U.S. patent application number 17/539146 was filed with the patent office on 2022-03-17 for nicorandil derivatives.
The applicant listed for this patent is UNICYCIVE THERAPEUTICS INC.. Invention is credited to Sundeep DUGAR, Shalabh GUPTA.
Application Number | 20220079927 17/539146 |
Document ID | / |
Family ID | |
Filed Date | 2022-03-17 |
United States Patent
Application |
20220079927 |
Kind Code |
A1 |
GUPTA; Shalabh ; et
al. |
March 17, 2022 |
NICORANDIL DERIVATIVES
Abstract
Disclosed herein are pyridyl compounds. Also described are
specific conjugated nicorandil compounds. Also disclosed are
pharmaceutical compositions that include the compounds. Methods of
using the pyridyl compounds are disclosed for the treatment of
diseases or conditions related to kidney or kidney functions.
Inventors: |
GUPTA; Shalabh; (Mountain
View, CA) ; DUGAR; Sundeep; (San Jose, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
UNICYCIVE THERAPEUTICS INC. |
Los Altos |
CA |
US |
|
|
Appl. No.: |
17/539146 |
Filed: |
November 30, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17439781 |
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PCT/US2020/023016 |
Mar 16, 2020 |
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17539146 |
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62819372 |
Mar 15, 2019 |
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International
Class: |
A61K 31/4425 20060101
A61K031/4425; A61K 31/4545 20060101 A61K031/4545; A61P 13/12
20060101 A61P013/12 |
Claims
1. A method for treating a disease or a condition related to kidney
in a mammal, where the method comprises administering to the mammal
an effective disease-treating or condition-treating amount of a
compound according to formula (I): ##STR00045## or a pharmaceutical
composition thereof, wherein X.sup.- is a counter ion; Y is
--C(H).sub.2--, --O--, or --N(R.sup.3)--; R.sup.1 is substituted or
unsubstituted C.sub.1-C.sub.4 alkyl, substituted or unsubstituted
C.sub.3-C.sub.7-cycloalkyl, or substituted or unsubstituted 4-7
membered heterocycloalkyl; R.sup.2 is H or C.sub.1-C.sub.4 alkyl;
and R.sup.3 is H or substituted or unsubstituted C.sub.1-C.sub.4
alkyl; or R.sup.1 and R.sup.3 are joined together to form a 4-7
membered substituted or unsubstituted heterocycloalkyl.
2. (canceled)
3. The method of claim 1, wherein R.sup.2 is H, Me, Et, or
i-Pr.
4. The method of claim 1, wherein R.sup.2 is H.
5. (canceled)
6. The method according to claim 1, wherein Y is --O--.
7. The method according to claim 1, wherein Y is
--N(R.sup.3)--.
8. The method according to claim 1, wherein the compound is
according to formula (IIa), (IIb), or (IIc): ##STR00046## wherein
X.sup.- is a counter ion; R.sup.1 is substituted or unsubstituted
C.sub.1-C.sub.4 alkyl, substituted or unsubstituted
C.sub.3-C.sub.7-cycloalkyl, or substituted or unsubstituted 4-7
membered heterocycloalkyl; R.sup.2 is H or C.sub.1-C.sub.4 alkyl;
and R.sup.3 is H or substituted or unsubstituted C.sub.1-C.sub.4
alkyl; or R.sup.1 and R.sup.3 are joined together to form a 4-7
membered substituted or unsubstituted heterocycloalkyl.
9. The method according to claim 1, wherein R.sup.1 is substituted
or unsubstituted C.sub.1-C.sub.4 alkyl.
10. The method according to claim 1, wherein R.sup.1 is
C.sub.1-C.sub.4 alkyl, unsubstituted or substituted with
C.sub.3-C.sub.7 cycloalkyl.
11. The method according to claim 1, wherein R.sup.1 is Me, Et,
i-Pr, n-Pr, n-Bu, i-Bu, sec-Bu, or t-Bu.
12. The method according to claim 1, wherein R.sup.1 is Me or Et
substituted with cyclopropyl, cyclobutyl, cyclopentyl, or
cyclohexyl.
13. The method according to claim 1, wherein R.sup.1 is
C.sub.3-C.sub.7-cycloalkyl unsubstituted or substituted with Me or
Et.
14. The method according to claim 1, wherein R.sup.1 is
cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
15. (canceled)
16. The method according to claim 1, wherein R.sup.3 is H.
17.-19. (canceled)
20. The method according to claim 1, wherein the compound is
according to formula (IIIa), or (IIIb): ##STR00047## wherein
X.sup.- is a counter ion; R.sup.2 is H or C.sub.1-C.sub.4 alkyl;
and R.sup.3 is H or substituted or unsubstituted C.sub.1-C.sub.4
alkyl.
21. The method according to claim 20, wherein R.sup.3 is H, Me, Et,
or i-Pr.
22. The method according to claim 20, wherein R.sup.3 is H.
23. The method according to claim 1, wherein R.sup.2 is H or
Me.
24. The method according to claim 1, wherein the compound is
according to formula (IIIb); and each R.sup.2 and R.sup.3 is H.
25. The method according to claim 1, wherein the compound is
according to formula (IVa): ##STR00048## wherein X.sup.- is a
counter ion.
26. The method according to claim 1, wherein the compound is
according to formula (Va): ##STR00049## wherein X.sup.- is a
counter ion.
27. The method according to claim 1, wherein X.sup.- is F.sup.-,
Cl.sup.-, Br.sup.-, I.sup.-, or MeSO.sub.2O.sup.-.
28. The method according to claim 1, wherein X.sup.- is Cl.sup.-,
or I.sup.-.
29. The method according to claim 1, wherein the pharmaceutical
composition comprises a pharmaceutically acceptable excipient.
30. The pharmaceutical composition of claim 29 that is formulated
for a route of administration selected from oral administration,
parenteral administration, buccal administration, nasal
administration, topical administration, or rectal
administration.
31. The method according to claim 1, wherein the disease or
condition is Chronic Kidney Disease, Diabetic Nephropathy, IgA
Nephropathy, Acute Kidney Failure, Acute tubular necrosis,
Transplant related Ischemia, Acute Kidney Disease and types of AKI
such as Cisplatin induced AKI, Aminoglycosides induced AKI,
Tenofovir induced AKI, Contrast Induced Nephropathy, AKI after
surgery for partial nephrectomy, AKI post kidney transplant, AKI in
patients with Dialysis, AKI after Cardiac surgery, AKI in patients
inside ICU, AKI caused by Cirrhosis or Sepsis and AKI caused by
hepatorenal syndrome.
32. The method according to claim 1, wherein the disease or
condition is Chronic Kidney Disease.
33. The method according to claim 1, wherein the disease or
condition is Acute Kidney Failure.
34. The method of claim 1, wherein the compound of formula (I) is
administered orally.
35. The method according to claim 1, wherein the compound is
according to formula (IVb): ##STR00050## wherein X.sup.- is a
counter ion.
36. The method according to claim 1, wherein the compound is
according to formula (Vb): ##STR00051## wherein X.sup.- is a
counter ion.
Description
FIELD OF THE INVENTION
[0001] Described herein are compounds, pharmaceutical compositions
and medicaments containing such compounds, and methods of using
such compounds and compositions for treating diseases or conditions
related to kidney or kidney functions.
BACKGROUND OF THE INVENTION
[0002] Kidney diseases such as Chronic Kidney Disease, Acute kidney
failure and Acute Kidney disease are major health concerns in USA.
Approximately 20 million people in the United States are currently
affected by chronic kidney disease (CKD), with half a million of
these diagnosed with the most severe form of known as end-stage
renal disease (ESRD). One of the major causes of chronic and ESRD
in the United States is diabetes, which results in approximately
50% of all cases. Apart from Diabetes, hypertension and
cardiovascular disease remains the leading cause of death for
patients with CKD.
[0003] Similar to CKD, Acute Kidney Injury (AKI), Acute Kidney
Failure (AKF) & diabetic nephropathy which eventually
progresses into CKD are also debilitating kidney diseases that
affect millions of people in USA as well as outside USA. AKI is a
relatively common condition in the intensive care unit and occurs
in 20% to 30% of critically ill patients, with approximately 6%
eventually requiring renal replacement therapy (1). The development
of AKI results in increased mortality, longer length of stay in
hospitals and eventually, increased healthcare costs (2). While in
most of the cases the epidemiological causes of AKI is
multifactorial (e.g., sepsis, ischemia/hypoperfusion), recent
studies have shown that nephrotoxic drugs will be contributing
factors in 19% to 25% of cases of severe acute renal failure in
patients with serious underlying diseases (3, 4). The use of
nephrotoxic drugs and resulting Acute Kidney Injury is referred to
as Drug Induced AKI which is a major problem with patients taking
drugs such as antibiotics, anticancer agents and anti-infectious
drugs
[0004] Treatment options for CKD, AKI or AKF range from Renal
Replacement Therapy (RRT), Transplant & radical surgery.
Angiotensin Converting Enzyme Inhibitors (ACEI) or Angiotensin
Receptor Blockers (ARBs) or protein-restricted diet have been used
in certain conditions to mitigate the effect of these kidney
diseases. However, in majority of the cases the damage is
irreversible and the patient needs to have transplant or be on
dialysis for remainder of their life. The following is summary of
drugs that are currently being used or developed for CKD. Renin
Inhibitors -Aliskerin, ACE inhibitors-Captopril, Ramipril and
Lisinopril, Angiotensin receptor inhibitors-Telmisartan, Losartan,
Mineralcorticoid antagonists-Spironolactone, Finerenone, CS-3150
and MT-3995. Drugs that target Glomerulus abnormalities such as
sulodexide, Atrasentan, Abatacept, Bis-T-23, rapamycin, lithium and
gamma-secretase inhibitors. A large number of drugs are currently
under clinical development for variety of pathways and targets that
result in CKD. These drugs are Canagliflozin, Pyridorin, ASP8232,
baricitinib, CCX140, CTP140, GKT137831, VPI-2690B, GS-4997,
PF-04634817, and Allopurinol.
[0005] Nicorandil is a vasodilatory drug used to treat angina and
acute heart failure. It is a nitrate and K+ATP channel agonist. In
addition to treat angina, nicorandil may be useful to treat kidney
diseases (Lee et al., J. Hypertension 2009, 27, 618-625; Iranirad
et al., Cardiology Journal (online) 2017, DOI
10.5603/cj.a2017.0028; Ko et al., Yonsei Med J. 2013, 54(4),
957-964; Tamura et al., Am. J. Physiol Renal Physiol 2012, 303,
339-349; Nawa et al., Int. J. Cardiology 2015, 195, 228-234; Tanabe
et al., Am. J. Physiol Renal Physiol 2012, 302, 151-160; and
US20110257202).
SUMMARY OF THE INVENTION
[0006] Described herein are pyridyl compounds and pharmaceutical
compositions thereof. Also described herein are methods for
treating diseases and conditions related to kidney using the
compounds and pharmaceutical compositions.
[0007] Also described herein are uses of the pyridyl compounds and
the pharmaceutical compositions in the treatment of kidney diseases
or conditions. Further described are pharmaceutical compositions
that include the pyridyl compounds. Specifically, described herein
are conjugated nicorandil compounds capable of forming nicorandil
in vivo and methods of use thereof to treat diseases and conditions
related to kidney.
[0008] Thus, in some embodiments, the present invention provides
methods for preventing, treating or ameliorating in a mammal a
disease or condition that is related to the kidney or kidney
function, which comprises administering to the mammal an effective
disease-treating or condition-treating amount of a compound
according to Formula (I) having the structure:
##STR00001## [0009] or a pharmaceutical composition thereof, [0010]
wherein X.sup.- is a counter ion; Y is --C(H).sub.2--, --O--, or
--N(R.sup.3)--; [0011] R.sup.1 is substituted or unsubstituted
C.sub.1-C.sub.4 alkyl, substituted or unsubstituted
C.sub.3-C.sub.7-cycloalkyl, or substituted or unsubstituted 4-7
membered heterocycloalkyl; [0012] R.sup.2 is H or C.sub.1-C.sub.4
alkyl; and [0013] R.sup.3 is H or substituted or unsubstituted
C.sub.1-C.sub.4 alkyl; or R.sup.1 and R.sup.3 are joined together
to form a 4-7 membered substituted or unsubstituted
heterocycloalkyl.
[0014] In some embodiments, the present invention provides use of a
compound according to Formula (I) having the structure:
##STR00002## [0015] in a treatment of a disease or a condition
related to kidney; [0016] wherein X.sup.- is a counter ion; Y is
--C(H).sub.2--, --O--, or --N(R.sup.3) [0017] R.sup.1 is
substituted or unsubstituted C.sub.1-C.sub.4 alkyl, substituted or
unsubstituted C.sub.3-C.sub.7-cycloalkyl, or substituted or
unsubstituted 4-7 membered heterocycloalkyl; [0018] R.sup.2 is H or
C1-C.sub.4 alkyl; and [0019] R.sup.3 is H or substituted or
unsubstituted C1-C.sub.4 alkyl; or R.sup.1 and R.sup.3 are joined
together to form a 4-7 membered substituted or unsubstituted
heterocycloalkyl.
[0020] In some embodiments, Y is --C(H).sub.2--. In some
embodiments, Y is --O--. In some embodiments, Y is --N(R.sup.3)--.
In particular embodiments, Y is --N(H)--.
[0021] In some embodiments, R.sup.2 is H, Me, Et, or i-Pr. In a
particular embodiment, R.sup.2 is H.
[0022] In some embodiments, R.sup.1 is ethyl substituted with
cyclohexyl.
[0023] In some embodiments, R.sup.1 is 2-cyclohexyl-ethyl.
[0024] In some embodiments, the disease or condition is Chronic
Kidney Disease, Diabetic Nephropathy, IgA Nephropathy, Acute Kidney
Failure, Acute tubular necrosis, Transplant related Ischemia, Acute
Kidney Disease and types of AKI such as Cisplatin induced AKI,
Aminoglycosides induced AKI, Tenofovir induced AKI, Contrast
Induced Nephropathy, AKI after surgery for partial nephrectomy, AKI
post kidney transplant, AKI in patients with Dialysis, AKI after
Cardiac surgery, AKI in patients inside ICU, AKI caused by
Cirrhosis or Sepsis and AKI caused by hepatorenal syndrome.
[0025] In a particular embodiment, the disease or condition is
Contrast Induced Nephropathy.
[0026] In a particular embodiment, the disease or condition is
Tenofovir induced AKI.
[0027] In a particular embodiment, the disease or condition is
Aminoglycosides induced AKI.
[0028] In a particular embodiment, the disease or condition is AKI
after surgery.
[0029] In a particular embodiment, the disease or condition is AKI
in patients with Dialysis.
[0030] In a particular embodiment, the disease or condition is
Diabetic Nephropathy.
[0031] In a more particular embodiment, the disease or condition is
chronic kidney disease or CKD.
[0032] In some embodiments, the compound is:
##STR00003##
[0033] wherein X.sup.-, and R.sup.2 are as described for formula
(I) herein.
[0034] In some embodiments, the compound is:
##STR00004##
[0035] wherein X.sup.-, and R.sup.2 are as described for formula
(I) herein.
[0036] In some embodiments, with respect to formula (IIIa) or
(IIIb), R.sup.2 is H or Me. In some embodiments, R.sup.3 is H, Me,
Et, or i-Pr. In particular embodiments, each R.sup.2 and R.sup.3 is
H.
[0037] In some embodiments, with respect to formula (IIIa) or
(IIIb), the compound is an R-isomer. In some embodiments, with
respect to formula (IIIa) or (IIIb), the compound is an
S-isomer.
[0038] In some embodiments, the compound is:
##STR00005##
wherein X.sup.- is as described for formula (I) herein.
[0039] In some embodiments, the compound is:
##STR00006##
wherein X.sup.- is as described for formula (I) herein.
[0040] In some embodiments, the compound is:
##STR00007##
wherein X.sup.- is as described for formula (I) herein.
[0041] In some embodiments, the compound is:
##STR00008##
wherein X.sup.- is as described for formula (I) herein.
[0042] In some embodiments, X.sup.- is Cl.sup.-. In another
embodiment, X.sup.- is Br.sup.-. In another embodiment, X.sup.- is
I.sup.-. In another embodiment, X.sup.- is F.sup.-. In another
embodiment, X.sup.- is MeSO.sub.2O.sup.-.
[0043] In some embodiments, the present invention provides
pharmaceutical compositions comprising a therapeutically effective
amount of a compound of formula (I) and a pharmaceutically
acceptable excipient. In some embodiments, the pharmaceutical
composition comprising the compound of formula (I) is formulated
for a route of administration selected from oral administration,
parenteral administration, buccal administration, nasal
administration, topical administration, or rectal administration.
In some embodiments, the present invention provides methods for
treating a disease or condition comprising administering to a
patient in need a therapeutically effective amount of a compound of
formula (I). In some embodiments the disease is selected from
Chronic Kidney Disease (CKD), Diabetic Nephropathy, IgA
Nephropathy, Acute Kidney Failure, Acute tubular necrosis,
Transplant related Ischemia, Acute Kidney Disease and types of AKI
such as Cisplatin induced AKI, Aminoglycosides induced AKI,
Tenofovir induced AKI, Contrast Induced Nephropathy, AKI after
surgery for partial nephrectomy, AKI post kidney transplant, AKI in
patients with Dialysis, AKI after Cardiac surgery, AKI in patients
inside ICU, AKI caused by Cirrhosis or Sepsis and AKI caused by
hepatorenal syndrome. In some embodiments, the present invention
provides a method for treating a CKD disease or condition
comprising administering to a patient in need a therapeutically
effective amount of a compound of formula (I). In some embodiments,
the disease is diabetic nephropathy. In some embodiments, the
disease or condition is acute kidney failure (AKI).
[0044] In some embodiments the disease or condition is acute kidney
failure and types of AKI such as Cisplatin induced AKI,
Aminoglycosides induced AKI, Tenofovir induced AKI, Contrast
Induced Nephropathy, AKI after surgery for partial nephrectomy, AKI
post kidney transplant, AKI in patients with Dialysis, AKI after
Cardiac surgery, AKI in patients inside ICU, AKI caused by
Cirrhosis or Sepsis and AKI caused by hepatorenal syndrome.
[0045] In some embodiments, the present invention provides a method
for treating Chronic Kidney Disease, Diabetic Nephropathy, IgA
Nephropathy, Acute Kidney Failure, Acute tubular necrosis,
Transplant related Ischemia, Acute Kidney Disease and types of AKI
such as Cisplatin induced AKI, Aminoglycosides induced AKI,
Tenofovir induced AKI, Contrast Induced Nephropathy, AKI after
surgery for partial nephrectomy, AKI post kidney transplant, AKI in
patients with Dialysis, AKI after Cardiac surgery, AKI in patients
inside ICU, AKI caused by Cirrhosis or Sepsis and AKI caused by
hepatorenal syndrome comprising administering to a patient in need
a therapeutically effective amount of a compound of Formula
(I).
[0046] It is understood that one of ordinary skill in the art to
provide compounds that are chemically stable and that can be
synthesized by techniques known in the art, as well as those set
forth herein.
[0047] In some embodiments, the present invention provides
pharmaceutical compositions, which include a therapeutically
effective amount of at least one of any of the compounds herein, or
a pharmaceutically acceptable salt, pharmaceutically active
metabolite, pharmaceutically acceptable prodrug, or
pharmaceutically acceptable solvate. In certain embodiments,
compositions provided herein further include a pharmaceutically
acceptable diluent, excipient and/or binder.
[0048] Pharmaceutical compositions formulated for administration by
an appropriate route and means containing effective concentrations
of one or more of the compounds provided herein, or
pharmaceutically effective derivatives thereof, that deliver
amounts effective for the treatment, prevention, or amelioration of
one or more symptoms of diseases, disorders or conditions that are
kidney related, are provided. The effective amounts and
concentrations are effective for ameliorating any of the symptoms
of any of the diseases, disorders or conditions disclosed
herein.
[0049] In certain embodiments, provided herein is a pharmaceutical
composition containing: i) a physiologically acceptable carrier,
diluent, and/or excipient; and ii) one or more compounds provided
herein.
[0050] In some embodiments, provided herein are methods for
treating a patient of treating a disease, disorder, or condition,
which related to kidney, in a patient, which includes administering
to the patient a therapeutically effective amount of at least one
of any of the compounds herein, or pharmaceutically acceptable
salt, pharmaceutically active metabolite, pharmaceutically
acceptable prodrug, or pharmaceutically acceptable solvate.
[0051] In some embodiments, compounds provided herein are
administered to a human.
[0052] In some embodiments, compounds provided herein are orally
administered.
[0053] In some embodiments, compounds provided herein are used for
the formulation of a medicament for treating a disease, disorder,
or condition, which is related to kidney. In some embodiments,
compounds provided herein are used for the formulation of a
medicament for kidney disease or condition.
[0054] Articles of manufacture including packaging material, a
compound or composition or pharmaceutically acceptable derivative
thereof provided herein, which is effective for treating the kidney
disease or condition, within the packaging material, and a label
that indicates that the compound or composition, or
pharmaceutically acceptable salt, pharmaceutically active
metabolite, pharmaceutically acceptable prodrug, or
pharmaceutically acceptable solvate thereof, is used for treating
the kidney disease or condition, are provided.
[0055] In some embodiments, provided herein is a method for
treating the kidney disease or condition in a subject in need
thereof by administering to the subject thereof a composition
containing a therapeutically effective amount of at least one
compound having the structure of formula (I). In some embodiments,
the subject in need is suffering from Chronic Kidney Disease,
Diabetic Nephropathy, IgA Nephropathy, Acute Kidney Failure, Acute
tubular necrosis, Transplant related Ischemia, Acute Kidney Disease
and types of AKI such as Cisplatin induced AKI, Aminoglycosides
induced AKI, Tenofovir induced AKI, Contrast Induced Nephropathy,
AKI after surgery for partial nephrectomy, AKI post kidney
transplant, AKI in patients with Dialysis, AKI after Cardiac
surgery, AKI in patients inside ICU, AKI caused by Cirrhosis or
Sepsis and AKI caused by hepatorenal syndrome.
[0056] In some embodiments, the subject in need is suffering from a
kidney condition or disease, e.g., Chronic Kidney Disease, Diabetic
Nephropathy, IgA Nephropathy, Acute Kidney Failure, Acute tubular
necrosis, Transplant related Ischemia, Acute Kidney Disease and
types of AKI such as Cisplatin induced AKI, Aminoglycosides induced
AKI, Tenofovir induced AKI, Contrast Induced Nephropathy, AKI after
surgery for partial nephrectomy, AKI post kidney transplant, AKI in
patients with Dialysis, AKI after Cardiac surgery, AKI in patients
inside ICU, AKI caused by Cirrhosis or Sepsis and AKI caused by
hepatorenal syndrome.
[0057] In some embodiments, provided herein is a method for
treating the kidney disease or condition by administering to a
subject in need thereof a composition containing a therapeutically
effective amount of at least one compound having the structure of
Formula (I)-(Vb). In some embodiments, kidney disease or condition
is Chronic Kidney Disease, Diabetic Nephropathy, IgA Nephropathy,
Acute Kidney Failure, Acute tubular necrosis, Transplant related
Ischemia, Acute Kidney Disease and types of AKI such as Cisplatin
induced AKI, Aminoglycosides induced AKI, Tenofovir induced AKI,
Contrast Induced Nephropathy, AKI after surgery for partial
nephrectomy, AKI post kidney transplant, AKI in patients with
Dialysis, AKI after Cardiac surgery, AKI in patients inside ICU,
AKI caused by Cirrhosis or Sepsis and AKI caused by hepatorenal
syndrome.
[0058] In any of the aforementioned embodiments are some
embodiments in which administration is enteral, parenteral, or
both, and wherein (a) an effective amount of a provided compound is
systemically administered to the mammal; (b) an effective amount of
a provided compound is administered orally to the mammal; (c) an
effective amount of a provided compound is intravenously
administered to the mammal; (d) an effective amount of a provided
compound is administered by inhalation; (e) an effective amount of
a provided compound is administered by nasal administration; or (f)
an effective amount of a provided compound is administered by
injection to the mammal; (g) an effective amount of a provided
compound is administered topically (dermal) to the mammal; (h) an
effective amount of a provided compound is administered by
ophthalmic administration; or (i) an effective amount of a provided
compound is administered rectally to the mammal.
[0059] In any of the aforementioned embodiments are some
embodiments comprising single administrations of an effective
amount of a provided compound including some embodiments in which
(i) a provided compound is administered once; (ii) a provided
compound is administered to the mammal multiple times over the span
of one day; (iii) continually; or (iv) continuously.
[0060] In any of the aforementioned embodiments are some
embodiments comprising multiple administrations of an effective
amount of a provided compound, including some embodiments in which
(i) a provided compound is administered in a single dose; (ii) the
time between multiple administrations is every 6 hours; (iii) a
provided compound is administered to the mammal every 8 hours. In
some embodiments, the method comprises a drug holiday, wherein the
administration of the compound is temporarily suspended or the dose
of the compound being administered is temporarily reduced; at the
end of the drug holiday, dosing of the compound is resumed. The
length of the drug holiday can vary from 2 days to 1 year.
[0061] Other objects, features and advantages of the methods and
compositions described herein will become apparent from the
following detailed description. It should be understood, however,
that the detailed description and the specific examples, while
indicating specific embodiments, are given by way of illustration
only, since various changes and modifications within the spirit and
scope of the present disclosure will become apparent to those
skilled in the art from this detailed description. The section
headings used herein are for organizational purposes only and are
not to be construed as limiting the subject matter described. All
documents, or portions of documents, cited in the application
including, but not limited to, patents, patent applications,
articles, books, manuals, and treatises are hereby expressly
incorporated by reference in their entirety for any purpose.
BRIEF DESCRIPTION OF DRAWINGS
[0062] FIG. 1 shows .sup.1H NMR of Compound A in DMSO-d6.
[0063] FIG. 2 shows conversion of Compound A to nicorandil in rat
plasma at various time points. Complete conversion to nicorandil
was observed with no trace of Compound A.
DETAILED DESCRIPTION OF THE INVENTION
Certain Terminology
[0064] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of skill in the art to which the claimed subject matter belongs. In
the event that there are a plurality of definitions for terms
herein, those in this section prevail. Where reference is made to a
URL or other such identifier or address, it is understood that such
identifiers can change and particular information on the internet
can come and go, but equivalent information can be found by
searching the internet. Reference thereto evidences the
availability and public dissemination of such information.
[0065] It is to be understood that the foregoing general
description and the following detailed description are exemplary
and explanatory only and are not restrictive of any subject matter
claimed. In this application, the use of the singular includes the
plural unless specifically stated otherwise. It must be noted that,
as used in the specification and the appended claims, the singular
forms "a," "an" and "the" include plural referents unless the
context clearly dictates otherwise. Use of the term "including" as
well as other forms, such as "include", "includes," and "included,"
is not limiting. Definition of standard chemistry terms may be
found in reference works, including Carey and Sundberg "Advanced
Organic Chemistry 4.sup.th Ed." Vols. A (2000) and B (2001), Plenum
Press, New York. Unless otherwise indicated, conventional methods
of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry,
recombinant DNA techniques and pharmacology, within the skill of
the art are employed. Unless specific definitions are provided, the
nomenclature employed in connection with, and the laboratory
procedures and techniques of, analytical chemistry, synthetic
organic chemistry, and medicinal and pharmaceutical chemistry
described herein are those known in the art. Standard techniques
can be used for chemical syntheses, chemical analyses,
pharmaceutical preparation, formulation, and delivery, and
treatment of patients. Standard techniques can be used for
recombinant DNA, oligonucleotide synthesis, and tissue culture and
transformation (e.g., electroporation, lipofection). Reactions and
purification techniques can be performed e.g., using kits of
manufacturer's specifications or as commonly accomplished in the
art or as described herein. The foregoing techniques and procedures
can be generally performed of conventional methods well known in
the art and as described in various general and more specific
references that are cited and discussed throughout the present
specification.
[0066] It is to be understood that the methods and compositions
described herein are not limited to the particular methodology,
protocols, cell lines, constructs, and reagents described herein
and as such may vary. It is also to be understood that the
terminology used herein is for the purpose of describing particular
embodiments only, and is not intended to limit the scope of the
methods and compositions described herein, which will be limited
only by the appended claims.
[0067] All publications and patents mentioned herein are
incorporated herein by reference in their entirety for the purpose
of describing and disclosing, for example, the constructs and
methodologies that are described in the publications, which might
be used in connection with the methods, compositions and compounds
described herein. The publications discussed herein are provided
solely for their disclosure prior to the filing date of the present
application. Nothing herein is to be construed as an admission that
the inventors described herein are not entitled to antedate such
disclosure by virtue of prior invention or for any other
reason.
[0068] "Alkyl" refers to a straight or branched hydrocarbon chain
radical consisting solely of carbon and hydrogen atoms, containing
no unsaturation, having from one to fifteen carbon atoms (e.g.,
C.sub.1-C.sub.15 alkyl).
[0069] In certain embodiments, an alkyl comprises one to thirteen
carbon atoms (e.g., C.sub.1-C.sub.13 alkyl). In certain
embodiments, an alkyl comprises one to eight carbon atoms (e.g.,
C.sub.1-C.sub.5 alkyl). In some embodiments, an alkyl comprises
five to fifteen carbon atoms (e.g., C.sub.5-C.sub.15 alkyl). In
certain embodiments, an alkyl comprises five to eight carbon atoms
(e.g., C.sub.5-C.sub.8 alkyl). The alkyl is attached to the rest of
the molecule by a single bond, for example, methyl (Me), ethyl
(Et), n-propyl (n-pr), 1-methylethyl (iso-propyl or i-Pr), n-butyl
(n-Bu), n-pentyl, 1,1-dimethylethyl (t-butyl, or t-Bu),
3-methylhexyl, 2-methylhexyl, and the like. Unless stated otherwise
specifically in the specification, an alkyl group is optionally
substituted as defined and described below and herein.
[0070] The alkyl group could also be a "lower alkyl" having 1 to 6
carbon atoms.
[0071] As used herein, C.sub.1-C.sub.x includes C.sub.1-C.sub.2,
C.sub.1-C.sub.3 . . . C.sub.1-C.sub.x.
[0072] "Alkenyl" refers to a straight or branched hydrocarbon chain
radical group consisting solely of carbon and hydrogen atoms,
containing at least one double bond, and having from two to twelve
carbon atoms. In certain embodiments, an alkenyl comprises two to
eight carbon atoms. In some embodiments, an alkenyl comprises two
to four carbon atoms. The alkenyl is attached to the rest of the
molecule by a single bond, for example, ethenyl (i.e., vinyl),
prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl,
penta-1,4-dienyl, and the like. Unless stated otherwise
specifically in the specification, an alkenyl group is optionally
substituted as defined and described below and herein.
[0073] "Alkynyl" refers to a straight or branched hydrocarbon chain
radical group consisting solely of carbon and hydrogen atoms,
containing at least one triple bond, having from two to twelve
carbon atoms. In certain embodiments, an alkynyl comprises two to
eight carbon atoms. In some embodiments, an alkynyl has two to four
carbon atoms. The alkynyl is attached to the rest of the molecule
by a single bond, for example, ethynyl, propynyl, butynyl,
pentynyl, hexynyl, and the like. Unless stated otherwise
specifically in the specification, an alkynyl group is optionally
substituted as defined and described below and herein.
[0074] "Alkylene" or "alkylene chain" refers to a straight or
branched divalent hydrocarbon chain linking the rest of the
molecule to a radical group, consisting solely of carbon and
hydrogen, containing no unsaturation and having from one to twelve
carbon atoms, for example, methylene, ethylene, propylene,
n-butylene, and the like. The alkylene chain is attached to the
rest of the molecule through a single bond and to the radical group
through a single bond. The points of attachment of the alkylene
chain to the rest of the molecule and to the radical group can be
through one carbon in the alkylene chain or through any two carbons
within the chain. Unless stated otherwise specifically in the
specification, an alkylene chain is optionally substituted as
defined and described below and herein.
[0075] "Alkenylene" or "alkenylene chain" refers to a straight or
branched divalent hydrocarbon chain linking the rest of the
molecule to a radical group, consisting solely of carbon and
hydrogen, containing at least one double bond and having from two
to twelve carbon atoms, for example, ethenylene, propenylene,
n-butenylene, and the like. The alkenylene chain is attached to the
rest of the molecule through a double bond or a single bond and to
the radical group through a double bond or a single bond. The
points of attachment of the alkenylene chain to the rest of the
molecule and to the radical group can be through one carbon or any
two carbons within the chain. Unless stated otherwise specifically
in the specification, an alkenylene chain is optionally substituted
as defined and described below and herein. "Aryl" refers to a
radical derived from an aromatic monocyclic or multicyclic
hydrocarbon ring system by removing a hydrogen atom from a ring
carbon atom. The aromatic monocyclic or multicyclic hydrocarbon
ring system contains only hydrogen and carbon from six to eighteen
carbon atoms, where at least one of the rings in the ring system is
fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)
.pi.-electron system in accordance with the Huckel theory. Aryl
groups include, but are not limited to, groups such as phenyl (Ph),
fluorenyl, and naphthyl. Unless stated otherwise specifically in
the specification, the term "aryl" or the prefix "ar-" (such as in
"aralkyl") is meant to include aryl radicals optionally substituted
as defined and described below and herein.
[0076] "Aralkyl" refers to a radical of the formula --R.sup.c-aryl
where R.sup.c is an alkylene chain as defined above, for example,
benzyl, diphenylmethyl and the like. The alkylene chain part of the
aralkyl radical is optionally substituted as described above for an
alkylene chain. The aryl part of the aralkyl radical is optionally
substituted as described above for an aryl group.
[0077] "Aralkenyl" refers to a radical of the formula
--R.sup.d-aryl where R.sup.d is an alkenylene chain as defined
above. The aryl part of the aralkenyl radical is optionally
substituted as described above for an aryl group. The alkenylene
chain part of the aralkenyl radical is optionally substituted as
defined above for an alkenylene group.
[0078] "Aralkynyl" refers to a radical of the formula
--R.sup.e-aryl, where R.sup.e is an alkynylene chain as defined
above. The aryl part of the aralkynyl radical is optionally
substituted as described above for an aryl group. The alkynylene
chain part of the aralkynyl radical is optionally substituted as
defined above for an alkynylene chain.
[0079] "Carbocyclyl" refers to a stable non-aromatic monocyclic or
polycyclic hydrocarbon radical consisting solely of carbon and
hydrogen atoms, which includes fused or bridged ring systems,
having from three to fifteen carbon atoms. In certain embodiments,
a carbocyclyl comprises three to ten carbon atoms. In some
embodiments, a carbocyclyl comprises five to seven carbon atoms.
The carbocyclyl is attached to the rest of the molecule by a single
bond. Carbocyclyl is optionally saturated, (i.e., containing single
C--C bonds only) or unsaturated (i.e., containing one or more
double bonds or triple bonds.) A fully saturated carbocyclyl
radical is also referred to as "cycloalkyl." Examples of monocyclic
cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl
is also referred to as "cycloalkenyl." Examples of monocyclic
cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl,
cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals
include, for example, adamantyl, norbornyl (i.e.,
bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl,
7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise
stated specifically in the specification, the term "carbocyclyl" is
meant to include carbocyclyl radicals that are optionally
substituted as defined and described below and herein. "Halo" or
"halogen" refers to bromo, chloro, fluoro or iodo substituents.
[0080] The terms "haloalkyl," "haloalkenyl," "haloalkynyl" and
"haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures
in which at least one hydrogen is replaced with a halogen atom. In
certain embodiments in which two or more hydrogen atoms are
replaced with halogen atoms, the halogen atoms are all the same as
one another. In some embodiments in which two or more hydrogen
atoms are replaced with halogen atoms, the halogen atoms are not
all the same as one another.
[0081] "Fluoroalkyl" refers to an alkyl radical, as defined above,
that is substituted by one or more fluoro radicals, as defined
above, for example, trifluoromethyl, difluoromethyl,
2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
The alkyl part of the fluoroalkyl radical is optionally substituted
as defined above for an alkyl group.
[0082] As used herein, the term "non-aromatic heterocycle",
"heterocycloalkyl" or "heteroalicyclic" refers to a non-aromatic
ring wherein one or more atoms forming the ring is a heteroatom. A
"non-aromatic heterocycle" or "heterocycloalkyl" group refers to a
cycloalkyl group that includes at least one heteroatom selected
from nitrogen, oxygen and sulfur. The radicals may be fused with an
aryl or heteroaryl. Heterocycloalkyl rings can be formed by three
to 14 ring atoms, such as three, four, five, six, seven, eight,
nine, or more than nine atoms. Heterocycloalkyl rings can be
optionally substituted. In certain embodiments, non-aromatic
heterocycles contain one or more carbonyl or thiocarbonyl groups
such as, for example, oxo- and thio-containing groups. Examples of
heterocycloalkyls include, but are not limited to, lactams,
lactones, cyclic imides, cyclic thioimides, cyclic carbamates,
tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine,
1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine,
1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane,
tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide,
barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin,
dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine,
tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,
pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline,
imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole,
1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine,
oxazolidinone, thiazoline, thiazolidine, and 1,3-oxathiolane.
Illustrative examples of heterocycloalkyl groups, also referred to
as non-aromatic heterocycles, include:
##STR00009##
and the like. The term heteroalicyclic also includes all ring forms
of the carbohydrates, including but not limited to the
monosaccharides, the disaccharides and the oligosaccharides.
Depending on the structure, a heterocycloalkyl group can be a
monoradical or a diradical (i.e., a heterocycloalkylene group).
[0083] "Heteroaryl" refers to a radical derived from a 3- to
18-membered aromatic ring radical that comprises two to seventeen
carbon atoms and from one to six heteroatoms selected from
nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical
is a monocyclic, bicyclic, tricyclic or tetracyclic ring system,
wherein at least one of the rings in the ring system is fully
unsaturated, i.e., it contains a cyclic, delocalized (4n+2)
7r-electron system in accordance with the Huckel theory.
[0084] Heteroaryl includes fused or bridged ring systems. In some
embodiments, heteroaryl rings have five, six, seven, eight, nine,
or more than nine ring atoms. The heteroatom(s) in the heteroaryl
radical is optionally oxidized. One or more nitrogen atoms, if
present, are optionally quaternized. The heteroaryl is attached to
the rest of the molecule through any atom of the ring(s). Examples
of heteroaryls include, but are not limited to, azepinyl,
acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,
benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,
benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,
benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,
benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl,
benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl,
benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl,
cinnolinyl, cyclopenta[d]pyrimidinyl,
6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,
5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl,
dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl,
furo[3,2-c]pyridinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl,
imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl,
isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl,
5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,
1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,
oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl,
1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl,
phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,
pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl,
pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl,
pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,
tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,
5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,
5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl,
thiadiazolyl, triazolyl, tetrazolyl, triazinyl,
thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl,
thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl). Unless
stated otherwise specifically in the specification, the term
"heteroaryl" is meant to include heteroaryl radicals as defined
above which are optionally substituted as defined and described
below and herein.
[0085] "N-heteroaryl" refers to a heteroaryl radical as defined
above containing at least one nitrogen and where the point of
attachment of the heteroaryl radical to the rest of the molecule is
through a nitrogen atom in the heteroaryl radical. An N-heteroaryl
radical is optionally substituted as described above for heteroaryl
radicals.
[0086] "C-heteroaryl" refers to a heteroaryl radical as defined
above and where the point of attachment of the heteroaryl radical
to the rest of the molecule is through a carbon atom in the
heteroaryl radical. A C-heteroaryl radical is optionally
substituted as described above for heteroaryl radicals.
[0087] "Heteroarylalkyl" refers to a radical of the formula
--R.sup.c-heteroaryl, where R.sup.c is an alkylene chain as defined
above. If the heteroaryl is a nitrogen-containing heteroaryl, the
heteroaryl is optionally attached to the alkyl radical at the
nitrogen atom. The alkylene chain of the heteroarylalkyl radical is
optionally substituted as defined above for an alkylene chain. The
heteroaryl part of the heteroarylalkyl radical is optionally
substituted as defined above for a heteroaryl group.
[0088] "Sulfanyl" refers to the --S-- radical.
[0089] "Sulfinyl" refers to the --S(.dbd.O)-- radical.
[0090] "Sulfonyl" refers to the --S(.dbd.O).sub.2-- radical.
[0091] "Amino" refers to the --NH.sub.2 radical.
[0092] "Cyano" refers to the --CN radical.
[0093] "Nitro" refers to the --NO.sub.2 radical.
[0094] "Oxa" refers to the --O-- radical.
[0095] "Oxo" refers to the .dbd.O radical.
[0096] "Imino" refers to the .dbd.NH radical.
[0097] "Thioxo" refers to the .dbd.S radical.
[0098] An "alkoxy" group refers to a (alkyl)O-- group, where alkyl
is as defined herein.
[0099] An "aryloxy" group refers to an (aryl)O-- group, where aryl
is as defined herein.
[0100] "Carbocyclylalkyl" means an alkyl radical, as defined
herein, substituted with a carbocyclyl group. "Cycloalkylalkyl"
means an alkyl radical, as defined herein, substituted with a
cycloalkyl group. Non-limiting cycloalkylalkyl groups include
cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
cyclohexylmethyl, and the like.
[0101] As used herein, the terms "heteroalkyl" "heteroalkenyl" and
"heteroalkynyl" include optionally substituted alkyl, alkenyl and
alkynyl radicals in which one or more skeletal chain atoms is a
heteroatom, e.g., oxygen, nitrogen, sulfur, silicon, phosphorus or
combinations thereof. The heteroatom(s) may be placed at any
interior position of the heteroalkyl group or at the position at
which the heteroalkyl group is attached to the remainder of the
molecule. Examples include, but are not limited to,
--CH.sub.2--O--CH.sub.3, --CH.sub.2--CH.sub.2--O--CH.sub.3,
--CH.sub.2--NH--CH.sub.3, --CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--CH.sub.2--NH--CH.sub.3,
--CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3,
--CH.sub.2--S--CH.sub.2--CH.sub.3,
--CH.sub.2--CH.sub.2,--S(O)--CH.sub.3,
--CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3, --CH.dbd.CHO--CH.sub.3,
--Si(CH.sub.3).sub.3, --CH.sub.2--CH.dbd.N--OCH.sub.3, and
--CH.dbd.CH--N(CH.sub.3)--CH.sub.3. In addition, up to two
heteroatoms may be consecutive, such as, by way of example,
--CH.sub.2--NH--OCH.sub.3 and
--CH.sub.2--O--Si(CH.sub.3).sub.3.
[0102] The term "heteroatom" refers to an atom other than carbon or
hydrogen. Heteroatoms are typically independently selected from
among oxygen, sulfur, nitrogen, silicon and phosphorus, but are not
limited to these atoms. In embodiments in which two or more
heteroatoms are present, the two or more heteroatoms can all be the
same as one another, or some or all of the two or more heteroatoms
can each be different from the others.
[0103] The term "bond," "direct bond" or "single bond" refers to a
chemical bond between two atoms, or two moieties when the atoms
joined by the bond are considered to be part of larger
substructure.
[0104] An "isocyanato" group refers to a --NCO group.
[0105] An "isothiocyanato" group refers to a --NCS group.
[0106] The term "moiety" refers to a specific segment or functional
group of a molecule. Chemical moieties are often recognized
chemical entities embedded in or appended to a molecule.
[0107] A "thioalkoxy" or "alkylthio" group refers to a --S-alkyl
group.
[0108] A "alkylthioalkyl" group refers to an alkyl group
substituted with a --S-alkyl group.
[0109] As used herein, the term "acyloxy" refers to a group of
formula RC(.dbd.O)O--.
[0110] "Carboxy" means a --C(O)OH radical.
[0111] As used herein, the term "acetyl" refers to a group of
formula --C(.dbd.O)CH.sub.3.
[0112] "Acyl" refers to the group --C(O)R.
[0113] As used herein, the term "trihalomethanesulfonyl" refers to
a group of formula X.sub.3CS(.dbd.O).sub.2-- where Y is a
halogen.
[0114] "Cyanoalkyl" means an alkyl radical, as defined herein,
substituted with at least one cyano group.
[0115] As used herein, the term "N-sulfonamido" or "sulfonylamino"
refers to a group of formula RS(.dbd.O).sub.2NH--.
[0116] As used herein, the term "O-carbamyl" refers to a group of
formula --OC(.dbd.O)NR.sub.2.
[0117] As used herein, the term "N-carbamyl" refers to a group of
formula ROC(.dbd.O)NH--.
[0118] As used herein, the term "O-thiocarbamyl" refers to a group
of formula --OC(.dbd.S)NR.sub.2.
[0119] As used herein, "N-thiocarbamyl" refers to a group of
formula ROC(.dbd.S)NH--.
[0120] As used herein, the term "C-amido" refers to a group of
formula --C(.dbd.O)NR.sub.2.
[0121] "Aminocarbonyl" refers to a --CONH.sub.2 radical.
[0122] As used herein, the term "N-amido" refers to a group of
formula RC(.dbd.O)NH--.
[0123] "Hydroxyalkyl" refers to an alkyl radical, as defined
herein, substituted with at least one hydroxy group. Non-limiting
examples of a hydroxyalkyl include, but are not limited to,
hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,
1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,
4-hydroxybutyl, 2,3-dihydroxypropyl,
1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl,
3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl.
[0124] "Alkoxyalkyl" refers to an alkyl radical, as defined herein,
substituted with an alkoxy group, as defined herein.
[0125] An "alkenyloxy" group refers to a (alkenyl)O-- group, where
alkenyl is as defined herein.
[0126] The term "alkylamine" refers to the --N(alkyl).sub.xH.sub.y
group, where x and y are selected from among x=1, y=1 and x=2, y=0.
When x=2, the alkyl groups, taken together with the N atom to which
they are attached, can optionally form a cyclic ring system.
[0127] "Alkylaminoalkyl" refers to an alkyl radical, as defined
herein, substituted with an alkylamine, as defined herein.
[0128] An "amide" is a chemical moiety with the formula --C(O)NHR
or --NHC(O)R, where R is selected from among alkyl, cycloalkyl,
aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic
(bonded through a ring carbon). An amide moiety may form a linkage
between an amino acid or a peptide molecule and a compound
described herein, thereby forming a prodrug. Any amine, or carboxyl
side chain on the compounds described herein can be amidified. The
procedures and specific groups to make such amides are known to
those of skill in the art and can readily be found in reference
sources such as Greene and Wuts, Protective Groups in Organic
Synthesis, 3.sup.rd Ed., John Wiley & Sons, New York, N.Y.,
1999, which is incorporated herein by reference in its
entirety.
[0129] The term "ester" refers to a chemical moiety with formula
--COOR, where R is selected from among alkyl, cycloalkyl, aryl,
heteroaryl (bonded through a ring carbon) and heteroalicyclic
(bonded through a ring carbon). Any hydroxy, or carboxyl side chain
on the compounds described herein can be esterified. The procedures
and specific groups to make such esters are known to those of skill
in the art and can readily be found in reference sources such as
Greene and Wuts, Protective Groups in Organic Synthesis, 3.sup.rd
Ed., John Wiley & Sons, New York, N.Y., 1999, which is
incorporated herein by reference in its entirety.
[0130] As used herein, the term "ring" refers to any covalently
closed structure. Rings include, for example, carbocycles (e.g.,
aryls and cycloalkyls), heterocycles (e.g., heteroaryls and
non-aromatic heterocycles), aromatics (e.g. aryls and heteroaryls),
and non-aromatics (e.g., cycloalkyls and non-aromatic
heterocycles). Rings can be optionally substituted. Rings can be
monocyclic or polycyclic.
[0131] As used herein, the term "ring system" refers to one, or
more than one ring.
[0132] The term "membered ring" can embrace any cyclic structure.
The term "membered" is meant to denote the number of skeletal atoms
that constitute the ring. Thus, for example, cyclohexyl, pyridine,
pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole,
furan, and thiophene are 5-membered rings.
[0133] The term "fused" refers to structures in which two or more
rings share one or more bonds.
[0134] As described herein, compounds of the invention may be
"optionally substituted". In general, the term "substituted,"
whether preceded by the term "optionally" or not, means that one or
more hydrogens of a designated moiety are replaced with a suitable
substituent. Unless otherwise indicated, an "optionally
substituted" group may have a suitable substituent at each
substitutable position of the group, and when more than one
position in any given structure may be substituted with more than
one substituent selected from a specified group, the substituent
may be either the same or different at every position. Combinations
of substituents envisioned by this invention are preferably those
that result in the formation of stable or chemically feasible
compounds. The term "stable," as used herein, refers to compounds
that are not substantially altered when subjected to conditions to
allow for their production, detection, and, in certain embodiments,
their recovery, purification, and use for one or more of the
purposes disclosed herein.
[0135] Suitable monovalent substituents on a substitutable carbon
atom of an "optionally substituted" group are independently
halogen; --(CH.sub.2).sub.0-4R.sup..smallcircle.;
--(CH.sub.2).sub.0-4OR.sup..smallcircle.;
--O(CH.sub.2).sub.0-4R.sup..smallcircle.,
--O--(CH.sub.2).sub.0-4C(O)OR.sup..smallcircle.;
--(CH.sub.2).sub.0-4CH(OR.sup..smallcircle.).sub.2;
--(CH.sub.2).sub.0-4SR.sup..smallcircle.; --(CH.sub.2).sub.0-4Ph,
which may be substituted with R.sup..smallcircle.;
--(CH.sub.2).sub.0-4O(CH.sub.2).sub.0-1Ph which may be substituted
with R.sup..smallcircle.; --CH.dbd.CHPh, which may be substituted
with R.sup..smallcircle.;
--(CH.sub.2).sub.0-4O(CH.sub.2).sub.0-1-pyridyl which may be
substituted with R.sup..smallcircle.; --NO.sub.2; --CN; --N.sub.3;
--(CH.sub.2).sub.0-4N(R.sup..smallcircle.).sub.2;
--(CH.sub.2).sub.0-4N(R.sup..smallcircle.)C(O)R.sup..smallcircle.;
--N(R.sup..smallcircle.)C(S)R.sup..smallcircle.;
--(CH.sub.2).sub.0-4N(R.sup..smallcircle.)C(O)NR.sup..smallcircle..sub.2;
--N(R.sup..smallcircle.)C(S)NR.sup..smallcircle..sub.2;
--(CH.sub.2).sub.0-4N(R.sup..smallcircle.)C(O)OR.sup..smallcircle.;
--N(R.sup..smallcircle.)N(R.sup..smallcircle.)C(O)R.sup..smallcircle.;
--N(R.sup..smallcircle.)N(R.sup..smallcircle.)C(O)NR.sup..smallcircle..su-
b.2;
--N(R.sup..smallcircle.)N(R.sup..smallcircle.)C(O)OR.sup..smallcircle-
.; --(CH.sub.2).sub.0-4C(O)R.sup..smallcircle.;
--C(S)R.sup..smallcircle.;
--(CH.sub.2).sub.0-4C(O)OR.sup..smallcircle.;
--(CH.sub.2).sub.0-4C(O)SR.sup..smallcircle.;
--(CH.sub.2).sub.0-4C(O)OSiR.sup..smallcircle..sub.3;
--(CH.sub.2).sub.0-4OC(O)R.sup..smallcircle.;
--OC(O)(CH.sub.2).sub.0-4SR--, SC(S)SR.sup..smallcircle.;
--(CH.sub.2).sub.0-4SC(O)R.sup..smallcircle.;
--(CH.sub.2).sub.0-4C(O)NR.sup..smallcircle..sub.2;
--C(S)NR.sup..smallcircle..sub.2; --C(S)SR.sup..smallcircle.;
--(CH.sub.2).sub.0-4OC(O)NR.sup..smallcircle..sub.2;
--C(O)N(OR.sup..smallcircle.)R.sup..smallcircle.;
--C(O)C(O)R.sup..smallcircle.;
--C(O)CH.sub.2C(O)R.sup..smallcircle.;
--C(NOR.sup..smallcircle.)R.sup..smallcircle.;
--(CH.sub.2).sub.0-4SSR.sup..smallcircle.;
--(CH.sub.2).sub.0-4S(O).sub.2R.sup..smallcircle.;
--(CH.sub.2).sub.0-4S(O).sub.2OR.sup..smallcircle.;
--(CH.sub.2).sub.0-4OS(O).sub.2R.sup..smallcircle.;
--S(O).sub.2NR.sup..smallcircle..sub.2;
--(CH.sub.2).sub.0-4S(O)R.sup..smallcircle.;
--N(R.sup..smallcircle.)S(O).sub.2NR.sup..smallcircle..sub.2;
--N(R.sup..smallcircle.)S(O).sub.2R.sup..smallcircle.;
--N(OR.sup..smallcircle.)R.sup..smallcircle.;
--C(NH)NR.sup..smallcircle..sub.2; --P(O).sub.2R.sup..smallcircle.;
--P(O)R.sup..smallcircle..sub.2; --OP(O)R.sup..smallcircle..sub.2;
--OP(O)(OR.sup..smallcircle.).sub.2; SiR.sup..smallcircle..sub.3;
--(C.sub.1-4 straight or branched
alkylene)O--N(R.sup..smallcircle.).sub.2; or --(C.sub.1-4 straight
or branched alkylene)C(O)O--N(R.sup..smallcircle.).sub.2, wherein
each R.sup..smallcircle. may be substituted as defined below and is
independently hydrogen, C.sub.1-aliphatic, --CH.sub.2Ph,
--O(CH.sub.2).sub.0-1Ph, --CH.sub.2-(5-6 membered heteroaryl ring),
or a 5-6-membered saturated, partially unsaturated, or aryl ring
having 0-4 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or, notwithstanding the definition above, two
independent occurrences of R.sup..smallcircle., taken together with
their intervening atom(s), form a 3-12-membered saturated,
partially unsaturated, or aryl mono- or bicyclic ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, which may be substituted as defined below.
[0136] Suitable monovalent substituents on R.sup..smallcircle. (or
the ring formed by taking two independent occurrences of
R.sup..smallcircle. together with their intervening atoms), are
independently halogen, --(CH.sub.2).sub.0-2R.sup..circle-solid.,
-(haloR.sup..circle-solid.), --(CH.sub.2).sub.0-2OH,
--(CH.sub.2).sub.0-2OR.sup..circle-solid.,
--(CH.sub.2).sub.0-2CH(OR.sup..circle-solid.).sub.2;
--O(haloR.sup..circle-solid.), --CN, --N.sub.3,
--(CH.sub.2).sub.0-2C(O)R.sup..circle-solid.,
--(CH.sub.2).sub.0-2C(O)OH,
--(CH.sub.2).sub.0-2C(O)OR.sup..circle-solid.,
--(CH.sub.2).sub.0-2SR.sup..circle-solid., --(CH.sub.2).sub.0-2SH,
--(CH.sub.2).sub.0-2NH.sub.2,
--(CH.sub.2).sub.0-2NHR.sup..circle-solid.,
--(CH.sub.2).sub.0-2NR.sup..circle-solid..sub.2, --NO.sub.2,
--SiR.sup..circle-solid..sub.3, --OSiR.sup..circle-solid..sub.3,
--C(O)SR.sup..circle-solid., --(C.sub.1-4 straight or branched
alkylene)C(O)OR.sup..circle-solid., or --SSR.sup..circle-solid.
wherein each R.sup..circle-solid. is unsubstituted or where
preceded by "halo" is substituted only with one or more halogens,
and is independently selected from C1-4 aliphatic, --CH.sub.2Ph,
--O(CH.sub.2).sub.0-1Ph, or a 5-6-membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur. Suitable divalent
substituents on a saturated carbon atom of R.sup..smallcircle.
include .dbd.O and .dbd.S.
[0137] Suitable divalent substituents on a saturated carbon atom of
an "optionally substituted" group include the following: .dbd.O,
.dbd.S, .dbd.NNR*.sub.2, .dbd.NNHC(O)R*, .dbd.NNHC(O)OR*,
.dbd.NNHS(O).sub.2R*, .dbd.NR*, .dbd.NOR*,
--O(C(R*.sub.2)).sub.2-3O--, or --S(C(R*.sub.2)).sub.2-3S--,
wherein each independent occurrence of R* is selected from
hydrogen, C.sub.1-6 aliphatic which may be substituted as defined
below, or an unsubstituted 5-6-membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur. Suitable divalent
substituents that are bound to vicinal substitutable carbons of an
"optionally substituted" group include: --O(CR*.sub.2).sub.2-3O--,
wherein each independent occurrence of R* is selected from
hydrogen, C.sub.1-6 aliphatic which may be substituted as defined
below, or an unsubstituted 5-6-membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur.
[0138] Suitable substituents on the aliphatic group of R* include
halogen, --R.sup..circle-solid., -(haloR.sup..circle-solid.), --OH,
--OR.sup..circle-solid., --O(haloR.sup..circle-solid.), --CN,
--C(O)OH, --C(O)OR.sup..circle-solid., --NH.sub.2,
--NHR.sup..circle-solid., --NR.sup..circle-solid..sub.2, or
--NO.sub.2, wherein each R.sup..circle-solid. is unsubstituted or
where preceded by "halo" is substituted only with one or more
halogens, and is independently C.sub.1-4 aliphatic, --CH.sub.2Ph,
--O(CH.sub.2).sub.0-1Ph, or a 5-6-membered saturated, partially
unsaturated, or aryl ring having 0-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur.
[0139] Suitable substituents on a substitutable nitrogen of an
"optionally substituted" group include --R.sup..dagger.,
--NR.sup..dagger..sub.2, --C(O)R.sup..dagger.,
--C(O)OR.sup..dagger., --C(O)C(O)R.sup..dagger.,
--C(O)CH.sub.2C(O)R.sup..dagger., --S(O).sub.2R.sup..dagger.,
--S(O).sub.2NR.sup..dagger..sub.2, --C(S)NR.sup..dagger..sub.2,
--C(NH)NR.sup..dagger..sub.2, or --N(Rt)S(O).sub.2Rt; wherein each
Rt is independently hydrogen, C.sub.1-6 aliphatic which may be
substituted as defined below, unsubstituted --OPh, or an
unsubstituted 5-6-membered saturated, partially unsaturated, or
aryl ring having 0-4 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, or, notwithstanding the definition
above, two independent occurrences of Rt, taken together with their
intervening atom(s) form an unsubstituted 3-12-membered saturated,
partially unsaturated, or aryl mono- or bicyclic ring having 0-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur.
[0140] Suitable substituents on the aliphatic group of Rt are
independently halogen, --R.sup..circle-solid.,
-(haloR.sup..circle-solid.), --OH, --OR.sup..circle-solid.,
--O(haloR.sup..circle-solid.), --CN, --C(O)OH,
--C(O)OR.sup..circle-solid., --NH.sub.2, --NHR.sup..circle-solid.,
--NR.sup..circle-solid..sub.2, or --NO.sub.2, wherein each
R.sup..circle-solid. is unsubstituted or where preceded by "halo"
is substituted only with one or more halogens, and is independently
C.sub.1-4 aliphatic, --CH.sub.2Ph, --O(CH.sub.2).sub.0-1Ph, or a
5-6-membered saturated, partially unsaturated, or aryl ring having
0-4 heteroatoms independently selected from nitrogen, oxygen, or
sulfur.
[0141] The term "nucleophile" or "nucleophilic" refers to an
electron rich compound, or moiety thereof.
[0142] The term "electrophile", or "electrophilic" refers to an
electron poor or electron deficient molecule, or moiety thereof.
Examples of electrophiles include, but in no way are limited to,
Michael acceptor moieties.
[0143] The term "acceptable" or "pharmaceutically acceptable", with
respect to a formulation, composition or ingredient, as used
herein, means having no persistent detrimental effect on the
general health of the subject being treated or does not abrogate
the biological activity or properties of the compound, and is
relatively nontoxic.
[0144] As used herein, "amelioration" of the symptoms of a
particular disease, disorder or condition by administration of a
particular compound or pharmaceutical composition refers to any
lessening of severity, delay in onset, slowing of progression, or
shortening of duration, whether permanent or temporary, lasting or
transient that can be attributed to or associated with
administration of the compound or composition.
[0145] "Bioavailability" refers to the percentage of the weight of
compounds disclosed herein, such as, compounds of any of Formula
(I)-(Vb) dosed that is delivered into the general circulation of
the animal or human being studied. The total exposure
(AUC.sub.(0-.infin.)) of a drug when administered intravenously is
usually defined as 100% bioavailable (F %). "Oral bioavailability"
refers to the extent to which compounds disclosed herein, such as,
compounds of any of Formula ((I)-(Vb) are absorbed into the general
circulation when the pharmaceutical composition is taken orally as
compared to intravenous injection.
[0146] "Blood plasma concentration" refers to the concentration of
compounds disclosed herein, such as, compounds of any of Formula
(I)-(Vb) in the plasma component of blood of a subject. It is
understood that the plasma concentration of compounds of any of
Formula (I)-(Vb) may vary significantly between subjects, due to
variability with respect to metabolism and/or possible interactions
with other therapeutic agents. In accordance with some embodiments
disclosed herein, the blood plasma concentration of the compounds
of any of Formula (I)-(Vb) may vary from subject to subject.
Likewise, values such as maximum plasma concentration (C.sub.max)
or time to reach maximum plasma concentration (T.sub.max), or total
area under the plasma concentration time curve
(AUC.sub.(0-.infin.)) may vary from subject to subject. Due to this
variability, the amount necessary to constitute "a therapeutically
effective amount" of a compound of any of Formula (I)-(Vb) may vary
from subject to subject.
[0147] The terms "co-administration" or the like, as used herein,
are meant to encompass administration of the selected therapeutic
agents to a single patient, and are intended to include treatment
regimens in which the agents are administered by the same or
different route of administration or at the same or different
time.
[0148] The terms "effective amount" or "therapeutically effective
amount," as used herein, refer to a sufficient amount of an agent
or a compound being administered which will relieve to some extent
one or more of the symptoms of the disease or condition being
treated. The result can be reduction and/or alleviation of the
signs, symptoms, or causes of a disease, or any other desired
alteration of a biological system. For example, an "effective
amount" for therapeutic uses is the amount of the composition
including a compound as disclosed herein required to provide a
clinically significant decrease in disease symptoms without undue
adverse side effects. An appropriate "effective amount" in any
individual case may be determined using techniques, such as a dose
escalation study. The term "therapeutically effective amount"
includes, for example, a prophylactically effective amount. An
"effective amount" of a compound disclosed herein is an amount
effective to achieve a desired pharmacologic effect or therapeutic
improvement without undue adverse side effects. It is understood
that "an effect amount" or "a therapeutically effective amount" can
vary from subject to subject, due to variation in metabolism of the
compound of any of Formula (I)-(Vb), age, weight, general condition
of the subject, the condition being treated, the severity of the
condition being treated, and the judgment of the prescribing
physician.
[0149] By way of example only, therapeutically effective amounts
may be determined by routine experimentation, including but not
limited to a dose escalation clinical trial.
[0150] The terms "enhance" or "enhancing" means to increase or
prolong either in potency or duration a desired effect. By way of
example, "enhancing" the effect of therapeutic agents refers to the
ability to increase or prolong, either in potency or duration, the
effect of therapeutic agents on during treatment of a disease,
disorder or condition. An "enhancing-effective amount," as used
herein, refers to an amount adequate to enhance the effect of a
therapeutic agent in the treatment of a disease, disorder or
condition.
[0151] When used in a patient, amounts effective for this use will
depend on the severity and course of the disease, disorder or
condition, previous therapy, the patient's health status and
response to the drugs, and the judgment of the treating
physician.
[0152] The term "identical," as used herein, refers to two or more
sequences or subsequences which are the same. In addition, the term
"substantially identical," as used herein, refers to two or more
sequences which have a percentage of sequential units which are the
same when compared and aligned for maximum correspondence over a
comparison window, or designated region as measured using
comparison algorithms or by manual alignment and visual inspection.
By way of example only, two or more sequences may be "substantially
identical" if the sequential units are about 60% identical, about
65% identical, about 70% identical, about 75% identical, about 80%
identical, about 85% identical, about 90% identical, or about 95%
identical over a specified region. Such percentages to describe the
"percent identity" of two or more sequences. The identity of a
sequence can exist over a region that is at least about 75-100
sequential units in length, over a region that is about 50
sequential units in length, or, where not specified, across the
entire sequence. This definition also refers to the complement of a
test sequence. By way of example only, two or more polypeptide
sequences are identical when the amino acid residues are the same,
while two or more polypeptide sequences are "substantially
identical" if the amino acid residues are about 60% identical,
about 65% identical, about 70% identical, about 75% identical,
about 80% identical, about 85% identical, about 90% identical, or
about 95% identical over a specified region. The identity can exist
over a region that is at least about 75-100 amino acids in length,
over a region that is about 50 amino acids in length, or, where not
specified, across the entire sequence of a polypeptide sequence. In
addition, by way of example only, two or more polynucleotide
sequences are identical when the nucleic acid residues are the
same, while two or more polynucleotide sequences are "substantially
identical" if the nucleic acid residues are about 60% identical,
about 65% identical, about 70% identical, about 75% identical,
about 80% identical, about 85% identical, about 90% identical, or
about 95% identical over a specified region. The identity can exist
over a region that is at least about 75-100 nucleic acids in
length, over a region that is about 50 nucleic acids in length, or,
where not specified, across the entire sequence of a polynucleotide
sequence.
[0153] The term "isolated," as used herein, refers to separating
and removing a component of interest from components not of
interest. Isolated substances can be in either a dry or semi-dry
state, or in solution, including but not limited to an aqueous
solution. The isolated component can be in a homogeneous state or
the isolated component can be a part of a pharmaceutical
composition that comprises additional pharmaceutically acceptable
carriers and/or excipients. By way of example only, nucleic acids
or proteins are "isolated" when such nucleic acids or proteins are
free of at least some of the cellular components with which it is
associated in the natural state, or that the nucleic acid or
protein has been concentrated to a level greater than the
concentration of its in vivo or in vitro production. Also, by way
of example, a gene is isolated when separated from open reading
frames which flank the gene and encode a protein other than the
gene of interest.
[0154] A "metabolite" of a compound disclosed herein is a
derivative of that compound that is formed when the compound is
metabolized. The term "active metabolite" refers to a biologically
active derivative of a compound that is formed when the compound is
metabolized. The term "metabolized," as used herein, refers to the
sum of the processes (including, but not limited to, hydrolysis
reactions and reactions catalyzed by enzymes, such as, oxidation
reactions) by which a particular substance is changed by an
organism. Thus, enzymes may produce specific structural alterations
to a compound. For example, cytochrome P450 catalyzes a variety of
oxidative and reductive reactions while uridine diphosphate
glucuronyl transferases catalyze the transfer of an activated
glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols,
carboxylic acids, amines and free sulfhydryl groups. Further
information on metabolism may be obtained from The Pharmacological
Basis of Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites
of the compounds disclosed herein can be identified either by
administration of compounds to a host and analysis of tissue
samples from the host, or by incubation of compounds with hepatic
cells in vitro and analysis of the resulting compounds. Both
methods are well known in the art. In some embodiments, metabolites
of a compound are formed by oxidative processes and correspond to
the corresponding hydroxy-containing compound. In some embodiments,
a compound is metabolized to pharmacologically active
metabolites.
[0155] The term "modulate," as used herein, means to interact with
a target either directly or indirectly so as to alter the activity
of the target, including, by way of example only, to enhance the
activity of the target, to inhibit the activity of the target, to
limit the activity of the target, or to extend the activity of the
target.
[0156] As used herein, the term "modulator" refers to a compound
that alters an activity of a molecule. For example, a modulator can
cause an increase or decrease in the magnitude of a certain
activity of a molecule compared to the magnitude of the activity in
the absence of the modulator. In certain embodiments, a modulator
is an inhibitor, which decreases the magnitude of one or more
activities of a molecule. In certain embodiments, an inhibitor
completely prevents one or more activities of a molecule. In
certain embodiments, a modulator is an activator, which increases
the magnitude of at least one activity of a molecule. In certain
embodiments the presence of a modulator results in an activity that
does not occur in the absence of the modulator.
[0157] The term "prophylactically effective amount," as used
herein, refers that amount of a composition applied to a patient
that will relieve to some extent one or more of the symptoms of a
disease, condition or disorder being treated. In such prophylactic
applications, such amounts may depend on the patient's state of
health, weight, and the like. It is considered well within the
skill of the art for one to determine such prophylactically
effective amounts by routine experimentation, including, but not
limited to, a dose escalation clinical trial.
[0158] As used herein, the term "selective binding compound" refers
to a compound that selectively binds to any portion of one or more
target proteins.
[0159] As used herein, the term "selectively binds" refers to the
ability of a selective binding compound to bind to a target
protein, with greater affinity than it binds to a non-target
protein. In certain embodiments, specific binding refers to binding
to a target with an affinity that is at least 10, 50, 100, 250,
500, 1000 or more times greater than the affinity for a
non-target.
[0160] As used herein, the term "selective modulator" refers to a
compound that selectively modulates a target activity relative to a
non-target activity. In certain embodiments, specific modulater
refers to modulating a target activity at least 10, 50, 100, 250,
500, 1000 times more than a non-target activity.
[0161] The term "substantially purified," as used herein, refers to
a component of interest that may be substantially or essentially
free of other components which normally accompany or interact with
the component of interest prior to purification. By way of example
only, a component of interest may be "substantially purified" when
the preparation of the component of interest contains less than
about 30%, less than about 25%, less than about 20%, less than
about 15%, less than about 10%, less than about 5%, less than about
4%, less than about 3%, less than about 2%, or less than about 1%
(by dry weight) of contaminating components. Thus, a "substantially
purified" component of interest may have a purity level of about
70%, about 75%, about 80%, about 85%, about 90%, about 95%, about
96%, about 97%, about 98%, about 99% or greater.
[0162] The term "subject" or "patient" as used herein, refers to an
animal which is the object of treatment, observation or experiment.
By way of example only, a subject may be, but is not limited to, a
mammal including, but not limited to, a human.
[0163] As used herein, the term "target activity" refers to a
biological activity capable of being modulated by a selective
modulator. Certain exemplary target activities include, but are not
limited to, binding affinity, signal transduction, enzymatic
activity, tumor growth, inflammation or inflammation-related
processes, and amelioration of one or more symptoms associated with
a disease or condition.
[0164] As used herein, the term "target protein" refers to a
molecule or a portion of a protein capable of being bound by a
selective binding compound.
[0165] The terms "treat," "treating" or "treatment", as used
herein, include alleviating, abating or ameliorating a disease or
condition symptoms, preventing additional symptoms, ameliorating or
preventing the underlying metabolic causes of symptoms, inhibiting
the disease or condition, e.g., arresting the development of the
disease or condition, relieving the disease or condition, causing
regression of the disease or condition, relieving a condition
caused by the disease or condition, or stopping the symptoms of the
disease or condition. The terms "treat," "treating" or "treatment",
include, but are not limited to, prophylactic and/or therapeutic
treatments.
[0166] As used herein, the IC.sub.50 refers to an amount,
concentration or dosage of a particular test compound that achieves
a 50% inhibition of a maximal response, in an assay that measures
such response.
[0167] As used herein, EC.sub.50 refers to a dosage, concentration
or amount of a particular test compound that elicits a
dose-dependent response at 50% of maximal expression of a
particular response that is induced, provoked or potentiated by the
particular test compound.
[0168] Methods described herein include administering to a subject
in need a composition containing a therapeutically effective amount
of one or more compounds described herein.
[0169] A number of animal models of are useful for establishing a
range of therapeutically effective doses of pyridyl compounds for
treating any of the foregoing diseases.
[0170] For example, dosing of pyridyl compounds for treating a
kidney disease can be assessed in a rat models as described
herein.
[0171] The therapeutic efficacy of a provided compound for one of
the foregoing diseases can be optimized during a course of
treatment.
Compounds
[0172] In the following description of pyridyl compounds suitable
for use in the methods described herein, definitions of referred-to
standard chemistry terms may be found in reference works (if not
otherwise defined herein), including Carey and Sundberg "Advanced
Organic Chemistry 4th Ed." Vols. A (2000) and B (2001), Plenum
Press, New York. Unless otherwise indicated, conventional methods
of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry,
recombinant DNA techniques and pharmacology, within the ordinary
skill of the art are employed unless specific definitions are
provided, the nomenclature employed in connection with, and the
laboratory procedures and techniques of, analytical chemistry,
synthetic organic chemistry, and medicinal and pharmaceutical
chemistry described herein are those known in the art. Standard
techniques can be used for chemical syntheses, chemical analyses,
pharmaceutical preparation, formulation, and delivery, and
treatment of patients.
[0173] Pyridyl compounds can be used for the manufacture of a
medicament for treating any of the foregoing conditions Chronic
Kidney Disease, Diabetic Nephropathy, IgA Nephropathy, Acute Kidney
Failure, Acute tubular necrosis, Transplant related Ischemia, Acute
Kidney Disease and types of AKI such as Cisplatin induced AKI,
Aminoglycosides induced AKI, Tenofovir induced AKI, Contrast
Induced Nephropathy, AKI after surgery for partial nephrectomy, AKI
post kidney transplant, AKI in patients with Dialysis, AKI after
Cardiac surgery, AKI in patients inside ICU, AKI caused by
Cirrhosis or Sepsis and AKI caused by hepatorenal syndrome.
[0174] Described herein are compounds of any of Formulae (I)-(Vb).
Also described herein are pharmaceutically acceptable salts,
pharmaceutically acceptable solvates, pharmaceutically active
metabolites, and pharmaceutically acceptable prodrugs of such
compounds. Pharmaceutical compositions that include at least one
such compound or a pharmaceutically acceptable salt,
pharmaceutically acceptable solvate, pharmaceutically active
metabolite or pharmaceutically acceptable prodrug of such compound,
are provided. In some embodiments, when compounds disclosed herein
contain an oxidizable nitrogen atom, the nitrogen atom can be
converted to an N-oxide by methods well known in the art. In
certain embodiments, isomers and chemically protected forms of
compounds having a structure represented by any of Formula (I)-(Vb)
are also provided.
[0175] In some embodiments, provided herein are pyridyl according
to compounds of formula (I).
[0176] In some embodiments, the present invention provides a
compound according to formula (I) having the structure:
##STR00010## [0177] or a pharmaceutical composition thereof, [0178]
wherein X.sup.- is a counter ion; Y is --C(H).sub.2--, --O--, or
--N(R.sup.3)--; [0179] R.sup.1 is substituted or unsubstituted
C1-C.sub.4 alkyl, substituted or unsubstituted
C.sub.3--C-cycloalkyl, or substituted or unsubstituted 4-7 membered
heterocycloalkyl; [0180] R.sup.2 is H or C.sub.1-C.sub.4 alkyl; and
[0181] R.sup.3 is H or substituted or unsubstituted C.sub.1-C.sub.4
alkyl; or R.sup.1 and R.sup.3 are joined together to form a 4-7
membered substituted or unsubstituted heterocycloalkyl.
[0182] In some embodiments, provided herein are uses of a compound
according to formula (I):
##STR00011## [0183] in a treatment of a disease or a condition
related to kidney; [0184] wherein X.sup.- is a counter ion; Y is
--C(H).sub.2--, --O--, or --N(R.sup.3)--; [0185] R.sup.1 is
substituted or unsubstituted C.sub.1-C.sub.4 alkyl, substituted or
unsubstituted C.sub.3-C.sub.7-cycloalkyl, or substituted or
unsubstituted 4-7 membered heterocycloalkyl; [0186] R.sup.2 is H or
C.sub.1-C.sub.4 alkyl; and [0187] R.sup.3 is H or substituted or
unsubstituted C.sub.1-C.sub.4 alkyl; or R.sup.1 and R.sup.3 are
joined together to form a 4-7 membered substituted or unsubstituted
heterocycloalkyl.
[0188] In some embodiments, R.sup.2 is H, Me, Et, or i-Pr.
[0189] In some embodiments, R.sup.2 is H.
[0190] In some embodiments, Y is --C(H).sub.2--.
[0191] In some embodiments, Y is --O--.
[0192] In some embodiments, Y is --N(R.sup.3)--.
[0193] In some embodiments, the compound is according to formula
(IIa), (IIb), or (IIc):
##STR00012## [0194] wherein [0195] X.sup.- is a counter ion; [0196]
R.sup.1 is substituted or unsubstituted C.sub.1-C.sub.4 alkyl,
substituted or unsubstituted C.sub.3-C.sub.7-cycloalkyl, or
substituted or unsubstituted 4-7 membered heterocycloalkyl; [0197]
R.sup.2 is H or C.sub.1-C.sub.4 alkyl; and [0198] R.sup.3 is H or
substituted or unsubstituted C.sub.1-C.sub.4 alkyl; or R.sup.1 and
R.sup.3 are joined together to form a 4-7 membered substituted or
unsubstituted heterocycloalkyl.
[0199] In some embodiments, R.sup.1 is substituted or unsubstituted
C.sub.1-C.sub.4 alkyl.
[0200] In some embodiments, R.sup.1 is C.sub.1-C.sub.4 alkyl,
unsubstituted or substituted with C.sub.3-C.sub.7 cycloalkyl.
[0201] In some embodiments, R.sup.1 is Me, Et, i-Pr, n-Pr, n-Bu,
i-Bu, sec-Bu, or t-Bu.
[0202] In some embodiments, R.sup.1 is Me or Et substituted with
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
[0203] In some embodiments, R.sup.1 is C.sub.3-C.sub.7-cycloalkyl
unsubstituted or substituted with Me or Et.
[0204] In some embodiments, R.sup.1 is cyclopropyl, cyclobutyl,
cyclopentyl or cyclohexyl.
[0205] In some embodiments, R.sup.3 is H or substituted or
unsubstituted C.sub.1-C.sub.4 alkyl.
[0206] In some embodiments, R.sup.3 is H.
[0207] In some embodiments, R.sup.3 is Me, Et, i-Pr, n-Pr, n-Bu,
i-Bu, sec-Bu, or t-Bu.
[0208] In some embodiments, R.sup.1 and R.sup.3 are joined together
to form a 4-7 membered substituted or unsubstituted
heterocycloalkyl.
[0209] In some embodiments, R.sup.1 and R.sup.3 are joined together
to form pyrrolidinyl, piperidinyl, or morpholinyl.
[0210] In some embodiments, the compound is according to formula
(IIIa), or (IIIb):
##STR00013## [0211] wherein [0212] X.sup.- is a counter ion; [0213]
R.sup.2 is H or C.sub.1-C.sub.4 alkyl; and [0214] R.sup.3 is H or
substituted or unsubstituted C.sub.1-C.sub.4 alkyl.
[0215] In some embodiments, R.sup.3 is H, Me, Et, or i-Pr.
[0216] In some embodiments, R.sup.3 is H.
[0217] In some embodiments, R.sup.2 is H or Me.
[0218] In some particular embodiments, the compound is according to
formula (IIIb); and each R.sup.2 and R.sup.3 is H.
[0219] In some embodiments, the compound is according to formula
(IVa), or (IVb):
##STR00014## [0220] wherein X.sup.- is a counter ion.
[0221] In some embodiments, the compound is according to formula
(Va), or (Vb):
##STR00015## [0222] wherein X.sup.- is a counter ion.
[0223] In some embodiments, the counter ion is any pharmaceutically
acceptable anion. In some embodiment, the counter ion is a halide
or a sulfonate. In a particular embodiment, the counter ion is
F.sup.-, Cl.sup.-, Br.sup.-, I.sup.-. In another particular
embodiment, the counter ion is benzene sulfonate or methyl
sulfonate.
[0224] In some embodiments, X.sup.- is F.sup.-, Cl.sup.-, Br.sup.-,
I.sup.-, or MeSO.sub.2O--.
[0225] In a particular embodiment, X.sup.- is Cl.sup.-, or I.sup.-.
In a more particular embodiment, X.sup.- is I.sup.-.
[0226] In some embodiments, the present invention provides, a
pharmaceutical composition comprising a compound according to
formula (I).
[0227] In some embodiments, the present invention provides, a
pharmaceutical composition comprising a therapeutically effective
amount of a compound of formula (I), and a pharmaceutically
acceptable excipient.
[0228] In some embodiments, the pharmaceutical composition is
formulated for a route of administration selected from oral
administration, parenteral administration, buccal administration,
nasal administration, topical administration, or rectal
administration.
[0229] In some embodiments, the present invention provides, methods
for treating a kidney disease or condition comprising administering
to a patient in need the pharmaceutical composition of the present
invention.
[0230] In some embodiments, the kidney disease is selected from
Chronic Kidney Disease, Diabetic Nephropathy, IgA Nephropathy,
Acute Kidney Failure, Acute tubular necrosis, Transplant related
Ischemia, Acute Kidney Disease and types of AKI such as Cisplatin
induced AKI, Aminoglycosides induced AKI, Tenofovir induced AKI,
Contrast Induced Nephropathy, AKI after surgery for partial
nephrectomy, AKI post kidney transplant, AKI in patients with
Dialysis, AKI after Cardiac surgery, AKI in patients inside ICU,
AKI caused by Cirrhosis or Sepsis and AKI caused by hepatorenal
syndrome.
[0231] In a particular embodiment, the disease or condition is
Contrast Induced Nephropathy.
[0232] In a particular embodiment, the disease or condition is
Tenofovir induced AKI.
[0233] In a particular embodiment, the disease or condition is
Aminoglycosides induced AKI.
[0234] In a particular embodiment, the disease or condition is AKI
after surgery.
[0235] In a particular embodiment, the disease or condition is AKI
in patients with Dialysis.
[0236] In a particular embodiment, the disease or condition is
Diabetic Nephropathy.
[0237] In a more particular embodiment, the disease or condition is
chronic kidney disease or CKD.
[0238] In some embodiments, the disease or condition is:
TABLE-US-00001 ACUTE CHRONIC Acute Kidney Injury (AKI) Chronic
Kidney Disease (CKD) Acute tubular necrosis IgA Nephropathy
Transplant related Ischemia Diabetic Nephropathy
[0239] In some embodiments, the disease or condition is:
TABLE-US-00002 ACUTE KIDNEY INJURY/DISEASE Post Surgery/ Other
causes Drug Induced AKI Transplant of AKI Cisplatin induced AKI in
AKI after surgery Cirrhosis patients with Head and Neck for partial
Cancer nephrectomy Aminoglycosides induced AKI AKI post Kidney
Hepatorenal in patients with Cystic Fibrosis transplant syndrome
Tenofovir induced AKI in AKI for patients Sepsis patients with Hep
B and HIV under dialysis Contrast induced AKI
[0240] In some embodiments, the compound is according to formula
(Va).
[0241] In some embodiments, the compound is according to formula
(Vb).
[0242] In some embodiments, the present invention provides, a
pharmaceutical composition comprising a pharmaceutically acceptable
carrier and a pharmaceutically effective amount of a compound
according to any one of the formulas described herein. In some
embodiments, the compound is according to any one of Formula
(I)-(Vb).
[0243] In some embodiments, the pharmaceutical composition is
formulated for a route of administration selected from oral
administration, parenteral administration, buccal administration,
nasal administration, topical administration, or rectal
administration.
[0244] In some embodiments, the carrier is a parenteral
carrier.
[0245] In some embodiments, the carrier is an oral carrier.
[0246] In some embodiments, the carrier is a topical carrier.
[0247] Any combination of the groups described above for the
various variables is contemplated herein.
[0248] It is understood that substituents and substitution patterns
on the compounds provided herein can be selected by one of ordinary
skill in the art to provide compounds that are chemically stable
and that can be synthesized by techniques known in the art, as well
as those set forth herein.
[0249] Throughout the specification, groups and substituents
thereof can be chosen by one skilled in the field to provide stable
moieties and compounds.
[0250] In some embodiments, the compounds of formula (I)-(Vb) are
used to treat patients suffering from kidney conditions or
diseases, including, but not limited to, Chronic Kidney Disease,
Diabetic Nephropathy, IgA Nephropathy, Acute Kidney Failure, Acute
tubular necrosis, Transplant related Ischemia, Acute Kidney Disease
and types of AKI such as Cisplatin induced AKI, Aminoglycosides
induced AKI, Tenofovir induced AKI, Contrast Induced Nephropathy,
AKI after surgery for partial nephrectomy, AKI post kidney
transplant, AKI in patients with Dialysis, AKI after Cardiac
surgery, AKI in patients inside ICU, AKI caused by Cirrhosis or
Sepsis and AKI caused by hepatorenal syndrome and other
diseases.
Preparation of Compounds
[0251] Compounds of any of Formula (I)-(Vb) may be synthesized
using synthetic reactions known to those of skill in the art or
using methods known in the art. The reactions can be employed in a
linear sequence to provide the compounds or they may be used to
synthesize fragments which are subsequently joined by the methods
known in the art.
[0252] The starting material used for the synthesis of the
compounds described herein may be synthesized or can be obtained
from commercial sources, such as, but not limited to, Aldrich
Chemical Co. (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma
Chemical Co. (St. Louis, Mo.). The compounds described herein, and
other related compounds having different substituents can be
synthesized using techniques and materials known to those of skill
in the art, such as described, for example, in March, ADVANCED
ORGANIC CHEMISTRY 4.sup.th Ed., (Wiley 1992); Carey and Sundberg,
ADVANCED ORGANIC CHEMISTRY 4.sup.th Ed., Vols. A and B (Plenum
2000, 2001); Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS
3.sup.rd Ed., (Wiley 1999); Fieser and Fieser's Reagents for
Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's
Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals
(Elsevier Science Publishers, 1989); Organic Reactions, Volumes
1-40 (John Wiley and Sons, 1991); and Larock's Comprehensive
Organic Transformations (VCH Publishers Inc., 1989). (all of which
are incorporated by reference in their entirety). Additional
methods for the synthesis of compounds described herein may be
found in International Patent Publication No. WO 01/01982901,
Arnold et al. Bioorganic & Medicinal Chemistry Letters 10
(2000) 2167-2170; Burchat et al. Bioorganic & Medicinal
Chemistry Letters 12 (2002) 1687-1690. General methods for the
preparation of compound as disclosed herein may be derived from
known reactions in the field, and the reactions may be modified by
the use of appropriate reagents and conditions, as would be
recognized by the skilled person, for the introduction of the
various moieties found in the formulae as provided herein.
[0253] The products of the reactions may be isolated and purified,
if desired, using conventional techniques, including, but not
limited to, filtration, distillation, crystallization,
chromatography and the like. Such materials may be characterized
using conventional means, including physical constants and spectral
data.
[0254] Compounds described herein may be prepared as a single
isomer or a mixture of isomers.
[0255] In some embodiments, representative compounds of Formula (I)
are prepared according to synthetic schemes and methods described
in a US patent to Dugar et al., U.S. Pat. No. 9,359,376.
Further Forms of Compounds
[0256] Compounds disclosed herein have a structure of Formula
(I)-(Vb). It is understood that when reference is made to compounds
described herein, it is meant to include compounds of any of
Formula (I), (IIa)-(IIc), (IIIa)-(IIIb), (IVa)-(IVb), or (Va)-(Vb)
as well as to all of the specific compounds that fall within the
scope of these generic formulae, unless otherwise indicated.
[0257] Compounds described herein may possess one or more
stereocenters and each center may exist in the R or S
configuration. Compounds presented herein include all
diastereomeric, enantiomeric, and epimeric forms as well as the
appropriate mixtures thereof. Stereoisomers may be obtained, if
desired, by methods known in the art as, for example, the
separation of stereoisomers by chiral chromatographic columns.
[0258] Diastereomeric mixtures can be separated into their
individual diastereomers on the basis of their physical chemical
differences by methods known, for example, by chromatography and/or
fractional crystallization. In some embodiments, enantiomers can be
separated by chiral chromatographic columns.
[0259] In some embodiments, enantiomers can be separated by
converting the enantiomeric mixture into a diastereomeric mixture
by reaction with an appropriate optically active compound (e.g.,
alcohol), separating the diastereomers and converting (e.g.,
hydrolyzing) the individual diastereomers to the corresponding pure
enantiomers. All such isomers, including diastereomers,
enantiomers, and mixtures thereof are considered as part of the
compositions described herein.
[0260] Methods and formulations described herein include the use of
N-oxides, crystalline forms, or pharmaceutically acceptable salts
of compounds described herein, as well as active metabolites of
these compounds having the same type of activity. In some
situations, compounds may exist as tautomers. All tautomers are
included within the scope of the compounds presented herein. In
addition, compounds described herein can exist in unsolvated as
well as solvated forms with pharmaceutically acceptable solvents
such as water, ethanol, and the like. Solvated forms of compounds
presented herein are also considered to be disclosed herein.
[0261] Compounds described herein include isotopically-labeled
compounds, which are identical to those recited in the various
formulas and structures presented herein, but for the fact that one
or more atoms are replaced by an atom having an atomic mass or mass
number different from the atomic mass or mass number usually found
in nature. Examples of isotopes that can be incorporated into the
present compounds include isotopes of hydrogen, carbon, nitrogen,
oxygen, fluorine and chlorine, such as .sup.2H, .sup.3H, .sup.13C,
.sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.35S, .sup.18F
.sup.36Cl, respectively. Certain isotopically-labeled compounds
described herein, for example those into which radioactive isotopes
such as .sup.3H and .sup.14C are incorporated, are useful in drug
and/or substrate tissue distribution assays. Further, substitution
with isotopes such as deuterium, i.e., .sup.2H, can afford certain
therapeutic advantages resulting from greater metabolic stability,
for example increased in vivo half-life or reduced dosage
requirements.
[0262] The salts are recovered by using at least one of the
following techniques: filtration, precipitation with a non-solvent
followed by filtration, evaporation of the solvent, or, in the case
of aqueous solutions, lyophilization.
[0263] Throughout the specification, groups and substituents
thereof can be chosen by one skilled in the field to provide stable
moieties and compounds.
Pharmaceutical Composition/Formulation
[0264] Pharmaceutical compositions may be formulated in a
conventional manner using one or more physiologically acceptable
carriers including excipients and auxiliaries which facilitate
processing of the active compounds into preparations which can be
used pharmaceutically. Proper formulation is dependent upon the
route of administration chosen. Any of the well-known techniques,
carriers, and excipients may be used as suitable and as understood
in the art. A summary of pharmaceutical compositions described
herein may be found, for example, in Remington: The Science and
Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing
Company, 1995); Hoover, John E., Remington's Pharmaceutical
Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A.
and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker,
New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug
Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins
1999), herein incorporated by reference in their entirety.
[0265] A pharmaceutical composition, as used herein, refers to a
mixture of a compound described herein, such as, for example,
compounds of any of Formula (I)-(Vb) with other chemical
components, such as carriers, stabilizers, diluents, dispersing
agents, suspending agents, thickening agents, and/or excipients.
The pharmaceutical composition facilitates administration of the
compound to an organism. In practicing the methods of treatment or
use provided herein, therapeutically effective amounts of compounds
described herein are administered in a pharmaceutical composition
to a mammal having a disease, disorder, or condition to be treated.
Preferably, the mammal is a human. A therapeutically effective
amount can vary widely depending on the severity of the disease,
the age and relative health of the subject, the potency of the
compound used and other factors. The compounds can be used singly
or in combination with one or more therapeutic agents as components
of mixtures.
[0266] In certain embodiments, compositions may also include one or
more pH adjusting agents or buffering agents, including acids such
as acetic, boric, citric, lactic, phosphoric and hydrochloric
acids; bases such as sodium hydroxide, sodium phosphate, sodium
borate, sodium citrate, sodium acetate, sodium lactate and
tris-hydroxymethylaminomethane; and buffers such as
citrate/dextrose, sodium bicarbonate and ammonium chloride. Such
acids, bases and buffers are included in an amount required to
maintain pH of the composition in an acceptable range.
[0267] In some embodiments, compositions may also include one or
more salts in an amount required to bring osmolality of the
composition into an acceptable range. Such salts include those
having sodium, potassium or ammonium cations and chloride, citrate,
ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or
bisulfite anions; suitable salts include sodium chloride, potassium
chloride, sodium thiosulfate, sodium bisulfite and ammonium
sulfate.
[0268] The term "pharmaceutical combination" as used herein, means
a product that results from the mixing or combining of more than
one active ingredient and includes both fixed and non-fixed
combinations of the active ingredients. The term "fixed
combination" means that the active ingredients, e.g. a compound
described herein and a co-agent, are both administered to a patient
simultaneously in the form of a single entity or dosage. The term
"non-fixed combination" means that the active ingredients, e.g. a
compound described herein and a co-agent, are administered to a
patient as separate entities either simultaneously, concurrently or
sequentially with no specific intervening time limits, wherein such
administration provides effective levels of the two compounds in
the body of the patient. The latter also applies to cocktail
therapy, e.g. the administration of three or more active
ingredients.
[0269] The pharmaceutical compositions described herein can be
administered to a subject by multiple administration routes,
including but not limited to, oral, parenteral (e.g., intravenous,
subcutaneous, intramuscular), intranasal, buccal, topical, rectal,
or transdermal administration routes. The pharmaceutical
compositions described herein include, but are not limited to,
aqueous liquid dispersions, self-emulsifying dispersions, solid
solutions, liposomal dispersions, aerosols, solid dosage forms,
powders, immediate release formulations, controlled release
formulations, fast melt formulations, tablets, capsules, pills,
delayed release formulations, extended release formulations,
pulsatile release formulations, multiparticulate formulations, and
mixed immediate and controlled release formulations.
[0270] Pharmaceutical compositions including a compound described
herein may be manufactured in a conventional manner, such as, by
way of example only, by means of conventional mixing, dissolving,
granulating, dragee-making, levigating, emulsifying, encapsulating,
entrapping or compression processes.
[0271] The pharmaceutical compositions will include at least one
compound described herein, such as, for example, a compound of any
of (I)-(Vb) as an active ingredient in free-acid or free-base form,
or in a pharmaceutically acceptable salt form. In addition, the
methods and pharmaceutical compositions described herein include
the use of N-oxides, crystalline forms, as well as active
metabolites of these compounds having the same type of activity. In
some situations, compounds may exist as tautomers. All tautomers
are included within the scope of the compounds presented herein.
Additionally, the compounds described herein can exist in
unsolvated as well as solvated forms with pharmaceutically
acceptable solvents such as water, ethanol, and the like. The
solvated forms of the compounds presented herein are also
considered to be disclosed herein.
[0272] "Antifoaming agents" reduce foaming during processing which
can result in coagulation of aqueous dispersions, bubbles in the
finished film, or generally impair processing. Exemplary
anti-foaming agents include silicon emulsions or sorbitan
sesquoleate.
[0273] "Antioxidants" include, for example, butylated
hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium
metabisulfite and tocopherol. In certain embodiments, antioxidants
enhance chemical stability where required.
[0274] In certain embodiments, compositions provided herein may
also include one or more preservatives to inhibit microbial
activity. Suitable preservatives include mercury-containing
substances such as merfen and thiomersal; stabilized chlorine
dioxide; and quaternary ammonium compounds such as benzalkonium
chloride, cetyltrimethylammonium bromide and cetylpyridinium
chloride.
[0275] Formulations described herein may benefit from antioxidants,
metal chelating agents, thiol containing compounds and other
general stabilizing agents. Examples of such stabilizing agents,
include, but are not limited to: (a) about 0.5% to about 2% w/v
glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1%
to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM
EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to
about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v.
polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k)
cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m)
divalent cations such as magnesium and zinc; or (n) combinations
thereof.
[0276] "Binders" impart cohesive qualities and include, e.g.,
alginic acid and salts thereof; cellulose derivatives such as
carboxymethylcellulose, methylcellulose (e.g., Methocel.RTM.),
hydroxypropylmethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose (e.g., Klucel.RTM.), ethylcellulose (e.g.,
Ethocel.RTM.), and microcrystalline cellulose (e.g., Avicel.RTM.);
microcrystalline dextrose; amylose; magnesium aluminum silicate;
polysaccharide acids; bentonites; gelatin;
polyvinylpyrrolidone/vinyl acetate copolymer; crosspovidone;
povidone; starch; pregelatinized starch; tragacanth, dextrin, a
sugar, such as sucrose (e.g., Dipac.RTM.), glucose, dextrose,
molasses, mannitol, sorbitol, xylitol (e.g., Xylitab.RTM.), and
lactose; a natural or synthetic gum such as acacia, tragacanth,
ghatti gum, mucilage of isapol husks, polyvinylpyrrolidone (e.g.,
Polyvidone.RTM. CL, Kollidon.RTM. CL, Polyplasdone.RTM. XL-10),
larch arabogalactan, Veegum.RTM., polyethylene glycol, waxes,
sodium alginate, and the like.
[0277] A "carrier" or "carrier materials" include any commonly used
excipients in pharmaceutics and should be selected on the basis of
compatibility with compounds disclosed herein, such as, compounds
of any of Formula (I)-(Vb) and the release profile properties of
the desired dosage form. Exemplary carrier materials include, e.g.,
binders, suspending agents, disintegration agents, filling agents,
surfactants, solubilizers, stabilizers, lubricants, wetting agents,
diluents, and the like. "Pharmaceutically compatible carrier
materials" may include, but are not limited to, acacia, gelatin,
colloidal silicon dioxide, calcium glycerophosphate, calcium
lactate, maltodextrin, glycerine, magnesium silicate,
polyvinylpyrrollidone (PVP), cholesterol, cholesterol esters,
sodium caseinate, soy lecithin, taurocholic acid,
phosphotidylcholine, sodium chloride, tricalcium phosphate,
dipotassium phosphate, cellulose and cellulose conjugates, sugars
sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride,
pregelatinized starch, and the like. See, e.g., Remington: The
Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack
Publishing Company, 1995); Hoover, John E., Remington's
Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975;
Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,
Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage
Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams
& Wilkins 1999).
[0278] "Dispersing agents," and/or "viscosity modulating agents"
include materials that control the diffusion and homogeneity of a
drug through liquid media or a granulation method or blend method.
In some embodiments, these agents also facilitate the effectiveness
of a coating or eroding matrix. Exemplary diffusion
facilitators/dispersing agents include, e.g., hydrophilic polymers,
electrolytes, Tween.RTM. 60 or 80, PEG, polyvinylpyrrolidone (PVP;
commercially known as Plasdone.RTM.), and the carbohydrate-based
dispersing agents such as, for example, hydroxypropyl celluloses
(e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methylcelluloses
(e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M),
carboxymethylcellulose sodium, methylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose phthalate,
hydroxypropylmethylcellulose acetate stearate (HPMCAS),
noncrystalline cellulose, magnesium aluminum silicate,
triethanolamine, polyvinyl alcohol (PVA), vinyl pyrrolidone/vinyl
acetate copolymer (S630), 4-(1,1,3,3-tetramethylbutyl)-phenol
polymer with ethylene oxide and formaldehyde (also known as
tyloxapol), poloxamers (e.g., Pluronics F68.RTM., F88.RTM., and
F108.RTM., which are block copolymers of ethylene oxide and
propylene oxide); and poloxamines (e.g., Tetronic 908.RTM., also
known as Poloxamine 908.RTM., which is a tetrafunctional block
copolymer derived from sequential addition of propylene oxide and
ethylene oxide to ethylenediamine (BASF Corporation, Parsippany,
N.J.)), polyvinylpyrrolidone K12, polyvinylpyrrolidone K17,
polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30,
polyvinylpyrrolidone/vinyl acetate copolymer (S-630), polyethylene
glycol, e.g., the polyethylene glycol can have a molecular weight
of about 300 to about 6000, or about 3350 to about 4000, or about
7000 to about 5400, sodium carboxymethylcellulose, methylcellulose,
polysorbate-80, sodium alginate, gums, such as, e.g., gum
tragacanth and gum acacia, guar gum, xanthans, including xanthan
gum, sugars, cellulosics, such as, e.g., sodium
carboxymethylcellulose, methylcellulose, sodium
carboxymethylcellulose, polysorbate-80, sodium alginate,
polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan
monolaurate, povidone, carbomers, polyvinyl alcohol (PVA),
alginates, chitosans and combinations thereof. Plasticizers such as
cellulose or triethyl cellulose can also be used as dispersing
agents. Dispersing agents particularly useful in liposomal
dispersions and self-emulsifying dispersions are dimyristoyl
phosphatidyl choline, natural phosphatidyl choline from eggs,
natural phosphatidyl glycerol from eggs, cholesterol and isopropyl
myristate.
[0279] Combinations of one or more erosion facilitator with one or
more diffusion facilitator can also be used in the present
compositions.
[0280] The term "diluent" refers to chemical compounds that are
used to dilute the compound of interest prior to delivery. Diluents
can also be used to stabilize compounds because they can provide a
more stable environment. Salts dissolved in buffered solutions
(which also can provide pH control or maintenance) are utilized as
diluents in the art, including, but not limited to a phosphate
buffered saline solution. In certain embodiments, diluents increase
bulk of the composition to facilitate compression or create
sufficient bulk for homogenous blend for capsule filling. Such
compounds include e.g., lactose, starch, mannitol, sorbitol,
dextrose, microcrystalline cellulose such as Avicel.RTM.; dibasic
calcium phosphate, dicalcium phosphate dihydrate; tricalcium
phosphate, calcium phosphate; anhydrous lactose, spray-dried
lactose; pregelatinized starch, compressible sugar, such as
Di-Pac.RTM. (Amstar); mannitol, hydroxypropylmethylcellulose,
hydroxypropylmethylcellulose acetate stearate, sucrose-based
diluents, confectioner's sugar; monobasic calcium sulfate
monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate,
dextrates; hydrolyzed cereal solids, amylose; powdered cellulose,
calcium carbonate; glycine, kaolin; mannitol, sodium chloride;
inositol, bentonite, and the like.
[0281] The term "disintegrate" includes both the dissolution and
dispersion of the dosage form when contacted with gastrointestinal
fluid. "Disintegration agents or disintegrants" facilitate the
breakup or disintegration of a substance. Examples of
disintegration agents include a starch, e.g., a natural starch such
as corn starch or potato starch, a pregelatinized starch such as
National 1551 or Amijel.RTM., or sodium starch glycolate such as
Promogel.RTM. or Explotab.RTM., a cellulose such as a wood product,
methylcrystalline cellulose, e.g., Avicel.RTM., Avicel.RTM. PH101,
Avicel.RTM. PH102, Avicel.RTM. PH105, Elcema.RTM. P100,
Emcocel.RTM., Vivacel.RTM., Ming Tia.RTM., and Solka-Floc.RTM.,
methylcellulose, croscarmellose, or a cross-linked cellulose, such
as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol.RTM.),
cross-linked carboxymethylcellulose, or cross-linked
croscarmellose, a cross-linked starch such as sodium starch
glycolate, a cross-linked polymer such as crosspovidone, a
cross-linked polyvinylpyrrolidone, alginate such as alginic acid or
a salt of alginic acid such as sodium alginate, a clay such as
Veegum.RTM. HV (magnesium aluminum silicate), a gum such as agar,
guar, locust bean, Karaya, pectin, or tragacanth, sodium starch
glycolate, bentonite, a natural sponge, a surfactant, a resin such
as a cation-exchange resin, citrus pulp, sodium lauryl sulfate,
sodium lauryl sulfate in combination starch, and the like.
[0282] "Drug absorption" or "absorption" typically refers to the
process of movement of drug from site of administration of a drug
across a barrier into a blood vessel or the site of action, e.g., a
drug moving from the gastrointestinal tract into the portal vein or
lymphatic system.
[0283] An "enteric coating" is a substance that remains
substantially intact in the stomach but dissolves and releases the
drug in the small intestine or colon. Generally, the enteric
coating comprises a polymeric material that prevents release in the
low pH environment of the stomach but that ionizes at a higher pH,
typically a pH of 6 to 7, and thus dissolves sufficiently in the
small intestine or colon to release the active agent therein.
[0284] "Erosion facilitators" include materials that control the
erosion of a particular material in gastrointestinal fluid. Erosion
facilitators are generally known to those of ordinary skill in the
art. Exemplary erosion facilitators include, e.g., hydrophilic
polymers, electrolytes, proteins, peptides, and amino acids.
[0285] "Filling agents" include compounds such as lactose, calcium
carbonate, calcium phosphate, dibasic calcium phosphate, calcium
sulfate, microcrystalline cellulose, cellulose powder, dextrose,
dextrates, dextran, starches, pregelatinized starch, sucrose,
xylitol, lactitol, mannitol, sorbitol, sodium chloride,
polyethylene glycol, and the like.
[0286] "Flavoring agents" and/or "sweeteners" useful in the
formulations described herein, include, e.g., acacia syrup,
acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian
cream, berry, black currant, butterscotch, calcium citrate,
camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble
gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola,
cool cherry, cool citrus, cyclamate, cylamate, dextrose,
eucalyptus, eugenol, fructose, fruit punch, ginger,
glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit,
honey, isomalt, lemon, lime, lemon cream, monoammonium
glyrrhizinate (MagnaSweet.RTM.), maltol, mannitol, maple,
marshmallow, menthol, mint cream, mixed berry, neohesperidine DC,
neotame, orange, pear, peach, peppermint, peppermint cream,
Prosweet.RTM. Powder, raspberry, root beer, rum, saccharin,
safrole, sorbitol, spearmint, spearmint cream, strawberry,
strawberry cream, stevia, sucralose, sucrose, sodium saccharin,
saccharin, aspartame, acesulfame potassium, mannitol, talin,
sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine,
thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry,
wintergreen, xylitol, or any combination of these flavoring
ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange,
cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime,
lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and
mixtures thereof.
[0287] "Lubricants" and "glidants" are compounds that prevent,
reduce or inhibit adhesion or friction of materials. Exemplary
lubricants include, e.g., stearic acid, calcium hydroxide, talc,
sodium stearyl fumerate, a hydrocarbon such as mineral oil, or
hydrogenated vegetable oil such as hydrogenated soybean oil
(Sterotex.RTM.), higher fatty acids and their alkali-metal and
alkaline earth metal salts, such as aluminum, calcium, magnesium,
zinc, stearic acid, sodium stearates, glycerol, talc, waxes,
Stearowet.RTM., boric acid, sodium benzoate, sodium acetate, sodium
chloride, leucine, a polyethylene glycol (e.g., PEG-4000) or a
methoxypolyethylene glycol such as Carbowax.TM., sodium oleate,
sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium
or sodium lauryl sulfate, colloidal silica such as Syloid.TM.,
Cab-O-Sil.RTM., a starch such as corn starch, silicone oil, a
surfactant, and the like.
[0288] A "measurable serum concentration" or "measurable plasma
concentration" describes the blood serum or blood plasma
concentration, typically measured in mg, .mu.g, or ng of
therapeutic agent per ml, dl, or 1 of blood serum, absorbed into
the bloodstream after administration. As used herein, measurable
plasma concentrations are typically measured in ng/ml or
.mu.g/ml.
[0289] "Pharmacodynamics" refers to the factors which determine the
biologic response observed relative to the concentration of drug at
a site of action.
[0290] "Pharmacokinetics" refers to the factors which determine the
attainment and maintenance of the appropriate concentration of drug
at a site of action.
[0291] "Plasticizers" are compounds used to soften the
microencapsulation material or film coatings to make them less
brittle. Suitable plasticizers include, e.g., polyethylene glycols
such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800,
stearic acid, propylene glycol, oleic acid, triethyl cellulose and
triacetin. In some embodiments, plasticizers can also function as
dispersing agents or wetting agents.
[0292] "Solubilizers" include compounds such as triacetin,
triethylcitrate, ethyl oleate, ethyl caprylate, sodium lauryl
sulfate, sodium doccusate, vitamin E TPGS, dimethylacetamide,
N-methylpyrrolidone, N-hydroxyethylpyrrolidone,
polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl
cyclodextrins, ethanol, n-butanol, isopropyl alcohol, cholesterol,
bile salts, polyethylene glycol 200-600, glycofurol, transcutol,
propylene glycol, and dimethyl isosorbide and the like.
[0293] "Stabilizers" include compounds such as any antioxidation
agents, buffers, acids, preservatives and the like.
[0294] "Steady state," as used herein, is when the amount of drug
administered is equal to the amount of drug eliminated within one
dosing interval resulting in a plateau or constant plasma drug
exposure.
[0295] "Suspending agents" include compounds such as
polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12,
polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or
polyvinylpyrrolidone K30, vinyl pyrrolidone/vinyl acetate copolymer
(S630), polyethylene glycol, e.g., the polyethylene glycol can have
a molecular weight of about 300 to about 6000, or about 3350 to
about 4000, or about 7000 to about 5400, sodium
carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, hydroxymethylcellulose acetate
stearate, polysorbate-80, hydroxyethylcellulose, sodium alginate,
gums, such as, e.g., gum tragacanth and gum acacia, guar gum,
xanthans, including xanthan gum, sugars, cellulosics, such as,
e.g., sodium carboxymethylcellulose, methylcellulose, sodium
carboxymethylcellulose, hydroxypropylmethylcellulose,
hydroxyethylcellulose, polysorbate-80, sodium alginate,
polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan
monolaurate, povidone and the like.
[0296] "Surfactants" include compounds such as sodium lauryl
sulfate, sodium docusate, Tween 60 or 80, triacetin, vitamin E
TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate,
polysorbates, polaxomers, bile salts, glyceryl monostearate,
copolymers of ethylene oxide and propylene oxide, e.g.,
Pluronic.RTM. (BASF), and the like. Some other surfactants include
polyoxyethylene fatty acid glycerides and vegetable oils, e.g.,
polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene
alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol
40. In some embodiments, surfactants may be included to enhance
physical stability or for other purposes.
[0297] "Viscosity enhancing agents" include, e.g., methyl
cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl
cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl
cellulose acetate stearate, hydroxypropylmethyl cellulose
phthalate, carbomer, polyvinyl alcohol, alginates, acacia,
chitosans and combinations thereof.
[0298] "Wetting agents" include compounds such as oleic acid,
glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate,
triethanolamine oleate, polyoxyethylene sorbitan monooleate,
polyoxyethylene sorbitan monolaurate, sodium docusate, sodium
oleate, sodium lauryl sulfate, sodium doccusate, triacetin, Tween
80, vitamin E TPGS, ammonium salts and the like.
Dosage Forms
[0299] The compositions described herein can be formulated for
administration to a subject via any conventional means including,
but not limited to, oral, parenteral (e.g., intravenous,
subcutaneous, or intramuscular), buccal, intranasal, rectal or
transdermal administration routes. As used herein, the term
"subject" is used to mean an animal, preferably a mammal, including
a human or non-human. The terms patient and subject may be used
interchangeably.
[0300] Moreover, the pharmaceutical compositions described herein,
which include a compound of any of Formula (I)-(Vb) can be
formulated into any suitable dosage form, including but not limited
to, aqueous oral dispersions, liquids, gels, syrups, elixirs,
slurries, suspensions and the like, for oral ingestion by a patient
to be treated, solid oral dosage forms, aerosols, controlled
release formulations, fast melt formulations, effervescent
formulations, lyophilized formulations, tablets, powders, pills,
dragees, capsules, delayed release formulations, extended release
formulations, pulsatile release formulations, multiparticulate
formulations, and mixed immediate release and controlled release
formulations.
[0301] Pharmaceutical preparations for oral use can be obtained by
mixing one or more solid excipient with one or more of the
compounds described herein, optionally grinding the resulting
mixture, and processing the mixture of granules, after adding
suitable auxiliaries, if desired, to obtain tablets or dragee
cores. Suitable excipients include, for example, fillers such as
sugars, including lactose, sucrose, mannitol, or sorbitol;
cellulose preparations such as, for example, maize starch, wheat
starch, rice starch, potato starch, gelatin, gum tragacanth,
methylcellulose, microcrystalline cellulose,
hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or
others such as: polyvinylpyrrolidone (PVP or povidone) or calcium
phosphate. If desired, disintegrating agents may be added, such as
the cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar,
or alginic acid or a salt thereof such as sodium alginate.
[0302] Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions may be used, which may
optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol
gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments may be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active compound doses.
[0303] Pharmaceutical preparations which can be used orally include
push-fit capsules made of gelatin, as well as soft, sealed capsules
made of gelatin and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in
admixture with filler such as lactose, binders such as starches,
and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds may
be dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers may be added. All formulations for oral administration
should be in dosages suitable for such administration.
[0304] In some embodiments, the solid dosage forms disclosed herein
may be in the form of a tablet, (including a suspension tablet, a
fast-melt tablet, a bite-disintegration tablet, a
rapid-disintegration tablet, an effervescent tablet, or a caplet),
a pill, a powder (including a sterile packaged powder, a
dispensable powder, or an effervescent powder) a capsule (including
both soft or hard capsules, e.g., capsules made from animal-derived
gelatin or plant-derived HPMC, or "sprinkle capsules"), solid
dispersion, solid solution, bioerodible dosage form, controlled
release formulations, pulsatile release dosage forms,
multiparticulate dosage forms, pellets, granules, or an aerosol. In
some embodiments, the pharmaceutical composition is in the form of
a powder. In some embodiments, the pharmaceutical composition is in
the form of a tablet, including but not limited to, a fast-melt
tablet. Additionally, pharmaceutical compositions described herein
may be administered as a single capsule or in multiple capsule
dosage form. In some embodiments, the pharmaceutical composition is
administered in two, or three, or four, capsules or tablets.
[0305] In some embodiments, solid dosage forms, e.g., tablets,
effervescent tablets, and capsules, are prepared by mixing
particles of a compound of any of Formula (I)-(Vb) with one or more
pharmaceutical excipients to form a bulk blend composition. When
referring to these bulk blend compositions as homogeneous, it is
meant that the particles of the compound of any of Formula (I)-(Vb)
are dispersed evenly throughout the composition so that the
composition may be readily subdivided into equally effective unit
dosage forms, such as tablets, pills, and capsules. The individual
unit dosages may also include film coatings, which disintegrate
upon oral ingestion or upon contact with diluent. These
formulations can be manufactured by conventional pharmacological
techniques.
[0306] Conventional pharmacological techniques include, e.g., one
or a combination of methods: (1) dry mixing, (2) direct
compression, (3) milling, (4) dry or non-aqueous granulation, (5)
wet granulation, or (6) fusion. See, e.g., Lachman et al., The
Theory and Practice of Industrial Pharmacy (1986). Other methods
include, e.g., spray drying, pan coating, melt granulation,
granulation, fluidized bed spray drying or coating (e.g., wurster
coating), tangential coating, top spraying, tableting, extruding
and the like.
[0307] The pharmaceutical solid dosage forms described herein can
include a compound described herein and one or more
pharmaceutically acceptable additives such as a compatible carrier,
binder, filling agent, suspending agent, flavoring agent,
sweetening agent, disintegrating agent, dispersing agent,
surfactant, lubricant, colorant, diluent, solubilizer, moistening
agent, plasticizer, stabilizer, penetration enhancer, wetting
agent, anti-foaming agent, antioxidant, preservative, or one or
more combination thereof. In some embodiments, using standard
coating procedures, such as those described in Remington's
Pharmaceutical Sciences, 20th Edition (2000), a film coating is
provided around the formulation of the compound of any of Formula
(I)-(Vb). In some embodiments, some or all of the particles of the
compound of any of Formula (I)-(Vb) are coated. In some
embodiments, some or all of the particles of the compound of any of
Formula (I)-(Vb), are microencapsulated. In still some embodiments,
the particles of the compound of any of Formula (I)-(Vb) are not
microencapsulated and are uncoated.
[0308] Suitable carriers for use in the solid dosage forms
described herein include, but are not limited to, acacia, gelatin,
colloidal silicon dioxide, calcium glycerophosphate, calcium
lactate, maltodextrin, glycerine, magnesium silicate, sodium
caseinate, soy lecithin, sodium chloride, tricalcium phosphate,
dipotassium phosphate, sodium stearoyl lactylate, carrageenan,
monoglyceride, diglyceride, pregelatinized starch,
hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate
stearate, sucrose, microcrystalline cellulose, lactose, mannitol
and the like.
[0309] Suitable filling agents for use in the solid dosage forms
described herein include, but are not limited to, lactose, calcium
carbonate, calcium phosphate, dibasic calcium phosphate, calcium
sulfate, microcrystalline cellulose, cellulose powder, dextrose,
dextrates, dextran, starches, pregelatinized starch,
hydroxypropylmethycellulose (HPMC), hydroxypropylmethycellulose
phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS),
sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride,
polyethylene glycol, and the like.
[0310] In order to release the compound of any of Formula (I)-(Vb)
from a solid dosage form matrix as efficiently as possible,
disintegrants are often used in the formulation, especially when
the dosage forms are compressed with binder. Disintegrants help
rupturing the dosage form matrix by swelling or capillary action
when moisture is absorbed into the dosage form. Suitable
disintegrants for use in the solid dosage forms described herein
include, but are not limited to, natural starch such as corn starch
or potato starch, a pregelatinized starch such as National 1551 or
Amijel.RTM., or sodium starch glycolate such as Promogel.RTM. or
Explotab.RTM., a cellulose such as a wood product,
methylcrystalline cellulose, e.g., Avicel.RTM., Avicel.RTM. PH101,
Avicel.RTM. PH102, Avicel.RTM. PH105, Elcema.RTM. P100,
Emcocel.RTM., Vivacel.RTM., Ming Tia.RTM., and Solka-Floc.RTM.,
methylcellulose, croscarmellose, or a cross-linked cellulose, such
as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol.RTM.),
cross-linked carboxymethylcellulose, or cross-linked
croscarmellose, a cross-linked starch such as sodium starch
glycolate, a cross-linked polymer such as crospovidone, a
cross-linked polyvinylpyrrolidone, alginate such as alginic acid or
a salt of alginic acid such as sodium alginate, a clay such as
Veegum.RTM. HV (magnesium aluminum silicate), a gum such as agar,
guar, locust bean, Karaya, pectin, or tragacanth, sodium starch
glycolate, bentonite, a natural sponge, a surfactant, a resin such
as a cation-exchange resin, citrus pulp, sodium lauryl sulfate,
sodium lauryl sulfate in combination starch, and the like.
[0311] Binders impart cohesiveness to solid oral dosage form
formulations: for powder filled capsule formulation, they aid in
plug formation that can be filled into soft or hard shell capsules
and for tablet formulation, they ensure the tablet remaining intact
after compression and help assure blend uniformity prior to a
compression or fill step. Materials suitable for use as binders in
the solid dosage forms described herein include, but are not
limited to, carboxymethylcellulose, methylcellulose (e.g.,
Methocel.RTM.), hydroxypropylmethylcellulose (e.g. Hypromellose USP
Pharmacoat-603, hydroxypropylmethylcellulose acetate stearate
(Agoate HS-LF and HS), hydroxyethylcellulose,
hydroxypropylcellulose (e.g., Klucel.RTM.), ethylcellulose (e.g.,
Ethocel.RTM.), and microcrystalline cellulose (e.g., Avicel.RTM.),
microcrystalline dextrose, amylose, magnesium aluminum silicate,
polysaccharide acids, bentonites, gelatin,
polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone,
povidone, starch, pregelatinized starch, tragacanth, dextrin, a
sugar, such as sucrose (e.g., Dipac.RTM.), glucose, dextrose,
molasses, mannitol, sorbitol, xylitol (e.g., Xylitab.RTM.),
lactose, a natural or synthetic gum such as acacia, tragacanth,
ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone
(e.g., Povidone.RTM. CL, Kollidon.RTM. CL, Polyplasdone.RTM. XL-10,
and Povidone.RTM. K-12), larch arabogalactan, Veegum.RTM.,
polyethylene glycol, waxes, sodium alginate, and the like.
[0312] In general, binder levels of 20-70% are used in
powder-filled gelatin capsule formulations. Binder usage level in
tablet formulations varies whether direct compression, wet
granulation, roller compaction, or usage of other excipients such
as fillers which itself can act as moderate binder. Formulators
skilled in art can determine the binder level for the formulations,
but binder usage level of up to 70% in tablet formulations is
common.
[0313] Suitable lubricants or glidants for use in the solid dosage
forms described herein include, but are not limited to, stearic
acid, calcium hydroxide, talc, corn starch, sodium stearyl
fumerate, alkali-metal and alkaline earth metal salts, such as
aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates,
magnesium stearate, zinc stearate, waxes, Stearowet.RTM., boric
acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a
polyethylene glycol or a methoxypolyethylene glycol such as
Carbowax.TM., PEG 4000, PEG 5000, PEG 6000, propylene glycol,
sodium oleate, glyceryl behenate, glyceryl palmitostearate,
glyceryl benzoate, magnesium or sodium lauryl sulfate, and the
like.
[0314] Suitable diluents for use in the solid dosage forms
described herein include, but are not limited to, sugars (including
lactose, sucrose, and dextrose), polysaccharides (including
dextrates and maltodextrin), polyols (including mannitol, xylitol,
and sorbitol), cyclodextrins and the like.
[0315] The term "non water-soluble diluent" represents compounds
typically used in the formulation of pharmaceuticals, such as
calcium phosphate, calcium sulfate, starches, modified starches and
microcrystalline cellulose, and microcellulose (e.g., having a
density of about 0.45 g/cm.sup.3, e.g. Avicel, powdered cellulose),
and talc.
[0316] Suitable wetting agents for use in the solid dosage forms
described herein include, for example, oleic acid, glyceryl
monostearate, sorbitan monooleate, sorbitan monolaurate,
triethanolamine oleate, polyoxyethylene sorbitan monooleate,
polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds
(e.g., Polyquat 10.RTM.), sodium oleate, sodium lauryl sulfate,
magnesium stearate, sodium docusate, triacetin, vitamin E TPGS and
the like.
[0317] Suitable surfactants for use in the solid dosage forms
described herein include, for example, sodium lauryl sulfate,
sorbitan monooleate, polyoxyethylene sorbitan monooleate,
polysorbates, polaxomers, bile salts, glyceryl monostearate,
copolymers of ethylene oxide and propylene oxide, e.g.,
Pluronic.RTM. (BASF), and the like.
[0318] Suitable suspending agents for use in the solid dosage forms
described here include, but are not limited to,
polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12,
polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or
polyvinylpyrrolidone K30, polyethylene glycol, e.g., the
polyethylene glycol can have a molecular weight of about 300 to
about 6000, or about 3350 to about 4000, or about 7000 to about
5400, vinyl pyrrolidone/vinyl acetate copolymer (S630), sodium
carboxymethylcellulose, methylcellulose,
hydroxy-propylmethylcellulose, polysorbate-80,
hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum
tragacanth and gum acacia, guar gum, xanthans, including xanthan
gum, sugars, cellulosics, such as, e.g., sodium
carboxymethylcellulose, methylcellulose, sodium
carboxymethylcellulose, hydroxypropylmethylcellulose,
hydroxyethylcellulose, polysorbate-80, sodium alginate,
polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan
monolaurate, povidone and the like.
[0319] Suitable antioxidants for use in the solid dosage forms
described herein include, for example, e.g., butylated
hydroxytoluene (BHT), sodium ascorbate, and tocopherol.
[0320] It should be appreciated that there is considerable overlap
between additives used in the solid dosage forms described herein.
Thus, the above-listed additives should be taken as merely
exemplary, and not limiting, of the types of additives that can be
included in solid dosage forms described herein. The amounts of
such additives can be readily determined by one skilled in the art,
according to the particular properties desired.
[0321] In some embodiments, one or more layers of the
pharmaceutical composition are plasticized. Illustratively, a
plasticizer is generally a high boiling point solid or liquid.
Suitable plasticizers can be added from about 0.010% to about 50%
by weight (w/w) of the coating composition. Plasticizers include,
but are not limited to, diethyl phthalate, citrate esters,
polyethylene glycol, glycerol, acetylated glycerides, triacetin,
polypropylene glycol, polyethylene glycol, triethyl citrate,
dibutyl sebacate, stearic acid, stearol, stearate, and castor
oil.
[0322] Compressed tablets are solid dosage forms prepared by
compacting the bulk blend of the formulations described above. In
various embodiments, compressed tablets which are designed to
dissolve in the mouth will include one or more flavoring agents. In
some embodiments, the compressed tablets will include a film
surrounding the final compressed tablet. In some embodiments, the
film coating can provide a delayed release of the compound of any
of Formula (I)-(Vb) from the formulation. In some embodiments, the
film coating aids in patient compliance (e.g., Opadry.RTM. coatings
or sugar coating). Film coatings including Opadry.RTM. typically
range from about 1% to about 3% of the tablet weight. In some
embodiments, the compressed tablets include one or more
excipients.
[0323] A capsule may be prepared, for example, by placing the bulk
blend of the formulation of the compound of any of Formula
(I)-(Vb), described above, inside of a capsule. In some
embodiments, the formulations (non-aqueous suspensions and
solutions) are placed in a soft gelatin capsule. In some
embodiments, the formulations are placed in standard gelatin
capsules or non-gelatin capsules such as capsules comprising HPMC.
In some embodiments, the formulation is placed in a sprinkle
capsule, wherein the capsule may be swallowed whole or the capsule
may be opened and the contents sprinkled on food prior to eating.
In some embodiments, the therapeutic dose is split into multiple
(e.g., two, three, or four) capsules. In some embodiments, the
entire dose of the formulation is delivered in a capsule form.
[0324] In various embodiments, the particles of the compound of any
of Formula (I)-(Vb) and one or more excipients are dry blended and
compressed into a mass, such as a tablet, having a hardness
sufficient to provide a pharmaceutical composition that
substantially disintegrates within less than about 30 minutes, less
than about 35 minutes, less than about 40 minutes, less than about
45 minutes, less than about 50 minutes, less than about 55 minutes,
or less than about 60 minutes, after oral administration, thereby
releasing the formulation into the gastrointestinal fluid.
[0325] In some embodiments, dosage forms may include
microencapsulated formulations. In some embodiments, one or more
other compatible materials are present in the microencapsulation
material. Exemplary materials include, but are not limited to, pH
modifiers, erosion facilitators, anti-foaming agents, antioxidants,
flavoring agents, and carrier materials such as binders, suspending
agents, disintegration agents, filling agents, surfactants,
solubilizers, stabilizers, lubricants, wetting agents, and
diluents.
[0326] Materials useful for the microencapsulation described herein
include materials compatible with compounds of any of Formula
(I)-(Vb) which sufficiently isolate the compound of any of (I)-(Vb)
from other non-compatible excipients. Materials compatible with
compounds of any of Formula (I)-(Vb) are those that delay the
release of the compounds of any of Formula (I)-(Vb), in vivo.
[0327] Exemplary microencapsulation materials useful for delaying
the release of the formulations including compounds described
herein, include, but are not limited to, hydroxypropyl cellulose
ethers (HPC) such as Klucel.RTM. or Nisso HPC, low-substituted
hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methyl
cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat.RTM.,
Metolose SR, Methocel.RTM.-E, Opadry YS, PrimaFlo, Benecel MP824,
and Benecel MP843, methylcellulose polymers such as
Methocel.RTM.-A, hydroxypropylmethylcellulose acetate stearate
Aqoat (HF-LS, HF-LG, HF-MS) and Metolose.RTM., Ethylcelluloses (EC)
and mixtures thereof such as E461, Ethocel.RTM., Aqualon.RTM.-EC,
Surelease.RTM., Polyvinyl alcohol (PVA) such as Opadry AMB,
hydroxyethylcelluloses such as Natrosol.RTM.,
carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC)
such as Aqualon.RTM.-CMC, polyvinyl alcohol and polyethylene glycol
co-polymers such as Kollicoat IR.RTM., monoglycerides (Myverol),
triglycerides (KLX), polyethylene glycols, modified food starch,
acrylic polymers and mixtures of acrylic polymers with cellulose
ethers such as Eudragit.RTM. EPO, Eudragit.RTM. L30D-55,
Eudragit.RTM. FS 30D Eudragit.RTM. L100-55, Eudragit.RTM. L100,
Eudragit.RTM. S100, Eudragit.RTM. RD100, Eudragit.RTM. E100,
Eudragit.RTM. L12.5, Eudragit.RTM. S12.5, Eudragit.RTM. NE30D, and
Eudragit.RTM. NE 40D, cellulose acetate phthalate, sepifilms such
as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures
of these materials.
[0328] In some embodiments, plasticizers such as polyethylene
glycols, e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and
PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin
are incorporated into the microencapsulation material. In some
embodiments, the microencapsulating material useful for delaying
the release of the pharmaceutical compositions is from the USP or
the National Formulary (NF). In some embodiments, the
microencapsulation material is Klucel. In some embodiments, the
microencapsulation material is methocel.
[0329] Microencapsulated compounds of any of Formula (I)-(Vb) may
be formulated by methods known by one of ordinary skill in the art.
Such known methods include, e.g., spray drying processes, spinning
disk-solvent processes, hot melt processes, spray chilling methods,
fluidized bed, electrostatic deposition, centrifugal extrusion,
rotational suspension separation, polymerization at liquid-gas or
solid-gas interface, pressure extrusion, or spraying solvent
extraction bath. In addition to these, several chemical techniques,
e.g., complex coacervation, solvent evaporation, polymer-polymer
incompatibility, interfacial polymerization in liquid media, in
situ polymerization, in-liquid drying, and desolvation in liquid
media could also be used. Furthermore, other methods such as roller
compaction, extrusion/spheronization, coacervation, or nanoparticle
coating may also be used.
[0330] In some embodiments, the particles of compounds of any of
Formula (I)-(Vb) are microencapsulated prior to being formulated
into one of the above forms. In still some embodiments, some or
most of the particles are coated prior to being further formulated
by using standard coating procedures, such as those described in
Remington's Pharmaceutical Sciences, 20th Edition (2000).
[0331] In some embodiments, the solid dosage formulations of the
compounds of any of Formula (I)-(Vb) are plasticized (coated) with
one or more layers. Illustratively, a plasticizer is generally a
high boiling point solid or liquid. Suitable plasticizers can be
added from about 0.01% to about 50% by weight (w/w) of the coating
composition. Plasticizers include, but are not limited to, diethyl
phthalate, citrate esters, polyethylene glycol, glycerol,
acetylated glycerides, triacetin, polypropylene glycol,
polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic
acid, stearol, stearate, and castor oil.
[0332] In some embodiments, a powder including the formulations
with a compound of any of Formula (I)-(Vb), described herein, may
be formulated to include one or more pharmaceutical excipients and
flavors. Such a powder may be prepared, for example, by mixing the
formulation and optional pharmaceutical excipients to form a bulk
blend composition. Additional embodiments also include a suspending
agent and/or a wetting agent. This bulk blend is uniformly
subdivided into unit dosage packaging or multi-dosage packaging
units.
[0333] In still some embodiments, effervescent powders are also
prepared in accordance with the present disclosure. Effervescent
salts have been used to disperse medicines in water for oral
administration. Effervescent salts are granules or coarse powders
containing a medicinal agent in a dry mixture, usually composed of
sodium bicarbonate, citric acid and/or tartaric acid. When salts of
the compositions described herein are added to water, the acids and
the base react to liberate carbon dioxide gas, thereby causing
"effervescence." Examples of effervescent salts include, e.g., the
following ingredients: sodium bicarbonate or a mixture of sodium
bicarbonate and sodium carbonate, citric acid and/or tartaric acid.
Any acid-base combination that results in the liberation of carbon
dioxide can be used in place of the combination of sodium
bicarbonate and citric and tartaric acids, as long as the
ingredients were suitable for pharmaceutical use and result in a pH
of about 6.0 or higher.
[0334] In some embodiments, the formulations described herein,
which include a compound of Formula (I), are solid dispersions.
Methods of producing such solid dispersions are known in the art
and include, but are not limited to, for example, U.S. Pat. Nos.
4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269, and U.S.
Pub. Appl 2004/0013734, each of which is specifically incorporated
by reference. In some embodiments, the formulations described
herein are solid solutions. Solid solutions incorporate a substance
together with the active agent and other excipients such that
heating the mixture results in dissolution of the drug and the
resulting composition is then cooled to provide a solid blend which
can be further formulated or directly added to a capsule or
compressed into a tablet. Methods of producing such solid solutions
are known in the art and include, but are not limited to, for
example, U.S. Pat. Nos. 4,151,273, 5,281,420, and 6,083,518, each
of which is specifically incorporated by reference.
[0335] The pharmaceutical solid oral dosage forms including
formulations described herein, which include a compound of any of
(I)-(Vb) can be further formulated to provide a controlled release
of the compound of Formula (I). Controlled release refers to the
release of the compound of any of Formula (I)-(Vb) from a dosage
form in which it is incorporated according to a desired profile
over an extended period of time. Controlled release profiles
include, for example, sustained release, prolonged release,
pulsatile release, and delayed release profiles. In contrast to
immediate release compositions, controlled release compositions
allow delivery of an agent to a subject over an extended period of
time according to a predetermined profile. Such release rates can
provide therapeutically effective levels of agent for an extended
period of time and thereby provide a longer period of pharmacologic
response while minimizing side effects as compared to conventional
rapid release dosage forms. Such longer periods of response provide
for many inherent benefits that are not achieved with the
corresponding short acting, immediate release preparations.
[0336] In some embodiments, the solid dosage forms described herein
can be formulated as enteric coated delayed release oral dosage
forms, i.e., as an oral dosage form of a pharmaceutical composition
as described herein which utilizes an enteric coating to affect
release in the small intestine of the gastrointestinal tract. The
enteric coated dosage form may be a compressed or molded or
extruded tablet/mold (coated or uncoated) containing granules,
powder, pellets, beads or particles of the active ingredient and/or
other composition components, which are themselves coated or
uncoated. The enteric coated oral dosage form may also be a capsule
(coated or uncoated) containing pellets, beads or granules of the
solid carrier or the composition, which are themselves coated or
uncoated.
[0337] The term "delayed release" as used herein refers to the
delivery so that the release can be accomplished at some generally
predictable location in the intestinal tract more distal to that
which would have been accomplished if there had been no delayed
release alterations. In some embodiments the method for delay of
release is coating. Any coatings should be applied to a sufficient
thickness such that the entire coating does not dissolve in the
gastrointestinal fluids at pH below about 5, but does dissolve at
pH about 5 and above. It is expected that any anionic polymer
exhibiting a pH-dependent solubility profile can be used as an
enteric coating in the methods and compositions described herein to
achieve delivery to the lower gastrointestinal tract. In some
embodiments the polymers described herein are anionic carboxylic
polymers. In some embodiments, the polymers and compatible mixtures
thereof, and some of their properties, include, but are not limited
to:
[0338] Shellac, also called purified lac, a refined product
obtained from the resinous secretion of an insect. This coating
dissolves in media of pH>7;
[0339] Acrylic polymers. The performance of acrylic polymers
(primarily their solubility in biological fluids) can vary based on
the degree and type of substitution. Examples of suitable acrylic
polymers include methacrylic acid copolymers and ammonium
methacrylate copolymers. The Eudragit series E, L, S, RL, RS and NE
(Rohm Pharma) are available as solubilized in organic solvent,
aqueous dispersion, or dry powders. The Eudragit series RL, NE, and
RS are insoluble in the gastrointestinal tract but are permeable
and are used primarily for colonic targeting. The Eudragit series E
dissolve in the stomach. The Eudragit series L, L-30D and S are
insoluble in stomach and dissolve in the intestine;
[0340] Cellulose Derivatives. Examples of suitable cellulose
derivatives are: ethyl cellulose; reaction mixtures of partial
acetate esters of cellulose with phthalic anhydride. The
performance can vary based on the degree and type of substitution.
Cellulose acetate phthalate (CAP) dissolves in pH>6. Aquateric
(FMC) is an aqueous based system and is a spray dried CAP
pseudolatex with particles <1 .mu.m. Other components in
Aquateric can include pluronics, Tweens, and acetylated
monoglycerides. Other suitable cellulose derivatives include:
cellulose acetate trimellitate (Eastman); methylcellulose
(Pharmacoat, Methocel); hydroxypropylmethyl cellulose phthalate
(HPMCP); hydroxypropylmethyl cellulose succinate (HPMCS); and
hydroxypropylmethylcellulose acetate succinate (e.g., AQOAT (Shin
Etsu)). The performance can vary based on the degree and type of
substitution. For example, HPMCP such as, HP-50, HP-55, HP-55S,
HP-55F grades are suitable. The performance can vary based on the
degree and type of substitution. For example, suitable grades of
hydroxypropylmethylcellulose acetate succinate include, but are not
limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF), which
dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH.
These polymers are offered as granules, or as fine powders for
aqueous dispersions;
[0341] Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves in
pH>5, and it is much less permeable to water vapor and gastric
fluids.
[0342] In some embodiments, the coating can, and usually does,
contain a plasticizer and possibly other coating excipients such as
colorants, talc, and/or magnesium stearate, which are well known in
the art. Suitable plasticizers include triethyl citrate (Citroflex
2), triacetin (glyceryl triacetate), acetyl triethyl citrate
(Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl
phthalate, tributyl citrate, acetylated monoglycerides, glycerol,
fatty acid esters, propylene glycol, and dibutyl phthalate. In
particular, anionic carboxylic acrylic polymers usually will
contain 10-25% by weight of a plasticizer, especially dibutyl
phthalate, polyethylene glycol, triethyl citrate and triacetin.
Conventional coating techniques such as spray or pan coating are
employed to apply coatings. The coating thickness must be
sufficient to ensure that the oral dosage form remains intact until
the desired site of topical delivery in the intestinal tract is
reached.
[0343] Colorants, detackifiers, surfactants, antifoaming agents,
lubricants (e.g., carnuba wax or PEG) may be added to the coatings
besides plasticizers to solubilize or disperse the coating
material, and to improve coating performance and the coated
product.
[0344] In some embodiments, the formulations described herein,
which include a compound of Formula (I), are delivered using a
pulsatile dosage form. A pulsatile dosage form is capable of
providing one or more immediate release pulses at predetermined
time points after a controlled lag time or at specific sites.
Pulsatile dosage forms including the formulations described herein,
which include a compound of any of Formula (I)-(Vb) may be
administered using a variety of pulsatile formulations known in the
art. For example, such formulations include, but are not limited
to, those described in U.S. Pat. Nos. 5,011,692, 5,017,381,
5,229,135, and 5,840,329, each of which is specifically
incorporated by reference. Other pulsatile release dosage forms
suitable for use with the present formulations include, but are not
limited to, for example, U.S. Pat. Nos. 4,871,549, 5,260,068,
5,260,069, 5,508,040, 5,567,441 and 5,837,284, all of which are
specifically incorporated by reference. In some embodiments, the
controlled release dosage form is pulsatile release solid oral
dosage form including at least two groups of particles, (i.e.
multiparticulate) each containing the formulation described herein.
The first group of particles provides a substantially immediate
dose of the compound of any of (I)-(Vb) upon ingestion by a mammal.
The first group of particles can be either uncoated or include a
coating and/or sealant. The second group of particles includes
coated particles, which includes from about 2% to about 75%, from
about 2.5% to about 70%, or from about 40% to about 70%, by weight
of the total dose of the compound of any of Formula (I)-(Vb) in
said formulation, in admixture with one or more binders. The
coating includes a pharmaceutically acceptable ingredient in an
amount sufficient to provide a delay of from about 2 hours to about
7 hours following ingestion before release of the second dose.
Suitable coatings include one or more differentially degradable
coatings such as, by way of example only, pH sensitive coatings
(enteric coatings) such as acrylic resins (e.g., Eudragit.RTM. EPO,
Eudragit.RTM. L30D-55, Eudragit.RTM. FS 30D Eudragit.RTM. L100-55,
Eudragit.RTM. L100, Eudragit.RTM. S100, Eudragit.RTM. RD100,
Eudragit.RTM. E100, Eudragit.RTM. L12.5, Eudragit.RTM. S12.5, and
Eudragit.RTM. NE30D, Eudragit.RTM. NE 40D.RTM.) either alone or
blended with cellulose derivatives, e.g., ethylcellulose, or
non-enteric coatings having variable thickness to provide
differential release of the formulation that includes a compound of
any of Formula (I).
[0345] Many other types of controlled release systems known to
those of ordinary skill in the art and are suitable for use with
the formulations described herein. Examples of such delivery
systems include, e.g., polymer-based systems, such as polylactic
and polyglycolic acid, plyanhydrides and polycaprolactone; porous
matrices, nonpolymer-based systems that are lipids, including
sterols, such as cholesterol, cholesterol esters and fatty acids,
or neutral fats, such as mono-, di- and triglycerides; hydrogel
release systems; silastic systems; peptide-based systems; wax
coatings, bioerodible dosage forms, compressed tablets using
conventional binders and the like. See, e.g., Liberman et al.,
Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990);
Singh et al., Encyclopedia of Pharmaceutical Technology, 2.sup.nd
Ed., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848,
4,968,509, 5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105,
5,700,410, 5,977,175, 6,465,014 and 6,932,983, each of which is
specifically incorporated by reference.
[0346] In some embodiments, pharmaceutical compositions are
provided that include particles of the compounds of any of Formula
(I)-(Vb), described herein and at least one dispersing agent or
suspending agent for oral administration to a subject. The
formulations may be a powder and/or granules for suspension, and
upon admixture with water, a substantially uniform suspension is
obtained.
[0347] Liquid formulation dosage forms for oral administration can
be aqueous suspensions selected from the group including, but not
limited to, pharmaceutically acceptable aqueous oral dispersions,
emulsions, solutions, elixirs, gels, and syrups. See, e.g., Singh
et al., Encyclopedia of Pharmaceutical Technology, 2.sup.nd Ed.,
pp. 754-757 (2002). In addition to the particles of compound of
Formula (A), the liquid dosage forms may include additives, such
as: (a) disintegrating agents; (b) dispersing agents; (c) wetting
agents; (d) at least one preservative, (e) viscosity enhancing
agents, (f) at least one sweetening agent, and (g) at least one
flavoring agent. In some embodiments, the aqueous dispersions can
further include a crystalline inhibitor.
[0348] The aqueous suspensions and dispersions described herein can
remain in a homogenous state, as defined in The USP Pharmacists'
Pharmacopeia (2005 edition, chapter 905), for at least 4 hours. The
homogeneity should be determined by a sampling method consistent
with regard to determining homogeneity of the entire composition.
In some embodiments, an aqueous suspension can be re-suspended into
a homogenous suspension by physical agitation lasting less than 1
minute. In some embodiments, an aqueous suspension can be
re-suspended into a homogenous suspension by physical agitation
lasting less than 45 seconds. In yet some embodiments, an aqueous
suspension can be re-suspended into a homogenous suspension by
physical agitation lasting less than 30 seconds. In still some
embodiments, no agitation is necessary to maintain a homogeneous
aqueous dispersion.
[0349] Examples of disintegrating agents for use in the aqueous
suspensions and dispersions include, but are not limited to, a
starch, e.g., a natural starch such as corn starch or potato
starch, a pregelatinized starch such as National 1551 or
Amijel.RTM., or sodium starch glycolate such as Promogel.RTM. or
Explotab.RTM.; a cellulose such as a wood product,
methylcrystalline cellulose, e.g., Avicel.RTM., Avicel.RTM. PH101,
Avicel.RTM. PH102, Avicel.RTM. PH105, Elcema.RTM. P100,
Emcocel.RTM., Vivacel.RTM., Ming Tia.RTM., and Solka-Floc.RTM.,
methylcellulose, croscarmellose, or a cross-linked cellulose, such
as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol.RTM.),
cross-linked carboxymethylcellulose, or cross-linked
croscarmellose; a cross-linked starch such as sodium starch
glycolate; a cross-linked polymer such as crospovidone; a
cross-linked polyvinylpyrrolidone; alginate such as alginic acid or
a salt of alginic acid such as sodium alginate; a clay such as
Veegum.RTM. HV (magnesium aluminum silicate); a gum such as agar,
guar, locust bean, Karaya, pectin, or tragacanth; sodium starch
glycolate; bentonite; a natural sponge; a surfactant; a resin such
as a cation-exchange resin; citrus pulp; sodium lauryl sulfate;
sodium lauryl sulfate in combination starch; and the like.
[0350] In some embodiments, the dispersing agents suitable for the
aqueous suspensions and dispersions described herein are known in
the art and include, for example, hydrophilic polymers,
electrolytes, Tween.RTM. 60 or 80, PEG, polyvinylpyrrolidone (PVP;
commercially known as Plasdone.RTM.), and the carbohydrate-based
dispersing agents such as, for example, hydroxypropylcellulose and
hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L),
hydroxypropyl methylcellulose and hydroxypropyl methylcellulose
ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M),
carboxymethylcellulose sodium, methylcellulose,
hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate,
hydroxypropylmethyl-cellulose acetate stearate, noncrystalline
cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl
alcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer
(Plasdone.RTM., e.g., S-630), 4-(1,1,3,3-tetramethylbutyl)-phenol
polymer with ethylene oxide and formaldehyde (also known as
tyloxapol), poloxamers (e.g., Pluronics F68.RTM., F88.RTM., and
F108.RTM., which are block copolymers of ethylene oxide and
propylene oxide); and poloxamines (e.g., Tetronic 908.RTM., also
known as Poloxamine 908.RTM., which is a tetrafunctional block
copolymer derived from sequential addition of propylene oxide and
ethylene oxide to ethylenediamine (BASF Corporation, Parsippany,
N.J.)). In some embodiments, the dispersing agent is selected from
a group not comprising one of the following agents: hydrophilic
polymers; electrolytes; Tween.RTM. 60 or 80; PEG;
polyvinylpyrrolidone (PVP); hydroxypropylcellulose and
hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L);
hydroxypropyl methylcellulose and hydroxypropyl methylcellulose
ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and
Pharmacoat.RTM. USP 2910 (Shin-Etsu)); carboxymethylcellulose
sodium; methylcellulose; hydroxyethylcellulose;
hydroxypropylmethyl-cellulose phthalate;
hydroxypropylmethyl-cellulose acetate stearate; non-crystalline
cellulose; magnesium aluminum silicate; triethanolamine; polyvinyl
alcohol (PVA); 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with
ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics
F68.RTM., F88.RTM., and F108.RTM., which are block copolymers of
ethylene oxide and propylene oxide); or poloxamines (e.g., Tetronic
908.RTM., also known as Poloxamine 908.RTM.).
[0351] Wetting agents suitable for the aqueous suspensions and
dispersions described herein are known in the art and include, but
are not limited to, cetyl alcohol, glycerol monostearate,
polyoxyethylene sorbitan fatty acid esters (e.g., the commercially
available Tweens.RTM. such as e.g., Tween 20.RTM. and Tween 80.RTM.
(ICI Specialty Chemicals)), and polyethylene glycols (e.g.,
Carbowaxs 3350.RTM. and 1450.RTM., and Carbopol 934.RTM. (Union
Carbide)), oleic acid, glyceryl monostearate, sorbitan monooleate,
sorbitan monolaurate, triethanolamine oleate, polyoxyethylene
sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium
oleate, sodium lauryl sulfate, sodium docusate, triacetin, vitamin
E TPGS, sodium taurocholate, simethicone, phosphotidylcholine and
the like
[0352] Suitable preservatives for the aqueous suspensions or
dispersions described herein include, for example, potassium
sorbate, parabens (e.g., methylparaben and propylparaben), benzoic
acid and its salts, other esters of parahydroxybenzoic acid such as
butylparaben, alcohols such as ethyl alcohol or benzyl alcohol,
phenolic compounds such as phenol, or quaternary compounds such as
benzalkonium chloride. Preservatives, as used herein, are
incorporated into the dosage form at a concentration sufficient to
inhibit microbial growth.
[0353] Suitable viscosity enhancing agents for the aqueous
suspensions or dispersions described herein include, but are not
limited to, methyl cellulose, xanthan gum, carboxymethyl cellulose,
hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
Plasdon.RTM. S-630, carbomer, polyvinyl alcohol, alginates, acacia,
chitosans and combinations thereof. The concentration of the
viscosity enhancing agent will depend upon the agent selected and
the viscosity desired.
[0354] Examples of sweetening agents suitable for the aqueous
suspensions or dispersions described herein include, for example,
acacia syrup, acesulfame K, alitame, anise, apple, aspartame,
banana, Bavarian cream, berry, black currant, butterscotch, calcium
citrate, camphor, caramel, cherry, cherry cream, chocolate,
cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton
candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate,
dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger,
glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit,
honey, isomalt, lemon, lime, lemon cream, monoammonium
glyrrhizinate (MagnaSweet*), maltol, mannitol, maple, marshmallow,
menthol, mint cream, mixed berry, neohesperidine DC, neotame,
orange, pear, peach, peppermint, peppermint cream, Prosweet.RTM.
Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol,
spearmint, spearmint cream, strawberry, strawberry cream, stevia,
sucralose, sucrose, sodium saccharin, saccharin, aspartame,
acesulfame potassium, mannitol, talin, sucralose, sorbitol, swiss
cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla,
walnut, watermelon, wild cherry, wintergreen, xylitol, or any
combination of these flavoring ingredients, e.g., anise-menthol,
cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint,
honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus,
orange-cream, vanilla-mint, and mixtures thereof. In some
embodiments, the aqueous liquid dispersion can comprise a
sweetening agent or flavoring agent in a concentration ranging from
about 0.001% to about 1.0% the volume of the aqueous dispersion. In
some embodiments, the aqueous liquid dispersion can comprise a
sweetening agent or flavoring agent in a concentration ranging from
about 0.005% to about 0.5% the volume of the aqueous dispersion. In
yet some embodiments, the aqueous liquid dispersion can comprise a
sweetening agent or flavoring agent in a concentration ranging from
about 0.010% to about 1.0% the volume of the aqueous
dispersion.
[0355] In addition to the additives listed above, the liquid
formulations can also include inert diluents commonly used in the
art, such as water or other solvents, solubilizing agents, and
emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl
alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl
benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide,
sodium lauryl sulfate, sodium doccusate, cholesterol, cholesterol
esters, taurocholic acid, phosphotidylcholine, oils, such as
cottonseed oil, groundnut oil, corn germ oil, olive oil, castor
oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol,
polyethylene glycols, fatty acid esters of sorbitan, or mixtures of
these substances, and the like.
[0356] In some embodiments, the pharmaceutical compositions
described herein can be self-emulsifying drug delivery systems
(SEDDS). Emulsions are dispersions of one immiscible phase in
another, usually in the form of droplets. Generally, emulsions are
created by vigorous mechanical dispersion. SEDDS, as opposed to
emulsions or microemulsions, spontaneously form emulsions when
added to an excess of water without any external mechanical
dispersion or agitation. An advantage of SEDDS is that only gentle
mixing is required to distribute the droplets throughout the
solution. Additionally, water or the aqueous phase can be added
just prior to administration, which ensures stability of an
unstable or hydrophobic active ingredient. Thus, the SEDDS provides
an effective delivery system for oral and parenteral delivery of
hydrophobic active ingredients. SEDDS may provide improvements in
the bioavailability of hydrophobic active ingredients. Methods of
producing self-emulsifying dosage forms are known in the art and
include, but are not limited to, for example, U.S. Pat. Nos.
5,858,401, 6,667,048, and 6,960,563, each of which is specifically
incorporated by reference.
[0357] It is to be appreciated that there is overlap between the
above-listed additives used in the aqueous dispersions or
suspensions described herein, since a given additive is often
classified differently by different practitioners in the field, or
is commonly used for any of several different functions. Thus, the
above-listed additives should be taken as merely exemplary, and not
limiting, of the types of additives that can be included in
formulations described herein. The amounts of such additives can be
readily determined by one skilled in the art, according to the
particular properties desired.
Intranasal Formulations
[0358] Intranasal formulations are known in the art and are
described in, for example, U.S. Pat. Nos. 4,476,116, 5,116,817 and
6,391,452, each of which is specifically incorporated by reference.
Formulations that include a compound of any of Formula (I)-(Vb)
which are prepared according to these and other techniques
well-known in the art are prepared as solutions in saline,
employing benzyl alcohol or other suitable preservatives,
fluorocarbons, and/or other solubilizing or dispersing agents known
in the art. See, for example, Ansel, H. C. et al., Pharmaceutical
Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995).
Preferably these compositions and formulations are prepared with
suitable nontoxic pharmaceutically acceptable ingredients. These
ingredients are known to those skilled in the preparation of nasal
dosage forms and some of these can be found in REMINGTON: THE
SCIENCE AND PRACTICE OF PHARMACY, 21st edition, 2005, a standard
reference in the field. The choice of suitable carriers is highly
dependent upon the exact nature of the nasal dosage form desired,
e.g., solutions, suspensions, ointments, or gels. Nasal dosage
forms generally contain large amounts of water in addition to the
active ingredient. Minor amounts of other ingredients such as pH
adjusters, emulsifiers or dispersing agents, preservatives,
surfactants, gelling agents, or buffering and other stabilizing and
solubilizing agents may also be present. The nasal dosage form
should be isotonic with nasal secretions.
[0359] For administration by inhalation, the compounds of any of
Formula (I)-(Vb), described herein may be in a form as an aerosol,
a mist or a powder. Pharmaceutical compositions described herein
are conveniently delivered in the form of an aerosol spray
presentation from pressurized packs or a nebuliser, with the use of
a suitable propellant, e.g., dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide
or other suitable gas. In the case of a pressurized aerosol, the
dosage unit may be determined by providing a valve to deliver a
metered amount. Capsules and cartridges of, such as, by way of
example only, gelatin for use in an inhaler or insufflator may be
formulated containing a powder mix of the compound described herein
and a suitable powder base such as lactose or starch.
Buccal Formulations
[0360] Buccal formulations that include compounds of any of Formula
(I)-(Vb) may be administered using a variety of formulations known
in the art. For example, such formulations include, but are not
limited to, U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and
5,739,136, each of which is specifically incorporated by reference.
In addition, the buccal dosage forms described herein can further
include a bioerodible (hydrolysable) polymeric carrier that also
serves to adhere the dosage form to the buccal mucosa. The buccal
dosage form is fabricated so as to erode gradually over a
predetermined time period, wherein the delivery of the compound of
any of Formula (I)-(Vb), is provided essentially throughout. Buccal
drug delivery, as will be appreciated by those skilled in the art,
avoids the disadvantages encountered with oral drug administration,
e.g., slow absorption, degradation of the active agent by fluids
present in the gastrointestinal tract and/or first-pass
inactivation in the liver. With regard to the bioerodible
(hydrolysable) polymeric carrier, it will be appreciated that
virtually any such carrier can be used, so long as the desired drug
release profile is not compromised, and the carrier is compatible
with the compound of any of Formula (I)-(Vb), and any other
components that may be present in the buccal dosage unit.
Generally, the polymeric carrier comprises hydrophilic
(water-soluble and water-swellable) polymers that adhere to the wet
surface of the buccal mucosa. Examples of polymeric carriers useful
herein include acrylic acid polymers and co, e.g., those known as
"carbomers" (Carbopol.RTM., which may be obtained from B.F.
Goodrich, is one such polymer). Other components may also be
incorporated into the buccal dosage forms described herein include,
but are not limited to, disintegrants, diluents, binders,
lubricants, flavoring, colorants, preservatives, and the like. For
buccal or sublingual administration, the compositions may take the
form of tablets, lozenges, or gels formulated in a conventional
manner.
Transdermal Formulations
[0361] Transdermal formulations described herein may be
administered using a variety of devices which have been described
in the art. For example, such devices include, but are not limited
to, U.S. Pat. Nos. 3,598,122, 3,598,123, 3,710,795, 3,731,683,
3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073,
3,996,934, 4,031,894, 4,060,084, 4,069,307, 4,077,407, 4,201,211,
4,230,105, 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280,
5,869,090, 6,923,983, 6,929,801 and 6,946,144, each of which is
specifically incorporated by reference in its entirety.
[0362] The transdermal dosage forms described herein may
incorporate certain pharmaceutically acceptable excipients which
are conventional in the art. In some embodiments, the transdermal
formulations described herein include at least three components:
(1) a formulation of a compound of any of Formula (I); (2) a
penetration enhancer; and (3) an aqueous adjuvant. In addition,
transdermal formulations can include additional components such as,
but not limited to, gelling agents, creams and ointment bases, and
the like. In some embodiments, the transdermal formulation can
further include a woven or non-woven backing material to enhance
absorption and prevent the removal of the transdermal formulation
from the skin. In some embodiments, the transdermal formulations
described herein can maintain a saturated or supersaturated state
to promote diffusion into the skin.
[0363] Formulations suitable for transdermal administration of
compounds described herein may employ transdermal delivery devices
and transdermal delivery patches and can be lipophilic emulsions or
buffered, aqueous solutions, dissolved and/or dispersed in a
polymer or an adhesive. Such patches may be constructed for
continuous, pulsatile, or on demand delivery of pharmaceutical
agents. Still further, transdermal delivery of the compounds
described herein can be accomplished by means of iontophoretic
patches and the like. Additionally, transdermal patches can provide
controlled delivery of the compounds of any of Formula (I)-(Vb).
The rate of absorption can be slowed by using rate-controlling
membranes or by trapping the compound within a polymer matrix or
gel. Conversely, absorption enhancers can be used to increase
absorption. An absorption enhancer or carrier can include
absorbable pharmaceutically acceptable solvents to assist passage
through the skin. For example, transdermal devices are in the form
of a bandage comprising a backing member, a reservoir containing
the compound optionally with carriers, optionally a rate
controlling barrier to deliver the compound to the skin of the host
at a controlled and predetermined rate over a prolonged period of
time, and means to secure the device to the skin.
Injectable Formulations
[0364] Formulations that include a compound of any of Formula
(I)-(Vb), suitable for intramuscular, subcutaneous, or intravenous
injection may include physiologically acceptable sterile aqueous or
non-aqueous solutions, dispersions, suspensions or emulsions, and
sterile powders for reconstitution into sterile injectable
solutions or dispersions. Examples of suitable aqueous and
non-aqueous carriers, diluents, solvents, or vehicles including
water, ethanol, polyols (propyleneglycol, polyethylene-glycol,
glycerol, cremophor and the like), suitable mixtures thereof,
vegetable oils (such as olive oil) and injectable organic esters
such as ethyl oleate. Proper fluidity can be maintained, for
example, by the use of a coating such as lecithin, by the
maintenance of the required particle size in the case of
dispersions, and by the use of surfactants. Formulations suitable
for subcutaneous injection may also contain additives such as
preserving, wetting, emulsifying, and dispensing agents. Prevention
of the growth of microorganisms can be ensured by various
antibacterial and antifungal agents, such as parabens,
chlorobutanol, phenol, sorbic acid, and the like. It may also be
desirable to include isotonic agents, such as sugars, sodium
chloride, and the like. Prolonged absorption of the injectable
pharmaceutical form can be brought about by the use of agents
delaying absorption, such as aluminum monostearate and gelatin.
[0365] For intravenous injections, compounds described herein may
be formulated in aqueous solutions, preferably in physiologically
compatible buffers such as Hank's solution, Ringer's solution, or
physiological saline buffer. For transmucosal administration,
penetrants appropriate to the barrier to be permeated are used in
the formulation. Such penetrants are generally known in the art.
For other parenteral injections, appropriate formulations may
include aqueous or nonaqueous solutions, preferably with
physiologically compatible buffers or excipients. Such excipients
are generally known in the art.
[0366] Parenteral injections may involve bolus injection or
continuous infusion. Formulations for injection may be presented in
unit dosage form, e.g., in ampoules or in multi-dose containers,
with an added preservative. The pharmaceutical composition
described herein may be in a form suitable for parenteral injection
as a sterile suspensions, solutions or emulsions in oily or aqueous
vehicles, and may contain formulatory agents such as suspending,
stabilizing and/or dispersing agents. Pharmaceutical compositions
for parenteral administration include aqueous solutions of the
active compounds in water-soluble form. Additionally, suspensions
of the active compounds may be prepared as appropriate oily
injection suspensions. Suitable lipophilic solvents or vehicles
include fatty oils such as sesame oil, or synthetic fatty acid
esters, such as ethyl oleate or triglycerides, or liposomes.
Aqueous injection suspensions may contain substances which increase
the viscosity of the suspension, such as sodium carboxymethyl
cellulose, sorbitol, or dextran. Optionally, the suspension may
also contain suitable stabilizers or agents which increase the
solubility of the compounds to allow for the preparation of highly
concentrated solutions. Alternatively, the active ingredient may be
in powder form for constitution with a suitable vehicle, e.g.,
sterile pyrogen-free water, before use.
Formulations
[0367] In certain embodiments, delivery systems for pharmaceutical
compounds may be employed, such as, for example, liposomes and
emulsions. In certain embodiments, compositions provided herein can
also include an mucoadhesive polymer, selected from among, for
example, carboxymethylcellulose, carbomer (acrylic acid polymer),
poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic
acid/butyl acrylate copolymer, sodium alginate and dextran.
[0368] In some embodiments, the compounds described herein may be
administered topically and can be formulated into a variety of
topically administrable compositions, such as solutions,
suspensions, lotions, gels, pastes, medicated sticks, balms, creams
or ointments. Such pharmaceutical compounds can contain
solubilizers, stabilizers, tonicity enhancing agents, buffers and
preservatives.
[0369] The compounds described herein may also be formulated in
rectal compositions such as enemas, rectal gels, rectal foams,
rectal aerosols, suppositories, jelly suppositories, or retention
enemas, containing conventional suppository bases such as cocoa
butter or other glycerides, as well as synthetic polymers such as
polyvinylpyrrolidone, PEG, and the like. In suppository forms of
the compositions, a low-melting wax such as, but not limited to, a
mixture of fatty acid glycerides, optionally in combination with
cocoa butter is first melted.
Examples of Methods of Dosing and Treatment Regimens
[0370] The compounds described herein can be used in the
preparation of medicaments for the treatment of diseases or
conditions related to kidney. In addition, a method for treating
any of the diseases or conditions described herein in a subject in
need of such treatment, involves administration of pharmaceutical
compositions containing at least one compound of any of Formula
(I)-(Vb), described herein, or a pharmaceutically acceptable salt,
pharmaceutically acceptable N-oxide, pharmaceutically active
metabolite, pharmaceutically acceptable prodrug, or
pharmaceutically acceptable solvate thereof, in therapeutically
effective amounts to said subject.
[0371] The compositions containing the compound(s) described herein
can be administered for prophylactic and/or therapeutic treatments.
In therapeutic applications, the compositions are administered to a
patient already suffering from a disease or condition, in an amount
sufficient to cure or at least partially arrest the symptoms of the
disease or condition. Amounts effective for this use will depend on
the severity and course of the disease or condition, previous
therapy, the patient's health status, weight, and response to the
drugs, and the judgment of the treating physician. It is considered
well within the skill of the art for one to determine such
therapeutically effective amounts by routine experimentation
(including, but not limited to, a dose escalation clinical
trial).
[0372] In prophylactic applications, compositions containing the
compounds described herein are administered to a patient
susceptible to or otherwise at risk of a particular disease,
disorder or condition. Such an amount is defined to be a
"prophylactically effective amount or dose." In this use, the
precise amounts also depend on the patient's state of health,
weight, and the like. It is considered well within the skill of the
art for one to determine such prophylactically effective amounts by
routine experimentation (e.g., a dose escalation clinical trial).
When used in a patient, effective amounts for this use will depend
on the severity and course of the disease, disorder or condition,
previous therapy, the patient's health status and response to the
drugs, and the judgment of the treating physician.
[0373] In the case wherein the patient's condition does not
improve, upon the doctor's discretion the administration of the
compounds may be administered chronically, that is, for an extended
period of time, including throughout the duration of the patient's
life in order to ameliorate or otherwise control or limit the
symptoms of the patient's disease or condition.
[0374] In the case wherein the patient's status does improve, upon
the doctor's discretion the administration of the compounds may be
given continuously; alternatively, the dose of drug being
administered may be temporarily reduced or temporarily suspended
for a certain length of time (i.e., a "drug holiday"). The length
of the drug holiday can vary between 2 days and 1 year, including
by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7
days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50
days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days,
250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The
dose reduction during a drug holiday may be from 10%-100%,
including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%,
40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or
100%.
[0375] Once improvement of the patient's conditions has occurred, a
maintenance dose is administered if necessary. Subsequently, the
dosage or the frequency of administration, or both, can be reduced,
as a function of the symptoms, to a level at which the improved
disease, disorder or condition is retained. Patients can, however,
require intermittent treatment on a long-term basis upon any
recurrence of symptoms.
[0376] The amount of a given agent that will correspond to such an
amount will vary depending upon factors such as the particular
compound, disease or condition and its severity, the identity
(e.g., weight) of the subject or host in need of treatment, but can
nevertheless be routinely determined in a manner known in the art
according to the particular circumstances surrounding the case,
including, e.g., the specific agent being administered, the route
of administration, the condition being treated, and the subject or
host being treated. The desired dose may conveniently be presented
in a single dose or as divided doses administered simultaneously
(or over a short period of time) or at appropriate intervals, for
example as two, three, four or more sub-doses per day.
[0377] The pharmaceutical composition described herein may be in
unit dosage forms suitable for single administration of precise
dosages. In unit dosage form, the formulation is divided into unit
doses containing appropriate quantities of one or more compound.
The unit dosage may be in the form of a package containing discrete
quantities of the formulation. Non-limiting examples are packaged
tablets or capsules, and powders in vials or ampoules. Aqueous
suspension compositions can be packaged in single-dose
non-reclosable containers. Alternatively, multiple-dose reclosable
containers can be used, in which case it is typical to include a
preservative in the composition. By way of example only,
formulations for parenteral injection may be presented in unit
dosage form, which include, but are not limited to ampoules, or in
multi-dose containers, with an added preservative.
[0378] The foregoing ranges are merely suggestive, as the number of
variables in regard to an individual treatment regime is large, and
considerable excursions from these recommended values are not
uncommon. Such dosages may be altered depending on a number of
variables, not limited to the activity of the compound used, the
disease or condition to be treated, the mode of administration, the
requirements of the individual subject, the severity of the disease
or condition being treated, and the judgment of the
practitioner.
[0379] Toxicity and therapeutic efficacy of such therapeutic
regimens can be determined by standard pharmaceutical procedures in
cell cultures or experimental animals, including, but not limited
to, the determination of the LD.sub.50 (the dose lethal to 50% of
the population) and the ED.sub.50 (the dose therapeutically
effective in 50% of the population). The dose ratio between the
toxic and therapeutic effects is the therapeutic index and it can
be expressed as the ratio between LD.sub.50 and ED.sub.50.
Compounds exhibiting high therapeutic indices are preferred. The
data obtained from cell culture assays and animal studies can be
used in formulating a range of dosage for use in human. The dosage
of such compounds lies preferably within a range of circulating
concentrations that include the ED.sub.50 with minimal toxicity.
The dosage may vary within this range depending upon the dosage
form employed and the route of administration utilized.
Kits/Articles of Manufacture
[0380] For use in the therapeutic applications described herein,
kits and articles of manufacture are also described herein. Such
kits can include a carrier, package, or container that is
compartmentalized to receive one or more containers such as vials,
tubes, and the like, each of the container(s) including one of the
separate elements to be used in a method described herein. Suitable
containers include, for example, bottles, vials, syringes, and test
tubes. The containers can be formed from a variety of materials
such as glass or plastic.
[0381] The articles of manufacture provided herein contain
packaging materials. Packaging materials for use in packaging
pharmaceutical products are well known to those of skill in the
art. See, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252.
Examples of pharmaceutical packaging materials include, but are not
limited to, blister packs, bottles, tubes, inhalers, pumps, bags,
vials, containers, syringes, bottles, and any packaging material
suitable for a selected formulation and intended mode of
administration and treatment. A wide array of formulations of the
compounds and compositions provided herein are contemplated as are
a variety of treatments for any disease, disorder, or condition
that would benefit by using the compounds of the invention.
[0382] For example, the container(s) can include one or more
compounds described herein, optionally in a composition or in
combination with another agent as disclosed herein. The
container(s) optionally have a sterile access port (for example the
container can be an intravenous solution bag or a vial having a
stopper pierceable by a hypodermic injection needle). Such kits
optionally comprising a compound with an identifying description or
label or instructions relating to its use in the methods described
herein.
[0383] A kit typically may include one or more additional
containers, each with one or more of various materials (such as
reagents, optionally in concentrated form, and/or devices)
desirable from a commercial and user standpoint for use of a
compound described herein. Non-limiting examples of such materials
include, but not limited to, buffers, diluents, filters, needles,
syringes; carrier, package, container, vial and/or tube labels
listing contents and/or instructions for use, and package inserts
with instructions for use. A set of instructions will also
typically be included.
[0384] A label can be on or associated with the container. A label
can be on a container when letters, numbers or other characters
forming the label are attached, molded or etched into the container
itself; a label can be associated with a container when it is
present within a receptacle or carrier that also holds the
container, e.g., as a package insert. A label can be used to
indicate that the contents are to be used for a specific
therapeutic application. The label can also indicate directions for
use of the contents, such as in the methods described herein.
[0385] In certain embodiments, the pharmaceutical compositions can
be presented in a pack or dispenser device which can contain one or
more unit dosage forms containing a compound provided herein. The
pack can for example contain metal or plastic foil, such as a
blister pack. The pack or dispenser device can be accompanied by
instructions for administration. The pack or dispenser can also be
accompanied with a notice associated with the container in form
prescribed by a governmental agency regulating the manufacture,
use, or sale of pharmaceuticals, which notice is reflective of
approval by the agency of the form of the drug for human or
veterinary administration. Such notice, for example, can be the
labeling approved by the U.S. Food and Drug Administration for
prescription drugs, or the approved product insert. Compositions
containing a compound provided herein formulated in a compatible
pharmaceutical carrier can also be prepared, placed in an
appropriate container, and labeled for treatment of an indicated
condition.
EXAMPLES
[0386] The following specific and non-limiting examples are to be
construed as merely illustrative, and do not limit the present
disclosure in any way whatsoever. Without further elaboration, it
is believed that one skilled in the art can, based on the
description herein, utilize the present disclosure to its fullest
extent. All publications cited herein are hereby incorporated by
reference in their entirety. Where reference is made to a URL or
other such identifier or address, it is understood that such
identifiers can change and particular information on the internet
can come and go, but equivalent information can be found by
searching the internet. Reference thereto evidences the
availability and public dissemination of such information.
[0387] The examples below as well as throughout the application,
the following abbreviations have the following meanings. If not
defined, the terms have their generally accepted meanings. [0388]
aq=aqueous [0389] Boc=tert-butyloxycarbonyl [0390] t-BuOH=tertiary
butanol [0391] DCE=1,2-dichloroethane [0392] DCM=dichloromethane
[0393] DIAD=diisopropyl azodicarboxylate [0394] DIEA or
DIPEA=N,N-diisopropylethylamine [0395] DMAP=dimethylaminopyridine
[0396] DMF=dimethylformamide [0397] DMSO=dimethylsulfoxide [0398]
ESI=electron spray ionization [0399] EA=ethyl acetate [0400] g=gram
[0401] HCl=hydrogen chloride [0402] HPLC=high performance liquid
chromatography [0403] hr=hour [0404] .sup.1H NMR=proton nuclear
magnetic resonance [0405] IPA=isopropyl alcohol [0406]
KOAc=potassium acetate [0407] LC-MS=liquid chromatography mass
spectroscopy [0408] M=molar [0409] MeCN=acetonitrile [0410]
MeOH=methanol [0411] mg=milligram [0412] min=minute [0413]
ml=milliliter [0414] mM=millimolar [0415] mmol=millimole [0416]
m.p.=melting point [0417] MS=mass spectrometry [0418]
m/z=mass-to-charge ratio [0419] N=normal [0420]
NIS=N-iodosuccinimide [0421] nM=nanomolar [0422] nm=nanometer
[0423]
Pd(dppf)Cl.sub.2=[1,1'-Bis(diphenylphosphino)ferrocene]dichloropal-
laoium(II) [0424] PE=petroleum ether [0425]
PyBOP=benzotriazol-1-yl-oxytripyrrolidinophosphonium
hexafluorophosphate [0426] quant.=quantitative [0427] RP=reverse
phase [0428] RT, rt or r.t.=room temperature [0429] Sat.=saturated
[0430] TEA=triethylamine [0431] TFA=trifluoroacetic acid [0432]
.mu.L=microliter [0433] .mu.M=micromolar
##STR00016##
[0433] wherein X, Y, R.sup.1, and R.sup.2 are as described
herein.
EXAMPLES
Example 1
Preparation of
1-(((3,3-dimethylbutanoyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyr-
idin-1-ium iodide (Compound 1)
##STR00017##
[0435] To a solution of nicorandil, (2-(nicotinamido)-ethylnitrate)
(0.23 mmol) in acetonitrile (3 mL) was added iodomethyl isopropyl
carbamate (0.28 mmol) dropwise. The resulting mixture was stirred
overnight at RT. The progress of the reaction was monitored by TLC.
The excess of acetonitrile was removed under vacuum and the
resulting residue was dissolved in MeOH and washed with an excess
of diethyl ether. This process was repeated twice and the solvent
was evaporated under vacuum to get titled compound 1 as a yellow
sticky solid.
[0436] m/z 340.1 (M+).
Example 2
Preparation of
3-((2-(nitrooxy)ethyl)carbamoyl)-1-(((piperidine-1-carbonyl)oxy)methyl)py-
ridin-1-ium iodide (Compound 2) (Dugar et al. U.S. Pat. No.
9,359,376)
##STR00018##
[0438] To a solution of nicorandil, (2-(nicotinamido)-ethylnitrate)
(0.56 mmol) in acetonitrile (5 mL) was added iodomethyl
1-piperidinyl carbamate (0.68 mmol) dropwise. The resulting mixture
was stirred overnight at RT. The progress of the reaction was
monitored by TLC. The excess of acetonitrile was removed under
vacuum and the resulting residue was dissolved in MeOH and washed
with an excess of diethyl ether. This process was repeated twice
and the solvent was evaporated under vacuum to get titled compound
2 as a yellow solid (0.230 g, 84%). (mp 117-120.degree. C.)
[0439] m/z 353.2 (M.sup.+)
Example 3
Preparation of
1-(((diisopropylcarbamoyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyr-
idin-1-ium iodide (Compound 3)
##STR00019##
[0441] To a solution of nicorandil, (2-(nicotinamido)-ethylnitrate)
(0.71 mmol) in acetonitrile (5 mL) was added iodomethyl
diisopropylcarbamate (0.71 mmol) dropwise. The resulting mixture
was stirred overnight at RT. The progress of the reaction was
monitored by TLC. The excess of acetonitrile was removed under
vacuum and the resulting residue was dissolved in MeOH and washed
with an excess of diethyl ether. This process was repeated twice
and the solvent was evaporated under vacuum to get titled compound
3 as a yellow solid (0.220 g, 85%). (mp 122-125.degree. C.).
[0442] m/z 369.2 (M.sup.+)
Example 4
Preparation of
1-(((tert-butoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyri-
din-1-ium iodide (Compound 4)
##STR00020##
[0444] To a solution of nicorandil, (2-(nicotinamido)-ethylnitrate)
(0.47 mmol) in acetonitrile (mL) was added tert-butyl (iodomethyl)
carbonate (0.52 mmol) dropwise. The resulting mixture was stirred
overnight at RT. The progress of the reaction was monitored by TLC.
The excess of acetonitrile was removed under vacuum and the
resulting residue was dissolved in MeOH and washed with an excess
of diethyl ether. This process was repeated twice and the solvent
was evaporated under vacuum to get titled compound 4 as a yellow
sticky solid (0.120 g, 54%).
[0445] m/z 342.1 (M+)
Example 5
Preparation of
1-(((isopropoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyrid-
in-1-ium iodide (Compound 5)
##STR00021##
[0447] To a solution of nicorandil, (2-(nicotinamido)-ethylnitrate)
(0.47 mmol) in acetonitrile (5 mL) was added iodomethyl isopropyl
carbonate (0.56 mmol) dropwise. The resulting mixture was stirred
overnight at RT. The progress of the reaction was monitored by TLC.
The excess of acetonitrile was removed under vacuum and the
resulting residue was dissolved in MeOH and washed with an excess
of diethyl ether. This process was repeated twice and the solvent
was evaporated under vacuum to get titled compound 5 as a brown
sticky material (0.130 g, 60%).
[0448] m/z 328.1 (M+)
Example 6
Preparation of
(R)-1-(((sec-butoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)p-
yridin-1-ium iodide (Compound 6) (Dugar et al. U.S. Pat. No.
9,359,376)
##STR00022##
[0450] To a solution of nicorandil, (2-(nicotinamido)-ethylnitrate)
(0.28 mmol) in acetonitrile (3 mL) was added (R)-sec-butyl
(iodomethyl) carbonate (0.28 mmol) dropwise. The resulting mixture
was stirred overnight at RT. The progress of the reaction was
monitored by TLC. The excess of acetonitrile was removed under
vacuum and the resulting residue was dissolved in MeOH and washed
with an excess of diethyl ether. This process was repeated twice
and the solvent was evaporated under vacuum to get titled compound
6 as a yellow semisolid.
[0451] m/z 342.5 (M.sup.+).
Example 7
Preparation of
(S)-1-(((sec-butoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)p-
yridin-1-ium iodide (Compound 7) (Dugar et al. U.S. Pat. No.
9,359,376)
##STR00023##
[0453] To a solution of nicorandil, (2-(nicotinamido)-ethylnitrate)
(0.28 mmol) in acetonitrile (3 mL) was added iodomethyl
(S)-sec-butyl (iodomethyl) carbonate (0.28 mmol) dropwise. The
resulting mixture was stirred overnight at RT. The progress of the
reaction was monitored by TLC. The excess of acetonitrile was
removed under vacuum and the resulting residue was dissolved in
MeOH and washed with an excess of diethyl ether. This process was
repeated twice and the solvent was evaporated under vacuum to get
titled compound 7 as a yellow semisolid.
[0454] m/z 342.5 (M+).
Example 8
Preparation of
(S)-1-(((1-cyclohexylethylcarbamoyl)oxy)methyl)-3-((2-(nitroxy)ethyl)carb-
amoyl)pyridine-1-ium iodide (Compound 8) (Compound A) (Dugar et al.
U.S. Pat. No. 9,359,376)
##STR00024##
[0456] To a solution of nicorandil, (2-(nicotinamido)-ethylnitrate)
(0.28 mmol) in acetonitrile (3 mL) was added iodomethyl
(S)-(1-cyclohexylethyl) carbamate (0.28 mmol) dropwise. The
resulting mixture was stirred overnight at RT. The progress of the
reaction was monitored by TLC. The excess of acetonitrile was
removed under vacuum and the resulting residue was dissolved in
MeOH and washed with an excess of diethyl ether. This process was
repeated twice and the solvent was evaporated under vacuum to get
titled compound 8 as a yellow solid (mp 94-98.degree. C.).
[0457] m/z 395.5 (M+).
[0458] .sup.1H NMR (300 MHz, DMSO-d.sub.6). .delta. 9.53 (s, 1H),
9.45 (s, 1H), 9.28 (d, J=6.3 Hz, 1H), 9.03 (d, J=8.1 Hz, 1H), 8.36
(dd, J=8.1, 6.3 Hz, 1H), 7.81 (d, J=9 6.3 Hz, 1H), 6.43 (dd,
J=15.5, 6.6 Hz, 2H), 4.69 (t, J=5.1 Hz, 2H), 3.71 (dd, J=10.5, 5.1
Hz, 2H), 3.41 (m, 1H), 1.61 (m, 5H), 0.79-1.25 (m, 9H).
Example 9
Preparation of
(R)-1-(((1-cyclohexylethylcarbamoyl)oxy)methyl)-3-((2-(nitroxy)ethyl)carb-
amoyl)pyridine-1-ium iodide (Compound 9) (Dugar et al. U.S. Pat.
No. 9,359,376)
##STR00025##
[0460] To a solution of nicorandil, (2-(nicotinamido)-ethylnitrate)
(0.28 mmol) in acetonitrile (3 mL) was added iodomethyl
(R)-(1-cyclohexylethyl) carbamate (0.28 mmol) dropwise. The
resulting mixture was stirred overnight at RT. The progress of the
reaction was monitored by TLC. The excess of acetonitrile was
removed under vacuum and the resulting residue was dissolved in
MeOH and washed with an excess of diethyl ether. This process was
repeated twice and the solvent was evaporated under vacuum to get
titled compound 9 as a yellow solid. (mp 98-102.degree. C.)
[0461] m/z 395.5 (M+).
Example 10
Preparation of 1
1-((isobutyryloxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-ium
iodide (Compound 10)
##STR00026##
[0463] To a solution of nicorandil, (2-(nicotinamido)-ethylnitrate)
(0.47 mmol) in acetonitrile (5 mL) was added iodomethyl isobutyrate
(0.71 mmol) dropwise. The resulting mixture was stirred overnight
at RT. The progress of the reaction was monitored by TLC. The
excess of acetonitrile was removed under vacuum and the resulting
residue was dissolved in MeOH and washed with an excess of diethyl
ether. This process was repeated twice and the solvent was
evaporated under vacuum to get titled compound 10 as a brown sticky
material.
[0464] m/z 312.1 (M+)
Example 11
Preparation of
1-(1-((diisopropylcarbamoyl)oxy)ethyl)-3-((2-(nitrooxy)ethyl)carbamoyl)py-
ridin-1-ium iodide (Compound 11)
##STR00027##
[0466] To a solution of nicorandil, (2-(nicotinamido)-ethylnitrate)
(0.23 mmol) in acetonitrile (3 mL) was added 1-iodoethyl
diisopropylcarbamate (0.23 mmol) dropwise. The resulting mixture
was stirred overnight at RT. The progress of the reaction was
monitored by TLC. The excess of acetonitrile was removed under
vacuum and the resulting residue was dissolved in MeOH and washed
with an excess of diethyl ether. This process was repeated twice
and the solvent was evaporated under vacuum to get titled compound
11 as a yellow sticky material (0.042 g, 35%).
[0467] m/z 383.4 (M.sup.+).
Example 12
Preparation of
1-(((ethoxycarbonyl)oxy)methyl)-3-((2-(nitrooxy)ethyl)carbamoyl)pyridin-1-
-ium iodide (Compound 12)
##STR00028##
[0469] To a solution of nicorandil, (2-(nicotinamido)-ethylnitrate)
(0.47 mmol) in acetonitrile (5 mL) was added ethyl (iodomethyl)
carbonate (0.71 mmol) dropwise. The resulting mixture was stirred
overnight at RT. The progress of the reaction was monitored by TLC.
The excess of acetonitrile was removed under vacuum and the
resulting residue was dissolved in MeOH and washed with an excess
of diethyl ether. This process was repeated twice and the solvent
was evaporated under vacuum to get titled compound 12 as a brown
sticky material (0.150 g, 77%).
[0470] m/z 314.1 (M.sup.+)
Example 13
Preparation of
1-(((isopropylcarbamoyl)oxy)methyl)-3-((2-(nitroxy)ethyl)carbamoyl)pyridi-
ne-1-ium iodide (Compound 13) (Dugar et al. U.S. Pat. No.
9,359,376)
##STR00029##
[0472] To a solution of nicorandil, (2-(nicotinamido)-ethylnitrate)
(0.28 mmol) in acetonitrile (3 mL) was added iodomethyl isopropyl
carbamate (0.28 mmol) dropwise. The resulting mixture was stirred
overnight at RT. The progress of the reaction was monitored by TLC.
The excess of acetonitrile was removed under vacuum and the
resulting residue was dissolved in MeOH and washed with an excess
of diethyl ether. This process was repeated twice and the solvent
was evaporated under vacuum to get titled compound 13 as a yellow
sticky solid (0.085 g, 88%).
[0473] m/z 327 (M.sup.+).
[0474] .sup.1H NMR (DMSO-d6, 300 MHz): .delta. ppm 9.54 (s, 1H),
9.43-9.46 (m, 1H), 9.27-9.29 (d, 1H), 9.01-9.04 (d, 1H), 8.33-8.38
(m, 1H), 7.86-7.88 (m, 1H), 6.41 (s, 2H), 4.67-4.70 (t, 2H),
3.69-3.74 (m, 2H), 3.52-3.63 (m, 1H), 1.04-1.11 (m, 6H).
TABLE-US-00003 TABLE 1 Representative Compounds of the Invention
Compound # Structure Salt Nicorandil ##STR00030## N/A 1
##STR00031## Iodide 2 ##STR00032## Iodide 3 ##STR00033## Iodide 4
##STR00034## Iodide 5 ##STR00035## Iodide 6 ##STR00036## Iodide 7
##STR00037## Iodide 8 ##STR00038## Iodide 9 ##STR00039## Iodide 10
##STR00040## Iodide 11 ##STR00041## Iodide 12 ##STR00042## Iodide
13 ##STR00043## Iodide
Additional Exemplary Compounds of the Invention
[0475] Other compounds of the invention have been or can be
prepared according to the synthetic methods, or some variations
thereof, described herein. The compounds can be prepared from
readily available starting materials using the following general
methods and procedures. It will be appreciated that where typical
or preferred process conditions (i.e., reaction temperatures,
times, mole ratios of reactants, solvents, pressures, etc.) are
given; other process conditions can also be used unless otherwise
stated. Optimum reaction conditions may vary with the particular
reactants or solvent used, but such conditions can be determined by
one skilled in the art by routine optimization procedures.
[0476] The following additional compounds are or can be prepared
from readily available starting materials using the following
general methods and procedures:
##STR00044##
Pharmacokinetics Testing
Example 101 (PK) Pharmacokinetics (PK) Protocol: Rat
[0477] Pharmacokinetics study was carried out to evaluate the
plasma exposure of Compound A in rat. The dosing vehicle used in
this study was PEG400. 1,3.10 mg/kg oral dosing was done in
overnight fasted SD rats and the parent drug generated was
monitored. Also presence of modified drug was checked. After oral
(PO) dosing blood was collected by serial bleeding at 8 different
time points in heparinised tubes. Blood samples were centrifuged at
10,000 rpm for 5 min. at 4.degree. C. to obtain the plasma, which
were aspirated into separate labeled tubes and stored at
-80.degree. C. Extraction solvent was added to plasma, was vortexed
and shaken on shaker for 10 minutes, centrifuged at 10,000 rpm for
10 minutes at 4.degree. C. Supernatant was kept for analysis.
Acetonitrile and plasma calibration curves were generated and
percentage of drug recovery from plasma determined. Quantitative
analysis was done by liquid chromatography tandem mass spectrometer
(API3000 LC-MS/MS). Cmax, Tmax, AUC and t1/2 were calculated using
Graph Pad PRISM version 5.04 and the results are depicted in Table
2.
TABLE-US-00004 TABLE 2 Pharmacokinetics parameters for Compound A
(1, 3, 10 mg/kg oral dose in SD rats) Parameters Compound A
Compound A Compound A Nicorandil Rat PK (1 mpk oral) (3 mpk oral)
(10 mpk oral) (3 mpk oral) Cmax (nM) 2529.42 9083.49 34705.8
7767.31 Tmax (hr) 2.00 1.17 2.0 1.17 AUC (nM-hr) 9788 46437.67
127639.0 20347.50 Elimination 2.28 3.67 2.1 3.43 t.sub.1/2 (hr)
Example 102 (PK)
Pharmacokinetics (PK) Protocol: Dog
[0478] Pharmacokinetics study was carried out to evaluate the
plasma exposure of Compound A in dog. Male Beagle dogs which were
fasted overnight were dosed 3 mg/kg Compound A by oral route. 0.5
ml blood was collected at each time point from the femoral vein via
direct stick at defined time points. in tubes containing
anticoagulant. Blood samples were centrifuged at 10,000 rpm for 5
min. at 4.degree. C. to obtain the plasma, which were aspirated
into separate labeled tubes and stored at -80.degree. C. Extraction
solvent was added to plasma, was vortexed and shaken on shaker for
10 minutes, centrifuged at 10,000 rpm for 10 minutes at 4.degree.
C. Supernatant was kept for analysis. Acetonitrile and plasma
calibration curves were generated and percentage of drug recovery
from plasma determined. Quantitative analysis was done by liquid
chromatography tandem mass spectrometer (API3000 LC-MS/MS). Cmax,
Tmax, AUC and t1/2 were calculated using Graph Pad PRISM version
5.04 and the results are depicted in Table 3.
TABLE-US-00005 TABLE 3 Pharmacokinetics parameters for Compound A
(3 mg/kg oral dose in Beagle dog) Parameters Compound A
(Nicorandil) Dog PK (3 mpk oral) (3 mpk oral) Cmax (nM) 9284 2113
Tmax (hr) 0.7 0.3 AUC (nM-hr) 17714 3685 Elimination t.sub.1/2(hr)
2.5 3.2
[0479] Compound A showed excellent plasma exposure in rat and dog.
In both the cases only parent drug was detected in plasma and no
modified drug was detected. Plasma exposure in rat displayed dose
linearity. In dog, plasma exposure was significantly higher as
shown by higher AUC and Cmax Pharmacokinetics parameters for
Compound A (3 mg/kg oral dose in Beagle dog) (Table 4).
TABLE-US-00006 TABLE 4 Rat Pharmacokinetic Data (3 mpk (eq.), PO)
Measuring plasma levels of Nicorandil. T.sub.max T.sub.1/2
C.sub.max AUC Compd # (min) (hr) (.mu.M) (.mu.M) 1 10 1.25 14.2
20.6 2 10 1.63 45.4 57.1 3 30 2.4 16.4 32.2 4 30 2.42 6.2 12.5 5 33
1.98 2.6 4.5 6 36 2.52 12.4 23.7 7 40 2.56 5 10 8 70 3.67 9.1 46.4
9 70 2.54 11.7 33.2 Nicorandil 70 3.43 7.8 20.4 10 80 3.3 5.8 15 11
80 2.07 5.1 16.1 12 102 4.82 3.5 11.1 13 110 4.85 6.6 28.5
Example 201 (Pharm Assays)
Efficacy Studies of Compound a in Diabetic Nephropathy
[0480] Animal Studies Using eNOSKO Mice
[0481] All animal experiments will be performed in accordance the
INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE (IACUC) protocols. Male
C57BL/6J-Nos3tm1nc mice (eNOSKO mice) will be purchased from
Jackson Laboratory (Bar Harbor, Me.) at 8 wk of age. Mice will be
fed a standard laboratory chow ad libitum. Diabetic nephropathy
will be induced by intraperitoneal injections of streptozotocin (50
mg/kg/day for 5 consecutive days) dissolved in 10 mM citrate
buffer, pH 4.5. Diabetes is defined as nonfasting blood glucose 250
mg/dl using a blood glucose meter (One Touch Ultra; Life Scan,
Milpitas, Calif.). Only mice that developed hyperglycemia at 4 wk
will be included in the study. Mice will be divided into four
subgroups: 1) a nondiabetic group, 2) a Compound A-treated
nondiabetic group, 3) a diabetic group, and 4) a Compound A-treated
diabetic group (n 8/group) (Tanabe et al., Am. J. Physiol Renal
Physiol 2012, 302, 151-160). At 4 wk when the onset of diabetes is
confirmed in all animals, 30 mg/kg of Compound A (Chugai
Pharmaceutical, Tokyo, Japan) will be started. To constantly
administer the same amount of Compound A (30 mg/kg/day), the
concentration of Compound A in the drinking water will be adjusted
every 4 days along with as per the water intake volume. Water
bottles will be monitored daily throughout the study to ensure no
leakage occurred. Systolic blood pressure will be measured every
other week using a tail-cuff sphygmomanometer (Visitech BP-2000;
Visitech Systems, Apex, N.C.). Urine will be collected overnight
using metabolic cages (Techniplast, Exton, Pa.). All the mice will
be euthanized 8 wk after starting Compound A treatment to obtain
blood samples and kidney tissues.
Laboratory Studies
[0482] Urine albumin, urine 8-hydroxy-2-deoxyguanosine (8-OHdG),
and urine creatinine will be measured with Albuwell M (Exocell,
Philadelphia, Pa.), an OxiSelect Oxidative DNA Damage ELISA Kit
(Cell Biolabs, San Diego, Calif.), and Creatinine LiquiColor Test
(Enzymatic Methodology; Stanbio, Boerne, Tex.), respectively. Serum
creatinine concentration will be analyzed with HPLC-tandem mass
spectrometry (MS/MS; Applied Biosystems 3200 Qtrap). Creatinine and
[2H3] creatinine (CDN isotopes) will be detected in the multiple
reaction monitoring mode, monitoring the transitions of the m/z
from 114 to 44.2 and m/z from 117 to 47.2, respectively. Serum
levels of P-selectin and ICAM-1 will be measured with a Mouse
P-selectin/CD62 Quantikine ELISA kit and Mouse ICAM-1/CD54
Quantikine ELISA kit, respectively (R&D Systems, Minneapolis,
Minn.).
Histological Analysis
[0483] Formalin-fixed, paraffin-embedded sections (2.5-m) will be
stained with the periodic acid-Schiff reagent (PAS) for light
microscopy. On coronal sections of the kidney, all glomeruli
(50-100 glomeruli) will be examined for evaluation of mesangiolysis
and glomerulosclerosis. Glomerulosclerosis will be defined as
obstruction of the capillary lumen caused by mesangial expansion or
collapsed capillaries, whereas the degree of mesangiolysis will be
calculated as the number of glomeruli with mesangiolysis
(dissolution of the mesangial matrix) divided by that of total
glomeruli. Kidney sections will be observed by two investigators in
a blinded manner.
Immunohistochemistry
[0484] Either formalin or methyl Carnoy's solution-fixed,
paraffin-embedded sections will be used for immunohistochemistry.
The following antibodies will be used as primary antibodies: 1)
rabbit anti-type IV collagen antibody (Chemicon International,
Temecula, Calif.); 2) rat anti-mouse F4/80 antibody (Serotec,
Raleigh, N.C.); 3) rabbit anti-WT-1 antibody (Santa Cruz
Biotechnology, Santa Cruz, Calif.); 4) goat anti-8-OHdG antibody
(Abcam, Cambridge, Mass.); 5) rabbit anti-nitrotyrosine antibody
(Chemicon); and 6) rabbit anti-NPHS2 (podocin) antibody (Abcam).
Briefly, after deparaffinization, the sections will be treated with
3% H2O2 for 10 min to inactivate endogenous peroxidase activity.
For F4/80, 8-OHdG, and nitrotyrosine, the sections will be treated
with 10 mM citrate buffer (pH 6.0) for 30 min in a steamer for
antigen retrieval. After incubation with a background sniper
(Biocare Medical, Concord, Calif.) for 15 min, sections will be
incubated with primary antibodies overnight at 4.degree. C. The
sections will be also incubated with rabbit anti-IgG secondary
antibodies for 30 min before immunoperoxidase staining will be
conducted using the Mach2 rabbit HRP polymer (Biocare Medical).
Slides will be counterstained with methyl green. The number of
positive cells for F4/80 will be counted in all glomeruli at 400
magnification in each section. After immunohistochemistry for WT-1
will be performed, podocyte number per glomerulus will be
calculated using the Weibel-Gomez method. Ten representative
glomeruli will be analyzed on each section for this calculation. To
assess the type IV collagen- and podocin-positive area, the digital
images at 400 magnification will be analyzed using Image scope
software (Aperio Technologies, Vista, Calif.). The percent positive
area will be determined as the 3,3-diaminobenzidine-positive pixel
values per examined interest area from all glomeruli in each
section. Immunofluorescence in the Mouse Kidney Double
immunofluorescence staining will be performed. Briefly, frozen
sections (4-m) will be fixed in acetone for 10 min. The sections
will be blocked with 5% animal serum complex and then incubated
overnight with primary antibodies, rabbit anti-ABCC9 (sulfonylurea
receptor 2; SUR-2) antibody (Abcam), rabbit anti-cGMP antibody
(Chemicon), or mouse monoclonal anti-synaptopodin antibody (Novus
Biologicals, Littleton, Colo.), at 4.degree. C. After incubation
with either Alexa Fluor 488-labeled goat anti-rabbit IgG
(Invitrogen, Carlsbad, Calif.) or Alexa Fluor 546-labeled goat
antimouse IgG (Invitrogen) for 2 h at room temperature, sections
will be mounted with vectashield anti-fade mounting medium (Vector
Labs, Burlingame, Calif.). A laser-scanning confocal microscope LSM
510 META (Carl Zeiss Microimaging, Thornwood, N.Y.) will be used to
obtain images.
Western Blotting
[0485] Kidney tissues will be homogenized in cell lysis buffer
(Cell Signaling, vDanvers, Mass.) at 4.degree. C. Briefly, samples
will be processed for SDS-PAGE and electrotransferred onto a
nitrocellulose membranes. A rabbit anti-nitrotyrosine (Chemicon)
antibody, rabbit anti-actin antibodies (Sigma-Aldrich, St. Louis,
Mo.), an HRP-labeled antirabbit IgG antibody (Cell Signaling), and
Immun Star HRP (Bio-Rad, Hercules, Calif.) will be used. The
density of each band will be determined using National Institutes
of Health Image software and expressed as a value relative to the
density of the corresponding band of actin.
Cell Culture
[0486] Conditionally immortalized human podocytes will be cultured
in RPMI 1640 medium (Mediatech, Manassas, Va.) supplemented with
10% FBS, penicillin (100 U/l), streptomycin (100 g/l), and
Insulin-Transferrin-Selenium A supplements (Invitrogen). Cells will
be cultured at 33.degree. C. to enhance the expression of large T
antigen and propagate podocytes, followed by incubation for 10 days
at 37.degree. C. to induce differentiation into mature podocytes
before initiation of experiments. For the experimental studies,
podocytes will be cultured in DMEM with 5.5 mM normal glucose (NG),
NG19.5 mM mannitol (NGMan), 25 mM high glucose (HG), and HG105 M
Compound A (HGNico) for 72 h.
PCR
[0487] Total RNA will be extracted from cultured podocytes using an
RNeasy Mini Kit (Qiagen, Chatsworth, Calif.). The first-strand cDNA
will be synthesized from 1 g of total RNA using an iScript cDNA
Synthesis Kit (Bio-Rad). For the detection of SUR2A and SUR2B mRNA,
the following oligonucleotide primers will be used: SUR2A,
5=-TGAGGGTATTTTAGTGGAGTGTG-3=(forward) and
5=-CAAAGTGGAAAAGAGGCCATTC-3=(reverse); SUR2B,
5=-TGGTGACAATAGCTCATCGAG-3=(forward) and
5=-TCCATTTTCCTGAGCCAAGAG-3=(reverse); and-actin,
5=-TGAGATGCGTTGTTACAGGAAG-3=(forward) and
5=-GTGGACTTGGGAGAGGACTG-3=(reverse). The PCR program will be
optimized and performed as denaturation at 95.degree. C. for 3 min
followed by 50 cycles of amplification (SUR2A and SUR2B, 95.degree.
C. for 30 s, 54.degree. C. for 30 s, 72.degree. C. for 1 min;
-actin, 95.degree. C. for 30 s, 56.degree. C. for 30 s, 72.degree.
C. for 1 min, respectively) using the MyiQ Single-Color Real-Time
PCR Detection System (Bio-Rad). The amount of PCR products will be
normalized with -actin mRNA to determine the relative expression
ratio for SUR2A and SUR2B mRNA.
ROS Detection Assay in Cultured Podocytes
[0488] An Image-iT LIVE Green Reactive Oxygen Species Detection Kit
(Invitrogen) will be used to measure the generation of ROS.
Briefly, podocytes will be incubated in PBS containing 25 M 5-(and
6)-carboxy-2=,7=-dichlorodihydrofluorescein diacetate
(carboxy-H2DCFDA) for 30 min at 37.degree. C. in the dark. This
probe is converted by intracellular esterase and ROS to
carboxy-DCF, which emits a bright green fluorescence. After
incubation, the cells will be washed with PBS three times and
observed by a laser-scanning confocal microscope LSM 510 META (Carl
Zeiss) to obtain images. The intensity in podocytes will be
measured by Zen 2009 software (Carl Zeiss). A total of 10 fields
(at 400) will be examined to determine the averaged value of cells
in each image.
Cell Number
[0489] A conventional MTT assay will be used to assess cultured
podocyte number. Podocytes will be seeded in 96-well plates at
10,000 cells/well and allowed to differentiate at 37.degree. C. for
10 days. Seventy two hours after stimulation by NG or HG medium
with or without Compound A, 20 l of thiazolyl blue tetrazolium
bromide (Sigma-Aldrich) dissolved in PBS at 5 mg/ml will be added
into each well containing 100 l of medium, and the plate will be
incubated for 3 h at 37.degree. C. MTT solvent (4 mM HCl and 0.1%
P-40 in isopropanol) will be used before absorbance will be read at
590 nm with a reference filter of 620 nm. Data will be expressed as
values relative to NG.
Statistical Analysis
[0490] All values are expressed as means SD. Statistical analysis
will be performed with ANOVA using Tukey's (for in vivo
experiments) or Bonferroni's (in vitro experiments) method to
compare four groups. A level of P<0.05 will be considered
statistically significant.
Example 202 (Pharm Assays)
Efficacy Studies of Compound A in Chronic Kidney Disease
Animal Studies Using Remnant Kidney (RK) Model to Study CKD
[0491] All animal experiments will be performed in accordance with,
and approved by, the Institute Animal Care and Use Committee of the
institution. Male Sprague-Dawley rats (200-240 g) will undergo
baseline blood pressure (BP) and renal function assessments and
will be randomly assigned to the RK group or the sham-operated
control group. For the RK group, a right subcapsular nephrectomy
will be performed and followed by surgical resection of the upper
and lower one-thirds of the left kidney (Tamura et al., Am. J.
Physiol Renal Physiol 2012, 303, 339-349). Rats will be divided
into four subgroups: 1) sham group, 2) RK group, 3) RK with low
dose Compound A (3 mg/kg/day), and 4) RK with high dose Compound A
(30 mg/kg/day) (n 7 for each group). All rats will be fed ad
libitum. Two weeks after surgery, rats will be randomized based on
blood urea nitrogen (BUN) level before starting Compound A
treatment (Chugai Pharmaceutical, Tokyo, Japan). To constantly
administer the same amount of Compound A (30 mg/kg/day), the
concentration of Compound A in the drinking water will be adjusted
every 4 days, along with the water intake volume. Water bottles
will be monitored daily throughout the study to ensure that no
leakage occurred. Systolic BP will be measured at 0, 4, and 12 wk
using a tail-cuff sphygmomanometer (Visitech BP-2000; Visitech
Systems, Apex, N.C.). Urine will be collected overnight using
metabolic cages (Techniplast, Exton, Pa.) before death. All of the
rats will be killed at 12 wk to obtain blood samples and kidney
tissues.
Laboratory Studies
[0492] Urine albumin, urine 8-hydroxy-2=-deoxyguanosine (8-OHdG),
xanthine oxidase activity, and urine creatinine will be measured
with Nephrat (Exocell, Philadelphia, Pa.), OxiSelect Oxidative DNA
Damage ELISA Kit (Cell Biolaboratories, San Diego, Calif.),
xanthine oxidase assay kit (Cayman, Ann Arbor, Mich.), and
Creatinine LiquiColor Test (enzymatic methodology; Stanbio, Boerne,
Tex.), respectively. Uric acid concentration in the renal cortex
will be determined with the Quantichrom uric acid assay kit
(Bioassay System, Hayward, Calif.). In contrast, serum levels of
uric acid, BUN, and creatinine will be determined by VetACE
Clinical Chemistry System (Alfa Will besermann, NJ). Serum
cystatin-C concentration will be determined by Mouse/Rat Cystatin-C
ELISA kit (R&D Systems, Minneapolis, Minn.). To examine the
renal NO, the concentration of urinary nitrate (N03) and nitrite
(NO2) will be determined by NO analyzer 280i (SIEVERS, Boulder,
Colo.).
Histological Analysis
[0493] Formalin-fixed, paraffin-embedded sections (2.5 m) will be
stained with the periodic acid-Schiff reagent for light microscopy.
On coronal sections of the kidney, all glomeruli (50-100 glomeruli)
will be examined to evaluate glomerulosclerosis. Glomerulosclerosis
will be defined as obstruction of capillary lumen caused by
mesangial expansion or collapsed capillaries. Kidney sections will
be observed by two investigators in a blinded manner. Primary
antibodies for immunohistochemistry and Western blotting. Goat
anti-human type IV collagen antibody (Southern Biotech, Birmingham,
Ala.) and mouse anti-rat CD68 antibody (AbD Serotec, Oxford, UK)
will be used for glomerular injury. Rabbit antihuman
[0494] WT-1 antibody (Santa Cruz, Santa Cruz, Calif.) and rabbit
anti-human NPHS2 (podocin) antibody (Abcam, Cambridge, Mass.) will
be used to detect podocytes. To examine the tubulointerstitial
injury, goat anti-human type III collagen antibody (Southern
Biotech) will be used. Mouse anti-rat CD11b/c equivalent antibody
(OX42) (Abcam) will be for identifying the phenotype of immune cell
in the interstitium. Goat ant-human sulfonylurea receptor (SUR)-2B
(C-15) antibody (Santa Cruz) and rabbit anti-human ABCC9 antibody
(Abcam) will be for detecting of SUR. Rabbit anti-rat manganese SOD
(MnSOD) (Enzo Life Sciences, Farmingdale, N.Y.), rabbit anti-human
xanthine oxidase (H-110) antibody (Santa Cruz), mouse
anti-nitrotyrosine antibody (Millipore, Billerica, Mass.), mouse
anti-GAPDH antibody (Millipore), and rabbit anti-mouse heme
oxygenase-1 antibody (Stressgen, Ann Arbor, Mich.) will be also
used.
Immunohistochemistry
[0495] Either formalin or methyl Carnoy's solution-fixed,
paraffin-embedded sections will be used for immunohistochemistry.
To identify the cell type, serial section (1.5 m) technique will be
used with specific markers of cell type. Briefly, after
deparaffinization, the sections will be treated with 3% H2O2 for 10
min to inactivate endogenous peroxidase activity. For WT-1, CD68,
CD11b/c, and SUR2, the sections will be treated with 10 mM citrate
buffer (pH 6.0) for 30 min in a steamer for antigen retrieval. The
sections will be incubated with primary antibodies overnight at
4.degree. C., followed by treatment with secondary antibodies for
30 min. Color development will be achieved using diaminobenzidine
with/without nickel chloride. All glomeruli at 400 magnification or
15 fields (each field/0.4 mm2) in each section will be used to
count the number of positive cells for CD68, CD11b/c, or WT-1. To
assess the type IV collagen and podocin positive area, the digital
images at 400 magnification will be analyzed using Image scope
software (Aperio Technologies, Vista, Calif.). The percent positive
area will be determined as the diaminobenzidine-positive pixel per
total pixel in interest area from all glomeruli in each section.
Likewise, positive area for type III collagen in interstitium will
be also determined as percent positive area with 15 fields (each
field/0.4 mm2).
Western Blotting
[0496] Kidney cortex will be homogenized in cell lysis buffer (Cell
Signaling, Danvers, Mass.) at 4.degree. C. Briefly, samples will be
processed for SDS-PAGE, and electrotransferred onto a
nitrocellulose membrane. After overnight incubation with primary
antibody at 4.degree. C., membrane will be incubated with secondary
antibody linked with horseradish peroxidase for 1 h at RT. Signal
will be detected by Immun Star HRP (Bio-Rad, Hercules, Calif.). The
density of each band will be determined using National Institutes
of Health Image software and expressed as a value relative to the
density of the corresponding band of the -actin or GAPDH.
Cell Culture
[0497] RAW264.7 cells (ATCC, Manassas, Va.), a macrophage cell
line, will be cultured in Dulbecco's modified Eagle's medium
(Cellgro, Manassas, Va.), supplemented with 10% FBS, penicillin
(100 U/l), and streptomycin (100 g/1). Subconfluent cells will be
stimulated with angiotensin II (Sigma-Aldrich) at 37.degree. C.
after pretreatment of various concentrations of Compound A for 30
min in serum-free medium. Eight hours after glibenclamide (Sigma)
exposure, xanthine oxidase expression will be examined. Each
experiment will be repeated at least four times.
Statistical Analysis
[0498] All values are expressed as means SE. Statistical analysis
will be performed with ANOVA using Tukey's method. A level of
P<0.05 will be considered statistically significant.
Example 203 (Pharm Assays)
Efficacy Studies of Compound A in Acute Kidney Injury
Animal Studies in Drug Induced AKI Model
[0499] All animal experiments will be performed in accordance with,
and approved by, the Institute Animal Care and Use Committee of the
institution. Adult male Wistar rats (150-200 g) will be used for
the studies. They will be housed in standard rat cages (421
.ANG..about.290 .ANG..about.190 mm). All animals will be exposed to
12 h light-dark cycles and allowed access ad libitum to drinking
water and rat chow.
Drug Dose that Results in AKI
[0500] A rat model of Tenofovir disoproxil fumarate (TDF)
nephrotoxicity which was standardized recently in Isaac laboratory
will be used (8). TDF at a dose of 600 mg/kg body wt/day orally for
5 weeks (which is 12.times.clinical dose) results in severe damage
to the mitochondria of proximal tubules as seen in humans and thus
will be utilized for the purpose of this study.
Experimental Design
[0501] The rats will be assigned randomly into two groups and will
be treated as follows:
[0502] Group I (control): The rats in this group (n=6) received
sterile water alone by gavage
[0503] Group II: The rats (n=6) in this group received 600 mg/kg
body weight TDF dissolved in sterile water by gavage for 5 weeks.
Control animals will be treated with sterile water on the same
schedule as TDF treatment and will be killed at the same time for
TDF-treated and control rats.
Measurements
Fluid and Food Intake, Mortality Checks, Clinical Observations, and
Body Weights
[0504] Animals will be checked daily for clinical signs of
toxicity, morbidity, or death. Body weights will be measured
weekly. All the rats will be sacrificed 24 h after the final dose
of TDF/sterile water. Twenty-four hours before sacrifice, the rats
will be placed individually in metabolic cages, and urine will be
collected for biochemical analysis. On the 36th day, blood samples
will be collected from the rats under halothane anesthesia, by
cardiac puncture into tubes and allowed to clot at room
temperature. Thereafter, serum will be separated by centrifugation
at 1200.times.g for 15 min at 4.degree. C. for clinical chemistry.
Both the kidneys will be removed and weighed. One kidney will be
cut in cross section; a part will be fixed in 10% buffered formalin
for light microscopy, and the remaining part will be fixed in 3%
glutaraldehyde for electron microscopy. The other kidney will be
stored at -70.degree. C. until used.
Morphological Examination of the Kidney
[0505] After fixation of kidney tissues in 10% buffered formalin
for 24 h at room temperature, the slices will be embedded in
paraffin and then sectioned. Four micrometer-thick paraffin
sections will be stained with hematoxylin and eosin (H&E) for
light microscope examination using a conventional protocol. A
minimum of eight fields for each kidney section will be examined
and assigned for severity of changes by an observer blinded to the
treatments of the animals. Tubular injury will be graded on a
semiquantitative scale. Tubular injury will be defined as tubular
epithelial necrosis, cast formation, tubular dilatation, and the
loss of the brush border. Tubular injury will be scored by grading
the percentage of affected tubules under 10 randomly selected,
nonoverlapping fields (magnification, 200.times.) as follows: 0,
0%; 1, 10%; 2, 11-25%; 3, 26-45%; 4, 46-75%; and 5, 76-100%. To
score injured tubules, whole tubule numbers per field will be
considered as standard under a magnification of 200.times.. The
grading percentage will be calculated in each field as follows:
Injury score (%)=Number of injured tubules/Number of whole
tubules.times.100.
Fine Structure of Kidney Tissues
[0506] Electron microscope (EM) Studies: The kidney tissues will be
fixed in 3% glutaraldehyde and will behed in buffer, postfixed by
1% osmium tetraoxide and will behed in buffer, and, dehydrated in
increasing concentrations of alcohol. The tissues will be will
behed with propylene oxide and embedded in epoxy-resin embedding
medium. Sections (0.5 .mu.m) will be cut with glass knives and
stained with toluidine blue for orientation. Ultrathin
(900A.degree.) sections will be cut with a diamond knife, stained
with uranyl acetate and lead citrate and examined by EM, evaluated
and photographed. Each EM photomicrograph will be reviewed
independently by two investigators. Parameters included the
presence of structurally abnormal mitochondria, increased numbers
of mitochondrial profiles per field, intramitochondrial lamellar
bodies, abnormal cristae density, cristae reduplication,
mitochondrial swelling, and intramitochondrial paracrystals. The
extent of mitochondrial ultrastructural injury in the proximal
tubular cells will be then quantitatively assessed (at a scale of
0-5) based on the cell injury staging system. This staging system
enumerates the characteristic progression of ultrastructural
changes that occurs within cells in various models of inflammatory
injury. The association between the degree of mitochondrial injury
and the defined stages of cellular injury will be employed to
quantify and standardize the severity of ultrastructural injury to
the proximal tubular mitochondria.
Serum Clinical Chemistry
[0507] Serum will be separated and used for the estimation of
phosphate, potassium, bicarbonate, uric acid, glucose, urea, and
creatinine.
Urinalysis
[0508] Urine samples will be centrifuged to remove suspended
material, and the supernatants will be used for the estimation of
bicarbonate, phosphate, potassium, and uric acid. Glucose and
protein will be semiquantified by dipstick. Low molecular weight
proteins in urine will be detected by sodium dodecyl sulfate
polyacrylamide gel electrophoresis (SDS PAGE).
Detection of Low Molecular Weight Proteins in Urine by SDS PAGE
[0509] Urine proteins will be measured by Lowry's method and
fractionated by SDS-PAGE using 8% resolving gel and 5% stacking
gel. Each sample containing 100 .mu.g of urinary protein will be
mixed with a protein dissociation buffer in the ratio of 1:1 and
kept in a boiling water bath for 5 min. Samples will be briefly
centrifuged; they will be then loaded onto wells. Running gel
buffer (pH 8.6) will be added to an electrophoresis tank. The
apparatus will be connected to the power pack and will be run at 70
V until the sample reached the separating gel. The voltage applied
will be increased to 90V at this point. Electrophoresis will be
stopped when the marker dye reached near the end of the gel. After
electrophoretic separation, the gel will be stained with Coomassie
blue solution (0.01% Coomassie brilliant blue R 250, 50% (v/v)
methanol, and 10% (v/v) glacial acetic acid) for 3 h at room
temperature and subsequently destained in the destaining solution
(50% (v/v) methanol and 10% (v/v) acetic acid) for 2 h. The gel
image will be captured and analyzed by a gel documentation system
(Alpha Innotech), using Alpha Ease software.
Measurement of Parameters of Mitochondrial Function
Preparation of Kidney Homogenate
[0510] The kidney tissue obtained will be will behed in ice-cold
saline, decapsulated, and minced into small pieces using a pair of
sharp scissors, and immediately homogenized (10% w/v) in the
homogenization buffer containing 0.05 M HEPES and 125 mM KCL pH
7.4, using a Potter-Elvehjem homogenizer at 5000 rpm for 3 min
(10-15 strokes). The homogenates will be centrifuged at 7500 rpm
for 10 min. The supernatant will be used for the biochemical
assays.
Isolation of Kidney Mitochondria
[0511] The kidney tissues will be homogenized (5%) using the
homogenizing buffer consisting of 220 mM Mannitol/70 mM sucrose/5
mM Tris/1 mM EGTA; pH 7.4. The homogenates will be centrifuged at
4000.ANG..about.g for 10 min, and the nuclear pellet will be
discarded. Crude mitochondrial fractions will be obtained by
centrifuging at 12,000.times. for 20 min, and the pellet will be
will washed thrice with wash buffer containing 220 mM mannitol/70
mM sucrose/20 mM HEPES; pH 7.4. The final pellet will be suspended
in the same buffer. The purity of the mitochondria will be
established by enrichment of marker enzyme, succinate
dehydrogenase. The isolated mitochondria will be used for assessing
their function and also for measuring the activities of
mitochondria.
Mitochondrial Swelling
[0512] Swelling of mitochondria will be determined by following the
decrease in the absorbance at 540 nm for 10 min. Mitochondrial
suspension will be added to a cuvette containing buffer (250 mM
sucrose/5 mM HEPES, pH 7.4). The combination will be quickly mixed,
and the change in the absorbance will be measured at 540 nm for 10
min in a spectrophotometer.
Example 301: Pharmaceutical Compositions
[0513] The compositions described below are presented with a
compound of Formula (I)-(Vb) for illustrative purposes.
Example 301a: Parenteral Composition
[0514] To prepare a parenteral pharmaceutical composition suitable
for administration by injection, 100 mg of a compound of Formula
((I)-(Vb) is dissolved in DMSO and then mixed with 10 mL of 0.9%
sterile saline. The mixture is incorporated into a dosage unit form
suitable for administration by injection.
Example 301b: Oral Composition
[0515] To prepare a pharmaceutical composition for oral delivery,
100 mg of a compound of Formula (I)-(Vb) is mixed with 750 mg of
starch. The mixture is incorporated into an oral dosage unit for,
such as a hard gelatin capsule, which is suitable for oral
administration.
Example 301c: Sublingual (Hard Lozenge) Composition
[0516] To prepare a pharmaceutical composition for buccal delivery,
such as a hard lozenge, mix 100 mg of a compound of Formula
(I)-(Vb) with 420 mg of powdered sugar mixed, with 1.6 mL of light
corn syrup, 2.4 mL distilled water, and 0.42 mL mint extract. The
mixture is gently blended and poured into a mold to form a lozenge
suitable for buccal administration.
Example 301d: Inhalation Composition
[0517] To prepare a pharmaceutical composition for inhalation
delivery, 20 mg of a compound of Formula (I)-(Vb) is mixed with 50
mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride
solution. The mixture is incorporated into an inhalation delivery
unit, such as a nebulizer, which is suitable for inhalation
administration.
Example 301e: Rectal Gel Composition
[0518] To prepare a pharmaceutical composition for rectal delivery,
100 mg of a compound of Formula (I)-(Vb) is mixed with 2.5 g of
methylcellulose (1500 mPa), 100 mg of methylparaben, 5 g of
glycerin and 100 mL of purified water. The resulting gel mixture is
then incorporated into rectal delivery units, such as syringes,
which are suitable for rectal administration.
Example 301f: Topical Gel Composition
[0519] To prepare a pharmaceutical topical gel composition, 100 mg
of a compound of (I)-(Vb) is mixed with 1.75 g of hydroxypropyl
cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate
and 100 mL of purified alcohol USP. The resulting gel mixture is
then incorporated into containers, such as tubes, which are
suitable for topical administration.
[0520] It is understood that the examples and embodiments described
herein are for illustrative purposes only and that various
modifications or changes in light thereof will be suggested to
persons skilled in the art and are to be included within the spirit
and purview of this application and scope of the appended claims.
All publications, patents, and patent applications cited herein are
hereby incorporated by reference in their entirety for all
purposes.
[0521] At least some of the chemical names of compounds of the
invention as given and set forth in this application, may have been
generated on an automated basis by use of a commercially available
chemical naming software program, and have not been independently
verified In the instance where the indicated chemical name and the
depicted structure differ, the depicted structure will control. In
the chemical structures where a chiral center exists in a structure
but no specific stereochemistry is shown for the chiral center,
both enantiomers associated with the chiral structure are
encompassed by the structure.
REFERENCES
[0522] 1) Breyer M D, Susztak K. The next generation of
therapeutics for chronic kidney disease. Nat Rev Drug Discov. 2016
August; 15(8):568-88 [0523] 2) Uchino S. The epidemiology of acute
renal failure in the world. Curr Opin CritCare. 2006 December;
12(6):538-43 [0524] 3) Chertow G M, Burdick E, Honour M, Bonventre
J V, Bates D W. Acute kidney injury, mortality, length of stay, and
costs in hospitalized patients. J Am Soc Nephrol. 2005 November;
16(11):3365-70. [0525] 4) Uchino S, Kellum J A, Bellomo R, Doig G
S, Morimatsu H, Morgera S, Schetz M, TanI, Bouman C, Macedo E,
Gibney N, Tolwani A, Ronco C; Beginning and Ending Supportive
Therapy for the Kidney (BEST Kidney) Investigators. Acute renal
failure in critically ill patients: a multinational, multicenter
study. JAMA. 2005 Aug. 17; 294(7):813-8 [0526] 5) Mehta R L,
Pascual M T, Soroko S, Savage B R, Himmelfarb J, Ikizler T A,
Paganini E P, Chertow G M; Program to Improve Care in Acute Renal
Disease. Spectrum of acute renal failure in the intensive care
unit: the PICARD experience. Kidney Int. 2004 October;
66(4):1613-21 [0527] 6) Pannu N, Nadim M K. An overview of
drug-induced acute kidney injury. Crit Care Med. 2008 April; 36(4
Suppl: S216-23) [0528] 7) Awdishu L, Mehta R L. The 6R's of drug
induced nephrotoxicity. BMC Nephrol. 2017 Apr. 3; 18(1):124 [0529]
8) Ramamoorthy H, Abraham P, Isaac B. Mitochondrial dysfunction and
electron transport chain complex defect in a rat model of tenofovir
disoproxil fumarate nephrotoxicity. J Biochem Mol Toxicol. 2014
June; 28(6):246-55
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