U.S. patent application number 15/675862 was filed with the patent office on 2018-06-14 for synthetic triterpenoids and methods of use in the treatment of disease.
This patent application is currently assigned to REATA PHARMACEUTICALS, INC.. The applicant listed for this patent is REATA PHARMACEUTICALS, INC., TRUSTEES OF DARTMOUTH COLLEGE. Invention is credited to Gordon W. GRIBBLE, Tadashi HONDA, Robert M. Kral, Karen T. LIBY, Colin J. MEYER, Michael B. SPORN.
Application Number | 20180161311 15/675862 |
Document ID | / |
Family ID | 40377326 |
Filed Date | 2018-06-14 |
United States Patent
Application |
20180161311 |
Kind Code |
A1 |
SPORN; Michael B. ; et
al. |
June 14, 2018 |
SYNTHETIC TRITERPENOIDS AND METHODS OF USE IN THE TREATMENT OF
DISEASE
Abstract
The present invention concerns methods for treating and
preventing renal/kidney disease, insulin resistance/diabetes, fatty
liver disease, and/or endothelial dysfunction/cardiovascular
disease using synthetic triterpenoids, optionally in combination
with a second treatment or prophylaxis.
Inventors: |
SPORN; Michael B.;
(Turnbridge, VT) ; LIBY; Karen T.; (West Lebanon,
NH) ; GRIBBLE; Gordon W.; (Lebanon, NH) ;
HONDA; Tadashi; (Port Jefferson Station, NY) ; Kral;
Robert M.; (Grapevine, TX) ; MEYER; Colin J.;
(Southlake, TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
REATA PHARMACEUTICALS, INC.
TRUSTEES OF DARTMOUTH COLLEGE |
Irving
Hanover |
TX
NH |
US
US |
|
|
Assignee: |
REATA PHARMACEUTICALS, INC.
Irving
TX
TRUSTEES OF DARTMOUTH COLLEGE
Hanover
NH
|
Family ID: |
40377326 |
Appl. No.: |
15/675862 |
Filed: |
August 14, 2017 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13886053 |
May 2, 2013 |
9757359 |
|
|
15675862 |
|
|
|
|
13359381 |
Jan 26, 2012 |
8455544 |
|
|
13886053 |
|
|
|
|
12352473 |
Jan 12, 2009 |
8129429 |
|
|
13359381 |
|
|
|
|
61109114 |
Oct 28, 2008 |
|
|
|
61020624 |
Jan 11, 2008 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 9/00 20180101; A61P
9/14 20180101; A61K 31/275 20130101; A61P 3/08 20180101; A61P 37/06
20180101; A61P 25/00 20180101; A61P 9/10 20180101; A61P 37/02
20180101; A61P 1/16 20180101; A61P 21/00 20180101; A61P 27/02
20180101; A61P 13/12 20180101; A61P 3/00 20180101; A61P 5/50
20180101; A61P 9/12 20180101; A61K 31/277 20130101; A61P 1/04
20180101; A61K 31/4164 20130101; A61P 13/00 20180101; A61P 3/10
20180101; A61P 3/04 20180101; A61P 17/00 20180101; A61P 3/06
20180101; A61K 31/4174 20130101; A61P 9/08 20180101; A61K 31/275
20130101; A61K 2300/00 20130101; A61K 31/4164 20130101; A61K
2300/00 20130101 |
International
Class: |
A61K 31/4174 20060101
A61K031/4174; A61K 31/277 20060101 A61K031/277; A61K 31/4164
20060101 A61K031/4164; A61K 31/275 20060101 A61K031/275 |
Claims
1. A method for treating renal/kidney disease (RKD), insulin
resistance, diabetes, endothelial dysfunction, fatty liver disease,
or cardiovascular disease (CVD) in a patient comprising,
administering to the patient a pharmaceutically effective amount of
a compound having the structure: ##STR00014## wherein R.sub.1 is:
--CN, or C.sub.1-C.sub.15-acyl or C.sub.1-C.sub.15-alkyl, wherein
either of these groups is heteroatom-substituted or
heteroatom-unsubstituted; or a pharmaceutically acceptable salt,
hydrate or solvate thereof, wherein the patient is human.
2. The method of claim 1, wherein the patient has RKD.
3. The method of claim 2, wherein the RKD is diabetic nephropathy
(DN).
4-16. (canceled)
17. The method of claim 1, wherein the patient has insulin
resistance.
18. The method of claim 1, wherein the patient has diabetes.
19-24. (canceled)
25. The method of claim 1, wherein the patient has CVD.
26. (canceled)
27. The method of claim 1, wherein the patient has endothelial
dysfunction.
28-40. (canceled)
41. The method of claim 1, wherein the compound is administered
orally.
42. (canceled)
43. The method of claim 1, wherein the compound is formulated as a
solid dispersion.
44-50. (canceled)
51. The method of claim 1, wherein the daily dose is from about 10
mg to about 200 mg of the compound.
52. The method of claim 51, wherein the daily dose is about 25 mg
of the compound.
53. (canceled)
54. (canceled)
55. The method of claim 1, wherein the daily dose is from about 0.1
mg to about 30 mg of the compound.
56-58. (canceled)
59. The method of claim 55, wherein the daily dose is from about 5
mg to about 30 mg of the compound.
60-66. (canceled)
67. The method of claim 1, further comprising a second therapy,
wherein the second therapy comprises administering to the patient a
pharmaceutically effective amount of a second drug.
68. (canceled)
69. The method of claim 67, wherein the second drug is a
cholesterol lowering drug, an anti-hyperlipidemic, a calcium
channel blocker, an anti-hypertensive, or an HMG-CoA reductase
inhibitor.
70. (canceled)
71. (canceled)
72. The method of claim 67, wherein the second drug is a
statin.
73. The method of claim 72, wherein the statin is atorvastatin,
cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin,
pravastatin, rosuvastatin or simvastatin.
74-117. (canceled)
118. The method of claim 1, wherein the compound is further defined
as: ##STR00015##
119. The method of claim 118, wherein at least a portion of the
compound of claim 118 is present as a polymorphic form, wherein the
polymorphic form is a crystalline form having an X-ray diffraction
pattern (CuK.alpha.) comprising significant diffraction peaks at
about 8.8, 12.9, 13.4, 14.2 and 17.4 .degree.2.theta..
120. (canceled)
121. The method of claim 118, wherein at least a portion of the
compound of claim 118 is present as a polymorphic form, wherein the
polymorphic form is an amorphous form having an X-ray diffraction
pattern (CuK.alpha.) with a halo peak at approximately 13.5
.degree.2.theta., substantially as shown in FIG. 12C, and a T.sub.g
in the range of about 120.degree. C. to about 135.degree. C.
122-131. (canceled)
132. The method of claim 118, wherein the compound is formulated as
a pharmaceutical composition comprising (i) a therapeutically
effective amount of the compound and (ii) an excipient is (A) a
carbohydrate, carbohydrate derivative, or carbohydrate polymer, (B)
a synthetic organic polymer, (C) an organic acid salt, (D) a
protein, polypeptide, or peptide, or (E) a high molecular weight
polysaccharide.
133-136. (canceled)
137. The method of claim 132, wherein the excipient is a
methacrylic acid-ethyl acrylate copolymer.
138-157. (canceled)
158. The method of claim 67, wherein the second drug is an
anti-hypertensive.
159. The method of claim 158, wherein the anti-hypertensive is an
angiotensin II receptor blocker.
160. The method of claim 158, wherein the anti-hypertensive is an
angiotensin-converting enzyme inhibitor.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/886,053, filed May 2, 2013, which is a
continuation of U.S. patent application Ser. No. 13/359,381, filed
Jan. 26, 2012, now U.S. Pat. No. 8,455,544, which is a continuation
of U.S. patent application Ser. No. 12/352,473, filed Jan. 12,
2009, now U.S. Pat. No. 8,124,429, which claims priority to U.S.
Provisional Application No. 61/109,114, filed Oct. 28, 2008 and
U.S. Provisional Application No. 61/020,624 filed on Jan. 11, 2008,
each of which are specifically incorporated herein by reference
without disclaimer.
BACKGROUND OF THE INVENTION
I. Field of the Invention
[0002] The present invention relates generally to the fields of
biology and medicine. More particularly, it concerns compositions
and methods for treating and/or preventing renal/kidney disease
(RKD), insulin resistance, diabetes, endothelial dysfunction, fatty
liver disease, and cardiovascular disease (CVD).
II. Description of Related Art
[0003] Renal failure, resulting in inadequate clearance of
metabolic waste products from the blood and abnormal concentrations
of electrolytes in the blood, is a significant medical problem
throughout the world, especially in developed countries. Diabetes
and hypertension are among the most important causes of chronic
renal failure, also known as chronic kidney disease (CKD), but it
is also associated with other conditions such as lupus or systemic
cardiovascular disease. Dysfunction of the vascular endothelium
commonly occurs in such conditions and is believed to be a major
contributing factor in the development of chronic kidney disease.
Acute renal failure may arise from exposure to certain drugs (e.g.,
acetaminophen) or toxic chemicals or from ischemia-reperfusion
injury associated with shock or surgical procedures such as
transplantation, and may ultimately result in CKD. In many
patients, CKD advances to end-stage renal disease (ESRD) in which
the patient requires kidney transplantation or regular dialysis to
continue living. Both of these procedures are highly invasive and
associated with significant side effects and quality of life
issues. Although there are effective treatments for some
complications of renal failure, such as hyperparathyroidism and
hyperphosphatemia, no available treatment has been shown to halt or
reverse the underlying progression of renal failure. Thus, agents
that can improve compromised renal function would represent a
significant advance in the treatment of renal failure.
[0004] Triterpenoids, biosynthesized in plants by the cyclization
of squalene, are used for medicinal purposes in many Asian
countries; and some, like ursolic and oleanolic acids, are known to
be anti-inflammatory and anti-carcinogenic (Huang et al., 1994;
Nishino et al., 1988). However, the biological activity of these
naturally-occurring molecules is relatively weak, and therefore the
synthesis of new analogs to enhance their potency was undertaken
(Honda et al., 1997; Honda et al., 1998). An ongoing effort for the
improvement of anti-inflammatory and antiproliferative activity of
oleanolic and ursolic acid analogs led to the discovery of
2-cyano-3,12-dioxooleane-1,9(11)-dien-28-oic acid (CDDO) and
related compounds (Honda et al., 1997, 1998, 1999, 2000a, 2000b,
2002; Suh et al., 1998; 1999; 2003; Place et al., 2003; Liby et
al., 2005). Several potent derivatives of oleanolic acid were
identified, including
methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO-Me; RTA
402). RTA 402 suppresses the induction of several important
inflammatory mediators, such as iNOS, COX-2, TNF.alpha., and
IFN.gamma., in activated macrophages. RTA 402 has also been
reported to activate the Keap1/Nrf2/ARE signaling pathway resulting
in the production of several anti-inflammatory and antioxidant
proteins, such as heme oxygenase-1 (HO-1). These properties have
made RTA 402 a candidate for the treatment of neoplastic and
proliferative diseases, such as cancer. The ability of this
compound and related molecules to treat and/or prevent kidney
disease and cardiovascular disease remains untested.
SUMMARY OF THE INVENTION
[0005] The present invention provides new methods for treating
and/or preventing renal/kidney disease (RKD), insulin resistance,
diabetes, endothelial dysfunction, fatty liver disease,
cardiovascular disease (CVD), and related disorders. Compounds
covered by the generic or specific formulas below or specifically
named are referred to as "compounds of the invention," "compounds
of the present invention," or "synthetic triterpenoids" in the
present application.
[0006] In one aspect of the present prevention, methods are
provided for treating or preventing renal/kidney disease (RKD),
insulin resistance, diabetes, endothelial dysfunction, fatty liver
disease, or cardiovascular disease (CVD) in a subject comprising,
administering to said subject a pharmaceutically effective amount
of a compound having the structure:
##STR00001##
wherein R.sub.1 is: --CN, or C.sub.1-C.sub.15-acyl or
C.sub.1-C.sub.15-alkyl, wherein either of these groups is
heteroatom-substituted or heteroatom-unsubstituted; or a
pharmaceutically acceptable salt, hydrate or solvate thereof.
[0007] In some embodiments, methods are provided for treating RKD.
In some variations, the RKD is diabetic nephropathy (DN). In other
variations, the RKD results from a toxic insult, for example,
wherein the toxic insult results from an imaging agent or a drug.
For example, the drug may be a chemotherapeutic agent. In a further
variation, the RKD results from ischemia/reperfusion injury. In yet
a further variation, the RKD results from diabetes or hypertension.
In still further variations, the RKD results from an autoimmune
disease. In other variations, the RKD is chronic RKD. In still
other variations, the RKD is acute RKD.
[0008] In some embodiments, the subject has undergone or is
undergoing dialysis. In some embodiments, the subject has undergone
or is a candidate to undergo kidney transplant. In some
embodiments, the subject has RKD and insulin resistance. In some
variations on the above embodiments, the subject has RKD, insulin
resistance and endothelial dysfunction. In some embodiments, the
subject has RKD and diabetes. In some embodiments, the subject has
insulin resistance.
[0009] In some embodiments, the subject has diabetes. The
pharmaceutically effective amount of the compound may also
effectively treat one or more complications associated with
diabetes. For example, the complications can be selected from the
group consisting of obesity, hypertension, atherosclerosis,
coronary heart disease, stroke, peripheral vascular disease,
hypertension, nephropathy, neuropathy, myonecrosis, diabetic foot
ulcers and other diabetic ulcers, retinopathy and metabolic
syndrome (syndrome X). Also, for example, the complication can be
metabolic syndrome (syndrome X). In some variations, the diabetes
results from insulin resistance.
[0010] In some embodiments, the subject has RKD and endothelial
dysfunction. In other embodiments, the subject has RKD and
cardiovascular disease. In some embodiments, the subject has CVD.
In some variations, the CVD results from endothelial
dysfunction.
[0011] In some embodiments, the subject has endothelial dysfunction
and/or insulin resistance. In some embodiments, the subject has
fatty liver disease. In some variations, the fatty liver disease is
non-alcoholic fatty liver disease. In other variations, the fatty
liver disease is alcoholic fatty liver disease. In some variations,
the subject has fatty liver disease and one or more of the
following disorders: renal/kidney disease (RKD), insulin
resistance, diabetes, endothelial dysfunction, and cardiovascular
disease (CVD).
[0012] In some embodiments, the methods further comprise
identifying a subject in need of treatment of any of the diseases,
dysfunctions, resistances or disorders listed herein. In some
embodiments, the subject has a family or patient history of any of
the diseases, dysfunctions, resistances or disorders listed herein.
In some embodiments, the subject exhibits symptoms of any of the
diseases, dysfunctions, resistances or disorders listed herein.
[0013] In another aspect of the invention, a method is provided for
improving glomerular filtration rate or creatinine clearance in a
subject comprising, administering to said subject a
pharmaceutically effective amount of a compound having the
structure of Formula I, or a pharmaceutically acceptable salt,
hydrate or solvate thereof.
[0014] In some embodiments, the compound is administered locally.
In some embodiments, the compound is administered systemically. In
some embodiments, the compound is administered orally,
intraadiposally, intraarterially, intraarticularly, intracranially,
intradermally, intralesionally, intramuscularly, intranasally,
intraocularally, intrapericardially, intraperitoneally,
intrapleurally, intraprostatically, intrarectally, intrathecally,
intratracheally, intratumorally, intraumbilically, intravaginally,
intravenously, intravesicularlly, intravitreally, liposomally,
locally, mucosally, orally, parenterally, rectally,
subconjunctivally, subcutaneously, sublingually, topically,
transbuccally, transdermally, vaginally, in cremes, in lipid
compositions, via a catheter, via a lavage, via continuous
infusion, via infusion, via inhalation, via injection, via local
delivery, via localized perfusion, bathing target cells directly,
or any combination thereof. For example, in some variations, the
compound is administered intravenously, intra-arterially or orally.
For example, in some variations, the compound is administered
orally.
[0015] In some embodiments, the compound is formulated as a hard or
soft capsule, a tablet, a syrup, a suspension, a solid dispersion,
a wafer, or an elixir. In some variations, the soft capsule is a
gelatin capsule. In variations, the compound is formulated as a
solid dispersion. In some variations the hard capsule, soft
capsule, tablet or wafer further comprises a protective coating. In
some variations, the formulated compound comprises an agent that
delays absorption. In some variations, the formulated compound
further comprises an agent that enhances solubility or
dispersibility. In some variations, the compound is dispersed in a
liposome, an oil in water emulsion or a water in oil emulsion.
[0016] In some embodiments, the pharmaceutically effective amount
is a daily dose from about 0.1 mg to about 500 mg of the compound.
In some variations, the daily dose is from about 1 mg to about 300
mg of the compound. In some variations, the daily dose is from
about 10 mg to about 200 mg of the compound. In some variations,
the daily dose is about 25 mg of the compound. In other variations,
the daily dose is about 75 mg of the compound. In still other
variations, the daily dose is about 150 mg of the compound. In
further variations, the daily dose is from about 0.1 mg to about 30
mg of the compound. In some variations, the daily dose is from
about 0.5 mg to about 20 mg of the compound. In some variations,
the daily dose is from about 1 mg to about 15 mg of the compound.
In some variations, the daily dose is from about 1 mg to about 10
mg of the compound. In some variations, the daily dose is from
about 1 mg to about 5 mg of the compound.
[0017] In some embodiments, the pharmaceutically effective amount
is a daily dose is 0.01-25 mg of compound per kg of body weight. In
some variations, the daily dose is 0.05-20 mg of compound per kg of
body weight. In some variations, the daily dose is 0.1-10 mg of
compound per kg of body weight. In some variations, the daily dose
is 0.1-5 mg of compound per kg of body weight. In some variations,
the daily dose is 0.1-2.5 mg of compound per kg of body weight.
[0018] In some embodiments, the pharmaceutically effective amount
is administered in a single dose per day. In some embodiments, the
pharmaceutically effective amount is administered in two or more
doses per day.
[0019] In some embodiments, the treatment method further comprises
a second therapy. In some variations, the second therapy comprises
administering to said subject a pharmaceutically effective amount
of a second drug. In some embodiments, the second drug is a
cholesterol lowering drug, an anti-hyperlipidemic, a calcium
channel blocker, an anti-hypertensive, or an HMG-CoA reductase
inhibitor. Non-limiting examples of second drugs are amlodipine,
aspirin, ezetimibe, felodipine, lacidipine, lercanidipine,
nicardipine, nifedipine, nimodipine, nisoldipine and nitrendipine.
Further non-limiting examples of second drugs are atenolol,
bucindolol, carvedilol, clonidine, doxazosin, indoramin, labetalol,
methyldopa, metoprolol, nadolol, oxprenolol, phenoxybenzamine,
phentolamine, pindolol, prazosin, propranolol, terazosin, timolol
and tolazoline. In some variations, the second drug is a statin.
Non-limiting examples of statins are atorvastatin, cerivastatin,
fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin,
rosuvastatin and simvastatin. In some variations, the second drug
is a dipeptidyl peptidase-4 (DPP-4) inhibitor. Non-limiting
examples of DPP-4 inhibitors are sitagliptin, vildagliptin,
SYR-322, BMS 477118 and GSK 823093. In some variations, the second
drug is a biguanide. For example, the biguanide can be metformin.
In some variations, the second drug is a thiazolidinedione (TZD).
Non-limiting examples of TZDs are pioglitazone, rosiglitazone and
troglitazone. In some variations, the second drug is a sulfonylurea
derivative. Non-limiting examples of sulfonyl urea derivatives are
tolbutamide, acetohexamide, tolazamide, chlorpropamide, glipizide,
glyburide, glimepiride and gliclazide. In some variations, the
second drug is a meglitinide. Non-limiting examples of meglitinides
include repaglinide, mitiglinide and nateglinide. In some
variations, the second drug is insulin. In some variations, the
second drug is an alpha-glucosidase inhibitor. Non-limiting
examples of alpha-glucosidase inhibitors are acarbose, miglitol and
voglibose. In some variations, the second drug is a glucagon-like
peptide-1 analog. Non-limiting examples of glucagon-like peptide-1
analogs are exenatide and liraglutide. In some variations, the
second drug is a gastric inhibitory peptide analog. In some
variations, the second drug is a GPR40 agonist. In some variations,
the second drug is a GPR119 agonist. In some variations the second
drug is a GPR30 agonist. In some variations, the second drug is a
glucokinase activator. In some variations, the second drug is a
glucagon receptor antagonist. In some variations, the second drug
is an amylin analog. A non-limiting example of an amylin analog is
pramlintide. In some variations, the second drug is an IL-1.beta.
receptor antagonist. A non-limiting examples of a IL-13 receptor
antagonist is anakinra. In some variations, the second drug is an
endocannabinoid receptor antagonist or inverse agonist. A
non-limiting example of a endocannabinoid receptor antagonist or
inverse agonist is rimonabant. In some variations, the second drug
is Orlistat. In some variations, the second drug is Sibutramine. In
some variations, the second drug is a growth factor. Non-limiting
examples of growth factors are TGF-.beta.1, TGF-.beta.2,
TGF-.beta.1.2, VEGF, insulin-like growth factor I or II, BMP2,
BMP4, BMP7, a GLP-1 analog, a GIP analog, a DPP-IV inhibitor, a
GPR119 agonist, a GPR40 agonist, gastrin, EGF, betacellulin, KGF,
NGF, insulin, growth hormone, HGF, an FGF, an FGF homologue, PDGF,
Leptin, prolactin, placental lactogen, PTHrP, activin, inhibin, and
INGAP. Further non-limiting examples of growth factors are
parathyroid hormone, calcitonin, interleukin-6, and
interleukin-11.
[0020] In some embodiments, the subject is a primate. In some
variations, the primate is a human. In other variations, the
subject is a cow, horse, dog, cat, pig, mouse, rat or guinea
pig.
[0021] In some embodiments, the compound is defined as:
##STR00002##
wherein Y is: --H, hydroxy, amino, halo, or
C.sub.1-C.sub.14-alkoxy, C.sub.2-C.sub.14-alkenyloxy,
C.sub.2-C.sub.14-alkynyloxy, C.sub.1-C.sub.14-aryloxy,
C.sub.2-C.sub.14-aralkoxy, C.sub.1-C.sub.14-alkylamino,
C.sub.2-C.sub.14-alkenylamino, C.sub.2-C.sub.14-alkynylamino,
C.sub.1-C.sub.14-arylamino, C.sub.3-C.sub.10-aryl, or
C.sub.2-C.sub.14-aralkylamino, wherein any of these groups is
heteroatom-substituted or heteroatom-unsubstituted; or a
pharmaceutically acceptable salt, hydrate or solvate thereof.
[0022] In some embodiments, Y is a heteroatom-unsubstituted
C.sub.1-C.sub.4-alkylamino, such that the compound of the invention
is, for example:
##STR00003##
[0023] In some embodiments, Y is a heteroatom-substituted or
heteroatom-unsubstituted C.sub.2-C.sub.4-alkylamino, such that the
compound of the invention is, for example:
##STR00004##
[0024] In some embodiments, Y is a heteroatom-substituted or
heteroatom-unsubstituted C.sub.1-C.sub.4-alkoxy, such as a
heteroatom-unsubstituted C.sub.1-C.sub.2-alkoxy. For example, one
non-limiting example of such a compound is:
##STR00005##
[0025] In some embodiments, at least a portion of the CDDO-Me is
present as a polymorphic form, wherein the polymorphic form is a
crystalline form having an X-ray diffraction pattern (CuK.alpha.)
comprising significant diffraction peaks at about 8.8, 12.9, 13.4,
14.2 and 17.4 .degree.2.theta.. In non-limiting examples, the X-ray
diffraction pattern (CuK.alpha.) is substantially as shown in FIG.
12A or FIG. 12B. In other variations, at least a portion of the
CDDO-Me is present as a polymorphic form, wherein the polymorphic
form is an amorphous form having an X-ray diffraction pattern
(CuK.alpha.) with a halo peak at approximately 13.5
.degree.2.theta., substantially as shown in FIG. 12C, and a
T.sub.g. In some variations, the compound is an amorphous form. In
some variations, the compound is a glassy solid form of CDDO-Me,
having an X-ray powder diffraction pattern with a halo peak at
about 13.5 .degree. 2.theta., as shown in FIG. 12C, and a T.sub.g.
In some variations, the T.sub.g value falls within a range of about
120.degree. C. to about 135.degree. C. In some variations, the
T.sub.g value is from about 125.degree. C. to about 130.degree.
C.
[0026] In some embodiments, Y is hydroxy, such that the compound of
the invention is, for example:
##STR00006##
[0027] In some embodiments, the compound is:
##STR00007##
[0028] In some embodiments, the compound is defined as:
##STR00008##
wherein Y' is a heteroatom-substituted or heteroatom-unsubstituted
C.sub.1-C.sub.14-aryl; or a pharmaceutically acceptable salt,
hydrate or solvate thereof.
[0029] In some embodiments, the compound is:
##STR00009##
[0030] In some variations of the above methods, the compound is
substantially free from optical isomers thereof. In some variations
of the above methods, the compound is in the form of a
pharmaceutically acceptable salt. In other variations of the above
methods, the compound is not a salt.
[0031] In some embodiments, the compound is formulated as a
pharmaceutical composition comprising (i) a therapeutically
effective amount of the compound and (ii) an excipient is selected
from the group consisting of (A) a carbohydrate, carbohydrate
derivative, or carbohydrate polymer, (B) a synthetic organic
polymer, (C) an organic acid salt, (D) a protein, polypeptide, or
peptide, and (E) a high molecular weight polysaccharide. In some
variations, the excipient is a synthetic organic polymer. In some
variations, the excipient is selected from the group consisting of
a hydroxpropyl methyl cellulose, a
poly[1-(2-oxo-1-pyrrolidinyl)ethylene or copolymer thereof, and a
methacrylic acid-methylmethacrylate copolymer. In some variations,
the excipient is hydroxpropyl methyl cellulose phthalate ester. In
some variations, the excipient is PVP/VA. In some variations, the
excipient is a methacrylic acid-ethyl acrylate copolymer (1:1). In
some variations, the excipient is copovidone.
[0032] Any embodiment discussed herein with respect to one aspect
of the invention applies to other aspects of the invention as well,
unless specifically noted.
[0033] Other objects, features and advantages of the present
invention will become apparent from the following detailed
description and any accompanying drawings. It should be understood,
however, that the detailed description and any specific examples or
drawings provided, while indicating specific embodiments of the
invention, are given by way of illustration only, since various
changes and modifications within the spirit and scope of the
invention will become apparent to those skilled in the art from
this detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] The following drawings form part of the present
specification and are included to further demonstrate certain
aspects of the present invention. The invention may be better
understood by reference to one or more of these drawings in
combination with the detailed description of specific embodiments
presented herein.
[0035] FIGS. 1a-d-RTA 402 reduces renal damage following
ischemia-reperfusion. Mice were administered RTA 402 at 2 mg/kg or
simply the vehicle (sesame oil) daily by oral gavage beginning on
Day 2. On Day 0, a clamp was placed on the left renal artery for 17
minutes and then removed to induce ischemia-reperfusion. (FIG. 1a)
On Day 1, blood was collected from animals that were subjected to
clamping and "sham" control animals that underwent surgery without
clamping of the renal artery. Blood urea nitrogen (BUN) levels were
measured as a surrogate for renal damage. (FIGS. 1b-d) Sections of
kidneys from RTA 402-treated or vehicle-treated mice were scored
for histological damage (FIGS. 1b & 1d) and inflammation (FIG.
1c). (FIG. 1d) Black arrows (vehicle group) show two of many
severely damaged tubules in the outer medulla. Red arrows (RTA 402
group) show two of many undamaged tubules in the outer medulla.
[0036] FIGS. 2a-c-RTA 402 reduces cisplatin-induced renal toxicity.
Rats were administered RTA 402 at 10 mg/kg or simply the vehicle
(sesame oil) every day by oral gavage beginning on Day -1. On Day
0, the rats received an intravenous injection of cisplatin at 6
mg/kg. Blood samples were drawn on the indicated days and the
levels of creatinine (FIG. 2a) and blood urea nitrogen (BUN) (FIG.
2b) were measured as markers of renal damage. A statistically
significant difference was observed between the vehicle-treated and
RTA 402-treated groups on Day 3 (creatinine) and Day 5 (creatinine
and BUN). (FIG. 2c) Less damage to the proximal tubules is observed
in RTA 402-treated animals compared to vehicle-treated animals.
[0037] FIGS. 3a-d-RTA 402 reduces serum creatinine levels in
monkeys, dogs, and rats. (FIG. 3a) Cynomolgus monkeys were
administered RTA 402 orally at the indicated doses once daily for
28 days. The percent reduction of serum creatinine on Day 28 in RTA
402-treated monkeys relative to vehicle-treated control monkeys is
shown. (FIG. 3b) RTA 402 was administered orally to beagle dogs at
the indicated doses daily for three months. Control animals
received vehicle (sesame oil). The percent change in serum
creatinine at the three-month time point relative to baseline is
shown. (FIG. 3c) Sprague-Dawley rats were administered RTA 402
orally at the indicated doses once daily for a period of one month.
The percent reduction of serum creatinine at study completion in
RTA 402-treated rats relative to vehicle-treated control rats is
shown. (FIG. 3d) Sprague-Dawley rats were administered the
amorphous form of RTA 402 orally at the indicated doses once daily
for a period of three months. The percent reduction of serum
creatinine at study completion in RTA 402-treated rats relative to
vehicle-treated control rats is shown. Note: in FIGS. 3a, 3c and
3d, "% reduction" on the vertical axis indicates percent change.
For example, a reading of -15 on this axis indicates a 15%
reduction in serum creatinine.
[0038] FIGS. 4A-B--RTA 402 reduces serum creatinine levels and
increases the estimated glomerular filtration rate (eGFR) in human
patients with cancer. FIG. 4A: Serum creatinine was measured in RTA
402-treated patients enrolled in a Phase I clinical trial for the
treatment of cancer. The patients were administered RTA 402 (p.o.)
once daily for 21 days at doses ranging from 5 to 1,300 mg/day. The
percent reduction of serum creatinine relative to baseline levels
is shown for the indicated study days. Significant decreases in
serum creatinine levels were observed on Days 15 and 21. FIG. 4B:
The estimated glomerular filtration rate (eGFR) was calculated for
the patients in FIG. 4A. Significant improvements in the eGFR were
observed in both groups. All patients: n=24; patients with baseline
.gtoreq.1.5: n=5. For FIGS. 4A and 4B, * indicatesp .ltoreq.0.04;
.dagger. indicatesp=0.01, and .dagger-dbl. indicates p.ltoreq.0.01.
Note: in FIG. 4A, "% Reduction from Baseline" on the vertical axis
indicates percent change. For example, a reading of -15 on this
axis indicates a 15% reduction in serum creatinine.
[0039] FIG. 5--RTA 402 increases GFR in human patients with cancer.
Estimated glomerular filtration rate (eGFR) was measured in RTA
402-treated patients enrolled in a multi-month clinical trial for
the treatment of cancer. All patients (n=11) dosed through six
months were included in the analysis. The dosing information for
these patients is provided in Example 5, below.
[0040] FIG. 6--RTA 402 Activity Correlates with Severity. Reduction
of hemoglobin A1c is presented as a fraction of the initial
baseline value. Groups with higher baselines, e.g., mean baseline
.gtoreq.7.0% A1c or .gtoreq.7.6% A1c, showed greater reduction. The
intent-to-treat (ITT) group includes all patients (n=53), including
those starting at a normal A1c value.
[0041] FIG. 7--RTA 402 Activity is Dose Dependent. Reduction of
hemoglobin A1c is presented relative to the initial baseline value.
The bar graph shows mean results for all patients, all patients
with baseline A1c values .gtoreq.7.0%, individual dose cohorts from
the .gtoreq.7.0% group, and patients with Stage 4 renal disease
(GFR 15-29 mL/min), wherein n is the number of patients in each
group.
[0042] FIG. 8--RTA 402 Reduces Circulating Endothelial Cells (CECs)
and iNOS-positive CECs. The change in the mean number of CECs in
cells/mL is shown for intent-to-treat (ITT) and elevated baseline
groups, both before and after the 28 day RTA treatment. The
reduction for the Intent-to-treat group was approximately 20%, and
the reduction in the elevated baseline group (>5 CECs/ml) was
approximately 33%. The fraction of iNOS-positive CECs was reduced
approximately 29%.
[0043] FIG. 9--Reversible Dose Dependent GFR Increase in 28 Days.
Treatment with RTA 402 increases GFR dose-dependently. All
evaluable patients were included. An improvement of >30% was
noted in patients with Stage 4 renal disease.
[0044] FIGS. 10A-B--Reduction of Markers of Diabetic Nephropathy
Severity and Outcome. Improvements in Adiponectin (FIG. 10A) and
Angiotensin II (FIG. 10B), which are elevated in diabetic
nephropathy (DN) patients and correlate with renal disease
severity. Adiponectin predicts all-cause mortality and end stage
renal disease in DN patients. All available data included.
[0045] FIGS. 11A-C--RTA 402 Significantly Reduces Uremic Solutes.
The graphs present mean changes in BUN (FIG. 11A), phosphorus (FIG.
11B), and uric acid (FIG. 11C) for all patients and for those
patients showing elevated baseline values of a particular
solute.
[0046] FIGS. 12A-C--X-ray Powder Diffraction (XRPD) Spectra of
Forms A and B of RTA 402. FIG. 12A shows unmicronized Form A; FIG.
12B shows micronized Form A;
[0047] FIG. 12C shows Form B.
[0048] FIG. 13--Modulated Differential Scanning Calorimetry (MDSC)
Curve of Form A RTA 402. The section of the curve shown in the
expanded view is consistent with a glass transition temperature
(T.sub.g).
[0049] FIG. 14--Modulated Differential Scanning Calorimetry (MDSC)
Curve of Form B RTA 402. The section of the curve shown in the
expanded view is consistent with a glass transition temperature
(T.sub.g).
[0050] FIG. 15--Improved Bioavailability of Form B (Amorphous) in
Cynomolgus Monkeys. The figure shows a representative plot of the
area under the curve for Form A and Form B, following a 4.1 mg/kg
oral administration to cynomolgus monkeys. Each data point
represents the mean plasma concentration of CDDO methyl ester in 8
animals. Error bars represent the standard deviation within the
sampled population.
DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
I. The Present Invention
[0051] The present invention concerns new methods for the treatment
and prevention of renal disease and related disorders, including
diabetes and cardiovascular disease, involving the use of
triterpenoids.
II. Definitions
[0052] As used herein, the term "amino" means --NH.sub.2; the term
"nitro" means --NO.sub.2; the term "halo" designates --F, --Cl,
--Br or --I; the term "mercapto" means --SH; the term "cyano" means
--CN; the term "silyl" means --SiH.sub.3, and the term "hydroxy"
means --OH.
[0053] The term "heteroatom-substituted," when used to modify a
class of organic radicals (e.g., alkyl, aryl, acyl, etc.), means
that one, or more than one, hydrogen atom of that radical has been
replaced by a heteroatom, or a heteroatom containing group.
Examples of heteroatoms and heteroatom containing groups include:
hydroxy, cyano, alkoxy, .dbd.O, .dbd.S, --NO.sub.2,
--N(CH.sub.3).sub.2, amino, or --SH. Specific
heteroatom-substituted organic radicals are defined more fully
below.
[0054] The term "heteroatom-unsubstituted," when used to modify a
class of organic radicals (e.g., alkyl, aryl, acyl, etc.) means
that none of the hydrogen atoms of that radical have been replaced
with a heteroatom or a heteroatom containing group. Substitution of
a hydrogen atom with a carbon atom, or a group consisting of only
carbon and hydrogen atoms, is not sufficient to make a group
heteroatom-substituted. For example, the group
--C.sub.6H.sub.4C.ident.CH is an example of a
heteroatom-unsubstituted aryl group, while --C.sub.6H.sub.4F is an
example of a heteroatom-substituted aryl group. Specific
heteroatom-unsubstituted organic radicals are defined more fully
below.
[0055] The term "alkyl" includes straight-chain alkyl groups,
branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl
heteroatom-substituted cycloalkyl groups, and cycloalkyl
heteroatom-substituted alkyl groups. The term
"heteroatom-unsubstituted C.sub.n-alkyl" refers to a radical having
a linear or branched, cyclic or acyclic structure, further having
no carbon-carbon double or triple bonds, further having a total of
n carbon atoms, all of which are nonaromatic, 3 or more hydrogen
atoms, and no heteroatoms. For example, a heteroatom-unsubstituted
C.sub.1-C.sub.10-alkyl has 1 to 10 carbon atoms. The groups,
--CH.sub.3, --CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH(CH.sub.2).sub.2 (cyclopropyl),
--CH.sub.2CH.sub.2CH.sub.2CH.sub.3, --CH(CH.sub.3)CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3,
--CH.sub.2C(CH.sub.3).sub.3, cyclobutyl, cyclopentyl, and
cyclohexyl, are all examples of heteroatom-unsubstituted alkyl
groups. The term "heteroatom-substituted C.sub.n-alkyl" refers to a
radical having a single saturated carbon atom as the point of
attachment, no carbon-carbon double or triple bonds, further having
a linear or branched, cyclic or acyclic structure, further having a
total of n carbon atoms, all of which are nonaromatic, 0, 1, or
more than one hydrogen atom, at least one heteroatom, wherein each
heteroatom is independently selected from the group consisting of
N, O, F, Cl, Br, I, Si, P, and S. For example, a
heteroatom-substituted C.sub.1-C.sub.10-alkyl has 1 to 10 carbon
atoms. The following groups are all examples of
heteroatom-substituted alkyl groups: trifluoromethyl, --CH.sub.2F,
--CH.sub.2C.sub.1, --CH.sub.2Br, --CH.sub.2OH, --CH.sub.2OCH.sub.3,
--CH.sub.2OCH.sub.2CH.sub.3, --CH.sub.2OCH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2OCH(CH.sub.3).sub.2, --CH.sub.2OCH(CH.sub.2).sub.2,
--CH.sub.2OCH.sub.2CF.sub.3, --CH.sub.2OCOCH.sub.3,
--CH.sub.2NH.sub.2, --CH.sub.2NHCH.sub.3,
--CH.sub.2N(CH.sub.3).sub.2, --CH.sub.2NHCH.sub.2CH.sub.3,
--CH.sub.2N(CH.sub.3)CH.sub.2CH.sub.3,
--CH.sub.2NHCH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2NHCH(CH.sub.3).sub.2, --CH.sub.2NHCH(CH.sub.2).sub.2,
--CH.sub.2N(CH.sub.2CH.sub.3).sub.2, --CH.sub.2CH.sub.2F,
--CH.sub.2CH.sub.2C.sub.1, --CH.sub.2CH.sub.2Br,
--CH.sub.2CH.sub.2I, --CH.sub.2CH.sub.2OH,
--CH.sub.2CH.sub.2OCOCH.sub.3, --CH.sub.2CH.sub.2NH.sub.2,
--CH.sub.2CH.sub.2N(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2NHCH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2N(CH.sub.3)CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2NHCH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH.sub.2NHCH(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2NHCH(CH.sub.2).sub.2,
--CH.sub.2CH.sub.2N(CH.sub.2CH.sub.3).sub.2,
--CH.sub.2CH.sub.2NHCO.sub.2C(CH.sub.3).sub.3, and
--CH.sub.2Si(CH.sub.3).sub.3.
[0056] The term "heteroatom-unsubstituted C.sub.n-alkenyl" refers
to a radical having a linear or branched, cyclic or acyclic
structure, further having at least one nonaromatic carbon-carbon
double bond, but no carbon-carbon triple bonds, a total of n carbon
atoms, three or more hydrogen atoms, and no heteroatoms. For
example, a heteroatom-unsubstituted C.sub.2-C.sub.10-alkenyl has 2
to 10 carbon atoms. Heteroatom-unsubstituted alkenyl groups
include: --CH.dbd.CH.sub.2, --CH.dbd.CHCH.sub.3,
--CH.dbd.CHCH.sub.2CH.sub.3, --CH.dbd.CHCH.sub.2CH.sub.2CH.sub.3,
--CH.dbd.CHCH(CH.sub.3).sub.2, --CH.dbd.CHCH(CH.sub.2).sub.2,
--CH.sub.2CH.dbd.CH.sub.2, --CH.sub.2CH.dbd.CHCH.sub.3,
--CH.sub.2CH.dbd.CHCH.sub.2CH.sub.3,
--CH.sub.2CH.dbd.CHCH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH.dbd.CHCH(CH.sub.3).sub.2,
--CH.sub.2CH.dbd.CHCH(CH.sub.2).sub.2, and
--CH.dbd.CH--C.sub.6H.sub.5. The term "heteroatom-substituted
C.sub.n-alkenyl" refers to a radical having a single nonaromatic
carbon atom as the point of attachment and at least one nonaromatic
carbon-carbon double bond, but no carbon-carbon triple bonds,
further having a linear or branched, cyclic or acyclic structure,
further having a total of n carbon atoms, 0, 1, or more than one
hydrogen atom, and at least one heteroatom, wherein each heteroatom
is independently selected from the group consisting of N, O, F, Cl,
Br, I, Si, P, and S. For example, a heteroatom-substituted
C.sub.2-C.sub.10-alkenyl has 2 to 10 carbon atoms. The groups,
--CH.dbd.CHF, --CH.dbd.CHCl and --CH.dbd.CHBr, are examples of
heteroatom-substituted alkenyl groups.
[0057] The term "heteroatom-unsubstituted C.sub.n-alkynyl" refers
to a radical having a linear or branched, cyclic or acyclic
structure, further having at least one carbon-carbon triple bond, a
total of n carbon atoms, at least one hydrogen atom, and no
heteroatoms. For example, a heteroatom-unsubstituted
C.sub.2-C.sub.10-alkynyl has 2 to 10 carbon atoms. The groups,
--C.ident.CH, --C.ident.CCH.sub.3, and --C.ident.CC.sub.6H.sub.5
are examples of heteroatom-unsubstituted alkynyl groups. The term
"heteroatom-substituted C.sub.n-alkynyl" refers to a radical having
a single nonaromatic carbon atom as the point of attachment and at
least one carbon-carbon triple bond, further having a linear or
branched, cyclic or acyclic structure, and having a total of n
carbon atoms, 0, 1, or more than one hydrogen atom, and at least
one heteroatom, wherein each heteroatom is independently selected
from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. For
example, a heteroatom-substituted C.sub.2-C.sub.10-alkynyl has 2 to
10 carbon atoms. The group, --C.ident.CSi(CH.sub.3).sub.3, is an
example of a heteroatom-substituted alkynyl group.
[0058] The term "heteroatom-unsubstituted C.sub.n-aryl" refers to a
radical having a single carbon atom as a point of attachment,
wherein the carbon atom is part of an aromatic ring structure
containing only carbon atoms, further having a total of n carbon
atoms, 5 or more hydrogen atoms, and no heteroatoms. For example, a
heteroatom-unsubstituted C.sub.6-C.sub.10-aryl has 6 to 10 carbon
atoms. Examples of heteroatom-unsubstituted aryl groups include
phenyl, methylphenyl, (dimethyl)phenyl,
--C.sub.6H.sub.4CH.sub.2CH.sub.3,
--C.sub.6H.sub.4CH.sub.2CH.sub.2CH.sub.3,
--C.sub.6H.sub.4CH(CH.sub.3).sub.2,
--C.sub.6H.sub.4CH(CH.sub.2).sub.2,
--C.sub.6H.sub.3(CH.sub.3)CH.sub.2CH.sub.3,
--C.sub.6H.sub.4CH.dbd.CH.sub.2, --C.sub.6H.sub.4CH.dbd.CHCH.sub.3,
--C.sub.6H.sub.4C.ident.CH, --C.sub.6H.sub.4C.ident.CCH.sub.3,
naphthyl, and the radical derived from biphenyl. The term
"heteroatom-unsubstituted aryl" includes carbocyclic aryl groups,
biaryl groups, and radicals derived from polycyclic fused
hydrocarbons (PAHs). The term "heteroatom-substituted C.sub.n-aryl"
refers to a radical having either a single aromatic carbon atom or
a single aromatic heteroatom as the point of attachment, further
having a total of n carbon atoms, at least one hydrogen atom, and
at least one heteroatom, further wherein each heteroatom is
independently selected from the group consisting of N, O, F, Cl,
Br, I, Si, P, and S. For example, a heteroatom-unsubstituted
C.sub.1-C.sub.10-heteroaryl has 1 to 10 carbon atoms. The term
"heteroatom-substituted aryl" includes heteroaryl groups. It also
includes those groups derived from the compounds: pyrrole, furan,
thiophene, imidazole, oxazole, isoxazole, thiazole, isothiazole,
triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and
the like. Further examples of heteroatom-substituted aryl groups
include the groups: --C.sub.6H.sub.4F, --C.sub.6H.sub.4C.sub.1,
--C.sub.6H.sub.4Br, --C.sub.6H.sub.4I, --C.sub.6H.sub.4OH,
--C.sub.6H.sub.4OCH.sub.3, --C.sub.6H.sub.4OCH.sub.2CH.sub.3,
--C.sub.6H.sub.4OCOCH.sub.3, --C.sub.6H.sub.4OC.sub.6H.sub.5,
--C.sub.6H.sub.4NH.sub.2, --C.sub.6H.sub.4NHCH.sub.3,
--C.sub.6H.sub.4NHCH.sub.2CH.sub.3,
--C.sub.6H.sub.4CH.sub.2C.sub.1, --C.sub.6H.sub.4CH.sub.2Br,
--C.sub.6H.sub.4CH.sub.2OH, --C.sub.6H.sub.4CH.sub.2OCOCH.sub.3,
--C.sub.6H.sub.4CH.sub.2NH.sub.2,
--C.sub.6H.sub.4N(CH.sub.3).sub.2,
--C.sub.6H.sub.4CH.sub.2CH.sub.2C.sub.1,
--C.sub.6H.sub.4CH.sub.2CH.sub.2OH,
--C.sub.6H.sub.4CH.sub.2CH.sub.2OCOCH.sub.3,
--C.sub.6H.sub.4CH.sub.2CH.sub.2NH.sub.2,
--C.sub.6H.sub.4CH.sub.2CH.dbd.CH.sub.2, --C.sub.6H.sub.4CF.sub.3,
--C.sub.6H.sub.4CN, --C.sub.6H.sub.4C.ident.CSi(CH.sub.3).sub.3,
--C.sub.6H.sub.4COH, --C.sub.6H.sub.4COCH.sub.3,
--C.sub.6H.sub.4COCH.sub.2CH.sub.3,
--C.sub.6H.sub.4COCH.sub.2CF.sub.3,
--C.sub.6H.sub.4COC.sub.6H.sub.5, --C.sub.6H.sub.4CO.sub.2H,
--C.sub.6H.sub.4CO.sub.2CH.sub.3, --C.sub.6H.sub.4CONH.sub.2,
--C.sub.6H.sub.4CONHCH.sub.3, --C.sub.6H.sub.4CON(CH.sub.3).sub.2,
furanyl, thienyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl,
imidazoyl, quinolyl and indolyl.
[0059] The term "heteroatom-unsubstituted C.sub.n-aralkyl" refers
to a radical having a single saturated carbon atom as the point of
attachment, further having a total of n carbon atoms, wherein at
least 6 of the carbon atoms form an aromatic ring structure
containing only carbon atoms, 7 or more hydrogen atoms, and no
heteroatoms. For example, a heteroatom-unsubstituted
C.sub.7-C.sub.10-aralkyl has 7 to 10 carbon atoms. Examples of
heteroatom-unsubstituted aralkyls include phenylmethyl (benzyl) and
phenylethyl. The term "heteroatom-substituted C.sub.n-aralkyl"
refers to a radical having a single saturated carbon atom as the
point of attachment, further having a total of n carbon atoms, 0,
1, or more than one hydrogen atom, and at least one heteroatom,
wherein at least one of the carbon atoms is incorporated in an
aromatic ring structure, further wherein each heteroatom is
independently selected from the group consisting of N, O, F, Cl,
Br, I, Si, P, and S. For example, a heteroatom-substituted
C.sub.2-C.sub.10-heteroaralkyl has 2 to 10 carbon atoms.
[0060] The term "heteroatom-unsubstituted C.sub.n-acyl" refers to a
radical having a single carbon atom of a carbonyl group as the
point of attachment, further having a linear or branched, cyclic or
acyclic structure, further having a total of n carbon atoms, 1 or
more hydrogen atoms, a total of one oxygen atom, and no additional
heteroatoms. For example, a heteroatom-unsubstituted
C.sub.1-C.sub.10-acyl has 1 to 10 carbon atoms. The groups, --COH,
--COCH.sub.3, --COCH.sub.2CH.sub.3, --COCH.sub.2CH.sub.2CH.sub.3,
--COCH(CH.sub.3).sub.2, --COCH(CH.sub.2).sub.2, --COC.sub.6H.sub.5,
--COC.sub.6H.sub.4CH.sub.3, --COC.sub.6H.sub.4CH.sub.2CH.sub.3,
--COC.sub.6H.sub.4CH.sub.2CH.sub.2CH.sub.3,
--COC.sub.6H.sub.4CH(CH.sub.3).sub.2,
--COC.sub.6H.sub.4CH(CH.sub.2).sub.2, and
--COC.sub.6H.sub.3(CH.sub.3).sub.2, are examples of
heteroatom-unsubstituted acyl groups. The term
"heteroatom-substituted C.sub.n-acyl" refers to a radical having a
single carbon atom as the point of attachment, the carbon atom
being part of a carbonyl group, further having a linear or
branched, cyclic or acyclic structure, further having a total of n
carbon atoms, 0, 1, or more than one hydrogen atom, at least one
additional heteroatom in addition to the oxygen of the carbonyl
group, wherein each additional heteroatom is independently selected
from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. For
example, a heteroatom-substituted C.sub.1-C.sub.10-acyl has 1 to 10
carbon atoms. The term heteroatom-substituted acyl includes
carbamoyl, thiocarboxylate, and thiocarboxylic acid groups. The
groups, --COCH.sub.2CF.sub.3, --CO.sub.2H, --CO.sub.2CH.sub.3,
--CO.sub.2CH.sub.2CH.sub.3, --CO.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CO.sub.2CH(CH.sub.3).sub.2, --CO.sub.2CH(CH.sub.2).sub.2,
--CONH.sub.2, --CONHCH.sub.3, --CONHCH.sub.2CH.sub.3,
--CONHCH.sub.2CH.sub.2CH.sub.3, --CONHCH(CH.sub.3).sub.2,
--CONHCH(CH.sub.2).sub.2, --CON(CH.sub.3).sub.2,
--CON(CH.sub.2CH.sub.3)CH.sub.3, --CON(CH.sub.2CH.sub.3).sub.2 and
--CONHCH.sub.2CF.sub.3, are examples of heteroatom-substituted acyl
groups.
[0061] The term "heteroatom-unsubstituted C.sub.n-alkoxy" refers to
a group, having the structure --OR, in which R is a
heteroatom-unsubstituted C.sub.n-alkyl, as that term is defined
above. Heteroatom-unsubstituted alkoxy groups include: --OCH.sub.3,
--OCH.sub.2CH.sub.3, --OCH.sub.2CH.sub.2CH.sub.3,
--OCH(CH.sub.3).sub.2, and --OCH(CH.sub.2).sub.2. The term
"heteroatom-substituted C.sub.n-alkoxy" refers to a group, having
the structure --OR, in which R is a heteroatom-substituted
C.sub.n-alkyl, as that term is defined above. For example,
--OCH.sub.2CF.sub.3 is a heteroatom-substituted alkoxy group.
[0062] The term "heteroatom-unsubstituted C.sub.n-alkenyloxy"
refers to a group, having the structure --OR, in which R is a
heteroatom-unsubstituted C.sub.n-alkenyl, as that term is defined
above. The term "heteroatom-substituted C.sub.n-alkenyloxy" refers
to a group, having the structure --OR, in which R is a
heteroatom-substituted C.sub.n-alkenyl, as that term is defined
above.
[0063] The term "heteroatom-unsubstituted C.sub.n-alkynyloxy"
refers to a group, having the structure --OR, in which R is a
heteroatom-unsubstituted C.sub.n-alkynyl, as that term is defined
above. The term "heteroatom-substituted C.sub.n-alkynyloxy" refers
to a group, having the structure --OR, in which R is a
heteroatom-substituted C.sub.n-alkynyl, as that term is defined
above.
[0064] The term "heteroatom-unsubstituted C.sub.n-aryloxy" refers
to a group, having the structure --OAr, in which Ar is a
heteroatom-unsubstituted C.sub.n-aryl, as that term is defined
above. An example of a heteroatom-unsubstituted aryloxy group is
--OC.sub.6H.sub.5. The term "heteroatom-substituted
C.sub.n-aryloxy" refers to a group, having the structure --OAr, in
which Ar is a heteroatom-substituted C.sub.n-aryl, as that term is
defined above.
[0065] The term "heteroatom-unsubstituted C.sub.n-aralkyloxy"
refers to a group, having the structure --OR.sub.Ar, in which
R.sub.Ar is a heteroatom-unsubstituted C.sub.n-aralkyl, as that
term is defined above. The term "heteroatom-substituted
C.sub.n-aralkyloxy" refers to a group, having the structure
--OR.sub.Ar, in which R.sub.Ar is a heteroatom-substituted
C.sub.n-aralkyl, as that term is defined above.
[0066] The term "heteroatom-unsubstituted C.sub.n-acyloxy" refers
to a group, having the structure --OAc, in which Ac is a
heteroatom-unsubstituted C.sub.n-acyl, as that term is defined
above. A heteroatom-unsubstituted acyloxy group includes
alkylcarbonyloxy and arylcarbonyloxy groups. For example,
--OCOCH.sub.3 is an example of a heteroatom-unsubstituted acyloxy
group. The term "heteroatom-substituted C.sub.n-acyloxy" refers to
a group, having the structure --OAc, in which Ac is a
heteroatom-substituted C.sub.n-acyl, as that term is defined above.
A heteroatom-substituted acyloxy group includes alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,
aminocarbonyl, and alkylthiocarbonyl groups.
[0067] The term "heteroatom-unsubstituted C.sub.n-alkylamino"
refers to a radical having a single nitrogen atom as the point of
attachment, further having one or two saturated carbon atoms
attached to the nitrogen atom, further having a linear or branched,
cyclic or acyclic structure, containing a total of n carbon atoms,
all of which are nonaromatic, 4 or more hydrogen atoms, a total of
1 nitrogen atom, and no additional heteroatoms. For example, a
heteroatom-unsubstituted C.sub.1-C.sub.10-alkylamino has 1 to 10
carbon atoms. The term "heteroatom-unsubstituted
C.sub.n-alkylamino" includes groups, having the structure --NHR, in
which R is a heteroatom-unsubstituted C.sub.n-alkyl, as that term
is defined above. A heteroatom-unsubstituted alkylamino group would
include --NHCH.sub.3, --NHCH.sub.2CH.sub.3,
--NHCH.sub.2CH.sub.2CH.sub.3, --NHCH(CH.sub.3).sub.2,
--NHCH(CH.sub.2).sub.2, --NHCH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--NHCH(CH.sub.3)CH.sub.2CH.sub.3, --NHCH.sub.2CH(CH.sub.3).sub.2,
--NHC(CH.sub.3).sub.3, --N(CH.sub.3).sub.2,
--N(CH.sub.3)CH.sub.2CH.sub.3, --N(CH.sub.2CH.sub.3).sub.2,
N-pyrrolidinyl, and N-piperidinyl. The term "heteroatom-substituted
C.sub.n-alkylamino" refers to a radical having a single nitrogen
atom as the point of attachment, further having one or two
saturated carbon atoms attached to the nitrogen atom, no
carbon-carbon double or triple bonds, further having a linear or
branched, cyclic or acyclic structure, further having a total of n
carbon atoms, all of which are nonaromatic, 0, 1, or more than one
hydrogen atom, and at least one additional heteroatom, that is, in
addition to the nitrogen atom at the point of attachment, wherein
each additional heteroatom is independently selected from the group
consisting of N, O, F, Cl, Br, I, Si, P, and S. For example, a
heteroatom-substituted C.sub.1-C.sub.10-alkylamino has 1 to 10
carbon atoms. The term "heteroatom-substituted C.sub.n-alkylamino"
includes groups, having the structure --NHR, in which R is a
heteroatom-substituted C.sub.n-alkyl, as that term is defined
above.
[0068] The term "heteroatom-unsubstituted C.sub.n-alkenylamino"
refers to a radical having a single nitrogen atom as the point of
attachment, further having one or two carbon atoms attached to the
nitrogen atom, further having a linear or branched, cyclic or
acyclic structure, containing at least one nonaromatic
carbon-carbon double bond, a total of n carbon atoms, 4 or more
hydrogen atoms, a total of one nitrogen atom, and no additional
heteroatoms. For example, a heteroatom-unsubstituted
C.sub.2-C.sub.10-alkenylamino has 2 to 10 carbon atoms. The term
"heteroatom-unsubstituted C.sub.n-alkenylamino" includes groups,
having the structure --NHR, in which R is a
heteroatom-unsubstituted C.sub.n-alkenyl, as that term is defined
above. Examples of heteroatom-unsubstituted C.sub.n-alkenylamino
groups also include dialkenylamino and alkyl(alkenyl)amino groups.
The term "heteroatom-substituted C.sub.n-alkenylamino" refers to a
radical having a single nitrogen atom as the point of attachment
and at least one nonaromatic carbon-carbon double bond, but no
carbon-carbon triple bonds, further having one or two carbon atoms
attached to the nitrogen atom, further having a linear or branched,
cyclic or acyclic structure, further having a total of n carbon
atoms, 0, 1, or more than one hydrogen atom, and at least one
additional heteroatom, that is, in addition to the nitrogen atom at
the point of attachment, wherein each additional heteroatom is
independently selected from the group consisting of N, O, F, Cl,
Br, I, Si, P, and S. For example, a heteroatom-substituted
C.sub.2-C.sub.10-alkenylamino has 2 to 10 carbon atoms. The term
"heteroatom-substituted C.sub.n-alkenylamino" includes groups,
having the structure --NHR, in which R is a heteroatom-substituted
C.sub.n-alkenyl, as that term is defined above.
[0069] The term "heteroatom-unsubstituted C.sub.n-alkynylamino"
refers to a radical having a single nitrogen atom as the point of
attachment, further having one or two carbon atoms attached to the
nitrogen atom, further having a linear or branched, cyclic or
acyclic structure, containing at least one carbon-carbon triple
bond, a total of n carbon atoms, at least one hydrogen atoms, a
total of one nitrogen atom, and no additional heteroatoms. For
example, a heteroatom-unsubstituted C.sub.2-C.sub.10-alkynylamino
has 2 to 10 carbon atoms. The term "heteroatom-unsubstituted
C.sub.n-alkynylamino" includes groups, having the structure --NHR,
in which R is a heteroatom-unsubstituted C.sub.n-alkynyl, as that
term is defined above. An alkynylamino group includes
dialkynylamino and alkyl(alkynyl)amino groups. The term
"heteroatom-substituted C.sub.n-alkynylamino" refers to a radical
having a single nitrogen atom as the point of attachment, further
having one or two carbon atoms attached to the nitrogen atom,
further having at least one nonaromatic carbon-carbon triple bond,
further having a linear or branched, cyclic or acyclic structure,
and further having a total of n carbon atoms, 0, 1, or more than
one hydrogen atom, and at least one additional heteroatom, that is,
in addition to the nitrogen atom at the point of attachment,
wherein each additional heteroatom is independently selected from
the group consisting of N, O, F, Cl, Br, I, Si, P, and S. For
example, a heteroatom-substituted C.sub.2-C.sub.10-alkynylamino has
2 to 10 carbon atoms. The term "heteroatom-substituted
C.sub.n-alkynylamino" includes groups, having the structure --NHR,
in which R is a heteroatom-substituted C.sub.n-alkynyl, as that
term is defined above.
[0070] The term "heteroatom-unsubstituted C.sub.n-arylamino" refers
to a radical having a single nitrogen atom as the point of
attachment, further having at least one aromatic ring structure
attached to the nitrogen atom, wherein the aromatic ring structure
contains only carbon atoms, further having a total of n carbon
atoms, 6 or more hydrogen atoms, a total of one nitrogen atom, and
no additional heteroatoms. For example, a heteroatom-unsubstituted
C.sub.6-C.sub.10-arylamino has 6 to 10 carbon atoms. The term
"heteroatom-unsubstituted C.sub.n-arylamino" includes groups,
having the structure --NHR, in which R is a
heteroatom-unsubstituted C.sub.n-aryl, as that term is defined
above. A heteroatom-unsubstituted arylamino group includes
diarylamino and alkyl(aryl)amino groups. The term
"heteroatom-substituted C.sub.n-arylamino" refers to a radical
having a single nitrogen atom as the point of attachment, further
having a total of n carbon atoms, at least one hydrogen atom, at
least one additional heteroatoms, that is, in addition to the
nitrogen atom at the point of attachment, wherein at least one of
the carbon atoms is incorporated into one or more aromatic ring
structures, further wherein each additional heteroatom is
independently selected from the group consisting of N, O, F, Cl,
Br, I, Si, P, and S. For example, a heteroatom-substituted
C.sub.6-C.sub.10-arylamino has 6 to 10 carbon atoms. The term
"heteroatom-substituted C.sub.n-arylamino" includes groups, having
the structure --NHR, in which R is a heteroatom-substituted
C.sub.n-aryl, as that term is defined above. A
heteroatom-substituted arylamino group includes heteroarylamino
groups.
[0071] The term "heteroatom-unsubstituted C.sub.n-aralkylamino"
refers to a radical having a single nitrogen atom as the point of
attachment, further having one or two saturated carbon atoms
attached to the nitrogen atom, further having a total of n carbon
atoms, wherein at least 6 of the carbon atoms form an aromatic ring
structure containing only carbon atoms, 8 or more hydrogen atoms, a
total of one nitrogen atom, and no additional heteroatoms. For
example, a heteroatom-unsubstituted C.sub.7-C.sub.10-aralkylamino
has 7 to 10 carbon atoms. The term "heteroatom-unsubstituted
C.sub.n-aralkylamino" includes groups, having the structure --NHR,
in which R is a heteroatom-unsubstituted C.sub.n-aralkyl, as that
term is defined above. An aralkylamino group includes
diaralkylamino groups. The term "heteroatom-substituted
C.sub.n-aralkylamino" refers to a radical having a single nitrogen
atom as the point of attachment, further having at least one or two
saturated carbon atoms attached to the nitrogen atom, further
having a total of n carbon atoms, 0, 1, or more than one hydrogen
atom, at least one additional heteroatom, that is, in addition to
the nitrogen atom at the point of attachment, wherein at least one
of the carbon atom incorporated into an aromatic ring, further
wherein each heteroatom is independently selected from the group
consisting of N, O, F, Cl, Br, I, Si, P, and S. For example, a
heteroatom-substituted C.sub.7-C.sub.10-aralkylamino has 7 to 10
carbon atoms. The term "heteroatom-substituted
C.sub.n-aralkylamino" includes groups, having the structure --NHR,
in which R is a heteroatom-substituted C.sub.n-aralkyl, as that
term is defined above. The term "heteroatom-substituted
aralkylamino" includes the term "heteroaralkylamino."
[0072] The term amido includes N-alkyl-amido, N-aryl-amido,
N-aralkyl-amido, acylamino, alkylcarbonylamino, arylcarbonylamino,
and ureido groups. The group, --NHCOCH.sub.3, is an example of a
heteroatom-unsubstituted amido group. The term
"heteroatom-unsubstituted C.sub.n-amido" refers to a radical having
a single nitrogen atom as the point of attachment, further having a
carbonyl group attached via its carbon atom to the nitrogen atom,
further having a linear or branched, cyclic or acyclic structure,
further having a total of n carbon atoms, 1 or more hydrogen atoms,
a total of one oxygen atom, a total of one nitrogen atom, and no
additional heteroatoms. For example, a heteroatom-unsubstituted
C.sub.1-C.sub.10-amido has 1 to 10 carbon atoms. The term
"heteroatom-unsubstituted C.sub.n-amido" includes groups, having
the structure --NHR, in which R is a heteroatom-unsubstituted
C.sub.n-acyl, as that term is defined above. The term
"heteroatom-substituted C.sub.n-amido" refers to a radical having a
single nitrogen atom as the point of attachment, further having a
carbonyl group attached via its carbon atom to the nitrogen atom,
further having a linear or branched, cyclic or acyclic structure,
further having a total of n aromatic or nonaromatic carbon atoms,
0, 1, or more than one hydrogen atom, at least one additional
heteroatom in addition to the oxygen of the carbonyl group and the
nitrogen atom at the point of attachment, wherein each additional
heteroatom is independently selected from the group consisting of
N, O, F, Cl, Br, I, Si, P, and S. For example, a
heteroatom-substituted C.sub.1-C.sub.10-amido has 1 to 10 carbon
atoms. The term "heteroatom-substituted C.sub.n-amido" includes
groups, having the structure --NHR, in which R is a
heteroatom-unsubstituted C.sub.n-acyl, as that term is defined
above. The group, --NHCO.sub.2CH.sub.3, is an example of a
heteroatom-substituted amido group.
[0073] In addition, atoms making up the compounds of the present
invention are intended to include all isotopic forms of such atoms.
Isotopes, as used herein, include those atoms having the same
atomic number but different mass numbers. By way of general example
and without limitation, isotopes of hydrogen include tritium and
deuterium, and isotopes of carbon include .sup.13C and .sup.14C.
Similarly, it is contemplated that one or more carbon atom(s) of a
compound of the present invention may be replaced by a silicon
atom(s). Similarly, it is contemplated that one or more oxygen
atom(s) of a compound of the present invention may be replaced by a
sulfur or a selenium atom(s).
[0074] Any undefined valency on an atom of a structure shown in
this application implicitly represents a hydrogen atom bonded to
the atom.
[0075] The use of the word "a" or "an," when used in conjunction
with the term "comprising" in the claims and/or the specification
may mean "one," but it is also consistent with the meaning of "one
or more," "at least one," and "one or more than one."
[0076] Throughout this application, the term "about" is used to
indicate that a value includes the inherent variation of error for
the device, the method being employed to determine the value, or
the variation that exists among the study subjects.
[0077] The terms "comprise," "have" and "include" are open-ended
linking verbs. Any forms or tenses of one or more of these verbs,
such as "comprises," "comprising," "has," "having," "includes" and
"including," are also open-ended. For example, any method that
"comprises," "has" or "includes" one or more steps is not limited
to possessing only those one or more steps and also covers other
unlisted steps.
[0078] The term "effective," as that term is used in the
specification and/or claims, means adequate to accomplish a
desired, expected, or intended result.
[0079] The term "hydrate" when used as a modifier to a compound
means that the compound has less than one (e.g., hemihydrate), one
(e.g., monohydrate), or more than one (e.g., dihydrate) water
molecules associated with each compound molecule, such as in solid
forms of the compound.
[0080] As used herein, the term "IC.sub.50" refers to an inhibitory
dose which is 50% of the maximum response obtained.
[0081] An "isomer" of a first compound is a separate compound in
which each molecule contains the same constituent atoms as the
first compound, but where the configuration of those atoms in three
dimensions differs.
[0082] As used herein, the term "patient" or "subject" refers to a
living mammalian organism, such as a human, monkey, cow, sheep,
goat, dog, cat, mouse, rat, guinea pig, or transgenic species
thereof. In certain embodiments, the patient or subject is a
primate. Non-limiting examples of human subjects are adults,
juveniles, infants and fetuses.
[0083] "Pharmaceutically acceptable" means that which is useful in
preparing a pharmaceutical composition that is generally safe,
non-toxic and neither biologically nor otherwise undesirable and
includes that which is acceptable for veterinary use as well as
human pharmaceutical use.
[0084] "Pharmaceutically acceptable salts" means salts of compounds
of the present invention which are pharmaceutically acceptable, as
defined above, and which possess the desired pharmacological
activity. Such salts include acid addition salts formed with
inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like; or with
organic acids such as 1,2-ethanedisulfonic acid,
2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid,
3-phenylpropionic acid,
4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid),
4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, acetic acid,
aliphatic mono- and dicarboxylicacids, aliphatic sulfuric acids,
aromatic sulfuric acids, benzenesulfonic acid, benzoic acid,
camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid,
cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid,
glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid,
heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid,
laurylsulfuric acid, maleic acid, malic acid, malonic acid,
mandelic acid, methanesulfonic acid, muconic acid,
o-(4-hydroxybenzoyl)benzoic acid, oxalic acid,
p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids,
propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic
acid, stearic acid, succinic acid, tartaric acid,
tertiarybutylacetic acid, trimethylacetic acid, and the like.
Pharmaceutically acceptable salts also include base addition salts
which may be formed when acidic protons present are capable of
reacting with inorganic or organic bases. Acceptable inorganic
bases include sodium hydroxide, sodium carbonate, potassium
hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable
organic bases include ethanolamine, diethanolamine,
triethanolamine, tromethamine, N-methylglucamine and the like. It
should be recognized that the particular anion or cation forming a
part of any salt of this invention is not critical, so long as the
salt, as a whole, is pharmacologically acceptable. Additional
examples of pharmaceutically acceptable salts and their methods of
preparation and use are presented in Handbook of Pharmaceutical
Salts: Properties and Use (P. H. Stahl & C. G. Wermuth eds.,
Verlag Helvetica Chimica Acta, 2002),
[0085] As used herein, "predominantly one enantiomer" means that a
compound contains at least about 85% of one enantiomer, or more
preferably at least about 90% of one enantiomer, or even more
preferably at least about 95% of one enantiomer, or most preferably
at least about 99% of one enantiomer. Similarly, the phrase
"substantially free from other optical isomers" means that the
composition contains at most about 15% of another enantiomer or
diastereomer, more preferably at most about 10% of another
enantiomer or diastereomer, even more preferably at most about 5%
of another enantiomer or diastereomer, and most preferably at most
about 1% of another enantiomer or diastereomer.
[0086] "Prevention" or "preventing" includes: (1) inhibiting the
onset of a disease in a subject or patient which may be at risk
and/or predisposed to the disease but does not yet experience or
display any or all of the pathology or symptomatology of the
disease, and/or (2) slowing the onset of the pathology or
symptomatology of a disease in a subject or patient which may be at
risk and/or predisposed to the disease but does not yet experience
or display any or all of the pathology or symptomatology of the
disease.
[0087] The term "saturated" when referring to an atom means that
the atom is connected to other atoms only by means of single
bonds.
[0088] A "stereoisomer" or "optical isomer" is an isomer of a given
compound in which the same atoms are bonded to the same other
atoms, but where the configuration of those atoms in three
dimensions differs. "Enantiomers" are stereoisomers of a given
compound that are mirror images of each other, like left and right
hands. "Diastereomers" are stereoisomers of a given compound that
are not enantiomers.
[0089] "Therapeutically effective amount" or "pharmaceutically
effective amount" means that amount which, when administered to a
subject or patient for treating a disease, is sufficient to effect
such treatment for the disease.
[0090] "Treatment" or "treating" includes (1) inhibiting a disease
in a subject or patient experiencing or displaying the pathology or
symptomatology of the disease (e.g., arresting further development
of the pathology and/or symptomatology), (2) ameliorating a disease
in a subject or patient that is experiencing or displaying the
pathology or symptomatology of the disease (e.g., reversing the
pathology and/or symptomatology), and/or (3) effecting any
measurable decrease in a disease in a subject or patient that is
experiencing or displaying the pathology or symptomatology of the
disease.
[0091] As used herein, the term "water soluble" means that the
compound dissolves in water at least to the extent of 0.010
mole/liter or is classified as soluble according to literature
precedence.
[0092] Other abbreviations used herein are as follows: DMSO,
dimethyl sulfoxide; NO, nitric oxide; iNOS, inducible nitric oxide
synthase; COX-2, cyclooxygenase-2; NGF, nerve growth factor; IBMX,
isobutylmethylxanthine; FBS, fetal bovine serum; GPDH, glycerol
3-phosphate dehydrogenase; RXR, retinoid X receptor; TGF-.beta.,
transforming growth factor-.beta.; IFN.gamma. or IFN-.gamma.,
interferon-.gamma.; LPS, bacterial endotoxic lipopolysaccharide;
TNF.alpha. or TNF-.alpha., tumor necrosis factor-.alpha.;
IL-1.beta., interleukin-1.beta.; GAPDH, glyceraldehyde-3-phosphate
dehydrogenase; MTBE, methyl-tert-butylether; MTT,
3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; TCA,
trichloroacetic acid; HO-1, inducible heme oxygenase.
[0093] The above definitions supersede any conflicting definition
in any of the reference that is incorporated by reference
herein.
III. Synthetic Triterpenoids
[0094] Triterpenoids, biosynthesized in plants by the cyclization
of squalene, are used for medicinal purposes in many Asian
countries; and some, like ursolic and oleanolic acids, are known to
be anti-inflammatory and anti-carcinogenic (Huang et al., 1994;
Nishino et al., 1988). However, the biological activity of these
naturally-occurring molecules is relatively weak, and therefore the
synthesis of new analogs to enhance their potency was undertaken
(Honda et al., 1997; Honda et al., 1998). Subsequent research has
identified a number of synthetic compounds that have improved
activity as compared to the naturally-occurring triterpenoids.
[0095] The ongoing efforts for the improvement of anti-inflammatory
and antiproliferative activity of oleanolic and ursolic acid
analogs led to the discovery of
2-cyano-3,12-dioxooleane-1,9(11)-dien-28-oic acid (CDDO, RTA 402)
and related compounds (e.g., CDDO-Me, TP-225, CDDO-Im) (Honda et
al., 1997, 1998, 1999, 2000a, 2000b, 2002; Suh et al., 1998; 1999;
2003; Place et al., 2003; Liby et al., 2005). In the case of
inducing cytoprotective genes through Keap1-Nrf2-antioxidant
response element (ARE) signaling, a recent structure activity
evaluation of 15 triterpenoids noted the importance of Michael
acceptor groups on both the A and C rings, a nitrile group at C-2
of the A ring, and that substituents at C-17 affected
pharmacodynamic action in vivo (Yates et al., 2007).
##STR00010##
In general, CDDO is the prototype for a large number of compounds
in a family of agents that have been shown useful in a variety of
contexts. For example, CDDO-Me and CDDO-Im are reported to possess
the ability to modulate transforming growth factor-.beta.
(TGF-.beta.)/Smad signaling in several types of cells (Suh et al.,
2003; Minns et al., 2004; Mix et al., 2004). Both are known to be
potent inducers of heme-oxygenase-1 and Nrf2/ARE signaling (Liby et
al., 2005), and a series of synthetic triterpenoid (TP) analogs of
oleanolic acid have also been shown to be potent inducers of the
phase 2 response, that is elevation of NAD(P)H-quinone
oxidoreductase and heme oxygenase 1 (HO-1), which is a major
protector of cells against oxidative and electrophile stress
(Dinkova-Kostova et al., 2005). Like previously identified phase 2
inducers, the TP analogs were shown to use the antioxidant response
element-Nrf2-Keap1 signaling pathway.
[0096] RTA 402 (bardoxolone methyl), one of the compounds for use
with the methods of this invention, is an Antioxidant Inflammation
Modulator (AIM) in clinical development for inflammation and
cancer-related indications that inhibits immune-mediated
inflammation by restoring redox homeostasis in inflamed tissues. It
induces the cytoprotective transcription factor Nrf2 and suppresses
the activities of the pro-oxidant and pro-inflammatory
transcription factors NF-.kappa.B and STAT3. In vivo, RTA 402 has
demonstrated significant single agent anti-inflammatory activity in
several animal models of inflammation such as renal damage in the
cisplatin model and acute renal injury in the ischemia-reperfusion
model. In addition, significant reductions in serum creatinine have
been observed in patients treated with RTA 402.
[0097] In one aspect of the invention, the compounds of the present
invention may be used for treating a subject having a renal disease
or condition caused by elevated levels of oxidative stress in one
or more tissues. The oxidative stress may be accompanied by either
acute or chronic inflammation. The oxidative stress may be caused
by acute exposure to an external agent such as ionizing radiation
or a cytotoxic chemotherapy agent (e.g., doxorubicin), by trauma or
other acute tissue injury, by ischemia/reperfusion injury, by poor
circulation or anemia, by localized or systemic hypoxia or
hyperoxia, or by other abnormal physiological states such as
hyperglycemia or hypoglycemia.
[0098] Accordingly, in pathologies involving oxidative stress alone
or oxidative stress exacerbated by inflammation, treatment may
comprise administering to a subject a therapeutically effective
amount of a compound of this invention, such as those described
above or throughout this specification. Treatment may be
administered preventively in advance of a predictable state of
oxidative stress (e.g., organ transplantation or the administration
of therapy to a cancer patient), or it may be administered
therapeutically in settings involving established oxidative stress
and inflammation.
[0099] Newer amide derivatives of CDDO have now also been found to
be promising agents, for example for their ability to pass through
the blood brain barrier. In addition to the methyl amide of CDDO
(CDDO-MA), as reported in Honda et al. (2002), the invention
provides for the use of additional CDDO amide derivatives, such as
the ethyl amide (CDDO-EA), as well fluorinated amide derivatives of
CDDO, such as the 2,2,2-trifluoroethyl amide derivative of CDDO
(CDDO-TFEA).
[0100] The compounds of the present invention can be prepared
according to the methods taught by Honda et al. (1998), Honda et
al. (2000b), Honda et al. (2002), Yates et al. (2007), and U.S.
Pat. Nos. 6,326,507 and 6,974,801, which are all incorporated
herein by reference.
[0101] Non-limiting examples of triterpenoids that may be used in
accordance with the methods of this invention are shown here.
##STR00011## ##STR00012##
[0102] The compounds for use with the present invention, such as
those of the table above, are structurally similar to RTA 402 and
in many cases exhibit similar biological properties, as has been
noted above. As additional examples, Table 1 summarizes in vitro
results for several of these compounds in which RAW264.7
macrophages were pre-treated with DMSO or drugs at various
concentrations (nM) for 2 hours, then treated with 20 ng/ml
IFN.gamma. for 24 hours. NO concentration in media was determined
using a Griess reagent system; cell viability was determined using
WST-1 reagent. NQO1 CD represents the concentration required to
induce a two-fold increase in the expression of NQO1, an
Nrf2-regulated antioxidant enzyme, in Hepa1c1c7 murine hepatoma
cells (Dinkova-Kostova et al., 2005). All these results are orders
of magnitude more active than, for example, the parent oleanolic
acid molecule. In part because induction of antioxidant pathways
resulting from Nrf2 activation provides important protective
effects against oxidative stress and inflammation, compounds
related to RTA 402 may also provide significant benefits similar to
those presented for RTA 402 in this application, and these related
compounds may, therefore, be used for the treatment and/or
prevention of diseases, such as: renal/kidney disease (RKD),
insulin resistance, diabetes, endothelial dysfunction, fatty liver
disease, cardiovascular disease (CVD), and related disorders.
TABLE-US-00001 TABLE 1 Suppression of IFN.gamma.-induced NO
production. RAW264.7 (20 ng/ml IFN.gamma.) Hepa1c1c7 cells Working
ID NO IC.sub.50 WST-1 IC.sub.50 NQO1 CD RTA 401 ~10 nM >200 nM
2.3 nM RTA 402 2.2 nM 80 nM 1.0 nM RTA 403 ~0.6 nM 100 nM 3.3 nM
RTA 404 5.8 nM 100 nM n/a RTA 405 6 nM ~200 nM n/a TP-225 ~0.4 nM
75 nM 0.28 nM
[0103] The synthesis of CDDO-MA is discussed in Honda et al.
(2002), which is incorporated herein by reference. The syntheses of
CDDO-EA and CDDO-TFEA are presented in Yates et al. (2007), which
is incorporated herein by reference, and shown in the Scheme 1
below.
##STR00013##
IV. Polymorphic Forms of CDDO-Me
[0104] Polymorphic forms of the compounds of the present invention,
e.g., Forms A and B of CDDO-Me, may be used in accordance with the
methods of this inventions. Form B displays a bioavailability that
is surprisingly better than that of Form A (FIG. 15). Specifically
the bioavailability of Form B was higher than that of Form A
CDDO-Me in monkeys when the monkeys received equivalent dosages of
the two forms orally, in gelatin capsules (U.S. application Ser.
No. 12/191,176, filed Aug. 13, 2008).
[0105] "Form A" of CDDO-Me (RTA 402) is unsolvated (non-hydrous)
and can be characterized by a distinctive crystal structure, with a
space group of P4.sub.32.sub.12 (no. 96) unit cell dimensions of
a=14.2 .ANG., b=14.2 .ANG. and c=81.6 .ANG., and by a packing
structure, whereby three molecules are packed in helical fashion
down the crystallographic b axis. In some embodiments, Form A can
also be characterized by X-ray powder diffraction (XRPD) pattern
(CuK.alpha.) comprising significant diffraction peaks at about 8.8,
12.9, 13.4, 14.2 and 17.4.sup.020. In some variations, the X-ray
powder diffraction of Form A is substantially as shown in FIG. 12A
or FIG. 12B.
[0106] Unlike Form A, "Form B" of CDDO-Me is in a single phase but
lacks such a defined crystal structure. Samples of Form B show no
long-range molecular correlation, i.e., above roughly 20 .ANG..
Moreover, thermal analysis of Form B samples reveals a glass
transition temperature (T.sub.g) in a range from about 120.degree.
C. to about 130.degree. C. (FIG. 14). In contrast, a disordered
nanocrystalline material does not display a T.sub.g but instead
only a melting temperature (T.sub.m), above which crystalline
structure becomes a liquid. Form B is typified by an XRPD spectrum
(FIG. 12C) differing from that of Form A (FIG. 12A or FIG. 12B).
Since it does not have a defined crystal structure, Form B likewise
lacks distinct XRPD peaks, such as those that typify Form A, and
instead is characterized by a general "halo" XRPD pattern. In
particular, the non-crystalline Form B falls into the category of
"X-ray amorphous" solids because its XRPD pattern exhibits three or
fewer primary diffraction halos. Within this category, Form B is a
"glassy" material.
[0107] Form A and Form B of CDDO-Me are readily prepared from a
variety of solutions of the compound. For example, Form B can be
prepared by fast evaporation or slow evaporation in MTBE, THF,
toluene, or ethyl acetate. Form A can be prepared in several ways,
including via fast evaporation, slow evaporation, or slow cooling
of a CDDO-Me solution in ethanol or methanol. Preparations of
CDDO-Me in acetone can produce either Form A, using fast
evaporation, or Form B, using slow evaporation.
[0108] Various means of characterization can be used together to
distinguish Form A and Form B CDDO-Me from each other and from
other forms of CDDO-Me. Illustrative of the techniques suitable for
this purpose are solid state Nuclear Magnetic Resonance (NMR),
X-ray powder diffraction (compare FIGS. 12A & B with FIG. 12C),
X-ray crystallography, Differential Scanning Calorimetry (DSC)
(compare FIG. 13 with FIG. 14), dynamic vapor sorption/desorption
(DVS), Karl Fischer analysis (KF), hot stage microscopy, modulated
differential screening calorimetry, FT-IR, and Raman spectroscopy.
In particular, analysis of the XRPD and DSC data can distinguish
Form A, Form B, and a hemibenzenate forms of CDDO-Me (U.S.
application Ser. No. 12/191,176, filed Aug. 13, 2008.)
[0109] Additional details regarding polymorphic forms of CDDO-Me
are described in U.S. Provisional Application No. 60/955,939, filed
Aug. 15, 2007, and the corresponding non-provisional U.S.
application Ser. No. 12/191,176, filed Aug. 13, 2008, which are
both incorporated herein by reference in their entireties.
V. Use of Triterpenoids for the Treatment of Chronic Kidney
Disease, Insulin Resistance/Diabetes and Endothelial
Dysfunction/Cardiovascular Disease
[0110] The compounds and methods of this invention may be used for
treating various aspects of renal/kidney disease, including both
acute and chronic indications. In general, the method will comprise
administering to the subjects pharmaceutically effective amounts of
a compound of this invention.
[0111] Inflammation contributes significantly to the pathology of
chronic kidney disease (CKD). There is also a strong mechanistic
link between oxidative stress and renal dysfunction. The
NF-.kappa.B signaling pathway plays an important role in the
progression of CKD as NF-.kappa.B regulates the transcription of
MCP-1, a chemokine that is responsible for the recruitment of
monocytes/macrophages resulting in an inflammatory response that
ultimately injures the kidney (Wardle, 2001). The Keap1/Nrf2/ARE
pathway controls the transcription of several genes encoding
antioxidant enzymes, including heme oxygenase-1 (HO-1). Ablation of
the Nrf2 gene in female mice results in the development of
lupus-like glomerular nephritis (Yoh et al., 2001; Ma et al.,
2006). Furthermore, several studies have demonstrated that HO-1
expression is induced in response to renal damage and inflammation
and that this enzyme and its products--bilirubin and carbon
monoxide--play a protective role in the kidney (Nath et al.,
2006).
[0112] The glomerulus and the surrounding Bowman's capsule
constitute the basic functional unit of the kidney. Glomerular
filtration rate (GFR) is the standard measure of renal function.
Creatinine clearance is commonly used to measure GFR. However, the
level of serum creatinine is commonly used as a surrogate measure
of creatinine clearance. For instance, excessive levels of serum
creatinine are generally accepted to indicate inadequate renal
function and reductions in serum creatinine over time are accepted
as an indication of improved renal function. Normal levels of
creatinine in the blood are approximately 0.6 to 1.2 milligrams
(mg) per deciliter (dl) in adult males and 0.5 to 1.1 milligrams
per deciliter in adult females.
[0113] Acute kidney injury (AKI) can occur following
ischemia-reperfusion, treatment with certain pharmacological agents
such as cisplatin and rapamycin, and intravenous injection of
radiocontrast media used in medical imaging. As in CKD,
inflammation and oxidative stress contribute to the pathology of
AKI. The molecular mechanisms underlying radiocontrast-induced
nephropathy (RCN) are not well understood; however, it is likely
that a combination of events including prolonged vasoconstriction,
impaired kidney autoregulation, and direct toxicity of the contrast
media all contribute to renal failure (Tumlin et al., 2006).
Vasoconstriction results in decreased renal blood flow and causes
ischemia-reperfusion and the production of reactive oxygen species.
HO-1 is strongly induced under these conditions and has been
demonstrated to prevent ischemia-reperfusion injury in several
different organs, including the kidney (Nath et al., 2006).
Specifically, induction of HO-1 has been shown to be protective in
a rat model of RCN (Goodman et al., 2007). Reperfusion also induces
an inflammatory response, in part though activation of NF-.kappa.B
signaling (Nichols, 2004). Targeting NF-.kappa.B has been proposed
as a therapeutic strategy to prevent organ damage (Zingarelli et
al., 2003).
[0114] Without being bound by theory, the potency of the compounds
of the present invention, e.g., RTA 402, is largely derived from
the addition of .alpha.,.beta.-unsaturated carbonyl groups. In in
vitro assays, most activity of the compounds can be abrogated by
the introduction of dithiothreitol (DTT), N-acetyl cysteine (NAC),
or glutathione (GSH); thiol containing moieties that interact with
.alpha.,.beta.-unsaturated carbonyl groups (Wang et al., 2000;
Ikeda et al., 2003; 2004; Shishodia et al., 2006). Biochemical
assays have established that RTA 402 directly interacts with a
critical cysteine residue (C179) on IKK.beta. (see below) and
inhibits its activity (Shishodia et al., 2006; Ahmad et al., 2006).
IKK.beta. controls activation of NF-.kappa.B through the
"classical" pathway which involves phosphorylation-induced
degradation of I.kappa.B resulting in release of NF-.kappa.B dimers
to the nucleus. In macrophages, this pathway is responsible for the
production of many pro-inflammatory molecules in response to
TNF.alpha. and other pro-inflammatory stimuli.
[0115] RTA 402 also inhibits the JAK/STAT signaling pathway at
multiple levels. JAK proteins are recruited to transmembrane
receptors (e.g., IL-6R) upon activation by ligands such as
interferons and interleukins. JAKs then phosphorylate the
intracellular portion of the receptor causing recruitment of STAT
transcription factors. The STATs are then phosphorylated by JAKs,
form dimers, and translocate to the nucleus where they activate
transcription of several genes involved in inflammation. RTA 402
inhibits constitutive and IL-6-induced STAT3 phosphorylation and
dimer formation and directly binds to cysteine residues in STAT3
(C259) and in the kinase domain of JAK1 (C1077). Biochemical assays
have also established that the triterpenoids directly interact with
critical cysteine residues on Keap1 (Dinkova-Kostova et al., 2005).
Keap1 is an actin-tethered protein that keeps the transcription
factor Nrf2 sequestered in the cytoplasm under normal conditions
(Kobayashi & Yamamoto, 2005). Oxidative stress results in
oxidation of the regulatory cysteine residues on Keap1 and causes
the release of Nrf2. Nrf2 then translocates to the nucleus and
binds to antioxidant response elements (AREs) resulting in
transcriptional activation of many antioxidant and
anti-inflammatory genes. Another target of the Keap1/Nrf2/ARE
pathway is heme oxygenase 1 (HO-1). HO-1 breaks down heme into
bilirubin and carbon monoxide and plays many antioxidant and
anti-inflammatory roles (Maines & Gibbs, 2005). HO-1 has
recently been shown to be potently induced by the triterpenoids
(Liby et al., 2005), including RTA 402. RTA 402 and many structural
analogs have also been shown to be potent inducers of the
expression of other Phase 2 proteins (Yates et al., 2007).
[0116] RTA 402 is a potent inhibitor of NF-.kappa.B activation.
Furthermore, RTA 402 activates the Keap1/Nrf2/ARE pathway and
induces expression of HO-1. As described below, RTA 402 has
demonstrated activity in two animal models of AKI. Furthermore,
reduced serum creatinine levels and improvement of glomerular
filtration have been observed in the majority of human patients
that have been treated with RTA 402 (see Examples below).
Significant improvements have now been observed in a Phase II study
of patients with diabetic nephropathy. The findings indicate that
RTA 402 may be used to improve renal function in patients with
diabetic nephropathy through suppression of renal inflammation and
improvement of glomerular filtration.
[0117] As noted above, both diabetes and essential hypertension are
major risk factors for the development of chronic kidney disease
and, ultimately, renal failure. Both of these conditions, along
with indicators of systemic cardiovascular disease such as
hyperlipidemia, are frequently present in the same patient,
especially if that patient is clinically obese. Although the
unifying factors are not completely understood, dysfunction of the
vascular endothelium has been implicated as a significant
pathological factor in systemic cardiovascular disease, chronic
kidney disease, and diabetes (see, e.g., Zoccali, 2006). Acute or
chronic oxidative stress in vascular endothelial cells has been
implicated in the development of endothelial dysfunction, and is
strongly associated with chronic inflammatory processes. Therefore,
an agent capable of relieving oxidative stress and concomitant
inflammation in the vascular endothelium may alleviate dysfunction
and restore endothelial homeostasis. Without being bound by theory,
compounds of the invention, by stimulating Nrf2-regulated
endogenous antioxidant mechanisms, have shown the highly unusual
ability to improve parameters related to renal function (e.g.,
serum creatinine and estimated glomerular filtration rate),
glycemic control and insulin resistance (e.g., hemoglobin A1c), and
systemic cardiovascular disease (e.g., circulating endothelial
cells) in patients having abnormal clinical values for these
parameters. Currently, combination therapy is typically required in
such patients to achieve improvements in measures of glycemic
control and cardiovascular disease, including the use of
angiotensin-converting enzyme inhibitors or angiotensin II receptor
blockers to alleviate hypertension and slow the progression of
chronic kidney disease. By achieving simultaneous and clinically
meaningful improvements in all of these parameters, especially
measures of renal function, compounds of the invention represent a
significant improvement over currently available therapies. In some
aspects, the compounds of the present invention may be used to
treat a combination of the above conditions as a single therapy, or
in combination with fewer additional therapies than would currently
be used.
[0118] These findings also indicate that administration of RTA 402
may be used to protect patients from kidney damage such as from
exposure to radiocontrast agents, as in the case of
radiocontrast-induced nephropathy (RCN), as well as in other
contexts. In one aspect, the compounds of this invention may be
used to treat ischemia-reperfusion- and/or chemotherapy-induced
acute renal injury. For example, the results shown in Examples 2
and 3 below demonstrate that RTA 402 is protective in animal models
of ischemia-reperfusion- and chemotherapy-induced acute renal
injury.
[0119] Serum creatinine has been measured in several animal models
treated with RTA 402. Significant reductions of serum creatinine
levels relative to baseline levels or levels in control animals
have been observed in cynomolgus monkeys, beagle dogs, and
Sprague-Dawley rats (FIGS. 3A-D). This effect has been observed in
rats with both forms of RTA 402 (crystalline and amorphous).
[0120] RTA 402 reduces serum creatinine in patients. For example,
improvements were observed in cancer patients receiving RTA 402. In
humans, nephrotoxicity is a dose-limiting side-effect of treatment
with cisplatin. Cisplatin-induced damage to the proximal tubules is
thought to be mediated by increased inflammation, oxidative stress,
and apoptosis (Yao et al., 2007). Serum creatinine has also been
measured in patients with chronic kidney disease (CKD) enrolled in
an open label Phase II clinical trial of RTA 402 (Example 6). This
study was designed with multiple endpoints, in categories of
insulin resistance, endothelial dysfunction/CVD, and CKD, including
measurements of hemoglobin A1c (A1c), a widely used phase 3
endpoint for glycemic control.
[0121] A1c is a minor component of hemoglobin to which glucose is
bound. A1c also is referred to as glycosylated or glucosylated
hemoglobin. A1c may be separated by charge and size from the other
hemoglobin A components in blood using high performance liquid
chromatography (HPLC). Because A1c is not affected by short-term
fluctuations in blood glucose concentrations, for example, due to
meals, blood can be drawn for A1c testing without regard to when
food was eaten. In healthy, non-diabetic patients the A1c level is
less than 7% of total hemoglobin. The normal range is 4-5.9%. In
poorly controlled diabetes, it can be 8.0% or above. It has been
demonstrated that the complications of diabetes can be delayed or
prevented if the A1c level can be kept close to 7%.
[0122] Recently approved agents typically only reduce A1c levels an
amount of 0.4 to 0.80 over six months of treatment, with 28 day
improvements typically smaller. The table below shows six-month
Hemoglobin A1c Reductions by two approved agents, sitagliptin and
pramlintide acetate (Aschner et al., 2006; Goldstein et al., 2007;
Pullman et al., 2006).
TABLE-US-00002 Duration of DM Mean Drug (years) Study Design A1c
Change Sitagliptin 4.3 +/-placebo with 8.0 -0.8 A1c .gtoreq. 7.0
4.4 +/-metformin with 8.9 -0.7 A1c .gtoreq. 7.5 6.1 pioglitazone
+/- 8.1 -0.7 sitagliptin; A1c .gtoreq. 7.0 Pramlintide 13
+/-insulin 9.1 -0.4 acetate
[0123] In comparison, RTA 402 reduces A1c in 28 days in refractory
diabetics on top of standard of care. The treatment showed an
intent-to-treat reduction of 0.34 (n=21) and an elevated baseline
(.gtoreq.7.0 at baseline) reduction of 0.50 (n=16). These results
are presented in greater detail in the Examples section below. See
also FIGS. 6 and 7.
[0124] In another aspect, the compounds of this invention may also
be used to improve insulin sensitivity and/or glycemic control. For
example, hyperinsulinemic euglycemic clamp test results in the
study detailed in Example 6 showed that treatment with RTA 402
improved glycemic control. The hyperinsulinemic euglycemic clamp
test is a standard method for investigating and quantifying insulin
sensitivity. It measures the amount of glucose necessary to
compensate for an increased insulin level without causing
hypoglycemia (DeFronzo et al., 1979).
[0125] The typical procedure is as follows: Through a peripheral
vein, insulin is infused at 10-120 mU per m.sup.2 per minute. In
order to compensate for the insulin infusion, glucose 20% is
infused to maintain blood sugar levels between 5 and 5.5
mmol/liter. The rate of glucose infusion is determined by checking
the blood sugar levels every 5 to 10 minutes.
[0126] Typically, low-dose insulin infusions are more useful for
assessing the response of the liver, whereas high-dose insulin
infusions are useful for assessing peripheral (i.e., muscle and
fat) insulin action.
[0127] Results are typically evaluated as follows: The rate of
glucose infusion during the last 30 minutes of the test determines
insulin sensitivity. If high levels (7.5 mg/min or higher) are
required, the patient is insulin-sensitive. Very low levels (4.0
mg/min or lower) indicate that the body is resistant to insulin
action. Levels between 4.0 and 7.5 mg/min may not be definitive and
may suggest "impaired glucose tolerance," an early sign of insulin
resistance.
[0128] The methods of this invention may be used to improve renal
function. As shown in Example 6, treatment using RTA 402 has been
shown to improve six measures of renal function and status,
including serum creatinine based eGFR, creatinine clearance, BUN,
Cystatin C, Adiponectin, and Angiotensin II. RTA 402 was shown to
increase GFR in a dose-dependent manner and with high response rate
(86%; n=22). As also shown in FIG. 9, the 28 day GFR improvements
were reversible after the drug was withdrawn.
[0129] In some embodiments, treatment methods of this invention
result in improved levels of Adiponectin and/or Angiotensin II.
Adiponectin and Angiotensin II are typically elevated in DN
patients and correlate with renal disease severity. Adiponectin
(also referred to as Acrp30, apM1) is a hormone known to modulate a
number of metabolic processes, including glucose regulation and
fatty acid catabolism. Adiponectin is secreted from adipose tissue
into the bloodstream and is abundant in plasma relative to many
other hormones. Levels of the hormone are inversely correlated with
body fat percentage in adults, while the association in infants and
young children is more unclear. The hormone plays a role in the
suppression of the metabolic derangements that may result in type 2
diabetes, obesity, atherosclerosis and non-alcoholic fatty liver
disease (NAFLD). Adiponectin can be used to predict all-cause
mortality and end stage renal disease in DN patients.
[0130] The compounds and methods of this invention may be used for
treating various aspects of cardiovascular disease (CVD). The
treatment methods of this invention have been found to reduce
circulating endothelial cells (CECs) in human patients. CECs are
markers of endothelial dysfunction and vascular injury. Endothelial
dysfunction is a systemic inflammatory process that is linked to
cardiovascular and end-organ damage. Elevated CECs typically
correlate with the development, progression, and death from CVD.
They also typically correlate with chronic kidney disease and
decreased GFR. Historical normal levels are .ltoreq.5 cells/mL.
[0131] Typical features of endothelial dysfunction include the
inability of arteries and arterioles to dilate fully in response to
an appropriate stimulus. This creates a detectable difference in
subjects with endothelial dysfunction versus a normal, healthy
endothelium. Such a difference can be tested by a variety of
methods including iontophoresis of acetylcholine, intra-arterial
administration of various vasoactive agents, localised heating of
the skin or temporary arterial occlusion by inflating a blood
pressure cuff to high pressures. Testing can also take place in the
coronary arteries themselves. These techniques are thought to
stimulate the endothelium to release nitric oxide (NO) and possibly
some other agents, which diffuse into the surrounding vascular
smooth muscle causing vasodilation.
[0132] For example, according to the Phase II study results
(Example 6), patients treated with RTA 402 for 28 days showed a
reduction in cardiovascular inflammatory markers in the form of a
reduction in the number of circulating endothelial cells. The
reduction in CECs for the intent-to-treat group (n=20) was 27%; the
reduction for the elevated baseline group (n=14) was 40% (p=0.02)
and nine of those patients showed a normal level for CECs
post-treatment. These results are consistent with a reversal of
endothelial dysfunction.
[0133] The treatment methods of this invention have been found to
reduce matrix metallopeptidase 9 (MMP-9), soluble adhesion
molecules and tumor necrosis factor (TNF.alpha.) in most patients.
High levels of these typically correlate with poor cardiovascular
outcomes.
VI. Pharmaceutical Formulations and Routes of Administration
[0134] Administration of the compounds of the present invention to
a patient will follow general protocols for the administration of
pharmaceuticals, taking into account the toxicity, if any, of the
drug. It is expected that the treatment cycles would be repeated as
necessary.
[0135] The compounds of the present invention may be administered
by a variety of methods, e.g., orally or by injection (e.g.
subcutaneous, intravenous, intraperitoneal, etc.). Depending on the
route of administration, the active compounds may be coated by a
material to protect the compound from the action of acids and other
natural conditions which may inactivate the compound. They may also
be administered by continuous perfusion/infusion of a disease or
wound site. Specific examples of formulations, including a
polymer-based dispersion of CDDO-Me that showed improved oral
bioavailability, are provided in U.S. application Ser. No.
12/191,176, filed Aug. 13, 2008, which is incorporated herein by
reference in its entirety. It will be recognized by those skilled
in the art that other methods of manufacture may be used to produce
dispersions of the present invention with equivalent properties and
utility (see Repka et al., 2002 and references cited therein). Such
alternative methods include but are not limited to solvent
evaporation, extrusion, such as hot melt extrusion, and other
techniques.
[0136] To administer the therapeutic compound by other than
parenteral administration, it may be necessary to coat the compound
with, or co-administer the compound with, a material to prevent its
inactivation. For example, the therapeutic compound may be
administered to a patient in an appropriate carrier, for example,
liposomes, or a diluent. Pharmaceutically acceptable diluents
include saline and aqueous buffer solutions. Liposomes include
water-in-oil-in-water CGF emulsions as well as conventional
liposomes (Strejan et al., 1984).
[0137] The therapeutic compound may also be administered
parenterally, intraperitoneally, intraspinally, or intracerebrally.
Dispersions may be prepared in, e.g., glycerol, liquid polyethylene
glycols, mixtures thereof, and in oils. Under ordinary conditions
of storage and use, these preparations may contain a preservative
to prevent the growth of microorganisms.
[0138] Pharmaceutical compositions suitable for injectable use
include sterile aqueous solutions (where water soluble) or
dispersions and sterile powders for the extemporaneous preparation
of sterile injectable solutions or dispersion. In all cases, the
composition must be sterile and must be fluid to the extent that
easy syringability exists. It must be stable under the conditions
of manufacture and storage and must be preserved against the
contaminating action of microorganisms such as bacteria and fungi.
The carrier may be a solvent or dispersion medium containing, for
example, water, ethanol, polyol (such as, glycerol, propylene
glycol, and liquid polyethylene glycol, and the like), suitable
mixtures thereof, and vegetable oils. The proper fluidity can be
maintained, for example, by the use of a coating such as lecithin,
by the maintenance of the required particle size in the case of
dispersion and by the use of surfactants. Prevention of the action
of microorganisms can be achieved by various antibacterial and
antifungal agents, for example, parabens, chlorobutanol, phenol,
ascorbic acid, thimerosal, and the like. In many cases, it will be
preferable to include isotonic agents, for example, sugars, sodium
chloride, or polyalcohols such as mannitol and sorbitol, in the
composition. Prolonged absorption of the injectable compositions
can be brought about by including in the composition an agent which
delays absorption, for example, aluminum monostearate or
gelatin.
[0139] Sterile injectable solutions can be prepared by
incorporating the therapeutic compound in the required amount in an
appropriate solvent with one or a combination of ingredients
enumerated above, as required, followed by filtered sterilization.
Generally, dispersions are prepared by incorporating the
therapeutic compound into a sterile carrier which contains a basic
dispersion medium and the required other ingredients from those
enumerated above. In the case of sterile powders for the
preparation of sterile injectable solutions, the preferred methods
of preparation are vacuum drying and freeze-drying which yields a
powder of the active ingredient (i.e., the therapeutic compound)
plus any additional desired ingredient from a previously
sterile-filtered solution thereof.
[0140] The therapeutic compound can be orally administered, for
example, with an inert diluent or an assimilable edible carrier.
The therapeutic compound and other ingredients may also be enclosed
in a hard or soft shell gelatin capsule, compressed into tablets,
or incorporated directly into the subject's diet. For oral
therapeutic administration, the therapeutic compound may be
incorporated with excipients and used in the form of ingestible
tablets, buccal tablets, troches, capsules, elixirs, suspensions,
syrups, wafers, and the like. The percentage of the therapeutic
compound in the compositions and preparations may, of course, be
varied. The amount of the therapeutic compound in such
therapeutically useful compositions is such that a suitable dosage
will be obtained.
[0141] It is especially advantageous to formulate parenteral
compositions in dosage unit form for ease of administration and
uniformity of dosage. Dosage unit form as used herein refers to
physically discrete units suited as unitary dosages for the
subjects to be treated; each unit containing a predetermined
quantity of therapeutic compound calculated to produce the desired
therapeutic effect in association with the required pharmaceutical
carrier. The specification for the dosage unit forms of the
invention are dictated by and directly dependent on (a) the unique
characteristics of the therapeutic compound and the particular
therapeutic effect to be achieved, and (b) the limitations inherent
in the art of compounding such a therapeutic compound for the
treatment of a selected condition in a patient.
[0142] The therapeutic compound may also be administered topically
to the skin, eye, or mucosa. Alternatively, if local delivery to
the lungs is desired the therapeutic compound may be administered
by inhalation in a dry-powder or aerosol formulation.
[0143] The actual dosage amount of a compound of the present
invention or composition comprising a compound of the present
invention administered to a subject may be determined by physical
and physiological factors such as age, sex, body weight, severity
of condition, the type of disease being treated, previous or
concurrent therapeutic interventions, idiopathy of the subject and
on the route of administration. These factors may be determined by
a skilled artisan. The practitioner responsible for administration
will typically determine the concentration of active ingredient(s)
in a composition and appropriate dose(s) for the individual
subject. The dosage may be adjusted by the individual physician in
the event of any complication.
[0144] In some embodiments, the pharmaceutically effective amount
is a daily dose from about 0.1 mg to about 500 mg of the compound.
In some variations, the daily dose is from about 1 mg to about 300
mg of the compound. In some variations, the daily dose is from
about 10 mg to about 200 mg of the compound. In some variations,
the daily dose is about 25 mg of the compound. In other variations,
the daily dose is about 75 mg of the compound. In still other
variations, the daily dose is about 150 mg of the compound. In
further variations, the daily dose is from about 0.1 mg to about 30
mg of the compound. In some variations, the daily dose is from
about 0.5 mg to about 20 mg of the compound. In some variations,
the daily dose is from about 1 mg to about 15 mg of the compound.
In some variations, the daily dose is from about 1 mg to about 10
mg of the compound. In some variations, the daily dose is from
about 1 mg to about 5 mg of the compound.
[0145] In some embodiments, the pharmaceutically effective amount
is a daily dose is 0.01-25 mg of compound per kg of body weight. In
some variations, the daily dose is 0.05-20 mg of compound per kg of
body weight. In some variations, the daily dose is 0.1-10 mg of
compound per kg of body weight. In some variations, the daily dose
is 0.1-5 mg of compound per kg of body weight. In some variations,
the daily dose is 0.1-2.5 mg of compound per kg of body weight.
[0146] In some embodiments, the pharmaceutically effective amount
is a daily dose is of 0.1-1000 mg of compound per kg of body
weight. In some variations, the daily dose is 0.15-20 mg of
compound per kg of body weight. In some variations, the daily dose
is 0.20-10 mg of compound per kg of body weight. In some
variations, the daily dose is 0.40-3 mg of compound per kg of body
weight. In some variations, the daily dose is 0.50-9 mg of compound
per kg of body weight. In some variations, the daily dose is 0.60-8
mg of compound per kg of body weight. In some variations, the daily
dose is 0.70-7 mg of compound per kg of body weight. In some
variations, the daily dose is 0.80-6 mg of compound per kg of body
weight. In some variations, the daily dose is 0.90-5 mg of compound
per kg of body weight. In some variations, the daily dose is from
about 1 mg to about 5 mg of compound per kg of body weight.
[0147] An effective amount typically will vary from about 0.001
mg/kg to about 1,000 mg/kg, from about 0.01 mg/kg to about 750
mg/kg, from about 0.1 mg/kg to about 500 mg/kg, from about 0.2
mg/kg to about 250 mg/kg, from about 0.3 mg/kg to about 150 mg/kg,
from about 0.3 mg/kg to about 100 mg/kg, from about 0.4 mg/kg to
about 75 mg/kg, from about 0.5 mg/kg to about 50 mg/kg, from about
0.6 mg/kg to about 30 mg/kg, from about 0.7 mg/kg to about 25
mg/kg, from about 0.8 mg/kg to about 15 mg/kg, from about 0.9 mg/kg
to about 10 mg/kg, from about 1 mg/kg to about 5 mg/kg, from about
100 mg/kg to about 500 mg/kg, from about 1.0 mg/kg to about 250
mg/kg, or from about 10.0 mg/kg to about 150 mg/kg, in one or more
dose administrations daily, for one or several days (depending, of
course, of the mode of administration and the factors discussed
above). Other suitable dose ranges include 1 mg to 10,000 mg per
day, 100 mg to 10,000 mg per day, 500 mg to 10,000 mg per day, and
500 mg to 1,000 mg per day. In some particular embodiments, the
amount is less than 10,000 mg per day with a range, for example, of
750 mg to 9,000 mg per day.
[0148] The effective amount may be less than 1 mg/kg/day, less than
500 mg/kg/day, less than 250 mg/kg/day, less than 100 mg/kg/day,
less than 50 mg/kg/day, less than 25 mg/kg/day, less than 10
mg/kg/day, or less than 5 mg/kg/day. It may alternatively be in the
range of 1 mg/kg/day to 200 mg/kg/day. For example, regarding
treatment of diabetic patients, the unit dosage may be an amount
that reduces blood glucose by at least 40% as compared to an
untreated subject. In another embodiment, the unit dosage is an
amount that reduces blood glucose to a level that is within +10% of
the blood glucose level of a non-diabetic subject.
[0149] In other non-limiting examples, a dose may also comprise
from about 1 micro-gram/kg/body weight, about 5 microgram/kg/body
weight, about 10 microgram/kg/body weight, about 50
microgram/kg/body weight, about 100 microgram/kg/body weight, about
200 microgram/kg/body weight, about 350 microgram/kg/body weight,
about 500 microgram/kg/body weight, about 1 milligram/kg/body
weight, about 5 milli-gram/kg/body weight, about 10
milligram/kg/body weight, about 50 milligram/kg/body weight, about
100 milligram/kg/body weight, about 200 milligram/kg/body weight,
about 350 milligram/kg/body weight, about 500 milligram/kg/body
weight, to about 1000 mg/kg/body weight or more per administration,
and any range derivable therein. In non-limiting examples of a
derivable range from the numbers listed herein, a range of about 1
mg/kg/body weight to about 5 mg/kg/body weight, a range of about 5
mg/kg/body weight to about 100 mg/kg/body weight, about 5
microgram/kg/body weight to about 500 milligram/kg/body weight,
etc., can be administered, based on the numbers described
above.
[0150] In certain embodiments, a pharmaceutical composition of the
present invention may comprise, for example, at least about 0.1% of
a compound of the present invention. In other embodiments, the
compound of the present invention may comprise between about 2% to
about 75% of the weight of the unit, or between about 25% to about
60%, for example, and any range derivable therein.
[0151] Single or multiple doses of the agents are contemplated.
Desired time intervals for delivery of multiple doses can be
determined by one of ordinary skill in the art employing no more
than routine experimentation. As an example, subjects may be
administered two doses daily at approximately 12 hour intervals. In
some embodiments, the agent is administered once a day.
[0152] The agent(s) may be administered on a routine schedule. As
used herein a routine schedule refers to a predetermined designated
period of time. The routine schedule may encompass periods of time
which are identical or which differ in length, as long as the
schedule is predetermined. For instance, the routine schedule may
involve administration twice a day, every day, every two days,
every three days, every four days, every five days, every six days,
a weekly basis, a monthly basis or any set number of days or weeks
there-between. Alternatively, the predetermined routine schedule
may involve administration on a twice daily basis for the first
week, followed by a daily basis for several months, etc. In other
embodiments, the invention provides that the agent(s) may taken
orally and that the timing of which is or is not dependent upon
food intake. Thus, for example, the agent can be taken every
morning and/or every evening, regardless of when the subject has
eaten or will eat.
[0153] Non-limiting specific formulations include CDDO-Me polymer
dispersions (see U.S. application Ser. No. 12/191,176, filed Aug.
13, 2008, which is incorporated herein by reference). Some of the
formulations reported therein exhibited higher bioavailability than
either the micronized Form A or nanocrystalline Form A
formulations. Additionally, the polymer dispersion based
formulations demonstrated further surprising improvements in oral
bioavailability relative to the micronized Form B formulations. For
example, the methacrylic acid copolymer, Type C and HPMC-P
formulations showed the greatest bioavailability in the subject
monkeys.
VII. Combination Therapy
[0154] In addition to being used as a monotherapy, the compounds of
the present invention may also find use in combination therapies.
Effective combination therapy may be achieved with a single
composition or pharmacological formulation that includes both
agents, or with two distinct compositions or formulations,
administered at the same time, wherein one composition includes a
compound of this invention, and the other includes the second
agent(s). Alternatively, the therapy may precede or follow the
other agent treatment by intervals ranging from minutes to
months.
[0155] Various combinations may be employed, such as when a
compound of the present invention is "A" and "B" represents a
secondary agent, non-limiting examples of which are described
below:
TABLE-US-00003 A/B/A B/A/B B/B/A A/A/B A/B/B B/A/A A/B/B/B B/A/B/B
B/B/B/A B/B/A/B A/A/B/B A/B/A/B A/B/B/A B/B/A/A B/A/B/A B/A/A/B
A/A/A/B B/A/A/A A/B/A/A A/A/B/A
[0156] It is contemplated that other anti-inflammatory agents may
be used in conjunction with the treatments of the current
invention. For example, other COX inhibitors may be used, including
arylcarboxylic acids (salicylic acid, acetylsalicylic acid,
diflunisal, choline magnesium trisalicylate, salicylate,
benorylate, flufenamic acid, mefenamic acid, meclofenamic acid and
triflumic acid), arylalkanoic acids (diclofenac, fenclofenac,
alclofenac, fentiazac, ibuprofen, flurbiprofen, ketoprofen,
naproxen, fenoprofen, fenbufen, suprofen, indoprofen, tiaprofenic
acid, benoxaprofen, pirprofen, tolmetin, zomepirac, clopinac,
indomethacin and sulindac) and enolic acids (phenylbutazone,
oxyphenbutazone, azapropazone, feprazone, piroxicam, and isoxicam.
See also U.S. Pat. No. 6,025,395, which is incorporated herein by
reference.
[0157] Dietary and nutritional supplements with reported benefits
for treatment or prevention of Parkinson's, Alzheimer's, multiple
sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis,
inflammatory bowel disease, and all other diseases whose
pathogenesis is believed to involve excessive production of either
nitric oxide (NO) or prostaglandins, such as acetyl-L-carnitine,
octacosanol, evening primrose oil, vitamin B6, tyrosine,
phenylalanine, vitamin C, L-dopa, or a combination of several
antioxidants may be used in conjunction with the compounds of the
current invention.
[0158] Other particular secondary therapies include
immunosuppressants (for transplants and autoimmune-related RKD),
anti-hypertensive drugs (for high blood pressure-related RKD, e.g.,
angiotensin-converting enzyme inhibitors and angiotensin receptor
blockers), insulin (for diabetic RKD), lipid/cholesterol-lowering
agents (e.g., HMG-CoA reductase inhibitors such as atorvastatin or
simvastatin), treatments for hyperphosphatemia or
hyperparathyroidism associated with CKD (e.g., sevelamer acetate,
cinacalcet), dialysis, and dietary restrictions (e.g., protein,
salt, fluid, postassium, phosphorus).
VIII. Examples
[0159] The following examples are included to demonstrate preferred
embodiments of the invention. It should be appreciated by those of
skill in the art that the techniques disclosed in the examples
which follow represent techniques discovered by the inventor to
function well in the practice of the invention, and thus can be
considered to constitute preferred modes for its practice. However,
those of skill in the art should, in light of the present
disclosure, appreciate that many changes can be made in the
specific embodiments which are disclosed and still obtain a like or
similar result without departing from the spirit and scope of the
invention.
Example 1--Materials and Methods
[0160] Chemicals.
[0161] Triterpenoids were synthesized as previously described in
Honda et al. (1998), Honda et a. (2000b), Honda et al. (2002) and
Yates et al. (2007), which are all incorporated herein by
reference.
Example 2--Mouse Ischemia-Reperfusion Results
[0162] In a mouse model of ischemic acute renal failure, the renal
artery is clamped for approximately twenty minutes. After this
time, the clamp is removed and the kidney is reperfused with blood.
Ischemia-reperfusion results in renal damage and decreased renal
function which can be assessed by blood urea nitrogen (BUN) levels,
which become elevated following renal damage. As shown in FIGS.
1a-d, surgically-induced ischemia-reperfusion increased BUN levels
by approximately 2-fold. However, in animals treated with 2 mg/kg
RTA 402 orally once daily beginning two days prior to the surgery,
the BUN levels were significantly reduced (p<0.01) relative to
vehicle-treated animals and were similar to the levels in animals
that underwent sham surgeries (FIGS. 1a-c). Histological measures
of kidney damage and inflammation were also significantly improved
by treatment with RTA 402 (FIG. 1d). These data indicate that RTA
402 is protective against ischemia-reperfusion induced tissue
damage.
Example 3--Rat Chemotherapy-Induced Acute Renal Injury Results
[0163] In another model of acute renal injury, rats were injected
intravenously with the antineoplastic agent cisplatin. In humans,
nephrotoxicity is a dose-limiting side effect of treatment with
cisplatin. Cisplatin-induced damage to the proximal tubules is
thought to be mediated by increased inflammation, oxidative stress,
and apoptosis (Yao et al., 2007). Rats treated with a single dose
of cisplatin at 6 mg/kg developed renal insufficiency as measured
by increased blood levels of creatinine and BUN. Treatment with 10
mg/kg RTA 402 by oral gavage beginning one day prior to treatment
with cisplatin and continuing every day significantly reduced blood
levels of creatinine and BUN (FIGS. 2a-b). Histological evaluation
of the kidneys demonstrated an improvement in the extent of
proximal tubule damage in RTA 402-treated animals compared to
vehicle-treated animals (FIG. 2c).
Example 4--Reduction of Serum Creatinine Levels in Several
Species
[0164] Serum creatinine has been measured in several animal species
treated with RTA 402 in the course of toxicology studies.
Significant reductions of serum creatinine levels relative to
baseline levels or levels in control animals have been observed in
cynomolgus monkeys, beagle dogs, and Sprague-Dawley rats (FIGS.
3a-d). This effect has been observed in rats with crystalline and
amorphous forms of RTA 402.
Example 5--Reduced Serum Creatinine and Increased eGFR in Cancer
Patients
[0165] Serum creatinine has also been measured in patients with
cancer enrolled in a Phase I clinical trial of RTA 402. These
patients received RTA 402 once daily at doses from 5 to 1,300
mg/day for a total of twenty-one days every 28 days. A reduction in
serum creatinine by greater than 15% was observed as early as eight
days following treatment initiation and persisted through the end
of the cycle (FIG. 4A). This reduction was maintained in those
patients that received six or more cycles of treatment with RTA
402. A subset of patients with pre-existing renal damage (baseline
serum creatinine levels of at least 1.5 mg/dl) also had significant
reductions in serum creatinine levels following treatment with RTA
402. In these patients, serum creatinine levels decreased
progressively throughout the cycle such that the Day 21 levels were
approximately 25% lower than baseline levels (FIG. 4A). These
results can be summarized as shown in the table below.
TABLE-US-00004 Sub-set with elevated All baseline serum patients
creatinine levels Number of patients who received 45 8 drug for at
least 3 weeks % of Patients with Decrease on Day 21 87% 100% %
Serum Creatinine Decrease from -18.3% -24.5% Baseline p-value
(Baseline versus Day 21) 0.001 0.0007
[0166] The estimated glomerular filtration rate (eGFR)
significantly improved in the patients treated with RTA 402 (FIG.
4B).
[0167] FIG. 5 shows the results following at least six months of
RTA 402 treatment in eleven cancer patients, showing that eGFR
improved in an approximately continuous manner. Some of these
patients were enrolled in the Phase I study, whereas others were
enrolled in a study of RTA 402 (in combination with gemcitabine) in
patients with pancreatic cancer. The results can be summarized as
shown in Table 2, below.
TABLE-US-00005 TABLE 2 eGFR in Patients Receiving RTA 402 for 6
Cycles. Solid Tumor Study Pancreatic Study Pt ID: 402 406 408 409
410 421 427 1001 1104 1105 1106 Dose (mg): 5 80 150 150/300 300/600
1300/900 1300 150 300/150 300 300 Cycle (each BL 109.7 94.2 73.2
48.4 49.9 52.5 70.1 68.8 67.3 82.4 89.0 cycle is 28 1 109.7 125.9
82.1 62.6 69.6 58.6 101.3 78.9 95.7 106.6 106.3 days) 2 109.7 107.9
77.4 62.6 63.4 66.2 78.3 109.9 71.6 89.3 106.3 3 95.7 107.9 69.4
62.6 63.4 75.8 88.4 135.7 141.2 106.6 106.3 4 95.7 125.9 77.4 57.0
69.6 N/A 101.3 175.5 95.7 106.6 131.2 5 109.7 107.9 77.4 69.2 63.4
88.4 101.3 175.5 114.4 131.6 131.2 6 95.7 125.9 87.4 69.2 69.6 75.8
101.3 135.7 114.4 170.3 131.2
Example 6--Phase 2 Study in Patients with Diabetic Nephropathy
[0168] Serum creatinine has also been measured in patients with
chronic kidney disease (CKD) enrolled in an open label Phase II
clinical trial of RTA 402. These patients received RTA 402 once
daily at three dose levels, 25 mg, 75 mg and 150 mg, for a total of
28 days.
[0169] The study was designed with multiple endpoints, in
categories of insulin resistance, endothelial dysfunction/CVD, and
CKD. These can be summarized as follows:
TABLE-US-00006 Endothelial Dysfunction/ Chronic Kidney Insulin
Resistance/Diabetes Cardiovascular Disease Hgb A1c CECs GFR
GDR/Euglycemic Clamp C-Reactive Protein Serum Creatinine (CRP)
Glucose E-Selectin Creatinine Clearance VCAM Cystatin C Cytokines
Adiponectin Angiotensin II
[0170] A primary outcome measure for this study is determining the
effects of RTA 402 administered orally at the three dose strengths
on the glomerular filtration rate (as estimated by the MDRD
formula) in patients with diabetic nephropathy.
[0171] Secondary outcome measures include: (1) an evaluation of the
safety and tolerability of oral RTA 402 administered orally at the
three different doses, in this patient population; (2) an
evaluation of the effects of RTA 402 administered orally at the
three dose strengths on the serum creatinine level, creatinine
clearance, and urine albumin/creatinine ratio in patients with
diabetic nephropathy; (3) an evaluation of the effects of RTA 402
administered orally at the three dose strengths on hemoglobin A1c
in all patients enrolled and on insulin response by the
hyperinsulinemic euglycemic clamp test in patients enrolled at only
one of the study centers; (4) an evaluation of the effects of RTA
402 at the three different doses on a panel of markers of
inflammation, renal injury, oxidative stress, and endothelial cell
dysfunction.
[0172] The patient population selected for this study all had type
2 diabetes with CKD. Most had been diagnosed with poor glycemic
control for two decades. CKD was established through elevated serum
creatinine (SCr) levels. Most of the patients had been diagnosed
with cardiovascular disease (CVD) and most were receiving standard
of care (SOC) treatment for diabetes, CKD and CVD, (e.g., insulin,
ACEI/ARB, .beta.-blocker, diuretic, and statin). The baseline
demographic can be summarized as follows:
TABLE-US-00007 Age 59 Diabetes Duration (yrs) 15.4 Diabetic
Nephropathy 100% Non-renal Diabetic Complications.sup.1 100%
Hypertensive 100% Hgb A1c(%) 7.9% Failed Oral Antihyperglycemics
90% ACEI/ARB Use 80% Statin Use 50% .sup.1Includes neuropathy and
retinopathy All values represent the mean; n = 10; 1.sup.st 10
patients to complete study
[0173] The patient inclusion criteria were as follows: (1)
diagnosis of type 2 diabetes; (2) serum creatinine in women 1.3-3.0
mg/dL (115-265 .mu.mol/L), inclusive, and in men 1.5-3.0 mg/dL
(133-265 .mu.mol/L), inclusive; (3) patient must agree to practice
effective contraception; (4) patient must have a negative urine
pregnancy test within 72 hours prior to the first dose of study
medication; (5) patient is willing and able to cooperate with all
aspects of the protocol and is able to communicate effectively; (6)
patient is willing and able to provide written informed consent to
participate in this clinical study.
[0174] The patient exclusion criteria were the following: (1)
patients having type 1 (insulin-dependent; juvenile onset)
diabetes; (2) patients with known non-diabetic renal disease
(nephrosclerosis superimposed on diabetic nephropathy acceptable),
or with renal allograft; (3) patients having cardiovascular disease
as follows: unstable angina pectoris within 3 months of study
entry; myocardial infarction, coronary artery bypass graft surgery,
or percutaneous transluminal coronary angioplasty/stent within 3
months of study entry; transient ischemic attack within 3 months of
study entry; cerebrovascular accident within 3 months of study
entry; obstructive valvular heart disease or hypertrophic
cardiomyopathy; second or third degree atrioventricular block not
successfully treated with a pacemaker; (4) patients with need for
chronic (>2 weeks) immunosuppressive therapy, including
corticosteroids (excluding inhaled or nasal steroids) within 3
months of study entry; (5) patients with evidence of hepatic
dysfunction including total bilirubin >1.5 mg/dL (>26
micromole/L) or liver transaminase (aspartate aminotransferase
[AST] or alanine transferase [ALT])>1.5 times upper limit of
normal; (6) if female, patient is pregnant, nursing or planning a
pregnancy; (7) patients with any concurrent clinical conditions
that in the judgment of the investigator could either potentially
pose a health risk to the patient while involved in the study or
could potentially influence the study outcome; (8) patients having
known hypersensitivity to any component of the study drug; (9)
patients having known allergy to iodine; (10) patients having
undergone diagnostic or intervention procedure requiring a contrast
agent within the last 30 days prior to entry into the study; (11)
patients with change or dose-adjustment in any of the following
medications: ACE inhibitors, angiotensin II blockers, non-steroidal
anti inflammatory drugs (NSAIDs), or COX-2 inhibitors within 3
months; other anti-hypertensive, and other anti-diabetic
medications within 6 weeks prior to entry into the study; (12)
patients having a history of drug or alcohol abuse or having
positive test results for any drug of abuse (positive urine drug
test and/or alcohol breathalyzer test); (13) patients having
participated in another clinical study involving investigational or
marketed products within 30 days prior to entry into the study or
would concomitantly participate in such a study; (14) patients
unable to communicate or cooperate with the Investigator due to
language problems, poor mental development or impaired cerebral
function.
[0175] As of the end of September 2008, there were 32 of 60
patients enrolled in this study. All but one patient was receiving
insulin and standard-of-care oral antihyper-glycemics.
[0176] Treatment with RTA 402 was observed to reduce hemoglobin %
A1c in 28 days in refractory diabetics on top of standard of care.
The treatment showed an intent-to-treat reduction of approximately
0.25 (n=56) and an elevated baseline (.gtoreq.7.0 at baseline)
reduction of 0.50 (n=35). Hemoglobin % A1c reduction as a function
of baseline severity is shown in FIG. 6, and reduction as a
function of dosage is shown in FIG. 7. Patients with advanced
(Stage 4) renal disease (GFR from 15-29 ml/min) showed a mean % A1c
reduction of approximately 0.77. All reductions were statistically
significant.
[0177] Hyperinsulinemic euglycemic clamp test results showed that
the 28 day treatment also improved glycemic control and insulin
sensitivity in the patients, as measured by glucose disposal rate
(GDR). Patients exhibited improvements in GDR after the 28 day
treatment, with more severely impaired patients (GDR<4) showing
statistically significant improvements (p.ltoreq.0.02). The
hyperinsulinemic euglycemic clamp test was performed at Baseline
(Day -1) and at the end of the study on Day 28. The test measures
the rate of glucose infusion (GINF) necessary to compensate for an
increased insulin level without causing hypoglycemia; this value is
used to derive the GDR.
[0178] In short, the hyperinsulinemic euglycemic clamp test takes
about 2 hours. Through a peripheral vein, insulin is infused at
10-120 mU per m.sup.2 per minute. In order to compensate for the
insulin infusion, glucose 20% is infused to maintain blood sugar
levels between 5 and 5.5 mmol/L. The rate of glucose infusion is
determined by checking the blood sugar levels every 5 to 10
minutes. The rate of glucose infusion during the last 30 minutes of
the test is used to determine insulin sensitivity as determined by
the glucose metabolism rate (M) in mg/kg/min.
[0179] The following protocol guidelines are in place for the
hyperinsulinemic euglycemic clamp test: [0180] 1) Subject to fast
8-10 hours prior to the clamp procedure. [0181] 2) The morning of
the clamp measure vital signs and weight. [0182] 3) Start a
retrograde line in one hand with 11/4'', 18-20 gauge catheter for
drawing samples. [0183] 4) Prepare IV tubing with 2 three-way stop
cocks and j-loop extension tubing. Spike tubing to a liter bag of
0.9% NaCl to run at KVO (keep vein open, about 10 cc/hr) until the
start of the procedure. [0184] 5) Apply a heating pad covered in a
pillow case with a pad separating the heating pad from the
subject's hand. (Enables the collection of shunted arterialized
blood from venous catheterization) [0185] 6) Monitor the
temperature (approximately 150.degree. F./65.degree. C.) generated
by the heating pad before and during the clamp, to maintain
arterialization. [0186] 7) Start another line opposite the draw
side in the distal forearm with 11/4'', 18-20 gauge catheter for
the infusion line. Prepare IV tubing with 2 three-way stop cocks.
[0187] 8) Hang a 500 ml bag of 20% dextrose and attach to port on
the infusion side [0188] 9) Prepare the insulin infusion [0189] a.
Remove 53 cc (50 cc of overfill) of saline from a 500 cc bag of
0.9% NaCl and discard [0190] b. Draw 8 cc of blood from subject
using sterile technique and inject into a tiger top tube [0191] c.
Centrifuge the tiger top tube. Withdraw 2 cc of serum and inject
into the 500 cc bag of 0.9% NaCl [0192] d. Add 100 units of insulin
to the bag with the serum and mix well (0.2 U insulin/ml) [0193] e.
Connect IV tubing with duo-vent spike into the 0.9% NaCl bag [0194]
f. Place on Baxter pump [0195] 10) Time and draw all basal blood
samples (Baseline fasting blood glucose values will be obtained
prior to beginning the insulin prime). [0196] 11) Perform insulin
infusion rate calculations for a priming dose and 60 mU/m.sup.2
insulin infusion. This background insulin is to suppress endogenous
hepatic glucose production. Lean subjects can be suppressed with 40
mU/m.sup.2; obese, insulin resistant subjects require 80
mU/m.sup.2. 60 mU/m.sup.2 should be sufficient to suppress the
suggested study population with a BMI of 27-40 kg/m.sup.2. The
suggested 60 mU/m.sup.2 insulin infusion may need to be adjusted if
the BMI is amended. [0197] 12) 0.5 mL samples will be drawn every
five minutes and the readings from the YSI Blood Glucose Analyzer
will be used to determine/adjust the glucose infusion rate
(mg/kg/min). Any additional laboratory tests required by the
protocol will be in addition to the blood volume. The clamp will
last 120 minutes which is believed to be a sufficient duration for
determining insulin sensitivity. [0198] 13) Label and save all YSI
printouts for source documents. [0199] 14) The glucose infusion
rates from the last 30 minutes of the euglycemic clamp will be
adjusted using space correction. This will be used to determine the
glucose metabolism rate (M mg/kg/min), which represents the
subject's sensitivity to insulin.
[0200] As shown in FIG. 8, RTA 402 reduces circulating endothelial
cells (CECs). The mean number of CECs in cells/mL is shown for
intent-to-treat (ITT) and elevated baseline groups, both before and
after the 28 day RTA treatment. The reduction for the
Intent-to-treat group was approximately 20%, and the reduction in
the elevated baseline group (>5 CECs/ml) was approximately 33%.
The fraction of iNOS-positive CECs was reduced approximately 29%.
Normalization of CEC values (.ltoreq.5 cells/mL) was observed in 11
out of the 19 patients with elevated baseline.
[0201] CECs were isolated from whole blood by using CD146 Ab (an
antibody to the CD146 antigen that is expressed on endothelial
cells and leukocytes). After CEC isolation, a FITC (fluorescein
isothiocyanate) conjugated CD105 Ab (a specific antibody for
endothelial cells) is used to identify CECs using the
CellSearch.TM. system. A fluorescent conjugate of CD45 Ab was added
to stain the leukocytes, and these were then gated out. For a
general overview of this method, see Blann et al., (2005), which is
incorporated herein by reference in its entirety. CEC samples were
also assessed for the presence of iNOS by immunostaining. Treatment
with RTA 402 reduced iNOS-positive CECs by approximately 29%,
further indicating that RTA 402 reduces inflammation in endothelial
cells.
[0202] RTA 402 was shown to improve significantly eight measures of
renal function and status, including serum creatinine based eGFR
(FIG. 9), creatinine clearance, BUN (FIG. 11A), serum phosphorus
(FIG. 11B), serum uric acid (FIG. 11C), Cystatin C, Adiponectin
(FIG. 10A), and Angiotensin II (FIG. 10B). Adiponectin predicts
all-cause mortality and end stage renal disease in DN patients.
Adiponectin and Angiotensin II, which are elevated in DN patients,
correlate with renal disease severity (FIGS. 10A-B). Effects on
BUN, phosphorus, and uric acid are shown in FIGS. 11A-C.
[0203] Patients treated with higher doses (75 or 150 mg) of RTA 402
showed modest elevations (approximately 20 to 25%) in proteinuria.
This is consistent with studies indicating that better GFR
performance correlates with increased proteinuria. For example, in
a long-term clinical study of more than 25,000 patients, treatment
with ramipril (an ACE inhibitor) slowed the rate of eGFR decline
more effectively than either telmisartan (an angiotensin receptor
blocker) or the combination of ramipril and telmisartan (Mann et
al., 2008). Conversely, proteinuria increased more in the ramipril
group than in the other two groups. Major renal outcomes were also
better with either drug alone than with combination therapy,
although proteinuria increased least in the combination therapy
group. Other studies have shown that drugs that reduce GFR, such as
ACE-inhibitors, also reduce proteinuria (Lozano et al., 2001;
Sengul et al., 2006). Other studies have shown that drugs that
acutely increase GFR, such as certain calcium channel blockers,
increase proteinuria up to 60% during short-term dosing (Agodoa et
al., 2001; Viberti et al., 2002).
[0204] All of the compositions and/or methods disclosed and claimed
herein can be made and executed without undue experimentation in
light of the present disclosure. While the compositions and methods
of this invention have been described in terms of preferred
embodiments, it will be apparent to those of skill in the art that
variations may be applied to the compositions and/or methods and in
the steps or in the sequence of steps of the method described
herein without departing from the concept, spirit and scope of the
invention. More specifically, it will be apparent that certain
agents which are both chemically and physiologically related may be
substituted for the agents described herein while the same or
similar results would be achieved. All such similar substitutes and
modifications apparent to those skilled in the art are deemed to be
within the spirit, scope and concept of the invention as defined by
the appended claims.
IX. References
[0205] The following references, to the extent that they provide
exemplary procedural or other details supplementary to those set
forth herein, are specifically incorporated herein by reference.
[0206] U.S. Pat. No. 6,025,395 [0207] U.S. Pat. No. 6,326,507
[0208] U.S. Pat. No. 6,974,801 [0209] U.S. Patent Prov. 60/955,939
[0210] U.S. patent application Ser. No. 12/191,176 [0211] Agodoa et
al., JAMA, 285:2719-2728, 2001. [0212] Ahmad et al., J. Biol.
Chem., 281:3576-3579, 2006. [0213] Aschner et al., Diabetes Care,
29(12):2632-2637, 2006. [0214] Blann et al., Thromb. Haemost., 93:
228-35 (2005). [0215] DeFronzo et al., Am. J. Physiol.,
237(3):E214-223, 1979. [0216] Dinkova-Kostova et al., Proc. Natl.
Acad. Sci. USA, 102(12):4584-4589, 2005. [0217] Goldstein et al.,
Diabetes Care, 30(8):1979-1987, 2007. [0218] Goodman et al., Kidney
Int., 72:945-953, 2007. [0219] Honda et al., Bioorg. Med. Chem.
Lett., 12:1027-1030, 2002. [0220] Honda et al., Bioorg. Med. Chem.
Lett., 19:2711-2714, 1998. [0221] Honda et al., Bioorg. Med. Chem.
Lett., 9:3429-3434, 1999. [0222] Honda et al., J. Med. Chem.,
43:1866-1877, 2000a. [0223] Honda et al., J. Med. Chem.,
43:4233-4246, 2000b. [0224] Honda et al., Med. Chem. Lett.,
7:1623-1628, 1997. [0225] Honda et al., Org. Biomol. Chem.,
1:4384-4391, 2003. [0226] Huang et al., Cancer Res., 54:701-708,
1994. [0227] Ikeda et al., Cancer Res., 63: 5551-5558, 2003. [0228]
Ikeda et al., Mol. Cancer Ther., 3:39-45, 2004. [0229] Kobayashi
& Yamamoto, Antioxid. Redox. Signal., 7:385-394, 2005. [0230]
Liby et al., Cancer Res., 65:4789-4798, 2005. [0231] Liu, J.
Ethnopharmacol., 49:57-68, 1995. [0232] Lozano et al., Nephrol.
Dial. Transplant., 16[Suppl 1]:85-89, 2001. [0233] Ma et al., Am.
J. Pathol., 168:1960-1974, 2006. [0234] Mann et al., The Lancet,
372: 547-553, 2008. [0235] Maines & Gibbs, Biochem. Biophys.
Res. Commun., 338:568-577, 2005. [0236] Minns et al.,
Gastroenterology, 127:119-26, 2004. [0237] Mix et al., Mol.
Pharmacol., 65:309-318, 2004. [0238] Nath, Kidney Int., 70,
432-443, 2006. [0239] Nichols, Drug News Perspect., 17:99-104,
2004. [0240] Nishino et al., Cancer Res., 48:5210-5215, 1988.
[0241] Place et al., Clin. Cancer Res., 9:2798-2806, 2003. [0242]
Pullman et al., Vasc. Health Risk Manag., 2(3):203-212, 2006.
[0243] Repka, M A, McGinity, J W, Zhang, F, Koleng, J J, Hot-melt
extrusion technology. In: Enclopedia of Pharmaceutical Technology,
2.sup.nd ed, New York, N.Y.: Marcel Dekker, 2002: 203-206. [0244]
Sengul et al., Diab. Res. Clin. Pract., 71:210-219, 2006. [0245]
Shishodia et al., Clin. Cancer Res., 12(6): 1828-1838, 2006. [0246]
Suh et al., Cancer Res., 63:1371-1376, 2003. [0247] Suh et al.,
Cancer Res., 58:717-723, 1998. [0248] Suh et al., Cancer Res.,
59(2):336-341, 1999. [0249] Tumlin et al., Am. J. Cardiol.,
98:14K-20K, 2006. [0250] Viberti et al., Circulation, 106:672-678,
2002. [0251] Wang et al., Mol. Endocrinol., 14:1550-1556, 2000.
[0252] Wardle, Nephrol. Dial. Transplant., 16, 1764-1768 2001.
[0253] Wermuth and Stahl, In: Pharmaceutical Salts: Properties,
Selection and Use-A Handbook, Verlag Helvetica Chimica Acta, 2002.
[0254] Yao et al., Am. J. Med. Sci., 334(2):115-24, 2007. [0255]
Yates et al., Mol. Cancer Ther., 6(1):154-162, 2007. [0256] Yoh et
al., Kidney Int., 60, 1343-1353, 2001. [0257] Zingarelli et al.,
Crit Care Med., 31, S105-S111, 2003. [0258] Zoccali, J. Amer. Soc.
Nephrol, 17:S61-S-63, 2006.
* * * * *