U.S. patent application number 12/948159 was filed with the patent office on 2011-06-02 for cancer treatment method.
Invention is credited to Connie ERICKSON-MILLER.
Application Number | 20110129550 12/948159 |
Document ID | / |
Family ID | 44069083 |
Filed Date | 2011-06-02 |
United States Patent
Application |
20110129550 |
Kind Code |
A1 |
ERICKSON-MILLER; Connie |
June 2, 2011 |
CANCER TREATMENT METHOD
Abstract
Invented is a method of treating cancer or a pre-cancerous
syndrome in a mammal, including a human, in need thereof which
comprises the administration of an effective amount of a
non-peptide thrombopoietin (TPO) receptor agonist or TPO cell cycle
activator and a chemotherapeutic agent to such mammal, suitably a
human.
Inventors: |
ERICKSON-MILLER; Connie;
(Collegeville, PA) |
Family ID: |
44069083 |
Appl. No.: |
12/948159 |
Filed: |
November 17, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12166686 |
Jul 2, 2008 |
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12948159 |
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PCT/US2008/054046 |
Feb 15, 2008 |
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12166686 |
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60977216 |
Oct 3, 2007 |
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60969192 |
Aug 31, 2007 |
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60952289 |
Jul 27, 2007 |
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60949347 |
Jul 12, 2007 |
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60908205 |
Mar 27, 2007 |
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60892552 |
Mar 2, 2007 |
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60890236 |
Feb 16, 2007 |
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Current U.S.
Class: |
424/649 ;
514/19.3; 514/381; 514/404 |
Current CPC
Class: |
A61K 31/4155 20130101;
A61K 38/17 20130101; A61K 31/497 20130101; A61K 31/655 20130101;
A61K 38/17 20130101; A61K 33/24 20130101; A61K 31/655 20130101;
A61K 31/41 20130101; A61P 35/02 20180101; A61K 2300/00 20130101;
A61K 31/4152 20130101; A61K 31/496 20130101; A61K 9/0053 20130101;
A61K 31/4152 20130101; A61P 35/00 20180101; A61K 33/24 20130101;
A61K 31/41 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 45/06
20130101 |
Class at
Publication: |
424/649 ;
514/19.3; 514/404; 514/381 |
International
Class: |
A61K 33/24 20060101
A61K033/24; A61K 38/17 20060101 A61K038/17; A61K 31/4152 20060101
A61K031/4152; A61K 31/41 20060101 A61K031/41; A61P 35/00 20060101
A61P035/00 |
Claims
1. A method of treating a cancer which is known to enter noncycling
cell phases in a mammal in need thereof which comprises the in vivo
administration of an effective amount of a) at least one TPO cell
cycle activator, and b) at least one chemotherapeutic agent.
2. The method of claim 1 wherein the mammal is a human.
3. The method of claim 2 wherein the cancer is selected from:
Lymphoblastic T cell leukemia, Chronic myelogenous leukemia,
Chronic lymphocytic leukemia, Hairy-cell leukemia, acute
lymphoblastic leukemia, Chronic neutrophilic leukemia, Acute
lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large
cell leukemia, Mantle cell leukemia, Megakaryoblastic leukemia,
multiple myeloma, acute myelogenous leukemia (AML), promyelocytic
leukemia, acute megakaryocytic leukemia, and Erythroleukemia.
4. The method of claim 2 wherein the TPO cell cycle activator is
AMG531.
5. The method of claim 3 wherein the TPO cell cycle activator is
AMG531.
6. The method of claim 2 wherein the chemotherapeutic agent is
selected from: gemcitabine, carboplatin, cisplatin, cytarabine,
thalidomide, Revlimid.RTM. and decitabine.
7. The method of claim 3 wherein the chemotherapeutic agent is
selected from: gemcitabine, carboplatin, cisplatin, cytarabine,
thalidomide, Revlimid.RTM. and decitabine.
8. The method of claim 4 wherein the chemotherapeutic agent is
selected from: gemcitabine, carboplatin, cisplatin, cytarabine,
thalidomide, Revlimid.RTM. and decitabine.
9. The method of claim 5 wherein the chemotherapeutic agent is
selected from: gemcitabine, carboplatin, cisplatin, cytarabine,
thalidomide, Revlimid.RTM. and decitabine.
10. A method of treating a pre-cancerous syndrome in a human in
need thereof which comprises the in vivo administration of an
effective amount of a) at least one TPO cell cycle activator, and
b) at least one chemotherapeutic agent.
11. The method of claim 10 wherein the pre-cancerous syndrome is
selected from: cervical intraepithelial neoplasia, monoclonal
gammapathy of unknown significance (MGUS), myelodysplastic
syndrome, aplastic anemia, cervical lesions, skin nevi
(pre-melanoma), prostatic intraepithleial (intraductal) neoplasia
(PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe
hepatitis or cirrhosis.
12. The method of claim 11 wherein the chemotherapeutic agent is
selected from: gemcitabine, carboplatin, cisplatin, cytarabine,
thalidomide, Revlimid.RTM. and decitabine.
13. A method of treating a cancer in a human in need thereof which
comprises the in vivo administration of an effective amount of: a)
a non-peptide thrombopoietin (TPO) receptor agonist, and b) a
chemotherapeutic agent.
14. The method of claim 13 wherein the cancer is selected from:
brain (gliomas), glioblastomas, astrocytomas, glioblastoma
multiforme, leukemias, Bannayan-Zonana syndrome, Cowden disease,
Lhermitte-Duclos disease, breast, inflammatory breast cancer,
Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma,
medulloblastoma, colon, head and neck, kidney, lung, liver,
melanoma, ovarian, pancreatic, prostate, sarcoma, osteosarcoma,
giant cell tumor of bone, thyroid, Lymphoblastic T cell leukemia,
Chronic myelogenous leukemia, Chronic lymphocytic leukemia,
Hairy-cell leukemia, acute lymphoblastic leukemia, acute
myelogenous leukemia, Chronic neutrophilic leukemia, Acute
lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large
cell leukemia, Mantle cell leukemia, Megakaryoblastic leukemia,
multiple myeloma, acute megakaryocytic leukemia, and
Erythroleukemia, malignant lymphoma, hodgkins lymphoma,
non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's
lymphoma, follicular lymphoma, neuroblastoma, bladder cancer,
urothelial cancer, lung cancer, vulval cancer, cervical cancer,
endometrial cancer, renal cancer, mesothelioma, esophageal cancer,
salivary gland cancer, hepatocellular cancer, gastric cancer,
nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST
(gastrointestinal stromal tumor) and testicular cancer.
15. The method of claim 14 wherein the non-peptide thrombopoietin
(TPO) receptor agonist is selected from:
3'-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden-
e]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid;
3-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene-
]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl;
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)t-
hiazol-2-yl]carbamoyl}pyridine-2-yl)piperidine-4-carboxylic acid;
3'-{N'-[1-(3,5-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; and
2'-hydroxy-3'-{N'-[2-oxo-1-(4-propyl-phenyl)-1,2-dihydro-indol-3-ylidene]-
-hydrazino}-biphenyl-4-carboxylic acid; or a pharmaceutically
acceptable salt thereof, and the chemotherapeutic agent is selected
from: gemcitabine, carboplatin, cisplatin, cytarabine, thalidomide,
Revlimid.RTM. and decitabine.
16. The method of claim 15 wherein the non-peptide thrombopoietin
(TPO) receptor agonist is
3'-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden-
e]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid, or a
pharmaceutically acceptable salt thereof.
17. The method of claim 16 wherein the non-peptide thrombopoietin
(TPO) receptor agonist is
3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4--
ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid
bis-(monoethanolamine).
18. A method of treating a pre-cancerous syndrome in a human in
need thereof which comprises the in vivo administration of an
effective amount of: a) a non-peptide thrombopoietin (TPO) receptor
agonist, and b) a chemotherapeutic agent.
19. The method of claim 18 wherein the cancer is selected from:
cervical intraepithelial neoplasia, monoclonal gammapathy of
unknown significance (MGUS), myelodysplastic syndrome, aplastic
anemia, cervical lesions, skin nevi (pre-melanoma), prostatic
intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in
situ (DCIS), colon polyps and severe hepatitis and cirrhosis.
20. The method of claim 19 wherein the non-peptide thrombopoietin
(TPO) receptor agonist is selected from:
3'-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden-
e]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid;
3-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene-
]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl;
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)t-
hiazol-2-yl]carbamoyl}pyridine-2-yl)piperidine-4-carboxylic acid;
3'-{N'-[1-(3,5-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid; and
2'-hydroxy-3'-{N'[2-oxo-1-(4-propyl-phenyl)-1,2-dihydro-indol-3-ylidene]--
hydrazino}-biphenyl-4-carboxylic acid; or a pharmaceutically
acceptable salt thereof, and the chemotherapeutic agent is selected
from: gemcitabine, carboplatin, cisplatin, cytarabine, thalidomide,
Revlimid.RTM. and decitabine.
21. The method of claim 20 wherein the non-peptide thrombopoietin
(TPO) receptor agonist is
3'-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden-
e]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid, or a
pharmaceutically acceptable salt thereof.
22. The method of claim 21 wherein the non-peptide thrombopoietin
(TPO) receptor agonist is
3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4--
ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid
bis-(monoethanolamine).
Description
[0001] This application is a Continuation-in-Part of U.S.
application Ser. No. 12/166,686, filed on Jul. 2, 2008, which is a
Continuation-in-Part of International Application No. PCT/U.S.
2008/054046 filed Feb. 15, 2008, which claims the benefit of U.S.
Provisional Application Nos. 60/977,216 filed Oct. 3, 2007,
60/969,192 filed Aug. 31, 2007, 60/952,289 filed Jul. 27, 2007,
60/949,347 filed Jul. 12, 2007, 60/908,205 filed Mar. 27, 2007,
60/892,552 filed Mar. 2, 2007 and 60/890,236 filed Feb. 16,
2007.
FIELD OF THE INVENTION
[0002] This invention relates to a method of treating cancer and
pre-cancerous syndromes in a mammal, including a human, in need
thereof which comprises the administration of an effective amount
of a combination of at least one non-peptide thrombopoietin (TPO)
receptor agonist or TPO cell cycle activator and at least one
chemotherapeutic agent to such mammal. Suitably, the method relates
to methods of treating cancers and pre-cancerous syndromes by
administration of
3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4--
ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid and
pharmaceutically acceptable salts, thereof, suitably the
bis-(monoethanolamine) salt, (hereinafter the
bis-(monoethanolamine) salt is Compound A and the corresponding
salt free compound is Compound B) and at least one chemotherapeutic
agent.
BACKGROUND OF THE INVENTION
[0003] Thrombopoietin (TPO) has been shown to be the main humoral
regulator in situations involving thrombocytopenia. See, e.g.,
Metcalf Nature 369:519-520 (1994). TPO has been shown in several
studies to increase platelet counts, increase platelet size, and
increase isotope incorporation into platelets of recipient animals.
Because platelets (thrombocytes) are necessary for blood clotting
and when their numbers are very low a patient is at risk of death
from catastrophic hemorrhage, TPO is considered to have potential
useful applications in both the diagnosis and the treatment of
various hematological disorders, for example, diseases primarily
due to platelet defects. In addition, studies have provided a basis
for the projection of efficacy of TPO therapy in the treatment of
thrombocytopenia, and particularly thrombocytopenia resulting from
chemotherapy, radiation therapy, or bone marrow transplantation as
treatment for cancer or lymphoma. See e.g., McDonald (1992) Am. J.
Ped. Hematology/Oncology 14: 8-21 (1992).
[0004] The slow recovery of platelet levels in patients suffering
from thrombocytopenia is a serious problem, and has lead to the
search for small molecule non-peptide TPO receptor agonists that
are able to accelerate platelet regeneration. (e.g. see,
International Application Number PCT/U.S. 01/16863, having
International Filing Date May 24, 2001, which specifically
discloses Compound B, in Example 3, and the use of non-peptide TPO
receptor agonists in combination with further active
ingredients).
[0005] Compound A is disclosed in International Application No.
PCT/U.S. 03/16255, having an International filing date of May 21,
2003; International Publication Number WO 03/098002 and an
International Publication date of Dec. 4, 2003.
[0006] Non-peptide TPO receptor agonists, including Compound A, are
disclosed for the treatment of degenerative diseases/injuries in
International Application No. PCT/U.S. 04/013468, having an
International filing date of Apr. 29, 2004; International
Publication Number WO 04/096154 and an International Publication
date of Nov. 11, 2004.
[0007] Formulations containing Compound A, suitably at 12.5 mg, 25
mg, 50 mg, 75 mg, and 100 mg tablets based on weight of the free or
unsalted compound, are disclosed in International Application No.
PCT/U.S. 2007/074918, having an
[0008] International filing date of Aug. 1, 2007, International
Publication Number WO 08/136843 and an International Publication
date of Nov. 13, 2008, which is incorporated herein by
reference.
[0009] The present invention concerns novel therapeutic uses of
known classes of compounds, non-peptide TPO receptor agonists and
TPO cell cycle activators.
SUMMARY OF THE INVENTION
[0010] This invention relates to a method of treating cancer in a
mammal, including a human, in need thereof which comprises
administering to such mammal a therapeutically effective amount of
a non-peptide TPO receptor agonist or a TPO cell cycle activator
and at least one chemotherapeutic agent.
[0011] This invention relates to a method of treating pre-cancerous
syndromes in a mammal, including a human, in need thereof which
comprises administering to such mammal a therapeutically effective
amount of a non-peptide TPO receptor agonist or a TPO cell cycle
activator and at least one chemotherapeutic agent.
[0012] Included among the non-peptide TPO receptor agonists of the
invention are compounds of Formula (I):
##STR00001##
wherein:
[0013] R, R.sup.1, R.sup.2 and R.sup.3 are each independently
selected from hydrogen, C.sub.1-6alkyl, --(CH.sub.2).sub.pOR.sup.4,
--C(O)OR.sup.4, formyl, nitro, cyano, halogen, aryl, substituted
aryl, substituted alkyl, --S(O).sub.nR.sup.4, cycloalkyl,
--NR.sup.5R.sup.6, protected --OH, --CONR.sup.5R.sup.6, phosphonic
acid, sulfonic acid, phosphinic acid, --SO.sub.2NR.sup.5R.sup.6,
and a heterocyclic methylene substituent as represented by Formula
(III),
##STR00002##
[0014] where, [0015] p is 0-6, [0016] n is 0-2, [0017] V, W, X and
Z are each independently selected from O, S and NR.sup.16, where
R.sup.16 is selected from: hydrogen, alkyl, cycloalkyl,
C.sub.1-C.sub.12aryl, substituted alkyl, substituted cycloalkyl and
substituted C.sub.1-C.sub.12aryl, [0018] R.sup.4 is selected from:
hydrogen, alkyl, cycloalkyl, C.sub.1-C.sub.12aryl, substituted
alkyl, substituted cycloalkyl and substituted C.sub.1-C.sub.12aryl,
and [0019] R.sup.5 and R.sup.6 are each independently selected from
hydrogen, alkyl, substituted alkyl, C.sub.3-6cycloalkyl, and aryl,
[0020] or R.sup.5 and R.sup.6 taken together with the nitrogen to
which they are attached represent a 5 to 6 member saturated ring
containing up to one other heteroatom selected from oxygen and
nitrogen; [0021] m is 0-6; and [0022] AR is a cyclic or polycyclic
aromatic ring containing from 3 to 16 carbon atoms and optionally
containing one or more heteroatoms, provided that when the number
of carbon atoms is 3 the aromatic ring contains at least two
heteroatoms and when the number of carbon atoms is 4 the aromatic
ring contains at least one heteroatom, and optionally substituted
with one or more substituents selected from the group consisting
of: alkyl, substituted alkyl, aryl, substituted cycloalkyl,
substituted aryl, aryloxy, oxo, hydroxy, alkoxy, cycloalkyl,
acyloxy, amino, N-acylamino, nitro, cyano, halogen, --C(O)OR.sup.4,
--C(O)NR.sup.10R.sup.11, --S(O).sub.2NR.sup.10R.sup.11,
--S(O).sub.nR.sup.4 and protected --OH, [0023] where n is 0-2,
[0024] R.sup.4 is hydrogen, alkyl, cycloalkyl,
C.sub.1-C.sub.12aryl, substituted alkyl, substituted cycloalkyl and
substituted C.sub.1-C.sub.12aryl, and [0025] R.sup.10 and R.sup.11
are independently hydrogen, cycloalkyl, C.sub.1-C.sub.12aryl,
substituted cycloalkyl, substituted C.sub.1-C.sub.12aryl, alkyl or
alkyl substituted with one or more substituents selected from the
group consisting of: alkoxy, acyloxy, aryloxy, amino, N-acylamino,
oxo, hydroxy, --C(O)OR.sup.4, --S(O).sub.nR.sup.4,
--C(O)NR.sup.4R.sup.4, --S(O).sub.2NR.sup.4R.sup.4, nitro, cyano,
cycloalkyl, substituted cycloalkyl, halogen, aryl, substituted aryl
and protected --OH, [0026] or R.sup.10 and R.sup.11 taken together
with the nitrogen to which they are attached represent a 5 to 6
member saturated ring containing up to one other heteroatom
selected from oxygen and nitrogen, [0027] where R.sup.4 is as
described above and n is 0-2;
[0028] and pharmaceutically acceptable salts thereof;
[0029] provided that at least one of R, R.sup.1, R.sup.2 and
R.sup.3 is a substituted aryl group or a heterocyclic methylene
substituent as represented in Formula (III).
[0030] This invention relates to a method of treating cancer in a
mammal, including a human, in need thereof which comprises
administering to such mammal a therapeutically effective amount of
a non-peptide TPO receptor agonist of Formula (I) and at least one
chemotherapeutic agent.
[0031] This invention relates to a method of treating pre-cancerous
syndromes in a mammal, including a human, in need thereof which
comprises administering to such mammal a therapeutically effective
amount of a non-peptide TPO receptor agonist of Formula (I) and at
least one chemotherapeutic agent.
[0032] Included in the present invention are pharmaceutical
compositions comprising a pharmaceutical carrier and compounds
useful in the methods of the invention.
[0033] Also included in the present invention are methods of
co-administering the combinations of the present invention with
further active ingredients.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] FIG. 1 shows the in vitro response of CCRF-CEM Lymphoblastic
T cell leukemia cells treated with Compound A.
[0035] FIG. 2 shows the in vitro response of K562 Chronic
Myelogenous leukemia cells treated with Compound A.
[0036] FIG. 3 shows the in vitro response of MOLT-4 Acute
Lymphoblastic T cell leukemia cells treated with Compound A.
[0037] FIG. 4 shows the in vitro response of RPMI-8226 Plasmacytoma
cells treated with Compound A.
[0038] FIG. 5 shows the in vitro response of SR Immunoblastic Large
Cell Leukemia cells treated with Compound A.
[0039] FIG. 6 shows the in vitro response of HepG2 cells treated
with Compound A.
DETAILED DESCRIPTION OF THE INVENTION
[0040] This invention relates to methods of treating cancer and
pre-cancerous syndromes in a mammal, including a human, in need
thereof which comprises administering to such mammal a
therapeutically effective amount of a non-peptide
[0041] TPO receptor agonist, including compounds of Formula (I) as
described herein, or a TPO cell cycle activator and at least one
chemotherapeutic agent to such mammal.
[0042] Suitably, the invention relates to a method of treating
cancer in a mammal, including a human, wherein the cancer is
selected from: brain (gliomas), glioblastomas, astrocytomas,
glioblastoma multiforme, leukemias, Bannayan-Zonana syndrome,
Cowden disease, Lhermitte-Duclos disease, breast, inflammatory
breast cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma,
ependymoma, medulloblastoma, colon, head and neck, kidney, lung,
liver, melanoma, ovarian, pancreatic, prostate, sarcoma,
osteosarcoma, giant cell tumor of bone and thyroid.
[0043] Suitably, the invention relates to a method of treating
cancer in a mammal, including a human, wherein the cancer is
selected from: Lymphoblastic T cell leukemia, Chronic myelogenous
leukemia, Chronic lymphocytic leukemia, Hairy-cell leukemia, acute
lymphoblastic leukemia, acute myelogenous leukemia, Chronic
neutrophilic leukemia, Acute lymphoblastic T cell leukemia,
Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell
leukemia, Megakaryoblastic leukemia, multiple myeloma, acute
megakaryocytic leukemia, and Erythroleukemia.
[0044] Suitably, the invention relates to a method of treating
cancer in a mammal, including a human, wherein the cancer is
selected from: malignant lymphoma, hodgkins lymphoma, non-hodgkins
lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma and
follicular lymphoma.
[0045] Suitably, the invention relates to a method of treating
cancer in a mammal, including a human, wherein the cancer is
selected from: neuroblastoma, bladder cancer, urothelial cancer,
lung cancer, vulval cancer, cervical cancer, endometrial cancer,
renal cancer, mesothelioma, esophageal cancer, salivary gland
cancer, hepatocellular cancer, gastric cancer, nasopharangeal
cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal
stromal tumor) and testicular cancer.
[0046] Suitably, the invention relates to a method of treating
pre-cancerous syndromes in a mammal, including a human, wherein the
pre-cancerous syndrome is selected from: cervical intraepithelial
neoplasia, monoclonal gammapathy of unknown significance (MGUS),
myelodysplastic syndrome, aplastic anemia, cervical lesions, skin
nevi (pre-melanoma), prostatic intraepithleial (intraductal)
neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and
severe hepatitis or cirrhosis (especially viral induced hepatitis),
all of which can progress to cancer.
[0047] Included among compounds of Formula (I) that are useful in
the current invention are those having Formula (VI):
##STR00003##
wherein: [0048] R, R.sup.1, R.sup.2 and R.sup.3 are each
independently selected from hydrogen, C.sub.1-6alkyl,
C.sub.1-6alkoxy, --(CH.sub.2).sub.pOR.sup.4, --C(O)OR.sup.4,
formyl, nitro, cyano, halogen, aryl, substituted aryl, substituted
alkyl, --S(O).sub.nR.sup.4, cycloalkyl, --NR.sup.5R.sup.6,
protected --OH, --CONR.sup.5R.sup.6, phosphonic acid, sulfonic
acid, phosphinic acid and --SO.sub.2NR.sup.5R.sup.6, [0049] where
[0050] p is 0-6, [0051] n is 0-2, [0052] R.sup.4 is hydrogen,
alkyl, cycloalkyl, C.sub.1-C.sub.12aryl, substituted alkyl,
substituted cycloalkyl and substituted C.sub.1-C.sub.12aryl, and
[0053] R.sup.5 and R.sup.6 are each independently selected from
hydrogen, alkyl, substituted alkyl, C.sub.3-6cycloalkyl, and aryl,
[0054] or R.sup.5 and R.sup.6 taken together with the nitrogen to
which they are attached represent a 5 to 6 member saturated ring
containing up to one other heteroatom selected from oxygen and
nitrogen; [0055] R.sup.15 is selected from the group consisting of
alkyl, C.sub.1-C.sub.12aryl, hydroxy, alkoxy, substituted alkyl,
substituted C.sub.1-C.sub.12aryl and halogen; [0056] m is 0-6; and
[0057] Y is selected from alkyl, substituted alkyl and a cyclic or
polycyclic aromatic ring containing from 3 to 14 carbon atoms and
optionally containing from one to three heteroatoms, provided that
when the number of carbon atoms is 3 the aromatic ring contains at
least two heteroatoms and when the number of carbon atoms is 4 the
aromatic ring contains at least one heteroatom, and optionally
substituted with one or more substituents selected from the group
consisting of: alkyl, substituted alkyl, C.sub.1-C.sub.12aryl,
substituted cycloalkyl, substituted C.sub.1-C.sub.12aryl, hydroxy,
aryloxy, alkoxy, cycloalkyl, nitro, cyano, halogen and protected
--OH;
[0058] and pharmaceutically acceptable salts, thereof;
[0059] provided that at least one of R, R.sup.1, R.sup.2 and
R.sup.3 is a substituted aryl group.
[0060] Included among the compounds useful in the present invention
are those having Formula (VI) in which, either:
[0061] R is a substituted aryl; and R.sup.1 is hydrogen;
or:
[0062] R is hydrogen; and R.sup.1 is a substituted aryl; and in
either case:
[0063] R.sup.2 and R.sup.3 are each independently selected from
hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy, nitro, cyano, halogen,
aryl, substituted aryl, substituted alkyl, cycloalkyl, phosphonic
acid, phosphinic acid and sulfonic acid;
[0064] R.sup.15 is selected from the group consisting of alkyl,
substituted alkyl, C.sub.1-C.sub.12aryl, alkoxy and halogen;
[0065] m is 0-4; and
[0066] Y is selected from, [0067] phenyl, pyridinyl and
pyrimidinyl, where the phenyl, pyridinyl and pyrimidinyl are
optionally substituted with from one to three substituents selected
from the group consisting of: alkyl, substituted alkyl,
C.sub.1-C.sub.12aryl, substituted C.sub.1-C.sub.12aryl, alkoxy and
halogen;
[0068] and pharmaceutically acceptable salts thereof.
[0069] Included among the compounds useful in the present invention
are those having Formula (VI) in which,
[0070] R is a substituted C.sub.1-C.sub.12aryl; [0071] and
[0072] R.sup.1 is hydrogen;
[0073] R.sup.2 and R.sup.3 are each independently selected from
hydrogen, C.sub.1-6alkyl, C.sub.1-6alkoxy, nitro, cyano, halogen,
substituted alkyl and cycloalkyl;
[0074] R.sup.15 is selected from the group consisting of alkyl,
substituted alkyl, C.sub.1-C.sub.12aryl, alkoxy and halogen;
[0075] m is 0-2; and
[0076] Y is selected from, [0077] phenyl, pyridinyl and
pyrimidinyl, where the phenyl, pyridinyl and pyrimidinyl are
optionally substituted with from one to three substituents selected
from the group consisting of: alkyl, substituted alkyl,
C.sub.1-C.sub.12aryl, substituted C.sub.1-C.sub.12aryl, alkoxy and
halogen;
[0078] and pharmaceutically acceptable salts thereof.
[0079] Included among the compounds useful in the present invention
are those having Formula (VI) in which,
[0080] R is a substituted phenyl or pyridinyl ring; and
[0081] R.sup.1 is hydrogen;
[0082] R.sup.2 and R.sup.3 are each independently selected from
hydrogen, C.sub.1-6alkyl, substituted alkyl and halogen;
[0083] R.sup.15 is selected from the group consisting of
C.sub.1-4alkyl, C.sub.1-4 alkoxy, C.sub.1-C.sub.12aryl and
halogen;
[0084] m is 0; and
[0085] Y is selected from, [0086] phenyl, pyridinyl and
pyrimidinyl, where the phenyl, pyridinyl and pyrimidinyl is
optionally substituted with from one to three substituents selected
from the group consisting of: alkyl, substituted alkyl,
C.sub.1-C.sub.12aryl, substituted C.sub.1-C.sub.12aryl, alkoxy and
halogen;
[0087] and pharmaceutically acceptable salts thereof.
[0088] Included among the compounds useful in the present invention
are:
3'-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-yliden-
e]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid;
3-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene-
]hydrazino}-2-hydroxy-3'-(tetrazol-5-yl)biphenyl;
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)t-
hiazol-2-yl]carbamoyl}pyridine-2-yl)piperidine-4-carboxylic acid;
3'-{N'-[1-(3,5-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid;
2'-hydroxy-3'-{N'-[2-oxo-1-(4-propyl-phenyl)-1,2-dihydro-indol-3-ylidene]-
-hydrazino}-biphenyl-4-carboxylic acid; and and pharmaceutically
acceptable salts thereof.
[0089] Included among the non-peptide TPO receptor agonists of the
invention are the non-peptide compounds described in: [0090] WO
02/59099; [0091] WO 02/59100; [0092] EP 1 207 155; [0093] EP 1 253
142A1; [0094] WO 01/92211 A1; [0095] WO 01/53267-A1; [0096] WO
03/62233 [0097] WO 02/62775 [0098] EP 1 104 674-A1; and [0099] WO
01/07423-A1.
[0100] Included among the compounds of the above listed
applications that are useful in the present invention are:
[0101]
N-[4-(5-bromo-2-thienyl)-1,3-thiazol-2-yl]-4-[(Z)-(2,4-dioxo-1,3-th-
iazolidin-5-ylidene)methyl]benzamide;
[0102]
N-[4-(3,4-dimethylphenyl)-1,3-thiazol-2-yl]-4-[(Z)-(2,4-dioxo-1,3-t-
hiazolidin-5-ylidene)methyl]benzamide;
[0103]
N-{4-[4-(1,1-dimethylethyl)phenyl]-1,3-thiazol-2-yl}-4-[(Z)-(2,4-di-
oxo-1,3-thiazolidin-5-ylidene)methyl] benzamide;
[0104]
N-[4-(3,4-dichlorophenyl)-1,3-thiazol-2-yl]-4-[(Z)-(2,4-dioxo-1,3-t-
hiazolidin-5-ylidene)methyl]benzamide; and
[0105]
(2E)-3-[4-({[4-(3,4-dichlorophenyl)-1,3-thiazol-2-yl]amino}carbonyl-
)phenyl]-2-methyl-2-propenoic acid;
[0106] and/or pharmaceutically acceptable salts thereof.
[0107] Included among the non-peptide TPO receptor agonists of the
invention are the non-peptide compounds described in: [0108] WO
99/11262.
[0109] Included among the non-peptide TPO receptor agonists of the
invention are the non-peptide compounds described in:
[0110] International Application No. PCT/US05/018924, having an
International filing date of May 27, 2005; International
Publication Number WO 05/118551 and an International Publication
date of Dec. 15, 2005,
[0111] International Application No. PCT/US05/038055, having an
International filing date of Oct. 21, 2005; International
Publication Number WO 06/047344 and an International Publication
date of May 4, 2006,
[0112] International Application No. PCT/US06/045129, having an
International filing date of Nov. 21, 2006; International
Publication Number WO 07/062078 and an International Publication
date of May 31, 2007, and
[0113] International Application No. PCT/US07/006547, having an
International filing date of Mar. 14, 2007; International
Publication Number WO 07/106564 and an International Publication
date of Sep. 20, 2007.
[0114] The compounds that are final products in WO 05/118551, WO
06/047344, WO 07/062078 and WO 07/106564 are useful in the present
invention, these compounds are included herein by reference.
[0115] The compound that is the product of Example 4 in WO
07/106564,
3'-{N'-[1-(3,5-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-indol-
-3-ylidene]-hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid, as the
salt free compound or in the form of a pharmaceutically acceptable
salt, hydrate, solvate or ester, is a compound useful in the
present invention.
[0116] The compound that is the product of Example 6 in WO
07/106564,
2'-hydroxy-3'-{N'-[2-oxo-1-(4-propyl-phenyl)-1,2-dihydro-indol-3-ylidene]-
-hydrazino}-biphenyl-4-carboxylic acid, as the salt free compound
or in the form of a pharmaceutically acceptable salt, hydrate,
solvate or ester, is a compound useful in the present
invention.
[0117] Included among the non-peptide TPO receptor agonists of the
invention is the non-peptide compound described in:
[0118] International Application No. PCT/JP03/012419, having an
International filing date of Sep. 29, 2003; International
Publication Number WO 04/029049 and an International Publication
date of Apr. 8, 2004, 2005.
[0119] The compound that is the final product in WO 04/029049, both
the salt and non-salt forms, is useful in the present invention,
these compounds are included herein by reference.
[0120] Suitably, the compound that is the final product in WO
04/029049 is
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)t-
hiazol-2-yl]carbamoyl}pyridine-2-yl)piperidine-4-carboxylic acid,
as the salt free compound (hereinafter Compound E), or in the form
of a pharmaceutically acceptable salt hydrate solvate or ester
thereof. Suitably, the salt is a maleic acid salt (hereinafter
Compound F). The structure of Compound F is indicated below.
##STR00004##
[0121] Non-peptide TPO receptor agonists are included in the
pharmaceutical compositions of the invention and used in the
methods of the invention.
[0122] By the term "protected hydroxy" or "protected --OH" as used
herein, is meant the alcoholic or carboxylic-OH groups which can be
protected by conventional blocking groups in the art such as
described in "Protective Groups In Organic Synthesis" by Theodora
W. Greene, Wiley-Interscience, 1981, New York. Compounds containing
protected hydroxy groups may also be useful as intermediates in the
preparation of the pharmaceutically active compounds of the
invention.
[0123] By the term "aryl" as used herein, unless otherwise defined,
is meant a cyclic or polycyclic aromatic ring containing from 1 to
14 carbon atoms and optionally containing from one to five
heteroatoms, provided that when the number of carbon atoms is 1 the
aromatic ring contains at least four heteroatoms, when the number
of carbon atoms is 2 the aromatic ring contains at least three
heteroatoms, when the number of carbons is 3 the aromatic ring
contains at least two heteroatoms and when the number of carbon
atoms is 4 the aromatic ring contains at least one heteroatom.
[0124] By the term "C.sub.1-C.sub.12aryl" as used herein, unless
otherwise defined, is meant phenyl, naphthalene,
3,4-methylenedioxyphenyl, pyridine, biphenyl, quinoline,
pyrimidine, quinazoline, thiophene, furan, pyrrole, pyrazole,
imidazole and tetrazole.
[0125] When referring to compounds of Formula (I) and (II), the
term "substituted" as used herein, unless otherwise defined, is
meant that the subject chemical moiety has one or more substituents
selected from the group consisting of: --CO.sub.2R.sup.20, aryl,
--C(O)NHS(O).sub.2R.sup.20, --NHS(O).sub.2R.sup.20, hydroxyalkyl,
alkoxy, --C(O)NR.sup.21R.sup.22, acyloxy, alkyl, amino,
N-acylamino, hydroxy, --(CH.sub.2).sub.gC(O)OR.sup.8,
--S(O).sub.nR.sup.8, nitro, tetrazole, cyano, oxo, halogen,
trifluoromethyl, protected -OH and a heterocyclic methylene
substituent as represented by Formula (III),
##STR00005##
where g is 0-6; R.sup.8 is hydrogen or alkyl; R.sup.20 is selected
form hydrogen, C.sub.1-C.sub.4alkyl, aryl and trifluoromethyl;
R.sup.21 and R.sup.22 are independently selected form hydrogen,
C.sub.1-C.sub.4alkyl, aryl and trifluoromethyl; V, W, X and Z are
each independently selected from O, S, and NR.sup.16, where
R.sup.16 is selected from: hydrogen, alkyl, cycloalkyl,
C.sub.1-C.sub.12aryl, substituted alkyl, substituted cycloalkyl and
substituted C.sub.1-C.sub.12aryl; and n is 0-2.
[0126] When referring to compounds of Formula (V) and (VI), the
term "substituted" as used herein, unless otherwise defined, is
meant that the subject chemical moiety has one or more substituents
selected from the group consisting of: --CO.sub.2R.sup.20, aryl,
--C(O)NHS(O).sub.2R.sup.20, --NHS(O).sub.2R.sup.20, hydroxyalkyl,
alkoxy, --C(O)NR.sup.21R.sup.22, acyloxy, alkyl, amino,
N-acylamino, hydroxy, --(CH.sub.2).sub.gC(O)OR.sup.8,
--S(O).sub.nR.sup.8, nitro, tetrazole, cyano, oxo, halogen,
trifluoromethyl and protected --OH, where g is 0-6, R.sup.8 is
hydrogen or alkyl, R.sup.20 is selected form hydrogen,
C.sub.1-C.sub.4alkyl, aryl and trifluoromethyl, and R.sup.21 and
R.sup.22 are independently selected form hydrogen,
C.sub.1-C.sub.4alkyl, aryl and trifluoromethyl, and n is 0-2.
[0127] By the term "alkoxy" as used herein is meant -Oalkyl where
alkyl is as described herein including --OCH.sub.3 and
--OC(CH.sub.3).sub.2CH.sub.3.
[0128] The term "cycloalkyl" as used herein unless otherwise
defined, is meant a nonaromatic, unsaturated or saturated, cyclic
or polycyclic C.sub.3-C.sub.12.
[0129] Examples of cycloalkyl and substituted cycloalkyl
substituents as used herein include: cyclohexyl,
4-hydroxy-cyclohexyl, 2-ethylcyclohexyl, propyl
4-methoxycyclohexyl, 4-methoxycyclohexyl, 4-carboxycyclohexyl,
cyclopropyl and cyclopentyl.
[0130] By the term "acyloxy" as used herein is meant --OC(O)alkyl
where alkyl is as described herein. Examples of acyloxy
substituents as used herein include: --OC(O)CH.sub.3,
--OC(O)CH(CH.sub.3).sub.2 and --OC(O)(CH.sub.2).sub.3CH.sub.3.
[0131] By the term "N-acylamino" as used herein is meant
--N(H)C(O)alkyl, where alkyl is as described herein. Examples of
N-acylamino substituents as used herein include:
--N(H)C(O)CH.sub.3, --N(H)C(O)CH(CH.sub.3).sub.2 and
--N(H)C(O)(CH.sub.2).sub.3CH.sub.3.
[0132] By the term "aryloxy" as used herein is meant -Oaryl where
aryl is phenyl, naphthyl, 3,4-methylenedioxyphenyl, pyridyl or
biphenyl optionally substituted with one or more substituents
selected from the group consisting of: alkyl, hydroxyalkyl, alkoxy,
trifuloromethyl, acyloxy, amino, N-acylamino, hydroxy,
--(CH.sub.2).sub.gC(O)OR.sup.8, --S(O).sub.nR.sup.8, nitro, cyano,
halogen and protected --OH, where g is 0-6, R.sup.8 is hydrogen or
alkyl, and n is 0-2. Examples of aryloxy substituents as used
herein include: phenoxy, 4-fluorophenyloxy and biphenyloxy.
[0133] By the term "heteroatom" as used herein is meant oxygen,
nitrogen or sulfur.
[0134] By the term "halogen" as used herein is meant a substituent
selected from bromide, iodide, chloride and fluoride.
[0135] By the term "alkyl" and derivatives thereof and in all
carbon chains as used herein is meant a linear or branched,
saturated or unsaturated hydrocarbon chain, and unless otherwise
defined, the carbon chain will contain from 1 to 12 carbon atoms.
Examples of alkyl substituents as used herein include: --CH.sub.3,
--CH.sub.2--CH.sub.3, --CH.sub.2--CH.sub.2--CH.sub.3,
--CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3,
--(CH.sub.2).sub.3--CH.sub.3, --CH.sub.2--CH(CH.sub.3).sub.2,
--CH(CH.sub.3)--CH.sub.2--CH.sub.3, --CH.dbd.CH.sub.2, and
--C.dbd.C--CH.sub.3.
[0136] By the term "treating" and derivatives thereof as used
herein, is meant prophylatic and therapeutic therapy. Prophylactic
therapy is appropriate, for example, when a subject is considered
at high risk for developing cancer, such as when a subject has a
strong family history of cancer, or when a subject has been exposed
to a carcinogen.
[0137] Prophylactic use of the compounds of this invention is
contemplated whenever numerous causative factors are present in a
subject. Prophylactic uses of the methods of this invention include
but are not limited to treatment of heavy smokers with no
detectable cancer or when a subject has been exposed to high levels
radiation.
[0138] By the phrases "to a therapeutic extent", "treating" and
"therapeutically effective amount" and derivatives thereof as used
herein, unless otherwise defined, is meant that amount of the
presently invented combination that will elicit the biological or
medical response of a tissue, system, animal or human that is being
sought, for instance, by a researcher or clinician. Furthermore,
the term "therapeutically effective amount" means any amount which,
as compared to a corresponding subject who has not received such
amount, results in improved treatment, healing, prevention,
lessening in severity or amelioration of cancer.
[0139] Cancer is known to have many causative factors. This
invention relates to the treatment of cancer regardless of the
factor or factors causing the condition. The pharmaceutically
active combinations of this invention are also useful in treating
cancer when the causative factor or factors of the condition are
unknown or have yet to be identified.
[0140] A skilled physician will be able to determine the
appropriate situation in which subjects are susceptible to or at
risk of, for example, lung cancer for administration by methods of
the present invention.
[0141] By the phrase "non-peptide" as used herein is meant a
chemical compound, or a protein or peptide not comprised primarily
of natural amino acids. Suitably, the "non-peptide" is a small
molecule chemical compound having a molecular weight under 1,500
daltons, suitably under 1,000 daltons.
[0142] By the term "primarily" as used above is meant about 60% by
weight of naturally occurring amino acid residue.
[0143] Certain of the compounds described herein may contain one or
more chiral atoms, or may otherwise be capable of existing as two
enantiomers. Accordingly, the compounds of this invention include
mixtures of enantiomers as well as purified enantiomers or
enantiomerically enriched mixtures. Also, it is understood that all
tautomers and mixtures of tautomers are included within the scope
of the compounds of the invention.
[0144] Certain compounds described herein may form a solvate which
is understood to be a complex of variable stoichiometry formed by a
solute (for example, a compound of Formula I of a salt thereof) and
a solvent. Such solvents for the purpose of the invention may not
interfere with the biological activity of the solute. Examples of
suitable solvents include, but are not limited to, water, methanol,
ethanol and acetic acid. Preferably the solvent used is a
pharmaceutically acceptable solvent. Examples of suitable
pharmaceutically acceptable solvents include, without limitation,
water, ethanol and acetic acid. Most preferably the solvent used is
water.
[0145] The compounds of the invention are included in the
pharmaceutical compositions of the invention and used in the
methods of the invention. Where a --COOH or --OH group is present,
pharmaceutically acceptable esters can be employed, for example
methyl, ethyl, pivaloyloxymethyl, and the like for --COOH, and
acetate maleate and the like for --OH, and those esters known in
the art for modifying solubility or hydrolysis characteristics, for
use as sustained release or prodrug formulations.
[0146] The pharmaceutically acceptable salts of the compounds of
the invention are readily prepared by those of skill in the
art.
[0147] The compounds of Formula I are disclosed and claimed, along
with pharmaceutically acceptable salts, hydrates, solvates and
esters thereof, as being useful as an agonist of the TPO receptor,
particularly in enhancing platelet production and particularly in
the treatment of thrombocytopenia, in International Application No.
PCT/US01/16863, having an International filing date of May 24,
2001; International Publication Number WO 01/89457 and an
International Publication date of Nov. 29, 2001, the entire
disclosure of which is hereby incorporated by reference. Compounds
of Formulas I and pharmaceutically acceptable salts, hydrates,
solvates and esters thereof, are prepared as described in
International Application No. PCT/US01/16863. The
bis-(monoethanolamine) salt of a compound described in
International Application No. PCT/US01/16863, is described in
International Application No. PCT/US03/16255, having an
International filing date of May 21, 2003; International
Publication Number WO 03/098992 and an International Publication
date of Dec. 4, 2003.
[0148] It is known that certain cancers, particularly various types
of leukemia, are unresponsive to treatment with chemotherapeutic
agents. One reason attributed to this phenomenon is the
unresponsiveness of noncycling cells, such as leukemic cells in
resting G.sub.0 phase, to cell cycle-dependent cytotoxic agents
such as chemotherapeutic agents. Synchronized recruitment of
leukemic cells into activated phases of the cell cycle activating
cytokine (granulocyte-macrophage colony-stimulating factor)
[GM-CSF] has resulted in significant increased sensitivity to
cytotoxic agents. Experimental Hematology 32 (2004) 188-194.
[0149] In one embodiment of this invention, TPO (thrombopoietin)
directed peptides which bind the TPO receptor as described in U.S.
Pat. Nos. 5,869,451; 5,932,546; 6,083,913; 6,121,238; 5,869,451;
6,251,864; 6,506,362 and 6,465,430 as well as TPO modified with
polyethylene glycol, TPO modified by glycosylation as described by
Elliot, et al. (Nature Biotechnology 21:414-421, 2003) and AMG531
(Amgen, Thousand Oaks, Calif.) (discussed in N. Engl. J. Med. 2006;
355; 1672-1681) (hereinafter collectively referred to, unless
otherwise defined, as TPO cell cycle activator(s)), suitably for
use herein the TPO cell cycle activator is AMG531, are used in
combination with chemotherapeutic agents, examples of
chemotherapeutic agents for use in this invention include:
gemcitabine, carboplatin, cisplatin, cytarabine, thalidomide,
lenolidomide (Revlimid.RTM.) and decitabine, to treat cancers which
are known to enter noncycling cell phases, particularly various
types of leukemia, such as Lymphoblastic T cell leukemia, Chronic
myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell
leukemia, acute lymphoblastic leukemia, Chronic neutrophilic
leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma,
Immunoblastic large cell leukemia, Mantle cell leukemia,
Megakaryoblastic leukemia, multiple myeloma, acute myelogenous
leukemia (AML), promyelocytic leukemia, acute megakaryocytic
leukemia, and Erythroleukemia. Additional compounds for use in
combination with TPO cell cycle activator, suitably AMG531, as
described herein are disclosed in Tefferi, Mayo Clin. Proc.
November 2010; 85(11): 1042-1045.
[0150] In one embodiment of this invention, non-peptide TPO
receptor agonist; suitably Compound A, suitably Compound B,
suitably Compound C, suitably Compound D; are used in combination
with chemotherapeutic agents, examples of chemotherapeutic agents
for use in this invention include: gemcitabine, carboplatin,
cisplatin, cytarabine, thalidomide, lenolidomide (Revlimid.RTM.)
and decitabine, to treat cancer, suitably cancers which are known
to enter noncycling cell phases, particularly various types of
leukemia, such as Lymphoblastic T cell leukemia, Chronic
myelogenous leukemia, Chronic lymphocytic leukemia, Hairy-cell
leukemia, acute lymphoblastic leukemia, Chronic neutrophilic
leukemia, Acute lymphoblastic T cell leukemia, Plasmacytoma,
Immunoblastic large cell leukemia, Mantle cell leukemia,
Megakaryoblastic leukemia, multiple myeloma, acute myelogenous
leukemia (AML), promyelocytic leukemia, acute megakaryocytic
leukemia, and Erythroleukemia. Additional compounds for use in
combination with a non-peptide TPO receptor agonist; suitably
Compound A, suitably Compound B, suitably Compound C, suitably
Compound D; as described herein are disclosed in Tefferi, Mayo
Clin. Proc. November 2010; 85(11): 1042-1045.
[0151] The treatment of cancer, as described herein, is
accomplished by the administration of a non-peptide TPO receptor
agonist or TPO cell cycle activator and at least one
chemotherapeutic agent and is not limited to any particular
mechanism of action.
[0152] The treatment of pre-cancerous syndromes, as described
herein, is accomplished by the administration of a non-peptide TPO
receptor agonist or TPO cell cycle activator and at least one
chemotherapeutic agent and is not limited to any particular
mechanism of action.
[0153] When referring to the treatment of pre-cancerous syndromes,
the term "co-administering" and derivatives thereof as used herein
is meant either simultaneous administration or any manner of
separate sequential administration of a non-peptide TPO receptor
agonist, as described herein, or TPO cell cycle activator and at
least one chemotherapeutic agent, and a further active ingredient
or ingredients, known to be useful in the treatment of
pre-cancerous syndromes. The term further active ingredient or
ingredients, as used herein, includes any compound or therapeutic
agent known to or that demonstrates advantageous properties when
administered to a patient in need of treatment for pre-cancerous
syndromes. Preferably, if the administration is not simultaneous,
the compounds are administered in a close time proximity to each
other. Furthermore, it does not matter if the compounds are
administered in the same dosage form, e.g. one compound may be
administered topically and another compound may be administered
orally.
[0154] When referring to the treatment of cancer, the term
"co-administering" and derivatives thereof as used herein is meant
either simultaneous administration or any manner of separate
sequential administration of a non-peptide TPO receptor agonist, as
described herein, or TPO cell cycle activator and at least one
chemotherapeutic agent and a further active ingredient or
ingredients, known to be useful in the treatment of cancer,
including chemotherapy and radiation treatment. The term further
active ingredient or ingredients, as used herein, includes any
compound or therapeutic agent known to or that demonstrates
advantageous properties when administered to a patient in need of
treatment for cancer or arthritis. Preferably, if the
administration is not simultaneous, the compounds are administered
in a close time proximity to each other. Furthermore, it does not
matter if the compounds are administered in the same dosage form,
e.g. one compound may be administered topically and another
compound may be administered orally.
[0155] Typically, any anti-neoplastic agent that has activity
versus a susceptible tumor being treated may be co-administered in
the treatment of cancer in the present invention. Examples of such
agents can be found in Cancer Principles and Practice of Oncology
by V. T. Devita and S. Hellman (editors), 6.sup.th edition
(February 15, 2001), Lippincott Williams & Wilkins Publishers.
A person of ordinary skill in the art would be able to discern
which combinations of agents would be useful based on the
particular characteristics of the drugs and the cancer involved.
Typical anti-neoplastic agents useful in the present invention
include, but are not limited to, anti-microtubule agents such as
diterpenoids and vinca alkaloids; platinum coordination complexes;
alkylating agents such as nitrogen mustards, oxazaphosphorines,
alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents
such as anthracyclins, actinomycins and bleomycins; topoisomerase
II inhibitors such as epipodophyllotoxins; antimetabolites such as
purine and pyrimidine analogues and anti-folate compounds;
topoisomerase I inhibitors such as camptothecins; hormones and
hormonal analogues; signal transduction pathway inhibitors;
non-receptor tyrosine kinase angiogenesis inhibitors;
immunotherapeutic agents; proapoptotic agents; and cell cycle
signaling inhibitors.
[0156] Examples of a further active ingredient or ingredients
(anti-neoplastic agent) for use in combination or co-administered
with the combinations of the current invention are chemotherapeutic
agents.
[0157] Anti-microtubule or anti-mitotic agents are phase specific
agents active against the microtubules of tumor cells during M or
the mitosis phase of the cell cycle. Examples of anti-microtubule
agents include, but are not limited to, diterpenoids and vinca
alkaloids.
[0158] Diterpenoids, which are derived from natural sources, are
phase specific anti-cancer agents that operate at the G.sub.2/M
phases of the cell cycle. It is believed that the diterpenoids
stabilize the .beta.-tubulin subunit of the microtubules, by
binding with this protein. Disassembly of the protein appears then
to be inhibited with mitosis being arrested and cell death
following. Examples of diterpenoids include, but are not limited
to, paclitaxel and its analog docetaxel.
[0159] Paclitaxel,
5.beta.,20-epoxy-1,2.alpha.,4,7.beta.,10.beta.,13.alpha.-hexa-hydroxytax--
11-en-9-one 4,10-diacetate 2-benzoate 13-ester with
(2R,3S)-N-benzoyl-3-phenylisoserine; is a natural diterpene product
isolated from the Pacific yew tree Taxus brevifolia and is
commercially available as an injectable solution TAXOL.RTM.. It is
a member of the taxane family of terpenes. It was first isolated in
1971 by Wani et al. J. Am. Chem, Soc., 93:2325. 1971), who
characterized its structure by chemical and X-ray crystallographic
methods. One mechanism for its activity relates to paclitaxel's
capacity to bind tubulin, thereby inhibiting cancer cell growth.
Schiff et al., Proc. Natl, Acad, Sci. USA, 77:1561-1565 (1980);
Schiff et al., Nature, 277:665-667 (1979); Kumar, J. Biol, Chem,
256: 10435-10441 (1981). For a review of synthesis and anticancer
activity of some paclitaxel derivatives see: D. G. I. Kingston et
al., Studies in Organic Chemistry vol. 26, entitled "New trends in
Natural Products Chemistry 1986", Attaur-Rahman, P. W. Le Quesne,
Eds. (Elsevier, Amsterdam, 1986) pp 219-235.
[0160] Paclitaxel has been approved for clinical use in the
treatment of refractory ovarian cancer in the United States
(Markman et al., Yale Journal of Biology and Medicine, 64:583,
1991; McGuire et al., Ann. Intern, Med., 111:273,1989) and for the
treatment of breast cancer (Holmes et al., J. Nat. Cancer Inst.,
83:1797,1991.) It is a potential candidate for treatment of
neoplasms in the skin (Einzig et. al., Proc. Am. Soc. Clin. Oncol.,
20:46) and head and neck carcinomas (Forastire et. al.,
[0161] Sem. Oncol., 20:56, 1990). The compound also shows potential
for the treatment of polycystic kidney disease (Woo et. al.,
Nature, 368:750. 1994), lung cancer and malaria. Treatment of
patients with paclitaxel results in bone marrow suppression
(multiple cell lineages, Ignoff, R.J. et. al, Cancer Chemotherapy
Pocket Guide, 1998) related to the duration of dosing above a
threshold concentration (50 nM) (Kearns, C. M. et. al., Seminars in
Oncology, 3(6) p.16-23, 1995).
[0162] Docetaxel, (2R,3S)-N-carboxy-3-phenylisoserine,N-tert-butyl
ester, 13-ester with
5.beta.-20-epoxy-1,2.alpha.,4,7.beta.,10.beta.,13.alpha.-hexahydroxytax-1-
1-en-9-one 4-acetate 2-benzoate, trihydrate; is commercially
available as an injectable solution as TAXOTERE.RTM.. Docetaxel is
indicated for the treatment of breast cancer. Docetaxel is a
semisynthetic derivative of paclitaxel q.v., prepared using a
natural precursor, 10-deacetyl-baccatin III, extracted from the
needle of the European Yew tree. The dose limiting toxicity of
docetaxel is neutropenia.
[0163] Vinca alkaloids are phase specific anti-neoplastic agents
derived from the periwinkle plant. Vinca alkaloids act at the M
phase (mitosis) of the cell cycle by binding specifically to
tubulin. Consequently, the bound tubulin molecule is unable to
polymerize into microtubules. Mitosis is believed to be arrested in
metaphase with cell death following. Examples of vinca alkaloids
include, but are not limited to, vinblastine, vincristine, and
vinorelbine.
[0164] Vinblastine, vincaleukoblastine sulfate, is commercially
available as VELBAN.RTM. as an injectable solution. Although, it
has possible indication as a second line therapy of various solid
tumors, it is primarily indicated in the treatment of testicular
cancer and various lymphomas including Hodgkin's Disease; and
lymphocytic and histiocytic lymphomas. Myelosuppression is the dose
limiting side effect of vinblastine.
[0165] Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is
commercially available as ONCOVIN.RTM. as an injectable solution.
Vincristine is indicated for the treatment of acute leukemias and
has also found use in treatment regimens for Hodgkin's and
non-Hodgkin's malignant lymphomas. Alopecia and neurologic effects
are the most common side effect of vincristine and to a lesser
extent myelosupression and gastrointestinal mucositis effects
occur.
[0166] Vinorelbine, 3',4'-didehydro
-4'-deoxy-C'-norvincaleukoblastine
[R-(R*,R*)-2,3-dihydroxybutanedioate (1:2)(salt)], commercially
available as an injectable solution of vinorelbine tartrate
(NAVELBINE.RTM.), is a semisynthetic vinca alkaloid. Vinorelbine is
indicated as a single agent or in combination with other
chemotherapeutic agents, such as cisplatin, in the treatment of
various solid tumors, particularly non-small cell lung, advanced
breast, and hormone refractory prostate cancers. Myelosuppression
is the most common dose limiting side effect of vinorelbine.
[0167] Platinum coordination complexes are non-phase specific
anti-cancer agents, which are interactive with DNA. The platinum
complexes enter tumor cells, undergo, aquation and form intra- and
interstrand crosslinks with DNA causing adverse biological effects
to the tumor. Examples of platinum coordination complexes include,
but are not limited to, cisplatin and carboplatin.
[0168] Cisplatin, cis-diamminedichloroplatinum, is commercially
available as PLATINOL.RTM. as an injectable solution. Cisplatin is
primarily indicated in the treatment of metastatic testicular and
ovarian cancer and advanced bladder cancer. The primary dose
limiting side effects of cisplatin are nephrotoxicity, which may be
controlled by hydration and diuresis, and ototoxicity.
[0169] Carboplatin, platinum, diammine
[1,1-cyclobutane-dicarboxylate(2-)--O,O'], is commercially
available as PARAPLATIN.RTM. as an injectable solution. Carboplatin
is primarily indicated in the first and second line treatment of
advanced ovarian carcinoma. Bone marrow suppression is the dose
limiting toxicity of carboplatin.
[0170] Alkylating agents are non-phase anti-cancer specific agents
and strong electrophiles. Typically, alkylating agents form
covalent linkages, by alkylation, to DNA through nucleophilic
moieties of the DNA molecule such as phosphate, amino, sulfhydryl,
hydroxyl, carboxyl, and imidazole groups. Such alkylation disrupts
nucleic acid function leading to cell death. Examples of alkylating
agents include, but are not limited to, nitrogen mustards such as
cyclophosphamide, melphalan, and chlorambucil; alkyl sulfonates
such as busulfan; nitrosoureas such as carmustine; and triazenes
such as dacarbazine.
[0171] Cyclophosphamide,
2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine
2-oxide monohydrate, is commercially available as an injectable
solution or tablets as CYTOXAN.RTM.. Cyclophosphamide is indicated
as a single agent or in combination with other chemotherapeutic
agents, in the treatment of malignant lymphomas, multiple myeloma,
and leukemias. Alopecia, nausea, vomiting and leukopenia are the
most common dose limiting side effects of cyclophosphamide.
[0172] Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is
commercially available as an injectable solution or tablets as
ALKERAN.RTM.. Melphalan is indicated for the palliative treatment
of multiple myeloma and non-resectable epithelial carcinoma of the
ovary. Bone marrow suppression is the most common dose limiting
side effect of melphalan.
[0173] Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic
acid, is commercially available as LEUKERAN.RTM. tablets.
Chlorambucil is indicated for the palliative treatment of chronic
lymphatic leukemia, and malignant lymphomas such as lymphosarcoma,
giant follicular lymphoma, and Hodgkin's disease. Bone marrow
suppression is the most common dose limiting side effect of
chlorambucil.
[0174] Busulfan, 1,4-butanediol dimethanesulfonate, is commercially
available as MYLERAN.RTM. TABLETS. Busulfan is indicated for the
palliative treatment of chronic myelogenous leukemia. Bone marrow
suppression is the most common dose limiting side effects of
busulfan.
[0175] Carmustine, 1,3[bis(2-chloroethyl)-1-nitrosourea, is
commercially available as single vials of lyophilized material as
BiCNU.RTM.. Carmustine is indicated for the palliative treatment as
a single agent or in combination with other agents for brain
tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's
lymphomas. Delayed myelosuppression is the most common dose
limiting side effects of carmustine.
[0176] Dacarbazine,
5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, is
commercially available as single vials of material as
DTIC-Dome.RTM.. Dacarbazine is indicated for the treatment of
metastatic malignant melanoma and in combination with other agents
for the second line treatment of Hodgkin's Disease. Nausea,
vomiting, and anorexia are the most common dose limiting side
effects of dacarbazine.
[0177] Antibiotic anti-neoplastics are non-phase specific agents,
which bind or intercalate with DNA. Typically, such action results
in stable DNA complexes or strand breakage, which disrupts ordinary
function of the nucleic acids leading to cell death. Examples of
antibiotic anti-neoplastic agents include, but are not limited to,
actinomycins such as dactinomycin, anthrocyclins such as
daunorubicin and doxorubicin; and bleomycins.
[0178] Dactinomycin, also know as Actinomycin D, is commercially
available in injectable form as COSMEGEN.RTM.. Dactinomycin is
indicated for the treatment of Wilm's tumor and rhabdomyosarcoma.
Nausea, vomiting, and anorexia are the most common dose limiting
side effects of dactinomycin.
[0179] Daunorubicin,
(8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-.alpha.-L-lyxo-hexopyranos-
yl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12
naphthacenedione hydrochloride, is commercially available as a
liposomal injectable form as DAUNOXOME.RTM. or as an injectable as
CERUBIDINE.RTM.. Daunorubicin is indicated for remission induction
in the treatment of acute nonlymphocytic leukemia and advanced HIV
associated Kaposi's sarcoma. Myelosuppression is the most common
dose limiting side effect of daunorubicin.
[0180] Doxorubicin, (8S,
10S)-10-[(3-amino-2,3,6-trideoxy-.alpha.-L-lyxo-hexopyranosyl)oxy]-8-glyc-
oloyl, 7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12
naphthacenedione hydrochloride, is commercially available as an
injectable form as RUBEX.RTM. or ADRIAMYCIN RDF.RTM.. Doxorubicin
is primarily indicated for the treatment of acute lymphoblastic
leukemia and acute myeloblastic leukemia, but is also a useful
component in the treatment of some solid tumors and lymphomas.
Myelosuppression is the most common dose limiting side effect of
doxorubicin.
[0181] Bleomycin, a mixture of cytotoxic glycopeptide antibiotics
isolated from a strain of Streptomyces verticillus, is commercially
available as BLENOXANE.RTM.. Bleomycin is indicated as a palliative
treatment, as a single agent or in combination with other agents,
of squamous cell carcinoma, lymphomas, and testicular carcinomas.
Pulmonary and cutaneous toxicities are the most common dose
limiting side effects of bleomycin.
[0182] Topoisomerase II inhibitors include, but are not limited to,
epipodophyllotoxins.
[0183] Epipodophyllotoxins are phase specific anti-neoplastic
agents derived from the mandrake plant. Epipodophyllotoxins
typically affect cells in the S and G.sub.2 phases of the cell
cycle by forming a ternary complex with topoisomerase II and DNA
causing DNA strand breaks. The strand breaks accumulate and cell
death follows. Examples of epipodophyllotoxins include, but are not
limited to, etoposide and teniposide.
[0184] Etoposide, 4'-demethyl-epipodophyllotoxin
9[4,6-0-(R)-ethylidene-.beta.-D-glucopyranoside], is commercially
available as an injectable solution or capsules as VePESID.RTM. and
is commonly known as VP-16. Etoposide is indicated as a single
agent or in combination with other chemotherapy agents in the
treatment of testicular and non-small cell lung cancers.
Myelosuppression is the most common side effect of etoposide. The
incidence of leucopenia tends to be more severe than
thrombocytopenia.
[0185] Teniposide, 4'-demethyl-epipodophyllotoxin
9[4,6-0-(R)-thenylidene-.beta.-D-glucopyranoside], is commercially
available as an injectable solution as VUMON.RTM. and is commonly
known as VM-26. Teniposide is indicated as a single agent or in
combination with other chemotherapy agents in the treatment of
acute leukemia in children. Myelosuppression is the most common
dose limiting side effect of teniposide. Teniposide can induce both
leucopenia and thrombocytopenia.
[0186] Antimetabolite neoplastic agents are phase specific
anti-neoplastic agents that act at S phase (DNA synthesis) of the
cell cycle by inhibiting DNA synthesis or by inhibiting purine or
pyrimidine base synthesis and thereby limiting DNA synthesis.
Consequently, S phase does not proceed and cell death follows.
Examples of antimetabolite anti-neoplastic agents include, but are
not limited to, fluorouracil, methotrexate, cytarabine,
mecaptopurine, thioguanine, and gemcitabine.
[0187] 5-fluorouracil, 5-fluoro-2,4-(1H,3H) pyrimidinedione, is
commercially available as fluorouracil. Administration of
5-fluorouracil leads to inhibition of thymidylate synthesis and is
also incorporated into both RNA and DNA. The result typically is
cell death. 5-fluorouracil is indicated as a single agent or in
combination with other chemotherapy agents in the treatment of
carcinomas of the breast, colon, rectum, stomach and pancreas.
Myelosuppression and mucositis are dose limiting side effects of
5-fluorouracil. Other fluoropyrimidine analogs include 5-fluoro
deoxyuridine (floxuridine) and 5-fluorodeoxyuridine
monophosphate.
[0188] Cytarabine, 4-amino-1-.beta.-D-arabinofuranosyl-2 (1
H)-pyrimidinone, is commercially available as CYTOSAR-U.RTM. and is
commonly known as Ara-C. It is believed that cytarabine exhibits
cell phase specificity at S-phase by inhibiting DNA chain
elongation by terminal incorporation of cytarabine into the growing
DNA chain. Cytarabine is indicated as a single agent or in
combination with other chemotherapy agents in the treatment of
acute leukemia. Other cytidine analogs include 5-azacytidine and
2',2'-difluorodeoxycytidine (gemcitabine). Cytarabine induces
leucopenia, thrombocytopenia, and mucositis.
[0189] Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate,
is commercially available as PURINETHOL.RTM.. Mercaptopurine
exhibits cell phase specificity at S-phase by inhibiting DNA
synthesis by an as of yet unspecified mechanism. Mercaptopurine is
indicated as a single agent or in combination with other
chemotherapy agents in the treatment of acute leukemia.
Myelosuppression and gastrointestinal mucositis are expected side
effects of mercaptopurine at high doses. A useful mercaptopurine
analog is azathioprine.
[0190] Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, is
commercially available as TABLOID.RTM.. Thioguanine exhibits cell
phase specificity at S-phase by inhibiting DNA synthesis by an as
of yet unspecified mechanism. Thioguanine is indicated as a single
agent or in combination with other chemotherapy agents in the
treatment of acute leukemia. Myelosuppression, including
leucopenia, thrombocytopenia, and anemia, is the most common dose
limiting side effect of thioguanine administration. However,
gastrointestinal side effects occur and can be dose limiting. Other
purine analogs include pentostatin, erythrohydroxynonyladenine,
fludarabine phosphate, and cladribine.
[0191] Gemcitabine, 2'-deoxy-2', 2'-difluorocytidine
monohydrochloride (.beta.-isomer), is commercially available as
GEMZAR.RTM.. Gemcitabine exhibits cell phase specificity at S-phase
and by blocking progression of cells through the G1/S boundary.
Gemcitabine is indicated in combination with cisplatin in the
treatment of locally advanced non-small cell lung cancer and alone
in the treatment of locally advanced pancreatic cancer.
Myelosuppression, including leucopenia, thrombocytopenia, and
anemia, is the most common dose limiting side effect of gemcitabine
administration.
[0192] Methotrexate, N-[4[[(2,4-diamino-6-pteridinyl)
methyl]methylamino] benzoyl]-L-glutamic acid, is commercially
available as methotrexate sodium. Methotrexate exhibits cell phase
effects specifically at S-phase by inhibiting DNA synthesis, repair
and/or replication through the inhibition of dyhydrofolic acid
reductase which is required for synthesis of purine nucleotides and
thymidylate. Methotrexate is indicated as a single agent or in
combination with other chemotherapy agents in the treatment of
choriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, and
carcinomas of the breast, head, neck, ovary and bladder.
Myelosuppression (leucopenia, thrombocytopenia, and anemia) and
mucositis are expected side effect of methotrexate
administration.
[0193] Camptothecins, including, camptothecin and camptothecin
derivatives are available or under development as Topoisomerase I
inhibitors. Camptothecins cytotoxic activity is believed to be
related to its Topoisomerase I inhibitory activity. Examples of
camptothecins include, but are not limited to irinotecan,
topotecan, and the various optical forms of
7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptoth-
ecin described below.
[0194] Irinotecan HCl,
(4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)
carbonyloxy]-1H-pyrano[3',4',6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)--
dione hydrochloride, is commercially available as the injectable
solution CAMPTOSAR.RTM..
[0195] Irinotecan is a derivative of camptothecin which binds,
along with its active metabolite SN-38, to the topoisomerase I-DNA
complex. It is believed that cytotoxicity occurs as a result of
irreparable double strand breaks caused by interaction of the
topoisomerase I: DNA: irintecan or SN-38 ternary complex with
replication enzymes. Irinotecan is indicated for treatment of
metastatic cancer of the colon or rectum. The dose limiting side
effects of irinotecan HCl are myelosuppression, including
neutropenia, and GI effects, including diarrhea.
[0196] Topotecan HCl,
(S)-10-[(dimethylamino)methyI]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4',6,7]-
indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione monohydrochloride,
is commercially available as the injectable solution HYCAMTIN.RTM..
Topotecan is a derivative of camptothecin which binds to the
topoisomerase I-DNA complex and prevents religation of singles
strand breaks caused by Topoisomerase I in response to torsional
strain of the DNA molecule. Topotecan is indicated for second line
treatment of metastatic carcinoma of the ovary and small cell lung
cancer. The dose limiting side effect of topotecan HCl is
myelosuppression, primarily neutropenia.
[0197] Also of interest, is the camptothecin derivative of formula
A following, currently under development, including the racemic
mixture (R,S) form as well as the R and S enantiomers:
##STR00006##
known by the chemical name
"7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(R,S)-camptotheci-
n (racemic mixture) or
"7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(R)-camptothecin
(R enantiomer) or
"7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20(S)-camptothecin
(S enantiomer). Such compound as well as related compounds are
described, including methods of making, in U.S. Pat. Nos.
6,063,923; 5,342,947; 5,559,235; 5,491,237 and pending U.S. patent
application Ser. No. 08/977,217 filed Nov. 24, 1997.
[0198] Hormones and hormonal analogues are useful compounds for
treating cancers in which there is a relationship between the
hormone(s) and growth and/or lack of growth of the cancer. Examples
of hormones and hormonal analogues useful in cancer treatment
include, but are not limited to, adrenocorticosteroids such as
prednisone and prednisolone which are useful in the treatment of
malignant lymphoma and acute leukemia in children;
aminoglutethimide and other aromatase inhibitors such as
anastrozole, letrazole, vorazole, and exemestane useful in the
treatment of adrenocortical carcinoma and hormone dependent breast
carcinoma containing estrogen receptors; progestrins such as
megestrol acetate useful in the treatment of hormone dependent
breast cancer and endometrial carcinoma;
[0199] estrogens, androgens, and anti-androgens such as flutamide,
nilutamide, bicalutamide, cyproterone acetate and 5a-reductases
such as finasteride and dutasteride, useful in the treatment of
prostatic carcinoma and benign prostatic hypertrophy;
anti-estrogens such as tamoxifen, toremifene, raloxifene,
droloxifene, iodoxyfene, as well as selective estrogen receptor
modulators (SERMS) such those described in U.S. Pat. Nos.
5,681,835, 5,877,219, and 6,207,716, useful in the treatment of
hormone dependent breast carcinoma and other susceptible cancers;
and gonadotropin-releasing hormone (GnRH) and analogues thereof
which stimulate the release of leutinizing hormone (LH) and/or
follicle stimulating hormone (FSH) for the treatment prostatic
carcinoma, for instance, LHRH agonists and antagagonists such as
goserelin acetate and luprolide.
[0200] Signal transduction pathway inhibitors are those inhibitors,
which block or inhibit a chemical process which evokes an
intracellular change. As used herein this change is cell
proliferation or differentiation. Signal tranduction inhibitors
useful in the present invention include inhibitors of receptor
tyrosine kinases, non-receptor tyrosine kinases, SH2/SH3domain
blockers, serine/threonine kinases, phosphotidyl inositol-3
kinases, myo-inositol signaling, and Ras oncogenes.
[0201] Several protein tyrosine kinases catalyse the
phosphorylation of specific tyrosyl residues in various proteins
involved in the regulation of cell growth. Such protein tyrosine
kinases can be broadly classified as receptor or non-receptor
kinases.
[0202] Receptor tyrosine kinases are transmembrane proteins having
an extracellular ligand binding domain, a transmembrane domain, and
a tyrosine kinase domain. Receptor tyrosine kinases are involved in
the regulation of cell growth and are generally termed growth
factor receptors. Inappropriate or uncontrolled activation of many
of these kinases, i.e. aberrant kinase growth factor receptor
activity, for example by over-expression or mutation, has been
shown to result in uncontrolled cell growth. Accordingly, the
aberrant activity of such kinases has been linked to malignant
tissue growth. Consequently, inhibitors of such kinases could
provide cancer treatment methods. Growth factor receptors include,
for example, epidermal growth factor receptor (EGFr), platelet
derived growth factor receptor (PDGFr), erbB2, erbB4, vascular
endothelial growth factor receptor (VEGFr), tyrosine kinase with
immunoglobulin-like and epidermal growth factor homology domains
(TIE-2), insulin growth factor-I (IGFI) receptor, macrophage colony
stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth
factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC),
ephrin (eph) receptors, and the RET protooncogene. Several
inhibitors of growth receptors are under development and include
ligand antagonists, antibodies, tyrosine kinase inhibitors and
anti-sense oligonucleotides. Growth factor receptors and agents
that inhibit growth factor receptor function are described, for
instance, in Kath, John C., Exp. Opin. Ther. Patents (2000)
10(6):803-818; Shawver et al DDT Vol 2, No. 2 February 1997; and
Lofts, F. J. et al, "Growth factor receptors as targets", New
Molecular Targets for Cancer Chemotherapy, ed. Workman, Paul and
Kerr, David, CRC press 1994, London.
[0203] Tyrosine kinases, which are not growth factor receptor
kinases are termed non-receptor tyrosine kinases. Non-receptor
tyrosine kinases for use in the present invention, which are
targets or potential targets of anti-cancer drugs, include cSrc,
Lck, Fyn, Yes, Jak, cAbl, FAK (Focal adhesion kinase), Brutons
tyrosine kinase, and Bcr-Abl. Such non-receptor kinases and agents
which inhibit non-receptor tyrosine kinase function are described
in Sinh, S. and Corey, S. J., (1999) Journal of Hematotherapy and
Stem Cell Research 8 (5): 465-80; and Bolen, J. B., Brugge, J. S.,
(1997) Annual review of Immunology. 15: 371-404.
[0204] SH2/SH3 domain blockers are agents that disrupt SH2 or SH3
domain binding in a variety of enzymes or adaptor proteins
including, PI3-K p85 subunit, Src family kinases, adaptor molecules
(Shc, Crk, Nck, Grb2) and Ras-GAP. SH2/SH3 domains as targets for
anti-cancer drugs are discussed in Smithgall, T.E. (1995), Journal
of Pharmacological and Toxicological Methods. 34(3) 125-32.
[0205] Inhibitors of Serine/Threonine Kinases including MAP kinase
cascade blockers which include blockers of Raf kinases (rafk),
Mitogen or Extracellular
[0206] Regulated Kinase (MEKs), and Extracellular Regulated Kinases
(ERKs); and Protein kinase C family member blockers including
blockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota,
zeta). IkB kinase family (IKKa, IKKb), PKB family kinases, akt
kinase family members, and TGF beta receptor kinases. Such
Serine/Threonine kinases and inhibitors thereof are described in
Yamamoto, T., Taya, S., Kaibuchi, K., (1999), Journal of
Biochemistry. 126 (5) 799-803; Brodt, P, Samani, A., and Navab, R.
(2000), Biochemical Pharmacology, 60. 1101-1107; Massague, J.,
Weis-Garcia, F. (1996) Cancer Surveys. 27:41-64; Philip, P.A., and
Harris, A.L. (1995), Cancer Treatment and Research. 78: 3-27,
Lackey, K. et al Bioorganic and Medicinal Chemistry Letters, (10),
2000, 223-226; U.S. Pat. No. 6,268,391; and Martinez-lacaci, L., et
al, Int. J. Cancer (2000), 88(1), 44-52.
[0207] Inhibitors of Phosphotidyl inositol-3 Kinase family members
including blockers of PI3-kinase, ATM, DNA-PK, and Ku may also be
useful in the present invention. Such kinases are discussed in
Abraham, R. T. (1996), Current Opinion in Immunology. 8 (3) 412-8;
Canman, C. E., Lim, D. S. (1998), Oncogene 17 (25) 3301-3308;
Jackson, S. P. (1997), International Journal of Biochemistry and
Cell Biology. 29 (7):935-8; and Zhong, H. et al, Cancer res, (2000)
60(6), 1541-1545.
[0208] Also of interest in the present invention are Myo-inositol
signaling inhibitors such as phospholipase C blockers and
Myoinositol analogues. Such signal inhibitors are described in
Powis, G., and Kozikowski A., (1994) New Molecular Targets for
Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press
1994, London.
[0209] Another group of signal transduction pathway inhibitors are
inhibitors of Ras Oncogene. Such inhibitors include inhibitors of
farnesyltransferase, geranyl-geranyl transferase, and CAAX
proteases as well as anti-sense oligonucleotides, ribozymes and
immunotherapy. Such inhibitors have been shown to block ras
activation in cells containing wild type mutant ras, thereby acting
as antiproliferation agents. Ras oncogene inhibition is discussed
in Scharovsky, O. G., Rozados, V. R., Gervasoni, S. I. Matar, P.
(2000), Journal of Biomedical Science. 7(4) 292-8; Ashby, M. N.
(1998), Current Opinion in Lipidology. 9 (2) 99-102; and BioChim.
Biophys. Acta, (19899) 1423(3):19-30.
[0210] As mentioned above, antibody antagonists to receptor kinase
ligand binding may also serve as signal transduction inhibitors.
This group of signal transduction pathway inhibitors includes the
use of humanized antibodies to the extracellular ligand binding
domain of receptor tyrosine kinases. For example lmclone C225 EGFR
specific antibody (see Green, M. C. et al, Monoclonal Antibody
Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26(4),
269-286); Herceptin erbB2 antibody (see Tyrosine Kinase Signalling
in Breast cancer:erbB Family Receptor Tyrosine Kniases, Breast
cancer Res., 2000, 2(3), 176-183); and 2CB VEGFR2 specific antibody
(see Brekken, R. A. et al, Selective Inhibition of VEGFR2 Activity
by a monoclonal Anti-VEGF antibody blocks tumor growth in mice,
Cancer Res. (2000) 60, 5117-5124).
[0211] Non-receptor kinase angiogenesis inhibitors may also be
useful in the present invention. Inhibitors of angiogenesis related
VEGFR and TIE2 are discussed above in regard to signal transduction
inhibitors (both receptors are receptor tyrosine kinases).
Angiogenesis in general is linked to erbB2/EGFR signaling since
inhibitors of erbB2 and EGFR have been shown to inhibit
angiogenesis, primarily VEGF expression. Accordingly, non-receptor
tyrosine kinase inhibitors, may be used in combination with the
compounds of the present invention. For example, anti-VEGF
antibodies, which do not recognize VEGFR (the receptor tyrosine
kinase), but bind to the ligand; small molecule inhibitors of
integrin (alpha.sub.v beta.sub.3) that will inhibit angiogenesis;
endostatin and angiostatin (non-RTK) may also prove useful in
combination with the disclosed compounds. (See Bruns C J et al
(2000), Cancer Res., 60: 2926-2935; Schreiber A B, Winkler M E, and
Derynck R. (1986), Science, 232: 1250-1253; Yen L et al. (2000),
Oncogene 19: 3460-3469).
[0212] Agents used in immunotherapeutic regimens may also be useful
in combination with the compounds of formula (I). There are a
number of immunologic strategies to generate an immune response.
These strategies are generally in the realm of tumor vaccinations.
The efficacy of immunologic approaches may be greatly enhanced
through combined inhibition of signaling pathways using a small
molecule inhibitor. Discussion of the immunologic/tumor vaccine
approach against erbB2/EGFR are found in Reilly R T et al. (2000),
Cancer Res. 60: 3569-3576; and Chen Y, Hu D, Eling D J, Robbins J,
and Kipps T J. (1998), Cancer Res. 58: 1965-1971.
[0213] Agents used in proapoptotic regimens (e.g., bcl-2 antisense
oligonucleotides) may also be used in the combination of the
present invention. Members of the Bcl-2 family of proteins block
apoptosis. Upregulation of bcl-2 has therefore been linked to
chemoresistance. Studies have shown that the epidermal growth
factor (EGF) stimulates anti-apoptotic members of the bcl-2 family
(i.e., mcl-1). Therefore, strategies designed to downregulate the
expression of bcl-2 in tumors have demonstrated clinical benefit
and are now in Phase II/III trials, namely Genta's G3139 bcl-2
antisense oligonucleotide. Such proapoptotic strategies using the
antisense oligonucleotide strategy for bcl-2 are discussed in Water
J S et al. (2000), J. Clin. Oncol. 18: 1812-1823; and Kitada S et
al. (1994), Antisense Res. Dev. 4: 71-79.
[0214] Cell cycle signalling inhibitors inhibit molecules involved
in the control of the cell cycle. A family of protein kinases
called cyclin dependent kinases (CDKs) and their interaction with a
family of proteins termed cyclins controls progression through the
eukaryotic cell cycle. The coordinate activation and inactivation
of different cyclin/CDK complexes is necessary for normal
progression through the cell cycle. Several inhibitors of cell
cycle signalling are under development. For instance, examples of
cyclin dependent kinases, including CDK2, CDK4, and CDK6 and
inhibitors for the same are described in, for instance, Rosania et
al, Exp. Opin. Ther. Patents (2000) 10(2):215-230.
[0215] In one embodiment, the cancer treatment method of the
claimed invention includes the co-administration a compound of
Formula (I) or a pharmaceutically acceptable salt thereof at least
one chemotherapeutic agent.and at least one anti-neoplastic agent,
such as one selected from the group consisting of anti-microtubule
agents, platinum coordination complexes, alkylating agents,
antibiotic agents, topoisomerase II inhibitors, antimetabolites,
topoisomerase I inhibitors, hormones and hormonal analogues, signal
transduction pathway inhibitors, non-receptor tyrosine kinase
angiogenesis inhibitors, immunotherapeutic agents, proapoptotic
agents, and cell cycle signaling inhibitors.
[0216] The current invention relates to the use of a non-peptide
thrombopoietin (TPO) receptor agonist or a TPO cell cycle activator
and at least one chemotherapeutic agent in the treatment of
pre-cancerous syndromes in mammals, including humans.
[0217] The current invention relates to the use of a non-peptide
thrombopoietin (TPO) receptor agonist or a TPO cell cycle activator
and at least one chemotherapeutic agent in the treatment of cancer
in mammals, including humans.
[0218] TPO is known to have various effects including
anti-apototic/survival effects on megakaryocytes, platelets and
stem cells, and proliferative effects on stem cells and
megakaryocytic cells (Kuter D. J. Seminars in Hematology, 2000, 37,
41-9). These TPO activities effectively increase the number of stem
and progenitor cells so that there is synergistic effects when TPO
is used in conjunction with other cytokines that induce
differentiation.
[0219] The non-peptide TPO receptor agonists of the current
invention are also useful in acting on cells for survival and/or
proliferation in conjunction with other agents known to act on
cells for survival and/or proliferation. Such other agents include
but are not limited to: G-CSF, GM-CSF, TPO, M-CSF, EPO, Gro-beta,
IL-11, SCF, FLT3 ligand, LIF, IL-3, IL-6, IL-1, Progenipoietin,
NESP, SD-01, or IL-5 or a biologically active derivative of any of
the aforementioned agents, KT6352 (Shiotsu Y. et al., Exp. Hemat.
1998, 26, 1195-1201), uteroferrin (Laurenz J C., et al. Comp.
Biochem. & Phys., Part A. Physiology., 1997, 116, 369-77), FK23
(Hasegawa T., et al. Int. J. Immunopharm., 1996, 18 103-112) and
other molecules identified as having anti-apoptotic, survival or
proliferative properties for stem cells, progenitor cells, or other
cells expressing TPO Receptors.
[0220] One skilled in the art can readily determine by known
methods if a compound is a non-peptide TPO receptor agonist and
thus included within the scope of the current invention. By way of
example, the following assays can be employed:
Luciferase Assay
[0221] Compounds are tested for potency as agonists of the TPO
receptor in a Luciferase assay such as described in Lamb, et al.,
Nucleic Acids Research 23:3283-3289 (1995) and Seidel, et al.,
Proc. Natl. Acad. Sci., USA 92: 3041-3045 (1995) by substituting a
TPO-responsive BaF3 cell line (Vigon et al. Proc. Natl. Acad. Sci.
USA 1992, 89, 5640-5644) for the HepG2 cells utilized therein. The
murine BaF3 cells express TPO receptors and closely match the
pattern of STAT (signal transducers and activators of
transcription) activation observed in primary murine and human bone
marrow cells.
Proliferation Assay
[0222] Compounds are tested in an in vitro proliferation assay
using the human UT7TPO cell line. UT7TPO cells are a human
megakaryoblastic cell line that express Tpo-R, whose survival and
growth is dependent on the presence of TPO (Komatsu et al. Blood
1996, 87,4552).
Differentiation Assay
[0223] Compounds are tested for their ability in stimulating the
maturation of megakaryocytes from human bone marrow cells. In this
assay, purified human CD34+ progenitor cells are incubated in
liquid culture with test compounds for 10 days and the number of
cells expressing the transmembrane glycoprotein CD41 (gpIIb), a
megakaryocytic marker, is then measured by flow cytometry (see
Cwirla, S. E. et al Science, 1997, 276, 1696).
[0224] The ability of non-peptide TPO receptor agonists to treat
cancer is demonstrated by activity in the following Assays.
Cancer Proliferation Assay
[0225] Flat-bottom 96-well microtiter tissue culture plates
(Costar, Cambridge, Mass.) were used for the assay. Cultures were
performed in replicates of 4 wells; each well contained
1.times.10.sup.4 cells. Six concentrations of Compound A (ranging
from 40 .mu.g/mL to 100 ng/mL) were tested in the absence and
presence of 10 ng/mL G-CSF, 100 ng/mL of TPO or 5 U/mL of EPO.
Cells were also tested in medium alone, G-CSF alone, TPO alone, or
EPO alone to establish 100% of control values. The final volume in
each well was 200 .mu.l. Plates were placed in a humidified 5%
CO.sub.2 incubator at 37.degree. C. for 3 days. Proliferation was
measured by the uptake of tritiated thymidine (.sup.3H-TdR) by
pulsing wells with 1 .mu.Ci of .sup.3H-TdR for the final 18 hours
of incubation, harvesting the plate on a Brandel 96-well cell
harvester (Gaithersburg, Md.) and measuring radioactivity on the
filter mats in a Wallac 1450 Microbeta TriLux scintillation counter
(Turku, Finland). The effect of Compound A was determined by
comparing the results of cells treated with test compound with
control cells (100% of control).
TABLE-US-00001 Compound A Cell Line Description IC50 (ug/mL)
CCRF-CEM Lymphoblastic T cell leukemia 0.74 K562 Chronic
myelogenous leukemia 1.80 MOLT-4 Acute lymphoblastic T cell
leukemia 0.56 RPMI-8226 Plasmacytoma 5.90 SR Immunoblastic large
cell leukemia 0.77
See FIGS. 1 to 5
[0226] Activation of Akt in Human Platelets Treated with TPO or
Compound A
[0227] Washed human platelets from healthy volunteers were treated
with vehicle (V) [0.33% DMSO], 100 ng/mL TPO [recombinant human
thrombopoietin obtained from R&D Systems, Inc., Minneapolis,
Min., USA, or SB (SB=Compound A in Blot 1) (10 mM) for 15 minutes
alone, or 13 minutes alone followed by 2 minutes with 1 mM ADP
(+ADP). Protein extracts were probed for Akt (Ser473) activation.
Results are representative of 3 individual experiments.
[0228] Compound A was compared to TPO in human platelets through
the examination of a signal transduction pathway known to be
activated through TPOR [TPO receptor] stimulation; specifically,
Pi3K/Akt pathway activation [Chen, J., et al., Blood, 86, 4054-4062
(1995); Kojima, H., et al., Thrombosis & Haemostassis, 74,
1541-1545 (1995); Ezumi, Y., et al., FEBS Letters, 374, 48-52
(1995)]. Treatment of washed platelet preparations with TPO (Blot
1) resulted in significant Akt activation, as demonstrated through
the use of phoshorylation-specific antibodies directed against Akt.
However, no activation was observed when Compound A was used
(termed SB in Blot 1). In addition, preincubation with TPO resulted
in the significant enhancement of activation of Akt in combination
with ADP (1 .mu.M) as compared to TPO or ADP alone (no activation
observed). Further, on enhanced activation was observed when
platelets were incubated with Compound A prior to addition of
ADP.
[0229] These results indicate that TPOR stimulation by the
non-peptide TPO receptor agonist, Compound A, did not result in Akt
phoshorylation, where stimulation by TPO did result in Akt
phoshorylation. Because Akt activity is implicated in certain
cancers, these results provide one possible explanation for the
anti cancer activity of non-peptide TPO receptor agonist generally
and specifically Compound A.
Liver Cancer Assay
[0230] HepG2 is a human hepatocellular carcinoma cell line. Active
cell determinations were performed on HepG2 cells by plating
2.times.10.sup.4 cells/mL in 96-well plates in culture medium
containing 10% FBS and incubating overnight in 5% CO2 at
37.degree.. Cells were then treated with Compound A at 0, 0.1, 0.4,
1, 4, 10, 40 ug/mL and incubated for 72 hours. Cell proliferation
was measured using the CellTiter Glo (Promega) reagent according to
the manufacturer's protocol. Data is the mean of n=4 wells reported
as the percent of the control (0 ug/mL of Compound A).
[0231] Compound A induced a decrease in the number of viable cells
with an IC50 of approximately 6 ug/mL.
See FIG. 6
Solid Tumor Cell Line Proliferation Assays
Cell Titer glo Methodology:
[0232] Cells in log phase growth were seeded in a 96-well plate at
2500 cells/well in 50 uL medium and incubated at 37.degree. C., 5%
CO.sub.2 overnight. Compound A was diluted in medium and added at
0.1, 0.4, 1, 4, 10 and 40 ug/mL. Following a 72 hr incubation at
37.degree. C., 5% CO.sub.2,, The CellTiter-Glo Luminescent Cell
Viability Assay (ProMega Corp)was performed according to the
manufacturer's instructions. Briefly following a 30 min room
temperature incubation 100 uL CELLTiter Glo reagent was added to
each well and mixed for 2 minutes.
[0233] Luminescence was recorded following a 10 minute room
temperature incubation using a PerkinElmer Microbeta luminescence
counter. IC50 was determined by EXCel Fit 4.2.1. The effect of
Compound A is indicated in the table below.
TABLE-US-00002 IC50 Cell line Cell type (.mu.g/mL) Assay Format
NCI-H23 NSCLC 13.9 Cell Titer Glo HOP-92 NSCLC 13.5 Cell Titer Glo
EKVX NSCLC 12.7 Cell Titer Glo NCI-H226 NSCLC 11.0 Cell Titer Glo
HOP-62 NSCLC 10.6 Cell Titer Glo A549 NSCLC 9.10 Cell Titer Glo
NCI-H322M NSCLC 8.30 Cell Titer Glo NCI-H522 NSCLC 5.90 Cell Titer
Glo NCI-H460 NSCLC 5.70 Cell Titer Glo HepG2 Hepatocellular
carcinoma 5.61 Cell Titer Glo
[0234] References describing Cell Titer glo Methodology include the
following: Zhelev et al, Cancer Chemother Pharmacol 2004:
53:267-275; McCabe, et al (2006) Cancer Res. 66 , 8109-8115; and
Gauduchon, et al (2005) Clin. Cancer Res. 11 , 2345-2354.
[0235] The combinations of the present invention are tested for
efficacy, advantageous and synergistic properties according to
known procedures such as described in, Molina et al., Clin. Cancer
Res 2008;14(23) Dec. 1, 2008 and Giaccone et al, Int. J. Canc: 118,
209-214 (2006), both of which are incorporated herein by
reference.
[0236] The administration of a therapeutically effective amount of
the combinations of the invention are advantageous over the
individual component compounds in that the combinations will
provide one or more of the following improved properties when
compared to the individual administration of a therapeutically
effective amount of a component compound: i) a greater anticancer
effect than the most active single agent, ii) synergistic or highly
synergistic anticancer activity, iii) a dosing protocol that
provides enhanced anticancer activity with reduced side effect
profile, iv) a reduction in the toxic effect profile, v) an
increase in the therapeutic window, or vi) an increase in the
bioavailability of one or both of the component compounds.
[0237] Many current treatments for cancer and precancerous
syndromes are toxic to the patient and/or are known to trigger
adverse events which require the patient to stop the treatment
periodically in order to recover from the toxic effects and/or to
allow the adverse events to subside. This recovery period also
provides the cancer or precancerous syndrome the opportunity to
re-establish. One advantage of the combinations of the invention,
is that the non-peptide TPO receptor agonists, suitably a compound
selected from the following:
[0238]
3'-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4--
ylidene]hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid;
[0239]
3-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-y-
lidene]hydrazino}-2-hydroxy-3'-tetrazol-5-ylbiphenyl;
[0240]
1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin--
1-yl)thiazol-2-yl]carbamoyl}pyridine-2-yl)piperidine-4-carboxylic
acid;
[0241]
3'-{N'-[1-(3,5-Dimethyl-phenyl)-2-oxo-6-trifluoromethyl-1,2-dihydro-
-indol-3-ylidene]-hydrazino}-2'-hydroxybiphenyl-3-carboxylic acid;
and
[0242]
2'-hydroxy-3'-{N'-[2-oxo-1-(4-propyl-phenyl)-1,2-dihydro-indol-3-yl-
idene]-hydrazino}-biphenyl-4-carboxylic acid;
or a pharmaceutically acceptable salt thereof, or the TPO cell
cycle activator, in combination with at least one chemotherapeutic
agent, is that the combination is considered generally less toxic
than standard anticancer therapies and are capable of being
administered on a daily basis over a long period of time, suitably
for over two weeks, suitably for over one month, suitably for over
three months, suitably for over six months, suitably for over nine
months, suitably for over a year, suitably chronic administration
thereby providing continuous treatment of the cancer or
precancerous syndrome. This advantage in the treatment of cancer
and precancerous syndromes can be realized whether the combination
is being administered alone or whether another anti-neoplastic
agent is being co-administered. Even when the co-administered
anti-neoplastic agent is periodically stopped, one or more agents
of the combination can continue to be administered in order to
provide sustained treatment of the cancer or precancerous
syndrome.
[0243] The present invention therefore provides a method of
treating cancer in a mammal, including a human, including wherein
the cancer is selected from: brain (gliomas), glioblastomas,
astrocytomas, glioblastoma multiforme, eukemias, Bannayan-Zonana
syndrome, Cowden disease, Lhermitte-Duclos disease, breast,
inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma,
Rhabdomyosarcoma, ependymoma, medulloblastoma, colon, head and
neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate,
sarcoma, osteosarcoma, giant cell tumor of bone, thyroid,
[0244] Lymphoblastic T cell leukemia, Chronic myelogenous leukemia,
Chronic lymphocytic leukemia, Hairy-cell leukemia, acute
lymphoblastic leukemia, acute myelogenous leukemia, Chronic
neutrophilic leukemia, Acute lymphoblastic T cell leukemia,
Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell
leukemia, Megakaryoblastic leukemia, multiple myeloma, acute
megakaryocytic leukemia, and Erythroleukemia,
[0245] malignant lymphoma, hodgkins lymphoma, non-hodgkins
lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma,
follicular lymphoma,
[0246] neuroblastoma, bladder cancer, urothelial cancer, lung
cancer, vulval cancer, cervical cancer, endometrial cancer, renal
cancer, mesothelioma, esophageal cancer, salivary gland cancer,
hepatocellular cancer, gastric cancer, nasopharangeal cancer,
buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal
tumor) and testicular cancer,
which comprises the administration an effective amount of at least
one non-peptide thrombopoietin (TPO) receptor agonist or TPO cell
cycle activator and at least one chemotherapeutic agent to a
mammal, including a human, in need thereof.
[0247] The present invention therefore provides a method of
treating pre-cancerous syndromes in a mammal, including a human,
wherein the pre-cancerous syndrome is selected from: cervical
intraepithelial neoplasia, monoclonal gammapathy of unknown
significance (MGUS), myelodysplastic syndrome, aplastic anemia,
cervical lesions, skin nevi (pre-melanoma), prostatic
intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in
situ (DCIS), colon polyps and severe hepatitis or cirrhosis,
which comprises the administration an effective amount of at least
one non-peptide thrombopoietin (TPO) receptor agonist or TPO cell
cycle activator and at least one chemotherapeutic agent to a
mammal, including a human, in need thereof.
[0248] The individual agents of the combinations may be
administered to a patient in need thereof by any conventional route
of administration, including, but not limited to, intravenous,
intramuscular, oral, subcutaneous, intradermal, and parenteral.
[0249] The individual agents of the combinations of the present
invention are incorporated into convenient dosage forms such as
capsules, tablets, or injectable preparations. Solid or liquid
pharmaceutical carriers are employed. Solid carriers include,
starch, lactose, calcium sulfate dihydrate, terra alba, sucrose,
talc, gelatin, agar, pectin, acacia, magnesium stearate, and
stearic acid. Liquid carriers include syrup, peanut oil, olive oil,
saline, and water. Similarly, the carrier or diluent may include
any prolonged release material, such as glyceryl monostearate or
glyceryl distearate, alone or with a wax. The amount of solid
carrier varies widely but, preferably, will be from about 25 mg to
about 1 g per dosage unit. When a liquid carrier is used, the
preparation will be in the form of a syrup, elixir, emulsion, soft
gelatin capsule, sterile injectable liquid such as an ampoule, or
an aqueous or nonaqueous liquid suspension.
[0250] The pharmaceutical preparations are made following
conventional techniques of a pharmaceutical chemist involving
mixing, granulating, and compressing, when necessary, for tablet
forms, or mixing, filling and dissolving the ingredients, as
appropriate, to give the desired oral or parenteral products.
[0251] Doses of the individual agents of the combinations of the
present invention in a pharmaceutical dosage unit or units as
described above will be an efficacious, nontoxic quantity
preferably selected from the range of 0.001-100 mg/kg of active
compound, preferably 0.002-50 mg/kg. When treating a human patient
in need of a combination of the invention, each selected dose is
administered preferably from 1-6 times daily, orally or
parenterally. Preferred forms of parenteral administration include
topically, rectally, transdermally, by injection and continuously
by infusion. Oral dosage units for human administration suitably
contain from 0.05 to 3500 mg, suitably from 0.1 to 3000 mg,
suitably from 10 to 200 mg of each active compound. Oral
administration, which uses lower dosages is preferred. Parenteral
administration, at high dosages, however, also can be used when
safe and convenient for the patient.
[0252] Optimal dosages to be administered may be readily determined
by those skilled in the art, and will vary with the particular
agent or agents in use, the strength of the preparation, the mode
of administration, and the advancement of the disease condition.
Additional factors depending on the particular patient being
treated will result in a need to adjust dosages, including patient
age, weight, diet, and time of administration.
[0253] The method of this invention of treating cancer in mammals,
including humans, comprises administering to a subject in need
thereof a therapeutically effective amount of a pharmaceutically
active combination of the present invention.
[0254] The present invention relates to the use of a non-peptide
thrombopoietin (TPO) receptor agonist or TPO cell cycle activator
and at least one chemotherapeutic agent in the treatment of cancer
in a mammal, including a human.
[0255] The present invention relates to the in vivo administration
of a combination of a non-peptide thrombopoietin (TPO) receptor
agonist or TPO cell cycle activator and at least one
chemotherapeutic agent in the treatment of cancer in a mammal,
including a human.
[0256] The invention also provides for the use of a combination of
a non-peptide thrombopoietin (TPO) receptor agonist or TPO cell
cycle activator and at least one chemotherapeutic agent in the
manufacture of a medicament for use in therapy.
[0257] The invention also provides for a pharmaceutical composition
for use in the treatment of cancer which comprises a combination of
a non-peptide thrombopoietin (TPO) receptor agonist or TPO cell
cycle activator and at least one chemotherapeutic agent and a
pharmaceutically acceptable carrier or carriers.
[0258] The method of this invention of treating pre-cancerous
syndromes in mammals, including humans, comprises administering to
a subject in need thereof a therapeutically effective amount of a
combination of a non-peptide thrombopoietin (TPO) receptor agonist
or TPO cell cycle activator and at least one chemotherapeutic agent
of the present invention.
[0259] The present invention relates to the use of a combination of
a non-peptide thrombopoietin (TPO) receptor agonist or TPO cell
cycle activator and at least one chemotherapeutic agent in the
treatment of pre-cancerous syndromes in a mammal, including a
human.
[0260] The present invention relates to the in vivo administration
of a combination of a non-peptide thrombopoietin (TPO) receptor
agonist or TPO cell cycle activator and at least one
chemotherapeutic agent in the treatment of pre-cancerous syndromes
in a mammal, including a human.
[0261] The invention also provides for the use of a combination of
a non-peptide thrombopoietin (TPO) receptor agonist or TPO cell
cycle activator and at least one chemotherapeutic agent in the
manufacture of a medicament for use in the treatmet of
pre-cancerous syndromes in mammals including humans.
[0262] The invention also provides for a pharmaceutical composition
for use in the treatment of pre-cancerous syndromes which comprises
a combination of a non-peptide thrombopoietin (TPO) receptor
agonist or TPO cell cycle activator and at least one
chemotherapeutic agent and a pharmaceutically acceptable carrier or
carriers.
[0263] The invention also provides for the use of a combination of
a non-peptide thrombopoietin (TPO) receptor agonist or TPO cell
cycle activator and at least one chemotherapeutic agent in the
manufacture of a medicament for use in the treatmet of
pre-cancerous syndromes.
[0264] In addition, the pharmaceutically active combinations of the
present invention can be co-administered with further active
ingredients, such as other compounds known to treat cancer.
[0265] In addition, the pharmaceutically active combinations of the
present invention can be co-administered with further active
ingredients, such as other compounds known to treat pre-cancerous
syndromes.
[0266] Contemplated Equivalents--It will be appreciated by the
person of ordinary skill in the art that the compounds of Formulas
I and VI may also exist in tautomeric forms. For example, in
Formula I, the double bond that is drawn between the two nitrogen
atoms exists between the lower nitrogen atom and the AR
substituent. Tautomeric forms of the compounds of Formulas I and VI
are exemplified by the following Formula (X):
##STR00007##
where the `R` groups are as defined above. All such compounds are
included in the scope of the invention and inherently included in
the definition of the compounds of Formulas I and VI.
[0267] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description, utilize the
present invention to its fullest extent. The following Examples
are, therefore, to be construed as merely illustrative and not a
limitation of the scope of the present invention in any way.
EXPERIMENTAL DETAILS
EXAMPLE 1
Capsule Composition
[0268] An oral dosage form for administering an agent of the
present invention is produced by filing a standard two piece hard
gelatin capsule with the ingredients in the proportions shown in
Table I, below.
TABLE-US-00003 TABLE I INGREDIENTS AMOUNTS
3'-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5- 25 mg
dihydropyrazol-4-ylidene]hydrazino}-2'-hydroxybiphenyl-3-
carboxylic acid Mannitol 55 mg Talc 16 mg Magnesium Stearate 4
mg
EXAMPLE 2
Injectable Parenteral Composition
[0269] An injectable form for administering an agent of the present
invention is produced by stirring 1.5% by weight of
3-{N'-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene-
]hydrazino}-2-hydroxy-3'-(tetrazol-5-yl)biphenyl, in 10% by volume
propylene glycol in water.
EXAMPLE 3
Tablet Composition
[0270] The sucrose, microcrystalline cellulose and a non-peptide
TPO agonist, as shown in Table II below, are mixed and granulated
in the proportions shown with a 10% gelatin solution. The wet
granules are screened, dried, mixed with the starch, talc and
stearic acid, then screened and compressed into a tablet containing
one agent of the present invention.
TABLE-US-00004 TABLE II INGREDIENTS AMOUNTS
3'-{N'-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5- 20 mg
dihydropyrazol-4-ylidene]hydrazino}-2'-hydroxybiphenyl-
3-carboxylic acid Microcrystalline cellulose 30 mg sucrose 4 mg
starch 2 mg talc 1 mg stearic acid 0.5 mg
[0271] While the preferred embodiments of the invention are
illustrated by the above, it is to be understood that the invention
is not limited to the precise instructions herein disclosed and
that the right to all modifications coming within the scope of the
following claims is reserved.
* * * * *