U.S. patent application number 14/731722 was filed with the patent office on 2015-09-24 for combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells, or angiogenesis.
The applicant listed for this patent is Boehringer Ingelheim International GmbH. Invention is credited to Anke BAUM, Frank HILBERG, Gerd MUNZERT, Flavio SOLCA, Martin Friedrich STEFANIC, Jacobus C.A. van MEEL.
Application Number | 20150265610 14/731722 |
Document ID | / |
Family ID | 33424438 |
Filed Date | 2015-09-24 |
United States Patent
Application |
20150265610 |
Kind Code |
A1 |
STEFANIC; Martin Friedrich ;
et al. |
September 24, 2015 |
COMBINATIONS FOR THE TREATMENT OF DISEASES INVOLVING CELL
PROLIFERATION, MIGRATION OR APOPTOSIS OF MYELOMA CELLS, OR
ANGIOGENESIS
Abstract
The present invention relates to a pharmaceutical combination
for the treatment of diseases which involves cell proliferation,
migration or apoptosis of myeloma cells, or angiogenesis. The
invention also relates to a method for the treatment of said
diseases, comprising co-administration of effective amounts of
specific active compounds and/or co-treatment with radiation
therapy, in a ratio which provides an additive and synergistic
effect, and to the combined use of these specific compounds and/or
radiotherapy for the manufacture of corresponding pharmaceutical
combination preparations.
Inventors: |
STEFANIC; Martin Friedrich;
(Warthausen, DE) ; HILBERG; Frank; (Vienna,
AT) ; MUNZERT; Gerd; (Ulm, DE) ; SOLCA;
Flavio; (Vienna, AT) ; BAUM; Anke; (Moedling,
AT) ; van MEEL; Jacobus C.A.; (Moedling, AT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Boehringer Ingelheim International GmbH |
Ingelheim am Rhein |
|
DE |
|
|
Family ID: |
33424438 |
Appl. No.: |
14/731722 |
Filed: |
June 5, 2015 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14071166 |
Nov 4, 2013 |
|
|
|
14731722 |
|
|
|
|
12912110 |
Nov 9, 2010 |
|
|
|
14071166 |
|
|
|
|
Current U.S.
Class: |
424/133.1 ;
424/158.1; 424/174.1; 424/649; 424/85.1; 424/94.1; 514/254.09;
514/44R |
Current CPC
Class: |
A61K 31/517 20130101;
A61P 27/02 20180101; A61K 31/56 20130101; A61P 29/00 20180101; A61P
9/10 20180101; A61K 31/404 20130101; A61P 43/00 20180101; A61P
35/00 20180101; A61P 3/10 20180101; A61K 31/404 20130101; A61P
35/02 20180101; A61K 45/06 20130101; A61K 31/517 20130101; A61K
31/56 20130101; A61K 31/496 20130101; A61K 31/496 20130101; A61P
19/02 20180101; A61K 31/553 20130101; A61P 17/06 20180101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101 |
International
Class: |
A61K 31/496 20060101
A61K031/496; A61K 45/06 20060101 A61K045/06 |
Claims
1. A pharmaceutical combination comprising therapeutically
effective amounts of: (i)
(Z)-3-(1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-
-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, or a
pharmaceutically acceptable salt thereof; and (ii) at least a
further chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent selected from synthetic small molecule
VEGF receptor antagonists, small molecule growth factor receptor
antagonists, inhibitors of the EGF receptor, excluding
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, and/or
VEGF receptor and/or integrin receptors or any other protein
tyrosine kinase receptors which are not classified under the
synthetic small-molecules, inhibitors directed to EGF receptor
and/or VEGF receptor and/or integrin receptors or any other protein
tyrosine kinase receptors, which are fusion proteins, compounds
which interact with nucleic acids and which are classified as
alkylating agents or platinum compounds, compounds which interact
with nucleic acids and which are classified as anthracyclines, as
DNA intercalators or as DNA cross-linking agents, DNA minor-groove
binding compounds, anti-metabolites, naturally occurring,
semi-synthetic or synthetic bleomycin type antibiotics, inhibitors
of DNA transcribing enzymes selected from topoisomerase I and
topoisomerase II inhibitors, chromatin modifying agents, mitosis
inhibitors, anti-mitotic agents, cell-cycle inhibitors, proteasome
inhibitors, enzymes, hormones, hormone antagonists, hormone
inhibitors, inhibitors of steroid biosynthesis, steroids,
cytokines, hypoxia-selective cytotoxins, inhibitors of cytokines,
lymphokines, antibodies directed against cytokines, oral and
parenteral tolerance induction agents, supportive agents, chemical
radiation sensitizers and protectors, photo-chemically activated
drugs, synthetic poly- or oligonucleotides optionally modified or
conjugated, non-steroidal anti-inflammatory drugs, cytotoxic
antibiotics, antibodies targeting the surface molecules of cancer
cells, inhibitors of metalloproteinases, metals, inhibitors of
oncogenes, inhibitors of gene transcription or of RNA translation
or protein expression, complexes of rare earth elements, and
photo-chemotherapeutic agents; wherein said pharmaceutical
combination is optionally adapted for a co-treatment with
radiotherapy or radio-immunotherapy, in the form of a combined
preparation for simultaneous, separate or sequential use.
2. The pharmaceutical combination in accordance with claim 1,
wherein (ii) is selected from vatalanib (PTK-787/ZK222584),
SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474, AZD-2171,
CP-547632, CEP-7055, AG-013736, IM-842, GW-786034, gefitinib,
erlotinib, CI-1033 GW-2016, iressa (ZD-1839), tarceva (OSI-774),
PKI-166, EKB-569, HKI-272, herceptin, BAY-43-9006, BAY-57-9006,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu-
ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline or a
pharmaceutically acceptable salt thereof, atrasentan, rituximab,
cetuximab, Avastin.TM. (bevacizumab), IMC-1C11, erbitux (C-225),
DC-101, EMD-72000, vitaxin, imatinib, VEGFtrap, melphalan,
cyclophosphamide, an oxazaphosphorine, cisplatin, carboplatin,
oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin,
streptozocin, carmustine (BCNU), lomustine (CCNU), busulfan,
ifosfamide, streptozocin, thiotepa, chlorambucil, mechlorethamine,
an ethyleneimine compound, an alkylsulphonate, daunorubicin,
doxorubicin (adriamycin), liposomal doxorubicin (doxil),
epirubicin, idarubicin, mitoxantrone, amsacrine, dactinomycin,
distamycin or a derivative thereof, netropsin, pibenzimol,
mitomycin, CC-1065, a duocarmycin, mithramycin, chromomycin,
olivomycin, propamidine, stilbamidine, an anthramycin, an
aziridine, a nitrosourea or a derivative thereof, cytarabine,
5-fluorouracile (5-FU), uracil mustard, fludarabine, gemcitabine,
capecitabine, mercaptopurine, cladribine, thioguanine,
methotrexate, pentostatin, hydroxyurea, folic acid, a phleomycin, a
bleomycin or a derivative or salt thereof, CHPP, BZPP, MTPP, BAPP,
liblomycin, an acridine or a derivative thereof, a rifamycin, an
actinomycin, adramycin, irinotecan (camptosar), topotecan, an
amsacrine or analogue thereof, a tricyclic carboxamide, SAHA,
MD-275, trichostatin A, CBHA, LAQ824, valproic acid, paclitaxel
(taxol), docetaxel, taxotere, navelbine, vinblastin, vincristin,
vindesine, vinorelbine, colchicine or a derivative thereof,
maytansine, an ansamitocin, rhizoxin, phomopsin, dolastatin, an
epipodophyllotoxin, etoposide, teniposide, a steganacin,
combretastatin, amphetinile, procarbazine, bortezomib,
asparaginase, pegylated asparaginase (pegaspargase),a
thymidine-phosphorylase inhibitor, estramustine (T-66), megestrol,
flutamide, casodex, anandron, cyproterone acetate,
aminogluthetimide, anastrozole, formestan, letrozole leuprorelin,
buserelin, goserelin, triptorelin, tamoxifen or its citrate salt,
droloxifene, trioxifene, raloxifene, zindoxifene, ICI 164,384, ICI
182,780, aminoglutethimide, formestane, fadrozole, finasteride,
ketoconazole, leuprolide, prednisone, prednisolone,
methylprednisolone, dexamethasone, budenoside, fluocortolone,
triamcinolone, interferon .beta., IL-10, IL-12, etanercept,
thalidomide, its R- and S-enantiomers and its derivatives, revimid
(CC-5013), a leukotrien antagonist, mitomycin C, an aziridoquinone,
a 2-nitroimidazole, a nitroacridine, a nitroquinoline, a
nitropyrazoloacridine, a "dual-function" nitro aromatic, a nitro
aromatic deactivated mustard, a N-oxide of a nitrogen mustard, a
metal complex of a nitrogen mustard, an anti-CD3 antibody, an
anti-CD25 antibody, a tolerance induction agent, minodronic acid or
a derivative thereof selected from YM-529, Ono-5920 and YH-529,
zoledronic acid monohydrate, ibandronate sodium hydrate, clodronate
disodium, metronidazole, misonidazole, benznidazole, nimorazole,
RSU-1069, SR-4233, bromodeoxyuridine, iododeoxyuridine, WR-2721,
porfimer, photofrin, a benzoporphyrin derivative, a pheophorbide
derivative, merocyanin 540 (MC-540), tin etioporpurin, oblimersen,
a non-steroidal anti-inflammatory drug selected from
acetylsalicyclic acid, mesalazin, ibuprofen, naproxen,
flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen,
pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen,
tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen,
indomethacin, sulindac, tolmetin, zomepirac, nabumetone,
diclofenac, fenclofenac, alclofenac, bromfenac, ibufenac,
aceclofenac, acemetacin, fentiazac, clidanac, etodolac, oxpinac,
mefenamic acid, meclofenamic acid, flufenamic acid, nifluminic
acid, tolfenamic acid, diflunisal, flufenisal, piroxicam,
tenoxicam, lornoxicam, nimesulide, meloxicam, celecoxib and
rofecoxib, or a pharmaceutically acceptable salt of a non-steroidal
anti-inflammatory drug, a cytotoxic antibiotic, apolizumab, 1D09C3,
TIMP-1, TIMP-2, Zinc, P53, Rb, an heterocyclic complex of a
lanthanide, PUVA, an inhibitor of the transcription factor complex
ESX/DRIP130/Sur-2, geldanamycin or its derivative
17-allylaminogeldanamycin (17-AAG), IM-842, tetrathiomolybdate,
squalamine, combrestatin A4, TNP-470, marimastat, neovastat,
bicalutamide, abarelix, oregovomab, mitumomab, TLK-286,
alemtuzumab, ibritumomab, temozolomide, denileukin diftitox,
aldesleukin, dacarbazine, floxuridine, plicamycin, mitotane,
pipobroman, plicamycin, tamloxifen and testolactone.
3. The pharmaceutical combination in accordance with claim 1,
wherein (ii) is selected from paclitaxel (taxol), docetaxel,
taxotere, navelbine, vinblastin, vincristin, vindesine,
vinorelbine, melphalan, cyclophosphamide, an oxazaphosphorine,
cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin,
iproplatin, mitomycin, streptozocin, carmustine (BCNU), lomustine
(CCNU), busulfan, ifosfamide, streptozocin, thiotepa, chlorambucil,
mechlorethamine, thalidomide, its R- and S-enantiomers and its
derivatives, revimid (CC-5013), an ethyleneimine compound, an
alkylsulphonate, daunorubicin, doxorubicin (adriamycin), liposomal
doxorubicin (doxil), epirubicin, idarubicin, mitoxantrone,
amsacrine, dactinomycin, distamycin or a derivative thereof,
netropsin, pibenzimol, mitomycin, CC-1065, a duocarmycin,
mithramycin, chromomycin, olivomycin, a phtalanilide such as
propamidine or stilbamidine, an anthramycin, an aziridine, a
nitrosourea or a derivative thereof, a pyrimidine or purine
analogue, cytarabine, 5-fluorouracile (5-FU), uracil mustard,
fludarabine, gemcitabine, capecitabine, mercaptopurine, cladribine,
thioguanine, methotrexate, pentostatin, hydroxyurea, folic acid, an
acridine or a derivative thereof, a rifamycin, an actinomycin,
adramycin, irinotecan (camptosar), topotecan, an amsacrine or
analogue thereof, a tricyclic carboxamide, SAHA, MD-275,
trichostatin A, CBHA, LAQ824, valproic acid, bortezomib, vatalanib
(PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474,
AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842, GW-786034,
BAY-43-9006, BAY-57-9006, gefitinib, erlotinib, CI-1033, GW-2016,
iressa (ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272,
herceptin,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu-
ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline or a
pharmaceutically acceptable salt thereof, an inhibitor of the
transcription factor complex ESX/DRIP130/Sur-2, heat shock protein
HSP90 modulator geldanamycin and its derivative
17-allylaminogeldanamycin (17-AAG), atrasentan, rituximab,
cetuximab, Avastin.TM. (bevacizumab), IMC-1C11, erbitux (C-225),
DC-101, EMD-72000, vitaxin, imatinib, apolizumab and 1D09C3.
4. The pharmaceutical combination in accordance with any of claims
1 to 3, wherein (i) is the monoethanesulfonate salt of
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone.
5. A pharmaceutical combination preparation kit, comprising a
therapeutically effective amount of: (i)
(Z)-3-(1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-
-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, or a
pharmaceutically acceptable salt thereof; and (ii) at least a
further chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent selected from synthetic small molecule
VEGF receptor antagonists, small molecule growth factor receptor
antagonists, inhibitors of the EGF receptor, excluding
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, and/or
VEGF receptor and/or integrin receptors or any other protein
tyrosine kinase receptors which are not classified under the
synthetic small-molecules, inhibitors directed to EGF receptor
and/or VEGF receptor and/or integrin receptors or any other protein
tyrosine kinase receptors, which are fusion proteins, compounds
which interact with nucleic acids and which are classified as
alkylating agents or platinum compounds, compounds which interact
with nucleic acids and which are classified as anthracyclines, as
DNA intercalators or as DNA cross-linking agents, DNA minor-groove
binding compounds, anti-metabolites, naturally occurring,
semi-synthetic or synthetic bleomycin type antibiotics, inhibitors
of DNA transcribing enzymes selected from topoisomerase I and
topoisomerase II inhibitors, chromatin modifying agents, mitosis
inhibitors, anti-mitotic agents, cell-cycle inhibitors, proteasome
inhibitors, enzymes, hormones, hormone antagonists, hormone
inhibitors, inhibitors of steroid biosynthesis, steroids,
cytokines, hypoxia-selective cytotoxins, inhibitors of cytokines,
lymphokines, antibodies directed against cytokines, oral and
parenteral tolerance induction agents, supportive agents, chemical
radiation sensitizers and protectors, photo-chemically activated
drugs, synthetic poly- or oligonucleotides optionally modified or
conjugated, non-steroidal anti-inflammatory drugs, cytotoxic
antibiotics, antibodies targeting the surface molecules of cancer
cells, inhibitors of metalloproteinases, metals, inhibitors of
oncogenes, inhibitors of gene transcription or of RNA translation
or protein expression, complexes of rare earth elements, and
photo-chemotherapeutic agents; and optionally adapted for a
co-treatment with radiotherapy or radio-immunotherapy,
characterised in that (i) is comprised within a first compartment
and (ii) is comprised within a second compartment, such that the
administration to a patient in need thereof can be simultaneous,
separate or sequential.
6. The pharmaceutical combination preparation kit in accordance
with claim 5, wherein (i) is the monoethanesulfonate salt of
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone.
7. The pharmaceutical combination preparation kit in accordance
with claim 5, wherein(ii) is selected from vatalanib
(PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474,
AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842, GW-786034,
gefitinib, erlotinib, CI-1033 GW-2016, iressa (ZD-1839), tarceva
(OSI-774), PKI-166, EKB-569, HKI-272, herceptin, BAY-43-9006,
BAY-57-9006,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu-
ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline or a
pharmaceutically acceptable salt thereof, atrasentan, rituximab,
cetuximab, Avastin.TM. (bevacizumab), IMC-1C11, erbitux (C-225),
DC-101, EMD-72000, vitaxin, imatinib, VEGFtrap, melphalan,
cyclophosphamide, an oxazaphosphorine, cisplatin, carboplatin,
oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin,
streptozocin, carmustine (BCNU), lomustine (CCNU), busulfan,
ifosfamide, streptozocin, thiotepa, chlorambucil, mechlorethamine,
an ethyleneimine compound, an alkylsulphonate, daunorubicin,
doxorubicin (adriamycin), liposomal doxorubicin (doxil),
epirubicin, idarubicin, mitoxantrone, amsacrine, dactinomycin,
distamycin or a derivative thereof, netropsin, pibenzimol,
mitomycin, CC-1065, a duocarmycin, mithramycin, chromomycin,
olivomycin, propamidine, stilbamidine, an anthramycin, an
aziridine, a nitrosourea or a derivative thereof, cytarabine,
5-fluorouracile (5-FU), uracil mustard, fludarabine, gemcitabine,
capecitabine, mercaptopurine, cladribine, thioguanine,
methotrexate, pentostatin, hydroxyurea, folic acid, a phleomycin, a
bleomycin or a derivative or salt thereof, CHPP, BZPP, MTPP, BAPP,
liblomycin, an acridine or a derivative thereof, a rifamycin, an
actinomycin, adramycin, irinotecan (camptosar), topotecan, an
amsacrine or analogue thereof, a tricyclic carboxamide, SAHA,
MD-275, trichostatin A, CBHA, LAQ824, valproic acid, paclitaxel
(taxol), docetaxel, taxotere, navelbine, vinblastin, vincristin,
vindesine, vinorelbine, colchicine or a derivative thereof,
maytansine, an ansamitocin, rhizoxin, phomopsin, dolastatin, an
epipodophyllotoxin, etoposide, teniposide, a steganacin,
combretastatin, amphetinile, procarbazine, bortezomib,
asparaginase, pegylated asparaginase (pegaspargase),a
thymidine-phosphorylase inhibitor, estramustine (T-66), megestrol,
flutamide, casodex, anandron, cyproterone acetate,
aminogluthetimide, anastrozole, formestan, letrozole leuprorelin,
buserelin, goserelin, triptorelin, tamoxifen or its citrate salt,
droloxifene, trioxifene, raloxifene, zindoxifene, ICI 164,384, ICI
182,780, aminoglutethimide, formestane, fadrozole, finasteride,
ketoconazole, leuprolide, prednisone, prednisolone,
methylprednisolone, dexamethasone, budenoside, fluocortolone,
triamcinolone, interferon 13, IL-10, IL-12, etanercept,
thalidomide, its R- and S-enantiomers and its derivatives, revimid
(CC-5013), a leukotrien antagonist, mitomycin C, an aziridoquinone,
a 2-nitroimidazole, a nitroacridine, a nitroquinoline, a
nitropyrazoloacridine, a "dual-function" nitro aromatic, a nitro
aromatic deactivated mustard, a N-oxide of a nitrogen mustard, a
metal complex of a nitrogen mustard, an anti-CD3 antibody, an
anti-CD25 antibody, a tolerance induction agent, minodronic acid or
a derivative thereof selected from YM-529, Ono-5920 and YH-529,
zoledronic acid monohydrate, ibandronate sodium hydrate, clodronate
disodium, metronidazole, misonidazole, benznidazole, nimorazole,
RSU-1069, SR-4233, bromodeoxyuridine, iododeoxyuridine, WR-2721,
porfimer, photofrin, a benzoporphyrin derivative, a pheophorbide
derivative, merocyanin 540 (MC-540), tin etioporpurin, oblimersen,
a non-steroidal anti-inflammatory drug selected from
acetylsalicyclic acid, mesalazin, ibuprofen, naproxen,
flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen,
pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen,
tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen,
indomethacin, sulindac, tolmetin, zomepirac, nabumetone,
diclofenac, fenclofenac, alclofenac, bromfenac, ibufenac,
aceclofenac, acemetacin, fentiazac, clidanac, etodolac, oxpinac,
mefenamic acid, meclofenamic acid, flufenamic acid, nifluminic
acid, tolfenamic acid, diflunisal, flufenisal, piroxicam,
tenoxicam, lornoxicam, nimesulide, meloxicam, celecoxib and
rofecoxib, or a pharmaceutically acceptable salt of a non-steroidal
anti-inflammatory drug, a cytotoxic antibiotic, apolizumab, 1D09C3,
TIMP-1, TIMP-2, Zinc, P53, Rb, an heterocyclic complex of a
lanthanide, PUVA, an inhibitor of the transcription factor complex
ESX/DRIP130/Sur-2, geldanamycin or its derivative
17-allylaminogeldanamycin (17-AAG), IM-842, tetrathiomolybdate,
squalamine, combrestatin A4, TNP-470, marimastat, neovastat,
bicalutamide, abarelix, oregovomab, mitumomab, TLK-286,
alemtuzumab, ibritumomab, temozolomide, denileukin diftitox,
aldesleukin, dacarbazine, floxuridine, plicamycin, mitotane,
pipobroman, plicamycin, tamloxifen and testolactone.
8. The pharmaceutical combination preparation kit in accordance
with claim 5, wherein(ii) is selected from paclitaxel (taxol),
docetaxel, taxotere, navelbine, vinblastin, vincristin, vindesine,
vinorelbine, melphalan, cyclophosphamide, an oxazaphosphorine,
cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin,
iproplatin, mitomycin, streptozocin, carmustine (BCNU), lomustine
(CCNU), busulfan, ifosfamide, streptozocin, thiotepa, chlorambucil,
mechlorethamine, thalidomide, its R- and S-enantiomers and its
derivatives, revimid (CC-5013), an ethyleneimine compound, an
alkylsulphonate, daunorubicin, doxorubicin (adriamycin), liposomal
doxorubicin (doxil), epirubicin, idarubicin, mitoxantrone,
amsacrine, dactinomycin, distamycin or a derivative thereof,
netropsin, pibenzimol, mitomycin, CC-1065, a duocarmycin,
mithramycin, chromomycin, olivomycin, a phtalanilide such as
propamidine or stilbamidine, an anthramycin, an aziridine, a
nitrosourea or a derivative thereof, a pyrimidine or purine
analogue, cytarabine, 5-fluorouracile (5-FU), uracil mustard,
fludarabine, gemcitabine, capecitabine, mercaptopurine, cladribine,
thioguanine, methotrexate, pentostatin, hydroxyurea, folic acid, an
acridine or a derivative thereof, a rifamycin, an actinomycin,
adramycin, irinotecan (camptosar), topotecan, an amsacrine or
analogue thereof, a tricyclic carboxamide, SAHA, MD-275,
trichostatin A, CBHA, LAQ824, valproic acid, bortezomib, vatalanib
(PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474,
AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842, GW-786034,
BAY-43-9006, BAY-57-9006, gefitinib, erlotinib, CI-1033, GW-2016,
iressa (ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272,
herceptin,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu-
ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline or a
pharmaceutically acceptable salt thereof, an inhibitor of the
transcription factor complex ESX/DRIP130/Sur-2, heat shock protein
HSP90 modulator geldanamycin and its derivative
17-allylaminogeldanamycin (17-AAG), atrasentan, rituximab,
cetuximab, Avastin.TM. (bevacizumab), IMC-1C11, erbitux (C-225),
DC-101, EMD-72000, vitaxin, imatinib, apolizumab and 1D09C3.
9. The pharmaceutical combination preparation kit in accordance
with claim 8, wherein the formulation of the selected protein
tyrosine kinase receptor antagonist is for oral administration.
10. A method of treating cancer diseases, which method comprises
simultaneous, separate or sequential administration of effective
amounts of: (i)
(Z)-3-(1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methy-
l-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
or a pharmaceutically acceptable salt thereof; and (ii) at least a
further chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent selected from synthetic small molecule
VEGF receptor antagonists, small molecule growth factor receptor
antagonists, inhibitors of the EGF receptor, excluding
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, and/or
VEGF receptor and/or integrin receptors or any other protein
tyrosine kinase receptors which are not classified under the
synthetic small-molecules, inhibitors directed to EGF receptor
and/or VEGF receptor and/or integrin receptors or any other protein
tyrosine kinase receptors, which are fusion proteins, compounds
which interact with nucleic acids and which are classified as
alkylating agents or platinum compounds, compounds which interact
with nucleic acids and which are classified as anthracyclines, as
DNA intercalators or as DNA cross-linking agents, DNA minor-groove
binding compounds, anti-metabolites, naturally occurring,
semi-synthetic or synthetic bleomycin type antibiotics, inhibitors
of DNA transcribing enzymes selected from topoisomerase I and
topoisomerase II inhibitors, chromatin modifying agents, mitosis
inhibitors, anti-mitotic agents, cell-cycle inhibitors, proteasome
inhibitors, enzymes, hormones, hormone antagonists, hormone
inhibitors, inhibitors of steroid biosynthesis, steroids,
cytokines, hypoxia-selective cytotoxins, inhibitors of cytokines,
lymphokines, antibodies directed against cytokines, oral and
parenteral tolerance induction agents, supportive agents, chemical
radiation sensitizers and protectors, photo-chemically activated
drugs, synthetic poly- or oligonucleotides optionally modified or
conjugated, non-steroidal anti-inflammatory drugs, cytotoxic
antibiotics, antibodies targeting the surface molecules of cancer
cells, inhibitors of metalloproteinases, metals, inhibitors of
oncogenes, inhibitors of gene transcription or of RNA translation
or protein expression, complexes of rare earth elements, and
photo-chemotherapeutic agents; in the form of a combined
preparation optionally adapted for a co-treatment with radiotherapy
or radio-immunotherapy.
11. The method in accordance with claim 10, wherein(ii) is selected
from vatalanib (PTK-787/ZK222584), SU-5416, SU-6668, SU-11248,
SU-14813, AZD-6474, AZD-2171, CP-547632, CEP-7055, AG-013736,
IM-842, GW-786034, gefitinib, erlotinib, CI-1033 GW-2016, iressa
(ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272, herceptin,
BAY-43-9006, BAY-57-9006,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu-
ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline or a
pharmaceutically acceptable salt thereof, atrasentan, rituximab,
cetuximab, Avastin.TM. (bevacizumab), IMC-1C11, erbitux (C-225),
DC-101, EMD-72000, vitaxin, imatinib, VEGFtrap, melphalan,
cyclophosphamide, an oxazaphosphorine, cisplatin, carboplatin,
oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin,
streptozocin, carmustine (BCNU), lomustine (CCNU), busulfan,
ifosfamide, streptozocin, thiotepa, chlorambucil, mechlorethamine,
an ethyleneimine compound, an alkylsulphonate, daunorubicin,
doxorubicin (adriamycin), liposomal doxorubicin (doxil),
epirubicin, idarubicin, mitoxantrone, amsacrine, dactinomycin,
distamycin or a derivative thereof, netropsin, pibenzimol,
mitomycin, CC-1065, a duocarmycin, mithramycin, chromomycin,
olivomycin, propamidine, stilbamidine, an anthramycin, an
aziridine, a nitrosourea or a derivative thereof, cytarabine,
5-fluorouracile (5-FU), uracil mustard, fludarabine, gemcitabine,
capecitabine, mercaptopurine, cladribine, thioguanine,
methotrexate, pentostatin, hydroxyurea, folic acid, a phleomycin, a
bleomycin or a derivative or salt thereof, CHPP, BZPP, MTPP, BAPP,
liblomycin, an acridine or a derivative thereof, a rifamycin, an
actinomycin, adramycin, irinotecan (camptosar), topotecan, an
amsacrine or analogue thereof, a tricyclic carboxamide, SAHA,
MD-275, trichostatin A, CBHA, LAQ824, valproic acid, paclitaxel
(taxol), docetaxel, taxotere, navelbine, vinblastin, vincristin,
vindesine, vinorelbine, colchicine or a derivative thereof,
maytansine, an ansamitocin, rhizoxin, phomopsin, dolastatin, an
epipodophyllotoxin, etoposide, teniposide, a steganacin,
combretastatin, amphetinile, procarbazine, bortezomib,
asparaginase, pegylated asparaginase (pegaspargase),a
thymidine-phosphorylase inhibitor, estramustine (T-66), megestrol,
flutamide, casodex, anandron, cyproterone acetate,
aminogluthetimide, anastrozole, formestan, letrozole leuprorelin,
buserelin, goserelin, triptorelin, tamoxifen or its citrate salt,
droloxifene, trioxifene, raloxifene, zindoxifene, ICI 164,384, ICI
182,780, aminoglutethimide, formestane, fadrozole, finasteride,
ketoconazole, leuprolide, prednisone, prednisolone,
methylprednisolone, dexamethasone, budenoside, fluocortolone,
triamcinolone, interferon 13, IL-10, IL-12, etanercept,
thalidomide, its R- and S-enantiomers and its derivatives, revimid
(CC-5013), a leukotrien antagonist, mitomycin C, an aziridoquinone,
a 2-nitroimidazole, a nitroacridine, a nitroquinoline, a
nitropyrazoloacridine, a "dual-function" nitro aromatic, a nitro
aromatic deactivated mustard, a N-oxide of a nitrogen mustard, a
metal complex of a nitrogen mustard, an anti-CD3 antibody, an
anti-CD25 antibody, a tolerance induction agent, minodronic acid or
a derivative thereof selected from YM-529, Ono-5920 and YH-529,
zoledronic acid monohydrate, ibandronate sodium hydrate, clodronate
disodium, metronidazole, misonidazole, benznidazole, nimorazole,
RSU-1069, SR-4233, bromodeoxyuridine, iododeoxyuridine, WR-2721,
porfimer, photofrin, a benzoporphyrin derivative, a pheophorbide
derivative, merocyanin 540 (MC-540), tin etioporpurin, oblimersen,
a non-steroidal anti-inflammatory drug selected from
acetylsalicyclic acid, mesalazin, ibuprofen, naproxen,
flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen,
pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen,
tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen,
indomethacin, sulindac, tolmetin, zomepirac, nabumetone,
diclofenac, fenclofenac, alclofenac, bromfenac, ibufenac,
aceclofenac, acemetacin, fentiazac, clidanac, etodolac, oxpinac,
mefenamic acid, meclofenamic acid, flufenamic acid, nifluminic
acid, tolfenamic acid, diflunisal, flufenisal, piroxicam,
tenoxicam, lornoxicam, nimesulide, meloxicam, celecoxib and
rofecoxib, or a pharmaceutically acceptable salt of a non-steroidal
anti-inflammatory drug, a cytotoxic antibiotic, apolizumab, 1D09C3,
TIMP-1, TIMP-2, Zinc, P53, Rb, an heterocyclic complex of a
lanthanide, PUVA, an inhibitor of the transcription factor complex
ESX/DRIP130/Sur-2, geldanamycin or its derivative
17-allylaminogeldanamycin (17-AAG), IM-842, tetrathiomolybdate,
squalamine, combrestatin A4, TNP-470, marimastat, neovastat,
bicalutamide, abarelix, oregovomab, mitumomab, TLK-286,
alemtuzumab, ibritumomab, temozolomide, denileukin diftitox,
aldesleukin, dacarbazine, floxuridine, plicamycin, mitotane,
pipobroman, plicamycin, tamloxifen and testolactone.
12. The method in accordance with claim 10, wherein(ii) is selected
from paclitaxel (taxol), docetaxel, taxotere, navelbine,
vinblastin, vincristin, vindesine, vinorelbine, melphalan,
cyclophosphamide, an oxazaphosphorine, cisplatin, carboplatin,
oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin,
streptozocin, carmustine (BCNU), lomustine (CCNU), busulfan,
ifosfamide, streptozocin, thiotepa, chlorambucil, mechlorethamine,
thalidomide, its R- and S-enantiomers and its derivatives, revimid
(CC-5013), an ethyleneimine compound, an alkylsulphonate,
daunorubicin, doxorubicin (adriamycin), liposomal doxorubicin
(doxil), epirubicin, idarubicin, mitoxantrone, amsacrine,
dactinomycin, distamycin or a derivative thereof, netropsin,
pibenzimol, mitomycin, CC-1065, a duocarmycin, mithramycin,
chromomycin, olivomycin, a phtalanilide such as propamidine or
stilbamidine, an anthramycin, an aziridine, a nitrosourea or a
derivative thereof, a pyrimidine or purine analogue, cytarabine,
5-fluorouracile (5-FU), uracil mustard, fludarabine, gemcitabine,
capecitabine, mercaptopurine, cladribine, thioguanine,
methotrexate, pentostatin, hydroxyurea, folic acid, an acridine or
a derivative thereof, a rifamycin, an actinomycin, adramycin,
irinotecan (camptosar), topotecan, an amsacrine or analogue
thereof, a tricyclic carboxamide, SAHA, MD-275, trichostatin A,
CBHA, LAQ824, valproic acid, bortezomib, vatalanib
(PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474,
AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842, GW-786034,
BAY-43-9006, BAY-57-9006, gefitinib, erlotinib, CI-1033, GW-2016,
iressa (ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272,
herceptin,
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu-
ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline or a
pharmaceutically acceptable salt thereof, an inhibitor of the
transcription factor complex ESX/DRIP130/Sur-2, heat shock protein
HSP90 modulator geldanamycin and its derivative
17-allylaminogeldanamycin (17-AAG), atrasentan, rituximab,
cetuximab, Avastin.TM. (bevacizumab), IMC-1C11, erbitux (C-225),
DC-101, EMD-72000, vitaxin, imatinib, apolizumab and 1D09C3.
13. The method in accordance with any one of claims 10 to 12,
characterised in that (i) is the monoethanesulfonate salt of
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone.
14. The method in accordance with claim 10, wherein the formulation
of (i) is for oral administration.
15. The method in accordance with claim 10, characterised in that
(i) is administered in a daily dosage such that the plasma level of
the active substance lies between 10 and 500 ng/ml for at least 12
hours of a 24 hours dosing interval.
16. The method in accordance with claim 10, wherein the cancer
disease is selected from prostate cancer, renal cell cancers,
bladder cancers, ovarian cancers, cervical cancers, endometrial
cancers, lung cancer, colorectal cancers, pancreatic cancer,
gastric cancer, oesophageal cancers, hepatocellular cancers,
cholangiocellular cancers, head and neck cancer, malignant
mesothelioma, breast cancer, malignant melanoma or bone and soft
tissue sarcomas, multiple myeloma, acute myelogenous leukemia,
chronic myelogenous leukemia, myelodysplastic syndrome and acute
lymphoblastic leukemia.
17. The method in accordance with claim 16, wherein the cancer
disease is selected from colorectal cancers.
Description
FIELD OF THE INVENTION
[0001] This invention relates to a method for the treatment of
diseases involving cell proliferation, migration or apoptosis of
myeloma cells, or angiogenesis, which method comprises
co-administration to a person in need of such treatment and/or
co-treatment of a person in need of such treatment with effective
amounts of: [0002] (i) a selected protein tyrosine kinase receptor
antagonist; and [0003] (ii) at least a further chemotherapeutic or
naturally occurring, semi-synthetic or synthetic therapeutic agent;
and/or [0004] (iii) radiotherapy or radio-immunotherapy.
[0005] This invention relates also to suitable pharmaceutical
compositions comprising effective amounts of: [0006] (i) a selected
protein tyrosine kinase receptor antagonist; and [0007] (ii) at
least a further chemotherapeutic or naturally occurring,
semi-synthetic or synthetic therapeutic agent; and optionally
adapted for a co-treatment with radiotherapy or
radio-immunotherapy, as a combined preparation for simultaneous,
separate or sequential use in the treatment of diseases involving
cell proliferation, migration or apoptosis of myeloma cells, or
angiogenesis, and especially for inhibiting tumour growth, survival
and metastasis.
[0008] This invention relates also to the combined use of effective
amounts of: [0009] (i) a selected protein tyrosine kinase receptor
antagonist; and [0010] (ii) at least a further chemotherapeutic or
naturally occurring, semi-synthetic or synthetic therapeutic agent;
for the manufacture of a pharmaceutical combined preparation for
simultaneous, separate or sequential use in the treatment of
diseases involving cell proliferation, migration or apoptosis of
myeloma cells, or angiogenesis, and especially for inhibiting
tumour growth, survival and metastasis, optionally in combination
with a co-treatment with radiotherapy or radio-immunotherapy.
[0011] This invention relates also to the use of an effective
amount of a selected protein tyrosine kinase receptor antagonist,
for the manufacture of a pharmaceutical composition adapted for a
simultaneous, separate or sequential co-treatment with radiotherapy
or radio-immunotherapy of diseases involving cell proliferation,
migration or apoptosis of myeloma cells, or angiogenesis, and
especially for inhibiting tumour growth, survival and
metastasis.
BACKGROUND OF THE INVENTION
[0012] In the last decade, the biological activity of several types
and sub-types of the protein tyrosin kinase receptor family have
been characterised such as, for example, the epidermal growth
factor receptor EGFR and its subtypes ErbB-2 and ErbB-4 (Brignola
et al., Journal of Biological Chemistry, Vol. 277, No. 2, pp.
1576-1585, 2002) or the vascular endothelial growth factor
receptors VEGFR 1-3 together with its ligand VEGF and its four
sub-types known to date (Jung et al., European Journal of Cancer,
Vol. 38, pp. 1133-1140, 2002). Similar studies reported in previous
reports show that the overexpression of some of these receptors is
implicated in multiple forms of cancer. For example, studies have
provided evidence that the epidermal growth factor EGF acts as a
growth factor in tumours, and that the vascular endothelial growth
factor VEGF is one of the most common mediators of tumor
angiogenesis, which is essential for the growth and metastasis of
solid tumours. Inhibitors of the receptors have thus been and are
still evaluated for cancer therapy (see for example the article of
Cerrington et al. In Advances in Cancer Research, Academic Press
2000, pp. 1-38).
[0013] Recent studies have also suggested to combine several
receptor antagonists together, or in further combination with a
chemotherapeutic agent or radiation. For example, WO 02/070008
suggests the combination of an antagonist specifically directed
against the VEGF receptor with an antagonist specifically directed
against the EGF receptor, optionally together with radiation or a
chemotherapeutic agent, for the inhibition of tumour growth. As
example of suitable specific antagonists, WO 02/070008 discloses
monoclonal antibodies directed against the VEGF receptor and
monoclonal antibodies directed against the EGF receptor.
[0014] Thus, a large number of protein tyrosine kinase receptor
antagonists are currently in clinical development for the treatment
of cancer (see for example the Expert Opinion Review of Laid &
Cherrington in Expert Opin. Invest. Drugs, Vol. 12, No. 1, pp.
51-64, 2003). However, proof of efficacy for these substances, used
alone or with other cancer therapies, in the treatment of
oncological diseases, has so far not been achieved, either because
of a lack of additional benefit over the standard therapy or
because of the discovery of unacceptable side-effects.
[0015] For example, it has been recently published that an
angiogenesis inhibitor which has already been clinically tested,
also in conjunction with chemotherapy, namely the inhibitor with
code name SU5416, developed by Pharmacia for the treatment of
cancer, was associated with disturbing side effect, namely
thromboembolic events (Ken Garber and Ann Arbor, Nature
Biotechnology, Vol. 20, pp. 1067-1068, November 2002).
[0016] For the treatment of diseases of oncological nature, a large
number of chemotherapeutic agents have already been suggested,
which can be used as mono-therapy (treatment with one agent) or as
combination therapy (simultaneous, separate or sequential treatment
with more than one agent) and/or which may be combined with
radiotherapy or radio-immunotherapy. In this respect,
chemotherapeutic agent means a naturally occurring, semi-synthetic
or synthetic chemical compound which, alone or via further
activation, for example with radiations in the case of
radio-immunotherapy, inhibits or kills growing cells, and which can
be used or is approved for use in the treatment of diseases of
oncological nature, which are commonly also denominated as cancers.
In the literature, these agents are generally classified according
to their mechanism of action. In this matter, reference can be
made, for example, to the classification made in "Cancer
Chemotherapeutic Agents", American Chemical Society, 1995, W. O.
Foye Ed.
[0017] Thus, within the meaning of the present invention, the
following classes of chemotherapeutic agents are especially of
interest, although not representing a limitation: [0018] Synthetic
small molecule VEGF receptor antagonists [0019] Small molecule
growth factor (GF) receptor antagonists [0020] Inhibitors of the
EGF receptor and/or VEGF receptor and/or integrin receptors or any
other protein tyrosine kinase receptors, which are not classified
under the synthetic small-molecules [0021] Inhibitors directed to
EGF receptor and/or VEGF receptor and/or integrin receptors or any
other protein tyrosine kinase receptors, which are fusion proteins
[0022] Compounds which interact with nucleic acids and which are
classified as alkylating agents or platinum compounds [0023]
Compounds which interact with nucleic acids and which are
classified as anthracyclines, as DNA intercalators or as DNA
cross-linking agents [0024] Anti-metabolites [0025] Naturally
occurring, semi-synthetic or synthetic bleomycin type antibiotics
(BLM-group antibiotics) [0026] Inhibitors of DNA transcribing
enzymes, especially topoisomerase I or topoisomerase II inhibitors
[0027] Chromatin modifying agents [0028] Mitosis inhibitors,
anti-mitotic agents, or cell-cycle inhibitors [0029] Proteasome
inhibitors [0030] Enzymes [0031] Hormones, hormone antagonists or
hormone inhibitors, or inhibitors of steroid biosynthesis [0032]
Steroids [0033] Cytokines, hypoxia-selective cytotoxins, inhibitors
of cytokines, lymphokines, antibodies directed against cytokines or
oral and parenteral tolerance induction strategies [0034]
Supportive agents [0035] Chemical radiation sensitizers and
protectors [0036] Photochemically activated drugs [0037] Synthetic
poly- or oligonucleotides [0038] Other chemotherapeutic or
naturally occurring, semi-synthetic or synthetic therapeutic
agents, such as cytotoxic antibiotics, antibodies targeting surface
molecules of cancer cells, inhibitors of metalloproteinases,
inhibitors of oncogenes, inhibitors of gene transcription or of RNA
translation or protein expression, or complexes of rare earth
elements
[0039] Further classes of compounds, so-far not classified as
chemotherapeutic agents, which are naturally occurring,
semi-synthetic or synthetic therapeutic agents, such as the
non-steroidal anti-inflammatory drugs, especially the
cyclooxygenase (COX) inhibitors and more specifically the COX-2
inhibitors, are also of interest for combination therapies.
[0040] Even if the concept of combining several therapeutic agents
or therapies already has been suggested, and although various
combination therapies are under investigation and in clinical
trials, there is still a need for new and efficient therapeutic
agents for the treatment of diseases in which cell proliferation,
migration or apoptosis of myeloma cells, or angiogenesis, and there
is still a need to develop further combinations which can show
increased efficacy and reduced side-effects.
[0041] These diseases may as well be of oncological nature, which
includes all types of malignant neoplasias or cancers, or of
non-oncological nature, such as diabetic retinopathy, rheumatoid
arthritis or psoriasis.
SUMMARY OF THE INVENTION
[0042] It has now been found that co-administration to a person in
need of such treatment and/or co-treatment of a person in need of
such treatment with effective amounts of [0043] (i) a selected
protein tyrosine kinase receptor antagonist, and [0044] (ii) at
least a further chemotherapeutic or naturally occurring,
semi-synthetic or synthetic therapeutic agent, and/or [0045] (iii)
radiotherapy or radioimmunotherapy, provides unexpected advantages
in the treatment of diseases in which cell proliferation, migration
or apoptosis of myeloma cells, or angiogenesis are involved, to a
person in need of such treatment, with high efficacy, in comparison
to administration of any of these substances alone and/or treatment
with radiotherapy or radioimmunotherapy.
[0046] It has been further found that this co-administration or
co-treatment is especially efficient if the selected protein
tyrosine kinase receptor antagonist is an antagonist of at least
one receptor selected from VEGFR1 to 3, PDGFR.alpha. and .beta.,
FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit.
[0047] It has been further found that this co-administration or
co-treatment is especially efficient if the selected protein
tyrosine kinase receptor antagonist is an antagonist of at least
one receptor selected from VEGFR 1 to 3, PDGFR.alpha. and .beta.,
FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, and further an
antagonist of a src tyrosine kinase family member, and especially
of src, lck, lyn and fyn, and/or further an antagonist of at least
one complex of a cyclin dependent kinase with its specific cyclin
or with a viral cyclin, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6,
CDK7, CDK8 and CDK9 with their specific cyclins A, B1, B2, C, D1,
D2, D3, E, F, G1, G2, H, I and K, and/or further an inhibitor of
the paracrine IL-6 secretion.
[0048] Further it has been found that the diseases which can be
treated by the combination in accordance with the present invention
are all kind of diseases in which cell proliferation, migration or
apoptosis of myeloma cells, or angiogenesis are involved, which can
be of oncological nature such as all types of malignant neoplasias
or cancers, or of non-oncological nature, such as diabetic
retinopathy, rheumatoid arthritis, or psoriasis.
[0049] Further it has been found that the combination treatment in
accordance with the present invention is especially efficient for
inhibiting tumour growth, survival and metastasis.
[0050] Further it has been found that the combination treatment in
accordance with the present invention is especially efficient with
selected active substances, selected dosages and selected dosage
forms.
[0051] Thus, the present invention provides a method for the
treatment of diseases involving cell proliferation, migration or
apoptosis of myeloma cells, or angiogenesis, which method comprises
simultaneous, separate or sequential co-administration of effective
amounts of: [0052] (i) an antagonist of at least one receptor
selected from VEGFR 1 to 3, PDGGR.alpha. and .beta., FGFR1, 2 and
3, EGFR, HER2, IGF1R, HGFR or c-Kit, which is further an antagonist
of a src tyrosine kinase family member, or a polymorph, metabolite
or pharmaceutically acceptable salt thereof; and [0053] (ii) at
least a further chemotherapeutic or naturally occurring,
semi-synthetic or synthetic therapeutic agent; in the form of a
combined preparation, optionally adapted for a co-treatment with
radiotherapy or radio-immunotherapy, to a person in need of such
treatment.
[0054] The present invention provides also a method for the
treatment of diseases involving cell proliferation, migration or
apoptosis of myeloma cells, or angiogenesis, which method comprises
a simultaneous, separate or sequential co-treatment with an
effective amount of an antagonist of at least one receptor selected
from VEGFR 1 to 3, PDGFR.alpha. and .beta., FGFR1, 2 and 3, EGFR,
HER2, IGF1R, HGFR or c-Kit, which is further an antagonist of a src
tyrosine kinase family member, or with a polymorph, metabolite or
pharmaceutically acceptable salt thereof, and with radiotherapy or
radio-immunotherapy.
[0055] The protein tyrosine kinase receptor antagonist used in the
method in accordance with the present invention is preferably an
antagonist of at least one receptor selected from VEGFR 1 to 3,
PDGFR .alpha. and .beta., FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR,
c-Kit, and further an antagonist of a src-tyrosine kinase family
member, and especially of src, lck, lyn or fyn.
[0056] In a further preferred embodiment, the protein tyrosine
kinase receptor antagonist may further be an antagonist of at least
one complex of a cyclin dependent kinase with its specific cyclin
or with a viral cyclin, such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6,
CDK7, CDK8 and CDK9 with their specific cyclins A, B1, B2, C, D1,
D2, D3, E, F, G1, G2, H, I and K, and/or further an inhibitor of
the paracrine IL-6 secretion.
[0057] In one preferred embodiment, the protein tyrosine kinase
receptor antagonist is selected from specific compounds.
[0058] The further chemotherapeutic or naturally occurring,
semi-synthetic or synthetic therapeutic agent used in the method in
accordance with the present invention can be any available
chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent, and more particularly the
chemotherapeutic agents which are commonly used for the treatment
of cancer. Preferred chemotherapeutic agents are selected from the
following groups: synthetic small molecule VEGF receptor
antagonists, small molecule growth factor (GF) receptor
antagonists, inhibitors of the EGF receptor and/or VEGF receptor
and/or integrin receptors or any other protein tyrosine kinase
receptors which are not classified under the synthetic
small-molecules, inhibitors directed to EGF receptor and/or VEGF
receptor and/or integrin receptors or any other protein tyrosine
kinase receptors, which are fusion proteins, compounds which
interact with nucleic acids and which are classified as alkylating
agents or platinum compounds, compounds which interact with nucleic
acids and which are classified as anthracyclines, as DNA
intercalators (including DNA minor-groove binding compounds) or as
DNA cross-linking agents, anti-metabolites, naturally occurring,
semi-synthetic or synthetic bleomycin type antibiotics (BLM-group
antibiotics), inhibitors of DNA transcribing enzymes, and
especially the topoisomerase I or topoisomerase II inhibitors,
chromatin modifying agents, mitosis inhibitors, anti-mitotic
agents, cell-cycle inhibitors, proteasome inhibitors, enzymes,
hormones, hormone antagonists or hormone inhibitors, or inhibitors
of steroid biosynthesis, steroids, cytokines, hypoxia-selective
cytotoxins, inhibitors of cytokines, lymphokines, antibodies
directed against cytokines or oral and parenteral tolerance
induction strategies, supportive agents, chemical radiation
sensitizers and protectors, photochemically activated drugs,
synthetic poly- or oligonucleotides, optionally modified or
conjugated, non-steroidal anti-inflammatory drugs, cytotoxic
antibiotics, antibodies targeting surface molecules of cancer
cells, inhibitors of metalloproteinases, metals, inhibitors of
oncogenes, inhibitors of gene transcription or of RNA translation
or protein expression, complexes of rare earth elements, or
photo-chemotherapeutic agents.
[0059] In one preferred embodiment, amongst the chemotherapeutic or
naturally occurring, semi-synthetic or synthetic therapeutic
agents, specific compounds are preferred.
[0060] In one embodiment, the disease treated in the method in
accordance with the present invention is preferably an oncological
disease. In a preferred embodiment, the disease is selected from
solid tumours, such as urogenital cancers (such as prostate cancer,
renal cell cancers, bladder cancers), gynecological cancers (such
as ovarian cancers, cervical cancers, endometrial cancers), lung
cancer, gastrointestinal cancers (such as colorectal cancers,
pancreatic cancer, gastric cancer, oesophageal cancers,
hepatocellular cancers, cholangiocellular cancers), head and neck
cancer, malignant mesothelioma, breast cancer, malignant melanoma
or bone and soft tissue sarcomas, and haematologic neoplasias, such
as multiple myeloma, acute myelogenous leukemia, chronic
myelogenous leukemia, myelodysplastic syndrome and acute
lymphoblastic leukemia. In a preferred embodiment, the disease is
hormone sensitive or hormone refractory prostate cancer, ovarian
carcinoma, or small cell lung cancer.
[0061] In another embodiment, the disease treated in the method in
accordance with the present invention is preferably a
non-oncological disease selected from diabetic retinopathy,
rheumatoid arthritis or psoriasis.
[0062] Thus, the beneficial efficacy of the methods in accordance
with the invention are mainly based on the additive and synergistic
effects of the combined treatment, or to an improved tolerability
of the treatment by the patient due, for example, to the
administration of lower doses of the therapeutic agents
involved.
[0063] The unexpected advantages mentioned above may also be due to
a more efficient apoptosis induction by the chemotherapeutic agent,
once the constitutively active survival signal of the protein
tyrosin kinase receptor, mediated by the tumour, is inhibited by
the selected protein tyrosine kinase receptor antagonist.
[0064] In the case of the use of an antagonist of protein tyrosine
kinase receptors or an inhibitor of other mediators involved in
angiogenesis, such as for example the vascular endothelial growth
factors (VEGF), the vascular permeability factors, the basic
fibroblast growth factor (bFGF), interleukin-6 (IL-6) or
interleukin-8 (IL-8), the epidermal growth factor (EGF) or the
platelet-derived growth factor (PDGF), one of the advantages of the
method and composition in accordance with the present invention
lies in a targeting of the treatment to tumour-associated
vasculature rather than, or together with, the tumour itself, in
order to cut the energy supply of cancerous cells.
[0065] A further advantage is that an induction or reinstatement of
the sensitivity towards the chemotherapeutic agent is expected in
patients treated with the combination of chemotherapeutic agents
for which the sensitivity gets lost in the course of the treatment
and of a VEGFR antagonist. This is especially the case of patients
suffering from refractory multiple myeloma and treated with
steroids as chemotherapeutic agent. A combination treatment with
steroids and a VEGFR antagonist is expected to restore the steroid
sensitivity of patients suffering from refractory multiple
myeloma.
[0066] According to the present invention, a synergistic combined
preparation is meant to comprise an amount of the selected protein
tyrosine kinase receptor antagonist, or of a polymorph, metabolite
or pharmaceutically acceptable salt of this active compound, and an
amount of the further chemotherapeutic or naturally occurring,
semi-synthetic or synthetic therapeutic agent, and/or radiotherapy
or radio-immunotherapy, wherein the amount of the individual
therapeutic agents alone is insufficient to achieve the therapeutic
effect achieved by the administration of the combination of said
therapeutic agents, and wherein the combined effects of the amounts
of the therapeutic agents is greater than the sum of the
therapeutic effects achievable with the amounts of the individual
therapeutic agents.
[0067] Viewed from a different aspect, the present invention also
relates to a pharmaceutical combination for the treatment of
diseases in which cell proliferation, migration or apoptosis of
myeloma cells, or angiogenesis are involved, comprising a selected
specific protein tyrosine kinase receptor antagonist and a further
chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent, and/or radiotherapy or
radio-immunotherapy, as a combined preparation for simultaneous,
separate or sequential use in treatment of said diseases,
optionally together with one or more pharmaceutically acceptable
diluents and/or carriers.
[0068] Viewed from a different aspect, the present invention also
relates to a pharmaceutical combination preparation kit for the
treatment of diseases involving cell proliferation, migration or
apoptosis of myeloma cells, or angiogenesis, comprising a
therapeutically effective amount of a selected protein tyrosine
kinase receptor antagonist, or of a polymorph, metabolite or
pharmaceutically acceptable salt thereof, and a therapeutically
effective amount of a further chemotherapeutic or naturally
occurring, semi-synthetic or synthetic therapeutic agent,
characterised in that the protein tyrosine kinase receptor
antagonist is comprised within a first compartment and the further
chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent is comprised within a second
compartment, such that the administration to a patient in need
thereof can be simultaneous, separate or sequential, said
combination preparation kit being optionally further adapted for a
co-treatment with radiotherapy or radio-immunotherapy.
[0069] In one embodiment in accordance with the present invention,
in each compartment of the pharmaceutical combination preparation
kit, each active substance is formulated for an oral
administration.
[0070] Viewed from a further aspect, the present invention thus
also provides the use of a selected protein tyrosine kinase
receptor antagonist in combination with a further chemotherapeutic
or naturally occurring, semi-synthetic or synthetic therapeutic
agent, and/or adapted for a co-treatment with radiotherapy or
radio-immunotherapy, for the manufacture of a pharmaceutical
combination preparation for the treatment of the diseases or
indications mentioned hereinbefore.
[0071] Within the meaning of the present invention, effective
amounts of therapeutic agents and/or of a therapeutic treatment by
radiotherapy or radio-immunotherapy means amounts of the agents
and/or of the treatment by radiotherapy or radio-immunotherapy
which are effective to achieve a therapeutic effect when used in
combination.
DETAILED DESCRIPTION OF THE INVENTION
[0072] The diseases
[0073] As already mentioned hereinbefore, the diseases which can be
treated by the combination in accordance with the present invention
are all kind of diseases in which cell proliferation, migration or
apoptosis of myeloma cells, or angiogenesis are involved, which can
be of oncological nature such as all types of malignant neoplasias
or cancers, or of non-oncological nature, such as diabetic
retinopathy, rheumatoid arthritis, or psoriasis. Among cancers,
selected specific target indications are solid tumours, such as
urogenital cancers (such as prostate cancer, renal cell cancers,
bladder cancers), gynecological cancers (such as ovarian cancers,
cervical cancers, endometrial cancers), lung cancer,
gastrointestinal cancers (such as colorectal cancers, pancreatic
cancer, gastric cancer, oesophageal cancers, hepatocellular
cancers, cholangiocellular cancers), head and neck cancer,
malignant mesothelioma, breast cancer, malignant melanoma or bone
and soft tissue sarcomas, and haematologic neoplasias, such as
multiple myeloma, acute myelogenous leukemia, chronic myelogenous
leukemia, myelodysplastic syndrome and acute lymphoblastic
leukemia.
[0074] The combination treatment in accordance with the present
invention is especially efficient for inhibiting tumour growth,
survival and metastasis.
[0075] Of special interest for the combination treatment is the
treatment of hormone sensitive or hormone refractory prostate
cancer, ovarian carcinoma, non small cell lung cancer, small cell
lung cancer, or multiple myeloma. [0076] The selected protein
tyrosine kinase receptor antagonist
[0077] As already mentioned hereinbefore, the selected protein
tyrosine kinase receptor antagonists that can be used in the
context of the present invention include all substances that
inhibit the stimulation or activation of a protein tyrosine kinase
receptor by a protein tyrosine kinase receptor ligand. In the case
of a protein tyrosine kinase receptor belonging to the family of
the growth factor receptors, such inhibition of stimulation or
activation inhibits the growth of cells that express the
receptor.
[0078] Some examples of growth factor receptors involved in
tumorigenesis are the receptors for epidermal growth factor (EGFR),
vascular endothelial growth factors (VEGFRs), platelet-derived
growth factor (PDGFR), insulin-like growth factor (IGFR), nerve
growth factor (NGFR), and fibroblast growth factor (FGFR).
[0079] By inhibition of stimulation or activation of protein
tyrosine kinase receptor is meant any decrease in the activation of
the receptor, which need not completely prevent or stop activation
of the receptor.
[0080] Moreover, inhibition of the receptor stimulation or
activation, as defined by the present invention, means inhibition
resulting from interaction of the antagonist and the receptor or
its ligand. By interaction is meant sufficient physical or chemical
interaction between the antagonist and the receptor, such that
protein tyrosin kinase activity is inhibited. One of skill in the
art would appreciate that examples of such chemical interactions,
which include association or bonding, are known in the art and
include covalent bonding, ionic bonding, hydrogen bonding, etc. . .
. , between the antagonist and the receptor or its ligand.
[0081] Increased protein tyrosine kinase receptor stimulation or
activation can result from higher levels of ligand, receptor gene
amplification, increased transcription of the receptor or mutations
that cause unregulated receptor signalling. Amplification of the
gene encoding the receptor results in an increased number of
ligands binding to the receptor, which can further stimulate cell
proliferation. The protein tyrosine kinase receptor may also be
over-expressed in the absence of gene amplification, presumably
through mutations that increase its transcription, mRNA
translation, or stability of the protein. Protein tyrosine kinase
receptor mutants of the EGFR type have already been identified in
gliomas, non-small cell lung carcinomas, ovarian carcinomas and
prostate carcinomas, that have a constitutively active protein
tyrosin kinase, suggesting a role for high-level EGFR activity
rather than EGFR over-expression in these cancers (see for example
Pedersen et al., Ann. Oncol., Vol. 12(6), pp. 745-60, 2001).
[0082] In one embodiment in accordance with the present invention,
the selected protein tyrosine kinase receptor antagonist inhibits
the binding of the protein tyrosine kinase receptor to its
ligand.
[0083] Binding of a ligand to an external, extracellular domain of
the receptor stimulates receptor dimerization, autophosphorylation
of the receptor, activation of the receptor's internal, cytoplasmic
protein tyrosin kinase domain, and initiation of multiple signal
transduction pathways involved in regulation of DNA synthesis, cell
division, vasculogenesis or angiogenesis. The inhibition produced
by the presence of the antagonist will consequently reduce this
stimulation.
[0084] In another embodiment in accordance with the present
invention, the selected protein tyrosine kinase receptor antagonist
binds directly to the receptor. The antagonist can bind externally
to the extra-cellular portion of the receptor, which may or may not
inhibit binding of the ligand, or internally to the protein
tyrosine kinase domain. Examples of such antagonists include,
without limitation, biological molecules, such as antibodies (and
functional equivalents thereof) specific for the receptor, and
synthetic kinase inhibitors that act directly on the cytoplasmic
domain of the receptor, such as the so-called "small molecule
tyrosine kinase inhibitors". A non-exhaustive list of small
molecule tyrosine kinase inhibitors can be found in the review
article of Laid & Cherrington, Expert Opinion Invest. Drugs,
Vol. 12, No. 1, 2003, the content of which is incorporated herein
by reference.
[0085] Additional protein tyrosine kinase receptor antagonists can
easily be determined using well-known methods. The selected
receptor antagonists to be used in the present invention inhibit
the protein tyrosin kinase activity of the receptor, which
generally involves phosphorylation events. Accordingly,
phosphorylation assays may for example be useful in determining
antagonists useful in the context of the present invention. In
addition, methods specific for detection of the receptor expression
can be utilized. These include immunohistochemistry for detection
of protein expression, fluorescence in situ hybridization for
detection of gene amplification, competitive radioligand binding
assays, solid matrix blotting techniques, such as Northern and
Southern blots, reverse transcriptase polymerase chain reaction and
ELISA.
[0086] In accordance with the present invention, the selected
protein tyrosine kinase receptor antagonist is preferably an
antagonist of at least one receptor selected from VEGFR 1 to 3,
PDGFR .alpha. and .beta., FGFR1,2 and 3, EGFR, HER2, IGF1R, HGFR,
c-Kit, and further an antagonist of one of the src-tyrosine kinase
family members, and especially src, lck, lyn or fyn, or a
polymorph, metabolite or pharmaceutically acceptable salt thereof.
The selected protein tyrosine kinase receptor antagonist may
further be an antagonist of at least one complex of a cyclin
dependent kinase with its specific cyclin or with a viral cyclin,
such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9
with their specific cyclins A, B1, B2, C, D1, D2, D3, E, F, G1, G2,
H, I and K, and/or further an inhibitor of the paracrine IL-6
secretion.
[0087] In a further embodiment in accordance with the present
invention, the combination of the active substances is intended for
the treatment of oncological diseases involving angiogenesis.
[0088] Tumour angiogenesis plays an important role in the
progression of human malignancies. Inhibition of this process is
thought to be an excellent point of therapeutic intervention in the
treatment of cancer. Signal transduction through the vascular
endothelial growth factor receptor 2 (VEGFR-2) has been shown to
play a pivotal role in the proliferation, survival and migration of
endothelial cells in tumour angiogenesis.
[0089] In this matter, potent and orally available low molecular
weight antagonists of VEGFR-2 have been developed as new compounds
which are useful for the treatment of diseases involving cell
proliferation, migration or apoptosis of myeloma cells, or
angiogenesis, and especially as new cancer therapeutic agents.
These antagonists are thus inhibitors of the activity of the
receptor. Some of these antagonists are also antagonists of further
growth factor receptors, such as VEGFR-3, PDGFR .alpha. and .beta.,
FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR, c-Kit, and some also
antagonists of the src-tyrosine kinase family members src, lck, lyn
and fyn.
[0090] These compounds are disclosed in WO 02/36564, WO 99/52869,
WO 00/18734, WO 00/73297, WO 01/27080, WO 01/27081 and WO 01/32651
The cited documents are herewith incorporated by reference with
respect to any aspects disclosed relating to these specific
compounds.
[0091] The following compounds are particularly representative and
are all combined inhibitors of VEGFR-2 and lck which may be used as
the selected protein tyrosine kinase receptor antagonist within the
meaning of the present invention. [0092] (A)
(Z)-3-(1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulfonyl-amino)-phenylamin-
o)-1-phenyl-methylene)-2-indolinone; [0093] (B)
(Z)-3-(1-(4-(N-(3-dimethylaminopropyl)-N-propionyl-amino)-phenylamino)-1--
phenyl-methylene)-2-indolinone; [0094] (C)
(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-5-(but-
ylcarbamoyl)-2-indolinone; [0095] (D)
(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cycl-
ohexylmethyl-carbamoyl)-2-indolinone; [0096] (E)
(Z)-3-(1-(4-(N-methylsulfonyl-N-(2-dimethylamino-ethyl)-amino)-phenylamin-
o)-1-phenyl-methylen)-5-(cyclohexylmethyl-carbamoyl)-2-indolinone;
[0097] (F)
(Z)-3-(1-(4-(butylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cyc-
lohexylmethyl-carbamoyl)-2-indolinone; [0098] (G)
(Z)-3-(1-(4-(pyrrolidin-1-yl-methyl)-phenylamino)-1-phenyl-methylen)-5-(c-
yclohexylmethyl-carbamoyl)-2-indolinone; [0099] (H)
(Z)-3-(1-(4-(diethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(cyclo-
hexylmethyl-carbamoyl)-2-indolinone; [0100] (I)
(Z)-3-(1-(4-(diethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3--
chlorobenzyl)-carbamoyl)-2-indolinone; [0101] (J)
(Z)-3-(1-(4-(diethanolaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(but-
ylcarbamoyl)-2-indolinone; [0102] (K)
(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3-
-chlorobenzyl)-carbamoyl)-2-indolinone; [0103] (L)
(Z)-3-(1-(4-(N-acetyl-N-(2-dimethylamino-ethyl)-amino)-phenylamino)-1-phe-
nyl-methylen)-5-(N-(3-chlorobenzyl)-carbamoyl)-2-indolinone; [0104]
(M)
(Z)-3-(1-(4-(butylaminomethyl)-phenylamino)-1-phenyl-methylen)-5-(N-(3-ch-
lorobenzyl)-carbamoyl)-2-indolinone; [0105] (N)
(Z)-3-(1-(4-(dimethylaminomethyl)-phenylamino)-1-phenyl-methylene)-6-meth-
oxycarbonyl-2-indolinone; [0106] (O)
(Z)-3-(1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-phenylamino)-1-ph-
enyl-methylene)-6-methoxycarbonyl-2-indolinone; [0107] (P)
(Z)-3-(1-(4-(ethylaminomethyl)-phenylamino)-1-phenyl-methylene)-6-methoxy-
carbonyl-2-indolinone; [0108] (Q)
(Z)-3-(1-(4-(1-methyl-imidazol-2-yl)-phenylamino)-1-phenyl-methylene)-6-m-
ethoxycarbonyl-2-indolinone; [0109] (R)
(Z)-3-(1-(4-(N-(dimethylaminomethylcarbonyl)-N-methyl-amino)-phenylamino)-
-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone; [0110] (S)
(Z)-3-(1-(4-(methylaminomethyl)-anilino)-1-phenyl-methylene)-6-methoxycar-
bonyl-2-indolinone; [0111] (T)
(Z)-3-(1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-
-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone;
and [0112] (U)
4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-q-
uinazoline, as well as their polymorphs, metabolites or
pharmaceutically acceptable salts.
[0113] Compounds (A) to (B) are described in WO 00/18734, compounds
(C) to (M) are described in WO 00/73297, compounds (N) to (T) are
described in WO 01/27081, compound (U) is described in WO
01/32651.
[0114] Especially representative is the potent and orally available
low molecular weight antagonist of VEGFR 1 to 3, PDGGR.alpha. and
.beta., FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR and c-Kit, which is
further an antagonist of the src tyrosine kinase family members,
and especially of src, lck, lyn and fyn, further an antagonist of
the complex of cyclin dependent kinases with their specific cyclins
or with a viral cyclin, and further an inhibitor of the paracrine
IL-6 secretion, disclosed, for example, in WO 01/27081, as
exemplified compound number 473, as well as its polymorphs,
metabolites or pharmaceutically acceptable salts. This compound,
referred to as (T) in the above list, is
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone.
[0115] When compared to the other above exemplified compounds, this
compound is further particularly preferred due to its high potency
as inhibitor and its better toxicologic profile.
[0116] Particularly preferred is the monoethanesulfonate salt of
this compound, namely the monoethanesulfonate salt of
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
disclosed for example in unpublished German patent application DE
102 33 500.1, unpublished PCT/03/07822 and unpublished US patent
application 10/623,971.
[0117] In accordance with what is disclosed in DE 102 33 500.1,
unpublished PCT/03/07822 and unpublished U.S. patent application
Ser. No. 10/623,971, the monoethanesulfonate salt of
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone has the
following chemical structure:
##STR00001##
[0118] This compound may be selectively obtained by a suitable
choice of manufacturing conditions, preferably in its crystalline
hemihydrate form.
[0119] This compound is characterised by a melting point of
T=305.+-.5.degree. C. (determined by DSC=Differential Scanning
Calorimetry, using a Mettler-Toledo DSC82 apparatus; heating rate:
10 K/min).
[0120] For the manufacture of the monoethanesulfonate salt of
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, a
procedure in accordance with the following may be used.
[0121] The starting material used to prepare the
monoethanesulfonate salt of
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino-
)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone may
be the free base
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methy-
l-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
which may be obtained in accordance with a method known from the
prior art and described, for example, in WO 01/27081.
[0122] Thus, in a first step and in accordance with what is
described in WO 01/27081,
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone is
prepared as follows.
[0123] 10.5 g (30.0 mmol)
1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone
(prepared as described in WO 01/27081) and 8.60 g (33.0 mmol)
N-[(4-methyl-piperazin-1-yl)-methylcarbonyl]-N-methyl-p-phenylendiamine
(prepared as described in WO 01/27081) are dissolved in 80 ml
dimethylformamide and mixed for 1 hour at 80.degree. C. After
cooling, 6.50 ml piperidine is added and the whole is further mixed
for 2 hours at room temperature. Water is added, the liquid over
the resulting precipitate is sucked up, and the precipitate is
washed again with a low quantity of water. The residue is suspended
in 200 ml methanol, the liquid is sucked up, and the remaining
residue washed with cold water and diethylether. The resulting
product is vacuum dried at 110.degree. C. [0124] Recovered product:
12.4 g (77% of theoretical value) [0125] IR-spectroscopy: 1610,
1655, 1711 cm.sup.-1 [0126] T.sub.Smp.=253.degree. C. [0127]
Molecular formula: C.sub.31H.sub.33N.sub.5O.sub.4 [0128]
Electrospray-mass spectrometry: m/z=540 [M+H].sup.30 [0129] Element
analysis:
TABLE-US-00001 [0129] calculated C 68.99 H 6.16 N 12.98 found C
68.32 H 6.29 N 12.85
[0130] In a second step, and in accordance with what what is
disclosed in DE 102 33 500.1, the monoethanesulfonate salt of
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone will be
obtained as follows.
[0131] 605 g (1.12 mol)
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone are
suspended in 9 litres methanol and heated to 50.degree. C. 183.7 g
(1.121 mol) of a 70% aqueous solution of ethanesulfonate is added.
The resulting solution is cooled to 40.degree. C. and mixed with
4.5 litres ter-butylmethylether. Cristallisation occurs after a few
minutes. In order to achieve a complete precipitation, the whole is
mixed for 16 hours at room temperature. After cooling to a
temperature of 10.degree. C., the liquid is sucked up, the
precipitate is washed with 2 litres ter-butylmethylether and vacuum
dried at 40.degree. C. [0132] Recovered product: 638 g (87.6% of
theoretical value) [0133] T.sub.Smp.=305.+-.5.degree. C. (DSC 10
K/min) [0134] Purity (measured by HPLC): 99.4% [0135] Water
content: 1.0 bis 2.0% (KF)
[0136] The monoethanesulfonate salt of
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone can be
very easily dissolved in physiologically acceptable solubilization
agents.
[0137] Additionally, the compound MES(T) is orally bioavailable in
mice.
[0138] The monoethanesulfonate salt of
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone inhibits
the human VEGFR-2 kinase (huVEGFR-2) with an IC.sub.50 of 21 nM,
the murine VEGFR-2 kinase (huVEGFR-2) with an IC.sub.50 of 13 nM,
and the proliferation of VEGF stimulated endothelial cells (HUVEC:
IC.sub.50=9 nM, HSMEC: IC.sub.50=12 nM).
[0139] Furthermore, FGFR-1 and PDGGR.alpha., two members of the
split kinase domain family of receptors important in angiogenic
signaling, are additionally inhibited by this compound with
IC.sub.50's of 69 nM and 59 nM respectively.
[0140] The compound MES(T) is thus highly selective when tested
against a panel of numerous different kinases, as shown in the
following Table I.
TABLE-US-00002 TABLE I Kinase IC.sub.50 [nM] huVEGFR-2 21 muVEGFR-2
13 VEGFR-3 13 InsR >4000 IGF1R >1000 EGFR >50000 HER2
>50000 FGFR1 69 FGFR3 137 PDGFR.alpha. 59 CDK1 >10000 CDK2
>10000 CDK4 >10000 Lck 16 Lyn 195 Src 156
[0141] Noteworthy is also that this specific antagonist shows a
long lasting inhibition of the receptor VEGFR-2. On the molecular
and cellular level a short exposure of the compound MES(T) to cells
(e.g. endothelial cells) is enough to inhibit the activation of the
receptor kinase itself and downstream signalling molecules (e.g.
the MAP kinase, MAPK) as well as cellular proliferation for at
least 32 h.
[0142] The results of the following experiment evidences this
long-lasting inhibition effect. In order to determine the duration
of the inhibition induced by MES(T) on the receptor, washout
experiments were performed. HUVEC and NIH 3T3 KDR cells were
exposed to MES(T) for a limited period of time, MES(T) was washed
away and cell proliferation (HUVEC) or VEGFR-2
activation/phosphorylation was analysed after various periods of
time. As shown in FIG. 1, the autophosphorylation of VEGFR-2 is
blocked for at least 32 h after a 1 hour exposure with 50 nM
MES(T). After 8 h, 24 h, and 32 h without MES(T), the cells were
again stimulated with VEGF and the receptor activation was
analysed. Even after 32 h no receptor activation could be observed.
This strongly suggests that MES(T) exhibits sustained effects on
the receptor kinase even when the MES(T) plasma concentration are
very low.
[0143] The results of the following in vivo xenograft experiment
evidences the effect on tumour cells of compound MES(T). In order
to determine this effect, nude mice bearing subcutaneous FaDu
tumours (FaDu tumours are constituted of human squamous carcinoma
cells) were orally treated with the compound MES(T). As shown in
FIG. 2, when the mice were treated twice weekly with a dose of 100
mg/kg, a reduction of tumour growth with a T/C (Tumour/Control)
value of 31% can be seen. By increasing the dose to 200 mg/kg
orally twice weekly an even better anti-tumour effect is
expected.
[0144] This indicates that this antagonist is particularly suitable
for a sequential co-administration and/or co-treatment with another
chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent, and/or radiotherapy or
radio-immunotherapy. The scheduled treatment regimen with this
antagonist may be, for example, an alternate treatment one day
on/one day off, one day on/two days off, one week on/one week off,
or even two weeks on/two weeks off.
[0145] The monoethanesulfonate salt of
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone is thus
clearly a potent and orally available VEGFR-2 kinase inhibitor and
anti-tumour agent.
[0146] With regard to all aspects of the invention, suitable
selected protein tyrosine kinase receptor antagonists are also the
active in vivo metabolites of the selected protein tyrosine kinase
receptor antagonists. For example, an active in vivo metabolite of
the protein tyrosine kinase receptor antagonist
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone may be
the unesterified compound
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-carbonyl-2-indolinone.
[0147] Within the meaning of the present invention, all the
above-exemplified compounds, and especially the compound (T) and
its monoethanesulfonate salt MES(T), may also be used as
mono-therapy for the treatment of the above-mentioned diseases,
namely all kind of diseases in which cell proliferation, migration
or apoptosis of myeloma cells, or angiogenesis are involved, which
can be of oncological nature such as all types of malignant
neoplasias or cancers, or of non-oncological nature, such as
diabetic retinopathy, rheumatoid arthritis, or psoriasis. Among
cancers, selected specific target indications for a
mono-therapeutic treatment are solid tumours, such as urogenital
cancers (such as prostate cancer, renal cell cancers, bladder
cancers), gynecological cancers (such as ovarian cancers, cervical
cancers, endometrial cancers), lung cancer, gastrointestinal
cancers (such as colorectal cancers, pancreatic cancer, gastric
cancer, oesophageal cancers, hepatocellular cancers,
cholangiocellular cancers), head and neck cancer, malignant
mesothelioma, breast cancer, malignant melanoma or bone and soft
tissue sarcomas, and haematologic neoplasias, such as multiple
myeloma, acute myelogenous leukemia, chronic myelogenous leukemia,
myelodysplastic syndrome and acute lymphoblastic leukemia. Of
special interest is the treatment of hormone sensitive or hormone
refractory prostate cancer, ovarian carcinoma, non small cell lung
cancer, small cell lung cancer, or multiple myeloma. The
above-exemplified compounds are especially efficient for inhibiting
tumour growth, survival and metastasis. [0148] The further
chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agent
[0149] This compound may preferably be selected from the following
classes and examples of compounds, although this list is not to be
considered as limitative. [0150] Synthetic small molecule VEGF
receptor antagonists
[0151] Synthetic small molecule VEGF receptor antagonists of
particular interest are the antagonists of the VEGF receptor of
type 2, which are as well antagonists of the basic fibroblast
growth factor (bFGF) and of the platelet derived growth factor
(PDGF) receptors. Representative compounds are, for example,
indolinone derivatives, such as those described in WO 02/36564, WO
99/52869, WO 00/18734, WO 00/73297, WO 01/27080, WO 01/27081 and WO
01/32651. Further representative small molecule VEGF receptor
antagonists are the compounds described in WO 01/60814, WO
99/48868, WO 98/35958, and especially the compounds vatalanib
(PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474,
AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842 (a dipeptide of
L-Glutamyl and L-Tryptophan) or GW-786034. [0152] Small molecule
growth factor (GF) receptor antagonists
[0153] Small molecule growth factor (GF) receptor antagonists of
particular interest are the antagonists of the protein tyrosin
kinase (PTK) receptors, especially the antagonists of the epidermal
growth factor (EGF) receptor, the dual antagonists of the epidermal
growth factor (EGF) and of the human epidermal growth factor of
type 2 (HE type 2) receptors or the antagonists of the
mitogen-activated protein kinase (MAPK). Representative compounds
which are dual EGFR and HER-2 antagonists are, for example, the
quinazoline derivatives disclosed in WO 00/78735 and WO 02/50043,
gefitinib, erlotinib, CI-1033 and GW-2016. Representative compounds
which are only EGFR antagonists are, for example, iressa (ZD-1839),
tarceva (OSI-774), PKI-166, EKB-569, HKI-272 and herceptin.
Representative compounds which are antagonists of the
mitogen-activated protein kinase (MAPK) are BAY-43-9006 (a Raf
protein kinase family inhibitor) and BAY-57-9006 (a Kdr tyrosine
kinase inhibitor).
[0154] A preferred compound in this class is the quinazoline
derivative disclosed in WO 02/50043 as exemplified compound of
Example 1(10), namely
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, or the
tautomers, the stereoisomers and the salts thereof, particularly
the physiologically acceptable salts thereof with inorganic or
organic acids or bases. Most preferred is the di-maleic acid salt
of this compound, which can easily be obtained in accordance with
the following procedure. 6,0 kg (12,35 mol) of
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline are
heated up to 70.degree. C. in 84 liter of ethanol. A solution of
2,94 kg (25,31 mol) maleic acid in 36 liter ethanol is added. At
the beginning of crystallisation, the reaction mixture is cooled to
20.degree. C. and stirred for 2 hours. The reaction mixture is
cooled to 0.degree. C. and stirred for 3 hours. The precipitate is
suction filtered. The filter cake is washed with 19 liter of
ethanol and vacuum-dried at 40.degree. C.
[0155] A further preferred compound in this class is the
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu-
ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, or
the salts thereof. The chemical structural formula of this compound
is
##STR00002##
[0156] This compound may be obtained in three steps using the
following manufacturing conditions. [0157] Preparation of the
starting compound I:
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[(diethoxy-phosphoryl)-acetylami-
no]-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline [0158] 60.07 g of
diethoxyphosphorylacetic acid are placed in 750 ml of
N,N-dimethylformamide and at ambient temperature combined with
48.67 g of N,N'-carbonyldiimidazole. After the development of gas
has ceased 90.00 g of
4-[(3-chloro-4-fluoro-phenyl)amino]-6-amino-[(S)-(tetrahydrofuran-3-yl-
)oxy]-quinazoline are added and the reaction mixture is stirred for
about 4-5 hours at ambient temperature until the reaction is
complete. The reaction mixture is then heated gently in the water
bath and 750 ml of water are added twice. The thick suspension is
stirred overnight and the next morning another 350 ml of water are
added. The suspension is cooled in the ice bath, stirred for one
hour and suction filtered. The filter cake is washed again with 240
ml of N,N-dimethylformamide/water (1:2) and 240 ml of
diisopropylether and dried at 40.degree. C. in the circulating air
dryer. [0159] Yield: 117.30 g of (88% of theory) [0160] R.sub.f
value: 0.37 (silica gel, methylene chloride/methanol=9:1) [0161]
Mass spectrum (ESI.sup.+): m/z=553, 555 [M+H].sup.+ [0162]
Preparation of the starting compound II:
Homomorpholin-4-yl-acetaldehyde-hydrochloride [0163] Prepared by
stirring (2.5 hours) 4-(2,2-dimethoxy-ethyl)-homomorpholine with
semi-concentrated hydrochloric acid at 80.degree. C. The solution
obtained is further reacted directly as below-described. [0164]
Preparation of the final compound:
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)--
1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline
[0165] A solution of 3.9 g of
4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(diethoxy-phosphoryl)-acetylamin-
o]-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline (starting compound
I) in 20 ml of tetrahydrofuran is added to a solution of 300 mg of
lithium chloride in 20 ml of water at ambient temperature. Then
2.35 g of potassium hydroxide flakes are added and the reaction
mixture is cooled to -3.degree. C. in an ice/acetone cooling bath.
The solution of the above-obtained homomorpholin-4-yl-acetaldehyde
hydrochloride (staring compound II) is then added drop wise within
5 min at a temperature of 0.degree. C. After the addition has ended
the reaction mixture is stirred for another 10 min at 0.degree. C.
and for a further hour at ambient temperature. For working up 100
ml of ethyl acetate are added and the aqueous phase is separated
off. The organic phase is washed with saturated sodium chloride
solution, dried over magnesium sulphate and evaporated down. The
crude product is purified by chromatography over a silica gel
column using ethyl acetate/methanol/conc. methanolic ammonia as
eluant. The product obtained is stirred with a little di-isopropyl
ether, suction filtered and dried. [0166] Yield: 2.40 g of (63% of
theory) [0167] R.sub.f value: 0.09 (silica gel, ethyl
acetate/methanol/conc. aqueous ammonia=90:10:1) [0168] Mass
spectrum (ESI.sup.+): m/z=542, 544 [M+H].sup.+ [0169] Inhibitors of
the EGF receptor and/or VEGF receptor and/or integrin receptors or
any other protein tyrosine kinase receptors, which are not
classified under the synthetic small-molecules
[0170] Inhibitors of the EGF receptor and/or VEGF receptor and/or
integrin receptors or any other protein tyrosine kinase receptors,
which are not classified under the synthetic small-molecules, which
are of special interest, are the monoclonal antibodies directed to
EGF receptor and/or VEGF receptor and/or integrin receptors or any
other protein tyrosine kinase receptors. Representative compounds
are, for example, atrasentan (integrin antagonist), rituximab,
cetuximab, Avastin.TM. (bevacizumab), IMC-1C11, erbitux (C-225),
DC-101, EMD-72000 (humanized EGF receptor-specific monoclonal
antibody), vitaxin (antibody directed against the .alpha.,
.beta..sub.3 integrin), and imatinib (c-Kit inhibitor). Monoclonal
antibodies which can specifically recognize their antigen epitopes
on the relevant receptors, are in this respect of further special
interest. The use of such antibodies, which were successful in
vitro and in animal models, have not shown satisfying efficacy in
patients as mono-drug therapy. Similar results were obtained when
other anti-angiogenic or EGF receptor antagonists than antibodies
were used in clinical trials. It seems that tumours, if some
specific sites are blocked, may use other cell surface molecules to
compensate for said original blocking. Thus, tumours do not really
shrink during various anti-angiogenic or anti-proliferative
therapies. For these reasons, combination therapies were in this
case already proposed to circumvent this problem using, for
example, monoclonal antibodies together with specific cytotoxic or
chemotherapeutic agents or in combination with radiotherapy or
radio-immunotherapy. Indeed, clinical trials have shown that these
combination therapies are more efficient than the corresponding
mono-administrations. [0171] Inhibitors directed to EGF receptor
and/or VEGF receptor and/or integrin receptors or any other protein
tyrosine kinase receptors, which are fusion proteins
[0172] A representative compound of this class is, for example, the
compound with name VEGFtrap, developed by the pharmaceutical
companies Regeneron and Aventis. [0173] Compounds which interact
with nucleic acids and which are classified as alkylating agents or
platinum compounds
[0174] Compounds which interact with nucleic acids and which are
classified as alkylating agents or platinum compounds, have already
been described for their use for the treatment of diseases of
oncological nature. Representative classes and examples of
compounds are melphalan, cyclophosphamide, oxazaphosphorines,
cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin,
iproplatin, mitomycin, streptozocin, carmustine (BCNU), lomustine
(CCNU), busulfan, ifosfamide, streptozocin, thiotepa, chlorambucil,
nitrogen mustards (such as mechlorethamine), ethyleneimine
compounds and alkylsulphonates. [0175] Compounds which interact
with nucleic acids and which are classified as anthracyclines, as
DNA intercalators or as DNA cross-linking agents
[0176] Compounds which interact with nucleic acids and which are
classified as anthracyclines, as DNA intercalators (including DNA
minor-groove binding compounds) or as DNA cross-linking agents are
also of interest for the treatment of diseases of oncological
nature. Representative classes and examples of compounds are
daunorubicin, doxorubicin (adriamycin), liposomal doxorubicin
(doxil), epirubicin, idarubicin, mitoxantrone, amsacrine,
dactinomycin, distamycin and derivatives, netropsin, pibenzimol,
mitomycin, CC-1065 (Streptomyces zelensis fermentation product),
duocarmycins, mithramycin, chromomycin, olivomycin, phtalanilides
(propamidine, stilbamidine), anthramycins, aziridines or
nitrosoureas and their derivatives. [0177] Anti-metabolites
[0178] Representative classes of anti-metabolites of interest are
the pyrimidine and purine analogues or antagonists such as
fluoropyrimidines and thiopurines, or inhibitors of the nucleoside
diphosphate reductase. Representative compounds are, for example,
cytarabine, 5-fluorouracile (5-FU), uracil mustard, fludarabine,
gemcitabine, capecitabine, mercaptopurine, cladribine, thioguanine,
methotrexate, pentostatin, hydroxyurea, or folic acid. [0179]
Naturally occurring, semi-synthetic or synthetic bleomycin type
antibiotics (BLM-group antibiotics)
[0180] Representative classes and compounds of interest are the
phleomycins, bleomycins, bleomycin derivatives and salts, CHPP,
BZPP, MTPP, BAPP, liblomycin. These agents are believed to mediate
their therapeutic effects via degradation of chromosomal DNA or RNA
degradation (especially selective tRNA strand scission). [0181]
Inhibitors of DNA transcribing enzymes, especially topoisomerase I
or topoisomerase II inhibitors
[0182] A representative class and examples of compounds of interest
are the acridines and acridine derivatives, rifamycins,
actinomycins, adramycin, camptothecins (irinotecan or camptosar,
topotecan), amsacrines and analogues, and the tricyclic
carboxamides. [0183] Chromatin modifying agents
[0184] A representative class of compounds of interest are the
histonedeacetylase inhibitors, such as SAHA (suberoylanilide
hydroxamic acid), MD-275, trichostatin A, CBHA (M-carboxycinnamic
acid bishydroxamide), LAQ824, or valproic acid. [0185] Mitosis
inhibitors, anti-mitotic agents, or cell-cycle inhibitors
[0186] Representative classes and examples of compounds of interest
are the anti-cancer drugs from plants, such as the taxanes
(paclitaxel or taxol, docetaxel or taxotere), the vinca alkaloids
(navelbine, vinblastin, vincristin, vindesine or vinorelbine), the
tropolone alkaloids (colchicine and derivatives), the macrolides
(maytansine, ansamitocins, rhizoxin), the antimitotic peptides
(phomopsin, dolastatin), the epipodophyllotoxins or the derivatives
of podophyllotoxin (etoposide, teniposide), the steganacins and the
antimitotic carbamate derivatives (combretastatin, amphetinile), or
procarbazine. These compounds are cdk inhibitors, tubulin binders
or inhibitors of the polo-like kinase. [0187] Proteasome
inhibitors
[0188] A representative compound of interest belonging to this
class is, for example, Velcade.TM. (bortezomib or PS-341). [0189]
Enzymes
[0190] Representative compounds and classes of interest are, for
example, asparaginase, pegylated asparaginase (pegaspargase), and
the thymidine-phosphorylase inhibitors. [0191] Hormones, hormone
antagonists or hormone inhibitors, or inhibitors of steroid
biosynthesis
[0192] Representative classes and examples of hormones of interest
are, for example, the gestagens and estrogens, such as estramustine
or T-66, or megestrol. Representative classes and examples of
hormone antagonists or inhibitors of interest are, for example, the
anti-androgens, such as flutamide, casodex, anandron and
cyproterone acetate, the aromatase inhibitors, such as
amonogluthetimide, anastrozole, formestan and letrozole, the GNrH
analogues, such as leuprorelin, buserelin, goserelin and
triptorelin, the anti-estrogens, such as tamoxifen and especially
its citrate salt, droloxifene, trioxifene, raloxifene, zindoxifene,
the derivatives of 17.beta.-estradiol (ICI 164,384 and ICI
182,780), aminoglutethimide, formestane, fadrozole, finasteride, or
ketoconazole, or the LH-RH antagonist leuprolide. Steroid hormone
inhibitors are especially suitable for the treatment of breast and
prostate cancer. [0193] Steroids
[0194] Representative compounds of interest are, for example,
prednisone, prednisolone, methylprednisolone, dexamethasone,
budenoside, fluocortolone and triamcinolone. The reasons why
steroids may be used in the treatment of some cancers and the
effects obtained with steroids in the treatment of cancer depends
on the type of cancer to be treated. In the treatment of solid
tumors, steroids are in first line used to control the symptoms. In
the case of brain metastasis, they belong to the standard therapy
for reducing oedema. They are also used to control the inflammation
which surrounds the tumor lesions. In the treatment of haematologic
malignant neoplasias of lymphatic cell lines (ALL, non-Hodgkin
lymphoma, myeloma), due to their cytolytic effect, steroids are
used as a real anti-tumor therapy, alone or in combination with
classical chemotherapeutic agents. The naturally occuring steroid
tetrahydrocortisol, the synthetic cyclodextrin derivative
.beta.-cyclodextrine tetradecasulfate and the tetracycline
derivative minocycline, due to their antiangiogenic activity, have
been suggested for a combination treatment with cytotoxic standard
anticancer therapies, such as platinum, melphalan,
cyclophosphamide, adriamycin, bleomycin or radiation based
therapies (Teicher et al., Cancer research, Vol. 52, pp. 6702-6704,
1992). The steroid dexamethasone has also been tested as primary
treatment of multiple myeloma (Dimopoulos et al., Blood, Vol.
80(4), pp. 887-890, 1992).Furthermore, evaluation studies of
combination therapies using dexamethasone and thalidomide, a
substance known for its activity as TNF-.alpha. synthesis inhibitor
and cytokine antagonist, have been disclosed recently. These
studies focussed on previously untreated multiple myeloma (Weber et
al., Journal of Clinical Oncology, Vol. 21, No. 1, pp. 16-19,
2003), newly diagnosed myeloma (Rajkumar et al., Journal of
Clinical Oncology, Vol. 20, No. 21, pp. 4319-4323, 2002) and
multiple myeloma after intensive chemotherapy (Ann. Oncol., Vol.
13, No. 7, pp. 1116-1119, 2002).
[0195] With regard to all aspects of the invention, suitable
steroids for the combination treatment are meant to include in a
non-limiting manner prednisone, prednisolone, methylprednisolone,
dexamethasone, budenoside, fluocortolone and triamcinolone. The
preferred steroid is dexamethasone. [0196] Cytokines,
hypoxia-selective cytotoxins, inhibitors of cytokines, lymphokines,
antibodies directed against cytokines or oral and parenteral
tolerance induction agents
[0197] Representative classes and examples of compounds of interest
are interferons (especially interferon .beta.), interleukins
(especially IL-10 and 12), anti-TNF.alpha. antibodies (etanercept),
Immunomodulatory drugs (or IMiDs, especially inhibitors of the
TNF-.alpha. production, such as thalidomide, its R- and
S-enantiomers and its derivatives, or revimid (CC-5013)),
leukotrien antagonists, mitomycin C, aziridoquinones (BMY-42355,
AZQ, EO-9), 2-nitroimidazoles (misonidazole, NLP-1, NLA-1),
nitroacridines, nitroquinolines, nitropyrazoloacridines,
"dual-function" nitro aromatics (RSU-1069, RB-6145), nitro aromatic
deactivated mustards (CB-1954), N-oxides of nitrogen mustards
(nitromin), metal complexes of nitrogen mustards, anti-CD3 or
anti-CD25 antibodies, genetically modified enteric bacteria to
achieve tolerance. [0198] Supportive agents
[0199] A representative class of compounds of interest are, for
example, the biphosphonates and their derivatives, such as, for
example, minodronic acid (YM-529, Ono-5920, YH-529), zoledronic
acid monohydrate, ibandronate sodium hydrate, clodronate disodium.
These compounds are in clinical development or have been recently
approved for the treatment of bone metastasis from breast/lung
cancer and for the treatment of multiple myeloma (Drugs of the
Future 2002, 27(10), pp. 935-941). [0200] Chemical radiation
sensitizers and protectors
[0201] Representative classes and compounds of interest are, for
example, the nitroimidazoles (metronidazole, misonidazole,
benznidazole, nimorazole) and further nitroaryl compounds such as
RSU-1069, the nitroxyl and N-oxides such as SR-4233, the
halogenated pyrimidine analogues (bromodeoxyuridine,
iododeoxyuridine), or the thiophosphates (for example WR-2721) as
radiation protectors. [0202] Photochemically activated drugs
[0203] Representative classes and compounds of interest are, for
example, porfimer, photofrin, the benzoporphyrin derivatives, the
pheophorbide derivatives, merocyanin 540 (MC-540), and tin
etioporpurin. [0204] Synthetic poly- or oligonucleotides
[0205] Synthetic poly- or oligonucleotides, which may optionally be
modified or conjugated are also of interest. Representative classes
of poly- or oligonucleotides are, for example, anti-templates RNAs
and DNAs (synthetic or chemically modified oligonucleotides which
are inactive per se but capable of competing with functional
template-primers for their specific binding site on an enzyme and
thereby blocking their functions), anti-sense RNAs and DNAs
(sequence-specific inhibitors of protein synthesis which hybridize
with complementary base sequences of a given m-RNA, such as
oblimersen), especially directed against onco-genes, growth factor
genes or tumor suppressor genes, antigene poly- or oligonucleotides
(oligonucleotides capable of forming triplex DNA structures which
selectively inhibit the transcription of a target gene), and
ribozymes. [0206] Non-steroidal anti-inflammatory drugs
[0207] Non-steroidal inflammatory drugs (NSAIDs) represent also an
interesting class of compounds which may be used for a combination
therapy within the meaning of the present invention.
Cyclo-oxygenase (COX) inhibitors are of special interest, such as
the non-selective COX inhibitors acetylsalicyclic acid, mesalazin,
ibuprofen, naproxen, flurbiprofen, fenoprofen, fenbufen,
ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin,
pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen,
tiaprofenic acid, fluprofen, indomethacin, sulindac, tolmetin,
zomepirac, nabumetone, diclofenac, fenclofenac, alclofenac,
bromfenac, ibufenac, aceclofenac, acemetacin, fentiazac, clidanac,
etodolac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic
acid, nifluminic acid, tolfenamic acid, diflunisal, flufenisal,
piroxicam, tenoxicam, lornoxicam and nimesulide or the
pharmaceutically acceptable salts thereof, or the selective COX
inhibitors meloxicam, celecoxib or rofecoxib. The selective COX-2
inhibitor meloxicam is especially preferred. [0208] Other
chemotherapeutic or naturally occurring, semi-synthetic or
synthetic therapeutic agents
[0209] Further classes and examples of compounds are of interest
for a combination therapy within the meaning of the present
invention, such as, for example, cytotoxic antibiotics, antibodies
targeting surface molecules of cancer cells (especially HLA-DR
antibodies such as, for example, apolizumab and 1D09C3), inhibitors
of metalloproteinases (TIMP-1, TIMP-2), Zinc, inhibitors of
oncogenes (especially c-myc, Ras, v-raf or c-src inhibitors, such
as P53 and Rb), inhibitors of gene transcription (especially the
inhibitors of the transcription factor complex ESX/DRIP130/Sur-2
which controls the expression of Her-2, such as those described in
WO 03/097855) or of RNA translation or protein expression
(especially the inhibitors of HER-2 expression, such as the heat
shock protein HSP90 modulator geldanamycin and its derivative
17-allylaminogeldanamycin or 17-AAG), complexes of rare earth
elements such as the heterocyclic complexes of lanthanides
described for example in German Patent Nr. 101 38 538,
photo-chemotherapeutic agents (PUVA, a combination of psoralen (P)
and long-wave ultraviolet radiation (UVA)), IM-842,
tetrathiomolybdate, squalamine, combrestatin A4, TNP-470,
marimastat, neovastat, bicalutamide, abarelix, oregovomab,
mitumomab, TLK-286, alemtuzumab, ibritumomab, temozolomide,
denileukin diftitox, aldesleukin, dacarbazine, floxuridine,
plicamycin, mitotane, pipobroman, plicamycin, tamloxifen,
testolactone.
[0210] In a preferred embodiment in accordance with the present
invention, the further chemotherapeutic or naturally occurring,
semi-synthetic or synthetic therapeutic agent is selected from
synthetic small molecule VEGF receptor antagonists, small molecule
growth factor receptor antagonists, inhibitors of the EGF receptor
and/or VEGF receptor and/or integrin receptors or any other protein
tyrosine kinase receptors which are not classified under the
synthetic small-molecules, inhibitors directed to EGF receptor
and/or VEGF receptor and/or integrin receptors or any other protein
tyrosine kinase receptors, which are fusion proteins, compounds
which interact with nucleic acids and which are classified as
alkylating agents or platinum compounds, compounds which interact
with nucleic acids and which are classified as anthracyclines, as
DNA intercalators or as DNA cross-linking agents, including DNA
minor-groove binding compounds, anti-metabolites, naturally
occurring, semi-synthetic or synthetic bleomycin type antibiotics,
inhibitors of DNA transcribing enzymes, and especially the
topoisomerase I or topoisomerase II inhibitors, chromatin modifying
agents, mitosis inhibitors, anti-mitotic agents, cell-cycle
inhibitors, proteasome inhibitors, enzymes, hormones, hormone
antagonists, hormone inhibitors, inhibitors of steroid
biosynthesis, steroids, cytokines, hypoxia-selective cytotoxins,
inhibitors of cytokines, lymphokines, antibodies directed against
cytokines, oral and parenteral tolerance induction agents,
supportive agents, chemical radiation sensitizers and protectors,
photo-chemically activated drugs, synthetic poly- or
oligonucleotides, optionally modified or conjugated, non-steroidal
anti-inflammatory drugs, cytotoxic antibiotics, antibodies
targeting surface molecules of cancer cells, and especially the
HLA-DR antibodies such as, inhibitors of metalloproteinases,
metals, inhibitors of oncogenes, inhibitors of gene transcription
or of RNA translation or protein expression, complexes of rare
earth elements, or photo-chemotherapeutic agents.
[0211] In a further preferred embodiment in accordance with the
present invention, the further chemotherapeutic or naturally
occurring, semi-synthetic or synthetic therapeutic agent is
selected from a small molecule VEGF receptor antagonist such as
vatalanib (PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813,
AZD-6474, AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842 or
GW-786034, a dual EGFR/HER2 antagonist such as gefitinib,
erlotinib, CI-1033 or GW-2016, an EGFR antagonist such as iressa
(ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272 or
herceptin, an antagonist of the mitogen-activated protein kinase
such as BAY-43-9006 or BAY-57-9006, a quinazoline derivative such
as
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline or
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu-
ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, or a
pharmaceutically acceptable salt thereof, a protein kinase receptor
antagonist which is not classified under the synthetic small
molecules such as atrasentan, rituximab, cetuximab, Avastin.TM.
(bevacizumab), IMC-1C11, erbitux (C-225), DC-101, EMD-72000,
vitaxin, imatinib, a protein tyrosine kinase inhibitor which is a
fusion protein such as VEGFtrap, an alkylating agent or a platinum
compound such as melphalan, cyclophosphamide, an oxazaphosphorine,
cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin,
iproplatin, mitomycin, streptozocin, carmustine (BCNU), lomustine
(CCNU), busulfan, ifosfamide, streptozocin, thiotepa, chlorambucil,
a nitrogen mustard such as mechlorethamine, an ethyleneimine
compound, an alkylsulphonate, daunorubicin, doxorubicin
(adriamycin), liposomal doxorubicin (doxil), epirubicin,
idarubicin, mitoxantrone, amsacrine, dactinomycin, distamycin or a
derivative thereof, netropsin, pibenzimol, mitomycin, CC-1065, a
duocarmycin, mithramycin, chromomycin, olivomycin, a phtalanilide
such as propamidine or stilbamidine, an anthramycin, an aziridine,
a nitrosourea or a derivative thereof, a pyrimidine or purine
analogue or antagonist or an inhibitor of the nucleoside
diphosphate reductase such as cytarabine, 5-fluorouracile (5-FU),
uracil mustard, fludarabine, gemcitabine, capecitabine,
mercaptopurine, cladribine, thioguanine, methotrexate, pentostatin,
hydroxyurea, or folic acid, a phleomycin, a bleomycin or a
derivative or salt thereof, CHPP, BZPP, MTPP, BAPP, liblomycin, an
acridine or a derivative thereof, a rifamycin, an actinomycin,
adramycin, a camptothecin such as irinotecan (camptosar) or
topotecan, an amsacrine or analogue thereof, a tricyclic
carboxamide, an histonedeacetylase inhibitor such as SAHA, MD-275,
trichostatin A, CBHA, LAQ824, or valproic acid, an anti-cancer drug
from plants such as paclitaxel (taxol), docetaxel or taxotere, a
vinca alkaloid such as navelbine, vinblastin, vincristin, vindesine
or vinorelbine, a tropolone alkaloid such as colchicine or a
derivative thereof, a macrolide such as maytansine, an ansamitocin
or rhizoxin, an antimitotic peptide such as phomopsin or
dolastatin, an epipodophyllotoxin or a derivative of
podophyllotoxin such as etoposide or teniposide, a steganacin, an
antimitotic carbamate derivative such as combretastatin or
amphetinile, procarbazine, a proteasome inhibitor such as
Velcade.TM. (bortezomib or PS-341), an enzyme such as asparaginase,
pegylated asparaginase (pegaspargase) or a thymidine-phosphorylase
inhibitor, a gestagen or an estrogen such as estramustine (T-66) or
megestrol, an anti-androgen such as flutamide, casodex, anandron or
cyproterone acetate, an aromatase inhibitor such as
aminogluthetimide, anastrozole, formestan or letrozole, a GNrH
analogue such as leuprorelin, buserelin, goserelin or triptorelin,
an anti-estrogen such as tamoxifen or its citrate salt,
droloxifene, trioxifene, raloxifene or zindoxifene, a derivative of
17.beta.-estradiol such as ICI 164,384 or ICI 182,780,
aminoglutethimide, formestane, fadrozole, finasteride,
ketoconazole, a LH-RH antagonist such as leuprolide, a steroid such
as prednisone, prednisolone, methylprednisolone, dexamethasone,
budenoside, fluocortolone or triamcinolone, an interferon such as
interferon .beta., an interleukin such as IL-10 or IL-12, an
anti-TNF.alpha. antibody such as etanercept, an immunomodulatory
drug such as thalidomide, its R- and S-enantiomers and its
derivatives, or revimid (CC-5013), a leukotrien antagonist,
mitomycin C, an aziridoquinone such as BMY-42355, AZQ or EO-9, a
2-nitroimidazole such as misonidazole, NLP-1 or NLA-1, a
nitroacridine, a nitroquinoline, a nitropyrazoloacridine, a
"dual-function" nitro aromatic such as RSU-1069 or RB-6145,
CB-1954, a N-oxide of nitrogen mustard such as nitromin, a metal
complex of a nitrogen mustard, an anti-CD3 or anti-CD25 antibody, a
tolerance induction agent, a biphosphonate or derivative thereof
such as minodronic acid or its derivatives (YM-529, Ono-5920,
YH-529), zoledronic acid monohydrate, ibandronate sodium hydrate or
clodronate disodium, a nitroimidazole such as metronidazole,
misonidazole, benznidazole or nimorazole, a nitroaryl compound such
as RSU-1069, a nitroxyl or N-oxide such as SR-4233, an halogenated
pyrimidine analogue such as bromodeoxyuridine, iododeoxyuridine, a
thiophosphate such as WR-2721, a photo-chemically activated drug
such as porfimer, photofrin, a benzoporphyrin derivative, a
pheophorbide derivative, merocyanin 540 (MC-540) or tin
etioporpurin, an anti-template or an anti-sense RNA or DNA such as
oblimersen, a non-steroidal inflammatory drug such as
acetylsalicyclic acid, mesalazin, ibuprofen, naproxen,
flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen,
pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen,
tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen,
indomethacin, sulindac, tolmetin, zomepirac, nabumetone,
di-clofenac, fenclofenac, alclofenac, bromfenac, ibufenac,
ace-clofenac, acemetacin, fentiazac, clidanac, etodolac, oxpinac,
mefenamic acid, meclofenamic acid, flufenamic acid, nifluminic
acid, tolfenamic acid, diflunisal, flufenisal, piroxicam,
tenoxicam, lornoxicam, nimesulide, meloxicam, celecoxib, rofecoxib,
or a pharmaceutically acceptable salt of a non-steroidal
inflammatory drug, a cytotoxic antibiotic, an antibody targeting
the surface molecules of cancer cells such as apolizumab or 1D09C3,
an inhibitor of metalloproteinases such as TIMP-1 or TIMP-2, Zinc,
an inhibitor of oncogenes such as P53 and Rb, a complex of rare
earth elements such as the heterocyclic complexes of lanthanides, a
photo-chemotherapeutic agent such as PUVA, an inhibitor of the
transcription factor complex ESX/DRIP130/Sur-2, an inhibitor of
HER-2 expression, such as the heat shock protein HSP90 modulator
geldanamycin and its derivative 17-allylaminogeldanamycin or
17-AAG, or a therapeutic agent selected from IM-842,
tetrathiomolybdate, squalamine, combrestatin A4, TNP-470,
marimastat, neovastat, bicalutamide, abarelix, oregovomab,
mitumomab, TLK-286, alemtuzumab, ibritumomab, temozolomide,
denileukin diftitox, aldesleukin, dacarbazine, floxuridine,
plicamycin, mitotane, pipobroman, plicamycin, tamloxifen or
testolactone.
[0212] In a further preferred embodiment in accordance with the
present invention, the further chemotherapeutic or naturally
occurring, semi-synthetic or synthetic therapeutic agent is
selected from an anti-cancer drug from plants such as paclitaxel
(taxol), docetaxel or taxotere, a vinca alkaloid such as navelbine,
vinblastin, vincristin, vindesine or vinorelbine, a vinca alkaloid
such as navelbine, vinblastin, vincristin, vindesine or
vinorelbine, an alkylating agent or a platinum compound such as
melphalan, cyclophosphamide, an oxazaphosphorine, cisplatin,
carboplatin, oxaliplatin, satraplatin, tetraplatin, iproplatin,
mitomycin, streptozocin, carmustine (BCNU), lomustine (CCNU),
busulfan, ifosfamide, streptozocin, thiotepa, chlorambucil, a
nitrogen mustard such as mechlorethamine, an immunomodulatory drug
such as thalidomide, its R- and S-enantiomers and its derivatives,
or revimid (CC-5013)), an ethyleneimine compound, an
alkylsulphonate, daunorubicin, doxorubicin (adriamycin), liposomal
doxorubicin (doxil), epirubicin, idarubicin, mitoxantrone,
amsacrine, dactinomycin, distamycin or a derivative thereof,
netropsin, pibenzimol, mitomycin, CC-1065, a duocarmycin,
mithramycin, chromomycin, olivomycin, a phtalanilide such as
propamidine or stilbamidine, an anthramycin, an aziridine, a
nitrosourea or a derivative thereof, a pyrimidine or purine
analogue or antagonist or an inhibitor of the nucleoside
diphosphate reductase such as cytarabine, 5-fluorouracile (5-FU),
uracil mustard, fludarabine, gemcitabine, capecitabine,
mercaptopurine, cladribine, thioguanine, methotrexate, pentostatin,
hydroxyurea, or folic acid, an acridine or a derivative thereof, a
rifamycin, an actinomycin, adramycin, a camptothecin such as
irinotecan (camptosar) or topotecan, an amsacrine or analogue
thereof, a tricyclic carboxamide, an histonedeacetylase inhibitor
such as SAHA, MD-275, trichostatin A, CBHA, LAQ824, or valproic
acid, a proteasome inhibitor such as Velcade.TM. (bortezomib or
PS-341), a small molecule VEGF receptor antagonist such as
vatalanib (PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813,
AZD-6474, AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842 or
GW-786034, an antagonist of the mitogen-activated protein kinase
such as BAY-43-9006 or BAY-57-9006, a dual EGFR/HER2 antagonist
such as gefitinib, erlotinib, CI-1033 or GW-2016, an EGFR
antagonist such as iressa (ZD-1839), tarceva (OSI-774), PKI-166,
EKB-569, HKI-272 or herceptin, a quinazoline derivative such as
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline or
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu-
ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, or a
pharmaceutically acceptable salt thereof, an inhibitor of the
transcription factor complex ESX/DRIP130/Sur-2, an inhibitor of
HER-2 expression, such as the heat shock protein HSP90 modulator
geldanamycin and its derivative 17-allylaminogeldanamycin or
17-AAG, a protein kinase receptor antagonist which is not
classified under the synthetic small molecules such as atrasentan,
rituximab, cetuximab, Avastin.TM. (bevacizumab), IMC-1C11, erbitux
(C-225), DC-101, EMD-72000, vitaxin, imatinib, or an antibody
targeting the surface molecules of cancer cells such as apolizumab
or 1D09C3.
[0213] In a further preferred embodiment in accordance with the
present invention, the further chemotherapeutic or naturally
occurring, semi-synthetic or synthetic therapeutic agent is
selected from the above-mentioned quinazoline derivative disclosed
in WO 02/50043 as exemplified compound of Example 1(10), namely
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, or the
tautomers, the stereoisomers and the salts thereof, particularly
the physiologically and pharmaceutically acceptable salts thereof
with inorganic or organic acids or bases.
[0214] In a further preferred embodiment in accordance with the
present invention, the further chemotherapeutic or naturally
occurring, semi-synthetic or synthetic therapeutic agent is
selected from the di-maleic acid salt of the compound
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, or the
tautomers or stereoisomers thereof.
[0215] In a further preferred embodiment in accordance with the
present invention, the further chemotherapeutic or naturally
occurring, semi-synthetic or synthetic therapeutic agent is
selected from
4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu-
ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline or
the physiologically and pharmaceutically acceptable salts thereof
with inorganic or organic acids or bases. [0216] Radiation therapy,
radio-immunotherapy or pre-targeted radioimmunotherapy
[0217] Radiation therapy, radio-immunotherapy or pre-targeted
radioimmunotherapy are used for the treatment of diseases of
oncological nature. "Radiotherapy", or radiation therapy, means the
treatment of cancer and other diseases with ionizing radiation.
Ionizing radiation deposits energy that injures or destroys cells
in the area being treated (the target tissue) by damaging their
genetic material, making it impossible for these cells to continue
to grow. Radiotherapy may be used to treat localized solid tumors,
such as cancers of the skin, tongue, larynx, brain, breast, lung or
uterine cervix. It can also be used to treat leukemia and lymphoma,
i.e. cancers of the blood-forming cells and lymphatic system,
respectively. One type of radiation therapy commonly used involves
photons, e.g. X-rays. Depending on the amount of energy they
possess, the rays can be used to destroy cancer cells on the
surface of or deeper in the body. The higher the energy of the
x-ray beam, the deeper the x-rays can go into the target tissue.
Linear accelerators and betatrons are machines that produce x-rays
of increasingly greater energy. The use of machines to focus
radiation (such as x-rays) on a cancer site is called external beam
radiotherapy. Gamma rays are another form of photons used in
radiotherapy. Gamma rays are produced spontaneously as certain
elements (such as radium, uranium, and cobalt 60) release radiation
as they decompose, or decay. Another technique for delivering
radiation to cancer cells is to place radioactive implants directly
in a tumor or body cavity. This is called internal radiotherapy.
Brachytherapy, interstitial irradiation, and intracavitary
irradiation are types of internal radiotherapy. In this treatment,
the radiation dose is concentrated in a small area, and the patient
stays in the hospital for a few days. Internal radiotherapy is
frequently used for cancers of the tongue, uterus, and cervix. A
further technique is intra-operative irradiation, in which a large
dose of external radiation is directed at the tumor and surrounding
tissue during surgery. Another approach is particle beam radiation
therapy. This type of therapy differs from photon radiotherapy in
that it involves the use of fast-moving subatomic particles to
treat localized cancers. Some particles (neutrons, pions, and heavy
ions) deposit more energy along the path they take through tissue
than do x-rays or gamma rays, thus causing more damage to the cells
they hit. This type of radiation is often referred to as high
linear energy transfer (high LET) radiation. Radio-sensitizers make
the tumour cells more likely to be damaged, and radio-protectors
protect normal tissues from the effects of radiation. Hyperthermia,
the use of heat, may also be used for sensitizing tissue to
radiation. Another option involves the use of radio-labeled
antibodies to deliver doses of radiation directly to the cancer
site (radio-immunotherapy). There are numerous methods available in
the art to link a radioisotope to an antibody. For example, for the
radio-iodination of the antibody, a method as disclosed in WO
93/05804 may be employed. Another option is to use a linker
molecule between the antibody and the radioisotope, e.g. MAG-3
(U.S. Pat. No. 5,082,930, EP 0 247 866), MAG-2 GABA (U.S. Pat. No.
5,681,927, EP 0 284 071), and N2S2 (phenthioate, U.S. Pat. No.
4,897,255, U.S. Pat. No. 5,242,679, EP 0 188 256). A further option
is pre-targeted radio-immunotherapy, which may be used to minimize
the radiation toxicity by separating the long-circulating antibody
and the rapidly cleared radionuclide (Drugs of the future 2003,
28(2), pp. 167-173). Detailed protocols for radiotherapy are
readily available to the expert (Cancer Radiotherapy: Methods and
Protocols (Methods in Molecular Medicine), Huddart R A Ed., Human
Press 2002). The expert knows how to determine an appropriate
dosing and application schedule, depending on the nature of the
disease and the constitution of the patient. In particular, the
expert knows how to assess dose-limiting toxicity (DLT) and how to
determine the maximum tolerated dose (MTD) accordingly. [0218]
Co-administration and/or co-treatment therapies
[0219] Co-administration of the selected protein tyrosine kinase
receptor antagonist and of the further chemotherapeutic or
naturally occurring, semi-synthetic or synthetic therapeutic agent,
and/or co-treatment with radiotherapy or radio-immunotherapy, is
meant to include administration and/or treatment sequential in time
or si-multaneous administration and/or treatment. For sequential
administration and/or treatment, the selected protein tyrosine
kinase receptor antagonist can be administered before or after
administration of the further chemotherapeutic or naturally
occurring, semi-synthetic or synthetic therapeutic agent, and/or
before or after treatment with radiotherapy or
radio-immunotherapy.
[0220] The active compounds can be administered orally, bucally,
parenterally, by inhalation spray, rectally or topically, the oral
administration being preferred. Parenteral administration may
include subcutaneous, intravenous, intramuscular and intrasternal
injections and infusion techniques.
[0221] The active compounds can be orally administered in a wide
variety of different dosage forms, i.e., they may be formulated
with various pharmaceutically acceptable inert carriers in the form
of tablets, capsules, lozenges, troches, hard candies, powders,
sprays, aqueous suspensions, elixirs, syrups, and the like. Such
carriers include solid diluents or fillers, sterile aqueous media
and various non-toxic organic solvents. Moreover, such oral
pharmaceutical formulations can be suitably sweetened and/or
flavoured by means of various agents of the type commonly employed
for such purposes. In general, the compounds of this invention are
present in such oral dosage forms at concentration levels ranging
from about 0.5% to about 90% by weight of the total composition, in
amounts which are sufficient to provide the desired unit dosages.
Other suitable dosage forms for the compounds of this invention
include controlled release formulations and devices well known to
those who practice in the art.
[0222] For purposes of oral administration, tablets containing
various excipients such as sodium citrate, calcium carbonate and
calcium phosphate may be employed along with various disintegrants
such as starch and preferably potato or tapioca starch, alginic
acid and certain complex silicate, together with binding agents
such as polyvinylpyrrolidone, sucrose, gelatine and acacia.
Additionally, lubricating agents such as magnesium stearate, sodium
lauryl sulfate and talc or compositions of a similar type may also
be employed as fillers in soft and hard-filled gelatine capsules;
included lactose or milk sugar as well as high molecular weight
polyethylene glycols. When aqueous suspensions and/or elixirs are
desired for oral administration, the essential active ingredient
therein may be combined with various sweetening or flavouring
agents, colouring matter or dyes and, if so desired, emulsifying
agents and/or water, ethanol, propylene glycol, glycerine and
various like combinations thereof.
[0223] For purposes of oral administration, an especially suitable
pharmaceutical formulation for the selected protein kinase receptor
antagonist in accordance with the present invention is soft
gelatine capsules. Suitable soft gelatine capsules for the
encapsulation of pharmaceutical compounds and the process for their
preparation are described, for example, in GB patent No. 395546,
U.S. Pat. No. 2,720,463, U.S. Pat. No. 2,870,062, U.S. Pat. No.
4,829,057, and in the following publications: ANON
(Verpack-Rundsch., Vol. 21, No. 1, January 1970, pp. 136-138),
Lachman et al. (The Theory and Practice of Industrial Pharmacy,
Chap. 13, published by Lea & Febiger, 1970), Ebert (Soft
Gelatine Capsules: A Unique Dosage Form, reprint from
Pharmaceutical Technology, October 1977) and R. F. Jimerson (Soft
Gelatine Capsule Update, Drug Development and Industrial Pharmacy,
Vol. 12 (8 & 9), pp. 1133-1144, 1986).
[0224] For purposes of parenteral administration, solutions of the
compounds in sesame or peanut oil or in aqueous propylene glycol
may be employed, as well as sterile aqueous solutions of the
corresponding pharmaceutically acceptable salts. Such aqueous
solutions should be suitably buffered if necessary, and the liquid
diluent rendered isotonic with sufficient saline or glucose. These
particular aqueous solutions are especially suitable for
intravenous, intramuscular and subcutaneous injection purposes. In
this connection, the sterile aqueous media employed are readily
obtained by standard techniques well known to those skilled in the
art. For instance, distilled water is ordinarily used as the liquid
diluent and the final preparation is passed through a suitable
bacterial filter such as a sintered glass filter or a diatomaceous
earth or unglazed porcelain filter. Preferred filters of this type
include the Berkefeld, the Chamberland and the Asbestos Disk-Metal
Seitz filter, wherein the fluid is sucked into a sterile container
with the aid of a suction pump. The necessary steps should be taken
throughout the preparation of these inject-able solutions to insure
that the final products are obtained in a sterile condition.
[0225] For purposes of transdermal administration, the dosage form
of the particular compound or compounds may include, by way of
example, solutions, lotions, ointments, creams, gels,
suppositories, rate-limiting sustained release formulations and
devices therefore. Such dosage forms comprise the particular
compound or compounds and may include ethanol, water, penetration
enhancer and inert carriers such as gel-producing materials,
mineral oil, emulsifying agents, benzyl alcohol and the like.
[0226] In accordance with one embodiment, the selected protein
tyrosine kinase receptor antagonist, or its polymorph or
pharmaceutically acceptable salt, may be administered in a daily
dosage such that the plasma level of the active substance lies
between 10 and 500 ng/ml for at least 12 hours of a 24 hours dosing
interval.
[0227] In accordance with a further embodiment, the selected
protein tyrosine kinase receptor antagonist, or its polymorph or
pharmaceutically acceptable salt, may be administered in a daily
dosage of between 2 mg and 20 mg/kg body weight.
[0228] The further chemotherapeutic or naturally occurring,
semi-synthetic or synthetic therapeutic agent may be administered
using suitable dosage forms, dosage levels and devices well known
to those who practice in the art. In accordance with one
embodiment, if the further chemotherapeutic or naturally occurring,
semi-synthetic or synthetic therapeutic agent is a steroid, the
steroid may be administered in a daily dosage of 5 to 500 mg.
[0229] As already mentioned hereinbefore, detailed protocols for
radiotherapy are readily available to the expert. The expert knows
how to determine an appropriate dosing and application schedule,
depending on the nature of the disease and the constitution of the
patient. In particular, the expert knows how to assess
dose-limiting toxicity (DLT) and how to determine the maximum
tolerated dose (MTD) accordingly.
In Vitro and In Vivo Combination Studies Showing the Potency to
Inhibit the Proliferation and/or to Induce the Apoptosis of Tumour
Cells
[0230] In the following examples of combinations, in vitro
experiments with representative cell lines or in vivo experiments
with nude mice carrying specific tumours, illustrate the potency of
the combination of a selected protein tyrosine kinase antagonist
with a further chemotherapeutic agent and/or with radiotherapy to
inhibit the proliferation of endothelial or tumour cells and/or to
induce the apoptosis of tumour cells. These examples are thus
illustrative of the present invention.
Examples of Combinations
[0231] 1. Combination of an antagonist of at least one receptor
selected from VEGFR 1 to 3, PDGGR.alpha. and .beta., FGFR1, 2 and
3, EGFR, HER2, IGF1R, HGFR or c-Kit, which is further an antagonist
of a src tyrosine kinase family member, or a polymorph, metabolite
or pharmaceutically acceptable salt thereof, and of a steroid, for
the treatment of refractory or relapsed multiple myeloma
[0232] In vitro studies performed with the monoethanesulfonate salt
of
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
(compound MES(T)) have shown that this specific compound has
unexpected properties which makes it especially suitable for the
treatment of the diseases in accordance with the present invention,
especially when combined with a steroid, and more specifically with
dexamethasone.
[0233] Amongst these unexpected properties, the following are of
particular relevance for the target indications: Tyrosine kinase
inhibition of VEGFR1 to 3, FGFR1 and 3, PDGFR .alpha.; Inhibition
of src-tyrosine kinase family members and potential inhibition of
the proliferation of myeloma cells; Inhibition of the
neo-angiogenesis induced by VEGF and bFGF; Inhibition of the
paracrine IL-6 secretion; Inhibition of the cell contact mediated
IL-6 secretion; Inhibition of the autocrine VEGF and bFGF effects;
Direct induction of apoptosis on cell lines with t(4; 14).
[0234] This specific compound appears to be further especially
suitable for the treatment of multiple myeloma. The following
recent findings constitute a line of evidence for the selection of
this specific compound for this indication: Neovascularization
parallels infiltration of bone marrow in a murine multiple myeloma
model (Yaccoby et al., Blood 1998, Vol. 92(8), pp. 2908-2913) and
in multiple myeloma patients undergoing progression (Vacca et al.,
Blood 1999, Vol. 93(9), pp. 3064-3073; Kumar et al., Blood 2002,
Blood First Edition Paper, Pre-published Online October 17, 2002,
DOI 10.1182/blood-2002-08-2441); VEGF has been shown to be a potent
stimulus of angiogenesis (Toi et al., Lancet Oncol. 2001, Vol. 2,
pp. 667-673); VEGF is expressed in and secreted by multiple myeloma
cells (Dankbar et al., Blood 2000, Vol. 95(8), pp. 2630-2636;
Bellamy et al., Cancer Res. 1999, Vol. 59(3), pp. 728-33); VEGF
induces IL-6 secretion from marrow stromal cells, which in turn
augments VEGF expression from clonal plasma cells (Dankbar et al.,
Blood 2000, Vol. 95(8), pp. 2630-2636); IL-6 is considered a major
growth factor for multiple myeloma cells in vivo (Klein et al.,
Blood 1995, Vol. 85(4), pp. 863-872); IL-6 inhibits
Dexamethasone-induced myeloma cell death (Hardin et al., Blood
1994, Vol. 84(9), pp. 3063-3070); VEGF induces proliferation and
triggers migration of multiple myeloma cells (Podar et al., Blood
2001, Vol. 98(2), pp. 428-435); VEGF enhances osteoclastic bone
resorption, which is a characteristic feature of multiple myeloma
(Nakagawa et al., FEBS Lett. 2000, Vol. 473(2), pp. 161-164; Niida
et al., J. Exp. Med. 1999, Vol. 190(2), pp. 293-298); FGFR3 induces
proliferation, inhibits apoptosis and is involved in progression of
myeloma cells (Chesi et al., Blood 2001, Vol. 97(3), pp. 729-736;
Plowright et al., Blood 2000, Vol. 95(3), pp. 992-998); FGFR3 is
dysregulated and constitutively activated in a subset of myeloma
patients (Chesi et al., Blood 2001, Vol. 97(3), pp. 729-736; Chesi
et al., Nat. Genet. 1997, Vol. 16(3), pp. 260-264); Src family
kinases are involved in proliferative responses induced in myeloma
(Ishikawa et al.; Blood 2002, Vol. 99(6), pp. 2172-2178).
[0235] The following results of in vitro experiments evidence that
the properties of the compound MES(T) make it especially suitable
for the treatment of multiple myeloma.
[0236] In the first experiment, the inhibition effect of the
compound MES(T) on the secretion of IL-6 by bone marrow stromal
cells (BMSC cells) was investigated, at different concentrations
(0, 10, 50, 125, 250 and 500 nM) of MES(T), in native conditions
(native) and in conditions of stimulation of the cells with the
bFGF (+bFGF) or with the VEGF (+VEGF) growth factors. For
comparison, the inhibition effect with inhibition of anti-bFGF
(+anti-bFGF), anti-VEGF (+anti-VEGF) and a combination of anti-bFGF
and anti-VEGF (+anti-VEGF+anti-bFGF) were also investigated. The
results of the experiment are shown in the following Table II.
TABLE-US-00003 TABLE II Inhibition of IL-6 secretion by BMSC cells
+ anti-VEGF MES (T) + + + + + concentration native bFGF VEGF
anti-bFGF anti-VEGF anti-bFGF 0 nM 124.2 216.9 107.4 77.7 118.9
71.1 10 nM 130.2 150.5 122.3 68.9 148.6 68.1 50 nM 170.4 179.7
130.7 81.3 155.2 63.4 125 nM 97.5 91.2 141.0 42.4 166.7 86.1 250 nM
76.5 76.9 65.5 33.0 89.4 45.0 500 nM 39.6 43.4 14.8 20.2 16.2
13.5
[0237] The results of this experiment show that the compound MES(T)
at concentration of .gtoreq.250 nM inhibits basal (native) as well
as bFGF/VEGF-stimulated IL-6 secretion of bone marrow stromal cells
(BMSC cells), and that the inhibition is more potent than the
inhibition obtained with the antibodies. Since the bFGF and VEGF
growth factors (released by myeloma cells) have been previously
shown to stimulate BMSC cells and the microvascular endothelium to
produce and secrete IL-6, which itself stimulates myeloma cells to
produce both the bFGF and VEGF growth factors, an inhibition of
IL-6 secretion by the compound in accordance with the present
invention shows its potency for the treatment of multiple
myeloma.
[0238] In a further experiment, the inhibition effect of the
compound MES(T) on the secretion of IL-6 in transwell and contact
co-cultures of myeloma cells (U-266 myeloma cell lines) and bone
marrow stromal cells (BMSC cells) was investigated, at different
concentrations (0, 50, 125, 250 and 500 nM) of MES(T). For
comparison, the inhibition effect on BMSC mono-cultures (native)
and, as control, the level of secretion of U266 mono-cultures, were
also investigated. The results of the experiment are shown in the
following Table III.
TABLE-US-00004 TABLE III Inhibition of IL-6 secretion MES(T) BMSC
Transwell Contact U266 concen- mono- U-266 + BMSC U-266 + BMSC
mono- tration cultures co-cultures co-cultures cultures 0 nM 153.5
336.1 348.1 2.0 50 nM 213.4 354.5 125 nM 192.1 297.6 259.6 250 nM
69.9 231.1 199.4 500 nM 38.6 123.9 114.7
[0239] The results of this experiment show that the compound MES(T)
is able to decrease to its basal (native) value the level of IL-6
secretion of BMSC cultures stimulated by myeloma cells in transwell
and contact co-cultures. Thus, it can be concluded that the
compound MES(T) interferes with the myeloma-stroma interaction
targeting the bone marrow microenvironment by significantly
diminishing NF.kappa.B-dependent IL-6 production. This further
shows the potency of the compound in accordance with the present
invention for the treatment of multiple myeloma.
[0240] In further experiments, it could be shown that the compound
MES(T) provides pro-apoptotic effects in t(14; 16) MM1.s myeloma
cells (MM1.s myeloma cells carrying the translocation t(14; 16)),
and that the compound MES(T) enhances the apoptosis induced by
dexamethasone.
[0241] Due to these properties, it can be concluded that the
compound MES(T)is especially suitable for a combination treatment
of refractory or relapsed multiple myeloma with a steroid, and
especially dexamethasone. [0242] 2. Combination of an antagonist of
at least one receptor selected from VEGFR 1 to 3, PDGGR.alpha. and
.beta., FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, which is
further an antagonist of a src tyrosine kinase family member, or a
polymorph, metabolite or pharmaceutically acceptable salt thereof,
and of a dual antagonist of the epidermal growth factor (EGF)
receptor and of the human epidermal growth factor of type 2 (HE
type 2) receptor, for the treatment of prostate cancer, non-small
cell lung cancer or colorectal cancer
[0243] The following experiment was performed in order to
investigate the effect of a combination therapy with suboptimal
doses of an antagonist of at least one receptor selected from VEGFR
1 to 3, PDGGR.alpha. and .beta., FGFR1, 2 and 3, EGFR, HER2, IGF1R,
HGFR or c-Kit, which is further an antagonist of a src tyrosine
kinase family member, namely the di-chloride salt of
(Z)-3-(1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-
-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
(compound referred to as C12(T)), which is the di-chloride salt of
above exemplified compound (T), and a dual antagonist of the
epidermal growth factor (EGF) receptor and of the human epidermal
growth factor of type 2 (HE type 2) receptor, namely the compound
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute-
n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,
(compound referred to as EGFR/HER2 inh., and described in WO
02/50043 as exemplified compound of Example 1(10)), on the
reduction of tumour growth, in comparison to the mono-therapies at
the same doses.
[0244] For this purpose, nude mice (NMRI nu/nu) were injected
subcutaneously with SKOV-3 cells (human ovarian carcinoma). Mice
carrying established tumours were randomised into control and
treatment groups (N=10). The mice in the control group only
received the carrier solution (0.5% Natrosol), the second group was
treated daily per os with 15 mg/kg EGFR/HER2 inh., the third
received once daily 50 mg/kg C12(T), and the fourth group of mice
was treated with the combination of 15 mg/kg EGFR/HER2 inh. and 50
mg/kg C12(T). FIG. 3 shows the results of the experiment.
[0245] Daily per os treatment was initially performed for 31 days.
At this time point some of the mice from the control group carried
tumours bigger than 2000 mm.sup.3 and therefore had to be
sacrificed. The calculated treated tumour to control tumour (T/C)
ratio at this time point was 35% for the group treated with 15
mg/kg EGFR/HER2 inh., 32% for the group treated with 50 mg/kg
C12(T), and 13% for the group treated with the combination. This
result clearly demonstrates the anti-tumour effect of the
combination of a VEGFR-2 and an EGFR/HER-2 inhibitor in vivo.
Furthermore, continuing the treatment until day 64 shows extremely
slow tumour growth in the combination group in comparison to the
single treatment group where the tumours eventually are growing to
comparable sizes as the control treated tumours.
[0246] From the results of this experiment, it can thus be
concluded that the combination of compounds targeting different
mechanisms involved in and important for tumour growth such as the
VEGFR-2 inhibitor C12(T), inhibiting tumour angiogenesis, and the
combined EGFR/HER-2 inhibitor EGFR/HER2 inh., inhibiting the
proliferative signalling through the class I receptor tyrosine
kinases, have a synergistic anti-tumour efficacy. Thus, all
combinations of inhibitors of tumour angiogenesis (e.g. the
indolinone derivatives described in WO 02/36564, WO 99/52869, WO
00/18734, WO 00/73297, WO 01/27080, WO 01/27081 or WO 01/32651, the
small molecule VEGF receptor antagonists described in WO 01/60814,
WO 99/48868, WO 98/35958, and especially the compounds vatalanib
(PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474,
AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842 or GW-786034, the
monoclonal antibodies directed to the VEGF receptor, and especially
Avastin.TM. (bevacizumab)or IMC-1C11) with EGFR inhibitors (e.g.
iressa (ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272 or
herceptin) or combined EGFR/HER-2 inhibitors (e.g. the quinazoline
derivatives disclosed in WO 00/78735 and WO 02/50043, gefitinib,
erlotinib, CI-1033 or GW-2016) will expectedly have the same or
similar effects for anti-tumour therapies. [0247] 3. Combination
treatment of an antagonist of at least one receptor selected from
VEGFR 1 to 3, PDGGR.alpha. and .beta., FGFR1, 2 and 3, EGFR, HER2,
IGF1R, HGFR or c-Kit, which is further an antagonist of a src
tyrosine kinase family member, or a polymorph, metabolite or
pharmaceutically acceptable salt thereof (e.g. the compound
MES(T)), and of radiation therapy for the treatment of breast
cancer or ovarian cancer [0248] 4. Combination of an antagonist of
at least one receptor selected from VEGFR 1 to 3, PDGGR.alpha. and
.beta., FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, which is
further an antagonist of a src tyrosine kinase family member, or a
polymorph, metabolite or pharmaceutically acceptable salt thereof
(e.g. the compound MES(T)), and of a further antagonist of VEGFR 2,
PDGFR or bFGFR (e.g. vatalanib (PTK-787, ZD-6474, or the monoclonal
antibody Avastin.TM.) or an antagonist of EGFR (e.g. tarceva
(OSI-774)), for the treatment of colorectal cancer, solid tumours,
breast cancer, non-small cell lung cancer, small cell lung cancer
or multiple myeloma [0249] 5. Combination of an antagonist of at
least one receptor selected from VEGFR 1 to 3, PDGFR.alpha. and
.beta., FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, which is
further an antagonist of a src tyrosine kinase family member, or a
polymorph, metabolite or pharmaceutically acceptable salt thereof
(e.g. the compound MES(T)), and of an antimetabolite (e.g.
gemcitabine) and a platinum compound (e.g. cisplatin), or of an
anticancer drug from plants (e.g. paclitaxel) and a platinum
compound (e.g. carboplatin), for the treatment of non-small cell
lung cancer or ovarian carcinoma [0250] 6. Combination of an
antagonist of at least one receptor selected from VEGFR 1 to 3,
PDGFR.alpha. and .beta., FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or
c-Kit, which is further an antagonist of a src tyrosine kinase
family member, or a polymorph, metabolite or pharmaceutically
acceptable salt thereof (e.g. the compound MES(T)), and of hormone
antagonists (e.g. leuprorelin and flutamide), for a continuous
and/or intermittent treatment of metastatic hormone sensitive
prostate cancer [0251] 7. Combination of an antagonist of at least
one receptor selected from VEGFR 1 to 3, PDGFR.alpha. and .beta.,
FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, which is further
an antagonist of a src tyrosine kinase family member, or a
polymorph, metabolite or pharmaceutically acceptable salt thereof
(e.g. the compound MES(T)), and of a derivative of podophyllotoxin
(e.g. etoposide) and a platinum compound (e.g. carboplatin or
cisplatin), for the treatment of small cell lung cancer [0252] 8.
Combination of an antagonist of at least one receptor selected from
VEGFR 1 to 3, PDGGR.alpha. and .beta., FGFR1, 2 and 3, EGFR, HER2,
IGF1R, HGFR or c-Kit, which is further an antagonist of a src
tyrosine kinase family member, or a polymorph, metabolite or
pharmaceutically acceptable salt thereof (e.g. the compound
MES(T)), and of an anticancer drug from plants (e.g. paclitaxel or
taxol), for the treatment of ovarian carcinoma, small cell lung
cancer or prostate cancer [0253] 9. Combination of an antagonist of
at least one receptor selected from VEGFR 1 to 3, PDGGR.alpha. and
.beta., FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, which is
further an antagonist of a src tyrosine kinase family member, or a
polymorph, metabolite or pharmaceutically acceptable salt thereof
(e.g. the compound MES(T)), and of an anticancer drug from plants
(e.g. taxotere) for the treatment of prostate cancer [0254] 10.
Combination of an antagonist of at least one receptor selected from
VEGFR 1 to 3, PDGGR.alpha. and .beta., FGFR1, 2 and 3, EGFR, HER2,
IGF1R, HGFR or c-Kit, which is further an antagonist of a src
tyrosine kinase family member, or a polymorph, metabolite or
pharmaceutically acceptable salt thereof (e.g. the compound
MES(T)), and of a platinum compound (e.g. carboplatin) and an
anticancer drug from plants (e.g. paclitaxel), for the treatment of
ovarian carcinoma, especially after debulking surgery [0255] 11.
Combination of an antagonist of at least one receptor selected from
VEGFR 1 to 3, PDGGR.alpha. and .beta., FGFR1, 2 and 3, EGFR, HER2,
IGF1R, HGFR or c-Kit, which is further an antagonist of a src
tyrosine kinase family member, or a polymorph, metabolite or
pharmaceutically acceptable salt thereof (e.g. the compound
MES(T)), and of a topoisomerase I inhibitor (e.g. topotecan) and an
anthracycline (e.g. doxorubicin), for the treatment of ovarian
cancer [0256] 12. Combination of an antagonist of at least one
receptor selected from VEGFR 1 to 3, PDGGR.alpha. and .beta.,
FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, which is further
an antagonist of a src tyrosine kinase family member, or a
polymorph, metabolite or pharmaceutically acceptable salt thereof
(e.g. the compound MES(T)), and of a topoisomerase I inhibitor
(e.g. topotecan), for the treatment of small cell lung cancer or
ovarian carcinoma [0257] 13. Combination of an antagonist of at
least one receptor selected from VEGFR 1 to 3, PDGGR.alpha. and
.beta., FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, which is
further an antagonist of a src tyrosine kinase family member, or a
polymorph, metabolite or pharmaceutically acceptable salt thereof
(e.g. the compound MES(T)), and of an anticancer drug from plants
(e.g. docetaxel) and a steroid hormone (e.g. estramustine), for the
treatment of hormone refractory prostate cancer [0258] 14.
Combination of an antagonist of at least one receptor selected from
VEGFR 1 to 3, PDGFR.alpha. and .beta., FGFR1, 2 and 3, EGFR, HER2,
IGF1R, HGFR or c-Kit, which is further an antagonist of a src
tyrosine kinase family member, or a polymorph, metabolite or
pharmaceutically acceptable salt thereof (e.g. the compound
MES(T)), and of a vinca alkaloid (e.g. navelbine) for the treatment
of lung cancer [0259] 15. Combination of an antagonist of at least
one receptor selected from VEGFR 1 to 3, PDGFR.alpha. and .beta.,
FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or c-Kit, which is further
an antagonist of a src tyrosine kinase family member, or a
polymorph, metabolite or pharmaceutically acceptable salt thereof
(e.g. the compound MES(T)), and of a platinum compound (e.g.
carboplatin or cis-platin, preferably carboplatin) for the
treatment of ovarian carcinoma or non-small cell lung cancer [0260]
16. Combination of an antagonist of at least one receptor selected
from VEGFR 1 to 3, PDGFR.alpha. and .beta., FGFR1, 2 and 3, EGFR,
HER2, IGF1R, HGFR or c-Kit, which is further an antagonist of a src
tyrosine kinase family member, or a polymorph, metabolite or
pharmaceutically acceptable salt thereof (e.g. the compound
MES(T)), and of a COX-2 inhibitor (e.g. celecoxib, rofecoxib or
meloxicam), for the treatment of colon or rectal cancer [0261] 17.
Combination of an antagonist of at least one receptor selected from
VEGFR 1 to 3, PDGGR.alpha. and .beta., FGFR1, 2 and 3, EGFR, HER2,
IGF1R, HGFR or c-Kit, which is further an antagonist of a src
tyrosine kinase family member, or a polymorph, metabolite or
pharmaceutically acceptable salt thereof (e.g. the compound
MES(T)), and of a 5-alpha reductase inhibitor (e.g. finasteride),
for the treatment of prostate cancer [0262] 18. Combination of an
antagonist of at least one receptor selected from VEGFR 1 to 3,
PDGGR.alpha. and .beta., FGFR1, 2 and 3, EGFR, HER2, IGF1R, HGFR or
c-Kit, which is further an antagonist of a src tyrosine kinase
family member, or a polymorph, metabolite or pharmaceutically
acceptable salt thereof (e.g. the compound MES(T)), and of a
photo-chemotherapeutic agent (PUVA, a combination of psoralen (P)
and long-wave ultraviolet radiation (UVA)), for the treatment of
psoriasis
[0263] Essentially, for the treatment of oncological diseases, the
rationale for the combination treatment in accordance with the
present invention is that there is a therapeutic advantage for the
cancer patient to combine specific and mechanistically acting
molecules with more broadly acting therapeutic concepts in the
following ways: [0264] Through the combination the target cells
will have less chance to survive through possible escape
mechanisms; [0265] When compared to the doses used in a
mono-therapy, due to an additive or synergistic effect of the
combination, the required respective doses of the drugs can be
reduced; [0266] Scheduling of the respective drugs in a combination
reduces the likelihood of the tumour cells to develop resistances
against the drugs, leads to a better delivery of certain drugs to
the tumour (reduction of intratumoral pressure) and may activate
further death pathways in the tumour cells.
[0267] Thus, by targeting different cellular structures and
compartments, the combination therapies in accordance with the
present invention are expected to provide a clinically relevant
benefit in survival or time to tumour progression for larger
patient population as the corresponding mono-therapies. As a result
of the specific anti-angiogenic therapy with, for example, the
compound MES(T), tumours seem to be less capable of recovering from
the damage caused by conventional chemotherapy. Also, by blocking
the effects of VEGF on vascular permeability, a decline of the
interstitial pressure in tumours seems to occur, allowing a greater
penetration of the cytotoxic drugs. Maintenance therapy with a
specific anti-angiogenic agent such as, for example, the compound
MES(T), after standard cytoreduction, seems also to result in a
consolidation of the response obtained with the cytotoxic therapy.
This approach is substantiated by preclinical evidence that
combinations of anti-angiogenic compounds with cytotoxic therapies
result in synergistic anti-tumour activity.
[0268] For the treatment of non-oncological diseases, the rationale
for the combination treatment in accordance with the present
invention is also that there is a therapeutic advantage for the
patient to combine specific and mechanistically acting molecules
with more broadly acting therapeutic concepts. The expected effect
of this combination is to avoid possible escape mechanisms for the
target cells, to reduce the required respective doses of the drugs
in comparison to the doses used in a mono-therapy (due to the
additive or synergistic effect of the combination), and to reduce
the likelihood of the target cells to develop resistances against
the drugs.
LEGEND TO THE FIGURES
[0269] FIG. 1
[0270] Inhibition of VEGFR-2 phosphorylation after varying exposure
of compound MES(T) on NIH3T3 KDR cells. The upper panel shows a
Western blot probed with an antibody specific for phosphorylated
tyrosine residues (.alpha.-PY). The lower panel shows a Western
blot using an antibody specific for VEGFR-2 (.alpha.-KDR).
[0271] FIG. 2
[0272] Evolution of the tumour volume in nude mice bearing
subcutaneous FaDu tumours, untreated (dotted line), treated orally
twice weekly with a dose of 50 mg/kg of compound MES(T) (black
line), or treated orally twice weekly with a dose of 100 mg/kg of
compound MES(T) (gray line).
[0273] FIG. 3
[0274] Evolution of the tumour volume in nude mice bearing
subcutaneous ovarian cancer SKOV-3 tumours, untreated (dashes),
treated daily per os with 15 mg/kg EGFR/HER2 inh. (triangles),
treated daily with 50 mg/kg C12(T) (squares), or treated with the
combination of 15 mg/kg EGFR/HER2 inh. and 50 mg/kg C12(T)
(losanges).
* * * * *