NZ623622B2 - Combination therapy for ovarian cancer - Google Patents
Combination therapy for ovarian cancer Download PDFInfo
- Publication number
- NZ623622B2 NZ623622B2 NZ623622A NZ62362212A NZ623622B2 NZ 623622 B2 NZ623622 B2 NZ 623622B2 NZ 623622 A NZ623622 A NZ 623622A NZ 62362212 A NZ62362212 A NZ 62362212A NZ 623622 B2 NZ623622 B2 NZ 623622B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- gemcitabine
- cisplatin
- administered
- platinum agent
- imidazo
- Prior art date
Links
- 206010033128 Ovarian cancer Diseases 0.000 title claims abstract description 24
- 238000002648 combination therapy Methods 0.000 title description 5
- SDUQYLNIPVEERB-QPPQHZFASA-N Gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 claims abstract description 76
- 229960005277 gemcitabine Drugs 0.000 claims abstract description 76
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims abstract description 70
- LXZZYRPGZAFOLE-UHFFFAOYSA-L transplatin Chemical compound [H][N]([H])([H])[Pt](Cl)(Cl)[N]([H])([H])[H] LXZZYRPGZAFOLE-UHFFFAOYSA-L 0.000 claims abstract description 50
- 229960004316 cisplatin Drugs 0.000 claims abstract description 48
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 35
- 229910052697 platinum Inorganic materials 0.000 claims abstract description 35
- 229960004562 Carboplatin Drugs 0.000 claims abstract description 30
- OLESAACUTLOWQZ-UHFFFAOYSA-L Carboplatin Chemical compound O=C1O[Pt]([N]([H])([H])[H])([N]([H])([H])[H])OC(=O)C11CCC1 OLESAACUTLOWQZ-UHFFFAOYSA-L 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 28
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- 239000003814 drug Substances 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- CQVKMVQRSNNAGO-UHFFFAOYSA-N 2-[4-formyl-3-methyl-N-(2-methylsulfonyloxyethyl)anilino]ethyl methanesulfonate Chemical class CC1=CC(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)=CC=C1C=O CQVKMVQRSNNAGO-UHFFFAOYSA-N 0.000 claims description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-Aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 1
- 201000011510 cancer Diseases 0.000 abstract description 5
- XPPBBJCBDOEXDN-UHFFFAOYSA-N 5-[2-tert-butyl-4-(4-fluorophenyl)-1H-imidazol-5-yl]-3-(2,2-dimethylpropyl)imidazo[4,5-b]pyridin-2-amine Chemical compound N1=C2N(CC(C)(C)C)C(N)=NC2=CC=C1C=1N=C(C(C)(C)C)NC=1C1=CC=C(F)C=C1 XPPBBJCBDOEXDN-UHFFFAOYSA-N 0.000 abstract 2
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- 229960005144 Gemcitabine hydrochloride Drugs 0.000 description 1
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- 229940098779 methanesulfonic acid Drugs 0.000 description 1
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- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
- A61K31/282—Platinum compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
The disclosure relates to the use of 5-[2-tert-butyl-5-(4-fluoro-phenyl)-1H-imidazol-4-yl]-3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin-2-ylamine (also called ralimetinib or LY2228820) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of ovarian cancer wherein said medicament is to be administered in combination with gemcitabine and a platinum agent selected from cisplatin and carboplatin. cancer wherein said medicament is to be administered in combination with gemcitabine and a platinum agent selected from cisplatin and carboplatin.
Description
COMBINATION THERAPY FOR OVARIAN CANCER
Ovarian cancer is the second most common gynecologic cancer and the deadliest
in terms of absolute number. Treatment usually involves chemotherapy and surgery, and
sometimes radiotherapy.
Unfortunately, a cure for ovarian cancer still remains elusive and there exists a
need for more and different therapies that may prove to be effective in treating ovarian
cancer. It is an object of the present invention to go some way towards meeting this need,
and/or to at least provide the public with a useful choice.
Several classes of anti-cancer drugs used to treat various types of cancers
including ovarian cancer have been identified, including platinum containing drugs and
pyrimidine analogs. Cisplatin (also known as cisplatinum or cis-
diamminedichloroplatinum(II)) was the first member of a class of platinum-containing
anti-cancer drugs, which now also includes carboplatin. These platinum complexes react
in vivo, binding to and causing crosslinking of DNA, which ultimately triggers apoptosis
(programmed cell death).
Gemcitabine hydrochloride (hereafter referred to as gemcitabine) is a pyrimidine
analog. It is currently used to treat various types of cancers including in combination
with carboplatin for the treatment of ovarian cancer.
While it is reported in the literature that gemcitabine plus cisplatin is a well
tolerated and active regimen in patients with recurrent ovarian cancer, the present
inventors have discovered that when these agents are used in combination with 5-[2-tert-
butyl(4-fluoro-phenyl)-1H-imidazolyl](2,2-dimethyl-propyl)-3H-imidazo[4,5-
b]pyridinylamine, a compound disclosed in US 7,582,652 that is currently undergoing
clinical investigation as a possible treatment for a variety of cancer indications, the triple
combination provides an improvement in efficacy over the combination of gemcitabine
plus cisplatin.
-[2-tert-butyl(4-fluoro-phenyl)-1H-imidazolyl](2,2-dimethyl-propyl)-3H-
imidazo[4,5-b]pyridinylamine
Furthermore, since the combination of carboplatin and gemcitabine are also
currently used for the treatment of ovarian cancer, and it is also reported in the literature
that comparable efficacy is seen in the treatment of ovarian cancer between carboplatin
compared to cisplatin (however with less toxicity observed with carboplatin), the current
inventors conclude that the triple combination of gemcitabine, carboplatin, and 5-[2-tert-
butyl(4-fluoro-phenyl)-1H-imidazolyl](2,2-dimethyl-propyl)-3H-imidazo[4,5-
b]pyridinylamine may be more efficacious than a combination of gemcitabine and
carboplatin along with the potential benefit of reduced toxicity by administering
carboplatin instead of cisplatin.
Described herein is a method of treating ovarian cancer in a mammal comprising
administering a combination of gemcitabine, a platinum agent selected from the group
consisting of cisplatin and carboplatin, and 5-[2-tert-butyl(4-fluoro-phenyl)-1H-
imidazolyl](2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridinylamine or a
pharmaceutically acceptable salt. In a further embodiment, administration is on the same
day. In another further embodiment, the administration is during a 21-day treatment
cycle. In another further embodiment, gemcitabine and the platinum agent are
administered up to 2 days after 5-[2-tert-butyl(4-fluoro-phenyl)-1H-imidazolyl]
(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridinylamine or a pharmaceutically
acceptable salt is administered and gemcitabine is administered again up to 7 days later.
In another further embodiment, the pharmaceutically acceptable salt is the
dimethanesulfonate salt.
Described herein is a method of treating ovarian cancer in a mammal undergoing
concurrent therapy with 5-[2-tert-butyl(4-fluoro-phenyl)-1H-imidazolyl](2,2-
dimethyl-propyl)-3H-imidazo[4,5-b]pyridinylamine or a pharmaceutically acceptable
salt thereof comprising administering a combination of gemcitabine and a platinum agent
selected from the group consisting of cisplatin and carboplatin. In a further embodiment,
the pharmaceutically acceptable salt is the dimethanesulfonate salt.
Described herein is a method of treating ovarian cancer in a mammal undergoing
concurrent therapy with 5-[2-tert-butyl(4-fluoro-phenyl)-1H-imidazolyl](2,2-
dimethyl-propyl)-3H-imidazo[4,5-b]pyridinylamine or a pharmaceutically acceptable
salt thereof and a platinum agent selected from the group consisting of cisplatin and
carboplatin comprising administering gemcitabine. In a further embodiment, the
pharmaceutically acceptable salt is the dimethanesulfonate salt.
Described herein is a method of treating ovarian cancer in a mammal undergoing
concurrent therapy with 5-[2-tert-butyl(4-fluoro-phenyl)-1H-imidazolyl](2,2-
dimethyl-propyl)-3H-imidazo[4,5-b]pyridinylamine or a pharmaceutically acceptable
salt thereof and gemcitabine comprising administering a platinum agent selected from the
group consisting of cisplatin and carboplatin. In a further embodiment, the
pharmaceutically acceptable salt is the dimethanesulfonate salt.
Described herein is a method of treating ovarian cancer in a mammal undergoing
concurrent therapy with gemcitabine and a platinum agent selected from the group
consisting of cisplatin and carboplatin comprising administering 5-[2-tert-butyl(4-
fluoro-phenyl)-1H-imidazolyl](2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridin
ylamine or a pharmaceutically acceptable salt thereof. In a further embodiment, the
pharmaceutically acceptable salt is the dimethanesulfonate salt.
Described herein is 5-[2-tert-butyl(4-fluoro-phenyl)-1H-imidazolyl](2,2-
dimethyl-propyl)-3H-imidazo[4,5-b]pyridinylamine, or a pharmaceutically acceptable
salt thereof, for use in combination therapy with gemcitabine and a platinum agent
selected from cisplatin and carboplatin in the treatment of ovarian cancer. In a further
embodiment, the administration of 5-[2-tert-butyl(4-fluoro-phenyl)-1H-imidazolyl]-
3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridinylamine, or a pharmaceutically
acceptable salt thereof, precedes that of gemcitabine and the platinum agent. In another
further embodiment, the administration of 5-[2-tert-butyl(4-fluoro-phenyl)-1H-
imidazolyl](2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridinylamine, or a
pharmaceutically acceptable salt thereof, gemcitabine and the platinum agent is within 24
hours. In another further embodiment, gemcitabine and the platinum agent are
administered up to 2 days after administration of 5-[2-tert-butyl(4-fluoro-phenyl)-1H-
imidazolyl](2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridinylamine, or a
pharmaceutically acceptable salt thereof, and gemcitabine is administered again up to 7
days later. In another further embodiment, administration of gemcitabine and the
platinum agent precedes that of 5-[2-tert-butyl(4-fluoro-phenyl)-1H-imidazolyl]
(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridinylamine, or a pharmaceutically
acceptable salt thereof. In another further embodiment, gemcitabine and the platinum
agent are administered simultaneously. In another further embodiment, the platinum
agent is cisplatin. In another further embodiment, the platinum agent is carboplatin. In
another further embodiment, the administration is during a 21-day treatment cycle. In
another further embodiment, the pharmaceutically acceptable salt is the
dimethanesulfonate salt.
The present invention relates to the use of 5-[2-tert-butyl(4-fluoro-phenyl)-1H-
imidazolyl](2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridinylamine, or a
pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the
treatment of ovarian cancer wherein said medicament is to be administered in
combination with gemcitabine and a platinum agent selected from cisplatin and
carboplatin. In a further embodiment, the administration of 5-[2-tert-butyl(4-fluoro-
phenyl)-1H-imidazolyl](2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridinylamine
or a pharmaceutically acceptable salt precedes that of gemcitabine and the platinum agent.
In another further embodiment, the administration of 5-[2-tert-butyl(4-fluoro-phenyl)-
1H-imidazolyl](2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridinylamine or a
pharmaceutically acceptable salt, gemcitabine, and the platinum agent is within 24 hours.
In another further embodiment, gemcitabine and the platinum agent are administered up
to 2 days after 5-[2-tert-butyl(4-fluoro-phenyl)-1H-imidazolyl](2,2-dimethyl-
propyl)-3H-imidazo[4,5-b]pyridinylamine or a pharmaceutically acceptable salt is
administered and gemcitabine is administered again up to 7 days later. In another further
embodiment, administration of gemcitabine and the platinum agent precedes that of 5-[2-
tert-butyl(4-fluoro-phenyl)-1H-imidazolyl](2,2-dimethyl-propyl)-3H-
imidazo[4,5-b]pyridinylamine or a pharmaceutically acceptable salt thereof. In
another further embodiment, gemcitabine and the platinum agent are administered
simultaneously. In another further embodiment the platinum agent is cisplatin. In
another further embodiment the platinum agent is carboplatin. In another further
embodiment thereof, the administration is during a 21-day treatment cycle. In another
further embodiment, the pharmaceutically acceptable salt is the dimethanesulfonate salt.
In the description in this specification reference may be made to subject matter
which is not within the scope of the appended claims. That subject matter should be
readily identifiable by a person skilled in the art and may assist in putting into practice the
invention as defined in the appended claims.
-[2-Tert-butyl(4-fluoro-phenyl)-1H-imidazolyl](2,2-dimethyl-propyl)-
3H-imidazo[4,5-b]pyridinylamine can be made according to the procedures as
described in US 7,582,652. Alternatively, the molecule can be made following
procedures provided herein. The reagents and starting materials are readily available to
one of ordinary skill in the art or may be made by procedures which are selected from
standard techniques of organic and heterocyclic chemistry, or techniques which are
analogous to the syntheses of known structurally similar compounds. The naming of the
following Preparations and Reference Example 1 is generally done using the IUPAC naming
feature in Symyx Isentris® version 3.2.
Preparation 1
6-Chloro-N-(2,2-dimethylpropyl)nitro-pyridinamine
Cl N N
2,6-Dichloronitropyridine (30 g,152.34 mmol) is dissolved in methyl tert-butyl
ether (300 mL) to obtain a yellow solution which is then cooled to 0–5 °C. To this
solution is added triethylamine (20 mL, 143.49 mmol), followed by a slow addition of
neopentylamine (16 mL, 136.40 mmol). After the addition is complete the reaction
mixture is stirred at 5 °C for 2 hours and then at room temperature overnight. The next
day (after about 18 hours) the reaction is shown as complete by thin layer
chromatography (20% ethyl acetate in hexane). The reaction mixture is washed with
water (100 mL) and brine (100 mL). The organic portion is dried over MgSO , filtered,
and then concentrated to a residue. Isopropyl alcohol (20 mL) is added. Crystals appear
and are collected by filtration with washing using cold isopropyl alcohol (15 mL) to
obtain the title compound (32 g, 86%).
Preparation 2
-Chloro(2,2-dimethylpropyl)imidazo[4,5-b]pyridinamine hydrobromide
Cl N
6-Chloro-N-(2,2-dimethylpropyl)nitro-pyridinamine (24.4 g, 0.10 mol) is
charged into a 1 L autoclave with toluene (300 mL).
In a beaker 5% Pt/C (1.5 g) is mixed with water (12 mL) and 50%
hypophosphorous acid (0.25 mL) with stirring for 10 minutes. The Pt/C catalyst
preparation is charged into the autoclave. The reaction mixture is heated to 75 C at 50
psi of hydrogen. After 3 hours, GC analysis indicates the starting material is less than 1%
present. The reaction is stopped and cooled down to room temperature. The reaction
mixture is filtered through a pad of CELITE and the filter cake rinsed with methanol.
The filtrate containing the product, 6-chloro-N2-(2,2-dimethylpropyl)pyridine-2,3-
diamine, is concentrated under vacuum to a volume of about 100 mL and used directly in
the cyclization without further purification.
The above solution is diluted with methanol (150 mL) and cooled in an ice bath.
Cyanogen bromide (11 g, 0.105 mol) is added in one portion. The reaction is allowed to
warm to ambient temperature with stirring as the ice bath warms up. The reaction is
complete after about 5 to 10 hours.
The reaction mixture is concentrated under vacuum to about 4 volumes (to collect
about 6 volumes of distillate) under vacuum. Methyl tert-butyl ether (6 volumes, 180
mL) is added. The mixture is cooled in an ice bath and stirred for 1 hour. The material is
filtered to provide the title compound (22.0 g, 76%) as an off-white solid.
Preparation 3
3-(2,2-Dimethylpropyl)[(E)(4-fluorophenyl)vinyl]imidazo[4,5-b]pyridinamine
Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (CAS
No: 8879199) (100.4 mg, 141.8 µmol) is charged to a pear shaped flask and the solid
deoxygenated with 5 vacuum/nitrogen cycles. 1-Butanol (55 mL) is added and then the
flask contents are deoxygenated with 3 vacuum (30 sec each)/nitrogen cycles followed by
2 more vacuum (60 sec each)/nitrogen cycles with stirring. A complete solution is not
achieved, but rather a hazy mixture.
To a 3-neck, round-bottomed flask equipped with a Claisen adapter, mechanical
stirrer, thermocouple, reflux condenser, and rubber septum is added 5-chloro(2,2-
dimethylpropyl)imidazo[4,5-b]pyridinamine hydrobromide (22.65 g, 70.9 mmol), and
then the headspace is deoxygenated with a slight nitrogen sweep for 15 minutes. To the
fluffy white solid is added 1-butanol (46 mL), diisopropylethylamine (34.48 g, 46.5 mL,
266.8 mmol), and 4-fluorostyrene (11.66 g; 11.4 mL, 95.5 mmol), each via syringe. After
deoxygenating this mixture by sparging with nitrogen for 40 minutes, the catalyst/butanol
mixture is added via syringe. The slurry is sparged for 10 minutes with nitrogen, and then
the headspace is swept for 5 minutes with nitrogen. The reaction is allowed to stir at
118–120° C overnight. After 18 hours, the mixture is cooled with stirring. Precipitation
or crystallization occurs between 45 °C and 70 °C. Starting at a temperature of 41 °C,
deionized water (100 mL) is added dropwise over 10 minutes to yield a slurry. After
stirring and cooling to 26 °C, an ice bath is applied for cooling the flask contents. After 1
hour, ethanol and more ice are added to the bath and the temperature is lowered to -2 °C.
The mixture is held at -2 to -5 °C for 1 hour, then filtered through a polypropylene pad
(good filtration), rinsed with deionized water (4 volumes), followed by heptane (3
volumes). The material is pulled air dry by vacuum for 10 minutes and further dried in a
vacuum oven at 40 °C to provide the title compound as an off-white solid (20.25 g, 88%).
H NMR (300 MHz, DMSO-d ): 7.51 (m, 2H); 7.41 (d, 1H); 7.32 (d, 1H); 7.19 (m,
3H); 7.08 (d, 1H); 6.79 (s, 2H); 3.89 (s, 2H); 1.00 (s, 9H).
Preparation 4
1-[2-Amino(2,2-dimethylpropyl)imidazo[4,5-b]pyridinyl](4-
fluorophenyl)ethane-1,2-dione
3-(2,2-Dimethylpropyl)[(E)(4-fluorophenyl)vinyl]imidazo[4,5-b]pyridine
amine (100.0 g, 308.26 mmol) is mixed with dimethyl sulfoxide (200 mL) in a 2 L, 3-
neck, round-bottomed flask equipped with a reflux condenser, thermocouple, and
mechanical stirrer. After stirring for 10 minutes, 48% hydrogen bromide (28.69 g, 170.20
mmol) is added over 4 minutes to the gray slurry. An exotherm from 22 °C to 33 °C is
observed. To the reaction mixture is added acetic acid (9.28 g, 154.53 mmol). After
stirring 1.8 hours, additional 48% hydrogen bromide (31.75 g, 188.35 mmol) is added.
The reaction mixture is heated and becomes thick. Acetic acid (400 mL, 6.98 mol) is
added. After reaching 91 °C, dimethyl sulfoxide (50 mL) and 40% H SO (100 mL) are
added. The temperature is increased to 100 °C. After 3 hours, additional 40% H SO
(300 mL) is added and a Dean-Stark trap is installed to remove low boiling solvents such
as dimethyl sulfide. After stirring another 17 hours at 100 °C, another portion of 40%
H SO (80 mL) is charged to the reaction. The reaction is stirred 1 hour and then
deionized water (300 mL) is added. The reaction is stirred for 3 hours and then the
temperature is increased to 103 °C followed by addition of more deionized water
(200 mL). After 2.5 hours more of stirring another portion of deionized water (200 mL)
is added. Stirring and heating is continued another 1.5 hours at which time the heat is
shut off (28 hours total from the time of the first addition of 40% H SO . The reaction
2 4)
mixture is allowed to crystallize, while cooling to ambient temperature overnight. The
product is filtered, rinsed with deionized water (2 × 200 mL), and then dried in a vacuum
oven at 50 °C.
The solid material (as the salt) is treated with 1 M sodium hydroxide (550 mL)
with stirring for 18 hours. The slurry is filtered, rinsed with deionized water (500 mL),
and dried in a vacuum oven at 50 °C to afford the title compound (83.7 g, 77%). H
NMR (300 MHz, DMSO-d ): 7.95 (d, 1H); 7.87 (m, 2H); 7.60 (d, 1H); 7.58 (s, 2H);
7.39 (t, 2H); 3.60 (s, 2H); 0.61 (s, 9H).
Preparation 4A (Alternate procedure)
1-[2-Amino(2,2-dimethylpropyl)imidazo[4,5-b]pyridinyl](4-
fluorophenyl)ethane-1,2-dione
3-(2,2-Dimethylpropyl)[(E)(4-fluorophenyl)vinyl]imidazo[4,5-b]pyridin
amine (1.00 g, 2.93 mmol) is suspended in 1,4-dioxane (4 mL) and 50% sulfuric acid
(1 mL) in a 3-neck, round-bottomed flask equipped with a thermocouple and reflux
condenser. The mixture becomes a clear solution and is heated to reflux (90–93 °C
internal and 115 °C oil bath temperature). Hydrogen bromide (400 µL, 3.56 mmol) and
dimethyl sulfoxide (2.50 mL, 35.20 mmol) are added respectively. The reaction mixture
is heated at reflux using an oil bath and nitrogen was introduced at a rate of about one
bubble/second. After 1 hour, a second portion of 50% sulfuric acid (3 mL, 21.4 mmol) is
added. After 5 hours, a third portion of 50% sulfuric acid (4 mL, 31 mmol) is added and
the reaction is continued under reflux overnight. HPLC analysis shows the product to be
> 93%. The oil bath is removed and the reaction allowed to cool to about 70 °C at which
time water (5 mL) is added. After cooling to room temperature (about 30 minutes) the
mixture is filtered, and the cake is washed with water (10 mL) to obtain the hydrogen
sulfate salt of the product (1.33 g).
The above salt is added to 1 N sodium hydroxide (50 mL) and stirred at room
temperature for 30 minutes to obtain a light yellow suspension. The mixture is filtered
and the light yellow solid washed with water (3 × 10 mL) and then dried at 55 °C under
vacuum to provide the title compound (0.91 g, 88%).
Reference Example 1
-[2-tert-Butyl(4-fluorophenyl)-1H-imidazolyl](2,2-
dimethylpropyl)imidazo[4,5-b]pyridinamine dimethanesulfonate
5-[2-tert-Butyl(4-fluoro-phenyl)-1H-imidazolyl](2,2-dimethyl-propyl)-3H-
imidazo[4,5-b]pyridinylamine dimethansulfonate
2 MeSO H
1-[2-Amino(2,2-dimethylpropyl)imidazo[4,5-b]pyridinyl](4-
fluorophenyl)ethane-1,2-dione (354 g, 1 mol) is mixed with ethanol (2.8 L), ammonium
acetate (550.0 g, 7.1 mol), and trimethyl acetaldehyde (110 g, 1.3 mol). The reaction is
heated at about 70 °C (the reaction temperature is kept below refluxing to help suppress
the sublimation of NH OAc) until the disappearance of the dione as monitored by HPLC
or LC-MS. After the completion of the reaction (usually overnight), the mixture is
concentrated under vacuum. Ethyl acetate (5.3 L) and water (3.5 L) are added, followed
by 1 N NaOH (1.4 L). The mixture is stirred for 20–30 minutes at room temperature.
The phases are separated and the aqueous phase is extracted with ethyl acetate (2.8 L).
The combined ethyl acetate portions are washed twice with 10 volumes of brine. The
ethyl acetate solution is evaporated to about 1.2 L (about 3 volumes). Ethanol (2.8 L) is
added and the mixture heated to about 65 °C. Methanesulfonic acid (240.0 g, 2.5 mol) in
ethyl acetate (600 mL) is added in a fast dropwise fashion. The mixture is maintained at
about 65 °C for 3 hours. The heat source is removed and the reaction is cooled to room
temperature with stirring for 2 hours more. The solid product is collected by filtration,
rinsed with ethyl acetate (500 mL), and dried in a vacuum oven at about 45 °C to obtain
the title compound (490 g, 80%). ES/MS m/z 421.5 (M+1). H NMR (300 MHz,
DMSO-d ): 8.99 (s, 2H), 7.90 (d, 1H, J = 9.0 Hz); 7.86 (d, 1H, J = 9.0 Hz); 7.60 (dd,
2H, J = 9.0 Hz), 7.34 (dd, 2H, J = 9.0 Hz); 3.68 (s, 2H); 2.35 (s, 6H); 1.51 (s, 9H); 0.71
(s, 9H).
The following Examples illustrate improved efficacy of the triple combination
administration of the compounds, 5-[2-tert-butyl(4-fluoro-phenyl)-1H-imidazolyl]-
3-(2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridinylamine (dimethanesulfonate salt
(Compound A)), gemcitabine, and a platinum agent over the dual combination of
gemcitabine and a platinum agent in mouse xenograft studies of human ovarian cancer. It
should be understood that the Examples are set forth by way of illustration and not
limitation, and that various modifications may be made by one of ordinary skill in the art.
Example 1
In vivo triple combination with Compound A, gemcitabine, and cisplatin
The purpose of this study is to compare the dual combination treatment of
gemcitabine and cisplatin and the triple combination treatment (including Compound A)
in a xenograft mouse model of human ovarian cancer to determine which is more
efficacious.
Human tumor mouse xenografts are generated from early passages of the
following ovarian cancer cell lines: A-2780 (National Cancer Institute), SK-OV-3x.luc
(SK-OV-3 cell line modified to express luciferase (#1, medium expressing), Indiana
University). A-2780 ovarian cancer cells are grown in RPMI 1640 with L-glutamine, 25
mM HEPES (Invitrogen 22400-089) supplemented with 1mM pyruvate and 10%
Certified Fetal Bovine Serum (Gibco 16000, FBS). SK-OV-3x.luc cells (ovarian cancer
cells) are grown in McCoy's 5A Medium with L-glutamine (Invitrogen 16600-082)
supplemented with non-essential amino acids, 1 mM pyruvate and 10% FBS.
Harlan athymic nude mice (6-7 weeks old) are housed with ad libitum feed and
water, and are acclimated for one week prior to subcutaneous xenograft implantation in
the right rear flank with a defined number of cells. A-2780 or SK-OV-3x.luc implants
consist of 0.1 mL of cells (2 or 5 x 10 cells, respectively) in serum-free media with
0.1 mL MATRIGEL® (BD Biosciences) for a final volume of 0.2 mL. Tumors are
allowed to develop to a volume of 120-150 mm and are then randomized into treatment
groups to attain a consistent average tumor size across all groups. Each treatment group
of the SK-OV-3x.luc study is 12 animals; each group of the A-2780 study is 20 animals.
Compound A is prepared weekly in hydroxyethylcellulose (HEC) 1% / TWEEN®
80 0.25% / Antifoam 0.05% (HEC/TWEEN®) and stored at 4 C. A dose of 30 mg/kg
Compound A for the SK-OV-3x.luc treatment group (or 10 mg/kg for the A-2780
treatment group), or its vehicle, is administered orally by gastric gavage three times daily
(TID) in a volume of 0.2 mL for 3 weeks. The treatment protocol includes a two day
initial treatment with Compound A prior to introduction of the gemcitabine and cisplatin
treatments.
Cisplatin and gemcitabine are diluted in PBS, prepared and administered weekly
as 0.2 mL intraperitoneal injections. The volume is administered as a constant as
illustrated in Table 1.
Table 1
To Achieve
Gemcitabine at:
100 mg/kg 0.2 mL x 25 mg/mL
50 mg/kg 0.2 mL x 12.3 mg/mL
mg/kg 0.2 mL x 6.21 mg/mL
Cisplatin at:
4 mg/kg 0.2 mL x 0.5 mg/mL
2 mg/kg 0.2 mL x 0.25 mg/mL
1 mg/kg 0.2 mL x 0.12 mg/mL
Once weekly (QW) treatments of gemcitabine and cisplatin are given
commencing on the third day at 0.5 and 1 hour, respectively, after the 7th dose
(corresponding to just over two full days of Compound A dosing) of Compound A or
vehicle each week. The highest doses of gemcitabine and cisplatin are selected based on
efficacy as single agents, and fixed ratio dilutions of these are dosed in combination
(sequential administration as separate compounds): 100 mg/kg gemcitabine + 4 mg/kg
cisplatin (100+4); 50 mg/kg gemcitabine + 2 mg/kg cisplatin (50+2); or 25 mg/kg
gemcitabine + 1 mg/kg cisplatin (25+1). The SK-OV-3x.luc and A-2780 treatment
groups are administered the triple combination therapy according to the following dosing
regimens. Corresponding vehicles are employed where no treatment is indicated.
1. HEC/TWEEN®, 0.2 mL, oral, TIDx21 / PBS ,
0.2 mL+0.2 mL, IP, QWx3
2. Compound A, 10 (or 30) mg/kg, oral, TIDx21 / PBS ,
0.2+0.2 mL, IP, QWx3
3. HEC/TWEEN®, 0.2 mL, oral, TIDx21 / gemcitabine+cisplatin
(25+1) mg/kg, IP, QWx3
4. HEC/TWEEN®, 0.2 mL, oral, TIDx21 / gemcitabine +cisplatin
(50+2) mg/kg, IP, QWx3
. HEC/TWEEN®, 0.2 mL, oral, TIDx21 / gemcitabine +cisplatin
(100+4) mg/kg, IP, QWx3
6. Compound A, 10 (or 30) mg/kg, oral, TIDx21 / gemcitabine
+cisplatin, 25+1 mg/kg, IP, QWx3
7. Compound A, 10 (or 30) mg/kg, oral, TIDx21 / gemcitabine
+cisplatin, 50+2 mg/kg, IP, QWx3
8. Compound A, 30 mg/kg, oral, TIDx21 / gemcitabine +cisplatin,
100+4 mg/kg, IP, QWx3*
*SK-OV-3x.luc study only
Tumor volume and body weight are recorded and analyzed twice weekly using a
data capture and analysis tool. Tumor volume (mm ) is estimated by using the formula: v
= l x w x 0.536 where l = larger of measured diameter and w = smaller of perpendicular
diameter. Antitumor activity is calculated as a percent reduction of treated (T) tumor
volume relative to untreated control (C) tumor volume [1-(T/C)] x 100. Tumor volume
data are transformed to a log scale to equalize variance across time and treatment groups.
The log volume data are analyzed with a two-way repeated measures analysis of variance
by time and treatment using the MIXED procedures in SAS software (version 8.2). The
correlation model for the repeated measures is spatial power. Treated groups are
compared to the control group at each time point. The MIXED procedure is also used
separately for each treatment group to calculate adjusted mean and standard error at each
time point. Both analyses account for the autocorrelation within each animal and the loss
of data that occurs when animals with large tumors are removed from the study early.
The adjusted mean and standard error are plotted for each treatment group versus time.
By convention, p-values 0.05 indicate significant differences in tumor growth.
Maximal percentage of weight loss and final tumor volume measurements are presented
with the resultant statistical comparison of tumor growth inhibition between the
individual and combination treatments.
The final average tumor volume of SK-OV-3x.luc xenografts treated for 3 weeks
with Compound A alone, or with lower dose combinations of gemcitabine and cisplatin
(25+1, 50+2) administered on a once weekly schedule, is not significantly different from
vehicle control (Table 2). The highest gemcitabine + cisplatin combination (100+4)
yields tumor growth inhibition relative to vehicle control. The co-treatment of each of the
gemcitabine + cisplatin treated animals with Compound A results in an enhancement of
tumor growth inhibition. The combinations of 25+1, 50+2 and 100+4 with Compound A
achieve or surpass the anti-tumor response to the 100+4 combination.
The triple combination treatment of each of the 25+1 and 50+2 gemcitabine +
cisplatin treated animals with Compound A results in an improvement of tumor growth
inhibition over the dual combination of gemcitabine + cisplatin as shown in Table 2.
Specifically, the combinations of 25+1, 50+2, and 100+4 with Compound A significantly
surpass the anti-tumor response to their respective 25+1, 50+2, and 100+4 dual
combination.
Table 2: SK-OV-3x.luc tumor growth inhibition with gemcitabine, cisplatin and
Compound A combination treatments
significance (p values)
Max % final tumor
wt. loss volume vehicle A (G+C) final n
vehicle 0.0 505 ± 51 . . . 12
A 1.4 522 ± 54 NS . . 10
+1 5.2 407 ± 39 NS NS . 12
50+2 4.1 524 ± 54 NS NS . 12
100+4 13.7 337 ± 43 0.010 0.007 . 11
+1/A 5.4 253 ± 42 <0.001 <0.001 0.002 11
50+2/A 7.7 364 ± 30 0.030 0.021 0.017 10
100+4/A 13.1 202 ± 15 <0.001 <0.001 0.001 11
Each gemcitabine + cisplatin (G+C) /A combination is compared to its matched
combination (G+C) only.
In a second model, A2780 ovarian tumor model, the triple combination treatment
of each of the gemcitabine + cisplatin treated animals with Compound A results in an
improvement of tumor growth inhibition over the dual combination of gemcitabine
+cisplatin, as shown in Table 3. Specifically, the combinations of 25+1 and 50+2 with
Compound A significantly surpass the anti-tumor response to the 25+1 and 50+2 dual
combination.
Table 3: A-2780 tumor growth inhibition with gemcitabine, cisplatin and Compound A
combination treatments
significance (p values)
Max % final tumor
wt. loss volume vehicle A (G+C) final n
vehicle 1.8 2257 ± 279 . . . 20
A 3.0 1828 ± 208 NS . . 20
+1 4.6 536 ± 58 <0.001 <0.001 . 19
50+2 5.1 381 ± 39 <0.001 <0.001 . 19
100+4 7.4 219 ± 22 <0.001 <0.001 . 20
+1/A 7.9 361 ± 34 <0.001 <0.001 0.009 19
50+2/A 8.6 218 ± 14 <0.001 <0.001 <0.001 20
Each gemcitabine + cisplatin (G+C) /A combination is compared to its matched
combination (G+C) only. (100+4) is not evaluated in combination with Compound A.
Example 2
In vivo triple combination therapy with Compound A, gemcitabine, and carboplatin
Carboplatin (25 mg/kg - 100 mg/kg) may be substituted for cisplatin essentially as
described in Example 1.
The compounds described in the present invention are preferably formulated as
pharmaceutical compositions administered by a variety of routes. Most preferably, such
compositions are for oral, intravenous, or intraperitoneal administration. Such
pharmaceutical compositions and processes for preparing the same are well known in the
art. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (D.
Troy, et al., eds., 21 ed., Lippincott Williams & Wilkins, 2005).
The compounds described in the present invention are generally effective over a
wide dosage range. The amount of 5-[2-tert-butyl(4-fluoro-phenyl)-1H-imidazol
yl](2,2-dimethyl-propyl)-3H-imidazo[4,5-b]pyridinylamine administered normally
falls within the range of about 100-420 mg every 12 hours for 10 days, more preferably
100-300 mg every 12 hours for 10 days, and most preferably 200 mg every 12 hours for
days or alternatively 300 mg every 12 hours for 10 days. It is anticipated that 5-[2-
tert-butyl(4-fluoro-phenyl)-1H-imidazolyl](2,2-dimethyl-propyl)-3H-
imidazo[4,5-b]pyridinylamine will be administered for at least two days prior to the
initiation of the gemcitabine and cisplatin or gemcitabine and carboplatin regimen.
According to the FDA approved dosing regimen, the combination administration
of gemcitabine and carboplatin should be administered intravenously at a dose of
1000 mg/m2 over 30 minutes on days 1 and 8 of each 21-day treatment cycle.
Carboplatin AUC 4 should be administered intravenously on day 1 after gemcitabine
administration. Patients should be monitored prior to each dose with a complete blood
count, including differential counts. Patients should have an absolute granulocyte count
≥1500 x 106/L and a platelet count ≥100,000 x 106/L prior to each cycle.
Dose Modifications
Gemcitabine dosage adjustment for hematological toxicity within a cycle of
treatment is based on the granulocyte and platelet counts taken on day 8 of therapy. If
marrow suppression is detected, gemcitabine dosage should be modified according to
guidelines in Table 4.
Table 4: Day 8 Dosage Reduction Guidelines for Gemcitabine in Combination with
Carboplatin
Absolute granulocyte count Platelet count (x 106/L) % of full
(x 106/L) dose
≥1500 and ≥100,000 100
1000-1499 and/or 75,000-99,999 50
<1000 and/or <75,000 Hold
In general, for severe (Grade 3 or 4) non-hematological toxicity, except
nausea/vomiting, therapy with gemcitabine should be held or decreased by 50%
depending on the judgment of the treating physician. For carboplatin dosage adjustment,
see manufacturer's prescribing information.
Dose adjustment for gemcitabine in combination with carboplatin for subsequent
cycles is based upon observed toxicity. The dose of gemcitabine in subsequent cycles
should be reduced to 800 mg/m on days 1 and 8 in case of any of the following
hematologic toxicities:
Absolute granulocyte count < 500 x 10 /L for more than 5 days
Absolute granulocyte count < 100 x 10 /L for more than 3 days febrile
neutropenia
Platelets < 25,000 x 10 /L
Cycle delay of more than one week due to toxicity
If any of the above toxicities recur after the initial dose reduction, for the
subsequent cycle, gemcitabine should be given on day 1 only at 800 mg/m .
It is believed that cisplatin could be administered in a similar manner to
carboplatin.
In some instances dosage levels below the lower limit of the aforesaid range may
be more than adequate, while in other cases still larger doses may be employed without
causing any harmful side effect, and therefore the above dosage range is not intended to
limit the scope of the invention in any way. It will be understood that the amount of the
compound actually administered will be determined by a physician, in the light of the
relevant circumstances, including the condition to be treated, the chosen route of
administration, the actual compound or compounds administered, the age, weight, and
response of the individual patient, and the severity of the patient's symptoms.
The term “comprising” as used in this specification and claims means “consisting
at least in part of”. When interpreting statements in this specification and claims which
include the term “comprising”, other features besides the features prefaced by this term in
each statement can also be present.
In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose of
providing a context for discussing the features of the invention. Unless specifically stated
otherwise, reference to such external documents is not to be construed as an admission
that such documents, or such sources of information, in any jurisdiction, are prior art, or
form part of the common general knowledge in the art.
Claims (10)
1. Use of 5-[2-tert-butyl(4-fluoro-phenyl)-lH-imidazolyl](2,2-dimethyl- 5 propyl)-3H-imidazo[4,5-b]pyridinylamine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of ovarian cancer wherein said medicament is to be administered in combination with gemcitabine and a platinum agent selected from cisplatin and carboplatin. 10
2. Use according to claim 1 wherein administration of the medicament precedes that of gemcitabine and the platinum agent.
3. Use according to claim 1 or 2 wherein gemcitabine and the platinum agent are administered up to 2 days after administration of the medicament and gemcitabine is 15 administered again up to 7 days later.
4. Use according to claim 1 wherein administration of gemcitabine and the platinum agent precedes that of the medicament. 20
5. Use according to claim 1 or 2 wherein gemcitabine and the platinum agent are administered simultaneously.
6. Use according to any one of claims 1-5 wherein the platinum agent is cisplatin. 25
7. Use according to any one of claims 1-5 wherein the platinum agent is carboplatin.
8. Use according to any one of claims 1-7 wherein the medicament is administered during a 21-day treatment cycle.
9. Use according to any one of claims 1-8 wherein the pharmaceutically acceptable salt is the dimethanesulfonate salt.
10. Use according to any one of claims 1-9 substantially as herein described with 5 reference to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161558582P | 2011-11-11 | 2011-11-11 | |
US61/558,582 | 2011-11-11 | ||
PCT/US2012/062634 WO2013070460A1 (en) | 2011-11-11 | 2012-10-31 | Combination therapy for ovarian cancer |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ623622A NZ623622A (en) | 2015-07-31 |
NZ623622B2 true NZ623622B2 (en) | 2015-11-03 |
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