U.S. patent application number 14/566343 was filed with the patent office on 2015-04-02 for niacin mimetics, and methods of use thereof.
The applicant listed for this patent is Arisaph Pharmaceuticals, Inc., Trustees of Tufts College. Invention is credited to William W. Bachovchin, Christopher P. Kiritsy, Hung-sen Lai, Daniel P. O'Connell, Wengen Wu.
Application Number | 20150094303 14/566343 |
Document ID | / |
Family ID | 45371840 |
Filed Date | 2015-04-02 |
United States Patent
Application |
20150094303 |
Kind Code |
A1 |
Bachovchin; William W. ; et
al. |
April 2, 2015 |
Niacin Mimetics, and Methods of Use Thereof
Abstract
Disclosed are heterocyclylalkyl-substituted and
heteroaralkyl-substituted pyridines, and pharmaceutically
acceptable salts and prodrugs thereof, that are active against a
range of mammalian therapeutic indications.
Inventors: |
Bachovchin; William W.;
(Cambridge, MA) ; Lai; Hung-sen; (Andover, MA)
; O'Connell; Daniel P.; (Somerville, MA) ; Wu;
Wengen; (Medford, MA) ; Kiritsy; Christopher P.;
(Waban, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Trustees of Tufts College
Arisaph Pharmaceuticals, Inc. |
Boston
Boston |
MA
MA |
US
US |
|
|
Family ID: |
45371840 |
Appl. No.: |
14/566343 |
Filed: |
December 10, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13168629 |
Jun 24, 2011 |
8937063 |
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14566343 |
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61358245 |
Jun 24, 2010 |
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Current U.S.
Class: |
514/232.2 ;
514/235.5 |
Current CPC
Class: |
A61P 35/00 20180101;
A61P 9/10 20180101; A61P 7/00 20180101; A61P 25/02 20180101; A61K
45/06 20130101; A61K 31/40 20130101; A61P 1/16 20180101; A61P 9/00
20180101; A61P 25/00 20180101; A61P 3/04 20180101; A61K 31/47
20130101; A61P 25/28 20180101; A61P 43/00 20180101; A61P 11/04
20180101; A61K 31/397 20130101; A61P 5/14 20180101; A61P 17/00
20180101; A61K 31/22 20130101; A61P 29/00 20180101; A61K 31/455
20130101; A61K 31/616 20130101; A61P 1/00 20180101; A61P 19/02
20180101; A61P 3/06 20180101; A61P 19/08 20180101; C07D 213/80
20130101; A61K 31/192 20130101; A61P 3/10 20180101; A61K 31/5377
20130101; A61P 11/00 20180101; A61P 9/04 20180101; A61P 9/08
20180101; A61K 31/404 20130101; A61K 31/44 20130101; A61K 31/505
20130101; A61P 9/12 20180101; A61K 31/167 20130101; A61K 31/366
20130101; A61P 3/00 20180101; A61P 13/02 20180101; A61K 31/167
20130101; A61K 2300/00 20130101; A61K 31/192 20130101; A61K 2300/00
20130101; A61K 31/22 20130101; A61K 2300/00 20130101; A61K 31/366
20130101; A61K 2300/00 20130101; A61K 31/397 20130101; A61K 2300/00
20130101; A61K 31/40 20130101; A61K 2300/00 20130101; A61K 31/404
20130101; A61K 2300/00 20130101; A61K 31/44 20130101; A61K 2300/00
20130101; A61K 31/455 20130101; A61K 2300/00 20130101; A61K 31/47
20130101; A61K 2300/00 20130101; A61K 31/505 20130101; A61K 2300/00
20130101; A61K 31/5377 20130101; A61K 2300/00 20130101; A61K 31/616
20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/232.2 ;
514/235.5 |
International
Class: |
C07D 213/80 20060101
C07D213/80; A61K 45/06 20060101 A61K045/06; A61K 31/5377 20060101
A61K031/5377 |
Claims
1. A method of reducing a serum or plasma level of at least one
lipid selected from the group consisting of total cholesterol,
low-density lipoprotein (LDL) cholesterol, triglycerides, and
lipoprotein (a), comprising orally administering to a human in need
thereof an effective amount of a niacin analog or a
pharmaceutically acceptable salt thereof, wherein said oral
administration is characterized by reduced flushing and reduced
hepatocellular damage, as compared to oral administration of an
equimolar dose of immediate-release niacin.
2. The method of claim 1, wherein peak concentration (C.sub.max)
for the niacin analog is 40 percent or less of C.sub.max for the
equimolar oral dose of immediate-release niacin.
3. The method of claim 1, wherein the ratio of peak concentration
to area under the curve at 24 hours (C.sub.max/AUC.sub.0-24) for
the niacin analog is 0.35 h.sup.-1 or less.
4. The method of claim 1, wherein the time to peak concentration
(t.sub.max) for the niacin analog is in the range of 1 to 5
hours.
5. The method of claim 1, wherein the niacin analog has an
EC.sub.50 for .beta.-arrestin-mediated GPR109A function which is at
least 10 times greater than the EC.sub.50 of niacin for
.beta.-arrestin-mediated GPR109A function.
6. The method of claim 1, wherein the niacin analog when
administered orally to a human also increases a serum or plasma
level of high-density lipoprotein (HDL) cholesterol.
7. The method of claim 1, wherein said oral administration is
characterized by substantially no increase in serum levels of
aspartate aminotransferase (AST), alanine aminotransferase (ALT),
or both.
8. The method of claim 1, further comprising administering to the
human a statin.
9. The method of claim 8, wherein the statin is selected from the
group consisting of atorvastatin, cerivastatin, fluvastatin,
lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and
simvastatin.
10. (canceled)
11. A pharmaceutical composition, comprising a niacin analog or a
pharmaceutically acceptable salt thereof, and at least one
pharmaceutically acceptable excipient; wherein said composition is
formulated for oral administration; the niacin analog when
administered orally to a human reduces a serum or plasma level of
at least one lipid selected from the group consisting of total
cholesterol, low-density lipoprotein (LDL) cholesterol,
triglycerides, and lipoprotein (a); and oral administration of the
composition is characterized by reduced flushing and reduced
hepatocellular damage, as compared to administration of an
equimolar oral dose of niacin.
12. The pharmaceutical composition of claim 11, wherein peak
concentration (C.sub.max) for the niacin analog is 40 percent or
less of C.sub.max for the equimolar oral dose of niacin.
13. The pharmaceutical composition of claim 11, wherein the ratio
of peak concentration to area under the curve at 24 hours
(C.sub.max/AUC.sub.0-24) for the niacin analog is 0.35 h.sup.-1 or
less.
14. The pharmaceutical composition of claim 11, wherein the time to
peak concentration (t.sub.max) for the niacin analog is in the
range of 30 minutes to 5 hours.
15. The pharmaceutical composition of claim 11, wherein the niacin
analog has an EC.sub.50 for .beta.-arrestin-mediated GPR109A
function which is at least 10 times greater than the EC.sub.50 of
niacin for .beta.-arrestin-mediated GPR109A function.
16. The pharmaceutical composition of claim 11, wherein the niacin
analog when administered orally to a human also increases a serum
or plasma level of high-density lipoprotein (HDL) cholesterol.
17. The pharmaceutical composition of claim 11, wherein the niacin
analog when administered orally to a human induces substantially no
increase in serum levels of aspartate aminotransferase (AST),
alanine aminotransferase (ALT), or both.
18. The pharmaceutical composition of claim 11, wherein the niacin
analog when administered orally to a human induces substantially no
increase in serum levels of uric acid, glucose, or both.
19-114. (canceled)
115. The pharmaceutical composition of claim 11, wherein the niacin
analog has an EC.sub.50 for reducing serum cholesterol, LDL and/or
triglycerides which, in the average human patient population, is no
more than 20 percent of the half maximal concentration of the
niacin analog which would cause cutaneous vasodilation (flushing)
in the average human patient population.
116. The pharmaceutical composition of claim 115, wherein the
EC.sub.50 of the niacin analog for reducing serum cholesterol, LDL
and/or triglycerides is no more than 1 percent of the half maximal
concentration of the niacin analog which would cause cutaneous
vasodilation (flushing) in the average human patient
population.
117. The pharmaceutical composition of claim 11, wherein the niacin
analog has an EC.sub.50 for reducing serum cholesterol, LDL and/or
triglycerides which, in the average human patient population, is no
more than 20 percent of the concentration of the niacin analog
which would cause increases in serum levels of aspartate
aminotransferase (AST) and alanine aminotransferase (ALT) requiring
discontinuation of administration of the pharmaceutical
composition.
118. The pharmaceutical composition of claim 11, wherein said
niacin analog when administered once per day is effective in
reducing a serum lipid without causing treatment-limiting (i)
hepatotoxicity and (ii) elevations in uric acid levels or glucose
levels or both, that would require such treatment to be
discontinued.
119. The pharmaceutical composition of claim 11, further comprising
a statin.
120. The pharmaceutical composition of claim 119, wherein the
statin is selected from the group consisting of atorvastatin,
cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin,
pravastatin, rosuvastatin and simvastatin.
121. (canceled)
122. A method of treating hyperlipidemia, hypercholesterolemia,
lipodystrophy, dyslipidemia, atherosclerosis or coronary artery
disease, comprising the step of administering orally to a patient
in need thereof a therapeutically effective amount of a
pharmaceutical composition of claim 11.
123. A method of treating metabolic syndrome, obesity, fatty liver
disease, or diabetes, comprising the step of administering orally
to a patient in need thereof a therapeutically effective amount of
a pharmaceutical composition of claim 11.
124. A method of raising serum high-density lipoprotein (HDL)
levels, comprising the step of administering orally to a patient in
need thereof a therapeutically effective amount of a pharmaceutical
composition of claim 11.
125. A method of lowering serum low-density lipoprotein (LDL)
levels or lowering serum lipoprotein (a) levels, comprising the
step of administering orally to a patient in need thereof a
therapeutically effective amount of a pharmaceutical composition of
claim 11.
126. A method of treating congestive heart failure, cardiovascular
disease, hypertension, coronary heart disease, angina, pellagra,
Hartnup's syndrome, carcinoid syndrome, arterial occlusive disease,
hypothyroidism, vasoconstriction, osteoarthritis, rheumatoid
arthritis, Alzheimer's disease, a disorder of the peripheral and
central nervous system, a hematological disease, cancer,
inflammation, a respiratory disease, or a gastroenterological
disease, comprising the step of administering orally to a patient
in need thereof a therapeutically effective amount of a
pharmaceutical composition of claim 11.
127-135. (canceled)
Description
RELATED APPLICATION
[0001] This application claims the benefit of priority to U.S.
Provisional Patent Application Ser. No. 61/358,245, filed Jun. 24,
2010, the contents of which are hereby incorporated by
reference.
BACKGROUND
[0002] Hyperlipidemia and hypercholesterolemia are conditions that
have a well established correlation with increased risk of other
conditions, such as heart attacks, atherosclerosis, and other
deleterious ailments. There are numerous agents available for
lowering cholesterol and lipid levels, including gemfibrizol,
probucol, and, more recently, the "statins" (e.g., lovastatin).
[0003] Niacin (nicotinic acid), a water soluble B-complex vitamin,
is used orally for the treatment of hyperlipidemia. Niacin has been
shown to be effective in reducing total plasma cholesterol (C),
low-density lipoproteins LDL-C and very low density lipoprotein
triglycerides (VLDL-triglycerides), all of which are associated
with health risks. Simultaneously, niacin raises serum levels of
high density lipoproteins (HDL-C), which are considered a "healthy"
lipoprotein, in patients with types II, III, IV, and V
hyperlipoproteinemia.
[0004] Although the mechanism by which niacin alters lipid profiles
has not been well defined, its mechanisms of action have been shown
to include inhibition of free fatty acid release from adipose
tissue (see Carlson, L. A., Froberg, S. O. and Nye, E. R.,
Nicotinic acid in the rat. 11. Acute effects of nicotinic acid on
plasma, liver, heart, and muscle lipids, Acta Med Scand 180:
571-579, 1966), and increased lipoprotein lipase activity (see
Priego, J. G., Pina, M., Armijo, M., Sunkel, C. and Maroto, M. L.,
Action of etofibrate, clofibrate and nicotinic acid on the
metabolism of lipids in normolipemic rats. Short term effects and
method of action, Arch Farmacol Toxicol 5: 29-42, 1979). More than
30 million Americans have elevated blood LDL-C levels. HMG-CoA
reductase inhibitors (statins) are the most widely used class of
drugs for treating patients with elevated levels of LDL-C. Niacin,
however, is the only drug recommended by the American Heart
Association for HDL improvement in primary prevention of
cardiovascular diseases in addition to lowering LDL-C. Niacin
therapy is not only cost-effective as a monotherapy, but it is also
beneficial as a combination therapy because it complements the
effects of other classes of lipid-lowering drugs. However, niacin
is a second or third choice for isolated hypercholesterolemia
because of a high incidence of side effects associated with oral
niacin therapy. Nevertheless, it has a therapeutic advantage as a
monotherapy when reduction of both LDL-C and triglycerides are
desired, such as for patients with severe combined
hyperlipidemia.
[0005] Niacin may also be used in combination with other
cholesterol-lowering agents, such as the "statins", to maximize
lipid-lowering activity. One study showed that a niacin/lovastatin
combination is highly effective in lowering LDL-C, triglycerides
and lipoprotein (a) (Lp(a)) while retaining niacin's potency in
raising HDL-C(Kashyap, M. L., Evans R., Simmons, P. D., Kohler, R.
M. and McGoven, M. E., New combination niacin/statin formulation
shows pronounced effects on major lipoproteins and well tolerated,
J Am Coll Card Suppl. A 35: 326, 2000).
[0006] Niacin has been widely used for reducing serum cholesterol
levels because it is considered a cost-effective therapy. Daily
oral doses of 2-3 g niacin in humans reduce levels of total-C and
LDL-C by an average of 20% to 30%, reduce triglyceride levels 35%
to 55%, increase HDL-C 20% to 35%, and reduce Lp(a). Niacin also
reduces total mortality as well as mortality from coronary artery
disease (see The Coronary Drug Project Research Group, JAMA 231:
360-381, 1975; and Canner, P. L., Berge, K. G., Wenger, N. K.,
Stamler, J., Friedman, L., Prineas, R. J. and Friedewald, W.,
Fifteen year mortality in Coronary Drug Project patients: long-term
benefit with niacin, J Am Coll Cardiol 8: 1245-1255, 1986.) and it
helps to slow or reverse the progression of atherosclerosis (see
Blankenhorn, D. H., Nessim, S. A., Johnson, R. L., Samnarco, M. E.,
Azen, S. P. and Cashin-Hemphill, L., Beneficial effects of combined
colestipol-niacin therapy on coronary atherosclerosis and coronary
venous bypass grafts, JAMA 257: 3233-3240, 1987; and
Cashin-Hemphill L.; Mack, W. J., Pogoda, J. M., Samnarco, M. E.,
Azen, S. P. and Blankenhorn, D. H., Beneficial effects of
colestipol-niacin on coronary atherosclerosis. A 4-year follow-up,
JAMA 264: 3013-3017, 1990).
[0007] Unfortunately, oral niacin therapy has side effects that
limit its utility. Although niacin is a vitamin, it must be used in
therapeutic doses to lower cholesterol. At these doses, both
immediate-release and sustained-release niacin can have several
side effects. The most common side effect of niacin is flushing, a
warm feeling in the skin usually associated with redness and
sometimes itching. Flushing is not dangerous, but most patients
find it very uncomfortable, which seriously limits patient
compliance with niacin therapy. Niacin-induced flushing can be
substantially attenuated by pretreatment with cyclooxygenase
inhibitors, suggesting that the vasodilation is caused by a
prostaglandin-mediated mechanism (see Carlson, L. A., Nicotinic
acid and inhibition of fat mobilizing lipolysis. Present status, of
effects on lipid metabolism, Adv Exp Med Biol 109: 225-23 8,
1978).
[0008] Liver function tests are always monitored in patients taking
niacin since elevation of serum transaminase levels has been
associated with niacin treatment, and sustained-release niacin
formulations have been associated with more serious liver problems
(see McKenney, J. M., Proctor, J. D., Harris, S., and Chinchili, V.
M., A comparison of the efficacy and toxic effects of sustained- vs
immediate-release niacin in hypercholesterolemic patients, JAMA
271: 672-777, 1994; and Stafford, R. S., Blumenthal, D. and
Pasternak, R. C., Variations in cholesterol management practices of
U.S. physicians, J Am Coll Cardiol 29: 139-146, 1997). Other known
side effects of oral niacin therapy include activation of peptic
ulcers, gout, and worsening of diabetes control. Accordingly, the
safety and efficacy of oral niacin therapy is undermined by the
need for careful clinical monitoring and the compound's side-effect
profile.
SUMMARY
[0009] One aspect of the present invention relates to naiacin
analogs, as defined herein, and methods of use thereof against one
or more mammalian or human therapeutic indications.
[0010] One aspect of the present invention relates to
heterocyclylalkyl-substituted and heteroaralkyl-substituted
pyridines, and pharmaceutically acceptable salts thereof, that are
active against a range of mammalian maladies. In certain
embodiments, said pyridines or salts thereof comprise at the
3-position or 5-position a substituent comprising a functional
group that is substantially anionic at physiological pH. In certain
embodiments, said pyridines or salts thereof comprise at the
2-position or 6-position a substituent comprising a functional
group that is electron donating to the pyridine ring. In certain
embodiments, said pyridines or salts thereof comprise at the
5-position a substituent comprising a functional group that is
substantially anionic at physiological pH; and at the 2-position a
substituent comprising a functional group that is electron donating
to the pyridine ring.
[0011] An aspect of the invention is a method of reducing a serum
or plasma level of at least one lipid selected from the group
consisting of total cholesterol, low-density lipoprotein (LDL)
cholesterol, triglycerides, and lipoprotein (a), comprising orally
administering to a human in need thereof an effective amount of a
niacin analog or a pharmaceutically acceptable salt thereof,
wherein said oral administration is characterized by reduced
flushing and reduced hepatocellular damage, as compared to oral
administration of an equimolar dose of immediate-release
niacin.
[0012] In one embodiment, peak concentration (C.sub.max) for the
niacin analog is 40 percent or less of C.sub.max for the equimolar
oral dose of immediate-release niacin.
[0013] In one embodiment, the ratio of peak concentration to area
under the curve at 24 hours (C.sub.max/AUC.sub.0-24) for the niacin
analog is 0.35 h.sup.-1 or less.
[0014] In one embodiment, the time to peak concentration
(t.sub.max) for the niacin analog is in the range of 1 to 5
hours.
[0015] In one embodiment, the niacin analog has an EC.sub.50 for
.beta.-arrestin-mediated GPR109A function which is at least 10
times greater than the EC.sub.50 of niacin for
.beta.-arrestin-mediated GPR109A function.
[0016] In one embodiment, the niacin analog when administered
orally to a human also increases a serum or plasma level of
high-density lipoprotein (HDL) cholesterol.
[0017] In one embodiment, the oral administration is characterized
by substantially no increase in serum levels of aspartate
aminotransferase (AST), alanine aminotransferase (ALT), or
both.
[0018] In one embodiment, the method further comprises
administering to the human a statin. In one embodiment, the statin
is selected from the group consisting of atorvastatin,
cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin,
pravastatin, rosuvastatin and simvastatin.
[0019] In one embodiment, the method further comprises
administering to the human at least one additional therapeutic
agent selected from the group consisting of 11.beta. HSD-1
inhibitors, 5HT transporter inhibitors, 5HT2c agonists, 5-LO or
FLAP inhibitors, .alpha.-glucosidase inhibitors, ABCA1 enhancers,
ACC inhibitors, AcylCoA:cholesterol O-acyltransferase inhibitors,
acyl-estrogens, antidiabetic agents, anti-dyslipidemic agents,
anti-hypertensive agents, anti-oxidants, Apo A1 mimetics, Apo A1
modulators, Apo E mimetics, apolipoprotein-B secretion/microsomal
triglyceride transfer protein (apo-B/MTP) inhibitors, appetite
suppressants, aspirin, .beta.3 agonists, bile acid reabsorption
inhibitors, bile acid sequestrants, bombesin agonists, BRS3
agonists, CB.sub.1 antagonists/inverse agonists, CCK-A agonists,
cholesterol absorption inhibitor, cholesterol transport inhibitors,
cholesteryl ester transfer protein (CETP) inhibitors, CNTF, CNTF
agonists/modulators, a combination of ezetimibe and simvastatin
and/or atorvastatin, CSL-111, dehydroepiandrosterone, delipidated
HDL, DGAT antisense oligos, DGAT1 inhibitors, DGAT2 inhibitors,
dicarboxylate transporter inhibitors, dopamine agonists, DP
receptor antagonists, ezetimibe, FAS inhibitors, fatty acid binding
protein (FABP) inhibitors, fatty acid transporter inhibitors, fatty
acid transporter protein (FATP) inhibitors, flush inhibitors, FXR
receptor modulators, galanin receptor antagonists, gemcabene,
ghrelin antagonists, ghrelin antibodies, GLP-1 agonists,
glucagon-like peptide-1 receptor agonists, glucocorticoid
agonists/antagonists, glucose transporter inhibitors, HDL mimetics,
HMG CoA reductase inhibitor compounds, HMG-CoA synthetase
inhibitors, hormone sensitive lipase antagonists, human
agouti-related proteins (AGRP), H.sub.3 antagonists/inverse
agonists, inorganic cholesterol sequestrants, L-4f, lapaquistat,
leptin agonists/modulators, leptins, lipase inhibitors, lipoprotein
synthesis inhibitors, lorapoprant, low density lipoprotein receptor
inducers or activators, Lp(a) reducers, LXR receptor agonists, lyn
kinase inhibitor, Mc3r agonists, Mc4r agonists, MCH1R antagonists,
MCH2R agonists/antagonists, melanin concentrating hormone
antagonists, mGluR5 antagonists, microsomal triglyceride transport
inhibitors, monoamine reuptake inhibitors, natural water soluble
fibers, NE transporter inhibitors, neuromedin U receptor agonists,
neuropeptide-Y antagonists, niacin or niacin receptor agonists,
nicotinic acid, noradrenergic anorectic agents, NPY1 antagonists,
NPY2 agonists, NPY4 agonists, NPY5 antagonists, non-steroidal
anti-inflammatory drug (NSAID) agents, omega-3 fatty acids, opioid
antagonists, orexin receptor antagonists, PDE inhibitors,
phentermine, phosphate transporter inhibitors, phytopharm compound
57, plant stanols and/or fatty acid esters of plant stanols,
platelet aggregation inhibitors, PPAR-.alpha. agonists,
PPAR-.delta. agonists, PPAR-.delta. partial agonists, PPAR-.gamma.
agonists, probucol, renin angiotensin inhibitors, reversed-4F,
SCD-1 inhibitors, serotonin reuptake inhibitors, SGLT2 inhibitors,
squalene epoxidase inhibitors, squalene synthesis inhibitors,
sterol biosynthesis inhibitors, sympathomimetic agonists, thyroid
hormone .beta. agonists, thyromimetic agents, topiramate,
triglyceride synthesis inhibitors, UCP-1 activators, UCP-2
activators, UCP-3 activators, and urocortin binding protein
antagonists.
[0020] An aspect of the invention is a pharmaceutical composition,
comprising a niacin analog or a pharmaceutically acceptable salt
thereof, and at least one pharmaceutically acceptable excipient;
wherein said composition is formulated for oral administration; the
niacin analog when administered orally to a human reduces a serum
or plasma level of at least one lipid selected from the group
consisting of total cholesterol, low-density lipoprotein (LDL)
cholesterol, triglycerides, and lipoprotein (a); and oral
administration of the composition is characterized by reduced
flushing and reduced hepatocellular damage, as compared to
administration of an equimolar oral dose of niacin.
[0021] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein peak serum or plasma
concentration (C.sub.max) for the niacin analog is 40 percent or
less of C.sub.max for the equimolar oral dose of niacin. In one
embodiment, peak serum or plasma concentration (C.sub.max) for the
niacin analog is 35 percent or less of C.sub.max for the equimolar
oral dose of niacin. In one embodiment, peak serum or plasma
concentration (C.sub.max) for the niacin analog is 30 percent or
less of C.sub.max for the equimolar oral dose of niacin. In one
embodiment, peak serum or plasma concentration (C.sub.max) for the
niacin analog is 25 percent or less of C.sub.max for the equimolar
oral dose of niacin. In one embodiment, peak serum or plasma
concentration (C.sub.max) for the niacin analog is 20 percent or
less of C.sub.max for the equimolar oral dose of niacin. In one
embodiment, peak serum or plasma concentration (C.sub.max) for the
niacin analog is 15 percent or less of C.sub.max for the equimolar
oral dose of niacin. In one embodiment, peak serum or plasma
concentration (C.sub.max) for the niacin analog is 10 percent or
less of C.sub.max for the equimolar oral dose of niacin. In one
embodiment, peak serum or plasma concentration (C.sub.max) for the
niacin analog is 5 percent or less of C.sub.max for the equimolar
oral dose of niacin. In one embodiment, peak serum or plasma
concentration (C.sub.max) for the niacin analog is 1 percent or
less of C.sub.max for the equimolar oral dose of niacin. For each
of the foregoing embodiments, it is to be understood that
comparison is made with an immediate release formulation of niacin.
Methods useful for measuring the concentration are disclosed in
detail hereinbelow.
[0022] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein the ratio of peak serum or
plasma concentration (C.sub.max) to area under the curve at 24
hours (AUC.sub.0-24) (i.e., the ratio C.sub.max/AUC.sub.0-24) for
the niacin analog is 0.35 h.sup.-1 or less. In one embodiment, the
ratio of peak concentration to area under the curve at 24 hours
(C.sub.max/AUC.sub.0-24) for the niacin analog is 0.30 h.sup.-1 or
less. In one embodiment, the ratio of peak concentration to area
under the curve at 24 hours (C.sub.max/AUC.sub.0-24) for the niacin
analog is 0.25 h.sup.-1 or less. In one embodiment, the ratio of
peak concentration to area under the curve at 24 hours
(C.sub.max/AUC.sub.0-24) for the niacin analog is 0.20 h.sup.-1 or
less. In one embodiment, the ratio of peak concentration to area
under the curve at 24 hours (C.sub.max/AUC.sub.0-24) for the niacin
analog is 0.15 h.sup.-1 or less. In one embodiment, the ratio of
peak concentration to area under the curve at 24 hours
(C.sub.max/AUC.sub.0-24) for the niacin analog is 0.10 h.sup.-1 or
less. In one embodiment, the ratio of peak concentration to area
under the curve at 24 hours (C.sub.max/AUC.sub.0-24) for the niacin
analog is 0.05 h.sup.-1 or less. In one embodiment, the ratio of
peak concentration to area under the curve at 24 hours
(C.sub.max/AUC.sub.0-24) for the niacin analog is 0.01 h.sup.-1 or
less.
[0023] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein the time to peak serum or
plasma concentration (t.sub.max) for the niacin analog is in the
range of 30 minutes to 5 hours. In one embodiment, the time to peak
concentration (t.sub.max) for the niacin analog is in the range of
1 to 5 hours. In one embodiment, the time to peak concentration
(t.sub.max) for the niacin analog is in the range of 1 to 4 hours.
In one embodiment, the time to peak concentration (t.sub.max) for
the niacin analog is in the range of 1 to 3 hours. In one
embodiment, the time to peak concentration (t.sub.max) for the
niacin analog is in the range of 1 to 2 hours.
[0024] In an embodiment, the niacin analog has an EC.sub.50 for
.beta.-arrestin-mediated GPR109A function which is at least 10
times greater than the EC.sub.50 of niacin for
.beta.-arrestin-mediated GPR109A function.
[0025] In an embodiment, the niacin analog, when administered
orally to a human, also increases a serum or plasma level of
high-density lipoprotein (HDL) cholesterol.
[0026] In an embodiment, the niacin analog, when administered
orally to a human, induces substantially no increase in serum
levels of aspartate aminotransferase (AST), alanine
aminotransferase (ALT), or both.
[0027] In an embodiment, the niacin analog, when administered
orally to a human, induces substantially no increase in serum
levels of uric acid, glucose, or both.
[0028] Another aspect of the invention relates to a pharmaceutical
composition, comprising a compound of the present invention or a
pharmaceutically acceptable salt thereof; and a pharmaceutically
acceptable excipient. Yet another aspect of the invention relates
to a pharmaceutical composition, comprising a compound of the
present invention or a pharmaceutically acceptable salt thereof;
niacin; and a pharmaceutically acceptable excipient.
[0029] Another aspect of the invention relates to a pharmaceutical
composition, comprising a compound of the present invention or a
pharmaceutically acceptable salt thereof; a statin selected from
the group consisting of atorvastatin, cerivastatin, fluvastatin,
lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and
simvastatin; and a pharmaceutically acceptable excipient. The
present invention also relates to a pharmaceutical composition,
comprising a compound of the present invention or a
pharmaceutically acceptable salt thereof; niacin; a statin selected
from the group consisting of atorvastatin, cerivastatin,
fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,
rosuvastatin and simvastatin; and a pharmaceutically acceptable
excipient. Additional therapeutic agents which can be
co-administered with compounds of the invention are discussed
below.
[0030] Niacin, or nicotinic acid, has established efficacy for the
treatment of dyslipidemia, but the clinical use of niacin has been
limited by cutaneous flushing, a well-recognized associated adverse
effect. Flushing, which is estimated at a prevalence as high as 25%
to 40%, has been cited as the major reason for the discontinuation
of niacin therapy. A number of studies have established that
moderate doses of prostaglandin inhibitors reduce the cutaneous
flushing response from niacin administration. Other strategies for
reducing flushing include regular consistent dosing, the use of
extended-release formulations, patient education, dosing with meals
or at bedtime, and the avoidance of alcohol, hot beverages, spicy
foods, and hot baths or showers close to or after dosing. In
certain embodiments, compounds of the present invention can have
reduced occurrence or severity of flushing when administered to an
animal, particularly a human patient.
[0031] For instance, compounds of the present invention do not
cause flushing in the male C57BL/6 murine model of flushing, as
measured by laser Doppler flowmetry, when administered at doses of
up to 100 mg/kg, and even more preferably when administered at
doses up to 200, 300, or even 500 mg/kg.
[0032] In certain embodiments, compounds of the present invention
can be characterized by causing less flushing when administered
orally when compared to the amount equivalent molar amount of
NIASPAN.RTM. (niacin extended-release tablets, Abbott
Laboratories). In certain embodiments, compounds of the present
invention when administered orally to an average patient
population, shows a reduction in the number of patients reporting
flushing of greater than or equal to 5 on the visual analog scale
orally when compared to the equivalent molar amount of
NIASPAN.RTM..
[0033] The present invention also relates to a method of treating a
disease, disorder, or condition selected from the group consisting
of hyperlipidemia, hypercholesterolemia, lipodystrophy,
dyslipidemia, atherosclerosis, and coronary artery disease,
comprising the step of administering to a mammal in need thereof a
therapeutically effective amount of a compound or pharmaceutical
composition of the present invention.
[0034] Another aspect of the present invention relates to a method
of treating a disease, disorder, or condition selected from the
group consisting of metabolic syndrome, obesity, fatty liver
disease, and diabetes, comprising the step of administering to a
mammal in need thereof a therapeutically effective amount of a
compound or pharmaceutical composition of the present
invention.
[0035] Another aspect of the present invention relates to a method
of raising serum high-density lipoprotein (HDL) levels, comprising
the step of: administering to a mammal in need thereof a
therapeutically effective amount of a compound or pharmaceutical
composition of the present invention.
[0036] Another aspect of the present invention relates to a method
of lowering serum low-density lipoprotein (LDL) levels or lowering
serum lipoprotein (a) levels, comprising the step of administering
to a mammal in need thereof a therapeutically effective amount of a
compound or pharmaceutical composition of the present
invention.
[0037] Another aspect of the present invention relates to a method
of increasing the serum total concentrations of adiponectin,
comprising the step of administering to a mammal in need thereof a
therapeutically effective amount of a compound or pharmaceutical
composition of the present invention.
[0038] Another aspect of the present invention relates to a method
of treating a disease, disorder, or condition selected from the
group consisting of congestive heart failure, cardiovascular
disease, hypertension, coronary heart disease, angina, pellagra,
Hartnup's syndrome, carcinoid syndrome, arterial occlusive disease,
hypothyroidism, vasoconstriction, osteoarthritis, rheumatoid
arthritis, Alzheimer's disease, disorders of the peripheral and
central nervous system, hematological diseases, cancer,
inflammation, respiratory diseases, and gastroenterological
diseases, comprising the step of administering to a mammal in need
thereof a therapeutically effective amount of a compound or
pharmaceutical composition of the present invention.
[0039] The invention further provides a packaged pharmaceutical
preparation of the invention, including an insert, label or other
form of instruction to the patient to take the niacin analog
once-a-day within 2 or 3 hours of waking, optionally with food.
[0040] Additional aspects, embodiments, and advantages of the
invention are discussed below in detail.
BRIEF DESCRIPTION OF THE FIGURES
[0041] FIG. 1. Liquid chromatography-mass spectroscopy (LC-MS)
trace for ARI-001 received from Shanghai SpeedChem (Shanghai,
China). UV absorption at 215 nm was used to determine purity. The
area of the peak at 3.59 min represents 98.9% of the total peak
area of the trace.
[0042] FIG. 2. Relative stability of ARI-001 under storage
conditions as defined in the text. Total area representing the peak
for ARI-001 was calculated and then normalized to the total area of
peaks identified on the LC-MS trace. This is expressed as % of
total peaks. Upper graph, powder formulation; (.box-solid.)
standard conditions: 50.degree. C., no specified humidity. Lower
graph, liquid formulation; (.diamond.) room temperature (rt);
(.box-solid.) 4.degree. C.; (.tangle-solidup.) 20.degree. C.
[0043] FIG. 3. Overlaid FPLC traces of pooled plasma from hamsters
on either a normal chow diet (solid line) or a high fat+high sugar
(HF/HS) diet (dotted line).
[0044] FIG. 4. FPLC traces of pooled plasma from hamsters receiving
vehicle (solid line), 1200 mg/kg (mpk) niacin (dotted line), or
2240 mg/kg ARI-001 (dashed line).
[0045] FIG. 5. Lipid parameter changes as a function of dose of
ARI-001 (represented in mmol/kg/d). ARI-001 (.box-solid. and
connecting line) demonstrates a dose-dependent effect on lipid
values in HF/HS hamsters. Niacin (.diamond.) showed significance
with respect to changes in total cholesterol (TC), high-density
lipoporotein (HDL), and low-density lipoprotein (LDL) only.
[0046] FIGS. 6 and 7. Correlation between lipid parameters and
plasma concentrations of ARI-001. Each lipid parameter achieved
statistically significant negative correlations with ARI-001
concentrations, except for HDL, which was statistically significant
and positive. The linear correlation line is drawn (solid line), as
well as the 95% confidence zone of the correlation line (dashed
curves). Pearson r correlation coefficients are given for each data
set, with 95% confidence interval in parentheses. P-values are the
results of 2-tailed unpaired t-tests.
[0047] FIG. 8. (Left graph) Correlation between liver and plasma
concentrations of ARI-001 in HF/HS hamsters dosed for 18 days. The
values for each tissue have been transformed by logarithm, and
therefore, the axes are unitless. (Right graph) Correlation between
adipose and plasma concentrations in the same animals. Adipose
concentrations have been transformed by the function "logarithm+1",
which makes any values between -1 and 0 into positive values. This
is done for clarity and does not otherwise distort the distribution
of the data set.
[0048] FIGS. 9-11. Correlations between liver concentrations of
ARI-001 in HF/HS hamsters and values of different lipid parameters;
also, correlations between adipose tissue concentrations of ARI-001
in HF/HS hamsters and values of different lipid parameters. All
values are the logarithm of the lipid values versus the logarithm
of the tissue concentrations. Correlations are between tissue
concentration and lipid values in the same animals. Adipose
concentrations have been transformed by the function "logarithm+1",
which makes any values between -1 and 0 into positive values. This
is done for clarity and does not otherwise distort the distribution
of the data set.
[0049] FIGS. 12A and B. Liver function test parameters from high
fat-fed hamsters dosed orally with vehicle, niacin, or ARI-001 for
18 days. Percent changes are given relative to vehicle. P-values
are reported from 2-tailed unpaired t-tests comparing to vehicle.
FIG. 12A, aspartate aminotransferase (AST). FIG. 12B, alanine
aminotransferase (ALT).
[0050] FIG. 13. Glucose values measured in plasma from an 18 day
study of HF/HS hamsters dosed daily with vehicle, niacin, or
ARI-001. Percent changes are reported in comparison to the vehicle
group values. P-value is determined from a 2-tailed t-test.
[0051] FIG. 14. Plasma concentrations of ARI-001 from mice dosed
with a single administration of ARI-001 either orally (PO) or
intraperitoneally (IP).
[0052] FIGS. 15A-15D. Plasma concentrations of ARI-001 from mice
dosed with multiple daily oral administrations of ARI-001 for 30
consecutive days. Four different doses were used. Each mouse
received the same indicated dose of ARI-001 every day for 30
days.
[0053] FIGS. 16A and 16B. Summary of C.sub.max and AUC parameters
for ARI-001 from 30-day multiple administration study in wild type
mice. Values are plotted as the mean with standard error. There was
no significant change in either parameter as a function of time.
(.largecircle.) 996 mg/kg/d; (.quadrature.) 1493 mg/kg/d;
(.gradient.) 2240 mg/kg/d; (.diamond.) 3360 mg/kg/d.
[0054] FIG. 17. Plasma concentrations of ARI-001 in Golden Syrian
Hamsters on high fat/high sugar diet after single administration of
ARI-001 at 5.9 mmol/kg.
[0055] FIG. 18. Plasma concentrations of ARI-001 in fasted monkeys
after single administration of ARI-001 either (.diamond-solid.) 96
mg/kg intravenously (IV) or (.largecircle.) 288 mg/kg (mpk) orally
(PO). Y-axis is logarithmic scale for clarity. (Inset): Same data,
with the y-axis on a linear scale.
[0056] FIG. 19. Plasma concentrations of ARI-001 after single
administration of 288 mg/kg orally to (.diamond-solid.) fed monkeys
or to (.largecircle.) fasted monkeys. Values are mean with standard
error.
[0057] FIG. 20. Plasma concentrations of ARI-001 after repeated
daily administration of 288 mg/kg orally to fasted monkeys. Values
are mean with standard error. (.diamond-solid.) Samples drawn on
day 1. (.largecircle.) Samples drawn on day 7.
[0058] FIG. 21. ARI-001 fails to recruit beta-arrestin to the cell
membrane of cells expressing the niacin receptor GPR109A. Ligand
refers to niacin or ARI-001, as indicated. RLU, relative light
units, as measured in chemiluminescent read-out for G
protein-coupled receptor activity.
[0059] FIG. 22. Dose response for triglyceride lowering on single
oral doses of ARI-001 to human patients. The percent change is the
mean percent change in triglycerides at 4 hours post dose.
[0060] FIG. 23. Serum concentration of ARI-001 over time following
single oral administration of indicated amounts of ARI-001 to human
patients.
DETAILED DESCRIPTION
[0061] One aspect of the invention relates to niacin analogs for
use in raising serum HDL levels in mammals. In certain embodiments,
the compounds of the invention have equal or greater HDL-raising
ability than niacin while having less or no propensity to induce
flushing, an undesirable side effect of niacin itself when used in
doses sufficient to raise serum HDL levels. Some non-flushing
niacin analogs are described in U.S. Patent Application Publication
No. 2009/0312355, which is hereby incorporated by reference in its
entirety. In certain embodiments, key structural features of the
compounds disclosed herein appear to include the placement of a
heterocyclylalkyl or heteroaralkyl group para to the carboxyl group
in niacin.
DEFINITIONS
[0062] For convenience, certain terms employed in the
specification, examples, and appended claims are collected here.
All definitions, as defined and used herein, supersede dictionary
definitions, definitions in documents incorporated by reference,
and/or ordinary meanings of the defined terms.
[0063] The articles "a" and "an" are used herein to refer to one or
to more than one (i.e., to at least one) of the grammatical object
of the article. By way of example, "an element" means one element
or more than one element.
[0064] The phrase "and/or," as used herein in the specification and
in the claims, should be understood to mean "either or both" of the
elements so conjoined, i.e., elements that are conjunctively
present in some cases and disjunctively present in other cases.
Multiple elements listed with "and/or" should be construed in the
same fashion, i.e., "one or more" of the elements so conjoined.
Other elements may optionally be present other than the elements
specifically identified by the "and/or" clause, whether related or
unrelated to those elements specifically identified. Thus, as a
non-limiting example, a reference to "A and/or B", when used in
conjunction with open-ended language such as "comprising" can
refer, in one embodiment, to A only (optionally including elements
other than B); in another embodiment, to B only (optionally
including elements other than A); in yet another embodiment, to
both A and B (optionally including other elements); etc.
[0065] As used herein in the specification and in the claims, "or"
should be understood to have the same meaning as "and/or" as
defined above. For example, when separating items in a list, "or"
or "and/or" shall be interpreted as being inclusive, i.e., the
inclusion of at least one, but also including more than one, of a
number or list of elements, and, optionally, additional unlisted
items. Only terms clearly indicated to the contrary, such as "only
one of" or "exactly one of," or, when used in the claims,
"consisting of," will refer to the inclusion of exactly one element
of a number or list of elements. In general, the term "or" as used
herein shall only be interpreted as indicating exclusive
alternatives (i.e., "one or the other but not both") when preceded
by terms of exclusivity, such as "either," "one of," "only one of,"
or "exactly one of" "Consisting essentially of," when used in the
claims, shall have its ordinary meaning as used in the field of
patent law.
[0066] As used herein in the specification and in the claims, the
phrase "at least one," in reference to a list of one or more
elements, should be understood to mean at least one element
selected from any one or more of the elements in the list of
elements, but not necessarily including at least one of each and
every element specifically listed within the list of elements and
not excluding any combinations of elements in the list of elements.
This definition also allows that elements may optionally be present
other than the elements specifically identified within the list of
elements to which the phrase "at least one" refers, whether related
or unrelated to those elements specifically identified. Thus, as a
non-limiting example, "at least one of A and B" (or, equivalently,
"at least one of A or B," or, equivalently "at least one of A
and/or B") can refer, in one embodiment, to at least one,
optionally including more than one, A, with no B present (and
optionally including elements other than B); in another embodiment,
to at least one, optionally including more than one, B, with no A
present (and optionally including elements other than A); in yet
another embodiment, to at least one, optionally including more than
one, A, and at least one, optionally including more than one, B
(and optionally including other elements); etc.
[0067] It should also be understood that, unless clearly indicated
to the contrary, in any methods claimed herein that include more
than one step or act, the order of the steps or acts of the method
is not necessarily limited to the order in which the steps or acts
of the method are recited.
[0068] In the claims, as well as in the specification above, all
transitional phrases such as "comprising," "including," "carrying,"
"having," "containing," "involving," "holding," "composed of," and
the like are to be understood to be open-ended, i.e., to mean
including but not limited to. Only the transitional phrases
"consisting of" and "consisting essentially of" shall be closed or
semi-closed transitional phrases, respectively, as set forth in the
United States Patent Office Manual of Patent Examining Procedures,
Section 2111.03.
[0069] The terms "co-administration" and "co-administering" refer
to both concurrent administration (administration of two or more
therapeutic agents at the same time) and time varied administration
(administration of one or more therapeutic agents at a time
different from that of the administration of an additional
therapeutic agent or agents), as long as the therapeutic agents are
present in the patient to some extent at the same time.
[0070] The term "solvate" refers to a pharmaceutically acceptable
form of a specified compound, with one or more solvent molecules,
that retains the biological effectiveness of such compound.
Examples of solvates include compounds of the invention in
combination with solvents such, for example, water (to form the
hydrate), isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl
acetate, acetic acid, ethanolamine, or acetone. Also included are
formulations of solvate mixtures such as a compound of the
invention in combination with two or more solvents.
[0071] The definition of each expression, e.g., alkyl, m, n, and
the like, when it occurs more than once in any structure, is
intended to be independent of its definition elsewhere in the same
structure.
[0072] It will be understood that "substitution" or "substituted
with" includes the implicit proviso that such substitution is in
accordance with permitted valence of the substituted atom and the
substituent, and that the substitution results in a stable
compound, e.g., a compound which does not spontaneously undergo
transformation such as by rearrangement, cyclization, elimination,
or other reaction.
[0073] The term "substituted" is also contemplated to include all
permissible substituents of organic compounds. In a broad aspect,
the permissible substituents include acyclic and cyclic, branched
and unbranched, carbocyclic and heterocyclic, aromatic and
nonaromatic substituents of organic compounds. Illustrative
substituents include, for example, those described herein below.
The permissible substituents may be one or more and the same or
different for appropriate organic compounds. For purposes of this
invention, the heteroatoms such as nitrogen may have hydrogen
substituents and/or any permissible substituents of organic
compounds described herein which satisfy the valences of the
heteroatoms.
[0074] The term "lower" when appended to any of the groups listed
below indicates that the group contains less than seven carbons
(i.e., six carbons or less). For example "lower alkyl" refers to an
alkyl group containing 1-6 carbons, and "lower alkenyl" refers to
an alkyenyl group containing 2-6 carbons.
[0075] The term "unsaturated," as used herein, pertains to
compounds and/or groups which have at least one carbon-carbon
double bond or carbon-carbon triple bond.
[0076] The term "aliphatic," as used herein, pertains to compounds
and/or groups which are linear or branched, but not cyclic (also
known as "acyclic" or "open-chain" groups).
[0077] The term "cyclic," as used herein, pertains to compounds
and/or groups which have one ring, or two or more rings (e.g.,
spiro, fused, bridged). "Monocyclic" refers to compounds and/or
groups with one ring; and "bicyclic" refers to compounds/and or
groups with two rings.
[0078] The term "aromatic" refers to a planar or polycyclic
structure characterized by a cyclically conjugated molecular moiety
containing 4n+2 electrons, wherein n is the absolute value of an
integer. Aromatic molecules containing fused, or joined, rings also
are referred to as bicyclic aromatic rings. For example, bicyclic
aromatic rings containing heteroatoms in a hydrocarbon ring
structure are referred to as bicyclic heteroaryl rings.
[0079] The term "hydrocarbon" as used herein refers to an organic
compound consisting entirely of hydrogen and carbon.
[0080] For purposes of this invention, the chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87,
inside cover.
[0081] The term "heteroatom" as used herein is art-recognized and
refers to an atom of any element other than carbon or hydrogen.
Illustrative heteroatoms include boron, nitrogen, oxygen,
phosphorus, sulfur and selenium.
[0082] The term "alkyl" means an aliphatic or cyclic hydrocarbon
radical containing from 1 to 20, 1 to 15, or 1 to 10 carbon atoms.
Representative examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,
2-methylcyclopentyl, 1-(1-ethylcyclopropyl)ethyl and
1-cyclohexylethyl.
[0083] The term "cycloalkyl" is a subset of alkyl which refers to
cyclic hydrocarbon radical containing from 3 to 15, 3 to 10, or 3
to 7 carbon atoms. Representative examples of cycloalkyl include,
but are not limited to, cyclopropyl and cyclobutyl.
[0084] The term "alkenyl" as used herein means a straight or
branched chain hydrocarbon radical containing from 2 to 10 carbons
and containing at least one carbon-carbon double bond formed by the
removal of two hydrogens. Representative examples of alkenyl
include, but are not limited to, ethenyl, 2-propenyl,
2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl,
2-methyl-1-heptenyl, and 3-decenyl.
[0085] The term "alkynyl" as used herein means a straight or
branched chain hydrocarbon radical containing from 2 to 10 carbon
atoms and containing at least one carbon-carbon triple bond.
Representative examples of alkynyl include, but are not limited, to
acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and
1-butynyl.
[0086] The term "alkylene," is art-recognized, and as used herein
pertains to a diradical obtained by removing two hydrogen atoms of
an alkyl group, as defined above.
[0087] The term "carbocyclyl" as used herein means a monocyclic or
multicyclic (e.g., bicyclic, tricyclic, etc.) hydrocarbon radical
containing from 3 to 12 carbon atoms that is completely saturated
or has one or more unsaturated bonds, and for the avoidance of
doubt, the degree of unsaturation does not result in an aromatic
ring system (e.g., phenyl). Examples of carbocyclyl groups include
1-cyclopropyl, 1-cyclobutyl, 2-cyclopentyl, 1-cyclopentenyl,
3-cyclohexyl, 1-cyclohexenyl and 2-cyclopentenylmethyl.
[0088] The term "heterocyclyl", as used herein refers to a radical
of a non-aromatic, ring system, including, but not limited to,
monocyclic, bicyclic and tricyclic rings, which can be completely
saturated or which can contain one or more units of unsaturation,
for the avoidance of doubt, the degree of unsaturation does not
result in an aromatic ring system, and have 3 to 12 atoms including
at least one heteroatom, such as nitrogen, oxygen, or sulfur. For
purposes of exemplification, which should not be construed as
limiting the scope of this invention, the following are examples of
heterocyclic rings: aziridinyl, azirinyl, oxiranyl, thiiranyl,
thiirenyl, dioxiranyl, diazirinyl, azetyl, oxetanyl, oxetyl,
thietanyl, thietyl, diazetidinyl, dioxetanyl, dioxetenyl,
dithietanyl, dithietyl, furyl, dioxalanyl, pyrrolyl, oxazolyl,
thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,
triazinyl, isothiazolyl, isoxazolyl, thiophenyl, pyrazolyl,
tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
triazinyl, tetrazinyl, quinolinyl, isoquinolinyl, quinoxalinyl,
quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl,
benzimidazolyl, benzothiazolyl, benzoxadiazolyl, benzthiadiazolyl,
indolyl, benztriazolyl, naphthyridinyl, azepines, azetidinyl,
morpholinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl,
piperidinyl, pyrrolidinyl, quinicludinyl, thiomorpholinyl,
tetrahydropyranyl and tetrahydrofuranyl. The heterocyclyl groups of
the invention are substituted with 0, 1, 2, 3, 4 or 5 substituents
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy,
alkyenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy,
haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio,
fluoroalkylthio, alkyenylthio, alkynylthio, sulfonic acid,
alkylsulfonyl, haloalkylsulfonyl, fluoroalkylsulfonyl,
alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl,
haloalkoxysulfonyl, fluoroalkoxysulfonyl, alkenyloxysulfonyl,
alkynyloxysulfony, aminosulfonyl, sulfinic acid, alkylsulfinyl,
haloalkylsulfinyl, fluoroalkylsulfinyl, alkenylsulfinyl,
alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfinyl,
fluoroalkoxysulfinyl, alkenyloxysulfinyl, alkynyloxysulfiny,
aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl,
fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxyl,
alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl,
alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,
haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy,
alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy,
fluoroalkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy,
haloalkoxysulfonyloxy, fluoroalkoxysulfonyloxy,
alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy,
haloalkylsulfinyloxy, fluoroalkylsulfinyloxy, alkenylsulfinyloxy,
alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy,
fluoroalkoxysulfinyloxy, alkenyloxysulfinyloxy,
alkynyloxysulfinyloxy, aminosulfinyloxy, amino, amido,
aminosulfonyl, aminosulfinyl, cyano, nitro, azido, phosphinyl,
phosphoryl, silyl, silyloxy, and any of said substiuents bound to
the heterocyclyl group through an alkylene moiety (e.g.,
methylene).
[0089] The term "aryl," as used herein means a phenyl, naphthyl,
phenanthrenyl, or anthracenyl group. The aryl groups of the present
invention can be optionally substituted with 1, 2, 3, 4 or 5
substituents independently selected from the group consisting of
alkyl, alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy,
alkoxy, alkyenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy,
haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio,
fluoroalkylthio, alkyenylthio, alkynylthio, sulfonic acid,
alkylsulfonyl, haloalkylsulfonyl, fluoroalkylsulfonyl,
alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl,
haloalkoxysulfonyl, fluoroalkoxysulfonyl, alkenyloxysulfonyl,
alkynyloxysulfony, aminosulfonyl, sulfinic acid, alkylsulfinyl,
haloalkylsulfinyl, fluoroalkylsulfinyl, alkenylsulfinyl,
alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfinyl,
fluoroalkoxysulfinyl, alkenyloxysulfinyl, alkynyloxysulfiny,
aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl,
fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxyl,
alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl,
alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,
haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy,
alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy,
fluoroalkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy,
haloalkoxysulfonyloxy, fluoroalkoxysulfonyloxy,
alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy,
haloalkylsulfinyloxy, fluoroalkylsulfinyloxy, alkenylsulfinyloxy,
alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy,
fluoroalkoxysulfinyloxy, alkenyloxysulfinyloxy,
alkynyloxysulfinyloxy, aminosulfinyloxy, amino, amido,
aminosulfonyl, aminosulfinyl, cyano, nitro, azido, phosphinyl,
phosphoryl, silyl, silyloxy, and any of said substiuents bound to
the heterocyclyl group through an alkylene moiety (e.g.,
methylene).
[0090] The term "arylene," is art-recognized, and as used herein
pertains to a diradical obtained by removing two hydrogen atoms of
an aryl ring, as defined above.
[0091] The term "arylalkyl" or "aralkyl" as used herein means an
aryl group, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Representative
examples of aralkyl include, but are not limited to, benzyl,
2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl.
[0092] The term "biaryl," as used herein means an aryl-substituted
aryl, an aryl-substituted heteroaryl, a heteroaryl-substituted aryl
or a heteroaryl-substituted heteroaryl, wherein aryl and heteroaryl
are as defined herein. Representative examples include
4-(phenyl)phenyl and 4-(4-methoxyphenyl)pyridinyl.
[0093] The term "heteroaryl" as used herein include radicals of
aromatic ring systems, including, but not limited to, monocyclic,
bicyclic and tricyclic rings, which have 3 to 12 atoms including at
least one heteroatom, such as nitrogen, oxygen, or sulfur. For
purposes of exemplification, which should not be construed as
limiting the scope of this invention: aminobenzimidazole,
benzimidazole, azaindolyl, benzo(b)thienyl, benzimidazolyl,
benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,
benzotriazolyl, benzoxadiazolyl, furanyl, imidazolyl,
imidazopyridinyl, indolyl, indolinyl, indazolyl, isoindolinyl,
isoxazolyl, isothiazolyl, isoquinolinyl, oxadiazolyl, oxazolyl,
purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl,
pyrrolyl, pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl,
quinolinyl, quinazolinyl, triazolyl, thiazolyl, thiophenyl,
tetrahydroindolyl, tetrazolyl, thiadiazolyl, thienyl,
thiomorpholinyl, triazolyl or tropanyl. The heteroaryl groups of
the invention are substituted with 0, 1, 2, 3, 4 or 5 substituents
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy,
alkyenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy,
haloalkoxy, fluoroalkyloxy, sulfhydryl, alkylthio, haloalkylthio,
fluoroalkylthio, alkyenylthio, alkynylthio, sulfonic acid,
alkylsulfonyl, haloalkylsulfonyl, fluoroalkylsulfonyl,
alkenylsulfonyl, alkynylsulfonyl, alkoxysulfonyl,
haloalkoxysulfonyl, fluoroalkoxysulfonyl, alkenyloxysulfonyl,
alkynyloxysulfony, aminosulfonyl, sulfinic acid, alkylsulfinyl,
haloalkylsulfinyl, fluoroalkylsulfinyl, alkenylsulfinyl,
alkynylsulfinyl, alkoxysulfinyl, haloalkoxysulfinyl,
fluoroalkoxysulfinyl, alkenyloxysulfinyl, alkynyloxysulfiny,
aminosulfinyl, formyl, alkylcarbonyl, haloalkylcarbonyl,
fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxyl,
alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl,
alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy,
haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy,
alkynylcarbonyloxy, alkylsulfonyloxy, haloalkylsulfonyloxy,
fluoroalkylsulfonyloxy, alkenylsulfonyloxy, alkynylsulfonyloxy,
haloalkoxysulfonyloxy, fluoroalkoxysulfonyloxy,
alkenyloxysulfonyloxy, alkynyloxysulfonyloxy, alkylsulfinyloxy,
haloalkylsulfinyloxy, fluoroalkylsulfinyloxy, alkenylsulfinyloxy,
alkynylsulfinyloxy, alkoxysulfinyloxy, haloalkoxysulfinyloxy,
fluoroalkoxysulfinyloxy, alkenyloxysulfinyloxy,
alkynyloxysulfinyloxy, aminosulfinyloxy, amino, amido,
aminosulfonyl, aminosulfinyl, cyano, nitro, azido, phosphinyl,
phosphoryl, silyl, silyloxy, and any of said substituents bound to
the heteroaryl group through an alkylene moiety (e.g.,
methylene).
[0094] The term "heteroarylene," is art-recognized, and as used
herein pertains to a diradical obtained by removing two hydrogen
atoms of a heteroaryl ring, as defined above.
[0095] The term "heteroarylalkyl" or "heteroaralkyl" as used herein
means a heteroaryl, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of heteroarylalkyl include, but are not
limited to, pyridin-3-ylmethyl and 2-(thien-2-yl)ethyl.
[0096] The term "fused bicyclyl" as used herein means the radical
of a bicyclic ring system wherein the two rings are ortho-fused,
and each ring, contains a total of four, five, six or seven atoms
(i.e., carbons and heteroatoms) including the two fusion atoms, and
each ring can be completely saturated, can contain one or more
units of unsaturation, or can be completely unsaturated (e.g., in
some case, aromatic). For the avoidance of doubt, the degree of
unsaturation in the fused bicyclyl does not result in an aryl or
heteroaryl moiety.
[0097] The term "halo" or "halogen" means --Cl, --Br, --I or
--F.
[0098] The term "haloalkyl" means an alkyl group, as defined
herein, wherein at least one hydrogen is replaced with a halogen,
as defined herein. Representative examples of haloalkyl include,
but are not limited to, chloromethyl, 2-fluoroethyl,
trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
[0099] The term "fluoroalkyl" means an alkyl group, as defined
herein, wherein some or all of the hydrogens are replaced with
fluorines.
[0100] The term "haloalkylene," as used herein pertains to
diradical obtained by removing two hydrogen atoms of an haloalkyl
group, as defined above.
[0101] The term "hydroxy" as used herein means an --OH group.
[0102] The term "alkoxy" as used herein means an alkyl group, as
defined herein, appended to the parent molecular moiety through an
oxygen atom. Representative examples of alkoxy include, but are not
limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,
tert-butoxy, pentyloxy, and hexyloxy. The terms "alkyenyloxy",
"alkynyloxy", "carbocyclyloxy", and "heterocyclyloxy" are likewise
defined.
[0103] The term "haloalkoxy" as used herein means an alkoxy group,
as defined herein, wherein at least one hydrogen is replaced with a
halogen, as defined herein. Representative examples of haloalkoxy
include, but are not limited to, chloromethoxy, 2-fluoroethoxy,
trifluoromethoxy, and pentafluoroethoxy. The term "fluoroalkyloxy"
is likewise defined.
[0104] The term "aryloxy" as used herein means an aryl group, as
defined herein, appended to the parent molecular moiety through an
oxygen. The term "heteroaryloxy" as used herein means a heteroaryl
group, as defined herein, appended to the parent molecular moiety
through an oxygen. The terms "heteroaryloxy" is likewise
defined.
[0105] The term "arylalkoxy" or "arylalkyloxy" as used herein means
an arylalkyl group, as defined herein, appended to the parent
molecular moiety through an oxygen. The term "heteroarylalkoxy" is
likewise defined. Representative examples of aryloxy and
heteroarylalkoxy include, but are not limited to,
2-chlorophenylmethoxy, 3-trifluoromethyl-phenylethoxy, and
2,3-dimethylpyridinylmethoxy.
[0106] The term "sulfhydryl" or "thio" as used herein means a --SH
group.
[0107] The term "alkylthio" as used herein means an alkyl group, as
defined herein, appended to the parent molecular moiety through a
sulfur. Representative examples of alkylthio include, but are not
limited, methylthio, ethylthio, tert-butylthio, and hexylthio. The
terms "haloalkylthio", "fluoroalkylthio", "alkyenylthio",
"alkynylthio", "carbocyclylthio", and "heterocyclylthio" are
likewise defined.
[0108] The term "arylthio" as used herein means an aryl group, as
defined herein, appended to the parent molecular moiety through an
sulfur. The term "heteroarylthio" is likewise defined.
[0109] The term "arylalkylthio" or "aralkylthio" as used herein
means an arylalkyl group, as defined herein, appended to the parent
molecular moiety through a sulfur. The term "heteroarylalkylthio"
is likewise defined.
[0110] The term "sulfonyl" as used herein refers to
--S(.dbd.O).sub.2-- group.
[0111] The term "sulfonic acid" as used herein refers to
--S(.dbd.O).sub.2OH.
[0112] The term "alkylsulfonyl" as used herein means an alkyl
group, as defined herein, appended to the parent molecular moiety
through a sulfonyl group, as defined herein. Representative
examples of alkylsulfonyl include, but are not limited to,
methylsulfonyl and ethylsulfonyl. The terms "haloalkylsulfonyl",
"fluororalkylsulfonyl", "alkenylsulfonyl", "alkynylsulfonyl",
"carbocyclylsulfonyl", "heterocyclylsulfonyl", "arylsulfonyl",
"aralkylsulfonyl", "heteroarylsulfonyl" and "heteroaralkylsulfonyl"
are likewise defined.
[0113] The term "alkoxysulfonyl" as used herein means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through a sulfonyl group, as defined herein. Representative
examples of alkoxysulfonyl include, but are not limited to,
methoxysulfonyl, ethoxysulfonyl and propoxysulfonyl. The terms
"haloalkoxysulfonyl", "fluoroalkoxysulfonyl", "alkenyloxysulfonyl",
"alkynyloxysulfonyl", "carbocyclyloxysulfonyl",
"heterocyclyloxysulfonyl", "aryloxysulfonyl", "aralkyloxysulfonyl",
"heteroaryloxysulfonyl" and "heteroaralkyloxysulfonyl" are likewise
defined.
[0114] The terms triflyl, tosyl, mesyl, and nonaflyl are
art-recognized and refer to trifluoromethanesulfonyl,
p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl
groups, respectively. The terms triflate, tosylate, mesylate, and
nonaflate are art-recognized and refer to trifluoromethanesulfonate
ester, p-toluenesulfonate ester, methanesulfonate ester, and
nonafluorobutanesulfonate ester functional groups and molecules
that contain said groups, respectively.
[0115] The term "aminosulfonyl" as used herein means an amino
group, as defined herein, appended to the parent molecular moiety
through a sulfonyl group.
[0116] The term "sulfinyl" as used herein refers to --S(.dbd.O)--
group. Sulfinyl groups are as defined above for sulfonyl groups.
The term "sulfinic acid" as used herein refers to
--S(.dbd.O)OH.
[0117] The term "oxy" refers to a --O-- group.
[0118] The term "carbonyl" as used herein means a --C(.dbd.O)--
group.
[0119] The term "thiocarbonyl" as used herein means a --C(.dbd.S)--
group.
[0120] The term "formyl" as used herein means a --C(.dbd.O)H
group.
[0121] The term "acyl" as used herein refers to any group or
radical of the form --C(.dbd.O)R, where R is an organic group. An
example of the acyl group is the acetyl group
(--C(.dbd.O)CH.sub.3).
[0122] The term "alkylcarbonyl" as used herein means an alkyl
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of alkylcarbonyl include, but are not limited to, acetyl,
1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
The terms "haloalkylcarbonyl", "fluoroalkylcarbonyl",
"alkenylcarbonyl", "alkynylcarbonyl", "carbocyclylcarbonyl",
"heterocyclylcarbonyl", "arylcarbonyl", "aralkylcarbonyl",
"heteroarylcarbonyl", and "heteroaralkylcarbonyl" are likewise
defined.
[0123] The term "carboxyl" as used herein means a --CO.sub.2H
group.
[0124] An "isostere of a carboxyl group" as used herein refers to a
group which is isosteric to a carboxyl group. Examples of isosters
of a carboxyl group include tetrazolyl, oxazolidinonyl,
3-isoxazolyl, hydroxyisoxazolyl, sulfonic acid, sulfinic acid,
acylsulphonamide, phosphonic acid, phosphinic acid, hydantoin,
pyrrolidionyl, boronic acid, hydroxamic acid, acylcyanamide and
oxadiazolonyl.
[0125] The term "alkoxycarbonyl" as used herein means an alkoxy
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of alkoxycarbonyl include, but are not limited to,
methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl. The terms
"haloalkoxycarbonyl", "fluoroalkoxycarbonyl", "alkenyloxycarbonyl",
"alkynyloxycarbonyl", "carbocyclyloxycarbonyl",
"heterocyclyloxycarbonyl", "aryloxycarbonyl", "aralkyloxycarbonyl",
"heteroaryloxycarbonyl", and "heteroaralkyloxycarbonyl" are
likewise defined.
[0126] The term "alkylcarbonyloxy" as used herein means an
alkylcarbonyl group, as defined herein, appended to the parent
molecular moiety through an oxygen atom. Representative examples of
alkylcarbonyloxy include, but are not limited to, acetyloxy,
ethylcarbonyloxy, and tert-butylcarbonyloxy. The terms
"haloalkylcarbonyloxy", "fluoroalkylcarbonyloxy",
"alkenylcarbonyloxy", "alkynylcarbonyloxy",
"carbocyclylcarbonyloxy", "heterocyclylcarbonyloxy",
"arylcarbonyloxy", "aralkylcarbonyloxy", "heteroarylcarbonyloxy",
and "heteroaralkylcarbonyloxy" are likewise defined.
[0127] The term "alkylsulfonyloxy" as used herein means an
alkylsulfonyl group, as defined herein, appended to the parent
molecular moiety through an oxygen atom. The terms
"haloalkylsulfonyloxy", "fluoroalkylsulfonyloxy",
"alkenylsulfonyloxy", "alkynylsulfonyloxy",
"carbocyclylsulfonyloxy", "heterocyclylsulfonyloxy",
"arylsulfonyloxy", "aralkylsulfonyloxy", "heteroarylsulfonyloxy",
"heteroaralkylsulfonyloxy", "haloalkoxysulfonyloxy",
"fluoroalkoxysulfonyloxy", "alkenyloxysulfonyloxy",
"alkynyloxysulfonyloxy", "carbocyclyloxysulfonyloxy",
"heterocyclyloxysulfonyloxy", "aryloxysulfonyloxy",
"aralkyloxysulfonyloxy", "heteroaryloxysulfonyloxy" and
"heteroaralkyloxysulfonyloxy" are likewise defined.
[0128] The term "amino" or "amine" as used herein refers to
--NH.sub.2 and substituted derivatives thereof wherein one or both
of the hydrogens are independently replaced with substituents
selected from the group consisting of alkyl, haloalkyl,
fluoroalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,
aralkyl, heteroaryl, heteroaralkyl, alkylcarbonyl,
haloalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl,
alkynylcarbonyl, carbocyclylcarbonyl, heterocyclylcarbonyl,
arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl,
heteroaralkylcarbonyl and the sufonyl and sulfinyl groups defined
above; or when both hydrogens together are replaced with an
alkylene group (to form a ring which contains the nitrogen).
Representative examples include, but are not limited to
methylamino, acetylamino, and dimethylamino.
[0129] The term "amido" as used herein means an amino group, as
defined herein, appended to the parent molecular moiety through a
carbonyl.
[0130] The term "cyano" as used herein means a --C.ident.N
group.
[0131] The term "nitro" as used herein means a --NO.sub.2
group.
[0132] The term "azido" as used herein means a --N.sub.3 group.
[0133] The term "phosphinyl" or "phosphino" as used herein includes
--PH.sub.3 and substituted derivatives thereof wherein one, two or
three of the hydrogens are independently replaced with substituents
selected from the group consisting of alkyl, haloalkyl,
fluoroalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,
aralkyl, heteroaryl, heteroaralkyl, alkoxy, haloalkoxy,
fluoroalkyloxy, alkenyloxy, alkynyloxy, carbocyclyloxy,
heterocyclyloxy, aryloxy, aralkyloxy, heteroaryloxy,
heteroaralkyloxy, and amino.
[0134] The term "phosphoryl" as used herein refers to
--P(.dbd.O)OH.sub.2 and substituted derivatives thereof wherein one
or both of the hydroxyls are independently replaced with
substituents selected from the group consisting of alkyl,
haloalkyl, fluoroalkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkoxy,
haloalkoxy, fluoroalkyloxy, alkenyloxy, alkynyloxy, carbocyclyloxy,
heterocyclyloxy, aryloxy, aralkyloxy, heteroaryloxy,
heteroaralkyloxy, and amino.
[0135] The term "silyl" as used herein includes H.sub.3Si-- and
substituted derivatives thereof wherein one, two or three of the
hydrogens are independently replaced with subsitutuents selected
from alkyl, haloalkyl, fluoroalkyl, alkenyl, alkynyl, carbocyclyl,
heterocyclyl, aryl, aralkyl, heteroaryl, and heteroaralkyl.
Representative examples include trimethylsilyl (TMS),
tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl
(TBS/TBDMS), triisopropylsilyl (TIPS), and
[2-(trimethylsilyl)ethoxy]methyl (SEM).
[0136] The term "silyloxy" as used herein means a silyl group, as
defined herein, is appended to the parent molecule through an
oxygen atom.
[0137] The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent
methyl, ethyl, phenyl, trifluoromethanesulfonyl,
nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl,
respectively. A more comprehensive list of the abbreviations
utilized by organic chemists of ordinary skill in the art appears
in the first issue of each volume of the Journal of Organic
Chemistry; this list is typically presented in a table entitled
Standard List of Abbreviations.
[0138] The term "treating" as used herein, encompasses the
administration and/or application of one or more compounds
described herein, to a subject, for the purpose of providing
prevention of or management of, and/or remedy for a condition.
"Treatment" for the purposes of this disclosure, may, but does not
have to, provide a cure; rather, "treatment" may be in the form of
management of the condition. When the compounds described herein
are used to treat unwanted proliferating cells, including cancers,
"treatment" includes partial or total destruction of the
undesirable proliferating cells with minimal destructive effects on
normal cells. A desired mechanism of treatment of unwanted rapidly
proliferating cells, including cancer cells, at the cellular level
is apoptosis.
[0139] The term "to treat" as used herein thus embraces not only to
cure, but also to slow the progression of and/or reduce the
severity of a disease, disorder, or condition. In one embodiment,
"treat" can encompass "prevent".
[0140] The term "preventing" as used herein includes either
preventing or slowing the onset of a clinically evident disease
progression altogether or preventing or slowing the onset of a
preclinically evident stage of a disease in individuals at risk.
This includes prophylactic treatment of those at risk of developing
a disease.
[0141] The term "subject" for purposes of treatment includes any
human or animal subject who has been diagnosed with, has symptoms
of, or is at risk of developing a disorder. For methods of
prevention the subject is any human or animal subject.
[0142] The term "optionally deuterated" as used herein refers to
any radical, as described above, wherein one or more hydrogens has
been replaced with a deuterium. Examples of deuterated alkyl
include --CD.sub.2H and --CD.sub.3.
[0143] The term "polyol" as used herein refers to small molecules
and polymers which have more than one hydroxyl.
[0144] As used herein, a "carbohydrate" (or, equivalently, a
"sugar") is a saccharide (including monosaccharides,
oligosaccharides and polysaccharides) and/or a molecule (including
oligomers or polymers) derived from one or more monosaccharides,
e.g., by reduction of carbonyl groups, by oxidation of one or more
terminal groups to carboxylic acids, by replacement of one or more
hydroxy group(s) by a hydrogen atom, an amino group, a thiol group
or similar heteroatomic groups, etc. The term "carbohydrate" also
includes derivatives of these compounds. In some cases, the
carbohydrate may be a pentose (i.e., having 5 carbons) or a hexose
(i.e., having 6 carbons); and in certain instances, the
carbohydrate may be an oligosaccharide comprising pentose and/or
hexose units, e.g., including those described above.
[0145] "Carbohydrate" and "sugar" as used herein also includes
sugar-mimetics and sugar-like moieties. Sugar-mimetics are well
known to one of ordinary skill in the art and include those
described in detail in "Essentials of Glycobiology" Edited by
Varki, A., et al, Cold Spring Harbor Laboratory Press. Cold Spring
Harbor, N. Y. 2002. For example, sugar-mimetic groups contemplated
by the present invention include cyclitols, such as a cycloalkane
containing one hydroxyl group on each of three or more ring atoms,
as defined by IUPAC convention. In other embodiments, such cyclitol
moieties include inositols such as scyllo-inositol. Suitable
sugar-like moieties include acyclic sugar groups. Such groups
include linear alkytols and erythritols, to name but a few. It will
be appreciated that sugar groups can exist in either cyclic or
acyclic form. Accordingly, acyclic forms of a sugar group are
contemplated by the present invention as a suitable sugar-like
moieties.
[0146] The term "polythiol" as used herein refers to small
molecules and polymers which have more than one thiol.
Compounds
[0147] Niacin, also known as nicotinic acid, has the structure
##STR00001##
[0148] One aspect of the invention relates to a compound
represented by structure I, or a pharmaceutically acceptable salt
thereof:
##STR00002##
[0149] wherein
[0150] A is a heterocyclyl or heteroaryl, optionally deuterated,
containing from 5 to 12 ring atoms, including X and N, which is
optionally substituted with 1-3 substituents, independently
selected from the group consisting of alkyl, alkenyl, alkynyl,
aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano,
sulfonic acid, alkylsulfoxyl, arylsulfoxyl, heteroarylsulfoxyl,
aralkylsulfoxyl, heteroaralkylsulfoxyl, alkenylsulfoxyl,
alkynylsulfoxyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,
aralkylsulfonyl, heteroaralkylsulfonyl, alkenylsulfonyl,
alkynylsulfonyl, hydroxyl, alkoxyl, aryloxyl, heteroaryloxyl,
aralkyloxy, heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol,
alkylthio, arylthio, aralkylthio, heteroaralkylthio, alkenylthio,
alkynylthio, formyl, acyl, formyloxy, acyloxy, formylthio,
acylthio, amine, alkylamine, arylamine, heteroarylamine,
aralkylamine, heteroaralkylamine, alkenylamine, alkynylamine,
formylamine, acylamine, carboxyl, alkyloxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,
heteroaralkyloxycarbonyl, amido, alkylaminecarbonyl,
arylaminecarbonyl, heteroarylaminecarbonyl, aralkylaminecarbonyl,
and heteroaralkylaminecarbonyl;
[0151] X is O, S, N or N(R.sup.6);
[0152] Z is
##STR00003##
or an isostere of a carboxyl group;
[0153] X.sup.1 is O or S;
[0154] X.sup.2 is O or S;
[0155] R is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,
heteroaryl, heteroaralkyl, fused bicyclyl, carboxyalkyl,
arylalkenylaryl, amido-substituted acetylaminoalkyl,
carboxy-substituted acetylaminoalkyl,
hydroxyalkylthioalkylthioalkyl, alkoxycarbonyloxyalkyl,
alkylcarbonyloxyalkyl, or amidoalkyl;
[0156] R.sup.2 is hydrogen, lower alkyl, lower alkenyl, lower
alkynyl, halogen, hydroxyl, amine, carboxyl, cycloalkyl, aryl,
heteroaryl, aralkyl, heteroaralkyl, cyano, or nitro;
[0157] R.sup.3 is hydrogen, lower alkyl, lower alkenyl, lower
alkynyl, halogen, hydroxyl, amine, carboxyl, cycloalkyl, aryl,
heteroaryl, aralkyl, heteroaralkyl, cyano, or nitro;
[0158] R.sup.5 is selected independently for each occurrence from
the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano, sulfonic
acid, alkylsulfoxyl, arylsulfoxyl, heteroarylsulfoxyl,
aralkylsulfoxyl, heteroaralkylsulfoxyl, alkenylsulfoxyl,
alkynylsulfoxyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,
aralkylsulfonyl, heteroaralkylsulfonyl, alkenylsulfonyl,
alkynylsulfonyl, hydroxyl, alkoxyl, aryloxyl, heteroaryloxyl,
aralkyloxy, heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol,
alkylthio, arylthio, aralkylthio, heteroaralkylthio, alkenylthio,
alkynylthio, formyl, acyl, formyloxy, acyloxy, formylthio,
acylthio, amine, alkylamine, arylamine, heteroarylamine,
aralkylamine, heteroaralkylamine, alkenylamine, alkynylamine,
formylamine, acylamine, carboxyl, alkyloxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,
heteroaralkyloxycarbonyl, amido, alkylaminecarbonyl,
arylaminecarbonyl, heteroarylaminecarbonyl, aralkylaminecarbonyl,
and heteroaralkylaminecarbonyl;
[0159] R.sup.6 is hydrogen or lower alkyl; and
[0160] m is 1, 2, 3, or 4.
[0161] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein A represents a
heterocyclyl.
[0162] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein A represents a
heteroaryl.
[0163] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein A is a radical of a
monocyclic ring having 5, 6 or 7 ring atoms.
[0164] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein A is a radical of a bicyclic
ring having 9, 10, 11 or 12 ring atoms.
[0165] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein X is O.
[0166] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein X is S.
[0167] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein X is N.
[0168] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein X is N(R.sup.6).
[0169] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein X is N(H).
[0170] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein A is pyrrolidinyl,
imidazolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl,
oxadiazolidinyl, piperidinyl, piperazinyl, thiomorpholinyl or
morpholinyl.
[0171] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein A is imidazolyl, pyrazolyl,
isoxoazolyl, oxazolyl, isothiazolyl, thiazolyl, oxinyl, furazanyl,
oxadiazolyl, thiadiazolyl, triazolyl, dithiazolyl, diazinyl,
oxazinyl, thiazinyl, triazinyl, tetrazinyl, diazepinyl or
thiazepinyl.
[0172] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein A is substituted with 1-3
substituents independently selected from the group consisting of
lower alkyl, halogen, nitro, cyano, sulfonic acid, hydroxyl,
alkoxyl, thiol, alkylthio, formyl, acyl, formyloxy, acyloxy,
formylthio, acylthio, amine, alkylamine, formylamine, acylamine and
carboxyl.
[0173] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein A is substituted with 1
substituent independently selected from the group consisting of
lower alkyl, halogen, nitro, cyano, sulfonic acid, hydroxyl,
alkoxyl, thiol, alkylthio, formyl, acyl, formyloxy, acyloxy,
formylthio, acylthio, amine, alkylamine, formylamine, acylamine and
carboxyl.
[0174] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein A is not substituted.
[0175] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein R.sup.2 is hydrogen or lower
alkyl.
[0176] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein R.sup.2 is hydrogen.
[0177] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein R.sup.3 is hydrogen or lower
alkyl.
[0178] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein R.sup.3 is hydrogen.
[0179] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein R.sup.2 is hydrogen; and
R.sup.3 is lower alkyl.
[0180] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein R.sup.2 is lower alkyl; and
R.sup.3 is hydrogen.
[0181] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein R.sup.2 is hydrogen; and
R.sup.3 is hydrogen.
[0182] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein m is 1.
[0183] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein m is 2.
[0184] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein m is 3.
[0185] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein m is 4.
[0186] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein R.sup.5 is selected
independently for each occurrence from the group consisting of
hydrogen, lower alkyl, halogen, nitro, cyano, sulfonic acid,
hydroxyl, alkoxyl, thiol, alkylthio, formyl, acyl, formyloxy,
acyloxy, formylthio, acylthio, amine, alkylamine, formylamine,
acylamine and carboxyl.
[0187] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein R.sup.5 is hydrogen.
[0188] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein Z is carboxyl.
[0189] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein Z is a carboxyl isostere.
[0190] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein Z is tetrazolyl,
oxazolidinonyl, sulfonic acid, sulfinic acid, acylsulphonamide,
phosphonic acid, phosphinic acid, hydantoin, pyrrolidione,
3-isoxazolyl, or boronic acid.
[0191] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein Z is
##STR00004##
[0192] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein X.sup.1 is O.
[0193] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein X.sup.1 is S.
[0194] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein X.sup.2 is O.
[0195] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein X.sup.2 is S.
[0196] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein X.sup.1 is O; and X.sup.2 is
O.
[0197] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein R is lower alkyl.
[0198] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein R is hydrogen.
[0199] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein R is
##STR00005## ##STR00006##
[0200] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein R represents an aliphatic
group which is hydrolyzed to carboxyl under physiological
conditions.
[0201] Another aspect of the invention relates to a compound
represented by structure II, or a pharmaceutically acceptable salt
thereof,
##STR00007##
[0202] wherein, independently for each occurrence,
[0203] W is a polyol or polythiol;
[0204] p is 2-500 inclusive;
[0205] R.sup.1 is
##STR00008##
and is either appended to the polyol through an oxygen atom of the
polyol or is appended to the polythiol through a sulfur atom of the
polythiol;
[0206] A is a heterocyclyl or heteroaryl, optionally deuterated,
containing from 5 to 12 ring atoms, including X and N, which is
optionally substituted with 1-3 substituents, independently
selected from the group consisting of alkyl, alkenyl, alkynyl,
aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano,
sulfonic acid, alkylsulfoxyl, arylsulfoxyl, heteroarylsulfoxyl,
aralkylsulfoxyl, heteroaralkylsulfoxyl, alkenylsulfoxyl,
alkynylsulfoxyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,
aralkylsulfonyl, heteroaralkylsulfonyl, alkenylsulfonyl,
alkynylsulfonyl, hydroxyl, alkoxyl, aryloxyl, heteroaryloxyl,
aralkyloxy, heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol,
alkylthio, arylthio, aralkylthio, heteroaralkylthio, alkenylthio,
alkynylthio, formyl, acyl, formyloxy, acyloxy, formylthio,
acylthio, amine, alkylamine, arylamine, heteroarylamine,
aralkylamine, heteroaralkylamine, alkenylamine, alkynylamine,
formylamine, acylamine, carboxyl, alkyloxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,
heteroaralkyloxycarbonyl, amido, alkylaminecarbonyl,
arylaminecarbonyl, heteroarylaminecarbonyl, aralkylaminecarbonyl,
and heteroaralkylaminecarbonyl;
[0207] X is O, S, N or N(R.sup.6);
[0208] X.sup.1 is O or S;
[0209] R is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,
heteroaryl, heteroaralkyl, fused bicyclyl, carboxyalkyl, or
arylalkenylaryl;
[0210] R.sup.2 is hydrogen, lower alkyl, lower alkenyl, lower
alkynyl, halogen, hydroxyl, amine, carboxyl, cycloalkyl, aryl,
heteroaryl, aralkyl, heteroaralkyl, cyano, or nitro;
[0211] R.sup.3 is hydrogen, lower alkyl, lower alkenyl, lower
alkynyl, halogen, hydroxyl, amine, carboxyl, cycloalkyl, aryl,
heteroaryl, aralkyl, heteroaralkyl, cyano, or nitro;
[0212] R.sup.5 is selected independently for each occurrence from
the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano, sulfonic
acid, alkylsulfoxyl, arylsulfoxyl, heteroarylsulfoxyl,
aralkylsulfoxyl, heteroaralkylsulfoxyl, alkenylsulfoxyl,
alkynylsulfoxyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,
aralkylsulfonyl, heteroaralkylsulfonyl, alkenylsulfonyl,
alkynylsulfonyl, hydroxyl, alkoxyl, aryloxyl, heteroaryloxyl,
aralkyloxy, heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol,
alkylthio, arylthio, aralkylthio, heteroaralkylthio, alkenylthio,
alkynylthio, formyl, acyl, formyloxy, acyloxy, formylthio,
acylthio, amine, alkylamine, arylamine, heteroarylamine,
aralkylamine, heteroaralkylamine, alkenylamine, alkynylamine,
formylamine, acylamine, carboxyl, alkyloxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,
heteroaralkyloxycarbonyl, amido, alkylaminecarbonyl,
arylaminecarbonyl, heteroarylaminecarbonyl, aralkylaminecarbonyl,
and heteroaralkylaminecarbonyl;
[0213] R.sup.6 is hydrogen or lower alkyl; and
[0214] m is 1, 2, 3, or 4.
[0215] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein W is a polythiol.
[0216] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein W is a polyol.
[0217] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein said polyol is a
carbohydrate.
[0218] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein said polyol is maltitol,
sorbitol, xylitol or isomalt.
[0219] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein said polyol is sorbitol.
[0220] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein said polyol is inositol.
[0221] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein p is 2, 3, 4, 5, or 6.
[0222] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein p is 2-100 inclusive. In
certain embodiments, the invention relates to any one of the
aforementioned compounds, wherein p is 2-50 inclusive. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein p is 2-10 inclusive.
[0223] In certain embodiments, the invention relates to any one of
the aforementioned compounds, wherein p is 2. In certain
embodiments, the invention relates to any one of the aforementioned
compounds, wherein p is 3. In certain embodiments, the invention
relates to any one of the aforementioned compounds, wherein p is 4.
In certain embodiments, the invention relates to any one of the
aforementioned compounds, wherein p is 5. In certain embodiments,
the invention relates to any one of the aforementioned compounds,
wherein p is 6.
[0224] It has been discovered that at least certain of the
compounds of the invention have desirable physiological attributes
of niacin, with reduced undesirable physiological side effects of
niacin. For example, compounds of the invention have the ability to
modulate at least one lipid in a desirable fashion, without
restrictive side effects, or without the degree of restrictive side
effects, characteristic of niacin.
[0225] Additionally, it has been discovered that at least certain
of the compounds of the invention do not appear to engage the
high-affinity niacin receptor GPR109A in a manner similar to
niacin. GPR109A, also referred to as PUMA-G and HM74A, is a member
of the nicotinic acid receptor family of G protein-coupled
redeptors (GPCRs). Wise A et al. (2003) J Biol Chem 278:99-74; Soga
T et al. (2003) Biochem Biophys Res Comm 303:364-9. In GPR109A
knockout mice, the effects of niacin on both lipids and flushing
are eliminated. The flushing effect, but not the lipid modifying
effects, of niacin has been ascribed to GPR109A activation of ERK
1/2 MAP kinase, mediated by arrestin beta 1 (beta
(.beta.)-arrestin). In arrestin beta 1 knockout mice, niacin's
effect on flushing has been reported to be greatly reduced while
the lipid modifying effects are maintained. Walters R W et al.
(2009) J Clin Invest 119:1312-21. Significantly, at least certain
of the compounds of the invention have greatly reduced ability to
induce recruitment of .beta.-arrestin to the membrane of cells
expressing GPR109A, have greatly reduced flushing effect compared
to niacin, yet maintain clinically significant desirable
lipid-modifying effects.
[0226] Many of the compounds of the invention may be provided as
salts with pharmaceutically compatible counterions (i.e.,
pharmaceutically acceptable salts). A "pharmaceutically acceptable
salt" means any non-toxic salt that, upon administration to a
recipient, is capable of providing, either directly or indirectly,
a compound or a prodrug of a compound of this invention. A
"pharmaceutically acceptable counterion" is an ionic portion of a
salt that is not toxic when released from the salt upon
administration to a recipient. Pharmaceutically compatible salts
may be formed with many acids, including but not limited to
hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic,
etc. Salts tend to be more soluble in aqueous or other protonic
solvents than are the corresponding free base forms.
[0227] Acids commonly employed to form pharmaceutically acceptable
salts include inorganic acids such as hydrogen bisulfide,
hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric
acid, as well as organic acids such as para-toluenesulfonic,
salicylic, tartaric, bitartaric, ascorbic, maleic, besylic,
fumaric, gluconic, glucuronic, formic, glutamic, methanesulfonic,
ethanesulfonic, benzenesulfonic, lactic, oxalic,
para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and
acetic acid, and related inorganic and organic acids. Such
pharmaceutically acceptable salts thus include sulfate,
pyrosulfate, bisulfate, sulfite, bisulfate, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, chloride, bromide, iodide, acetate, propionate,
decanoate, caprylate, acrylate, formate, isobutyrate, caprate,
heptanoate, propiolate, oxalate, malonate, succinate, suberate,
sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate,
benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,
hydroxybenzoate, methoxybenzoate, phthalate, terephathalate,
sulfonate, xylenesulfonate, phenylacetate, phenylpropionate,
phenylbutyrate, citrate, lactate, .beta.-hydroxybutyrate,
glycolate, maleate, tartrate, methanesulfonate, propanesulfonate,
naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the
like salts. Exemplary pharmaceutically acceptable acid addition
salts include those formed with mineral acids such as hydrochloric
acid and hydrobromic acid, and especially those formed with organic
acids such as maleic acid.
[0228] Suitable bases for forming pharmaceutically acceptable salts
with acidic functional groups include, but are not limited to,
hydroxides of alkali metals such as sodium, potassium, and lithium;
hydroxides of alkaline earth metal such as calcium and magnesium;
hydroxides of other metals, such as aluminum and zinc; ammonia, and
organic amines, such as unsubstituted or hydroxy-substituted mono-,
di-, or trialkylamines; dicyclohexylamine; tributyl amine;
pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine;
mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-,
bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or
tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy
lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine,
or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids
such as arginine, lysine, and the like.
[0229] Certain compounds of the invention and their salts may exist
in more than one crystal form and the present invention includes
each crystal form and mixtures thereof.
[0230] Certain compounds of the invention and their salts may also
exist in the form of solvates, for example hydrates, and the
present invention includes each solvate and mixtures thereof.
[0231] Certain compounds of the invention may contain one or more
chiral centers, and exist in different optically active forms. When
compounds of the invention contain one chiral center, the compounds
exist in two enantiomeric forms and the present invention includes
both enantiomers and mixtures of enantiomers, such as racemic
mixtures. The enantiomers may be resolved by methods known to those
skilled in the art, for example by formation of diastereoisomeric
salts which may be separated, for example, by crystallization;
formation of diastereoisomeric derivatives or complexes which may
be separated, for example, by crystallization, gas-liquid or liquid
chromatography; selective reaction of one enantiomer with an
enantiomer-specific reagent, for example enzymatic esterification;
or gas-liquid or liquid chromatography in a chiral environment, for
example on a chiral support for example silica with a bound chiral
ligand or in the presence of a chiral solvent. It will be
appreciated that where the desired enantiomer is converted into
another chemical entity by one of the separation procedures
described above, a further step may be used to liberate the desired
enantiomeric form. Alternatively, specific enantiomers may be
synthesized by asymmetric synthesis using optically active
reagents, substrates, catalysts or solvents, or by converting one
enantiomer into the other by asymmetric transformation.
[0232] When a compound of the invention contains more than one
chiral center, it may exist in diastereoisomeric forms. The
diastereoisomeric compounds may be separated by methods known to
those skilled in the art, for example chromatography or
crystallization and the individual enantiomers may be separated as
described above. The present invention includes each
diastereoisomer of compounds of the invention and mixtures
thereof.
[0233] Certain compounds of the invention may exist in different
tautomeric forms or as different geometric isomers, and the present
invention includes each tautomer and/or geometric isomer of
compounds of the invention and mixtures thereof.
[0234] Certain compounds of the invention may exist in different
stable conformational forms which may be separable. Torsional
asymmetry due to restricted rotation about an asymmetric single
bond, for example because of steric hindrance or ring strain, may
permit separation of different conformers. The present invention
includes each conformational isomer of compounds of the invention
and mixtures thereof.
[0235] Certain compounds of the invention may exist in zwitterionic
form and the present invention includes each zwitterionic form of
compounds of the invention and mixtures thereof.
[0236] The present invention also includes prodrugs. As used herein
the term "prodrug" refers to an agent which is converted into the
parent drug in vivo by some physiological chemical process (e.g., a
prodrug on being brought to the physiological pH is converted to
the desired drug form). Pro-drugs are often useful because, in some
situations, they may be easier to administer than the parent drug.
They may, for instance, be bioavailable by oral administration
whereas the parent drug is not. The prodrug may also have improved
solubility in pharmacological compositions over the parent drug. An
example, without limitation, of a prodrug would be a compound of
the present invention wherein it is administered as an ester (the
"prodrug") to facilitate transmittal across a cell membrane where
water solubility is not beneficial, but then it is metabolically
hydrolyzed to the carboxylic acid once inside the cell where water
solubility is beneficial. Pro-drugs have many useful properties.
For example, a prodrug may be more water soluble than the ultimate
drug, thereby facilitating intravenous administration of the drug.
A prodrug may also have a higher level of oral bioavailability than
the ultimate drug. After administration, the prodrug is
enzymatically or chemically cleaved to deliver the ultimate drug in
the blood or tissue.
[0237] Exemplary prodrugs upon cleavage release the corresponding
free acid, and such hydrolyzable ester-forming residues of the
compounds of this invention include but are not limited to
carboxylic acid substituents (e.g., --C(O).sub.2H or a moiety that
contains a carboxylic acid) wherein the free hydrogen is replaced
by (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.12)alkanoyloxymethyl,
(C.sub.4-C.sub.9)1-(alkanoyloxy)ethyl,
1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,
alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,
1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,
1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon
atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon
atoms, 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon
atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,
di-N,N--(C.sub.1-C.sub.2)alkylamino(C.sub.2-C.sub.3)alkyl (such as
.beta.-dimethylaminoethyl), carbamoyl-(C.sub.1-C.sub.2)alkyl,
N,N-di(C.sub.1-C.sub.2)-alkylcarbamoyl-(C.sub.1-C.sub.2)alkyl and
piperidino-, pyrrolidino- or morpholino(C.sub.2-C.sub.3)alkyl.
[0238] Other exemplary prodrugs release an alcohol or amine of a
compound of the invention wherein the free hydrogen of a hydroxyl
or amine substituent is replaced by
(C.sub.1-C.sub.6)alkanoyloxymethyl,
1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
1-methyl-1-((C.sub.1-C.sub.6)alkanoyloxy)ethyl,
(C.sub.1-C.sub.6)alkoxycarbonyl-oxymethyl,
N--(C.sub.1-C.sub.6)alkoxycarbonylamino-methyl, succinoyl,
(C.sub.1-C.sub.6)alkanoyl, .alpha.-amino(C.sub.1-C.sub.4)alkanoyl,
arylactyl and .alpha.-aminoacyl, or
.alpha.-aminoacyl-.alpha.-aminoacyl wherein said .alpha.-aminoacyl
moieties are independently any of the naturally occurring L-amino
acids found in proteins, --P(O)(OH).sub.2,
--P(O)(O(C.sub.1-C.sub.6)alkyl).sub.2 or glycosyl (the radical
resulting from detachment of the hydroxyl of the hemiacetal of a
carbohydrate).
[0239] The phrase "protecting group" as used herein means temporary
substituents which protect a potentially reactive functional group
from undesired chemical transformations. Examples of such
protecting groups include esters of carboxylic acids, silyl ethers
of alcohols, and acetals and ketals of aldehydes and ketones,
respectively. The field of protecting group chemistry has been
reviewed (Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 2.sup.nd ed.; Wiley: New York, 1991). Protected
forms of the inventive compounds are included within the scope of
this invention.
[0240] The term "chemically protected form," as used herein,
pertains to a compound in which one or more reactive functional
groups are protected from undesirable chemical reactions, that is,
are in the form of a protected or protecting group (also known as a
masked or masking group). It may be convenient or desirable to
prepare, purify, and/or handle the active compound in a chemically
protected form.
[0241] By protecting a reactive functional group, reactions
involving other unprotected reactive functional groups can be
performed, without affecting the protected group; the protecting
group may be removed, usually in a subsequent step, without
substantially affecting the remainder of the molecule. See, for
example, Protective Groups in Organic Synthesis (T. Green and P.
Wuts, Wiley, 1991), and Protective Groups in Organic Synthesis (T.
Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).
[0242] For example, a hydroxy group may be protected as an ether
(--OR) or an ester (--OC(.dbd.O)R), for example, as: a t-butyl
ether; a benzyl, benzhydryl (diphenylmethyl), or trityl
(triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl
ether; or an acetyl ester (--OC(.dbd.O)CH.sub.3,--OAc).
[0243] For example, an aldehyde or ketone group may be protected as
an acetal or ketal, respectively, in which the carbonyl group
(C(.dbd.O)) is converted to a diether (C(OR).sub.2), by reaction
with, for example, a primary alcohol. The aldehyde or ketone group
is readily regenerated by hydrolysis using a large excess of water
in the presence of acid.
[0244] For example, an amine group may be protected, for example,
as an amide (--NRC(.dbd.O)R) or a urethane (--NRC(.dbd.O)OR), for
example, as: a methyl amide (--NHC(.dbd.O)CH.sub.3); a benzyloxy
amide (--NHC(.dbd.O)OCH.sub.2C.sub.6H.sub.5NHCbz); as a t-butoxy
amide (--NHC=(.dbd.O)OC(CH.sub.3).sub.3,--NHBoc); a
2-biphenyl-2-propoxy amide
(--NHC(.dbd.O)OC(CH.sub.3).sub.2C.sub.6H.sub.4C.sub.6H.sub.5NHBoc),
as a 9-fluorenylmethoxy amide (--NHFmoc), as a 6-nitroveratryloxy
amide (--NHNvoc), as a 2-trimethylsilylethyloxy amide (--NHTeoc),
as a 2,2,2-trichloroethyloxy amide (--NHTroc), as an allyloxy amide
(--NHAlloc), as a 2-(phenylsulfonyl)ethyloxy amide (--NHPsec); or,
in suitable cases (e.g., cyclic amines), as a nitroxide
radical.
[0245] For example, a carboxylic acid group may be protected as an
ester or an amide, for example, as: a benzyl ester; a t-butyl
ester; a methyl ester; or a methyl amide.
[0246] For example, a thiol group may be protected as a thioether
(--SR), for example, as: a benzyl thioether; or an acetamidomethyl
ether (--SCH.sub.2NHC(.dbd.O)CH.sub.3).
Pharmaceutical Compositions
[0247] The invention provides pharmaceutical compositions
comprising one or more of the above-referenced compounds. In one
aspect, the present invention provides pharmaceutically acceptable
compositions which comprise a therapeutically effective amount of
one or more of the compounds described above, formulated together
with one or more pharmaceutically acceptable carriers (additives)
and/or diluents.
[0248] Alternatively or in addition, the invention provides
pharmaceutical compositions characterized by having at least one
desired therapeutic effect of niacin and a reduction or absence of
at least one undesirable side effect of niacin.
[0249] In one aspect, the invention provides a pharmaceutical
composition, comprising a niacin analog or a pharmaceutically
acceptable salt thereof, and at least one pharmaceutically
acceptable excipient; wherein said composition is formulated for
oral administration; the niacin analog when administered orally to
a human reduces a serum or plasma level of at least one lipid
selected from the group consisting of total cholesterol,
low-density lipoprotein (LDL) cholesterol, triglycerides, and
lipoprotein (a); and oral administration of the composition is
characterized by reduced flushing and reduced hepatocellular
damage, as compared to administration of an equimolar oral dose of
niacin.
[0250] A "niacin analog" as used herein is a structural analog of
niacin, other than niacin (nicotinic acid), that, when administered
orally to a subject, has at least one lipid-modulating effect that
is characteristic of orally administered niacin. A niacin analog
has a structure similar to that of niacin, but differing from
niacin in respect of at least one atom, functional group,
substituent, or substructure, which are replaced with other atoms,
groups, substituents, or substructures. Niacin analogs of the
invention specifically exclude timed-, sustained-, and
extended-release formulations of niacin, including niacin
formulated together with a polymer, such as polyethylene glycol or
hydroxypropyl methylcellulose (hypromellose).
[0251] In one embodiment, the niacin analog is a
pyridine-containing compound.
[0252] In one embodiment, the niacin analog is not
##STR00009##
[0253] In one embodiment, the niacin analog specifically excludes
6-[2-(pyrrolidin-1-yl)ethyl]pyridine and 4-pyridin-3-yl-but-3-enoic
acid disclosed in US Patent Application Publication No. US
2009/0312355 A1.
[0254] In one embodiment, the niacin analog specifically excludes
any one or more of
##STR00010##
[0255] In one embodiment, the niacin analog specifically excludes a
compound represented by structure A, or a pharmaceutically
acceptable salt thereof:
##STR00011##
wherein
[0256] R represents independently for each occurrence H, alkyl,
alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl,
fluoride, chloride, bromide, iodide, nitro, cyano, sulfonic acid,
alkylsulfoxyl, arylsulfoxyl, heteroarylsulfoxyl, aralkylsulfoxyl,
heteroaralkylsulfoxyl, alkenylsulfoxyl, alkynylsulfoxyl,
alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,
heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,
alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,
alkenyloxy, alkynyloxy, thiol, alkylthio, arylthio, aralkylthio,
heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl,
formyloxy, acyloxy, formylthio, acylthio, amino, alkylamino,
arylamino, heteroarylamino, aralkylamino, heteroaralkylamino,
alkenylamino, alkynylamino, formylamino, acylamino, carboxylate,
alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,
aralkyloxycarbonyl, heteroaralkyloxycarbonyl, carboxamido,
alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl,
aralkylaminocarbonyl, or heteroaralkylaminocarbonyl;
[0257] R' represents independently for each occurrence H, alkyl,
alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl,
alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl,
heteroaralkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, hydroxyl,
alkoxyl, aryloxyl, heteroaryloxyl, aralkyloxy, heteroaralkyloxy,
alkenyloxy, alkynyloxy, formyl, acyl, amino, alkylamino, arylamino,
heteroarylamino, aralkylamino, heteroaralkylamino, alkenylamino,
alkynylamino, formylamino, acylamino, alkyloxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,
heteroaralkyloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl,
heteroarylaminocarbonyl, aralkylaminocarbonyl, or
heteroaralkylaminocarbonyl; or the two instances of R' taken
together represent --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, --(CH.sub.2).sub.5--, or
--(CH.sub.2).sub.6--;
[0258] R'' represents independently for each occurrence H, alkyl,
alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;
and
[0259] n is 1, 2, 3, or 4.
[0260] The niacin analog, when administered orally to a human,
reduces a serum or plasma level of at least one lipid selected from
the group consisting of total cholesterol, low-density lipoprotein
(LDL) cholesterol, triglycerides, and lipoprotein (a). The niacin
analog is said to reduce a serum or plasma level of at least one
lipid when such serum or plasma level is reduced by a measurable
amount as compared to a pre-treatment, baseline, or control level.
In one embodiment, the niacin analog is said to reduce a serum or
plasma level of at least one lipid when such serum or plasma level
is reduced by at least 5 percent of the pre-treatment, baseline, or
control level; that is, the serum or plasma level is reduced to no
more than 95 percent of the pre-treatment, baseline, or control
level. In one embodiment, the niacin analog is said to reduce a
serum or plasma level of at least one lipid when such serum or
plasma level is reduced by at least 10 percent of the
pre-treatment, baseline or control level. In one embodiment, the
niacin analog is said to reduce a serum or plasma level of at least
one lipid when such serum or plasma level is reduced by at least 15
percent of the pretreatment, baseline or control level. In one
embodiment, the niacin analog is said to reduce a serum or plasma
level of at least one lipid when such serum or plasma level is
reduced by at least 20 percent of the pretreatment, baseline or
control level.
[0261] As used herein, "flushing" refers to objective cutaneous
vasodilation, frequently accompanied by redness and/or a subjective
experience of a warm feeling in the skin, the latter with or
without itching. Flushing can be measured objectively using
objective measurements such as Doppler capillary blood flow
measurements. Alternatively or in addition, flushing can be
measured using a so-called visual analog scale (VAS), which can be
either observer-based or subject-based. The VAS typically involves
scoring a sign or symptom on a scale ranging from zero (0) to ten
(10), where zero corresponds to complete absence of the sign or
symptom being scored, and ten corresponds to an unbearable or
maximum amount or degree of the sign or symptom being scored.
[0262] As used herein, "hepatocellular damage" refers to toxic
injury to liver parenchymal cells. Hepatocellular damage can be
assessed using any suitable method. In one embodiment,
hepatocellular damage is assessed by measuring one or more serum
liver enzymes. In one embodiment, one such liver enzyme is
aspartate aminotransferase (AST, also referred to as SGOT). In one
embodiment, one such liver enzyme is alanine aminotransferase (ALT,
also referred to as SGPT). Serum levels of AST and ALT are commonly
measured in clinical practice, and it is not necessary to describe
methods for their measurement here. Normal serum levels both of AST
and ALT are generally 0-35 U/L. In contrast to ALT, which is found
primarily in the liver, AST is also found in other tissues,
including heart, skeletal muscle, kidney, and brain, and is thus
somewhat less specific as an indicator of liver dysfunction.
Although elevated serum levels of AST or ALT may be observed in a
variety of nonhepatic conditions, including myocardial infarction,
these conditions are usually readily distinguished clinically from
liver disease. In liver disease, elevations of serum AST and ALT
reflect hepatic necrosis, a severe form of hepatocellular
damage.
[0263] Oral administration of the composition is characterized by
reduced flushing and reduced hepatocellular damage, as compared to
administration of an equimolar oral dose of niacin. In this
context, flushing is said to be reduced when it is reduced by a
measurable amount or degree as compared to a corresponding degree
of flushing associated with administration of an equimolar oral
dose of niacin. In one embodiment, flushing is said to be reduced
when the maximum degree or amount of flushing is reduced by a
measurable degree or amount as compared to the maximum degree or
amount of flushing associated with administration of an equimolar
oral dose of niacin.
[0264] In one embodiment, flushing is said to be reduced when
Doppler capillary blood flow in relevant tissue is reduced by at
least 2 percent as compared to Doppler capillary blood flow in
corresponding relevant tissue associated with administration of an
equimolar oral dose of niacin; i.e., the flow is reduced to no more
than 98 percent of the Doppler capillary blood flow in
corresponding relevant tissue associated with administration of an
equimolar oral dose of niacin. In one embodiment, flushing is said
to be reduced when Doppler capillary blood flow in relevant tissue
is reduced by at least 5 percent as compared to Doppler capillary
blood flow in corresponding relevant tissue associated with
administration of an equimolar oral dose of niacin. In one
embodiment, flushing is said to be reduced when Doppler capillary
blood flow in relevant tissue is reduced by at least 10 percent as
compared to Doppler capillary blood flow in corresponding relevant
tissue associated with administration of an equimolar oral dose of
niacin.
[0265] In one embodiment, flushing is said to be reduced when VAS
score for relevant tissue is reduced by at least one (1) (on a
scale from 0 to 10) as compared to VAS score for corresponding
relevant tissue associated with administration of an equimolar oral
dose of niacin; i.e., the VAS score reduced to no more than one
less than the VAS score for corresponding relevant tissue
associated with administration of an equimolar oral dose of niacin.
For example, in one such an embodiment, flushing is said to be
reduced when the maximum VAS score is 5 whereas the maximum VAS
score for corresponding relevant tissue associated with
administration of an equimolar oral dose of niacin is 6-10.
[0266] Of course, any of the foregoing comparisons can,
advantageously, be made on a population basis. For example, mean or
median values of AST, ALT, or VAS score can be compared. Likewise,
mean or median values of maximum AST, maximum ALT, or maximum VAS
score can be compared.
[0267] Comparison is made to an equimolar oral dose of niacin. An
equimolar oral dose of niacin refers to an equimolar oral dose of
niacin in any form, including, for example immediate-, timed-,
sustained-, and extended-release formulations of niacin. In one
embodiment, an equimolar oral dose is formulated in an analogous
fashion, e.g., in tablet form wherein each individual tablet is
comprised of the same or essentially the same molar amount of
active agent. Thus, for example, comparison can be made, in one
embodiment, between oral doses given as single tablets, each tablet
containing 8.2 mmol of active agent (e.g., 1 g of niacin). As an
alternative example, comparison can be made, in another embodiment,
between oral doses given as two single tablets, each tablet
containing 4.1 mmol of active agent (e.g., 0.5 g of niacin).
[0268] Except as may be indicated otherwise herein, all
pharmacokinetic comparisons to "niacin" are comparisons to
so-called immediate-release formulation of niacin.
[0269] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein peak serum or plasma
concentration (C.sub.max) for the niacin analog is 40 percent or
less of C.sub.max for the equimolar oral dose of niacin. In one
embodiment, peak serum or plasma concentration (C.sub.max) for the
niacin analog is 35 percent or less of C.sub.max for the equimolar
oral dose of niacin. In one embodiment, peak serum or plasma
concentration (C.sub.max) for the niacin analog is 30 percent or
less of C.sub.max for the equimolar oral dose of niacin. In one
embodiment, peak serum or plasma concentration (C.sub.max) for the
niacin analog is 25 percent or less of C.sub.max for the equimolar
oral dose of niacin. In one embodiment, peak serum or plasma
concentration (C.sub.max) for the niacin analog is 20 percent or
less of C.sub.max for the equimolar oral dose of niacin. In one
embodiment, peak serum or plasma concentration (C.sub.max) for the
niacin analog is 15 percent or less of C.sub.max for the equimolar
oral dose of niacin. In one embodiment, peak serum or plasma
concentration (C.sub.max) for the niacin analog is 10 percent or
less of C.sub.max for the equimolar oral dose of niacin. In one
embodiment, peak serum or plasma concentration (C.sub.max) for the
niacin analog is 5 percent or less of C.sub.max for the equimolar
oral dose of niacin. In one embodiment, peak serum or plasma
concentration (C.sub.max) for the niacin analog is 1 percent or
less of C.sub.max for the equimolar oral dose of niacin. For each
of the foregoing embodiments, it is to be understood that
comparison is made with an immediate release formulation of niacin.
Methods useful for measuring the concentration are disclosed in
detail hereinbelow.
[0270] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein peak serum or plasma
concentration (C.sub.max) for the compound is 1 to 40 percent of
C.sub.max for the equimolar oral dose of niacin. In one embodiment,
peak serum or plasma concentration (C.sub.max) for the compound is
1 to 35 percent of C.sub.max for the equimolar oral dose of niacin.
In one embodiment, peak serum or plasma concentration (C.sub.max)
for the compound is 1 to 30 percent of C.sub.max for the equimolar
oral dose of niacin. In one embodiment, peak serum or plasma
concentration (C.sub.max) for the compound is 1 to 25 percent of
C.sub.max for the equimolar oral dose of niacin. In one embodiment,
peak serum or plasma concentration (C.sub.max) for the compound is
1 to 20 percent of C.sub.max for the equimolar oral dose of niacin.
In one embodiment, peak serum or plasma concentration (C.sub.max)
for the compound is 1 to 15 percent of C.sub.max for the equimolar
oral dose of niacin. In one embodiment, peak serum or plasma
concentration (C.sub.max) for the compound is 1 to 10 percent of
C.sub.max for the equimolar oral dose of niacin. For each of the
foregoing embodiments, it is to be understood that comparison is
made with an immediate release formulation of niacin. Methods
useful for measuring the concentration are disclosed in detail
hereinbelow.
[0271] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein the ratio of peak serum or
plasma concentration (C.sub.max) to area under the curve at 24
hours (AUC.sub.0-24) (i.e., the ratio C.sub.max/AUC.sub.0-24) for
the niacin analog is 0.35 h.sup.-1 or less. In one embodiment, the
ratio of peak concentration to area under the curve at 24 hours
(C.sub.max/AUC.sub.0-24) for the niacin analog is 0.30 h.sup.-1 or
less. In one embodiment, the ratio of peak concentration to area
under the curve at 24 hours (C.sub.max/AUC.sub.0-24) for the niacin
analog is 0.25 h.sup.-1 or less. In one embodiment, the ratio of
peak concentration to area under the curve at 24 hours
(C.sub.max/AUC.sub.0-24) for the niacin analog is 0.20 h.sup.-1 or
less. In one embodiment, the ratio of peak concentration to area
under the curve at 24 hours (C.sub.max/AUC.sub.0-24) for the niacin
analog is 0.15 h.sup.-1 or less. In one embodiment, the ratio of
peak concentration to area under the curve at 24 hours
(C.sub.max/AUC.sub.0-24) for the niacin analog is 0.10 h.sup.-1 or
less. In one embodiment, the ratio of peak concentration to area
under the curve at 24 hours (C.sub.max/AUC.sub.0-24) for the niacin
analog is 0.05 h.sup.-1 or less. In one embodiment, the ratio of
peak concentration to area under the curve at 24 hours
(C.sub.max/AUC.sub.0-24) for the niacin analog is 0.01 h.sup.-1 or
less.
[0272] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein the ratio of peak serum or
plasma concentration (C.sub.max) to area under the curve at 24
hours (AUC.sub.0-24) (i.e., the ratio C.sub.max/AUC.sub.0-24) for
the compound is 0.10 h.sup.-1 to 0.35 h.sup.-1. In one embodiment,
the ratio of peak concentration to area under the curve at 24 hours
(C.sub.max/AUC.sub.0-24) for the compound is 0.10 h.sup.-1 to 0.30
h.sup.-1. In one embodiment, the ratio of peak concentration to
area under the curve at 24 hours (C.sub.max/AUC.sub.0-24) for the
compound is 0.10 h.sup.-1 to 0.25 h.sup.-1. In one embodiment, the
ratio of peak concentration to area under the curve at 24 hours
(C.sub.max/AUC.sub.0-24) for the compound is 0.10 h.sup.-1 to 0.20
h.sup.-1.
[0273] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein the time to peak serum or
plasma concentration (t.sub.max) for the niacin analog is in the
range of 30 minutes to 5 hours. In one embodiment, the time to peak
concentration (t.sub.max) for the niacin analog is in the range of
1 to 5 hours. In one embodiment, the time to peak concentration
(t.sub.max) for the niacin analog is in the range of 1 to 4 hours.
In one embodiment, the time to peak concentration (t.sub.max) for
the niacin analog is in the range of 1 to 3 hours. In one
embodiment, the time to peak concentration (t.sub.max) for the
niacin analog is in the range of 1 to 2 hours.
[0274] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein the niacin analog has an
EC.sub.50 for .beta.-arrestin-mediated GPR109A function which is at
least 10 times greater than the EC.sub.50 of niacin for
.beta.-arrestin-mediated GPR109A function. EC.sub.50 refers to the
concentration at which a particular effect achieves 50 percent of
its maximum. .beta.-arrestin-mediated GPR109A function is described
elsewhere herein. In one embodiment, the niacin analog has an
EC.sub.50 for .beta.-arrestin-mediated GPR109A function which is at
least 20 times greater than the EC.sub.50 of niacin for
.beta.-arrestin-mediated GPR109A function. In one embodiment, the
niacin analog has an EC.sub.50 for .beta.-arrestin-mediated GPR109A
function which is at least 30 times greater than the EC.sub.50 of
niacin for 3-arrestin-mediated GPR109A function. In one embodiment,
the niacin analog has an EC.sub.50 for .beta.-arrestin-mediated
GPR109A function which is at least 40 times greater than the
EC.sub.50 of niacin for .beta.-arrestin-mediated GPR109A function.
In one embodiment, the niacin analog has an EC.sub.50 for
.beta.-arrestin-mediated GPR109A function which is at least 50
times greater than the EC.sub.50 of niacin for
.beta.-arrestin-mediated GPR109A function. In one embodiment, the
niacin analog has an EC.sub.50 for .beta.-arrestin-mediated GPR109A
function which is at least 100 times greater than the EC.sub.50 of
niacin for .beta.-arrestin-mediated GPR109A function.
[0275] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein the niacin analog, when
administered orally to a human, also increases a serum or plasma
level of high-density lipoprotein (HDL) cholesterol. The serum or
plasma level of HDL cholesterol increases by at least a measurable
amount compared to a pre-treatment, baseline, or control level. For
example, in one embodiment, serum or plasma level of HDL
cholesterol increases by at least 5 percent compared to a
pre-treatment, baseline, or control level. In one embodiment, serum
or plasma level of HDL cholesterol increases by at least 10 percent
compared to a pre-treatment, baseline, or control level. In one
embodiment, serum or plasma level of HDL cholesterol increases by
at least 15 percent compared to a pre-treatment, baseline, or
control level. In one embodiment, serum or plasma level of HDL
cholesterol increases by at least 20 percent compared to a
pre-treatment, baseline, or control level. In one embodiment, serum
or plasma level of HDL cholesterol increases by at least 25 percent
compared to a pre-treatment, baseline, or control level.
[0276] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein the niacin analog, when
administered orally to a human, induces substantially no increase
in serum levels of aspartate aminotransferase (AST), alanine
aminotransferase (ALT), or both. In one embodiment, "substantially
no increase" in this context means less than a 20 percent increase
over a pre-treatment, baseline, or control level.
[0277] In one embodiment, "substantially no increase" means less
than a 10 percent increase over a pre-treatment, baseline, or
control level.
[0278] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein the niacin analog, when
administered orally to a human, induces substantially no increase
in serum levels of uric acid, glucose, or both. Normal serum levels
of uric acid are 1.5-8.0 mg/dL. In one embodiment, "substantially
no increase in serum level of uric acid" means less than a 10
percent increase over a pre-treatment, baseline, or control level.
Normal fasting plasma levels of glucose are ca. 75-115 mg/dL.
Normal random (2 h postprandial) plasma levels of glucose are
ca.<140 mg/dL. In one embodiment, "substantially no increase in
serum level of glucose" means less than a 20 percent increase over
a pre-treatment, baseline, or control level. In one embodiment,
"substantially no increase in serum level of glucose" means less
than a 15 percent increase over a pre-treatment, baseline, or
control level. In one embodiment, "substantially no increase in
serum level of glucose" means less than a 10 percent increase over
a pre-treatment, baseline, or control level.
[0279] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein the niacin analog is
represented by structure I:
##STR00012##
[0280] wherein [0281] A is a heterocyclyl or heteroaryl, optionally
deuterated, containing from 5 to 12 ring atoms, including X and N,
which is optionally substituted with 1-3 substituents,
independently selected from the group consisting of alkyl, alkenyl,
alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, nitro,
cyano, sulfonic acid, alkylsulfoxyl, arylsulfoxyl,
heteroarylsulfoxyl, aralkylsulfoxyl, heteroaralkylsulfoxyl,
alkenylsulfoxyl, alkynylsulfoxyl, alkylsulfonyl, arylsulfonyl,
heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl,
alkenylsulfonyl, alkynylsulfonyl, hydroxyl, alkoxyl, aryloxyl,
heteroaryloxyl, aralkyloxy, heteroaralkyloxy, alkenyloxy,
alkynyloxy, thiol, alkylthio, arylthio, aralkylthio,
heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl,
formyloxy, acyloxy, formylthio, acylthio, amine, alkylamine,
arylamine, heteroarylamine, aralkylamine, heteroaralkylamine,
alkenylamine, alkynylamine, formylamine, acylamine, carboxyl,
alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,
aralkyloxycarbonyl, heteroaralkyloxycarbonyl, amido,
alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl,
aralkylaminecarbonyl, and heteroaralkylaminecarbonyl; [0282] X is
O, S, N or N(R.sup.6); [0283] Z is
##STR00013##
[0283] or an isostere of a carboxyl group; [0284] X.sup.1 is O or
S; [0285] X.sup.2 is O or S; [0286] R is hydrogen, alkyl,
haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, fused
bicyclyl, carboxyalkyl, or arylalkenylaryl; [0287] R.sup.2 is
hydrogen, lower alkyl, lower alkenyl, lower alkynyl, halogen,
hydroxyl, amine, carboxyl, cycloalkyl, aryl, heteroaryl, aralkyl,
heteroaralkyl, cyano, or nitro; [0288] R.sup.3 is hydrogen, lower
alkyl, lower alkenyl, lower alkynyl, halogen, hydroxyl, amine,
carboxyl, cycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl,
cyano, or nitro; [0289] R.sup.5 is selected independently for each
occurrence from the group consisting of hydrogen, alkyl, alkenyl,
alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, nitro,
cyano, sulfonic acid, alkylsulfoxyl, arylsulfoxyl,
heteroarylsulfoxyl, aralkylsulfoxyl, heteroaralkylsulfoxyl,
alkenylsulfoxyl, alkynylsulfoxyl, alkylsulfonyl, arylsulfonyl,
heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl,
alkenylsulfonyl, alkynylsulfonyl, hydroxyl, alkoxyl, aryloxyl,
heteroaryloxyl, aralkyloxy, heteroaralkyloxy, alkenyloxy,
alkynyloxy, thiol, alkylthio, arylthio, aralkylthio,
heteroaralkylthio, alkenylthio, alkynylthio, formyl, acyl,
formyloxy, acyloxy, formylthio, acylthio, amine, alkylamine,
arylamine, heteroarylamine, aralkylamine, heteroaralkylamine,
alkenylamine, alkynylamine, formylamine, acylamine, carboxyl,
alkyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl,
aralkyloxycarbonyl, heteroaralkyloxycarbonyl, amido,
alkylaminecarbonyl, arylaminecarbonyl, heteroarylaminecarbonyl,
aralkylaminecarbonyl, and heteroaralkylaminecarbonyl; [0290]
R.sup.6 is hydrogen or lower alkyl; and [0291] m is 1, 2, 3, or
4.
[0292] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein A represents
heterocyclyl.
[0293] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein A represents
heteroaryl.
[0294] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein A is a radical of a
monocyclic ring having 5, 6 or 7 ring atoms.
[0295] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein A is a radical of a
bicyclic ring having 9, 10, 11 or 12 ring atoms.
[0296] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein X is O.
[0297] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein X is S.
[0298] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein X is N.
[0299] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein X is N(R.sup.6).
[0300] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein X is N(H).
[0301] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein A is pyrrolidinyl,
imidazolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl,
oxadiazolidinyl, piperidinyl, piperazinyl, thiomorpholinyl or
morpholinyl.
[0302] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein A is imidazolyl,
pyrazolyl, isoxoazolyl, oxazolyl, isothiazolyl, thiazolyl, oxinyl,
furazanyl, oxadiazolyl, thiadiazolyl, triazolyl, dithiazolyl,
diazinyl, oxazinyl, thiazinyl, triazinyl, tetrazinyl, diazepinyl or
thiazepinyl.
[0303] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein A is substituted with 1-3
substituents independently selected from the group consisting of
lower alkyl, halogen, nitro, cyano, sulfonic acid, hydroxyl,
alkoxyl, thiol, alkylthio, formyl, acyl, formyloxy, acyloxy,
formylthio, acylthio, amine, alkylamine, formylamine, acylamine and
carboxyl.
[0304] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein A is substituted with 1
substituent independently selected from the group consisting of
lower alkyl, halogen, nitro, cyano, sulfonic acid, hydroxyl,
alkoxyl, thiol, alkylthio, formyl, acyl, formyloxy, acyloxy,
formylthio, acylthio, amine, alkylamine, formylamine, acylamine and
carboxyl.
[0305] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein A is not substituted.
[0306] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein R.sup.2 is hydrogen or
lower alkyl.
[0307] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein R.sup.2 is hydrogen.
[0308] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein R.sup.3 is hydrogen or
lower alkyl.
[0309] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein R.sup.3 is hydrogen.
[0310] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein R.sup.2 is hydrogen; and
R.sup.3 is lower alkyl.
[0311] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein R.sup.2 is lower alkyl;
and R.sup.3 is hydrogen.
[0312] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein R.sup.2 is hydrogen; and
R.sup.3 is hydrogen.
[0313] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein m is 1.
[0314] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein m is 2.
[0315] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein m is 3.
[0316] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein m is 4.
[0317] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein R.sup.5 is selected
independently for each occurrence from the group consisting of
hydrogen, lower alkyl, halogen, nitro, cyano, sulfonic acid,
hydroxyl, alkoxyl, thiol, alkylthio, formyl, acyl, formyloxy,
acyloxy, formylthio, acylthio, amine, alkylamine, formylamine,
acylamine and carboxyl.
[0318] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein R.sup.5 is hydrogen.
[0319] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein Z is carboxyl.
[0320] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein Z is a carboxyl
isostere.
[0321] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein Z is tetrazolyl,
oxazolidinonyl, sulfonic acid, sulfinic acid, acylsulphonamide,
phosphonic acid, phosphinic acid, hydantoin, pyrrolidione,
3-isoxazolyl, or boronic acid.
[0322] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein Z is
##STR00014##
[0323] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein X.sup.1 is O.
[0324] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein X.sup.1 is S.
[0325] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein X.sup.2 is O.
[0326] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein X.sup.2 is S.
[0327] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein X.sup.1 is O; and X.sup.2
is O.
[0328] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein R is lower alkyl.
[0329] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein R is hydrogen.
[0330] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein R is
##STR00015##
[0331] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein R represents an aliphatic
group which is hydrolyzed to carboxyl under physiological
conditions.
[0332] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein the niacin analog is a
compound represented by structure II, or a pharmaceutically
acceptable salt thereof,
##STR00016##
[0333] wherein, independently for each occurrence,
[0334] W is a polyol or polythiol;
[0335] p is 2-500 inclusive;
[0336] R.sup.1 is
##STR00017##
and is either appended to the polyol through an oxygen atom of the
polyol or is appended to the polythiol through a sulfur atom of the
polythiol;
[0337] A is a heterocyclyl or heteroaryl, optionally deuterated,
containing from 5 to 12 ring atoms, including X and N, which is
optionally substituted with 1-3 substituents, independently
selected from the group consisting of alkyl, alkenyl, alkynyl,
aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano,
sulfonic acid, alkylsulfoxyl, arylsulfoxyl, heteroarylsulfoxyl,
aralkylsulfoxyl, heteroaralkylsulfoxyl, alkenylsulfoxyl,
alkynylsulfoxyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,
aralkylsulfonyl, heteroaralkylsulfonyl, alkenylsulfonyl,
alkynylsulfonyl, hydroxyl, alkoxyl, aryloxyl, heteroaryloxyl,
aralkyloxy, heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol,
alkylthio, arylthio, aralkylthio, heteroaralkylthio, alkenylthio,
alkynylthio, formyl, acyl, formyloxy, acyloxy, formylthio,
acylthio, amine, alkylamine, arylamine, heteroarylamine,
aralkylamine, heteroaralkylamine, alkenylamine, alkynylamine,
formylamine, acylamine, carboxyl, alkyloxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,
heteroaralkyloxycarbonyl, amido, alkylaminecarbonyl,
arylaminecarbonyl, heteroarylaminecarbonyl, aralkylaminecarbonyl,
and heteroaralkylaminecarbonyl;
[0338] X is O, S, N or N(R.sup.6);
[0339] X.sup.1 is O or S;
[0340] R is hydrogen, alkyl, haloalkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl,
heteroaryl, heteroaralkyl, fused bicyclyl, carboxyalkyl, or
arylalkenylaryl;
[0341] R.sup.2 is hydrogen, lower alkyl, lower alkenyl, lower
alkynyl, halogen, hydroxyl, amine, carboxyl, cycloalkyl, aryl,
heteroaryl, aralkyl, heteroaralkyl, cyano, or nitro;
[0342] R.sup.3 is hydrogen, lower alkyl, lower alkenyl, lower
alkynyl, halogen, hydroxyl, amine, carboxyl, cycloalkyl, aryl,
heteroaryl, aralkyl, heteroaralkyl, cyano, or nitro;
[0343] R.sup.5 is selected independently for each occurrence from
the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,
heteroaryl, aralkyl, heteroaralkyl, halogen, nitro, cyano, sulfonic
acid, alkylsulfoxyl, arylsulfoxyl, heteroarylsulfoxyl,
aralkylsulfoxyl, heteroaralkylsulfoxyl, alkenylsulfoxyl,
alkynylsulfoxyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,
aralkylsulfonyl, heteroaralkylsulfonyl, alkenylsulfonyl,
alkynylsulfonyl, hydroxyl, alkoxyl, aryloxyl, heteroaryloxyl,
aralkyloxy, heteroaralkyloxy, alkenyloxy, alkynyloxy, thiol,
alkylthio, arylthio, aralkylthio, heteroaralkylthio, alkenylthio,
alkynylthio, formyl, acyl, formyloxy, acyloxy, formylthio,
acylthio, amine, alkylamine, arylamine, heteroarylamine,
aralkylamine, heteroaralkylamine, alkenylamine, alkynylamine,
formylamine, acylamine, carboxyl, alkyloxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl,
heteroaralkyloxycarbonyl, amido, alkylaminecarbonyl,
arylaminecarbonyl, heteroarylaminecarbonyl, aralkylaminecarbonyl,
and heteroaralkylaminecarbonyl;
[0344] R.sup.6 is hydrogen or lower alkyl; and
[0345] m is 1, 2, 3, or 4.
[0346] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein W is a polythiol.
[0347] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein W is a polyol.
[0348] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein said polyol is a
carbohydrate.
[0349] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein said polyol is maltitol,
sorbitol, xylitol or isomalt.
[0350] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein said polyol is
sorbitol.
[0351] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein said polyol is
inositol.
[0352] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein p is 2, 3, 4, 5, or 6.
[0353] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein p is 2-100 inclusive. In
certain embodiments, the invention relates to any one of the
aforementioned compositions, wherein p is 2-50 inclusive. In
certain embodiments, the invention relates to any one of the
aforementioned compositions, wherein p is 2-10 inclusive.
[0354] In certain embodiments, the invention relates to any one of
the aforementioned compositions, wherein p is 2. In certain
embodiments, the invention relates to any one of the aforementioned
compositions, wherein p is 3. In certain embodiments, the invention
relates to any one of the aforementioned compositions, wherein p is
4. In certain embodiments, the invention relates to any one of the
aforementioned compositions, wherein p is 5. In certain
embodiments, the invention relates to any one of the aforementioned
compositions, wherein p is 6.
[0355] In another aspect, the agents of the invention can be
administered as such, or administered in mixtures with
pharmaceutically acceptable carriers and can also be administered
in conjunction with other agents. Conjunctive therapy thus includes
sequential, simultaneous and separate, or co-administration of one
or more compound of the invention, wherein the therapeutic effects
of the first administered has not entirely disappeared when the
subsequent compound is administered. In other words, the terms
"co-administration" and "co-administering," as used herein, refer
to both concurrent administration (administration of two or more
therapeutic agents at the same time) and time varied administration
(administration of one or more therapeutic agents at a time
different from that of the administration of an additional
therapeutic agent or agents), as long as the therapeutic agents are
present in the patient to some extent at the same time.
[0356] As described in detail below, the pharmaceutical
compositions of the present invention may be specially formulated
for administration in solid or liquid form, including those adapted
for the following: (1) oral administration, for example, drenches
(aqueous or non-aqueous solutions or suspensions), tablets, e.g.,
those targeted for buccal, sublingual, and systemic absorption,
capsules, boluses, powders, granules, pastes for application to the
tongue; (2) parenteral administration, for example, by intravenous,
intramuscular, intraperitoneal, subcutaneous, or epidural injection
or infusion as, for example, a sterile solution or suspension, or
sustained-release formulation; (3) topical application, for
example, as a cream, ointment, or a controlled-release patch or
spray applied to the skin; (4) intravaginally or intrarectally, for
example, as a pessary, cream or foam; (5) sublingually; (6)
ocularly; (7) transdermally; (8) nasally; (9) pulmonary; or (10)
intrathecally.
[0357] The phrase "therapeutically effective amount" as used herein
means that amount of a compound, material, or composition
comprising a compound of the present invention which is effective
for producing some desired therapeutic effect in at least a
sub-population of cells in an animal at a reasonable benefit/risk
ratio applicable to any medical treatment.
[0358] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0359] The phrase "pharmaceutically-acceptable carrier" as used
herein means a pharmaceutically-acceptable material, composition or
vehicle, such as a liquid or solid filler, diluent, excipient,
manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc
stearate, or steric acid), or solvent encapsulating material,
involved in carrying or transporting the subject compound from one
organ, or portion of the body, to another organ, or portion of the
body. Each carrier must be "acceptable" in the sense of being
compatible with the other ingredients of the formulation and not
injurious to the patient. Some examples of materials which can
serve as pharmaceutically-acceptable carriers include: (1) sugars,
such as lactose, glucose and sucrose; (2) starches, such as corn
starch and potato starch; (3) cellulose, and its derivatives, such
as sodium carboxymethyl cellulose, ethyl cellulose and cellulose
acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc;
(8) excipients, such as cocoa butter and suppository waxes; (9)
oils, such as peanut oil, cottonseed oil, safflower oil, sesame
oil, olive oil, corn oil and soybean oil; (10) glycols, such as
propylene glycol; (11) polyols, such as glycerin, sorbitol,
mannitol and polyethylene glycol; (12) esters, such as ethyl oleate
and ethyl laurate; (13) agar; (14) buffering agents, such as
magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16)
pyrogen-free water; (17) isotonic saline; (18) Ringer's solution;
(19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters,
polycarbonates and/or polyanhydrides; and (22) other non-toxic
compatible substances employed in pharmaceutical formulations.
[0360] As set out above, certain embodiments of the present
compounds may contain a basic functional group, such as amino or
alkylamino, and are, thus, capable of forming
pharmaceutically-acceptable salts with pharmaceutically-acceptable
acids. The term "pharmaceutically-acceptable salts" in this
respect, refers to the relatively non-toxic, inorganic and organic
acid addition salts of compounds of the present invention. These
salts can be prepared in situ in the administration vehicle or the
dosage form manufacturing process, or by separately reacting a
purified compound of the invention in its free base form with a
suitable organic or inorganic acid, and isolating the salt thus
formed during subsequent purification. Representative salts include
the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate,
nitrate, acetate, valerate, oleate, palmitate, stearate, laurate,
benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,
succinate, tartrate, napthylate, mesylate, glucoheptonate,
lactobionate, and laurylsulphonate salts and the like. See, for
example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci.
66:1-19.
[0361] The pharmaceutically acceptable salts of the subject
compounds include the conventional nontoxic salts or quaternary
ammonium salts of the compounds, e.g., from non-toxic organic or
inorganic acids. For example, such conventional nontoxic salts
include those derived from inorganic acids such as hydrochloride,
hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like;
and the salts prepared from organic acids such as acetic,
propionic, succinic, glycolic, stearic, lactic, malic, tartaric,
citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic,
glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic,
fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic,
oxalic, isothionic, and the like.
[0362] In other cases, the compounds of the present invention may
contain one or more acidic functional groups and, thus, are capable
of forming pharmaceutically-acceptable salts with
pharmaceutically-acceptable bases. The term
"pharmaceutically-acceptable salts" in these instances refers to
the relatively non-toxic, inorganic and organic base addition salts
of compounds of the present invention. These salts can likewise be
prepared in situ in the administration vehicle or the dosage form
manufacturing process, or by separately reacting the purified
compound in its free acid form with a suitable base, such as the
hydroxide, carbonate or bicarbonate of a
pharmaceutically-acceptable metal cation, with ammonia, or with a
pharmaceutically-acceptable organic primary, secondary or tertiary
amine Representative alkali or alkaline earth salts include the
lithium, sodium, potassium, calcium, magnesium, and aluminum salts
and the like. Representative organic amines useful for the
formation of base addition salts include ethylamine, diethylamine,
ethylenediamine, ethanolamine, diethanolamine, piperazine and the
like. (See, for example, Berge et al., supra)
[0363] Wetting agents, emulsifiers and lubricants, such as sodium
lauryl sulfate and magnesium stearate, as well as coloring agents,
release agents, coating agents, sweetening, flavoring and perfuming
agents, preservatives and antioxidants can also be present in the
compositions.
[0364] Examples of pharmaceutically-acceptable antioxidants
include: (1) water soluble antioxidants, such as ascorbic acid,
cysteine hydrochloride, sodium bisulfate, sodium metabisulfite,
sodium sulfite and the like; (2) oil-soluble antioxidants, such as
ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated
hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol,
and the like; and (3) metal chelating agents, such as citric acid,
ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid,
phosphoric acid, and the like.
[0365] Formulations of the present invention include those suitable
for oral, nasal, topical (including buccal and sublingual), rectal,
vaginal and/or parenteral administration. The formulations may
conveniently be presented in unit dosage form and may be prepared
by any methods well known in the art of pharmacy. The amount of
active ingredient which can be combined with a carrier material to
produce a single dosage form will vary depending upon the host
being treated, the particular mode of administration. The amount of
active ingredient which can be combined with a carrier material to
produce a single dosage form will generally be that amount of the
compound which produces a therapeutic effect. Generally, out of one
hundred percent, this amount will range from about 0.1 percent to
about ninety-nine percent of active ingredient, preferably from
about 5 percent to about 70 percent, most preferably from about 10
percent to about 30 percent.
[0366] In certain embodiments, a formulation of the present
invention comprises an excipient selected from the group consisting
of cyclodextrins, celluloses, liposomes, micelle forming agents,
e.g., bile acids, and polymeric carriers, e.g., polyesters and
polyanhydrides; and a compound of the present invention. In certain
embodiments, an aforementioned formulation renders orally
bioavailable a compound of the present invention.
[0367] Methods of preparing these formulations or compositions
include the step of bringing into association a compound of the
present invention with the carrier and, optionally, one or more
accessory ingredients. In general, the formulations are prepared by
uniformly and intimately bringing into association a compound of
the present invention with liquid carriers, or finely divided solid
carriers, or both, and then, if necessary, shaping the product.
[0368] Formulations of the invention suitable for oral
administration may be in the form of capsules, cachets, pills,
tablets, lozenges (using a flavored basis, usually sucrose and
acacia or tragacanth), powders, granules, or as a solution or a
suspension in an aqueous or non-aqueous liquid, or as an
oil-in-water or water-in-oil liquid emulsion, or as an elixir or
syrup, or as pastilles (using an inert base, such as gelatin and
glycerin, or sucrose and acacia) and/or as mouth washes and the
like, each containing a predetermined amount of a compound of the
present invention as an active ingredient. A compound of the
present invention may also be administered as a bolus, electuary or
paste.
[0369] In solid dosage forms of the invention for oral
administration (capsules, tablets, pills, dragees, powders,
granules, trouches and the like), the active ingredient is mixed
with one or more pharmaceutically-acceptable carriers, such as
sodium citrate or dicalcium phosphate, and/or any of the following:
(1) fillers or extenders, such as starches, lactose, sucrose,
glucose, mannitol, and/or silicic acid; (2) binders, such as,
carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,
sucrose and/or acacia; (3) humectants, such as glycerol; (4)
disintegrating agents, such as agar-agar, calcium carbonate, potato
or tapioca starch, alginic acid, certain silicates, and sodium
carbonate; (5) solution retarding agents, such as paraffin; (6)
absorption accelerators, such as quaternary ammonium compounds and
surfactants, such as poloxamer and sodium lauryl sulfate; (7)
wetting agents, such as, cetyl alcohol, glycerol monostearate, and
non-ionic surfactants; (8) absorbents, such as kaolin and bentonite
clay; (9) lubricants, such as talc, calcium stearate, magnesium
stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc
stearate, sodium stearate, stearic acid, and mixtures thereof; (10)
coloring agents; and (11) controlled-release agents, such as
crospovidone or ethyl cellulose. In the case of capsules, tablets
and pills, the pharmaceutical compositions may also comprise
buffering agents. Solid compositions of a similar type may also be
employed as fillers in soft and hard-shelled gelatin capsules using
such excipients as lactose or milk sugars, as well as high
molecular weight polyethylene glycols and the like.
[0370] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared using binder (for example, gelatin or hydroxypropylmethyl
cellulose), lubricant, inert diluent, preservative, disintegrant
(for example, sodium starch glycolate or cross-linked sodium
carboxymethyl cellulose), surface-active or dispersing agent.
Molded tablets may be made by molding in a suitable machine a
mixture of the powdered compound moistened with an inert liquid
diluent.
[0371] The tablets, and other solid dosage forms of the
pharmaceutical compositions of the present invention, such as
dragees, capsules, pills and granules, may optionally be scored or
prepared with coatings and shells, such as enteric coatings and
other coatings well known in the pharmaceutical-formulating art.
They may also be formulated so as to provide slow or controlled
release of the active ingredient therein using, for example,
hydroxypropylmethyl cellulose in varying proportions to provide the
desired release profile, other polymer matrices, liposomes and/or
microspheres. They may be formulated for rapid release, e.g.,
freeze-dried. They may be sterilized by, for example, filtration
through a bacteria-retaining filter, or by incorporating
sterilizing agents in the form of sterile solid compositions which
can be dissolved in sterile water, or some other sterile injectable
medium immediately before use. These compositions may also
optionally contain opacifying agents and may be of a composition
that they release the active ingredient(s) only, or preferentially,
in a certain portion of the gastrointestinal tract, optionally, in
a delayed manner. Examples of embedding compositions which can be
used include polymeric substances and waxes. The active ingredient
can also be in micro-encapsulated form, if appropriate, with one or
more of the above-described excipients.
[0372] Liquid dosage forms for oral administration of the compounds
of the invention include pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active ingredient, the liquid dosage forms may
contain inert diluents commonly used in the art, such as, for
example, water or other solvents, solubilizing agents and
emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, oils (in particular,
cottonseed, groundnut, corn, germ, olive, castor and sesame oils),
glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty
acid esters of sorbitan, and mixtures thereof.
[0373] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, coloring, perfuming and
preservative agents.
[0374] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, and mixtures thereof.
[0375] Formulations of the pharmaceutical compositions of the
invention for rectal or vaginal administration may be presented as
a suppository, which may be prepared by mixing one or more
compounds of the invention with one or more suitable non-irritating
excipients or carriers comprising, for example, cocoa butter,
polyethylene glycol, a suppository wax or a salicylate, and which
is solid at room temperature, but liquid at body temperature and,
therefore, will melt in the rectum or vaginal cavity and release
the active compound.
[0376] Formulations of the present invention which are suitable for
vaginal administration also include pessaries, tampons, creams,
gels, pastes, foams or spray formulations containing such carriers
as are known in the art to be appropriate.
[0377] Dosage forms for the topical or transdermal administration
of a compound of this invention include powders, sprays, ointments,
pastes, creams, lotions, gels, solutions, patches and inhalants.
The active compound may be mixed under sterile conditions with a
pharmaceutically-acceptable carrier, and with any preservatives,
buffers, or propellants which may be required.
[0378] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, excipients, such
as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures
thereof.
[0379] Powders and sprays can contain, in addition to a compound of
this invention, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays can additionally contain
customary propellants, such as chlorofluorohydrocarbons and
volatile unsubstituted hydrocarbons, such as butane and
propane.
[0380] Transdermal patches have the added advantage of providing
controlled delivery of a compound of the present invention to the
body. Such dosage forms can be made by dissolving or dispersing the
compound in the proper medium. Absorption enhancers can also be
used to increase the flux of the compound across the skin. The rate
of such flux can be controlled by either providing a rate
controlling membrane or dispersing the compound in a polymer matrix
or gel.
[0381] Ophthalmic formulations, eye ointments, powders, solutions
and the like, are also contemplated as being within the scope of
this invention.
[0382] Pharmaceutical compositions of this invention suitable for
parenteral administration comprise one or more compounds of the
invention in combination with one or more
pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions, or sterile
powders which may be reconstituted into sterile injectable
solutions or dispersions prior to use, which may contain sugars,
alcohols, antioxidants, buffers, bacteriostats, solutes which
render the formulation isotonic with the blood of the intended
recipient or suspending or thickening agents.
[0383] Examples of suitable aqueous and nonaqueous carriers that
may be employed in the pharmaceutical compositions of the invention
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils, such as olive oil, and injectable organic
esters, such as ethyl oleate. Proper fluidity can be maintained,
for example, by the use of coating materials, such as lecithin, by
the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0384] These compositions may also contain adjuvants, such as
preservatives, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms upon the subject
compounds may be ensured by the inclusion of various antibacterial
and antifungal agents, for example, paraben, chlorobutanol, phenol
sorbic acid, and the like. It may also be desirable to include
isotonic agents, such as sugars, sodium chloride, and the like into
the compositions. In addition, prolonged absorption of the
injectable pharmaceutical form may be brought about by the
inclusion of agents which delay absorption, such as aluminum
monostearate and gelatin.
[0385] In some cases, in order to prolong the effect of a drug, it
is desirable to slow the absorption of the drug from subcutaneous
or intramuscular injection. This result may be accomplished by the
use of a liquid suspension of crystalline or amorphous material
having poor water solubility. The rate of absorption of the drug
then depends upon its rate of dissolution which, in turn, may
depend upon crystal size and crystalline form. Alternatively,
delayed absorption of a parenterally-administered drug form is
accomplished by dissolving or suspending the drug in an oil
vehicle.
[0386] Injectable depot forms are made by forming microencapsule
matrices of the subject compounds in biodegradable polymers, such
as polylactide-polyglycolide. Depending on the ratio of drug to
polymer, and the nature of the particular polymer employed, the
rate of drug release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations are also prepared
by entrapping the drug in liposomes or microemulsions which are
compatible with body tissue.
[0387] When the compounds of the present invention are administered
as pharmaceuticals, to humans and animals, they can be given per se
or as a pharmaceutical composition containing, for example, 0.1 to
99% (more preferably, 10 to 30%) of active ingredient in
combination with a pharmaceutically acceptable carrier.
[0388] The preparations of the present invention may be given
orally, parenterally, topically, or rectally. They are of course
given in forms suitable for each administration route. For example,
they are administered in tablets or capsule form, by injection,
inhalation, eye lotion, ointment, suppository, administration by
injection, infusion or inhalation; topical by lotion or ointment;
and rectal by suppositories.
[0389] The phrases "parenteral administration" and "administered
parenterally" as used herein mean modes of administration other
than enteral and topical administration, usually by injection, and
include, without limitation, intravenous, intramuscular,
intraarterial, intrathecal, intracapsular, intraorbital,
intracardiac, intradermal, intraperitoneal, transtracheal,
subcutaneous, subcuticular, intraarticular, subcapsular,
subarachnoid, intraspinal and intrasternal injection and
infusion.
[0390] The phrases "systemic administration," "administered
systemically," "peripheral administration" and "administered
peripherally" as used herein mean the administration of a compound,
drug or other material other than directly into the central nervous
system, such that it enters the patient's system and, thus, is
subject to metabolism and other like processes, for example,
subcutaneous administration.
[0391] Compounds may be administered to humans and other animals
for therapy by any suitable route of administration, including
orally, nasally, as by, for example, a spray, rectally,
intravaginally, parenterally, intracisternally and topically, as by
powders, ointments or drops, including buccally and
sublingually.
[0392] Regardless of the route of administration selected, the
compounds of the present invention, which may be used in a suitable
hydrated form, and/or the pharmaceutical compositions of the
present invention, are formulated into pharmaceutically-acceptable
dosage forms by conventional methods known to those of skill in the
art.
[0393] Actual dosage levels of the active ingredients in the
pharmaceutical compositions of this invention may be varied so as
to obtain an amount of the active ingredient which is effective to
achieve the desired therapeutic response for a particular patient,
composition, and mode of administration, without being toxic to the
patient.
[0394] The selected dosage level will depend upon a variety of
factors including the activity of the particular compound of the
present invention employed, or the ester, salt or amide thereof,
the route of administration, the time of administration, the rate
of excretion or metabolism of the particular compound being
employed, the rate and extent of absorption, the duration of the
treatment, other drugs, compounds and/or materials used in
combination with the particular compound employed, the age, sex,
weight, condition, general health and prior medical history of the
patient being treated, and like factors well known in the medical
arts.
[0395] A physician or veterinarian having ordinary skill in the art
can readily determine and prescribe the effective amount of the
pharmaceutical composition required. For example, the physician or
veterinarian could start doses of the compounds of the invention
employed in the pharmaceutical composition at levels lower than
that required in order to achieve the desired therapeutic effect
and gradually increase the dosage until the desired effect is
achieved.
[0396] In general, a suitable daily dose of a compound of the
invention will be that amount of the compound which is the lowest
dose effective to produce a therapeutic effect. Such an effective
dose will generally depend upon the factors described above.
Generally, oral, intravenous, intracerebroventricular and
subcutaneous doses of the compounds of this invention for a
patient, when used for the indicated effects, will range from about
0.0001 to about 100 mg per kilogram of body weight per day.
[0397] Oral administration in humans is specifically contemplated
by the invention. Oral dosing in adult humans is typically on the
order of 0.05 grams (50 mg) to 10 grams per day, given as a single
dose or in divided doses. In one embodiment, oral dosing to adult
humans is 0.5 grams (500 mg) to 10 grams per day, given as a single
dose or in divided doses. In one embodiment, oral dosing to adult
humans is 0.5 to 8 grams per day, given as a single dose or in
divided doses. In one embodiment, oral dosing to adult humans is
0.5 to 6 grams per day, given as a single dose or in divided doses.
In one embodiment, oral dosing to adult humans is 0.5 to 4 grams
per day, given as a single dose or in divided doses. In one
embodiment, oral dosing to adult humans is 0.5 to 2 grams per day,
given as a single dose or in divided doses.
[0398] In one embodiment, oral dosing to adult humans is 0.5 to 1
gram per day, given as a single dose or in divided doses.
[0399] If desired, the effective daily dose of the active compound
may be administered as two, three, four, five, six or more
sub-doses administered separately at appropriate intervals
throughout the day, optionally, in unit dosage forms. Exemplary
dosing is one administration per day.
[0400] While it is possible for a compound of the present invention
to be administered alone, it is preferable to administer the
compound as a pharmaceutical formulation (composition).
[0401] The compounds according to the invention may be formulated
for administration in any convenient way for use in human or
veterinary medicine, by analogy with other pharmaceuticals.
[0402] In another aspect, the present invention provides
pharmaceutically acceptable compositions which comprise a
therapeutically effective amount of one or more of the subject
compounds, as described above, formulated together with one or more
pharmaceutically acceptable carriers (additives) and/or diluents.
As described in detail below, the pharmaceutical compositions of
the present invention may be specially formulated for
administration in solid or liquid form, including those adapted for
the following: (1) oral administration, for example, drenches
(aqueous or non-aqueous solutions or suspensions), tablets,
boluses, powders, granules, pastes for application to the tongue;
(2) parenteral administration, for example, by subcutaneous,
intramuscular or intravenous injection as, for example, a sterile
solution or suspension; (3) topical application, for example, as a
cream, ointment or spray applied to the skin, lungs, or mucous
membranes; or (4) intravaginally or intrarectally, for example, as
a pessary, cream or foam; (5) sublingually or buccally; (6)
ocularly; (7) transdermally; or (8) nasally.
[0403] The patient receiving this treatment is any animal in need,
including primates, in particular humans, and other mammals, such
as equines, cattle, swine and sheep; and poultry and pets in
general.
[0404] The compound of the invention can be administered as such or
in admixtures with pharmaceutically acceptable carriers and can
also be administered in conjunction with at least one other active
compound. Conjunctive therapy thus includes sequential,
simultaneous and separate administration of the active compound in
a way that the therapeutical effects of the first administered one
is not entirely disappeared when the subsequent is
administered.
[0405] Micelles.
[0406] Microemulsification technology improves bioavailability of
some lipophilic (water insoluble) pharmaceutical agents. Examples
include Trimetrine (Dordunoo, S. K., et al., Drug Development and
Industrial Pharmacy, 17(12), 1685-1713, 1991 and REV 5901 (Sheen,
P. C., et al., J Pharm Sci 80(7), 712-714, 1991). Among other
things, microemulsification provides enhanced bioavailability by
preferentially directing absorption to the lymphatic system instead
of the circulatory system, which thereby bypasses the liver, and
prevents destruction of the compounds in the hepatobiliary
circulation.
[0407] While all suitable amphiphilic carriers are contemplated,
exemplary carriers are generally those that have
Generally-Recognized-as-Safe (GRAS) status, and that can both
solubilize the compound of the present invention and microemulsify
it at a later stage when the solution comes into a contact with a
complex water phase (such as one found in human gastro-intestinal
tract). Usually, amphiphilic ingredients that satisfy these
requirements have HLB (hydrophilic to lipophilic balance) values of
2-20, and their structures contain straight chain aliphatic
radicals in the range of C-6 to C-20. Examples are
polyethylene-glycolized fatty glycerides and polyethylene
glycols.
[0408] Commercially available amphiphilic carriers are particularly
contemplated, including Gelucire-series, Labrafil, Labrasol, or
Lauroglycol (all manufactured and distributed by Gattefosse
Corporation, Saint Priest, France), PEG-mono-oleate, PEG-di-oleate,
PEG-mono-laurate and di-laurate, Lecithin, Polysorbate 80, etc
(produced and distributed by a number of companies in USA and
worldwide).
[0409] Polymers.
[0410] Hydrophilic polymers suitable for use in the present
invention are those which are readily water-soluble, can be
covalently attached to a vesicle-forming lipid, and which are
tolerated in vivo without toxic effects (i.e., are biocompatible).
Suitable polymers include polyethylene glycol (PEG), polylactic
(also termed polylactide), polyglycolic acid (also termed
polyglycolide), a polylactic-polyglycolic acid copolymer, and
polyvinyl alcohol. Exemplary polymers are those having a molecular
weight of from about 100 or 120 Daltons up to about 5,000 or 10,000
Daltons, and more preferably from about 300 Daltons to about 5,000
Daltons. In one embodiment, the polymer is polyethyleneglycol
having a molecular weight of from about 100 to about 5,000 Daltons,
and more preferably having a molecular weight of from about 300 to
about 5,000 Daltons. In one embodiment, the polymer is
polyethyleneglycol of 750 Daltons (PEG(750)). Polymers may also be
defined by the number of monomers therein; an embodiment of the
present invention utilizes polymers of at least about three
monomers, such PEG polymers consisting of three monomers
(approximately 150 Daltons).
[0411] Other hydrophilic polymers which may be suitable for use in
the present invention include polyvinylpyrrolidone,
polymethoxazoline, polyethyloxazoline, polyhydroxypropyl
methacrylamide, polymethacrylamide, polydimethylacrylamide, and
derivatized celluloses such as hydroxymethylcellulose or
hydroxyethylcellulose.
[0412] In certain embodiments, a formulation of the present
invention comprises a biocompatible polymer selected from the group
consisting of polyamides, polycarbonates, polyalkylenes, polymers
of acrylic and methacrylic esters, polyvinyl polymers,
polyglycolides, polysiloxanes, polyurethanes and co-polymers
thereof, celluloses, polypropylene, polyethylenes, polystyrene,
polymers of lactic acid and glycolic acid, polyanhydrides,
poly(ortho)esters, poly(butic acid), poly(valeric acid),
poly(lactide-co-caprolactone), polysaccharides, proteins,
polyhyaluronic acids, polycyanoacrylates, and blends, mixtures, or
copolymers thereof.
[0413] Cyclodextrins.
[0414] Cyclodextrins are cyclic oligosaccharides, consisting of 6,
7 or 8 glucose units, designated by the Greek letters alpha, beta
and gamma, respectively. The glucose units are linked by
alpha-1,4-glucosidic bonds. As a consequence of the chair
conformation of the sugar units, all secondary hydroxyl groups (at
C-2, C-3) are located on one side of the ring, while all the
primary hydroxyl groups at C-6 are situated on the other side. As a
result, the external faces are hydrophilic, making the
cyclodextrins water-soluble. In contrast, the cavities of the
cyclodextrins are hydrophobic, since they are lined by the hydrogen
of atoms C-3 and C-5, and by ether-like oxygens. These matrices
allow complexation with a variety of relatively hydrophobic
compounds, including, for instance, steroid compounds such as
17-beta-estradiol (see, e.g., van Uden et al. Plant Cell Tiss. Org.
Cult. 38:1-3-113 (1994)). The complexation takes place by Van der
Waals interactions and by hydrogen bond formation. For a general
review of the chemistry of cyclodextrins, see, Wenz, Agnew. Chem.
Int. Ed. Engl., 33:803-822 (1994).
[0415] The physico-chemical properties of the cyclodextrin
derivatives depend strongly on the kind and the degree of
substitution. For example, their solubility in water ranges from
insoluble (e.g., triacetyl-beta-cyclodextrin) to 147% soluble (w/v)
(G-2-beta-cyclodextrin). In addition, they are soluble in many
organic solvents. The properties of the cyclodextrins enable the
control over solubility of various formulation components by
increasing or decreasing their solubility.
[0416] Numerous cyclodextrins and methods for their preparation
have been described. For example, Parmeter (I), et al. (U.S. Pat.
No. 3,453,259; incorporated by reference) and Gramera, et al. (U.S.
Pat. No. 3,459,731; incorporated by reference) describe
electroneutral cyclodextrins. Other derivatives include
cyclodextrins with cationic properties (Parmeter (II), U.S. Pat.
No. 3,453,257; incorporated by reference), insoluble crosslinked
cyclodextrins (Solms, U.S. Pat. No. 3,420,788; incorporated by
reference), and cyclodextrins with anionic properties (Parmeter
(III), U.S. Pat. No. 3,426,011; incorporated by reference). Among
the cyclodextrin derivatives with anionic properties, carboxylic
acids, phosphorous acids, phosphinous acids, phosphonic acids,
phosphoric acids, thiophosphonic acids, thiosulphinic acids, and
sulfonic acids have been appended to the parent cyclodextrin (see,
Parmeter (III), supra). Furthermore, sulfoalkyl ether cyclodextrin
derivatives have been described by Stella, et al. (U.S. Pat. No.
5,134,127; incorporated by reference).
[0417] Liposomes.
[0418] Liposomes consist of at least one lipid bilayer membrane
enclosing an aqueous internal compartment. Liposomes may be
characterized by membrane type and by size. Small unilamellar
vesicles (SUVs) have a single membrane and typically range between
0.02 and 0.05 .mu.m in diameter; large unilamellar vesicles (LUVS)
are typically larger than 0.05 .mu.m. Oligolamellar large vesicles
and multilamellar vesicles have multiple, usually concentric,
membrane layers and are typically larger than 0.1 .mu.m. Liposomes
with several nonconcentric membranes, i.e., several smaller
vesicles contained within a larger vesicle, are termed
multivesicular vesicles.
[0419] One aspect of the present invention relates to formulations
comprising liposomes containing a compound of the present
invention, where the liposome membrane is formulated to provide a
liposome with increased carrying capacity. Alternatively or in
addition, the compound of the present invention may be contained
within, or adsorbed onto, the liposome bilayer of the liposome. The
compound of the present invention may be aggregated with a lipid
surfactant and carried within the liposome's internal space; in
these cases, the liposome membrane is formulated to resist the
disruptive effects of the active agent-surfactant aggregate.
[0420] According to one embodiment of the present invention, the
lipid bilayer of a liposome contains lipids derivatized with
polyethylene glycol (PEG), such that the PEG chains extend from the
inner surface of the lipid bilayer into the interior space
encapsulated by the liposome, and extend from the exterior of the
lipid bilayer into the surrounding environment.
[0421] Active agents contained within liposomes of the present
invention are in solubilized form. Aggregates of surfactant and
active agent (such as emulsions or micelles containing the active
agent of interest) may be entrapped within the interior space of
liposomes according to the present invention. A surfactant acts to
disperse and solubilize the active agent, and may be selected from
any suitable aliphatic, cycloaliphatic or aromatic surfactant,
including but not limited to biocompatible lysophosphatidylcholines
(LPCs) of varying chain lengths (for example, from about C14 to
about C20). Polymer-derivatized lipids such as PEG-lipids may also
be utilized for micelle formation as they will act to inhibit
micelle/membrane fusion, and as the addition of a polymer to
surfactant molecules decreases the critical micelle concentration
(CMC) of the surfactant and aids in micelle formation. Examples are
surfactants with CMCs in the micromolar range; higher CMC
surfactants may be utilized to prepare micelles entrapped within
liposomes of the present invention, however, micelle surfactant
monomers could affect liposome bilayer stability and would be a
factor in designing a liposome of a desired stability.
[0422] Liposomes useful in the present invention may be prepared by
any of a variety of techniques that are known in the art. See,
e.g., U.S. Pat. No. 4,235,871; Published PCT applications WO
96/14057; New RRC, Liposomes: A practical approach, IRL Press,
Oxford (1990), pages 33-104; Lasic D D, Liposomes from physics to
applications, Elsevier Science Publishers BV, Amsterdam, 1993.
[0423] For example, liposomes useful in the present invention may
be prepared by diffusing a lipid derivatized with a hydrophilic
polymer into preformed liposomes, such as by exposing preformed
liposomes to micelles composed of lipid-grafted polymers, at lipid
concentrations corresponding to the final mole percent of
derivatized lipid which is desired in the liposome. Liposomes
containing a hydrophilic polymer can also be formed by
homogenization, lipid-field hydration, or extrusion techniques, as
are known in the art.
[0424] In one aspect of the present invention, the liposomes have
substantially homogeneous sizes in a selected size range. One
effective sizing method involves extruding an aqueous suspension of
the liposomes through a series of polycarbonate membranes having a
selected uniform pore size; the pore size of the membrane will
correspond roughly with the largest sizes of liposomes produced by
extrusion through that membrane. See e.g., U.S. Pat. No.
4,737,323.
[0425] Release Modifiers.
[0426] The release characteristics of a formulation of the present
invention depend on the encapsulating material, the concentration
of encapsulated drug, and the presence of release modifiers. For
example, release can be manipulated to be pH dependent using a pH
sensitive coating that releases only at a low pH, as in the
stomach, or a higher pH, as in the intestine. An enteric coating
can be used to prevent release from occurring until after passage
through the stomach. Multiple coatings or mixtures of cyanamide
encapsulated in different materials can be used to obtain an
initial release in the stomach, followed by later release in the
intestine. Release can also be manipulated by inclusion of salts or
pore forming agents, which can increase water uptake or release of
drug by diffusion from the capsule. Excipients which modify the
solubility of the drug can also be used to control the release
rate. Agents which enhance degradation of the matrix or release
from the matrix can also be incorporated. They can be added to the
drug, added as a separate phase (i.e., as particulates), or can be
co-dissolved in the polymer phase depending on the compound. In all
cases the amount should be between 0.1 and thirty percent (w/w
polymer). Types of degradation enhancers include inorganic salts,
such as ammonium sulfate and ammonium chloride, organic acids, such
as citric acid, benzoic acid, and ascorbic acid, inorganic bases,
such as sodium carbonate, potassium carbonate, calcium carbonate,
zinc carbonate, and zinc hydroxide, and organic bases, such as
protamine sulfate, spermine, choline, ethanolamine, diethanolamine,
and triethanolamine and surfactants, such as Tween.RTM. and
Pluronic.RTM.. Pore forming agents which add microstructure to the
matrices (i.e., water soluble compounds, such as inorganic salts
and sugars) are added as particulates. The range should be between
one and thirty percent (w/w polymer).
[0427] Uptake can also be manipulated by altering residence time of
the particles in the gut. This can be achieved, for example, by
coating the particle with, or selecting as the encapsulating
material, a mucosal adhesive polymer. Examples include most
polymers with free carboxyl groups, such as chitosan, celluloses,
and especially polyacrylates (as used herein, polyacrylates refers
to polymers including acrylate groups and modified acrylate groups
such as cyanoacrylates and methacrylates).
[0428] One aspect of the invention relates to a pharmaceutical
composition, comprising a compound of the present invention or a
pharmaceutically acceptable salt thereof; and a pharmaceutically
acceptable excipient.
[0429] In certain embodiments, the present invention relates to any
one of the aforementioned pharmaceutical compositions, wherein the
pharmaceutical preparation has an EC.sub.50 for reducing serum
cholesterol, LDL and/or triglycerides which, in the average human
patient population, is no more than 20 percent of the half maximal
concentration of pharmaceutical preparation which would cause
cutaneous vasodilation (flushing) in the average patient
population.
[0430] In certain embodiments, the present invention relates to any
one of the aforementioned pharmaceutical compositions, wherein the
EC.sub.50 for reducing serum cholesterol, LDL and/or triglycerides
is no more than 1 percent of the half maximal concentration of
pharmaceutical preparation which would cause cutaneous vasodilation
(flushing) in the average patient population.
[0431] In certain embodiments, the present invention relates to any
one of the aforementioned pharmaceutical compositions, wherein the
pharmaceutical preparation has an EC.sub.50 for reducing serum
cholesterol, LDL and/or triglycerides which, in the average human
patient population, is no more than 20 percent of the concentration
of pharmaceutical preparation which would cause increases in serum
levels of aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) requiring discontinuation of administration
of the pharmaceutical preparation.
[0432] In certain embodiments, the present invention relates to any
one of the aforementioned pharmaceutical compositions, wherein said
composition is effective in reducing a serum lipid without causing
treatment-limiting (i) hepatotoxicity and (ii) elevations in uric
acid levels or glucose levels or both, following administration to
said patient that would require such treatment to be discontinued
when said composition is ingested by said patient once per day.
[0433] In certain embodiments, the present invention relates to any
one of the aforementioned pharmaceutical compositions formulated in
combination with a statin.
[0434] In certain embodiments, the present invention relates to any
one of the aforementioned pharmaceutical compositions, wherein the
statin is selected from the group consisting of atorvastatin,
cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin,
pravastatin, rosuvastatin and simvastatin.
[0435] In certain embodiments, the present invention relates to any
one of the aforementioned pharmaceutical compositions formulated in
combination with at least one additional therapeutic agent selected
from the group consisting of 11.beta. HSD-1 inhibitors, 5HT
transporter inhibitors, 5HT2c agonists, 5-LO or FLAP inhibitors,
.alpha.-glucosidase inhibitors, ABCA1 enhancers, ACC inhibitors,
AcylCoA:cholesterol O-acyltransferase inhibitors, acyl-estrogens,
antidiabetic agents, anti-dyslipidemic agents, anti-hypertensive
agents, anti-oxidants, Apo A1 mimetics, Apo A1 modulators, Apo E
mimetics, apolipoprotein-B secretion/microsomal triglyceride
transfer protein (apo-B/MTP) inhibitors, appetite suppressants,
aspirin, .beta.3 agonists, bile acid reabsorption inhibitors, bile
acid sequestrants, bombesin agonists, BRS3 agonists, CB.sub.1
antagonists/inverse agonists, CCK-A agonists, cholesterol
absorption inhibitor, cholesterol transport inhibitors, cholesteryl
ester transfer protein (CETP) inhibitors, CNTF, CNTF
agonists/modulators, a combination of ezetimibe and simvastatin
and/or atorvastatin, CSL-111, dehydroepiandrosterone, delipidated
HDL, DGAT antisense oligos, DGAT1 inhibitors, DGAT2 inhibitors,
dicarboxylate transporter inhibitors, dopamine agonists, DP
receptor antagonists, ezetimibe, FAS inhibitors, fatty acid binding
protein (FABP) inhibitors, fatty acid transporter inhibitors, fatty
acid transporter protein (FATP) inhibitors, flush inhibitors, FXR
receptor modulators, galanin receptor antagonists, gemcabene,
ghrelin antagonists, ghrelin antibodies, GLP-1 agonists,
glucagon-like peptide-1 receptor agonists, glucocorticoid
agonists/antagonists, glucose transporter inhibitors, HDL mimetics,
HMG CoA reductase inhibitor compounds, HMG-CoA synthetase
inhibitors, hormone sensitive lipase antagonists, human
agouti-related proteins (AGRP), H.sub.3 antagonists/inverse
agonists, inorganic cholesterol sequestrants, L-4f, lapaquistat,
leptin agonists/modulators, leptins, lipase inhibitors, lipoprotein
synthesis inhibitors, lorapoprant, low density lipoprotein receptor
inducers or activators, Lp(a) reducers, LXR receptor agonists, lyn
kinase inhibitor, Mc3r agonists, Mc4r agonists, MCH1R antagonists,
MCH2R agonists/antagonists, melanin concentrating hormone
antagonists, mGluR5 antagonists, microsomal triglyceride transport
inhibitors, monoamine reuptake inhibitors, natural water soluble
fibers, NE transporter inhibitors, neuromedin U receptor agonists,
neuropeptide-Y antagonists, niacin or niacin receptor agonists,
nicotinic acid, noradrenergic anorectic agents, NPY1 antagonists,
NPY2 agonists, NPY4 agonists, NPY5 antagonists, non-steroidal
anti-inflammatory drug (NSAID) agents, omega-3 fatty acids, opioid
antagonists, orexin receptor antagonists, PDE inhibitors,
phentermine, phosphate transporter inhibitors, phytopharm compound
57, plant stanols and/or fatty acid esters of plant stanols,
platelet aggregation inhibitors, PPAR-.alpha. agonists,
PPAR-.delta. agonists, PPAR-.delta. partial agonists, PPAR-.gamma.
agonists, probucol, renin angiotensin inhibitors, reversed-4F,
SCD-1 inhibitors, serotonin reuptake inhibitors, SGLT2 inhibitors,
squalene epoxidase inhibitors, squalene synthesis inhibitors,
sterol biosynthesis inhibitors, sympathomimetic agonists, thyroid
hormone .beta. agonists, thyromimetic agents, topiramate,
triglyceride synthesis inhibitors, UCP-1 activators, UCP-2
activators, UCP-3 activators, and urocortin binding protein
antagonists.
[0436] In certain embodiments, the present invention relates to a
pharmaceutical composition, comprising a compound of the present
invention or a pharmaceutically acceptable salt thereof; niacin;
and a pharmaceutically acceptable excipient.
[0437] In certain embodiments, the present invention relates to a
pharmaceutical composition, comprising a compound of the present
invention or a pharmaceutically acceptable salt thereof; niacin; a
statin selected from the group consisting of atorvastatin,
cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin,
pravastatin, rosuvastatin and simvastatin; and a pharmaceutically
acceptable excipient.
[0438] In certain embodiments, the present invention relates to a
pharmaceutical composition, comprising a compound of the present
invention or a pharmaceutically acceptable salt thereof; a
glitazone selected from the group consisting of troglitazone,
rosiglitazone, and pioglitazone; and a pharmaceutically acceptable
excipient.
[0439] In certain embodiments, the present invention relates to a
pharmaceutical composition, comprising a compound of the present
invention or a pharmaceutically acceptable salt thereof; niacin; a
glitazone selected from the group consisting of troglitazone,
rosiglitazone, and pioglitazone; and a pharmaceutically acceptable
excipient.
[0440] In certain embodiments, the present invention relates to a
pharmaceutical composition, comprising a compound of the present
invention or a pharmaceutically acceptable salt thereof; a fibrate
selected from the group consisting of fenofibrate and bezafibrate;
and a pharmaceutically acceptable excipient.
[0441] In certain embodiments, the present invention relates to a
pharmaceutical composition, comprising a compound of the present
invention or a pharmaceutically acceptable salt thereof; niacin; a
fibrate selected from the group consisting of fenofibrate and
bezafibrate; and a pharmaceutically acceptable excipient.
Methods
[0442] An aspect of the invention relates to a method of treating a
disease, disorder, or condition selected from the group consisting
of hyperlipidemia, hypercholesterolemia, lipodystrophy,
dyslipidemia, atherosclerosis and coronary artery disease,
comprising the step of administering to a mammal in need thereof a
therapeutically effective amount of a compound of the present
invention or a pharmaceutically acceptable salt thereof. In one
embodiment, the mammal is a human.
[0443] An aspect of the invention relates to a method of treating a
disease, disorder, or condition selected from the group consisting
of hyperlipidemia, hypercholesterolemia, lipodystrophy,
dyslipidemia, atherosclerosis and coronary artery disease,
comprising the step of administering to a mammal in need thereof a
therapeutically effective amount of a pharmaceutical composition of
the present invention. In one embodiment, the mammal is a
human.
[0444] An aspect of the invention relates to a method of treating a
disease, disorder, or condition selected from the group consisting
of metabolic syndrome, obesity, fatty liver disease, and diabetes,
comprising the step of administering to a mammal in need thereof a
therapeutically effective amount of a compound of the present
invention or a pharmaceutically acceptable salt thereof. In one
embodiment, the mammal is a human.
[0445] An aspect of the invention relates to a method of treating a
disease, disorder, or condition selected from the group consisting
of metabolic syndrome, obesity, fatty liver disease, and diabetes,
comprising the step of administering to a mammal in need thereof a
therapeutically effective amount of a pharmaceutical composition of
the present invention. In one embodiment, the mammal is a
human.
[0446] An aspect of the invention relates to a method of raising
serum high-density lipoprotein (HDL) levels, comprising the step
of: administering to a mammal in need thereof a therapeutically
effective amount of a compound of the present invention or a
pharmaceutically acceptable salt thereof. In one embodiment, the
mammal is a human.
[0447] An aspect of the invention relates to a method of raising
serum high-density lipoprotein (HDL) levels, comprising the step
of: administering to a mammal in need thereof a therapeutically
effective amount of a pharmaceutical composition of the present
invention. In one embodiment, the mammal is a human.
[0448] An aspect of the invention relates to a method of lowering
serum low-density lipoprotein (LDL) levels or lowering serum
lipoprotein (a) levels, comprising the step of administering to a
mammal in need thereof a therapeutically effective amount of a
compound of the present invention or a pharmaceutically acceptable
salt thereof. In one embodiment, the mammal is a human.
[0449] An aspect of the invention relates to a method of lowering
serum low-density lipoprotein (LDL) levels or lowering serum
lipoprotein (a) levels, comprising the step of administering to a
mammal in need thereof a therapeutically effective amount of a
pharmaceutical composition of the present invention. In one
embodiment, the mammal is a human.
[0450] An aspect of the invention relates to a method of treating a
disease, disorder, or condition selected from the group consisting
of congestive heart failure, cardiovascular disease, hypertension,
coronary heart disease, angina, pellagra, Hartnup's syndrome,
carcinoid syndrome, arterial occlusive disease, hypothyroidism,
vasoconstriction, osteoarthritis, rheumatoid arthritis, Alzheimer's
disease, disorders of the peripheral and central nervous system,
hematological diseases, cancer, inflammation, respiratory diseases,
and gastroenterological diseases, comprising the step of
administering to a mammal in need thereof a compound of the present
invention or a pharmaceutically acceptable salt thereof. In one
embodiment, the mammal is a human.
[0451] An aspect of the invention relates to a method of treating a
disease, disorder, or condition selected from the group consisting
of congestive heart failure, cardiovascular disease, hypertension,
coronary heart disease, angina, pellagra, Hartnup's syndrome,
carcinoid syndrome, arterial occlusive disease, hypothyroidism,
vasoconstriction, osteoarthritis, rheumatoid arthritis, Alzheimer's
disease, disorders of the peripheral and central nervous system,
hematological diseases, cancer, inflammation, respiratory diseases,
and gastroenterological diseases, comprising the step of
administering to a mammal in need thereof a pharmaceutical
composition of the present invention. In one embodiment, the mammal
is a human.
[0452] In certain embodiments, the present invention relates to any
one of the aforementioned methods, further comprising
co-administering a therapeutically effective amount of a statin. In
one such embodiment, the co-administering is co-administering
orally.
[0453] In certain embodiments, the present invention relates to any
one of the aforementioned methods, further comprising
co-administering a therapeutically effective amount of a statin;
wherein the statin is selected from the group consisting of
atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,
pitavastatin, pravastatin, rosuvastatin and simvastatin. In one
such embodiment, the co-administering is co-administering
orally.
[0454] In certain embodiments, the present invention relates to any
one of the aforementioned methods, further comprising
co-administering a therapeutically effective amount of at least one
additional therapeutic agent selected from the group consisting of
11.beta. HSD-1 inhibitors, 5HT transporter inhibitors, 5HT2c
agonists, 5-LO or FLAP inhibitors, .alpha.-glucosidase inhibitors,
ABCA1 enhancers, ACC inhibitors, AcylCoA:cholesterol
O-acyltransferase inhibitors, acyl-estrogens, antidiabetic agents,
anti-dyslipidemic agents, anti-hypertensive agents, anti-oxidants,
Apo A1 mimetics, Apo A1 modulators, Apo E mimetics,
apolipoprotein-B secretion/microsomal triglyceride transfer protein
(apo-B/MTP) inhibitors, appetite suppressants, aspirin, .beta.3
agonists, bile acid reabsorption inhibitors, bile acid
sequestrants, bombesin agonists, BRS3 agonists, CB.sub.1
antagonists/inverse agonists, CCK-A agonists, cholesterol
absorption inhibitor, cholesterol transport inhibitors, cholesteryl
ester transfer protein (CETP) inhibitors, CNTF, CNTF
agonists/modulators, a combination of ezetimibe and simvastatin
and/or atorvastatin, CSL-111, dehydroepiandrosterone, delipidated
HDL, DGAT antisense oligos, DGAT1 inhibitors, DGAT2 inhibitors,
dicarboxylate transporter inhibitors, dopamine agonists, DP
receptor antagonists, ezetimibe, FAS inhibitors, fatty acid binding
protein (FABP) inhibitors, fatty acid transporter inhibitors, fatty
acid transporter protein (FATP) inhibitors, flush inhibitors, FXR
receptor modulators, galanin receptor antagonists, gemcabene,
ghrelin antagonists, ghrelin antibodies, GLP-1 agonists,
glucagon-like peptide-1 receptor agonists, glucocorticoid
agonists/antagonists, glucose transporter inhibitors, HDL mimetics,
HMG CoA reductase inhibitor compounds, HMG-CoA synthetase
inhibitors, hormone sensitive lipase antagonists, human
agouti-related proteins (AGRP), H.sub.3 antagonists/inverse
agonists, inorganic cholesterol sequestrants, L-4f, lapaquistat,
leptin agonists/modulators, leptins, lipase inhibitors, lipoprotein
synthesis inhibitors, lorapoprant, low density lipoprotein receptor
inducers or activators, Lp(a) reducers, LXR receptor agonists, lyn
kinase inhibitor, Mc3r agonists, Mc4r agonists, MCH1R antagonists,
MCH2R agonists/antagonists, melanin concentrating hormone
antagonists, mGluR5 antagonists, microsomal triglyceride transport
inhibitors, monoamine reuptake inhibitors, natural water soluble
fibers, NE transporter inhibitors, neuromedin U receptor agonists,
neuropeptide-Y antagonists, niacin or niacin receptor agonists,
nicotinic acid, noradrenergic anorectic agents, NPY1 antagonists,
NPY2 agonists, NPY4 agonists, NPY5 antagonists, non-steroidal
anti-inflammatory drug (NSAID) agents, omega-3 fatty acids, opioid
antagonists, orexin receptor antagonists, PDE inhibitors,
phentermine, phosphate transporter inhibitors, phytopharm compound
57, plant stanols and/or fatty acid esters of plant stanols,
platelet aggregation inhibitors, PPAR-.alpha. agonists,
PPAR-.delta. agonists, PPAR-.delta. partial agonists, PPAR-.gamma.
agonists, probucol, renin angiotensin inhibitors, reversed-4F,
SCD-1 inhibitors, serotonin reuptake inhibitors, SGLT2 inhibitors,
squalene epoxidase inhibitors, squalene synthesis inhibitors,
sterol biosynthesis inhibitors, sympathomimetic agonists, thyroid
hormone .beta. agonists, thyromimetic agents, topiramate,
triglyceride synthesis inhibitors, UCP-1 activators, UCP-2
activators, UCP-3 activators, and urocortin binding protein
antagonists. In one such embodiment, the co-administering is
co-administering orally.
[0455] In certain embodiments, the present invention relates to any
one of the aforementioned methods, further comprising
co-administering a therapeutically effective amount of at least one
additional therapeutic agent selected from the group consisting of
HMG CoA reductase inhibitors, aspirin, cholesteryl ester transfer
protein inhibitors, NSAIDs, fibrates, a proprotein convertase
subtilisin/kexin type (PCSK9), inorganic cholesterol sequestrants,
AcylCoA:cholesterol O-acyltransferase inhibitors, CETP inhibitors,
PPAR .alpha. agonists, PPAR .gamma. agonists, bile acid
reabsorption inhibitors, triglyceride synthesis inhibitors,
lipoprotein receptor activators, DGAT1 inhibitors, SCD-1
inhibitors, lipase inhibitors, DP receptor antagonists, apo A1
modulators, cholesterol transport inhibitors, metformin, niacin
receptor modulators, and DPP-IV inhibitors. In one such embodiment,
the co-administering is co-administering orally.
[0456] In certain embodiments, the present invention relates to any
one of the aforementioned methods, further comprising
co-administering a therapeutically effective amount of at least one
additional therapeutic agent selected from the group consisting of
HMG CoA reductase inhibitors, cholesteryl ester transfer protein
inhibitors, aspirin, NSAIDs, fibrates, DP receptor antagonists,
ezetimibe or a combination of ezetimibe and simvastatin. In one
such embodiment, the co-administering is co-administering
orally.
[0457] In certain embodiments, the present invention relates to any
one of the aforementioned methods, further comprising
co-administering a therapeutically effective amount of at least one
HMG CoA reductase inhibitor selected from lovastatin, simvastatin,
pravastatin, atorvastatin, fluvastatin, cerivastatin, rivastatin,
rosuvastatin calcium and pitavastatin. In one such embodiment, the
co-administering is co-administering orally.
[0458] In certain embodiments, the present invention relates to any
one of the aforementioned methods, further comprising
co-administering simvastatin. In one such embodiment, the
co-administering is co-administering orally.
[0459] In certain embodiments, the present invention relates to any
one of the aforementioned methods, further comprising
co-administering a cholesteryl ester transfer protein inhibitor. In
one such embodiment, the co-administering is co-administering
orally.
[0460] In certain embodiments, the present invention relates to any
one of the aforementioned methods, further comprising
co-administering ezetimibe, aspirin, ibuprofen, acetaminophen, or a
combination of ezetimibe and simvastatin. In one such embodiment,
the co-administering is co-administering orally.
[0461] An aspect of the invention relates to a method of treating
hyperlipidemia, comprising the step of co-administering to a mammal
in need thereof a therapeutically effective amount of a compound of
the present invention; and a therapeutically effective amount of
niacin. In one embodiment, the co-administering is co-administering
orally. In one embodiment, the mammal is a human.
[0462] An aspect of the invention relates to a method of treating
hyperlipidemia, comprising the step of co-administering to a mammal
in need thereof a therapeutically effective amount of a
pharmaceutical composition of the present invention; and a
therapeutically effective amount of niacin. In one embodiment, the
co-administering is co-administering orally. In one embodiment, the
mammal is a human.
[0463] An aspect of the invention relates to a method of raising
serum high-density lipoprotein (HDL) levels in a mammal, comprising
the step of co-administering to a mammal in need thereof a
therapeutically effective amount of a compound of the present
invention; and a therapeutically effective amount of niacin. In one
embodiment, the co-administering is co-administering orally. In one
embodiment, the mammal is a human.
[0464] An aspect of the invention relates to a method of raising
serum high-density lipoprotein (HDL) levels in a mammal, comprising
the step of co-administering to a mammal in need thereof a
therapeutically effective amount of a pharmaceutical composition of
the present invention; and a therapeutically effective amount of
niacin. In one embodiment, the co-administering is co-administering
orally. In one embodiment, the mammal is a human.
[0465] An aspect of the invention relates to a method of lowering
serum low-density lipoprotein (LDL) levels in a mammal, comprising
the step of co-administering to a mammal in need thereof a
therapeutically effective amount of a compound of the present
invention; and a therapeutically effective amount of niacin. In one
embodiment, the co-administering is co-administering orally. In one
embodiment, the mammal is a human.
[0466] An aspect of the invention relates to a method of lowering
serum low-density lipoprotein (LDL) levels in a mammal, comprising
the step of co-administering to a mammal in need thereof a
therapeutically effective amount of a pharmaceutical composition of
the present invention; and a therapeutically effective amount of
niacin. In one embodiment, the co-administering is co-administering
orally. In one embodiment, the mammal is a human.
[0467] An aspect of the invention relates to a method of lowering
serum lipoprotein (a) (Lp(a)) levels in a mammal, comprising the
step of co-administering to a mammal in need thereof a
therapeutically effective amount of a compound of the present
invention; and a therapeutically effective amount of niacin. In one
embodiment, the co-administering is co-administering orally. In one
embodiment, the mammal is a human.
[0468] An aspect of the invention relates to a method of lowering
serum lipoprotein (a) (Lp(a)) levels in a mammal, comprising the
step of co-administering to a mammal in need thereof a
therapeutically effective amount of a pharmaceutical composition of
the present invention; and a therapeutically effective amount of
niacin. In one embodiment, the co-administering is co-administering
orally. In one embodiment, the mammal is a human.
[0469] An aspect of the invention relates to a method of treating
hyperlipidemia, hypercholesterolemia, atherosclerosis, coronary
artery disease, congestive heart failure, cardiovascular disease,
hypertension, coronary heart disease, angina, pellagra, Hartnup's
syndrome, carcinoid syndrome, arterial occlusive disease, obesity,
hypothyroidism, vasoconstriction, osteoarthritis, rheumatoid
arthritis, diabetes, Alzheimer's disease, lipodystrophy, or
dyslipidemia, comprising the step of co-administering to a mammal
in need thereof a therapeutically effective amount of a compound of
the present invention; a therapeutically effective amount of
niacin; and a therapeutically effective amount of a statin selected
from the group consisting of atorvastatin, cerivastatin,
fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,
rosuvastatin and simvastatin. In one embodiment, the
co-administering is co-administering orally. In one embodiment, the
mammal is a human.
[0470] An aspect of the invention relates to a method of treating
hyperlipidemia, hypercholesterolemia, atherosclerosis, coronary
artery disease, congestive heart failure, cardiovascular disease,
hypertension, coronary heart disease, angina, pellagra, Hartnup's
syndrome, carcinoid syndrome, arterial occlusive disease, obesity,
hypothyroidism, vasoconstriction, osteoarthritis, rheumatoid
arthritis, diabetes, Alzheimer's disease, lipodystrophy, or
dyslipidemia, comprising the step of co-administering to a mammal
in need thereof a therapeutically effective amount of a
pharmaceutical composition of the present invention; a
therapeutically effective amount of niacin; and a therapeutically
effective amount of a statin selected from the group consisting of
atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,
pitavastatin, pravastatin, rosuvastatin and simvastatin. In one
embodiment, the co-administering is co-administering orally. In one
embodiment, the mammal is a human.
[0471] An aspect of the invention relates to a method of treating
hyperlipidemia, comprising the step of co-administering to a mammal
in need thereof a therapeutically effective amount of a compound of
the present invention; a therapeutically effective amount of
niacin; and a therapeutically effective amount of a statin selected
from the group consisting of atorvastatin, cerivastatin,
fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,
rosuvastatin and simvastatin. In one embodiment, the
co-administering is co-administering orally. In one embodiment, the
mammal is a human.
[0472] An aspect of the invention relates to a method of treating
hyperlipidemia, comprising the step of co-administering to a mammal
in need thereof a therapeutically effective amount of a
pharmaceutical composition of the present invention; a
therapeutically effective amount of niacin; and a therapeutically
effective amount of a statin selected from the group consisting of
atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin,
pitavastatin, pravastatin, rosuvastatin and simvastatin. In one
embodiment, the co-administering is co-administering orally. In one
embodiment, the mammal is a human.
[0473] An aspect of the invention relates to a method of raising
serum high-density lipoprotein (HDL) levels in a mammal, comprising
the step of co-administering to a mammal in need thereof a
therapeutically effective amount of a compound of the present
invention; a therapeutically effective amount of niacin; and a
therapeutically effective amount of a statin selected from the
group consisting of atorvastatin, cerivastatin, fluvastatin,
lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and
simvastatin. In one embodiment, the co-administering is
co-administering orally. In one embodiment, the mammal is a
human.
[0474] An aspect of the invention relates to a method of raising
serum high-density lipoprotein (HDL) levels in a mammal, comprising
the step of co-administering to a mammal in need thereof a
therapeutically effective amount of a pharmaceutical composition of
the present invention; a therapeutically effective amount of
niacin; and a therapeutically effective amount of a statin selected
from the group consisting of atorvastatin, cerivastatin,
fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,
rosuvastatin and simvastatin. In one embodiment, the
co-administering is co-administering orally. In one embodiment, the
mammal is a human.
[0475] An aspect of the invention relates to a method of lowering
serum low-density lipoprotein (LDL) levels in a mammal, comprising
the step of co-administering to a mammal in need thereof a
therapeutically effective amount of a compound of the present
invention; a therapeutically effective amount of niacin; and a
therapeutically effective amount of a statin selected from the
group consisting of atorvastatin, cerivastatin, fluvastatin,
lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and
simvastatin. In one embodiment, the co-administering is
co-administering orally. In one embodiment, the mammal is a
human.
[0476] An aspect of the invention relates to a method of lowering
serum low-density lipoprotein (LDL) levels in a mammal, comprising
the step of co-administering to a mammal in need thereof a
therapeutically effective amount of a pharmaceutical composition of
the present invention; a therapeutically effective amount of
niacin; and a therapeutically effective amount of a statin selected
from the group consisting of atorvastatin, cerivastatin,
fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,
rosuvastatin and simvastatin. In one embodiment, the
co-administering is co-administering orally. In one embodiment, the
mammal is a human.
[0477] An aspect of the invention relates to a method of lowering
serum lipoprotein (a) (Lp(a)) levels in a mammal, comprising the
step of co-administering to a mammal in need thereof a
therapeutically effective amount of a compound of the present
invention; a therapeutically effective amount of niacin; and a
therapeutically effective amount of a statin selected from the
group consisting of atorvastatin, cerivastatin, fluvastatin,
lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and
simvastatin. In one embodiment, the co-administering is
co-administering orally. In one embodiment, the mammal is a
human.
[0478] An aspect of the invention relates to a method of lowering
serum lipoprotein (a) (Lp(a)) levels in a mammal, comprising the
step of co-administering to a mammal in need thereof a
therapeutically effective amount of a pharmaceutical composition of
the present invention; a therapeutically effective amount of
niacin; and a therapeutically effective amount of a statin selected
from the group consisting of atorvastatin, cerivastatin,
fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,
rosuvastatin and simvastatin. In one embodiment, the
co-administering is co-administering orally. In one embodiment, the
mammal is a human.
[0479] In certain embodiments, the present invention relates to any
one of the aforementioned methods and the attendant limitations,
wherein said statin is lovastatin or atorvastatin.
[0480] An aspect of the invention relates to a method of treating
diabetes in a mammal, comprising the step of co-administering to a
mammal in need thereof a therapeutically effective amount of a
compound of the present invention or a pharmaceutically acceptable
salt thereof; and a glitazone selected from the group consisting of
troglitazone, rosiglitazone, and pioglitazone. In one embodiment,
the co-administering is co-administering orally. In one embodiment,
the mammal is a human.
[0481] An aspect of the invention relates to a method of treating
diabetes in a mammal, comprising the step of co-administering to a
mammal in need thereof a therapeutically effective amount of a
pharmaceutical composition of the present invention; and a
glitazone selected from the group consisting of troglitazone,
rosiglitazone, and pioglitazone. In one embodiment, the
co-administering is co-administering orally. In one embodiment, the
mammal is a human.
[0482] An aspect of the invention relates to a method of treating
diabetes in a mammal, comprising the step of co-administering to a
mammal in need thereof a therapeutically effective amount of a
compound of the present invention or a pharmaceutically acceptable
salt thereof; niacin; and a glitazone selected from the group
consisting of troglitazone, rosiglitazone, and pioglitazone. In one
embodiment, the co-administering is co-administering orally. In one
embodiment, the mammal is a human.
[0483] An aspect of the invention relates to a method of treating
diabetes in a mammal, comprising the step of co-administering to a
mammal in need thereof a therapeutically effective amount of a
pharmaceutical composition of the present invention; niacin; and a
glitazone selected from the group consisting of troglitazone,
rosiglitazone, and pioglitazone. In one embodiment, the
co-administering is co-administering orally. In one embodiment, the
mammal is a human.
[0484] An aspect of the invention relates to a method of treating
diabetes in a mammal, comprising the step of co-administering to a
mammal in need thereof a therapeutically effective amount of a
compound of the present invention or a pharmaceutically acceptable
salt thereof; and a fibrate selected from the group consisting of
fenofibrate and bezafibrate. In one embodiment, the
co-administering is co-administering orally. In one embodiment, the
mammal is a human.
[0485] An aspect of the invention relates to a method of treating
diabetes in a mammal, comprising the step of co-administering to a
mammal in need thereof a therapeutically effective amount of a
pharmaceutical composition of the present invention; and a fibrate
selected from the group consisting of fenofibrate and bezafibrate.
In one embodiment, the co-administering is co-administering orally.
In one embodiment, the mammal is a human.
[0486] An aspect of the invention relates to a method of treating
diabetes in a mammal, comprising the step of co-administering to a
mammal in need thereof a therapeutically effective amount of a
compound of the present invention or a pharmaceutically acceptable
salt thereof; niacin; and a fibrate selected from the group
consisting of fenofibrate and bezafibrate. In one embodiment, the
co-administering is co-administering orally. In one embodiment, the
mammal is a human.
[0487] An aspect of the invention relates to a method of treating
diabetes in a mammal, comprising the step of co-administering to a
mammal in need thereof a therapeutically effective amount of a
pharmaceutical composition of the present invention; niacin; and a
fibrate selected from the group consisting of fenofibrate and
bezafibrate. In one embodiment, the co-administering is
co-administering orally. In one embodiment, the mammal is a
human.
[0488] In certain embodiments, the present invention relates to any
one of the aforementioned methods and the attendant limitations,
wherein said mammal is a primate, bovine, ovine, rodent, equine,
canine, or feline.
[0489] In certain embodiments, the present invention relates to any
one of the aforementioned methods and the attendant limitations,
wherein said mammal is a human.
[0490] In certain embodiments, the present invention relates to any
one of the aforementioned methods and the attendant limitations,
wherein said compound, compounds, or pharmaceutical composition are
administered orally.
[0491] In certain embodiments, the present invention relates to any
one of the aforementioned methods and the attendant limitations,
wherein said compound, compounds, or pharmaceutical composition are
administered intravenously.
[0492] In certain embodiments, the present invention relates to any
one of the aforementioned methods and the attendant limitations,
wherein said compound, compounds, or pharmaceutical composition are
administered sublingually.
[0493] In certain embodiments, the present invention relates to any
one of the aforementioned methods and the attendant limitations,
wherein said compound, compounds, or pharmaceutical composition are
administered by inhalation.
[0494] In certain embodiments, the present invention relates to any
one of the aforementioned methods and the attendant limitations,
wherein said compound, compounds, or pharmaceutical composition are
administered ocularly.
[0495] In certain embodiments, the present invention relates to any
one of the aforementioned methods and the attendant limitations,
wherein said compound, compounds, or pharmaceutical composition are
administered transdermally.
[0496] In certain embodiments, the present invention relates to any
one of the aforementioned methods and the attendant limitations,
wherein said compound, compounds, or pharmaceutical composition are
administered rectally.
[0497] In certain embodiments, the present invention relates to any
one of the aforementioned methods and the attendant limitations,
wherein said compound, compounds, or pharmaceutical composition are
administered vaginally.
[0498] In certain embodiments, the present invention relates to any
one of the aforementioned methods and the attendant limitations,
wherein said compound, compounds, or pharmaceutical composition are
administered topically.
[0499] In certain embodiments, the present invention relates to any
one of the aforementioned methods and the attendant limitations,
wherein said compound, compounds, or pharmaceutical composition are
administered intramuscularly.
[0500] In certain embodiments, the present invention relates to any
one of the aforementioned methods and the attendant limitations,
wherein said compound, compounds, or pharmaceutical composition are
administered subcutaneously.
[0501] In certain embodiments, the present invention relates to any
one of the aforementioned methods and the attendant limitations,
wherein said compound, compounds, or pharmaceutical composition are
administered buccally.
[0502] In certain embodiments, the present invention relates to any
one of the aforementioned methods and the attendant limitations,
wherein said compound, compounds, or pharmaceutical composition are
administered nasally.
EXEMPLIFICATION
[0503] The invention now being generally described, it will be more
readily understood by reference to the following, which is included
merely for purposes of illustration of certain aspects and
embodiments of the present invention, and is not intended to limit
the invention.
Example 1
Synthetic Schemes
A. Compound ARI-001
[0504] Reaction conditions: i. HCHO, Morpholine.HCl, n-PrOH,
100.degree. C.; ii. NaOH, then HCl.
##STR00018##
[0505] 6-methyl-nicotinic acid methyl ester (4.5 g, 30 mmol),
morpholine hydrochloride (1.85 g, 15 mmol), n-PrOH (18 mL) and
formaldehyde solution (in water, 37%) (1.2 g, 15 mmol) were added
to a 50 mL flask equipped with a condenser. The reaction mixture
was refluxing with a pre-heated 100.degree. C. oil bath for 2.5 hr
under argon. Then the mixture was allowed to stand at room
temperature overnight and a yellow needle crystal was precipitated
out (If there was no precipitation formed at room temperature, cold
room (4.degree. C.) or even -10.degree. C. fridge would be
recommended). Isolated the crystal by filtration and washed with a
little ethyl ether to afford the crude product of step 1 as a HCl
salt (1.5 g, 35% yield; purity was about 95%, the double Mannich
addition by-product was about 3%). This crude product was further
purified by one time re-crystallized from n-PrOH and MeOH to give
the purer product of step 1 as an off-white or pale yellow powder
(1.2 g, 28% yield; purity was 99.1%, the double Mannich addition
by-product was 0.9%).
[0506] The product of step 1 (1.5 g, 5 mmol) was dissolved in MeOH
(20 mL) and water (10 mL), 1 N LiOH (15 mL) was added under
ice-water cooling. The resulting mixture was stirred at room
temperature overnight, and then adjusted pH to 2-3 with 2N HCl.
After condensed under vacuum the residue was then further purified
with preparative HPLC eluting with solvent acetonitrile and water
(5 mM HCl added) to afford 1.2 g of the target compound ARI-001 as
a white powder (HCl salt, total yield was about 30% for two steps
when used the crude product of step 1).
B. Compound ARI-002
[0507] Reaction conditions: i. HCHO, Morpholine.HCl
##STR00019##
C. Compound ARI-001D
[0508] Reaction conditions: i. HCHO, Morpholine-d8.HCl; ii. NaOH,
then HCl.
##STR00020##
D. Compound ARI-005
[0509] Reaction conditions: i. 5-Indanol, EDAC, DMAP.
##STR00021##
E. Compound ARI-006 (Hexa ARI-001 Inositol)
##STR00022##
[0511] Reaction conditions: i. imyo-Inositol, EDCI, DMAP.
##STR00023##
F. Compound ARI-008
##STR00024##
[0513] Reaction conditions: i. D-Sorbitol, EDAC, DMAP.
##STR00025##
G. Compound ARI-010
[0514] Reaction conditions: i. ARI-001, EDAC, DMAP; ii. Bu.sub.4NI,
BCl.sub.3.
##STR00026##
Example 2
In Vitro Studies
[0515] ARI-001 was synthesized as described above. Purity was
determined independently before use in experiments by examination
via liquid chromatography-mass spectroscopy (LC-MS). A sample of
material was dissolved in water/acetonitrile and injected onto a
Discovery C-18 reverse phase column. The mobile phase began as
2%:98% acetonitrile:water, which was held for three minutes, after
which a linear gradient was started that ran over 6 minutes,
increasing the percent of acetonitrile until a final ratio of
98%:2% acetonitrile:water was reached. This final ratio was held
for 3 minutes. UV detection was collected at 215 nm, as shown in
FIG. 1. The major peak was identified as ARI-001.
[0516] The purity was determined by the ratio of the area of the
major peak (3.59 minutes) to the sum of areas of all peaks. Purity
was determined to be 98.9%. The minor peaks were not
identified.
[0517] Stability was determined by storing ARI-001 under 50.degree.
C. with no specified humidity requirement. At various time points
over the course of 3 months (90 days), a small sample (<5 mg) of
ARI-001 was collected for analysis using LC-MS under the same
conditions as used for purity determination (vide supra). FIG. 2
shows the time course of stability of ARI-001 under such
conditions.
[0518] Under standard conditions (50.degree. C., unregulated
humidity), ARI-001 remained 98.9% pure for a period of 65 days.
Only by 90 days at 50.degree. C. did ARI-001 begin to show any
degradation. After 90 days, the compound was found to be 95.9%
pure.
Example 3
In Vivo Studies
[0519] To investigate the effects of ARI-001 on lipid modulation, a
hamster model was developed and utilized in the setting of chronic
administration of compound. This model, its development, and the
effects of ARI-001 are described herein.
[0520] Effects of Diet Modification on the Lipid Profile of
Hamsters.
[0521] Like other rodents, the lipid profile in Golden Syrian
hamsters predominantly consists of HDL, with little LDL or VLDL
cholesterol. However, on a high-fat diet, hamsters experience an
increase in the cholesterol pool, including triglycerides and free
fatty acids. Adding a sugar to the drinking water source such as
10% fructose expands the triglyceride pool significantly, including
the VLDL. On this diet, the hamster becomes a useful model for
investigating the role of modulators on triglycerides and VLDL, and
LDL cholesterol. Indeed, literature sources have utilized this
model to investigate triglyceride and free fatty acid modulating
compounds such as fenofibrate.
[0522] We examined the effects of diet modulation on the lipid
profile of male Syrian Golden hamsters. Hamsters were ordered from
Charles River Labs (Wilmington, Mass.), and requested to be 111-120
g in weight (correspondingly 56-61 days old). Hamsters were kept in
cages of 4-5 per cage, and maintained on a standard light cycle of
12 hours on/12 hours off. All diets were obtained from Dyets, Inc.
(Bethlehem, Pa.). "Normal Diet" was a standard rodent chow, catalog
#5001, produced into pellets. Water and this standard chow diet
were available to this group of hamsters ad libitum. Food was added
to cages as needed, but no less frequently than twice per week.
"High Fat Diet" was the same standard rodent chow supplemented with
the following: 11.5% corn oil, 11.5% coconut oil, 0.5% cholesterol,
and 0.25% deoxycholate. This is also available directly from Dyets,
Inc., as catalog #611201. Both diets were ordered in 10 kg batches
and stored at 4.degree. C. for durations of the experiments (4-8
weeks), and at -20.degree. C. for longer storage (up to six
months). Water and this high fat diet were available to this group
of hamsters ad libitum. The "High Fat+Fructose" group was fed the
same fat-supplemented chow as the "high fat diet" group (#611201),
but water was supplemented with fructose to a final concentration
of 10%. Fructose was supplied from Now Foods (catalog #6931) and
distributed by Lucky Vitamin (catalog #WB48432). Fructose water was
prepared by adding 400 g of fructose to 4 L of water and stirring
at room temperature until dissolved. Fructose water was stored at
4.degree. C. until use. When provided to hamsters, fructose water
was kept in a water bottle in the hamster cages at room
temperature, exactly as standard water was. Fructose water and high
fat chow were provided to this group of hamsters ad libitum. All
animals remained on their respective diets for 21 days.
[0523] To begin this experiment, hamsters were randomly assigned to
groups defined by the diet modifications above. After a fixed time,
blood was collected from hamsters (N=3-4) to determine the lipid
contents of the plasma. Because of limitations in the ability to
adequately collect blood from hamsters, all blood samples were
obtained via a terminal cardiac puncture preceded by asphyxiation
with carbon dioxide. Blood (approximately 2 mL volume) was
collected with a 22G needle into a 5 mL syringe and transferred to
a K.sub.2EDTA tube. The samples were kept on ice until
centrifugation (14,000 rpm for 10 minutes at 4.degree. C.) to
separate plasma. Plasma was then aliquoted to tubes for storage at
-80.degree. C. until analysis.
[0524] Lipid parameters were determined using commercially
available kits from Wako USA (Richmond, Va.) according to
manufacturer's directions.
TABLE-US-00001 TABLE 1 Lipid values from hamsters on one of three
different diets for 21 days. Hamsters were sacrificed and their
plasma was analyzed as described. Values represent the average of
measurements of each parameter (N = 3), with standard deviation.
TC: total cholesterol; HDL: high-density lipoprotein cholesterol;
LDL: low-density lipoprotein cholesterol; TG: triglycerides; FFA:
free fatty acids. TC (.+-.SD) HDL (.+-.SD) LDL (.+-.SD) TG (.+-.SD)
FFA (.+-.SD) Day 21 (mg/dL) (mg/dL) (mg/dL) (mg/dL) (mEq/L) Normal
Diet 115 .+-. 8 63 .+-. 6 17 .+-. 3 325 .+-. 89 0.76 .+-. 0.02 High
Fat Diet 680 .+-. 82*** 130 .+-. 16 384 .+-. 20*** 1129 .+-. 123**
1.65 .+-. 0.42* High Fat + 654 .+-. 135** 97 .+-. 41 282 .+-. 85**
1658 .+-. 673* 2.17 .+-. 0.43** Fructose *p < 0.05 compared to
Normal Diet within the same parameter **p < 0.01 compared to
Normal Diet within the same parameter ***p < 0.001 compared to
Normal Diet within the same parameter
[0525] Lipid values from control animals (zero days on any of the
three diets described above) were essentially indistinguishable
(see Table 1). By day 21, both diet modifications had significant
effects on the lipid profiles of these hamsters when compared to
animals on normal chow diet. All parameters were significantly
increased from control (p<0.05 in all groups), with the
exception of HDL. As predicted, the addition of fructose to the
high fat diet further increased the triglyceride and free fatty
acid concentrations to a greater extent than the high fat diet
alone. HDL was unchanged from the normal diet group, regardless of
the diet modification.
[0526] Fast protein liquid chromatography (FPLC) was used to
separate the different cholesterol subpopulations from samples of
hamster plasma. Briefly, plasma from each animal within a given
cohort was pooled together and applied to an AKTA liquid handling
system with a Superose 6 10/300 GL column (product #14-5172-01, GE
Life Sciences). 250 .mu.L of sample was applied to the injection
system, diluted with 5 mL of buffer (100 mM Na.sub.2HPO.sub.4, 100
mM NaCl, pH 7.5), loaded onto the column, and eluted with 23.5 mL
of buffer at a flow rate of 1.0 mL/min, into fractions of size 0.24
mL. Each fraction was individually measured for cholesterol
concentration using the total cholesterol kit from Wako as
described above with the following modification: sample volume was
increased to 30 .mu.L and the reagent volume was decreased to 60
.mu.L.
[0527] FPLC traces produce continuous curves with three distinct
peaks, representing each of the cholesterol subpopultions: VLDL,
LDL, and HDL. Because the column used in this experiment is a
size-exclusion column, the largest particles appear first, while
the smallest appear last. Hence, VLDL is the first peak on the
trace, followed by LDL, with HDL appearing last. If each of these
peaks is assumed to take a Gaussian distribution, one can
deconvolute the FPLC trace into each of these three components to
determine the contribution that each component makes to the whole
curve.
[0528] FIG. 3 illustrates the FPLC traces of plasma pooled from
hamsters on two different diets for three weeks. The VLDL curve is
vastly expanded on the high fat+fructose diet. The LDL peak is also
much higher. Interestingly, there is very little difference in the
HDL peak, indicating that the diet modification has a much more
powerful effect on the non-HDL cholesterol population. This model
then lends itself to being a useful means by which to measure the
effects of ARI-001 on VLDL and LDL cholesterol.
[0529] ARI-001 Lowers LDL Cholesterol, Triglycerides, and Free
Fatty Acid Levels in HF/HS Hamsters.
[0530] Male Golden Syrian hamsters were purchased from Charles
River Labs (111-120 g, 56-61 days) and acclimated to a high
fat+fructose (herein, referred to as "HF/HS") diet as described
above for two weeks. Hamsters were assigned into cohorts by body
weight after two weeks' acclimation to the diet. Twelve hamsters
were assigned to the vehicle group, 9 were assigned to receive
niacin at a dose of 1200 mg/kg, 10 were assigned to receive ARI-001
at a dose of 1120 mg/kg, and 10 were assigned to receive ARI-001 at
a dose of 2240 mg/kg. At the end of this diet acclimation period,
hamsters were orally gavaged with 1 mL of a solution of vehicle
(water), niacin, or ARI-001 at one of the two doses. Hamsters were
dosed once per day for a total of 18 days. All animals remained on
the above-described HF/HS diet throughout the dosing period. Dosing
solutions for each cohort were prepared for 7 days at a time,
although enough was prepared to last for 8 days. Each solution was
stored at room temperature between administrations. Cohorts were
defined according to Table 2 below. Because of the molecular weight
difference between niacin and ARI-001, doses are given in both
mg/kg and mmol/kg. Note that 1200 mg/kg of niacin is equivalent to
2240 mg/kg of ARI-001 on a molar basis.
TABLE-US-00002 TABLE 2 Assignments to cohorts for 18 day dosing
study in HF/HS hamsters. Dose Dose Compound (mg/kg) (mmol/kg)
Animals Days Vehicle 0 0 12 18 Niacin 1200 9.75 10 18 ARI-001 1120
4.88 10 18 ARI-001 2240 9.75 10 18
[0531] As shown in Table 3, ARI-001 given via oral gavage for 18
days at 2240 mg/kg lowered the LDL-cholesterol and total
cholesterol levels in a HF/HS hamster model. ARI-001 also lowered
triglycerides and free fatty acid levels, with very little
variation between animals as illustrated by the small standard
deviation. At the molar equivalent dose of 1200 mg/kg, niacin was
unable to confer these effects in this animal model, suggesting
that ARI-001 is at least 1.67-times more efficacious than niacin
with respect to the LDL cholesterol parameter, and at least
1.54-times more efficacious than niacin with respect to the total
cholesterol parameter. Of note are the triglyceride and free fatty
acid values, which demonstrated responders among all animals in the
2240 mg/kg ARI-001 group. That there is a very small standard
deviation among these data points reflects the impressive response
rate among these animals. The HDL/TC ratio was calculated by
dividing each individual hamster's HDL cholesterol level by his
total cholesterol level. The fraction that resulted is the HDL/TC
ratio. This parameter was higher than the vehicle cohort's, with
impressive statistical significance (p<0.001). This does not
likely represent a powerful increase in HDL, as the absolute HDL
value measured was increased by only 33% in the 2240 mg/kg ARI-001
group compared to vehicle. Rather, the very powerful change in the
HDL/TC ratio likely represents a system-wide reduction in
cholesterol populations, with the exception of HDL, which was not
only spared from such reductions, but was possibly increased.
TABLE-US-00003 TABLE 3 Lipid parameters from HF/HS hamsters dosed
orally with vehicle, niacin, or ARI- 001 for 18 days. TC, total
cholesterol. Values given are mean .+-. standard deviation. P-
values are reported from 2-tailed unpaired t-tests comparing to
vehicle treated within the same parameter. TC HDL LDL TG FFA
(mg/dL) .+-. (mg/dL) .+-. (mg/dL) .+-. (mg/dL) .+-. (mEq/L) .+-.
HDL/TC .+-. Cohort SD SD SD SD SD SD Vehicle 857 .+-. 422 139 .+-.
32 253 .+-. 82 1065 .+-. 465 1.95 .+-. 0.53 0.21 .+-. 0.11 Niacin:
552* .+-. 183 79 .+-. 26*** 170 .+-. 52* 1555 .+-. 808 1.82 .+-.
0.69 0.17 .+-. 0.11 1200 mg/kg ARI-001: 653 .+-. 194 142 .+-. 34
253 .+-. 91 957 .+-. 550 1.39 .+-. 0.65* 0.24 .+-. 0.14 1120 mg/kg
ARI-001: 343 .+-. 104** 186 .+-. 74* 114 .+-. 33*** 138 .+-. 80***
0.75 .+-. 0.15*** 0.48 .+-. 0.07*** 2240 mg/kg *p < 0.05
compared to Vehicle within the same parameter **p < 0.01
compared to Vehicle within the same parameter ***p < 0.001
compared to Vehicle within the same parameter
[0532] The measured HDL values were borderline significant (p=0.06)
between the 2240 mg/kg ARI-001 group and vehicle. There was a
considerable increase in significance when considering the
calculated HDL/TC values. The FPLC traces also demonstrated a
significant difference in lipid profile between these two groups.
FPLC was performed as described above. Curves were deconvoluted as
described above. Not only were the VLDL and the LDL peaks
considerably decreased compared to vehicle, but the HDL curve was
notably larger in the ARI-001 trace. See FIG. 4.
[0533] Male Golden Syrian hamsters from the previously described
experiment demonstrated a dose dependence on ARI-001 with respect
to lipid alteration. 2240 mg/kg is an effective dose for 18 days of
daily treatment for nearly all parameters: total cholesterol, LDL
cholesterol, triglycerides, and free fatty acids. However, 1120
mg/kg shows only modest effects on these parameters, with only the
free fatty acids parameter demonstrating a statistically
significant effect compared to vehicle. Nonetheless, the trend is
clear between the doses for all lipid parameters investigated, as
shown in FIG. 5. Moreover, at the molar equivalent dose, ARI-001
effects a more powerful response than niacin in all lipid
parameters measured.
[0534] ARI-001 Lowers LDL Cholesterol, Triglycerides, and Free
Fatty Acids in a Time-Dependent Manner.
[0535] Thirty-two male Golden Syrian hamsters were acclimated over
two weeks to a HF/HS diet as described above. After a two week
induction period, animals were assigned to cohorts for 18 days of
study on either vehicle or ARI-001 (1120 mg/kg), or to cohorts for
28 days of study on either vehicle or ARI-001 (1120 mg/kg). Each of
the four groups had 8 hamsters. Solutions were prepared and stored
as described above Animals were dosed a volume of 1 mL per day for
either 18 or 28 consecutive days, as previously described. At the
end of the study, hamsters were sacrificed, their blood collected
into K.sub.2EDTA tubes, plasma separated by centrifugation and
frozen until analysis. All lipids were analyzed using commercially
available kits (Wako USA) as described above. In Table 4 below,
both 18-day and 28-day vehicle animals are combined into a single
vehicle group (N=16).
TABLE-US-00004 TABLE 4 Lipid parameters from HF/HS hamsters dosed
orally with vehicle or ARI-001 for 18 days or 28 days. Values given
are mean .+-. standard deviation. P-values are reported from
2-tailed unpaired t-tests comparing to vehicle treated within the
same parameter. TC HDL LDL TG FFA (mg/dL) .+-. (mg/dL) .+-. (mg/dL)
.+-. (mg/dL) .+-. (mEq/L) .+-. HDL/TC .+-. Cohort SD SD SD SD SD SD
Vehicle 796 .+-. 253 135 .+-. 40 363 .+-. 85 1023 .+-. 630 1.30
.+-. 0.45 0.19 .+-. 0.09 ARI-001: 668 .+-. 239 153 .+-. 30 346 .+-.
121 833 .+-. 410 1.06 .+-. 0.56 0.27 .+-. 0.15 1120 mg/kg, 18 Days
ARI-001: 420 .+-. 85*** 138 .+-. 26 175 .+-. 80*** 388 .+-. 82**
0.56 .+-. 0.12*** 0.34 .+-. 0.09*** 1120 mg/kg, 28 Days **p <
0.01 compared to Vehicle within the same parameter ***p < 0.001
compared to Vehicle within the same parameter
[0536] ARI-001 showed favorable effects on lipids when a dose of
1120 mg/kg was carried out to 28 days. When hamsters were dosed for
28 days instead of 18 days, all lipid parameters measured achieved
a statistically significant difference compared to vehicle, except
for HDL, which showed no difference compared to vehicle. The
reductions seen at 1120 mg/kg for 28 days were greater than after
18 days of dosing. However, these reductions were not nearly as
impressive as those seen with 18 days at the higher dose of 2240
mg/kg.
[0537] Correlation Between Plasma Lipid Biomarkers and ARI-001
Plasma Concentrations.
[0538] Plasma from the 19 hamsters dosed with ARI-001 in the above
described 18-day study was analyzed for concentrations of ARI-001.
Concentrations were determined for these samples, which were
collected 24 hours after the final dose was administered. Briefly,
plasma drug concentrations for the non-GLP pharmacokinetic
experiments were determined by LC-MS using an Applied Biosystems
4000Qtrap spectrometer with electrospray ionization. Samples were
prepared for analysis by precipitation of plasma proteins with cold
methanol. HPLC of the samples was done with an Agilent Eclipse C18
column and a methanol/water gradient containing 0.1% formic acid
and 5 mM ammonium acetate. ARI-001 was detected using multiple
reaction monitoring (MRM) in the positive ion mode. For
quantitation, a standard curve was measured by addition of known
amounts of ARI-001 to plasma from untreated animals and preparing
in a manner identical to the samples from treated animals. All
plasma samples were spiked with 10 ng/mL of isotope-enriched
ARI-001 which served as an internal standard for the LC-MS
measurements. All compound concentrations are reported in .mu.M.
For correlation analysis, plasma concentrations of ARI-001 in a
given animal were paired with that same animal's lipid parameter.
All animals from both dosing groups (1120 mg/kg and 2240 mg/kg)
were included in the analysis. These correlations are graphed in
FIG. 6 and FIG. 7. Pearson r values were determined using all data
points, as was the two-tailed P-value for the data set.
[0539] Lipid parameter changes correlated well with plasma levels
of drug measured 24 hours after the final dose. Indeed, total
cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and
free fatty acid levels all achieved statistically significant
levels of correlation (p<0.01). Correlation with triglycerides
were especially notable for having a very high degree of
statistical significance, p<0.001. These significant
correlations give support to the idea that ARI-001 is directly
responsible for modulation in lipid values. Moreover, these data
corroborate the dose-response effects seen in FIG. 5.
[0540] ARI-001 Concentrations in Tissues Correlate with Plasma
Lipid Levels.
[0541] Tissue samples were harvested from hamsters in the
above-described 18-day experiment to determine the concentrations
of ARI-001 in both liver and adipose tissue. Briefly, liver and
adipose samples were harvested at the termination of the
experiment; the samples were flash frozen in liquid nitrogen and
then stored at -80.degree. C. until used for analysis. To prepare
for analysis, a sample of liver was excised from the frozen mass,
weighed, and homogenized with a tissue grinder followed by
sonication in buffer. The solid materials were then removed by
centrifugation. To prepare for LC-MS analysis, the homogenate was
then treated to the same preparation technique described for plasma
preparation (vide supra). A sample of adipose was excised from the
frozen mass, and transferred to a mortar and pestle cooled with
liquid nitrogen. During grinding, liquid nitrogen was added to
ensure the sample of adipose remained solid. The ground sample was
transferred to a tared tube to weigh total sample. This ground
sample was extracted with methanol, and this compound-containing
methanol was separated from lipid by cooling to -20.degree. C.
After drying, the methanol sample was dissolved in water; the
samples were then prepared for LC-MS analysis in the same way that
liver and plasma were (vida supra).
[0542] Liver concentrations were reported as ng of ARI-001 per mL
of homogenized tissue sample extracted into buffer. Concentrations
in adipose were reported as ng of ARI-001 per mg of tissue
recovered from the grinding process. Because of the distribution of
tissue concentrations and lipid parameters, the logarithm
transformation was used on all liver samples when determining
correlation. Additionally, adipose concentrations were transformed
as logarithm +1, since the logarithm transformation produced
negative values for these tissue samples. These transformations
allowed the data to be more graphed more conveniently. Finally,
these transformations are valid because the nature of the Pearson r
correlation coefficient is invariant to both logarithm
transformation and to transposition.
[0543] FIG. 8 graphs the correlation between concentrations of
ARI-001 in plasma versus liver (left), and in plasma versus adipose
(right). Both of these correlations were highly statistically
significant, with p<0.01 for each pair of parameters. FIGS. 9-11
graph the correlations between the concentrations of ARI-001 in
each tissue sample versus the lipid parameters TC, HDL, LDL, TG,
and FFA. All concentration measurements and all lipid parameters
were transformed via logarithm. Pearson r was determined using all
data points illustrated. P-value was determined for a 2-tailed
t-test using all data points illustrated.
[0544] ARI-001 Increases ABCA1, ApoAI, SR-BI, CETP, and Adiponectin
mRNA in HF/HS Hamsters.
[0545] Investigation of a possible mechanism that could lead to the
increase in HDL cholesterol focused on changes in the mRNA levels
of several genes related to the regulation of HDL. Hamster livers
and adipose were prepared in manners similar to that described for
ARI-001 concentration determination. Briefly, to prepare for
analysis, a sample of liver was excised from the frozen mass,
weighed, and homogenized with a tissue grinder followed by
sonication in buffer. The solid materials were then removed by
centrifugation. The resulting lysate was used in qPCR analysis to
quantify the specific mRNA measured (vide infra) using primers
designed for the specific sequences of interest. All mRNA
quantities were normalized to vehicle-treated animal, and mRNA
levels were expressed as a fold increase or decrease relative to
vehicle-treated. The adipose was treated in a similar manner to the
liver: a sample of adipose was excised from the frozen mass, and
transferred to a mortar and pestle cooled with liquid nitrogen.
During grinding, liquid nitrogen was added to ensure the sample of
adipose remained solid. The ground sample was transferred to a
tared tube to weigh total sample. This ground sample was treated
with buffer and prepared for qPCR to quantify specific mRNA
quantities.
TABLE-US-00005 TABLE 5 Relative concentrations of ABCA1, ApoAI,
SR-BI, CETP mRNA per mg of liver tissue, and likewise adipose CETP
and adiponectin mRNA per mg of adipose tissue, from high fat-fed
hamsters in vehicle-, niacin-, or ARI-001-treated cohorts. Values
are given as a fold- change compared to the mean of the vehicle
values. Niacin: ARI-001: Message Vehicle 1200 mg/kg 2240 mg/kg
Liver ABCA1 1.02 .+-. 0.18 0.80 .+-. 0.18 1.54 .+-. 0.48** Liver
ApoAI 1.04 .+-. 0.28 1.17 .+-. 0.19 1.72 .+-. 0.24*** Liver SR-BI
1.00 .+-. 0.25 0.79 .+-. 0.18 1.50 .+-. 0.33** Liver CETP 1.00 .+-.
0.45 1.03 .+-. 0.55 2.05 .+-. 0.38*** Adipose CETP 1.00 .+-. 0.46
1.12 .+-. 0.33 1.72 .+-. 0.70* Adipose 1.00 .+-. 0.43 1.67 .+-.
0.32*** 2.00 .+-. 0.23*** Adiponectin
[0546] Both ABCA1 and ApoAI mRNA levels were higher in the
ARI-001-treated arms relative to vehicle control animals. Indeed, a
statistically significant correlation was seen between HDL and
ApoAI mRNA levels. This suggests a possible mechanism by which
ARI-001 may increase HDL in this hamster model.
TABLE-US-00006 TABLE 6 Correlations between ABCA1, ApoAI, SR-BI,
and CETP mRNA per mg of liver tissue vs HDL levels, and likewise
between CETP and adiponectin mRNA per mg of adipose tissue vs HDL
levels, from high fat-fed hamsters in vehicle-, niacin-, or
ARI-001-treated cohorts. Correlation Vehicle Niacin: 1200 mg/kg
ARI-001: 2240 mg/kg [HDL] vs Liver ABCA1 -0.007 (-0.60 . . . 0.60)
-0.40 (-0.84 . . . 0.36) 0.49 (-0.33 . . . 0.89) [HDL] vs Liver
ApoAI 0.32 (-0.34 . . . 0.77) 0.19 (-0.54 . . . 0.76) 0.80 (0.21 .
. . 0.96)* [HDL] vs Liver SR-BI 0.46 (-0.19 . . . 0.83) 0.46 (-0.29
. . . 0.86) -0.10 (-0.75 . . . 0.65) [HDL] vs Liver CETP 0.18
(-0.47 . . . 0.70) -0.13 (-0.73 . . . 0.58) 0.30 (-0.52 . . . 0.83)
[HDL] vs Adipose CETP -0.03 (-0.62 . . . 0.58) 0.54 (-0.19 . . .
0.89) 0.85 (0.28 . . . 0.98)* [HDL] vs Adipose 0.43 (-0.22 . . .
0.82) 0.31 (-0.48 . . . 0.81) -0.22 (-0.83 . . . 0.64)
Adiponectin
Example 4
Safety Pharmacology Studies (Non-GLP Preliminary Studies)
[0547] Because niacin is known to be associated with liver toxicity
and glucose intolerance in a chronic dosing setting, we examined
whether ARI-001, a niacin mimetic, could be associated with similar
issues. In order to investigate this, we examined the common liver
functional enzymes AST and ALT in the plasma of hamsters from
experiment described above in Example 3. These animals were dosed
for 18 consecutive days, while being on a HF/HS diet for a total of
nearly 5 weeks. We also examined the glucose levels in the plasma
of these animals. For pharmacokinetic studies, we utilized wild
type mice for both single and repeated administration study.
Finally, pharmacokinetic studies were corroborated by data from
single and repeated administration to monkeys.
A. Effects on Liver Function
[0548] ARI-001 Improves Liver Function Tests from Chronically Dosed
High Fat-Fed Hamsters.
[0549] Certain formulations of niacin are known to cause
hepatotoxicity in humans. This led to an investigation of liver
function tests (AST, ALT) from plasma of hamsters dosed for 18 days
with ARI-001. AST and ALT were measured using commercially
available kits (Bio-Quant Diagnostic Kits, San Diego, Calif.). As
expected, AST and ALT values from untreated hamsters (vehicle
group) were very high, as the high fat diet leads to hepatomegaly
and fatty liver. This disease state is reflected in the elevated
AST and ALT levels. In contrast, AST and ALT levels from ARI-001
treated animals were significantly lower than vehicle. Indeed, AST
was drastically reduced at the 2240 mg/kg dose, and even
significantly reduced at the 1120 mg/kg dose. ALT values were
similarly reduced, again in a dose-dependent manner. See FIG. 12A
and FIG. 12B.
B. Effects on Glucose Tolerance
[0550] ARI-001 has No Effect on Glucose Levels Among High Fat-Fed
Hamsters.
[0551] Niacin is known to adversely affect glucose levels among
diabetic patients. The hamster model used in this experiment did
produce a population with elevated glucose levels, as demonstrated
by the vehicle group in FIG. 13. Consistent with effects seen in
humans, the glucose of niacin-treated animals was increased
relative to vehicle. However, neither dose of ARI-001 produced any
significant change in glucose levels in comparison to the vehicle
cohort.
Example 5
Pharmacokinetic Studies
A. Mouse In Vivo Studies
[0552] Single-Dose Pharmacokinetic Study of ARI-001 in Wild Type
Mice.
[0553] Wild type C57BL/6 mice were dosed with a single
administration of ARI-001 in solution either via oral gavage (PO)
or via intraperitoneal injection (IP). Blood samples were then
collected at various time points over a 24-hour period; plasma was
then analyzed for concentrations of ARI-001 as described earlier.
ARI-001 was administered at either a dose of 2240 mg/kg as a single
bolus via oral gavage, or a dose of 448 mg/kg as a single bolus via
intraperitoneal injection. See FIG. 14.
[0554] Single-dose administration of ARI-001 via oral gavage and
intraperitoneal injection produced pharmacokinetic curves with
parameters described in Table 7. By the 24 hour timepoint, the
remaining concentration of ARI-001 was undetectable.
TABLE-US-00007 TABLE 7 Pharmacokinetic parameters from single
administration of ARI-001 in wild type mice. ARI-001 C.sub.max
(.mu.M) t.sub.1/2 (h) t.sub.max (h) AUC (.mu.M*h) PO 289 1.5 0.5
1096 IP 450 0.5 0.25 439
[0555] Multiple Administration Pharmacokinetic Study of ARI-001 in
Wild Type Mice.
[0556] Wild type C57BL/6 mice were dosed with ARI-001 in solution
via oral gavage daily for 30 consecutive days. Over the course of
five 24-hour periods, blood was collected, and the resultant plasma
was analyzed for concentrations of ARI-001. Four doses were used:
996 mg/kg, 1493 mg/kg, 2240 mg/kg, and 3360 mg/kg. As expected,
C.sub.max levels and total 24-hour exposure (AUC) were
dose-dependent. However, these values were time-independent, as
there was no trend observed between these parameters and days of
administration. See FIGS. 15A-15D and FIGS. 16A-16B.
B. Further Mouse In Vivo Studies
[0557] Single-Dose Pharmacokinetic Study in Wild Type Mice.
[0558] Wild type C57BL/6 mice were dosed with a single
administration of niacin, ARI-001, or compound 2230C (disclosed in
US Patent Application Pub. No. 2009/0312355 A1, incorporated herein
by reference) in solution via single bolus oral gavage (PO).
Compound 2230C has the structure
##STR00027##
Blood samples were then collected at various time points over a
24-hour period; plasma was then analyzed for concentrations of
niacin, ARI-001, and 2230C as described earlier. Results are shown
in Table 8.
TABLE-US-00008 TABLE 8 Comparison of pharmacokinetic parameters of
niacin, ARI-001, and 2230C from single oral administration in wild
type mice. Niacin ARI-001 2230C C.sub.max (.mu.M) 4,089 309 126 AUC
(.mu.M h) 11,696 1,097 686 half-life (t.sub.1/2) (h) 1.75 1.43 3.47
t.sub.max (h) 0.50 0.38 0.31 C.sub.max (% Niacin) 100 7.5 3.0 AUC
(% Niacin) 100 9.4 5.8 C.sub.max/AUC.sub.0-24 (h.sup.-1) 0.35 0.28
0.18 C.sub.24 h/C.sub.max (%) 0.02 n.d. 2.1 n.d., not done
C. Golden Syrian Hamster In Vivo Studies
[0559] Single-Dose Pharmacokinetic Study of ARI-001 in Golden
Syrian Hamsters.
[0560] The pharmacokinetic profile of ARI-001 was evaluated in
HF/HS Golden Syrian hamsters given aa single oral dose of 5.9
mmol/kg of ARI-001. Plasma samples were collected via cardiac
puncture from five animals at each time point to measure plasma
concentrations of ARI-001 over 24 hours. Results are shown in FIG.
17.
D. Monkey In Vivo Studies
[0561] Single-Dose Pharmacokinetic Study of ARI-001 in Macaque
Monkeys. Fasted monkeys were given a single administration of
ARI-001 in solution either via oral gavage (PO) or via intravenous
injection (IV). Blood samples were collected at various time points
over a 24-hour period; plasma was then analyzed for concentrations
of ARI-001. ARI-001 was administered at either a dose of 288 mg/kg
as a single bolus via oral gavage, or a dose of 96 mg/kg as a
single bolus via IV injection. Results are shown in FIG. 18.
[0562] Single-Dose Pharmacokinetic Study of ARI-001 in Fed or
Fasted Monkeys.
[0563] Fed monkeys were fed and allowed some time to digest before
being administered ARI-001 as a solution via oral gavage as
previously described. Results are shown in FIG. 19.
[0564] Pharmacokinetics of Multiple Administrations of ARI-001 to
Fasted Monkeys.
[0565] ARI-001 was administered to monkeys via oral gavage once per
day for a total of seven days. Blood samples were collected after
the first and after the last administrations to measure plasma
concentrations of ARI-001. There was very little difference between
the plasma concentrations on day 1 versus day 7. The greatest point
of discrepancy was in the C.sub.max value, which was higher on day
7 than on day 1. The concentrations 24 hours after either the first
or the last doses were essentially identical. See FIG. 20.
Example 6
ARI-001 Fails to Recruit .beta.-Arrestin to the Cell Membrane of
Cells Expressing High Affinity Niacin Receptor GPR109A
[0566] It has been demonstrated that niacin-induced cutaneous
flushing is mediated by activation of the niacin receptor, GPR109A,
in a .beta.-arrestin-dependent manner. Walters R W et al. (2009) J
Clin Invest 119:1312-21. Assay-ready PathHunter eXpress
.beta.-Arrestin cells expressing GPR109A were plated at 10,000
cells/well in a 96-well plate and stimulated with either niacin or
ARI-001, each over a range of concentrations, for 90 minutes. G
protein-coupled receptor (GPCR) activity was detected by measuring
the interaction of .beta.-arrestin with the activated GPCR using
3-galactosidase enzyme fragment complementation. Following
stimulation with either niacin or ARI-001, signal was detected
using the chemiluminescent PathHunter Detection Reagents.
Representative results are shown in FIG. 21.
[0567] Unlike niacin, stimulation of GPR109A with ARI-001 at
concentrations up to 10 mM failed to recruit .beta.-arrestin to the
membrane of cells expressing GPR109A. Since niacin-induced flushing
is known to be mediated by activation of GPR109A in a
.beta.-arrestin-dependent manner, this finding is consistent with
the observation that ARI-001 has greatly reduced flushing side
effect compared to niacin.
Example 7
Summary of Pharmacological Studies of ARI-001 in Animal Models
[0568] A number of pharmacokinetic, safety, and efficacy studies
for ARI-001 have been completed in a variety of animals, including
mice, rats, Golden Syrian hamsters, dogs, and monkeys. Overall,
results from these studies have established the following.
[0569] ARI-001 decreased plasma levels of total cholesterol, LDL-C,
TG and FFA while increasing the absolute level of HDL-C and
HDL-C/TC ratio. The lipid altering effects of a once-daily dose of
ARI-001 were more pronounced than the lipid effects observed with
nearly 2-fold higher dose of niacin given once a day.
[0570] ARI-001 given once daily for 28 days produced a greater
change in plasma lipid levels compared with the same dose of
ARI-001 given once daily for 18 days.
[0571] ARI-001 given once daily produced highly significant changes
in plasma lipids, greater than or equal to the lipid altering
effects observed with the same total dose of ARI-001 given twice
daily. Additionally, once daily ARI-001 was more potent than niacin
in effecting desirable lipid changes.
[0572] Changes in plasma levels of TC, HDL-C, TG, LDL-C and FFA
correlated with plasma concentrations of ARI-001 present in
plasma
[0573] Plasma and liver concentrations of ARI-001 are
proportionately related.
[0574] Liver concentration of ARI-001 correlated with decreases in
plasma TC, LDL-C, TG and FFA and increases in plasma HDL-C.
[0575] ARI-001 showed no evidence of capillary vasodilation or
hyperemia (a proxy of flush) in experiments using Doppler capillary
blood flow measurements in mice. Additionally, clinical symptoms of
"flushing" were not observed over 28 days in rats or dogs.
Example 8
Human Clinical Trial with ARI-001
[0576] A randomized, double-blind, placebo-controlled study is
performed with sequential escalating doses by cohort with
observations for 30 hours post dosing and return visit on 8th day.
Study subjects are healthy male and female adult volunteers, age
18-60 years, with LDL-C>130 mg/dL and weight<85 kg. Subjects
are randomly assigned to receive study drug or placebo.
[0577] Five periods of single dose escalation, with 8 subjects per
cohort (6 drug: 2 placebo) involve a total 40 subjects.
Appropriately blinded matching placebos are provided. Cohort 1
receives 500 mg of ARI-001 formulated as a single oral tablet, plus
eleven placebo tablets; Cohort 2, 1000 mg taken as two 500 mg
tablets of ARI-001, plus ten placebo tablets; Cohort 3, 2000 mg
taken as four 500 mg tablets of ARI-001, plus eight placebo
tablets; Cohort 4, 4000 mg taken as eight 500 mg tablets of
ARI-001, plus four placebo tablets; Corhort 5, 6000 mg taken as
twelve 500 mg tablets of ARI-001. Placebo-only subjects take twelve
placebo tablets. Each tablet is a compressed, film-coated tablet
suitable for oral administration.
[0578] Primary objectives of the study are to evaluate the safety
and tolerability of single doses of ARI-001 in healthy adult
volunteers, at doses ranging from 500 mg to 6000 mg.
[0579] Secondary objectives of the study are to establish the
pharmacokinetic profile of ARI-001 in blood after a single dose in
healthy volunteers; observe changes in fasting triglycerides, free
fatty acid and other lipid biomarkers; correlate the dose level and
plasma drug exposures over time with any changes in fasting
triglycerides, free fatty acid and other lipid biomarkers; and
establish the effect of ARI-001 on symptoms of flushing by visual
analog score (VAS).
[0580] Pharmacokinetic samples are collected at 0-45 min pre-dose
and at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 30 and 168 hours after
dosing. The actual time of each plasma collection is recorded.
[0581] At each collection, 3 mL of blood is collected into a
Vacutainer tube containing EDTA (purple top) and refrigerated
immediately. Within 30 minutes of collection, the plasma fraction
is separated by centrifugation at 2,000 rpm for 15 minutes at
4.degree. C. Analysis of all samples is performed at a central
laboratory.
[0582] On Day 1, pre-dose, the following procedures are performed:
[0583] Clinical laboratory tests including liver function (ALT,
AST, serum bilirubin), CK, hematology, APTT, PT, urinalysis and
lipid chemistry panel (LDL-C, HDL-C, free fatty acids,
triglycerides, LPA and ApoA-1) [0584] 12-lead ECG [0585] Vital
signs [0586] VAS [0587] Baseline plasma PK [0588] Urine collection
for baseline PK between midnight and 0 hours (dosing)
[0589] After study drug administration, the following procedures
are performed. [0590] Clinical laboratory tests including liver
function (ALT, AST, serum bilirubin), CK, hematology and APTT, PT
at 6, 12 and 24 hours post-dose [0591] Lipid chemistry panel
(LDL-C, HDL-C, free fatty acids, triglycerides, Lp(a) and ApoA-1)
at 4, 12 and 24 hours post-dose [0592] 12-lead ECG at 1, 2, 4, 6,
8, 12 and 24 hours post-dose [0593] Urinalysis at 24 hours
post-dose [0594] Vital signs at 6, 12, 24 and 30 hours post-dose
[0595] VAS at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
[0596] Physical examination at 24 hours post-dose and a brief
clinical examination at 30 hours post-dose [0597] Collect blood
sample for PK at 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24 and 30 hours
posts-dose [0598] Collect blood sample for troponin at 4 hours
post-dose [0599] Collect urine for PK in 6 hour intervals at 0 to
6, 6 to 12, 12 to 18, 18 to 24, and 24 to 30 hours after
dosing.
[0600] Preliminary results from this human clinical trial include
the remarkable observation that no patients exhibited any signs of
flushing at any dose of ARI-001, up to and including the 6000 mg
dose.
[0601] Additional preliminary results are shown in FIG. 22, which
illustrates dose response for triglyceride lowering in humans on
single oral doses of ARI-001 as measured 4 hours after dosing.
[0602] Further preliminary results are shown in FIG. 23, which
illustrates serum concentration of ARI-001 as measured over 24
hours in humans following single oral doses, ranging from 500 mg to
6000 mg, of ARI-001. C.sub.max for the 2000 mg dose of ARI-001 was
about 7500 ng/mL (7.5 mg/mL); C.sub.max for 1500 mg of niacin
(roughly equimolar dose) was about 30,000 ng/mL (30 mg/mL).
INCORPORATION BY REFERENCE
[0603] All publications and patents mentioned herein are hereby
incorporated by reference in their entirety as if each individual
publication or patent was specifically and individually indicated
to be incorporated by reference. In case of conflict, the present
application, including any definitions herein, will control.
EQUIVALENTS
[0604] While specific embodiments of the subject invention have
been discussed, the above specification is illustrative and not
restrictive. Many variations of the invention will become apparent
to those skilled in the art upon review of this specification. The
appended claims are not intended to claim all such embodiments and
variations, and the full scope of the invention should be
determined by reference to the claims, along with their full scope
of equivalents, and the specification, along with such
variations.
* * * * *