NZ619488B2 - A synergistic pharmaceutical combination for the treatment of squamous cell carcinoma of head and neck - Google Patents
A synergistic pharmaceutical combination for the treatment of squamous cell carcinoma of head and neck Download PDFInfo
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- NZ619488B2 NZ619488B2 NZ619488A NZ61948812A NZ619488B2 NZ 619488 B2 NZ619488 B2 NZ 619488B2 NZ 619488 A NZ619488 A NZ 619488A NZ 61948812 A NZ61948812 A NZ 61948812A NZ 619488 B2 NZ619488 B2 NZ 619488B2
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- New Zealand
- Prior art keywords
- compound
- cisplatin
- cells
- combination
- lapatinib
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- 230000002085 persistent Effects 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 150000003057 platinum Chemical class 0.000 description 1
- 150000003058 platinum compounds Chemical class 0.000 description 1
- 229920000314 poly p-methyl styrene Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Inorganic materials [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- OCFVSFVLVRNXFJ-UHFFFAOYSA-N potassium hydride Inorganic materials [H-].[K+] OCFVSFVLVRNXFJ-UHFFFAOYSA-N 0.000 description 1
- OFPTZWGZSRJCOT-MSPNRCMCSA-M potassium;2-[(1S,2S,3R,4S,5S,6R)-3-(diaminomethylideneamino)-4-[(2R,3R,4R,5S)-3-[(2S,3S,4S,5R,6S)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy-4-formyl-4-hydroxy-5-methyloxolan-2-yl]oxy-2,5,6-trihydroxycyclohexyl]guanidine;(2S,5R,6R)-3,3-d Chemical compound [K+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)CC1=CC=CC=C1.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@H]1[C@H](N=C(N)N)[C@@H](O)[C@H](N=C(N)N)[C@@H](O)[C@@H]1O OFPTZWGZSRJCOT-MSPNRCMCSA-M 0.000 description 1
- VLYFRFHWUBBLRR-UHFFFAOYSA-L potassium;sodium;carbonate Chemical compound [Na+].[K+].[O-]C([O-])=O VLYFRFHWUBBLRR-UHFFFAOYSA-L 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002062 proliferating Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000000306 recurrent Effects 0.000 description 1
- 230000002829 reduced Effects 0.000 description 1
- 230000000284 resting Effects 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 230000002441 reversible Effects 0.000 description 1
- 238000007157 ring contraction reaction Methods 0.000 description 1
- 229910052594 sapphire Inorganic materials 0.000 description 1
- 239000010980 sapphire Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 150000003384 small molecules Chemical group 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- JUJBNYBVVQSIOU-UHFFFAOYSA-M sodium;4-[2-(4-iodophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].C1=CC([N+](=O)[O-])=CC=C1N1[N+](C=2C=CC(I)=CC=2)=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=N1 JUJBNYBVVQSIOU-UHFFFAOYSA-M 0.000 description 1
- QGMRQYFBGABWDR-OGFXRTJISA-M sodium;5-ethyl-5-[(2R)-pentan-2-yl]pyrimidin-3-ide-2,4,6-trione Chemical compound [Na+].CCC[C@@H](C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-OGFXRTJISA-M 0.000 description 1
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229930003347 taxol Natural products 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 239000003104 tissue culture media Substances 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Classifications
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- A61K31/282—Platinum compounds
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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Abstract
Disclosed herein is a pharmaceutical combination for use in the treatment of squamous cell carcinoma, comprising a CDK inhibitor selected from benzopyran (chromene) compounds of formula (I), wherein the substituents are as defined in the specification; and one or more antineoplastic agents selected from sorafenib, lapatinib, erlotinib, cisplatin, 5-fluorouracil, docetaxel or cetuximab. The said pharmaceutical combination exhibits synergy when used in the treatment of squamous cell carcinoma of head and neck (SCCHN). Also disclosed is the use of the pharmaceutical composition comprising the said combination for the manufacture of a medicament for the treatment of squamous cell carcinoma of head and neck (SCCHN). from sorafenib, lapatinib, erlotinib, cisplatin, 5-fluorouracil, docetaxel or cetuximab. The said pharmaceutical combination exhibits synergy when used in the treatment of squamous cell carcinoma of head and neck (SCCHN). Also disclosed is the use of the pharmaceutical composition comprising the said combination for the manufacture of a medicament for the treatment of squamous cell carcinoma of head and neck (SCCHN).
Description
PLSCDK11_12
A Synergistic Pharmaceutical Combination for the Treatment of Squamous Cell
Carcinoma of Head and Neck
Field of Invention:
The present invention relates to a pharmaceutical combination comprising a cyclin
dependent kinase (CDK) inhibitor selected from the compounds of formula I (as described
herein) or a ceutically acceptable salt thereof and one or more antineoplastic agents for
use in the treatment of squamous cell carcinoma of head and neck (SCCHN). The
pharmaceutical ation of the present invention exhibits synergy when used in the treatment
of squamous cell oma of head and neck (SCCHN). Thus, the present ion relates to a
synergistic pharmaceutical combination. The present invention further relates to a
pharmaceutical composition comprising said combination and a method of treating squamous
cell oma of head and neck (SCCHN) in a subject by administrating said pharmaceutical
combination to said subject.
Background of Invention:
Cancer is a group of es characterized by the unusual control of cell growth. There
are over 100 different types of cancers, which are fied by the type of cells initially affected
such as bladder cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney
(renal cell) cancer, leukemia, small cell lung cancer, non- small cell lung cancer, pancreatic
, prostate cancer, thyroid cancer, skin cancer, non-hodgkin's lymphoma and melanoma and
head and neck cancer. Squamous cell carcinoma represents more than 90% of all head and
neck s. Head and neck us cell carcinomas make up the vast majority of head and
neck cancers, and arise from mucosal es throughout the ical region. These include
tumors of the nasal cavities, sal sinuses, oral cavity, nasopharynx, oropharynx,
hypopharynx, and larynx.
In fact, head and neck cancer (HNC) is the sixth most common cancer worldwide, with
an annual incidence of >640,000 cases worldwide. More than 90% of head and neck cancers are
of squamous histology (HNSCC). Thirty-five percent to 45% of head and neck cancer patients
tely die from their disease. In the United States alone, squamous cell carcinoma of the
head and neck comprises about 4% of all malignancies. This corresponds to an
estimated 17 per 100,000 persons with newly diagnosed squamous cell carcinoma of the head
and neck per year (Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008, CA Cancer J. Clin.
2008 Mar-Apr; 58(2):71-96). Squamous cell carcinoma of head and neck (SCCHN) remains a
challenging al problem, due to persisting high rate of local and distant failure, as well as
PLSCDK11_12
the occurrence of second primaries. Some molecular ed therapy used in squamous cell
cancers of the head and neck include cetuximab, bevacizumab, erlotinib and reovirus. The best
quality data are available for cetuximab, a recombinant monoclonal antibody, since the 2006
publication of a ized clinical trial ing radiation treatment plus cetuximab versus
ion treatment alone otherapy plus mab for squamous-cell carcinoma of the
head and neck". N Engl J Med 2006; 354 (6): 567–78). Another study evaluated the impact of
adding cetuximab to conventional chemotherapy involving use of cisplatin versus cisplatin
alone. This study found no improvement in survival or disease-free survival with the addition
of cetuximab to the conventional herapy (J Clin Oncol. 2005; 23 (34): 8646–54).
r, another study completed in March 2007 found that there was an
improvement in survival. This study is referred to as EXTREME (Erbitux in First-Line
Treatment of Recurrent or Metastatic Head and Neck Cancer) study which is a
European enter phase III trial.
Further, it is well established in the art that CDK (Cyclin-dependent kinase) inhibitors
are useful in anti-proliferative therapies for diseases characterized by excessive cell growth
such as cancers and immunological disorders involving unwanted proliferation of leukocytes.
Flavone derivatives useful as CDK inhibitors are described in PCT Patent Publication No.
WO2004-004632 (U.S. Patent 7,271,193) which patent application specifically relates to the
compounds for inhibition of cyclin-dependent kinases, process for their preparation, methods of
inhibiting cyclin-dependent kinases and of inhibiting cell proliferation, use of such compounds
in the treatment of erative disorders including cancers. PCT Published application No.
WO2005-053699 (U.S. Patent 207) relates to a pharmaceutical product comprising a CDK
inhibitor and 1-(2-C-cyanodioxy-p-D-arabino-pentofuranosyl)-N4-palmitoyl cytosine or a
metabolite thereof, as a combined preparation for simultaneous, sequential or te
administration. PCT Published application No. WO2008-122779 (U.S. Patent Appl. Pub. 2010-
0143350) describes combination of CDK inhibitor with a tyrosine kinase inhibitor and use
thereof in the treatment of erative disorders. PCT Published application No. WO2008-
139271 (U.S. Patent Appl. Pub. 2010-0305057) relates to pharmaceutical combination
comprising a cytotoxic oplastic agent selected from paclitaxel, docetaxel, doxorubicin or
gemcitabine and at least one cyclin dependent kinase (CDK) inhibitor for use in the ent of
cancer. PCT hed application No. WO2010-128443 describes a combination for the
treatment of cancer wherein the combination comprises radiation and at least one cyclin
dependent kinase (CDK) inhibitor or a pharmaceutically acceptable salt or a solvate f.
Although combinations of anticancer agents have been proven to have a significant
PLSCDK11_12
advance in various cancer treatment protocols including squamous-cell carcinoma of the head
and neck (SCCHN), there are still l unmet needs and room for improvements in
medications for the treatment of SCCHN, which are difficult to treat, or which have shown
ance to treatment with the conventional antineoplastic agents. More particularly, the
development of novel combination approach for delivering known anticancer agents having
different mechanism of action would represent an important advance in the art.
Although the protocol involving combination of anticancer agents having different
mechanism of action may work in case of some combinations, it may not work in the same
manner for other combination of anticancer agents and such combination may not always
result in a ation having ageous therapeutic effects. r, the ors of the
t invention have found that a pharmaceutical combination of ncer agents comprising
a cyclin dependant kinase (CDK) inhibitor and one or more antineoplastic agent provides
greater efficacy than when the CDK inhibitors or the antineoplastic agents are used alone for
the ent of squamous-cell carcinoma of the head and neck (SCCHN).
Summary of the Invention:
In a first , the present invention provides use of a pharmaceutical
composition comprising a therapeutically effective amount of a CDK inhibitor selected from
the compounds of formula I ;
wherein Ar is a phenyl group, which is unsubstituted or substituted by 1, 2, or 3 identical or
different substituents selected from halogen; nitro, cyano, C1-C4-alkyl, trifluoromethyl, hydroxyl
or C1-C4-alkoxy; or a pharmaceutically acceptable salt or e thereof; in combination with a
therapeutically effective amount of one or more antineoplastic agents selected from sorafenib,
lapatinib, erlotinib, cisplatin, 5-fluorouracil , docetaxel or cetuximab, for the manufacture of a
medicament for the treatment of squamous cell carcinoma of head and neck.
Also bed herein is a pharmaceutical combination for use in the treatment of
squamous cell carcinoma of the head and neck (SCCHN), comprising a cyclin dependent kinase
PLSCDK11_12
(CDK) inhibitor selected from the compounds of formula (I) or a pharmaceutically acceptable
salt thereof and one or more antineoplastic agents selected from sorafenib, lapatinib, erlotinib,
cisplatin, 5-fluorouracil, xel or cetuximab.
Also described herein are pharmaceutical compositions for use in the ent of
squamous cell carcinoma of the head and neck (SCCHN), comprising a ation of a cyclin
dependent kinase (CDK) inhibitor selected from the nds of formula (I) or a
pharmaceutically able salt or solvates thereof and one or more oplastic agents
selected from sorafenib, lapatinib, erlotinib, cisplatin, 5-fluorouracil, docetaxel or cetuximab
along with at least one pharmaceutically acceptable carrier.
Also described herein is a method for the treatment of squamous cell carcinoma of the
head and neck (SCCHN) in a subject, comprising administering to the t a eutically
effective amount of a cyclin dependent kinase (CDK) inhibitor selected from the compounds
of formula (I) or pharmaceutically acceptable salts thereof in combination with a
therapeutically effective amount of one or more antineoplastic agents selected from sorafenib,
lapatinib, erlotinib, cisplatin, 5-fluorouracil, xel or cetuximab.
Also described herein is a pharmaceutical ation for use in the treatment of
squamous cell carcinoma of the head and neck (SCCHN); comprising a therapeutically effective
amount of a cyclin dependent kinase (CDK) inhibitor selected from the compounds of formula
(I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of one or
more antineoplastic agents selected from sorafenib, lapatinib, erlotinib, cisplatin, 5-fluorouracil,
docetaxel or cetuximab, n said combination exhibits synergistic effect.
Also described herein is a kit comprising a cyclin dependent kinase (CDK) tor
selected from the compounds of formula (I) and one or more antineoplastic agents ed
from sorafenib, lapatinib, erlotinib, cisplatin, 5-fluorouracil, docetaxel or cetuximab; wherein
said kit may further e a e insert comprising printed instructions directing the use of
the combined treatment as a method for treating squamous cell carcinoma of the head and neck.
Other aspects and further scope of ability of the present invention will become apparent
from the detailed description to follow.
Brief description of the drawings:
Fig. 1a is a graphical representation of the percentage inhibition results of dosing of sorafenib
and lapatinib in SCC25 cells.
Fig. 1b is a graphical representation of the percentage inhibition results of dosing of compound
PLSCDK11_12
A and compound B in SCC25 cells.
Fig. 2a is a graphical representation of the percentage inhibition results of dosing of sorafenib
and lapatinib in Detroit-562 cells
Fig. 2b is a graphical representation of the tage inhibition results of dosing of
compound A and compound B in Detroit-562 cells.
Fig. 3a is a graphical representation of the percentage inhibition results of dosing of nib
and nib in FADU cells.
Fig. 3b is a graphical representation of the percentage tion results of dosing of
compound A and nd B in FADU cells.
Fig. 4a is a graphical representation of the percentage inhibition results of dosing of erlotinib
in Detroit-562 cells.
Fig. 4b is a graphical representation of the percentage inhibition results of dosing of erlotinib
in FADU cells.
Fig. 5a is a graphical representation of the percentage tion results of dosing of tin,
5-fluorouracil and docetaxel in Detroit-562 cells.
Fig. 5b is a graphical representation of the percentage inhibition results of dosing of tin,
-fluorouracil and docetaxel in FADU cells.
Figure 6a is graphical representation of the percentage cytotoxicity results of single and
ation dosing of compound A and sorafenib in SCC-25 cells.
Figure 6b is graphical representation of the percentage cytotoxicity results of single and
combination dosing of compound B and sorafenib in SCC-25 cells.
Figure 7a is graphical representation of the percentage cytotoxicity results of single and
combination dosing of compound A and sorafenib in Detroit-562 cells.
Figure 7b is graphical representation of the percentage cytotoxicity results of single and
combination dosing of compound B and sorafenib in Detroit-562 cells.
Figure 8a is graphical representation of the percentage cytotoxicity results of single and
ation dosing of nd A and sorafenib in FADU cells.
Figure 8b is graphical representation of the percentage cytotoxicity results of single and
combination dosing of compound B and sorafenib in FADU cells.
Figure 9a is graphical representation of the percentage cytotoxicity results of single and
ation dosing of compound A and lapatinib in SCC-25 cells.
Figure 9b is graphical representation of the percentage cytotoxicity results of single and
combination dosing of compound B and lapatinib in SCC-25 cells.
Figure 10a is graphical representation of the percentage cytotoxicity results of single and
PLSCDK11_12
combination dosing of compound A and lapatinib in Detroit-562 cells.
Figure 10b is graphical representation of the percentage cytotoxicity results of single and
combination dosing of compound B and lapatinib in Detroit-562 cells.
Figure 11a is cal representation of the percentage xicity results of single and
combination dosing of compound A and lapatinib in FADU cells.
Figure 11b is cal representation of the percentage cytotoxicity results of single and
ation dosing of compound B and lapatinib in FADU cells.
Figure 12a is graphical representation of the percentage cytotoxicity results of single and
combination dosing of compound A and erlotinib in Detroit-562 cells.
Figure 12b is graphical representation of the percentage xicity results of single and
combination dosing of compound A and erlotinib in FADU cells.
Figure 13a is graphical representation of the tage cytotoxicity results of single and
ation dosing of compound A, cisplatin and 5-FU in Detroit-562 cells.
Figure 13b is graphical representation of the percentage cytotoxicity results of single and
combination dosing of compound A, cisplatin and 5-fluorouracil in FADU cells.
Figure 14a is cal representation of the percentage cytotoxicity results of single and
combination dosing of compound A, docetaxel, cisplatin and 5-FU in Detroit-562 cells.
Figure 14b is graphical entation of the percentage cytotoxicity results of single and
combination dosing of compound A, docetaxel, cisplatin and 5-FU in FADU cells.
Figure 15a is graphical representation of activation of Caspase 3 in SCC-25 cells with single
and combination dosing of sorafenib and compound A.
Figure 15b is graphical representation of activation of Caspase 3 in SCC-25 cells with single
and combination dosing of sorafenib and compound B.
Figure 16a is graphical representation of activation of Caspase 3 in SCC-25 cells with single
and combination dosing of lapatinib and compound A.
Figure 16b is graphical entation of activation of Caspase 3 in SCC-25 cells with single
and combination dosing of lapatinib and compound B.
Figure 17a is graphical representation of body weight profile in FaDu xenografts treated with
single and combination dosing of compound A, cisplatin and cetuximab.
Figure 17b is graphical entation of tumor growth inhibition in FaDu xenografts treated
with single and combination dosing of compound A, cisplatin and cetuximab.
Detailed description of the invention:
The present invention relates to pharmaceutical combinations for use in the treatment of
PLSCDK11_12
us cell carcinoma of the head and neck (SCCHN), comprising a cyclin dependent
kinase (CDK) inhibitor ed from the compounds of formula (I) (as described herein) or a
pharmaceutically acceptable salt thereof and one or more oplastic agents selected from
sorafenib, lapatinib, erlotinib, cisplatin, 5-fluorouracil, docetaxel or cetuximab, wherein said
combination exhibits synergistic effect.
Described herein is a pharmaceutical composition for use in the treatment of squamous
cell carcinoma of the head and neck (SCCHN) comprising a therapeutically effective amount of
a cyclin dependent kinase (CDK) inhibitor selected from the compounds of formula (I) or a
pharmaceutically acceptable salt thereof and one or more oplastic agents selected from
sorafenib, lapatinib, erlotinib, cisplatin, 5-fluorouracil, docetaxel or mab, and ally a
ceutically acceptable carrier.
Also described herein is a method for the treatment of squamous cell carcinoma of
head and neck in a subject, which comprises administering to the said subject a
eutically effective amount of a CDK inhibitor selected from the compounds of formula
(I) (as described ) or a ceutically acceptable salt or solvate thereof; and a
therapeutically effective amount of one or more antineoplastic agents selected from
the group consisting of sorafenib, lapatinib, erlotinib, cisplatin, 5-fluorouracil and
docetaxel or a pharmaceutically acceptable salt thereof; wherein the said CDK tor and the
said antineoplastic agents contained in the combination are administered either simultaneously
or sequentially.
The general terms used hereinbefore and hereinafter preferably have within the context of
this disclosure the following meanings, unless otherwise indicated. Thus, the definitions of the
general terms as used in the context of the present invention are provided herein below:
The singular forms "a," "an," and "the" include plural reference unless the context
clearly dictates otherwise.
The phrase “a cyclin dependent kinase (CDK) inhibitor” or “CDK tor” as used
herein means a compound that exhibits activity against one or more known cyclin
dependent kinases. In the context of the present invention the CDK inhibitor is a pyrrolidine
substituted flavone compound sed in PCT Published Application No. WO2004004632,
which application is incorporated herein by reference in its entirety. The CDK inhibitor
according to the present invention is specifically selected from a compound of Formula I as
described herein below or a pharmaceutically acceptable salt or solvate thereof. Further, the
term “CDK inhibitor” as used herein may either refer to the compound of formula I and/or a
pharmaceutically acceptable salt or solvate of the compound of formula I.
PLSCDK11_12
The term “antineoplastic agent” is synonymous to "a chemotherapeutic agent" or “an
anticancer agent” and refers to a therapeutic agent, which acts by inhibiting or ting the
growth of neoplasms. The term eoplastic agent” or “anti-cancer agent” in general refers to
the compounds which prevent the cancer cells from multiplying (i.e. anti-proliferative agents).
In general, the antineoplastic agent(s) fall into two classes, anti-proliferative cytotoxic agents
and anti-proliferative cytostatic agents. Cytotoxic agents prevent cancer cells from multiplying
by: (1) interfering with the cell's ability to replicate DNA; and (2) ng cell death and/or
apoptosis in the cancer cells. The cytostatic agents act via modulating, interfering or inhibiting
the processes of cellular signal transduction which regulate cell proliferation.
The phrase "pharmaceutically acceptable salts" refers to the acid addition salt of
compound of formula I (as described herein) and of an antineoplastic agent, wherein the acid
is selected from an inorganic acid such as hloric acid, hydrobromic acid; or an
organic acid such as benzene sulfonic acid, maleic acid, oxalic acid, fumaric acid, succinic
acid, p-toluenesulfonic acid and maleic acid.
As used herein, the term “combination” or “pharmaceutical combination”, means the
combined administration of the anti-cancer agents namely the CDK inhibitor selected from the
nds represented by a I and one or more antineoplastic agents which acts by
inhibiting or preventing the growth of neoplasms or the administration of the anti-cancer agents
namely the CDK inhibitor ed from the compounds represented by formula I and the
antineoplastic agents selected from cytostatic or cytotoxic ; which may be administered
independently at the same time or separately within time als that especially allow that the
combination partners to show a synergistic effect.
As used herein, the term "synergistic" or “synergy” means that the effect achieved with
the combinations of ncer agents encompassed in this invention is greater than the sum
of the effects that result from using anti-cancer agents namely the CDK inhibitor of formula
(I) or a pharmaceutically acceptable salt thereof, antineoplastic agent(s) or a pharmaceutically
acceptable salt thereof, as a monotherapy. Advantageously, such synergy provides greater
efficacy at the same doses, and/or ts or delays the build-up of multi-drug resistance.
As used herein the term "therapeutically effective amount" in reference to the
treatment of us cell carcinoma of head and neck refers to an amount capable of invoking
one or more of the following effects in a subject receiving the combination of the present
invention: (i) inhibition, to some extent, of tumor growth, including, slowing down and
complete growth arrest; (ii) reduction in the number of tumor cells; (iii) ion in tumor size;
(iv) inhibition (i.e., ion, g down or complete stopping) of tumor cell infiltration into
PLSCDK11_12
peripheral ; (v) inhibition (i.e., ion, slowing down or complete stopping) of
metastasis; (vi) enhancement of anti-tumor immune response, which may, but does not have to,
result in the regression of the tumor; and/or (vii) relief, to some extent, of one or more
symptoms associated with squamous cell carcinoma of head and neck (SCCHN).
The term "subject" as used herein, refers to an animal, preferably a , most
preferably a human, who has been the object of treatment, observation or experiment. The term
subject may be interchangeably used with the term nt” in the context of the present
invention.
As used herein, the term "simultaneously” means that two or more therapeutic agents
(anticancer agents) are administered concurrently, "sequentially" means that two or more
therapeutic agents are available to act therapeutically within the same rame and
"separately" means that the gap between stering one agent and the other is significant i.e.
the first administered agent may no longer be present in the bloodstream in a therapeutically
effective amount when the second agent is administered.
The term “caspase3 activity” as used herein refers to increase in apoptosis in cancer
cells.
The term “apoptosis” refers to a type of cell death in which a series of molecular steps in
a cell leads to its death. This is the body’s normal way of getting rid of unneeded or abnormal
cells. The process of apoptosis may be blocked in cancer cells. Also called programmed cell
death. (Dictionary of cancer terms, National Cancer ute). The term asing apoptosis"
is defined as an se in the rate of programmed cell death, i.e. more cells are induced into
the death process as compared to exposure (contact) with either the antineoplastic agent alone or
the CDK inhibitor alone.
The phrase aceutically acceptable carrier” refers to one or more disintegrating
agents, binders, excipients, lubricants and the like which are well known to those skilled in
the art.
In the t invention there is provided the use of a pharmaceutical combination of
anti-cancer agents for the manufacture of a medicament for use in the treatment of squamous
cell carcinoma of head and neck (SCCHN). The present ors have conducted an extensive
research for the development of the pharmaceutical combination of anti-cancer agents and
arrived at the present synergistic ceutical combination. It has been found that
pharmaceutical combination comprising a cyclin dependent kinase (CDK) inhibitor selected from
the compounds of formula I or a pharmaceutically acceptable salt thereof and one or more
antineoplastic agent exhibits synergistic effect when used in the treatment of squamous cell
PLSCDK11_12
carcinoma of the head and neck (SCCHN).
The CDK inhibitor is a pyrrolidine substituted flavone compound that inhibits cyclin
ent kinases. The CDK inhibitor used in the pharmaceutical combination of the present
invention is selected from the compounds of formula I or pharmaceutically acceptable salts or
solvates f as described herein below. The compounds of formula I are promising CDK
inhibitors, which can inhibit proliferation of many cancer cells. As indicated herein above the
CDK inhibitors of formula (I) may be used in the form of their pharmaceutically acceptable
salts. The salts encompassed within the term “pharmaceutically acceptable salts” refer to nontoxic
salts of the compounds of this invention. Representative salts include, but are not limited
to acetate, benzoate, benzenesulfonate, onate, chloride, citrate,
hydrochloride, mesylate, methylsulfonate, tartrate, tosylate and trifluoroacetate. Preferred salts
of compounds of formula (I) include hloride salt, methanesulfonic acid and
oroacetic acid salt.
In one embodiment, the CDK inhibitor used in the pharmaceutical combination of the
present invention is selected from the compounds represented by the following formula I,
wherein, Ar is a phenyl group, which is unsubstituted or substituted by 1, 2, or 3 cal or
different substituents ed from : halogen, nitro, cyano, C1-C4-alkyl, trifluoromethyl,
hydroxyl or C1-C4-alkoxy; or a pharmaceutically acceptable salt or solvate thereof.
As indicated herein above the salts of CDK tor refers to non-toxic salts of the
compounds of formula (I) of this invention. Representative salts include, but are not limited to
acetate, benzoate, benzenesulfonate, bicarbonate, chloride, e, hydrochloride, te,
methylsulfonate, tartrate, tosylate and trifluoroacetate. Preferred salts of compounds of
formula (I) include hydrochloride salt, methanesulfonic acid and trifluoroacetic acid salt.
In an ment of the invention, the CDK inhibitor is the (+)-trans isomer of the
compound of formula I, as indicated in Formula IA below,
PLSCDK11_12
wherein Ar is a phenyl group, which is unsubstituted or substituted by 1, 2, or 3 identical or
different substituents selected from :halogen, nitro, cyano, C1-C4-alkyl, trifluoromethyl,
yl or C1-C4-alkoxy; or a pharmaceutically acceptable salt or solvate thereof.
In another ment of the present invention, the CDK inhibitor used in the
pharmaceutical combination of the present invention is a compound of formula I wherein the
phenyl group is tuted by 1, 2 or 3 identical or ent substituents selected from:
chlorine, bromine, fluorine or iodine, alkyl or oromethyl; or a pharmaceutically
able salt or solvate thereof.
In another embodiment of the present invention, the CDK inhibitor used in the
pharmaceutical combination of the present invention is a compound of formula I n the
phenyl group is substituted by chlorine; or a pharmaceutically acceptable salt or solvate thereof.
In another embodiment of the present invention, the CDK tor used in the
pharmaceutical combination of present invention is a compound of formula I wherein the
phenyl group is substituted by two different substituents selected from chlorine and
trifluoromethyl; or a pharmaceutically acceptable salt or solvate thereof.
It will be appreciated by those skilled in the art that the CDK inhibitors represented by
the compounds of formula (I) contain at least two chiral centers and hence, exist in the form of
two different optical isomers (i.e. (+) or (-) enantiomers). All such enantiomers and mixtures
thereof ing racemic mixtures are included within the scope of the invention. The
enantiomers of the compound of formula I can be obtained by methods disclosed in PCT
Application Publication No. WO2004004632 incorporated herein by reference or the
enantiomers of the compound of formula I can also be obtained by methods well known in
the art, such as chiral HPLC and enzymatic tion.
Alternatively, the enantiomers of the compounds of formula I can be synthesized by
using optically active starting materials. The manufacture of the compounds of formula I,
which may be in the form of pharmaceutically acceptable salts and solvates, and the manufacture
11_12
of oral and/or parenteral pharmaceutical composition containing the above compounds are
generally disclosed in PCT Application ation No. 004632. This patent
application, which is incorporated herein by reference, discloses that the CDK inhibitors
represented by formula I exhibit significant anticancer efficacy. As indicated herein above
the CDK tors of formula I may be used in the form of their salts. red salts of
compounds of formula I include hydrochloride, methanesulfonic acid and oroacetic acid
salt.
According to another embodiment of the present invention, the CDK inhibitor used in
the pharmaceutical combination of the present invention is selected from (+)-trans (2-
Chloro-phenyl)-5,7-dihydroxy(2-hydroxy-methylmethyl-pyrrolidinyl)- chromenone
hloride (referred to herein as compound A) or (+)-trans[2[(2- Chloro
trifluoromethyl-phenyl)-5,7-dihydroxy(2-hydroxymethylmethyl- pyrrolidinyl)-chromen-
4-one hydrochloride (referred to herein as compound B).
In an embodiment of the t invention, the CDK inhibitor used in the
pharmaceutical combination is (+)-trans(2-Chloro-phenyl)-5,7-dihydroxy(2- hydroxymethylmethyl-pyrrolidinyl
)-chromenone hydrochloride (compound A).
In further embodiment of the present invention, the CDK inhibitor used in the
ceutical combination is (+)-trans[2[(2-Chlorotrifluoromethyl-phenyl)-5,7-
oxy(2-hydroxymethylmethyl-pyrrolidinyl)-chromenone hydrochloride
(compound B).
The antineoplastic agents are the compounds that prevent cancer cells from
multiplying (i.e. anti-proliferative ). In the present invention anti-neoplastic agent
included in the pharmaceutical combination may be selected from either cytostatic or cytotoxic
agents.
According to an ment of the invention, an anti-neoplastic agent used in the
pharmaceutical combination of the present invention is a cytostatic agent.
According to another embodiment of the invention, an anti-neoplastic agent used in the
pharmaceutical combination of the present invention is a cytotoxic agent.
According to an embodiment of the invention, when the anti-neoplastic agent used in
the pharmaceutical combination of the present invention is a cytostatic agent, it is selected from
small molecules such as sorafenib, lapatinib or erlotinib or a chimeric monoclonal dy such
as cetuximab.
According to another ment of the invention, when the anti-neoplastic agent
used in the pharmaceutical combination of the present invention is a cytotoxic agent, it is
PLSCDK11_12
selected from cisplatin, 5-fluorouracil and/or docetaxel or pharmaceutically acceptable salts
thereof.
According to another embodiment of the invention, the pharmaceutical combination
comprising a CDK inhibitor selected from the compounds of formula (I) or a ceutically
acceptable salt thereof, and one or more antineoplastic agents, may further include use of
radiation therapy for the treatment of squamous cell carcinoma of the head and neck (SCCHN).
The specified anti-neoplastic agents used in the present ion are commercially
readily available.
Sorafenib is a kinase tor that decreases tumor cells proliferation in vitro.
Sorafenib was shown to inhibit multiple intracellular (CRAF, BRAF and mutant BRAF)
and cell surface kinases (KIT, FLT-3, RET, VEGFR-1 to 3 and PDGFR-β. Several of these
kinases are thought to be involved in tumor cell signaling, angiogenesis and apoptosis.
Sorafenib inhibited tumor growth and angiogenesis of human hepatocellular carcinoma and
renal cell oma and several other human tumor xenografts in immunocompromised mice.
It is chemically named as 4-(4-{3-[4-
chloro(trifluoromethyl)phenyl]ureido}phenoxy)N2-methylpyridinecarboxamide-
4-methylbenzenesulfonate. Sorafenib is commercially available and is marketed as Nexavar
® by Bayer in the United States for the treatment of patients with advanced renal cell oma
(RCC) and those with unresectable hepatocellular carcinoma (HCC). It is also approved by the
European Medicines Agency for the treatment of patients with HCC and ts with
advanced RCC with whom prior IFN-α or interleukinbased y had failed or considered
to be unsuitable for such therapy ("Preclinical overview of sorafenib, a multikinase inhibitor
that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling". Molecular
Cancer Therapeutics2008; 7 (10): 3129–40).
Lapatinib, is a 4-anilinoquinazoline kinase inhibitor of the ellular tyrosine kinase
domains of both mal Growth Factor or (EGFR [ErbB1]) and of human Epidermal
Receptor Type 2 (HER2[ErbB2]) ors. Lapatinib inhibits ErbB-driven tumor cell growth in
vitro and in various animal models. It is present as the drate of the ditosylate salt, with
chemical name N-(3-chloro{[(3- fluorophenyl) methyl]oxy}phenyl)[5-({[2-
(methylsulfonyl) ethyl] amino}methyl)- 2-furanyl]quinazolinaminebis(4-
methylbenzenesulfonate)monohydrate. Lapatinib late monohydrate is a dual tyrosine
inhibitor which interrupts the HER2 growth receptor and is used in ation therapy for
HER2-positive breast cancer ("Lapatinib in the ent of breast cancer" Expert Review of
Anticancer Therapy (Future Drugs) 7 (9): 1183–92). It is marketed under the brand name
PLSCDK11_12
TYKERB® in the United States by GlaxoSmithKline and is available commercially.
Lapatinib inhibits the ne kinase activity associated with two oncogenes, EGFR (epidermal
growth factor or) and HER2/neu (Human EGFR type 2) (“A unique structure for epidermal
growth factor receptor bound to GW572016 (Lapatinib): relationships among protein
conformation, inhibitor off-rate, and receptor activity in tumor cells” Cancer Res. 2004 Sep 15;
64(18): 6652-9). Lapatinib inhibits receptor signal processes by binding to the ATP-binding
pocket of the EGFR/HER2 protein kinase domain, preventing self-phosphorylation and
subsequent activation of the signal mechanism ("Lapatinib: a novel dual tyrosine kinase
inhibitor with activity in solid tumors". Annals of Pharmacotherapy: 40 (2); 261–269).
Erlotinib is an EGFR tor. The drug follows gefitinib (Iressa®), which was the
first drug of this type. Gefitinib and erlotinib are commercially ble epidermal growth
factor or tyrosine kinase tors TKIs) that are widely used for the treatment of
non-small-cell lung cancer (NSCLC). Erlotinib ically targets the epidermal growth factor
receptor (EGFR) tyrosine kinase, which is highly expressed and occasionally mutated in various
forms of cancer. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site
of the receptor (J Clin Oncol, 2007;25:1960-1966).
Cisplatin is a platinum compound which acts as a cytotoxic anticancer agent. This
platinum-based chemotherapy drug, which kills the cancer cells by damaging DNA and
inducing apoptosis. Cisplatin is commercially available for the treatment of various types of
s, including sarcomas, some carcinomas (e.g. small cell lung cancer, and n
), lymphomas, and germ cell tumors. Cisplatin is a non cell cycle specific cytotoxic agent
which is effective t cells that are actively dividing as well as those that are merely resting
before entering the cell cycle and reacts in vivo, binding to and causing cross linking of DNA
which ultimately triggers apoptosis (programmed cell death).
uracil (5-FU) is an antimetabolite and a cytotoxic anti-cancer agent. 5-FU inhibits
DNA synthesis and cell death and penetrates cerebrospinal fluid well. 5-FU is cially
ble as an antimetabolite that interferes with RNA and DNA synthesis. 5-FU is
therapeutically useful for certain types of carcinoma, such as carcinoma of the colon, rectum,
breast, stomach and pancreas.
xel is an antineoplastic agent belonging to the taxoid family that acts by
disrupting the microtubular network in cells that is essential for mitotic and interphase cellular
functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into
stable microtubules while simultaneously inhibiting their disassembly. This leads to the
production of ubule bundles without normal function and to the stabilization of
PLSCDK11_12
ubules, which results in the inhibition of mitosis in cells. Docetaxel's binding to
microtubules does not alter the number of protofilaments in the bound microtubules, a e
which differs from most spindle poisons currently in clinical use. Docetaxel is marketed
worldwide under the name Taxotere® by Sanofi- and available commercially.
Cetuximab is a inant, chimeric monoclonal antibody directed t the
epidermal growth factor (EGFR) with antineoplastic activity. mab binds to the
ellular domain of the EGFR, thereby preventing the activation and subsequent
dimerization of the receptor; the decrease in receptor activation and dimerization may result in
an tion in signal uction and anti-proliferative s. This agent may inhibit EGFR-
dependent primary tumor growth and metastasis. Cetuximab is commercially available as
Erbitux® for treatment of metastatic colorectal cancer and head and neck cancer.
According to another ment, the present invention relates to the use of a
pharmaceutical combination for the manufacture of a medicament for use in the treatment of
squamous cell carcinoma of head and neck (SCCHN) wherein the combination comprises a
cyclin dependent kinase (CDK) tor selected from the compounds of formula I or a
ceutically acceptable salt or a solvate thereof and one or more of antineoplastic
agents selected from sorafenib, lapatinib, erlotinib, cisplatin, 5-fluorouracil or docetaxel or a
pharmaceutically acceptable salt thereof or the monoclonal antibody cetuximab.
In another embodiment, the present invention is directed to the use of a pharmaceutical
ation for the manufacture of a medicament for use in the treatment of squamous cell
carcinoma of head and neck (SCCHN) wherein the combination comprises a cyclin
dependent kinase (CDK) inhibitor selected from the compounds of formula I or a
pharmaceutically able salt or a solvate thereof and sorafenib.
Another embodiment of the present invention provides the use of a pharmaceutical
combination for the manufacture of a medicament for use in the treatment of squamous cell
carcinoma of head and neck wherein the combination comprises a cyclin dependent kinase
(CDK) inhibitor selected from the compounds of a I or a pharmaceutically able salt
or a e thereof and lapatinib.
In another embodiment, the present invention is directed to the use of a pharmaceutical
combination for the manufacture of a medicament for use in the treatment of squamous cell
carcinoma of head and neck wherein the combination comprises a cyclin dependent kinase
(CDK) inhibitor selected from the compounds of formula I or a pharmaceutically acceptable
salt or a solvate thereof and erlotinib.
Another embodiment of the present invention provides the use of a pharmaceutical
PLSCDK11_12
ation for the manufacture of a medicament for use in the treatment of us cell
carcinoma of head and neck wherein the combination comprises a cyclin dependent kinase
(CDK) inhibitor selected from the compounds of formula I or a pharmaceutically acceptable
salt or a solvate thereof; cisplatin and 5-fluorouracil or a pharmaceutically acceptable salt
thereof.
In another embodiment, the t invention is directed to the use of a
pharmaceutical combination for the manufacture of a medicament for use in the treatment of
squamous cell carcinoma of head and neck wherein the combination comprises a cyclin
dependent kinase (CDK) inhibitor ed from the compounds of formula I or a
pharmaceutically acceptable salt or a solvate thereof; docetaxel, cisplatin and 5-fluorouracil or
a pharmaceutically acceptable salt thereof.
Further embodiment of the present ion provides the use of a pharmaceutical
combination for the manufacture of a medicament for use in the treatment of squamous cell
carcinoma of head and neck wherein the ation comprises a CDK inhibitor selected
from compound A or compound B and one or more anti-neoplastic agents selected from
sorafenib, lapatinib, erlotinib, cisplatin, 5-fluorouracil or docetaxel or a pharmaceutically
acceptable salt thereof.
In another embodiment, the t invention provides the use of a pharmaceutical
ation for the manufacture of a medicament for use in the treatment of squamous cell
carcinoma of head and neck wherein the combination ses compound A and
sorafenib or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention is directed to the use of a pharmaceutical
combination for the manufacture of a medicament for use in the treatment of squamous cell
carcinoma of head and neck wherein the combination ses nd A and
nib or a ceutically acceptable salt thereof.
In another embodiment, the present invention is directed to the use of a pharmaceutical
combination for the manufacture of a ment for use in the treatment of squamous cell
carcinoma of head and neck n the combination comprises compound A and
erlotinib or a ceutically acceptable salt thereof.
In another embodiment, the present invention is directed to the use of a
pharmaceutical combination for the manufacture of a medicament for use in the treatment of
squamous cell oma of head and neck wherein the combination comprises compound A,
cisplatin and 5-fluorouracil or a pharmaceutically acceptable salt thereof.
Further embodiment of the present invention is directed to the use of a
PLSCDK11_12
pharmaceutical combination for the manufacture of a medicament for use in the treatment of
squamous cell carcinoma of head and neck n the combination comprises compound A,
docetaxel, cisplatin and 5-fluorouracil or a pharmaceutically acceptable salt thereof.
In another ment, the present invention is directed to the use of a pharmaceutical
combination for the manufacture of a medicament for use in the treatment of squamous cell
carcinoma of head and neck wherein the combination comprises compound B and
sorafenib or a pharmaceutically acceptable salt thereof.
In another embodiment, the present invention is directed to the use of a pharmaceutical
combination for the manufacture of a medicament for use in the treatment of squamous cell
carcinoma of head and neck wherein the combination comprises the compound B and lapatinib
or a pharmaceutically acceptable salt thereof.
ing to r embodiment of the present invention, the pharmaceutical
ation comprising the CDK inhibitor selected from the compounds of formula I and an
antineoplastic agent selected from nib, lapatinib or nib or the pharmaceutical
ation comprising the CDK inhibitor selected from the nds of formula I, and an
oplastic agent selected from cisplatin and 5-fluorouracil or the pharmaceutical
combination comprising the CDK inhibitor selected from the compounds of formula I, and an
antineoplastic agent selected from tin, 5-fluorouracil and docetaxel, is not exclusively
limited to those combinations which are obtained by physical association of said ingredients, but
also encompass those which permit a separate administration, which can be simultaneous,
sequential or spaced out over a period of time so as to obtain maximum efficacy of the
ation. Thus, the pharmaceutical combination may be administered simultaneously or
sequentially for an effective treatment of squamous cell carcinoma of head and neck.
According to another embodiment, the present invention is ed to the use of a
pharmaceutical ation for the manufacture of a medicament for use in the treatment of
squamous cell carcinoma comprising radiation, a CDK inhibitor selected from the compounds
of formula I and one or more antineoplastic agents selected from sorafenib, lapatinib, erlotinib,
cisplatin, 5-fluorouracil or docetaxel or a pharmaceutically acceptable salt thereof.
According to another embodiment, the present invention is directed to the use
of a pharmaceutical combination for the manufacture of a medicament for use in the treatment of
squamous cell carcinoma comprising radiation, a CDK inhibitor selected from compound A or
nd B and one or more antineoplastic agents selected from sorafenib, lapatinib, nib,
cisplatin, 5- fluorouracil or docetaxel or a pharmaceutically acceptable salt f.
According to another embodiment, the present invention relates to the use of a
11_12
pharmaceutical combination for the manufacture of a medicament for use in the ent of
squamous cell oma of head and neck (SCCHN) wherein the combination ses a
cyclin dependent kinase (CDK) inhibitor selected from compound A or compound B,
tin and or a pharmaceutically acceptable salt thereof and the monoclonal antibody,
cetuximab.
According to r ment, the present ion relates to the use of a
pharmaceutical combination for the manufacture of a medicament for use in the treatment of
us cell oma of head and neck (SCCHN) wherein the combination comprises
ion, a cyclin dependent kinase (CDK) inhibitor selected from compound A or nd B
or a pharmaceutically acceptable salt thereof and the monoclonal antibody, cetuximab.
Also described herein is a pharmaceutical composition which comprises a therapeutically
effective amount of a CDK inhibitor selected from the compounds of formula I (as described
herein) or a pharmaceutically acceptable salt or solvate thereof in combination with a
therapeutically effective amount of one or more antineoplastic agents selected from the
group consisting of sorafenib, lapatinib, erlotinib, docetaxel, cisplatin and 5-fluorouracil or a
pharmaceutically acceptable salt thereof; in association with a pharmaceutically acceptable
carrier.
Also described herein is a pharmaceutical composition which comprises a therapeutically
effective amount of a CDK inhibitor selected from the compounds of a I or a
pharmaceutically acceptable salt or solvate thereof and a therapeutically effective amount of
nib in association with a pharmaceutically able carrier.
Also described herein is a pharmaceutical composition which comprises a
therapeutically effective amount of a CDK inhibitor selected from the compounds of formula
I or a pharmaceutically acceptable salt or solvate thereof and a therapeutically effective
amount of lapatinib in association with a pharmaceutically acceptable carrier.
Also described herein is a pharmaceutical composition which comprises a
therapeutically effective amount of a CDK inhibitor selected from the compounds of formula
I or a pharmaceutically acceptable salt or solvate thereof and a therapeutically effective
amount of erlotinib in association with a pharmaceutically acceptable carrier.
Also bed herein is a pharmaceutical composition which comprises a therapeutically
effective amount of a CDK inhibitor selected from the compounds of formula I or a
pharmaceutically acceptable salt or solvate thereof, a therapeutically effective amount of
cisplatin and a therapeutically effective amount of 5-fluorouracil or a pharmaceutically
acceptable salt thereof; in association with a pharmaceutically acceptable carrier.
PLSCDK11_12
Also described herein is a pharmaceutical composition which comprises a eutically
effective amount of a CDK tor ed from the compound A or compound B and
therapeutically effective amount of one or more antineoplastic agents or a pharmaceutically
acceptable salt thereof; in association with a pharmaceutically able carrier.
Also described herein is a pharmaceutical composition which comprises a therapeutically
effective amount of a CDK inhibitor ed from compound A or compound B and a
therapeutically effective amount of one or more antineoplastic agents selected from the
group consisting of nib, lapatinib, erlotinib, cisplatin and 5-fluorouracil or
pharmaceutically acceptable salt thereof; in association with a pharmaceutically acceptable
carrier.
Also described herein is a pharmaceutical ition which comprises a eutically
effective amount of compound A and a therapeutically effective amount of sorafenibin
association with a pharmaceutically acceptable carrier.
Also described herein is a pharmaceutical composition which comprises a therapeutically
ive amount of compound A and a therapeutically effective amount of lapatinib in
association with a ceutically acceptable r.
Also described herein is a pharmaceutical composition which comprises a
therapeutically effective amount of compound B and a therapeutically effective amount
of sorafenib in association with a pharmaceutically acceptable carrier.
Also described herein is a pharmaceutical composition which comprises a therapeutically
effective amount of compound B and a therapeutically effective amount of lapatinib in
ation with a pharmaceutically acceptable carrier.
Also described herein is a pharmaceutical composition which comprises a therapeutically
effective amount of nd A and a therapeutically effective amount of erlotinib in
association with a pharmaceutically acceptable carrier.
Also described herein is a pharmaceutical composition which comprises a therapeutically
effective amount of each of the compound A, cisplatin and 5-fluorouracil or a
pharmaceutically acceptable salt thereof; in association with a pharmaceutically acceptable
carrier.
Also described herein is a pharmaceutical composition which comprises a therapeutically
effective amount of each of the nd A, docetaxel, cisplatin and 5-fluorouracil or a
pharmaceutically acceptable salt f; in association with a pharmaceutically acceptable
carrier.
Also described herein is a method for the treatment of squamous cell carcinoma of head
PLSCDK11_12
and neck in a subject, which comprises administering to said subject a therapeutically ive
amount of a CDK inhibitor selected from the compounds of formula (I) or a pharmaceutically
acceptable salt or solvate thereof and a eutically effective amount of an anti-neoplastic
agent selected from sorafenib, lapatinib or erlotinib; wherein said CDK inhibitor and said anti-
neoplastic agent or ceutically acceptable salt thereof is administered simultaneously or
sequentially.
Also described herein is a method for the treatment of squamous cell carcinoma of head
and neck in a t, which comprises administering to said subject a therapeutically effective
amount of a CDK inhibitor selected from the compounds of a (I) or a pharmaceutically
acceptable salt or solvate thereof; a eutically effective amount of each of cisplatin and 5-
fluorouracil or a pharmaceutically acceptable salt thereof; wherein said CDK inhibitor, cisplatin
and 5-fluorouracil are administered simultaneously or sequentially.
Also described herein is a method for the treatment of squamous cell carcinoma of head
and neck in a subject, which comprises administering to said subject a therapeutically effective
amount of a CDK inhibitor ed from the compound A or compound B and a
therapeutically effective amount of antineoplastic agent selected from sorafenib, lapatinib or
erlotinib; wherein said compound A or nd B and antineoplastic agent is administered
simultaneously or sequentially.
Also described herein is a method for the treatment of squamous cell oma of head
and neck in a subject, which ses stering to said subject a therapeutically effective
amount of a CDK inhibitor selected from the nd A or compound B and a
therapeutically effective amount of sorafenib; wherein said compound A or compound B and
sorafenib is administered simultaneously or sequentially.
Also described herein is a method for the treatment of squamous cell carcinoma of head
and neck in a subject, which comprises administering to said subject a therapeutically ive
amount of a CDK inhibitor selected from the compound A or compound B and a
therapeutically effective amount of lapatinib or a pharmaceutically acceptable salt thereof;
wherein said compound A or compound B and lapatinib is administered simultaneously or
sequentially.
Also described herein is a method for the treatment of squamous cell carcinoma of
head and neck in a subject, which comprises administering to said subject a
eutically effective amount of compound A or a pharmaceutically acceptable salt or
solvate thereof and a therapeutically ive amount of erlotinib; wherein said compound A
and erlotinib is administered simultaneously or sequentially.
PLSCDK11_12
Also described herein is to a method for the treatment of squamous cell carcinoma of
head and neck in a subject, which comprises administering to said subject a therapeutically
effective amount of compound A or a pharmaceutically acceptable salt or solvate thereof; a
therapeutically effective amount of cisplatin and 5-fluorouracil or a pharmaceutically acceptable
salt thereof; wherein said nd A, cisplatin and 5-fluorouracil are administered
simultaneously or sequentially.
Also described herein is a method for the treatment of squamous cell carcinoma of head
and neck in a subject, which comprises administering to said subject a therapeutically effective
amount of CDK inhibitor selected from the compounds of formula (I) or a ceutically
acceptable salt or solvate thereof and a therapeutically effective amount of an antineoplastic
agent or a pharmaceutically acceptable salt thereof; wherein said CDK inhibitor and said
anti-neoplastic agent or their pharmaceutically acceptable salts are stered sequentially.
Also described herein is a method for the treatment of squamous cell carcinoma of head
and neck in a t comprising administering to said subject a eutically effective
amount of compound A or compound B; a therapeutically effective amount of an
antineoplastic agent selected from sorafenib, lapatinib or nib; wherein said compound A
or nd B and antineoplastic agent selected from sorafenib, lapatinib or nib is
administered sequentially such that compound A or compound B is stered before or
after the administration of nib or lapatinib or erlotinib.
Also described herein is a method for the treatment of squamous cell oma of head
and neck in a subject sing administering to said subject a therapeutically effective
amount of compound A and a therapeutically effective amount of sorafenib; wherein said
compound A and sorafenib is administered sequentially such that compound A is administered
before or after the stration of sorafenib.
Also described herein is a method for the treatment of squamous cell carcinoma of head
and neck in a subject comprising administering to said t a therapeutically effective
amount of compound B and a therapeutically effective amount of sorafenib; wherein said
compound B and sorafenib is administered sequentially such that compound B is administered
before or after the administration of sorafenib.
Also described herein is a method for the treatment of squamous cell carcinoma of head
and neck in a subject comprising administering to said subject a therapeutically effective
amount of compound A and a therapeutically effective amount of lapatinib; wherein said
compound A and lapatinib is administered sequentially such that compound A is administered
before or after the administration of lapatinib.
PLSCDK11_12
Also described herein is a method for the treatment of squamous cell carcinoma of head
and neck in a subject sing administering to said subject a therapeutically effective
amount of nd B and a therapeutically effective amount of lapatinib; wherein said
compound B and lapatinib is stered sequentially such that compound B is administered
before or after the stration of lapatinib.
Also described herein is a method for the treatment of squamous cell carcinoma of head
and neck in a subject comprising administering to said subject a therapeutically effective
amount of compound A; a therapeutically effective amount of nib; wherein said compound
A and erlotinib is administered sequentially such that compound A is administered before or
after the administration of nib.
Also described herein is a method for the ent of squamous cell oma of head
and neck in a subject comprising stering to said subject a therapeutically effective
amount of compound A; a therapeutically effective amount of each of cisplatin; and 5-
fluorouracil or a ceutically acceptable salt thereof; wherein said compound A, cisplatin
and 5- fluorouracil or a pharmaceutically acceptable salt thereof are administered sequentially
such that compound A is administered before or after the stration of cisplatin and/or 5-
fluorouracil.
Also described herein is a method for the treatment of squamous cell carcinoma of head
and neck in a subject sing administering to said subject a therapeutically effective
amount of compound A; a therapeutically effective amount of each of docetaxel; cisplatin and
-fluorouracil or a pharmaceutically acceptable salt thereof; wherein said compound A,
docetaxel, cisplatin and 5-fluorouracil or a pharmaceutically acceptable salt thereof are
administered sequentially such that compound A is administered before or after the
administration of docetaxel, and/or cisplatin and/or 5-fluorouracil.
In r embodiment the present invention provides use of ation of a CDK
inhibitor selected from the compound of formula I or pharmaceutically acceptable salt or solvate
thereof and one or more antineoplastic agents selected from sorafenib, lapatinib, erlotinib,
cisplatin, 5-fluorouracil, docetaxel or cetuximab or a pharmaceutically acceptable salt thereof for
the manufacture of a medicament for the treatment or prevention of squamous cell carcinoma of
the head and neck (SCCHN).
Another embodiment of the present invention provides use of ceutical
composition comprising a therapeutically ive amount of CDK inhibitor selected from the
compounds of a (I) or a pharmaceutically acceptable salt thereof and an antineoplastic
agent selected from sorafenib, lapatinib, erlotinib, cisplatin, 5-fluorouracil, docetaxel or
PLSCDK11_12
cetuximab for the manufacture of a medicament for the treatment of squamous cell carcinoma of
the head and neck (SCCHN).
According to the present invention the administration of the double ation of
CDK inhibitor selected from the compound of formula I and an antineoplastic agent or a
pharmaceutically acceptable salt thereof selected from sorafenib, lapatinib or erlotinib
may produce s, such as the anti-cancer effects , greater than those achieved with any of
the CDK inhibitor or nib or lapatinib or erlotinib when used alone.
It is further provided by the present ion that the administration of a triple
combination of the CDK inhibitor selected from the compound of formula I as described herein,
cisplatin and 5-fluorouracil may produce effects, such as anti-cancer effects, greater than those
achieved with any of the CDK inhibitor or cisplatin or 5- fluorouracil used alone, greater than
those achieved with the combination of the CDK inhibitor, cisplatin and 5-fluorouracil.
The administration route of the pharmaceutical composition of the present invention is
not particularly limited. In one embodiment, the active ingredients (the anticancer agents
contained in the combination) comprised in the composition may have to be stered by
ent routes either orally or parenterally depending on the dosage form. The dosage form
suitable for oral stration may be a tablet or e, forms of parenteral stration
include intravenous injection, intravenous infusion, subcutaneous injection, transdermal
injection, intraperitoneal injection and so on. For rectal administration, for example as a
itory or the route of administration may be by direct injection into the tumour or by
regional ry or by local delivery. In the case of tablets for oral use, carriers which are
commonly used include lactose, corn starch, magnesium carbonate, talc, and sugar, and
lubricating agents such as magnesium te are commonly added. For oral administration in
e form, useful carriers include lactose, corn starch, ium carbonate, talc and sugar.
For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the
active ingredient are usually employed, and the pH of the solutions should be suitably adjusted
and buffered.
In practice of the present invention, CDK inhibitors selected from the compounds of
Formula I may be administered either orally or parenterally to generate and maintain good
blood levels thereof, while one or more antineoplastic agents may be administered
orally or parenterally, by intravenous, subcutaneous or intramuscular route or any other
suitable route of administration.
In one embodiment, the therapeutic agents (the CDK inhibitors and the antineoplastic
agents) contained in the combination of the invention are ated in accordance with
PLSCDK11_12
routine procedures as a pharmaceutical composition.
In practice, oral preparations for oral administration may be ed by adding to the
active ingredients fillers, and if necessary, binders, disintegrants, lubricants, coloring agents,
flavoring agents, etc. and formulating the resultant mixture according to tional
procedures into s, coated tablets, granules, subtle granules, powders, capsules or the
like. Examples of the filler include but not limited to lactose, corn starch, white sugar, glucose,
ol, crystalline cellulose, silicon dioxide, etc. Examples of the binder include but not
limited to polyvinyl alcohol, ethylcellulose, cellulose, gum arabic, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, etc. Examples of the lubricant include but not
limited to magnesium stearate, talc, silica, etc. The coloring agent may be any ng
agent which is approved to be added to pharmaceutical preparations. Examples of the flavoring
agent include but not limited to cocoa powder, l, aromatic powder, peppermint oil,
camphol, on powder, etc. Resultant tablets and granules may be appropriately coated
with, for example, sugar or gelatin ing to necessity. When the pharmaceutical
composition of the present invention is administered transdermally in the form of patch, it
is preferable to select the led free-form that does not form a salt. Injection preparations
may be produced as enous infusion preparations or enous, subcutaneous or
intramuscular injection preparations according to conventional procedures. Examples of the
suspending agent include but not limited to methylcellulose, polysolvate 80, hydroxyethyl
cellulose, gum arabic, powdered tragacanth, sodium carboxymethylcellulose, polyoxyethylene
sorbitan monolaurate, etc. Examples of the dissolution aid include but not limited to
polyoxyethylene hydrogenated castor oil, polysolvate 80, nicotinamide, yethylene
sorbitan monolaurate, macrogol, fatty acid ethyl ester from castor oil, etc. Examples of the
stabilizer include but not limited to sodium sulfite, sodium metasulfite, etc. Examples of the
preservative include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid,
phenol, cresol, chlorocresol etc.
Although the effective doses of eutic agents (the CDK tors and the
antineoplastic or anticancer agents) for administration vary depending on the severity of
symptom, the age, sex, body weight and sensitivity difference of the patient, the mode, time,
interval and duration of administration, the nature, formulation and type of the preparation, the
type of the active ingredient, etc. In certain embodiments, the therapeutic agents are
administered in a time frame where both agents are still active. One skilled in the art would
be able to ine such a time frame by determining the half life of the stered
therapeutic agents. As indicated herein before, the active ingredients contained in the
PLSCDK11_12
pharmaceutical composition can be administered simultaneously or sequentially. Those skilled
in the art will recognize that several ions are possible within the scope and spirit of this
invention.
For effective administration, the therapeutic agents of the pharmaceutical combination of
the present invention are ed in a particular dose range, for e the CDK inhibitor
selected from compound of a I such as the compound A may be provided in a general
dose range of 75 mg/m2/day to 200 mg/m2/day; another CDK inhibitor ed from
compound of formula I such as the Compound B may be ed in a l dose range of
50 mg to 350 mg orally. Further, among the oplastic agents, cisplatin may be
provided in a dose range of 40 mg/m2/day to 200 day, 5-fluourouracil may be provided
in dose range of 40 mg/m2/day to 200 mg/m2/day , xel may be provided in a general dose
range of 20 mg/m2/day to 75 mg/m2/day, sorafenib may be provided in at least an amount from
about 200 mg to 400mg (2x200 mg tablet) PO bid (orally twice a day), lapatinib may be
provided in a dose ranging from 500 to 1500 mg/d and erlotinib may be provided in a dose
range of about 150 mg/day to 300 mg/day.
Also described herein is a kit comprising a therapeutically effective amount of a CDK
inhibitor selected from the compound of a I or a pharmaceutically acceptable salt
thereof in combination with one or more antineoplastic agents selected from sorafenib,
lapatinib, erlotinib, cisplatin and 5- fluorouracil or a pharmaceutically acceptable salt thereof.
The combinations provided by this invention have been evaluated in certain assay
systems, the experimental details are as provided herein below.
The synergistic efficacy of the combination of present invention is demonstrated by
conducting the in vitro study involving use of a combination for example a CDK inhibitor of
formula I as described herein as nd A or compound B and one or more antineoplastic
agents selected from sorafenib, lapatinib, erlotinib, cisplatin, 5- fluorouracil or docetaxel. It
is clearly ted that the antineoplastic agents when used in combination with CDK
inhibitors in the treatment of squamous cell carcinoma of head and neck the apoptosis in
proliferative cells increases than when the cells are treated with the CDK inhibitor of a I
alone or antineoplastic agent alone. For instance, it is clearly established from the data described
herein that the CDK tor of formula I, compound described herein as the compound A or
compound B in combination with one or more antineoplastic agents selected from sorafenib,
lapatinib, erlotinib, cisplatin, 5-fluorouracil or docetaxel, are synergistically effective in the
treatment of squamous cell carcinoma of the head and neck. The synergism exhibited by the
pharmaceutical combination of the present invention is also demonstrated through in vivo study
PLSCDK11_12
data as indicated herein.
It is understood that modifications that do not substantially affect the activity of the s
embodiments of this invention are included within the invention disclosed herein. Accordingly,
the ing examples are intended to illustrate but not to limit the present invention.
Example 1:
A) General procedure for the preparation of the CDK inhibitors (the compounds of
Formula I):
The compounds of formula I may be prepared according to the methods disclosed in PCT Patent
Publication No. WO2004004632 and PCT Patent Publication No. WO2007148158 which are
orated herein by nce.
The general s for the ation of the compound of formula I, or a pharmaceutically
acceptable salt thereof, comprises the following steps:
a) ng the resolved enantiomerically pure (-)-trans enantiomer of the
intermediate compound of formula VIA,
with acetic anhydride in the presence of a Lewis acid catalyst to obtain a resolved
acetylated compound of formula VIIA,
b) reacting the resolved acetylated compound of formula VIIA with an acid of
formula ArCOOH or an acid chloride of formula ArCOCl or an acid anhydride of
PLSCDK11_12
formula (ArCO)2O or an ester of formula ArCOOCH3, wherein Ar is as defined
hereinabove in reference to the compound of formula I, in the presence of a base and a
solvent to obtain a ed compound of formula VIIIA;
c) treating the resolved compound of formula VIIIA with a base in a suitable solvent to
obtain the corresponding resolved β-diketone compound of a IXA;
wherein Ar is as defined above;
d) treating the resolved β-diketone compound of formula IXA with an acid such as
hydrochloric acid to obtain the ponding cyclized compound of formula XA,
PLSCDK11_12
e) subjecting the compound of formula XA to dealkylation by heating it with a dealkylating
agent at a temperature ranging from 0 °C to obtain the (+)-trans enantiomer of the
compound of formula I and, optionally, converting the subject compound into its
pharmaceutically acceptable salt.
The Lewis acid catalyst utilized in the step (a) above may be selected from: BF3, Et2O, zinc
chloride, aluminium chloride and titanium chloride.
The base utilized in the process step (b) may be selected from triethylamine, pyridine and a
DCC-DMAP combination (combination of N, N’-dicyclohexyl carbodiimide and 4-
dimethylaminopyridine).
It will be nt to those skilled in the art that the rearrangement of the compound of formula
VIIIA to the corresponding β-diketone compound of formula IXA is known as a Baker-
Venkataraman rearrangement (J. Chem. Soc., 1381 (1933) and Curr. Sci., 4,214 (1933)).
The base used in the process step (c) may be selected from: lithium hexamethyl disilazide,
sodium hexamethyldisilazide, potassium hexamethyldisilazide, sodium hydride and potassium
hydride. A red base is lithium hexamethyl zide.
The dealkylating agent used in process step (e) for the dealkylation of the compound of
formula IXA may be ed from: pyridine hydrochloride, boron tribromide,boron
oride etherate and aluminium oride. A preferred dealkylating agent is pyridine
hydrochloride.
Preparation of the starting compound of formula VIA involves reacting 1-methyl
piperidone with a solution of 1,3,5-trimethoxybenzene in glacial acetic acid, to yield
1-methyl(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine, which is reacted with boron
trifluoride diethyl etherate, sodium borohydride and tetrahydrofuran to yield 1- methyl(2,4,6-
trimethoxyphenyl)piperidinol. Conversion of 1-methyl(2,4,6- hoxyphenyl)piperidin-
3-ol to the compound of formula VIA involves ting the hydroxyl group present on the
piperidine ring of the compound, yl(2,4,6- trimethoxyphenyl)piperidinol to a
leaving group such as tosyl, mesyl, te or halide by treatment with an appropriate reagent
such as p-toluenesulfonylchloride, esulfonylchloride, triflic ide or
phosphorous pentachloride in the presence of oxygen nucleophiles such as triethylamine,
pyridine, potassium carbonate or sodium carbonate, followed by ring contraction in the presence
of oxygen nucleophiles such as sodium acetate or potassium acetate in an alcoholic solvent
such as isopropanol, ethanol or propanol.
PLSCDK11_12
B) Preparation of (+)-trans(2-Chloro-phenyl)-5,7-dihydroxy(2- ymethyl
methyl-pyrrolidinyl)-chromenone hloride (compound A)
Molten pyridine hydrochloride (4.1 g, 35.6 mmol) was added to (+)-trans(2-chloro- phenyl)-
8-(2-hydroxymethylmethyl-pyrrolidinyl)-5,7-dimethoxy-chromenone (0.4 g, 0.9 mmol)
and heated at 180 °C for 1.5 h. The reaction mixture was cooled to 25 °C, diluted with MeOH
(10 mL) and basified using Na2CO3 to pH 10. The mixture was filtered and the organic layer
was concentrated. The residue was suspended in water (5 mL), d for 30 min., filtered and
dried to obtain the compound, (+)-trans- 2-(2-chloro-phenyl)-5,7-dihydroxy(2-
hydroxymethylmethyl-pyrrolidinyl)- chromenone .
Yield: 0.25 g (70 %); IR (KBr): 3422, 3135, 1664, 1623, 1559 cm-1;
1H NMR (CDCl3, 300MHz): δ 7.56 (d, 1H), 7.36 (m, 3H), 6.36 (s, 1H), 6.20 (s, 1H), 4.02 (m,
1H), 3.70 (m, 2H), 3.15 (m, 2H), 2.88 (m, 1H), 2.58 (s, 3H), 2.35 (m, 1H), 1.88 (m, 1H); MS
(ES+): m/z 402 (M+1);
Analysis: C21H20ClNO5 C, 62.24 (62.71); H, 5.07 (4.97); N, 3.60 (3.48); Cl, 9.01 (8.83).
The compound as obtained above (0.2 g, 0.48 mmol) was suspended in IPA (5 mL) and 3.5
% HCl (25 ml) was added. The suspension was heated to get a clear solution. The solution was
cooled and solid filtered to obtain the compound, (+)-trans(2- Chlorophenyl)-5,7-dihydroxy-
ydroxymethylmethyl-pyrrolidinyl)-chromenone hydrochloride .
Yield: 0.21 g (97 %); mp: 188 – 192 °C ; [α]D25 = +21.3° (c = 0. 2, methanol);
1H NMR , 300MHz): δ 7.80 (d, 1H), 7.60 (m, 3H), 6.53 (s, 1H), 6.37 (s, 1H), 4.23 (m,
1H), 3.89 (m, 2H), 3.63 (m, 1H), 3.59 (dd, 1H), 3.38 (m, 1H), 2.90 (s, 3H), 2.45 (m, 1H), 2.35
(m, 1H); MS (ES+): m/z 402 (M +1)( free base).
This compound was subjected to chiral HPLC. Chiral HPLC was done using column Chiralcel
OD-H (250 x 4.6 mm) and solvent system haxane:ethanol (92:08) with TFA (0.4%). The s
are recorded at 264nm with solvent flow rate of 1mL/min. As depicted in the chiral HPLC
showed 100% e.e of the compound, (+)-trans(2-chloro- phenyl)-5,7-dihydroxy(2-hydroxymethylmethyl-pyrrolidinyl
)-chromenone hydrochloride.
C) Preparation of (+)-trans(2-chlorotrifluoromethyl-phenyl)-5,7-dihydroxy-
8-(2-hydroxymethylmethyl-pyrrolidinyl)-chromenone hydrochloride
(Compound B)
A mixture of the nd, (+)-trans(2-Chlorotrifluoromethylphenyl)(2-
11_12
ymethylmethyl pyrrolidinyl)-5,7-dimethoxy-chromenone (0.25 g, 0.5 mmol),
pyridine hydrochloride (0.25 g, 2.16 mmol) and a catalytic amount of quinoline was
heated at 180 °C for a period of 2.5 hrs. The reaction mixture was d with methanol
(25 ml) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed
with ol. The organic layer was concentrated and the e purified by column
chromatography using 0.1 % ammonia and 4.5 % methanol in chloroform as eluent to yield the
compound, (+)-trans(2-chloro trifluoromethylphenyl)-5,7-dihydroxy(2-hydroxymethylmethylpyrrolidinyl
)- chromenone, as a yellow solid.
Yield: 0.15 g (63.7 %);
1H NMR (CDCl3, 300MHz): δ 7.99 (m, 2H), 7.83 (d, 1H), 6.65 (s, 1H), 6.41 (s, 1H), 4.24 (m,
1H), 3.90 (m, 2H), 3.70 (m, 1H), 3.60 (m, 1H), 3.41 (m, 1H), 2.99 (s, 3H), 2.54 (m, 1H), 2.28
(m, 1H); MS (ES+): m/z 470 (M+1).
The nd (0.1 g, 0.2 mmol) as obtained above was suspended in methanol (2 mL) and
d with ethereal HCl and the organic solvent evaporated to yield the compound, (+)-trans
(2-chlorotrifluoromethyl-phenyl)-5,7-dihydroxy(2-hydroxymethylmethyl-pyrrolidin
yl)-chromenone hydrochloride.
Yield: 0.1g (92.8 %);
1H NMR (CDCl3, 300MHz): δ 8.02 (d, 2H), 7.83 (d, 1H), 6.64 (s, 1H), 6.41 (s, 1H), 4.23 (m,
1H), 3.73 (m, 2H), 3.68 (m, 1H), 3.51 (m, 1H), 3.39 (m, 1H), 2.99 (s, 3H), 2.54 (m, 1H), 2.31
(m, 1H).
IN VITRO STUDIES INVOLVING USE OF THE COMBINATION CONSISTING OF A
CDK INHIBITOR AND ONE OR MORE ANTINEOPLASTIC AGENTS
In vitro studies involving use of a combination comprising a CDK inhibitor selected from(+)-
trans(2-Chloro-phenyl)-5,7-dihydroxy(2-hydroxymethylmethyl- pyrrolidinyl)-
chromenone hydrochloride (compound A) and (+)-trans(2- chlorotrifluoromethylphenyl
)-5,7-dihydroxy(2-hydroxymethylmethyl- pyrrolidinyl)-chromenone
hydrochloride (compound B) and one or more anti-neoplastic agents selected from
sorafenib, lapatinib, erlotinib, docetaxel, cisplatin or 5- fluorouracil, ting the
synergistic effect of the combination of the present invention are illustrated in the
following examples.
PLSCDK11_12
Example 2:
Materials:
Sorafenib, lapatinib and erlotinib were obtained from LC Labs (USA). Cisplatin, 5- fluorouracil
and docetaxel were obtained from Sigma. CK-8 cytotoxicity kit was procured from Dojindo
Molecular Technologies, Japan. Culture media and fetal bovine serum (FBS) were obtained
from Sigma (St. Louis, MO) and Gibco (Paisley, Scotland) respectively. The head and neck
cancer cells SCC-25, Detroit 562, and FADU were obtained from the American Type Culture
Collection (ATCC, Manassas, VA). Cells were maintained in Dulbecco’s Modified Eagle
Medium , supplemented with 10% FBS, Penicillin-Streptomycin Solution Stabilized,
sterile- filtered, with 100 units penicilin/ml and 100 mg omycin/ml. The cells were
grown in 75-cm2 culture flasks and kept in a humidified (37°C, 5% CO2) tor.
Cells were ed on ng 80% confluence.
Cell proliferation Assay:
Logarithmically growing cells were plated at a density of 3 x 103 cells/well and allowed
to recover overnight. The cells were challenged with varying concentration of different
anticancer agents (compound A, compound B, sorafenib, lapatinib nib, cisplatin, docetaxel
and 5-fluorouracil) and the control cells received standard media containing dimethyl sulfoxide
(DMSO) vehicle at a concentration of 0.2%. After 72 hours, cell toxicity was ined by
CCK-8 (Cell Counting Kit-8 ) reagent (Dojindo Molecular Technologies, Japan); WST-8 (2-(2-
methoxynitrophenyl)(4- nitrophenyl)(2, 4-disulfophenyl)]-2H-tetrazolium, monosodium
salt) assay. In ance with the cturer’s instructions, 5µl/well CCK-8 reagent was
added and plates were incubated for 2 hours. The toxicity was determined by measuring the
ance on Tecan Sapphire multi-fluorescence micro-plate reader (Tecan, Germany,
GmbH) at a wavelength of 450 nm corrected to 650 nm and normalized to controls.
A CCK-8 dioactive colorimetric assay was carried out to characterize the in vitro
growth of , Detroit 562, and FADU as well as to test the antiproliferative
/cytotoxic activity of the anticancer agents, compound A, compound B,
sorafenib, lapatinib, erlotinib, cisplatin, docetaxel and 5-fluorouracil when used in
combination. CCK-8 allows convenient assays using Dojindo's tetrazolium salt, WST [8[(2-(2-
methoxynitrophenyl)(4-nitrophenyl)(2,4-disulfophenyl)-2H- tetrazolium, monosodium
salt], which produces a water-soluble an dye upon bioreduction in the ce of an
electron carrier, 1-Methoxy PMS. CCK-8 solution is added directly to the cells; no pre-mixing
11_12
of components is required. CCK-8 is a ive nonradioactive colorimetric assay for
determining the number of viable cells in cell proliferation and cytotoxicity assays. WST-8
is bio-reduced by cellular dehydrogenases to an orange formazan t that is soluble
in tissue culture medium. The amount of formazan produced is directly proportional to the
number of living cells. The detection sensitivity of cell proliferation assays using WST-8 is
higher than assays using the other tetrazolium salts such as MTT, XTT, MTS or WST-1. Optical
Density was determined at measurement wavelength of 450 nm and reference wave length of
630 nm.
Determination of 50 percent inhibitory concentrations (IC50) of the compound A,
compound B, sorafenib, lapatinib, erlotinib, xel, cisplatin and 5-FU.
In order to determine the IC50 of compound A, compound B, sorafenib and lapatinib, in SCC-
, Detroit 562 and FADU cells and IC50 of erlotinib, docetaxel, cisplatin and 5-FU in Detroit
562 and FADU cells, the cells were treated with the specified anticancer agents (“the test
compounds”) at the below mentioned concentrations. All the ncer agents in the following
doses of final concentration 0.03 µM, 0.1 µM,0.3 µM, 1 µM, 3 µM, 10 µM, 30 µM and 100 µM
were analyzed for their capacity to exhibit cytotoxicity ularly to exhibit 50% cytotoxicity.
The cells were seeded at a density of 3000 cells/well, in a 200 µL in tissue culture grade 96
well plate and were allowed to recover for 24 hrs in a humidified 5% ± 0.2 CO2 incubator at
37 0C ± 0.5 0C. After 24 hrs, 1 µL of 200 X (200 times higher than required concentration is
denoted as 200 X) test compound (compound A, compound B nib, sorafenib, erlotinib,
docetaxel, cisplatin and 5-fluorouracil) dissolved in neat dimethyl ide (DMSO) was
added to the cells. The final DMSO concentration was 0.5% in wells. Plates were
ted for 48 hrs in humidified 5% ± 0.2 CO2 incubator at 37 ± 0.5 0C. After 48 hrs the
plates were removed from CO2 incubator and 5 µL of Cell ng Kit (CCK-8) per well was
added. The same plate was kept at 370C for 3 hrs, and allowed to come to room temperature.
The absorbance at a wavelength of 450 nm was read on Tecan safire reader. The percent
cytotoxicity was calculated using the following formula.
t Cytotoxicity = (OD of Control – OD Treated cells X 100)
OD DMSO control
Dose se studies at 72 hr in SCC-25 cells showed that the Compound A, Compound B,
sorafenib and lapatinib inhibited 50% growth (IC50) at 0.4 µM, 1.1 µM, 2.7µM and 0.5µM
respectively. The results are presented in Table 1 and are graphically presented in Fig.
PLSCDK11_12
1a and 1b.
Dose se studies at 72 hr in Detroit-562 cells showed that the Compound A, Compound B,
sorafenib and lapatinib inhibited 50% growth (IC50) at 1.3 µM, 14.1 µM, 6.1 µM and 3.9
µM respectively. The results are presented in Table 2 and are graphically presented in Fig. 2a
and 2b.
Dose response studies at 72 hr in FADU cells showed that compound A, compound B, sorafenib
and lapatinib inhibited 50% growth (IC50) at 1.3 µM, 4.1 µM, 8.4 µM and 2.6µM
respectively. The results are ted in Table 3 and are graphically presented in Fig. 3a and
Dose-response s at 72 hr in Detroit-562 cells showed that compound A and nib
inhibited 50% growth (IC50) at 1.3 µM, and 2.3 µM respectively. The results are presented in
Table 4 and are graphically presented in Fig. 4a.
Dose-response studies at 72 hr in FADU cells showed that the compound A and erlotinib
inhibited 50% growth (IC50) at 1.3 µM, and 10.2 µM respectively. The results are presented in
Table 5 and are cally presented in Fig. 4b.
Dose-response studies at 72 hr in Detroit-562 cells showed that cisplatin, compound A and 5-FU
inhibited 50% growth (IC50) at 14.6 µM, 1.3 µM, and 6.3 µM respectively. The results are
presented in Table 6 and are graphically ented in Fig. 5a.
Dose-response studies at 72 hr in FADU cells showed that the cisplatin, compound A and 5-FU
inhibited 50% growth (IC50) at 8.3 µM, 1.3 µM, and 11.6 µM respectively. The results are
presented in Table 7 and are graphically represented in Fig. 5b.
Dose-response studies at 72 hr in Detroit-562 cells showed that xel, cisplatin,
compound A and 5-FU inhibited 10% growth (IC10) at 0.009 µM, 0.3µM, 0.1 µM and 0.31µM
and 50% growth (IC50) at 0.85µM , 14.6µM, 1.3 µM, and 6.3 µM respectively. The results
are presented in Table 6 and are graphically represented in Fig. 5a.
Dose-response studies at 72 hr in FADU cells showed that docetaxel, cisplatin, nd A and
-FU inhibited 10% growth (IC10) at 0.003µM, 0.25µM, 0.08 µM, and 0.31 µM and 50%
PLSCDK11_12
growth (IC50) at 0.16 µM, 8.3 µM, 1.3 µM, and 11.6 µM respectively.
The results are presented in Table 7 and are cally represented in Fig. 5b.
Similarly the IC30, IC70 and IC90 concentrations for all the tested compounds (anticancer
compounds) were established from dose in which particular compound shows 30 %, 70% and
90% activity respectively in the cytotoxicity assay.
Table 1 - 30 %, 50%, 70% and 90% inhibitory concentrations (IC30, IC50, IC70
and IC90) of nd A, compound B, nib and lapatinib in SCC-25 cells.
SCC-25 cells (Inhibitory conc. in µM )
Anti-cancer agent IC30 IC50 IC70 IC90
Compound A 0.1 0.4 4.1 33.3
Compound B 0.2 1.1 4.8 41.8
nib 0.18 2.7 6.8 11.7
nib 0.2 0.5 3.3 9.9
Table 2 - 30 %, 50%, 70% and 90% inhibitory concentrations (IC30, IC50, IC70
and IC90) of compound A, compound B, sorafenib and lapatinib in Detroit-562 cells.
Detroit – 562 cells (Inhibitory conc. in µM )
Anti-cancer agent IC30 IC50 IC70 IC90
Compound A 0.5 1.3 12.1 26.3
Compound B 2.7 14.1 25.2 44.6
Sorafenib 1.8 6.1 11.2 15.3
Lapatinib 1.0 3.9 7.6 12.6
Table 3 - 30 %, 50%, 70% and 90% inhibitory concentrations (IC30, IC50, IC70
and IC90) of compound A, compound B, sorafenib and lapatinib in FADU cells.
FADU cells (Inhibitory conc. in µM )
Anti-cancer agent IC30 IC50 IC70 IC90
Compound A 0.2 1.3 8.3 28.3
Compound B 2.3 4.1 9.6 31.4
PLSCDK11_12
Sorafenib 3.9 8.4 14.8 30.6
Lapatinib 0.8 2.6 8.7 14.3
Table 4 – 30 %, 50%, 70% and 90% inhibitory trations (IC30, IC50, IC70
and IC90) of compound A and erlotinib in t-562 cells.
Detroit-562 cells (Inhibitory conc. In µM )
Anti-cancer agent
IC30 IC50 IC70 IC90
Compound A 0.5 1.3 12.1 26.3
Erlotinib 1.4 2.3 6.3 10.7
Table 5 – 30 %, 50%, 70% and 90% inhibitory concentrations (IC30, IC50, IC70
and IC90) of compound A and nib in FADU cells.
FADU cells (Inhibitory conc. In µM )
Anti-cancer agent
IC30 IC50 IC70 IC90
Compound A 0.2 1.3 8.3 28.3
Erlotinib 0.9 10.2 30.7 63
Table 6 – 10%, 30 %, 50%, 70% and 90% inhibitory concentrations (IC10, IC30, IC50,
IC70 and IC90) of cisplatin, compound A, 5-FU and docetaxel in Detroit-562 cells.
Detroit-562 cells (Inhibitory conc. In µM )
Anti-cancer agent
IC10 IC30 IC50 IC70 IC90
Cisplatin 0.3 3 14.6 43.2 74.5
Compound A 0.1 0.5 1.3 12.1 26.3
-FU 0.31 1.1 6.3 17.6 33.4
Docetaxel 0.009 0.3 0.85 8.7 21.8
FADU cells (Inhibitory conc. In µM )
Anti-cancer agent
IC10 IC30 IC50 IC70 IC90
PLSCDK11_12
Cisplatin 0.25 3 8.3 30 74
Compound A 0.08 0.2 1.3 8.3 28.3
-FU 0.31 2.3 11.6 22.4 38.3
Docetaxel 0.003 0.06 0.16 0.71 35.6
Table 7 – 10%, 30 %, 50%, 70% and 90% inhibitory concentrations (IC10, IC30, IC50,
IC70 and IC90) of cisplatin, compound A , 5-FU and docetaxel in FADU cells
Example 4
Combination studies of compound A and sorafenib in SCC-25, Detroit-562 and
FADU cells.
A) SCC-25 cells
Sorafenib in the following dose of final concentration 0.18 µM and compound A in the following
doses of final concentration 0.1 µM, 0.4 µM and 4.1 µM were analyzed in single dose and in all
possible combinations of the dose range for the two anticancer agents mentioned above. The
sequence of treatment is as follows; the SCC-25 cells were treated with sorafenib for 0 to 24
hrs. At the end of 24 hrs the cells were washed two times with plain MEM (minimum essential
media) medium. Fresh MEM with 10% serum (200µL/well) was added, followed by treatment
with compound A from 24 hrs to 96 hrs. The results are presented in the ing Table 8 and
graphically presented in figure 6a.
Sr. ncer agent (SCC-25 cells) % Cytotoxicity Combination
No. (Inhibitory conc. in µM) index
1 Sorafenib IC30 13 -
2 nd A IC30 13 -
3 Compound A IC50 24 -
4 Compound A IC70 29 -
Sorafenib IC30 + nd A IC30 77 0.31
6 Sorafenib IC30 + Compound A IC50 85 0.35
7 Sorafenib IC30 + Compound A IC70 88 0.41
B) Detroit-562 cells.
Sorafenib in the following dose of final concentration 1.8 µM and compound A in the following
doses of final concentration 0.5 µM, 1.3 µM and 12.1 µM were analyzed in single dose and in all
possible combinations of the dose range for the two anticancer agents ned above. The
sequence of ent is as follows; t-562 cells were treated with sorafenib for 0 to 24 hrs.
PLSCDK11_12
At the end of 24 hrs the cells were washed two times with plain MEM medium. Fresh MEM
with 10% serum (200µL/well) was added, followed by treatment with compound A from 24
hrs to 96 hrs. The results are presented in the following Table 9 and cally presented in
figure 7a.
Sr. Anticancer agent (Detroit- 562 cells) % Cytotoxicity ation
No. (Inhibitory conc. in µM) index
1 nib IC30 14 -
2 Compound A IC30 15 -
3 Compound A IC50 25 -
4 Compound A IC70 30 -
Sorafenib IC30 + Compound A IC30 78 0.35
6 Sorafenib IC30 + Compound A IC50 84 0.37
7 Sorafenib IC30 + Compound A IC70 86 0.39
C) FADU cells
Sorafenib in the following dose of final concentration 3.9 µM and compound A in the following
doses of final concentration 0.2 µM, 1.3 µM and 8.3 µM were analyzed in single dose and in all
possible combinations of the dose range for the two anticancer agents mentioned above. The
sequence of ent is as follows; the FADU cells were treated with nib for 0 to 24
hrs. At the end of 24 hrs the cells were washed two times with plain MEM medium. Fresh
MEM with 10% serum (200 µL/well) was added, followed by treatment with compound A from
24 hrs to 96 hrs. The results are presented in the following Table 10 and graphically presented in
figure 8a.
Sr. No. Anticancer agent % Cytotoxicity ation
(FADU cells) (Inhibitory conc. in µM) index
1 Sorafenib IC30 21 -
2 Compound A IC30 12 -
3 Compound A IC50 18 -
4 Compound A IC70 26 -
Sorafenib IC30 + Compound A IC30 64 0.56
6 nib IC30 + Compound A IC50 86 0.61
7 Sorafenib IC30 + Compound A IC70 92 0.63
Example 5
Combination studies of compound B and sorafenib in SCC-25, Detroit-562 and FADU
cells.
A) SCC-25 cells
Sorafenib in the following dose of final concentration 0.18 µM and compound B in the following
PLSCDK11_12
doses of final concentration 0.2 µM, 1.1 µM and 4.8 µM were analyzed in single dose and in all
possible combinations of the dose range for the two anticancer agents mentioned above. The
sequence of treatment is as follows; the SCC-25 cells were treated with sorafenib for 0 to 24 hrs.
At the end of 24 hrs the cells were washed two times with plain MEM medium. Fresh MEM
with 10% serum (200 µL/well) was added, followed by treatment with compound B from 24 hrs
to 96 hrs. The results are presented in the following Table 11 and graphically presented in figure
Sr. Anticancer agent (SCC-25 cells) % Cytotoxicity Combination
No. (Inhibitory conc. in µM) index
1 Sorafenib IC30 13 -
2 Compound B IC30 16 -
3 Compound B IC50 19 -
4 Compound B IC70 26 -
nib IC30 + Compound B IC30 48 0.68
6 Sorafenib IC30 + Compound B IC50 51 0.73
7 Sorafenib IC30 + Compound B IC70 56 0.81
B) t-562 cells
Sorafenib in the following dose of final concentration 1.8 µM and nd B in the ing
doses of final concentration 2.7 µM, 14.1 µM and 25.2 µM were analyzed in single dose and in
all possible combinations of the dose range for the two anticancer agents mentioned above. The
sequence of treatment is as follows; the t-562 cells were treated with sorafenib for 0 to 24
hrs. At the end of 24 hrs the cells were washed two times with plain MEM medium. Fresh
MEM with 10% serum (200 µL/well) was added, followed by treatment with compound B from
24 hrs to 96 hrs. The results are presented in the following Table 12 and graphically presented in
figure 7b.
Sr. No. Anticancer agent (Detroit- 562 cells) % Cytotoxicity Combination
(Inhibitory conc. in µM) index
1 nib IC30 13 -
2 Compound B IC30 15 -
3 Compound B IC50 19 -
4 Compound B IC70 26 -
nib IC30 + Compound B IC30 65 0.67
6 Sorafenib IC30 + Compound B IC50 74 0.73
7 Sorafenib IC30 + Compound B IC70 86 0.76
C) FADU cells
Sorafenib in the following dose of final concentration 3.9 µM and compound B in the following
PLSCDK11_12
doses of final tration 2.3 µM, 4.1 µM and 9.6 µM were analyzed in single dose and in all
possible combinations of the dose range for the two drugs mentioned above. The sequence of
treatment is as follows; the FADU cells were d with sorafenib for 0 to 24 hrs. At the
end of 24 hrs the cells were washed two times with plain MEM medium. Fresh MEM with
10% serum (200 µL/well) was added, followed by treatment with compound B from 24 hrs to
96 hrs. The results are presented in the following Table 13 and cally presented in figure
Sr. Anticancer agent % Cytotoxicity Combination
No. (FADU cells) (Inhibitory conc. in µM) index
1 Sorafenib IC30 21 -
2 Compound B IC30 14 -
3 Compound B IC50 20 -
4 Compound B IC70 27 -
Sorafenib IC30 + Compound B IC30 59 0.74
6 Sorafenib IC30 + Compound B IC50 77 0.81
7 nib IC30 + Compound B IC70 88 0.84
Example 6
Combination studies of compound A and lapatinib in SCC-25, Detroit-562 and FADU
cells.
A) SCC-25 cancer cells
nib in the following dose of final tration 0.2 µM and compound A in the following
doses of final concentration 0.2µM, 0.5 µM and 3.3 µM were analyzed in single dose and in all
possible combinations of the dose range for the two drugs mentioned above. The sequence of
treatment is as follows; the SCC-25 cells were treated with lapatinib for 0 to 24 hrs. At the end
of 24 hrs the cells were washed two times with plain MEM medium. Fresh MEM with 10%
serum (200 µL/well) was added, followed by ent with compound A from 24 hrs to 96
hrs. The results are presented in the following Table 14 and graphically presented in figure 9a.
Sr. Anticancer agent (SCC-25 cells) % Cytotoxicity Combination
No. (Inhibitory conc. in µM) index
1 Lapatinib IC30 17 -
PLSCDK11_12
2 Compound A IC30 12 -
3 Compound A IC50 23 -
4 nd A IC70 26 -
Lapatinib IC30 + Compound A IC30 69 0.68
6 Lapatinib IC30 + Compound A IC50 83 0.71
7 Lapatinib IC30 + Compound A IC70 89 0.75
B) Detroit-562 cancer cells
Lapatinib in the following dose of final concentration 1 µM and compound A in the ing
doses of final concentration 0.5 µM, 1.3 µM and 12.1 µM were analyzed in single dose and in all
possible ations of the dose range for the two anticancer agents mentioned above. The
ce of treatment is as follows; the Detroit-562 cells were treated with lapatinib for 0 to 24
hrs. At the end of 24 hrs the cells were washed two times with plain MEM medium. Fresh
MEM with 10% serum (200 µL/well) was added, ed by treatment with compound A from
24 hrs to 96 hrs. The results are presented in the following Table 15 and graphically presented in
figure 10a.
Sr. Anticancer agent (Detroit -562 cells) % Cytotoxicity ation
No. (Inhibitory conc. in µM) index
1 Lapatinib IC30 16 -
2 Compound A IC30 11 -
3 Compound A IC50 22 -
4 Compound A IC70 25 -
Lapatinib IC30 + Compound A IC30 68 0.81
6 Lapatinib IC30 + Compound A IC50 82 0.88
7 Lapatinib IC30 + Compound A IC70 88 0.71
C) FADU cancer cells
Lapatinib in the following dose of final concentration 0.8 µM and compound A in the following
doses of final concentration 0.2 µM, 1.3 µM and 8.3 µM were analyzed in single dose and in all
possible combinations of the dose range for the two drugs mentioned above. The sequence of
treatment is as follows; the FADU cells were d with lapatinib for 0 to 24 hrs. At the
end of 24 hrs the cells were washed two times with plain MEM medium. Fresh MEM with
% serum (200 µL/well) was added, followed by treatment with compound A from 24 hrs to
96 hrs. The results are presented in the following Table 16 and graphically presented in figure
11a.
PLSCDK11_12
Sr. Anticancer agent % Combination
No. (FADU cells) (Inhibitory conc. in µM ) Cytotoxicity index
1 Lapatinib IC30 19 -
2 Compound A IC30 13 -
3 nd A IC50 22 -
4 Compound A IC70 24 -
Lapatinib IC30 + Compound A IC30 62 0.64
6 Lapatinib IC30 + Compound A IC50 85 0.69
7 Lapatinib IC30 + Compound A IC70 89 0.83
Example 7
Combination studies of compound B and lapatinib in SCC-25, Detroit-562 and FADU
cells.
A) SCC-25 cancer cells
Lapatinib in the following dose of final concentration 0.2 µM and compound B in the following
doses of final concentration 0.2 µM, 1.1 µM and 4.8 µM were analyzed in single dose and in all
possible combinations of the dose range for the two drugs mentioned above. The sequence of
treatment is as follows; the SCC-25 cells were treated with lapatinib for 0 to 24 hrs. At the end
of 24 hrs the cells were washed two times with plain MEM medium. Fresh MEM with 10%
serum (200 µL/well) was added, followed by treatment with compound A from 24 hrs to 96
hrs. The results are ted in the following Table 17 and graphically presented in figure 9b.
Sr. Anticancer agent 5 cells) % Cytotoxicity Combination
No. (Inhibitory conc. in µM) index
1 Lapatinib IC30 17 -
2 Compound B IC30 16 -
3 Compound B IC50 19 -
4 Compound B IC70 31 -
Lapatinib IC30 + Compound B IC30 62 0.61
6 Lapatinib IC30 + nd B IC50 73 0.81
7 Lapatinib IC30 + Compound B IC70 77 0.84
B) Detroit-562 cancer cells
Lapatinib in the following dose of final concentration 1.0 µM and compound B in the following
doses of final concentration 2.7 µM, 14.1 µM and 25.2 µM were analyzed in single dose and in
all possible combinations of the dose range for the two drugs mentioned above. The ce of
treatment is as follows; the Detroit-562 cells were treated with lapatinib for 0 to 24 hrs. At the
end of 24 hrs the cells were washed two times with plain MEM medium. Fresh MEM with
10% serum (200 µL/well) was added, followed by ent with compound A from 24 hrs to
PLSCDK11_12
96 hrs. The results are presented in the following Table 18 and graphically presented in figure
10b.
Sr. Anticancer agent (Detroit -562 cells) % Cytotoxicity Combination
No. (Inhibitory conc. in µM) index
1 nib IC30 16 -
2 Compound B IC30 15 -
3 Compound B IC50 18 -
4 Compound B IC70 30 -
Lapatinib IC30 + nd B IC30 70 0.71
6 Lapatinib IC30 + nd B IC50 87 0.65
7 Lapatinib IC30 + Compound B IC70 90 0.77
C) FADU cancer cells
Lapatinib in the following dose of final concentration 0.8 µM and nd B in the following
doses of final concentration 2.3 µM, 4.1 µM and 9.6 µM were analyzed in single dose and in all
possible combinations of the dose range for the two anticancer agents mentioned above. The
sequence of treatment is as follows; the FADU cells were treated with lapatinib for 0 to 24
hrs. At the end of 24 hrs the cells were washed two times with plain MEM . Fresh
MEM with 10% serum (200µL/well) was added, followed by treatment with compound A from
24 hrs to 96 hrs. The results are presented in the ing Table 19 and graphically presented in
figure 11b.
Sr. ncer agent % Cytotoxicity Combination
No. (FADU cells) (Inhibitory conc. in µM) index
1 Lapatinib IC30 19 -
2 Compound B IC30 21 -
3 Compound B IC50 26 -
4 Compound B IC70 33 -
Lapatinib IC30 + Compound B IC30 74 0.78
6 Lapatinib IC30 + Compound B IC50 89 0.91
7 Lapatinib IC30 + Compound B IC70 93 0.71
Example 8
Combination studies of compound A and erlotinib at IC30 concentration in Detroit-
562 cells
The combination of erlotinib and compound A was found to be synergistic at the IC30 of both
the anticancer agents. Erlotinib at IC30 showed cytotoxicity of 20.3% and Compound A at IC30,
showed cytotoxicity of 8.30%. However, when used as a combination of erlotinib IC30 for 24 hrs,
PLSCDK11_12
followed by compound A IC30 for 48 hrs showed an increase in cytotoxicity to the extent of 60%
was noted, which is 32% more cytotoxicity than the additive effect suggesting a synergistic
effect between the two anticancer agents in Detroit-562 cells with a combination index of 0.35.
The results are presented in the following Table 20 and graphically presented in figure 12a.
Sr. Anticancer agent (Detroit 562 cells) % xicity Combination
No. (Inhibitory conc. in µM) index
1 Erlotinib IC30 20.3 -
2 Erlotinib IC50 34.4 -
3 Erlotinib IC70 40.0 -
4 nd A IC30 8.30 -
Compound A IC50 33.80 -
6 Compound A IC70 34.32 -
7 Erlotinib IC30 + Compound A IC30 60.64 0.35
8 Erlotinib IC30 + Compound AIC50 77.17 0.36
9 Erlotinib IC30 + Compound A IC70 76.89 0.89
Example 9
Combination studies of compound A and nib in FADU cells
The combination of erlotinib and Compound A was found to be synergistic at the IC30 of both the
anticancer agents. erlotinib at IC30 showed cytotoxicity of 16% and Compound A at IC30,
showed xicity of 12.3%. r, when used as a ation of erlotinib at
concentration IC30 for 24hrs, followed by compound A at IC30 concentration for 48 hrs
showed an increase in cytotoxicity to the extent of 77% was noted, which is 49% more
cytotoxicity than the additive effect suggesting a synergistic effect between the two drugs in
FADU cells with a combination index of 0.23. The results are presented in the following
Table 21 and graphically presented in figure 12b.
Sr. Anticancer agent % xicity Combination
No. (FADU cells) (Inhibitory conc. in µM) index
1 nib IC30 16.24 -
2 Erlotinib IC50 35.64 -
3 Erlotinib IC70 41.1 -
4 Compound A IC30 12.3 -
Compound A IC50 26.54 -
6 Compound A IC70 31.78 -
7 Erlotinib IC30 + Compound A IC30 77.191 0.23
8 Erlotinib IC30 + Compound A IC50 80.286 0.31
9 Erlotinib IC30 + Compound A IC70 84.134 0.67
PLSCDK11_12
In Vitro s Involving Use of Triple Combination Consisting of compound A, cisplatin
and 5-FU
Example 10
Combination studies of compound A, cisplatin and 5-FU at the IC30 in Detroit-562 cells.
The combination of compound A and (cisplatin and 5-FU) was found to be synergistic at the
IC30 of each ncer agents. Compound A at IC30 showed cytotoxicity of 10.4 % and
(cisplatin and 5-FU) at IC30, showed cytotoxicity of 28.60 %. However, when used as a
combination of (cisplatin and 5-FU) IC30 for 24hrs, followed by compound A IC30 for 48 hrs an
increase in cytotoxicity to the extent of 71% was noted, which was 33% more cytotoxicity than
the additive effect suggesting a synergistic effect between the three anticancer agents in
Detroit-562 cells with a combination index of 0.39. While the double combination Cisplatin
and 5-FU showed a combination index of 0.9. The results are presented in the following Table
22 and graphically ted in figure 13a.
Sr. Anticancer agent (Detroit 562 cells) % Combination
No. itory conc. in µM) Cytotoxicity index
1 Cisplatin IC30 4.07 -
2 Cisplatin IC50 14.3 -
3 Cisplatin IC70 16.2 -
4 5-FU IC90 12.59 -
5-FU IC50 16.21 -
6 5-FU IC70 19.54 -
7 Compound A IC30 10.42 -
8 Compound A IC50 12.59 -
9 Compound A IC70 18.02 -
Cisplatin IC30 + 5-FU IC30 28.67 0.9
11 tin IC30 + 5-FU IC50 32.86 1.21
12 Cisplatin IC30 + 5-FU IC70 26.38 1.45
13 Cisplatin IC30 + 5-FU IC30 + Compound A IC30 68.38 0.22
14 Cisplatin IC30 + 5-FU IC50+ Compound A IC30 81.68 0.31
Cisplatin IC30+ 5-FU IC70 + Compound A IC30 75.22 0.39
16 Cisplatin IC30+ 5-FU IC30 + Compound A IC50 77.30 0.56
17 Cisplatin IC30) + 5-FU IC30+ Compound A IC70 75.75 0.64
Example 11
Combination studies of compound A, tin and 5-FU at the IC30 in FADU cells.
The ation of compound A and (cisplatin and 5-FU) was found to be synergistic at the
IC30 of each anticancer agent. Compound A at IC30 showed cytotoxicity of 6.1% and (cisplatin
PLSCDK11_12
and 5-FU) at IC30, showed cytotoxicity of 30.1%. However, when used as a combination of
(cisplatin and 5-FU) at IC30 concentration for 24hrs, followed by compound A IC30 for 48hrs,
an increase in cytotoxicity to the extent of 81% was noted, which was 44% more cytotoxicity
than the additive effect suggesting a synergistic effect between the three drugs in FADU cells
with a combination index of 0.23. While the double combination tin and 5-FU showed a
combination index of 0.89. The s are presented in the following Table 23 and graphically
presented in figure 13b.
Sr. Anticancer agent (FADU cells) % Combination
No. (Inhibitory conc. in µM) Cytotoxicity index
1 Cisplatin IC30 6.2 -
2 Cisplatin IC50 11.1 -
3 Cisplatin IC70 17.1 -
4 5-FU IC30 17.81 -
5-FU IC50 21.1 -
6 5-FU IC70 28.6 -
7 Compound A IC30 6.1 -
8 Compound A IC50 21.4 -
9 Compound A IC70 27.8 -
Cisplatin IC30 + 5-FU IC30 30.8 0.89
11 Cisplatin IC30 + 5-FU IC50 34.53 1.15
12 Cisplatin IC30 + 5-FU IC70 42.82 1.31
13 Cisplatin IC30+ 5-FU IC30 + nd A IC30 67.73 0.56
14 Cisplatin IC30+ 5-FU IC50 + Compound A IC30 72.43 0.67
Cisplatin IC30 + 5-FU IC70+ Compound A IC30 72.94 0.78
18 Cisplatin IC30 + 5-FU IC30 + Compound A IC50 82.40 0.31
19 Cisplatin IC30+ 5-FU IC30 + Compound A IC70 83.13 0.41
Example 12
Combination s of nd A, tin and 5-FU with docetaxel at the IC30
concentration in Detroit-562 cells.
The combination of compound A and (cisplatin and 5-FU) with Docetaxel was found to be
synergistic at the IC30 of each anticancer agent. nd A and Docetaxel at IC30 showed
cytotoxicity of 16.8% and 18.30 respectively (cisplatin and 5-FU) at IC30, showed cytotoxicity
of 31.3%. However, when used as a combination of Docetaxel at IC30 concentration for 12 hrs
followed by (cisplatin and 5-FU) at IC30 concentration for 12hrs, followed by compound A at
IC30 concentration for 48hrs an increase in cytotoxicity to the extent of 96.38 % was noted,
with a ation index of 0.29. The results are presented in the following Table 24 and
graphically presented in figure 14a.
PLSCDK11_12
Sr. Combination
Anticancer agent (Detroit 562 cells)
% Cytotoxicity index
No. (Inhibitory conc. in µM)
(C.I. values)
1 Docetaxel IC10 11.75 --
2 Docetaxel IC30 18.30 --
3 Cisplatin IC10 6.92 --
4 Cisplatin IC30 13.39 --
5-FU IC10 9.49 --
6 5-FU IC30 15.39 --
Compound A IC30 16.81 --
8 Compound A IC50 21.98 --
9 Cisplatin IC10 + 5FU IC10 33.09 0.91
Cisplatin IC30 + 5FU IC30 31.92 1.1
Docetaxel IC10 + (Cisplatin IC10 + 5FU IC10) 56.85 0.85
12 Docetaxel IC10 + atin IC30 + 5FU IC30) 61.77 0.93
Docetaxel IC30 + atin IC10 + 5FU IC10) 66.59 0.87
Docetaxel IC30 + (Cisplatin IC30 + 5FU IC30) 71.81 0.81
Docetaxel IC10 + (Cisplatin IC10 + 5FU IC10)
81.42 0.67
+ nd A IC30
18 Docetaxel IC10 + (Cisplatin IC30 + 5FU IC30)
89.46 0.62
+ nd A IC30
19 Docetaxel IC30 + (Cisplatin IC10 + 5FU IC10)
91.47 0.37
+ Compound A IC30
Docetaxel IC30 + (Cisplatin IC30 + 5FU IC30)
96.38 0.29
+ Compound A IC30
Example 13
Combination studies of nd A, cisplatin and 5-FU with docetaxel at the
IC30 concentration in FADU cells.
The combination of compound A and (cisplatin and 5-FU) with docetaxel was found to be
synergistic at the IC30 of each anticancer agent. Compound A and docetaxel at IC30
concentration showed cytotoxicity of 11.77% and 20.02 respectively. (cisplatin and 5- FU) at
IC30 concentration, showed cytotoxicity of 51.39%. However, when used as a combination of
PLSCDK11_12
docetaxel at IC30 concentration for 12 hrs followed by (cisplatin and 5- FU) at IC30 concentration
for 12hrs, followed by compound A at IC30 concentration for 48 hrs an increase in
cytotoxicity to the extent of 98.24% was noted, with a combination index of 0.12. The
results are presented in the following Table 25 and graphically presented in figure 14b.
Anticancer agent (FADU cells) Combination index
% xicity
(Inhibitory conc. in µM) (C.I. values)
Docetaxel IC10 14.69 --
Docetaxel IC30 20.02 --
Cisplatin IC10 9.16 --
Cisplatin IC30 9.08 --
-FU IC10 6.81 --
-FU IC30 19.29 --
Compound A IC30 11.77 --
Compound A IC50 23.86 --
Cisplatin IC10 + 5FU IC10 39.03 1.15
Cisplatin IC30 + 5FU IC30 51.39 0.91
Docetaxel IC10 + (Cisplatin IC10 + 5FU
59.95 0.94
IC10)
Docetaxel IC10 + (Cisplatin IC30 + 5FU
70.28 0.89
IC30)
xel IC30 + (Cisplatin IC10 + 5FU
71.16 0.84
IC10)
Docetaxel IC30 + (Cisplatin IC30 + 5FU
67.80 0.85
IC30)
Docetaxel IC10 + (Cisplatin IC10 + 5FU
74.93 0.63
IC10) + Compound A IC30
Docetaxel IC10 + (Cisplatin IC30 + 5FU
84.83 0.67
IC30) + Compound A IC30
Docetaxel IC30 + (Cisplatin IC10 + 5FU
92.67 0.31
IC10) + Compound A IC30
xel IC30 + (Cisplatin IC30 + 5FU
98.24 0.12
IC30) + Compound A IC30
Example 14
Analysis of cleaved Caspase-3 expression levels
This study was ted to evaluate the mechanisms by which the combination
PLSCDK11_12
consisting of sorafenib or lapatinib in combination with compound A or compound B blocks
proliferation and whether it can induce apoptosis in head and neck cancer cells. The cells were
seeded in l plates at a density of 7.5 X 103 cells/well. 24 h post seeding, the minimum
essential medium was replaced with a fresh minimum essential medium with 10% serum. The
anticancer agents (sorafenib or lapatinib in combination with compound A or nd B)
were treated with specific concentration as mentioned below in SCC-25, Detroit-562 and
FADU cells and incubated for 48 hrs. At the end of 48 hrs, to determine the protein expression,
the cells were in 96 well plate spin down at 800g for 5 minutes. Culture supernatant was
removed and 200 µL of caspase-3 assay buffer was added and plates were again spin
down at 800g for 5 minutes. Supernatant were removed and cells were lysed with 100 µL
caspase-3 lysis buffer and incubated for 30 min in l shaker at 300 rpm at room
temperature. Further plates were spin down at 800g for 10 minutes and 90 µL of the
atant was erred into new black well plate. To 90 µL of lysis solution 100 µL
of caspase-3 substrate was added and incubated for 30 minutes at 37’C. At the end of
incubation plates were read in Tecan Safire multimode reader with an excitation wavelength of
485 nm and emission wavelength of 535 nm.
A) Treatment pattern of sorafenib and nd A or compound B in SCC-25 cells for
assessing caspase-3 activity
The treatment with sorafenib for 24 hrs ed by either nd A or compound B for 48
hrs showed notable elevation of caspase3 expression than when used alone. It was also
ed that both compound A or compound B were more potent in inducing caspase-3
activity in combination as graphically represented in Fig 15a and Fig. 15b.
B) Treatment pattern of lapatinib and nd A or compound B in SCC-25 cells for
assessing caspase-3 activity
The treatment with nib for 24 hrs followed by either compound A or compound B for 48
hrs showed notable elevation of caspase3 expression than when used alone. It was also
observed that both compound A or compound B were more potent in inducing caspase-3
activity in ation as graphically represented in Fig. 16a and Fig. 16b.
Example 15
In vivo efficacy studies in human head and neck cancer FaDu (Hypopharyngeal squamous
cell carcinoma) xenografts
In-vivo studies were carried out according to the method described in Clinical cancer search,
2003,9, 6052-6061; the disclosure of which is incorporated herein by nce for the teaching
PLSCDK11_12
of the assay.
Objective
The objective of this study was to evaluate the antitumor activity of Compound A in
combination with cetuximab or in combination with both, cisplatin and cetuximab in human
head and neck cancer xenograft model of FaDu.
The in-vivo studies were carried out using Xenograft models in Severe combined immune
deficiency (SCID) mice strain –CbySmn.CB17-Prkdcscid /J, by the method described below.
The statistically icant number of mice per group (n=6) was chosen in order to be able to
statistically evaluate the study data.
Method
FaDu cells were grown in MEM um essential media) medium containing non-essential
amino acids and 10 % fetal calf serum in 5 % CO2 incubator at 37 °C. Cells were pelleted by
centrifugation at 1000 rpm for 10 minutes. Cells were resuspended in pre-chilled mixture of
saline to get a count of 6 x 106 cells per mL; 0.2 ml of this cell suspension was kept on ice and
injected by subcutaneous (s.c.) route in SCID mice. Mice were observed every alternate day for
palpable tumor mass. Once the tumor size reached a size of 3-5 mm in diameter, animals were
ized into respective groups of treatment and untreated controls. The ent groups
comprised of 5 groups viz. 1) nd A alone (Group 1); 2) cetuximab alone (Group 2); 3)
cisplatin alone (Group 3); 4) nd A + cetuximab (Group 4); and 5) Compound A +
cisplatin + cetuximab (Group 5). The control group received no treatment. In single drug
treatment i.e. in respect of Groups 1, 2 and 3, the nd A (35 mpk) was administered by
i.p route once daily for 5 days a week starting from day 1 of the week for 3 weeks with total of
doses; Cisplatin (1 mpk) was administered i.p. once a week on day 1 of the week with total of
3 doses. Cetuximab (2.5 mpk) was administered twice a week on days 1 and 4 of the week for 3
weeks with total of 6 doses. In the treatment with ation of drugs namely compound A
and cetuximab, the sequence that was followed included administration of nd A for 2h
followed by cetuximab :
In the treatment with combination of drugs namely compound A, cisplatin and cetuximab, the
sequence that was followed included administration of cisplatin for 2h followed by the
Compound A for 2h, followed by cetuximab. Measurement of tumor was done every 2-3 days
PLSCDK11_12
apart. Growth inhibition percentage (GI %) was calculated at the end of experiment.
Terminal procedures:
At the end of the experiment, animals were euthanized using high dose of pentobarbital sodium
(100 mg/kg i.p./i.v.) or exposure to carbon dioxide gas.
Results
The results are as presented in Table 26 and cally presented in Figure 17a. The Figure 17a
depicts the average group body weight over the period of drug (the eutic agents)
administration d. Figure 17b s the average % tumor weight of Head and Neck
carcinoma (Fadu) xenograft over a period of 18 days.
Table 26: Percent tumor growth inhibition at the end of treatment i.e. after 18 days.
Groups Tumor Growth inhibition (%)
Group 1 (Compound A ) 11
Group 2 (cisplatin) 4
Group 3 (cetuximab ) 45
Group 4 (combination of 79
Compound A and cetuximab)
Group 5 (combination of cisplatin, 77
Compound A and cetuximab)
The tumor growth inhibition was highly significant with p < 0.001 in the treatment groups
namely Group(s) 4 and 5 involving use of combination of antineoplastic agents with tumor
growth (TG) tion of 79% and. 77% respectively. There was no significant body weight loss
in all the treatment groups.
Conclusion
The combination of Compound A and cetuximab and the combination of Compound A,
cetuximab and cisplatin showed similar antitumor activity in the human head and neck cancer
xenograft model of FaDu and were significantly higher than either of the drugs alone.
PLSCDK11_12
Having thus bed in detail various embodiments of the present invention, it is to be
understood that the invention defined by the above paragraphs is not to be limited to particular
details set forth in the above description as many nt variations thereof are possible without
departing from the spirit or scope of the present invention.
PLSCDK11_12
Claims (11)
1. Use of a ceutical composition comprising a therapeutically effective amount of a CDK inhibitor selected from the compounds of formula I; wherein Ar is a phenyl group, which is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from halogen; nitro, cyano, C1-C4-alkyl, oromethyl, hydroxyl or alkoxy; or a pharmaceutically acceptable salt or solvate thereof; in combination with a therapeutically effective amount of one or more antineoplastic agents 10 selected from sorafenib, lapatinib, erlotinib, cisplatin, 5-fluorouracil, docetaxel or cetuximab, for the cture of a medicament for the treatment of squamous cell carcinoma of head and neck.
2. Use of a pharmaceutical composition according to claim 1, wherein in the compound 15 of formula I the phenyl group is substituted by 1, 2, or 3 identical or different substituents selected from: chlorine, bromine, fluorine or iodine, C1-C4-alkyl or trifluoromethyl; or a pharmaceutically acceptable salt or solvate thereof.
3. Use of a pharmaceutical composition ing to claim 2, wherein in the compound of 20 formula I the phenyl group is tuted by chlorine.
4. Use of a pharmaceutical composition according to claim 3, n the compound of formula I is (+)-trans(2-chloro-phenyl)-5,7-dihydroxy(2-hydroxymethylmethylpyrrolidinyl menone hydrochloride (Compound A).
5. Use of a ceutical composition according to claim 2, wherein in the compound of formula I the phenyl group is a substituted group substituted by 2 different substituents selected from chlorine and trifluoromethyl. PLSCDK11_12
6. Use of a pharmaceutical composition according to claim 5, wherein the compound of formula I is (+)-trans(2-chlorotrifluoromethyl-phenyl)-5,7-dihydroxy(2- hydroxymethylmethyl-pyrrolidinyl)-chromenone hydrochloride (Compound B).
7. Use of a pharmaceutical ition according to any one of the preceding claims 1 to 6, wherein said oplastic agent is sorafenib.
8. Use of a pharmaceutical composition according to any one of the preceding claims 1 to 10 6, wherein said antineoplastic agent is lapatinib.
9. Use of a ceutical composition ing to any one of the preceding claims 1 to 6, wherein said antineoplastic agent is erlotinib. 15
10. Use of a pharmaceutical composition according to any one of the preceding claims 1 to 6, wherein said antineoplastic agents are cisplatin and 5-fluorouracil.
11. Use according to any of claims 1 to 10 substantially as herein described with reference to any example thereof and with or without nce to the accompanying figures.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161491569P | 2011-05-31 | 2011-05-31 | |
US61/491,569 | 2011-05-31 | ||
PCT/IB2012/052698 WO2012164497A1 (en) | 2011-05-31 | 2012-05-30 | A synergistic pharmaceutical combination for the treatment of squamous cell carcinoma of head and neck |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ619488A NZ619488A (en) | 2015-09-25 |
NZ619488B2 true NZ619488B2 (en) | 2016-01-06 |
Family
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