U.S. patent application number 12/005068 was filed with the patent office on 2008-08-21 for caspase inhibitor prodrugs.
Invention is credited to Julian M.C. Golec, Michael Mortimore.
Application Number | 20080199454 12/005068 |
Document ID | / |
Family ID | 27734580 |
Filed Date | 2008-08-21 |
United States Patent
Application |
20080199454 |
Kind Code |
A1 |
Mortimore; Michael ; et
al. |
August 21, 2008 |
Caspase inhibitor prodrugs
Abstract
The present invention relates to compounds of formula I which
are prodrugs of caspase inhibitors and pharmaceutically acceptable
salts thereof. This invention further relates to the release of
caspase inhibitors from these compounds through selective bond
cleavage. This invention further relates to pharmaceutical
compositions comprising these compounds, which are particularly
well-suited for treatment of caspase-mediated diseases, including
inflammatory and degenerative diseases. This invention further
relates to methods for preparing compounds of this invention.
Inventors: |
Mortimore; Michael; (Burford
Oxfordshire, GB) ; Golec; Julian M.C.; (Ashbury,
GB) |
Correspondence
Address: |
ROPES & GRAY LLP
PATENT DOCKETING 39/361, 1211 AVENUE OF THE AMERICAS
NEW YORK
NY
10036-8704
US
|
Family ID: |
27734580 |
Appl. No.: |
12/005068 |
Filed: |
December 21, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10366192 |
Feb 11, 2003 |
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12005068 |
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60355889 |
Feb 11, 2002 |
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Current U.S.
Class: |
424/94.64 ;
435/1.1; 435/2; 435/374; 514/119; 514/80; 514/85; 514/89; 514/92;
514/94; 514/96; 540/522; 544/232; 544/39; 546/22; 548/112; 548/414;
549/8; 564/15 |
Current CPC
Class: |
C07C 235/52 20130101;
C07C 237/22 20130101; C07D 239/90 20130101; C07F 9/5728 20130101;
A61P 35/04 20180101; A61P 37/06 20180101; A61P 9/00 20180101; C07D
211/34 20130101; C07K 5/0202 20130101; C07D 271/06 20130101; C07C
271/28 20130101; C07D 209/26 20130101; C07D 209/86 20130101; C07F
9/10 20130101; C07C 271/22 20130101; C07D 209/94 20130101 |
Class at
Publication: |
424/94.64 ;
540/522; 548/414; 564/15; 544/232; 546/22; 544/39; 548/112; 549/8;
514/80; 514/119; 514/89; 514/94; 514/96; 514/92; 514/85; 435/374;
435/1.1; 435/2 |
International
Class: |
A61K 38/48 20060101
A61K038/48; C07D 487/06 20060101 C07D487/06; C07F 9/572 20060101
C07F009/572; C07F 9/06 20060101 C07F009/06; C07F 9/6512 20060101
C07F009/6512; C07F 9/59 20060101 C07F009/59; C07F 9/6547 20060101
C07F009/6547; C07F 9/6506 20060101 C07F009/6506; C07F 9/6553
20060101 C07F009/6553; A61K 31/675 20060101 A61K031/675; A61K
31/661 20060101 A61K031/661; A61K 31/67 20060101 A61K031/67; A61P
35/04 20060101 A61P035/04; A61P 9/00 20060101 A61P009/00; C12N 5/02
20060101 C12N005/02; A01N 1/02 20060101 A01N001/02 |
Claims
1. A compound of the formula I: ##STR00033## or a pharmaceutically
acceptable salt thereof, wherein: R.sup.1 is a saturated or
unsaturated, straight-chain or branched, substituted or
unsubstituted hydrocarbon chain; R.sup.2 is B or a phospholipid
head group; X is a direct covalent bond or a group C(O)LR.sup.3;
wherein L is a saturated or unsaturated, straight-chain or
branched, substituted or unsubstituted hydrocarbon chain having
from 2 to 15 carbon atoms, which optionally includes cyclic
elements, and is optionally interrupted by one or more atoms
selected from the group consisting of oxygen, sulfur and
N(R.sup.4), R.sup.3 is selected from the group consisting of O, S
and N(R.sup.4); wherein R.sup.4 is a saturated or unsaturated
hydrocarbon chain having 1 to 6 carbon atoms; and Y is a residue of
a caspase inhibitor.
2. The compound of claim 1, wherein the R.sup.1 hydrocarbon chain
has from 2 to 30 carbon atoms.
3. The compound of claim 2, wherein the R.sup.1 hydrocarbon chain
has from 2 to 24 carbon atoms.
4. The compound of claim 1, wherein R.sup.2 is a phospholipid head
group.
5. The compound of claim 4, wherein the phospholipid head group is
choline.
6. The compound of claim 1, wherein X is a direct covalent
bond.
7. The compound of claim 1, wherein Y is a reversible caspase
inhibitor.
8. The compound of claim 1, wherein Y is an irreversible caspase
inhibitor.
9. The compound of claim 1, wherein the caspase inhibitor is any
one of the caspase inhibitors depicted in FIGS. 1-20.
10. The compound of claim 1, wherein the caspase inhibitor is
selected from a structure in Table 1 below: TABLE-US-00002 TABLE 1
Structures of Selected Caspase Inhibitors Comp. No. Structure 1
##STR00034## 2 ##STR00035## 3 ##STR00036## 4 ##STR00037## 5
##STR00038## 6 ##STR00039## 7 ##STR00040## 8 ##STR00041## 9
##STR00042## 10 ##STR00043## 11 ##STR00044## 12 ##STR00045## 13
##STR00046## 14 ##STR00047## 15 ##STR00048## 16 ##STR00049## 17
##STR00050## 18 ##STR00051## 19 ##STR00052## 20 ##STR00053##
11. A pharmaceutical composition comprising: a) a compound
according to any one of claims 1-10; and b) a pharmaceutically
acceptable carrier.
12. A method for inhibiting caspase activity in a mammal in need
thereof comprising administering to said mammal a compound
according to any one of claims 1-10 or a composition according to
claim 11.
13. A method for treating or preventing a disease selected from the
group consisting of an IL-1 mediated disease, an apoptosis mediated
disease, an inflammatory disease, an autoimmune disease, a
destructive bone disorder, a proliferative disorder, an infectious
disease, a degenerative disease, a disease associated with cell
death, an excess dietary alcohol intake disease, a viral mediated
disease, uveitis, inflammatory peritonitis, osteoarthritis,
pancreatitis, asthma, adult respiratory distress syndrome,
glomerulonephritis, rheumatoid arthritis, systemic lupus
erythematosus, scleroderma, chronic thyroiditis, Grave's disease,
autoimmune gastritis, diabetes, autoimmune hemolytic anemia,
autoimmune neutropenia, thrombocytopenia, chronic active hepatitis,
myasthenia gravis, inflammatory bowel disease, Crohn's disease,
psoriasis, atopic dermatitis, scarring, graft vs. host disease,
organ transplant rejection, osteoporosis, leukemias and related
disorders, myelodysplastic syndrome, multiple myeloma-related bone
disorder, acute myelogenous leukemia, chronic myelogenous leukemia,
metastatic melanoma, Kaposi's sarcoma, multiple myeloma,
hemorrhagic shock, sepsis, septic shock, burns, Shigellosis,
Alzheimer's disease, Parkinson's disease, Huntington's disease,
Kennedy's disease, prion disease, cerebral ischemia, epilepsy,
myocardial ischemia, acute and chronic heart disease, myocardial
infarction, congestive heart failure, arteriosclerosis, coronary
artery bypass graft, spinal muscular atrophy, amyotrophic lateral
sclerosis, multiple sclerosis, HIV-related encephalitis, aging,
alopecia, neurological damage due to stroke, ulcerative colitis,
traumatic brain injury, spinal cord injury, hepatitis-B,
hepatitis-C, hepatitis-G, yellow fever, dengue fever, or Japanese
encephalitis, various forms of liver disease, renal disease,
polyaptic kidney disease, H. pylori-associated gastric and duodenal
ulcer disease, HIV infection, tuberculosis, and meningitis in a
mammal comprising administering to said mammal a compound according
to any one of claims 1-10 or a composition according to claim
11.
14. A method for treating complications associated with coronary
artery bypass grafts in a mammal comprising administering to said
mammal a compound according to any one of claims 1-10 or a
composition according to claim 11.
15. A method for treating cancer in a mammal comprising
administering to said mammal a compound according to any one of
claims 1-10 or a composition according to claim 11, wherein said
compound or composition is used as a component of
immunotherapy.
16. The method according to any one of claims 12-15, wherein said
mammal is a human.
17. A method for preserving cells comprising treating the cells
with a solution comprising an effective amount of a compound
according to any one of claims 1-10 or a composition according to
claim 11.
18. The method according to claim 17, wherein said compound or
composition is used for an organ transplant or for preserving blood
products.
19. The method according to any one of claims 12-15, wherein said
compound or composition is administered with an additional
therapeutic agent.
20. The method according to claim 19, wherein said additional
therapeutic agent is a thrombolytic agent.
21. The method according to claim 20, wherein said thrombolytic
agent is selected from the group consisting of tissue plasminogen
activator and streptokinase.
22. A method for decreasing IGIF or IFN-.gamma. production in a
mammal in need thereof comprising administering to said mammal a
compound according to any one of claims 1-10 or a composition
according to claim 11.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent
Application 60/355,889, filed Feb. 11, 2002, the content of which
is incorporated herein by reference.
TECHNICAL FIELD OF THE INVENTION
[0002] This invention relates to prodrugs of caspase inhibitors
comprising a phospholipid moiety covalently linked, via a bridging
group, to a caspase inhibitor, such that the active species is
released at the required site of action.
[0003] This invention also relates to processes for preparing these
prodrugs of caspase inhibitors.
[0004] This invention further relates to pharmaceutical
compositions comprising said prodrugs and to the use thereof for
the treatment of diseases and disorders related to inflammatory or
degenerative conditions.
BACKGROUND OF THE INVENTION
[0005] Apoptosis, or programmed cell death, is a principal
mechanism by which organisms eliminate unwanted cells. The
deregulation of apoptosis, either excessive apoptosis or the
failure to undergo it, has been implicated in a number of diseases
such as cancer, acute inflammatory and autoimmune disorders,
ischemic diseases and certain neurodegenerative disorders [see
generally Science, 281, pp. 1283-1312 (1998); and Ellis et al.,
Ann. Rev. Cell. Biol., 7, p. 663 (1991)].
[0006] Caspases are a family of cysteine protease enzymes that are
key mediators in the signaling pathways for apoptosis and cell
disassembly [N. A. Thornberry, Chem. Biol., 5, pp. R97-R103
(1998)]. These signaling pathways vary depending on cell type and
stimulus, but all apoptosis pathways appear to converge at a common
effector pathway leading to proteolysis of key proteins. Caspases
are involved in both the effector phase of the signaling pathway
and further upstream at its initiation. The upstream caspases
involved in initiation events become activated and in turn activate
other caspases that are involved in the later phases of
apoptosis.
[0007] The utility of caspase inhibitors to treat a variety of
mammalian disease states associated with an increase in cellular
apoptosis has been demonstrated using peptidic caspase inhibitors.
For example, in rodent models, caspase inhibitors have been shown
to reduce infarct size and inhibit cardiomyocyte apoptosis after
myocardial infarction, to reduce lesion volume and neurological
deficit resulting from stroke, to reduce post-traumatic apoptosis
and neurological deficit in traumatic brain injury, to be effective
in treating fulminant liver destruction, and to improve survival
after endotoxic shock [H. Yaoita et al., Circulation, 97, pp.
276-281 (1998); M. Endres et al., J. Cerebral Blood Flow and
Metabolism, 18, pp. 238-247, (1998); Y. Cheng et al., J. Clin.
Invest., 101, pp. 1992-1999 (1998); A. G. Yakovlev et al., J.
Neurosci., 17, pp. 7415-7424 (1997); I. Rodriquez et al., J. Exp.
Med., 184, pp. 2067-2072 (1996); and Grobmyer et al., Mol. Med., 5,
p. 585 (1999)]. However, due to their peptidic nature, such
inhibitors are typically characterized by undesirable
pharmacological properties, such as poor cellular penetration and
cellular activity, poor oral absorption, poor stability and rapid
metabolism [J. J. Plattner and D. W. Norbeck, in Drug Discovery
Technologies, C. R. Clark and W. H. Moos, Eds. (Ellis Horwood,
Chichester, England, 1990), pp. 92-126]. This has hampered their
development into effective drugs. These and other studies with
peptidic caspase inhibitors have demonstrated that an aspartic acid
residue is involved in a key interaction with the caspase enzyme
[K. P. Wilson et al., Nature, 370, pp. 270-275 (1994); and Lazebnik
et al., Nature, 371, p. 346 (1994)].
[0008] Accordingly, peptidyl and non-peptidyl aspartic acid
compounds are useful as caspase inhibitors. For examples,
WO96/03982 reports azaaspartic acid analogs effective as
interleukin-1.beta. converting enzyme ("ICE") inhibitors.
[0009] However, due to their acidic nature such peptidic and
non-peptidyl aspartic acid derivatives are charged at physiological
pH. This has inhibited their ability to cross the blood brain
barrier and to penetrate cells at therapeutically useful
levels.
[0010] Accordingly, it would be advantageous to have drug
derivatives that are targeted at the diseased organs, especially
the brain and central nervous system. In addition, it would be
advantageous to have drug derivatives that are targeted at the
diseased cells rather than at healthy cells, thus reducing
undesirable side-effects.
[0011] The use of prodrugs imparts desired characteristics such as
increased bioavailability or increased site-specificity for known
drugs. Various lipids and phospholipids can be used in the
preparation of particular types of prodrugs.
[0012] WO94/22483 reports cell permeable prodrugs, comprising a
pharmacologically active carboxylic acid such as branched-chain
aliphatic carboxylic acids (e.g., valproic acid), salicylic acids
(e.g., acetylsalicylic acid), steroidal carboxylic acids (e.g.,
lysergic and isolysergic acids, monoheterocyclic carboxylic acids
(e.g., nicotinic acid) and polyheterocyclic carboxylic acids (e.g.,
penicillins and cephalosporins), covalently linked to an
intracellular transporting adjuvant. One such embodiment of the
intracellular transporting adjuvant is a lysophospholipid.
[0013] WO99/02485 reports compounds of the formula:
##STR00001##
wherein R1 is a saturated or unsaturated chain of 1-5 carbons in
length; R2 is a saturated or unsaturated chain of 3-10 carbons in
length; and A is COOL or CONR'R'', wherein L is a lipid moiety
selected from the group consisting of glycerol, C.sub.3-20 fatty
acid monoglycerides, C.sub.3-20 fatty acid diglycerides,
hydroxy-C.sub.2-6-alkyl esters of C.sub.3-20 fatty acids,
hydroxy-C.sub.2-6-alkyl esters of lysophosphatidic acids, lyso
plasmalogens, lysophospholipids, lysophophatidic acid amides,
glycerophosphoric acids, sphingolipids,
lysophophatidylethanolamine, and N-mono and N,N-di-(C.sub.1-4)alkyl
derivatives of the amines thereof; and R' and R'' are each
independently selected from the group consisting of hydrogen and a
lower alkyl group comprising 1-5 carbon atoms.
[0014] WO00/31083 reports compounds of the formula:
##STR00002##
wherein R1 is a saturated or unsaturated, substituted or
unsubstituted hydrocarbon chain having from 2 to 30 carbon atoms;
R2 is H or a phospholipid head group; D is a residue of a
non-steroidal anti-inflammatory drug having a functional group
selected from the group consisting of carboxyl, hydroxyl, amine and
thiol, wherein D is attached through said functional group to a
bridging group, --C(O)-Z-X--, wherein Z is a saturated or
unsaturated carbon chain having from 2 to 15 atoms, and X is
selected from amino, hydroxy, thio and carbonyl groups, such that
when the functional group of D is carboxyl, X is selected from
amino, hydroxy and thio, and when the functional group of D is
amino, hydroxy or thio, X is a carbonyl group.
[0015] WO01/19320 reports compounds of the formula:
##STR00003##
wherein R1 is a saturated or unsaturated, straight-chain or
branched, substituted or unsubstituted hydrocarbon chain having
from 2 to 30 carbon atoms; R2 is H or a phospholipid head group; Z
is a saturated or unsaturated, straight-chain or branched,
substituted or unsubstituted hydrocarbon chain having from 2 to 15
carbon atoms, which may include cyclic elements, and optionally is
interrupted by one or more atoms selected from oxygen and sulfur
atoms; X is a direct covalent bond or selected from the group
consisting of O, S, NH and C(O) groups; and D is a residue of an
anti-proliferative drug, wherein the bound anti-proliferative drug
residue is an inactive form of the drug which is selectively
activated in cells and tissues with elevated phospholipase
activity.
[0016] WO02/11666 reports compounds of the formula:
##STR00004##
or a pharmaceutically acceptable salt thereof, wherein R1 and R2
are the same or different, saturated or unsaturated aliphatic chain
comprising from 2 to 30 carbon atoms; R.sup.3 is
A-[CH.sub.2].sub.m--B--[CH.sub.2].sub.n--C--[CH.sub.2].sub.p-D,
wherein m, n and p are each independently zero or an integer from 1
to 12, and A, B, C and D are each independently selected from a
covalent bond, amino, amido, oxygen, thio, carbonyl, carboxyl,
oxycarbonyl, thiocarbonyl, phosphate, amino phosphate, mono-, di-
and tri-amino phosphate group with the proviso that no two oxygen
atoms are directly connected to each other; Z.sub.1 and Z.sub.2 are
the same or different, each may be absent or independently selected
from a) hydrogen, sodium, lithium, potassium, ammonium, mono-, di-,
tri- and tetraalkylammonium, or b) together with the phospho group
form a phospho ester of glycerol, choline, ethanolamine, inositol,
serine, mono- or oligosaccharide.
[0017] WO03/000173 reports compounds of formula (I):
##STR00005##
and pharmaceutically acceptable salts thereof, wherein R.sup.1 is a
saturated or unsaturated chain of 1-18 carbons in length; and
R.sup.2 is a saturated or unsaturated chain of 1-18 carbons in
length, with the proviso that R.sup.1 and R.sup.2 are not both
propyl; and compounds of formula (II):
##STR00006##
and pharmaceutically acceptable salts thereof, wherein R.sup.1 is a
saturated or unsaturated chain of 1-18 carbons in length; R.sup.2
is a saturated or unsaturated chain of 1-18 carbons in length; and
A is selected from the group consisting of PO.sub.4--X, COOL and
COHR'--R'', wherein X is a hydrogen or choline, L is a lipid moiety
selected from the group consisting of glycerol, C.sub.3-20 fatty
acid monoglycerides, C.sub.3-20 fatty acid diglycerides,
hydroxy-C.sub.2-6-alkyl esters of C.sub.3-20 fatty acids,
hydroxy-C.sub.2-6-alkyl esters of lysophosphatidic acids, lyso
plasmalogens, lysophospholipids, lysophophatidic acid amides,
glycerophosphoric acids, sphingolipids,
lysophosphatidylethanolamine, and N-mono-(C.sub.1-4)alkyl and
N,N-di-(C.sub.1-4)alkyl and quaternary derivatives of the amines
thereof; and R' and R'' are each independently selected from the
group consisting of hydrogen and a lower alkyl group comprising 1-5
carbon atoms.
SUMMARY OF THE INVENTION
[0018] The present invention relates to prodrugs of caspase
inhibitors. These compounds have the general formula I:
##STR00007##
or a pharmaceutically acceptable salt thereof, wherein:
[0019] R.sup.1 is a saturated or unsaturated, straight-chain or
branched, substituted or unsubstituted hydrocarbon chain;
[0020] R.sup.2 is H or a phospholipid head group;
[0021] X is a direct covalent bond or a group C(O)LR.sup.3 wherein
L is a saturated or unsaturated, straight-chain or branched,
substituted or unsubstituted hydrocarbon chain having from 2 to 15
carbon atoms, which optionally includes cyclic elements, and is
optionally interrupted by one or more atoms selected from the group
consisting of oxygen, sulfur and N(R.sup.4); R.sup.3 is selected
from the group consisting of O, S and N(R.sup.4), wherein R.sup.4
is H or a saturated or unsaturated hydrocarbon chain having 1 to 6
carbon atoms; and
[0022] Y is a residue of a caspase inhibitor.
[0023] This invention further provides pharmaceutical compositions
comprising these prodrugs. This invention also relates to the
release of the caspase inhibitor from the prodrug by selective bond
cleavage. This invention also relates to methods of using said
pharmaceutical compositions for treatment of caspase-mediated
diseases including inflammatory and degenerative diseases. This
invention further relates to methods for preparing compounds of
this invention.
BRIEF DESCRIPTION OF THE FIGURES
[0024] FIG. 1 depicts compounds and pharmaceutical compositions of
this invention. Said compounds and compositions are also described
in PCT Publication WO 00/55114.
[0025] FIG. 2 depicts compounds and pharmaceutical compositions of
this invention. Said compounds and compositions are also described
in PCT Publication WO 00/55127.
[0026] FIG. 3 depicts compounds and pharmaceutical compositions of
this invention. Said compounds and compositions are also described
in PCT Publication WO 00/61542.
[0027] FIG. 4 depicts compounds and pharmaceutical compositions of
this invention. Said compounds and compositions are also described
in PCT Publication WO 01/05772.
[0028] FIG. 5 depicts compounds and pharmaceutical compositions of
this invention. Said compounds and compositions are also described
in PCT Publication WO 01/10383.
[0029] FIG. 6 depicts compounds and pharmaceutical compositions of
this invention. Said compounds and compositions are also described
in PCT Publication WO 01/16093.
[0030] FIG. 7 depicts compounds and pharmaceutical compositions of
this invention. Said compounds and compositions are also described
in PCT Publication WO 01/42216.
[0031] FIG. 8 depicts compounds and pharmaceutical compositions of
this invention. Said compounds and compositions are also described
in PCT Publication WO 01/72707.
[0032] FIG. 9 depicts compounds and pharmaceutical compositions of
this invention. Said compounds and compositions are also described
in PCT Publication WO 01/90070.
[0033] FIG. 10 depicts compounds and pharmaceutical compositions of
this invention. Said compounds and compositions are also described
in PCT Publication WO 01/94351.
[0034] FIG. 11 depicts compounds and pharmaceutical compositions of
this invention. Said compounds and compositions are also described
in PCT Publication WO 02/094263.
[0035] FIG. 12 depicts compounds and pharmaceutical compositions of
this invention. Said compounds and compositions are also described
in PCT Publication WO 02/42278.
[0036] FIG. 13 depicts compounds and pharmaceutical compositions of
this invention. Said compounds and compositions are also described
in U.S. Pat. No. 6,184,210.
[0037] FIG. 14 depicts compounds and pharmaceutical compositions of
this invention. Said compounds and compositions are also described
in U.S. Pat. No. 6,184,244.
[0038] FIG. 15 depicts compounds and pharmaceutical compositions of
this invention. Said compounds and compositions are also described
in U.S. Pat. No. 6,187,771.
[0039] FIG. 16 depicts compounds and pharmaceutical compositions of
this invention. Said compounds and compositions are also described
in U.S. Pat. No. 6,197,750.
[0040] FIG. 17 depicts compounds and pharmaceutical compositions of
this invention. Said compounds and compositions are also described
in U.S. Pat. No. 6,242,422.
[0041] FIG. 18 depicts compounds and pharmaceutical compositions of
this invention. Said compounds and compositions were also described
at the April 2001 American Chemical Society (ACS) meeting in San
Diego, Calif., USA.
[0042] FIG. 19 depicts compounds and pharmaceutical compositions of
this invention. Said compounds and compositions are also described
in PCT Publication WO 02/22611.
[0043] FIG. 20 depicts compounds and pharmaceutical compositions of
this invention. Said compounds and compositions are also described
in PCT Publication WO 02/085899.
DETAILED DESCRIPTION OF THE INVENTION
[0044] The present invention provides prodrug agents with improved
ability, relative to the corresponding drug, to inhibit caspases in
diseases where caspase activation is implicated. The present
invention also provides prodrugs of caspase inhibitors that undergo
activation within the disease-affected cells and tissues.
[0045] The prodrugs comprise a phospholipid moiety covalently
linked, via an optional bridging group, to a caspase inhibitor such
that the active species is preferentially released at the required
site of action. Preferably, the active species is released by
enzymatic cleavage.
[0046] Thus, the present invention provides a prodrug of general
formula I:
##STR00008##
or a pharmaceutically acceptable salt thereof, wherein:
[0047] R.sup.1 is a saturated or unsaturated, straight-chain or
branched, substituted or unsubstituted hydrocarbon chain;
[0048] R.sup.2 is H or a phospholipid head group;
[0049] X is a direct covalent bond or a group C(O)LR.sup.3 wherein
L is a saturated or unsaturated, straight-chain or branched,
substituted or unsubstituted hydrocarbon chain having from 2 to 15
carbon atoms, which optionally includes cyclic elements, and is
optionally interrupted by one or more atoms selected from the group
consisting of oxygen, sulfur and N(R.sup.4); R.sup.3 is selected
from the group consisting of O, S and N(R.sup.4), wherein R.sup.4
is a saturated or unsaturated hydrocarbon chain having 1 to 6
carbon atoms;
[0050] and Y is a residue of a caspase inhibitor.
[0051] In one embodiment, Y is a bound caspase inhibitor residue
which is an inactive form of the drug that is selectively released
in cells and tissues with elevated phospholipase activity. In
another embodiment, Y corresponds to a reversible caspase inhibitor
residue. In yet another embodiment, Y corresponds to an
irreversible caspase inhibitor residue.
[0052] In one embodiment of the invention, the R.sup.1 hydrocarbon
chain has from 2 to 30 carbon atoms.
[0053] In another embodiment, the R.sup.1 hydrocarbon chain has
from 2 to 24 carbon atoms.
[0054] In another embodiment, R.sup.2 is a phospholipid head group.
Preferably, the phospholipid head group is choline.
[0055] In another embodiment, X is a direct covalent bond.
[0056] In another embodiment of the present invention, the compound
is a caspase inhibitor as described in any of the following
documents, each of which is incorporated herein by reference: U.S.
Pat. No. ("USP") 6,187,771 (FIG. 15); American Chemical Society
("ACS") Meeting, San Diego, April 2001 (FIG. 18); U.S. Pat. No.
6,184,244 (FIG. 14); U.S. Pat. No. 6,242,422 (FIG. 17); U.S. Pat.
No. 6,197,750 (FIG. 16); WO 01/72707 (FIG. 8); WO 01/42216 (FIG.
7); WO 0.1/10383 (FIG. 5); WO 01/90070 (FIG. 9); WO 01/94351 (FIG.
10); WO 02/22611 (FIG. 19); WO 02/42278 (FIG. 12); WO 02/085899
(FIG. 20); WO 02/094263 (FIG. 11); WO 00/55127 (FIG. 2); WO
01/05772 (FIG. 4); U.S. Pat. No. 6,184,210 (FIG. 13); WO 00/61542
(FIG. 3); WO 01/16093 (FIG. 6); and WO 00/55114 (FIG. 1).
[0057] The structures of representative caspase inhibitors in each
of these documents are depicted in Table 1.
TABLE-US-00001 TABLE 1 Structures of Selected Caspase Inhibitors
Comp. No. Structure Citation 1 ##STR00009## USP 6,187,771 2
##STR00010## ACS Meeting,San Diego,April 2001 3 ##STR00011## USP
6,184,244 4 ##STR00012## USP 6,242,422 5 ##STR00013## USP 6,197,750
6 ##STR00014## WO 01/72707 7 ##STR00015## WO 01/42216 8
##STR00016## WO 01/10383 9 ##STR00017## WO 01/90070 10 ##STR00018##
WO 01/94351 11 ##STR00019## WO 02/22611 12 ##STR00020## WO 02/42278
13 ##STR00021## WO 02/085899 14 ##STR00022## WO 02/094263 15
##STR00023## WO 00/55127 16 ##STR00024## WO 01/05772 17
##STR00025## USP 6,184,210 18 ##STR00026## WO 00/61542 19
##STR00027## WO 01/16093 20 ##STR00028## WO 00/55114
[0058] It will be apparent to one skilled in the art that certain
compounds of this invention may exist in tautomeric forms or
hydrated forms, all such forms of the compounds being within the
scope of the invention. Unless otherwise stated, structures
depicted herein are also meant to include all stereochemical forms
of the structure; i.e., the R and S configurations for each
asymmetric center. Therefore, single stereochemical isomers as well
as enantiomeric and diastereomeric mixtures of the present
compounds are within the scope of the invention. Unless otherwise
stated, structures depicted herein are also meant to include
compounds that differ only in the presence of one or more
isotopically enriched atoms. For example, compounds having the
present structures except for the replacement of a hydrogen by a
deuterium or tritium, or the replacement of a carbon by a .sup.13C-
or .sup.14C-enriched carbon are within the scope of this
invention.
[0059] As used herein, the term "prodrug" refers to a derivative of
a biologically active compound, wherein the derivative has little
or no activity of the biologically active compound.
[0060] Examples of the substituents of the hydrocarbon chains
include, but are not limited to, halogen and small alkyl (e.g.,
C.sub.1-6alkyl). Examples of phospholipid head groups include, but
are not limited to, choline, ethanolamine, inositol,
monosaccharide, oligosaccharide, glycerol, phosphatidic acid and
serine.
[0061] Accordingly, the compound represented by formula I has
little or no caspase inhibitor activity. However, an active caspase
inhibitor is obtained by cleavage of the bond that links the
residue to the lipid portion of the compound of formula I. This
cleavage is preferably carried out enzymatically by, for example, a
phospholipase. When the cleavage is carried out by a phospholipase,
the residue is selectively cleaved in cells and tissues with
elevated phospholipase activity. Caspase inhibitor activity is
therefore obtained selectively in cells and tissues with elevated
phospholipase activity. This preferential release of the caspase
inhibitor is one embodiment of this invention.
[0062] Other mechanisms of cleavage, such as hydrolytic mechanisms
or cleavage by other enzymes are also within the scope of this
invention. These other mechanisms of cleavage may result in
non-preferential release of the caspase inhibitor.
[0063] The compounds of this invention may be prepared in general
by methods known to those skilled in the art for analogous
compounds, as illustrated by the general schemes and examples
below.
[0064] Therefore, one embodiment of this invention provides a
process for preparing a compound of formula I, comprising the step
of coupling compound 1:
##STR00029##
with a compound 2, YH, wherein compound. 2 comprises a carboxylic
acid group with H being the hydrogen of the carboxylic acid group
(R.sup.1, R.sup.2, and Y are as defined in any of the embodiments
of this invention). The coupling may be carried out under standard
carboxylic acid coupling conditions. As would be appreciated by a
skilled practitioner, appropriate functional groups in compound 1
and compound 2 may be protected [see, e.g., T. W. Greene & P.
G. M. Wutz, Protective Groups in Organic Synthesis, John Wiley
& Sons, New York, 1999].
[0065] The compounds of this invention may be assayed for their
ability to inhibit apoptosis, the release of IL-1.beta. or caspase
activity. Assays for each of the activities are known in the art
(see generally, WO 01/42216, the content of which is incorporated
herein by reference). However, as would be recognized by a skilled
practitioner, the prodrug compounds of this invention should be
active only in assays where the phospholipid prodrug moiety would
be cleaved, typically in in vivo assays.
[0066] One embodiment of this invention relates to a composition
comprising a compound of formula I or a pharmaceutically acceptable
salt thereof, and a pharmaceutically acceptable carrier.
[0067] Another embodiment of this invention provides a method for
inhibiting caspase activity in a mammal comprising administering to
said mammal a compound of formula I or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable
carrier.
[0068] This invention also provides methods of using the compounds
and compositions of this invention.
[0069] When pharmaceutically acceptable salts of the compounds of
this invention are utilized in these compositions, those salts are
preferably derived from inorganic or organic acids and bases.
Included among such acid salts are the following: acetate, adipate,
alginate, aspartate, benzoate, benzene sulfonate, bisulfate,
butyrate, citrate, camphorate, camphor sulfonate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate,
pamoate, pectinate, persulfate, 3-phenyl-propionate, picrate,
pivalate, propionate, succinate, tartrate, thiocyanate, tosylate
and undecanoate. Base salts include ammonium salts, alkali metal
salts, such as sodium and potassium salts, alkaline earth metal
salts, such as calcium and magnesium salts, salts with organic
bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and
salts with amino acids such as arginine, lysine, and so forth.
[0070] Also, the basic nitrogen-containing groups may be
quaternized with agents such as lower alkyl halides, e.g., methyl,
ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl
sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates,
long chain halides such as decyl, lauryl, myristyl and stearyl
chlorides, bromides and iodides, aralkyl halides, such as benzyl
and phenethyl bromides and others. Water or oil-soluble or
dispersible products are thereby obtained.
[0071] The compounds utilized in the compositions and methods of
this invention may also be modified by appending appropriate
functionalities to enhance selective biological properties. Such
modifications are known in the art and include those which increase
biological penetration into a given biological system (e.g., blood,
lymphatic system, central nervous system), increase oral
availability, increase solubility to allow administration by
injection, alter metabolism and/or alter rate of excretion.
[0072] Pharmaceutically acceptable carriers that may be used in
these compositions include, but are not limited to, ion exchangers,
alumina, aluminum stearate, lecithin, serum proteins, such as human
serum albumin, buffer substances such as phosphates, glycine,
sorbic acid, potassium sorbate, partial glyceride mixtures of
saturated vegetable fatty acids, water, salts or electrolytes, such
as protamine sulfate, disodium hydrogen phosphate, potassium
hydrogen phosphate, sodium chloride, zinc salts, colloidal silica,
magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based
substances, polyethylene glycol, sodium carboxymethylcellulose,
polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,
polyethylene glycol and wool fat.
[0073] According to a preferred embodiment, the compositions of
this invention are formulated for pharmaceutical administration to
a mammal, preferably a human being.
[0074] Such pharmaceutical compositions of the present invention
may be administered orally, parenterally, by inhalation spray,
topically, rectally, nasally, buccally, vaginally or via an
implanted reservoir. The term "parenteral" as used herein includes
subcutaneous, intravenous, intramuscular, intra-articular,
intra-synovial, intrasternal, intrathecal, intrahepatic,
intralesional and intracranial injection or infusion techniques.
Preferably, the compositions are administered orally or
intravenously.
[0075] Sterile injectable forms of the compositions of this
invention may be aqueous or oleaginous suspension. These
suspensions may be formulated according to techniques known in the
art using suitable dispersing or wetting agents and suspending
agents. The sterile injectable preparation may also be a sterile
injectable solution or suspension in a non-toxic parenterally
acceptable diluent or solvent, for example as a solution in
1,3-butanediol. Among the acceptable vehicles and solvents that may
be employed are water, Ringer's solution and isotonic sodium
chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose, any bland fixed oil may be employed including synthetic
mono- or di-glycerides. Fatty acids, such as oleic acid and its
glyceride derivatives are useful in the preparation of injectables,
as are natural pharmaceutically-acceptable oils, such as olive oil
or castor oil, especially in their polyoxyethylated versions. These
oil solutions or suspensions may also contain a long-chain alcohol
diluent or dispersant, such as carboxymethyl cellulose or similar
dispersing agents which are commonly used in the formulation of
pharmaceutically acceptable dosage forms including emulsions and
suspensions. Other commonly used surfactants, such as Tweens, Spans
and other emulsifying agents or bioavailability enhancers which are
commonly used in the manufacture of pharmaceutically acceptable
solid, liquid, or other dosage forms may also be used for the
purposes of formulation.
[0076] The pharmaceutical compositions of this invention may be
orally administered in any orally acceptable dosage form including,
but not limited to, capsules, tablets, aqueous suspensions or
solutions. In the case of tablets for oral use, carriers that are
commonly used include lactose and corn starch. Lubricating agents,
such as magnesium stearate, are also typically added. For oral
administration in a capsule form, useful diluents include lactose
and dried cornstarch. When aqueous suspensions are required for
oral use, the active ingredient is combined with emulsifying and
suspending agents. If desired, certain sweetening, flavoring or
coloring agents may also be added.
[0077] Alternatively, the pharmaceutical compositions of this
invention may be administered in the form of suppositories for
rectal administration. These may be prepared by mixing the agent
with a suitable non-irritating excipient which is solid at room
temperature but liquid at rectal temperature and therefore will
melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and polyethylene glycols.
[0078] The pharmaceutical compositions of this invention may also
be administered topically, especially when the target of treatment
includes areas or organs readily accessible by topical application,
including diseases of the eye, the skin, or the lower intestinal
tract. Suitable topical formulations are readily prepared for each
of these areas or organs.
[0079] Topical application for the lower intestinal tract may be
effected in a rectal suppository formulation (see above) or in a
suitable enema formulation. Topically-transdermal patches may also
be used.
[0080] For topical applications, the pharmaceutical compositions
may be formulated in a suitable ointment containing the active
component suspended or dissolved in one or more carriers. Carriers
for topical administration of the compounds of this invention
include, but are not limited to, mineral oil, liquid petrolatum,
white petrolatum, propylene glycol, polyoxyethylene,
polyoxypropylene, emulsifying wax and water. Alternatively, the
pharmaceutical compositions may be formulated in a suitable lotion
or cream containing the active components suspended or dissolved in
one or more pharmaceutically acceptable carriers. Suitable carriers
include, but are not limited to, mineral oil, sorbitan
monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,
2-octyldodecanol, benzyl alcohol and water.
[0081] For ophthalmic use, the pharmaceutical compositions may be
formulated as micronized suspensions in isotonic, pH adjusted
sterile saline, or, preferably, as solutions in isotonic, pH
adjusted sterile saline, either with or without a preservative such
as benzylalkonium chloride. Alternatively, for ophthalmic uses, the
pharmaceutical compositions may be formulated in an ointment such
as petrolatum.
[0082] The pharmaceutical compositions of this invention may also
be administered by nasal aerosol or inhalation. Such compositions
are prepared according to techniques well known in the art of
pharmaceutical formulation and may be prepared as solutions in
saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, fluorocarbons,
and/or other conventional solubilizing or dispersing agents.
[0083] The above-described compounds and compositions are
particularly useful in therapeutic applications relating to an IL-1
mediated disease, an apoptosis mediated disease, an inflammatory
disease, an autoimmune disease, a destructive bone disorder, a
proliferative disorder, an infectious disease, a degenerative
disease, a disease associated with cell death, an excess dietary
alcohol intake disease, a viral mediated disease, retinal
disorders, uveitis, inflammatory peritonitis, osteoarthritis,
pancreatitis, asthma, adult respiratory distress syndrome,
glomerulonephritis, rheumatoid arthritis, systemic lupus
erythematosus, scleroderma, chronic thyroiditis, Grave's disease,
autoimmune gastritis, diabetes, autoimmune hemolytic anemia,
autoimmune neutropenia, thrombocytopenia, chronic active hepatitis,
myasthenia gravis, inflammatory bowel disease, Crohn's disease,
psoriasis, atopic dermatitis, scarring, graft vs host disease,
organ transplant rejection, organ apoptosis after burn injury,
osteoporosis, leukemias and related disorders, myelodysplastic
syndrome, multiple myeloma-related bone disorder, acute myelogenous
leukemia, chronic myelogenous leukemia, metastatic melanoma,
Kaposi's sarcoma, multiple myeloma, hemorrhagic shock, sepsis,
septic shock, burns, Shigellosis, Alzheimer's disease, Parkinson's
disease, Huntington's disease, Kennedy's disease, prion disease,
cerebral ischemia, epilepsy, myocardial ischemia, acute and chronic
heart disease, myocardial infarction, congestive heart failure,
atherosclerosis, coronary artery bypass graft, spinal muscular
atrophy, amyotrophic lateral sclerosis, multiple sclerosis,
HIV-related encephalitis, aging, alopecia, neurological damage due
to stroke, ulcerative colitis, traumatic brain injury, spinal cord
injury, hepatitis-B, hepatitis-C, hepatitis-G, yellow fever, dengue
fever, Japanese encephalitis, various forms of liver disease, renal
disease, polycystic kidney disease, H. pylori-associated gastric
and duodenal ulcer disease, HIV infection, tuberculosis, and
meningitis. The compounds and compositions are also useful in
treating complications associated with coronary artery bypass
grafts. The compounds and compositions are also useful for
decreasing IGIF or IFN-.gamma. production. The compounds and
compositions are also useful in immunotherapy for treatment of
cancer.
[0084] The present compounds and compositions may also be used in
methods for preserving cells. These methods would be useful for
preserving organs, particularly those intended for transplant, or
blood products. Similar uses for caspase inhibitors have been
reported [Schierle et al., Nature Medicine, 1999, 5, 97]. The
method involves treating the cells or tissue to be preserved with a
solution comprising a compound of this invention. The amount of a
compound of this invention needed will depend on the effectiveness
of the free caspase inhibitor for the given cell type and the
length of time required to preserve the cells from apoptotic cell
death.
[0085] According to another embodiment, the compositions of this
invention may further comprise another therapeutic agent. Such
agents include, but are not limited to, thrombolytic agents such as
tissue plasminogen activator and streptokinase. When a second agent
is used, the second agent may be administered either as a separate
dosage form or as part of a single dosage form with the compounds
or compositions of this invention.
[0086] The amount of compound present in the compositions of this
invention should be sufficient to cause a detectable decrease in
the release of IL-1.beta., cellular apoptosis or caspase activity,
or in the severity of caspase-mediated diseases, as measured by any
of the assays known in the art.
[0087] Dosage levels of between about 0.01 and about 100 mg/kg body
weight per day, preferably between about 0.5 and about 75 mg/kg
body weight per day and more preferably between about 1 and about
50 mg/kg body weight per day of the active ingredient compound are
useful in a monotherapy.
[0088] Typically, a compound or composition of this invention will
be administered from about 1 to about 5 times per day or
alternatively, as a continuous infusion. Such administration can be
used as a chronic or acute therapy. The amount of active ingredient
that may be combined with the carrier materials to produce a single
dosage form will vary depending upon the host treated and the
particular mode of administration. A typical preparation will
contain from about 5% to about 95% active compound (w/w).
Preferably, such preparations contain from about 20% to about 80%
active compound.
[0089] When the compositions of this invention comprise a
combination of a compound of this invention and one or more
additional therapeutic or prophylactic agents, both the compound
and the additional agent should be present at dosage levels of
between about 10% to about 80% of the dosage normally administered
in a monotherapy regime.
[0090] Upon improvement of a patient's condition, a maintenance
dose of a compound, composition or combination of this invention
may be administered, if necessary. Subsequently, the dosage or
frequency of administration, or both, may be reduced, as a function
of the symptoms, to a level at which the improved condition is
retained. When the symptoms have been alleviated to the desired
level, treatment should cease. Patients may, however, require
intermittent treatment on a long-term basis upon any recurrence of
disease symptoms.
[0091] As the skilled practitioner will appreciate, lower or higher
doses than those recited above may be required. It should be
understood that a specific dosage and treatment regimens for any
particular patient will depend upon a variety of factors, including
the activity of the specific compound employed, the age, body
weight, general health, sex, diet, time of administration, rate of
excretion, drug combination, the severity and course of the
particular disease, the patient's disposition to the disease being
treated, and the judgment of the treating physician. The amount of
active ingredients will also depend upon the particular compound
and other therapeutic agent, if present, in the composition.
[0092] In a preferred embodiment, the invention provides a method
of treating a mammal, having one of the aforementioned diseases,
comprising the step of administering to said mammal a
pharmaceutically acceptable composition described above. In this
embodiment, if the patient is also administered another therapeutic
agent or caspase inhibitor, it may be delivered together with the
compound of this invention in a single dosage form, or, as a
separate dosage form. When administered as a separate dosage form,
the other caspase inhibitor or agent may be administered prior to,
at the same time as, or following administration of a
pharmaceutically acceptable composition comprising a compound of
this invention.
[0093] The compounds of this invention are particularly suitable
for methods involving inhibition of caspase activity. Without being
bound by theory, upon in vivo administration of a prodrug of this
invention, the phospholipid group is cleaved to provide a
corresponding acid-containing compound (e.g., a compound of Table
1). As would be recognized by a skilled practitioner, a prodrug of
this invention or the corresponding parent compound may be further
metabolized in vivo. Any such metabolites are included within the
scope of this invention.
[0094] In order that this invention be more fully understood, the
following examples are set forth. These examples are for the
purpose of illustration only and are not to be construed as
limiting the scope of the invention in any way.
EXAMPLE 1
##STR00030##
[0096] Scheme 1 depicts a synthetic route for obtaining compounds
of formula I, where compound 2 is a caspase inhibitor comprising a
carboxylic acid moiety. Reaction of a lipid compound 1 with a
compound 2, under standard carboxylic acid coupling conditions (for
example, the conditions as described below in Example 2) provides
compounds of formula I. Compounds of formula I may be isolated
using standard procedures.
[0097] In the lipid compound 1, the X--H moiety and/or the OH
moiety may be protected with a suitable protecting group. A lipid
compound 1 wherein both moieties are protected would have the
structure depicted by compound 3 below, wherein P is a suitable
protecting group (and wherein each P may be the same or different).
As would be recognized by a skilled practitioner, if the X--H
moiety of compound 1 is protected, the protecting group must be
removed prior to reacting compound 1 with compound 2. However, if
the O--H moiety is protected, the protecting group does not need to
be removed prior to reacting compound 1 with compound 2.
Furthermore, the deprotection of the X--H moiety may be done in
situ. Depending on the nature of the substituents on Y, suitable
protecting groups may be used in association with Y.
##STR00031##
EXAMPLE 2
##STR00032##
[0099] Scheme 2 depicts a synthetic route for obtaining compounds
of this invention where Y is the residue of a caspase inhibitor of
WO 01/72707 (wherein R.sup.1, R.sup.2, and X are as defined
herein). Reaction of a lipid compound 1 with compound 4 in the
presence of EDC [1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride] or CDI (1,1'-carbonyldiimidazole) under standard
carboxylic acid coupling conditions provides compound 5. Compound 5
may be isolated using standard procedures.
[0100] As described above in Example 1, the lipid compound 1, may
be protected with a suitable protecting group.
[0101] While we have described a number of embodiments of this
invention, it is apparent that our basic examples may be altered to
provide other embodiments, which utilize the compounds,
compositions, and methods of this invention.
* * * * *