U.S. patent application number 12/880347 was filed with the patent office on 2011-01-06 for n-(-3-methoxy-5-methylpyrazin-2-yl)-2-(4-'1,3,4-oxadiazol-2-yl!phenyl)pyri- dine-3 sulphonamide as an anticancer agent.
This patent application is currently assigned to ASTRAZENECA AB. Invention is credited to Marianne Bernice Ashford, Nigel Charles Barrass, Francis Thomas Boyle, Andrew Mark Hughes, Donna Johnson, Sian Tomiko Taylor, David Williams Tonge.
Application Number | 20110003831 12/880347 |
Document ID | / |
Family ID | 9942847 |
Filed Date | 2011-01-06 |
United States Patent
Application |
20110003831 |
Kind Code |
A1 |
Tonge; David Williams ; et
al. |
January 6, 2011 |
N-(-3-METHOXY-5-METHYLPYRAZIN-2-YL)-2-(4-'1,3,4-OXADIAZOL-2-YL!PHENYL)PYRI-
DINE-3 SULPHONAMIDE AS AN ANTICANCER AGENT
Abstract
The use of
N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyri-
dine-3-sulphonamide, or a pharmaceutically acceptable salt thereof,
in the treatment of cancer and/or pain in a warm blooded animal
such as man is described.
Inventors: |
Tonge; David Williams;
(Macclesfield, GB) ; Taylor; Sian Tomiko;
(Macclesfield, GB) ; Boyle; Francis Thomas;
(Macclesfield, GB) ; Hughes; Andrew Mark;
(Macclesfield, GB) ; Johnson; Donna;
(Macclesfield, GB) ; Ashford; Marianne Bernice;
(Macclesfield, GB) ; Barrass; Nigel Charles;
(Macclesfield, GB) |
Correspondence
Address: |
ASTRAZENECA R&D BOSTON
35 GATEHOUSE DRIVE
WALTHAM
MA
02451-1215
US
|
Assignee: |
ASTRAZENECA AB
Sodertalje
SE
|
Family ID: |
9942847 |
Appl. No.: |
12/880347 |
Filed: |
September 13, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10524963 |
Feb 18, 2005 |
7820679 |
|
|
PCT/GB03/03653 |
Aug 20, 2003 |
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12880347 |
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Current U.S.
Class: |
514/255.05 |
Current CPC
Class: |
A61P 9/00 20180101; A61P
25/02 20180101; A61P 35/04 20180101; A61P 35/00 20180101; A61P
23/00 20180101; A61K 31/497 20130101; A61P 35/02 20180101; A61P
29/00 20180101; A61P 43/00 20180101; A61P 25/04 20180101 |
Class at
Publication: |
514/255.05 |
International
Class: |
A61K 31/497 20060101
A61K031/497; A61P 35/00 20060101 A61P035/00; A61P 35/02 20060101
A61P035/02; A61P 35/04 20060101 A61P035/04 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 23, 2002 |
GB |
0219660.8 |
Claims
1-25. (canceled)
26. A method of treating cancer which comprises administering an
effective amount of
N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyri-
dine-3-sulphonamide, or a pharmaceutically acceptable salt thereof,
to a warm blooded animal such as man.
27. A method for reducing abnormal proliferation in a cancerous
cell or inducing differentiation of a cancerous cell which
comprises administering an effective amount of
N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyri-
dine-3-sulphonamide, or a pharmaceutically acceptable salt thereof,
to a warm blooded animal such as man.
28. A method of inducing apoptosis in a cancerous cell which
comprises administering an effective amount of
N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyri-
dine-3-sulphonamide, or a pharmaceutically acceptable salt thereof,
to a warm blooded animal such as man.
29. A method of providing an anti-angiogenic and vascular targeting
agent in blood vessels supplying a cancerous cell which comprises
administering an effective amount of
N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyri-
dine-3-sulphonamide, or a pharmaceutically acceptable salt thereof,
to a warm blooded animal such as man.
30. A method of providing an anti-angiogenic effect which comprises
administering an effective amount of
N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyri-
dine-3-sulphonamide, or a pharmaceutically acceptable salt thereof,
to a warm blooded animal such as man.
31. The method according to claim 26 wherein the cancer is
oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical
cancer, ewings tumour, neuroblastoma, Kaposis sarcoma, ovarian
cancer, breast cancer, colorectal cancer, prostate cancer, bladder
cancer, melanoma, lung cancer--non small cell lung cancer (NSCLC),
and small cell lung cancer (SCLC), gastric cancer, head and neck
cancer, renal cancer lymphoma and leukaemia.
32. The method according to claim 26 wherein the cancer is prostate
cancer.
33. The method according to claim 26 wherein the cancer is SCLC,
NSCLC, colorectal cancer, ovarian cancer and/or breast cancer.
34. The method according to claim 26 wherein the cancer is bladder
cancer, oesophageal cancer, gastric cancer, melanoma, cervical
cancer and/or renal cancer.
35. The method according to claim 26 wherein the cancer is
endometrial, liver, stomach, thyroid, rectal and/or brain
cancer.
36. The method according to claim 26 wherein the cancer is
SCLC.
37. The method according to claim 26 wherein the cancer is
NSCLC.
38. The method according to claim 26 wherein the cancer is
colorectal cancer.
39. The method according to claim 26 wherein the cancer is ovarian
cancer.
40. The method according to claim 26 wherein the cancer is breast
cancer.
41. The method according to claim 26 wherein the cancer is in a
metastatic state.
42. The method according to claim 26 wherein the cancer is in a
non-metastatic state.
43. The method according to claim 26 wherein the cancer is renal,
thyroid, lung, breast or prostate cancer and is producing bone
metastases.
44. A method of inhibiting bone metastases and inhibiting invasion
which comprises administering an effective amount of
N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyri-
dine-3-sulphonamide, or a pharmaceutically acceptable salt thereof,
to a warm blooded animal such as man.
45. A method of inhibiting bone metastases which comprises
administering an effective amount of
N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyri-
dine-3-sulphonamide, or a pharmaceutically acceptable salt thereof,
to a warm blooded animal such as man.
46. A method of preventing bone metastases which comprises
administering an effective amount of
N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyri-
dine-3-sulphonamide, or a pharmaceutically acceptable salt thereof,
to a warm blooded animal such as man.
47. A method of treating bone metastases which comprises
administering an effective amount of
N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyri-
dine-3-sulphonamide, or a pharmaceutically acceptable salt thereof,
to a warm blooded animal such as man.
Description
[0001] The present application refers to
N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-[1,3,4-oxadiazol-2-yl]phenyl)pyri-
dine-3-sulphonamide, or a pharmaceutically acceptable salt thereof,
hereafter "Compound (I)", and its use in the treatment of cancer in
a warm blooded animal such as man. The invention also relates to
the use of pharmaceutical compositions containing Compound (I), or
a pharmaceutically acceptable salt thereof, in a method of treating
cancer in a warm blooded animal such as man, and to the use of
Compound (I), or a pharmaceutically acceptable salt thereof, in the
manufacture of medicament for use in a method of treating cancer in
a warm blooded animal such as man. The invention also relates to
the use of pharmaceutical compositions containing Compound (I), or
a pharmaceutically acceptable salt thereof, in a method of treating
pain in a warm blooded animal such as man, and to the use of
Compound (I), or a pharmaceutically acceptable salt thereof, in the
manufacture of medicament for use treating pain in a warm blooded
animal such as man.
[0002] Cancer affects an estimated 10 million people worldwide.
This figure includes incidence, prevalence and mortality. More than
4.4 million cancer cases are reported from Asia, including 2.5
million cases from Eastern Asia, which has the highest rate of
incidence in the world. By comparison, Europe has 2.8 million
cases, North America 1.4 million cases, and Africa 627,000
cases.
[0003] In the UK and US, for example, more than one in three people
will develop cancer at some point in their life. Cancer mortality
in the U.S. is estimated to account for about 600,000 a year, about
one in every four deaths, second only to heart disease in percent
of all deaths, and second to accidents as a cause of death of
children 1-14 years of age. The estimated cancer incidence in the
U.S. is now about 1,380,000 new cases annually, exclusive of about
900,000 cases of non-melanotic (basal and squamous cell) skin
cancer.
[0004] Cancer is also a major cause of morbidity in the UK with
nearly 260,000 new cases (excluding non-melanoma skin cancer)
registered in 1997. Cancer is a disease that affects mainly older
people, with 65% of cases occurring in those over 65. Since the
average life expectancy in the UK has almost doubled since the mid
nineteenth century, the population at risk of cancer has grown.
Death rates from other causes of death, such as heart disease, have
fallen in recent years while deaths from cancer have remained
relatively stable. The result is that 1 in 3 people will be
diagnosed with cancer during their lifetime and 1 in 4 people will
die from cancer. In people under the age of 75, deaths from cancer
outnumber deaths from diseases of the circulatory system, including
ischaemic heart disease and stroke. In 2000, there were 151,200
deaths from cancer. Over one fifth (22 percent) of these were from
lung cancer, and a quarter (26 percent) from cancers of the large
bowel, breast and prostate.
[0005] Worldwide, the incidence and mortality rates of certain
types of cancer (of stomach, breast, prostate, skin, and so on)
have wide geographical differences which are attributed to racial,
cultural, and especially environmental influences. There are over
200 different types of cancer but the four major types, lung,
breast, prostate and colorectal, account for over half of all cases
diagnosed in the UK and US. Prostate cancer is the fourth most
common malignancy among men worldwide, with an estimated 400,000
new cases diagnosed annually, accounting for 3.9 percent of all new
cancer cases.
[0006] Current options for treating cancers include surgical
resection, external beam radiation therapy and/or systemic
chemotherapy. These are partially successful in some forms of
cancer, but are not successful in others. There is a clear need for
new therapeutic treatments.
[0007] Non-steroidal anti-inflammatory drugs (NSAIDS) and opiates
are the main classes of drugs in pain relief. However both possess
undesirable side effects. NSAIDS are known to cause
gastrointestinal irritation and opiates are known to be addictive.
There is thus also a clear need for new treatments for the
management and treatment of pain.
[0008] Recently, endothelin A receptor antagonists have been
identified as potentially of value in the treatment of cancer
(Cancer Research, 56, 663-668, Feb. 15, 1996 and Nature Medicine,
Volume 1, Number 9, September 1999, 944-949).
[0009] The endothelins are a family of endogenous 21 amino acid
peptides comprising three isoforms, endothelin-1 (ET-1),
endothelin-2 and endothelin-3. The endothelins are formed by
cleavage of the Trp.sup.21-Val.sup.22 bond of their corresponding
proendothelins by an endothelin converting enzyme. The endothelins
are among the most potent vasoconstrictors known and have a
characteristic long duration of action. They exhibit a wide range
of other activities including cell proliferation and mitogenesis,
extravasation and chemotaxis, and also interact with a number of
other vasoactive agents.
[0010] The endothelins are released from a range of tissue and cell
sources including vascular endothelium, vascular smooth muscle,
kidney, liver, uterus, airways, intestine and leukocytes. Release
can be stimulated by hypoxia, shear stress, physical injury and a
wide range of hormones and cytokines Elevated endothelin levels
have been found in a number of disease states in man including
cancers.
[0011] The present invention concerns the surprising finding that
Compound (I) is a particularly potent anti-cancer agent. Compound
(I) is described as an endothelin receptor antagonist in
WO96/40681, and although in WO96/40681 it is acknowledged that
elevated endothelin levels have been found in a number of disease
states in man including certain cancers, there is no hint or
suggestion that this compound would possess the particular
beneficial efficacious, metabolic and toxicological profiles that
makes it such a potent anti-cancer agent. WO96/40681 claims the
endothelin receptors described therein solely for cardiovascular
diseases. For example in the introduction it is stated these
compounds are useful in the treatment of diseases or medical
conditions including "hypertension, pulmonary hypertension, cardiac
or cerebral circulatory disease and renal disease". The claims list
the following medical disease states "hypertension, pulmonary
hypertension, congestive heart failure, dyslipidaemia,
atherosclerosis, restenosis, acute and chronic renal failure,
ischaemic stroke, subarachnoid haemorrhage, intermittent
claudication, critical limb ischaemia, asthma or organ failure
after general surgery or transplantation". There is no hint or
suggestion from WO96/40681 that this compound would possess the
particular beneficial efficacious, metabolic and toxicological
profiles that makes it such a potent anti-cancer agent. In fact,
the present inventors have surprisingly established that Compound
(I) is a specific endothelin-A (ET.sub.A) antagonist and has no
measurable activity against endothelin-B (ET.sub.B).
[0012] The ET.sub.A receptor has been shown, via a variety of
mechanisms, to be the more important pathological receptor of the
two identified endothelin receptors in oncology: in the reduction
of abnormal cell proliferation (Bagnato et. al., (1995), Clin
Cancer Res 1, 1059-1066); as a anti-apoptotic (Wu Wang et. al.,
(1997), Biochem J, 328, 733-737); as an anti-angiogenic agent
(Spinella et al., (2002), J. Biol. Chem, 227(31), 27850-27855); and
as an inhibitor of bone metastases (Guise et. al., ASCO (2000)
abstract 331 and Nelson, et. al., (1999), Urology 53, 1063-1069) in
addition to mediating pain which is a common co-morbidity in
cancer. It has been shown (Dahlof et al., (1990), J Hypertens, 8,
811-817) that large doses of endothelin-1 causes pain, and causes
pain sensitization, but that this can be inhibited by an ET.sub.A
antagonist (e.g. Davar et al., (1998), Neuroreport 9, 2279-2283 and
De Mello et al., (1998), Pain, 77, 261-269). Therefore in another
aspect of the invention, Compound (I) is administered for the
prevention or treatment of pain mediated by the endothelin system,
in particular that associated with elevated endothelin-1
levels.
[0013] Conversely, there is emerging evidence (e.g. Cattaruzza et.
al., (2002), FASEB J. 14(7), 991-998 and Okazawa et. al., (1998), J
Biol Chem, 273, 12581-12592) that the ET.sub.B receptor is involved
in apoptotic signalling. The blocking of pro-apoptotic pathways
would be undesirable in the treatment of cancer, hence a compound
that specifically targeted the ET.sub.A receptor while leaving the
ET.sub.B receptor unaffected would be of the greatest utility in
the treatment of cancer. Compound (I) is such a compound.
[0014] Compound (I) by acting specifically on the ET.sub.A receptor
has many advantages over endothelin antagonists that also have
measurable ET.sub.B activity. For instance Compound (I) could be
administered to a patient without the administrator or prescribing
medical practitioner needing to titrate the dose of Compound (I)
looking for signs of ET.sub.B activity (for example oedema).
Furthermore, larger doses could potentially be administered because
there would be no ET.sub.B side effects.
[0015] Another disadvantage of ET.sub.B inhibition is that it
causes a rise in plasma endothelin. Potentially, over the course of
treatment, for a mixed ET.sub.A/ET.sub.B inhibitor, or a compound
that selectively targeted the ET.sub.A receptor, but still had
measurable ET.sub.B activity, this would result in increasingly
larger doses of inhibitor being needed to have the same beneficial
ET.sub.A effects. A specific ET.sub.A inhibitor would not encounter
this problem.
[0016] Therefore according to the present invention, there is
provided Compound (I), or a pharmaceutically acceptable salt
thereof, for use in the treatment of cancer in a warm blooded
animal such as man.
[0017] In one aspect, where Compound (I), or a pharmaceutically
acceptable salt thereof, is referred to this refers to the compound
only. In another aspect this refers to a pharmaceutically
acceptable salt of Compound (I).
[0018] According to another feature of the present invention, there
is provided Compound (I), or a pharmaceutically acceptable salt
thereof, in the manufacture of a medicament for use in the
treatment of cancer in a warm blooded animal such as man.
[0019] According to a further feature of this aspect of the
invention there is provided a method of treating cancer which
comprises administering an effective amount of Compound (I), or a
pharmaceutically acceptable salt thereof, to a warm blooded animal
such as man.
[0020] According to a further feature of this aspect of the
invention there is provided a pharmaceutical composition which
comprises Compound (I), or a pharmaceutically acceptable salt
thereof, in association with a pharmaceutically acceptable diluent
or carrier for use in the treatment of cancer in a warm blooded
animal such as man.
[0021] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, in
the reduction of abnormal proliferation in a cancerous cell or
inducing differentiation of a cancerous cell in a warm blooded
animal such as man.
[0022] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, in
the manufacture of a medicament for use in the reduction of
abnormal proliferation in a cancerous cell or inducing
differentiation of a cancerous cell in a warm blooded animal such
as man.
[0023] In another aspect of the invention there is provided a
method for reducing abnormal proliferation in a cancerous cell or
inducing differentiation of a cancerous cell which comprises
administering an effective amount of Compound (I), or a
pharmaceutically acceptable salt thereof, to a warm blooded animal
such as man.
[0024] According to a further feature of this aspect of the
invention there is provided a pharmaceutical composition which
comprises Compound (I), or a pharmaceutically acceptable salt
thereof, in association with a pharmaceutically acceptable diluent
or carrier for use in the reduction of abnormal proliferation in a
cancerous cell or inducing differentiation of a cancerous cell in a
warm blooded animal such as man.
[0025] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, in
inducing apoptosis in a cancerous cell in a warm blooded animal
such as man.
[0026] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, in
the manufacture of a medicament for use in inducing apoptosis in a
cancerous cell in a warm blooded animal such as man.
[0027] In another aspect of the invention there is provided a
method of inducing apoptosis in a cancerous cell which comprises
administering an effective amount of Compound (I), or a
pharmaceutically acceptable salt thereof, to a warm blooded animal
such as man.
[0028] According to a further feature of this aspect of the
invention there is provided a pharmaceutical composition which
comprises Compound (I), or a pharmaceutically acceptable salt
thereof, in association with a pharmaceutically acceptable diluent
or carrier for use in inducing apoptosis in a cancerous cell in a
warm blooded animal such as man.
[0029] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, as
an anti-angiogenic and vascular targeting agent in blood vessels
supplying a cancerous cell in a warm blooded animal such as
man.
[0030] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, in
the manufacture of a medicament for use as an anti-angiogenic and
vascular targeting agent in blood vessels supplying a cancerous
cell in a warm blooded animal such as man.
[0031] In another aspect of the invention there is provided a
method of providing an anti-angiogenic and vascular targeting agent
in blood vessels supplying a cancerous cell which comprises
administering an effective amount of Compound (I), or a
pharmaceutically acceptable salt thereof, to a warm blooded animal
such as man.
[0032] According to a further feature of this aspect of the
invention there is provided a pharmaceutical composition which
comprises Compound (I), or a pharmaceutically acceptable salt
thereof, in association with a pharmaceutically acceptable diluent
or carrier for use as an anti-angiogenic and vascular targeting
agent in blood vessels supplying a cancerous cell in a warm blooded
animal such as man.
[0033] By the term "vascular targeting agent" it is to be
understood that the site of action of Compound (I) would be on the
vasculature itself rather than the tumour.
[0034] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, as
an anti-angiogenic agent in a warm blooded animal such as man.
[0035] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, in
the manufacture of a medicament for use as an anti-angiogenic agent
in a warm blooded animal such as man.
[0036] In another aspect of the invention there is provided a
method of providing an anti-angiogenic effect which comprises
administering an effective amount of Compound (I), or a
pharmaceutically acceptable salt thereof, to a warm blooded animal
such as man.
[0037] According to a further feature of this aspect of the
invention there is provided a pharmaceutical composition which
comprises Compound (I), or a pharmaceutically acceptable salt
thereof, in association with a pharmaceutically acceptable diluent
or carrier for use as an anti-angiogenic agent in a warm blooded
animal such as man.
[0038] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, as
an inhibitor of bone metastases and an inhibitor of invasion in a
warm blooded animal such as man.
[0039] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, in
the manufacture of a medicament for use as an inhibitor of bone
metastases and an inhibitor of invasion in a warm blooded animal
such as man.
[0040] In another aspect of the invention there is provided a
method of inhibiting bone metastases and inhibiting invasion which
comprises administering an effective amount of Compound (I), or a
pharmaceutically acceptable salt thereof, to a warm blooded animal
such as man.
[0041] According to a further feature of this aspect of the
invention there is provided a pharmaceutical composition which
comprises Compound (I), or a pharmaceutically acceptable salt
thereof, in association with a pharmaceutically acceptable diluent
or carrier for use as an inhibitor of bone metastases and an
inhibitor of invasion in a warm blooded animal such as man.
[0042] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, as
an inhibitor of bone metastases in a warm blooded animal such as
man.
[0043] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, in
the manufacture of a medicament for use as an inhibitor of bone
metastases in a warm blooded animal such as man.
[0044] In another aspect of the invention there is provided a
method of inhibiting bone metastases which comprises administering
an effective amount of Compound (I), or a pharmaceutically
acceptable salt thereof, to a warm blooded animal such as man.
[0045] According to a further feature of this aspect of the
invention there is provided a pharmaceutical composition which
comprises Compound (I), or a pharmaceutically acceptable salt
thereof, in association with a pharmaceutically acceptable diluent
or carrier for use as an inhibitor of bone metastases in a warm
blooded animal such as man.
[0046] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, in
the prevention of bone metastases in a warm blooded animal such as
man.
[0047] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, in
the manufacture of a medicament for use in the prevention of bone
metastases in a warm blooded animal such as man.
[0048] In another aspect of the invention there is provided a
method of preventing bone metastases which comprises administering
an effective amount of Compound (I), or a pharmaceutically
acceptable salt thereof, to a warm blooded animal such as man.
[0049] According to a further feature of this aspect of the
invention there is provided a pharmaceutical composition which
comprises Compound (I), or a pharmaceutically acceptable salt
thereof, in association with a pharmaceutically acceptable diluent
or carrier for use in the prevention of bone metastases in a warm
blooded animal such as man.
[0050] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, in
the treatment of bone metastases in a warm blooded animal such as
man.
[0051] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, in
the manufacture of a medicament for use in the treatment of bone
metastases in a warm blooded animal such as man.
[0052] In another aspect of the invention there is provided a
method of treating bone metastases which comprises administering an
effective amount of Compound (I), or a pharmaceutically acceptable
salt thereof, to a warm blooded animal such as man.
[0053] According to a further feature of this aspect of the
invention there is provided a pharmaceutical composition which
comprises Compound (I), or a pharmaceutically acceptable salt
thereof, in association with a pharmaceutically acceptable diluent
or carrier for use in the treatment of bone metastases in a warm
blooded animal such as man.
[0054] In a further aspect of the invention, there is provided the
inhibition, treatment and/or prevention of bone metastases, as
described herein, wherein the bone metastases are as a result of
renal, thyroid, lung, breast or prostate cancer.
[0055] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, in
the prevention or treatment of pain associated with elevated
endothelin-1 production in a warm blooded animal such as man.
[0056] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, in
the manufacture of a medicament for use in the prevention or
treatment of pain associated with elevated endothelin-1 production
in a warm blooded animal such as man.
[0057] In another aspect of the invention there is provided a
method of treating pain associated with elevated endothelin-1
production which comprises administering an effective amount of
Compound (I), or a pharmaceutically acceptable salt thereof, to a
warm blooded animal such as man.
[0058] According to a further feature of this aspect of the
invention there is provided a pharmaceutical composition which
comprises Compound (I), or a pharmaceutically acceptable salt
thereof, in association with a pharmaceutically acceptable diluent
or carrier for use in the prevention or treatment of pain
associated with elevated endothelin-1 production in a warm blooded
animal such as man.
[0059] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, in
the prevention or treatment of pain in a warm blooded animal such
as man.
[0060] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, in
the manufacture of a medicament for use in the prevention or
treatment of pain in a warm blooded animal such as man.
[0061] In another aspect of the invention there is provided a
method of treating pain which comprises administering an effective
amount of Compound (I), or a pharmaceutically acceptable salt
thereof, to a warm blooded animal such as man.
[0062] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, in
the prevention or treatment of pain associated with stimulation of
the ET.sub.A receptor in a warm blooded animal such as man.
[0063] In another aspect of the invention there is provided the use
of Compound (I), or a pharmaceutically acceptable salt thereof, in
the manufacture of a medicament for use in the prevention or
treatment of pain associated with stimulation of the ET.sub.A
receptor in a warm blooded animal such as man.
[0064] In another aspect of the invention there is provided a
method of treating pain associated with stimulation of the ET.sub.A
receptor which comprises administering an effective amount of
Compound (I), or a pharmaceutically acceptable salt thereof, to a
warm blooded animal such as man.
[0065] Where cancer is referred to, particularly it refers to
oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical
cancer, ewings tumour, neuroblastoma, Kaposis sarcoma, ovarian
cancer, breast cancer, colorectal cancer, prostate cancer, bladder
cancer, melanoma, lung cancer--non small cell lung cancer (NSCLC),
and small cell lung cancer (SCLC)--gastric cancer, head and neck
cancer, renal cancer, lymphoma and leukaemia. More particularly it
refers to prostate cancer. In addition, more particularly it refers
to SCLC, NSCLC, colorectal cancer, ovarian cancer and/or breast
cancer. In addition, more particularly it refers to SCLC. In
addition, more particularly it refers to NSCLC. In addition, more
particularly it refers to colorectal cancer. In addition, more
particularly it refers to ovarian cancer. In addition, more
particularly it refers to breast cancer. Furthermore, more
particularly it refers to bladder cancer, oesophageal cancer,
gastric cancer, melanoma, cervical cancer and/or renal cancer. In
addition it refers to endometrial, liver, stomach, thyroid, rectal
and/or brain cancer. In another aspect of the invention, the cancer
is not melanoma. In another embodiment of the invention,
particularly the cancer is in a metastatic state, and more
particularly the cancer produces metastases to the bone. In a
further embodiment of the invention, particularly the cancer is in
a metastatic state, and more particularly the cancer produces skin
metastases. In a further embodiment of the invention, particularly
the cancer is in a metastatic state, and more particularly the
cancer produces lymphatic metastases. In a further embodiment of
the invention, the cancer is in a non-metastatic state.
[0066] It is to be understood that when the cancer is in a
metastatic state, that Compound (I) acts at both the primary tumour
site and the metastases. Compound (I) both prevents, treats and
inhibits metastases.
[0067] In one aspect of the invention, where pain is referred to,
this is pain associated with raised endothelin-1 levels. In another
aspect of the invention this is pain associated with stimulation of
the ET.sub.A receptor resulting from situations where ET.sub.B
down-regulation has occurred leading to abnormal ET.sub.A
stimulation and/or elevation of endothelin-1 levels. Particularly
this is pain associated with cancer. More particularly it is pain
associated with prostate cancer.
[0068] According to a further feature of this aspect of the
invention there is provided a pharmaceutical composition which
comprises Compound (I), or a pharmaceutically acceptable salt
thereof, in association with a pharmaceutically acceptable diluent
or carrier for use in the prevention or treatment of pain
associated with stimulation of the ET.sub.A receptor in a warm
blooded animal such as man.
[0069] Additionally, Compound (I) is expected to be useful in the
treatment and/or prophylaxis of pain of different origins and
causes, including acute as well as chronic pain states. Examples
are pain caused by chemical, mechanical, radiation (including
sunburn), thermal (including burns), infectious or inflammatory
tissue trauma or cancer, postoperative pain, post-partum pain, the
pain associated with joint conditions (such as rheumatoid arthritis
and osteoarthritis), pain associated with dental conditions (such
as dental caries and gingivitis), myofascial and low back pain,
pain associated with bone disorders (such as osteoporosis,
hypercalcaemia of malignancy and Paget's disease) and the pain
associated with sports injuries and sprains.
[0070] Also neuropathic pain conditions of central or peripheral
origin could be treated or prevented with Compound (I). Examples of
these pain conditions are pain associated with trigeminal
neuralgia, pain associated with postherpetic neuralgia (PHN), pain
associated with diabetic mono/poly neuropathy, pain associated with
nerve trauma, pain associated with spinal cord injury, pain
associated with central post stroke, pain associated with multiple
sclerosis and pain associated with Parkinson's disease.
[0071] Other pain states of visceral origin such as caused by
ulcer, dysmenorrhea, endometriosis, irritable bowel syndrome,
dyspepsia, pelvic pain etc. could also be treated or prevented with
Compound (I).
[0072] Additionally, Compound (I) is expected to be useful in the
treatment and/or prophylaxis of additional types of pain for
example complex regional pain syndrome, vasospastic/ischemic pains
(e.g. Raynaud syndrome) and bone pain.
[0073] A further aspect of the invention is to use Compound (I) for
oral treatment of neuropathic or central pain states.
[0074] Suitable pharmaceutically-acceptable salts include, for
example, salts with alkali metal (such as sodium, potassium or
lithium), alkaline earth metals (such as calcium or magnesium),
ammonium salts, and salts with organic bases affording
physiologically acceptable cations, such as salts with methylamine,
dimethylamine, trimethylamine, piperidine and morpholine. In
addition, suitable pharmaceutically-acceptable salts include,
pharmaceutically-acceptable acid-addition salts with hydrogen
halides, sulphuric acid, phosphoric acid and with organic acids
such as citric acid, maleic acid, methanesulphonic acid and
p-toluenesulphonic acid.
LEGENDS TO FIGURES
[0075] FIG. 1: This is a Western Blot showing inhibition of ET-1
induced MAPK phosphorylation with Compound (I) in the osteoblast
cell line MC3T3.E1/J1 from study 2 below. The proteins have been
run on a gel then transferred over to a nitrocellulose membrane,
where they are probed for using the primary and secondary
antibodies. The following abbreviations are used:
[0076] SCM: serum containing media
[0077] SFM: serum free media
[0078] FIG. 2: This is a graph depicting, inhibition of ET-1
induced MAPK phosphorylation with Compound (I) in the osteoblast
cell line MC3T3.E1/J1 also from study 2.
[0079] The following in vivo and in vitro studies can be used to
determine the efficacy of Compound (I) in oncology.
1) Endothelin Human Receptor Binding Assay
[0080] Human recombinant ET.sub.A or ET.sub.B receptors were
expressed in mouse erythroleukaemic (MEL) cells and membranes
prepared for competition binding studies using .sup.125I-labelled
ET-1 as the radioligand. Incubations were carried out in triplicate
in the presence of Compound (I), 10.sup.-10-10.sup.-4 M in half log
increments, and inhibition of ET-1 binding was expressed as a
geometric mean pIC.sub.50 value with 95% confidence limits.
Results
[0081] The pIC.sub.50 (negative log of the concentration of
compound required to displace 50% of the ligand) for Compound (I)
at the ET.sub.A receptor was 8.27 [8.23-8.32] (n=4). Displacement
curves were normal with slopes close to unity. Compound (I) had no
measurable affinity for the ET.sub.B receptor with a mean
displacement of 1.2.+-.0.7% (n=3) at a concentration of 10.sup.-4
M, a figure well within the limits of sensitivity of the assay.
Conclusion
[0082] Compound (I) is a high affinity ligand for the human
ET.sub.A receptor and is ET.sub.A specific, having no significant
ET.sub.B receptor affinity.
2) Compound (I) as a Treatment for Metastatic Cancer: Osteoblast
Data--Inhibition of ET-1 induced MAPK Stimulation with Compound
(I)
[0083] Compound (I) may well have a role in the treatment of not
only primary tumours but also metastatic tumours and the
pathological production of new bone in and around metastatic
deposits. Described below is an experiment demonstrating the
utility of Compound (I) in treating the osteoblastic bone
pathology.
[0084] The important clinical pathology seen in the bone metastatic
regions of patients with advanced prostate cancer presents as an
inappropriate osteoblastic stimulation, i.e. the presence of
prostatic tumour metastases in bone results in the net production
of new bone and eventually an increase in bone density around the
metastatic deposit (reviewed in Cancer Metastasis Rev. 2001;
20(3-4):333-49). The hypothesised mechanism behind this pathology
is a release of ET-1 from the metastatic prostate cell in the early
establishment of the secondary bone tumour.
[0085] ET-1 stimulation of the osteoblast has been described as the
key step in the pathological formation of new bone in prostate bone
metastasis (Invest New Drugs. 2002; 20(2):173-82). It has been
shown that ET-1 acts to directly induce proliferation and
differentiation of the osteoblast, as well as stimulate the
osteoblast to produce other growth factors, by simulation of the
ET.sub.A receptor and subsequent phosphorylation of MAP kinase
(Bone. 1999; 24(4):315-20 and J Bone Miner Res. 2002;
17(10):1774-84). In this way stimulation of the ET.sub.A receptor
causes both growth of bone and also, by release of growth factors
into the local environment, survival and growth of the metastatic
tumour cell. The tumour cells and osteoblastic cells in a
metastatic deposit therefore participate in a "vicious cycle" in
which their proliferative responses support each other, overcoming
the normal regulatory mechanisms which control and limit bone
formation (Nat Rev Cancer. 2002; 2(8): 584-93).
[0086] In the experiments described below the present inventors
first demonstrate the ability of ET-1 to stimulate MAP kinase in
osteoblastic cells. This stimulation promotes proliferation of the
cells and activation of the pathways shown to be important in the
release of growth factors from the osteoblast.
[0087] The inventors then demonstrate that Compound (I), an
ET.sub.A antagonist is an effective antagonist of this ET-1
stimulation.
Method
[0088] The MC3T3. E1/J1 cell line was isolated from a parental cell
line, MC3T3-E1 (available from Invitrogen), which had in turn been
derived from newborn C57BL/6 mouse calvaria. The MC3T3 E1/J1 line
is described as an osteoblastic line. To initiate the experiments
described below, MC3T3.E1/J1 cells were plated at a density of
2.4.times.10.sup.4 cells/well (24 well plates) in serum containing
media and incubated for 48 hours. The cells were washed twice in
PBS and re-incubated for approximately 17 hours in serum starvation
media.
[0089] At this stage, cells were then incubated with or without
Compound (I) for 30 minutes then stimulated with growth factor
(PDGF or ET-1) for 3 minutes. All media was then removed and the
cells lysed and stored at -20.degree. C. for
electrophoresis/western blot, which localized phosphorylated MAPK
and phosphorylated Akt probing with anti-phospho-p44/42 MAPK (Thr
202/204) and anti-Phospho AKT (Ser 473) antibodies (both
commercially available from Cell Signalling Technology). The
protein bands were quantitated by densitometry, and plotted as
arbitrary densitometry units. Phosphorylated MAPK levels were
normalised to total MAPK levels.
Results
[0090] Stimulation of cells with ET-1 for 3 minutes resulted in
increased phosphorylation of MAPK in the osteoblast cell line
MC3T3.E1/J1. Stimulation of the cells with a standard growth
factor, PDGF, also resulted in increased phosphorylation of MAPK.
Compound (I) inhibited ET-1-induced MAPK phosphorylation in
osteoblasts.
Table 1 Inhibition of ET-1 Induced MAPK Phosphorylation with
Compound (I) in the Osteoblast Cell Line MC3T3.E1/J1
TABLE-US-00001 TABLE 1 Environment Average Complete Media 151.70
Serum Free Media 100.00 ET-1 100 nm 312.78 ET-1 100 nm 369.85 +
Compound (I) 20 .mu.m 109.18 + Compound (I) 10 .mu.m 105.15 +
Compound (I) 1 .mu.m 157.41 + Compound (I) 0.1 .mu.m 422.11
This data is represented in FIGS. 1 and 2.
[0091] Note: The above experiment is not reliant on use of the
particular MC3T3.E1/J1 cell line, it could, for example, be
performed using the commercially available parental cell line
MC3T3-E1.
3) Compound (I) as an Inhibitor of Angiogenesis
[0092] ET.sub.A receptor activation by ET-1 contributes to tumour
growth and progression, mediated by various mechanisms in the
literature to suggest that specifically inhibiting ET.sub.A will
produce beneficial effects on primary tumours quite separate to its
effects on bone metastases. These mechanisms include
anti-apoptosis, direct and indirect growth promotion and promotion
of cell motility (Nat Rev Cancer. 2003; 3(2): 110-6).
[0093] Of more recent and increasing interest is the role of ET-1
mediated by the ET.sub.A receptor as key players in tumour
angiogenesis (J Cardiovasc Pharmacol. 2000; 36: S135-9).
Mechanistic studies have now shown that the ET.sub.A receptor is
important in the production of the potent angiogenic factor VEGF
(Life Sci. 1998; 63(6): 477-84) by direct induction of a
hypoxia-inducible factor, HIF-1.alpha.(J Biol Chem. 2002; 277:
27850-5). The increasing literature to support the role of
endothelin and the ET.sub.A receptor in tumour angiogenesis was
reviewed very recently by Bagnato and Spinella, (Trends Endocrinol
Metab. 2003; 14(1): 44-50).
[0094] In the experiment described below we show the effect of
Compound (I) on the angiogenesis induced by newly formed tumours
following human tumour cell inoculation in animal models.
Method
[0095] Tumour cells were inoculated intra-dermally in nude mice,
Compound (I) 25 or 50 mg/kg or vehicle was given once daily p.o.
with the first dose given on the day after cell implantation and
the mice were sacrificed 5 days later. A 1 cm.sup.2 area with the
tumour at the centre was examined and the number of blood vessels
bifurcations within that area supplying the tumour were counted.
The number of vessels supplying tumours from animals treated with
test drug and vehicle were compared and the effect of Compound (I)
was calculated as a percentage reduction of vessel count.
Results
[0096] Compound (I) caused reductions in blood vessel density
around tumours in treated animals compared to vehicle controls.
Reductions in vessel counts by Compound (I) were seen around
tumours induced by both colon and prostate cell lines in five in
vivo studies.
Table 2 Inhibition of Angiogenesis in Primary Tumours Caused by
Compound (I)
TABLE-US-00002 [0097] TABLE 2 Cell Tumour Compound (I) Inhibition
of Line Type dose (mg/kg) vessel count .sup.1 LOVO Colon 50 20% (P
= 0.001) LOVO Colon 50 28% (P<0.001) LOVO Colon 25 28%
(P<0.001) DU145 Prostate 50 30% (P<0.05) DU145 Prostate 25
38% (P<0.001) 1 statistically analyzed by the ANOVA test
compared to vehicle controls
[0098] The above cells lines are commercially available. One source
is the ATCC (American Type Culture Collection). LOVO has ATCC
No=CCL-229. DU145 has ATCC No=HTB-81.
Discussion
[0099] We have shown that, in vitro, Compound (I) is an effective
inhibitor of ET-1 mediated activation of MAP kinase in osteoblasts
as well as being effective in inhibiting angiogenesis in primary
tumours in vivo. This confirms the potential for this agent as a
therapy in metastatic prostate cancer as it may have beneficial
effects in preventing pathological bone density increases (by
inhibition of osteoblastic proliferation), mediated by MAPK pathway
as well as inhibiting the release of growth factors which support
the survival and growth of tumour cells in the bone
microenvironment in addition to anti-angiogenesis effect at the
primary tumour.
4) Compound (I) as an Endothelin Receptor Antagonist in the Human
Endothelin System
[0100] Human forearm blood flow can be assessed by temporarily
impeding the venous drainage from the arm by the application of a
pneumatic cuff on the upper arm, which is then inflated to just
above venous pressure. The resulting arterial flow into the arm
with no corresponding venous drainage leads to engorgement and
swelling of the forearm, which can be detected with sensitive
strain gauges. Infusion of the arterial vasoconstrictor ET-1 into
the brachial artery leads to a reduction in forearm distension due
to decreased arterial inflow. This vasoconstriction is mediated via
endothelin receptors on the vascular endothelium and associated
smooth muscle.
Method
[0101] A study was performed to investigate the ability of Compound
(I) to antagonise the vasoconstrictor effect of ET-1 via endothelin
receptors in this model in healthy male subjects aged 18-65. Eight
subjects received single oral doses of 10 mg Compound (I), 30 mg
Compound (I) and placebo in a randomised, double blind manner on
study days at least 7 days apart. Forearm vasoconstriction in
response to ET1 was assessed between 2 and 4 hours post dosing with
Compound (I).
Results
[0102] Overall, Compound (I) produced a statistically significant
reduction in forearm blood flow in response to infused ET-1
compared to placebo (p=0.0210) with evidence of a dose response
between the doses investigated. This demonstrates that Compound (I)
is an endothelin receptor antagonist in the human endothelin
system.
5) Compound (I) in a Dose-Escalation Study to Assess the
Tolerability and Pharmacokinetics of Compound (I) Given Orally Once
Daily in Patient with Metastatic Prostate Cancer
[0103] The following study can be undertaken to determine the
maximum well tolerated dose (MWTD) of Compound (I) in subjects with
metastatic prostate cancer. This study will allow you to observe
the effect of Compound (I) on prostate-specific antigen (PSA),
observe the effect of Compound (I) on a serological biomarker of
bone metastasis and provide you with pharmacokinetic
characterization of Compound (I) in subjects with metastatic
prostate cancer.
Method
[0104] Patients with prostate cancer who have documented bone
metastases (confirmed by bone scan within 3 months of study entry)
can be used for this study. Compound (I) can be given orally once
daily in tablet form. 120 mg can be used as the starting dose.
Subjects can be given study medication for 28 days or until
withdrawal criteria are met. Each dose level can recruit up to
three subjects with metastatic prostate cancer.
[0105] A formal assessment of tolerability can be made in each
subject following one week of Compound (I) administration. Dose
escalation can occur when two subjects in any cohort have not
experienced a dose limiting toxicity (DLT) following one week of
continuous Compound (I) administration. The dose can escalate by a
factor of two at each step. If one subject at a particular dose
level has a DLT, then two additional subjects at the same dose
level must not experience DLTs in order to escalate to the next
dose level.
[0106] Subjects can continue therapy for twenty eight days unless
the withdrawal criteria are met. When a minimum of two subjects in
any cohort have been given a dose that is considered to be not well
tolerated at any time point after administration, dose escalation
will end, and the closest dose below this will be taken as the
MWTD.
[0107] The following outcomes can be observed:
[0108] Incidence and severity of adverse events;
[0109] PSA concentration (total and ratio of free to total) at 1,
2, and 4 weeks in subjects treated with Compound (I);
[0110] Change in PSA (total and ratio of free to total) from before
Compound (I) administration to 1, 2 and 4 weeks after Compound (I)
administration;
[0111] Change in a serum marker of bony metastatic involvement
(bone alkaline phosphatase) from the level before Compound (I)
administration to levels after 1, 2, and 4 weeks of Compound (I)
administration; and
[0112] Plasma concentrations and variables of Compound (I)
following a single dose and multiple doses at steady state.
Testing for Pain Relief
[0113] The analgesic effect of Compound (I) may be measured, for
example, in the murine model of cancer pain described by Wacnik et
al., Journal of Neuroscience (2001), 21, 9355.
[0114] In a further embodiment of the present invention Compound
(I), or a pharmaceutically acceptable salt thereof, is administered
to a cell or individual prior to the development of cancer. For
example, a person at risk of developing cancer may be treated with
Compound (I), or a pharmaceutically acceptable salt thereof, to
prevent or inhibit the development of cancer and/or to prevent the
development of metastases.
[0115] Compound (I), or a pharmaceutically acceptable salt thereof,
can be administered for therapeutic or prophylactic use to a warm
blooded animal such as man by methods known in the art.
Administration can occur directly at the tumour site, or
particularly, systemic administration.
[0116] Compound (I), or a pharmaceutically acceptable salt thereof,
can be administered for therapeutic or prophylactic use to a warm
blooded animal such as man in the form of conventional
pharmaceutical compositions. The composition may be in a form
suitable for oral administration, for example as a tablet or
capsule, for parenteral injection (including intravenous,
subcutaneous, intramuscular, intravascular or infusion) as a
sterile solution, suspension or emulsion, for topical
administration as an ointment or cream or for rectal administration
as a suppository. In general the above compositions may be prepared
in a conventional manner using conventional excipients. For
example, Compound (I) can be formulated as a tablet using the
following excipients: [0117] Compound (I); [0118] Lactose
monohydrate (filler); [0119] Croscarmellose sodium (disintegrant);
[0120] Povidone (binder); [0121] Magnesium stearate (lubricant);
[0122] Hypromellose (film coat component); [0123] Polyethylene
glycol 300 (film coat component); and [0124] Titanium dioxide (film
coat component).
[0125] The amount of Compound (I), or a pharmaceutically acceptable
salt thereof, administered would be that sufficient to provide the
desired pharmaceutical effect. For instance, Compound (I) could be
administered to a warm-blooded animal orally, at a unit dose less
than 1 g daily. Particularly Compound (I) could be administered to
a warm-blooded animal, at a unit dose of less than 250 mg per day.
In another aspect of the invention, Compound (I) could be
administered to a warm-blooded animal, at a unit dose of less than
130 mg per day. In a further aspect of the invention, Compound (I)
could be administered to a warm-blooded animal, at a unit dose of
less than 50 mg per day.
* * * * *