U.S. patent application number 16/563018 was filed with the patent office on 2019-12-26 for combination of a 6-oxo-1,6-dihydro-pyridazine derivative having anti-cancer activity with an egfr inhibitor.
This patent application is currently assigned to Merck Patent GmbH. The applicant listed for this patent is Merck Patent GmbH. Invention is credited to Friedhelm BLADT, Manja FRIESE-HAMIM.
Application Number | 20190388423 16/563018 |
Document ID | / |
Family ID | 52133768 |
Filed Date | 2019-12-26 |
![](/patent/app/20190388423/US20190388423A1-20191226-C00001.png)
United States Patent
Application |
20190388423 |
Kind Code |
A1 |
BLADT; Friedhelm ; et
al. |
December 26, 2019 |
Combination of a 6-oxo-1,6-dihydro-pyridazine derivative having
anti-cancer activity with an EGFR inhibitor
Abstract
A pharmaceutical composition of
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically
acceptable salt and/or solvate thereof in combination with
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.
Inventors: |
BLADT; Friedhelm;
(Heidelberg, DE) ; FRIESE-HAMIM; Manja;
(Moerfelden-Walldorf, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Merck Patent GmbH |
Darmstadt |
|
DE |
|
|
Assignee: |
Merck Patent GmbH
Darmstadt
DE
|
Family ID: |
52133768 |
Appl. No.: |
16/563018 |
Filed: |
September 6, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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15534527 |
Jun 9, 2017 |
|
|
|
PCT/EP2015/002265 |
Nov 12, 2015 |
|
|
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16563018 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 1/00 20180101; A61P
35/02 20180101; A61P 13/12 20180101; A61P 35/00 20180101; A61K
31/506 20130101; A61K 31/506 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/506 20060101
A61K031/506 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 12, 2014 |
EP |
14004200.3 |
Claims
1. A pharmaceutical composition or combination, comprising
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically
acceptable salt and/or solvate thereof and
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.
2. The pharmaceutical composition or combination according to claim
1, which comprises
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate and
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.
3-9. (canceled)
10. The pharmaceutical composition or combination according to
claim 1, wherein the 3
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide is present in an
amount of 300 to 900 mg.
11. The pharmaceutical composition or combination according to
claim 1, wherein the 3
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide is present in an
amount of 400 to 800 mg.
12. The pharmaceutical composition or combination according to
claim 1, wherein the
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically
acceptable salt and/or solvate thereof is present in an amount of
250 mg to 12500 mg.
13. The pharmaceutical composition or combination according to
claim 1, wherein the
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically
acceptable salt and/or solvate thereof is present in an amount of
800 mg to 8000 mg.
14. The pharmaceutical composition or combination according to
claim 1, wherein the
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically
acceptable salt and/or solvate thereof is present in an amount of
500 mg to 2000 mg.
15. The pharmaceutical composition or combination according to
claim 2, wherein the
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate is
present in an amount of 250 mg to 12500 mg.
16. The pharmaceutical composition or combination according to
claim 2, wherein the
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate is
present in an amount of 800 mg to 8000 mg.
17. The pharmaceutical composition or combination according to
claim 2, wherein the
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate is
present in an amount of 500 mg to 2000 mg.
18. The pharmaceutical composition or combination according to
claim 1, which is in a form suitable for intravenous infusion.
19. The pharmaceutical composition or combination according to
claim 2, which is in a form suitable for intravenous infusion.
20. The pharmaceutical composition or combination according to
claim 1, wherein the
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically
acceptable salt and/or solvate thereof and the
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide are present in a
synergistic amount.
21. The pharmaceutical composition or combination according to
claim 2, wherein the
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate and
the
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide are present in a
synergistic amount.
22. The pharmaceutical combination according to claim 1, which is
in a kit comprising separate packages of the
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically
acceptable salt and/or solvate thereof and of the
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.
23. The pharmaceutical combination according to claim 22, wherein
the kit further comprises instructions to administer the contents
of the kit to a subject for the treatment of a disease selected
from the group consisting of cancer of the head, neck, eye, mouth,
throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung,
colon, rectum, stomach, prostate, urinary bladder, uterine, cervix,
breast, ovaries, testicles or other reproductive organs, skin,
thyroid, blood, lymph nodes, kidney, liver, pancreas, brain,
central nervous system, and cancer, small cell lung cancer,
non-small cell lung cancer, squamous cell cancer of the head and
neck, and solid tumors and blood-borne tumors.
24. The pharmaceutical combination according to claim 1, which is
in a kit comprising separate packages of the
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate and
of the
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.
25. The pharmaceutical combination according to claim 24, wherein
the kit further comprises instructions to administer the contents
of the kit to a subject for the treatment of a disease selected
from the group consisting of cancer of the head, neck, eye, mouth,
throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung,
colon, rectum, stomach, prostate, urinary bladder, uterine, cervix,
breast, ovaries, testicles or other reproductive organs, skin,
thyroid, blood, lymph nodes, kidney, liver, pancreas, brain,
central nervous system, and cancer, small cell lung cancer,
non-small cell lung cancer, squamous cell cancer of the head and
neck, and solid tumors and blood-borne tumors.
26. The pharmaceutical composition according to claim 1, which
comprises
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically
acceptable salt and/or solvate thereof and
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)-pyrimidin-4-yl]amino]phenyl]prop-2-enamide.
27. The pharmaceutical composition according to claim 1, which
comprises
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate and
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.
Description
FIELD OF THE INVENTION
[0001] This invention relates to a pharmaceutical composition for
cancer disease, which comprises a compound having anti-cancer
activity, namely
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically
acceptable salt and/or solvate thereof in combination with
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.
BACKGROUND OF THE INVENTION
[0002] The invention had the object of finding novel pharmaceutical
compositions having valuable properties, in particular those which
can be used for the preparation of medicaments.
[0003] Moreover, aim of this invention are new compositions for the
prevention and treatment of neoplastic malignancies including, but
without being limited to, solid tumor cancers, cancers of the
lymphatic or blood system.
[0004] It has been found that the pharmaceutical compositions
according to the invention and pharmaceutically acceptable salts
and/or solvates thereof have very valuable pharmacological
properties while being well tolerated.
[0005] Most selective target therapies are when applied as single
agents only effective in highly addicted subpopulation of patients.
By combining selective target therapies with other targeted agents
the anti tumor effect can be enhanced by interfering with
cross-talking pathways, blocking different tumor-specific pathways
in parallel, or inhibiting the same tumor-specific pathway at
different levels to prevent or reduce the risk of progression.
PRIOR ART
[0006]
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-
-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile has been described
in WO 2009/006959 A1.
[0007]
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-
-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride
hydrate has been described in WO 2009/007074 A1.
[0008]
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluor-
omethyl)-pyrimidin-4-yl]amino]phenyl]prop-2-enamide
##STR00001##
[0009] is an EGFR inhibitor and has been described in WO
2012/061299.
[0010] The compound is useful in the treatment of
hyperproliferative diseases, such as cancer.
SUMMARY OF THE INVENTION
[0011] The invention relates to a pharmaceutical composition of
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically
acceptable salt and/or solvate thereof in combination with
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.
[0012] Moreover, the invention relates to a pharmaceutical
composition of
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate in
combination with
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.
[0013] Moreover, the invention relates to a pharmaceutical
composition of
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically
acceptable salt and/or solvate thereof in combination with
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide for the use for the
treatment of diseases selected from the group cancer of the head,
neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx,
chest, bone, lung, colon, rectum, stomach, prostate, urinary
bladder, uterine, cervix, breast, ovaries, testicles or other
reproductive organs, skin, thyroid, blood, lymph nodes, kidney,
liver, pancreas, brain, central nervous system, solid tumors and
blood-borne tumors.
[0014] Moreover, the invention relates to a pharmaceutical
composition of
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate in
combination with
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide for the use for the
treatment of cancer, selected from the group small cell lung cancer
(SCLC), non-small cell lung cancer (NSCLC), squamous cell cancer of
the head and neck (SCCHN).
[0015] Moreover, the invention relates to
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically
acceptable salt and/or solvate thereof for the use for the
treatment of cancer, wherein the medicament is to be used in
combination with
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)-pyrimidin-4-yl]amino]phenyl]prop-2-enamide.
[0016] Moreover, the invention relates to the use of
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically
acceptable salt and/or solvate thereof for the manufacture of a
medicament for the treatment of cancer, wherein the medicament is
to be used in combination with
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoro-
methyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.
[0017] Moreover, the invention relates to the use of
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate for
the manufacture of a medicament for the treatment of cancer,
wherein the medicament is to be used in combination with
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)-pyrimidin-4-yl]amino]phenyl]prop-2-enamide.
[0018] Moreover, the invention relates to the use of
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate for
the manufacture of a medicament for the treatment of cancer,
selected from the group colorectal, lung, breast, kidney, and
glioblastomas, wherein the medicament is to be used in combination
with
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.
[0019] Moreover, the invention relates to the use of
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate for
the manufacture of a medicament for the treatment of lung cancer,
wherein the medicament is to be used in combination with
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.
[0020] Moreover, the invention relates to the use of
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate for
the manufacture of a medicament for the treatment of cancer,
selected from the group small cell lung cancer (SCLC), non-small
cell lung cancer (NSCLC), squamous cell cancer of the head and neck
(SCCHN), wherein the medicament is to be used in combination with
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide.
[0021] Moreover, the invention relates to the use as described
above, wherein
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzy-
l}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a
pharmaceutically acceptable salt and/or solvate thereof or
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate is
administered to a patient in an amount of 250 mg to 12500 mg per
week, preferably in an amount of 800 mg to 8000 mg per week,
particularly preferably in an amount of 500 mg to 2000 mg per
week.
[0022] According to the present invention therapeutically active
compositions may also be provided by means of a pharmaceutical kit
comprising a package comprising
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically
acceptable salt and/or solvate thereof, and
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide, in single packages or
in separate containers.
[0023] The therapy with these combinations may include optionally
further treatment with radiation. The invention relates furthermore
to a new therapy form comprising the start of the administration of
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically
acceptable salt and/or solvate thereof prior to radiotherapy.
[0024] In this new therapy form comprising the start of the
administration of
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6--
oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically
acceptable salt and/or solvate thereof prior to radiotherapy, it is
a preferred feature that the
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically
acceptable salt and/or solvate thereof is administered prior and/or
during the administration of
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)-pyrimidin-4-yl]amino]phenyl]prop-2-enamide, preferably at least
during a significant part of the treatment regimen. In this
context, according to the present invention, radiation, or,
radiotherapy preferably has to be understood as a cancer
cotherapeutic agent.
[0025] The invention also relates to the optically active forms
(stereoisomers), the enantiomers, the racemates, the diastereomers
and the hydrates and solvates of these compounds.
[0026] The invention also relates to the solvates of the salts of
the compounds such as the mono- or dihydrate of the
hydrochloride.
[0027] The term solvates of the compounds is taken to mean
adductions of inert solvent molecules onto the compounds which form
owing to their mutual attractive force. Solvates are such as mono-
or dihydrates or alcoholates.
[0028] The expression "effective amount" denotes the amount of a
medicament or of a pharmaceutical active ingredient which causes in
a tissue, system, animal or human a biological or medical response
which is sought or desired, for example, by a researcher or
physician.
[0029] In addition, the expression "therapeutically effective
amount" denotes an amount which, compared with a corresponding
subject who has not received this amount, has the following
consequence:
[0030] improved treatment, healing, prevention or elimination of a
disease, syndrome, condition, complaint, disorder or side-effects
or also the reduction in the advance of a disease, complaint or
disorder.
[0031] The expression "therapeutically effective amount" also
encompasses the amounts which are effective for increasing normal
physiological function.
[0032] Pharmaceutical Salts and Other Forms
[0033] The said compounds according to the invention can be used in
their final non-salt form. On the other hand, the present invention
also encompasses the use of these compounds in the form of their
pharmaceutically acceptable salts, which can be derived from
various organic and inorganic acids and bases by procedures known
in the art. Pharmaceutically acceptable salt forms of the compounds
of the invention are for the most part prepared by conventional
methods. If the compound of the invention contains a carboxyl
group, one of its suitable salts can be formed by reacting the
compound with a suitable base to give the corresponding
base-addition salt. Such bases are, for example, alkali metal
hydroxides, including potassium hydroxide, sodium hydroxide and
lithium hydroxide; alkaline earth metal hydroxides, such as barium
hydroxide and calcium hydroxide; alkali metal alkoxides, for
example potassium ethoxide and sodium propoxide; and various
organic bases, such as piperidine, diethanolamine and
N-methylglutamine. The aluminium salts of the compounds of the
invention are likewise included. In the case of certain compounds
of the invention, acid-addition salts can be formed by treating
these compounds with pharmaceutically acceptable organic and
inorganic acids, for example hydrogen halides, such as hydrogen
chloride, hydrogen bromide or hydrogen iodide, other mineral acids
and corresponding salts thereof, such as sulfate, nitrate or
phosphate and the like, and alkyl- and monoarylsulfonates, such as
ethanesulfonate, toluenesulfonate and benzene-sulfonate, and other
organic acids and corresponding salts thereof, such as acetate,
trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate,
salicylate, ascorbate and the like. Accordingly, pharmaceutically
acceptable acid-addition salts of the compounds include the
following: acetate, adipate, alginate, arginate, aspartate,
benzoate, benzenesulfonate (besylate), bisulfate, bisulfite,
bromide, butyrate, camphorate, camphorsulfonate, caprylate,
chloride, chlorobenzoate, citrate, cyclopentanepropionate,
digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate,
ethanesulfonate, fumarate, galacterate (from mucic acid),
galacturonate, glucoheptanoate, gluconate, glutamate,
glycerophosphate, hemisuccinate, hemisulfate, heptanoate,
hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate,
lactate, lactobionate, malate, maleate, malonate, mandelate,
metaphosphate, methanesulfonate, methylbenzoate,
monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate,
oxalate, oleate, palmoate, pectinate, persulfate, phenylacetate,
3-phenylpropionate, phosphate, phosphonate, phthalate, but this
does not represent a restriction.
[0034] Furthermore, the base salts of the compounds according to
the invention include aluminium, ammonium, calcium, copper,
iron(III), iron(II), lithium, magnesium, manganese(III),
manganese(II), potassium, sodium and zinc salts, but this is not
intended to represent a restriction. Of the above-men-tioned salts,
preference is given to ammonium; the alkali metal salts sodium and
potassium, and the alkaline earth metal salts calcium and
magnesium. Salts of the compounds which are derived from
pharmaceutically acceptable organic non-toxic bases include salts
of primary, secondary and tertiary amines, substituted amines, also
including naturally occurring substituted amines, cyclic amines,
and basic ion exchanger resins, for example arginine, betaine,
caffeine, chloroprocaine, choline, N,N'-dibenzylethylenediamine
(benzathine), dicyclohexylamine, diethanolamine, diethylamine,
2-diethyl-aminoethanol, 2-dimethylaminoethanol, ethanolamine,
ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,
glucosamine, histidine, hydrabamine, isopropylamine, lidocaine,
lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine,
piperidine, polyamine resins, procaine, purines, theobromine,
triethanolamine, triethylamine, trimethylamine, tripropyl-amine and
tris(hydroxymethyl)methylamine (tromethamine), but this is not
intended to represent a restriction.
[0035] Compounds of the present invention which contain basic
nitrogen-containing groups can be quaternised using agents such as
(C.sub.1-C.sub.4)alkyl halides, for example methyl, ethyl,
isopropyl and tert-butyl chloride, bromide and iodide;
di(C.sub.1-C.sub.4)alkyl sulfates, for example dimethyl, diethyl
and diamyl sulfate; (Clo-C.sub.18)alkyl halides, for example decyl,
dodecyl, lauryl, myristyl and stearyl chloride, bromide and iodide;
and aryl(C.sub.1-C.sub.4)alkyl halides, for example benzyl chloride
and phenethyl bromide. Both water- and oil-soluble compounds
according to the invention can be prepared using such salts.
[0036] The above-mentioned pharmaceutical salts which are preferred
include acetate, trifluoroacetate, besylate, citrate, fumarate,
gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide,
isethionate, mandelate, meglumine, nitrate, oleate, phosphonate,
pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate,
tartrate, thiomalate, tosylate and tromethamine, but this is not
intended to represent a restriction.
[0037] Particular preference is given to hydrochloride,
dihydrochloride, hydrobromide, maleate, mesylate, phosphate,
sulfate and succinate.
[0038] The acid-addition salts of basic compounds are prepared by
bringing the free base form into contact with a sufficient amount
of the desired acid, causing the formation of the salt in a
conventional manner. The free base can be regenerated by bringing
the salt form into contact with a base and isolating the free base
in a conventional manner. The free base forms differ in a certain
respect from the corresponding salt forms thereof with respect to
certain physical properties, such as solubility in polar solvents;
for the purposes of the invention, however, the salts otherwise
correspond to the respective free base forms thereof.
[0039] As mentioned, the pharmaceutically acceptable base-addition
salts of the compounds are formed with metals or amines, such as
alkali metals and alkaline earth metals or organic amines.
Preferred metals are sodium, potassium, magnesium and calcium.
Preferred organic amines are N,N'-dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, ethylenediamine,
N-methyl-D-glucamine and procaine.
[0040] The base-addition salts of acidic compounds according to the
invention are prepared by bringing the free acid form into contact
with a sufficient amount of the desired base, causing the formation
of the salt in a conventional manner.
[0041] The free acid can be regenerated by bringing the salt form
into contact with an acid and isolating the free acid in a
conventional manner. The free acid forms differ in a certain
respect from the corresponding salt forms thereof with respect to
certain physical properties, such as solubility in polar solvents;
for the purposes of the invention, however, the salts otherwise
correspond to the respective free acid forms thereof.
[0042] If a compound according to the invention contains more than
one group which is capable of forming pharmaceutically acceptable
salts of this type, the invention also encompasses multiple salts.
Typical multiple salt forms include, for example, bitartrate,
diacetate, difumarate, dimeglumine, diphosphate, disodium and
trihydrochloride, but this is not intended to represent a
restriction.
[0043] With regard to that stated above, it can be seen that the
expression "phar-maceutically acceptable salt" in the present
connection is taken to mean an active ingredient which comprises a
compound of the invention in the form of one of its salts, in
particular if this salt form imparts improved pharmacokinetic
properties on the active ingredient compared with the free form of
the active ingredient or any other salt form of the active
ingredient used earlier. The pharmaceutically acceptable salt form
of the active ingredient can also provide this active ingredient
for the first time with a desired pharmacokinetic property which it
did not have earlier and can even have a positive influence on the
pharmacodynamics of this active ingredient with respect to its
therapeutic efficacy in the body.
[0044] The invention furthermore relates to medicaments comprising
at least one compound and/or pharmaceutically acceptable salts,
solvates, tautomers and stereoisomers thereof, including mixtures
thereof in all ratios, and optionally excipients and/or
adjuvants.
[0045] Pharmaceutical formulations can be administered in the form
of dosage units which comprise a predetermined amount of active
ingredient per dosage unit. Such a unit can comprise, for example,
0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably 5
mg to 100 mg, of a compound according to the invention, depending
on the condition treated, the method of administration and the age,
weight and condition of the patient, or pharmaceutical formulations
can be administered in the form of dosage units which comprise a
predetermined amount of active ingredient per dosage unit.
Preferred dosage unit formulations are those which comprise a daily
dose or part-dose, as indicated above, or a corresponding fraction
thereof of an active ingredient. Furthermore, pharmaceutical
formulations of this type can be prepared using a process which is
generally known in the pharmaceutical art.
[0046] Pharmaceutical formulations can be adapted for
administration via any desired suitable method, for example by oral
(including buccal or sublingual), rectal, nasal, topical (including
buccal, sublingual or transdermal), vaginal or parenteral
(including subcutaneous, intramuscular, intravenous or intradermal)
methods. Such formulations can be prepared using all processes
known in the pharmaceutical art by, for example, combining the
active ingredient with the excipient(s) or adjuvant(s).
[0047] Pharmaceutical formulations adapted for oral administration
can be administered as separate units, such as, for example,
capsules or tablets; powders or granules; solutions or suspensions
in aqueous or non-aqueous liquids; edible foams or foam foods; or
oil-in-water liquid emulsions or water-in-oil liquid emulsions.
[0048] Thus, for example, in the case of oral administration in the
form of a tablet or capsule, the active-ingredient component can be
combined with an oral, non-toxic and pharmaceutically acceptable
inert excipient, such as, for example, ethanol, glycerol, water and
the like. Powders are prepared by comminuting the compound to a
suitable fine size and mixing it with a pharmaceutical excipient
comminuted in a similar manner, such as, for example, an edible
carbohydrate, such as, for example, starch or mannitol. A flavour,
preservative, dispersant and dye may likewise be present.
[0049] Capsules are produced by preparing a powder mixture as
described above and filling shaped gelatine shells therewith.
Glidants and lubricants, such as, for example, highly disperse
silicic acid, talc, magnesium stearate, calcium stearate or
polyethylene glycol in solid form, can be added to the powder
mixture before the filling operation. A disintegrant or
solubiliser, such as, for example, agar-agar, calcium carbonate or
sodium carbonate, may likewise be added in order to improve the
availability of the medicament after the capsule has been
taken.
[0050] In addition, if desired or necessary, suitable binders,
lubricants and disintegrants as well as dyes can likewise be
incorporated into the mixture. Suitable binders include starch,
gelatine, natural sugars, such as, for example, glucose or
beta-lactose, sweeteners made from maize, natural and synthetic
rubber, such as, for example, acacia, tragacanth or sodium
alginate, carboxymethyl-cellulose, polyethylene glycol, waxes, and
the like. The lubricants used in these dosage forms include sodium
oleate, sodium stearate, magnesium stearate, sodium benzoate,
sodium acetate, sodium chloride and the like. The disintegrants
include, without being restricted thereto, starch, methylcellulose,
agar, bentonite, xanthan gum and the like. The tablets are
formulated by, for example, preparing a powder mixture, granulating
or dry-pressing the mixture, adding a lubricant and a disintegrant
and pressing the entire mixture to give tablets. A powder mixture
is prepared by mixing the compound comminuted in a suitable manner
with a diluent or a base, as described above, and optionally with a
binder, such as, for example, carboxymethylcellulose, an alginate,
gelatine or polyvinylpyrrolidone, a dissolution retardant, such as,
for example, paraffin, an absorption accelerator, such as, for
example, a quaternary salt, and/or an absorbant, such as, for
example, bentonite, kaolin or dicalcium phosphate. The powder
mixture can be granulated by wetting it with a binder, such as, for
example, syrup, starch paste, acadia mucilage or solutions of
cellulose or polymer materials and pressing it through a sieve. As
an alternative to granulation, the powder mixture can be run
through a tabletting machine, giving lumps of non-uniform shape,
which are broken up to form granules. The granules can be
lubricated by addition of stearic acid, a stearate salt, talc or
mineral oil in order to prevent sticking to the tablet casting
moulds. The lubricated mixture is then pressed to give tablets. The
compounds according to the invention can also be combined with a
free-flowing inert excipient and then pressed directly to give
tablets without carrying out the granulation or dry-pressing steps.
A transparent or opaque protective layer consisting of a shellac
sealing layer, a layer of sugar or polymer material and a gloss
layer of wax may be present. Dyes can be added to these coatings in
order to be able to differentiate between different dosage
units.
[0051] Oral liquids, such as, for example, solution, syrups and
elixirs, can be prepared in the form of dosage units so that a
given quantity comprises a pre-specified amount of the compound.
Syrups can be prepared by dissolving the compound in an aqueous
solution with a suitable flavour, while elixirs are prepared using
a non-toxic alcoholic vehicle. Suspensions can be formulated by
dispersion of the compound in a non-toxic vehicle. Solubilisers and
emulsifiers, such as, for example, ethoxylated isostearyl alcohols
and polyoxyethylene sorbitol ethers, preservatives, flavour
additives, such as, for example, peppermint oil or natural
sweeteners or saccharin, or other artificial sweeteners and the
like, can likewise be added.
[0052] The dosage unit formulations for oral administration can, if
desired, be en-capsulated in microcapsules. The formulation can
also be prepared in such a way that the release is extended or
retarded, such as, for example, by coating or embedding of
particulate material in polymers, wax and the like.
[0053] The compounds and salts, solvates, tautomers and
stereoisomers thereof can also be administered in the form of
liposome delivery systems, such as, for example, small unilamellar
vesicles, large unilamellar vesicles and multilamellar vesicles.
Liposomes can be formed from various phospholipids, such as, for
example, cholesterol, stearylamine or phosphatidylcholines.
[0054] The compounds and the salts, solvates, tautomers and
stereoisomers thereof can also be delivered using monoclonal
antibodies as individual carriers to which the compound molecules
are coupled. The compounds can also be coupled to soluble polymers
as targeted medicament carriers. Such polymers may encompass
polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropyl-methacrylamidophenol,
polyhydroxyethylaspartamidophenol or polyethylene oxide polylysine,
substituted by palmitoyl radicals. The compounds may furthermore be
coupled to a class of biodegradable polymers which are suitable for
achieving controlled release of a medicament, for example
polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric
acid, poly-orthoesters, polyacetals, polydihydroxypyrans,
polycyanoacrylates and crosslinked or amphipathic block copolymers
of hydrogels.
[0055] Pharmaceutical formulations adapted for transdermal
administration can be administered as independent plasters for
extended, close contact with the epidermis of the recipient. Thus,
for example, the active ingredient can be delivered from the
plaster by iontophoresis, as described in general terms in
Pharmaceutical Research, 3(6), 318 (1986).
[0056] Pharmaceutical compounds adapted for topical administration
can be for-mulated as ointments, creams, suspensions, lotions,
powders, solutions, pastes, gels, sprays, aerosols or oils.
[0057] For the treatment of the eye or other external tissue, for
example mouth and skin, the formulations are preferably applied as
topical ointment or cream. In the case of formulation to give an
ointment, the active ingredient can be employed either with a
paraffinic or a water-miscible cream base. Alternatively, the
active ingredient can be formulated to give a cream with an
oil-in-water cream base or a water-in-oil base.
[0058] Pharmaceutical formulations adapted for topical application
to the eye include eye drops, in which the active ingredient is
dissolved or suspended in a suitable carrier, in particular an
aqueous solvent.
[0059] Pharmaceutical formulations adapted for topical application
in the mouth encompass lozenges, pastilles and mouthwashes.
[0060] Pharmaceutical formulations adapted for rectal
administration can be ad-ministered in the form of suppositories or
enemas.
[0061] Pharmaceutical formulations adapted for nasal administration
in which the carrier substance is a solid comprise a coarse powder
having a particle size, for example, in the range 20-500 microns,
which is administered in the manner in which snuff is taken, i.e.
by rapid inhalation via the nasal passages from a container
containing the powder held close to the nose. Suitable formulations
for administration as nasal spray or nose drops with a liquid as
carrier substance encompass active-ingredient solutions in water or
oil.
[0062] Pharmaceutical formulations adapted for administration by
inhalation encom-pass finely particulate dusts or mists, which can
be generated by various types of pressurised dispensers with
aerosols, nebulisers or insufflators.
[0063] Pharmaceutical formulations adapted for vaginal
administration can be administered as pessaries, tampons, creams,
gels, pastes, foams or spray formulations.
[0064] Pharmaceutical formulations adapted for parenteral
administration include aqueous and non-aqueous sterile injection
solutions comprising antioxidants, buffers, bacteriostatics and
solutes, by means of which the formulation is rendered isotonic
with the blood of the recipient to be treated; and aqueous and
non-aqueous sterile suspensions, which may comprise suspension
media and thickeners. The formulations can be administered in
single-dose or multidose containers, for example sealed ampoules
and vials, and stored in freeze-dried (lyophilised) state, so that
only the addition of the sterile carrier liquid, for example water
for injection purposes, immediately before use is necessary.
Injection solutions and suspensions prepared in accordance with the
recipe can be prepared from sterile powders, granules and
tablets.
[0065] It goes without saying that, in addition to the above
particularly mentioned constituents, the formulations may also
comprise other agents usual in the art with respect to the
particular type of formulation; thus, for example, for-mulations
which are suitable for oral administration may comprise
flavours.
[0066] A therapeutically effective amount of a compound depends on
a number of factors, including, for example, the age and weight of
the animal, the precise condition that requires treatment, and its
severity, the nature of the formulation and the method of
administration, and is ultimately determined by the treating doctor
or vet. However, an effective amount of a compound according to the
invention is generally in the range from 0.1 to 100 mg/kg of body
weight of the recipient (mammal) per day and particularly typically
in the range from 1 to 10 mg/kg of body weight per day. Thus, the
actual amount per day for an adult mammal weighing 70 kg is usually
between 70 and 700 mg, where this amount can be administered as a
single dose per day or usually in a series of part-doses (such as,
for example, two, three, four, five or six) per day, so that the
total daily dose is the same. An effective amount of a salt,
solvate, tautomer and stereoisomer thereof can be determined as the
fraction of the effective amount of the compound according to the
invention per se. It can be assumed that similar doses are suitable
for the treatment of other conditions mentioned above.
[0067] A combined treatment of this type can be achieved with the
aid of simulta-neous, consecutive or separate dispensing of the
individual components of the treatment. Combination products of
this type employ the compounds according to the invention.
[0068] The anti-cancer treatment defined herein may be applied as a
sole therapy or may involve, in addition to the composition of the
invention, conventional surgery or radiotherapy.
[0069] "Treating" as used herein, means an alleviation, in whole or
in part, of symptoms associated with a disorder or disease, or
slowing, or halting of further progression or worsening of those
symptoms, or prevention or prophylaxis of the disease or disorder
in a subject at risk for developing the disease or disorder.
[0070] The term "effective amount" in connection with a compound
can mean an amount capable of alleviating, in whole or in part,
symptoms associated with a disorder or disease, or slowing or
halting further progression or worsening of those symptoms, or
preventing or providing prophylaxis for the disease or disorder in
a subject having or at risk for developing a disease disclosed
herein, such as cancer,
[0071] The term "therapeutically effective" or "therapeutically
effective amount" refers to an amount of a drug effective to treat
a disease or disorder in a mammal. In the case of cancer, the
therapeutically effective amount of the drug may reduce the number
of cancer cells; reduce the tumor size; inhibit (i.e., slow to some
extent and preferably stop) cancer cell infiltration into
peripheral organs; inhibit (i.e., slow to some extent and
preferably stop) tumor metastasis; inhibit, to some extent, tumor
growth; and/or relieve to some extent one or more of the symptoms
associated with the cancer. To the extent the drug may prevent
growth and/or kill existing cancer cells, it may be cytostatic
and/or cytotoxic. For cancer therapy, efficacy can, for example, be
measured by assessing the time to disease progression (TTP) and/or
determining the response rate (RR).
[0072] Preferably, the compounds are administered once a week,
preferably intravenously as infusion. Preferably the initial dose
is 100 to 1000 mg per m.sup.2 body surface, particularly preferably
between 200 and 600 mg per m.sup.2 body surface. Subsequent doses
are 50 to 600 mg per m.sup.2 body surface, particularly preferably
between 100 and 400 mg per m.sup.2 body surface.
[0073] Particularly preferably
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide is administered orally
in a tablet twice a day and
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate is
administered orally in a tablet once a day. More preferably, the
two compounds are administered at the same time orally.
[0074] Preferably, 3
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide is administered to a
patient once or twice a day in an amount of 300 to 900 mg per
administration, more preferably in an amount of 400 to 800 mg per
administration.
[0075] Use
[0076] The present compounds are suitable as pharmaceutical active
ingredients for mammals, especially for humans, in the treatment of
immune modulatory and stress response kinase-induced diseases.
These diseases include neoplastic malignancies including, but
without being limited to, solid tumor cancers, cancers of the
lymphatic or blood system, the proliferation of tumour cells,
pathological neovascularisation (or angiogenesis) which promotes
the growth of solid tumours, neurodegenerative diseases (Alzheimer,
demyelinating core disorders multiple sclerosis and the like),
immune related disorders like arthritis, psoriasis, lupus, or other
autoimmune diseases as well as chronic infections.
[0077] The present invention encompasses the use of the compounds
and/or physiologically acceptable salts and solvates thereof for
the preparation of a medicament for the treatment or prevention of
cancer. Preferred carcinomas for the treatment originate from the
group cerebral carcinoma, urogenital tract carcinoma, carcinoma of
the lymphatic system, stomach carcinoma, laryngeal carcinoma and
lung carcinoma. A further group of preferred forms of cancer are
monocytic leukaemia, lung adenocarcinoma, small-cell lung
carcinomas, pancreatic cancer, glioblastomas, melanomas and breast
carcinoma. A further group of preferred forms of cancer include,
but is not limited to, cervical cancer, neuroblastoma, testicular
cancer, macroglobulinemia and sarcomas.
[0078] The present invention specifically relates to compounds and
pharmaceutically acceptable salts, solvates, tautomers and
stereoisomers thereof, including mixtures thereof in all ratios,
for the use for the treatment of neoplastic malignancies (solid
tumor cancers, cancers of the lymphatic or blood system and the
like), of neurodegenerative diseases, immune related disorders like
arthritis, psoriasis, lupus, multiple sclerosis or other autoimmune
diseases as well as chronic infections.
[0079] Especial preference is given to the use for the treatment of
a disease where the disease is a neoplastic malignancies.
[0080] The neoplastic malignancies is preferably selected from the
group of tumours of the lung, squamous epithelium, the bladder, the
stomach, the kidneys, of head and neck, the oesophagus, the cervix,
the thyroid, the intestine, the liver, the brain, the prostate, the
urogenital tract, the lymphatic system, the stomach and/or the
larynx.
[0081] The neoplastic malignancies is furthermore preferably
selected from the group lung adenocarcinoma, small-cell lung
carcinomas, pancreatic cancer, glioblas-tomas, colon carcinoma and
breast carcinoma.
[0082] Preference is furthermore given to the use for the treatment
of a neoplastic malignancies of the blood and immune system,
preferably for the treatment of a tumour selected from the group of
acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic
leukaemia and/or chronic lymphatic leukaemia.
[0083] Representative cancers that compounds are useful for
treating or preventing include, but are not limited to, cancer of
the head, neck, eye, mouth, throat, esophagus, bronchus, larynx,
pharynx, chest, bone, lung, colon, rectum, stomach, prostate,
urinary bladder, uterine, cervix, breast, ovaries, testicles or
other reproductive organs, skin, thyroid, blood, lymph nodes,
kidney, liver, pancreas, brain, central nervous system, solid
tumors and blood-borne tumors.
[0084] Moreover, the present invention specifically relates to
compounds for the use for the treatment and/or prevention of
cancer, where the cancer to be treated is a solid tumour or a
tumour of the blood and immune system.
[0085] Moreover, the present invention specifically relates to
compounds, for the use for the treatment and/or prevention of
cancer, where the where the tumour originates from the group of
acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic
leukaemia and/or chronic lymphatic leukaemia.
[0086] Moreover, the present invention specifically relates to
compounds, for the use for the treatment and/or prevention of
cancer, where the solid tumour originates from the group of tumours
of the epithelium, the bladder, the stomach, the kidneys, of head
and neck, the esophagus, the cervix, the thyroid, the intestine,
the liver, the brain, the prostate, the uro-genital tract, the
lymphatic system, the stomach, the larynx, the bones, including
chondosarcoma and Ewing sarcoma, germ cells, including embryonal
tissue tumours, and/or the lung, from the group of monocytic
leukaemia, lung adenocarcinoma, small-cell lung carcinomas,
pancreatic cancer, glioblastomas, neurofibroma, angiosarcoma,
breast carcinoma and/or maligna melanoma.
[0087] The disclosed compounds of can be administered in
combination with other known therapeutic agents, including
anticancer agents. As used here, the term "anticancer agent"
relates to any agent which is administered to a patient with cancer
for the purposes of treating the cancer.
[0088] Demonstration that by combining
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate
with a third generation EGFR inhibitor,
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide, the efficacy of
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide can be improved in
lung cancer models, regardless of the EGFR T790M status. Evaluation
of the
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride
hydrate/N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(triflu-
oromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide combination in
EGFR T790M mutant model further demonstrated not only enhanced
activity compared to
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide but as well compared
to
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride
hydrate.
[0089] The enhanced efficacy in the combination group was observed
without increase in toxicity as indicated by the lack of
significant weight loss or death of animals compared to
monotherapies.
Combination of
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate and
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)-pyrimidin-4-yl]amino]phenyl]prop-2-enamide in the Human NSCLC
HCC827-GR-T790M Xenograft Model
[0090] Background:
[0091] The human NSCLC HCC827-GR-T790M is a EGFR del 19 mutant and
c-Met amplified lung xenograft model which exogenous expression of
the EGFR T790M resistant mutation. This model is resistant to EGFR
inhibitors erlotinib and afatinib due to the acquired resistance
through c-Met amplification and the EGFR T790M mutation.
[0092] Method:
[0093] Female NCr nude mice (7 weeks old) where subcutaneously
injected with human HCC827-GR-T790M tumor cells and were divided
into treatment groups (10 animals per group) after the tumors were
established. Respective groups were administered orally with the
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate
(100 mg/kg) or
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trif-
luoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide (100 mg/kg)
daily in monotherapy or in combination until group tumor volume
mean reached 300 mm.sup.3 or up to 32 days. Median tumor volume
(TV) change in % were calculated at day 14, where the vehicle group
was terminated and statistical analysis done with two way-RM
ANOVA.
[0094] Results:
[0095] Under
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate and
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)-pyrimidin-4-yl]amino]phenyl]prop-2-enamide monotherapy treatment
tumors progressed resulting in a median tumor volume change of 205%
(p<0.01) and 81% (p<0.0001), respectively. Combination of
both agents statistically significant enhanced anti-tumor activity
compared to best single agent
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide resulting in complete
tumor regression (median TV change of -87%, p<0.0001) in all
mice. After long term combination treatment up to 32 days,
non-palpable tumors were observed in 5 out of 8 mice. (Tumor
progression: median TV change >73%; tumor stasis/regression:
median TV change <73%; complete tumor regression: non palpable
tumors or tumor volume <20 mm.sup.3 compared to start tumor
volume.) Monotherapies and combination treatment have been
tolerated well.
Combination of
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate and
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)-pyrimidin-4-yl]amino]phenyl]prop-2-enamide in a Human DFCI081
Patient Derived NSCLC Xenograft (PDX)Model
[0096] Background:
[0097] The human DFC1081 NSCLC xenograft is a EGFR del 19 mutant
and c-Met amplified lung tumor and resistant to EGFR inhibitors
erlotinib and afatinib due to the activated c-Met pathway.
[0098] Method:
[0099] Female NCr nude mice (7 weeks old) where subcutaneously
injected with human DFC1081 tumor cells and were divided into
treatment groups (10 animals per group) after the tumors were
established. Respective groups were administered orally with the
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate
(100 mg/kg) or
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trif-
luoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide (100 mg/kg)
daily in monotherapy or in combination up to 18 days. Median tumor
volume (TV) change in % were calculated and statistical analysis
done with two way-RM ANOVA.
[0100] Results:
[0101]
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-
-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride
hydrate showed strong anti-tumor activity resulting in tumor
regression (TV change of -100%, p<0.0001). Complete tumor
regression in all mice has been observed at day 15. Under treatment
with
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxy-anilino]-5-(trifluoromethy-
l)pyrimidin-4-yl]amino]phenyl]prop-2-enamide, tumor progressed
resulting in a median tumor volume change of 700% (ns). Combination
of both agents did not statistically significant enhanced
anti-tumor activity compared to best single agent
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate but
complete tumor response in the combination group has been induced
in all mice earlier at day 11. (Tumor progression: median TV change
>73%; tumor stasis/regression: median TV change <73%;
complete tumor regression: non palpable tumors or tumor volume
<20 mm.sup.3 compared to start tumor volume.) Monotherapies and
combination treatment have been tolerated well.
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