U.S. patent application number 14/718300 was filed with the patent office on 2015-09-10 for composition for inhibition of cathepsin k.
This patent application is currently assigned to MERCK SHARP & DOHME CORP.. The applicant listed for this patent is Merck Sharp & Dohme Corp.. Invention is credited to Cameron Black, Anastasia Daifotis, Basil Avery Ince, Selwyn Aubrey Stoch.
Application Number | 20150250759 14/718300 |
Document ID | / |
Family ID | 37962942 |
Filed Date | 2015-09-10 |
United States Patent
Application |
20150250759 |
Kind Code |
A1 |
Daifotis; Anastasia ; et
al. |
September 10, 2015 |
COMPOSITION FOR INHIBITION OF CATHEPSIN K
Abstract
The present invention relates to the a method of inhibiting bone
resorption in a mammal in need thereof with an oral pharmaceutical
composition comprising a cathepsin K inhibitor, or a
pharmaceutically acceptable salt thereof, or a mixture thereof,
according to a continuous schedule having a dosage interval of once
weekly, biweekly, twice monthly or once monthly.
Inventors: |
Daifotis; Anastasia;
(Westfield, NJ) ; Stoch; Selwyn Aubrey; (Somerset,
NJ) ; Ince; Basil Avery; (Beijing, CN) ;
Black; Cameron; (Baie D'Urfe, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Merck Sharp & Dohme Corp. |
Rahway |
NJ |
US |
|
|
Assignee: |
MERCK SHARP & DOHME
CORP.
Rahway
NJ
|
Family ID: |
37962942 |
Appl. No.: |
14/718300 |
Filed: |
May 21, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14197992 |
Mar 5, 2014 |
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14718300 |
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11885421 |
Aug 29, 2007 |
8722734 |
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PCT/US2006/006622 |
Feb 24, 2006 |
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14197992 |
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60657982 |
Mar 2, 2005 |
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Current U.S.
Class: |
514/102 ;
514/167; 514/521; 558/426 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 31/592 20130101; A61P 1/00 20180101; A61P 1/04 20180101; A61K
9/20 20130101; A61K 31/44 20130101; A61K 31/277 20130101; A61K
31/427 20130101; A61K 31/415 20130101; A61P 19/10 20180101; A61P
43/00 20180101; A61P 29/00 20180101; A61K 31/275 20130101; A61K
9/2018 20130101; A61P 19/00 20180101; A61P 1/14 20180101; A61K
9/2054 20130101; C07C 317/32 20130101; A61K 31/592 20130101; A61P
19/08 20180101; A61K 31/59 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/277 20060101
A61K031/277; A61K 31/59 20060101 A61K031/59; A61K 9/20 20060101
A61K009/20; A61K 45/06 20060101 A61K045/06 |
Claims
1. A method of inhibiting bone resorption in a mammal in need
thereof comprising administering to the mammal a therapeutically
effective amount of a cathepsin K inhibitor, or a pharmaceutically
acceptable salt thereof, or a mixture thereof, characterized by a
single-dose AUC.sub.0-168 of about 2.00-80.0 .mu.M/hr and a
C.sub.min of about 10 nM to about 200 nM, as an oral unit dose
according to a once weekly, biweekly, twice monthly or once monthly
dosing regimen.
2. A method of inhibiting bone resorption in a mammal in need
thereof comprising administering to the mammal about 2.5 mg to
about 200 mg of a cathepsin K inhibitor according to Formula I:
##STR00005## wherein R.sup.1 is C.sub.1-3 alkyl which is
substituted with two to seven halo; R.sup.2 is hydrogen or halo; X
is N or CH; D is aryl or heteroaryl, wherein each said aryl or
heteroaryl group, which may be monocyclic or bicyclic, is
optionally substituted on either the carbon or the heteroatom with
one to four substituents independently selected from methyl,
C.sub.1-6 haloalkyl, halo or --SO.sub.2R.sup.4; R.sup.3 is
hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkynyl, halo, cyano, aryl,
heteroaryl, C.sub.3-8 cycloalkyl, heterocyclyl, --OR.sup.4,
--C(O)N(R.sup.5)(R.sup.6), --C(R.sup.5)(R.sup.6)OH,
--C(R.sup.5)(R.sup.6)N(R.sup.4).sub.2, --SO.sub.mR.sup.4,
--SO.sub.2N(R.sup.4)(R.sup.5), or
--SO.sub.2N(R.sup.5)C(O)(R.sup.7); wherein said alkyl, alkynyl,
aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally
substituted on either the carbon or the heteroatom with one to five
substituents independently selected from C.sub.1-6 alkyl or halo;
R.sup.4 is hydrogen, C.sub.1-6 alkyl, aryl, aryl(C.sub.1-4) alkyl,
heteroaryl, heteroaryl(C.sub.1-4)alkyl, C.sub.3-8 cycloalkyl,
C.sub.3-8 cycloalkyl(C.sub.1-4)alkyl, or
heterocyclyl(C.sub.1-4)alkyl; which are optionally substituted with
one, two, or three substituents independently selected from halo,
alkoxy or --SO.sub.2R.sup.7; R.sup.5 is hydrogen, C.sub.1-6 alkyl,
or C.sub.1-6 haloalkyl; R.sup.6 is hydrogen, C.sub.1-6 alkyl, or
C.sub.1-6 haloalkyl; Or R.sup.5 and R.sup.6 can be taken together
with the carbon or nitrogen atom between them to form a 3 to 6
membered ring; R.sup.7 is hydrogen or C.sub.1-6 alkyl which is
optionally substituted with one, two, or three substituents
independently selected from halo or cyano; m is an integer from
zero to two; or a salt, stereoisomer, N-oxide derivative, or a
mixture thereof, as an oral unit dose according to a once weekly,
biweekly, twice monthly or once monthly dosing regimen.
3. The method according to claim 2 wherein the cathepsin K
inhibitor is
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-{(1S)-2,2,2-trifluoro-1-[4'-
-(methylsulfonyl)-1,1'-biphenyl-4-yl]ethyl}-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-{(1S)-2,2,2-trifluoro-1-[2'-
-methyl-4'-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide;
N.sup.2-{(1S)-1-[4'-(aminosulfonyl)biphenyl-4-yl]-2,2,2-trifluoroethyl}-N-
.sup.1-(1-cyanocyclopropyl)-4-fluoro-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-[(1S)-2,2,2-trifluoro-1-(4'-
-fluorobiphenyl-4-yl)ethyl]-L-leucinamide;
N.sup.2-((1S)-1-{4'-[1-(aminocarbonyl)cyclopropyl]biphenyl-4-yl}-2,2,2-tr-
ifluoroethyl)-N.sup.1-(1-cyanocyclopropyl)-4-fluoro-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-((1S)-2,2,2-trifluoro-1-{4--
[4-(trifluoromethyl)-1,3-thiazol-2-yl]phenyl}ethyl)-L-leucinamide;
N.sup.2-((1S)-1-{4'-[1-(aminocarbonyl)cyclopropyl]-2'-fluorobiphenyl-4-yl-
}-2,2,2-trifluoroethyl)-N.sup.1-(1-cyanocyclopropyl)-4-fluoro-L-leucinamid-
e;
N.sup.1-(1-cyanocyclopropyl)-N.sup.2-((1S)-1-{4'-[(1R)-2,2-difluoro-1-h-
ydroxyethyl]biphenyl-4-yl}-2,2,2-trifluoroethyl)-4-fluoro-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-((1S)-2,2,2-trifluoro-1-{4--
[5-methyl-6-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-N.sup.2-{(1S)-1-[4'-(1-cyanocyclopropyl)biph-
enyl-4-yl]-2,2,2-trifluoroethyl}-4-fluoro-L-leucinamide;
N.sup.2-[(1S)-1-(4-{5-[1-(aminocarbonyl)cyclopropyl]-3-chloropyridin-2-yl-
}phenyl)-2,2,2-trifluoroethyl]-N.sup.1-(1-cyanocyclopropyl)-4-fluoro-L-leu-
cinamide;
N.sup.2-[(1S)-1-(5-{4-[1-(aminocarbonyl)cyclopropyl]phenyl}pyrid-
in-2-yl)-2,2,2-trifluoroethyl]-N.sup.1-(1-cyanocyclopropyl)-4-fluoro-L-leu-
cinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-((1S)-2,2,2-triflu-
oro-1-{5-[4-(methylsulfonyl)phenyl]pyridin-2-yl}ethyl)-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-{(1S)-2,2,2-trifluoro-1-[4'-
-(methylsulfinyl)-1,1'-biphenyl-4-yl]ethyl}-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-N.sup.2-{(1S)-2,2-difluoro-1-[4'-(methylsulf-
onyl)biphenyl-4-yl]ethyl}-4-fluoro-L-leucinamide; or a salt
thereof.
4. The method according to claim 3 wherein the cathepsin K
inhibitor is
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-{(1S)-2,2,2-trifluoro-1-[4'-
-(methylsulfonyl)-1, 1'-biphenyl-4-yl]ethyl}-L-leucinamide.
5. The method according to claim 4 further comprising an agent
selected from the group consisting of an organic bisphosphonate; an
estrogen receptor modulator; an androgen receptor modulator; an
inhibitor of osteoclast proton ATPase; an inhibitor of HMG-CoA
reductase; an integrin receptor antagonist; an osteoblast anabolic
agent; calcium; Vitamin D; a synthetic Vitamin D analogue; a
Nonsteroidal anti-inflammatory drug; a selective cyclooxygenase-2
inhibitor; an inhibitor of interleukin-1 beta; a LOX/COX inhibitor;
a RANKL inhibitor; and the pharmaceutically acceptable salts and
mixtures thereof.
6. The method according to claim 5 wherein the agent is Vitamin
D.
7. The method according to claim 6 wherein the amount of Vitamin D
is 2,400 IU, 5,600 IU, 7,000 IU, 8,400 IU, 11,200 IU, 14,000 IU,
15,400 IU, 16,800 IU or 19,600 IU.
8. The method according to claim 2 where the oral unit dose is a
tablet.
9. The method according to claim 2 where the oral unit dose is a
capsule.
10. The method according to claim 2 where the oral unit dose is a
liquid.
11. The method according to claim 4 where the mammal is identified
as suffering from or susceptible to upper gastrointestinal
disorders.
12. The method according to claim 11 wherein the upper
gastrointestinal disorder is gastrointestinal reflux disease,
esophagitis, dyspepsia or ulcers.
13. The method according to claim 2 for treating osteoporosis.
14. A pharmaceutical composition comprising about 2.5 mg to about
200 mg of a cathepsin K inhibitor selected from
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-{(1S)-2,2,2-trifluoro-1-[4'-
-(methylsulfonyl)-1,1'-biphenyl-4-yl]ethyl}-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-{(1S)-2,2,2-trifluoro-1-[2'-
-methyl-4'-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide;
N.sup.2-{(1S)-1-[4'-(aminosulfonyl)biphenyl-4-yl]-2,2,2-trifluoroethyl}-N-
.sup.1-(1-cyanocyclopropyl)-4-fluoro-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-[(1S)-2,2,2-trifluoro-1-(4'-
-fluorobiphenyl-4-yl)ethyl]-L-leucinamide;
N.sup.2-((1S)-1-{4'-[1-(aminocarbonyl)cyclopropyl]biphenyl-4-yl}-2,2,2-tr-
ifluoroethyl)-N.sup.1-(1-cyanocyclopropyl)-4-fluoro-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-((1S)-2,2,2-trifluoro-1-{4--
[4-(trifluoromethyl)-1,3-thiazol-2-yl]phenyl}ethyl)-L-leucinamide;
N.sup.2-(1S)-1-{4'-[1-(aminocarbonyl)cyclopropyl]-2'-fluorobiphenyl-4-yl}-
-2,2,2-trifluoroethyl)-N.sup.1-(1-cyanocyclopropyl)-4-fluoro-L-leucinamide-
;
N.sup.1-(1-cyanocyclopropyl)-N.sup.2-((1S)-1-{4'-[(1R)-2,2-difluoro-1-hy-
droxyethyl]biphenyl-4-yl}-2,2,2-trifluoroethyl)-4-fluoro-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-N.sup.2-((1S)-1-{4'-[(1S)-2,2-difluoro-1-hyd-
roxyethyl]biphenyl-4-yl}-2,2,2-trifluoroethyl)-4-fluoro-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-((1S)-2,2,2-trifluoro-1-{4--
[5-methyl-6-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-N.sup.2-{(1S)-1-[4'-(1-cyanocyclopropyl)biph-
enyl-4-yl]-2,2,2-trifluoroethyl}-4-fluoro-L-leucinamide;
N.sup.2-[(1S)-1-(4-{5-[1-(aminocarbonyl)cyclopropyl]-3-chloropyridin-2-yl-
}phenyl)-2,2,2-trifluoroethyl]-N.sup.1-(1-cyanocyclopropyl)-4-fluoro-L-leu-
cinamide;
N.sup.2-[(1S)-1-(5-{4-[1-(aminocarbonyl)cyclopropyl]phenyl}pyrid-
in-2-yl)-2,2,2-trifluoroethyl]-N.sup.1-(1-cyanocyclopropyl)-4-fluoro-L-leu-
cinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-((1S)-2,2,2-triflu-
oro-1-{5-[4-(methylsulfonyl)phenyl]pyridin-2-yl}ethyl)-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-{(1S)-2,2,2-trifluoro-1-[4'-
-(methylsulfinyl)-1,1'-biphenyl-4-yl]ethyl}-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-N.sup.2-{(1S)-2,2-difluoro-1-[4'-(methylsulf-
onyl)biphenyl-4-yl]ethyl}-4-fluoro-L-leucinamide;
(1R,2R)-N-(1-cyanocyclopropyl)-5,5-difluoro-2-[4-[4-(methylsulfonyl)pheny-
l]-1H-pyrazol-3-yl]cyclohexanecarboxamide;
(1R,2R)-N-(1-cyanocyclopropyl)-5,5-difluoro-2-[4-[4-(methylsulfonyl)pheny-
l]-1-methyl-1H-pyrazol-3-yl]cyclohexanecarboxamide;
(1R,2R)-N-(1-cyanocyclopropyl)-5,5-dichloro-2-[4-[4-(methylsulfonyl)pheny-
l]-1-methyl-1H-pyrazol-3-yl]cyclohexanecarboxamide;
(1R,2R)-N-(1-cyanocyclopropyl)-5,5-difluoro-2-[4-[4-(methylsulfonyl)pheny-
l]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]cyclohexanecarboxamide;
(1R,2R)-N-(1-cyanocyclopropyl)-5,5-dichloro-2-[4-[4-(methylsulfonyl)pheny-
l]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]cyclohexanecarboxamide;
or a salt thereof.
15. The pharmaceutical composition according to claim 14 wherein
the cathepsin K inhibitor is
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-{(1S)-2,2,2-trifluoro-1-[4'-
-(methylsulfonyl)-1,1'-biphenyl-4-yl]ethyl}-L-leucinamide or a salt
thereof.
16. The composition according to claim 15 which is oral.
17. The composition according to claim 16 which is a unit dose.
18. The composition according to claim 17 which is a weekly
dose.
19. The composition according to claim 18 wherein the cathepsin-K
inhibitor is
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-{(1S)-2,2,2-trifluoro-1-[4'-
-(methylsulfonyl)-1,1'-biphenyl-4-yl]ethyl}-L-leucinamide.
20. The composition according to claim 19 which is a tablet.
21. The composition according to claim 19 which is a capsule.
22. The composition according to claim 19 which is a powder.
23. The composition according to claim 19 which is a liquid.
24.-42. (canceled)
Description
BACKGROUND OF THE INVENTION
[0001] A variety of disorders in humans and other mammals involve
or are associated with abnormal bone resorption. Such disorders
include, but are not limited to, osteoporosis, glucocorticoid
induced osteoporosis, Paget's disease, abnormally increased bone
turnover, periodontal disease, tooth loss, bone fractures,
rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis,
osteogenesis imperfecta, hypercalcemia of malignancy, multiple
myeloma, and metastatic bone disease. One of the most common of
these disorders is osteoporosis, which in its most frequent
manifestation occurs in postmenopausal women. Osteoporosis is a
systemic skeletal disease characterized by a low bone mass and
microarchitectural deterioration of bone tissue, with a consequent
increase in bone fragility and susceptibility to fracture.
Osteoporotic fractures are a major cause of morbidity and mortality
in the elderly population. As many as 50% of women and a third of
men will experience an osteoporotic fracture. A large segment of
the older population already has low bone density and a high risk
of fractures. There is a significant need to both prevent and treat
osteoporosis and other conditions associated with bone resorption.
Because osteoporosis, as well as other disorders associated with
bone loss, are generally chronic conditions, it is believed that
appropriate therapy will typically require chronic treatment.
[0002] Cysteine protease inhibitors such as E-64
(trans-epoxysuccinyl-L-leucylamide-(4-guanidino) butane) are known
to be effective in inhibiting bone resorption. See Delaisse, J M et
al., 1987, Bone 8:305-313, which is hereby incorporated by
reference in its entirety. Recently, cathepsin K was cloned and
found specifically expressed in osteoclasts See Tezuka, K et al.,
1994, J Biol Chem 269:1106-1109; Shi, G P et al., 1995, FEBS Lett
357:129-134; Bromme, D and Okamoto, K, 1995, Biol Chem Hoppe Seyler
376:379-384; Bromme, D et al., 1996, J Biol Chem 271:2126-2132;
Drake, F H et al., 1996, J Biol Chem 271:12511-12516, which are
hereby incorporated by reference in their entirety. Concurrent to
the cloning, the autosomal recessive disorder, pycnodysostosis,
characterized by an osteopetrotic phenotype with a decrease in bone
resorption, was mapped to mutations present in the cathepsin K
gene. To date, all mutations identified in the cathepsin K gene are
known to eliminate collagenase activity. See Gelb, B D et al.,
1996, Science 273:1236-1238; Johnson, M R et al., 1996, Genome Res
6:1050-1055; Hou, W-S et al., 1999 J. Clin. Invest. 103, 731-738
which are hereby incorporated by reference in their entirety.
Therefore, it appears that cathepsin K is involved in osteoclast
mediated bone resorption.
[0003] Human type I collagen, the major collagen in bone is a good
substrate for cathepsin K. See Kafienah, W, et al., 1998, Biochem J
331:727-732, which is hereby incorporated by reference in its
entirety. In vitro experiments using antisense oligonucleotides to
cathepsin K, have shown diminished bone resorption in vitro, which
is probably due to a reduction in translation of cathepsin K mRNA.
See Inui, T, et al., 1997, J Biol Chem 272:8109-8112, which is
hereby incorporated by reference in its entirety. The crystal
structure of cathepsin K has been resolved. See McGrath, M E, et
al., 1997, Nat Struct Biol 4:105-109; Zhao, B, et al., 1997, Nat
Struct Biol 4: 109-11, which are hereby incorporated by reference
in their entirety. Also, selective peptide based inhibitors of
cathepsin K have been developed See Bromme, D, et al., 1996,
Biochem J 315:85-89; Thompson, S K, et al., 1997, Proc Natl Acad
Sci USA 94:14249-14254, which are hereby incorporated by reference
in their entirety. Accordingly, inhibitors of cathepsin K can
reduce bone resorption. Such inhibitors would be useful in treating
disorders involving bone resorption, such as osteoporosis.
[0004] Weekly and monthly compositions of a cathpesin K inhibitor
would provide therapeutic advantages over other therapies and would
enhance convenience, patient compliance and patient
satisfaction.
SUMMARY OF THE INVENTION
[0005] The present invention relates to an oral pharmaceutical
composition comprising a cathepsin K inhibitor, or a
pharmaceutically acceptable salt thereof, or a mixture thereof,
adapted for inhibiting bone resorption according to a continuous
schedule having a dosage interval of once weekly, biweekly, twice
monthly or once monthly.
DETAILED DESCRIPTION OF THE INVENTION
[0006] The present invention relates to the use of a cathepsin K
inhibitor, or a pharmaceutically acceptable salt thereof, or a
mixture thereof, for the manufacture of a medicament, characterized
by a single-dose AUC.sub.0-168 of about 2.00-80.0 .mu.M/hr and a
C.sub.min of about 10 nM to about 200 nM, as an oral unit dose for
inhibiting bone resorption in a mammal in need thereof according to
a continuous schedule having a dosage interval of once weekly,
biweekly, twice monthly or once monthly. The present invention also
relates to a method of inhibiting bone resorption in mammal in need
thereof by administering a cathepsin K inhibitor, or a salt
thereof, or a mixture thereof, characterized by a single-dose
AUC.sub.0-168 of about 2.00-80.0 .mu.M/hr and a C.sub.min of about
10 nM to about 200 nM, in an oral unit dose according to a
continuous schedule having a dosage interval of once weekly,
biweekly, twice monthly or once monthly.
[0007] In an embodiment of the invention, the mammal, specifically
a human, is identified as suffering from or susceptible to upper
gastrointestinal disorders. In a class of the embodiment, the upper
gastrointestinal disorder is gastrointestinal reflux disease
(GERD), esophagitis, dyspepsia (heartburn) or ulcers.
[0008] In an embodiment of the invention, the present invention
relates to the use of about 2.5 mg to about 250 mg of a cathepsin K
inhibitor according to Formula I:
##STR00001##
wherein R.sup.1 is C.sub.1-3 alkyl which is substituted with two to
seven halo; R.sup.2 is hydrogen or halo;
X is N or CH;
[0009] D is aryl or heteroaryl, wherein each said aryl or
heteroaryl group, which may be monocyclic or bicyclic, is
optionally substituted on either the carbon or the heteroatom with
one to four substituents independently selected from methyl,
C.sub.1-6 haloalkyl, halo or --SO.sub.2R.sup.4; R.sup.3 is
hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkynyl, halo, cyano, aryl,
heteroaryl, C.sub.3-8 cycloalkyl, heterocyclyl, --OR.sup.4,
--C(O)N(R.sup.5)(R.sup.6), --C(R.sup.5)(R.sup.6)OH,
--C(R.sup.5)(R.sup.6)N(R.sup.4).sub.2, --SO.sub.mR.sup.4,
--SO.sub.2N(R.sup.4)(R.sup.5), or
--SO.sub.2N(R.sup.5)C(O)(R.sup.7); wherein said alkyl, alkynyl,
aryl, heteroaryl, cycloalkyl and heterocyclyl groups are optionally
substituted on either the carbon or the heteroatom with one to five
substituents independently selected from C.sub.1-6 alkyl or halo;
R.sup.4 is hydrogen, C.sub.1-6 alkyl, aryl, aryl(C.sub.1-4) alkyl,
heteroaryl, heteroaryl(C.sub.1-4)alkyl, C.sub.3-8 cycloalkyl,
C.sub.3-8 cycloalkyl(C.sub.1-4)alkyl, or
heterocyclyl(C.sub.1-4)alkyl; which are optionally substituted with
one, two, or three substituents independently selected from halo,
alkoxy or --SO.sub.2R.sup.7; R.sup.5 is hydrogen, C.sub.1-6 alkyl,
or C.sub.1-6 haloalkyl; R.sup.6 is hydrogen, C.sub.1-6 alkyl, or
C.sub.1-6 haloalkyl; Or R.sup.5 and R.sup.6 can be taken together
with the carbon or nitrogen atom between them to form a 3 to 6
membered ring; R.sup.7 is hydrogen or C.sub.1-6 alkyl which is
optionally substituted with one, two, or three substituents
independently selected from halo or cyano; m is an integer from
zero to two; or a salt, stereoisomer, N-oxide derivative, or a
mixture thereof, for the manufacture of a medicament as an oral
unit dose for inhibiting bone resorption in a mammal in need
thereof according to a continuous schedule having a dosage interval
of once weekly, biweekly, twice monthly or once monthly.
[0010] In an embodiment of the invention, the present invention
relates to the use of about 2.5 mg to about 250 mg of a cathepsin K
inhibitor according to Formula II:
##STR00002##
wherein R.sup.1 is halo; R.sup.2 is halo; R.sup.3 is hydrogen,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-6 cycloalkyl, aryl or
heteroaryl; or a salt, stereoisomer, N-oxide derivative, or a
mixture thereof, for the manufacture of a medicament as an oral
unit dose for inhibiting bone resorption in a mammal in need
thereof according to a continuous schedule having a dosage interval
of once weekly, biweekly, twice monthly or once monthly.
[0011] In an embodiment of the invention, the present invention
relates to a method of inhibiting bone resorption in mammal in need
thereof by administering a cathepsin K inhibitor according to
formula I or II, or a pharmaceutically acceptable salt thereof, or
a mixture thereof, characterized by a single-dose AUC.sub.0-168 of
about 2.00-80.0 .mu.M/hr and a C.sub.min of about 10 nM to about
200 nM, in an oral unit dose according to a continuous schedule
having a dosage interval of once weekly, biweekly, twice monthly or
once monthly.
[0012] In a class of the embodiment, the present invention relates
to the use of an oral pharmaceutical composition comprising about
2.5 mg to about 250 mg of a compound selected from the group
consisting of:
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-{(1S)-2,2,2-trifluoro-1-[4'-
-(methylsulfonyl)-1,1'-biphenyl-4-yl]ethyl}-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-{(1S)-2,2,2-trifluoro-1-[2'-
-methyl-4'-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide;
N.sup.2-{(1S)-1-[4'-(aminosulfonyl)biphenyl-4-yl]-2,2,2-trifluoroethyl}-N-
.sup.1-(1-cyanocyclopropyl)-4-fluoro-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-[(1S)-2,2,2-trifluoro-1-(4'-
-fluorobiphenyl-4-yl)ethyl]-L-leucinamide;
N.sup.2-((1S)-1-{4'-[1-(aminocarbonyl)cyclopropyl]biphenyl-4-yl}-2,2,2-tr-
ifluoroethyl)-N.sup.1-(1-cyanocyclopropyl)-4-fluoro-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-((1S)-2,2,2-trifluoro-1-{4--
[4-(trifluoromethyl)-1,3-thiazol-2-yl]phenyl}ethyl)-L-leucinamide;
N.sup.2-((1S)-1-{4'-[1-(aminocarbonyl)cyclopropyl]-2'-fluorobiphenyl-4-yl-
}-2,2,2-trifluoroethyl)-N.sup.1-(1-cyanocyclopropyl)-4-fluoro-L-leucinamid-
e;
N.sup.1-(1-cyanocyclopropyl)-N.sup.2-((1S)-1-{4'-[(1R)-2,2-difluoro-1-h-
ydroxyethyl]biphenyl-4-yl}-2,2,2-trifluoroethyl)-4-fluoro-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-N.sup.2-((1S)-1-{4'-[(1S)-2,2-difluoro-1-hyd-
roxyethyl]biphenyl-4-yl}-2,2,2-trifluoroethyl)-4-fluoro-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-((1S)-2,2,2-trifluoro-1-{4--
[5-methyl-6-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-N.sup.2-{(1S)-1-[4'-(1-cyanocyclopropyl)biph-
enyl-4-yl]-2,2,2-trifluoroethyl}-4-fluoro-L-leucinamide;
N.sup.2-[(1S)-1-(4-{5-[1-(aminocarbonyl)cyclopropyl]-3-chloropyridin-2-yl-
}phenyl)-2,2,2-trifluoroethyl]-N.sup.1-(1-cyanocyclopropyl)-4-fluoro-L-leu-
cinamide;
N.sup.2-[(1S)-1-(5-{4-[1-(aminocarbonyl)cyclopropyl]phenyl}pyrid-
in-2-yl)-2,2,2-trifluoroethyl]-N.sup.1-(1-cyanocyclopropyl)-4-fluoro-L-leu-
cinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-(1S)-2,2,2-trifluo-
ro-1-{5-[4-(methylsulfonyl)phenyl]pyridin-2-yl}ethyl)-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-(1S)-2,2,2-trifluoro-1-[4'--
(methylsulfinyl)-1,1'-biphenyl-4-yl]ethyl}-L-leucinamide;
N.sup.1-(cyanocyclopropyl)-N.sup.2-{(1S)-2,2-difluoro-1-[4'-(methylsulfon-
yl)biphenyl-4-yl]ethyl}-4-fluoro-L-leucinamide;
(1R,2R)-N-(1-cyanocyclopropyl)-5,5-difluoro-2-[4-[4-(methylsulfonyl)pheny-
l]-1H-pyrazol-3-yl]cyclohexanecarboxamide;
(1R,2R)-N-(1-cyanocyclopropyl)-5,5-difluoro-2-[4-[4-(methylsulfonyl)pheny-
l]-1-methyl-1H-pyrazol-3-yl]cyclohexanecarboxamide;
(1R,2R)-N-(1-cyanocyclopropyl)-5,5-dichloro-2-[4-[4-(methylsulfonyl)pheny-
l]-1-methyl-1H-pyrazol-3-yl]cyclohexanecarboxamide;
(1R,2R)-N-(1-cyanocyclopropyl)-5,5-difluoro-2-[4-[4-(methylsulfonyl)pheny-
l]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]cyclohexanecarboxamide;
(1R,2R)-N-(1-cyanocyclopropyl)-5,5-dichloro-2-[4-[4-(methylsulfonyl)pheny-
l]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]cyclohexanecarboxamide;
and salts thereof.
[0013] In another embodiment of the invention, the present
invention relates to a method of inhibiting bone resorption in a
mammal in need thereof by administering a cathepsin K inhibitor
selected from the compounds described above.
[0014] In a class of the embodiment of the invention, the cathepsin
K inhibitor is
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-{(1S)-2,2,2-trifluoro-1-[4'-
-(methylsulfonyl)-1,1'-biphenyl-4-yl]ethyl}-L-leucinamide.
[0015] Methods of preparation for the above compounds are described
in International Publications WO 03/075836, which published on Sep.
18, 2003 and WO 2005/000800, which published on Jan. 6, 2005.
[0016] In an embodiment of the invention, the present invention
relates to the use of an oral pharmaceutical composition comprising
about 2.5 mg to about 250 mg of a cathepsin K inhibitor and another
agent selected from the group consisting of an organic
bisphosphonate; an estrogen receptor modulator; an androgen
receptor modulator; an inhibitor of osteoclast proton ATPase; an
inhibitor of HMG-CoA reductase; an integrin receptor antagonist; an
osteoblast anabolic agent; calcium; Vitamin D; a synthetic Vitamin
D analogue; a Nonsteroidal anti-inflammatory drug; a selective
cyclooxygenase-2 inhibitor; an inhibitor of interleukin-1 beta; a
LOX/COX inhibitor; a RANKL inhibitor; and the pharmaceutically
acceptable salts and mixtures thereof. In a class of the
embodiment, the agent is Vitamin D. In a subclass of the
embodiment, the amount of Vitamin D is 2,800, IU, 5,600 IU, 7,000
IU, 8,400 IU, 11,200 IU, 14,000 IU, 16,800 IU or 19,600 IU. In a
further subclass of the embodiment, the amount of Vitamin D to be
dosed weekly is 2,800, IU, 5,600 IU, 7,000 IU, 8,400 IU or 11,200
IU. In a further subclass of the embodiment, the amount of Vitamin
D to be dosed monthly is 11,200 IU, 14,000 IU, 15,400 IU, 16,800 IU
or 19,600 IU.
[0017] It is understood that substituents and substitution patterns
on the compounds described herein can be selected by one of
ordinary skill in the art to provide compounds that are chemically
and metabolically stable and that can be readily synthesized by
techniques known in the art, as well as those methods set forth
below, from readily available starting materials. If a substituent
is itself substituted with more than one group, it is understood
that these multiple groups may be on the same carbon or on
different carbons, so long as a stable structure results. The
phrase "optionally substituted with one or more substituents"
should be taken to be equivalent to the phrase "optionally
substituted with at least one substituent" and in such cases the
preferred embodiment will have from zero to three substituents.
[0018] As used herein, "alkyl" is intended to include both branched
and straight-chain saturated aliphatic hydrocarbon groups having
one to ten carbon atoms unless otherwise specified. For example,
C.sub.1-C.sub.10 as in "C.sub.1-C.sub.10 alkyl" is defined to
include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons in a
linear, branched, or cyclic arrangement. For example,
"C.sub.1-C.sub.10 alkyl" specifically includes methyl, ethyl,
propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so
on.
[0019] "Alkoxy" or "alkyloxy" represents an alkyl group as defined
above, unless otherwise indicated, wherein said alkyl group is
attached through an oxygen bridge. Examples of alkoxy include
methoxy, ethoxy and the like.
[0020] The term "cycloalkyl" or "carbocycle" shall mean cyclic
rings of alkanes of three to eight total carbon atoms, unless
otherwise indicated, or any number within this range (i.e.,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or
cyclooctyl).
[0021] The term "alkynyl" refers to a hydrocarbon radical straight
or branched, containing from 2 to 10 carbon atoms, unless otherwise
specified, containing at least 1 carbon to carbon triple bond. Up
to 3 carbon-carbon triple bonds may be present. Thus,
"C.sub.2-C.sub.6 alkynyl" means an alkynyl radical having from 2 to
6 carbon atoms. Alkynyl groups include ethynyl, propynyl and
butynyl. The straight, branched or cyclic portion of the alkynyl
group may contain triple bonds and may be substituted if a
substituted alkynyl group is indicated.
[0022] In certain instances, substituents may be defined with a
range of carbons that includes zero, such as
(C.sub.0-C.sub.6)alkylene-aryl. If aryl is taken to be phenyl, this
definition would include phenyl itself as well as --CH.sub.2Ph,
--CH.sub.2CH.sub.2Ph, CH(CH.sub.3) CH.sub.2CH(CH.sub.3)Ph, and so
on.
[0023] As used herein, "aryl" is intended to mean any stable
monocyclic or bicyclic carbon moiety of up to 12 atoms in each
ring, wherein at least one ring is aromatic. Examples of such aryl
groups include phenyl, naphthyl, tetrahydronaphthyl, indanyl,
biphenyl, phenanthryl, anthryl or acenaphthyl. A preferable example
of aryl is phenyl. In cases where the aryl substituent is bicyclic
and one ring is non-aromatic, it is understood that attachment is
via the aromatic ring.
[0024] The term "heteroaryl", as used herein, represents a stable
monocyclic, bicyclic or tricyclic group of up to 10 atoms in each
ring, wherein at least one ring is aromatic and contains from 1 to
4 heteroatoms selected from the group consisting of O, N and S.
Heteroaryl groups within the scope of this definition include but
are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl,
benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl,
carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl,
indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl,
isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl,
oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl,
pyridopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl,
quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,
thiazolyl, thienyl, triazolyl, dihydrobenzoimidazolyl,
dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,
dihydroindolyl, dihydroquinolinyl, methylenedioxybenzene,
benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, oxazolyl,
and tetrahydroquinoline. In cases where the heteroaryl substituent
is bicyclic and one ring is non-aromatic or contains no
heteroatoms, it is understood that attachment is via the aromatic
ring or via the heteroatom containing ring, respectively. If the
heteroaryl contains nitrogen atoms, it is understood that the
corresponding N-oxides thereof are also encompassed by this
definition.
[0025] As appreciated by those of skill in the art, "halo" or
"halogen" as used herein is intended to include chloro, fluoro,
bromo and iodo. The term "keto" means carbonyl (C.dbd.O).
[0026] The term "haloalkyl" means an alkyl radical as defined
above, unless otherwise specified, that is substituted with one to
five, preferably one to three halogen. Representative examples
include, but are not limited to trifluoromethyl, dichloroethyl, and
the like.
[0027] The term "arylalkyl" includes an alkyl portion where alkyl
is as defined above and to include an aryl portion where aryl is as
defined above. Examples of arylalkyl include, but are not limited
to, benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl,
fluorophenylethyl, and chlorophenylethyl. Examples of alkylaryl
include, but are not limited to, toluyl, ethylphenyl, and
propylphenyl.
[0028] The term "heteroarylalkyl" as used herein, shall refer to a
system that includes a heteroaryl portion, where heteroaryl is as
defined above, and contains an alkyl portion. Examples of
heteroarylalkyl include, but are not limited to, thienylmethyl,
thienylethyl, thienylpropyl, pyridylmethyl, pyridylethyl and
imidazoylmethyl.
[0029] The term "cycloalkylalkyl" includes an alkyl portion where
alkyl is as defined above and also includes a cycloalkyl portion
where cycloalkyl is as defined above. Examples of cycloalkylalkyl
include, but are not limited to, cyclopropylmethyl,
cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, and the
like.
[0030] The term "heterocyclylalkyl" as used herein, shall refer to
a system that includes a heterocyclyl portion, where heterocyclyl
is as defined above, and contains an alkyl portion. Examples of
heterocyclylalkyl include, but are not limited to, oxiranyl,
azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and
morpholinyl.
[0031] The term "heterocycle" or "heterocyclyl" as used herein is
intended to mean a 5- to 10-membered nonaromatic ring, unless
otherwise specified, containing from 1 to 4 heteroatoms selected
from the group consisting of O, N, S, SO, or SO.sub.2 and includes
bicyclic groups. "Heterocyclyl" therefore includes, but is not
limited to the following: piperazinyl, piperidinyl, pyrrolidinyl,
morpholinyl, thiomorpholinyl, tetrahydropyranyl,
dihydropiperidinyl, tetrahydrothiophenyl and the like. If the
heterocycle contains a nitrogen, it is understood that the
corresponding N-oxides thereof are also emcompassed by this
definition.
[0032] The cathepsin K inhibitors described herein also include
N-oxide derivatives and protected derivatives of compounds of
Formula I. For example, when compounds of Formula I contain an
oxidizable nitrogen atom, the nitrogen atom can be converted to an
N-oxide by methods well known in the art. Also when compounds of
Formula I contain groups such as hydroxy, carboxy, thiol or any
group containing a nitrogen atom(s), these groups can be protected
with a suitable protecting groups. A comprehensive list of suitable
protective groups can be found in T. W. Greene, Protective Groups
in Organic Synthesis, John Wiley & Sons, Inc. 1981, the
disclosure of which is incorporated herein by reference in its
entirety.
[0033] Whenever the term "alkyl" or "aryl" or either of their
prefix roots appear in a name of a substituent (e.g., aryl
C.sub.0-8 alkyl) it shall be interpreted as including those
limitations given above for "alkyl" and "aryl." Designated numbers
of carbon atoms (e.g., C.sub.1-10) shall refer independently to the
number of carbon atoms in an alkyl or cyclic alkyl moiety or to the
alkyl portion of a larger substituent in which alkyl appears as its
prefix root.
[0034] The cathepsin K inhibitors described herein can be
administered in such oral dosage forms as tablets, capsules (each
of which includes sustained release or timed release formulations),
pills, powders, granules, liquids, elixers, suspensions, syrups and
emulsions.
[0035] The dosage regimen utilizing the cathepsin K inhibitors
described herein is selected in accordance with a variety of
factors including type, species, age, weight, sex and medical
condition of the patient; the severity of the condition to be
treated; the route of administration; the renal and hepatic
function of the patient; and the particular compound or salt
thereof employed. An ordinarily skilled physician, veterinarian or
clinician can readily determine and prescribe the effective amount
of the drug required to prevent, counter or arrest the progress of
the condition.
[0036] The present invention also encompasses a pharmaceutical
composition useful in the treatment of osteoporosis or other bone
disorders, comprising the administration of a therapeutically
effective amount of the cathepsin K inhibitors described herein,
with or without pharmaceutically acceptable carriers or diluents.
Suitable compositions of this invention include aqueous solutions
comprising compounds of this invention and pharmacologically
acceptable carriers. An embodiment of the invention includes a
pharmaceutical composition comprising about 2.5 mg to about 200 mg
of a cathepsin K inhibitor selected from
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-{(1S)-2,2,2-trifluoro-1-[4'-
-(methylsulfonyl)-1,1'-biphenyl-4-yl]ethyl}-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-{(1S)-2,2,2-trifluoro-1-[2'-
-methyl-4'-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide;
N.sup.2-{(1S)-1-[4'-(aminosulfonyl)biphenyl-4-yl]-2,2,2-trifluoroethyl}-N-
.sup.1-(1-cyanocyclopropyl)-4-fluoro-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-[(1S)-2,2,2-trifluoro-1-(4'-
-fluorobiphenyl-4-yl)ethyl]-L-leucinamide;
N.sup.2-((1S)-1-{4'-[1-(aminocarbonyl)cyclopropyl]biphenyl-4-yl}-2,2,2-tr-
ifluoroethyl)-N.sup.1-(1-cyanocyclopropyl)-4-fluoro-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-((1S)-2,2,2-trifluoro-1-{4--
[4-(trifluoromethyl)-1,3-thiazol-2-yl]phenyl}ethyl)-L-leucinamide;
N.sup.2-((1S)-1-{4'-[1-(aminocarbonyl)cyclopropyl]-2'-fluorobiphenyl-4-yl-
}-2,2,2-trifluoroethyl)-N.sup.1-(1-cyanocyclopropyl)-4-fluoro-L-leucinamid-
e;
N.sup.1-(1-cyanocyclopropyl)-N.sup.2-((1S)-1-{4'-[(1R)-2,2-difluoro-1-h-
ydroxyethyl]biphenyl-4-yl}-2,2,2-trifluoroethyl)-4-fluoro-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-N.sup.2-((1S)-1-{4'-[(1S)-2,2-difluoro-1-hyd-
roxyethyl]biphenyl-4-yl}-2,2,2-trifluoroethyl)-4-fluoro-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-((1S)-2,2,2-trifluoro-1-{4[-
5-methyl-6-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-N.sup.2-{(1S)-1-[4'-(1-cyanocyclopropyl)biph-
enyl-4-yl]-2,2,2-trifluoroethyl}-4-fluoro-L-leucinamide;
N.sup.2-[(1S)-1-(4-{5-[1-(aminocarbonyl)cyclopropyl]-3-chloropyridin-2-yl-
}phenyl)-2,2,2-trifluoroethyl]-N.sup.1-(1-cyanocyclopropyl)-4-fluoro-L-leu-
cinamide;
N.sup.2-[(1S)-1-(5-{4-[1-(aminocarbonyl)cyclopropyl]phenyl}pyrid-
in-2-yl)-2,2,2-trifluoroethyl]-N.sup.1-(1-cyanocyclopropyl)-4-fluoro-L-leu-
cinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2((1S)-2,2,2-trifluo-
ro-1-{5-[4-(methylsulfonyl)phenyl]pyridin-2-yl}ethyl)-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-{(1S)-2,2,2-trifluoro-1-[4'-
-(methylsulfinyl)-1,1'-biphenyl-4-yl]ethyl}-L-leucinamide;
N.sup.1-(1-cyanocyclopropyl)-N.sup.2-{(1S)-2,2-difluoro-1-[4'-(methylsulf-
onyl)biphenyl-4-yl]ethyl}-4-fluoro-L-leucinamide;
(1R,2R)-N-(1-cyanocyclopropyl)-5,5-difluoro-2-[4-[4-(methylsulfonyl)pheny-
l]-1H-pyrazol-3-yl]cyclohexanecarboxamide;
(1R,2R)-N-(1-cyanocyclopropyl)-5,5-difluoro-2-[4-[4-(methylsulfonyl)pheny-
l]-1-methyl-1H-pyrazol-3-yl]cyclohexanecarboxamide;
(1R,2R)-N-(1-cyanocyclopropyl)-5,5-dichloro-2-[4-[4-(methylsulfonyl)pheny-
l]-1-methyl-1H-pyrazol-3-yl]cyclohexanecarboxamide;
(1R,2R)-N-(1-cyanocyclopropyl)-5,5-difluoro-2-[4-[4-(methylsulfonyl)pheny-
l]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]cyclohexanecarboxamide;
(1R,2R)-N-(1-cyanocyclopropyl)-5,5-dichloro-2-[4-[4-(methylsulfonyl)pheny-
l]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]cyclohexanecarboxamide;
or a salt thereof.
[0037] In a class of the embodiment, the cathepsin K inhibitor is
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-{(1S)-2,2,2-trifluoro-1-[4'-
-(methylsulfonyl)-1,1'-biphenyl-4-yl]ethyl}-L-leucinamide or a salt
thereof.
[0038] In one exemplary application, a suitable amount of compound
is administered to a mammal undergoing treatment for a cathepsin
dependent condition. Oral dosages of the present invention, when
used for the indicated effects, will range between about 0.01 mg
per kg of body weight per week (mg/kg/week) to about 10 mg/kg/week,
preferably 0.1 to 10 mg/kg/week, and most preferably 0.1 to 5.0
mg/kg/week. For oral administration, the compositions are
preferably provided in the form of tablets containing 2.5 mg, 3.5
mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 40 mg, 50 mg, 80 mg, 100 mg
and 200 mg of the active ingredient for the symptomatic adjustment
of the dosage to the patient to be treated. A medicament typically
contains from about 2.5 mg to about 200 mg of the active
ingredient, specifically, 2.5 mg, 3.5 mg, 5 mg, 10 mg, 20 mg, 25
mg, 35 mg, 40 mg, 50 mg, 80 mg, 100 mg and 200 mg of active
ingredient. Advantageously, the cathepsin K inhibitor may be
administered in a single weekly dose. Alternatively, the cathepsin
K inhibitor may be administered in a biweekly, twice monthly or
monthly dose.
[0039] The compounds of this invention may be administered to
mammals, preferably humans, either alone or, preferably, in
combination with pharmaceutically acceptable carriers or diluents,
optionally with known adjuvants, such as alum, in a pharmaceutical
composition, according to standard pharmaceutical practice. The
compounds can be administered orally.
[0040] In the case of tablets for oral use, carriers which are
commonly used include lactose and corn starch, and lubricating
agents, such as magnesium stearate, are commonly added. For oral
administration in capsule form, useful diluents include lactose and
dried corn starch. For oral use of a therapeutic compound according
to this invention, the selected compound may be administered, for
example, in the form of tablets or capsules, or as an aqueous
solution or suspension. For oral administration in the form of a
tablet or capsule, the active drug component can be combined with
an oral, non-toxic, pharmaceutically acceptable, inert carrier such
as lactose, starch, sucrose, glucose, methyl cellulose, magnesium
stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol
and the like; for oral administration in liquid form, the oral drug
components can be combined with any oral, non-toxic,
pharmaceutically acceptable inert carrier such as ethanol,
glycerol, water, polyethylene glycol, and the like. Moreover, when
desired or necessary, suitable binders, lubricants, disintegrating
agents and coloring agents can also be incorporated into the
mixture. Suitable binders include starch, gelatin, natural sugars
such as glucose or beta-lactose, corn sweeteners, natural and
synthetic gums such as acacia, tragacanth or sodium alginate,
carboxymethylcellulose, polyethylene glycol, waxes and the like.
Lubricants used in these dosage forms include sodium oleate, sodium
stearate, magnesium stearate, sodium benzoate, sodium acetate,
sodium chloride and the like. Disintegrators include, without
limitation, starch, methyl cellulose, agar, bentonite, xanthan gum
and the like. When aqueous suspensions are required for oral use,
the active ingredient is combined with emulsifying and suspending
agents. If desired, certain sweetening and/or flavoring agents may
be added. For intramuscular, intraperitoneal, subcutaneous and
intravenous use, sterile solutions of the active ingredient are
usually prepared, and the pH of the solutions should be suitably
adjusted and buffered. For intravenous use, the total concentration
of solutes should be controlled in order to render the preparation
isotonic.
[0041] The cathepsin K inhibitors described herein can also be
administered in the form of liposome delivery systems, such as
small unilamellar vesicles, large unilamellar vesicles and
multilamellar vesicles. Liposomes can be formed from a variety of
phospholipids, such as cholesterol, stearylamine or
phosphatidylcholines.
[0042] Cathepsin K inhibitors described herein may also be
delivered by the use of monoclonal antibodies as individual
carriers to which the compound molecules are coupled. The cathepsin
K inhibitors described herein may also be coupled with soluble
polymers as targetable drug carriers. Such polymers can include
polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamide-phenol,
polyhydroxy-ethylaspartamide-phenol, or
polyethyleneoxide-polylysine substituted with palmitoyl residues.
Furthermore, the cathepsin K inhibitors described herein may be
coupled to a class of biodegradable polymers useful in achieving
controlled release of a drug, for example, polylactic acid,
polyglycolic acid, copolymers of polyactic and polyglycolic acid,
polyepsilon caprolactone, polyhydroxy butyric acid,
polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates
and crosslinked or amphipathic block copolymers of hydrogels.
[0043] The present invention also encompasses a kit adapted for a
continuous dosing schedule of a cathepsin K inhibitor having a
dosing periodicity of once weekly, biweekly, twice monthly or once
monthly comprising a number of unit doses of a pharmaceutical
composition comprising a cathepsin K inhibitor, pharmaceutically
acceptable salts thereof, or a mixture thereof.
[0044] In an embodiment of the invention, the cathepsin K inhibitor
is
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-{(1S)-2,2,2-trifluoro-1-[4'-
-(methylsulfonyl)-1,1'-biphenyl-4-yl]ethyl}-L-leucinamide.
[0045] In a further embodiment of the invention, the kit is for
weekly administration. In a class of the invention, the unit doses
comprise from 2.5 mg to about 200 mg of the cathepsin K inhibitor.
In a subclass of the invention, the unit doses comprise 2.5 mg, 3.5
mg, 5 mg, 10 mg, 20 mg, 25 mg, 35 mg, 40 mg, 50 mg, 80 mg, 100 mg
or 200 mg of the cathepsin K inhibitor. In another class of the
invention, the kit is adapted for twice-weekly dosing. In a class
of the invention, the unit doses comprise from 2.5 mg to 50 mg of
the cathepsin K inhibitor. In a subclass of the invention, the unit
doses comprise from 2.5 mg to 25 mg of the cathepsin K inhibitor.
In another class of the invention, the kit is adapted for biweekly
or twice-monthly dosing. In a class of the invention, the unit
doses comprise from 2.5 mg to 50 mg of the cathepsin K inhibitor.
In a subclass of the invention, the unit doses comprise from 2.5 mg
to 25 mg of the cathepsin K inhibitor.
[0046] In an embodiment of the invention, the kit is a blister
pack. In a class of the invention, the kit further comprises a
memory aid designating the days in the treatment schedule in which
the dosages can be administered. In a subclass of the invention,
the memory aid is a calendar insert.
[0047] In an embodiment of the invention, the kit is adapted for
administration on the same day of each week. In a class of the
invention, the kit is adapted for weekly administration every
Sunday.
[0048] Another embodiment of the invention is a method of
inhibiting bone loss in a mammal in need thereof, comprising
administering to the mammal a therapeutically effective amount of
any of the compounds or any of the pharmaceutical compositions
described above. Another embodiment of the invention is a method of
reducing bone loss in a mammal in need thereof, comprising
administering to the mammal a therapeutically effective amount of
any of the compounds or any of the pharmaceutical compositions
described above. The utility of cathepsin K inhibitors in the
inhibition of bone resorption is known in the literature, see
Stroup, G B, Lark, M W, Veber, D F., Bhattacharrya, A, Blake, S,
Dare, L C, Erhard, K F, Hoffman, S J, James, I E, Marquis, R W, Ru,
Y, Vasko-Moser, J A, Smith, B R, Tomaszek, T and Gowen, M, "Potent
and selective inhibition of human cathepsin K leads to inhibition
of bone resorption in vivo in a nonhuman primate", J. Bone Miner.
Res., 16:1739-1746; 2001; and Votta, B J, Levy, M A, Badger, A,
Dodds, R A, James, I E, Thompson, S, Bossard, M J, Carr, T, Connor,
J R, Tomaszek, T A, Szewczuk, L, Drake, F H, Veber, D, and Gowen,
M, "Peptide aldehyde inhibitors of cathepsin K inhibit bone
resorption both in vivo and in vitro", J. Bone Miner. Res.
12:1396-1406; 1997.
[0049] Another embodiment of the invention is a method of treating
or preventing osteoporosis in a mammal in need thereof, comprising
administering to the mammal a therapeutically effective amount of
any of the compounds or any of the above pharmaceutical
compositions described above. The utility of cathepsin K inhibitors
in the treatment or prevention of osteoporosis is known in the
literature, see Saftig, P, Hunziker, Wehmeyer, O, Jones, S, Boyde,
A, Rommerskirch, W, Moritz, J D, Schu, P, and Vonfigura, K,
"Impaired osteoclast bone resorption leads to osteopetrosis in
cathepsin K-deficient mice", Proc. Natl. Acad. Sci. USA
95:13453-13458; 1998.
[0050] Another embodiment of the invention is a method of treating
or preventing rheumatoid arthritic condition in a mammal in need
thereof, comprising administering to the mammal a therapeutically
effective amount of any of the compounds or any of the
pharmaceutical compositions described above. It is known in the
literature that progressive destruction of the periarticular bone
is a major cause of joint dysfunction and disability in patients
with rheumatoid arthritis (RA), see Goldring S R, "Pathogenesis of
bone erosions in rheumatoid arthritis", Curr. Opin. Rheumatol.
2002; 14: 406-10. Analysis of joint tissues from patients with RA
have provided evidence that cathepsin K positive osteoclasts are
the cell types that mediate the focal bone resorption associated
with rheumatoid synovial lesion, see Hou, W-S, Li, W, Keyszer, G,
Weber, E, Levy, R, Klein, M J, Gravallese, E M, Goldring, S R,
Bromme, D, "Comparison of Cathepsin K and S expression within the
Rheumatoid and Osteoarthritic Synovium", Arthritis Rheumatism 2002;
46: 663-74. In addition, generalized bone loss is a major cause of
morbidity associated with severe RA. The frequency of hip and
spinal fractures is substantially increased in patients with
chronic RA, see Gould A, Sambrook, P, Devlin J et al, "Osteoclastic
activation is the principal mechanism leading to secondary
osteoporosis in rheumatoid arthritis", J. Rheumatol. 1998; 25:
1282-9. The utility of cathepsin K inhibitors in the treatment or
prevention of resorption in subarticular bone and of generalized
bone loss represent a rational approach for pharmacological
intervention on the progression of rheumatoid arthritis.
[0051] Another embodiment of the invention is a method of treating
or preventing the progression of osteoarthritis in a mammal in need
thereof, comprising administering to the mammal a therapeutically
effective amount of any of the compounds or any of the
pharmaceutical compositions described above. It is known in the
literature that osteoarthritis (OA) is accompanied with
well-defined changes in the joints, including erosion of the
articular cartilage surface, peri-articular endochondral
ossification/osteophytosis, and subchondral bony sclerosis and cyst
formation, see Oettmeier R, Abendroth, K, "Osteoarthritis and bone:
osteologic types of osteoarthritis of the hip", Skeletal Radiol.
1989; 18: 165-74. Recently, the potential contribution of
subchondral bone sclerosis to the initiation and progression of OA
have been suggested. Stiffened subchondral bone as the joint
responding to repetitive impulsive loading, is less able to
attenuate and distribute forces through the joint, subjecting it to
greater mechanical stress across the articular cartilage surface.
This in turn accelerates cartilage wear and fibrillate, see Radin,
E L and Rose R M, "Role of subchondral bone in the initiation and
progression of cartilage damage", Clin. Orthop. 1986; 213: 34-40
Inhibition of excessive subarticular bone resorption by an
anti-resorptive agent such as a cathepsin K inhibitor, will lead to
inhibition of subchondral bone turnover, thus may have a favorable
impact on OA progression.
[0052] In addition to the above hypothesis, cathepsin K protein
expression was recently identified in synovial fibroblasts,
macrophage-like cells, and chondrocytes from synovium and articular
cartilage specimens derived from OA patients, see Hou, W-S, Li, W,
Keyszer, G, Weber, E, Levy, R, Klein, M J, Gravallese, E M,
Goldring, S R, Bromme, D, "Comparison of Cathepsin K and S
expression within the Rheumatoid and Osteoarthritic Synovium",
Arthritis Rheumatism 2002; 46: 663-74; and Dodd, R A, Connor, J R,
Drake, F H, Gowen, M, "Expression of Cathepsin K messenger RNA in
giant cells and their precursors in human osteoarthritic synovial
tissues", Arthritis Rheumatism 1999; 42: 1588-93; and Konttinen, Y
T, Mandelin, J, Li, T-F, Salo, J, Lassus, J et al., "Acidic
cysteine endoproteinase cathepsin K in the degeneration of the
superficial articular hyaline cartilage in osteoarthritis",
Arthritis Rheumatism 2002; 46: 953-60. These recent studies thus
implicated the role of cathepsin K in the destruction of collagen
type II in the articular cartilage associated with the progression
of osteoarthritis. The utility of cathepsin K inhibitors in the
treatment or prevention of osteoarthritis as described in this
invention thus comprise of two different mechanisms, one is on the
inhibition of osteoclast-driven subchondral bone turnover, and two
is on the direct inhibition of collagen type II degeneration in the
synovium and cartilage of patients with OA.
[0053] Another embodiment of the invention is a method of treating
cancer in a mammal in need thereof, comprising administering to the
mammal a therapeutically effective amount of any of the compounds
or any of the pharmaceutical compositions described above. It is
known in the literature that cathepsin K is expressed in human
breast carcinoma, prostate cancer and chordoma and has matrix
degrading capabilities, see Littlewood-Evans A J, Bilbe G, Bowler W
B, Farley D, Wlodarski B, Kokubo T, Inaoka T, Sloane J, Evans D B,
Gallagher J A, "The osteoclast-associated protease cathepsin K is
expressed in human breast carcinoma", Cancer Res 1997 Dec.
1;57(23):5386-90; Brubaker K D, Vessella R L, True L D, Thomas R,
Corey E "Cathepsin K mRNA and protein expression in prostate cancer
progression", J Bone Miner Res 2003 18, 222-30; and Haeckel C,
Krueger S, Kuester D, Ostertag H, Samii M, Buehling F, Broemme D,
Czerniak B, Roessner A, "Expression of cathepsin K in chordoma",
Hum Pathol 2000 July; 31(7):834-40.
[0054] Another embodiment of the invention is a method of treating
atherosclerosis in a mammal in need thereof, comprising
administering to the mammal a therapeutically effective amount of
any of the compounds or any of the pharmaceutical compositions
described above. It is known in the literature that cathepsin K is
expressed in human atheroma and has significant elastase activity,
see Sukhova G K, Shi G P, Simon D I, Chapman H A, Libby P,
"Expression of the elastolytic cathepsins S and K in human atheroma
and regulation of their production in smooth muscle cells", J Clin
Invest 1998 August 102, 576-83.
[0055] Another embodiment of the invention is a method of treating
obesity and obesity related conditions in a mammal in need thereof,
comprising administering to the mammal a therapeutically effective
amount of any of the compounds or any of the pharmaceutical
compositions described above. It is known in the literature that
cathepsin K mRNA is increased in adipose tissue in several mouse
models of obesity. In lean and obese male humans, a significant
correlation between cathepsin K gene expression in adipose tissue
and body mass index is observed see Chiellini C, Costa M, Novelli S
E, Amri E Z, Benzi L, Bertacca A, Cohen P, Del Prato S, Friedman J
M, Maffei M, "Identification of cathepsin K as a novel marker of
adiposity in white adipose tissue", Cell Physiol 2003, 195, 309-21.
These data show that a relationship exists between cathepsin K and
adipogenesis and obesity.
[0056] Another embodiment of the invention is a method of treating
chronic obstructive pulmonary disease in a mammal in need thereof,
comprising administering to the mammal a therapeutically effective
amount of any of the compounds or any of the pharmaceutical
compositions described above. It is known in the literature that
cathepsin K plays a role in lung fibrosis, see Buhling, F, et al.,
"Pivotal role of cathepsin K in lung fibrosis", Am J Pathol. 2004
June; 164(6):2203-16.
[0057] Another embodiment of the invention is a method of treating
parasitic infections in a mammal in need thereof, comprising
administering to the mammal a therapeutically effective amount of
any of the compounds or any of the pharmaceutical compositions
described above. It is known in the literature that mammalian
cathepsins are related to the papain-like cysteine proteases which
play an important role in the life cycle of these parasites. Such
parasites are involved in the diseases of malaria, American
trypanosomiasis, African trypanosomiasis, leishmaniasis,
giardiasis, trichomoniasis, amoebiasis, schistosomiasis,
fascioliasis, paragonimiasis and intestinal roundworms, see
Lecaille F, Kaleta J, Bromme D, "Human and parasitic papain-like
cysteine proteases: their role in physiology and pathology and
recent developments in inhibitor design", Chem Rev 2002 102,
4459-88.
[0058] Another embodiment of the invention is a method of treating
severe acute respiratory syndrome (SARS) in a mammal in need
thereof, comprising administering to the mammal a therapeutically
effective amount of any of the compounds or any of the
pharmaceutical compositions described above.
[0059] Another embodiment of the invention is a method of treating
metastatic bone disease in a mammal in need thereof, comprising
administering to the mammal a therapeutically effective amount of
any of the compounds or any of the pharmaceutical compositions
described above. It is known in the literature that osteoclasts are
responsible for bone resorption and that bone destruction and
hypercalcemia induced by metastatic tumors are carried out by
osteoclasts. Accordingly, the inhibition of osteoclasts can prevent
bone destruction and bone metastasis, see Miyamoto, T and Suda, T,
"Differentiation and function of osteoclasts", Keio J Med 2003
March; 52(1):1-7.
[0060] Another embodiment of the invention is administering to a
mammal a therapeutically effective amount of any of the compounds
or any of the pharmaceutical compositions described above for the
treatment of mammalian diseases associated with cathepsin S
including Alzheimer's disease, atherosclerosis, chronic obstructive
pulmonary disease, neuropathic pain, nociceptive pain, cancer and
certain autoimmune disorders, including, but not limited to
juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris,
Graves' disease, myasthenia gravis, systemic lupus erythemotasus,
rheumatoid arthritis and Hashimoto's thyroiditis; allergic
disorders, including, but not limited to asthma; and allogenic
immune responses, including, but not limited to, rejection of organ
transplants or tissue grafts. It is known in the literature that
cathepsin S activity is associated with the above disease states,
see Munger J S, Haass C, Lemere C A, Shi G P, Wong W S, Teplow D B,
Selkoe D J, Chapman H A, "Lysosomal processing of amyloid precursor
protein to A beta peptides: a distinct role for cathepsin S",
Biochem J 1995 311, 299-305; Sukhova G K, Zhang Y, Pan J H, Wada Y,
Yamamoto T, Naito M, Kodama T, Tsimikas S, Witztum J L, Lu M L,
Sakara Y, Chin M T, Libby P, Shi G P, "Deficiency of cathepsin S
reduces atherosclerosis in LDL receptor-deficient mice", J Clin
Invest 2003 111, 897-906; Zheng T, Zhu Z, Wang Z, Homer R J, Ma B,
Riese R J Jr, Chapman H A Jr, Shapiro S D, Elias J A, "Inducible
targeting of IL-13 to the adult lung causes matrix
metalloproteinase- and cathepsin-dependent emphysema", J Clin
Invest 2000 106,1081-93; Shi G P, Sukhova G K, Kuzuya M, Ye Q, Du
J, Zhang Y, Pan J H, Lu M L, Cheng X W, Iguchi A, Perrey S, Lee A
M, Chapman H A, Libby P, "Deficiency of the cysteine protease
cathepsin S impairs microvessel growth", Circ Res 2003 92, 493-500;
and Nakagawa T Y, Brissette W H, Lira P D, Griffiths R J,
Petrushova N, Stock J, McNeish J D, Eastman S E, Howard E D, Clarke
S R, Rosloniec E F, Elliott E A, Rudensky A Y, "Impaired invariant
chain degradation and antigen presentation and diminished
collagen-induced arthritis in cathepsin S null mice", Immunity 1999
10, 207-17.
[0061] Exemplifying the invention is the use of any of the
compounds described above in the preparation of a medicament for
the treatment and/or prevention of osteoporosis in a mammal in need
thereof. Still further exemplifying the invention is the use of any
of the compounds described above in the preparation of a medicament
for the treatment and/or prevention of: bone loss, bone resorption,
bone fractures, metastatic bone disease and/or disorders related to
cathepsin functioning.
[0062] The cathepsin K inhibitors described herein can be used in
combination with other agents useful for treating
cathepsin-mediated conditions, including, but not limited to
osteoporosis, glucocorticoid induced osteoporosis, Paget's disease,
abnormally increased bone turnover, periodontal disease, tooth
loss, bone fractures, rheumatoid arthritis, osteoarthritis,
periprosthetic osteolysis, osteogenesis imperfecta, obesity,
atherosclerosis, chronic obstructive pulmonary disorder,
hypercalcemia of malignancy or multiple myeloma. The individual
components of such combinations can be administered separately at
different times during the course of therapy or concurrently in
divided or single combination forms. The instant invention is
therefore to be understood as embracing all such regimes of
simultaneous or alternating treatment and the term "administering"
is to be interpreted accordingly. It will be understood that the
scope of combinations of the compounds of this invention with other
agents useful for treating cathepsin-mediated conditions includes
in principle any combination with any pharmaceutical composition
useful for treating disorders related to estrogen functioning.
[0063] The scope of the invention therefore encompasses the use of
the cathepsin K inhibitors described herein in combination with a
second agent selected from: an organic bisphosphonate; an estrogen
receptor modulator; an androgen receptor modulator; an inhibitor of
osteoclast proton ATPase; an inhibitor of HMG-CoA reductase; an
integrin receptor antagonist; an osteoblast anabolic agent, such as
PTH; a Nonsteroidal anti-inflammatory drug; a selective
cyclooxygenase-2 inhibitor; an inhibitor of interleukin-1 beta; a
LOX/COX inhibitor; a RANKL inhibitor; and the pharmaceutically
acceptable salts and mixtures thereof. The scope of the invention
also encompasses a method of inhibiting bone resorption with the
cathepsin K inhibitors described herein in combination with a
second agent selected from: an organic bisphosphonate; an estrogen
receptor modulator; an androgen receptor modulator; an inhibitor of
osteoclast proton ATPase; an inhibitor of HMG-CoA reductase; an
integrin receptor antagonist; an osteoblast anabolic agent, such as
PTH; a Nonsteroidal anti-inflammatory drug; a selective
cyclooxygenase-2 inhibitor; an inhibitor of interleukin-1 beta; a
LOX/COX inhibitor; a RANKL inhibitor; and the pharmaceutically
acceptable salts and mixtures thereof.
[0064] The instant compounds are also useful in combination with
known agents useful for treating or preventing osteoporosis,
glucocorticoid induced osteoporosis, Paget's disease, abnormally
increased bone turnover, periodontal disease, tooth loss, bone
fractures, rheumatoid arthritis, osteoarthritis, periprosthetic
osteolysis, osteogenesis imperfecta, atherosclerosis, obesity,
chronic obstructive pulmonary disease, metastatic bone disease,
hypercalcemia of malignancy or multiple myeloma. Combinations of
the presently disclosed cathepsin K inhibitors with other agents
useful for treating or preventing osteoporosis or other bone
disorders are within the scope of the invention. A person of
ordinary skill in the art would be able to discern which
combinations of agents would be useful based on the particular
characteristics of the drugs and the disease involved. Such agents
include the following: an organic bisphosphonate; an estrogen
receptor modulator; an androgen receptor modulator; an inhibitor of
osteoclast proton ATPase; an inhibitor of HMG-CoA reductase; an
integrin receptor antagonist; an osteoblast anabolic agent, such as
PTH; calcium; Vitamin D or a synthetic Vitamin D analogue; a
Nonsteroidal anti-inflammatory drug; a selective cyclooxygenase-2
inhibitor; an inhibitor of interleukin-1 beta; a LOX/COX inhibitor;
RANKL inhibitor; and the pharmaceutically acceptable salts and
mixtures thereof. A preferred combination is a compound of the
present invention and an organic bisphosphonate. Another preferred
combination is a compound of the present invention and an estrogen
receptor modulator. Another preferred combination is a compound of
the present invention and an androgen receptor modulator. Another
preferred combination is a compound of the present invention and an
osteoblast anabolic agent.
[0065] "Organic bisphosphonate" includes, but is not limited to,
compounds of the chemical formula
##STR00003##
wherein n is an integer from 0 to 7 and wherein A and X are
independently selected from the group consisting of H, OH, halogen,
NH.sub.2, SH, phenyl, C.sub.1-C.sub.30 alkyl, C.sub.3-C.sub.30
branched or cycloalkyl, bicyclic ring structure containing two or
three N, C.sub.1-C.sub.30 substituted alkyl, C.sub.1-C.sub.10 alkyl
substituted NH.sub.2, C.sub.3-C.sub.10 branched or cycloalkyl
substituted NH.sub.2, C.sub.1-C.sub.10 dialkyl substituted
NH.sub.2, C.sub.1-C.sub.10 alkoxy, C.sub.1-C.sub.10 alkyl
substituted thio, thiophenyl, halophenylthio, C.sub.1-C.sub.10
alkyl substituted phenyl, pyridyl, furanyl, pyrrolidinyl,
imidazolyl, imidazopyridinyl, and benzyl, such that both A and X
are not selected from H or OH when n is 0; or A and X are taken
together with the carbon atom or atoms to which they are attached
to form a C.sub.3-C.sub.10 ring.
[0066] In the foregoing chemical formula, the alkyl groups can be
straight, branched, or cyclic, provided sufficient atoms are
selected for the chemical formula. The C.sub.1-C.sub.30 substituted
alkyl can include a wide variety of substituents, nonlimiting
examples which include those selected from the group consisting of
phenyl, pyridyl, furanyl, pyrrolidinyl, imidazonyl, NH.sub.2,
C.sub.1-C.sub.10 alkyl or dialkyl substituted NH.sub.2, OH, SH, and
C.sub.1-C.sub.10 alkoxy.
[0067] The foregoing chemical formula is also intended to encompass
complex carbocyclic, aromatic and hetero atom structures for the A
and/or X substituents, nonlimiting examples of which include
naphthyl, quinolyl, isoquinolyl, adamantyl, and
chlorophenylthio.
[0068] Pharmaceutically acceptable salts and derivatives of the
bisphosphonates are also useful herein. Non-limiting examples of
salts include those selected from the group consisting alkali
metal, alkaline metal, ammonium, and mono-, di-, tri-, or
tetra-C.sub.1-C.sub.10-alkyl-substituted ammonium. Preferred salts
are those selected from the group consisting of sodium, potassium,
calcium, magnesium, and ammonium salts. More preferred are sodium
salts. Non-limiting examples of derivatives include those selected
from the group consisting of esters, hydrates, and amides.
[0069] It should be noted that the terms "bisphosphonate" and
"bisphosphonates", as used herein in referring to the therapeutic
agents of the present invention are meant to also encompass
diphosphonates, biphosphonic acids, and diphosphonic acids, as well
as salts and derivatives of these materials. The use of a specific
nomenclature in referring to the bisphosphonate or bisphosphonates
is not meant to limit the scope of the present invention, unless
specifically indicated. Because of the mixed nomenclature currently
in use by those of ordinary skill in the art, reference to a
specific weight or percentage of a bisphosphonate compound in the
present invention is on an acid active weight basis, unless
indicated otherwise herein. For example, the phrase "about 5 mg of
a bone resorption inhibiting bisphosphonate selected from the group
consisting of alendronate, pharmaceutically acceptable salts
thereof, and mixtures thereof, on an alendronic acid active weight
basis" means that the amount of the bisphosphonate compound
selected is calculated based on 5 mg of alendronic acid.
[0070] Non-limiting examples of bisphosphonates useful herein
include the following:
[0071] Alendronate, which is also known as alendronic acid,
4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, alendronate
sodium or alendronate monosodium trihydrate,
4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium
trihydrate.
[0072] Alendronate is described in U.S. Pat. No. 4,922,007, to
Kieczykowski et al., issued May 1, 1990; U.S. Pat. No. 5,019,651,
to Kieczykowski et al., issued May 28, 1991; U.S. Pat. No.
5,510,517, to Dauer et al., issued Apr. 23, 1996; U.S. Pat. No.
5,648,491, to Dauer et al., issued Jul. 15, 1997, all of which are
incorporated by reference herein in their entirety.
[0073] Cycloheptylaminomethylene-1,1-bisphosphonic acid, YM 175,
Yamanouchi (incadronate, formerly known as cimadronate), as
described in U.S. Pat. No. 4,970,335, to Isomura et al., issued
Nov. 13, 1990, which is incorporated by reference herein in its
entirety.
[0074] 1,1-dichloromethylene-1,1-diphosphonic acid (clodronic
acid), and the disodium salt (clodronate, Procter and Gamble), are
described in Belgium Patent 672,205 (1966) and J. Org. Chem 32,
4111 (1967), both of which are incorporated by reference herein in
their entirety.
[0075] 1-hydroxy-3-(1-pyrrolidinyl)-propylidene-1,1-bisphosphonic
acid (EB-1053).
[0076] 1-hydroxyethane-1,1-diphosphonic acid (etidronic acid).
[0077]
1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic
acid, also known as BM-210955, Boehringer-Mannheim (ibandronate),
is described in U.S. Pat. No. 4,927,814, issued May 22, 1990, which
is incorporated by reference herein in its entirety.
[0078] 1-hydroxy-2-imidazo-(1,2-a)pyridin-3-yethylidene
(minodronate).
[0079] 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid
(neridronate).
[0080] 3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic
acid (olpadronate). 3-amino-1-hydroxypropylidene-1,1-bisphosphonic
acid (pamidronate).
[0081] [2-(2-pyridinyl)ethylidene]-1,1-bisphosphonic acid
(piridronate) is described in U.S. Pat. No. 4,761,406, which is
incorporated by reference in its entirety.
[0082] 1-hydroxy-2-(3-pyridinyl)-ethylidene-1,1-bisphosphonic acid
(risedronate).
[0083] (4-chlorophenyl)thiomethane-1,1-disphosphonic acid
(tiludronate) as described in U.S. Pat. No. 4,876,248, to Breliere
et al., Oct. 24, 1989, which is incorporated by reference herein in
its entirety.
[0084] 1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic
acid (zoledronate).
[0085] Nonlimiting examples of bisphosphonates include alendronate,
cimadronate, clodronate, etidronate, ibandronate, incadronate,
minodronate, neridronate, olpadronate, pamidronate, piridronate,
risedronate, tiludronate, and zolendronate, and pharmaceutically
acceptable salts and esters thereof. A particularly preferred
bisphosphonate is alendronate, especially a sodium, potassium,
calcium, magnesium or ammonium salt of alendronic acid.
Exemplifying the preferred bisphosphonate is a sodium salt of
alendronic acid, especially a hydrated sodium salt of alendronic
acid. The salt can be hydrated with a whole number of moles of
water or non whole numbers of moles of water. Further exemplifying
the preferred bisphosphonate is a hydrated sodium salt of
alendronic acid, especially when the hydrated salt is alendronate
monosodium trihydrate.
[0086] It is recognized that mixtures of two or more of the
bisphosphonate actives can be utilized.
[0087] The precise dosage of the organic bisphosphonate will vary
with the dosing schedule, the particular bisphosphonate chosen, the
age, size, sex and condition of the mammal or human, the nature and
severity of the disorder to be treated, and other relevant medical
and physical factors. Thus, a precise pharmaceutically effective
amount cannot be specified in advance and can be readily determined
by the caregiver or clinician. Appropriate amounts can be
determined by routine experimentation from animal models and human
clinical studies. Generally, an appropriate amount of
bisphosphonate is chosen to obtain a bone resorption inhibiting
effect, i.e. a bone resorption inhibiting amount of the
bisphosphonate is administered. For humans, an effective oral dose
of bisphosphonate is typically from about 1.5 to about 6000
.mu.g/kg body weight and preferably about 10 to about 2000 .mu.g/kg
of body weight. For alendronate monosodium trihydrate, common human
doses which are administered are generally in the range of about 2
mg/day to about 40 mg/day, preferably about 5 mg/day to about 40
mg/day. In the U.S. presently approved dosages for alendronate
monosodium trihydrate are 5 mg/day for preventing osteoporosis, 10
mg/day for treating osteoporosis, and 40 mg/day for treating
Paget's disease.
[0088] In alternative dosing regimens, the bisphosphonate can be
administered at intervals other than daily, for example once-weekly
dosing, twice-weekly dosing, biweekly dosing, and twice-monthly
dosing. In a once weekly dosing regimen, alendronate monosodium
trihydrate would be administered at dosages of 35 mg/week or 70
mg/week. "Selective estrogen receptor modulators" refers to
compounds which interfere or inhibit the binding of estrogen to the
receptor, regardless of mechanism. Examples of estrogen receptor
modulators include, but are not limited to, estrogen, progestogen,
estradiol, droloxifene, raloxifene, lasofoxifene, TSE-424,
tamoxifen, idoxifene, LY353381, LY117081, toremifene, fulvestrant,
4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]ph-
enyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,
4,4'-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and
SH646.
[0089] An "estrogen receptor beta modulator" is a compound that
selectively agonizes or antagonizes estrogen receptor beta
(ER.beta.). Agonizing ER.beta. increases transcription of the
tryptophan hydroxylase gene (TPH, the key enzyme in serotonin
synthesis) via an ER.beta. mediated event. Examples of estrogen
receptor beta agonists can be found in PCT International
publication WO 01/82923, which published on Nov. 8, 2001, and WO
02/41835, which published on May 20, 2002, both of which are hereby
incorporated by reference in their entirety.
[0090] "Androgen receptor modulators" refers to compounds which
interfere or inhibit the binding of androgens to the receptor,
regardless of mechanism. Examples of androgen receptor modulators
include finasteride and other 5.alpha.-reductase inhibitors,
nilutamide, flutamide, bicalutamide, liarozole, and abiraterone
acetate.
[0091] "An inhibitor of osteoclast proton ATPase" refers to an
inhibitor of the proton ATPase, which is found on the apical
membrane of the osteoclast, and has been reported to play a
significant role in the bone resorption process. This proton pump
represents an attractive target for the design of inhibitors of
bone resorption which are potentially useful for the treatment and
prevention of osteoporosis and related metabolic diseases. See
Farina, C et al., "Selective inhibitors of the osteoclast vacuolar
proton ATPase as novel bone antiresorptive agents", DDT, 4: 163-172
(1999), which is hereby incorporated by reference in its
entirety.
[0092] "HMG-CoA reductase inhibitors" refers to inhibitors of
3-hydroxy-3-methylglutaryl-CoA reductase. Compounds which have
inhibitory activity for HMG-CoA reductase can be readily identified
by using assays well-known in the art. For example, see the assays
described or cited in U.S. Pat. No. 4,231,938 at col. 6, and WO
84/02131 at pp. 30-33. The terms "HMG-CoA reductase inhibitor" and
"inhibitor of HMG-CoA reductase" have the same meaning when used
herein.
[0093] Examples of HMG-CoA reductase inhibitors that may be used
include but are not limited to lovastatin (MEVACOR.RTM.; see U.S.
Pat. Nos. 4,231,938, 4,294,926 and 4,319,039), simvastatin
(ZOCOR.RTM.; see U.S. Pat. Nos. 4,444,784, 4,820,850 and
4,916,239), pravastatin (PRAVACHOL.RTM.; see U.S. Pat. Nos.
4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589),
fluvastatin (LESCOL.RTM.; see U.S. Pat. Nos. 5,354,772, 4,911,165,
4,929,437, 5,189,164, 5,118,853, 5,290,946 and 5,356,896),
atorvastatin (LIPITOR.RTM.; see U.S. Pat. Nos. 5,273,995,
4,681,893, 5,489,691 and 5,342,952) and cerivastatin (also known as
rivastatin and BAYCHOL.RTM.; see U.S. Pat. No. 5,177,080). The
structural formulas of these and additional HMG-CoA reductase
inhibitors that may be used in the instant methods are described at
page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry
& Industry, pp. 85-89 (5 Feb. 1996) and U.S. Pat. Nos.
4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as
used herein includes all pharmaceutically acceptable lactone and
open-acid forms (i.e., where the lactone ring is opened to form the
free acid) as well as salt and ester forms of compounds which have
HMG-CoA reductase inhibitory activity, and therefore the use of
such salts, esters, open-acid and lactone forms is included within
the scope of this invention. An illustration of the lactone portion
and its corresponding open-acid form is shown below as structures I
and II.
##STR00004##
[0094] In HMG-CoA reductase inhibitors where an open-acid form can
exist, salt and ester forms may preferably be formed from the
open-acid, and all such forms are included within the meaning of
the term "HMG-CoA reductase inhibitor" as used herein. Preferably,
the HMG-CoA reductase inhibitor is selected from lovastatin and
simvastatin, and most preferably simvastatin. Herein, the term
"pharmaceutically acceptable salts" with respect to the HMG-CoA
reductase inhibitor shall mean non-toxic salts of the compounds
employed in this invention which are generally prepared by reacting
the free acid with a suitable organic or inorganic base,
particularly those formed from cations such as sodium, potassium,
aluminum, calcium, lithium, magnesium, zinc and
tetramethylammonium, as well as those salts formed from amines such
as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine,
ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine,
diethanolamine, procaine, N-benzylphenethylamine,
1-p-chlorobenzyl-2-pyrrolidine-1'-yl-methylbenz-imidazole,
diethylamine, piperazine, and tris(hydroxymethyl) aminomethane.
Further examples of salt forms of HMG-CoA reductase inhibitors may
include, but are not limited to, acetate, benzenesulfonate,
benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide,
calcium edetate, camsylate, carbonate, chloride, clavulanate,
citrate, dihydrochloride, edetate, edisylate, estolate, esylate,
fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,
hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,
hydroxynapthoate, iodide, isothionate, lactate, lactobionate,
laurate, malate, maleate, mandelate, mesylate, methylsulfate,
mucate, napsylate, nitrate, oleate, oxalate, pamaote, palmitate,
panthothenate, phosphate/diphosphate, polygalacturonate,
salicylate, stearate, subacetate, succinate, tannate, tartrate,
teoclate, tosylate, triethiodide, and valerate.
[0095] Ester derivatives of the described HMG-CoA reductase
inhibitor compounds may act as prodrugs which, when absorbed into
the bloodstream of a warm-blooded animal, may cleave in such a
manner as to release the drug form and permit the drug to afford
improved therapeutic efficacy.
[0096] As used above, "integrin receptor antagonists" refers to
compounds which selectively antagonize, inhibit or counteract
binding of a physiological ligand to the .alpha..sub.v.beta..sub.3
integrin, to compounds which selectively antagonize, inhibit or
counteract binding of a physiological ligand to the .alpha.v.beta.5
integrin, to compounds which antagonize, inhibit or counteract
binding of a physiological ligand to both the
.alpha..sub.v.beta..sub.3 integrin and the
.alpha..sub.v.beta..sub.5 integrin, and to compounds which
antagonize, inhibit or counteract the activity of the particular
integrin(s) expressed on capillary endothelial cells. The term also
refers to antagonists of the .alpha..sub.v.beta..sub.6,
.alpha..sub.v.beta..sub.8, .alpha..sub.1.beta..sub.1,
.alpha..sub.2.beta..sub.1, .alpha..sub.5.beta..sub.1,
.alpha..sub.6.beta..sub.1 and .alpha..sub.6.beta..sub.4 integrins.
The term also refers to antagonists of any combination of
.alpha..sub.v.beta..sub.3, .alpha..sub.v.beta..sub.5,
.alpha..sub.v.beta..sub.6, .alpha..sub.v.beta..sub.8,
.alpha..sub.1.beta..sub.1, .alpha..sub.2.beta..sub.1,
.alpha..sub.5.beta..sub.1, .alpha..sub.6.beta..sub.1 and
.alpha..sub.6.beta..sub.4 integrins. H. N. Lode and coworkers in
PNAS USA 96: 1591-1596 (1999) have observed synergistic effects
between an antiangiogenic .alpha.v integrin antagonist and a
tumor-specific antibody-cytokine (interleukin-2) fusion protein in
the eradication of spontaneous tumor metastases. Their results
suggested this combination as having potential for the treatment of
cancer and metastatic tumor growth. .alpha..sub.v.beta..sub.3
integrin receptor antagonists inhibit bone resorption through a new
mechanism distinct from that of all currently available drugs.
Integrins are heterodimeric transmembrane adhesion receptors that
mediate cell-cell and cell-matrix interactions. The .alpha. and
.beta. integrin subunits interact non-covalently and bind
extracellular matrix ligands in a divalent cation-dependent manner.
The most abundant integrin on osteoclasts is
.alpha..sub.v.beta..sub.3 (>10.sup.7/osteoclast), which appears
to play a rate-limiting role in cytoskeletal organization important
for cell migration and polarization. The .alpha..sub.v.beta..sub.3
antagonizing effect is selected from inhibition of bone resorption,
inhibition of restenosis, inhibition of macular degeneration,
inhibition of arthritis, and inhibition of cancer and metastatic
growth.
[0097] "An osteoblast anabolic agent" refers to agents that build
bone, such as PTH. The intermittent administration of parathyroid
hormone (PTH) or its amino-terminal fragments and analogues have
been shown to prevent, arrest, partially reverse bone loss and
stimulate bone formation in animals and humans. For a discussion
refer to Dempster, D W et al., "Anabolic actions of parathyroid
hormone on bone", Endocr Rev 14: 690-709 (1993). Studies have
demonstrated the clinical benefits of parathyroid hormone in
stimulating bone formation and thereby increasing bone mass and
strength. Results were reported by Neer, R M et al., New Eng J Med
344 1434-1441 (2001).
[0098] In addition, parathyroid hormone-related protein fragments
or analogues, such as PTHrP-(1-36) have demonstrated potent
anticalciuric effects [see Syed M A et al., "Parathyroid
hormone-related protein-(1-36) stimulates renal tubular calcium
re-absorption in normal human volunteers: implications for the
pathogenesis of humoral hypercalcemia of malignancy", JCEM 86:
1525-1531 (2001)] and may also have potential as anabolic agents
for treating osteoporosis.
[0099] "Vitamin D" includes, but is not limited to, vitamin D.sub.3
(cholecalciferol) and vitamin D.sub.2 (ergocalciferol), which are
naturally occurring, biologically inactive precursors of the
hydroxylated biologically active metabolites of vitamin D:
1.alpha.-hydroxy vitamin D; 25-hydroxy vitamin D, and
1.alpha.,25-dihydroxy vitamin D. Vitamin D.sub.2 and vitamin
D.sub.3 have the same biological efficacy in humans. When either
vitamin D.sub.2 or D.sub.3 enters the circulation, it is
hydroxylated by cytochrome P.sub.450-vitamin D-25-hydroxylase to
give 25-hydroxy vitamin D. The 25-hydroxy vitamin D metabolite is
biologically inert and is further hydroxylated in the kidney by
cytochrome P450-monooxygenase, 25 (OH) D-1.alpha.-hydroxylase to
give 1,25-dihydroxy vitamin D. When serum calcium decreases, there
is an increase in the production of parathyroid hormone (PTH),
which regulates calcium homeostasis and increases plasma calcium
levels by increasing the conversion of 25-hydroxy vitamin D to
1,25-dihydroxy vitamin D.
[0100] 1,25-dihydroxy vitamin D is thought to be responsible for
the effects of vitamin D on calcium and bone metabolism. The
1,25-dihydroxy metabolite is the active hormone required to
maintain calcium absorption and skeletal integrity. Calcium
homeostasis is maintained by 1,25 dihydroxy vitamin D by inducing
monocytic stem cells to differentiate into osteoclasts and by
maintaining calcium in the normal range, which results in bone
mineralization by the deposition of calcium hydroxyapatite onto the
bone surface, see Holick, M F, "Vitamin D photobiology, metabolism,
and clinical applications", In: DeGroot L, Besser H, Burger H G, et
al., eds. Endocrinology, 3.sup.rd ed., 990-1013 (1995). However,
elevated levels of 1.alpha.25-dihydroxy vitamin D.sub.3 can result
in an increase of calcium concentration in the blood and in the
abnormal control of calcium concentration by bone metabolism,
resulting in hypercalcemia. 1.alpha.,25-dihydroxy vitamin D.sub.3
also indirectly regulates osteoclastic activity in bone metabolism
and elevated levels may be expected to increase excessive bone
resorption in osteoporosis.
[0101] In embodiments of the present invention, an appropriate
amount of the vitamin D compound is chosen to provide adequate
vitamin D nutrition during the dosing interval without interfering
with the cathepsin K inhibitor's ability to obtain a bone
resorption inhibiting effect. For oral compositions of the present
invention comprising a cathepsin K inhibitor, and a vitamin D
compound, an amount of the vitamin D compound comprises from about
100 IU to about 60,000 IU. Non-limiting examples of an oral amount
of the vitamin D compound in embodiments of the present invention
include, but are not limited to, dosages of 2,800, IU, 5,600 IU,
7,000 IU, 8,400 IU, 11,200 IU, 14,000 IU, 16,800 IU or 19,600 IU.
Non-limiting examples of an oral amount of vitamin D for weekly
dosing are 2,800, IU, 5,600 IU, 7,000 IU, 8,400 IU and 11,200 IU.
Non-limiting examples of an oral amount of vitamin D for monthly
dosing are 11,200 IU, 14,000 IU, 15,400 IU, 16,800 IU and 19,600
IU.
[0102] "Synthetic vitamin D analogues" includes non-naturally
occurring compounds that act like vitamin D
[0103] "Calcium" includes, but is not limited to, calcium
carbonate, calcium citrate or any other compound containing
elemental calcium. Calcium is essential to human health and is
required for the structural integrity of the skeleton. The ionized
fraction of blood calcium is physiologicially important and is
tightly maintained by both parathyroid hormone (PTH) and 1,25
dihydroxy Vitamin D. As such, decreases in blood calcium (or the
mere insufficiency of dietary calcium) can readily affect PTH and
1,25 dihydroxy Vitamin D levels in such as way as to adversely
affect skeletal health. Provision of supplemental calcium
consequently tends to lower PTH levels, to diminish the removal of
calcium from skeletal stores and, in so doing, to benefit skeletal
health. Non-limiting examples of an oral amount of the calcium in
embodiments of the present invention include, but are not limited
to, dosages of 1200-1500 mgs of elemental calcium per day in
divided doses.
[0104] "Nonsteroidal anti-inflammatory drugs" or NSAIDs, inhibit
the metabolism of arachidonic acid to proinflammatory
prostaglandins via cyclooxygenase (COX)-1 and COX-2. Nonlimiting
examples of NSAIDs include: aspirin, ibuprofen, naproxen,
diclofenac, etodolac, fenoporfen, flubiprofen, indomethacin,
ketoprofen, ketorolac, meloxicam, nabumetone, oxaprozin, piroxicam,
sulindac, tolmetin, diflunisal, meclofenamate and
phenylbutazone.
[0105] A "selective cyclooxygenase-2 inhibitor," or COX-2
inhibitor, refers to a type of nonsteroidal anti-inflammatory drug
(NSAID), that inhibit the COX-2 coenzyme, which contributes to pain
and inflammation in the body. Nonlimiting examples of COX-2
inhibitors include: celecoxib, etoricoxib, parecoxib, rofecoxib,
valdecoxib and lumiracoxib.
[0106] An "inhibitor of interleukin-1 beta" or IL-1.beta. refers to
in inhibitors of IL-1, which is a soluble factor produced by
monocytes, macrophages, and other cells which activates
T-lymphocytes and potentiates their response to mitogens or
antigens. Nonlimiting examples of IL-1B inhibitors include
diacerein and rhein.
[0107] A "LOX/COX inhibitor" refers to an inhibitor or all three of
the major enzymes involved in arachidonic acid pathway--namely,
5-LOX, COX-1 and COX-2. A nonlimiting example of a LOX/COX
inhibitor is licofelone.
[0108] A "RANKL inhibitor" refers to an inhibitor of receptor
activator NF-kB ligand (RANKL), which has previously been called
osteoclast differentiation factor (ODF), osteoprotegerin ligand
(OPGL) and TNF-related activation induced cytokine (TRANCE). RANKL
is a key stimulator of osteoclast formation and maturation. A
nonlimiting example or a RANKL inhibitor is AMG-162.
[0109] If formulated as a fixed dose, such combination products
employ the compounds of this invention within the dosage range
described below and the other pharmaceutically active agent(s)
within its approved dosage range. Compounds of the instant
invention may alternatively be used sequentially with known
pharmaceutically acceptable agent(s) when a combination formulation
is inappropriate.
[0110] The term "AUC" or "Area Under the Curve" refers to the area
defined by the plasma concentration-time curve over a given time
period and represents the total exposure of the plasma to drug over
a given time period. AUC.sub.0-24 refers to the area under the
concentration-time curve for the first 24 hours following
administration of a compound. AUC.sub.0-168 refers to the area
under the concentration-time curve for the first 168 hours (one
week) following administration of a drug.
[0111] The term "C.sub.min" refers to the lowest concentration of
drug circulating in plasma over a given time period. The time of
minimal concentration is generally immediately prior to the
administration of another dosage of the drug.
[0112] The terms "once weekly" and "once-weekly dosing," as used
herein, means that a unit dosage, for example a unit dosage of a
cathepsin K inhibitor, is administered once a week, i.e., once
during a seven-day period, preferably on the same day of each week.
In the once-weekly dosing regimen, the unit dosage is generally
administered about every seven days. A non-limiting example of a
once-weekly dosing regimen would entail the administration of a
unit dosage of the cathepsin K inhibitor every Sunday. It is
customarily recommended that a unit dosage for once-weekly
administration is not administered on consecutive days, but the
once-weekly dosing regimen can include a dosing regimen in which
unit dosages are administered on two consecutive days falling
within two different weekly periods.
[0113] By "biweekly" dosing is meant that a unit dosage of the
cathepsin K inhibitor is administered once during a two week
period, i.e. one time during a fourteen day period, preferably on
the same day during each two week period. In the twice-weekly
dosing regimen, each unit dosage is generally administered about
every fourteen days. A nonlimiting example of a biweekly dosing
regimen would entail the administration of a unit dosage of the
cathepsin K inhibitor every other Sunday. It is preferred that the
unit dosage is not administered on consecutive days, but the
biweekly dosing regimen can include a dosing regimen in which the
unit dosage is administered on two consecutive days within two
different biweekly periods.
[0114] By "twice monthly" dosing is meant that a unit dosage of the
cathepsin K inhibitor is administered twice, i.e. two times, during
a monthly calendar period. With the twice monthly regimen, the
doses are preferably given on the same two dates of each month. In
the twice monthly dosing regimen, each unit dosage is generally
administered about every fourteen to sixteen days. A nonlimiting
example of a twice monthly dosing regimen would entail dosing on or
about the first of the month and on or about the fifteenth, i.e.
the midway point, of the month. It is preferred that the unit
dosages are not administered on the same or consecutive days but
the twice-monthly dosing regimen can include a dosing regimen in
which the unit dosages are administered on two consecutive days
within a monthly period, or different monthly periods. The twice
monthly regimen is defined herein as being distinct from, and not
encompassing, the biweekly dosing regimen because the two regimens
have a different periodicity and result in the administration of
different numbers of dosages over long periods of time. For
example, over a one year period, a total of about twenty four
dosages would be administered according to the twice monthly
regimen (because there are twelve calendar months in a year),
whereas a total of about twenty six dosages would be administered
according to the biweekly dosing regimen (because there are about
fifty-two weeks in a year).
[0115] The term "once monthly" is used in accordance with the
generally accepted meaning as a measure of time amounting to
approximately four weeks, approximately 30 days or 1/12 of a
calendar year.
[0116] The term, "upper gastrointestinal disorders" refers to
disorders associated with the upper gastrointestinal (GI) tract,
including, but not limited to, gastrointestinal reflux disease
(GERD), esophagitis, dyspepsia (heartburn) and ulcers.
[0117] The term "administration" and variants thereof (e.g.,
"administering" a compound) in reference to a compound of the
invention means introducing the compound or a prodrug of the
compound into the system of the animal in need of treatment. When a
compound of the invention or prodrug thereof is provided in
combination with one or more other active agents (e.g., a cytotoxic
agent, etc.), "administration" and its variants are each understood
to include concurrent and sequential introduction of the compound
or prodrug thereof and other agents. The present invention includes
within its scope prodrugs of the compounds of this invention. In
general, such prodrugs will be functional derivatives of the
compounds of this invention which are readily convertible in vivo
into the required compound. Thus, in the methods of treatment of
the present invention, the term "administering" shall encompass the
treatment of the various conditions described with the compound
specifically disclosed or with a compound which may not be
specifically disclosed, but which converts to the specified
compound in vivo after administration to the patient. Conventional
procedures for the selection and preparation of suitable prodrug
derivatives are described, for example, in "Design of Prodrugs,"
ed. Bundgaard, H, Elsevier, 1985, which is incorporated by
reference herein in its entirety. Metabolites of these compounds
include active species produced upon introduction of compounds of
this invention into the biological milieu.
[0118] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts.
[0119] The term "unit dose" as used herein describes a single
unitary dose that is administered entirely at one time.
[0120] The term "therapeutically effective amount" as used herein
means that amount of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue, system,
animal or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician.
[0121] The terms "treating" or "treatment" of a disease as used
herein includes: preventing the disease, i.e. causing the clinical
symptoms of the disease not to develop in a mammal that may be
exposed to or predisposed to the disease but does not yet
experience or display symptoms of the disease; inhibiting the
disease, i.e., arresting or reducing the development of the disease
or its clinical symptoms; or relieving the disease, i.e., causing
regression of the disease or its clinical symptoms.
[0122] The term "bone resorption," as used herein, refers to the
process by which osteoclasts degrade bone.
[0123] These and other aspects of the invention will be apparent
from the teachings contained herein.
[0124] The following examples are given for the purpose of
illustrating the present invention and shall not be construed as
limitations on the scope of the invention.
Pharmaceutical Compositions
[0125] For the following pharmaceutical compositions,
N.sup.1-(1-cyanocyclopropyl)-4-fluoro-N.sup.2-{(1S)-2,2,2-trifluoro-1-[4'-
-(methylsulfonyl)-1,1'-biphenyl-4-yl]ethyl}-L-leucinamide can be
used as an example of a cathepsin K inhibitor.
Composition 1
TABLE-US-00001 [0126] Ingredient Percentage in Tablet Cathepsin K
inhibitor 0.5-25% Lactose 30-50% Microcrystalline Cellulose 30-50%
Crosscamellose Sodium 3-5% Hydroxypropyl Cellose 2-4% Magnesium
Stearate 0.3-0.7%
Composition 2
TABLE-US-00002 [0127] Ingredient Percentage in Tablet Cathepsin K
inhibitor 0.5-25% Lactose 20-60% Microcrystalline Cellulose 20-60%
Crosscamellose Sodium 2-6% Hydroxypropyl Cellose 1-5% Magnesium
Stearate 0.2-0.8%
Composition 3
TABLE-US-00003 [0128] Ingredient Percentage in Tablet Cathepsin K
inhibitor 0.1-40% Lactose 10-70% Microcrystalline Cellulose 10-70%
Crosscamellose Sodium 1-7% Hydroxypropyl Cellose 1-6% Magnesium
Stearate 0.1-1%
Composition 4
TABLE-US-00004 [0129] Ingredient Percentage in Tablet Cathepsin K
inhibitor 0.5-25% Lactose 33.55-45.8% Microcrystalline Cellulose
33.55-45.8% Crosscamellose Sodium 4.0% Hydroxypropyl Cellose 3.0%
Magnesium Stearate 0.5%
* * * * *