl; or 2-substituted-oxazol-4-yl or 2,5
disubstituted-oxazol-4-yl; 4-substituted oxazol-2-yl or
4,5-disubstituted-oxazol-2-yl; wherein an indicated substituent is
selected from phenyl optionally substituted by one or more ring
system substituents, thienyl optionally substituted by one or more
ring system substituents, cycloalkyl optionally substituted by one
or more ring system substituents, lower alkyl optionally
substituted by one or more alkyl group substituents, branched alkyl
optionally substituted by one or more alkyl group substituents,
fluoro, chloro, alkoxy wherein the alkyl portion is optionally
substituted by one or more alkyl group substituents, aralkyloxy
wherein the aryl portion is optionally substituted with one or more
ring system substituents and the alkyl portion is optionally
substituted with one or more alkyl group substituents,
trifluoromethyl and trifluoromethyloxy..Iaddend.
.Iadd.31. A compound as claimed in claim 26, which is of formula
##STR00214## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 are
hydrogen R.sub.15, R.sub.16 are hydrogen; g=2, 3, 4 or 5; Z is
R.sub.21O.sub.2C--, R.sub.21OC--, or R.sub.21O--; R' and R'' are
independently hydrogen or ring system substituents or a
pharmaceutically acceptable salt thereof, or an N-oxide
thereof..Iaddend.
.Iadd.32. A compound according to claim 31, wherein Z is
--CO.sub.2H..Iaddend.
.Iadd.33. A compound according to claim 31, wherein R' is hydrogen;
and R'' is lower alkyl of 1 to about 4 carbon atoms..Iaddend.
.Iadd.34. A compound according to claim 31, wherein ##STR00215## is
2-substituted-oxazol-4-yl, wherein the substituent is unsubstituted
phenyl..Iaddend.
.Iadd.35. A compound according to claim 26, wherein ##STR00216## is
oxazolyl, which is substituted by unsubstituted
phenyl..Iaddend.
.Iadd.36. A compound, wherein the compound is ##STR00217##
##STR00218## or a pharmaceutically acceptable salt thereof, or an
N-oxide thereof..Iaddend.
.Iadd.37. A compound according to claim 26, wherein the compound is
##STR00219## or a pharmaceutically acceptable salt thereof, or an
N-oxide thereof..Iaddend.
.Iadd.38. A compound, wherein the compound is ##STR00220## or a
pharmaceutically acceptable salt thereof, or an N-oxide
thereof..Iaddend.
.Iadd.39. A pharmaceutical composition comprising a
pharmaceutically acceptable amount of the compound according to
claim 26 and a pharmaceutically acceptable carrier..Iaddend.
.Iadd.40. A method of treating a patient suffering from a
physiological disorder capable of being modulated by a compound
according to claim 26 having PPAR ligand binding activity,
comprising administering to the patient a pharmaceutically
effective amount of the compound, wherein the disorder is Type II
diabetes..Iaddend.
.Iadd.41. A method of treating a patient suffering from a
physiological disorder capable of being modulated by a compound
according to claim 26 having PPAR ligand binding activity,
comprising administering to the patient a pharmaceutically
effective amount of the compound, wherein the physiological
disorder is hypertension..Iaddend.
.Iadd.42. A method of treating a patient suffering from a
physiological disorder capable of being modulated by a compound
according to claim 26 having PPAR ligand binding activity,
comprising administering to the patient a pharmaceutically
effective amount of the compound, wherein the physiological
disorder is an eating disorder..Iaddend.
Description
BACKGROUND OF THE INVENTION
This invention is directed to the use of diaryl acid derivatives
and their pharmaceutical compositions as PPAR ligand receptor
binders. The PPAR ligand receptor binders of this invention are
useful as agonists or antagonists of the PPAR receptor.
FIELD OF THE INVENTION
Peroxisome proliferator-activated receptors (PPAR) can be
subdivided into three subtypes, namely: PPAR.alpha., PPAR.delta.,
and PPAR.gamma.. These are encoded by different genes (Motojima,
Cell Structure and Function, 18:267-277, 1993). Moreover, 2
isoforms of PPAR.gamma. also exist, PPAR.gamma..sub.1 and
.gamma..sub.2. These 2 proteins differ in their
NH.sub.2-terminal-30 amino acids and are the result of alternative
promoter usage and differential mRNA splicing (Vidal-Puig, Jimenez,
Linan, Lowell, Hamann, Hu, Spiegelman, Flier, Moller, J. Clin.
Invest., 97:2553-2561, 1996).
Biological processes modulated by PPAR are those modulated by
receptors, or receptor combinations, which are responsive to the
PPAR receptor ligands described herein. These processes include,
for example, plasma lipid transport and fatty acid catabolism,
regulation of insulin sensitivity and blood glucose levels, which
are involved in hypoglycemia/hyperinsulinism (resulting from, for
example, abnormal pancreatic beta cell function, insulin secreting
tumors and/or autoimmune hypoglycemia due to autoantibodies to
insulin, the insulin receptor, or autoantibodies that are
stimulatory to pancreatic beta cells), macrophage differentiation
which lead to the formation of atherosclerotic plaques,
inflammatory response, carcinogenesis, hyperplasia, adipocyte
differentiation.
Obesity is an excessive accumulation of adipose tissue. Recent work
in this area indicates that PPAR.gamma. plays a central role in the
adipocyte gene expression and differentiation. Excess adipose
tissue is associated with the development of serious medical
conditions, for example, non-insulin-dependent diabetes mellitus
(NIDDM), hypertension, coronary artery disease, hyperlipidemia
obesity and certain malignancies. The adipocyte may also influence
glucose homeostasis through the production of tumor necrosis factor
.alpha. (TNF.alpha.) and other molecules.
Non-insulin-dependent diabetes mellitus (NIDDM), or Type II
diabetes, is the more common form of diabetes, with 90-95% of
hyperglycemic patients experiencing this form of the disease. In
NIDDM there appears to be a reduction in the pancreatic .beta.-cell
mass, several distinct defects in insulin secretion or a decrease
in tissue sensitivity to insulin. The symptoms of this form of
diabetes include fatigue, frequent urination, thirst, blurred
vision, frequent infections and slow healing of sores, diabetic
nerve damage and renal disease.
Resistance to the metabolic actions of insulin is one of the key
features of non-insulin dependent diabetes (NIDDM). Insulin
resistance is characterised by impaired uptake and utilization of
glucose in insulin-sensitive target organs, for example, adipocytes
and skeletal muscle, and by impaired inhibition of hepatic glucose
output. The functional insulin deficiency and the failure of
insulin to supress hepatic glucose output results in fasting
hyperglycemia. Pancreatic .beta.-cells compensate for the insulin
resistance by secreting increased levels of insulin. However, the
.beta.-cells are unable to maintain this high output of insulin,
and, eventually, the glucose-induced insulin secretion falls,
leading to the deterioration of glucose homeostasis and to the
subsequent development of overt diabetes.
Hyperinsulinemia is also linked to insulin resistance,
hypertriglyceridaemia and increased plasma concentration of low
density lipoproteins. The association of insulin resistance and
hyperinsulinemia with these metabolic disorders has been termed
"Syndrome X" and has been strongly linked to an increased risk of
hypertension and coronary artery disease.
Metformin is known in the art to be used in the treatment of
diabetes in humans (U.S. Pat. No. 3,174,901). Metformin acts
primarily to decrease liver glucose production. Troglitazone.RTM.
is known to work primarily on enhancing the ability of skeletal
muscle to respond to insulin and take up glucose. It is known that
combination therapy comprising metformin and troglitazone can be
used in the treatment of abnormalities associated with diabetes
(DDT 3:79-88, 1998).
PPAR .gamma. activators, in particular Troglitazone.RTM., have been
found to convert cancerous tissue to normal cells in liposarcoma, a
tumor of fat (PNAS 96:3951-3956, 1999). Furthermore, it has been
suggested that PPAR .gamma. activators may be useful in the
treatment of breast and colon cancer (PNAS) 95:8806-8811, 1998,
Nature Medicine 4:1046-1052, 1998).
Moreover, PPAR.gamma. activators, for example Troglitazone.RTM.,
have been implicated in the treatment of polycystic ovary syndrome
(PCO). This is a syndrome in women that is characterized by chronic
anovulation and hyperandrogenism. Women with this syndrome often
have insulin resistance and an increased risk for the development
of noninsulin-dependent diabetes mellitus. (Dunaif, Scott,
Finegood, Quintana, Whitcomb, J. Clin. Endocrinol. Metab., 81:3299,
1996.
Furthermore, PPAR.gamma. activators have recently been discovered
to increase the production of progesterone and inhibit
steroidogenesis in granulosa cell cultures and therefore may be
useful in the treatment of climacteric. (U.S. Pat. No. 5,814,647
Urban et al. Sep. 29, 1998; B. Lohrke et al. Journal of
Endocrinology, 159, 429-39, 1998). Climacteric is defined as the
syndrome of endocrine, somatic and psychological changes occurring
at the termination of the reproductive period in the female.
Peroxisomes are cellular organelles which play a role in
controlling the redox potential and oxidative stress of cells by
metabolizing a variety of substrates such as hydrogen peroxide.
There are a number of disorders associated with oxidative stress.
For example, inflammatory response to tissue injury, pathogenesis
of emphysema, ischemia-associated organ injury (shock),
doxorubicin-induced cardiac injury, drug-induced hepatotoxicity,
atherosclerosis, and hyperoxic lung injuries, are each associated
with the production of reactive oxygen species and a change in the
reductive capacity of the cell. Therefore, it is envisaged that
PPAR.alpha. activators, among other things, regulate the redox
potential and oxidative stress in cells, would be effective in the
treatment of these disorders (Poynter et al, J. Biol. Chem. 273,
32833-41, 1998).
It has also been discovered that PPAR.alpha. agonists inhibit
NF.kappa.B-mediated transcription thereby modulating various
inflammatory responses such as the inducible nitric oxide synthase
(NOS) and cyclooxygenase-2 (COX-2) enzyme pathways (Pineda-Torra,
I. T al, 1999, Curr. Opinion in Lipidology, 10,151-9) and thus can
be used in the therapeutic intervention of a wide variety of
inflammatory diseases and other pathologies (Colville-Nash, et al.,
Journal of Immunology, 161, 978-84, 1998; Staels et al, Nature,
393, 790-3, 1998).
Peroxisome proliferators activate PPAR, which in turn, acts as a
transcription factor, and causes differentiation, cell growth and
proliferation of peroxisomes. PPAR activators are also thought to
play a role in hyperplasia and carcinogenesis as well as altering
the enzymatic capability of animal cells, such as rodent cells, but
these PPAR activators appear to have minimal negative effects in
human cells (Green, Biochem. Pharm. 43(3):393, 1992). Activation of
PPAR results in the rapid increase of gamma glutamyl transpeptidase
and catalase.
PPAR.alpha. is activated by a number of medium and long-chain fatty
acids and is involved in stimulating .beta.-oxidation of fatty
acids in tissues such as liver, heart, skeletal muscle, and brown
adipose tissue (Isseman and Green, supra; Beck et al., Proc. R.
Soc. Lond. 247:83-87, 1992; Gottlicher et al., Proc. Natl. Acad.
Sci. USA 89:4653-4657, 1992). Pharmacological PPAR.alpha.
activators, for example fenofibrate, clofibrate, genfibrozil, and
bezafibrate, are also involved in substantial reduction in plasma
triglycerides along with moderate reduction in LDL cholesterol, and
they are used particularly for the treatment of
hypertriglyceridemia, hyperlipidemia and obesity. PPAR.alpha. is
also known to be involved in inflammatory disorders. (Schoonjans,
K., Current Opionion in Lipidology, 8, 159-66, 1997).
The human nuclear receptor PPAR.delta. has been cloned from a human
osteosarcoma cell cDNA library and is fully described in A. Schmidt
et al., Molecular Endocrinology, 6:1634-1641 (1992), the contents
of which are hereby incorporated herein by reference. It should be
noted that PPAR.delta. is also referred to in the literature as
PPAR.beta. and as NUC1, and each of these names refers to the same
receptor. For example, in A. Schmidt et al., Molecular
Endocrinology, 6: pp. 1634-1641, 1992, the receptor is referred to
as NUC1. PPAR.delta. is observed in both embryo and adult tissues.
This receptor has been reported to be involved in regulating the
expression of some fat-specific genes, and plays a role in the
adipogenic process (Amri, E. et al., J. Biol. Chem. 270, 2367-71,
1995).
Atherosclerotic disease is known to be caused by a number of
factors, for example, hypertension, diabetes, low levels of high
density lipoprotein (HDL), and high levels of low density
lipoprotein (LDL). In addition to risk reduction via effects on
plasma lipid concentrations and other risk factors, PPAR.alpha.
agonists exert direct atheroprotective effects (Frick, M. H.,et al.
1997.. Circulation 96:2137-2143, de Faire, et al. 1997. Cardiovasc.
Drugs Ther. 11 Suppl 1:257-63:257-263).
It has recently been discovered that PPAR.delta. agonists are
useful in raising HDL levels and therefore useful in treating
atherosclerotic diseases. (Leibowitz et al.; WO/9728149).
Atherosclerotic diseases include vascular disease, coronary heart
disease, cerebrovascular disease and peripheral vessel disease.
Coronary heart disease includes CHD death, myocardial infarction,
and coronary revascularization. Cerebrovascular disease includes
ischemic or hemorrhagic stroke and transient ischemic attacks.
PPAR.gamma. subtypes are involved in activating adipocyte
differentiation, and are not involved in stimulating peroxisome
proliferation in the liver. Activation of PPAR.gamma. is implicated
in adipocyte differentiation through the activation of
adipocyte-specific gene expression (Lehmann, Moore, Smith-Oliver,
Wilkison, Willson, Kliewer, J. Biol. Chem., 270:12953-12956, 1995).
The DNA sequences for the PPAR.gamma. receptors are described in
Elbrecht et al., BBRC 224;431-437 (1996). Although peroxisome
proliferators, including fibrates and fatty acids, activate the
transcriptional activity of PPAR's, only prostaglandin J.sub.2
derivatives such as the arachidonic acid metabolite
15-deoxy-delta.sup.12, 14-prostaglandin J.sub.2 (15d-PGJ.sub.2)
have been identified as natural ligands specific for the
PPAR.gamma. subtype, which also binds thiazolidinediones. This
prostaglandin activates PPAR.gamma.-dependent adipogenesis, but
activates PPAR.alpha. only at high concentrations (Forman,
Tontonoz, Chen, Brun, Spiegelman, Evans, Cell, 83:803-812, 1995;
Kliewer, Lenhard, Wilson, Patel, Morris, Lehman, Cell, 83:813-819,
1995). This is further evidence that the PPAR family sub-types are
distinct from one another in their pharmacological response to
ligands.
It has been suggested that compounds activating both PPAR.alpha.
and PPAR.gamma. should be potent hypotriglyceridemic drugs, which
could be used in the treatment of dyslipidemia associated with
atherosclerosis, non-insulin dependent diabetes mellitus,Syndrome
X,. (Staels, B. et al., Curr. Pharm. Des., 3 (1), 1-14 (1997)) and
familial combined hyperlipidemia (FCH). Syndrome X is the syndrome
characterized by an initial insulin resistant state, generating
hyperinsulinaemia, dyslipidaemia and impaired glucose tolerance,
which can progress to non-insulin dependent diabetes mellitus (Type
II diabetes), characterized by hyperglycemia. FCH is characterized
by hypercholesterolemia and hypertriglyceridemia within the same
patient and family.
The present invention is directed to a series of compounds that are
useful in modulating PPAR receptors, as well as to a number of
other pharmaceutical uses associated therewith.
SUMMARY OF THE INVENTION
This invention provides new aromatic compounds and pharmaceutical
compositions prepared therewith that are PPAR ligand receptor
binders, and which are useful as agonists or antagonists of the
PPAR receptors. The invention also includes the discovery of new
uses for previously known compounds.
The compounds for use according to the invention, including the new
compounds of the present invention, are of formula I ##STR00002##
are independently aryl, fused arylcycloalkenyl, fused
arylcycloalkyl, fused arylheterocyclenyl, fused arylheterocyclyl,
heteroaryl, fused heteroarylcycloalkenyl, fused
heteroarylcycloalkyl, fused heteroarylheterocyclenyl, or fused
heteroarylheterocyclyl; A is --O--, --S--, --SO--, --SO.sub.2--,
--NR.sub.13--, --C(O)--, --N(R.sub.14)C(O)--, --C(O)N(R.sub.15)--,
--N(R.sub.14)C(O)N(R.sub.15)--, --C(R.sub.14).dbd.N--, ##STR00003##
B is --O--, --S--, --NR.sub.9--, a chemical bond, --C(O)--,
--N(R.sub.20)C(O)--, or --C(O)N(R.sub.20)--; E is a chemical bond
or an ethylene group; a is 0-6; b is 0-4; c is 0-4; d is 0-6; g is
1-5; h is 1-4; R.sub.1, R.sub.3, R.sub.5 and R.sub.7, are
independently hydrogen, halogen, alkyl, carboxyl, alkoxycarbonyl or
aralkyl; R.sub.2, R.sub.4, R.sub.6 and R.sub.8, are independently
--(CH.sub.2).sub.q--X; q is 0-3; X is hydrogen, halogen, alkyl,
alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl,
heteroaralkyl, hydroxy, alkoxy, aralkoxy, heteroaralkoxy, carboxyl,
alkoxycarbonyl, tetrazolyl, acyl, acylHNSO.sub.2--, --SR.sub.23,
Y.sup.1Y.sup.2N-- or Y.sup.3Y.sup.4NCO--; Y.sup.1 and Y.sup.2 are
independently hydrogen, alkyl, aryl, aralkyl or heteroaralkyl, or
one of Y.sup.1 and Y.sup.2 is hydrogen or alkyl and the other of
Y.sup.1 and Y.sup.2 is acyl or aroyl; Y.sup.3 and Y.sup.4 are
independently hydrogen, alkyl, aryl, aralkyl or heteroaralkyl; Z is
R.sub.21O.sub.2C--, R.sub.21OC--, cyclo-imide, --CN,
R.sub.21O.sub.2SHNCO--, R.sub.21O.sub.2SHN--,
(R.sub.21).sub.2NCO--, R.sub.21O--2,4-thiazolidinedionyl, or
tetrazolyl; and R.sub.19 and R.sub.21 are independently hydrogen,
alkyl, aryl, cycloalkyl, or aralkyl; R.sub.13, R.sub.17, R.sub.19
and R.sub.23 are independently R.sub.22OC--, R.sub.22NHOC--,
hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl,
heteoaralkyl, or aralkyl; R.sub.14, R.sub.15, R.sub.16, R.sub.18
and R.sub.20 are independently hydrogen, alkyl, aralkyl, carbonyl,
or alkoxycarbonyl; or R.sub.14, and R.sub.15 taken together with
the carbon and nitrogen atoms through which they are liked form a 5
or 6-membered azaheterocyclyl group; or when a is 2-6, then at
least one pair of vicinal R.sub.1 radicals taken together with the
carbon atoms to which the R.sub.1 radicals are linked form a
##STR00004## group; or when b is 2-4, then at least one pair of
vicinal R.sub.3 radicals taken together with the carbon atoms to
which the R.sub.3 radicals are linked form a ##STR00005## group; or
when c is 2-4, then at least one pair of vicinal R.sub.5 radicals
taken together with the carbon atoms to which the R.sub.5 radicals
are linked form a ##STR00006## group; or when d is 2-6, then at
least one pair of vicinal R.sub.7 radicals taken together with the
carbon atoms to which the R.sub.7 radicals are linked form a
##STR00007## group, or a 5-membered cycloalkyl group; or when d is
2-6, then at least one pair of non-vicinal R.sub.7 radicals taken
together with the carbon atoms to which the R.sub.7 radicals are
linked form a 5-membered cycloalkyl group; or germinal R.sub.5 and
R.sub.6 radicals taken together with the carbon atom through which
these radicals are linked form a 5 membered cycloalkyl group; or
geminal R.sub.7 and R.sub.8 radicals taken together with the carbon
atom through which these radicals are linked form a 5 membered
cycloalkyl group; and R.sub.22 is hydrogen, alkyl, aryl,
heteroaryl, cycloalkyl, heterocyclyl, heteroarylkyl, or aralkyl; or
a pharmaceutically acceptable salt thereof, an N-oxide thereof, a
hydrate thereof or a solvate thereof.
DETAILED DESCRIPTION OF THE INVENTION
As employed above and throughout the disclosure, the following
terms, unless otherwise indicated, shall be understood to have the
following meanings:
Definitions
In the present specification, the term "compounds for use according
to the invention", and equivalent expressions, are meant to embrace
compounds of general Formula (I) as hereinbefore described, which
expression includes the prodrugs, the pharmaceutically acceptable
salts, and the solvates, e.g. hydrates, where the context so
permits. Similarly, reference to intermediates, whether or not they
themselves are claimed, is meant to embrace their salts, and
solvates, where the context so permits. For the sake of clarity,
particular instances when the context so permits are sometimes
indicated in the text, but these instances are purely illustrative
and it is not intended to exclude other instances when the context
so permits.
"Prodrug" means a compound which is convertible in vivo by
metabolic means (e.g. by hydrolysis) to a compound of Formula (I),
including N-oxides thereof. For example an ester of a compound of
Formula (I) containing a hydroxy group may be convertible by
hydrolysis in vivo to the parent molecule. Alternatively an ester
of a compound of Formula (I) containing a carboxy group may be
convertible by hydrolysis in vivo to the parent molecule.
"Patient" includes both human and other mammals.
In the present invention, the moiety ##STR00008## encompasses both
the syn and anti configurations.
"Chemical bond" means a direct single bond between atoms.
"Acyl" means an H--CO-- or alkyl-CO-- group wherein the alkyl group
is as herein described. Preferred acyls contain a lower alkyl.
Exemplary acyl groups include formyl, acetyl, propanoyl,
2-methylpropanoyl, butanoyl and palmitoyl.
"Alkenyl" means an aliphatic hydrocarbon group containing a
carbon-carbon double bond and which may be a straight or branched
chain having about 2 to about 15 carbon atoms in the chain.
Preferred alkenyl groups have 2 to about 12 carbon atoms in the
chain and more preferably about 2 to about 4 carbon atoms in the
chain. Branched means that one or more lower alkyl groups such as
methyl, ethyl or propyl are attached to a linear alkenyl chain.
"Lower alkenyl" means about 2 to about 4 carbon atoms in the chain,
which may be straight or branched. The alkenyl group is optionally
substituted by one or more halo groups. Exemplary alkenyl groups
include ethenyl, propenyl, n-butenyl, i-butenyl,
3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl and decenyl.
"Alkoxy" means an alkyl-O-- group wherein the alkyl group is as
herein described. Exemplary alkoxy groups include methoxy, ethoxy,
n-propoxy, i-propoxy, n-butoxy and heptoxy.
"Alkoxycarbonyl" means an alkyl-O--CO-- group, wherein the alkyl
group is as herein defined. Exemplary alkoxycarbonyl groups include
methoxycarbonyl, ethoxycarbonyl, or t-butyloxycarbonyl.
"Alkyl" means an aliphatic hydrocarbon group which may be straight
or branched having about 1 to about 20 carbon atoms in the chain.
Preferred alkyl groups have 1 to about 13 carbon atoms in the
chain. Branched means that one or more lower alkyl groups such as
methyl, ethyl or propyl are attached to a linear alkyl chain.
"Lower alkyl" means about 1 to about 4 carbon atoms in the chain,
which may be straight or branched. The alkyl is optionally
substituted with one or more "alkyl group substituents" which may
be the same or different, and include halo, carboxy, cycloalkyl,
cycloalkenyl, heterocyclyl, heterocyclenyl, aryl, alkoxy,
alkoxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl,
Y.sup.1Y.sup.2NCO--, wherein Y.sup.1 and Y.sup.2 are independently
hydrogen, alkyl, aryl, aralkyl or heteroaralkyl, or Y.sup.1 and
Y.sup.2 taken together with the nitrogen atom to which Y.sup.1 and
Y.sup.2 are attached form heterocyclyl. Exemplary alkyl groups
include methyl, trifluoromethyl, ethyl, n-propyl, i-propyl,
n-butyl, t-butyl, n-pentyl, and 3-pentyl. Preferably, the alkyl
group substituent is selected from acyl, carboxy, carboxymethyl,
methoxycarbonylethyl, benzyloxycarbonylmethyl, and
pyridylmethyloxycarbonylmethyl and alkoxycarbonyl.
"Alkylsulfinyl" means an alkyl-SO-- group wherein the alkyl group
is as defined above. Preferred groups are those wherein the alkyl
group is lower alkyl.
"Alkylsulfonyl" means an alkyl-SO.sub.2-- group wherein the alkyl
group is as defined above. Preferred groups are those wherein the
alkyl group is lower alkyl.
"Alkylthio" means an alkyl-S-- group wherein the alkyl group is as
defined above. Exemplary alkylthio groups include methylthio,
ethylthio, i-propylthio and heptylthio.
"Aralkoxy" means an aralkyl-O-- group wherein the aralkyl group is
as defined herein. Exemplary aralkoxy groups include benzyloxy and
1- and 2-naphthalenemethoxy.
"Aralkoxycarbonyl" means an aralkyl-O--CO-- group wherein the
aralkyl group is as defined herein. An exemplary aralkoxycarbonyl
group is benzyloxycarbonyl.
"Aralkyl" means an aryl-alkyl- group wherein the aryl and alkyl
groups are as defined herein. Preferred aralkyls contain a lower
alkyl moiety. Exemplary aralkyl groups include benzyl, 2-phenethyl
and naphthalenemethyl.
"Aralkylsulfonyl" means an aralkyl-SO.sub.2-- group wherein the
aralkyl group is as defined herein.
"Aralkylsulfinyl" means an aralkyl-SO-- group wherein the aralkyl
group is as defined herein.
"Aralkylthio" means an aralkyl-S-- group wherein the aralkyl group
is as defined herein. An exemplary aralkylthio group is
benzylthio.
"Aroyl" means an aryl-CO-- group wherein the aryl group is as
defined herein. Exemplary aroyl groups include benzoyl and 1- and
2-naphthoyl.
"Aryl" means an aromatic monocyclic or multicyclic ring system of
about 6 to about 14 carbon atoms, preferably of about 6 to about 10
carbon atoms. The aryl is optionally substituted with one or more
"ring system substituents" which may be the same or different, and
are as defined herein. Exemplary aryl groups include phenyl,
naphthyl, substituted phenyl, and substituted naphthyl.
"Aryldiazo" means an aryl-diazo- group wherein the aryl and diazo
groups are as defined herein.
"Fused arylcycloalkenyl" means a fused aryl and cycloalkenyl as
defined herein. Preferred fused arylcycloalkenyls are those wherein
the aryl thereof is phenyl and the cycloalkenyl consists of about 5
to about 6 ring atoms. A fused arylcycloalkenyl group may be bonded
to the rest of the compound through any atom of the fused system
capable of such bondage. The fused arylcycloalkenyl may be
optionally substituted by one or more ring system substituents,
wherein the "ring system substituent" is as defined herein.
Exemplary fused arylcycloalkenyl groups include
1,2-dihydronaphthylenyl; indenyl; 1,4-naphthoquinonyl, and the
like.
"Fused arylcycloalkyl" means a fused aryl and cycloalkyl as defined
herein. Preferred fused arylcycloalkyls are those wherein the aryl
thereof is phenyl and the cycloalkyl consists of about 5 to about 6
ring atoms. A fused arylcycloalkyl group may be bonded to the rest
of the compound through any atom of the fused system capable of
such bonding. The fused arylcycloalkyl may be optionally
substituted by one or more ring system substituents, wherein the
"ring system substituent" is as defined herein. Exemplary fused
arylcycloalkyl groups include 1,2,3,4-tetrahydronaphthylenyl;
1,4-dimethyl-2,3-dihydronaphthalenyl;
2,3-dihydro-1,4-naphthoquinonyl, .alpha.-tetralonyl, and the
like.
"Fused arylheterocyclenyl" means a fused aryl and heterocylenyl
wherein the aryl and heterocyclenyl groups are as defined herein.
Preferred fused arylheterocyclenyl groups are those wherein the
aryl thereof is phenyl and the heterocyclenyl consists of about 5
to about 6 ring atoms. A fused arylheterocyclenyl group may be
bonded to the rest of the compound through any atom of the fused
system capable of such bonding. The designation of aza, oxa or thia
as a prefix before the heterocyclenyl portion of the fused
arylheterocyclenyl means that a nitrogen, oxygen or sulfur atom
respectively, is present as a ring atom. The fused
arylheterocyclenyl may be optionally substituted by one or more
ring system substituents, wherein the "ring system substituent" is
as defined herein. The nitrogen atom of a fused arylheterocyclenyl
may be a basic nitrogen atom. The nitrogen or sulphur atom of the
heterocyclenyl portion of the fused arylheterocyclenyl is also
optionally oxidized to the corresponding N-oxide, S-oxide or
S,S-dioxide. Exemplary fused arylheterocyclenyl include
3H-indolinyl, 2(1H)quinolinonyl, 2H-1-oxoisoquinolyl,
1,2-dihydroquinolinyl, (2H)quinolinyl N-oxide,
3,4-dihydroquinolinyl, 1,2-dihydroisoquinolinyl,
3,4-dihydroisoquinolinyl, chromonyl, 3,4-dihydroisoquinoxalinyl,
4-(3H)quinazolinonyl, 4H-chromen-2yl, and the like. Preferably,
2(1H)quinolinonyl, 1,2-dihydroquinolinyl, (2H)quinolinyl N-oxide,
or 4-(3H)quinazolinonyl.
"Fused arylheterocyclyl" means a fused aryl and heterocyclyl
wherein the aryl and heterocyclyl groups are as defined herein.
Preferred fused arylheterocyclyls are those wherein the aryl
thereof is phenyl and the heterocyclyl consists of about 5 to about
6 ring atoms. A fused arylheterocyclyl may be bonded to the rest of
the compound through any atom of the fused system capable of such
bonding. The designation of aza, oxa or thia as a prefix before the
heterocyclyl portion of the fused arylheterocyclyl means that a
nitrogen, oxygen or sulphur atom respectively is present as a ring
atom. The fused arylheterocyclyl group may be optionally
substituted by one or more ring system substituents, wherein the
"ring system substituent" is as defined herein. The nitrogen atom
of a fused arylheterocyclyl may be a basic nitrogen atom. The
nitrogen or sulphur atom of the heterocyclyl portion of the fused
arylheterocyclyl is also optionally oxidized to the corresponding
N-oxide, S-oxide or S,S-dioxide. Exemplary fused arylheterocyclyl
ring systems include indolinyl, 1,2,3,4-tetrahydroisoquinolinyl,
1,2,3,4-tetrahydroquinolinyl, 1H-2,3-dihydroisoindol-2-yl,
2,3-dihydrobenz[f]isoindol-2-yl,
1,2,3,4-tetrahydrobenz[g]isoquinolin-2-yl, chromanyl,
isochromanonyl, 2,3-dihydrochromonyl, 1,4-benzodioxan,
1,2,3,4-tetrahydroquinoxalinyl, and the like. Preferably,
1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinoxalinyl,
and 1,2,3,4-tetrahydroquinolinyl.
"Aryloxy" means an aryl-O-- group wherein the aryl group is as
defined herein. Exemplary groups include phenoxy and
2-naphthyloxy.
"Aryloxycarbonyl" means an aryl-O--CO-- group wherein the aryl
group is as defined herein. Exemplary aryloxycarbonyl groups
include phenoxycarbonyl and naphthoxycarbonyl.
"Arylsulfonyl" means an aryl-SO.sub.2-- group wherein the aryl
group is as defined herein.
"Arylsulfinyl" means an aryl-SO-- group wherein the aryl group is
as defined herein.
"Arylthio" means an aryl-S-- group wherein the aryl group is as
defined herein. Exemplary arylthio groups include phenylthio and
naphthylthio.
"Carbamoyl" is an NH.sub.2--CO-- group.
"Carboxy" means a HO(O)C-- (carboxylic acid) group.
"Compounds of the invention," and equivalent expressions, are meant
to embrace compounds of general Formula (I) as hereinbefore
described, which expression includes the prodrugs, the
pharmaceutically acceptable salts, and the solvates, e.g. hydrates,
where the context so permits. Similarly, reference to
intermediates, whether or not they themselves are claimed, is meant
to embrace their salts, and solvates, where the context so permits.
For the sake of clarity, particular instances when the context so
permits are sometimes indicated in the text, but these instances
are purely illustrative and it is not intended to exclude other
instances when the context so permits.
"Cycloalkoxy" means an cycloalkyl-O-- group wherein the cycloalkyl
group is as defined herein. Exemplary cycloalkoxy groups include
cyclopentyloxy and cyclohexyloxy.
"Cycloalkyl-alkoxy" means an cycloalkyl-alkylene-O-- group wherein
the cycloalkyl group and alkylene group are as defined herein.
Exemplary cycloalkyl-alkoxy groups include cyclopentylmethylene-oxy
and cyclohexylmethylene-oxy.
"Cycloalkenyl" means a non-aromatic mono- or multicyclic ring
system of about 3 to about 10 carbon atoms, preferably of about 5
to about 10 carbon atoms, and which contains at least one
carbon-carbon double bond. Preferred ring sizes of rings of the
ring system include about 5 to about 6 ring atoms. The cycloalkenyl
is optionally substituted with one or more "ring system
substituents" which may be the same or different, and are as
defined herein. Exemplary monocyclic cycloalkenyl include
cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. An
exemplary multicyclic cycloalkenyl is norbornylenyl.
"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system
of about 3 to about 10 carbon atoms, preferably of about 5 to about
10 carbon atoms. Preferred ring sizes of rings of the ring system
include about 5 to about 6 ring atoms. The cycloalkyl is optionally
substituted with one or more "ring system substituents" which may
be the same or different, and are as defined herein. Exemplary
monocyclic cycloalkyl include cyclopentyl, cyclohexyl, cycloheptyl,
and the like. Exemplary multicyclic cycloalkyl include 1-decalin,
norbornyl, adamant-(1- or 2-)yl, and the like.
"Cycloalkylene" means a bivalent, saturated carbocyclic group
having about 3 to about 6 carbon atoms. Preferred cycloalkylene
groups include 1,1-, 1,2-, 1,3-, and 1,4-cis or
trans-cyclohexylene, and 1,1-, 1,2-, and 1,3-cyclopentylene.
"Cyclo-imide" means a compound of formulae ##STR00009## The
cyclo-imide moiety may be attached to the parent molecule through
either a carbon atom or nitrogen atom of the carbamoyl moiety. An
exemplary imide group is N-phthalimide.
"Diazo" means a bivalent --N.dbd.N-- radical.
"Halo" means fluoro, chloro, bromo, or iodo. Preferred are fluoro,
chloro and bromo, more preferably fluoro and chloro.
"Halo" means fluoro, chloro, bromo, or iodo. Preferred are fluoro,
chloro and bromo, more preferably fluoro and chloro.
"Heteroaralkyl" means a heteroaryl-alkyl- group wherein the
heteroaryl and alkyl groups are as defined herein. Preferred
heteroaralkyls contain a lower alkyl moiety. Exemplary
heteroaralkyl groups include thienylmethyl, pyridylmethyl,
imidazolylmethyl and pyrazinylmethyl.
"Heteroaralkylthio" means a heteroaralkyl-S-- group wherein the
heteroaralkyl group is as defined herein. An exemplary
heteroaralkylthio group is 3-pyridinepropanthiol.
"Heteroaralkoxy" means an heteroaralkyl-O-- group wherein the
heteroaralkyl group is as defined herein. An exemplary
heteroaralkoxy group is 4-pyridylmethyloxy.
"Heteroaroyl" means an means an heteroaryl-CO-- group wherein the
heteroaryl group is as defined herein. Exemplary heteroaryl groups
include thiophenoyl, nicotinoyl, pyrrol-2-ylcarbonyl and 1- and
2-naphthoyl and pyridinoyl.
"Heteroaryldiazo" means an heteroaryl-diazo- group wherein the
heteroaryl and diazo groups are as defined herein.
"Heteroaryl" means an aromatic monocyclic or multicyclic ring
system of about 5 to about 14 carbon atoms, preferably about 5 to
about 10 carbon atoms, in which at least one of the carbon atoms in
the ring system is replaced by a hetero atom, i.e., other than
carbon, for example nitrogen, oxygen or sulfur. Preferred ring
sizes of rings of the ring system include about 5 to about 6 ring
atoms. The heteroaryl ring is optionally substituted by one or more
"ring system substituents" which may be the same or different, and
are as defined herein. The designation of aza, oxa or thia as a
prefix before the heteroaryl means that a nitrogen, oxygen or
sulfur atom is present, respectively, as a ring atom. A nitrogen
atom of an heteroaryl may be a basic nitrogen atom and also may be
optionally oxidized to the corresponding N-oxide. Exemplary
heteroaryl and substituted heteroaryl groups include pyrazinyl,
thienyl, isothiazolyl, oxazolyl, pyrazolyl, cinnolinyl, pteridinyl,
benzofuryl, furazanyl, pyrrolyl, 1,2,4-thiadiazolyl, pyridazinyl,
indazolyl, quinoxalinyl, phthalazinyl, imidazo [1,2-a]pyridine,
imidazo[2,1-b]thiazolyl, benzofurazanyl, azaindolyl,
benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidyl,
pyrrolopyridyl, imidazopyridyl, naphthyridinyl, benzoazaindole,
1,2,4-triazinyl, benzothiazolyl, furyl, imidazolyl, indolyl,
isoindolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl,
oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl,
pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,
1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl. Preferred
heteroaryl and substituted heteroaryl groups include quinolinyl,
indazolyl, indolyl, quinazolinyl, pyridyl, pyrimidinyl, furyl,
benzothiazolyl, quinoxalinyl, benzimidazolyl, benzothienyl, and
isoquinolinyl.
"Fused heteroarylcycloalkenyl" means a fused heteroaryl and
cycloalkenyl wherein the heteroaryl and cycloalkenyl groups are as
defined herein. Preferred fused heteroarylcycloalkenyls are those
wherein the heteroaryl thereof is phenyl and the cycloalkenyl
consists of about 5 to about 6 ring atoms. A fused
heteroarylcycloalkenyl may be bonded to the rest of the compound
through any atom of the fused system capable of such bonding. The
designation of aza, oxa or thia as a prefix before the heteroaryl
portion of the fused heteroarylcycloalkenyl means that a nitrogen,
oxygen or sulfur atom is present, respectively, as a ring atom. The
fused heteroarylcycloalkenyl may be optionally substituted by one
or more ring system substituents, wherein the "ring system
substituent" is as defined herein. The nitrogen atom of a fused
heteroarylcycloalkenyl may be a basic nitrogen atom. The nitrogen
atom of the heteroaryl portion of the fused heteroarylcycloalkenyl
may also be optionally oxidized to the corresponding N-oxide.
Exemplary fused heteroarylcycloalkenyl groups include
5,6-dihydroquinolyl; 5,6-dihydroisoquinolyl;
5,6-dihydroquinoxalinyl; 5,6-dihydroquinazolinyl;
4,5-dihydro-1H-benzimidazolyl; 4,5-dihydrobenzoxazolyl;
1,4-naphthoquinolyl, and the like.
"Fused heteroarylcycloalkyl" means a fused heteroaryl and
cycloalkyl wherein the heteraryl and cycloalkyl groups are as
defined herein. Preferred fused heteroarylcycloalkyls are those
wherein the heteroaryl thereof consists of about 5 to about 6 ring
atoms and the cycloalkyl consists of about 5 to about 6 ring atoms.
A fused heteroarylcycloalkyl may be bonded to the rest of the
compoun through any atom of the fused system capable of such
bonding. The designation of aza, oxa or thia as a prefix before the
heteroaryl portion of the fused heteroarylcycloalkyl means that a
nitrogen, oxygen or sulfur atom is present respectively as a ring
atom. The fused heteroarylcycloalkyl may be optionally substituted
by one or more ring system substituents, wherein the "ring system
substituent" is as defined herein. The nitrogen atom of a fused
heteroarylcycloalkyl may be a basic nitrogen atom. The nitrogen
atom of the heteroaryl portion of the fused heteroarylcycloalkyl
may also be optionally oxidized to the corresponding N-oxide.
Exemplary fused heteroarylcycloalkyl include
5,6,7,8-tetrahydroquinolinyl; 5,6,7,8-tetrahydroisoquinolyl;
5,6,7,8-tetrahydroquinoxalinyl; 5,6,7,8-tetrahydroquinazolyl;
4,5,6,7-tetrahydro-1H-benzimidazolyl;
4,5,6,7-tetrahydrobenzoxazolyl;
1H-4-oxa-1,5-diazanaphthalen-2-only;
1,3-dihydroimidazole-[4,5]-pyridin-2-onyl,
2,3-dihydro-1,4-dinaphthoquinonyl and the like, preferably,
5,6,7,8-tetrahydroquinolinyl or 5,6,7,8-tetrahydroisoquinolyl.
"Fused heteroarylheterocyclenyl" means a fused heteroaryl and
heterocyclenyl wherein the heteraryl and heterocyclenyl groups are
as defined herein. Preferred fused heteroarylheterocyclenyls are
those wherein the heteroaryl thereof consists of about 5 to about 6
ring atoms and the heterocyclenyl consists of about 5 to about 6
ring atoms. A fused heteroarylheterocyclenyl may be bonded to the
rest of the compound through any atom of the fused system capable
of such bonding. The designation of aza, oxa or thia as a prefix
before the heteroaryl or heterocyclenyl portion of the fused
heteroarylheterocyclenyl means that a nitrogen, oxygen or sulfur
atom is present respectively as a ring atom. The fused
heteroarylheterocyclenyl may be optionally substituted by one or
more ring system substituent, wherein the "ring system substituent"
is as defined herein. The nitrogen atom of a fused
heteroarylazaheterocyclenyl may be a basic nitrogen atom. The
nitrogen or sulphur atom or the heteroaryl or heterocyclenyl
portion of the fused heteroarylheterocyclenyl may also be
optionally oxidized to the corresponding N-oxide, S-oxide or
S,S-dioxide. Exemplary fused heteroarylheterocyclenyl groups
include 7,8-dihydro[1,7]naphthyridinyl;
1,2-dihydro[2,7]naphthyridinyl;
6,7-dihydro-3H-imidazo[4,5-c]pyridyl;
1,2-dihydro-1,5-naphthyridinyl; 1,2-dihydro-1,6-naphthyridinyl;
1,2-dihydro-1,7-naphthyridinyl; 1,2-dihydro-1,8-naphthyridinyl;
1,2-dihydro-2,6-naphthyridinyl, and the like.
"Fused heteroarylheterocyclyl" means a fused heteroaryl and
heterocyclyl wherein the heteroaryl and heterocyclyl groups are as
defined herein. Preferred fused heteroarylheterocyclyls are those
wherein the heteroaryl thereof consists of about 5 to about 6 ring
atoms and the heterocyclyl consists of about 5 to about 6 ring
atoms. A fused heteroarylheterocyclyl may be bonded to the rest of
the compound through any atom of the fused system capable of such
bonding. The designation of aza, oxa or thia as a prefix before the
heteroaryl or heterocyclyl portion of the fused
heteroarylheterocyclyl means that a nitrogen, oxygen or sulfur atom
is present respectively as a ring atom. The fused
heteroarylheterocyclyl may be optionally substituted by one or more
ring system substituent, wherein the "ring system substituent" is
as defined herein. The nitrogen atom of a fused
heteroarylheterocyclyl may be a basic nitrogen atom. The nitrogen
or sulphur atom of the heteroaryl or heterocyclyl portion of the
fused heteroarylheterocyclyl may also be optionally oxidized to the
corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary fused
heteroarylheterocyclyl groups include 2,3-dihydro-1H
pyrrol[3,4-b]quinolin-2-yl;
1,2,3,4-tetrahydrobenz[b][1,7]naphthyridin-2-yl;
1,2,3,4-tetrahydrobenz[b][1,6]naphthyridin-2-yl;
1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-2yl;
1,2,3,4-tetrahydro9H-pyrido[4,3-b]indol-2yl,
2,3,-dihydro-1H-pyrrolo[3,4-b]indol-2-yl;
1H-2,3,4,5-tetrahydroazepino[3,4-b]indol-2-yl;
1H-2,3,4,5-tetrahydroazepino[3,4-b]indol-3-yl;
1H-2,3,4,5-tetrahydroazepino[4,5-b]indol-2yl,
5,6,7,8-tetrahydro[1,7]napthyridinyl;
1,2,3,4-tetrhydro[2,7]naphthyridyl;
2,3-dihydro[1,4]dioxino[2,3-b]pyridyl;
2,3-dihydro[1,4]dioxino[2,3-b]pryidyl;
3,4-dihydro-2H-1-oxa[4,6]diazanaphthalenyl;
4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridyl;
6,7-dihydro[5,8]diazanaphthalenyl;
1,2,3,4-tetrahydro[1,5]napthyridinyl;
1,2,3,4-tetrahydro[1,6]napthyridinyl;
1,2,3,4-tetrahydro[1,7]napthyridinyl;
1,2,3,4-tetrahydro[1,8]napthyridinyl;
1,2,3,4-tetrahydro[2,6]napthyridinyl, and the like.
"Heteroarylsulfonyl" means an heteroaryl-SO.sub.2-- group wherein
the heteroaryl group is as defined herein. An examplary
heterarylsulfonyl groups is 3-pyridinepropansulfonyl.
"Heteroarylsulfinyl" means an heteroaryl-SO-- group wherein the
heteroaryl group is as defined herein.
"Heteroarylthio" means an heteroaryl-S-- group wherein the
heteroaryl group is as defined herein. Exemplary heteroaryl thio
groups include pyridylthio and quinolinylthio.
"Heterocyclenyl" means a non-aromatic monocyclic or multicyclic
hydrocarbon ring system of about 3 to about 10 carbon atoms,
preferably about 5 to about 10 carbon atoms, in which at least one
or more of the carbon atoms in the ring system is replaced by a
hetero atom, for example a nitrogen, oxygen or sulfur atom, and
which contains at least one carbon-carbon double bond or
carbon-nitrogen double bond. Preferred ring sizes of rings of the
ring system include about 5 to about 6 ring atoms. The designation
of aza, oxa or thia as a prefix before the heterocyclenyl means
that a nitrogen, oxygen or sulfur atom is present respectively as a
ring atom. The heterocyclenyl may be optionally substituted by one
or more ring system substituents, wherein the "ring system
substituent" is as defined herein. The nitrogen atom of an
heterocyclenyl may be a basic nitrogen atom. The nitrogen or
sulphur atom of the heterocyclenyl is also optionally oxidized to
the corresponding N-oxide, S-oxide or S,S-dioxide. Exemplary
monocyclic azaheterocyclenyl groups include
1,2,3,4-tetrahydrohydropyridine, 1,2-dihydropyridyl,
1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine,
1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl,
2-imidazolinyl, 2-pyrazolinyl, and the like. Exemplary
oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran,
dihydrofuryl, and fluorodihydrofuryl An exemplary multicyclic
oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl. Exemplary
monocyclic thiaheterocycleny rings include dihydrothiophenyl and
dihydrothiopyranyl.
"Heterocyclyl" means a non-aromatic saturated monocyclic or
multicyclic ring system of about 3 to about 10 carbon atoms,
preferably about 5 to about 10 carbon atoms, in which at least one
of the carbon atoms in the ring system is replaced by a hetero
atom, for example nitrogen, oxygen or sulfur. Preferred ring sizes
of rings of the ring system include about 5 to about 6 ring atoms.
The designation of aza, oxa or thia as a prefix before the
heterocyclyl means that a nitrogen, oxygen or sulfur atom is
present respectively as a ring atom. The heterocyclyl may be
optionally substituted by one or more "ring systenm substituents"
which may be the same or different, and are as defined herein. The
nitrogen atom of an heterocyclyl may be a basic nitrogen atom. The
nitrogen or sulphur atom of the heterocyclyl is also optionally
oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
Exemplary monocyclic heterocyclyl rings include piperidyl,
pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl,
thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuryl,
tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
Exemplary multicyclic heterocyclyl rings include
1,4diazabicyclo-[2.2.2]octane and 1,2-cyclohexanedicarboxylic acid
anhydride.
"Ring system substituent" includes hydrogen, alkyl, cycloalkyl,
heterocyclyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxy,
alkoxy, aryloxy, aralkoxy, cycloalkylalkyloxy, acyl, aroyl, halo,
nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,
aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,
alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio,
arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, fused
cycloalkyl, fused cycloalkenyl, fused heterocyclyl, fused
heterocyclenyl, arylazo, heteroarylazo, R.sup.aR.sup.bN--,
R.sup.cR.sup.dNCO--, R.sup.eO.sub.2CN--, and
R.sup.cR.sup.dNSO.sub.2-- wherein R.sup.a and R.sup.b are
independently hydrogen, alkyl, aryl, aralkyl or heteroaralkyl, or
one of R.sup.a and R.sup.b is hydrogen or alkyl and the other of
R.sup.a and R.sup.b is aroyl or heteroaroyl. R.sup.c and R.sup.d
are independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl,
cycloalkenyl, heterocyclyl, heterocyclenyl, aralkyl or
heteroaralkyl. Where the ring is cycloalkyl, cycloalkenyl,
heterocyclyl or heterocyclenyl, the ring system substituent may
also include methylene (H.sub.2C.dbd.), oxo (O.dbd.), thioxo
(S.dbd.), on carbon atom(s) thereof. Preferably, the ring
substituents are selected from oxo (O.dbd.), alkyl, aryl, alkoxy,
aralkoxy, halo, carboxy, alkoxycarbonyl, and R.sup.cO.sub.2CN--,
wherein R.sup.c is cycloalkyl.
"Tetrazolyl" means a group of formula ##STR00010## wherein the
hydrogen atom thereof is optionally replaced by alkyl, carboxyalkyl
or alkoxycarbonylalkyl.
"PPAR ligand receptor binder" means a ligand which binds to the
PPAR receptor. PPAR ligand receptor binders of this invention are
useful as agonists or antagonists of the PPAR-.alpha.,
PPAR-.delta., or PPAR-.gamma. receptor.
The term "pharmaceutically acceptable salt" refers to a relatively
non-toxic, inorganic or organic acid addition salt of a compound of
the present invention. A salt can be prepared in situ during the
final isolation and purification of a compound or by separately
reacting the purified compound in its free base form with a
suitable organic or inorganic acid and isolating the salt thus
formed. Representative salts include the hydrobromide,
hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate,
oxalate, valerate, oleate, palmitate, stearate, laurate, borate,
benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,
succinate, tartrate, naphthylate, mesylate, glucoheptonate,
lactiobionate, laurylsulphonate salts, and the like. (See, for
example S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm.
Sci., 66: 1-19, 1977, the contents of which are hereby incorporated
herein by reference.)
"Treating" means the partial or complete relieving or preventing of
one or more physiological or biochemical parameters associated with
PPAR activity.
The term "modulate" refers to the ability of a compound to either
directly (by binding to the receptor as a ligand) or indirectly (as
a precursor for a ligand or an inducer which promotes production of
a ligand from a precursor) induce expression of gene(s) maintained
under hormone control, or to repress expression of gene(s)
maintained under such control.
The term "obesity" refers generally to individuals who are at least
about 20-30% over the average weight for the person's age, sex and
height. Technically, "obese" is defined, for males, as individuals
whose body mass index is greater than 27.3 kg/m.sup.2. Those
skilled in the art readily recognize that the invention method is
not limited to those who fall within the above criteria. Indeed,
the invention method can also be advantageously practiced by
individuals who fall outside of these traditional criteria, for
example by those who are prone to obesity.
The phrase "amount effective to lower blood glucose levels" refers
to levels of a compound sufficient to provide circulating
concentrations high enough to accomplish the desired effect. Such a
concentration typically falls in the range of about 10 nM up to 2
.mu.M, with concentrations in the range of about 100 nm up to about
500 nM being preferred.
The phrase "amount effective to lower triclyceride levels" refers
to levels of a compound sufficient to provide circulating
concentrations high enough to accomplish the desired effect. Such a
concentration typically falls in the range of about 10 nM up to 2
.mu.M; with concentrations in the range of about 100 nm up to about
500 nM being preferred.
PREFERRED EMBODIMENTS
Preferred embodiments according to the invention includes the use
of compounds of Formula I (and their pharmaceutical compositions)
as binders for PPAR receptors.
More particularly, the use of compounds of Formula I that bind to
the PPAR-.alpha. receptor, compounds of Formula I that bind to the
PPAR-.delta. receptor, compounds of Formula I that bind to the
PPAR-.gamma. receptor, compounds of Formula I that bind to the
PPAR-.alpha. and the PPAR-.gamma. receptor, compounds of Formula I
that bind to the PPAR-.alpha. and the PPAR-.delta. receptor,
compounds of Formula I that bind to the PPAR-.gamma. and the
PPAR-.delta. receptor, compounds of Formula I that act as PPAR
receptor agonists, compounds of Formula I that act as PPAR-.alpha.
receptor agonists, compounds of Formula I that act as PPAR-.delta.
receptor agonists, compounds of Formula I that act as PPAR-.gamma.
receptor agonists, compounds of Formula I that act as both
PPAR-.alpha. and PPAR-.gamma. receptor agonists, compounds of
Formula I that act as both PPAR-.alpha. and PPAR-.delta. receptor
agonists, compounds of Formula I that act as both PPAR-.gamma. and
PPAR-.delta. receptor agonists, compounds of Formula I that act as
both PPAR-.alpha. receptor antagonists and PPAR-.gamma. receptor
agonists, compounds of Formula I that act as both PPAR-.alpha.
receptor antagonists and PPAR-.delta. receptor agonists, compounds
of Formula I and act as both PPAR-.gamma. receptor antagonists and
PPAR-.delta. receptor agonists, compounds of Formula I that act as
both PPAR-.alpha. receptor agonists and PPAR-.gamma. receptor
antagonists, compounds of Formula I that act as both PPAR-.alpha.
receptor agonists and PPAR-.delta. receptor antagonists, compounds
of Formula I that act as both PPAR-.gamma. receptor agonists and
PPAR-.delta. receptor antagonists, compounds of Formula I that act
as PPAR receptor antagonists, compounds of Formula I that act as
PPAR-.alpha. receptor antagonists, compounds of Formula I that act
as PPAR-.delta. receptor antagonists, compounds of Formula I that
act as PPAR-.gamma. receptor antagonists, compounds of Formula I
that act as both PPAR-.alpha. and PPAR-.gamma. receptor
antagonists, compounds of Formula I that act as both PPAR-.alpha.
and PPAR-.delta. receptor antagonists, and compounds of Formula I
that act as both PPAR-.gamma. and PPAR-.delta. receptor
antagonists.
An embodiment according to the invention is directed to treating a
patient suffering from a physiological disorder capable of being
modulated by a compound of Formula I having PPAR ligand binding
activity, comprising administering to the patient a
pharmaceutically effective amount of the compound, or a
pharmaceutically acceptable salt thereof. Physiological disorders
capable of being so modulated include, for example, cell
differentiation to produce lipid accumulating cells, regulation of
insulin sensitivity and blood glucose levels, which are involved in
hypoglycemia/hyperinsulinism (resulting from, for example, abnormal
pancreatic beta cell function, insulin secreting tumors and/or
autoimmune hypoglycemia due to autoantibodies to insulin,
autoantibodies to the insulin receptor, or autoantibodies that are
stimulatory to pancreatic beta cells), macrophage differentiation
which leads to the formation of atherosclerotic plaques,
inflammatory response, carcinogenesis, hyperplasia, adipocyte gene
expression, adipocyte differentiation, reduction in the pancreatic
.beta.-cell mass, insulin secretion, tissue sensitivity to insulin,
liposarcoma cell growth, chronic anovulation, hyperandrogenism,
progesterone production, steroidogenesis, redox potential and
oxidative stress in cells, nitric oxide synthase (NOS) production,
increased gamma glutamyl transpeptidase, catalase, plasma
triglycerides, HDL and LDL cholesterol levels and the like.
Another embodiment according to the invention is directed to a
method of treating a disease state in a patient with a
pharmaceutically effective amount of a compound of Formula I, or a
pharmaceutically acceptable salt thereof, wherein the disease is
associated with a physiological detrimental blood level of insulin,
glucose, free fatty acids (FFA), or triclycerides.
An embodiment according to the invention is directed to treating a
patient suffering from a physiological disorder associated with
physiologically detrimental levels of triclycerides in the blood,
by administering to the patient a pharmaceutically effective amount
of the compound, or of a pharmaceutically acceptable salt
thereof.
An embodiment according to the invention is the use of compounds of
Formula I and their pharmaceutical compositions as anti-diabetic,
anti-lipidemic, anti-hypertensive or anti-arteriosclerotic agents,
or in the treatment of obesity.
Another embodiment according to the invention is directed to a
method of treating hyperglycemia in a patient, by administering to
the patient a pharmaceutically effective amount to lower blood
glucose levels of a compound of Formula I, or a pharmaceutically
acceptable salt thereof. Preferably, the form of hyperglycemia
treated in accordance with this invention is Type II diabetes.
Another embodiment according to the invention is directed to a
method of reducing triglyceride levels in a patient, comprising
administering to the patient a therapeutically effective amount (to
lower triglyceride levels) of a compound of Formula I, or a
pharmaceutically acceptable salt thereof.
Another embodiment according to the invention is directed to a
method of treating hyperinsulinism in a patient, comprising
administering to the patient a therapeutically effective amount of
a compound of Formula I, or a pharmaceutically acceptable salt
thereof.
Another embodiment according to the invention is directed to a
method of treating insulin resistance in a patient, comprising
administering to the patient a therapeutically effective amount of
a compound of Formula I, or a pharmaceutically acceptable salt
thereof.
Another embodiment according to the invention is directed to a
method of treating cardiovascular disease, such as atherosclerosis
in a patient, comprising administering to the patient a
therapeutically effective amount of a compound of Formula I, or a
pharmaceutically acceptable salt thereof.
Another embodiment according to the invention is directed to
treating of hyperlipidemia in a patient, comprising administering
to the patient a therapeutically effective amount of a compound of
Formula I, or a pharmaceutically acceptable salt thereof.
Another embodiment according to the invention is directed to
treating of hypertension in a patient, comprising administering to
the patient a therapeutically effective amount of a compound of
Formula I, or a pharmaceutically acceptable salt thereof.
Another embodiment according to the invention is directed to
treating eating disorders in a patient, comprising administering to
the patient a therapeutically effective amount of a compound of
Formula I, or a pharmaceutically acceptable salt thereof. Treatment
of eating disorders includes the regulation of appetite andor food
intake in patients suffering from under-eating disorders such as
anorexia nervosa as well as over-eating disorders such as obesity
and anorexia bulimia.
Another embodiment according to the invention is directed to
treating a disease state associated with low levels of HDL
comprising administering to the patient a therapeutically effective
amount of a compound of Formula I, or a pharmaceutically acceptable
salt thereof. Diseases associated with low levels of HDL include
atherosclerotic diseases.
Another embodiment according to the invention is directed to
treating polycystic ovary syndrome comprising administering to the
patient a therapeutically effective amount of a compound of Formula
I, or a pharmaceutically acceptable salt thereof.
Another embodiment according to the invention is directed to
treating climacteric comprising administering to the patient a
therapeutically effective amount of a compound of Formula I, or a
pharmaceutically acceptable salt thereof.
Another embodiment according to the invention is directed to
treating inflammatory diseases such as rheumatoid arthritis,
chronic obstructive pulmonary disease (emphysema or chronic
bronchitis), or asthma comprising administering to the patient a
therapeutically effective amount of a compound of Formula I, or a
pharmaceutically acceptable salt thereof.
Another aspect of the invention is to provide a novel
pharmaceutical composition which is effective, in and of itself,
for utilization in a beneficial combination therapy because it
includes a plurality of active ingredients which may be utilized in
accordance with the invention.
In another aspect, the present invention provides a method for
treating a disease state in a patient, wherein the disease is
associated with a physiological detrimental level of insulin,
glucose, free fatty acids (FFA), or triglycerides, in the blood,
comprising administering to the patient a therapeutically effective
amount of a compound of Formula I, and also administering a
therapeutically effective amount of an additional hypoglycemic
agent.
In another aspect, the present invention provides a method for
treating a disease state in a patient, wherein the disease is
associated with a physiological detrimental level of insulin,
glucose, free fatty acids (FFA), or triglycerides, in the blood,
comprising administering to the patient a therapeutically effective
amount of a compound of Formula I, and also administering a
therapeutically effective amount of a biguanidine compound.
In another aspect, the present invention provides a method for
treating a disease state in a patient, wherein the disease is
associated with a physiological detrimental level of insulin,
glucose, free fatty acids (FFA), or triglycerides, in the blood,
comprising administering to the patient a therapeutically effective
amount of a compound of Formula I, and also administering a
therapeutically effective amount of metformin.
The invention also provides kits or single packages combining two
or more active ingredients useful in treating the disease. A kit
may provide (alone or in combination with a pharmaceutically
acceptable diluent or carrier), a compound of Formula (I) and an
additional hypoglycaemic agent (alone or in combination with
diluent or carrier).
There are many known hypoglycemic agents in the art, for example,
insulin; biguanidines, such as metformin and buformin;
sulfonylureas, such as acetohexamide, chloropropamide, tolazamide,
tolbutamide, glyburide, glypizide and glyclazide;
thiazolidinediones, such as troglitazone; .alpha.-glycosidase
inhibitors, such as acarbose and miglatol; and B.sub.3
adrenoreceptor agonists such as CL-316,243.
Since sulfonylureas are known to be capable of stimulating insulin
release, but are not capable of acting on insulin resistance, and
compounds of Formula I are able to act on insulin resistance, it is
envisaged that a combination of these medicaments could be used as
a remedy for conditions associated with both deficiency in insulin
secretion and insulin-resistance.
Therefore, the invention also provides a method of treating
diabetes mellitus of type II in a patient comprising administering
a compound of Formula I and one or more additional hypoglycemic
agents selected from the group consisting of sulfonylureas,
biguanidines, thiazolidinediones, B.sub.3-adrenoreceptor agonists,
.alpha.-glycosidase inhibitors and insulin.
The invention also provides a method of treating diabetes mellitus
of type II in a patient comprising administering a compound of
Formula I and a sulfonylurea selected from the group consisting of
acetohexamide, chlorpropamide, tolazamide, tolbutamide, glyburide,
glypizide and glyclazide.
The invention also provides a method of treating diabetes mellitus
of type II in a patient comprising administering a compound of
Formula I and a biguanidine selected from the group consisting of
metformin and buformin.
The invention also provides a method of treating diabetes mellitus
of type II in a patient comprising administering a compound of
Formula I and an .alpha.-glycosidase inhibitor selected from the
group consisting acarbose and miglatol.
The invention also provides a method of treating diabetes mellitus
of type II in a patient comprising administering a compound of
Formula I and an thiazolidinedione, for example, troglitazone.
As indicated above, a compound of Formula I may be administered
alone or in combination with one or more additional hypoglycemic
agents. Combination therapy includes administration of a single
pharmaceutical dosage formulation which contains a compound of
Formula I and one or more additional hypoglycemic agent, as well as
administration of the compound of Formula I and each additional
hypoglycemic agents in its own separate pharmaceutical dosage
formulation. For example, a compound of Formula I and hypoglycemic
agent can be administered to the patient together in a single oral
dosage composition such as a tablet or capsule, or each agent
administered in separate oral dosage formulations. Where separate
dosage formulations are used, the compound of Formula I and one or
more additional hypoglycemic agents can be administered at
essentially the same time, i.e., concurrently, or at separately
staggered times, i.e., sequentially.
For example, the compound of Formula I may be administered in
combination with one or more of the following additional
hypoglycemic agents: insulin; biguanidines such as metformin or
buformin; sulfonylureas such as acetohexamide, chloropropamide,
tolazamide, tolbutamide, glyburide, glypizide or glyclazide;
thiazolidinediones such as troglitazone; .alpha.-glycosidase
inhibitors such as acarbose or miglatol; or B.sub.3 adrenoreceptor
agonists such as CL-316,243.
The compound of Formula I is preferably administered with a
biguanidine, in particular, metformin.
The compounds of Formula I contain at least two aromatic or
hetero-aromatic rings, which may be designated as shown in Formula
II below, and for which their substitution pattern along the chain
with respect to each other also is shown below. ##STR00011##
A preferred aspect of the compounds of Formula II, is a compound
wherein ##STR00012## is selected from quinolinyl, benzothiophenyl,
benzoimidazolyl, quinazolinyl, benzothiazolyl, quinoxalinyl,
naphthyl, pyridyl, 1H-indazolyl, 1,2,3,4-tetrahydroquinolinyl,
benzofuranyl, thienyl, or indolyl, and one end of the linker,
Linker I, is attached to ##STR00013## preferably at the 2-position
of the ring moiety.
Another aspect of the compounds of Formula II is a compound wherein
##STR00014## is a 6-membered aryl or heteroaryl group and Linker I
and Linker II are attached to ##STR00015## at positions 1,3-, or
1,4- to each other.
Another aspect of the compounds of Formula II is a compound wherein
##STR00016## is a naphthyl group, Linker I and Linker II are
attached to ##STR00017## at positions 1,4-, or 2,4- to each other
on the naphthyl moiety.
A further preferred aspect of the compound of Formula II is
described by Formula V below: ##STR00018## where R.sub.7, R.sub.8,
c, d, E and Z are as defined above, c+d=1-3, and R' and R'' are
ring system substituents.
Another aspect of this invention is a compound of the invention
wherein ##STR00019## is optionally substituted aryl, optionally
substituted azaheteroaryl, or optionally substituted fused
arylheterocyclenyl or fused arylheterocyclyl; and ##STR00020## is
optionally substituted phenyl or optionally substituted naphthyl,
optionally substituted heteroaryl, or optionally substituted fused
arylheterocyclenyl.
Another aspect of this invention is a compound of the invention
wherein a=1 or 2; R.sub.1 and R.sub.2 is hydrogen; A is a chemical
bond; and b=0.
Another aspect of this invention is a compound of the invention
wherein a=0, 1, or 2, A is --C(O)N(R.sup.15)-- or
--N(R.sup.14)C(O)--, and b=0 or 1.
Another more preferred aspect of this invention is a compound of
the invention wherein R.sub.1 and R.sub.2 are both hydrogen, a=1, A
is --O-- and b=0.
Another more preferred aspect of this invention is a compound of
the invention wherein R.sub.1 and R.sub.2 are both hydrogen, a=2, A
is --O-- and b=0.
Another more preferred aspect of this invention is a compound of
the invention wherein a=0, A is --O-- or --NR.sub.13--; R.sub.13 is
hydrogen or alkyl; R.sub.3 and R.sub.4 are both independently
hydrogen; and b=1.
Another aspect of this invention is a compound of the invention
wherein a=0; A is ##STR00021## R.sub.15 and R.sub.16 are hydrogen;
g is 1, 2, 3 or 4; and b=0.
Another aspect of this invention is a compound of the invention
wherein a=0; A is --NR.sub.13--, b=1, R.sub.3 and R.sub.4 are
hydrogen, and R.sub.13 is hydrogen, alkyl, or
R.sub.22(O.dbd.)C--.
Another aspect of this invention is a compound of the invention
wherein a=2; then the vicinal R.sub.1 radicals taken together with
the carbon atoms through which these radicals are linked form a
##STR00022## group; R.sub.2 is hydrogen; A is a chemical bond or
--O--; and b=0.
Another aspect of this invention is a compound of the invention
wherein a=6; then at least one pair of vicinal R.sub.1 radicals
taken together with the carbon atoms through which these radicals
are linked form a ##STR00023## group; R.sub.2 is hydrogen or alkyl;
A is --O--; and b=0.
Another aspect of this invention is a compound of the invention
wherein a=1, 2 or 3; R.sub.1 and R.sub.2 are hydrogen; A is --O--;
and b=0.
Another aspect of this invention is a compound of the invention
wherein a=1; R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are hydrogen; A
is --O--; and b=1.
Another aspect of this invention is a compound of the invention
wherein a=2; A is ##STR00024## h=1 or 2; and b=0.
Another aspect of this invention is a compound of the invention
wherein c=0; d=0; B and E is a chemical bond; Z is
R.sub.21O.sub.2SHNCO--, and R.sub.21 is phenyl.
Another aspect of this invention is a compound of the invention
wherein c=0; d=2; B is --C(O)N(R.sub.20)--, E is a chemical bond; Z
is a tetrazolyl group or --CO.sub.2R.sub.21; R.sub.20 is hydrogen,
alkyl, alkoxycarbonyl.
Another aspect of this invention is a compound of the invention
wherein c=0 or 4; d=0 or 1; B and E is a chemical bond; Z is
tetrazolyl, NH.sub.2CO-- or --CO.sub.2R.sub.21; and R.sub.21 is
hydrogen or lower alkyl.
Another aspect of this invention is a compound of the invention
wherein c=0 or 1; d=0 or 1; B is --O-- or a chemical bond; E is a
chemical bond; and Z is tetrazolyl, NH.sub.2CO-- or
--CO.sub.2R.sub.21; and R.sub.21 is hydrogen or lower alkyl.
Another aspect of this invention is a compound of the invention
wherein c=0; d=1; B is --O-- or a chemical bond; E is a chemical
bond; R.sub.7 and R.sub.8 are hydrogen or alkyl; and Z is
tetrazolyl, NH.sub.2CO-- or --CO.sub.2R.sub.21; and R.sub.21 is
hydrogen or lower alkyl.
Another aspect of this invention is a compound of the invention
wherein c=2 or 4, then at least one pair of vicinal R.sub.5
radicals taken together with the carbon atoms to which the R.sub.5
radicals are linked form a ##STR00025## group; d=0; D and E is a
chemical bond; and Z is a tetrazolyl group or --CO.sub.2R.sub.21;
and R.sub.21 is hydrogen.
Another aspect of this invention is a compound of the invention
wherein c=0; d=3 or 4; B is --O--; E is a chemical bond; R.sub.7
and R.sub.8 are hydrogen or alkyl, or at least one of R.sub.7 is
carboxyl or alkoxycarbonyl; Z is tetrazolyl, --CO.sub.2R.sub.21 or
(R.sub.21).sub.2NC(O)--; and R.sub.21 is hydrogen or lower
alkyl.
Another aspect of this invention is a compound of the invention
wherein c=0; d=1, 2, or 3; B is --C(O)--; E is a chemical bond;
R.sub.7 and R.sub.8 are hydrogen or alkyl; Z is tetrazolyl or
--CO.sub.2R.sub.21; and R.sub.21 is hydrogen or lower alkyl.
Another aspect of this invention is a compound of the invention
wherein c=4; d=0; B and E are a chemical bond; R.sub.7 and R.sub.8
are hydrogen or alkyl; Z is tetrazolyl or --CO.sub.2R.sub.21; and
R.sub.21 is hydrogen or lower alkyl.
Another aspect of this invention is a compound of the invention
wherein c=0, 1 or 2; d=1, 2 or 3; B is --S-- or NR.sub.19, E are a
chemical bond; R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are hydrogen;
Z is tetrazoly or --CO.sub.2R.sub.21; and R.sub.21 is hydrogen or
lower alkyl.
Another aspect of this invention is a compound of the invention
wherein R.sub.6 and R.sub.8 are --(CH.sub.2).sub.q--X; q is 0, 1 or
2; and X is independently hydrogen, aralkyl or lower alkyl.
Another aspect of this invention is a compound of the invention
wherein at least one pair of geminal R.sub.5 and R.sub.6 radicals
taken together with the carbon atom through which these radicals
are linked form a 5-membered cycloalkyl group.
Another aspect of this invention is a compound of the invention
wherein at least one pair of geminal R.sub.7 and R.sub.8 radicals
taken together with the carbon atom through which these radicals
are linked form a 5-membered cycloalkyl group.
Another aspect of this invention is a compound of the invention
wherein Z is --CO.sub.2H, --CN or a tetrazolyl group.
A preferred aspect of this invention is a compound of the invention
wherein ##STR00026## is an optionally substituted quinolinyl,
quinoxalinyl, quinazolinyl, isoquinolinyl, N-alkyl-quinolin-4-onyl,
quinazolin-4-onyl, benzoxazolyl, benzimidazolyl, benzothiazolyl,
benzofuranyl, benzothiophenyl, indolinyl oxazolyl, thiazolyl,
oxadiazolyl isoxazolyl, imidazolyl, pyrazol-yl, thiadiazolyl,
triazolyl, pyridyl pyrimidinyl, pyrazinyl, pyridazinyl, phenyl, or
napthalenyl group, wherein the substituent is a ring system
substituent as defined herein, more preferably a substituent
selected from the group consisting of phenyl, substituted-phenyl,
thienyl, substituted thienyl, cycloalkyl, lower alkyl, branched
alkyl, fluoro, chloro, alkoxy, aralkyloxy, trifluoromethyl and
trifluoromethyloxy.
A more preferred aspect of this invention is a compound of the
invention wherein ##STR00027## is unsubstituted quinolin-2-yl,
3-substituted quinolin-2-yl, 4-substituted quinolin-2-yl,
6-substituted quinolin-2-yl or 7 substituted quinolin-2-yl; an
unsubstituted quinozalin-2-yl, 3-substituted quinozalin-2-yl,
6-substituted quinozalin-2-yl or 3,6-disubstituted quinozalin-2-yl;
unsubstituted quinazolin-2-yl, 4-substituted quinazolin-2-yl or
6-substituted quinazolin-2-yl; unsubstituted isoquinolin-3-yl,
6-substituted isoquinolin-3-yl or 7-substituted isoquinolin-3-yl;
3-substituted-quinazolin-4-on-2-yl; N-substituted
quinolin-4-on-2-yl; 2-substituted-oxazol-4-yl or 2,5
disubstituted-oxazol-4-yl; 4-substituted oxazol-2-yl or
4,5-disubstituted-oxazol-2-yl; 2-substituted thiazol-4-yl or
2,5-disubstituted thiazol-4-yl; 4-substituted thiazol-2-yl or
4,5-disubstituted-thiazol-2-yl;
5-substituted-[1,2,4]oxadiazol-3-yl;
3-substituted-[1,2,4]oxadiazol-5-yl; 5-substituted-imidazol-2-yl or
3,5-disubstituted-imidazol-2-yl; 2-substituted-imidazol-5-yl or
2,3-disubstituted-imidazol-5-yl; 3-substituted-isoxazol-5-yl;
5-substituted-isoxazol-3-yl; 5-substituted-[1,2,4]thiadiazol-3-yl;
3-substituted-[1,2,4]-thiadiazol-5-yl;
2-substituted-[1,3,4]-thiadiazol-5-yl;
2-substituted-[1,3,4]-oxadiazol-5-yl; 1-substituted-pyrazol-3-yl;
3-substituted-pyrazol-5-yl; 3-substituted-[1,2,4]-triazol-5-yl;
1-substituted-[1,2,4]-triazol-3-yl; 3-substituted pyridin-2-yl,
5-substituted pyridin-2-yl, 6-substituted pyridin-2-yl or
3,5-disubstituted pyridin-2-yl; 3-substituted pyrazin-2-yl,
5-substituted pyrazin-2-yl, 6-substituted pyrazin-2-yl or 3,5
disubstituted-pyrazin-2-yl; 5-substituted pyrimidin-2-yl or
6-substituted-pyrimidin-2-yl; 6-substituted-pyridazin-3-yl or
4,6-disubstituted-pyridazin-3-yl; unsubstituted napthalen-2-yl,
3-substituted napthalen-2-yl, 4-substituted napthalen-2-yl,
6-substituted napthalen-2-yl or 7 substituted napthalen-2-yl;
2-substituted phenyl, 4-substituted phenyl or 2,4-disubstituted
phenyl; unsubstituted-benzothiazol-2-yl or
5-substituted-benzothiazol-2-yl; unsubstituted benzoxazol-2yl or
5-substituted-benzoxazol-2yl; unsubstituted-benzimidazol-2-yl or
5-substituted-benzimidazol-2-yl; unsubstituted-thiophen-2yl,
3-substituted-thiophen-2yl, 6-substituted-thiophen-2yl or
3,6-disubstituted-thiophen-2yl; unsubstituted-benzofuran-2-y,
3-substituted-benzofuran-2-yl, 6-substituted-benzofuran-2-yl or
3,6-disubstituted-benzofuran-2-yl; 3-substituted-benzofuran-6-yl or
3,7-disubstituted-benzofuran-6-yl, wherein the substituent is a
ring system substituent as defined herein, more preferably a
substituent selected from the group consisting of phenyl,
substituted-phenyl, thienyl, substituted thienyl, cycloalkyl, lower
alkyl, branched alkyl, fluoro, chloro, alkoxy, aralkyloxy,
trifluoromethyl and trifluoromethyloxy.
Another more preferred aspect of this invention is a compound of
the invention wherein a=0, A is --O-- or --NR.sub.13--; R.sub.13 is
hydrogen or alkyl; R.sub.3 and R.sub.4 are both independently
hydrogen; b=1; and ArI is 3-substituted quinolin-2-yl,
4-substituted quinolin-2-yl, 6-substituted quinolin-2-yl, 7
substituted quinolin-2-yl, unsubstituted quinoxalin-2-yl,
3-substituted quinoxalin-2-yl, 6-substituted quinoxalin-2-yl,
3,6-disubstituted quinoxalin-2-yl, unsubstituted quinazolin-2-yl,
4-substituted quinazolin-2-yl, 6-substituted quinazolin-2-yl,
unsubstituted isoquinolin-3-yl, 6-substituted isoquinolin-3-yl,
7-substituted isoquinolin-3-yl, 4-substituted oxazol-2-yl,
4,5-disubstituted-oxazol-2-yl, 4-substituted-thiazol-2-yl,
4,5-disubstituted-thiazol-2-yl, 5-substituted-imidazol-2-yl,
3,5-disubstituted-imidazol-2-yl, 1-substituted-pyrazol-3-yl,
3-substituted-pyrazol-5-yl, 3-substituted pyridin-2-yl,
5-substituted pyridin-2-yl, 6-substituted pyridin-2-yl or
3,5-disubstituted pyridin-2-yl, 3-substituted pyrazin-2-yl,
5-substituted pyrazin-2-yl, 6-substituted pyrazin-2-yl, 3,5
disubstituted-pyrazin-2-yl, 5-substituted pyrimidin-2-yl,
6-substituted-pyrimidin-2-yl, 6-substituted-pyridazin-3-yl,
4,6-disubstituted-pyridazin-3-yl, unsubstituted-benzothiazol-2-yl,
5-substituted-benzothiazol-2-yl, unsubstituted-benzoxazol-2-yl,
5-substituted-benzoxazol-2-yl, unsubstituted benzimidazol-2-yl,
5-substituted-benzimidazol-2-yl, 3-substituted-benzofuran-6-yl or
3,7-disubstituted-benzofuran-6-yl.
Another aspect of this invention is a compound of formula I as
described by formula (Ia) below: ##STR00028## is independently
aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused
arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused
heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused
heteroarylheterocyclenyl, or fused heteroarylheterocyclyl; a=1;
b=0; R.sub.1 and R.sub.2 are hydrogen A is --O--; R.sub.5, R.sub.6,
R.sub.7, R.sub.8 are hydrogen; c=0; B and E are a chemical bond; Z
is R.sub.21O.sub.2C--, R.sub.21OC--, cyclo-imide, --CN,
R.sub.21O.sub.2SHNCO--, R.sub.21O.sub.2SHN--,
(R.sub.21).sub.2NCO--, R.sub.21O--2,4-thiazolidinedionyl, or
tetrazolyl; R' and R'' are ring system substituents as defined
herein, more preferably, R' is hydrogen, lower alkyl, halo, alkoxy,
aryloxy or aralkyloxy; and R'' is lower alkyl, hydrogen,
aralkyloxy, alkoxy, cycloalkylalkyloxy or halo.
Another aspect of this invention is a compound of formula I as
described by formula (Ia) wherein ##STR00029## is independently
aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused
arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused
heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused
heteroarylheterocyclenyl, or fused heteroarylheterocyclyl; a=1;
##STR00030## g=2, 3, 4 or 5; R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.15 and R.sub.16 are hydrogen; b=0 or 1; c=0; d=0; B and E are
a chemical bond; Z is --CO.sub.2H; R' and R'' are ring system
substituents as defined herein, more preferably, R' is hydrogen,
lower alkyl, halo, alkoxy, aryloxy or aralkyloxy; and R'' is lower
alkyl, alkoxy, aralkoxy, cycloalkylalkoxy or halo.
Another aspect of this invention is a compound of formula I as
described by formula (Ia) wherein ##STR00031## is independently
aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused
arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused
heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused
heteroarylheterocyclenyl, or fused heteroarylheterocyclyl; a=1;
##STR00032## g=2, 3, 4 or 5; R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.15 and R.sub.16 are hydrogen; b=0 or 1; c=0; d=0; B and E are
a chemical bond; Z is --CO.sub.2H; R' is hydrogen; and R'' is lower
alkyl.
Another aspect of this invention is a compound of formula I as
described by formula (Ia) wherein ##STR00033## is independently
aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused
arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused
heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused
heteroarylheterocyclenyl, or fused heteroarylheterocyclyl; a=1;
##STR00034## g=2, 3, 4 or 5; R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.15 and R.sub.16 are hydrogen; R.sub.7 and R.sub.8 are
independently hydrogen; b=0 or 1; c=0; d=1; B and E are a chemical
bond; Z is --CO.sub.2H; R' and R'' are ring system substituents as
defined herein, more preferably, R' is hydrogen, lower alkyl, halo,
alkoxy, aryloxy or aralkyloxy; and R'' is lower alkyl, alkoxy,
aralkoxy, cycloalkylalkoxy or halo.
Another aspect of this invention is a compound of formula I as
described by formula (Ia) wherein ##STR00035## is independently
aryl, fused arylcycloalkenyl, fused arylcycloalkyl, fused
arylheterocyclenyl, fused arylheterocyclyl, heteroaryl, fused
heteroarylcycloalkenyl, fused heteroarylcycloalkyl, fused
heteroarylheterocyclenyl, or fused heteroarylheterocyclyl; a=1;
##STR00036## g=2, 3, 4 or 5; R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.15 and R.sub.16 are independently hydrogen; R.sub.7 and
R.sub.8 are hydrogen b=0 or 1; c=0; d=1; B and E are a chemical
bond; Z is --CO.sub.2H; R' is hydrogen; and R'' is lower alkyl.
Another aspect of this invention is a compound of formula I as
described by formula (Ia) wherein: a=0-2; b=0-1; A is --O-- or
--NR.sub.13--; R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are
independently hydrogen; R.sub.13 is hydrogen, R.sub.22OC--, or
alkyl; c=0; d=0; B and E are a chemical bond; Z is --CO.sub.2H; R'
and R'' are ring system substituents as defined herein, more
preferably, R' is lower alkyl, halo, alkoxy, aryloxy or aralkyl;
and R'' is lower alkyl or halo.
A more preferred aspect of this invention is a compound of formula
I as described by formula (Ia) wherein: a 1 or 2; A is --O--; b=0;
R.sub.1, R.sub.2, R.sub.7 and R.sub.8 are independently hydrogen;
c=0; d=1; B and E are a chemical bond; R' is hydrogen, halo or
benzyloxy; R'' is lower alkyl, preferably methyl; Z is
--CO.sub.2H.
A more preferred aspect of this invention is a compound of formula
I as described by formula (Ia) wherein: a=1 or 2; A is --O--; b=0;
R.sub.1, R.sub.2, R.sub.7 and R.sub.8 are independently hydrogen;
c=0; d=1; B and E are a chemical bond; R' is hydrogen, halo or
benzyloxy; R'' is lower alkyl, preferably methyl; Z is
--CO.sub.2H.
A more preferred aspect of this invention is a compound of formula
I as described by formula (Ia) wherein: a=1 or 2; A is --O--; b=0;
R.sub.1, R.sub.2, R.sub.7, R.sub.8 are independently hydrogen; c=0;
B is --O--; d=1; B and E are a chemical bond; R' is halo; R'' is
lower alkyl, preferably methyl; Z is --CO.sub.2H.
A more preferred aspect of this invention is a compound of formula
I as described by formula (Ia) wherein: a=1; R.sub.1 and R.sub.2
are hydrogen A is --O--; b=0; c=0; d=0; B and E are a chemical
bond; R' is hydrogen, aralkoxy, or halo; R'' is lower alkyl,
preferably methyl; Z is --CO.sub.2H.
A more preferred aspect of this invention is a compound of formula
I as described by formula (Ia) wherein: a=1; A is --O--; b=0; c=0;
d=0; B and E are a chemical bond; R' is hydrogen; R'' is lower
alkyl; Z is --CO.sub.2H.
A more preferred aspect of this invention is a compound of formula
I as described by formula (Ia) wherein: ##STR00037## is aryl or
heteroaryl; a=1; A is --O--; b=0; c=0; d=0; B and E are a chemical
bond; R' is hydrogen; R'' is lower alkyl; Z is --CO.sub.2H.
A more preferred aspect of this invention is a compound of formula
I as described by formula (Ia) wherein: ##STR00038## is optionally
substituted azaheteroaryl; a=1; A is --O--; b=0; c=0; d=0; B and E
are a chemical bond; R' is hydrogen; R'' is lower alkyl; Z is
CO.sub.2H.
A more preferred aspect of this invention is a compound of formula
I as described by formula (Ia) wherein: ##STR00039## is optionally
substituted quinolinyl, or a 5-membered heteroaryl group wherein
the heteroaryl group is substituted by optionally substituted
phenyl or optionally substituted cyclohexyl; a=1; A is --O--; b=0;
c=0; d=0; B and E are a chemical bond; R' is hydrogen; R'' is lower
alkyl; Z is CO.sub.2H.
A preferred compound according to the invention is selected from
the group consisting of ##STR00040## ##STR00041## ##STR00042##
##STR00043## ##STR00044## ##STR00045## ##STR00046## ##STR00047##
##STR00048## ##STR00049## ##STR00050## ##STR00051## ##STR00052##
##STR00053## ##STR00054## ##STR00055## ##STR00056## ##STR00057##
##STR00058## ##STR00059## ##STR00060## ##STR00061## ##STR00062##
##STR00063## ##STR00064## ##STR00065## ##STR00066## ##STR00067##
##STR00068## ##STR00069## ##STR00070## ##STR00071##
A preferred compound according to the invention is selected from
the group consisting of ##STR00072## ##STR00073## ##STR00074##
##STR00075##
A preferred compound, selective for PPAR.gamma., is chosen from the
group consisting: ##STR00076## ##STR00077## ##STR00078##
A preferred compound, selective for PPAR.alpha., is chosen from the
group consisting: ##STR00079##
A preferred compound having PPAR.alpha. and PPAR.gamma. activity is
selected from the group consisting: ##STR00080##
A preferred compound having PPAR.alpha. and PPAR.delta. activity is
selected from the group consisting: ##STR00081##
This invention also encompasses all combinations of preferred
aspects of the invention described herein.
Compounds useful according to this invention can be prepared by the
methods disclosed herein as well as the specific examples and in
the following references which are incorporated herein by
reference: Galemmo, Robert A., Jr et. al, J. Med. Chem. (1990),
33(10), 2828-41; Youssefyeh, Raymond D. et al, J. Med. Chem.
(1990), 33(4), 1186-94; Youssefyeh, Raymond et. al, International
patent publication no. WO 8705510; Astles, Peter Charles et. al.,
International patent publication no. WO 9513262, Jayossi et al,
International patent application Ser. No. PCT/US00/11490 in the
name of Aventis Pharmeuticals Products Inc, filed on Apr. 28.sup.th
2000; and Jayossi et al, U.S. non-provisional patent application
titled "Therapeutic uses of Tri-Aryl Acid Derivatives" in the name
of Jayossi et al., Ser. No. 50/131,454 filed on Apr. 28.sup.th
1999, incorporated herein in their entirety.
Compounds useful according to this invention can be prepared in
segments, as is common to a long chain molecule. Thus, it is
convenient to synthesize these molecules by employing condensation
reactions at the A and B sites of the molecule. Compounds of
Formula I can be prepared by the application or adaptation of known
methods, by which is meant methods used heretofore or described in
the literature. For example, the synthetic methodology described in
the following publications, the contents of which are incorporated
herein by reference may be employed: "Development of a novel series
of (2-quinolinylmethoxy)phenyl-containing compounds as
high-affinity leukotriene receptor antagonists. 1. Initial
structure-activity relationships." J. Med. Chem. (1990), 33(4),
1186-1194; "The development of a novel series of
(quinolin-2-ylmethoxy)phenyl-containing compounds as high-affinity
leukotriene receptor antagonists. 3. Structural variation of the
acidic side chain to give antagonists of enhanced potency." J. Med.
Chem. (1990), 33(10), 2828-41; "A Novel Series of
[2-(Methylphenethylamino)-2-oxoethyl]benzene-Containing Leukotriene
B4 Antagonists: Initial Structure-Activity Relationships." J. Med.
Chem. (1996), 39(19), 3748-3755; and "Structure-Activity
Relationships Study of Two Series of Leukotriene B4 Antagonists:
Novel Indolyl and Naphthyl Compounds Substituted with a
2-[Methyl(2-phenethyl)amino]-2-oxoethyl Side Chain." J. Med. Chem.
(1996), 39(19), 3756-3768.
Additional methodologies which can be used to synthesize construct
compounds of this invention are described below. The coupling of an
aryl-halide with a terminal alkyne using a Pd(0) catalyst (the
Sonikashira coupling) or a variant thereof can be used to assemble
molecules as described in Scheme 100.
Partial reduction using mild hydrogenation conditions, for example
with a catalyst poison such as quinoline, can provide the cis
olefin. Isomerization of the olefin can be accomplished, if
desired, to provide the trans olefin. Either of these olefins can
be used as intermediates for further elaboration. They also are
compounds which, themselves, can act as PPAR modulators.
Reduction of the olefin can be accomplished by hydrogenation, for
example H.sub.2, Pd/C. ##STR00082##
A modification of this chemistry is shown in Scheme 101 below.
Coupling of the aryl halide and terminal alkyne provides an
intermediate which can be subsequently reduced as above and then
coupled with an intermediate having a leaving group L as described
in earlier sections. Alternatively, each alkyne or alkene
intermediate can be coupled with a fragment which contains a
leaving group L to provide the corresponding alkynyl and alkenyl
analogs. ##STR00083##
Additional chemistry which can be employed is shown in Scheme 102.
Heteroaromatic systems which have an acidic C--H bond can be
deprotonated with a base such as BuLi or a grignard reagent, and
the resulting anion can be reacted with an electrophile such as an
aldehyde, ketone, carboxylic acid derivative, epoxide, etc. as
shown. ##STR00084##
A further elaboration of this chemistry is shown in scheme 103,
wherein a heteroaromatic ring is deprotonated with a base such as
BuLi and the anion is condensed with an aldehyde. The resulting
alcohol can be deoxygenated using conditions such as Barton's tin
hydride mediated reduction of a thiono carbamate or zanthate or by
using conditions for the reduction of benzylic alcohols such as
Et3SiH, TFA. A representative example of the condensation product
is shown. ##STR00085##
In another embodiment of this invention Ar I or Ar II is defined as
a benzofuran. This type of ring system can be assembled in various
ways using literature methods (for examples, see Friedlichsen, W.
in Comprehensive Heterocyclic Chemstry II, Vol 2. Katritzky, A. R.;
Rees, C. W.; Scriven, E. F. V. Eds. Elsevier Science 1996). A
particularly suitable method with regard to this invention involves
formation of a 2-methoxycarbonyl substituted benzofuran from a
bromo substituted-ortho-hydroxy benzaldehyde, (Foster, R. T.;
Robertson, A.; Bushra, A.; J. Chem Soc., 1948, 2254) as illustrated
in scheme 104. Ring closure is carried out in the presence of base
such as sodium methoxide in methanol or lithium
hexamethyldisilazide in a solvent such as THF, DME, DMPU or a
mixture thereof, generally at a temperature between -78.degree. C.
and reflux. The resulting 2-methoxycarbonyl benzofuran can then be
further derivatized, as illustrated in scheme 104 or as described
elsewhere in this experimental section, to provide a variety of
appositely substituted benzofurans. ##STR00086##
In one particular embodiment of this invention, AR I or Ar II is
defined as a heterocycle such as pyridine, pyrimidine and
pyridazine. In principle, appropriately functionalized ring systems
of this kind can be prepared by functionalization of specific
precursors followed by ring synthesis or by derivatization of a
preformed ring system. There are numerous approaches to the
synthesis and functionalization of the aforementioned heterocyclic
frameworks in the chemical literature (for examples, see (a)
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. Eds. Comprehensive
Heterocyclic Chemistry II, Vol 5 and Vol 6. Elsevier Science 1996
and references therein). A particularly useful protocol with regard
to the current invention involves Mitsunobu etherification of
hydroxyl substituted heterocycles such as outlined in Scheme A.
Treatment of 5-bromo-pyridin-2-one (1, G, J.dbd.CH),
5-bromo-pyrimidin-2-one (2, G.dbd.N, J.dbd.CH) or
bromo-pyrazin-3-one (3, G.dbd.CH, J.dbd.N) with an alcohol under
Mitsunobu's conditions provides the corresponding bromo-substituted
heterocyclic ethers (4) (for typical procedures see Mitsunobu. O.,
Synthesis, 1981, 1). ##STR00087##
These heterocyclic bromides can be further functionalized in a
number of ways. For example, coupling with a vinyl stannane can be
effected under palladium(0) catalysis to provide systems with an
alkenyl side chain (5 and 6). The choice of catalyst and reaction
temperature depends on the substrate employed but is most commonly
tetrakistriphenylphosphine palladium,
bis(triphenylphosphine)palladium chloride,
1,1'-bis(diphenylphosphino)ferrocene/bis-dibenzylideneacetone
palladium or 1,2
bis(diphenylphosphino)ethane/bis(acetonitrile)dichloropalladium at
a temperature between 50 and 150.degree. C. Suitable solvents
include DMF, DMPU, HMPA, DMSO, toluene, and DME. (for examples see
Farina, V. Krishnamurthy, V.; Scott, W. J. Organic Reactions, 1997,
50, 1). Reduction of the olefin using, for example Wilkinson's
catalyst in a solvent such as toluene, THF or an alcohol at a
temperature between about 20 and 80.degree. C. provides the
corresponding alkane (7). Heterocyclic bromides such as (1) can
also be metalated (after protection of the carbonyl functionality
as a O-silyl ether by reaction with an appropriate silyl chloride
or triflate in the presence of a base such as triethylamine or
imidazole in a solvent such as dichloromethane or DMF) with an
alkyl lithium reagent generally at low temperature (below
-50.degree. C.) Suitable solvents for this process include THF or
diethyl ether, either alone or as mixtures with additives such as
HMPA, TMEDA or DABCO. The resulting aryl lithium species can then
be reacted with a variety of electrophiles such as aldehydes, alkyl
halides, oxiranes, aziridines or ab-unaturated carbonyls to provide
heterocycles substituted with a variety of functionalized side
chains. In particular, by using DMF as the electrophile, this
procedure can be used to install an aldehyde functional group on
the heterocycle (8). The aldehyde can then be further
functionalized by Wittig or Horner Emons reaction to produce olefin
substituted heterocyclic silyl ethers (9). (For examples see
Cadogan, J. I. G. Organophosphorus Reagents in Organic Synthesis,
Academic Press, 1979 and references therein). The silyl ether can
be cleaved using tetrabutyl ammonium fluoride in THF at room
temperature or above (For examples see Protective Groups in Organic
Synthesis, T. W. Greene and P. G. M. Wuts; John Wiley Publications
1998 and references therein). The resulting hydroxyl functionality
can be converted to the corresponding triflate using N-phenyl
triflimide and a base such as sodium hydride or sodium
hexamethyldisilazide in a solvent such as THF or DME at or below
room temperature. Coupling of the resulting triflate with a vinyl
(or alkynyl) stannane in the presence of lithium chloride and a
Pd(0) catalyst as described above produces the corresponding
bisalkenyl substituted heterocycles (10).
Bromo substituted heterocycles such as (11 and 12 scheme B) can be
converted into the analogous hydroxyl substituted system by first,
conversion to the borate ester (13) then oxidative cleavage of the
carbon boron bond with an oxidant such as aqueous hydrogen peroxide
in the presence of acid or base (such as acetic acid, sodium
carbonate or sodium hydroxide) or oxone in the presence of a base
(such as sodium carbonate) at or above 0.degree. C. (For examples
see Webb, K. S.; Levy, D. Tetrahedron Letts., 1995, 36, 5117. and
Koster, R.; Morita, Y. Angew. Chem., 1966, 78, 589).
##STR00088##
The resulting hydroxy substituted heterocycles (14) can be further
derivatized as already described above to give ether (15) or
alkenyl (16) substituted side chains. Certain heterocyclic bromides
or chlorides situated ortho or para to a ring nitrogen can be
readily displaced with an alcohol in the presence of base such as
sodium hydride in a solvent such as Toluene, DMSO, THF, DMPU or
HMPA at or above room temperature (For examples see Kelly, T. R. et
al. J. Amer. Chem. Soc., 1994, 116, 3657 and Newkome, G. R. et al.
J. Org. Chem., 1977, 42, 1500). In particular, alcoholysis of a
2,6-dibromo-pyridine using a controlled stoichiometric amount of
alcohol reagent provides the alkoxy substituted-bromo-pyridine.
Subsequent reaction of this product with a further equivalent of
another alcohol provides the unsymmetrically dialkoxy-substituted
heterocycle. ##STR00089##
Similar procedures using 2,4-dichloro-pyrimidine or
2,6-dibromo-pyridazine provides the corresponding
dialkoxy-substituted pyrimidines and pyridazines. A simple alkoxy
group positioned ortho to a nitrogen in these heterocyclic systems
can be hydrolyzed to the corresponding hydroxy substituent using
aqueous hydrochloric acid normally at or above room temperature
(Scheme D). ##STR00090##
For example, treatment of the 2-methoxy-6-alkenyl-substituted
pyridine (17) with hydrochloric acid provides the 6-alkenyl
substituted pyridin-2-one. This intermediate, in turn, can be
further derivatized to the corresponding 2-alkoxy (18) or 2-alkyl
(19) substituted systems as previously described. A methyl,
methylene or methine group positioned ortho to a ring nitrogen in
these heterocyclic systems can be deprotonated with a base such as
an alkyl lithium or LDA in a solvent such as THF ether or LIMPA,
generally at low temperature (below 0.degree. C.) and the resulting
anion reacted with electrophiles such as aldehydes epoxides alkyl
halides or a,b-unsaturated carbonyl compounds to provide a variety
of functionalized side chain substituents. ##STR00091##
For example (Scheme E), 2-alkoxy-4-methyl-pyrimidine (20) is
treated with LDA at -78.degree. C. followed by an aldehyde to give
the corresponding hydroxy adduct. Subsequent dehydration with
trifluoroacetic acid in a solvent such as dichloromethane followed
by hydrogenation of the resulting olefin provides the
4-alkyl-2-alkoxy-pyrimidine (21).
As illustrated above, compounds of Formula I can be prepared by art
recognized procedures from known compounds or readily preparable
intermediates. Thus, in order to prepare a compound of the formula:
##STR00092## the following reactions or combinations of reactions
can be employed: ##STR00093## wherein: R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, a, b, c, d, A, and B
are as defined above; E is a chemical bond; Z is --CN, --COOR.sub.3
or tetrazol, and L is a leaving group, such as halo, tosylate, or
mesylate. Where A or B is O or S, any base normally employed to
deprotonate an alcohol or thiol may be used, such as sodium
hydride, sodium hydroxide, triethylamine, sodium bicarbonate or
diisopropylethylamine.
Reaction temperatures are in the range of about room temperature to
reflux, and reaction times vary from about 2 to about 96 hours. The
reactions are usually carried out in a solvent that will dissolve
both reactants and is inert to both as well. Suitable solvents
include, but are not limited to, diethyl ether, tetrahydrofuran,
N,N-dimethylformamide, dimethylsulfoxide, dioxane and the like.
In the case where B is SO or SO.sub.2 treatment of the thio
compound with m-chlorobenzoic acid or sodium periodate results in
the sulfinyl compound. Preparation of the sulfonyl compound may be
accomplished by known procedures such as dissolving the sulfinyl
compound in acetic acid and treating with 30% H.sub.2O.sub.2.
Those compounds where B is --C(.dbd.O)-- may be prepared by the
following reaction sequence: ##STR00094##
Condensation of the aldehyde with 1,3-propanedithiol results in the
dithiane compound. This may be carried out in chloroform at reduced
temperatures of about -20.degree. C., while bubbling HCl gas into
the reaction mixture. The dithiane compound is then treated with
N-butyl lithium in nonpolar solvent at about -78.degree. C. and
then reacted with the substituted benzyl chloride. This results in
addition of Ring III to the molecule. The dithiane moiety is then
treated with a mercuric chloride-mercuric oxide mixture to form the
complex which is then split off leaving the desired compound.
Those compounds where A is a chemical bond may be prepared by known
coupling methods, for example, the reaction of an appropriate alkyl
halide with an appropriate organometallic reagent such as a lithium
organocopper reagent (See Posner, Org. React. 22, 235-400 (1975),
Normant, Synthesis 63-80 (1972), Posner, "An introduction to
Synthesis Using Organocopper Reagents" p. 68-81, Wiley, New York,
1980); coupling of an appropriate lithium organocopper reagent, or
Grignard reagent, with a suitable ester of sulfuric or sulfonic
acid (see "An introduction to Synthesis Using Organocopper
Reagents" p. 68-81, Wiley, New York, 1980, Kharasch and Reinmuth
"Grignard Reactions of Non Metallic Substances", pp1277-1286,
Prentice-Hall, Englewood Cliffs, N.J., 1954); or other known
reactions for forming alkyl bonds (See March "Advanced Organic
Chemistry" p. 1149, Third Edition, Wiley, NY, 1985). ##STR00095##
where X' is halide, an ester of a sulfuric acid, or a sulfonic acid
ester, and Y' is a lithium organocopper reagent or a Grignard
reagent.
There is no particular restriction on the nature of the reagent or
solvent to be employed, provided that it has no adverse effect on
the reaction or on the reagents involved.
Alternatively, compounds where A is a chemical bond may be prepared
by reduction of appropriate compounds, wherein A is an ethylene
moiety, with a suitable reducing agent, for example
H.sub.2/Pd/C.
There is no particular restriction on the solvent or nature of the
reducing agent to be used in this reaction, and any solvent and
reducing agent conventionally used in reactions of this type may
equally be used here, provided that it has no adverse effect on
other parts of the molecule. An example of a suitable reducing
agent is H.sub.2/Pd/C. Other reducing reagents are known in the
art. For example, see: Mitsui and Kasahara, in Zabicky, "The
Chemistry of Alkenes", vol. 2, pp. 175-214, Interscience, NY, 1970;
and Rylander "Catalytic Hydrogenation over Platinum Metals," pp.
59-120, Academic Press, NY, 1967.
Those compounds wherein E is an ethylene moiety are prepared by
reacting the appropriate aldehyde or ketone with a substituted
Wittig reagent of the formula ##STR00096## Condensation results in
formation of the double bond. The Wittig reagent is prepared by
known art recognized procedure, such as reaction of triphenyl
phosphine or diethylphosphone with a suitable substituted
alkyl/aryl bromide followed by treatment with a strong
organometallic base such as n-BuLi or NaOH, resulting in the
desired ylide. Conventional Wittig reaction conditions may be used
in accordance with standard practice, for examples see Bestmann and
Vostrowsky, Top. Curr. Chem. 109, 85-164 (1983), and Pommer and
Thieme, Top. Curr. Chem. 109, 165-188 (1983).
There is no particular restriction on the nature of the solvent to
be employed, provided that it has no adverse effect on the reaction
or on the reagents involved.
Of course this Wittig condensation may also take place when the
Wittig reagent is formed on Ring II position of the molecule, which
is then condensed with an aldehyde.
There is no particular restriction on the nature of the solvent to
be employed, provided that it has no adverse effect on the reaction
or on the reagents involved.
There is no particular restriction on the solvent or nature of the
reducing agent to be used in this reaction, and any solvent and
reducing agent conventionally used in reactions of this type may
equally be used here, provided that it has no adverse effect on
other parts of the molecule. An Example of a suitable reducing
agent is H.sub.2/Pd/C. Other reducing reagents are known in the
art. For example, see: Mitsui and Kasahara, in Zabicky, "The
Chemistry of Alkenes", vol. 2, p. 175-214, Interscience, NY, 1970;
and Rylander "Catalytic Hydrogenation over Platinum Metals", p.
59-120, Academic Press, NY, 1967.
The tetrazole may be formed from the nitrile at various stages of
the synthesis by treatment with hydrazoic acid formed in situ from
sodium azide and an acid.
When B is --N(R.sub.20)C(O)--, or --C(O)N(R.sub.20)-- then
condensation of the acid halide with the appropriate amine will
give the desired compound as shown below in the following scheme.
##STR00097##
Those compounds where B and/or E are a chemical bond may also be
synthesized by coupling methods analogous to those for compounds
where A is a chemical bond as described above.
Furthermore, compounds of the invention may be easily synthesized
by solid phase methods, as outlined below, using imputs (XI)-(XVII)
as listed in schemes 105 and Table 3 below: ##STR00098##
TABLE-US-00001 TABLE 3 ##STR00099## ##STR00100## ##STR00101##
##STR00102## (XI) (XII) (XIII) (XIV) ##STR00103## ##STR00104##
##STR00105## ##STR00106## ##STR00107## ##STR00108## ##STR00109##
##STR00110## ##STR00111## ##STR00112## ##STR00113## ##STR00114##
##STR00115## ##STR00116## ##STR00117## ##STR00118## ##STR00119##
##STR00120## ##STR00121## ##STR00122## ##STR00123## ##STR00124##
##STR00125## ##STR00126## ##STR00127## ##STR00128## ##STR00129##
(XV) R.sub.22COCl (XVI) R.sub.22NCO (XVII) ##STR00130##
##STR00131## ##STR00132## ##STR00133## ##STR00134## ##STR00135##
##STR00136## ##STR00137## ##STR00138## ##STR00139## ##STR00140##
##STR00141## ##STR00142## ##STR00143## ##STR00144## ##STR00145##
##STR00146## ##STR00147## ##STR00148## ##STR00149##
##STR00150##
Similarly, other compounds of the invention can be made by a
skilled person using the above mentioned methodology.
Compounds useful according to the invention also may be prepared by
the application or adaptation of other known methods, by which is
meant methods used heretofore or described in the literature, for
example those described by R. C. Larock in Comprehensive Organic
Transformations, VCH publishers, 1989.
In the reactions described hereinafter, it may be necessary to
protect reactive functional groups, for example, hydroxy, amino,
imino, thio or carboxy groups, where these are desired in the final
product, so as to avoid their unwanted participation in the
reactions. Conventional protecting groups may be used in accordance
with standard practice. For examples, see T. W. Green and P. G. M.
Wuts in "Protective Groups in Organic Chemistry" John Wiley and
Sons, 1991; and J. F. W. McOmie in "Protective Groups in Organic
Chemistry" Plenum Press, 1973.
According to a further feature of the present invention, compounds
useful according to the invention may be prepared by
interconversion of other compounds of the invention.
A compound of the invention that includes a group containing at
least one nitrogen ring atom, preferably imine (.dbd.N--), may be
converted to the corresponding compound wherein at least one
nitrogen ring atom of the group is oxidized to an N-oxide,
preferably by reacting with a peracid, for example, peracetic acid
in acetic acid or m-chloroperoxybenzoic acid in an inert solvent
such as dichloromethane, at a temperature from about room
temperature to reflux, preferably at elevated temperature.
The products of this invention may be obtained as racemic mixtures
of their dextro and levorotatory isomers, since at least one
asymmetric carbon atom may be present. When two asymmetric carbon
atoms are present, the product may exist as a mixtures of
diastereomers based on syn and anti configurations. These
diastereomers may be separated by fractional crystallization. Each
diastereomer may then be resolved into dextro and levorotatory
optical isomers by conventional methods.
It will also be apparent to those skilled in the art that certain
compounds of Formula I may exhibit geometrical isomerism.
Geometrical isomers include the cis and trans forms of compounds of
the invention having an alkenyl moiety. The present invention
comprises the individual geometrical isomers and stereoisomers and
mixtures thereof.
Such isomers can be separated from their mixtures, by the
application or adaptation of known methods, for example
chromatographic techniques and recrystallization techniques, or
they are separately prepared from the appropriate isomers of their
intermediates, for example, by the application or adaptation of
methods described herein.
Resolution may best be carried out in the intermediate stage where
it is convenient to combine the racemic compound with an optically
active compound by salt formation, ester formation, or amide
formation to form two diasteromeric products. If an acid is added
to an optically active base, then two diastereomeric salts are
produced which possesses different properties and different
solubilities and can be separated by fractional crystallization.
When the salts have been completely separated by repeated
crystallization, the base is split off by acid hydrolysis, and
enantiomerically purified acids are obtained.
Compounds useful according to the invention are useful in the form
of the free base or acid or in the form of a pharmaceutically
acceptable salt thereof. All forms are within the scope of the
invention.
Where a compound useful according to the invention is substituted
with a basic moiety, acid addition salts are formed and are simply
a more convenient form for use; in practice, use of the salt form
inherently amounts to use of the free base form. The acids which
can be used to prepare the acid addition salts include preferably
those which produce, when combined with the free base,
pharmaceutically acceptable salts, that is, salts whose anions are
non-toxic to the patient in pharmaceutical doses of the salts, so
that the beneficial pharmaceutical effects of these compounds in
the free base are not vitiated by side effects ascribable to the
anions. Although pharmaceutically acceptable salts of said basic
compounds are preferred, all acid addition salts are useful as
sources of the free base form even if the particular salt, per se,
is desired only as an intermediate product as, for example, when
the salt is formed only for purposes of purification, and
identification, or when it is used as an intermediate in preparing
a pharmaceutically acceptable salt by ion exchange procedures.
Pharmaceutically acceptable salts useful within the scope of the
invention are those derived from the following acids: mineral
acids, such as hydrochloric acid, trifluoroacetic acid, sulfuric
acid, phosphoric acid and sulfamic acid; and organic acids, such as
acetic acid, citric acid, lactic acid, tartaric acid, malonic acid,
methanesufonic acid, ethanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and
the like. The corresponding acid addition salts comprise:
hydrohalides, e.g., hydrochloride and hydrobromide,
trifluoroacetates, sulfates, phosphates, nitrates, sulfamates,
acetates, citrates, lactates, tartarates, malonates, oxalates,
salicylates, propionates, succinates, fumarates, maleates,
methylene-bis-.beta.-hydroxynaphthoates, gentisates, mesylates,
isothionates, di-p-toluyltartrates, methane-sulfonates,
ethanesulfonates, benzenesulfonates, p-toluene-sulfonates,
cyclohexylsulfamates and quinates, respectively.
The acid addition salts of the compounds useful according to the
invention are prepared by reaction of the free base with the
appropriate acid, by the application or adaptation of known
methods. For example, the acid addition salts of the compounds of
this invention are prepared either by dissolving the free base in
aqueous or aqueous-alcohol solution or other suitable solvents
containing the appropriate acid, and isolating the salt by
evaporating the solution, or by reacting the free base and acid in
an organic solvent, in which case the salt separates directly or
can be obtained by concentration of the solution.
The compounds useful according to the invention may be regenerated
from the acid addition salts by the application or adaptation of
known methods. For example, parent compounds useful according to
the invention can be regenerated from their acid addition salts by
treatment with an alkali, e.g., aqueous sodium bicarbonate solution
or aqueous ammonia solution.
Where a compound useful according to the invention is substituted
with an acidic moiety, base addition salts may be formed, and are
simply a more convenient form for use; in practice, use of the salt
form inherently amounts to use of the free acid form. The bases
which can be used to prepare the base addition salts include
preferably those which produce, when combined with the free acid,
pharmaceutically acceptable salts, that is, salts whose cations are
non-toxic to the animal organism in pharmaceutical doses of the
salts, so that the beneficial pharmaceutical effects on the
activity of the compounds of the present invention in the free acid
are not vitiated by side effects ascribable to the cations.
Pharmaceutically acceptable salts useful according to the
invention, include for example alkali and alkaline earth metal
salts, including those derived from the following bases: sodium
hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide,
aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc
hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine,
arginine, omithine, choline, N,N'-dibenzylethylenediamine,
chloroprocaine, diethanolamine, procaine, diethylamine,
N-benzylphenethylamine, piperazine,
tris(hydroxymethyl)aminomethane, tetramethylammonium hydroxide, and
the like.
Metal salts of compounds useful according to the present invention
may be obtained by contacting a hydride, hydroxide, carbonate or
similar reactive compound of the chosen metal in an aqueous or
organic solvent with the free acid form of the compound. The
aqueous solvent employed may be water or it may be a mixture of
water with an organic solvent, preferably an alcohol such as
methanol or ethanol, a ketone such as acetone, an aliphatic ether
such as tetrahydrofuran, or an ester such as ethyl acetate. Such
reactions are normally conducted at ambient temperature but they
may, if desired, be conducted with heating.
Amine salts of compounds useful according to the present invention
may be obtained by contacting an amine in an aqueous or organic
solvent with the free acid form of the compound. Suitable aqueous
solvents include water and mixtures of water with alcohols such as
methanol or ethanol, ethers such as tetrahydrofuran, nitrites such
as acetonitrile, or ketones such as acetone. Amino acid salts may
be similarly prepared.
The base addition salts of the compounds useful according to the
invention can be regenerated from the salts by the application or
adaptation of known methods. For example, parent compounds useful
according to the invention can be regenerated from their base
addition salts by treatment with an acid, e.g. hydrochloric
acid.
Salt forms useful according to the invention also include compounds
having a quarternarized nitrogen. The quarternarized salts are
formed by methods such as by alkylation of sp.sup.3 or sp.sup.2
hybridized nitrogen in the compounds.
As will be self-evident to those skilled in the art, some of the
compounds useful according to the invention do not form stable
salts. However, acid addition salts are most likely to be formed by
compounds useful according to the invention having a
nitrogen-containing heteroaryl group and/or wherein the compounds
contain an amino group as a substituent. Preferable acid addition
salts of the compounds useful according to the invention are those
wherein there is not an acid labile group.
As well as being useful in themselves as active compounds, the
salts of the compounds useful according to the invention are useful
for the purposes of purification of the compounds, for example by
exploitation of the solubility differences between the salts and
the parent compounds, side products and/or starting materials by
techniques well known to those skilled in the art.
Various substituents on the compounds useful according to the
invention, e.g., as defined in R, R.sub.1 and R.sub.2, can be
present in the starting compounds, added to any one of the
intermediates or added after formation of the final products by
known methods of substitution or conversion reactions. If the
substituents themselves are reactive, then the substituents can
themselves be protected according to the techniques known in the
art. A variety of protecting groups known in the art may be
employed. Examples of many of these possible groups may be found in
"Protective Groups in Organic Synthesis" by T. W. Green, John Wiley
and Sons, 1981. For example, nitro groups can be added to the
aromatic ring by nitration, and the nitro groups then converted to
other groups, such as amino, by reduction, and halo, by
diazotization of the amino group and replacement of the diazo
group. Acyl groups can be substituted onto the aryl groups by
Friedel-Crafts acylation. The acyl groups then can be transformed
to the corresponding alkyl groups by various methods, including the
Wolff-Kishner reduction and Clemmenson reduction. Amino groups can
be alkylated to form mono and dialkylamino groups; and mercapto and
hydroxy groups can be alkylated to form corresponding ethers.
Primary alcohols can be oxidized by oxidizing agents known in the
art to form carboxylic acids or aldehydes, and secondary alcohols
can be oxidized to form ketones. Thus, substitution or alteration
reactions can be employed to provide a variety of substituents
throughout the molecule of the starting material, intermediates, or
the final product.
The starting materials and intermediates are prepared by the
application or adaptation of known methods, for example methods as
described in the Reference Examples or their obvious chemical
equivalents.
The present invention is further exemplified but not limited by the
following examples, which illustrate the preparation of the
compounds according to the invention.
EXAMPLE 1
3-(2-Quinolinylmethyloxy)benzyl Alcohol
A mixture of 12.8 g (0.06 mol) of 2-quinolinylmethyl chloride HCl,
7.5 g (0.06 mol) of 3-hydroxybenzyl alcohol, and 18 g of potassium
carbonate in 50 ml of DMF is heated at 70.degree. C. overnight. The
reaction mixture is poured into water, and the precipitated product
is collected, filtered and dried to give
3-(2-quinolinylmethyloxy)benzyl alcohol.
EXAMPLE 2
When 2-quinolinylmethyl chloride of Example 1 above is replaced by
the quinoline compounds of Table 1 below, then the corresponding
product is obtained.
TABLE-US-00002 TABLE I 2-chloromethylquinoline
2-bromomethylquinoline 2-(1-chloroethyl)quinoline
2-(2-chloroethyl)quinoline 2-bromomethylquinoline
3-chloromethylquinoline 4-chloromethylquinoline
2-(.beta.-chloroethyl)quinoline 2-(.beta.-chloropropyl)quinoline
2-(.beta.-chloro-.beta.-phenethyl)quinoline
2-chloromethyl-4-methylquinoline 2-chloromethyl-6-methylquinoline
2-chloromethyl-8-methylquinoline 2-chloromethyl-6-methoxyquinoline
2-chloromethyl-6-nitroquinoline
2-chloromethyl-6,8-dimethylquinoline
EXAMPLE 3
When 3-hydroxybenzyl alcohol of Example 1 above is replaced by the
compounds of Table II below, then the corresponding product is
obtained.
TABLE-US-00003 TABLE II 1,2-benzenediol 1,3-benzenediol
1,4-benzenediol 2-mercaptophenol 3-mercaptophenol 4-mercaptophenol
1,3-dimercaptobenzene 1,4-dimercaptobenzene 3-hydroxybenzyl alcohol
3-hydroxyethylphenol 4-hydroxybenzyl alcohol 4-hydroxyethylphenol
2-methylresorsinol 5-methylresorsinol 5-methoxyresorsinol
5-methyl-1,4-dihydroxybenzene 3-(N-acetylamino)phenol
3-(N-acetylamino)benzyl alcohol 2-hydroxy-.alpha.-methylbenzyl
alcohol 2-hydroxy-.alpha.-ethylbenzyl alcohol
2-hydroxy-.alpha.-propylbenzyl alcohol
3-hydroxy-.alpha.-methylbenzyl alcohol
3-hydroxy-.alpha.-ethylbenzyl alcohol
3-hydroxy-.alpha.-propylbenzyl alcohol
4-hydroxy-.alpha.-methylbenzyl alcohol
4-hydroxy-.alpha.-ethylbenzyl alcohol
4-hydroxy-.alpha.-propylbenzyl alcohol
EXAMPLE 4
When the compounds of Table I, Example 2, are reacted with the
compounds of Table II, Example 3, under the conditions of Example
1, then the corresponding products are obtained.
EXAMPLE 5
3-(2-Quinolinylmethyloxy)benzyl Chloride
To a stirred solution of 14.5 g of 3-(2-quinolinylmethyloxy)benzyl
alcohol in 150 ml of CHCl.sub.3 is added dropwise 7.5 ml of thionyl
chloride during 10 min. The reaction mixture is stirred for 4 hours
at room temperature, and then washed with NaHCO.sub.3 solution. The
organic solution is separated, dried, and evaporated to give
3-(2-quinolinylmethyloxy)benzyl chloride, which is used without
further purification in the next step.
EXAMPLE 6
When the compounds prepared by Examples 2-4 are used in place of
3-(2-quinolinylmethyloxy)benzyl alcohol in Example 5, then the
corresponding chloride is prepared.
EXAMPLE 7
.alpha.-(3-Hydroxymethylphenoxy)acetonitrile
A mixture of 3-hydroxymethyl phenol (0.081 mol), bromoacetonitrile
(0.081 mol) and anhydrous potassium carbonate (0.081 mol) in
acetone (160 ml) and dimethylformamide (20 ml) is heated at reflux
for 48 hrs. The reaction mixture is filtered and evaporated. The
residue is diluted with ethyl acetate (150 ml), washed with 10%
aqueous sodium hydroxide solution (3.times.100 ml) and then with
brine (3.times.100 ml). The ethyl acetate solution is dried
(magnesium sulfate) and chromatographed using a silica gel column
(ca. 100 g) and eluted with 1:1 petroleum ether:ethylacetate (21).
The resultant oil is used directly in the next step.
EXAMPLE 8
.alpha.-(3-Chloromethylphenoxy)acetonitrile
.alpha.-(3-Hydroxymethylphenoxy)acetonitrile (0.055 mol) in
diethylether (150 ml) is stirred with thionyl chloride (0.060 mol)
and a few drops of dimethylformamide at 40.degree. C. for 1 hr.
Then the solution is washed with water and brine, and then
evaporated to give .alpha.-(3-chloromethylphenoxy)acetonitrile as a
yellow oil.
EXAMPLE 9
When bromoacetonitrile of Example 7 is replaced by the nitriles of
Table XII below then the corresponding product is prepared:
TABLE-US-00004 TABLE XII .alpha.-bromo-.alpha.-methylacetonitrile
.alpha.-bromo-.beta.-ethylacetonitrile .alpha.-bromopropionitrile
.beta.-bromopropionitrile
.beta.-bromo-.beta.-methylpropionitrile-bromobutyronitrile
.beta.-bromobutyronitrile .alpha.-bromobutyronitrile
EXAMPLE 10
When 3-hydroxymethylphenol of Example 7 is replaced by the
compounds of Table XIIIa below, then the corresponding products are
prepared.
TABLE-US-00005 TABLE XIIIa 2-hydroxymethylphenol
4-hydroxymethylphenol 3-mercaptobenzylalcohol
4-mercaptobenzylalcohol 3-hydroxymethyl-N-acetylamidine
4-hydroxymethyl-N-acetylamidine 4-hydroxymethylamidine
4-methyl-2-hydroxymethylphenol 2-methyl-5-hydroxymethylphenol
4-methyl-3-hydroxymethylphenol 5-methyl-3-hydroxymethylphenol
3-methyl-4-hydroxymethylphenol 2-methyl-4-hydroxymethylphenol
3-methyl-5-hydroxymethylphenol 4-methoxy-3-hydroxymethylphenol
3-methoxy-4-hydroxymethylphenol 2-methoxy-4-hydroxymethylphenol
5-methoxy-3-hydroxymethylphenol 3-methoxy-5-hydroxymethylphenol
2-methoxy-5-hydroxymethylphenol 2-(1'-hydroxyethyl)phenol
3-(1'-hydroxyethyl)phenol 4-(1'-hydroxyethyl)phenol
2-(2'-hydroxyethyl)phenol 3-(2'-hydroxyethyl)phenol
4-(2'-hydroxyethyl)phenol 2-(3'-hydroxypropyl)phenol
3-(3'-hydroxypropyl)phenol 4-(3'-hydroxypropyl)phenol
2-(2'-hydroxypropyl)phenol 3-(2'-hydroxypropyl)phenol
4-(2'-hydroxypropyl)phenol 2-(1'-hydroxypropyl)phenol
3-(1'-hydroxypropyl)phenol 4-(1'-hydroxypropyl)phenol
3-(4'-hydroxybutyl)phenyl 4-(4'-hydroxybutyl)phenyl
EXAMPLE 11
5-(3-Chloropropyl)tetrazole
A mixture of 3.5 g of 4-chlorobutyronitrile, 2.3 g of sodium azide
and 1.9 g of ammonium chloride in 50 ml of dimethyl-formamide is
stirred at 140.degree. C. for 20 hours. The reaction mixture is
poured onto ice, basified with 1N sodium hydroxide and extracted
twice with ethyl acetate. The aqueous fraction is acidified with
acetic acid and extracted with ethylacetate. Evaporation of the
ethyl acetate gives 5-(3-chloropropyl)-tetrazole, which is used
directly in the next step.
EXAMPLE 12
When 4-chlorobutyronitrile of Example 11 above is replaced by the
nitrites of Table XIX below then the corresponding tetrazole
product is obtained.
TABLE-US-00006 TABLE XIX chloroacetonitrile bromoacetonitrile
3-chloropropionitrile 4-chlorobutyronitrile 5-chloropentanonitrile
6-chlorohexanonitrile 2-chloropropionitrile
2-methyl-3-chloropropionitrile 2-chlorobutyronitrile
3-chlorobutyronitrile 4-methyl-5-chloropentanonitrile
2-methyl-3-chloropropionitrile 3-benzyl-4-chlorobutyronitrile
3-carboxymethyl-4-chlorobutyronitrile
3-methoxymethyl-4-chlorobutyronitrile
2,3-dimethyl-4-chloropentanonitrile
3,3-dimethyl-4-chloropentanonitrile
spiro-(3,3-cyclopropane)-4-chlorobutyronitrile
1-chloromethyl-2-cyanomethylcyclobutane
1-chloromethyl-2-cyanomethylcyclobutane
3-cyclopropylmethyl-4-chlorobutyronitrile
3-dimethylaminomethyl-4-chlorobutyronitrile
3-methylene-4-chlorobutyronitrile
3-propylidene-4-chlorobutyronitrile
EXAMPLE 13
Ethyl-4-benzyloxy-2-hydroxy-6-methyl-benzoate
Ethyl-2,4-dihydroxy-6-methyl benzoate (4 g, 21 mmol) is dissolved
in acetone (80 mL) and to this solution is added potassium
carbonate (2.9 g, 21 mmol) and benzyl bromide (2.5 mL, 21 mmol).
This mixture is heated at reflux for 16 hours. To the cooled
reaction is added ethyl acetate (100 mL) and water (100 mL). The
organic layer is washed with water (2.times.80 mL) and brine
(2.times.80 mL), then dried over magnesium sulfate and the solvent
removed in vacuo. The crude is purified by column chromatography
(silica, 10% ethyl acetate in hexanes) to give the title compound:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.38 (m, 5H), 6.41 (d,
1H), 6.38 (d, 1H), 5.05 (s, 2H), 4.40 (q, 2H), 2.51 (s, 3H), 1.40
(t, 3H).
EXAMPLE 13a
Ethyl 2,4-bis-(4-Fluoro-benzyloxy)-6-methyl-benzoate
The title compound is prepared using essentially the same procedure
used in EXAMPLE 13 except using the twice the amount of
4-fluorobenzyl bromide in place of benzyl bromide.
EXAMPLE 14
Ethyl-4-benzyloxy-2-methyl-6-(3-phenyl-propoxy)-benzoate
Ethyl-4-benzyloxy-2-hydroxy-6-methyl-benzoate (0.5 g, 1.8 mmol) is
dissolved in DMF (10 mL) and 60% sodium hydride (0.07 g, 1.8 mmol)
is added and stirred 20 minutes, forming a clear solution. Then
1-bromo-3-phenyl propane (0.27 mL, 1.8 mol) is added and this
mixture is heated at 100.degree. C. for 4 hours and stirred at room
temperature overnight. The solvent is removed in vacuo and the
residue purified by flash chromatography (silica, 5% ethyl acetate
in hexanes) to give the title compound: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.17-7.40 (m, 10H), 6.39 (d, 1H), 6.33 (d, 1H),
5.03 (s, 2H), 4.38 (q, 2H), 3.91 (t, 2H), 2.77 (t, 2H), 2.30 (s,
3H), 2.05 (m, 2H), 1.38 (t, 3H); MS (EI) 404 (M).sup.+.
The following compounds are prepared using essentially the same
procedure used in EXAMPLE 14 except using the cited bromide in
place of 1-bromo-3-phenyl propane.
EXAMPLE 14a
Ethyl-4-benzyloxy-2-cyclohexylmethoxy-6-methyl-benzoate
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.32-7.41 (m, 5H), 6.36
(m, 2H), 5.04 (s, 2H), 4.35 (q, 2H), 3.71 (d, 2H), 2.28 (s, 3H),
1.71 (m, 5H), 1.34 (t, 3H), 0.88-1.24 (m, 6H); MS (EI) 383
(M).sup.+. Prepared from cyclohexyl methyl bromide.
EXAMPLE 14b
Ethyl-4-benzyloxy-2-methyl-6-(4-methylpentyloxy)-benzoate
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.32-7.41 (m, 5H), 6.37
(d, 2H), 5.04 (s, 2H), 4.35 (q, 2H), 3.90 (t, 2H), 2.28 (s, 3H),
1.68-1.78 (m, 2H), 1.55-1.59 (m, 2H), 1.26-1.39 (m, 5H), 0.89 (d,
4H); MS (EI) 370 (M).sup.+. Prepared from
1-bromo-4-methylpentane.
EXAMPLE 15
4-Benzyloxy-2-methyl-6-(3-phenyl-propoxy)-benzoic Acid
Ethyl-4-benzyloxy-2-methyl-6-(3-phenyl-propoxy)-benzoate (0.57 g,
1.4 mmol) and 10 N sodium hydroxide (1.4 mL, 14 mmol) are combined
in ethanol (6 mL) and heated at reflux for 6 hours. The solvent is
removed in vacuo and dichloromethane is added to the residue. Then
1 N hydrochloric acid is added to acidify the mixture to pHI. The
aqueous layer is extracted once with dichloromethane and the
combined organic layers washed once with water. The organic layer
is dried over magnesium sulfate and the solvent removed in vacuo to
give the title compound as a tan solid. The solid is recrystallized
from ethyl acetate/petroleum ether to provide an analytically pure
sample; m.p. 109-111.degree. C., .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.18-7.41 (m, 10H), 6.55 (d, 1H), 6.41 (d, 1H), 5.07 (s,
2H), 4.10 (t, 2H). 2.81 (t, 2H), 2.62 (s, 3H), 2.16-2.21 (m, 2H);
MS (EI) 376 (M).sup.+.
The following compounds are prepared using essentially the same
procedure used in EXAMPLE 12 except using the cited ester in place
of ethyl-4-benzyloxy-2-(1-phenyl-3-propoxy)-6-methyl benzoate.
EXAMPLE 15a
4-Benzyloxy-2-cyclohexylmethoxy-6-methyl-benzoic Acid
M.p. 127-8.degree. C. (ethyl acetate/petroleum ether); .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.35-7.42 (m, 5H), 6.55 (d, 1H), 6.46
(d, 1H), 5.09 (s, 2H), 3.91 (d, 2H), 2.63 (s, 3H), 1.75-1.86 (m,
6H), 1.05-1.32 (m, 5H); MS (EI) 354 (M).sup.+. Prepared from
ethyl-4-benzyloxy-2-cyclohexylmethoxy-6-methyl-benzoate.
EXAMPLE 15b
4-Benzyloxy-2-methyl-6-(4-methyl-pentyloxy)-benzoic Acid
M.p. 83-5.degree. C. (ethyl acetate/petroleum ether); .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. 7.35-7.42 (m, 5H), 6.55 (d, 1H), 6.47
(d, 1H), 5.09 (s, 2H), 4.10 (t, 2H), 2.63 (s, 3H), 1.83-1.89 (m,
2H), 1.58-1.63 (m, 1H), 1.32-1.37 (m, 2H), 0.92 (d, 4H); MS (EI)
342 (M).sup.+. Prepared from
ethyl-4-benzyloxy-2-methyl-6-(4-methyl-pentyloxy)-benzoate.
EXAMPLE 15c
2,4-bis-(4-Fluoro-benzyloxy)-6-methyl-benzoic Acid
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.39-7.35 (m, 4H),
7.11-7.03 (m, 4H), 6.49 (d, 2H), 5.10 (s, 2H), 5.02 (s, 2H), 2.54
(s, 3H); MS (EI) 384 (M).sup.+. Prepared from ethyl
2,4-bis-(4-fluoro-benzyloxy)-6-methyl-benzoate.
EXAMPLE 16
2-(3-Iodophenoxymethyl)-naphthalene
To a solution of 3-iodophenol (4.0 g, 18 mmol) in ethanol (40 mL)
is added potassium hydroxide (1.0 g, 18 mmol) and 2-(bromomethyl)
naphthalene (4.0 g, 18 mmol) and this mixture is refluxed
overnight. The hot reaction is filtered and the filtrate is chilled
in ice. The ensuing precipitate is collected by filtration to give
the title compound. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.84-7.89 (m, 4H), 7.48-7.53 (m, 3H), 7.40 (d, 1H), 7.29-7.32 (m,
1H), 6.95-7.04 (m, 2H), 5.20 (s, 2H); MS (EI) 360 (M).sup.+.
EXAMPLE 17
6-[3-(Naphthalen-2-ylmethoxy)-phenyl]-hex-5-ynoic Acid
A solution of 2-(3-iodophenoxymethyl)-naphthalene (0.5 g, 1.4 mmol)
and hexynoic acid (0.19 g, 1.7 mmol) in piperidine (5 mL) is purged
with Argon for 20 minutes. Then bis(triphenylphosphine)palladium
dichloride (0.01 g, 0.014 mmol) and cuprous iodide (0.005 g, 0.028
mmol) are added and this mixture heated in an oil bath at
75.degree. C. for 1.5 hours and then allowed to come to room
temperature overnight. The solvent was removed in vacuo and the
residue purified by flash chromatography (silica, 4% methanol in
dichloromethane) to give the title compound. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.83-7.88 (m, 4H), 7.48-7.54 (m, 3H), 7.19 (t,
1H), 6.98-7.05 (m, 3H), 5.21 (s, 2H), 2.47 (t, 2H), 1.80-1.91 (m,
4H); MS (EI) 344 (M).sup.+.
EXAMPLE 18
6-[3-(Naphthalen-2-ylmethoxy)-phenyl]-hexanoic Acid
To a solution of 6-[3-(naphthalen-2-ylmethoxy)-phenyl]-hex-5-ynoic
acid (0.54 g, 1.4 mmol) in methanol (15 mL) is added 10% Pd/C (0.10
g) and this mixture is placed on a Parr apparatus and pressurized
to 43 psi with hydrogen. This reaction is allowed to shake
overnight. The reaction is filtered and the solvent removed in
vacuo. The residue is purified by flash chromatography (silica, 5%
methanol in dichloromethane) to give the title compound. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.83-7.89 (m, 4H), 7.46-7.56 (m,
3H), 7.17-7.22 (m, 1H), 6.77-6.85 (m, 3H), 5.21 (s, 2H), 2.59 (t,
2H), 2.31 (t, 2H), 1.58-1.70 (m, 6H); MS (EI) 348 (M).sup.+.
EXAMPLE 19
t-Butyl-diphenyl(3-iodo-benzyloxy)silane
To a solution of 3-iodo-benzyl alcohol (4.68 g, 20 mmol) in
CH.sub.2Cl.sub.2 (40 mL) is added imidazole (1.49 g, 22 mmol) and
t-butyldiphenylsilyl chloride (5.74 g, 22 mmol). The resulting
mixture is stirred for 1 h diluted with ether washed with water and
brine, dried over MgSO.sub.4 and concentrated to give the title
compound as an oil (9.41 g). MS (EI) 472 (M).sup.+.
EXAMPLE 20
6-[3-(t-Butyldiphenylsilyloxymethyl)-phenyl]-hex-5-ynol
To a solution of t-Butyl-diphenyl(3-iodo-benzyloxy)silane (8.49 g,
18 mmol) in THF (70 mL) is added hex-5-ynol (2.5 mL, 22 mmol) and
(Ph.sub.3P).sub.4Pd (990 mg, 0.85 mmol) and CuI (171 mg, 0.9 mmol).
This solution is degassed and placed under an argon atmosphere. To
this solution is added piperidine (5.4 mL, 54 mmol) and stirring
continued for 4 h. The reaction mixture is diluted with ether,
washed with water and brine, dried over MgSO.sub.4 and
concentrated. The residue is purified by flash chromatography
(silica, 30% ethyl acetate in hexanes) to give the title compound
as an oil (6.84 g). .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 7.70
(m, 4H), 7.40 (m, 6H), 7.27 (m, 4H), 4.71 (s, 2H), 3.71 (t, 2H),
2.47 (t, 2H), 1.74 (m, 4H), 1.10 (s, 9H).
EXAMPLE 21
6-[3-(t-Butyldiphenylsilyloxymethyl)-phenyl]-hexanol
To a solution of
6-[3-(t-Butyldiphenylsilyloxymethyl)-phenyl]-hex-5-ynol (880 mg, 2
mmol) in ethyl acetate (10 mL) is added Pd on Carbon (120 mg, 10%
Pd by wt.). The mixture is stirred under a hydrogen atmosphere for
17 h, purged with argon filtered through celite concentrated to
give the title compound (5.9 g) as an oil. MS (EI) 389
(M-tBu).sup.+.
EXAMPLE 22
6-[3-(t-Butyldiphenylsilyloxymethyl)-phenyl]-hexanoic Acid
To a solution of
6-[3-(t-Butyldiphenylsilyloxymethyl)-phenyl]-hexanol (5.9 g, 13.2
mmol) in acetonitrile (28 mL) is added CCl.sub.4 (28 mL) and water
(43 mL). To this mixture is added NaIO4 (11.7 g, 54 mmol) and
RuCl3(H2O) (100 mg, 0.5 mmol). The resulting mixture is stirred for
2 h then diluted with ethyl acetate, washed with water and brine,
dried over MgSO.sub.4 and activated charcoal, filtered through
celite and concentrated. The residue is purified by flash
chromatography (silica, 20% ethyl acetate/5% dichloromethane in
hexanes) to give the title compound (3.46 g) as an oil. MS (ESI)
461 (M+H).sup.+.
EXAMPLE 23
6-[3-(tert-Butyl-diphenyl-silanyloxymethyl)-phenyl]-hexanoic Acid
Methyl Ester
To a solution of
6-[3-(tert-butyl-diphenyl-silanyloxymethyl)-phenyl]-hexanoic acid
(3.3 g, 7.2 mmol) in DMF (15 mL) is added potassium carbonate (1.09
g, 7.9 mmol) and iodomethane (500 .mu.L, 7.9 mmol). The mixture is
stirred for 6 hrs then diluted with ether. The organic layer is
washed with water, brine, dried over MgSO.sub.4 and concentrated.
The residue is purified by flash chromatography (eluting with 10%
ether/hexanes) to give 2.42 g of title compound. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.70 (m, 4H), 7.38 (m, 6H), 7.20 (m, 2H),
7.12 (s, 1H), 7.06 (d, 1H), 4.76 (s, 2H), 3.65 (s, 3H), 2.59 (t,
2H), 2.30 (t, 2H), 1.64 (m, 4H), 1.37 (m, 2H), 1.10 (s, 9H).
EXAMPLE 24
6-(3-Hydroxymethyl-phenyl)-hexanoic Acid Methyl Ester
To a solution of
6-[3-(tert-butyl-diphenyl-silanyloxymethyl)-phenyl]-hexanoic acid
methyl ester (2.37 g, 5 mmol) in THF (10 mL) is added acetic acid
(283 .mu.L, 5 mmol) and 1M TBAF (5 mL). The solution is stirred for
2 hrs then diluted with EtOAc/ether (1:1). The organic layer is
washed with water, brine, dried over MgSO.sub.4 and concentrated.
The residue is purified by flash chromatography (eluting with 35%
ethyl acetate/hexanes) to give 1.12 g of title compound. MS (EI)
236 (M.sup.+).
EXAMPLE 25
6-(3-Bromomethyl-phenyl)-hexanoic Acid Methyl Ester
To a solution of 6-(3-hydroxymethyl-phenyl)-hexanoic acid methyl
ester (587 mg, 2.48 mmol) in THF (10 mL) is added
triphenylphosphine (716 mg, 2.73 mmol), stirred until homogeneous
then cooled to 0.degree. C. NBS (486 mg, 2.73 mmol) is added
portionwise and the reaction mixture stirred for 45 min. The
mixture is concentrated and the residue is purified by flash
chromatography (eluting with 10% ethyl acetate/hexanes) to give 682
mg of title compound. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
7.23 (m, 3H), 7.10 (m, 1H), 4.48 (s, 2H), 3.66 (s, 3H), 2.60 (t,
2H), 2.31 (t, 2H), 1.63 (m, 4H), 1.37 (m, 2H).
EXAMPLE 26
6-Methoxy-3-methyl-1,3-dihydro-indol-2-one
To a cooled solution (-78.degree. C.) of
6-methoxy-1,3-dihydro-indol-2-one (840 mg, 5.2 mmol, see Quallich,
G. J.; Morrissey, P. M. Synthesis 1993, 51-53) in THF (20 mL) is
added dropwise TMEDA (1.57 mL, 10.4 mL) followed by dropwise
addition of 2.5M n-BuLi (4.16 mL, 10.4 mmol). The mixture is
stirred for 15 min then warmed to -25.degree. C. Add dropwise
iodomethane (405 .mu.L, 6.5 mmol) and let stir for 20 min. The
reaction is quenched with sat NH.sub.4Cl soln, warmed to room temp
and diluted with EtOAc. The organic layer is washed with sat
NH.sub.4Cl soln, brine, dried over MgSO.sub.4 and concentrated. The
residue is purified by flash chromatography (eluting with 45% ethyl
acetate/hexanes) to give 679 mg of title compound.
MS (ESI) 178 (M+H).sup.+.
EXAMPLE 27
6-Methoxy-3,3-dimethyl-1,3-dihydro-indol-2-one
To a cooled solution (-78.degree. C.) of
6-methoxy-3-methyl-1,3-dihydro-indol-2-one (679 mg, 3.83 mmol) in
THF (13 mL) is added TMEDA (1.16 mL, 7.66 mmol) followed by
dropwise addition of 2.5M n-BuLi (3.06 mL, 7.66 mmol). The mixture
is stirred for 15 min then warmed to -25.degree. C. Add dropwise
iodomethane (275 .mu.L, 4.40 mmol) and let stir for 30 min. The
reaction is quenched with sat NH.sub.4Cl soln, warmed to room temp
and diluted with EtOAc. The organic layer is washed with sat
NH.sub.4Cl soin, brine, dried over MgSO.sub.4 and concentrated. The
residue is purified by flash chromatography (eluting with 35% ethyl
acetate/hexanes) to give 601 mg of title compound as a white
crystalline solid. MS (ESI) 192 (M+H).sup.+.
EXAMPLE 28
6-Methoxy-1,3,3-trimethyl-1,3-dihydro-indol-2-one
To a cooled solution (-5.degree.-0.degree. C.) of
6-methoxy-3,3-dimethyl-1,3-dihydro-indol-2-one (600 mg, 3.14 mmol)
in THF (10.5 mL) is added 60% NaH (132 mg, 3.30 mmol) and the
mixture stirred for 15 min. Add dropwise to the reaction mixture
iodomethane (215 .mu.L, 3.45 mmol), the cold bath is removed and
stirred for 2 hrs. The reaction is quenched with sat NH.sub.4Cl
soln, warmed to room temp and diluted with EtOAc.
The organic layer is washed with sat NH.sub.4Cl soln, brine, dried
over MgSO.sub.4 and concentrated. The residue is purified by flash
chromatography (eluting with 30% ethyl acetate/hexanes) to give 601
mg of title compound as a white crystalline solid. MS (ESI) 206
(M+H).sup.+.
EXAMPLE 29
6-Hydroxy-1,3,3-trimethyl-1,3-dihydro-indol-2-one
To a solution of 6-methoxy-1,3,3-trimethyl-1,3-dihydro-indol-2-one
(601 mg, 2.93 mmol) in acetic acid (880 .mu.L) is added hydrobromic
acid (48% in H.sub.2O) (8.8 mL). The resulting solution is heated
to reflux (105.degree.-110.degree. C.), stirred 2 hrs, then cooled
to room temp and concentrated under reduced pressure. The residue
is dissolved in EtOAc and the organic layer washed with water,
brine, dried over MgSO.sub.4 and concentrated. The residue is
purified by triturating with a small volume of ether to give 495 mg
of title compound as an off white solid. MS (ESI) 192
(M+H).sup.+.
EXAMPLE 30
6-[3-(1,3,3-Trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yloxymethyl)-phenyl]-he-
xanoic Acid Methyl Ester
To a solution of 6-hydroxy-1,3,3-trimethyl-1,3-dihydro-indol-2-one
(396 mg, 2.07 mmol) in DMF (7.6 mL) is added
6-(3-Bromomethyl-phenyl)-hexanoic acid methyl ester (682 mg, 2.28
mmol) and potassium carbonate (315 mg, 2.28 mmol). The resulting
mixture is heated to 60.degree. C., stirred for 2 hrs. then cooled
to room temp and diluted with EtOAc. The organic layer is washed
with water, brine, dried over MgSO.sub.4 and concentrated. The
residue is purified by flash chromatography (eluting with 30% ethyl
acetate/hexanes) to give 352 mg of title compound. MS (ESI) 410
(M+H).sup.+.
EXAMPLE 31
6-[3-(1,3,3-Trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yloxymethyl)-phenyl]-he-
xanoic Acid
To a solution of
6-[3-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-6-yloxymethyl)-phenyl]-h-
exanoic acid methyl ester (110 mg, 0.27 mmol) in (1:1)
THF/CH.sub.3OH (1 mL) is added 250 .mu.L water and 10N NaOH soln
(270 .mu.L). The mixture is stirred for 16 hrs, cooled to 5.degree.
C., adjusted to pH 4 with 2N HCl soln. and diluted with EtOAc. The
organic layer is washed with brine, dried over MgSO.sub.4 and
concentrated. The residue is purified by flash chromatography
(eluting with 50% ethyl acetate/5% methanol/hexanes) to give 67 mg
of title compound. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.29
(m, 3H), 7.14 (d, 1H), 7.09 (d, 1H), 6.63 (dd, 1H), 6.52 (d, 1H),
5.04 (s, 2H), 3.18 (s, 3H), 2.64 (t, 2H), 2.36 (t, 2H), 1.66 (m,
4H), 1.40 (m, 2H), 1.34 (s, 6H). MS (ESI) 396 (M+H).sup.+.
EXAMPLE 32a
Methyl 2,6-Dimethyl-benzoate
To a cooled (0.degree. C.) solution of 2,6-dimethylbenzoic acid
(20.2 g, 134 mmol) in dichloromethane (200 mL) is added DMF (1 mL)
followed by oxalyl chloride (14 mL, 162 mmol). On complete
addition, the cold bath is removed and stirring continued for 3 h.
The resulting solution is concentrated under vacuum and the residue
added slowly to a cooled (0.degree. C.) solution comprising
methanol (200 mL) and triethylamine (40 mL). On complete addition
the reaction mixture is stirred for 30 min. then poured into
hydrochloric acid solution (400 mL, 2N) which is then extracted
with ether. The ether extract is washed with hydrochloric acid
solution (1N), sokium bicarbonate solution and brine; then dried
over MgSO.sub.4 and concentrated to give the title compound which
is used without further purification. MS (EI) 164 (M).sup.+.
The following compound is prepared using essentially the same
procedure used in EXAMPLE 32a, except using the cited alcohol in
place of methanol.
EXAMPLE 32b
Isobutyl 2,6-Dimethyl-benzoate
MS (EI) 206 (M).sup.+. Prepared from 2-methyl-1-propanol
EXAMPLE 33a
Methyl 2-Bromomethyl-6-methyl-benzoate
To a solution of methyl 2,6-dimethyl-benzoate (22.0 g, 134 mmol,
EXAMPLE 1) in CCl.sub.4 (250 mL) is added N-bromo-succinimide (19
g, 107 mmol) followed by benzoyl peroxide (1.0 g, 4.0 mmol). The
resulting solution is warmed to reflux and stirred at this
temperature for 20 min. The reaction mixture is then allowed to
cool before being diluted with ether (200 mL), filtered and
concentrated. The residue is purified by flash chromatography
(silica, 4% acetone in hexanes) to give the title compound. This
product (approx. 85% purity, remainder is methyl
2,6-dimethyl-benzoate) is used without further purification. MS
(EI) 242, 244 (M.sup.+ Br pattern).
The following compound is prepared using essentially the same
procedure used in EXAMPLE 33a, 20 except using the cited ester in
place of methyl 2,6-dimethyl-benzoate.
EXAMPLE 33b
Isobutyl 2-Bromomethyl-6-methyl-benzoate
MS (EI) 286, 288 (M.sup.+ Br pattern). Prepared from isobutyl
2,6-dimethyl-benzoate (EXAMPLE 32b).
EXAMPLE 34a
3-(Quinolin-2-ylmethoxy)-propan-1-ol
1,3-Propanediol (6.0 mL, 85 mmol) is dissolved in 20% DMPU in THF
(80 mL) and cooled to 0.degree. C. Sodium hydride (60%, 3.6 mg, 90
mmol) is added portionwise, and the contents are allowed to stir
for 15 min. at 0.degree. C. 2-Chloromethylquinoline (7.64 g, 42.7
mmol) is added and the reaction is allowed to stir overnight. The
reaction is poured into water (700 mL) and extracted with ethyl
acetate (1.times.200 mL). Sodium chloride is added to the aqueous
layer and extracted again with ethyl acetate (2.times.200 mL). The
organic layers are pooled and washed with water (2.times.300 mL)
and brine (2.times.300 mL), dried over MgSO.sub.4, filtered and
reduced under vacuum to an oil. The crude material is purified by
flash chromatography (silica, 2.5% methanol in dichloromethane) to
give the title compound. MS (ESI) 218 (M+H).sup.+.
The following compounds are prepared using essentially the same
procedure used in EXAMPLE 34a, except using the cited diol in place
of 1,3-propanediol.
EXAMPLE 34b
4-(Quinolin-2-ylmethoxy)-butan-1-ol
MS (ESI) 232 (M+H).sup.+. Prepared from 1,4-butanediol.
EXAMPLE 34c
5-(Quinolin-2-ylmethoxy)-pentan-1-ol
MS (ESI) 246 (M+H).sup.+. Prepared from 1,5-pentanediol.
EXAMPLE 34d
2-(Quinolin-2-ylmethoxy)-ethanol
MS (ESI) 204 (M+H).sup.+. Prepared from ethylene glycol.
EXAMPLE 34e
2,2-Dimethyl-3-(quinolin-2-ylmethoxy)-propan-1-ol
MS (ESI) 246 (M+H).sup.+. Prepared from neopentyl glycol.
EXAMPLE 35a
Methyl
2-Methyl-6-[3-(quinolin-2-ylmethoxy)-propoxymethyl]-benzoate
3-(Quinolin-2-ylmethoxy)-propan-1-ol (4.6 g, 21.2 mmol, EXAMPLE 3a)
is dissolved in 20% DMPU in THF (50 mL) and cooled to 0.degree. C.
Sodium hydride (60%, 920 mg, 23 mmol) is added portionwise, and the
contents are allowed to stir for 15 min. at 0.degree. C. Methyl
2-bromomethyl-6-methyl-benzoate (77%, 7.25 g, 23 mmol, EXAMPLE 2a)
is added and the reaction is allowed to warm to r.t. and continue
to stir overnight. The reaction is poured into water (600 mL) and
extracted with ethyl acetate (3.times.200 mL). The organic
fractions are pooled and washed with water (3.times.250 mL) and
brine (2.times.300 mL), dried over MgSO.sub.4, filtered and reduced
under vacuum to an oil. The crude material is purified by flash
chromatography (silica, 2% methanol in dichloromethane) to give the
title compound. MS (ESI) 380 (M+H).sup.+.
The following compounds are prepared using essentially the same
procedure used in EXAMPLE 35a, except using the cited alcohol in
place of 3-(quinolin-2-ylmethoxy)-propan-1-ol.
EXAMPLE 35b
Methyl
2-Methyl-6-[4-(quinolin-2-ylmethoxy)-butoxymethyl]-benzoate
MS (ESI) 394 (M+H).sup.+. Prepared from
4-(quinolin-2-ylmethoxy)-butan-1-ol (EXAMPLE 34b).
EXAMPLE 35c
Methyl
2-Methyl-6-[5-(quinolin-2-ylmethoxy)-pentoxymethyl]-benzoate
MS (ESI) 408 (M+H).sup.+. Prepared from
5-(quinolin-2-ylmethoxy)-pentan-1-ol (EXAMPLE 34c).
EXAMPLE 35d
Methyl
2-[2,2-Dimethyl-3-(quinolin-2-ylmethoxy)-propoxymethyl]-6-methyl-be-
nzoate
MS (ESI) 408 (M+H).sup.+. Prepared from
2,2-dimethyl-3-(quinolin-2-ylmethoxy)-propan-1-ol (EXAMPLE
34e).
EXAMPLE 36a
2-Methyl-6-[3-(quinolin-2-ylmethoxy)-propoxymethyl]-benzoic
Acid
Methyl 2-methyl-6-[3-(quinolin-2-ylmethoxy)-propoxymethyl]-benzoate
(3.3 g, 8.7 mmol, EXAMPLE 35a) is dissolved in ethanol (81 mL). 10
N NaOH (9 mL, 90 mmol) is added and the contents are heated to
90.degree. C. overnight. The reaction is cooled to r.t., and the
volume reduced under vacuum. 2 N HCl (45 mL, 90 mmol) is added, and
the pH is adjusted to .about.4. The contents are poured into water
(400 mL) and extracted with dichloromethane (3.times.200 mL). The
organic layers are combined, washed with brine (2.times.300 mL),
dried over MgSO.sub.4, filtered and reduced under vacuum to
dryness. The crude material is purified by flash chromatography
(silica, 3% methanol in dichloromethane) to give the title
compound. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.27 (d, 2H),
7.86 (d, 1H), 7.73 (dd, 1H), 7.60-7.50 (m, 2H), 7.26-7.11 (m, 3H),
5.01 (s, 2H), 4.70 (s, 2H), 3.84 (t, 2H), 3.73 (t, 2H), 2.50 (s,
3H), 1.89 (quintet, 2H). MS (ESI) 366 (M+H).sup.+.
The following compounds are prepared using essentially the same
procedure used in EXAMPLE 36a, except using the cited ester in
place of methyl
2-methyl-6-[3-(quinolin-2-ylmethoxy)-propoxymethyl]-benzoate.
EXAMPLE 36b
2-Methyl-6-[4-(quinolin-2-ylmethoxy)-butoxymethyl]-benzoic Acid
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.29-8.22 (m, 2H), 7.83
(d, 1H), 7.77-7.71 (m, 1H), 7.62-7.54 (m, 2H), 7.28-7.15 (m, 3H),
4.93 (s, 2H), 4.63 (s, 2H), 3.66 (t, 2H), 3.55 (t, 2H), 2.52 (s,
3H), 1.84-1.70 (m, 4H), MS (ESI) 380 (M+H).sup.+. Prepared from
methyl
2-methyl-6-[4-(quinolin-2-ylmethoxy)-butoxymethyl]-benzoate.
EXAMPLE 36c
2-Methyl-6-[5-(quinolin-2-ylmethoxy)-pentoxymethyl]-benzoic
Acid
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.22 (d, 2H), 7.84 (d,
1H), 7.75-7.64 (m, 2H), 7.58-7.53 (m, 1H), 7.25-7.13 (m, 3H), 4.93
(s, 2H), 4.62 (s, 2H), 3.68 (t, 2H), 3.53 (t, 2H), 2.41 (s, 3H),
1.72-1.63 (m, 6H); MS (ESI) 394 (M+H).sup.+. Prepared from methyl
2-methyl-6-[5-(quinolin-2-ylmethoxy)-pentoxymethyl]-benzoate
(EXAMPLE 35c).
EXAMPLE 36d
2-[2,2-Dimethyl-3-(quinolin-2-ylmethoxy)-propoxymethyl]-6-methyl-benzoic
Acid
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.25 (d, 2H), 7.85 (d,
1H), 7.72 (t, 1H), 7.59-7.48 (m, 2H), 7.23-7.10 (m, 3H), 4.94 (s,
2H), 4.64 (s, 2H), 3.46 (s, 2H), 3.34 (s, 2H), 2.49 (s, 3H), 0.96
(s, 6H). MS (ESI) 3.94 (M+H).sup.+. Prepared from methyl
2-[2,2-dimethyl-3-(quinolin-2-ylmethoxy)-propoxymethyl]-6-methyl-benzoate
(EXAMPLE 35d).
The following compounds are prepared using essentially the same
procedure used in EXAMPLE 35a, except without DMPU as a co-solvent;
using the cited alcohol in place of
3-(quinolin-2-ylmethoxy)-propan-1-ol, the cited alkylating reagent
in place of methyl 2-bromomethyl-6-methyl-benzoate.
EXAMPLE 37a
{2-Methyl-6-[3-(quinolin-2-ylmethoxy)-propoxymethyl]-phenoxy}-acetonitrile
MS (ESI) 377 (M+H).sup.+. Prepared from
3-(quinolin-2-ylmethoxy)-propan-1-ol (EXAMPLE 34a) and
(2-bromomethyl-6-methyl-phenoxy)-acetonitrile.
EXAMPLE 37b
{2-Methyl-6-[4-(quinolin-2-ylmethoxy)-butoxymethyl]-phenoxy}-acetonitrile
MS (ESI) 391 (M+H).sup.+. Prepared from
4-(quinolin-2-ylmethoxy)-butan-1-ol (EXAMPLE 34b) and
(2-bromomethyl-6-methyl-phenoxy)-acetonitrile
EXAMPLE 37c
{2-Methyl-6-[2-(quinolin-2-ylmethoxy)-ethoxymethyl]-phenoxy}-acetonitrile
MS (ESI) 363 (M+H).sup.+. Prepared from
2-(quinolin-2-ylmethoxy)-ethanol (EXAMPLE 34d) and
(2-bromomethyl-6-methyl-phenoxy)-acetonitrile.
EXAMPLE 37d
{4-Chloro-2-methyl-6-[4-(quinolin-2-ylmethoxy)-butoxymethyl]-phenoxy}-acet-
onitrile
MS (ESI) 424 (M+H).sup.+. Prepared from
4-(quinolin-2-ylmethoxy)-butan-1-ol (EXAMPLE-34b) and
(2-bromomethyl-4-chloro-6-methyl-phenoxy)-acetonitrile.
EXAMPLE 37e
{4-Chloro-2-[2,2-dimethyl-3-(quinolin-2-ylmethoxy)-propoxymethyl]-6-methyl-
-phenoxyl}-acetonitrile
MS (ESI) 439 (M+H).sup.+. Prepared from
2,2-dimethyl-3-(quinolin-2-ylmethoxy)-propan-1-ol (EXAMPLE 34e) and
(2-bromomethyl-4-chloro-6-methyl-phenoxy)-acetonitrile.
EXAMPLE 38a
{2-Methyl-6-[3-(quinolin-2-ylmethoxy)-propoxvmethyl]-phenoxy}-acetic
Acid
{2-Methyl-6-[3-(quinolin-2-ylmethoxy)-propoxymethyl]-phenoxy}-acetonitril-
e (333 mg, 0.89 mmol, EXAMPLE 6a) is dissolved in ethanol (8 mL).
10 N NaOH (900 .mu.L, 9.0 mmol) is added and the contents heated to
60.degree. C. for 2 hrs. The reaction is cooled to r.t. and the pH
adjusted to .about.4 with 2 N HCl. The contents are partioned
between aq. NH.sub.4Cl (10%, 100 mL) and ethyl acetate (100 mL).
The aqueous layer is further extracted with ethyl acetate
(2.times.75 mL). The organic fractions are combined and washed with
sat. aq. NH.sub.4Cl (2.times.125 mL), dried over MgSO.sub.4,
filtered and reduced under vacuum to an oil. The crude material is
purified by flash chromatography (silica, 6% methanol in
dichloromethane) to give the title compound. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.29-8.21 (m, 2H), 7.82 (d, 1H), 7.75 (t, 1H),
7.56 (dd, 1H), 7.50 (d, 1H), 7.15 (dd, 2H), 7.00 (dd, 1H), 4.79 (s,
2H), 4.61 (s, 2H), 4.55 (s, 2H), 3.70-3.47 (m, 4H), 2.31 (s, 3H),
1.95 (m, 2H). MS (ESI) 396 (M+H).sup.+.
The following compounds are prepared using essentially the same
procedure used in EXAMPLE 38a, except using the cited nitrile in
place of
{2-methyl-6-[3-(quinolin-2-ylmethoxy)-propoxymethyl]-phenoxy}-acetonitril-
e.
EXAMPLE 38b
{2-Methyl-6-[4-(quinolin-2-ylmethoxy)-butoxymethyl]-phenoxy}-acetic
Acid
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.22-8.19 (m, 2H), 7.81
(d, 1H), 7.73 (dd, 1H), 7.55-7.50 (m, 2H), 7.17-7.13 (m, 2H), 7.01
(dd, 1H), 4.85 (s, 2H), 4.60 (s, 2H), 4.56 (s, 2H), 3.64-3.59 (m,
4H), 2.32 (s, 3H), 1.75 (m, 4H). MS (ESI) 410 (M+H).sup.+. Prepared
from
{2-methyl-6-[4-(quinolin-2-ylmethoxy)-butoxymethyl]phenoxy}-acetonitrile
(EXAMPLE 37b).
EXAMPLE 38c
{2-Methyl-6-[2-(quinolin-2-ylmethoxy)-ethoxymethyl]-phenoxy}-acetic
Acid
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.18-8.11 (m, 2H), 7.79
(d, 1H), 7.75-7.68 (m, 1H), 7.55-7.50 (m, 1H), 7.44 (d, 1H),
7.12-7.08 (m, 2H), 6.99-6.94 (m, 1H), 4.81 (s, 2H), 4.59 (s, 2H),
4.54 (s, 2H), 3.76-3.70 (m, 4H), 2.22 (s, 3H). MS (ESI) 382
(M+H).sup.+. Prepared from
{2-methyl-6-[2-(quinolin-2-ylmethoxy)-ethoxymethyl]-phenoxy}-acetonitrile
(EXAMPLE 37c).
EXAMPLE 38d
{4-Chloro-2-methyl-6-[4-(quinolin-2-ylmethoxy)-butoxymethyl]-phenoxy}-acet-
ic Acid
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.26-8.22 (m, 2H), 7.84
(d, 1H), 7.76-7.70 (m, 1H), 7.60-7.50 (m, 2H), 7.17-7.14 (m, 2H),
4.87 (s, 2H), 4.61 (s, 2H), 4.51 (s, 2H), 3.68-3.59 (m, 4H), 2.31
(s, 3H), 1.76 (s (broad), 4H). MS (ESI) 444 (M+H).sup.+. Prepared
from
{4-chloro-2-methyl-6-[4-(quinolin-2-ylmethoxy)-butoxymethyl]-phenoxy}-ace-
tonitrile (EXAMPLE 37d).
EXAMPLE 38e
{4-Chloro-2-[2,2-dimethyl-3-(quinolin-2-ylmethoxy)-propoxymethyl]-6-methyl-
-phenoxyl}-acetic Acid
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.33-8.15 (m, 1H),
8.15-7.98 (m, 1H), 7.97-7.30 (m, 4H), 7.20-7.00 (m, 2H), 4.78 (s,
2H), 4.55 (s, 2H), 3.37 (s, 2H), 3.27 (s, 2H), 2.31 (s, 3H), 0.94
(s, 6H). MS (ESI) 459 (M+H).sup.+. Prepared from
{4-chloro-2-[2,2-dimethyl-3-(quinolin-2-ylmethoxy)-propoxymethyl]-6-methy-
l-phenoxy}-acetonitrile (EXAMPLE 37e).
EXAMPLE 39a
N-(4-Hydroxy-butyl)-N-guinolin-2-ylmethyl-acetamide
To a solution of 4-amino-1-butanol (943 .mu.L, 10 mmol) in anhyd.
methanol (20 mL) is added 2-quinoline-carboxaldehyde (1.57 g, 10
mmol). The solution is allowed to stir at r.t. for 20 min. Solid
NaBH.sub.4 (380 mg, 10 mmol) is added portionwise, and the contents
are stirred at r.t. for 1 hr. A solution of acetyl chloride (704
.mu.L, 10 mmol) in dichloromethane (10 mL) is added dropwise over
15 min., and the contents are stirred at r.t. for another 2 hrs.
Water (100 mL) is added, and the contents are extracted with
dichloromethane (3.times.100 mL). The organic fractions are pooled
and washed with brine (2.times.150 mL), dried over MgSO.sub.4,
filtered and reduced under vacuum to an oil. The crude material is
purified by flash chromatography (silica, 3% methanol in
dichloromethane) to give the title compound. MS (ESI) 273
(M+H).sup.+.
The following compound is prepared using essentially the same
procedure used in EXAMPLE 39a, except using the cited amino alcohol
in place of 4-amino-1-butanol.
EXAMPLE 39b
N-(3-Hydroxy-propyl)-N-quinolin-2-ylmethyl-acetamide
MS (ESI) 259 (M+H).sup.+. Prepared from 3-amino-1-propanol.
EXAMPLE 40a
Methyl
2-[4-(Acetyl-quinolin-2-ylmethyl-amino)-butoxymethyl]-6-methyl-benz-
oate
N-(3-Hydroxy-propyl)-N-quinolin-2-ylmethyl-acetamide (410 mg, 1.5
mmol, EXAMPLE 39a) is dissolved in 20% DMPU in THF (3 mL) and
cooled to 0.degree. C. Sodium hydride (60%, 66 mg, 1.65 mmol) is
added and the contents are stirred for 10 min. Methyl
2-bromomethyl-6-methyl-benzoate (77%, 365 mg, 1.5 mmol, EXAMPLE 2a)
is added. The contents are allowed to come to r.t., and are stirred
overnight. The contents are poured into water (100 mL) and
extracted with ethyl acetate (3.times.75 mL). The organic fractions
are pooled and washed with water (2.times.100 mL) and brine
(2.times.100 mL), dried over MgSO.sub.4, filtered and reduced under
vacuum to an oil. The crude material is purified by flash
chromatography (silica, 3% methanol in dichloromethane) to give the
title compound. MS (ESI) 435 (M+H).sup.+.
The following compound is prepared using essentially the same
procedure used in EXAMPLE 40a, except using the cited alcohol in
place of N-(3-hydroxy-propyl)-N-quinolin-2-ylmethyl-acetamide.
EXAMPLE 40b
Methyl
2-[3-(Acetyl-quinolin-2-ylmethyl-amino)-propoxymethyl]-6-methyl-ben-
zoate
MS (ESI) 421 (M+H).sup.+. Prepared from
N-(3-hydroxy-propyl)-N-quinolin-2-ylmethyl-acetamide (EXAMPLE
39b).
EXAMPLE 41a
2-[4-(Acetyl-quinolin-2-ylmethyl-amino)-butoxymethyl]-6-methyl-benzoic
Acid
Methyl
2-[4-(acetyl-quinolin-2-ylmethyl-amino)-butoxymethyl]-6-methyl-ben-
zoate (375 mg, 0.86 mmol, EXAMPLE 40a) is dissolved in ethanol (7.5
mL). 10 N NaOH (860 .mu.L, 8.6 mmol) is added, and the contents are
heated to 90.degree. C. overnight. The reaction is cooled to r.t.
and 2 N HCl (4.3 mL) is added, followed by dropwise addition of 2 N
HCl to adjust the pH to .about.4-6. The contents are poured into
water (100 mL) and extracted with dichloromethane (3.times.75 mL).
The organic fractions are pooled and washed with brine (3.times.100
mL), dried over MgSO.sub.4, filtered and reduced under vacuum to
dryness. The crude material is purified by flash chromatography
(silica, 6% methanol in dichloromethane) to give the title
compound. .sup.1H NMR (300 MHz, CDCl.sub.3) Rotamers 2:1 .delta.
8.37 (d, 0.5H), 8.28-8.15 (m, 1.5H), 7.88-7.83 (m, 1.25H),
7.80-7.73 (m, 1.75H), 7.65-7.57 (m, 1.25H), 7.43 (d, 0.25H),
7.33-7.10 (m, 3H), 5.24 (s, 1.33H), 5.01 (s, 0.66H), 4.67 (s,
1.33H), 4.63 (s, 0.66H), 3.55-3.45 (m, 2.66), 3.39-3.32 (m, 1.33),
2.58 (s, 2H), 2.55 (s, 1H), 2.31 (s, 1H), 1.95-1.82 (m, 2H),
1.77-1.62 (m, 2H). MS (ESI) 421 (M+H).sup.+.
The following compound is prepared using essentially the same
procedure used in EXAMPLE 41a, except using the cited ester in
place of methyl
2-[4-(acetyl-quinolin-2-ylmethyl-amino)-butoxymethyl]-6-methyl-benzoate.
EXAMPLE 41b
2-[3-(Acetyl-quinolin-2-ylmethyl-amino)-propoxymethyl]-6-methyl-benzoic
Acid
.sup.1H NMR (300 MHz, CDCl.sub.3) Rotamers 9:1 .delta. 8.32-8.22
(m, 2H), 7.88-7.84 (m, 2H), 7.81-7.75 (m, 1H), 7.62-7.57 (m, 1H),
7.26-7.18 (m, 2H), 7.11-7.08 (m, 1H), 7.11-7.08 (m, 1H), 5.05 (s,
1.8H), 4.95 (s, 0.2H), 4.66 (s, 1.8H), 4.61 (s, 0.2H), 3.65-3.47
(m, 4H), 2.58 (s, 2.7), 2.51 (s, 0.3H), 2.31 (s, 0.3H), 2.14 (s,
2.7H), 2.00-1.92 (quintet, 2H). MS (ESI) 407 (M+H).sup.+. Prepared
from methyl
2-[3-(acetyl-quinolin-2-ylmethyl-amino)-propoxymethyl]-6-methyl-benzoate
(EXAMPLE 40b).
EXAMPLE 42a
4-(Quinolin-2-ylamino)-butan-1-ol
2-Chloroquinoline (3.26 g, 20 mmol) and 4-amino-1-butanol are
dissolved in anhyd. DMSO (10 mL) and heated to 140.degree. C. for 4
hrs. The reaction is cooled to r.t., poured into water (250 mL) and
extracted with ethyl acetate (3.times.100 mL). The organic
fractions are pooled and washed with brine (3.times.150 mL), dried
over MgSO.sub.4, filtered and reduced under vacuum to dryness. The
crude material is purified by flash chromatography (silica, 7%
methanol in dichloromethane) to give the title compound. MS (ESI)
217 (M+H).sup.+.
The following compound is prepared using essentially the same
procedure used in EXAMPLE 42a, except using the cited amino alcohol
in place of 4-amino-1-butanol.
EXAMPLE 42b
3-(Quinolin-2-ylamino)-propan-1-ol
MS (ESI) 203 (M+H).sup.+. Prepared from 3-amino-1-propanol.
EXAMPLE 43a
Methyl
2-Methyl-6-[4-(quinolin-2-ylamino)-butoxymethyl]-benzoate
4-(Quinolin-2-ylamino)-butan-1-ol (432 mg, 2.0 mmol, EXAMPLE 42a)
is dissolved in 20% DMPU in THF (5 mL) and cooled to 0.degree. C.
Sodium hydride (60%, 88 mg, 2.2 mmol) is added portionwise, and the
contents are stirred for 10 min. Methyl
2-bromomethyl-6-methyl-benzoate (77%, 631 mg, 2.0 mmol, EXAMPLE 2a)
is added and the contents are allowed to warm to r.t. and continue
to stir overnight. The reaction contents are poured into water (100
mL) and extracted with ethyl acetate (3.times.75 mL). Sodium
chloride is added to the aqueous layer on the second and third
extractions. The organic fractions are pooled, washed with brine
(2.times.150 mL), dried over MgSO.sub.4, filtered and reduced under
vacuum to an oil. The crude material is purified by flash
chromatography (silica, 3% methanol in dichloromethane) to give the
title compound. MS (ESI) 379 (M+H).sup.+.
The following compound is prepared using essentially the same
procedure used in EXAMPLE 43a, except using the cited alcohol in
place of 4-(quinolin-2-ylamino)-butan-1-ol.
EXAMPLE 43b
Methyl
2-Methyl-6-[3-(quinolin-2-ylamino)-propoxymethyl]-benzoate
MS (ESI) 365 (M+H).sup.+. Prepared from
3-(quinolin-2-ylamino)-propan-1-ol (EXAMPLE 42b). The following
compounds are prepared using essentially the same procedure used in
EXAMPLE 41a, except using the cited ester in place of methyl
2-[4-(acetyl-quinolin-2-ylmethyl-amino)-butoxymethyl]-6-methyl-benzoate.
EXAMPLE 44a
2-Methyl-6-[4-(quinolin-2-ylamino)-butoxymethyl]-benzoic Acid
.sup.1H NMR (300 MHz, DMSO) .delta. 7.79 (d, 1H), 7.56 (d, 1H),
7.48-7.39 (m, 2H), 7.25-7.00 (m, 4H), 6.72 (d, 1H), 4.46 (s, 2H),
3.42-3.36 (m, 4H), 2.27 (s, 3H), 1.67-1.59 (m, 4H). MS (ESI) 365
(M+H).sup.+. Prepared from methyl
2-methyl-6-[4-(quinolin-2-ylamino)-butoxymethyl]-benzoate (EXAMPLE
43a).
EXAMPLE 44b
2-Methyl-6-[3-(quinolin-2-ylamino)-propoxymethyl]-benzoic Acid
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.85 (d, 1H), 7.65-7.60.
(m, 1H), 7.48-7.45 (m, 1H), 7.27 (d, 1H), 7.19-7.06 (m, 3H), 6.70
(d, 1H), 4.70 (s, 2H), 3.78 (t, 2H), 3.57-3.51 (m, 2H), 2.54 (s,
3H), 2.14-2.06 (quintet, 2H). MS (ESI) 351 (M+H).sup.+. Prepared
from methyl
2-methyl-6-[3-(quinolin-2-ylamino)-propoxymethyl]-benzoate (EXAMPLE
43b).
The following compound is prepared using essentially the same
procedure used in EXAMPLE 35a, except using the cited alcohol in
place of 3-(quinolin-2-ylmethoxy)-propan-1-ol and the cited
alkylating reagent in place of methyl
2-bromomethyl-6-methyl-benzoate.
EXAMPLE 45
{2-Methyl-6-[3-(quinolin-2-ylamino)-propoxymethyl]-phenoxy}-acetonitrile
MS (ESI) 362 (M+H).sup.+. Prepared from
3-(quinolin-2-ylamino)-propan-1-ol and
(2-bromomethyl-6-methyl-phenoxy)-acetonitrile.
EXAMPLE 46
{2-Methyl-6-[3-(quinolin-2-ylamino)-propoxvmethyl]-phenoxy}-acetic
Acid
{2-Methyl-6-[3-(quinolin-2-ylamino)-propoxymethyl]-phenoxy}-acetonitrile
(270 mg, 0.75 mmol) is dissolved in ethanol (6 mL). 10 N NaOH (750
.mu.L, 7.5 mmol) is added, and the contents are heated to
60.degree. C. for 4 hrs. The reaction is cooled to r.t. 2 N HCl
(3.75 mL, 7.5 mmol) is added and the pH is adjusted to .about.4-6.
The contents are poured into water (150 mL) and extracted with
ethyl acetate (3.times.75 mL). The organic fractions were pooled
and washed with brine (3.times.100 mL), dried over MgSO.sub.4,
filtered and reduced under vacuum to dryness. The crude material
was pure enough to test as is to give the title compound. .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 11.04 (s (broad), 1H), 7.88 (d,
1H), 7.73 (d, 1H), 7.52-7.47 (m, 2H), 7.26-7.12 (m, 3H), 7.02-6.97
(m, 1H), 6.90 (d, 1H), 4.66 (s, 2H), 4.47 (s, 2H), 3.69 (t, 2H),
3.57-3.53 (m, 2H), 2.33 (s, 3H), 2.05 (quintet, 2H). MS (ESI) 381
(M+H).sup.+.
EXAMPLE 47a
Methyl 2-Methoxy-6-[4-(quinolin-2-ylmethoxy)-butoxy]-benzoate
4-(Quinolin-2-ylmethoxy)-butan-1-ol (1.62 g, 7.0 mmol) and methyl
2-hydroxy-6-methoxy-benzoate (1.72 g, 9.45 mmol, EXAMPLE 27) are
dissolved in anhyd. THF (10 mL). Triphenylphosphine (2.48 g, 9.45
mmol) is added and the contents cooled to -10.degree. C. A solution
of DEAD (1.54 mL, 9.8 mmol) in anhyd. THF (2.0 mL) is added
dropwise over 10 min., allowed to come to r.t. and stirred
overnight. The reaction is poured into water (200 mL) and extracted
with dichloromethane (3.times.75 mL). The organic fractions were
pooled and washed with brine (2.times.200 mL), dried over
MgSO.sub.4, filtered and reduced under vacuum to dryness. The crude
material was purified by flash chromatography (silica, 2.5%
methanol in dichloromethane) to give the title compound. MS (ESI)
396 (M+H).sup.+.
The following compound is prepared using essentially the same
procedure used in EXAMPLE 47a, except using the cited phenol in
place of methyl 2-hydroxy-6-methoxy-benzoate.
EXAMPLE 47b
Ethyl 2-Methyl-6-[4-(quinolin-2-ylmethoxy)-butoxy]-benzoate
MS (ESI) 394 (M+H).sup.+. Prepared from ethyl 6-methylsalicylate
(See, Hauser, Frank M., Synthesis 1980, 10, 814-15.
EXAMPLE 47c
Ethyl
4-Benzyloxy-2-methyl-6-[4-(quinolin-2-ylmethoxy)-butoxy]-benzoate
MS (ESI) 502 (M+H).sup.+. Prepared from ethyl
4-benzyloxy-2-hydroxy-6-methyl-benzoate. The following compounds
are prepared using essentially the same procedure used in the
previous EXAMPLEs, except using the cited ester in place of methyl
2-methyl-6-[3-(quinolin-2-ylmethoxy)-propoxymethyl]-benzoate.
EXAMPLE 48a
2-Methoxy-6-[4-(quinolin-2-ylmethoxy)-butoxy]-benzoic Acid
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.33 (d, 1H), 8.23 (d,
1H), 7.81 (d, 1H), 7.77 (t, 1H), 7.62 (d, 1H), 7.56 (t, 2H), 7.19
(t, 1H), 6.49 (t, 2H), 4.88 (s, 2H), 4.04 (t, 2H), 3.87 (s, 3H),
3.76 (t, 2H), 1.91-1.87 (m, 4H). MS (ESI) 382 (M+H).sup.+. Prepared
from methyl
2-methoxy-6-[4-(quinolin-2-ylmethoxy)-butoxy]-benzoate.
EXAMPLE 48b
2-Methyl-6-[4-(quinolin-2-ylmethoxy)-butoxy]-benzoic Acid
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.27-8.22 (m, 2H), 7.84
(d, 1H), 7.77 (t, 1H), 7.63 (d, 1H), 7.59 (t, 1H), 7.20-7.15 (m,
1H), 6.80 (d, 1H), 6.71 (d, 1H), 4.90 (s, 2H), 4.05 (t, 2H), 3.76
(t, 2H), 2.47 (s, 3H), 1.93-1.87 (m, 4H). MS (ESI) 366 (M+H).sup.+.
Prepared from ethyl
2-methyl-6-[4-(quinolin-2-ylmethoxy)-butoxy]-benzoate.
EXAMPLE 48c
4-Benzyloxy-2-methyl-6-[4-(quinolin-2-ylmethoxy)-butoxy]-benzoic
Acid
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.32 (d, 1H), 8.00 (d,
1H), 7.90 (d, 1H), 7.75-7.58 (m, 3H), 7.41-7.33 (m, 5H), 6.45 (s,
2H), 5.05 (s, 2H), 4.77 (s, 2H), 4.02 (t, 2H), 4.69 (t, 2H), 2.28
(s, 3H), 1.95-1.85 (m, 4H). MS (ESI) 473 (M+H).sup.+. Prepared from
ethyl
4-benzyloxy-2-methyl-6-[4-(quinolin-2-ylmethoxy)-butoxy]-benzoate.
EXAMPLE 49
3-(2-Phenyl-oxazol-4-ylmethoxy)-propan-1-ol
1,3-Propanediol (3.6 mL, 50 mmol) is dissolved in 10% DMPU in THF
and cooled to 0.degree. C. Sodium hydride is added portionwise
(60%, 400 mg, 10 mmol). The contents are stirred for 10 min at
0.degree. C., warmed to r.t. and stirred for another 10 min.
4-Chloromethyl-2-phenyl-oxazole (2.0 g, 10 mmol, EXAMPLE 21) is
added, and the contents heated to 60.degree. C. for 4 days. The
reaction is cooled to r.t., poured into water (200 mL) and
extracted with ethyl acetate (2.times.200 mL). The organic
fractions were pooled and washed with brine (2.times.200 mL), dried
over MgSO.sub.4, filtered and reduced under vacuum to an oil. The
crude material was purified by flash chromatography (silica, 2%
methanol in dichloromethane) to give the title compound. MS (ESI)
234 (M+H).sup.+.
EXAMPLE 50
Isobutyl
2-Methyl-6-[3-(2-phenyl-oxazol-4-ylmethoxy)-propoxymethyl]-benzoa-
te
3-(2-Phenyl-oxazol-4-ylmethoxy)-propan-1-ol (1.26 g, 5.4 mmol) is
dissolved in 10% DMPU in THF (20 mL) and cooled to 0.degree. C.
Sodium hydride (60%, 237 mg, 5.9 mmol) is added portionwise. The
contents are stirred for 10 min. at 0.degree. C., warmed to r.t.
and stirred for another 10 min. isobutyl
2-bromomethyl-6-methyl-benzoate (2.69 g, 5.4 mmol, EXAMPLE 2b) is
added, allowed to come to r.t. and stirred overnight. The reaction
is poured into water (200 mL) and extracted with ethyl acetate
(2.times.200 mL). The organic fractions were pooled and washed with
brine (2.times.200 mL), dried over MgSO.sub.4, filtered and reduced
under vacuum to an oil. The crude material was purified by flash
chromatography (silica, 15-20% ethyl acetate in hexane) to give the
title compound (1.06 g). MS (ESI) 438 (M+H).sup.+.
The following compound is prepared using essentially the same
procedure used in the previous EXAMPLEs, except using the cited
ester in place of methyl
2-methyl-6-[3-(quinolin-2-ylmethoxy)-propoxymethyl]-benzoate.
EXAMPLE 51
2-Methyl-6-[3-(2-phenyl-oxazol-4-ylmethoxy)-propoxymethyl]-benzoic
Acid
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.07-8.04 (m, 2H), 7.71
(s, 1H), 7.48-7.46 (m, 3H), 7.24-7.14 (m, 2H), 4.71 (s, 2H), 4.70
(s, 2H), 3.77 (t, 2H), 3.72 (t, 2H), 2.48 (s, 3H), 1.88 (quint,
2H). MS (ESI) 382 (M+H).sup.+. Prepared from isobutyl
2-methyl-6-[3-(2-phenyl-oxazol-4-ylmethoxy)-propoxymethyl]-benzoate.
EXAMPLE 52
4-Chloromethyl-2-phenyl-oxazole
Benzamide (1.21 g, 10 mmol) is mixed with 1,3-dichloroacetone (1.26
g, 10 mmol) and the mixture heated to 130.degree. C. and stirred at
this temperature for 1 h. The resulting mixture is then cooled,
diluted with ethyl acetate, washed with K.sub.2CO.sub.3 solution
(sat.), then brine, dried over MgSO.sub.4 and concentrated to give
the title compound as a solid, which is used without further
purification. MS (ESI) 194 (M+H, Cl pattern).sup.+.
EXAMPLE 53
2-Cyanomethoxy-3-methylbenzaldehyde
A mixture of 2-hydroxy-3-methylbenzaldehyde (10.2 g, 75.0 moles,
Aldrich), bromoacetonitrile (5.70 mL, 82.5 mmoles), and potassium
carbonate (11.4 g, 82.5 mmoles) in DMF (150 mL) is heated to
55.degree. C. for 3 hours, cooled, then diluted with ether. The
mixture is washed with distilled water, saturated NaCl solution,
then the organic layer dried over MgSO.sub.4 and concentrated to
give the title compound as a yellow solid. .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. 10.20 (s, 1H), 7.70 (d, 1H), 7.53 (d, 1H),
7.29 (m, 1H), 4.81 (s, 2H), 2.42 (s, 3H).
EXAMPLE 54
(2-Hydroxymethyl-6-methyl-phenoxy)-acetonitrile
A 2M triglyme solution of sodium borohydride (16.0 mL, 32.1 mmoles)
is slowly added to a cooled (-78.degree. C.) solution of
2-cyanomethoxy-3-methylbenzaldehyde (11.25 g, 64.2 mmoles) in THF
(180 mL). After stirring for one hour, the reaction is warmed to
0.degree. C. for two hours, then quenched with 2N HCl (16.8 mL) and
diluted with ether. The organic layer is isolated and washed with
twice with distilled water and brine, then dried over MgSO.sub.4.
The organic solution is concentrated to give the title compound as
a yellow oil.
EXAMPLE 55
(2-Bromomethyl-6-methyl-phenoxy)-acetonitrile
Triphenylphosphine (15.2 g, 57.8 mmoles) is added to
(2-Hydroxymethyl-6-methyl-phenoxy)-acetonitrile (9.3 g, 52.5
mmoles) in THF (175 mL). The mixture is stirred until homogeneous
and cooled to 0.degree. C., followed by addition, in three
portions, of N-bromosuccinimide (10.3 g, 57.8 mmoles). After 90
minutes the reaction is concentrated and the residue purified by
column chromatography (silica, 5:1 hex:EtOAc) to yield the title
compound as a pale yellow crystalline solid. MS (EI) 239, 241
(M).sup.+, Br pattern.
EXAMPLE 56
(4-Chloro-2,6-dimethyl-phenoxy)-acetonitrile
4-Chloro-2,6-dimethylphenol (5.0 g, 32 mmol), bromoacetonitrile
(2.2 mL, 32 mmol) and potassium carbonate (6.6 g, 48 mmol) are
combined with acetone (50 mL) and heated at reflux for 18 h. The
reaction is filtered, concentrated and the residue partitioned
between dichloromethane and water. The organic phase is washed with
1N HCl and water and is then dried over magnesium sulfate,
concentrated and purified by column chromatography (silica, 10%
ethyl acetate in hexanes) to provide the title compound. MS (EI)
195 (M).sup.+, Cl pattern.
EXAMPLE 57
(2-Bromomethyl-4-chloro-6-methyl-phenoxy)-acetonitrile
(4-Chloro-2,6-dimethyl-phenoxy)-acetonitrile (700 mg, 3.6 mmol),
N-bromosuccinimide (510 mg, 2.9 mmol) and benzoyl peroxide (72 mg,
0.29 mmol) are heated at reflux in carbon tetrachloride (10 mL) for
16 h. The reaction is cooled, filtered and the filtrate is
concentrated and purified by column chromatograpy (silica, 5% ethyl
acetate in hexanes) to provide the title compound. MS (ES) 273, 275
(M).sup.+, Br pattern.
EXAMPLE 58
Methyl 6-Methoxysalicylate
A mixture of 6-methoxysalicylic acid (10.0 g, 59.5 mmol) in
methanol (40 mL) and sulfuric acid (2 mL) is heated at reflux 48 h.
Although some acid remains the reaction is concentrated to remove
the methanol and partitioned between ethyl acetate and saturated
sodium carbonate solution. The organic phase is separated and
washed with sodium carbonate until no acid remains by TLC analysis.
The organic phase is dried and concentrated to provide the title
compound as a low melting solid.
EXAMPLE 59
Ethyl 4-Benzyloxy-2-hydroxy-6-methyl-benzoate
To a solution of ethyl-2,4-dihydroxy-6-methyl benzoate (4.22 g, 22
mmol) in acetone (80 mL) is added potassium carbonate (3.0 g, 22
mmol) and benzyl bromide (2.6 mL, 22 mmol) and this mixture is
heated under reflux overnight. The cooled reaction is diluted with
ethyl acetate (100 mL) and water (100 mL) and the organic layer
washed with water (2.times.80 mL) and brine (2.times.80 mL). The
organic layer is dried over magnesium sulfate and the solvent
removed to provide the title compound without further purification.
MS (EI) 286 (M).sup.+.
Solid Phase Synthesis of the Compounds of the Invention:
The following is an example of the solid phase synthesis of
compounds of the invention ##STR00151## Experimental
Procedures:
1. Acid Loading: ##STR00152##
A third neck 3 L round bottom flask is charged with 4-bromobutyric
acid (23.38 g, 140 mmoles) and DMF (1.5 L). The reaction flask is
fitted with an overhead stirrer. After stirring for 10 min in order
to dissolve the acid, the 2,6-dichlorobezoyl chloride (19.0 mL, 127
mmoles) and the pyridine (10.3 mL, 129 mmoles) are added in turn.
After stirring for 2.5 hours, the MicroKANs[1456, 15 mg of Wang
resin (1.7 mmole/g loading per microKAN), 25.5 micromoles/microKAN,
37.1 mmoles] are then added to the reaction flasks. The reaction is
allowed to stir for 18 hours. At the end of this period, the
reaction mixture is drained from the flask. DMF (1.5 L) is added to
the reaction flask. The flask is allowed to stir for approximately
15 minutes and the solvent is drained. The MicroKANs are washed,
stirred for 20 minutes and drained repeatedly in the following
washing sequence: DMF (2.times.6 L), THF (3.times.6 L),
dichloromethane (3.times.6 L) and ether (2.times.6 L). After the
final washing, the MicroKANs are dried by blowing a stream of
nitrogen through the flask with intermittent agitation. After
sufficient drying, the MicroKANs are sorted for the next
reaction.
2. Phenol Displacement: ##STR00153##
A three neck 3 L round bottom flask is charged with
4-hydroxybenzaldehyde (17.1 g, 140 mmoles) and DMF (1.5 L). The
reaction flask is fitted with an overhead stirrer and immersed in
an ice-water bath.
After approximately 15 minutes sodium hydride (60% dispersion in
oil, 6.48 g, 180 mmoles) is carefully added. After approximately 30
minutes, the ice-water bath is removed and the reaction allowed to
stir at ambient temperature for 1 hour. At the end of this time,
the MicroKANs [1274, 25.5 micromoles/microKAN, 32.5 mmoles] and
potassium iodide (1.0 g) are added to the reaction mixture. The
reaction flask is immersed in an oil bath, which is heated to
60.degree. C. After 14 hours, the reaction flask is removed from
the oil bath and allowed to cool to ambient temperature. The
reaction solvent is removed. DMF (1.2 L) is added to the reaction
flask. The flask is allowed to stir for approximately 15 minutes
and the solvent is drained. DMF:water (1:1, 1.2 L) is added to the
reaction flask. The flask is allowed to stir for approximately 15
minutes and the solvent is drained. This sequence is repeated at
least three times or until the effluent from the washing is clear.
Then the reaction flask is are washed repeatedly in the following
sequence: THF (2.times.4 L), dichloromethane (1.times.4 L) then
methanol (1.times.4 L), dichloromethane (1.times.4 L) then methanol
(1.times.4 L), dichloromethane (1.times.4 L) then methanol
(1.times.4 L), dichloromethane (1.times.4 L) and ether (1.times.4
L). After the final washing, the MicroKANs are dried by blowing a
stream of nitrogen through the flask with intermittent agitation.
After sufficient drying, the MicroKANs are sorted for the next
reaction.
3. Reductive Amination: ##STR00154##
A three neck 2 L round bottom flask is charged with the MicroKANs
[784, 25.5 micromoles/microKAN, 20.0 mmoles], trimethylorthoformate
(850 mL) and 3-phenyl-1-propylamine (22.99 g, 170 mmoles). The
reaction flask is fitted with an overhead stirrer. After 2 hours,
sodium cyanoborohydride (21.37 g, 340 mmoles) is added. After
approximately 10 minutes, acetic acid (17.0 mL, 297 mmoles) is
added. After stirring for an additional hour, the reaction flask is
drained. Methanol (800 mL) is added to the flask. After stirring
for approximately 10 minutes, the flask is drained. The MicroKANs
are washed in the following sequence: DMF (3.times.4 L),
dichloromethane (1.times.4 L) then methanol (1.times.4 L),
dichloromethane (1.times.4 L) then methanol (1.times.4 L),
dichloromethane (1.times.4 L) then methanol (1.times.4 L),
dichloromethane (1.times.4 L) and ether (1.times.4 L). After the
final washing the microKANS are dried by blowing a stream of
nitrogen through the flask with intermittent agitation. After
sufficient drying, the MicroKANs are sorted for the next
reaction.
4. Acylation: ##STR00155##
A three neck 2 L round bottom flask is charged with the MicroKANs
[784, 15 mg of resin (1.7 mmole/g loading) per MicroKAN, 25.5
micromoles/microKAN, 20.0 mmoles], and dichloromethane (800 mL).
The reaction flask is fitted with an overhead stirrer.
N,N-diisopropylethylamine (20.9 mL, 120 mmoles) and
4-N,N-dimethylaminopyridine (195 mg, 1.6 mmoles) are added. After
approximately 15 minutes, the acetyl chloride (6.3 g, 80.0 mmoles)
is added. The reaction mixture is allowed to stir for 61 hours,
after which the reaction flask is drained. Dichloromethane (800 mL)
is added to the reaction flask. After stirring for approximately 10
minutes, the flask is drained. This is repeated. The MicroKANs from
all of the acylation reactions are randomly combined into two
separate large flasks and washed repeatedly in the following
sequence: dichloromethane (1.times.4 L), THF (2.times.4 L),
dichloromethane (1.times.4 L) then methanol (1.times.4 L),
dichloromethane (1.times.4 L) then methanol (1.times.4 L),
dichloromethane (1.times.4 L) then methanol (1.times.4 L),
dichloromethane (1.times.4 L) and ether (1.times.4 L).
5. Cleavage:
The MicroKAN is sorted into individual wells of IRORI AccuCleave 96
cleavage stations. The well is charged with dichloromethane (600
mL) and then with a TFA:dichloromethane mixture (1:1, 600 mL).
After agitating for approximately forty minutes, the reaction well
is drained into 2 mL microtubes in an 96-well format. The reaction
well is again charged with dichloromethane (600 mL). After manual
agitation, this too is drained into the 2 mL microtubes in an
96-well format. The cleavage cocktail is removed in vacuo using a
Savant Speedvac. The concentrated products from the cleavage mother
plates are reconstituted with THF and transferred into two daughter
plates utilizing a Packard MultiProbe liquid handler. The daughter
plates are concentrated in vacuo utilizing a GenieVac.
Analytical: MS: m/z 370.2 (M+H.sup.+). Experimental Procedures:
##STR00156##
1. Acid Loading: ##STR00157##
A three neck 3 L round bottom flask is charged with 4-bromobutyric
acid (23.38 g, 140 mmoles) and DMF (1.5 L). The reaction flask is
fitted with an overhead stirrer. After stirring for 10 min in order
to dissolve the acid, the 2,6-dichlorobenzoyl chloride (19.0 mL,
127 mmoles) and the pyridine (10.3 mL, 129 mmoles) are added in
turn. After stirring for 2.5 hours, the MicroKANs[1456, 15 mg of
Wang resin (1.7 mmole/g loading per microKAN), 25.5
micromoles/microKAN, 37.1 mmoles] are then added to the reaction
flask. The reaction is allowed to stir for 18 hours. At the end of
this period, the reaction mixture is drained from the flask. DMF
(1.5 L) is added to the reaction flask. The flask is allowed to
stir for approximately 15 minutes, and then the solvent is drained.
The MicroKANs are washed, stirred for 20 minutes and drained
repeatedly in the following sequence: DMF (2.times.6 L), THF
(3.times.6 L), dichloromethane (3.times.6 L) and ether (2.times.6
L). After the final washing the MicroKANs are dried by blowing a
stream of nitrogen through the flask with intermittent agitation.
After sufficient drying, the MicroKANs are sorted for the next
reaction.
2. Phenol Displacement: ##STR00158##
A three neck 3 L round bottom flask is charged with
3-hydroxybenzaldehyde (17.1 g, 140 mmoles) and DMF (1.5 L). The
reaction flask is fitted with an overhead stirrer and immersed in
an ice-water bath. After approximately 15 minutes sodium hydride
(60% dispersion in oil, 6.48 g, 180 mmoles) is carefully added.
After approximately 30 minutes, the ice-water bath is removed and
the reaction allowed to stir at ambient temperature for 1 hour. At
the end of this time, the MicroKANs [1274, 25.5
micromoles/microKAN, 32.5 mmoles] and potassium iodide (1.0 g) are
added to the reaction mixture. The reaction flask is immersed into
an oil bath which is heated to 60.degree. C. After 14 hours, the
reaction flask is removed from the oilbath and allowed to cool to
ambient temperature. The reaction solvent is removed. DMF (1.2 L)
is added to the reaction flask. The flask is allowed to stir for
approximately 15 minutes and the solvent is drained. DMF:water
(1:1, 1.2 L) is added to the reaction flask. The flask is allowed
to stir for approximately 15 minutes, and then the solvent is
drained. This sequence is repeated at least three times or until
the effluent from the washing is clear. The reaction flasks are
washed repeatedly in the following sequence: THF (2.times.4 L),
dichloromethane (1.times.4 L) then methanol (1.times.4 L),
dichloromethane (1.times.4 L) then methanol (1.times.4 L),
dichloromethane (1.times.4 L) then methanol (1.times.4 L),
dichloromethane (1.times.4 L) and ether (1.times.4 L). After the
final washing, the MicroKANs are dried by blowing a stream of
nitrogen through the flask with intermittent agitation. After
sufficient drying, the MicroKANs are sorted for the next
reaction.
3. Reductive Amination: ##STR00159##
A three neck 2 L round bottom flask is charged with the MicroKANs
[784, 25.5 micromoles/microKAN, 20.0 mmoles], trimethylorthoformate
(850 mL) and 4-phenyl-1-butylamine (25.37 g, 170 mmoles). The
reaction flask is fitted with an overhead stirrer. After 2 hours,
sodium cyanoborohydride (21.37 g, 340 mmoles) is added. After
approximately 10 minutes, acetic acid (17.0 mL, 297 mmoles) is
added. After stirring for an additional hour, the reaction flask is
drained. Methanol (800 mL) is added to the flask.
After stirring for approximately 10 minutes, the flask is drained.
The MicroKANs following sequence: DMF (3.times.4 L),
dichloromethane (1.times.4 L) then methanol (1.times.4 L),
dichloromethane (1.times.4 L) then methanol (1.times.4 L),
dichloromethane (1.times.4 L) then methanol (1.times.4 L),
dichloromethane (1.times.4 L) and ether (1.times.4 L). After the
final washing the microKANS and dried by blowing a stream of
nitrogen through the flask with intermittent agitation. After
sufficient drying, the MicroKANs are sorted for the next
reaction.
4. Acylation: ##STR00160##
A three neck 2 L round bottom flask is charged with the MicroKANs
[784, 25.5 micromoles/microKAN 20.0 mmoles], and dichloromethane
(800 mL). The reaction flask is fitted with an overhead stirrer.
N,N-diisopropylethylamine (20.9 mL, 120 mmoles) is added. After
approximately 15 minutes, the phenyl isocyanate (9.5 g, 80.0
mmoles) is added. The reaction mixture is allowed to stir for 61
hours, after which the reaction flask is drained. Dichloromethane
(800 mL) is added to the reaction flask. After stirring for
approximately 10 minutes, the flask is drained. This is repeated.
The MicroKANs from all of the acylation reactions are randomly
combined into two separate large flasks and washed repeatedly in
the following sequence: dichloromethane (1.times.4 L), THF
(2.times.4 L), dichloromethane (1.times.4 L) then methanol
(1.times.4 L), dichloromethane (1.times.4 L) then methanol
(1.times.4 L), dichloromethane (1.times.4 L) then methanol
(1.times.4 L), dichloromethane (1.times.4 L) and ether (1.times.4
L).
5. Cleavage:
The MicroKAN is sorted into individual wells of IRORI AccuCleave 96
cleavage stations. The well is charged with dichloromethane (600
mL) and then with a TFA: dichloromethane mixture (1:1, 600 mL).
After agitating for approximately forty minutes, the reaction well
is drained into a 2 mL microtube in an 96-well format. The reaction
well is again charged with dichloromethane (600 mL). After manual
agitation, this too is drained into the 2 mL microtube in an
96-well format. The cleavage cocktail is removed in vacuo using a
Savant Speedvac. The concentrated product from the cleavage mother
plates is reconstituted with THF and transferred into two daughter
plates utilizing a Packard MultiProbe liquid handler. The daughter
plate is concentrated in vacuo utilizing a GenieVac.
Analytical: MS: m/z 461.3 (M+H.sup.+). Experimental Procedures:
##STR00161##
1. Acid Loading: ##STR00162##
A three neck 3 L round bottom flask is charged with 4-bromobutyric
acid (23.38 g, 140 mmoles) and DMF (1.5 L). The reaction flask is
fitted with an overhead stirrer. After stirring for 10 min in order
to dissolve the acid, the 2,6-dichlorobenzoyl chloride (19.0 mL,
127 mmoles) and the pyridine (10.3 mL, 129 mmoles) are added in
turn. After stirring for 2.5 hours, the MicroKANs [1456, 15 mg of
Wang resin (1.7 mmole/g loading per microKAN), 25.5
micromoles/microKAN, 37.1 mmoles] are then added to the reaction
flasks. The reaction is allowed to stir for 18 hours. At the end of
this period, the reaction mixture is drained from the flask. DMF
(1.5 L) is added to the reaction flask. The flask is allowed to
stir for approximately 15 minutes, and then the solvent is drained.
The MicroKANs are washed, stirred for 20 minutes and drained
repeatedly in the following sequence: DMF (2.times.6 L), THF
(3.times.6 L), dichloromethane (3.times.6 L) and ether (2.times.6
L). After the final washing, the MicroKANs are dried by blowing a
stream of nitrogen through the flask with intermittent agitation.
After sufficient drying, the MicroKANs are sorted for the next
reaction.
2. Phenol Displacement: ##STR00163##
A three neck 3 L round bottom flask is charged with
3-hydroxybenzaldehyde (17.1 g, 140 mmoles) and DMF (1.5 L). The
reaction flask is fitted with an overhead stirrer and immersed in
an ice-water bath. After approximately 15 minutes, sodium hydride
(60% dispersion in oil, 6.48 g, 180 mmoles) is carefully added.
After approximately 30 minutes, the ice-water bath is removed and
the reaction allowed to stir at ambient temperature for 1 hour. At
the end of this time, the MicroKANs [1274, 15 mg of resin (1.7
mmole/g loading) per MicroKAN, 25.5 micromoles/microKAN, 32.5
mmoles] and potassium iodide (1.0 g) are added to the reaction
mixture. The reaction flask is immersed in an oil bath, which is
heated to 60.degree. C. After 14 hours, the reaction flask is
removed from the oil bath and allowed to cool to ambient
temperature. The reaction solvent is removed. DMF (1.2 L) is added
to the reaction flask. The flask is allowed to stir for
approximately 15 minutes and the solvent is drained. DMF:water
(1:1, 1.2 L) is added to the reaction flask. The flask is allowed
to stir for approximately 15 minutes, and then the solvent is
drained. This sequence is repeated at least three times or until
the effluent from the washing is clear, the reaction flasks are
washed repeatedly in the following sequence: THF (2.times.4 L),
dichloromethane (1.times.4 L) then methanol (1.times.4 L),
dichloromethane (1.times.4 L) then methanol (1.times.4 L),
dichloromethane (1.times.4 L) then methanol (1.times.4 L),
dichloromethane (1.times.4 L) and ether (1.times.4 L). After the
final washing, the MicroKANs are dried by blowing a stream of
nitrogen through the flask with intermittent agitation. After
sufficient drying, the MicroKANs are sorted for the next
reaction.
3. Reductive Amination: ##STR00164##
A three neck 2 L round bottom flask is charged with the MicroKANs
[784, 15 mg of resin (1.7 mmole/g loading) per MicroKAN, 25.5
micromoles/microKAN, 20.0 mmoles], trimethylorthoformate (850 mL)
and 4-phenyl-1-butylamine (25.37 g, 170 mmoles). The reaction flask
is fitted with an overhead stirrer After 2 hours, sodium
cyanoborohydride (21.37 g, 340 mmoles) is added. After
approximately 10 minutes, acetic acid (17.0 mL, 297 mmoles) is
added. After stirring for an additional hour, the reaction flask is
drained. Methanol (800 mL) is added to the flask. After stirring
for approximately 10 minutes, the flask is drained. The MicroKANs
are washed in the following sequence: DMF (3.times.4 L),
dichloromethane (1.times.4 L) then methanol (1.times.4 L),
dichloromethane (1.times.4 L) then methanol (1.times.4 L),
dichloromethane (1.times.4 L) then methanol (1.times.4 L),
dichloromethane (1.times.4 L) and ether (1.times.4 L). After the
final washing, the microKANS and dried by blowing a stream of
nitrogen through the flask with intermittent agitation. After
sufficient drying, the MicroKANs are sorted for the next
reaction.
4. Acylations: ##STR00165##
A three neck 2 L round bottom flask is charged with the MicroKANs
[784, 15 mg of resin (1.7 mmole/g loading) per MicroKAN, 25.5
micromoles/microKAN, 20.0 mmoles], and dichloromethane (800 mL).
The reaction flask is fitted with an overhead stirrer.
N,N-diisopropylethylamine (20.9 mL, 120 mmoles) and
4-N,N-dimethylaminopyridine (195 mg, 1.6 mmoles) are added. After
approximately 15 minutes, the acetyl chloride (6.3 g 80.0 mmoles)
is added. The reaction is allowed to stir for 61 hours, and then
the reaction flask is drained. Dichloromethane (800 mL) is added to
the reaction flask. After stirring for approximately 10 minutes,
the flask is drained. This is repeated. The MicroKANs from all of
the acylation reactions are randomly combined into two separate
large flasks and washed repeatedly in the following sequence:
dichloromethane (1.times.4 L), THF (2.times.4 L), dichloromethane
(1.times.4 L) then methanol (1.times.4 L), dichloromethane
(1.times.4 L) then methanol (1.times.4 L), dichloromethane
(1.times.4 L) then methanol (1.times.4 L), dichloromethane
(1.times.4 L) and ether (1.times.4 L).
5. Cleavage:
The MicroKANs are sorted into individual wells of IRORI AccuCleave
96 cleavage stations. The well is charged with dichloromethane (600
mL) and then with a TFA:dichloromethane mixture (1:1, 600 mL).
After agitating for approximately forty minutes, the reaction well
is drained into 2 mL microtubes in an 96-well format. The reaction
well is again charged with dichloromethane (600 mL). After manual
agitation, this too is drained into the 2 mL microtubes in an
96-well format. The cleavage cocktail is removed in vacuo using a
Savant Speedvac. The concentrated products from the cleavage mother
plates are reconstituted with THF and transferred into two daughter
plates utilizing a Packard MultiProbe liquid handler. The daughter
plates are concentrated in vacuo utilizing a GenieVac.
Analytical: MS: m/z 384.2 (M+H.sup.+). ##STR00166## Experimental
Procedures:
1. Acid Loading: ##STR00167##
A three neck 3 L round bottom flask is charged with 4-bromobutyric
acid (23.38 g, 140 mmoles) and DMF (1.5 L). The reaction flask is
fitted with an overhead stirrer. After stirring for 10 min in order
to dissolve the acid, the 2,6-dichlorobenzoyl chloride (19.0 mL,
127 mmoles) and the pyridine (10.3 mL, 129 mmoles) are added in
turn. After stirring for 2.5 hours, the MicroKANs [1456, 15 mg, of
Wang resin (1.7 mmole/g loading per microKAN), 25.5
micromoles/microKAN, 37.1 mmoles] are then added to the reaction
flasks. The reaction is allowed to stir for 18 hours. At the end of
this period, the reaction mixture is drained from the flask. DMF
(1.5 L) is added to the reaction flask. The flask is allowed to
stir for approximately 15 minutes and the solvent is drained. The
MicroKANs are washed, stirred for 20 minutes and drained repeatedly
in the following sequence: DMF (2.times.6 L), THF (3.times.6 L),
dichloromethane (3.times.6 L) and ether (2.times.6 L). After the
final washing, the MicroKANs are dried by blowing a stream of
nitrogen through the flask with intermittent agitation. After
sufficient drying, the MicroKANs are sorted for the next
reaction.
2. Phenol Displacement: ##STR00168##
A three neck 3 L round bottom flask is charged with
4-hydroxybenzaldehyde (17.1 g, 140 mmoles) and DMF (1.5 L). The
reaction flask is fitted with an overhead stirrer and immersed in
an ice-water bath. After approximately 15 minutes, sodium hydride
(60% dispersion in oil, 6.48 g, 180 mmoles) is carefully added.
After approximately 30 minutes, the ice-water bath is removed and
the reaction allowed to stir at ambient temperature for 1 hour. At
the end of this time, the MicroKANs [1274, 15 mg of resin (1.7
mmole/g loading) per MicroKAN, 25.5 micromoles/microKAN, 32.5
mmoles] and potassium iodide (1.0 g) are added to the reaction
mixture. The reaction flask is immersed in an oil bath, which is
heated to 60.degree. C. After 14 hours, the reaction flask is
removed from the oil bath and allowed to cool to ambient
temperature. The reaction solvent is removed. DMF (1.2 L) is added
to the reaction flask. The flask is allowed to stir for
approximately 15 minutes, and the solvent is then drained. DMF:
water (1:1, 1.2 L) is added to the reaction flask. The flask is
allowed to stir for approximately 15 minutes, and the solvent is
then drained. This sequence is repeated at least three times or
until the effluent from the washing is clear. Then the reaction
flasks are washed repeatedly in the following sequence: THF
(2.times.4 L), dichloromethane (1.times.4 L) then methanol
(1.times.4 L), dichloromethane (1.times.4 L), then methanol
(1.times.4 L), dichloromethane (1.times.4 L), then methanol
(1.times.4 L), dichloromethane (1.times.4 L) and ether (1.times.4
L). After the final washing, the MicroKANs are dried by blowing a
stream of nitrogen through the flask with intermittent agitation.
After sufficient drying, the MicroKANs are sorted for the next
reaction.
3. Reductive Amination: ##STR00169##
A three neck 2 L round bottom flask is charged with the MicroKANs
[784, 25.5 micromoles/microKAN, 20.0 mmoles], trimethylorthoformate
(850 mL) and 3-phenyl-1-propylamine (22.99 g, 170 mmoles). The
reaction flask is fitted with an overhead stirrer. After 2 hours,
sodium cyanoborohydride (21.37 g, 340 mmoles) is added. After
approximately 10 minutes, acetic acid (17.0 mL, 297 mmoles) is
added. After stirring for an additional hour, the reaction flask is
drained. Methanol (800 mL) is added to the flask. After stirring
for approximately 10 minutes, the flask is drained. The MicroKANs
are washed in the following sequence: DMF (3.times.4 L),
dichloromethane (1.times.4 L) then methanol (1.times.4 L),
dichloromethane (1.times.4 L) then methanol (1.times.4 L),
dichloromethane (1.times.4 L) then methanol (1.times.4 L),
dichloromethane (1.times.4 L) and ether (1.times.4 L). After the
final washing, the MicroKANS are dried by blowing a stream of
nitrogen through the flask with intermittent agitation. After
sufficient drying, the MicroKANs are sorted for the next
reaction.
4. Acylation: ##STR00170##
A three neck 2 L round bottom flask is charged with the MicroKANs
[784, 25.5 micromoles/microKAN, 20.0 mmoles], and dichloromethane
(800 mL). The reaction flask is fitted with an overhead stirrer.
N,N-diisopropylethylamine (20.9 mL, 120 mmoles) and
4-N,N-dimethylaminopyridine (195 mg, 1.6 mmoles) are added. After
approximately 15 minutes, the methyl 4-chloro-4-oxobutyrate (12.0
g, 80.0 mmoles) is added. The reaction is allowed to stir for 61
hours, after which the reaction flask is drained. Dichloromethane
(800 mL) is added to the reaction flask. After stirring for
approximately 10 minutes, the flask is drained. This is repeated.
The MicroKANs from all of the acylation reactions are randomly
combined into two separate large flasks and washed repeatedly in
the following sequence: dichloromethane (1.times.4 L), THF
(2.times.4 L), dichloromethane (1.times.4 L) then methanol
(1.times.4 L), dichloromethane (1.times.4 L) then methanol
(1.times.4 L), dichloromethane (1.times.4 L) then methanol
(1.times.4 L), dichloromethane (1.times.4 L) and ether (1.times.4
L).
5. Cleavage:
The MicroKANs are sorted into an individual well of IRORI
AccuCleave 96 cleavage station. The well is charged with
dichloromethane (600 mL) and then with a ThA:dichloromethane
mixture (1:1, 600 mL). After agitating for approximately forty
minutes, the reaction well is drained into 2 mL microtubes in an
96-well format. The reaction well is again charged with
dichloromethane (600 mL). After manual agitation, this too is
drained into the 2 mL microtubes in an 96-well format. The cleavage
cocktail is removed in vacuo using a Savant Speedvac. The
concentrated products from the cleavage mother plates are
reconstituted with THF and transferred into two daughter plates
utilizing a Packard MultiProbe liquid handler. The daughter plates
are concentrated in vacuo utilizing a GenieVac.
Analytical: MS: m/z 442.2 (M+H.sub.+).
The methods described above are used to prepare the following
compounds of this invention. ##STR00171## ##STR00172## ##STR00173##
##STR00174## ##STR00175## ##STR00176## ##STR00177## ##STR00178##
##STR00179## ##STR00180## ##STR00181## ##STR00182## ##STR00183##
##STR00184## ##STR00185## ##STR00186## ##STR00187## ##STR00188##
##STR00189## ##STR00190## ##STR00191## ##STR00192## ##STR00193##
##STR00194## ##STR00195## ##STR00196##
Using a combination of the above Examples, various compounds may be
made within the scope of this invention.
Compounds according to the invention exhibit marked pharmacological
activities according to tests described in the literature, which
tests results are believed to correlate to pharmacological activity
in humans and other mammals. The following pharmacological test
results are typical characteristics of compounds of the present
invention.
The compounds of the present invention have potent activity as PPAR
ligand receptor binders and possess anti-diabetic, anti-lipidemic,
anti-hypertensive, and anti-arteriosclerotic activity and are also
anticipated to be effective in the treatment of diabetes, obesity
and other related diseases.
hPPAR.alpha. Binding Assay
The activity of the compounds of the invention as PPAR.alpha.
modulators may be examined in several relevant in vitro and in vivo
preclinical assays, for example benchmarking with a known
PPAR.alpha. modulator, for example,
[.sup.3H]-GW2331(2-(4-[2-(3-[2,4-Difluorophenyl]-1-heptylureido)-
-ethyl]phenoxy)-2-methylbutyric acid). (S. Kliewer, et al. Proc.
Natl. Acad. Sci. USA 94 (1997).
Human Peroxime Proliferator-activated Receptor a Ligand Binding
Domain(hPPAR.alpha.-LBD):
A binding assay for PPAR.alpha. could be carried out by the
following procedure: cDNAs encoding the putative ligand binding
domain of human PPAR.alpha. (amino acids 167-468) (Sher, T., Yi,
H.-F., McBride, O. W. & Gonzalez, F. J. (1993) Biochemistry 32,
5598-5604) are amplified by PCR (Polymerase Chain Reaction) and
inserted in frame into the BamHI site of pGEX-2T plasmid
(Pharmacia). The soluble fraction of GST-hPPAR.alpha. fusion
proteins or glutathione S-transferase (GST) alone are overexpressed
in E. coli BL21(DE3)pLysS cells and purified from bacteria extracts
as described in (S. Kliewer, et al. Proc. Natl. Acad. Sci. USA 94
(1997), 4318-4323).
Gel-Filtration Assays: 30 ml of 90 nM GST-hPPAR.alpha.-LBD is mixed
with 20 ml of 50 nM .sup.3H-GW2331 with or without 5 ml of 10 mM
test compounds in the binding buffer containing 10 mM Tris, 50 mM
KCl, 0.05% Tween 20 and 10 mM DTT. The reaction mixtures are
incubated in 96-well plates for 2 h at room temperature. 50 ml of
the reaction mixtures are then loaded on a 96-well gel filtration
block (following manufacture instructions)(EdgeBioSystems). The
block placed on top of a clean 96-well plate is centrifuged at
1,500 rpm for 2 min. The block is discarded. 100 ml of
Scintillation fluid is added to each well of the 96-well plate.
After overnight equilibration, the plate is counted in the
Microbeta counter (Wallac.).
Homogenous Scintillation Proximity Binding Assay.
For the Scarchard analysis, glutathione coated SPA beads (1.5
mg/ml)(Amersham) are mixed with GST-hPPAR.alpha.-LBD (10 mg/ml) in
the binding buffer. The resulting slurry is incubated at room
temperature with agitation for 15 min. 20 ml of the slurry is then
added in 30 ml of binding buffer containing various amount
.sup.3H-GW2331(10-500 nM). Non-specific binding is determined in
the present of 100 mM of GW2331. For the competition binding assay,
20 ml of the slurry is then added in 30 ml of the binding buffer
containing 75 nM of .sup.3H-GW2331 and 0.03-20 mM of the test
compounds. For the control experiments, the glutathione coated SPA
beads (1.5 mg/ml) are coated with GST proteins (10 mg/ml). 20 ml of
the slurry are mixed with 30 ml of 75 nM of .sup.3H-GW2331 with or
without 10 mM of GW2331. The above experiments are all performed in
a 96-well plates. The sealed plates with the reaction mixtures are
allowed to equilibrate for 2 h and counted in the Microbeta counter
(Wallac.).
hPPAR.gamma. Binding Assay
The activity of the compounds of the invention as PPAR.gamma.
modulators may be examined in several relevant in vitro and in vivo
preclinical assays, for example benchmarking with a known
PPAR.gamma. modulator, for example, [.sup.3H]-BRL 49853 (Lehman L.
J. et al, J. Biol. Chem. 270, 12953-12956; Lehman L. J. et al, J.
Biol. Chem. 272, 3406-3410 (1997), and Nichols, J. S.; et al
Analytical Biochemistry 257, 112-119(1998)).
Human Peroxime Proliferator-activated Receptor a Ligand Binding
Domain(hPPAR.gamma.-LBD).
A binding assay for PPAR.gamma. could be carried out by the
following procedure: cDNAs encoding the putative ligand binding
domain of human PPAR.gamma. (amino acids 176-477) (Green, M. E. et
al. Gene expression 281-299(1995)) are amplified by PCR (polymerase
chain reaction) and inserted in frame into the BanmHI site of
pGEX-2T plasmid (Pharmacia). The soluble fraction of
GST-hPPAR.gamma. fusion proteins or glutathione S-transferase (GST)
alone are overexpressed in E. coli BL21(DE3)pLysS cells and
purified from bacteria extracts.
Binding Assay: The fusion proteins, GST-PPAR.gamma.-LBD in PBS (5
mg/110 ml/well) are incubated in the glutathione coated 96 well
plates for 4 hours. Unbound proteins are then discarded and the
plates are washed two times with the wash buffer (10 mM Tris, 50 mM
KCl and 0.05% Tween-20). 100 ml of reaction mixtures containing 60
nM of .sup.3H-BRL-49853 and 10 mM of the testing compounds (10 ml
of 0.1 mM compounds from each well of the child plates) in the
binding buffer (10 mM Tris, 50 mM KCl and 10 mM DTT) are then added
and incubated at room temperature for 2.5 h. The reaction mixtures
are discarded and the plates are washed two times with the wash
buffer. 100 ml of scintillation fluid is added to each well and
plates are counted on .beta.-counter.
hPPAR.delta. Binding Assay
The activity of the compounds of the invention as PPAR.delta.
modulators may be examined in several relevant in vitro and in vivo
preclinical assays (See references WO 97/28149; Brown P. et al
Chemistry & Biology, 4, 909-18, (1997)), for example
benchmarking with a known PPAR.delta. modulator, for example
[.sup.3H.sub.2]GW2433 or [.sup.3H.sub.2]Compound X ##STR00197##
The hPPAR.delta. binding assay comprises the steps of: (a)
preparing multiple test samples by incubating separate aliquots of
the receptor hPPAR.delta. with a test compound in TEGM containing
5-10% COS-1 cell cytoplasmic lysate and 2.5 nM labeled
([.sup.3H]Compound X, 17 Ci/mmol) for a minimum of 12 hours, and
preferably for about 16 hours, at 4.degree. C., wherein the
concentration of the test compound in each test sample is
different, and preparing a control sample by incubating a further
separate aliquot of the receptor hPPAR.delta. under the same
conditions but without the test compound; then (b) removing unbound
ligand by adding dextran/gelatin-coated charcoal to each sample
while maintaining the samples at 4.degree. C. and allowing at least
10 minutes to pass, then (c) subjecting each of the test samples
and control sample from step (b) to centrifugation at 4.degree. C.
until the charcoal is pelleted; then (d) counting a portion of the
supernatant fraction of each of the test samples and the control
sample from step (c) in a liquid scintillation counter and
analyzing the results to determine the IC.sub.50 of the test
compound.
In the hPPAR.delta. binding assay, preferably at least four test
samples of varying concentrations of a single test compound are
prepared in order to determine the IC.sub.50.
The compounds useful according to the invention can be administered
to a patient in a variety of forms adapted to the chosen route of
administration, i.e., orally, or parenterally. Parenteral
administration in this respect includes administration by the
following routes: intravenous, intramuscular, subcutaneous,
intraocular, intrasynovial, transepthelially including transdermal,
opthalmic, sublingual and buccal; topically including opthalmic,
dermal, ocular, rectal and nasal inhalation via insufflation and
aerosol and rectal systemic.
The active compound may be orally administered, for example, with
an inert diluent or with an assimilable edible carrier, or it may
be enclosed in hard or soft shell gelatin capsules, or it may be
compressed into tablets, or it may be incorporated directly with
the food of the diet. For oral therapeutic administration, the
active compound may be incorporated with excipient and used in the
form of ingestible tablets, buccal tablets, troches, capsules,
elixirs, suspensions, syrups, wafers, and the like. Such
compositions and preparations should contain at least 0.1% of
active compound. The percentage of the compositions and
preparations may, of course, be varied and may conveniently be from
about 2% to about 6% of the weight of the unit. The amount of
active compound in such therapeutically useful compositions is such
that a suitable dosage will be obtained. Preferred compositions or
preparations according to the present invention are prepared so
that an oral dosage unit form contains between about 50 and 300 mg
of active compound.
The tablets, troches, pills, capsules and the like may also contain
the following: A binder such as gum tragacanth, acacia, corn starch
or gelatin; excipients such as dicalcium phosphate; a
disintegrating agent such as corn starch, potato starch, alginic
acid and the like; a lubricant such as magnesium stearate; and a
sweetening agent such as sucrose, lactose or saccharin may be added
or a flavoring agent such as peppermint, oil of wintergreen, or
cherry flavoring. When the dosage unit form is a capsule, it may
contain, in addition to materials of the above type, a liquid
carrier. Various other materials may be present as coatings or to
otherwise modify the physical form of the dosage unit. For
instance, tablets, pills, or capsules may be coated with shellac,
sugar or both. A syrup or elixir may contain the active compound,
sucrose as a sweetening agent, methyl and propylparabens a
preservatives, a dye and flavoring such as cherry or orange flavor.
Of course, any material used in preparing any dosage unit form
should be pharmaceutically pure and substantially non-toxic in the
amounts employed. In addition, the active compound may be
incorporated into sustained-release preparations and
formulations.
The active compound may also be administered parenterally or
intraperitoneally. Solutions of the active compound as a free base
or pharmacologically acceptable salt can be prepared in water
suitably mixed with a surfactant such as hydroxypropyl-cellulose.
Dispersion can also be prepared in glycerol, liquid polyethylene
glycols, and mixtures thereof and in oils. Under ordinary
conditions of storage and use, these preparations contain a
preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and must be
fluid to the extent that easy syringability exists. It may be
stable under the conditions of manufacture and storage and must be
preserved against the contaminating action of microorganisms such
as bacteria and fungi. The carrier can be a solvent or dispersion
medium containing, for example, water, ethanol, polyol (for
example, glycerol, propylene glycol, and liquid polyethylene
glycol, and the like), suitable mixtures thereof, and vegetable
oils. The 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 dispersion and by the use of
surfactants. The prevention of the action of microorganisms can be
brought about by various antibacterial and antifungal agents, for
example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal,
and the like. In many cases, it will be preferable to include
isotonic agents, for example, sugars or sodium chloride. Prolonged
absorption of the injectable compositions of agents delaying
absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by incorporating the
active compound in the required amount in the appropriate solvent
with various of the other ingredients enumerated above, as
required, followed by filtered sterilization. Generally,
dispersions are prepared by incorporating the various sterilized
active ingredient into a sterile vehicle which contains the basic
dispersion medium and the required other ingredients from those
enumerated above. In the case of sterile powders for the
preparation of sterile injectable solutions, the preferred methods
of preparation are vacuum drying and the freeze drying technique
which yield a powder of the active ingredient plus any additional
desired ingredient from previously sterile-filtered solution
thereof.
The therapeutic compounds useful according to this invention may be
administered to a patient alone or in combination with
pharmaceutically acceptable carrier, as noted above, the proportion
of which is determined by the solubility and chemical nature of the
compound, chosen route of administration and standard
pharmaceutical practice.
The physician will determine the dosage of the present therapeutic
agents which will be most suitable for prophylaxis or treatment and
it will vary with the form of administration and the particular
compound chosen, and also, it will vary with the particular patient
under treatment. He will generally wish to initiate treatment with
small dosages by small increments until the optimum effect under
the circumstances is reached. The therapeutic dosage will generally
be from 0.1 to 100 mM/day or from about 0.1 mg to about 50 mg/kg of
body weight per day, or 10 mg to about 50 mg/kg of body weight per
day, or more preferably 30 mg to about 50 mg/kg of body weight per
day, and higher, although it may be administered in several
different dosage units. Higher dosages are required for oral
administration.
The compounds useful according to the invention may be administered
as frequently as necessary in order to obtain the desired
therapeutic effect. Some patients may respond rapidly to a higher
or lower dose and may find much weaker maintenance doses adequate.
For other patients, it may be necessary to have long-term
treatments at the rate of 1 to 4 doses per day, in accordance with
the physiological requirements of each particular patient.
Generally, the active product may be administered orally 1 to 4
times per day. It goes without saying that, for other patients, it
will be necessary to prescribe not more than one or two doses per
day.
One skilled in the art will readily appreciate that the present
invention is well adapted to carry out the objects of the invention
and obtain the ends and advantages mentioned, as well as those
inherent therein. The compounds, compositions and methods described
herein are presented as representative of the preferred
embodiments, or intended to be exemplary and not intended as
limitations on the scope of the present invention.
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