U.S. patent application number 17/383691 was filed with the patent office on 2022-06-16 for combination products with tyrosine kinase inhibitors and their use.
The applicant listed for this patent is Novartis AG. Invention is credited to Mikhail AKIMOV, Christian CHATENAY-RIVAUDAY, Ying GONG, Moriko ITO, Bin PENG, Ralph TIEDT.
Application Number | 20220184090 17/383691 |
Document ID | / |
Family ID | |
Filed Date | 2022-06-16 |
United States Patent
Application |
20220184090 |
Kind Code |
A1 |
TIEDT; Ralph ; et
al. |
June 16, 2022 |
COMBINATION PRODUCTS WITH TYROSINE KINASE INHIBITORS AND THEIR
USE
Abstract
The present invention relates to pharmaceutical products
comprising a combination of (i) a MET inhibitor and (ii) an EGFR
inhibitor, or a pharmaceutically acceptable salt thereof,
respectively, or a prodrug thereof, which are jointly active in the
treatment of proliferative diseases, corresponding pharmaceutical
formulations, uses, methods, processes, commercial packages and
related invention embodiments.
Inventors: |
TIEDT; Ralph; (Pratteln,
CH) ; CHATENAY-RIVAUDAY; Christian; (Saint Louis,
FR) ; ITO; Moriko; (Winterthur, CH) ; AKIMOV;
Mikhail; (Wenslingen, CH) ; PENG; Bin;
(Shanghai, CN) ; GONG; Ying; (Shanghai,
CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Novartis AG |
Basel |
|
CH |
|
|
Appl. No.: |
17/383691 |
Filed: |
July 23, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16905161 |
Jun 18, 2020 |
11096947 |
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17383691 |
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15839964 |
Dec 13, 2017 |
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16905161 |
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14388334 |
Sep 26, 2014 |
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PCT/CN2013/073678 |
Apr 3, 2013 |
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15839964 |
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61619490 |
Apr 3, 2012 |
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International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/4709 20060101 A61K031/4709; A61K 31/498
20060101 A61K031/498; A61K 45/06 20060101 A61K045/06; A61K 31/4706
20060101 A61K031/4706; A61K 31/5025 20060101 A61K031/5025; A61K
31/517 20060101 A61K031/517; A61K 31/53 20060101 A61K031/53; C07D
239/94 20060101 C07D239/94; C07D 487/04 20060101 C07D487/04; C07D
491/04 20060101 C07D491/04 |
Claims
1-13. (canceled)
14. A method of treating cancer, which comprises simultaneous,
separate or sequential administration to a subject in need of such
treatment, (i) a MET tyrosine kinase inhibitor which is
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide, or a pharmaceutically acceptable salt thereof, and (ii)
an EGFR tyrosine kinase inhibitor, or a pharmaceutically acceptable
salt thereof.
15. The method of claim 14, wherein the EGFR tyrosine kinase
inhibitor is erlotinib, lapatinib, canertinib, pelitinib,
neratinib, or cetuximab, or a pharmaceutically acceptable salt
thereof.
16. The method of claim 14, wherein the cancer is breast cancer,
gastric cancer, lung cancer, cancer of the prostate, bladder cancer
or endometrial cancer.
17. The method of claim 14, wherein the cancer is adenocarcinoma,
rhabdomyosarcoma, osteosarcoma, urinary bladder carcinoma,
colorectal cancer or glioma.
18. The method of claim 14, wherein the cancer is lung cancer.
19. The method of claim 14, wherein the cancer is non-small cell
lung cancer.
20. A method of treating cancer, which comprises simultaneous,
separate or sequential administration to a subject in need of such
treatment, (i) a MET tyrosine kinase inhibitor which is
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide, or a pharmaceutically acceptable salt thereof, and (ii)
an EGFR tyrosine kinase inhibitor, or a pharmaceutically acceptable
salt thereof, wherein the subject has developed resistance to EGFR
inhibitor treatment.
21. The method of claim 20, wherein the EGFR tyrosine kinase
inhibitor is erlotinib, lapatinib, canertinib, pelitinib,
neratinib, or cetuximab, or a pharmaceutically acceptable salt
thereof.
22. The method of claim 20, wherein the cancer is breast cancer,
gastric cancer, lung cancer, cancer of the prostate, bladder cancer
or endometrial cancer.
23. The method of claim 20, wherein the cancer is adenocarcinoma,
rhabdomyosarcoma, osteosarcoma, urinary bladder carcinoma,
colorectal cancer or glioma.
24. The method of claim 20, wherein the cancer is lung cancer.
25. The method of claim 20, wherein the cancer is non-small cell
lung cancer.
26. A method of treating cancer, which comprises simultaneous,
separate or sequential administration to a subject in need of such
treatment, (i) a MET tyrosine kinase inhibitor which is
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
bhenzamide, or a pharmaceutically acceptable salt thereof, and (ii)
an EGFR tyrosine kinase inhibitor, or a pharmaceutically acceptable
salt thereof wherein the cancer has an aberration in the c-MET
pathway.
27. The method of claim 26, wherein the cancer further has an
aberration in the EGFR pathway.
28. The method of claim 26, wherein the aberration in the c-MET
pathway is c-MET gene amplification.
29. The method of claim 26, wherein the cancer is progressed after
EGFR inhibitor treatment.
30. The method of claim 26, wherein the subject has developed
resistance to EGFR inhibitor treatment.
Description
RELATED APPLICATIONS
[0001] The present disclosure is a continuation of U.S. patent
application Ser. No. 15/839,964 filed Dec. 13, 2017 which is a
continuation of U.S. patent application Ser. No. 14/388,334, filed
September 26, 2014, which is a National Stage Entry of
PCT/CN2013/073678, filed Apr. 3, 2013, which claims priority to
U.S. Provisional Application No. 61/619,490, filed Apr. 3, 2012,
which is incorporated by reference herein in its entirety.
SUMMARY OF THE INVENTION
[0002] The present invention relates to pharmaceutical
combinations, e.g. products, comprising a combination of (i) a MET
inhibitor and (ii) an EGFR (ErbB-1) inhibitor, or a
pharmaceutically acceptable salt thereof, respectively, or a
prodrug thereof, which are jointly active in the treatment of
proliferative diseases, corresponding pharmaceutical formulations,
uses, methods, processes, commercial packages and related invention
embodiments.
BACKGROUND OF THE INVENTION
[0003] Drugs that were designed to act against individual molecular
targets often are not appropriate to combat diseases with more than
one target as cause (multigenic diseases), such as cancer or other
proliferative diseases.
[0004] In order to combat such diseases, one approach is to use
single multi-target drugs--however, here it is required that the
targets causally involved into manifestation of a disease are all
hit by the drug considered. On the other hand, multi-target drugs
may lead to undesired side effects as they may also have impact on
targets not involved in the disease manifestation.
[0005] A different approach is to use a combination of drugs as
multi-target drugs. In the best scenario, this may lead to a
combined efficiency, e.g. synergy, thus even allowing a reduction
of side effects caused by the single drugs when used alone.
[0006] Occasionally, the components (combination partners) of such
drugs may impact separate targets to create a combination effect,
and thus may create a combination effect going beyond what is
achievable with the single compounds and/or when considering their
isolated effects, respectively, either in the same pathway or
separate pathways, within an individual cell or in separate cells
in separate tissues. Alternatively, one component may alter the
ability of another to reach its target, e.g. by inhibiting of
efflux pumps or the like. Yet alternatively, the combination
partners may bind to separate sites of the same target. These
variants of target connectivity hamper the search for appropriate
combinations by hugely increasing the possible types of
interactions that might be useful for combination or not.
[0007] However, a desired cooperation, or even a synergy, using
such drugs may not be found in many cases. As the number of
pairwise (r=2) drug combinations increases according to the formula
n!/(r!(n-r)!) with the number of agents n being tested (e.g.
testing 2000 agents would already generate 1,999,000 unique
pairwise combinations), an appropriate screening method allowing
high efficiency is necessary.
[0008] In addition, before any combination is considered, there is
a crucial requirement to identify the pathways, enzymes, metabolic
states or the like that are involved causally or in a supporting
way in the disease manifestation.
[0009] In many cases, it is not even known at all that a given
disease is multigenic.
[0010] Therefore, the search for appropriate combinations and
amounts can properly be described to correspond to finding a needle
in a haystack.
[0011] The proto-oncogen cMET (MET) encodes the protein Hepatocyte
Growth Factor Receptor (HGFR) which has tyrosine kinase activity
and is essential for embryonic development and wound healing. Upon
Hepatocyte Growth Factor (HGF) stimulation, MET induces several
biological responses, leading to invasive growth. Abnormal MET
activation triggers tumor growth, formation of new blood vessels
(angiogenesis) and metastasis, in various types of malignancies,
including cancers of the kidney, liver, stomach, breast and brain.
A number of MET kinase inhibitors are known, and alternatively
inhibitors of HGF-induced MET (=HGFR) activation. The biological
functions of c-MET (or c-MET signaling pathway) in normal tissues
and human malignancies such as cancer have been well documented
(Christensen, J. G. et al., Cancer Lett. 2005, 225(1):1-26; Corso,
S. et al., Trends in Mol. Med. 2005, 11(6):284-292).
[0012] A dysregulated c-Met (c-MET) pathway plays important and
sometimes causative (in the case of genetic alterations) roles in
tumor formation, growth, maintenance and progression (Birchmeier,
C. et al., Nat. Rev. Mol. Cell. Biol. 2003, 4(12):915-925;
Boccaccio, C. et al., Nat. Rev. Cancer 2006, 6(8):637-645;
Christensen, J. G. et al., Cancer Lett. 2005, 225(1):1-26). HGF
and/or c-Met are overexpressed in significant portions of most
human cancers, and are often associated with poor clinical outcomes
such as more aggressive disease, disease progression, tumor
metastasis and shortened patient survival. Further, patients with
high levels of HGF/c-Met proteins are more resistance to
chemotherapy and radiotherapy. In addition to the abnormal
HGF/c-Met expression, c-Met receptor can also be activated in
cancer patients through genetic mutations (both germline and
somatic) and gene amplification. Although gene amplification and
mutations are the most common genetic alterations that have been
reported in patients, the receptor can also be activated by
deletions, truncations, gene rearrangement.
[0013] The various cancers in which c-MET is implicated include,
but are not limited to: carcinomas (e.g., bladder, breast,
cervical, cholangiocarcinoma, colorectal, esophageal, gastric, head
and neck, kidney, liver, lung, nasopharygeal, ovarian, pancreas,
prostate, thyroid); musculoskeletal sarcomas (e.g., osteosarcaoma,
synovial sarcoma, rhabdomyosarcoma); soft tissue sarcomas (e.g.,
MFH/fibrosarcoma, leiomyosarcoma, Kaposi's sarcoma); hematopoietic
malignancies (e.g., multiple myeloma, lymphomas, adult T cell
leukemia, acute myelogenous leukemia, chronic myeloid leukemia);
and other neoplasms (e.g., glioblastomas, astrocytomas, melanoma,
mesothelioma and Wilm's tumor (www.vai.org/met/; Christensen, J. G.
et al., Cancer Lett. 2005, 225(1):1-26).
[0014] The notion that the activated c-MET pathway contributes to
tumor formation and progression and could be a good target for
effective cancer intervention has been further solidified by
numerous preclinical studies (Birchmeier, C. et al., Nat. Rev. Mol.
Cell Biol. 2003, 4(12):915-925; Christensen, J. G. et al., Cancer
Lett. 2005, 225(1):1-26; Corso, S. et al., Trends in Mol. Med.
2005, 11(6): 284-292). For example, studies showed that the tpr-met
fusion gene, overexpression of c-met and activated c-met mutations
(collectively referred to herein as MET) all caused oncogenic
transformation of various model cell lines and resulted in tumor
formation and metastasis in mice. More importantly, significant
anti-tumor (sometimes tumor regression) and anti-metastasis
activities have been demonstrated in vitro and in vivo with agents
that specifically impair and/or block HGF/c-MET signaling. Those
agents include anti-HGF and anti-c-Met antibodies, HGF peptide
antagonists, decoy c-Met receptor, c-Met peptide antagonists,
dominant negative c-Met mutations, c-Met specific antisense
oligonucleotides and ribozymes, and selective small molecule c-Met
kinase inhibitors (Christensen, J. G. et al., Cancer Lett. 2005,
225(1):1-26).
[0015] In addition to the established role in cancer, abnormal
HGF/MET signaling is also implicated in atherosclerosis, lung
fibrosis, renal fibrosis and regeneration, liver diseases, allergic
disorders, inflammatory and autoimmune disorders, cerebrovascular
diseases, cardiovascular diseases, conditions associated with organ
transplantation (Ma, H. et al., Atherosclerosis. 2002,
164(1):79-87; Crestani, B. et al., Lab. Invest. 2002,
82(8):1015-1022; Sequra-Flores, A. A. et al., Rev. Gastroenterol.
Mex. 2004, 69(4)243-250; Morishita, R. et al., Curr. Gene Ther.
2004, 4(2)199-206; Morishita, R. et al., Endocr. J. 2002,
49(3)273-284; Liu, Y., Curr. Opin. Nephrol. Hypertens. 2002,
11(1):23-30; Matsumoto, K. et al., Kidney Int. 2001,
59(6):2023-2038; Balkovetz, D. F. et al., Int. Rev. Cytol. 1999,
186:225-250; Miyazawa, T. et al., J. Cereb. Blood Flow Metab. 1998,
18(4)345-348; Koch, A. E. et al., Arthritis Rheum. 1996,
39(9):1566-1575; Futamatsu, H. et al., Circ. Res. 2005,
96(8)823-830; Eguchi, S. et al., Clin. Transplant. 1999,
13(6)536-544).
[0016] The Epidermal Growth Factor Receptor (EGFR, aka ErbB-1; HER1
in humans), is a receptor for ligands of the epidermal growth
factor family. Several types of cancers are known to be dependent
on EGFR over-activity or over-expression, such as lung cancer, anal
cancers, glioblastoma multiforme and many other mainly epithelial
cancers.
[0017] Cancer is often dependent on the genetic alteration of
receptor tyrosine kinases (RTKs) e.g. by point mutation, gene
amplification or chromosomal translocation which leads to
uncontrolled activity of these RTKs which thus become oncogenic.
Cell proliferation of cancer cells is dependent on the activity of
these aberrant RTKs.
[0018] When treating the resulting proliferative diseases, often
inhibitors of the oncogene RTK involved are used. However, often,
after a certain time of treatment, resistance to the drug used is
observed. One mechanism of resistance can involve the target RTK,
compromising binding or activity of the therapeutic agent. Another
mechanism is compensatory activation of an alternative kinase that
continues to drive cancer growth when the primary kinase is
inhibited. A well-characterized example covering both types of
mechanisms is acquired resistance to the epidermal growth factor
receptor (EGFR) gefitinib and erlotinib in non-small cancer (NSCLC)
carrying activating EGFR mutations (see Lynch, T. J., et al.,. N
Engl J Med, 350: 2129-2139, 2004; or Paez, J. G., et al., Science,
304: 1497-1500, 2004). For example, MET activation can compensate
for loss of EGFR activity (by inhibition) by downstream activation
of signal molecules such as HER3, such as MET amplification may
compensate, or its ligand hepatocyte growth factor may activate MET
(see Engelman, J. A., et al., Science, 316: 1039-1043, 2007; Yano,
S., et al., Cancer Res, 68: 9479-9487, 2008; and Turke, A. B., et
al., Cancer Cell, 17: 77-88, 2010). It is also known that
MET-dependent cancer cell lines (the proliferation of which depends
on the activity of MET) can be rescued from MET inhibitors by
ligand-induced EGFR activation (see Bachleitner-Hofmann, T., et
al.,. Mol Cancer Ther, 7: 3499-3508, 2008).
GENERAL DESCRIPTION OF THE INVENTION
[0019] Using cancer cells originally dependent on MET and/or EGFR
(that is, their activity), a by-pass of dependence through
ligand-mediated activation of alternative receptor tyrosine kinases
(RTKs) was observed. By-pass mechanisms were discovered when
treating MET- or FGFR-dependent lines with a corresponding
selective inhibitor (that is, MET-dependent lines with a MET
inhibitor and FGFR-dependent lines with an FGFR inhibitor) and at
the same time adding supernatants from cells transfected with cDNA
coding for various secreted proteins It could be shown that the MET
and FGFR RTKs can compensate for loss of each other, thus leading
to "rescue" of proliferating cells if only one of these RTKs is
inhibited by an appropriate drug.
[0020] It was surprisingly found that combined inhibition of these
RTKs can lead to synergistic anti-cancer activity especially when
MET and an FGFR RTK are both active and then, according to the
invention, can be inhibited simultaneously or jointly
sequentially.
SPECIFIC DESCRIPTION OF THE INVENTION
[0021] The present invention, according to a first embodiment,
relates to a pharmaceutical combination (e.g. combination product)
comprising (i) a MET inhibitor and (ii) an EGFR inhibitor, or a
pharmaceutically acceptable salt thereof, respectively, or a
prodrug thereof, respectively, and at least one pharmaceutically
acceptable carrier.
[0022] A further embodiment of this invention provides a
combination (e.g. combination product) comprising a quantity which
is jointly therapeutically effective against an EGFR tyrosine
kinase activity and/or MET tyrosine kinase activity mediated
disease, especially a cancer, comprising the combination partners
(i) EGFR tyrosine kinase inhibitor and (ii) MET tyrosine kinase
inhibitor, or, respectively, a pharmaceutically acceptable salt
thereof, and at least one pharmaceutically acceptable carrier
material.
[0023] A further embodiment relates to the use of the inventive
combination (e.g. combination product) for treating an EGFR
tyrosine kinase activity and/or MET tyrosine kinase activity
mediated disease, especially a cancer.
[0024] A further embodiment relates to the use of a combination of
(i) an EGFR tyrosine kinase inhibitor and (ii) a MET tyrosine
kinase inhibitor or, respectively, a pharmaceutically acceptable
salt thereof, for the manufacture of a medicament or a
pharmaceutical product for treating an EGFR tyrosine kinase
activity and/or MET tyrosine kinase activity mediated disease,
especially a cancer.
[0025] A further embodiment relates to a method of treating an EGFR
tyrosine kinase activity and/or MET tyrosine kinase activity
mediated disease, especially a cancer, with a combination of (i) an
EGFR tyrosine kinase inhibitor and (ii) a MET tyrosine kinase
inhibitor or, respectively, a pharmaceutically acceptable salt
thereof.
[0026] A further embodiment relates to a method for the treatment
of an EGFR tyrosine kinase activity and/or MET tyrosine kinase
activity mediated disease, especially a cancer, said method
comprising administering an effective amount of a combi-nation of
or a combination product comprising (i) an EGFR tyrosine kinase
inhibitor and (ii) a MET tyrosine kinase inhibitor to a subject in
need thereof, such as a warm-blooded animal, in particular a
human.
[0027] Yet a further embodiment of present invention relates to a
pharmaceutical product or a commercial package comprising a
combination product according to the invention described herein, in
particular together with instructions for simultaneous, separate or
sequential use (especially for being jointly active) thereof in the
treatment of an EGFR tyrosine kinase activity and/or MET tyrosine
kinase activity mediated disease, especially a cancer, in
particular for use in the treatment of an EGFR tyrosine kinase
activity and/or MET tyrosine kinase activity mediated disease,
especially a cancer.
[0028] A further embodiment of present invention relates to the use
of (i) an EGFR tyrosine kinase inhibitor and (ii) a MET tyrosine
kinase inhibitor or, respectively, a pharmaceutically acceptable
salt thereof, for the preparation of a combination (e.g. a
combination product) according to present invention.
[0029] The following definitions show more specific embodiments of
general features or expressions which can be used to replace one,
more than one or all general features or expressions in the
invention embodiments described hereinbefore and hereinafter, thus
leading to more specific invention embodiments.
[0030] Among the MET tyrosine kinase inhibitors useful according to
the invention, those disclosed in WO 2011/018454 (incorporated
herein by reference especially with regard to the classes of
compoounds and compounds disclosed therein) are a particular
embodiment, especially those of the formula (I),
##STR00001##
[0031] wherein
[0032] Y is C or N;
[0033] X is CH or N;
[0034] B is CH or N;
[0035] A is a ring;
[0036] such that when X is CH and B is N, ring A is ring Ai or ring
Aii;
##STR00002##
[0037] when X is N and B is N, ring A is Aiii;
##STR00003##
[0038] and when X is N and B is N, or X is N and B is CH, ring A is
Ai;
##STR00004##
[0039] R.sup.1 is a group selected from i, ii and iii:
##STR00005##
[0040] wherein R.sup.5 is heteroaryl;
[0041] R.sup.6 is hydrogen, deuterium, OH, methyl or halo;
[0042] R.sup.7 is hydrogen, deuterium, halo, or
(C.sub.1-C.sub.3)alkyl, wherein said (C.sub.1-C.sub.3)alkyl is
optionally substituted by one or more substituents independently
selected from OH and halo;
[0043] or R.sup.6 and R.sup.7, together with the carbon to which
they are attached form cyclopropyl, wherein said cyclopropyl is
optionally substituted by methyl;
[0044] n is 0, 1 or 2;
[0045] R.sup.2 is hydrogen, NH.sub.2, or (C.sub.1-C.sub.4)alkyl,
wherein said (C.sub.1-C.sub.4)alkyl is optionally substituted by
one or more substituents independently selected from OH, NH.sub.2
and halo;
[0046] R.sup.3 is hydrogen, --CON H.sub.2,
--CONH(C.sub.1-C.sub.4)alkyl, --CONHphenyl, wherein the phenyl of
said CONHphenyl is optionally substituted by one or more halo,
--(C.sub.1-C.sub.4)alkyl, --CO(C.sub.1-C.sub.4)alkyl,
--CO.sub.2(C.sub.1-C.sub.4)alkyl, phenyl, heteroaryl,
--COheteroaryl, 13 CSNH.sub.2, --CSNH(C.sub.1-C.sub.4)alkyl,
--CSNHbenzyl, --SO.sub.2(C.sub.1-C.sub.4)alkyl or
--COCH.sub.2heterocyclyl, said heterocyclyl being optionally
substituted by (C.sub.1-C.sub.3)alkyl;
[0047] R.sup.4 is hydrogen or (C.sub.1-C.sub.3)alkyl;
[0048] or R.sup.3 and R.sup.4 together with the nitrogen to which
they are attached form a 5 or 6 membered saturated or partially
unsaturated monocyclic group comprising 1 ring N atom to which
R.sup.3 and R.sup.4 are attached and optionally 1 additional ring
heteroatom independently selected from N, 0 and S, wherein said
monocyclic group is substituted by one or two .dbd.O
substituents;
[0049] or a pharmaceutically acceptable salt thereof.
[0050] Especially preferred of the group of compounds of the
formula I which are MET tyrosine kinase inhibitors is that with the
name
(E)-2-(1-(3-((7-fluoroquinolin-6-ylmethyl)imidazo[1,2-b]pyridazin-6-yl)et-
hylidene)hydrazinecarboxamide (also called Cpd. A in the following)
which has the formula:
##STR00006##
[0051] See WO 11 018454, Example 1.
[0052] Among the MET tyrosine kinase inhibitors useful according to
the invention, as a particular embodiment there are also to be
mentioned those disclosed, together with methods for their
manufacture, in WO 2008/064157 (incorporated herein by reference
especially with regard to the disclosed compounds and compound
classes), especially the compounds having Formula III:
##STR00007##
[0053] or pharmaceutically acceptable salts thereof or prodrugs
thereof, wherein: [0054] A is N or CR.sup.3; [0055] Cy.sup.1 is
aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally
substituted by 1, 2, 3, 4, or 5 --W--X--Y--Z; [0056] Cy.sup.2 is
aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionally
substituted by 1, 2, 3, 4, or 5 --W--X'--Y'--Z'; [0057] L.sup.1 is
(CR.sup.4R.sup.5)m,
(CR.sup.4R.sup.5).sub.p-(cycloalkylene)-(CR.sup.4R.sup.5).sub.q,
(CR.sup.4R.sup.5).sub.p-(arylene)-(CR.sup.4R.sup.5).sub.q,
(CR.sup.4R.sup.5).sub.p-(heterocycloalkylene)-(CR.sup.4R.sup.5).sub.q,
(CR.sup.4R.sup.5).sub.p-(heteroarylene)-(CR.sup.4R.sup.5).sub.q,
(CR.sup.4R.sup.5).sub.pO(CR.sup.4R.sup.5).sub.q,
(CR.sup.4R.sup.5).sub.pS(CR.sup.4R.sup.5).sub.q,
(CR.sup.4R.sup.5).sub.pC(O)(CR.sup.4R.sup.5).sub.q,
(CR.sup.4R.sup.5).sub.pC(O)NR.sup.6(CR.sup.4R.sup.5).sub.q,
(CR.sup.4R.sup.5).sub.pNR.sup.5(CR.sup.4R.sup.5).sub.q,
(CR.sup.4R.sup.5).sub.pNR.sup.5C(O)NR.sup.5(CR.sup.4R.sup.5).sub.q,
(CR.sup.4R.sup.5).sub.pOC(O)NR.sup.6(CR.sup.4R.sup.5).sub.q,
(CR.sup.4R.sup.5).sub.pNR.sup.6(CR.sup.4R.sup.5).sub.q,
(CR.sup.4R.sup.5).sub.pNR.sup.6C(O)NR.sup.6(CR.sup.4R.sup.5).sub.q,
(CR.sup.4R.sup.5).sub.pS(O)(CR.sup.4R.sup.5).sub.q,
(CR.sup.4R.sup.5).sub.pS(O)NR.sup.6(CR.sup.4R.sup.5).sub.q,
(CR.sup.4R.sup.5).sub.pS(O).sub.2(CR.sup.4R.sup.5).sub.q, or
(CR.sup.4R.sup.5).sub.pS(O).sub.2NR.sup.6(CR.sup.4R.sup.5).sub.q,
wherein said cycloalkylene, arylene, heterocycloalkylene, or
heteroarylene is optionally substituted with 1, 2, or 3
substituents independently selected from Cy.sup.3, halo, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halosulfanyl, CN, NO.sub.2, N.sub.3, OR.sup.a, SR.sup.a,
C(O)R.sup.b, C(O)NR.sup.cR.sup.d, C(O)OR.sup.a, OC(O)R.sup.b,
OC(O)NR.sup.cR.sup.d, NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.b,
NR.sup.cC(O)NR.sup.cR.sup.d, NR.sup.cC(O)OR.sup.a,
C(.dbd.NR.sup.gR.sup.d, NR.sup.cC(.dbd.NR.sup.g)NR.sup.cR.sup.d,
P(R.sup.f).sub.2, P(OR.sup.e).sub.2, P(O)OR.sup.eOR.sup.f,
S(O)R.sup.b, S(O)NR.sup.cR.sup.d, S(O)NR.sup.cR.sup.d,
S(O).sub.2R.sup.b, NR.sup.cS(O).sub.2R.sup.b, and
S(O).sub.2NR.sup.cR.sup.d;
[0058] L.sup.2 is (CR.sup.7R.sup.8),
(CR.sup.7R.sup.8).sub.5-(cycloalkylene)-(CR.sup.7R.sup.8).sub.t,
(CR.sup.7R.sup.8).sub.s-(arylene)-(CR.sup.7R.sup.8).sub.t,
(CR.sup.7R.sup.8).sub.s-(heterocycloalkylene)-(CR.sup.7R.sup.8).sub.t,
(CR.sup.7R.sup.8).sub.s-(heteroarylene)-(CR.sup.7R.sup.8).sub.t,
(CR.sup.7R.sup.8).sub.s-(heteroarylene)-(CR.sup.7R.sup.8).sub.t,
(CR.sup.7R.sup.8).sub.sC)(O)O(CR.sup.7R.sup.8.sub.t,
(CR.sup.7R.sup.8).sub.sOC(O)(CR.sup.7R.sup.8).sub.t,
CR.sup.7R.sup.8).sub.sOC(NR.sup.9(CR.sup.7R.sup.8).sub.t,
(CR.sup.7R.sup.8).sub.sNR.sup.9(CR.sup.7R.sup.8).sub.tt,
(CR.sup.7R.sup.8).sub.s, NR.sup.9C(O)NR.sup.8(CR.sup.7R.sup.8),
(CR.sup.7R.sup.8),
CR.sup.7R.sup.8).sub.sS(O)(CR.sup.7R.sup.8).sub.t,
(CR.sup.7R.sup.8).sub.sS(O)NR.sup.7(CR.sup.8R.sup.9).sub.t,
(CR.sup.7R.sup.8).sub.sS(O)(CR.sup.7R.sup.8(.sub.t, pr
(CR.sup.7R.sup.8_.sub.sS(O).sub.2MR.sup.9(CR.sup.7CR.sup.8).sub.t,
wherein said cycloalkylene, arylene, heterocycloalkylene, or
heteroarylene is optionally substituted with 1, 2, or 3
substituents independently selected from Cy.sup.4, halo, C.sub.1-6
alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl,
halosulfanyl, CN, NO.sub.2, N.sub.3, OR.sup.a1, SR.sup.a1,
C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1, C(O)NR.sup.c1, R.sup.d1,
C(O)OR.sup.a1, OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.c1R.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.9)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.9)NR.sup.c1R.sup.d1, P(R.sup.f1).sub.2,
P(O)R.sup.e1).sub.2, P(O)R.sup.e1R.sup.11, P(O)OR.sup.e1OR.sup.f1,
S(O)NR.sup.c1R.sup.d1, S(O).sub.2R.sup.b1,
NR.sup.c1S(O).sub.2R.sup.b1, and S(O).sub.2NR.sup.c1R.sup.d1;
[0059] R.sup.1 is H or --'--X''--Y''--Z'';
[0060] R.sup.2 is H, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, CN, NO.sub.2, OR.sup.A,
SRA, C(O)R.sup.B, C(O)NR.sup.CR.sup.D, C(O)OR.sup.A, OC(O)R.sup.B,
OC(O)NR.sup.CR.sup.D, NR.sup.CR.sup.D, NR.sup.CC(P)R.sup.B,
NR.sup.CC(O)NR.sup.CR.sup.D, NR.sup.CC(O)OR.sup.A, S(O)R.sup.B,
S(O)NR.sup.CR.sup.D, S(O).sub.2R.sup.B, NRCS(O).sub.2R.sup.B, or
S(O).sub.2NR.sup.CR.sup.D;
[0061] R.sup.3 is H, cycloalkyl, aryl, heterocycloalkyl,
heteroaryl, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, CN, NO.sub.2, OR.sup.A, SR.sup.A,
C(O)R.sup.8, C(O)NR.sup.CRD, C(O)OR.sup.A, OC(O)R.sup.B,
OC(O)NR.sup.CR.sup.D, NR.sup.CR.sup.D, NR.sup.CC(O)R.sup.B,
NR.sup.CC(O)NR.sup.CR.sup.D, NR.sup.CC(O)OR.sup.A, S(O)R.sup.B,
S(O)NR.sup.CR.sup.D, S(O).sub.2R.sup.B, NR.sup.CS(O).sub.2R.sup.B,
and S(O).sub.2NR.sup.CR.sup.D; wherein said cycloalkyl, aryl,
heterocycloalkyl, heteroaryl, or C.sub.1-6 alkyl is optionally
substituted with 1, 2, or 3 substituents independently selected
from Cy.sup.5, halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.1-6 haloalkyl, halosulfanyl, CN, NO.sub.2, N.sub.3,
OR.sup.a1, SR.sup.a1, C(O)R.sup.b1, C(O)NR.sup.c1R.sup.d1,
C(O)OR.sup.a1, OC(O)R.sup.b1, OC(O)NR.sup.c1R.sup.d1,
NR.sup.c1R.sup.d1, NR.sup.c1C(O)R.sup.b1,
NR.sup.c1C(O)NR.sup.cR.sup.d1, NR.sup.c1C(O)OR.sup.a1,
C(.dbd.NR.sup.g)NR.sup.c1R.sup.d1,
NR.sup.c1C(.dbd.NR.sup.g)NR.sup.c1R.sup.d1,
[0062] P(R.sup.11).sub.2, P(OR.sup.e1).sub.2, P(O)R.sup.e1R.sup.11,
P(O)OR.sup.e1OR.sup.11, S(O)R.sup.b1, S(O)NR.sup.c1R.sup.d1,
S(O).sup.2R.sup.b1, NR.sup.c1S(O).sub.2R.sup.b1, and
S(O).sub.2NR.sup.c1R.sup.d1; [0063] or R.sup.2 and
--L.sup.2-Cy.sup.2 are linked together to form a group of
formula:
##STR00008##
[0064] wherein ring B is a fused aryl or fused heteroaryl ring,
each optionally substituted with 1, 2, or 3 --W'--X'--Y'--Z';
[0065] R.sup.4 and R.sup.5 are independently selected from H, halo,
OH, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6alkynyl, C.sub.1-6
alkoxy, alkoxyalkyl, cyanoalkyl, heterocycloalkyl, cycloalkyl,
C.sub.1-6 haloalkyl, CN, and NO.sub.2; [0066] or R.sup.4 and
R.sup.5 together with the C atom to which they are attached form a
3, 4, 5, 6, or 7-membered cycloalkyl or heterocycloalkyl ring, each
optionally substituted by 1, 2, or 3 substituents independently
selected from halo, OH, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, alkoxyalkyl, cyanoalkyl,
heterocycloalkyl, cycloalkyl, C.sub.1-6 haloalkyl, CN, and
NO.sub.2;
[0067] R.sup.6 is H, C.sub.1-6 alkyl, C.sub.2-.sub.6 alkenyl, or
C.sub.2-.sub.6 alkynyl;
[0068] R.sup.7 and R.sup.8 are independently selected from H, halo,
OH, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, CN, and NO.sub.2;
[0069] or R.sup.7 and R.sup.8 together with the C atom to which
they are attached form a 3, 4, 5, 6, or 7-membered cycloalkyl or
heterocycloalkyl ring, each optionally substituted by 1, 2, or 3
substituent independently selected from halo, OH, C.sub.1-6 alkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, C.sub.1-6
haloalkyl, CN, and NO.sub.2;
[0070] R.sup.9 is H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, or
C.sub.2-6 alkynyl;
[0071] W, W, and W' are independently absent or independently
selected from C.sub.1-6 alkylene, C.sub.2-6 alkenylene, C.sub.2-6
alkynylene, O, S, NR.sup.h, CO, COO, CONR.sup.h, SO, SO.sub.2,
SONR.sup.h and NR.sup.hCONR.sup.i, wherein each of the C.sub.1-6
alkylene, C.sub.2-6 alkenylene, and C.sub.2-6 alkynylene is
optionally substituted by 1, 2 or 3 substituents independently
selected from halo, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, OH,
C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, amino, C.sub.1-6
alkylamino, and C.sub.2-8 dialkylamino;
[0072] X, X', and X'' are independently absent or independently
selected from C.sub.1-6 alkylene, C.sub.2-6 alkenylene, C.sub.2-6
alkynylene, arylene, cycloalkylene, heteroarylene, and
heterocycloalkylene, wherein each of the C.sub.1-6 alkylene,
C.sub.2-6 alkenylene, C.sub.2-6 alkynylene, arylene, cycloalkylene,
heteroarylene, and heterocycloalkylene is optionally substituted by
1, 2 or 3 substituents independently selected from halo, CN,
NO.sub.2, OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-8
alkoxyalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.2-8
alkoxyalkoxy, cycloalkyl, heterocycloalkyl, C(O )OR.sup.i,
C(O)NR.sup.hR.sup.i, amino, C.sub.1-6 alkylamino, and C.sub.2-8
dialkylamino;
[0073] Y, Y', and Y'' are independently absent or independently
selected from C.sub.1-6 alkylene, C.sub.2-6 alkenylene, C.sub.2-6
alkynylene, O, S, NR.sup.h, CO, COO, CONR.sup.h, SO, SO.sub.2,
SONRh, and NR.sup.hCONR.sup.i, wherein each of the C.sub.1-6
alkylene, C.sub.1-6 alkenylene, and C.sub.2-6 alkynylene is
optionally substituted by 1, 2 or 3 substituents independently
selected from halo, C.sub.1-6 alkyl, C.sub.3-6 haloalkyl, OH,
C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, amino, C.sub.1-6
alkylamino, and C.sub.1-6 dialkylamino;
[0074] Z, Z', and Z'' are independently selected from H, halo,
C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6
haloalkyl, halosulfanyl, CN, NO.sub.2, N.sub.3, OR.sup.a2,
SR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2, C(O)OR.sup.a2,
OC(O)R.sup.b2, OC(O)NR.sup.c2R.sup.d2, NR.sup.c2R.sup.d2,
NR.sup.c2C(O)R.sup.b2, NR.sup.c2C(O)NR.sup.c2R.sup.d2,
NR.sup.c2C(O)NR.sup.a2, C(.dbd.NR.sup.g)NR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.g)NR.sup.c2R.sup.d2, P(OR.sup.g2).sub.2,
P(O)R.sup.e2).sub.2, P(O)R.sup.e2R.sup.f2, P(O)OR.sup.e2OR.sup.f2,
S(O)R.sup.b2, S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, S(O).sub.2NR.sup.c2R.sup.d2, aryl,
cycloalkyl, heteroaryl, and heterocycloalkyl, wherein said
C.sub.1-3 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl,
cycloalkyl, heteroaryl, and heterocycloalkyl are optionally
substituted by 1, 2, 3, 4 or 5 substituents independently selected
from halo, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.02-6 alkynyl,
C.sub.1-6 haloalkyl, halosulfanyl, CN, NO.sub.2, N.sub.3,
OR.sup.a2, SR.sup.a2, C(O)R.sup.b2, C(O)NR.sup.c2R.sup.d2,
C(O)OR.sup.a2, OC(O)R.sup.b2, OC(O)NR.sup.c2R.sup.d2,
NR.sup.c2R.sup.d2, NR.sup.c2C(O)R.sup.b2,
NR.sup.c2C(O)NR.sup.c2R.sup.d2, NR.sup.c2C(O)OR.sup.a2,
C(.dbd.NR.sup.gNR.sup.c2R.sup.d2,
NR.sup.c2C(.dbd.NR.sup.gNR.sup.c2R.sup.d2, P(R.sup.f2).sub.2,
P(OR.sup.e2).sub.2, P(O)R.sup.e2R.sup.f2, P(O)OR.sup.e2OR.sup.f2,
S(O)R.sup.b2, S(O)NR.sup.c2R.sup.d2, S(O).sub.2R.sup.b2,
NR.sup.c2S(O).sub.2R.sup.b2, and S(O).sub.2NR.sup.c2R.sup.f2;
[0075] wherein two adjacent --W--X--Y--Z, together with the atoms
to which they are attached, optionally form a fused 4-20 membered
cycloalkyl ring or a fused 4-20 membered heterocyclo-alkyl ring,
each optionally substituted by 1, 2, or 3 substituents
independently selected from halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halosulfanyl, CN,
NO.sub.2, OR.sup.a3, SR.sup.a3, C(O)R.sup.b3,
C(O)NR.sup.c3R.sup.d3, C(O)OR.sup.a3, OC(O)R.sup.b3,
OC(O)NR.sup.c3R.sup.d3, NR.sup.c3R.sup.d3, NR.sup.c3C(O)R.sup.b3,
NR.sup.c3(O)NR.sup.c3R.sup.d3, NR.sup.c3C(O)OR.sup.a3,
C(.dbd.NR.sup.gNR.sup.c3R.sup.d3,
NR.sup.c3C(.dbd.NR.sup.g)NR.sup.c3R.sup.d3, S(O)R.sup.b3,
S(U)NR.sup.c3R.sup.d3, S(O).sub.2R.sup.b3,
NR.sup.c3S(O).sub.2R.sup.b3, S(O).sub.2NR.sup.c3R.sup.d3, aryl,
cycloalkyl, heteroaryl, and heterocycloalkyl;
[0076] wherein two adjacent --W--X'--Y'--Z', together with the
atoms to which they are attached, optionally form a fused 4-20
membered cycloalkyl ring or a fused 4-20 membered heterocycloalkyl
ring, each optionally substituted by 1, 2, or 3 substituents
independently selected from halo, CC.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halosulfanyl, CN,
NO.sub.2, OR.sup.a3, SR.sup.a3, C(O)R.sup.b3,
C(O)NR.sup.c3R.sup.d3, C(O)OR.sup.a3, OC(O)R.sup.b3,
OC(O)NR.sup.c3R.sup.d3, NR.sup.c3R.sup.d3, NR.sup.c3C(O)R.sup.b3,
NR.sup.32C(O)NR.sup.c3R.sup.d3, NR.sup.c3C(O)OR.sup.a3,
C(.dbd.NR.sup.g9)NR.sup.c3R.sup.d3,
NR.sup.c3C(.dbd.NR.sup.g)NR.sup.c3R.sup.d3, S(O)R.sup.b3,
S(O)NR.sup.c3R.sup.d3, S(O).sub.2R.sup.b3,
NR.sup.c3S(O).sub.2R.sup.b3, S(O).sub.2NR.sup.c3Rd.sup.3, aryl,
cycloalkyl, heteroaryl, and heterocycloalkyl;
[0077] Cy.sup.3, Cy.sup.4, and Cy.sup.5 are independently selected
from aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, each
optionally substituted by 1, 2, 3, 4, or 5 substituents
independently selected from halo, C.sub.1-6 alkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 haloalkyl, halosulfanyl, CN,
NO.sub.2, N.sub.3, OR.sup.a4, SR.sup.a4, C(O)R.sup.b4,
C(O)NR.sup.c4R.sup.d4, C(O)CR.sup.a4, OC(O)R.sup.b4,
OC(O)NR.sup.c4R.sup.d4, NR.sup.c4R.sup.d4, NR.sup.c4C(O)R.sup.b4,
NR.sup.c4C(O)NR.sup.c4R.sup.d4, NR.sup.c4C(O)CR.sup.4,
C(.dbd.NR9NR.sup.c4R.sup.d4,
NR.sup.c4C(.dbd.NR.sup.g9)NR.sup.c4R.sup.d4, P(R.sup.f4).sub.2,
P(OR.sup.4).sub.2, P(O)R.sup.e4R.sup.f4, P(O)OR.sup.e4OR.sup.f4,
S(O)R.sup.b4, S(O)NR.sup.c4R.sup.d4, S(O).sub.2R.sup.b4,
NR.sup.c4S(O).sub.2R.sup.b4, and S(O).sub.2NR.sup.c4R.sup.d4;
[0078] R.sup.A is H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl wherein
said C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl,
cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally
substituted with 1, 2, or 3 substituents independently selected
from OH, CN, amino, halo, and C.sub.1-4 alkyl;
[0079] R.sup.B is H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4
alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl wherein
said C.sub.1-4 alkyl, C.sub.2-4 alkenyl, or C.sub.2-4 alkynyl,
cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally
substituted with 1, 2, or 3 substituents independently selected
from OH, CN, amino, halo, and C.sub.1-4 alkyl;
[0080] R.sup.C and R.sup.D are independently selected from
H,C.sub.1-4 alkyl,C.sub.2-4 alkenyl, or C.sub.2-4 alkynyl, wherein
said C.sub.1-4 alkyl, C.sub.2-4 alkenyl, or C.sub.2-4 alkynyl, is
optionally substituted with 1, 2, or 3 substituents independently
selected from OH, CN, amino, halo, and C.sub.1-4 alkyl;
[0081] or R.sup.C and R.sup.D together with the N atom to which
they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl
group or heteroaryl group, each optionally substituted with 1, 2,
or 3 substituents independently selected from OH, CN, amino, halo,
and C.sub.1-4 alkyl;
[0082] R.sup.a, R.sup.a1, R.sup.a2, R.sup.a3, and Rao are
independently selected from H, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, cycloalkyl,
heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is
optionally substituted with 1, 2, or 3 substituents independently
selected from OH, CN, amino, halo, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, C.sub.1-6 haloalkyl, and C.sub.1-6 haloalkoxy;
[0083] R.sup.b, R.sup.b1, R.sup.b2, R.sup.b3, and R.sup.b4 are
independently selected from H, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, cycloalkyl,
heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl, and heterocycloalkylalkyl, wherein said C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, or heterocycloalkylalkyl is
optionally substituted with 1, 2, or 3 substituents independently
selected from OH, CN, amino, halo, C.sub.1-6 alkyl, C.sub.1-6
alkoxy, C.sub.1-6 haloalkyl, and C.sub.1-6 haloalkoxy;
[0084] R.sup.c and R.sup.d are independently selected from H,
C.sub.1-10 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein
said C.sub.1-10 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl is optionally substituted with 1, 2, or 3
substituents independently selected from OH, CN, amino, halo,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, and
C.sub.1-6 haloalkoxy;
[0085] or Rc and Rd together with the N atom to which they are
attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group or
heteroaryl group, each optionally substituted with 1, 2, or 3
substituents independently selected from OH, CN, amino, halo,
C.sub.1-.sub.6 alkyl, C.sub.1-.sub.6 alkoxy, C.sub.1-6 haloalkyl,
and C.sub.1-6 haloalkoxy;
[0086] R.sup.c1 and R.sup.d1 re independently selected from H,
C.sub.1-10 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein
said C.sub.1-10 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl is optionally substituted with 1, 2, or 3
substituents independently selected from OH, CN, amino, halo,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, and
C.sub.1-6 haloalkoxy;
[0087] or R.sup.c1 and R.sup.d1 together with the N atom to which
they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl
group or heteroaryl group, each optionally substituted with 1, 2,
or 3 substituents independently selected from OH, CN, amino, halo,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, and
C.sub.1-6 haloalkoxy;
[0088] R.sup.c2 and R.sup.d2 are independently selected from H,
C.sub.1-10 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl, heterocycloalkylalkyl,
arylcycloalkyl, arylheterocycloalkyl, arylheteroaryl, biaryl,
heteroarylcycloalkyl, heteroarylheterocycloalkyl, heteroarylaryl,
and biheteroaryl, wherein said C.sub.1-10 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl, heterocycloalkylalkyl, arylcycloalkyl,
arylheterocycloalkyl, arylheteroaryl, biaryl, heteroarylcycloalkyl,
heteroarylheterocycloalkyl, heteroarylaryl, and biheteroaryl are
each optionally substituted with 1, 2, or 3 substituents
independently selected from OH, CN, amino, halo, C.sub.-6 alkyl,
C.sub.1-6 alkoxy, C.sub.1-.sub.6 haloalkyl, C.sub.1-.sub.6
haloalkoxy, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl,
C(O)OR.sup.a4, C(O)R.sup.b4, S(O).sub.2R.sup.b3, alkoxyalkyl, and
alkoxyalkoxy;
[0089] or R.sup.c2 and R.sup.d2 together with the N atom to which
they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl
group or heteroaryl group, each optionally substituted with 1, 2,
or 3 substituents independently selected from OH, CN, amino, halo,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, 0.sub.1-.sub.6 halo-alkyl,
C.sub.1-6 haloalkoxy, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl,
C(O)OR.sup.a4, C(O)R.sup.b4, S(O).sub.2R.sup.b3, alkoxyalkyl, and
alkoxyalkoxy;
[0090] R.sup.c3 and R.sup.d3 are independently selected from H,
C.sub.1-10 alkyl, C.sub.2-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
.sub.6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkylalkyl, wherein said C.sub.1-10 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, heteroaryl,
cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,
cycloalkylalkyl or heterocycloalkyl-alkyl is optionally substituted
with 1, 2, or 3 substituents independently selected from OH, CN,
amino, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6
haloalkyl, and C.sub.1-6 haloalkoxy;
[0091] or R.sup.c3 and R.sup.d3 together with the N atom to which
they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl
group or heteroaryl group, each optionally substituted with 1, 2,
or 3 substituents independently selected from OH, CN, amino, halo,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, and
C.sub.1-6 haloalkoxy;
[0092] R.sup.d4 and R.sup.d4 are independently selected from H,
C.sub.1-10 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkenyl, C.sub.2-6
alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,
heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein
said C.sub.1-10 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,
arylalkyl, heteroarylalkyl, cycloalkylalkyl or
heterocycloalkyl-alkyl is optionally substituted with 1, 2, or 3
substituents independently selected from OH, CN, amino, halo,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, and
C.sub.1-6 haloalkoxy;
[0093] or R.sup.d4 and R.sup.d4 together with the N atom to which
they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl
group or heteroaryl group, each optionally substituted with 1, 2,
or 3 substituents independently selected from OH, CN, amino, halo,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkyl, and
C.sub.1-6 haloalkoxy;
[0094] R.sup.e, R.sup.el, R.sup.e2, and R.sup.e4 are independently
selected from H, C.sub.1-6 alkyl, C.sub.2-6 haloalkyl, C.sub.2-6
alkenyl, (C.sub.1-6 alkoxy)-C.sub.1-6 alkyl, C.sub.2-6 alkynyl,
aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,
cycloalkylalkyl, heteroarylalkyl, and heterocycloalkylalkyl;
[0095] R.sup.f, R.sup.11, R.sup.12, and R.sup.14 are independently
selected from H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl, and
heterocycloalkyl;
[0096] R.sup.9 is H, CN, and NO.sub.2;
[0097] R.sup.h and R.sub.1-6 are independently selected from H and
C.sub.1-6 alkyl;
[0098] R.sup.j is H, C.sub.1-6 alkyl, C.sub.2-6 haloalkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or
heterocycloalkylalkyl;
[0099] m is 0, 1, 2, 3, 4, 5, or 6;
[0100] p is 0, 1, 2, 3, or 4;
[0101] q is 0, 1, 2, 3, or 4;
[0102] r is 0, 1, 2, 3, 4, 5, or 6;
[0103] s is 0, 1, 2, 3, or 4; and
[0104] t is 0, 1, 2, 3, or 4.
[0105] In some embodiments, the compounds of formula III useful
according to the invention have Formula IIIA:
##STR00009##
[0106] In some embodiments, the compounds of formula III useful
according to the invention have Formula IIIB:
##STR00010##
[0107] especially wherein
[0108] A is CH or N, especially N;
[0109] L.sup.1 is (CR.sup.4R.sup.5).sub.m wherein each of R.sup.4
and R.sup.5, independently of the other, is H or C.sub.1-6 -alkyl
and m is 0, 1 or 2,
[0110] L.sup.2 is (CR.sup.7R.sup.8), wherein each of R.sup.7 and
R.sup.8, independently of the other, is H or C.sub.1-6 -alkyl and r
is 0, 1 or 2,
[0111] R.sup.1 is H, halo or C.sub.1-6 -alkyl;
[0112] R.sup.2 is H, halo or C.sub.1-6 -alkyl; and
[0113] Cy.sup.2 is aryl, especially phenyl, where said aryl or
phenyl is unsubstituted or substituted by one to 3 moieties
independently selected from the group concisting of
--C(.dbd.O)--NR.sup.c2R.sup.2 dand halo, wherein R.sup.c2 and
R.sup.d2 are independently selected from H, C.sub.1-10-alkyl and
C.sub.1-6 haloalkyl;
[0114] where the compounds may also or alternatively be present in
the form of a pharmaceutically acceptable salt.
[0115] Especially preferred of the group of compounds of the
formula Ill is that with the name
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide (also named Cpd. B hereinafter) which has the formula
##STR00011##
[0116] See WO 2008/064157, Example 7. This is the most preferred
MET tyrosine kinase inhibitor.
[0117] While the two MET inhibitors (Compound A and Compound B)
mentioned above are of particular interest, also other MET
inhibitors are included in the scope of the present invention.
[0118] Such other MET inhibitors (which also includes compounds or
antibodies active against HGF) are, for example, selected from the
following (including their pharmaceutically acceptable salts, and
prodrugs thereof):
[0119] Crizotinib (Pfizer) (aka PF02341066) (a highly preferred
compound) which has the formula
##STR00012##
[0120] cabozantinib (Exelixis) (aka XL-184) (a highly preferred
compound) which has the formula
##STR00013##
[0121] tivatinib (ArQule, daiichi, Kyowa) (aka ARQ-197) (a highly
preferred compound) which has the formula
##STR00014##
[0122] foretinib (Exelixis, GlaxoSmithKline) (aka XL-880) (a highly
preferred compound) which has the formula
##STR00015##
[0123] MGCD-265 (MethylGene) (a highly preferred compound) which
has the formula
##STR00016##
[0124] AMG-208 (Amgen) (see also WO 2008/008539) which has the
formula
##STR00017##
[0125] AMG-337 (Amgen);
[0126] JNJ-38877605 (Johnson & Johnson) (aka BVT051) (see also
WO 2007/075567) which has the formula
##STR00018##
[0127] MK-8033 (Merck & Co) which has the formula
##STR00019##
[0128] E-7050 (Eisai) which has the formula
##STR00020##
[0129] EMD-1204831 (Merck Serono);
[0130] EMD-1214063 (Merck Serono) (see also WO 2007/019933) which
has the formula
##STR00021##
[0131] amuvatinib (SuperGen) (aka MP-470) which has the formula
##STR00022##
[0132] LY-2875358 (Eli Lilly);
[0133] BMS-817378 (BristolMyersSquibb, Simcere) which has the
formula
##STR00023##
[0134] DP-3590 (Deciphera);
[0135] ASP-08001 (Suzhou Ascepion Pharmaceuticals);
[0136] HM-5016504 (Hutchison Medipharma);
[0137] PF-4217903 (Pfizer) (see also US2007/0265272) which has the
formula
##STR00024##
or
[0138] SGX523 (SGX) (see also WO 2008/051808) which has the
formula
##STR00025##
[0139] or antibodies or related molecules, e.g.
[0140] ficlatuzumab (AVEO) monoclonal antibody against HGF
(preferred); onartuzumab (Roche) monoclonal antibody against MET
(preferred); rilotuzumab (Amgen) monoclonal antibody against HGF
(preferred); Tak-701 (Takeda) monoclonal antibody against HGF);
LA-480 (Eli Lilly) monoclonal antibody against MET; and/or
LY.2875358 (Eli Lilly) monoclonal antibody against MET.
[0141] Among the EGFR tyrosine kinase inhibitors useful according
to the invention, those of the quinaolineamine class are to be
mentioned, in particular.
[0142] Especially, EGFR tyrosine kinase inhibitors disclosed in WO
96/30347 (which is incorporated herein by reference with regard to
the generic and specific compounds disclosed therein) are to be
mentioned here, as a first group, especially 4-(substituted
phenylamino)quinazoline derivatives of the formula
##STR00026##
[0143] and pharmaceutically acceptable salts and prodrugs thereof,
wherein
[0144] each Ra, Rb, Rc and Rd is independently selected from
hydrogen, halo, hydroxy, amino, hydroxyamino, carboxy, C.sub.1-8
alkoxycarbonyl, nitro, guanidino, ureido, carbamoyl, cyano,
trifluoromethyl, (R.sup.6).sub.2N-carbonyl and phenyl-W-alkyl
wherein W is selected from a single bond, O, S and NH; or each Ra
or Rb is independently selected from cyano-C.sub.1-6 alkyl and R9
wherein R9 is selected from the group consisting of R5, R50,
(R5).sub.2N, R7C(.dbd.O), R5ONH, A and R5Y; wherein R5 is C.sub.1-3
salkyl;
[0145] R6 is hydrogen or R5 wherein the R5s if more than one is
present are the same or different;
[0146] R7 is R5, R5O or (R6).sub.2N;
[0147] A is selected from piperidino, morpholino, pyrrolidino and
4-R6-piperazin-1-yl, imidazol-1-yl, 4-pyridon-1-yl,
carboxy-C.sub.1-3 alkyl, phenoxy, phenyl, phenylsulfanyl,
C.sub.2-8alkenyl, (R5).sub.2N-carbonyl-C.sub.1-3alkyl; and
[0148] Y is selected from S, SO, SO.sub.2; the alkyl moieties in
R5, R5O and (R5).sub.2N are optionally substituted with halo or R9
wherein R9 is defined as above, and wherein the resulting groups
are optionally substituted with halo or R9 with the proviso that a
nitrogen, oxygen or sulfur atom and another heteroatom can not be
attached to the same carbon atom, and with the further proviso that
Ra and Rb may not comprise more than three R9 units;
[0149] or each Ra or Rb is independently selected from
R5-sulfonylamino, phthalimido-C.sub.1-8 alkylsulfonylamino,
benzamido, benzenesulfonylamino, 3-phenylureido,
2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and
R10-C.sub.2-4alkanoylamino wherein R10 is selected from halo, R5O,
C.sub.2-4alkanoyloxy, B7C(.dbd.O) and (R6).sub.2N; and wherein said
benzamido or benzenesulfonylamino or phenyl or phenoxy or anilino
or phenylsulfanyl substituent in Ra or Rb may optionally bear one
or two halogens, C.sub.1-8 alkyl, cyano, methansulfonyl or
C.sub.1-8 alkoxy substituents; or any two Ra and Rb taken together
with the carbons to which they are attached comprise a 5-8 membered
ring comprising at least one or two heteroatoms selected from
oxygen, sulfur or nitrogen; and wherein the alkyl groups and alkyl
portions of the alkoxy or alkylamino groups may be straight chained
or if comprised of at least three carbons may be branched or
cyclic; each Rc and Rd is independently selected from hydrogen,
optionally substituted C.sub.1-8alkyl, optionally substituted
amino, halo, hydroxy, optionally substituted hydroxy; or from azido
or R11-ethynyl wherein R11 is selected from hydrogen, optionally
substituted C.sub.1-8alkyl wherein the substituents are selected
from hydrogen, amino, hydroxy, R5O, R5NH and (R5).sub.2N; and X is
N or C(CN), with the proviso that a substituent R5 may not comprise
another substitutent R5; especially the compound of the formula
##STR00027##
[0150] with the INN name erlotinib (marketed in Tarceva.RTM.,
Roche, Basel,
Switzerland)=N-(3-ethinylphenyl)-6,7-bis-(2-methoxyethoxy)quinazol-
in-4-amine, or a pharmaceutically acceptable salt thereof. Said
compound and its manufacture are disclosed e.g. in WO 9630347,
Example 20.
[0151] Especially, EGFR tyrosine kinase inhibitors disclosed in WO
96/33980 or U.S. Pat. No. 5,616,582 (which are incorporated herein
by reference with regard to the generic and specific compounds
disclosed therein) are to be mentioned here, as a second group,
especially 4-(substituted phenylamino)quinazoline derivatives of
the formula
##STR00028##
[0152] wherein
[0153] X is N; Ra is C.sub.1-6 alkyloxy;
[0154] Rb is di-(C.sub.1-8alkyl)-amino-C.sub.1-8alkoxy,
pyrrolidin-1-yl-C.sub.1-8alkoxy, piperidino-C.sub.1-8alkoxy,
morpholino-C.sub.1-8alkoxy, piperazin-1-yl-C.sub.1-8alkoxy,
4-C.sub.1-8alkylpiperazin-1-yl-C.sub.1-8alkoxy,
imidazol-1-yl-C.sub.1-8alkoxy,
di-(C.sub.1-8alkoxy-C.sub.1-8alkyl)-amino-C.sub.1-8alkoxy,
thiomorpholino-C.sub.1-8alkoxy, 1-oxothiomorpholino-C.sub.1-8alkoxy
or 1,1-dioxothiomorpholino-C.sub.1-8alkoxy, and wherein any of the
above-mentioned Rb substituents comprising a CH.sub.2 (methylene)
group which is not attached to a N or 0 atom optionally bears on
said CH.sub.2 group a hydroxy substituent;
[0155] and each of Rc and Rd is independently of the other halo,
trifluoromethyl or C.sub.1-8alkyl;
[0156] or a pharmaceutically acceptable salt or prodrug thereof,
most especially the compound of the formula
##STR00029##
[0157] with the INN name gefitinib (marketed in Irssa.RTM.,
AstraZeneca)=N-(3-hloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)pr-
opoxy]quinazolin-4-amine, or a pharmaceutically acceptable salt
thereof, see W=96/33980, Example 1. This compound or its
pharmaceutically acceptable salts are especially preferred in the
embodiments of the present invention.
[0158] Especially, EGFR tyrosine kinase inhibitors disclosed in
U.S. Pat. Nos. 6,391,874, 7,157,466, 6,828,320, 6,713,485 and in
particular U.S. Pat. No. 6,727,256 (=WO9935146) (which are
incorporated herein by reference with regard to the generic and
specific compounds disclosed therein) are to be mentioned here, as
a third group, especially 4-(substituted phenylamino)quinazoline
derivatives of the formula
##STR00030##
[0159] wherein X is N;
[0160] one of Ra and Rb is a group
CH.sub.3SO.sub.2CH.sub.2CH.sub.2NHCH.sub.2--Ar--, wherein Ar is
selected from phenyl, furanyl, thiophenyl, pyrrolyl and thiazolyl,
each of which may optionally be substituted by one or two
substituents selected from the group consisting of one or two halo,
C.sub.1-8salkyl and C.sub.1-8alkoxy;
[0161] the other of Ra and Rb is selected from the group consisting
of hydrogen, halo, hydroxy, C.sub.1-8alkyl, C.sub.1-8alkoxy,
C.sub.1-8salkylamino and di(CC.sub.1-8alkyl)amino;
[0162] one of Rc and Rd represents benzyl, halo-, dihalo- or
trihalobenzyl, trihalomethylbenzyl, benzoyl, pyridylmethyl,
pyridylmethoxy, phenoxy, benzyloxy, halo-, dihalo- or
trihalobenzyloxy, trihalomethylbenzyloxy, benzenesulphonyl or
hydrogen;
[0163] the other of Rc and Rd is hydrogen or hydroxy, halo,
C.sub.1-8alkyl, C.sub.1-8alkenyl, C.sub.2-8alkynyl,
C.sub.1-8alkoxy, amino, C.sub.1-8alkylamino,
di(C.sub.1-8alkyl)amino, C.sub.1-8alkylthio,
C.sub.1-8alkylsulphinyl, C.sub.1-8alkylsulphonyl,
C.sub.1-8alkylcarbonyl, carboxyl, carbamoyl,
C.sub.1-8alkoxycarbonyl, C.sub.1-8alkanoylamino,
N-(C.sub.1-8alkyl)carbamoyl, N,N-di(C.sub.1-8alkyl)carbamoyl,
cyano, nitro or trifluoromethyl;
[0164] or a pharmaceutically acceptable salt or prodrug thereof,
more especially the compound of the
##STR00031##
[0165] with the INN name lapatinib (marketed in Tykerb.RTM. (USA),
Tyverb.RTM. (EP), GlaxoSmithKline) with the hame
N-[3-chloro-4-(3-fluorobenzyloxy)phenyl]-6-{5-[4-(methylsulfonyl)-2-azabu-
tyl]-2-furyl} quinazolin-4-amine, or a pharmeceutically acceptable
salt or prodrug thereof, see e.g. WO9935146 (Example 29).
[0166] Especially, EGFR tyrosine kinase inhibitors disclosed in
WO97/38983 or especially WO2000031048 (which are incorporated
herein by reference with regard to the generic and specific
compounds disclosed therein) are to be mentioned here, as a fourth
group, especially 4-(substituted phenylamino)quinazoline
derivatives of the formula
##STR00032##
[0167] or pharmaceutically acceptable salts or prodrugs thereof,
wherein
[0168] X is N,
[0169] Ra is -D-E-F and Rb is --SR.sup.4*, halo, --OR.sup.4*,
--NHR.sup.3* or hydrogen, or
[0170] Rb is -D-E-F and Ra is --SR.sup.4*, halo, --OR.sup.4*,
--NHR.sup.3* or hydrogen,
[0171] wherein, respectively,
[0172] D is --N(R.sup.2*)--, --O--, --CH(R.sup.2*)--,
--N(R.sup.2*)--H--, --N(R.sup.2*)--O--, --CH(R.sup.2*)--NH--,
--CH(R.sup.2*)--O--, --CH(R.sup.2*)--CH.sub.2--,
--NH--CH(R.sup.2*)--, --O--CH(R.sup.2*)--, --S--CH(R.sup.2*)-- or
absent;
[0173] E is --C(.dbd.O)--, --S(.dbd.O).sub.2--,
--P(.dbd.O)(O)R.sup.2*)--or --S(.dbd.O)--,
[0174] F is --C(R.sup.1*).dbd.CHR.sup.5*, --C.dbd.C--R.sup.5*, or
--C(R.sup.1*).dbd.C.dbd.CHR.sup.5*; provided that when E is
S(.dbd.O).sub.2-- or --S(.dbd.O)--, D is not --NH--CH(R.sup.2*)--
or --O--CH(R.sup.2*)--;
[0175] R.sup.1* is hydrogen, halogen or C.sub.1-8alkyl,
[0176] R.sup.2*, R.sup.3* and R.sup.4* are independently hydrogen,
C.sub.1-8alkyl , --(CH.sub.2).sub.n--N-piperidinyl,
--(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2)n-Ni-piperazinyl(N.sub.4-C.sub.1-8alkyl),
--(CH.sub.2).sub.n--N-pyrrolidinyl,
--(CH.sub.2).sub.n---N-pyridinyl, --(CH.sub.2).sub.n--N-imidazolyl,
--(CH.sub.2).sub.n--N-morpholinyl,
--(CH.sub.2).sub.n---N-thiomorpholinyl,
--(CH.sub.2).sub.n--N-hexohydroazepinyl or substituted
C.sub.1-8alkyl, wherein the substituents are selected from --OH,
--NH.sub.2, or --N(B*)(A*) , wherein A* and B* are independently
hydrogen, C.sub.1-8alkyl, --(CH.sub.2).sub.n--OH,
--(CH.sub.2)n-N-piperidinyl, --(CH.sub.2).sub.n--N-piperazinyl,
--(CH.sub.2)n-Ni-piperazinyl(N.sub.4--C.sub.1-8alkyl) ,
--(CH.sub.2).sub.n--N--pyrrolidinyl, --(CH.sub.2).sub.n--N-pyridyl
and --(CH.sub.2).sub.n--N-imidazolyl;
[0177] Rc and Rd are independently hydrogen, halo, C.sub.1-8alkyl,
C.sub.3-8cyloalkyl, C.sub.1-8alkoxy, C.sub.3-8cyclo-alkoxy, nitro,
C.sub.1-8perfluoroalkyl, hydroxy, C.sub.1-8acyloxy, amino,
--NH(C.sub.1-8alkyl), --N(C.sub.1-8alkyl).sub.2,
--NH(C.sub.3-8cycloalkyl), --NH(C.sub.3-8cycloalkyl).sub.2,
hydroxymethyl, C.sub.1-8acyl, cyano, azido, C.sub.1-8thioalkyl,
C.sub.1-8sulfinylalkyl, C.sub.1-8sulfonylalkyl,
C.sub.3-8thiocycloalkyl, C.sub.3-8sulfinylcycloalkyl,
C.sub.3-8sulfonylcycloalkyl, mercaptoC.sub.1-8alkoxycarbonyl,
C.sub.3-8cycloalkoxycarbonyl, C.sub.2-8alkenyl,
C.sub.4-8cycloalkenyl, or C.sub.2-8alkynyl;
[0178] R.sup.5* is hydrogen, halo, C.sub.1-8perfluoroalkyl,
1,1-difluoro-C.sub.1-6alkyl, C.sub.1-6alkyl,
--(CH.sub.2).sub.n--N-piperindinyl, --(CH.sub.2).sub.n--N-
piperidinyl, --(CH.sub.2).sub.n--N.sub.1-piperazinyl,
(N.sub.4-C.sub.1-8alkyl), --(CH.sub.2).sub.n--N-pyrrolidinyl,
--(CH.sub.2).sub.n--N-pyridyl, --(CH.sub.2).sub.n--N-imidazolyl,
--(CH.sub.2).sub.n---N-morpholinyl,
--(CH.sub.2).sub.n--N-thiomorpholinyl, --CH.dbd.CH.sub.2,
--CH.dbd.CH--C.sub.1-8alkyl,
--(CH.sub.2).sub.n--N-hexahydroazepinyl,
--(CH.sub.2).sub.n--NH.sub.2,
--(CH.sub.2).sub.n--NH--(C.sub.1-8alkyl,
--(CH.sub.2).sub.n--N(C.sub.1-8alky).sub.2, -1-oxo-C.sub.1-3alkyl,
carboxy, C.sub.1-8alkoxycarbonyl, N--C.sub.1-8alkyl-carbamoyl,
phenyl or substituted phenyl, wherein the phenyl can have from one
to three substituents independently selected from Rc and Rd or a
monocyclic heteroaryl group selected from the group consisting of
pyridyl, thienyl and imidazolyl, and each C.sub.1-8alkyl group
above in R.sup.5* can be substituted with --OH, --NH.sub.2 or
NA*B*, where A* and B* are as defined above;
[0179] R.sup.6* is hydrogen or C.sub.1-8alkyl;
[0180] and n* is 1 to 8, especially 1 to 4; especially the compound
of the formula
##STR00033##
[0181] with the INN name canertinib (Pfizer) (e.g. used as
dihydrochloride))
N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-(3-morpholin-4-ylpropoxy)quinazol-
in-6-yl]prop-2-enamide, or a pharmaceutically acceptable salt or
prodrug thereof, see especially WO2000031048.
[0182] Especially, EGFR tyrosine kinase inhibitors disclosed in
WO2005028443 (which is incorporated herein by reference with regard
to the generic and specific compounds disclosed therein) are to be
mentioned here, as a fifth group, especially 4-(substituted
phenylamino)quinazoline derivatives of the formula
##STR00034##
[0183] wherein X is C--CN;
[0184] Ra is C.sub.1-8alkoxy;
[0185] Rb is amino- or N--[N'-mono- or
N',N'-di(C.sub.1-8alkyl)]amino)-C.sub.4-8alkenoyl)-amino;
[0186] Rc is halo or R.sub.2**--(CH.sub.2).sub.n**--R.sub.3**--
[0187] wherein R.sub.2** is a pyridyl, thiophenyl, pyrimidinyl,
thiazolyl or phenyl, each optionally substituted with up to three
substituents selected from C.sub.1-8alkyl, C.sub.1-8l alkoxy and
halogen, R.sub.3** is --O-- or --S-- and n** is 0 to 8, preferably
0 or 1;
[0188] and Rd is halo;
[0189] or a pharmaceutically acceptable salt or prodrug thereof,
especially the compound of the formula
##STR00035##
[0190] with the INN name pelitinib (Wyeth, owned by Pfizer) with
the name
2E)-N-[4-[(3-Chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolinyl]--
4-(dimethylamino)-2-butenamide, see WO2005028443 (Example 20), or
the compound of the formula
##STR00036##
[0191] with the INN name neratinib (Pfizer Inc.),
(2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-eth-
oxyquinolin-6- yl]-4-(dimethylamino)but-2-enamide, see e.g.
WO2005028443 Example 2;
[0192] or a pharmaceutically acceptable salt or prodrug thereof,
respectively.
[0193] Among the possible EGFR inhibitors, also antibodies may be
mentioned, e.g. Cetuximab (Erbitux.RTM.) (ImClone Systems,
Bristol-Myers Squibb and Merck KgaA) which is a chimeric
(mouse/human) monoclonal antibody, active as an epidermal growth
factor receptor (EGFR) inhibitor, which can be administered e.g.
intravenously.
[0194] A particular embodiment of the invention embodiments in each
case relates to the EGFR inhibitors of the formula
##STR00037##
[0195] wherein
[0196] X is N or C(CN);
[0197] Ra is selected from the group consisting of
C.sub.1-8alkyloxy or (C.sub.1-8alkyloxy, 1-piperidin-1-yl,
1-piperazin-1-yl, 4-C.sub.1-8alkyl-piperazin-1-yl, morpholin-1-yl,
thiomorpholino-1-yl , S-oxo-thiomorpholin-1-yl or
S,S-dioxothiomorpholinyl-1-yl)- C.sub.1-8alkyloxy;
[0198] Rb is selected from C.sub.3-8alkenoyl, {amino- or
N-[N'-mono- or
N',N'-di(C.sub.1-8alkyl)]amino}-C.sub.4-8alkenoyl)-amino,
[(C.sub.1-8alkylsulfonyl-CC.sub.1-8alkylamino)--C.sub.1-8alkyl]-furyl
or (C.sub.1-8alkyloxy, 1-piperidin-1-yl, 1-piperazin-1-yl,
4-C.sub.1-8alkyl-piperazin-1-yl, morpholin-1-yl, thiomorpholin-1-yl
, S-oxo-thiomorpholin-1-yl or
S,S-dioxothiomorpholinyl-1-yl)-C.sub.1-8alkyloxy;
[0199] Rc is halo or C.sub.2-8alkynyl; and
[0200] Rd is hydrogen, pyridinyl-C.sub.1-8alkyloxy or unsubstituted
or halogen substituted phenyl-C.sub.1-8alkyloxy;
[0201] especially wherein:
[0202] X is N or C(CN);
[0203] Ra is methoxy, ethoxy, 3-morpholinopropyloxy or
2-methoxyethoxy;
[0204] Rb is 4-(dimethylamino)-but-2-enoylamino, prop-2-enoylamino,
5-[(2-methylsulfonyl-ethyl)-aminomethyl]-furan-2-yl,
2-methoxyethoxy or 3-morpholinopropoxy;
[0205] Rc is chloro or ethynyl; and
[0206] Rd is hydrogen, fluoro, pyridin-2-ylmethoxy or
3-fluorophenyl-methoxy;
[0207] or a pharmaceutically acceptable salt or prodrug thereof,
respectively.
[0208] If not mentioned otherwise, the following definitions serve
to define more general expressions used above and below by specific
variants, thus defining more particular invention embodiments
wherein one, more than one or all general expressions are defined
by these following definitions:
[0209] In the preceding and following definitions, C.sub.1-8 is
preferably C.sub.1-6, more preferably C.sub.1-4,meaning a linear or
branched moiety with 1 to 8, 1 to 6 or 1 to 4 carbon atoms,
respectively.
[0210] In the preceding and following definitions, C.sub.2-8is
preferably C.sub.2-6,more preferably C.sub.2-4,meaning a linear or
branched moiety with 2 to 8, 2 to 6 or 2 to 4 carbon atoms,
respectively.
[0211] In the preceding and following definitions, C.sub.3-8 is
preferably C.sub.3-8, more preferably C.sub.3-4 meaning moiety with
3 to 8, 3 to 6 or 3 to 4 carbon atoms, respectively.
[0212] In the preceding and following definitions, C.sub.4-8 is
preferably C.sub.4-8, more preferably C.sub.4, meaning a linear or
branched moiety with 4 to 8, 4 to 6 or 4 carbon atoms,
respectively.
[0213] "Lower" refers to a group with up to 8, especially up to 6
carbon atoms, if not defined otherwise. For example, lower alkyl
refers to C.sub.1-8 alkyl, e.g. C.sub.1-8 alkyl, such as methyl,
ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or
tert-butyl.
[0214] At various places in the present specification, substituents
of compounds useful according to the invention are disclosed in
groups or in ranges. It is specifically intended that the invention
include each and every individual subcombination of the members of
such groups and ranges. For example, the term "C.sub.1-8alkyl" is
specifically intended to individually disclose methyl, ethyl,
C.sub.3 alkyl, C.sub.4 alkyl, C.sub.5 alkyl, and C.sub.6 alkyl.
[0215] It is further intended that the compounds useful according
to the invention are stable. As used herein "stable" refers to a
compound that is sufficiently robust to survive isolation to a
useful degree of purity from a reaction mixture, and preferably
capable of formulation into an efficacious therapeutic agent.
[0216] It is further appreciated that certain features of the
invention, which are, for clarity, described in the context of
separate embodiments, can also be provided in combination in a
single embodiment. Conversely, various features of the invention
which are, for brevity, described in the context of a single
embodiment, can also be provided separately or in any suitable
subcombination.
[0217] As used herein, the term "alkyl" (also in alkoxy, arylalkyl,
heteroarylalkyl, haloalkyl or the like) is meant to refer to a
saturated hydrocarbon group which is straight-chained or branched.
Example alkyl groups include methyl (Me), ethyl (Et), propyl (e.g.,
n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl),
pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like. An
alkyl group can contain from 1 to about 20, from 2 to about 20,
from 1 to about 10, from 1 to about 8, from 1 to about 6, from 1 to
about 4, or from 1 to about 3 carbon atoms.
[0218] As used herein, the term "alkylyene" refers to a linking
alkyl group.
[0219] As used herein, "alkenyl" refers to an alkyl group having
one or more double carbon-carbon bonds. Example alkenyl groups
include ethenyl, propenyl, and the like.
[0220] As used herein, "alkenylene" refers to a linking alkenyl
group.
[0221] As used herein, "alkynyl" refers to an alkyl group having
one or more triple carbon-carbon bonds. Example alkynyl groups
include ethynyl, propynyl, and the like.
[0222] As used herein, "alkynylene" refers to a linking alkynyl
group.
[0223] As used herein, "haloalkyl" refers to an alkyl group having
one or more halogen substituents. Example haloalkyl groups include
CF.sub.3, C.sub.2F.sub.5, CHF.sub.2, CCl.sub.3, CHCl.sub.2,
C.sub.2Cl.sub.5, and the like.
[0224] As used herein, "aryl" refers to monocyclic or polycyclic
(e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as,
for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl,
indenyl, and the like. In some embodiments, aryl groups have from 6
to about 20 carbon atoms.
[0225] As used herein, "arylene" refers to a linking aryl
group.
[0226] As used herein, "cycloalkyl" refers to non-aromatic
carbocycles including cyclized alkyl, alkenyl, and alkynyl groups.
Cycloalkyl groups can include mono- or polycyclic (e.g., having 2,
3 or 4 fused rings) ring systems, including spirocycles. In some
embodiments, cycloalkyl groups can have from 3 to about 20 carbon
atoms, 3 to about 14 carbon atoms, 3 to about 10 carbon atoms, or 3
to 7 carbon atoms. Cycloalkyl groups can further have 0, 1, 2, or 3
double bonds and/or 0, 1, or 2 triple bonds. Also included in the
definition of cycloalkyl are moieties that have one or more
aromatic rings fused (i.e., having a bond in common with) to the
cycloalkyl ring, for example, benzo derivatives of pentane,
pentene, hexane, and the like. A cycloalkyl group having one or
more fused aromatic rings can be attached though either the
aromatic or non-aromatic portion. One or more ring-forming carbon
atoms of a cycloalkyl group can be oxidized, for example, having an
oxo or sulfido substituent. Example cycloalkyl groups include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,
norbornyl, norpinyl, norcarnyl, adamantyl, and the like.
[0227] As used herein, "cycloalkylene" refers to a linking
cycloalkyl group.
[0228] As used herein, a "heteroaryl" group refers to an aromatic
heterocycle having at least one heteroatom ring member such as
sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic
and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Any
ring-forming N atom in a heteroaryl group can also be oxidized to
form an N-oxo moiety. Examples of heteroaryl groups include without
limitation, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl,
imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl,
benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl,
tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl,
benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and
the like. In some embodiments, the heteroaryl group has from 1 to
about 20 carbon atoms, and in further embodiments from about 3 to
about 20 carbon atoms. In some embodiments, the heteroaryl group
contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms.
In some embodiments, the heteroaryl group has 1 to about 4, 1 to
about 3, or 1 to 2 heteroatoms.
[0229] As used herein, "heteroarylene" refers to a linking
heteroaryl group.
[0230] As used herein, "heterocycloalkyl" or "heterocyclyl" refers
to a non-aromatic heterocycle where one or more of the ring-forming
atoms is a heteroatom such as an O, N, or S atom. Heterocycloalkyl
groups can include mono- or polycyclic (e.g., having 2, 3 or 4
fused rings) ring systems as well as spirocycles. Example
"heterocycloalkyl" groups include morpholino, thiomorpholino,
piperazinyl, tetrahydrofuranyl, tetrahydrothienyl,
2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane,
piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl,
pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, and the
like. Also included in the definition of heterocycloalkyl are
moieties that have one or more aromatic rings fused (i.e., having a
bond in common with) to the nonaromatic heterocyclic ring, for
example phthalimidyl, naphthalimidyl, and benzo derivatives of
heterocycles. A heterocycloalkyl group having one or more fused
aromatic rings can be attached though either the aromatic or
non-aromatic portion. Also included in the definition of
heterocycloalkyl are moieties where one or more ring-forming atoms
is substituted by 1 or 2 oxo or sulfido groups. In some
embodiments, the heterocycloalkyl group has from 1 to about 20
carbon atoms, and in further embodiments from about 3 to about 20
carbon atoms. In some embodiments, the heterocycloalkyl group
contains 3 to about 20, 3 to about 14, 3 to about 7, or 5 to 6
ring-forming atoms. In some embodiments, the heterocycloalkyl group
has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms. In some
embodiments, the heterocycloalkyl group contains 0 to 3 double
bonds. In some embodiments, the heterocycloalkyl group contains 0
to 2 triple bonds.
[0231] As used herein, "heterocycloalkylene" refers to a linking
heterocycloalkyl group.
[0232] As used herein, "biaryl" refers to an aryl group substituted
by another aryl group.
[0233] As used herein, "biheteroaryl" refers to a heteroaryl group
substituted by another heteroaryl group.
[0234] As used herein, "halo" or "halogen" includes fluoro, chloro,
bromo, and iodo.
[0235] As used herein, "alkoxy" refers to an --O-alkyl group.
Example alkoxy groups include methoxy, ethoxy, propoxy (e.g.,
n-propoxy and isopropoxy), t-butoxy, and the like.
[0236] As used herein, "acyl" includes an organic radical
corresponding to the residue of, for example, an organic acid from
which the hydroxyl group has been removed, i.e., a radical having
the formula R.sup.A--C(O)--, where R.sup.A may in particular be
aliphatic or substituted aliphatic, or it may for example be a
substituted or unsubstituted mono- or bi-cyclic ring. Thus, R may
be selected from lower C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.7
cycloalkyl, phenyl, benzyl or phenethyl group. Amongst others.
exemplary acyl is alkyl-carbonyl. Examples of acyl groups, include,
but are not limited to, acetyl, propionyl and butyryl. Lower acyl
is for example formyl or lower alkylcarbonyl, in particular
acetyl.
[0237] The MET and FGFR inhibitors can be manufactured as described
in the patent applications and patents mentioned above, which are
also incorporated by refererence especially with regard to their
manufacturing methods.
[0238] Compounds useful according to the invention can also include
all isotopes of atoms occurring in the intermediates or final
compounds. Isotopes include those atoms having the same atomic
number but different mass numbers. Examples of isotopes that can be
incorporated into compounds of the invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and
chlorine, such as .sup.2H, .sup.3H, .sup.11C, .sup.13C, .sup.15N,
.sup.18F .sup.31P, .sup.32P, .sup.35S, .sup.36Cl, .sup.125I
respectively. Various isotopically labeled compounds of the present
invention, for example those into which radioactive isotopes such
as .sup.3H, .sup.13C, and .sup.14C are incorporated. Such
isotopically labelled compounds are useful in metabolic studies
(preferably with .sup.14C), reaction kinetic studies (with, for
example .sup.2H or .sup.3H), detection or imaging techniques [such
as positron emission tomography (PET) or single-photon emission
computed tomography (SPECT) including drug or substrate tissue
distribution assays, or in radioactive treatment of patients. In
particular, an .sup.18F or labeled compound may be particularly
preferred for PET or SPECT studies. Further, substitution with
heavier isotopes such as deuterium (i.e., .sup.2H) may afford
certain therapeutic advantages resulting from greater metabolic
stability, for example increased in vivo half-life or reduced
dosage requirements. Isotopically labeled compounds of this
invention and prodrugs thereof can generally be prepared by
carrying out the procedures disclosed in the schemes or in the
examples and preparations described below by substituting a.
readily available isotopically labeled reagent for a
non-isotopically labeled reagent.
[0239] Further, substitution with heavier isotopes, particularly
deuterium (i.e., .sup.2H or D) may afford certain therapeutic
advantages resulting from greater metabolic stability, for example
increased in vivo half-life or reduced dosage requirements or an
improvement in therapeutic index. It is understood that deuterium
in this context is regarded as a substituent of a compound of the
formula (I). The concentration of such a heavier isotope,
specifically deuterium, may be defined by the isotopic enrichment
factor. The term "isotopic enrichment factor" as used herein means
the ratio between the isotopic abundance and the natural abundance
of a specified isotope. If a substituent in a compound of this
invention is denoted deuterium, such compound has an isotopic
enrichment factor for each designated deuterium atom of at least
3500 (52.5% deuterium incorporation at each designated deuterium
atom), at least 4000 (60% deuterium incorporation), at least 4500
(67.5% deuterium incorporation), at least 5000 (75% deuterium
incorporation), at least 5500 (82.5% deuterium incorporation), at
least 6000 (90% deuterium incorporation), at least 6333.3 (95%
deuterium incorporation), at least 6466.7 (97% deuterium
incorporation), at least 6600 (99% deuterium incorporation), or at
least 6633.3 (99.5% deuterium incorporation). In the compounds of
this invention any atom not specifically designated as a particular
isotope is meant to represent any stable isotope of that atom.
Unless otherwise stated, when a position is designated specifically
as "H" or "hydrogen", the position is understood to have hydrogen
at its natural abundance isotopic composition. Accordingly, in the
compounds of this invention any atom specifically designated as a
deuterium (D) is meant to represent deuterium, for example in the
ranges given above.
[0240] Isotopically-labeled MET and/or EGFR tyrosine kinase
inhibitor compounds forming part of a combination product according
to the invention can generally be prepared by conventional
techniques known to those skilled in the art or by processes
analogous to those described in the accompanying Examples and
Preparations using an appropriate isotopically-labeled reagents in
place of the non-labeled reagent previously employed.
[0241] The present invention embodiments also include
pharmaceutically acceptable salts of the compounds useful according
to the invention described herein. As used herein,
"pharmaceutically acceptable salts" refers to derivatives of the
disclosed compounds wherein the parent compound is modified by
converting an existing acid or base moiety to its salt form.
Examples of pharmaceutically acceptable salts include, but are not
limited to, mineral or organic acid salts of basic residues such as
amines; alkali or organic salts of acidic residues such as
carboxylic acids; and the like. The pharmaceutically acceptable
salts of the present invention include the conventional non-toxic
salts of the parent compound formed, for example, from non-toxic
inorganic or organic acids. The pharmaceutically acceptable salts
of the present invention can be synthesized from the parent
compound which contains a basic or acidic moiety by conventional
chemical methods. Generally, such salts can be prepared by reacting
the free acid or base forms of these compounds with a
stoichiometric amount of the appropriate base or acid in water or
in an organic solvent, or in a mixture of the two; generally,
nonaqueous media like ether, ethyl acetate, ethanol, isopropanol,
or acetonitrile are preferred. Lists of suitable salts are found in
Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing
Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical
Science, 66, 2 (1977), each of which is incorporated herein by
reference in its entirety.
[0242] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0243] The present invention also includes prodrugs of the
compounds useful according to the invention. As used herein,
"prodrugs" refer to any covalently bonded carriers which release
the active parent drug when administered to a mammalian subject.
Prodrugs can be prepared by modifying functional groups present in
the compounds in such a way that the modifications are cleaved,
either in routine manipulation or in vivo, to the parent compounds.
Prodrugs include compounds wherein hydroxyl, amino, sulfhydryl, or
carboxyl groups are bonded to any group that, when administered to
a mammalian subject, cleaves to form a free hydroxyl, amino,
sulfhydryl, or carboxyl group respectively. Examples of prodrugs
include, but are not limited to, acetate, formate and benzoate
derivatives of alcohol and amine functional groups in the compounds
of the invention. Preparation and use of prodrugs is discussed in
T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems,"
Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible
Carriers in Drug Design, ed. Edward B. Roche, American
Pharmaceutical Association and Pergamon Press, 1987, both of which
are hereby incorporated by reference in their entirety.
[0244] The compounds useful according to the invention (=being
included in a combination, especially a combination product,
according to the invention, respectively, or being used according
to the invention, optionally also including further co-agents as
defined below, that is, all active ingredients), as well as their
pharmaceutically acceptable salts or prodrugs, can also be present
as tautomers, N-oxides or solvates, e.g. hydrates. All these
variants, as well as any single one thereof or combination of two
or more to less than all such variants, are encompassed and to be
read herein where a compound included in the inventive combination
products, e.g. an EGFR tyrosine kinase inhibitor and/or a MET
tyrosine kinase inhibitor, is mentioned.
[0245] The present invention, according to a first embodiment
mentioned above and below, relates to a pharmaceutical combination,
especially a pharmaceutical combination product, comprising the
mentioned combination partners and at least one pharmaceutically
acceptable carrier.
[0246] "Combination" refers to formulations of the separate
partners with or without instructions for combined use or to
combination products. The combination partners may thus be entirely
separate pharmaceutical dosage forms or pharmaceutical compositions
that are also sold independently of each other and where just
instructions for their combined use are provided in the package
equipment, e.g. leaflet or the like, or in other information e.g.
provided to physicians and medical staff (e.g. oral communications,
communications in writing or the like), for simultaneous or
sequential use for being jointly active, especially as defined
below.
[0247] "Combination product" refers especially to either a fixed
combination in one dosage unit form, or a kit of parts for the
combined administration where an EGFR tyrosine kinase inhibitor and
a MET tyrosine kinase inhibitor (and optionally yet a further
combination partner (e.g. an other drug as explained below, also
referred to as "co-agent") may be administered independently at the
same time or separately within time intervals, especially where
these time intervals allow that the combination partners show a
cooperative (=joint), e.g. synergistic effect. The terms
"co-administration" or "combined administration" or the like as
utilized herein are meant to encompass administration of the
selected combination partner to a single subject in need thereof
(e.g. a patient), and are intended to include treatment regimens in
which the agents are not necessarily administered by the same route
of administration and/or at the same time.
[0248] The term "combination product" as used herein thus means a
pharmaceutical product that results from the mixing or combining of
more than one active ingredient and includes both fixed and
non-fixed combinations of the active ingredients (which may also be
combined).
[0249] The term "fixed combination" means that the active
ingredients, e.g. an EGFR tyrosine kinase inhibitor and MET
tyrosine kinase inhibitor, are both administered to a patient
simultaneously in the form of a single entity or dosage. In other
terms: the active ingredients arepresent in one dosage form, e.g.
in one tablet or in one capsule.
[0250] The term "non-fixed combination" means that the active
ingredients are both administered to a patient as separate entities
either simultaneously, concurrently or sequentially with no
specific time limits, wherein such administration provides
therapeutically effective levels of the two compounds in the body
of the patient. The latter also applies to cocktail therapy, e.g.
the administration of three or more active ingredients. The term
"non-fixed combination" thus defines especially a "kit of parts" in
the sense that the combination partners (i) EGFR tyrosine kinase
inhibitor and (ii) MET tyrosine kinase inhibitor (and if present
further one or more co-agents) as defined herein can be dosed
independently of each other or by use of different fixed
combinations with distinguished amounts of the combination
partners, i.e. simultaneously or at different time points, where
the combination partners may also be used as entirely separate
pharmaceutical dosage forms or pharmaceutical formulations that are
also sold independently of each other and just instructions of the
possibility of their combined use is or are provided in the package
equipment, e.g. leaflet or the like, or in other information e.g.
provided to physicians and medical staff. The independent
formulations or the parts of the kit of parts can then, e.g. be
administered simultaneously or chronologically staggered, that is
at different time points and with equal or different time intervals
for any part of the kit of parts. Very preferably, the time
intervals are chosen such that the effect on the treated disease in
the combined use of the parts is larger than the effect which would
be obtained by use of only any one of the combination partners (i)
and (ii), thus being jointly active. The ratio of the total amounts
of the combination partner (i) to the combination partner (ii) to
be administered in the combined preparation can be varied, e.g. in
order to cope with the needs of a patient sub-population to be
treated or the needs of the single patient which different needs
can be due to age, sex, body weight, etc. of the patients.
[0251] The invention also relates to (i) a MET inhibitor and (ii)
an EGFR inhibitor, or a pharmaceutically acceptable salt thereof,
for combined use in a method of treating an EGFR tyrosine kinase
activity and/or MET tyrosine kinase activity mediated disease,
especially a cancer.
[0252] In a further embodiment, the MET inhibitor and the EGFR
inhibitor for use according to the preceding paragraph are selected
as follows: the MET tyrosine kinase inhibitor is selected from the
group consisting of
(E)-2-(1-(3-(7-fluoroquinolin-6-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)et-
hylidene)hydrazinecarboxamide and/or (especially or)
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide, or a pharmaceutically acceptable salt or prodrug
thereof, respectively,
and the EGFR inhibitor is gefinitib and/or (especially or)
elotinib, or a pharmaceutically acceptable salt or prodrug
thereof.
[0253] The combination partners (i) and (ii) in any invention
embodiment are preferably formulated or used to be jointly
(prophylactically or especially therapeutically) active. This means
in particular that there is at least one beneficial effect, e.g. a
mutual enhancing of the effect of the combination partners (i) and
(ii), in particular a synergism, e.g. a more than additive effect,
additional advantageous effects (e.g. a further therapeutic effect
not found for any of the single compounds), less side effects, a
combined therapeutic effect in a non-effective dosage of one or
both of the combination partners (i) and (ii), and very preferably
a clear synergism of the combination partners (i) and (ii).
[0254] For example, the term "jointly (therapeutically) active" may
mean that the compounds may be given separately or sequentially (in
a chronically staggered manner, especially a sequence-specific
manner) in such time intervals that they preferably, in the
warm-blooded animal, especially human, to be treated, and still
show a (preferably synergistic) interaction (joint therapeutic
effect). A joint therapeutic effect can, inter alia, be determined
by following the blood levels, showing that both compounds are
present in the blood of the human to be treated at least during
certain time intervals, but this is not to exclude the case where
the compounds are jointly active although they are not present in
blood simultaneously.
[0255] The present invention thus pertains to a combination product
for simultaneous, separate or sequential use, such as a combined
preparation or a pharmaceutical fixed combination, or a combination
of such preparation and combination.
[0256] In the combination therapies of the invention, the compounds
useful according to the invention may be manufactured and/or
formulated by the same or different manufacturers. Moreover, the
combination partners may be brought together into a combination
therapy: (i) prior to release of the combination product to
physicians (e.g. in the case of a kit comprising the compound of
the invention and the other therapeutic agent); (ii) by the
physician themselves (or under the guidance of a physician) shortly
before administration; (iii) in the patient themselves, e.g. during
sequential administration of the compound of the invention and the
other therapeutic agent.
[0257] In certain embodiments, any of the above methods involve
further administering one or more other (e.g. third) co-agents,
especially a chemotherapeutic agent.
[0258] Thus, the invention relates in a further embodiment to a
combination product, particularly a pharmaceutical composition,
comprising a therapeutically effective amount of (i) an EGFR
tyrosine kinase inhibitor and (ii) a MET tyrosine kinase inhibitor,
or a pharmaceutically acceptable salt thereof, respectively, and at
least one third therapeutically active agent (co-agent), e.g.
another compound (i) and/or (ii) or a different co-agent. The
additional co-agent is preferably selected from the group
consisting of an anti-cancer agent; an anti-inflammatory agent.
[0259] Also in this case, the combination partners forming a
corresponding product according to the invention may be mixed to
form a fixed pharmaceutical composition or they may be administered
separately or pairwise (i.e. before, simultaneously with or after
the other drug substance(s)).
[0260] A combination product according to the invention can besides
or in addition be administered especially for cancer therapy in
combination with chemotherapy, radiotherapy, immunotherapy,
surgical intervention, or a combination of these. Long-term therapy
is equally possible as is adjuvant therapy in the context of other
treatment strategies, as described above. Other possible treatments
are therapy to maintain the patient's status after tumor
regression, or even chemopreventive therapy, for example in
patients at risk.
[0261] Possible anti-cancer agents (e.g. for chemotherapy) as
co-agents include, but are not limited to aromatase inhibitors;
antiestrogens; topoisomerase I inhibitors; topoisomerase II
inhibitors; microtubule active compounds; alkylating compounds;
histone deacetylase inhibitors; compounds which induce cell
differentiation processes; cyclooxygenase inhibitors; MMP
inhibittors; mTOR inhibitors; antineoplastic antimetabolites;
platin compounds; compounds targeting/decreasing a protein or lipid
kinase activity; anti-angiogenic compounds; compounds which target,
decrease or inhibit the activity of a protein or lipid phosphatase;
gonadorelin agonists; anti-androgens; methionine aminopeptidase
inhibitors; bisphosphonates; biological response modifiers;
anti-proliferative antibodies; heparanase inhibitors; inhibitors of
Ras oncogenic isoforms; telomerase inhibitors; proteasome
inhibitors; compounds used in the treatment of hematologic
malignancies; compounds which target, decrease or inhibit the
activity of Flt-3; Hsp90 inhibitors; kinesin spindle protein
inhibitors; MEK inhibitors; leucovorin; EDG binders; antileukemia
compounds; ri-bonucleotide reductase inhibittors;
S-adenosylmethionine decarboxylase inhibitors; angiostatic
steroids; corticosteroids; other chemotherapeutic compounds (as
defined below); photosensitizing compoounds.
[0262] Further, alternatively or in addition combination products
according to the invention may be used in combination with other
tumor treatment approaches, including surgery, ionizing radiation,
photodynamic therapy, implants, e.g. with corticosteroids,
hormones, or they may be used as radiosensitizers.
[0263] The term "aromatase inhibitor" as used herein relates to a
compound which inhibits the estrogen production, i.e. the
conversion of the substrates androstenedione and testosterone to
estrone and estradiol, respectively. The term includes, but is not
limited to steroids, especially atamestane, exemestane and
formestane and, in particular, non-steroids, especially
aminoglutethimide, roglethimide, pyridoglutethimide, trilostane,
testolactone, ketokonazole, vorozole, fadrozole, anastrozole and
letrozole.
[0264] The term "antiestrogen" as used herein relates to a compound
which antagonizes the effect of estrogens at the estrogen receptor
level. The term includes, but is not limited to tamoxifen,
fulvestrant, raloxifene and raloxifene hydrochloride.
[0265] The term "anti-androgen" as used herein relates to any
substance which is capable of inhibiting the biological effects of
androgenic hormones and includes, but is not limited to,
bicalutamide (CASODEX), which can be formulated, e.g. as disclosed
in U.S. Pat. No. 4,636,505.
[0266] The term "gonadorelin agonist" as used herein includes, but
is not limited to abarelix, goserelin and goserelin acetate. The
term "topoisomerase I inhibitor" as used herein includes, but is
not limited to topotecan, gimatecan, irinotecan, camptothecian and
its analogues, 9-nitrocamptothecin and the macromolecular
camptothecin conjugate PNU-166148 (compound Al in WO99/17804).
[0267] The term "topoisomerase II inhibitor" as used herein
includes, but is not limited to the anthracyclines such as
doxorubicin (including liposomal formulation, e.g. CAELYX),
daunorubicin, epirubicin, idarubicin and nemorubicin, the
anthraquinones mitoxantrone and losoxantrone, and the
podophillotoxines etoposide and teniposide.
[0268] The term "microtubule active compound" relates to
microtubule stabilizing, microtubule destabilizing compounds and
microtublin polymerization inhibitors including, but not limited to
taxanes, e.g. paclitaxel and docetaxel, vinca alkaloids, e.g.,
vinblastine, especially vinblastine sulfate, vincristine especially
vincristine sulfate, and vinorelbine, discodermolides, cochicine
and epothilones and derivatives thereof, e.g. epothilone B or D or
derivatives thereof.
[0269] The term "alkylating compound" as used herein includes, but
is not limited to, cyclophosphamide, ifosfamide, melphalan or
nitrosourea (BCNU or Gliadel).
[0270] The term "histone deacetylase inhibitors" or "HDAC
inhibitors" relates to compounds which inhibit the histone
deacetylase and which possess antiproliferative activity. This
includes compounds disclosed in WO 2/22577, especially
N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indo1-3-yl)ethyl]-amino]methyl]ph-
enyl]-2E-2- propenamide,
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]--
2E-2-propenamide and pharmaceutically acceptable salts thereof. It
further especially includes Suberoylanilide hydroxamic acid (SAHA).
Compounds which target, decrease or inhibit activity of histone
deacetylase (HDAC) inhibitors such as sodium butyrate and
suberoylanilide hydroxamic acid (SAHA) inhibit the activity of the
enzymes known as histone deacetylases. Specific HDAC inhibitors
include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and
compounds disclosed in U.S. Pat. No. 6,552,065, in particular,
N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-
ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically
acceptable salt thereof and
N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phe-
nyl]-2E-2-propenamide or a pharmaceutically acceptable salt
thereof, especially the lactate salt.
[0271] The term "antineoplastic antimetabolite" includes, but is
not limited to, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine,
DNA demethylating compounds, such as 5-azacytidine and decitabine,
methotrexate and edatrexate, and folic acid antagonists such as
pemetrexed.
[0272] The term "platin compound" as used herein includes, but is
not limited to, carboplatin, cis-platin, cisplatinum and
oxaliplatin.
[0273] The term "compounds targeting/decreasing a protein or lipid
kinase activity"; or a "protein or lipid phosphatase activity"; or
"further anti-angiogenic compounds" as used herein includes, but is
not limited to, c-Met tyrosine kinase and/or serine and/or
threonine kinase inhibitors or lipid kinase inhibitors, e.g.,
[0274] a) compounds targeting, decreasing or inhibiting the
activity of the platelet-derived growth factor-receptors (PDGFR),
such as compounds which target, decrease or inhibit the activity of
PDGFR, especially compounds which inhibit the PDGF receptor, e.g. a
N-phenyl-2-pyrimidine-amine derivative, e.g. imatinib, SU101,
SU6668 and GFB-111;
[0275] b) compounds targeting, decreasing or inhibiting the
activity of the insulin-like growth factor receptor I (IGF-IR),
such as compounds which target, decrease or inhibit the activity of
IGF-IR, especially compounds which inhibit the kinase activity of
IGF-I receptor, such as those compounds disclosed in WO 02/092599,
or antibodies that target the extracellular domain of IGF-I
receptor or its growth factors;
[0276] c) compounds targeting, decreasing or inhibiting the
activity of the Trk receptor tyrosine kinase family, or ephrin
kinase family inhibitors;
[0277] d) compounds targeting, decreasing or inhibiting the
activity of the Axl receptor tyrosine kinase family;
[0278] e) compounds targeting, decreasing or inhibiting the
activity of the Ret receptor tyrosine kinase;
[0279] f) compounds targeting, decreasing or inhibiting the
activity of the Kit/SCFR receptor tyrosine kinase, e.g.
imatinib;
[0280] g) compounds targeting, decreasing or inhibiting the
activity of the C-kit receptor tyrosine kinases--(part of the PDGFR
family), such as compounds which target, decrease or inhibit the
activity of the c-Kit receptor tyrosine kinase family, especially
compounds which inhibit the c-Kit receptor, e.g. imatinib;
[0281] h) compounds targeting, decreasing or inhibiting the
activity of members of the c-Abl family, their gene-fusion products
(e.g. BCR-Abl kinase) and mutants, such as compounds which target
decrease or inhibit the activity of c-Abl family members and their
gene fusion products, e.g. a N-phenyl-2-pyrimidine-amine
derivative, e.g. imatinib or nilotinib (AMN107); PD180970; AG957;
NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825)
[0282] i) compounds targeting, decreasing or inhibiting the
activity of members of the protein kinase C (PKC) and Raf family of
serine/threonine kinases, members of the MEK, SRC, JAK, FAK, PDK1,
PKB/Akt, and Ras/MAPK family members, and/or members of the
cyclin-dependent kinase family (CDK) and are especially those
staurosporine derivatives disclosed in US 5,093,330, e.g.
midostaurin; examples of further compounds include e.g. UCN-01,
safingol, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO
318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196;
isochinoline compounds such as those disclosed in WO 00/09495;
FTIs; PD184352 or QAN697 (a P13K inhibitor) or AT7519 (CDK
inhibitor);
[0283] j) compounds targeting, decreasing or inhibiting the
activity of protein-tyrosine kinase inhibitors, such as compounds
which target, decrease or inhibit the activity of protein-tyrosine
kinase inhibitors include imatinib mesylate (GLEEVEC) or
tyrphostin. A tyrphostin is preferably a low molecular weight
(Mr<1500) compound, or a pharmaceutically acceptable salt
thereof, especially a compound selected from the
benzylidenemalonitrile class or the S-arylbenzenemalonirile or
bi-substrate quinoline class of compounds, more especially any
compound selected from the group consisting of Tyrphostin
A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748;
Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer;
Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin
(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl
ester; NSC 680410, adaphostin);
[0284] k) compounds targeting, decreasing or inhibiting the
activity of the epidermal growth factor family of receptor tyrosine
kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and
their mutants, such as compounds which target, decrease or inhibit
the activity of the epidermal growth factor receptor family are
especially compounds, proteins or antibodies which inhibit members
of the EGF receptor tyrosine kinase family, e.g. EGF receptor,
ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, and
are in particular those compounds, proteins or monoclonal
antibodies generically and specifically disclosed in WO 97/02266,
e.g. the compound of ex. 39, or in EP 0 564 409, WO 99/03854, EP
0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063, U.S. Pat. No.
5,747,498, WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and,
especially, WO 96/30347 (e.g. compound known as CP 358774), WO
96/33980 (e.g. compound ZD 1839) and WO 95/03283 (e.g. compound
ZM105180); e.g. trastuzumab (Herceptin.TM.) cetuximab
(Erbitux.TM.), Iressa, Tarceva, OSI-774, CI-1033, EKB-569, GW-2016,
E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and
7H-pyrrolo-[2,3-d]pyrimidine derivatives which are disclosed in WO
03/013541; and
[0285] l) compounds targeting, decreasing or inhibiting the
activity of the c-Met receptor, such as compounds which target,
decrease or inhibit the activity of c-Met, especially compounds
which inhibit the kinase activity of c-Met receptor, or antibodies
that target the extracellular domain of c-Met or bind to HGF;
[0286] m) compounds targeting, decreasing or inhibiting the
activity of the Ron receptor tyrosine kinase.
[0287] Further anti-angiogenic compounds include compounds having
another mechanism for their activity, e.g. unrelated to protein or
lipid kinase inhibition e.g. thalidomide (THALOMID) and TN
P-470.
[0288] The term "Compounds which target, decrease or inhibit the
activity of a protein or lipid phosphatase" includes, but is not
limited to inhibitors of phosphatase 1, phosphatase 2A, or CDC25,
e.g. okadaic acid or a derivative thereof.
[0289] The term "Compounds which induce cell differentiation
processes" includes, but is not limited to e.g. retinoic acid,
.alpha.- .gamma.- or .delta.-tocopherol or .alpha.-.gamma.- or
.delta.-tocotrienol.
[0290] The term "cyclooxygenase inhibitor" as used herein includes,
but is not limited to, e.g. Cox-2 inhibitors, 5-alkyl substituted
2-arylaminophenylacetic acid and derivatives, such as celecoxib
(CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a
5-alkyl-2-arylaminophenylacetic acid, e.g.
5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid,
lumiracoxib.
[0291] The term "bisphosphonates" as used herein includes, but is
not limited to, etridonic, clodronic, tiludronic, pamidronic,
alendronic, ibandronic, risedronic and zoledronic acid.
[0292] The term "mTOR inhibitors" relates to compounds which
inhibit the mammalian target of rapamycin (mTOR) and which possess
antiproliferative activity such as sirolimus (Rapamune.RTM.),
everolimus (Certican.TM.), CCI-779 and ABT578.
[0293] The term "heparanase inhibitor" as used herein refers to
compounds which target, decrease or inhibit heparin sulfate
degradation. The term includes, but is not limited to, PI-88.
[0294] The term "biological response modifier" as used herein
refers to a lymphokine or interferons, e.g. interferon .gamma..
[0295] The term "inhibitor of Ras oncogenic isoforms", e.g. H-Ras,
K-Ras, or N-Ras, as used herein refers to compounds which target,
decrease or inhibit the oncogenic activity of Ras e.g. a "farnesyl
transferase inhibitor" e.g. L-744832, DK8G557 or R115777
(Zarnestra).
[0296] The term "telomerase inhibitor" as used herein refers to
compounds which target, decrease or inhibit the activity of
telomerase. Compounds which target, decrease or inhibit the
activity of telomerase are especially compounds which inhibit the
telomerase receptor, e.g. telomestatin.
[0297] The term "methionine aminopeptidase inhibitor" as used
herein refers to compounds which target, decrease or inhibit the
activity of methionine aminopeptidase. Compounds which target,
decrease or inhibit the activity of methionine aminopeptidase are
e.g. bengamide or a derivative thereof.
[0298] The term "proteasome inhibitor" as used herein refers to
compounds which target, decrease or inhibit the activity of the
proteasome. Compounds which target, decrease or inhibit the
activity of the proteasome include e.g. Bortezomid (Velcade.TM.)and
MLN 341.
[0299] The term "matrix metalloproteinase inhibitor" or ("MMP"
inhibitor) as used herein includes, but is not limited to, collagen
peptidomimetic and nonpeptidomimetic inhibitors, tetracycline
derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat
and its orally bioavailable analogue marimastat (BB-2516),
prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY
12-9566, TAA211, MM1270B or AAJ996.
[0300] The term "compounds used in the treatment of hematologic
malignancies" as used herein includes, but is not limited to,
FMS-like tyrosine kinase inhibitors e.g. compounds targeting,
decreasing or inhibiting the activity of FMS-like tyrosine kinase
receptors (Flt-3R); interferon, 1-b-D-arabinofuransylcytosine
(ara-c) and bisulfan; and ALK inhibitors e.g. compounds which
target, decrease or inhibit anaplastic lymphoma kinase.
[0301] The term "Compounds which target, decrease or inhibit the
activity of FMS-like tyrosine kinase receptors (Flt-3R)" are
especially compounds, proteins or antibodies which inhibit members
of the Flt-3R receptor kinase family, e.g. PKC412, midostaurin, a
staurosporine derivative, SU11248 and MLN518.
[0302] The term "HSP90 inhibitors" as used herein includes, but is
not limited to, compounds targeting, decreasing or inhibiting the
intrinsic ATPase activity of HSP90; degrading, targeting,
decreasing or inhibiting the HSP90 client proteins via the
ubiquitin proteosome pathway. Compounds targeting, decreasing or
inhibiting the intrinsic ATPase activity of HSP90 are especially
compounds, (17AAG, 17-DMAG), a geldanamycin derivative; other
geldanamycin related compounds; radicicol and HDAC
inhibitors;IPI-504, CNF1010, CNF2024, CNF1010 from Conforma
Therapeutics; temozolomide, AUY922 from Novartis.
[0303] The term "antiproliferative antibodies" as used herein
includes, but is not limited to erbitux, bevacizumab, rituximab,
PRO64553 (anti-CD40) and 2C4 Antibody. By antibodies is meant e.g.
intact monoclonal antibodies, polyclonal antibodies, multispecific
antibodies formed from at least 2 intact antibodies, and antibodies
fragments so long as they exhibit the desired biological
activity.
[0304] The term "antileukemic compounds" includes, for example,
Ara-C, a pyrimidine analog, which is the 2'-alpha-hydroxy ribose
(arabinoside) derivative of deoxycytidine. Also included is the
purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and
fludarabine phosphate. For the treatment of acute myeloid leukemia
(AML), compounds of formula (I) can be used in combination with
standard leukemia therapies, especially in combination with
therapies used for the treatment of AML. In particular, compounds
of formula (I) can be administered in combination with, e.g.,
farnesyl transferase inhibitors and/or other drugs useful for the
treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16,
Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.
[0305] "Somatostatin receptor antagonists" as used herein refers to
compounds which target, treat or inhibit the somatostatin receptor
such as octreotide, and SOM230.
[0306] "Tumor cell damaging approaches" refer to approaches such as
ionizing radiation. The term "ionizing radiation" referred to above
and hereinafter means ionizing radiation that occurs as either
electromagnetic rays (such as X-rays and gamma rays) or particles
(such as alpha and beta particles). Ionizing radiation is provided
in, but not limited to, radiation therapy and is known in the art.
See Hellman, Principles of Radiation Therapy, Cancer, in Principles
and Practice of Oncology, Devita et al., Eds., 4.sup.1h Edition,
Vol. 1, pp. 248-275 (1993).
[0307] The term "EDG binders" as used herein refers a class of
immunosuppressants that modulates lymphocyte recirculation, such as
FTY720.
[0308] The term "kinesin spindle protein inhibitors" is known in
the field and includes SB715992 or SB743921 from GlaxoSmithKline,
pentamidine/chlorpromazine from CombinatoRx.
[0309] The term "MEK inhibitors" is known in the field and includes
ARRY142886 from Array PioPharma, AZD6244 from AstraZeneca, PD181461
from Pfizer, leucovorin.
[0310] The term "ribonucleotide reductase inhibitors" includes, but
is not limited to to pyrimidine or purine nucleoside analogs
including, but not limited to, fludarabine and/or cytosine
arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine,
6-mercaptopurine (especially in combination with ara-C against ALL)
and/or pentostatin. Ribonucleotide reductase inhibitors are
especially hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione
derivatives, such as PL-1, PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or
PL-8 mentioned in Nandy et al., Acta Oncologica, Vol. 33, No. 8,
pp. 953-961 (1994).
[0311] The term "S-adenosylmethionine decarboxylase inhibitors" as
used herein includes, but is not limited to the compounds disclosed
in US 5,461,076.
[0312] Also included are in particular those compounds, proteins or
monoclonal antibodies of VEGF/VEGFR disclosed in WO 98/35958, e.g.
1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a
pharmaceutically acceptable salt thereof, e.g. the succinate, or in
WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819 and
EP 0 769 947; those as described by Prewett et al, Cancer Res, Vol.
59, pp. 5209-5218 (1999); Yuan et al., Proc Natl Acad Sci USA, Vol.
93, pp. 14765-14770 (1996); Zhu et al., Cancer Res, Vol. 58, pp.
3209-3214 (1998); and Mordenti et al., Toxicol Pathol, Vol. 27, No.
1, pp. 14-21 (1999); in WO 00/37502 and WO 94/10202; ANGIOSTATIN,
described by O'Reilly et al., Cell, Vol. 79, pp. 315-328 (1994);
ENDOSTATIN, described by O'Reilly et al., Cell, Vol. 88, pp.
277-285 (1997); anthranilic acid amides; ZD4190; ZD6474; SU5416;
SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor
antibodies, e.g. rhuMAb and RHUFab, VEGF aptamer e.g. Macugon;
FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgG1 antibody,
Angiozyme (RPI 4610) and Bevacizumab.
[0313] "Photodynamic therapy" as used herein refers to therapy
which uses certain chemicals known as photosensitizing compounds to
treat or prevent cancers. Examples of photodynamic therapy includes
treatment with compounds, such as e.g. VISUDYNE and porfimer
sodium.
[0314] "Angiostatic steroids" as used herein refers to compounds
which block or inhibit angiogenesis, such as, e.g., anecortave,
triamcinolone. hydrocortisone, 11-.alpha.-epihydrocotisol,
cortexolone, 17.alpha.-hydroxyprogesterone, corticosterone,
desoxycorticosterone, testosterone, estrone and dexamethasone.
[0315] "Corticosteroids" as used herein includes, but is not
limited to compounds, such as e.g. fluocinolone, dexamethasone; in
particular in the form of implants.
[0316] Other chemotherapeutic compounds include, but are not
limited to, plant alkaloids, hormonal compounds and antagonists;
biological response modifiers, preferably lymphokines or
interferons; antisense oligonucleotides or oligonucleotide
derivatives; shRNA or siRNA; or miscellaneous compounds or
compounds with other or unknown mechanism of action.
[0317] A combination product according to the invention may also be
used in combination with or comprise one or more further drug
substances selected from the group of anti-inflammatory drug
substances; antihistamine drug substances; bronchodilatatory drug
substances, NSAID; antagonists of chemokine receptors.
[0318] Suitable anti-inflammatory drugs include steroids, in
particular glucocorticosteroids such as budesonide, beclamethasone
dipropionate, fluticasone propionate, ciclesonide or mometasone
furoate, or steroids described in WO 02/88167, WO 02/12266, WO
02/100879, WO 02/00679 (especially those of Examples 3, 11, 14, 17,
19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101), WO
03/035668, WO 03/048181, WO 03/062259, WO 03/064445, WO 03/072592,
non-steroidal glucocorticoid receptor agonists such as those
described in WO 00/00531, WO 02/10143, WO 03/082280, WO 03/082787,
WO 03/104195, WO 04/005229;
[0319] LTB4 antagonists such LY293111, CGS025019C, CP-195543,
SC-53228, BIIL 284, ONO 4057, SB 209247 and those described in US
5451700; LTD4 antagonists such as montelukast and zafirlukast; PDE4
inhibitors such as cilomilast, Roflumilast (Byk Gulden),V-11294A
(Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough),
Arofylline (Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis),
AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID(TM) CC-10004
(Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa
Hakko Kogyo), and those disclosed in WO 92/19594, WO 93/19749, WO
93/19750, WO 93/19751, WO 98/18796, WO 99/16766, WO 01/13953, WO
03/104204, WO 03/104205, WO 03/39544, WO 04/000814, WO 04/000839,
WO 04/005258, WO 04/018450, WO 04/018451, WO 04/018457, WO
04/018465, WO 04/ 018431, WO 04/018449, WO 04/018450, WO 04/018451,
WO 04/018457, WO 04/018465, WO 04/019944, WO 04/019945, WO
04/045607 and WO 04/037805; A2a agonists such as those disclosed in
EP 409595A2, EP 1052264, EP 1241176, WO 94/17090, WO 96/02543, WO
96/02553, WO 98/28319, WO 99/24449, WO 99/24450, WO 99/24451, WO
99/38877, WO 99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO
99/67266, WO 00/23457, WO 00/77018, WO 00/78774, WO 01/23399, WO
01/27130, WO 01/27131, WO 01/60835, WO 01/94368, WO 02/00676, WO
02/22630, WO 02/96462, WO 03/086408, WO 04/ 039762, WO 04/039766,
WO 04/045618 and WO 04/046083; A2b antagonists such as those
described in WO 02/42298; and beta-2 adrenoceptor agonists such as
albuterol (salbutamol), metaproterenol, terbutaline, salmeterol
fenoterol, procaterol, and especially, formoterol and
pharmaceutically acceptable salts thereof, and compounds (in free
or salt or solvate form) of formula I of WO 0075114, which document
is incorporated herein by reference, preferably compounds of the
Examples thereof, especially a compound of formula
##STR00038##
[0320] and pharmaceutically acceptable salts thereof, as well as
compounds (in free or salt or solvate form) of formula I of WO
04/16601, and also compounds of WO 04/033412.
[0321] Suitable bronchodilatory drugs include anticholinergic or
antimuscarinic compounds, in particular ipratropium bromide,
oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and
glycopyrrolate, but also those described in WO 01/04118, WO
02/51841, WO 02/53564, WO 03/00840, WO 03/87094, WO 04/05285, WO
02/00652, WO 03/53966, EP 424021, U.S. Pat. No. 5,171,744, U.S.
Pat. No. 3714357, WO 03/33495 and WO 04/018422.
[0322] Suitable chemokine receptors include, e.g. CCR-1, CCR-2,
CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1,
CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists such as
Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, Takeda
antagonists such as
N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbony-
l]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-amin-ium
chloride (TAK-770), and CCR-5 antagonists described in U.S. Pat.
No. 6,166,037 (particularly claims 18 and 19), WO 00/66558
(particularly claim 8), WO 00/66559 (particularly claim 9), WO
04/018425 and WO 04/026873.
[0323] Suitable antihistamine drug substances include cetirizine
hydrochloride, acetaminophen, clemastine fumarate, promethazine,
loratidine, desloratidine, diphenhydramine and fexofenadine
hydrochloride, activastine, astemizole, azelastine, ebastine,
epinastine, mizolastine and tefenadine as well as those disclosed
in WO 03/099807, WO 04/026841 and JP 2004107299.
[0324] The structure of the active agents identified by code nos.,
generic or trade names may be taken from the actual edition of the
standard compendium "The Merck Index" or from databases, e.g.
Patents International (e.g. IMS World Publications). The
corresponding content thereof is hereby incorporated by
reference.
[0325] The term "pharmaceutically effective" preferably relates to
an amount that is therapeutically or in a broader sense also
prophylactically effective against the progression of a disease or
disorder as disclosed herein.
[0326] The term "a commercial package" as used herein defines
especially a "kit of parts" in the sense that the components (a)
MET tyrosine kinase inhibitor and (b) FGFR tyrosine kinase
inhibitor as defined above and below, and optionally further
co-agents, can be dosed independently or by use of different fixed
combinations with distinguished amounts of the components (a) and
(b), i.e., simultaneously or at different time points. Moreover,
these terms comprise a commercial package comprising (especially
combining) as active ingredients components (a) and (b), together
with instructions for simultaneous, sequential (chronically
staggered, in time-specific sequence, preferentially) or (less
preferably) separate use thereof in the delay of progression or
treatment of a proliferative disease. The parts of the kit of parts
can then, e.g., be administered simultaneously or chronologically
staggered, that is at different time points and with equal or
different time intervals for any part of the kit of parts. Very
preferably, the time intervals are chosen such that the effect on
the treated disease in the combined use of the parts is larger than
the effect which would be obtained by use of only any one of the
combination partners (a) and (b) (as can be determined according to
standard methods. The ratio of the total amounts of the combination
partner (a) to the combination partner (b) to be administered in
the combined preparation can be varied, e.g., in order to cope with
the needs of a patient sub-population to be treated or the needs of
the single patient which different needs can be due to the
particular disease, age, sex, body weight, etc. of the patients.
Preferably, there is at least one beneficial effect, e.g., a mutual
enhancing of the effect of the combination partners (a) and (b), in
particular a more than additive effect, which hence could be
achieved with lower doses of each of the combined drugs,
respectively, than tolerable in the case of treatment with the
individual drugs only without combination, producing additional
advantageous effects, e.g., less side effects or a combined
therapeutic effect in a non-effective dosage of one or both of the
combination partners (components) (a) and (b), and very preferably
a strong synergism of the combination partners (a) and (b).
[0327] Both in the case of the use of the combination of components
(a) and (b) and of the commercial package, any combination of
simultaneous, sequential and separate use is also possible, meaning
that the components (a) and (b) may be administered at one time
point simultaneously, followed by administration of only one
component with lower host toxicity either chronically, e.g., more
than 3-4 weeks of daily dosing, at a later time point and
subse-quently the other component or the combination of both
components at a still later time point (in subsequent drug
combination treatment courses for an optimal effect) or the
like.
[0328] The combination products according to the present invention
are appropriate for the treatment of various diseases that are
mediated by, especially depend on, the activity of EGFR and/or MET
tyrosine kinase, respectively. They can thus be used in the
treatment of any of the diseases that can be treated by EGFR
tyrosine kinase inhibitors and MET tyrosine kinase inhibitors.
[0329] The term "FGFR tyrosine kinase activity and/or MET tyrosine
kinase activity mediated disease" refers especially to a disease in
which activity of one or both kinases leads to abnormal activity of
the regulatory pathways including one of both kinases, especially
where one or both of the kinases is overactive, e.g. due to
overexpression, mutation or relative lack of activity of other
regulatory pathways in the cell, e.g. where there is amplification,
constitutive activation and/or overactivation of preceding or
subsequent regulatory elements.
[0330] EGFR inhibitors are e.g. useful in the treatment of one or
more of the diseases which respond to an inhibition of EGFR
activity, especially a neoplastic or tumor disease, especially
solid tumor, more especially those cancers in which EGFR kinases
are implicated including breast cancer, gastric cancer, lung
cancer, cancer of the prostate, bladder cancer and endometrial
cancer. Further cancers include cancer of the kidney, liver,
adrenal glands, stomach, ovaries, colon, rectum, pancreas, vagina
or thyroid, sarcoma, glioblastomas and numerous tumours of the neck
and head, as well as leukemias and multiple myeloma. Especially
preferred are cancers of breast or ovary; lung cancer, e.g. NSCLC
or SCLC; head and neck, renal, colorectal, pancreas, bladder,
gastric or prostate cancer; or glioma; in particular, glioma or
colon, rectum or colorectal cancer or more particularly lung cancer
are to be mentioned. Also diseases dependent on ligands of EGFR,
such as EGF; TGF-.alpha.; HB-EGF; amphiregulin; epiregulin;
betacellulin, are included.
[0331] MET inhibitors are e.g. useful in the treatment of MET
related diseases, especially cancers that display evidence for
simultaneous activation of MET and FGFR, including gene
amplification, activating mutations, expression of cognate RTK
ligands, phosphorylation of RTKs at residues indicative of
activation, e.g. where the cancer is selected from the group
consisting of brain cancer, stomach cancer, genital cancer, urinary
cancer, prostate cancer, (urinary) bladder cancer (superficial and
muscle invasive), breast cancer, cervical cancer, colon cancer,
colorectal cancer, glioma (including glioblastoma, anaplastic
astrocytoma, oligoastrocytoma, oligodendroglioma), esophageal
cancer, gastric cancer, gastrointestinal cancer, liver cancer,
hepatocellular carcinoma (HCC) including childhood HCC, head and
neck cancer (including head and neck squamous-cell carcinoma,
nasopharyngeal carcinoma), Hurthle cell carcinoma, epithelial
cancer, skin cancer, melanoma (including malignant melanoma),
mesothelioma, lymphoma, myeloma (including multiple myeloma),
leukemias, lung cancer (including non-small cell lung cancer
(including all histological subtypes: adenocarcinoma, squamous cell
carcinoma, bronchoalveolar carcinoma, large-cell carcinoma, and
adenosquamous mixed type), small-cell lung cancer), ovarian cancer,
pancreatic cancer, prostate cancer, kidney cancer (including but
not limited to papillary renal cell carcinoma), intestine cancer,
renal cell cancer (including hereditary and sporadic papillary
renal cell cancer, Type I and Type II, and clear cell renal cell
cancer); sarcomas, in particular osteosarcomas, clear cell
sarcomas, and soft tissue sarcomas (including alveolar and (e.g.
embryonal) rhabdomyosarcomas, alveolar soft part sarcomas); thyroid
carcinoma (papillary and other subtypes).
[0332] MET inhibitors are e.g. also useful in the treatment of
cancer wherein the cancer is stomach, colon, liver, genital,
urinary, melanoma, or prostate. In a particular embodiment, the
cancer is liver or esophageal.
[0333] MET inhibitors are e.g. also useful in the treatment of
colon cancer, including metastases, e.g. in the liver, and of
non-small-cell lung carcinoma.
[0334] MET inhibitors are e.g. also may be used in the treatment of
hereditary papillary renal carcinoma (Schmidt, L. et al. Nat.
Genet. 16, 68-73, 1997) and other proliferative diseases in which
c-MET is overexpressed or constitutively activated by mutations
(Jeffers and Vande Woude. Oncogene 18, 5120-5125, 1999; and
reference cited therein) or chromosomal rearrangements (e.g.
TPR-MET; Cooper et al. Nature 311, 29-33, 1984; Park. et al. Cell
45, 895-904, 1986).
[0335] MET inhibitors are e.g. further useful in the treatment of
additional cancers and conditions as provided herein or known in
the art.
[0336] MET inhibitors are e.g. also suitable for the treatment of
one or more inflammatory conditions.
[0337] In a further embodiment, the inflammatory condition is due
to an infection. In one embodiment, the method of treatment would
be to block pathogen infection. In a particular embodiment, the
infection is a bacterial infection, e.g., a Listeria infection.
See, e.g., Shen et al. Cell 103: 501-10, (2000) whereby a bacterial
surface protein activates c-Met kinase through binding to the
extra-cellular domain of the receptor, thereby mimicking the effect
of the cognate ligand HGF/SF.
[0338] The combination product of the present invention is
especially appropriate for treatment of any of the cancers
mentioned above amenable to EGFR or Met inhibitor treatment,
especially a cancer selected from adenocarcinoma (especially of the
breast or more especially of the lung), rhabdomyosarcoma,
osteosarcoma, urinary bladder carcinoma, colorectal cancer and
glioma.
[0339] The term "a therapeutically effective amount" of a compound
of the present invention refers to an amount of the compound of the
present invention that will elicit the biological or medical
response of a subject, for example, reduction or inhibition of an
enzyme or a protein activity, or ameliorate symptoms, alleviate
conditions, slow or delay disease progression, or prevent a
disease, etc. In one non-limiting embodiment, the term "a
therapeutically effective amount" refers to the amount of the
compound of the present invention that, when administered to a
subject, is effective to (1) at least partially alleviating,
inhibiting, preventing and/or ameliorating a condition, or a
disorder or a disease (i) mediated by cMet (MET) and/or mediated by
EGFR activity, or (ii) characterized by activity (normal or
abnormal) of cMet and/or of EGFR; or (2) reducing or inhibiting the
activity of cMet and/or of EGFR; or (3) reducing or inhibiting the
expression of cMet and/or EGFR. In another non-limiting embodiment,
the term "a therapeutically effective amount" refers to the amount
of the compound of the present invention that, when administered to
a cell, or a tissue, or a non-cellular biological material, or a
medium, is effective to at least partially reducing or inhibiting
the activity of cMet and/or EGFR; or at least partially reducing or
inhibiting the expression of MET and/or EGFR.
[0340] As used herein, the term "subject" refers to an animal.
Typically the animal is a mammal. A subject also refers to for
example, primates (e.g., humans), cows, sheep, goats, horses, dogs,
cats, rabbits, rats, mice, fish, birds and the like. In certain
embodiments, the subject is a primate. In yet other embodiments,
the subject is a human.
[0341] "And/or" means that each one or both or all of the
components or features of a list are possible variants, especially
two or more thereof in an alternative or cumulative way.
[0342] As used herein, the term "inhibit", "inhibition" or
"inhibiting" refers to the reduction or suppression of a given
condition, symptom, or disorder, or disease, or a significant
decrease in the baseline activity of a biological activity or
process.
[0343] As used herein, the term "treat", "treating" or "treatment"
of any disease or disorder refers in one embodiment, to
ameliorating the disease or disorder (i.e., slowing or arresting or
reducing the development of the disease or at least one of the
clinical symptoms thereof). In another embodiment "treat",
"treating" or "treatment" refers to alleviating or ameliorating at
least one physical parameter including those which may not be
discernible by the patient. In yet another embodiment, "treat",
"treating" or "treatment" refers to modulating the disease or
disorder, either physically, (e.g., stabilization of a discernible
symptom), physiologically, (e.g., stabilization of a physical
parameter), or both. In yet another embodiment, "treat", "treating"
or "treatment" refers to preventing or delaying the onset or
development or progression of the disease or disorder.
[0344] The term "treatment" comprises, for example, the
prophylactic or especially therapeutic administration of the
combination partners to a warm-blooded animal, preferably to a
human being, in need of such treatment with the aim to cure the
disease or to have an effect on disease regression or on the delay
of progression of a disease.
[0345] As used herein, a subject is "in need of" a treatment if
such subject would benefit biologically, medically or in quality of
life from such treatment.
[0346] As used herein, the term "a," "an," "the" and similar terms
used in the context of the present invention (especially in the
context of the claims) are to be construed to cover both the
singular and plural unless otherwise indicated herein or clearly
contradicted by the context.
[0347] The combinations according to the invention can be prepared
in a manner known per se and are those suitable for enteral, such
as oral or rectal, and parenteral administration to mammals
(warm-blooded animals), including man, comprising a therapeutically
effective amount of at least one pharmacologically active
combination partner alone or in combination with one or more
pharmaceutically acceptable carriers, especially suitable for
enteral or parenteral application. In one embodiment of the
invention, one or more of the active ingredients are administered
orally.
[0348] As used herein, the term "carrier" or "pharmaceutically
acceptable carrier" includes any and all solvents, dispersion
media, coatings, surfactants, antioxidants, preservatives (e.g.,
antibacterial agents, antifungal agents), isotonic agents,
absorption delaying agents, salts, preservatives, drugs, drug
stabilizers, binders, excipients, disintegration agents,
lubricants, sweetening agents, flavoring agents, dyes, and the like
and combinations thereof, as would be known to those skilled in the
art (see, for example, Remington's Pharmaceutical Sciences, 18th
Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as
any conventional carrier is incompatible with the active
ingredient, its use in the therapeutic or pharmaceutical
compositions is contemplated.
[0349] The pharmaceutical combination product according to the
invention (as fixed combination, or as kit, e.g. as combination of
a fixed combination and individual formulations for one or both
combination partners oras kit of individual formulations of the
combination partners) comprises the combination partners (at least
one MET tyrosine kinase inhibitor, at least one EGFR tyrosine
kinase inhibitor, and optionally one or more further co-agents) of
the present invention and one or more pharmaceutically acceptable
carrier materials (carriers, excipients). The combination products
or the combination partners constituting it can be formulated for
particular routes of administration such as oral administration,
parenteral administration, and rectal administration, etc. In
addition, the combination products of the present invention can be
made up in a solid form (including without limitation capsules,
tablets, pills, granules, powders or suppositories), or in a liquid
form (including without limitation solutions, suspensions or
emulsions). The combination products and/or their combination
partners can be subjected to conventional pharmaceutical operations
such as sterilization and/or can contain conventional inert
diluents, lubricating agents, or buffering agents, as well as
adjuvants, such as preservatives, stabilizers, wetting agents,
emulsifers and buffers, etc.
[0350] In one embodiment, the pharmaceutical compositions are
tablets or gelatin capsules comprising the active ingredient
together with one or more commonly known carriers, e.g. one or more
carriers selected from the group consisting of [0351] a) diluents,
e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose
and/or glycine; [0352] b) lubricants, e.g., silica, talcum, stearic
acid, its magnesium or calcium salt and/or polyethyleneglycol; for
tablets also [0353] c) binders, e.g., magnesium aluminum silicate,
starch paste, gelatin, tragacanth, methylcellulose, sodium
carboxymethylcellulose and/or polyvinylpyrrolidone; if desired
[0354] d) disintegrants, e.g., starches, agar, alginic acid or its
sodium salt, or effervescent mixtures; and [0355] e) absorbents,
colorants, flavors and sweeteners.
[0356] Tablets may be either film coated or enteric coated
according to methods known in the art.
[0357] Suitable compositions for oral administration especially
include an effective amount of one or more or in case of fixed
combination formulations each of the combination partners (active
ingredients) in the form of tablets, lozenges, aqueous or oily
suspensions, dispersible powders or granules, emulsion, hard or
soft capsules, or syrups or elixirs. Compositions intended for oral
use are prepared according to any method known in the art for the
manufacture of pharmaceutical compositions and such compositions
can contain one or more agents selected from the group consisting
of sweetening agents, flavoring agents, coloring agents and
preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets may contain the active
ingredient(s) in admixture with nontoxic pharmaceutically
acceptable excipients which are suitable for the manufacture of
tablets. These excipients are, for example, inert diluents, such as
calcium carbonate, sodium carbonate, lactose, calcium phosphate or
sodium phosphate; granulating and disintegrating agents, for
example, corn starch, or alginic acid; binding agents, for example,
starch, gelatin or acacia; and lubricating agents, for example
magnesium stearate, stearic acid or talc. The tablets are uncoated
or coated by known techniques to delay disintegration and
absorption in the gastrointestinal tract and thereby provide a
sustained action over a longer period. For example, a time delay
material such as glyceryl monostearate or glyceryl distearate can
be employed. Formulations for oral use can be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example,
peanut oil, liquid paraffin or olive oil.
[0358] Certain injectable compositions (especially useful e.g.
where antibodies are used as EGFR inhibitors) are aqueous isotonic
solutions or suspensions, and suppositories are advantageously
prepared from fatty emulsions or suspensions. Said compositions may
be sterilized and/or contain adjuvants, such as preserving,
stabilizing, wetting or emulsifying agents, solution promoters,
salts for regulating the osmotic pressure and/or buffers. In
addition, they may also contain other therapeutically valuable
substances. Said compositions are prepared according to
conventional mixing, granulating or coating methods, respectively,
and contain about 0.1-75%, or contain about 1-50%, of the active
ingredient.
[0359] Suitable compositions for transdermal application include an
effective amount of one or more active ingredients with a suitable
carrier. Carriers suitable for transdermal delivery include
absorbable pharmacologically acceptable solvents to assist passage
through the skin of the host. For example, transdermal devices are
in the form of a bandage comprising a backing member, a reservoir
containing the compound optionally with carriers, optionally a rate
controlling barrier to deliver the compound of the skin of the host
at a controlled and predetermined rate over a prolonged period of
time, and means to secure the device to the skin.
[0360] Suitable compositions for topical application, e.g., to the
skin and eyes, include aqueous solutions, suspensions, ointments,
creams, gels or sprayable formulations, e.g., for delivery by
aerosol or the like. Such topical delivery systems will in
particular be appropriate for dermal application, e.g., for the
treatment of skin cancer, e.g., for prophylactic use in sun creams,
lotions, sprays and the like. They are thus particularly suited for
use in topical, including cosmetic, formulations well-known in the
art. Such may contain solubilizers, stabilizers, tonicity enhancing
agents, buffers and preservatives.
[0361] As used herein a topical application may also pertain to an
inhalation or to an intranasal application. They may be
conveniently delivered in the form of a dry powder (either alone,
as a mixture, for example a dry blend with lactose, or a mixed
component particle, for example with phospholipids) from a dry
powder inhaler or an aerosol spray presentation from a pressurised
container, pump, spray, atomizer or nebuliser, with or without the
use of a suitable propellant.
[0362] The invention relates also to a kit of parts or a fixed
pharmaceutical composition comprising an effective amount,
especially an amount effective in the treatment of one of the
above-mentioned diseases of at least one MET tyrosine kinase
inhibitor, at least one EGFR tyrosine kinase inhibitor, or a
pharmaceutically acceptable salt thereof, respectively, and
optionally of at least one further co-agent, or a pharmaceutically
acceptable salt thereof, together with one or more pharmaceutically
acceptable carriers that are suitable for topical, enteral, for
example oral or rectal, or parenteral administration and that may
be inorganic or organic, solid or liquid.
[0363] In all formulations, the active ingredient(s) forming part
of a combination product according to the present invention can be
present each in a relative amount of 0.5 to 95% of weight of the
corresponding formulation (regarding the formulation as such, that
is without packaging and leaflet), e.g. from 1 to 90, 5 to 95, 10
to 98 or 10 to 60 or 40 to 80% by weight, respectively.
[0364] The dosage of the active ingredient to be applied to a
warm-blooded animal depends upon a variety of factors including
type, species, age, weight, sex and medical condition of the
patient; the severity of the condition to be treated; the route of
administration; the renal and hepatic function of the patient; and
the particular compound employed. A physician, clinician or
veterinarian of ordinary skill can readily determine and prescribe
the effective amount of the drug required to prevent, counter or
arrest the progress of the condition. Optimal precision in
achieving concentration of drug within the range that yields
efficacy without toxicity requires a regimen based on the kinetics
of the drug's availability to target sites. This involves a
consideration of the distribution, equilibrium, and elimination of
a drug. The dose of each of the combination partners or a
pharmaceutically acceptable salt thereof to be administered to
warm-blooded animals, for example humans of approximately 70 kg
body weight, is preferably from approximately 3 mg to approximately
5 g, more preferably from approximately 10 mg to approximately 1.5
g per person per day, e.g. divided preferably into 1 to 3 single
doses, e.g. for use once or twice daily, which may, for example, be
of the same size. Usually, children receive half of the adult
dose.
[0365] The pharmaceutical combination product of the present
invention can e.g. be in unit dosage of about 1-1000 mg of active
ingredient(s) for a subject of about 50-70 kg, or about 1-500 mg or
about 1-250 mg or about 1-150 mg or about 0.5-100 mg, or about 1-50
mg of for any one or in particular the sum of active ingredients;
or (especially for the EGFR inhibitor) 50 to 900, 60 to 850, 75 to
800 or 100 to 600 mg, respectively, for any one or in particular
the sum of active ingredients. The therapeutically effective dosage
of a compound, the pharmaceutical composition, or the combinations
thereof, is dependent on the species of the subject, the body
weight, age and individual condition, the disorder or disease or
the severity thereof being treated. A physician, clinician or (in
animal use) veterinarian of ordinary skill can readily determine
the effective amount of each of the active ingredients necessary to
prevent, treat or inhibit the progress of the disorder or
disease.
[0366] Specific embodiments of the invention are also given in the
claims which are incorporated here by reference, as well as in the
Examples.
DESCRIPTION OF THE FIGURES
[0367] FIG. 1: Graphic representation of the in vitro effect of a
combination of the MET inhibitor
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide and the EGFR inhibitor gefitinib which overcomes
resistance to single agent gefitinib in HCC827 GR lung cancer
cells; round spots: gefitinib; squares:
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide; triangles: gefitinib and
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide combination.
[0368] FIG. 2: Graphic representation of the in vitro effect of
exogenous HGF (hepatocyte growth factor) which renders HCC827 cells
resistant to gefitinib.
[0369] FIG. 3: Graphic representation of the first combination
experiment of the MET inhibitor
2-fluoroN-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]b-
enzamide and the EGFR inhibitor gefitinib in mice (in vivo) given
in the Examples. Female athymic mice bearing HCC827GR5 subcutaneous
xenografts were treated with
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide, gefitinib, a combination of both agents or vehicle
control at the indicated doses and schedules. Treatments started 11
days post tumor cells implantation and lasted 13 consecutive days.
Statistics on .DELTA. tumor volumes and A body weights were
performed with a one-way ANOVA, post hoc Dunnett's (*p<0.05 vs.
vehicle controls) to compare treatment groups against the vehicle
control group, and a one-way ANOVA, post hoc Tukey's fort pair-wise
comparisons (*p<0.05 between linked groups). Left side: Tumor
volumes over time. Right graph: Body weights over time.
[0370] FIG. 4: Graphic representation of the second combination
experiment of the MET inhibitor
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide and the EGFR inhibitor gefitinib in mice (in vivo) given
in the Examples. Female athymic mice bearing HCC827GR5 subcutaneous
xenografts were treated with
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide, gefitinib, a combination of both agents or vehicle
control at the indicated doses and schedules. Treatments started 11
days post tumor cells implantation and lasted 13 consecutive days.
Statistics on A tumor volumes and A body weights were performed
with a one-way ANOVA, post hoc Dunnett's (*p<0.05 vs. vehicle
controls) to compare groups versus vehicle, and a one-way ANOVA,
post hoc Tukey's fort pair-wise comparisons (*p<0.05 between
linked groups).
[0371] FIG. 5: Graphic representation of the change of tumor
volumes over time after treatment discontinuation in mice (in vivo)
as described in more detail in the Examples. Female athymic mice
bearing HCC827GR5 subcutaneous xenografts were treated with
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide, gefitinib, a combination of both agents or vehicle
control at the indicated doses and schedules. Treatments started 11
days post tumor cells implantation and lasted 13 consecutive days.
At the end of the second efficacy experiment (day 24 post cell
injection), the groups treated with
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide and the combination group were split into two groups of
four animals each. Four animals were kept under observation,
without any treatment (left panel) while the two other groups of 4
animals each were kept under daily treatment as before (right
panel). Tumor volumes and body weights were recorded only once a
week. Horizontal lines are set at 100 and 500 mm.sup.3 tumor
volumes.
EXAMPLES
[0372] The following Examples illustrate the invention and provide
specific embodiments, however without limiting the scope of the
invention.
Abbreviations of Companies and Cell Depositories
[0373] ATCC =American Type Culture Collection, Manassas, Va.,
USA
[0374] Amimed =trademark of BioConcept, Allschwil, Switzerland
[0375] Applied Biosystems =Applied Biosystems, Foster City, Calif.,
USA
[0376] Gibco=belonging to Life Technologies Corporation, Grand
Island, N.Y., USA
[0377] Pepro Tech=PeproTech, Rocky Hill, N.J., USA
[0378] Quiagen=Quiagen AG, Hilden, Germany
[0379] TPP=Techno Plastic Products AG, Trasadingen, Switzerland
Other Abbreviations
[0380] DMSO=dimethyl sulfoxide
Example 1: In-Vitro Combination of the MET Inhibitor
2-fluoro-N-methyl-4-[(7-guinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide and the EGFR Inhibitor Gefitinib in a Lung Cancer
Model
[0381] In order to confirm the rationale of combined treatment, a
combination of the title compounds was tested in the lung cancer
cell line HCC827 and its gefinitib-resistant derivative, HCC827 GR.
It could be shown that the combination of the MET inhibitor and the
EGFR inhibitor was more effective as follows:
Methods
[0382] HCC827 GR (gefitinib resistant) were obtained from Dr. Pasi
A. Janne (Dana-Farber Cancer Institute, Boston, Mass., USA), see
also J. A. Engelman et al., Science 316, 1039 ff (2007). Cell line
identity has been confirmed by SNP genotyping. Parental HCC827
cells are commercially available from ATCC (ATCC Number CRL-2868).
All two NSCLC lines were grown in RPMI 1640 medium (Amimed,
catalogue number 1-41F01-I) supplemented with 10% heat inactivated
FCS, (Amimed, catalogue number 2-01F16-I), 2 mM L-glutamine
(Amimed, catalogue number 5-10K00-H), 1 mM sodium pyruvate (Amimed,
catalogue number 5-60F00-H) and 10 mM HEPES (Gibco, catalogue
number 15630). Cells were incubated at 37.degree. C. in a
humidified atmosphere with 5% CO.sub.2. DNA was extracted with a
DNeasy Blood and Tissue Kit (QIAGEN, Inc).
[0383] The MET inhibitor and gefitinib 10 mM stock solutions were
prepared in DMSO and stored at -20.degree. C.
Proliferation Assays
[0384] Cells were seeded at 3000 per well in 96-well-plates (TPP,
flat bottom, tissue culture-treated, product #92096). 24 h later, a
10-point dilution series of each compound was prepared in DMSO. For
gefitinib: 3-fold steps, ranging from 10 mM to 0.5 .mu.M; for
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide: 3-fold steps, ranging from 1 .mu.M to 0.05 .mu.M.
Compounds were then diluted 1000-fold in growth medium in two steps
and added to cells in triplicates, resulting in a final volume of
100 .mu.L per well and maximal final compound concentrations of 10
.mu.M for gefitinib and 1 .mu.M for
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]tri-
azin-2-yl]benzamide. A DMSO-only control was included. For
combination treatment, the gefitinib and
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide dilution series were added to cells simultaneously, i.e.
compounds were mixed at a constant ratio of 10:1. Recombinant human
HGF (PeproTech, catalogue number 100-39) was added together with
compounds at a constant concentration as indicated in the
respective experiments. Cells were incubated for 72 to 96 h and the
amount of viable cells was then assessed using a resazurin sodium
salt dye reduction readout (commercially known as AlamarBlue.RTM.
assay, Invitrogen, Life Technologies Corporation, Grand Island,
N.Y., USA). Values were normalized and plotted as either "% of
control" with the DMSO control set to 100%, or as "fold seeded
cells". In this case a resazurin readout of separate wells with
untreated cells was obtained 24 h after seeding in order to
determine a "seeded cells" value for normalization. Plotting of the
data and curve-fitting were done with GraphPad Prism version 5.00
for Windows (GraphPad Software, Inc., La Jolla, Calif., USA).
Results
[0385] FIG. 1 shows the results of the experiments. The HCC827
cells were, as expected, highly sensitive to gefinitib with an
IC.sub.50 of 3 to 4 nM.
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-
-yl]benzamide did not show any substantial effect on proliferation
of the HCC827 cells or any contribution to the effect of the
gefitinib/2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]tri-
azin-2-yl]benzamide combination. In clear contrast, HCC827 GR cells
were fully resistant to gefitinib alone, and the effect of
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide monotherapy was modest. However, the combination of both
agents inhibited proliferation as efficiently as gefinitib
inhibited parental (not GR) cells, with an IC.sub.50 of around 4 nM
gefitinib abd 0.4 nM
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide in a 10:1 mixture.
Example 2: Exogenous HGF as an Alternative Way of MET Activation
Causes Resistance of HCC827 Cells to Gefitinib
Experimental
[0386] HCC827 cells were treated with a dilution series of
gefitinib in the presence or absence of 50 ng/ml recombinant HGF
(PeproTech, catalogue number 100-39) Cell viability was measured
after 96 hours using an AlamarBlue assay. The initial amount of
cells was quantified at the time of compound addition (dashed
line), and cell growth on the y axis is expressed as a multiple of
this value.
Results
[0387] Growth of HCC827 cells exposed to a serial dilution of
gefitinib in the presence or absence of a fixed combination of
recombinant hepatocyte growth factor (HGF) was examined. As shown
in FIG. 2, for the gefitinib-sensitive lung cancer cell line HCC827
HGF-mediated MET activation could partially revert growth
inhibition caused by gefitinib, confirming the concept that MET
activity can compensate for loss of EGFR activity in lung cancer
models. Addition of MET inhibitor
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide would then be expected to revert the "rescue" of growth
of the cells caused by HGF.
[0388] By quantitative Gene copy number analysis using qPCT (not
shown) it was found that the average MET copy number in HCC827 GR
and HCC827 cells were 7.50.+-.0.18 and 1.92.+-.0.36, respectively,
thus confirming the concept that the acquired resistance of HCC827
GR to the EGFR inhibitor gefitinib is based on MET
amplification.
Example 3: In-Vivo Combination of the MET Inhibitor
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide and the EGFR Inhibitor Gefitinib in a Lung Cancer
Model
[0389]
2-Fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-
-2-yl]benzamide was tested against HCC827 GR5 subcutaneous
xenografts, either alone or in combination with gefitinib. This
tumor model harbors an activating EGFR mutation as well as
amplification of the MET gene.
[0390] Experiments were conducted under approval by the Basel
Cantonal Veterinary Office.
[0391] Experiments were performed in female Hsd: Athymic nude-nu
CPB mice obtained from Harlan Wnkelmann, Germany. Animally were
approximately 11 weeks of age at treatment start and housed under
Optimized Hygienic Conditions (OHC) in Macrolon type III cages
(max. 5 animals per cage) with free access to food and water.
[0392] HCC827GR5 (see also J.A. Engelman et al., Science 316, 1039
ff (2007); gefitinib resistant lung tumor cells) were obtained from
Dr. Pasi Janne (Dana-Farber Cancer Institute, Boston, Mass., USA).
Cell line identity has been confirmed by SNP genotyping. Cells were
grown in RPMI 1640 medium (Amimed #1-41F01-1) supplemented with 10%
heat inactivated FCS, (Amimed #2-01F16-I), 2 mM L-glutamine (Amimed
# 5-10K00-H), 1 mM sodium pyruvate (Amimed #5-60F00-H) and 10 mM
HEPES (Gibco # 15630). Selective pressure was maintained on the
cells by keeping a 0.1 pM gefitinib concentration in the cell
culture medium at all times. Cells were incubated at 37.degree. C.
in a humidified atmosphere with 5% CO.sub.2.
[0393] HCC827GR5 tumors were established by subcutaneous injection
of 5.times.106 cells in 115p1 HBSS (Hank's buffered salt solution)
containing 50% Matrigel (v/v) (gelatinous protein mixture secreted
by Engelbreth-Holm-Swarm (EHS) mouse sarcoma cells, BD Biosciences,
Franklin Lakes, N.J., USA) into the right flank of mice. with a 13
gauge trocar needle under Forene.RTM. (Isofluran; Abott,
Switzerland) anesthesia. In the efficacy experiments, treatments
started when the tumors reached an average size of 150 mm.sup.3, 11
days post tumor implantation. In the PK/PD experiment, treatments
were started when the mean tumor size was 450mm.sup.3, 15 days post
tumor implantation.
[0394]
2-Fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-
-2-yl]benzamide was formulated in 0.25% methylcellulose and 0.05%
Tween 80 in water, using a water bath sonicator (33 kHz, 1 hour).
The application volumes were 10ml/kg for the single agents and for
the vehicle control group or 5ml/kg when the test compounds were
given in combination. All indicated doses refer to free base
equivalent of
2-Fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide (dihydrochloride salt). Gefitinib was formulated in
N-methyl-2-pyrrolidone:PEG300:Solutol HS15:water (10:30:20:40
v/v).
[0395] (Trademarks: Tween 80=Polysorbat 80 (ICI Americas, Inc.,
USA); Solutol H515=Macrogol 15 Hydroxystearate (BASF, Ludwigshafen,
Germany)).
[0396] Tumor volumes were measured with calipers and determined
according to the formula length.times.diameter.sup.2.times..pi./6.
In addition to presenting changed of tumor volumes over the course
of treatments, antitumor activity is expressed as T/C % ((mean
change of tumor volume of treated animals/mean change of tumor
volume of control animals).times.100). Regressions (%) were
calculated according to the formula ((mean tumor volume at end of
treatment--mean tumor volume at start of treatment)/mean tumor
volume at start of treatment).times.100. Body weights and tumor
volumes were recorded twice a week.
[0397] Statistics: Were applicable, data is presented as mean
.+-.SEM. For all tests, the level of significance was set at
p<0.05. For tumor volumes, comparisons between treatment groups
and vehicle control group were done using one-way ANOVA followed by
Dunnett's test. Pairwise comparisons were done using a one way
ANOVA followed by Tukey's test. The level of significance of body
weight change within a group between the start and the end of the
treatment period was determined using a paired t-test. Comparisons
of delta body weighs between treatment and vehicle control groups
were performed by a one-way ANOVA followed by a post hoc Dunnett's
test. Calculations were performed using GraphPad Prism 4 for
Windows (GraphPad Software Inc.). In addition, an approximation of
drug interactions was made using the method described by Clarke
(Clarke R., Breast Cancer Research and Treatment 46, 255-278
(1997)). This was applied to delta tumor volumes and can estimate
interactions from limited data. In short, the combination data was
assessed using the method presented by Clarke which can estimate
interactions from limited data. For compound A, B or the
combination AB (with control group C), antagonism is predicted when
the calculation AB/C>A/C.times.B/C, additive effect:
AB/C=A/C.times.B/C, synergistic interactions are predicted to occur
when AB/C<A/C.times.B/C.
[0398] In one experiment, see FIG. 3, female athymic nude mice were
treated orally once a day with 3 mg/kg
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide, alone or in combination with 25mg/kg gefitinib. Vehicle
controls consisted of animals receiving a daily oral administration
of 0.25% methylcellulose and 0.05% Tween 80 in water. All
administration volumes were 10 ml/kg except in the combination
chemotherapy group, where each single agent was administered at
5m1/kg. When administered as single agents, both
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide and gefitinib produced a statistically significant
antitumor effect (p<0.05, ANOVA), with 22.9% regressions and a
T/C of 32.5%, respectively. When given in combination,
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide and gefitinib produced statistically significant
regressions of 87.3% (p<0.05, ANOVA). A post hoc Tukey'a
analysis also showed that the antitumor effects produced by
gefitinib administered as a single agent was statistically
different from both
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-
yl]benzamide alone and in combination (p<0.05, ANOVA). In
addition,
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide administered as a single agent did not produce a
significant effect when compared to the combination (p>0.05,
ANOVA, post hoc Tukey's). The body weight changes in all treatment
groups were not significantly different from the vehicle control
group (p>0.05, one way ANOVA, post hoc Dunnett's), and the body
weight increase during the treatment period was significant only in
the vehicle control group (p<0.05, paired t-test). Moreover, an
analysis of possible compound interactions with the method
described by Clarke (loc. cit.) indicated a synergistic antit umor
effect with the combination of
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide (3mg/kg) and gefitinib (25 mg/kg), see Table 1:
TABLE-US-00001 TABLE 1 Evaluation of the antitumor effect of the
combination of 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-
imidazo[1,2-b]triazin-2-yl]benzamide ("MET inhibitor") and
gefitinib ("EGFR inhibitor") by Clarke`s method: A B (MET (EGFR AB
C inhibitor) inhibitor) (combination) A/C B/C A/C .times. B/C AB/C
Difference Result Delta 532 -60.2 173.1 -228.4 -0.113 0.325 -0.037
-0.429 -0.39 Synergy tumor volume The combination data was assessed
using the method presented by Clarke which can estimate
interactions from limited data. For compound A, B or the
combination AB (with control gropus C), antagonism is predicted
when the calculation AB/C > A/C .times. B/C, additive effect:
AB/C = A/C .times. B/C, synergistic interactions are predicted to
occur when AB/C < A/C .times. B/C.
[0399] In a further experiment, see FIG. 4, female athymic nude
mice were treated orally once a day with 3 mg/kg
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide, alone or in combination with 25mg/kg gefitinib. Vehicle
controls consisted of animals receiving a daily oral administration
of 0.25% methylcellulose and 0.05% Tween 80 in water. All
administration volumes were 10 ml/kg except in the combination
chemotherapy group, where each single agent was administered at 5
ml/kg. When administered as single agents, both
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-
yl]benzamide and gefitinib produced a statistically significant
antitumor effect (p<0.05, ANOVA), with 21.4% regressions and a
T/C of 49.4%, respectively. When given in combination,
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide and gefitinib produced statistically significant
regressions of 86.4% (p<0.05, ANOVA). A post hoc Tukey's
analysis showed that the antitumor effects produced by gefitinib
administered as a single agent was statistically different from
both
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-
yl]benzamide alone and in combination (p<0.05, ANOVA). In
addition,
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide administered as a single agent did not produce a
significant effect when compared to the combination (p>0.05,
ANOVA, post hoc Tukey's).The body weight changes in all treatment
groups were not significantly different from the vehicle control
group (p>0.05, one way ANOVA, post hoc Dunnett's). The body
weight increase was statistically significant in all groups
excepted the combination group (p<0.05, paired t-test). See FIG.
4.
[0400] As in the previous study, an analysis of possible compound
interactions with the method described by Clarke (Clarke 1997)
indicated a synergistic antitumor effect with the combination of
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide (3 mg/kg) and gefitinib (25mg/kg), see Table 2:
TABLE-US-00002 TABLE 2 Evaluation of the antitumor effect of the
combination of 2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-
imidazo[1,2-b]triazin-2-yl]benzamide ("MET inhibitor") and
gefitinib ("EGFR inhibitor") by Clarke`s method: A B (MET (EGFR AB
C inhibitor) inhibitor) (combination) A/C B/C A/C .times. B/C AB/C
Difference Result Delta 527.9 -55.7 261 -219.2 -0.106 0.494 -0.052
-0.415 -0.36 Synergy tumor volume (explanation see under Table
1)
[0401] In a further experiment, female athymic mice bearing
HCC827GR5 subcutaneous xenografts were treated with
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide, gefitinib, a combination of both agents or vehicle
control at the doses and schedules indicated in FIG. 5. Treatments
started 11 days post tumor cells implantation and lasted 13
consecutive days. At the end of the second efficacy experiment (day
24 post cell injection), the groups treated with
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide and the combination group were split into two groups of
four animals each. Four animals were kept under observation,
without any treatment (left panel) while the two other groups of 4
animals each were kept under daily treatment as before (right
panel). Tumor volumes and body weights were recorded only once a
week. Horizontal lines are set at 100 and 500 mm.sup.3 tumor
volumes, respectively. The tumors in the animals previously treated
with
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide alone kept growing to a mean+/-SEM volume of 516+/-112
mm.sup.3, while the tumors of the animals in the combination group
reached 90+/-27 mm.sup.3, see FIG. 5, left graph. In contrast, the
animals in the groups where treatments were extended increased only
to a mean of 400+/31 80 mm.sup.3 for the
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide -treated animals. The tumors in the animals that received
the combination therapy continued to regress from a mean volume of
33+/-1.3 to 26.3+/-2.8 mm.sup.3 (representing a mean of 89.2%
regression from the initial volume).
[0402] Discussion: The MET inhibitor
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide at a dose of 3 mg/kg showed slight statistically
significant tumor regressions. These regressions were significantly
increased when
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide was combined with gefitinib. As a single agent, gefitinib
administered at a dose of 25 mg/kg consistently caused
statistically significant antitumor effects, but never regressions.
Pharmacodynamic analysis showed that the MET signaling pathway was
down regulated for at least 8 hours after administration of the MET
inhibitor and that this down regulation was reinforced by the
simultaneous administration of the EGFR inhibitor gefitinib,
accounting for strong tumor regressions of more than 80% in the
combination groups. The analysis of the drug concentrations after
repeated dosing (not shown) showed that the levels of gefitinib
were increased by 2- to 4-fold when it was administered in
combination. Therefore it is possible that the incrased exposure to
gefitinib in the tumor tissue contributes to the improved antitumor
effects observed in the combination groups.
[0403] Example 4:
2-Fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide is an ATP-competitive and reversible small molecule
inhibitor against the c-MET kinase that possesses a high potency
(IC50=0.13.+-.0.05 nM in in vitro kinase assay) and selectivity
(with >10,000-fold selectivity over a panel of 56 other human
kinases). Potent activity (IC50 values: 0.2-2 nM) has also been
demonstrated in cell-based biochemical and functional assays that
measure c-MET-mediated signal transduction, as well as
c-MET-dependent cell proliferation, survival and migration. In
c-MET-driven or HGF/c-MET-driven xenograft mouse tumor models, oral
dosing of
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide demonstrated significant in vivo activity in blocking
both c-MET phosphorylation and tumor growth. In addition,
combination with the EGFR inhibitor Gefitinib was effective in
vitro and in vivo in suppressing growth of a Gefitinib-resistant
lung cancer model harboring a Gefitinib-sensitive EGFR mutation and
c-MET amplification. Gene copy number variation and mRNA expression
profiling of a large panel of cancer cell lines originating from
various lineages suggested that c-MET amplification exists in
several cancer types but is relatively more frequent in cancers of
the lung, stomach, breast and ovary. HGF expression also displays
lineage association and is more frequently detected in cancers of
the blood, brain, soft tissue, lung and liver. Pharmacogenetic
profiling of these cancer cell lines with a large panel of targeted
agents indicates that c-MET amplification or simultaneous HGF and
c-MET expression is highly predictive of response to c-MET
inhibitors including
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]tri-
azin-2-yl]benzamide. Furthermore, among 484 classes of compounds
classified by target, c-MET inhibitors are the most active class of
compounds in inhibiting the growth of cell lines with c-MET
amplification or simultaneous HGF and c-MET expression.
Importantly, cell lines with simultaneous HGF and c-MET expression
are also relatively resistant to EGFR inhibitors compared to cell
lines with similar c-MET level that lack HGF expression.
Example 5: Clinical Trial for Non-Small Cell Lung Varcinoma
(NSCLC)
[0404] A safety and efficacy study of
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide and gefitinib in patients with EGFR mutated,
c-MET-amplified NSCLC who have progressed after EGFRi treatment is
conducted. The trial is a Phase IB/II, open label, multicenter
study of
2-fluoro-N-methyl-4-[(7-quinolin-6-yl-methyl)-imidazo[1,2-b]triazin-2-yl]-
benzamide administered orally in combination with gefitinib in
adult patients with EGFR mutated, c-MET-amplified non-small cell
lung cancer who have progressed after EGFR inhibitor treatment.
Inclusion Criteria are
[0405] Documented EGFR mutation -Documented c-MET amplification
-Prior clinical benefit on EGFR inhibitors and then subsequent
progression
[0406] No starting of other treatment since progression on EGFR
inhibitors
[0407] .gtoreq.18 year old-Life expectancy of .gtoreq.3 months
[0408] ECOG performance status .ltoreq.2
[0409] Gender: Both; Minimum age 16 Years
Exclusion Criteria
[0410] Unable to swallow tables once or twice daily
[0411] Previous treatment with c-MET inhibitor
[0412] Any unresolved toxicity form previous anticancer therapy
greater than grade 1-History of cystic fibrosis
[0413] History of acute or chronic pancreatitis
[0414] Unable to undergo MRI or CT sans
[0415] Known history of HIV
[0416] Undergone a bone marrow or sold organ transplant
[0417] Clinically significant wound or lung tumor lesions with
increased likelihood of bleeding
[0418] Pregnant or nursing Other protocol-defined
inclusion/exclusion criteria may apply
[0419] The following data are obtained:
Primary Outcome Measures
TABLE-US-00003 [0420] Safety Outcome Measure TimeFrame Description
Type 1) Phase Ib: Frequency and first cycle of study cycle = 28 Yes
characteristics of treatment days dose limiting toxicities
Secondary Outcome Measures
TABLE-US-00004 [0421] Safety Outcome Measure TimeFrame Description
Type Overall survival (OS) From date of OS is defined as the time
No treatment until from the date of treatment last patient is off
to the date of death from study treatment any cause. Safety via
monitoring the frequency, 30 days post SAE collection ends 30 Yes
duration, and severity of AEs and SAEs, study treatment days after
the last study changes in physical examination, clinical related
procedure. laboratory parameters, vital signs and ECGs Inhibition
of c-MET signaling by pre- and Day 15 of cycle 1 cycle 1 = 28 days
No post- treatment immunohistochemistry of p-c-MET, Plasma
concentration of 2-fluoro-N- Day 1 of cycle 4 cycle 4 = 28 days No
methyl-4-[(7-quinolin-6-yl-methyl)-
imidazo[1,2-b]triazin-2-yl]benzamide and gefitinib, PK parameters
including but not limited to AUC, Cmax, Tmax, half-life,
accumulation ratio. Progression free survival (PFS) From date of
PFS is defined as the time No treatment to the from the date of
treatment date of to the date of event defined progression as the
first documented disease progression per RECIST or death due to any
cause.
[0422] Example 6: A Phase IB/II, open label, multicenter study of
Compound A or Compound B administered orally in combination with
gefitinib in adult patients with EGFR mutated, c-MET-amplified
non-Small Cell Lung Cancer who have Progressed after EGFR Inhibitor
Treatment
Protocol Summary
TABLE-US-00005 [0423] Protocol Title a Phase Ib/II, open-label,
dose escalation and multicenter study of Compound A or Compound B
administered orally in combination with gefitinib in adult patients
with EGFR mutated and c-MET amplified NSCLC who have progressed
after EGFR inhibitor treatment Brief title Study of efficacy and
safety Compound A or Compound B + gefitinib in patients with NSCLC
who have progressed after EGFR inhibitor treatment Sponsor and
Clinical Novartis Phase Phase Ib/II Investigation type Drug Study
type Interventional Purpose and rationale This study is designed to
explore if the combination of the c-MET inhibitor, Compound A or
Compound B, and the EGFR inhibitor, gefitinib, will provide
meaningful clinical benefit to patients whose tumors have
aberrations in both c-MET and EGFR pathways. Primary Objective(s)
and 1) Phase lb: To estimate the MTD or RP2D of Compound A or
Compound B in combination with gefitinib in NSCLC patients who have
c-MET gene amplification 2) Phase II: To estimate overall clinical
activity of Compound A or Compound B in combination with gefitinib
in NSCLC patients with c-MET gene amplification Secondary
Objectives 1) To determine safety and tolerability of Compound A or
Compound B in combination with gefitinib 2) To estimate time
dependent clinical activity of Compound A or Compound B in
combination with gefitinib 3) To assess the pharmacodynamic effect
of Compound A or Compound B in combination with gefitinib 4) To
characterize the PK profile of Compound A or Compound B and
gefitinib in NSCLC patient population and to assess potential drug
interaction between Compound A or Compound B and gefitinib Study
design Open label, single arm, with a Phase Ib Part and a Phase II
Part Population Approximately 58 male or female, at least 18 years
old patients with EGFR mutated and c-MET amplified NSCLC who have
progressed after EGFR inhibitor treatment Inclusion criteria
Confirmed c-MET pathway dysregulation EGFR mutated NSCLC patient
who have developed acquired resistance to EGFR inhibitor treatment
Measurable disease as determined by RECIST version 1.1 ECOG
performance status .ltoreq.2 Exclusion criteria Previous treatment
with a c-MET inhibitor or HGF-targeting therapy Previous radiation
therapy completed less than 4 weeks prior to dosing and, if
present, any acute toxicity > grade 1 History of cystic fibrosis
History of acute or chronic pancreatitis, surgery of pancreas or
any risk factors that may increase the risk of pancreatitis
Investigational and All patients will be treated with Compound A or
Compound B and gefitinib reference therapy administered orally,
beginning on Cycle 1 Day 1. Each cycle will have 28 days. All
patients will continue to receive study treatment until disease
progression, intolerable toxicity, withdrawal of consent, or
discontinuation of treatment for any other reason Efficacy
assessments Tumor response assessment as per RECIST v1.1. Safety
assessments Incidence, frequency, and category of DLT during the
first cycle of Compound A or Compound B treatment (escalation
phase) Frequency, duration, and severity of AEs, SAEs Other
assessments Compound A or Compound B and gefitinib pharmacokinetics
assessment in blood samples Biomarker assessments Data analysis
Data will be summarized using descriptive statistics (continuous
data) and/or contingency tables (categorical data) for demographic
and baseline characteristics, efficacy measurements, safety
measurements, and all relevant PK and PD measures. The Bayesian
logistic regression model with overdose control will be used to
recommend the dose levels that will be used for dose cohorts that
occur after the initial dose cohort. Key words Compound A or
Compound B, gefitinib, NSCLC, acquired resistance criteria, c-MET
dysregulation
* * * * *