NZ722879B2 - A 6-oxo-1,6-dihydro-pyridazine derivative for the use for the treatment of renal cell carcinoma (rcc) - Google Patents
A 6-oxo-1,6-dihydro-pyridazine derivative for the use for the treatment of renal cell carcinoma (rcc) Download PDFInfo
- Publication number
- NZ722879B2 NZ722879B2 NZ722879A NZ72287914A NZ722879B2 NZ 722879 B2 NZ722879 B2 NZ 722879B2 NZ 722879 A NZ722879 A NZ 722879A NZ 72287914 A NZ72287914 A NZ 72287914A NZ 722879 B2 NZ722879 B2 NZ 722879B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- oxo
- dihydro
- renal cell
- rcc
- cell carcinoma
- Prior art date
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- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 230000002093 peripheral Effects 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 239000000546 pharmaceutic aid Substances 0.000 description 1
- 230000003285 pharmacodynamic Effects 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-M phenylacetate Chemical compound [O-]C(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-M 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L phosphate Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- NJRWNWYFPOFDFN-UHFFFAOYSA-L phosphonate(2-) Chemical compound [O-][P]([O-])=O NJRWNWYFPOFDFN-UHFFFAOYSA-L 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000004977 physiological function Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 229920000747 poly(lactic acid) polymer Polymers 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920002721 polycyanoacrylate Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L propanedioate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 239000011241 protective layer Substances 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 102220240796 rs553605556 Human genes 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- RCOSUMRTSQULBK-UHFFFAOYSA-N sodium;propan-1-olate Chemical compound [Na+].CCC[O-] RCOSUMRTSQULBK-UHFFFAOYSA-N 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N stearylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229940071103 sulfosalicylate Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 201000010874 syndrome Diseases 0.000 description 1
- 229920003051 synthetic elastomer Polymers 0.000 description 1
- 239000005061 synthetic rubber Substances 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000004881 tumor cells Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 239000000225 tumor suppressor protein Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- AEMOLEFTQBMNLQ-BKBMJHBISA-N α-D-galacturonic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-BKBMJHBISA-N 0.000 description 1
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0031—Rectum, anus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/02—Suppositories; Bougies; Bases therefor; Ovules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile or a pharmaceutically acceptable salt and/or solvate thereof for the use for the treatment of renal cell carcinoma (RCC).
Description
(12) Granted patent specificaon (19) NZ (11) 722879 (13) B2
(47) Publicaon date: 2021.12.24
(54) A 6-OXO-1,6-DIHYDRO-PYRIDAZINE DERIVATIVE FOR THE USE FOR THE TREATMENT OF RENAL
CELL CARCINOMA (RCC)
(51) Internaonal Patent ficaon(s):
A61K 31/506 A61P 35/00
(22) Filing date: (73) Owner(s):
2014.12.16 MERCK PATENT GMBH
(23) Complete specificaon filing date: (74) Contact:
2014.12.16 HENRY HUGHES IP D
(30) aonal Priority Data: (72) Inventor(s):
EP 14000036.5 2014.01.07 BLADT, Friedhelm
FRIESE-HAMIM, Manja
(86) Internaonal Applicaon No.:
2014/003365
(87) Internaonal Publicaon number:
WO/2015/104042
(57) Abstract:
3-(1-{3-[5-(1-methyl-piperidinylmethoxy)-pyrimidinyl]-benzyl}6-oxo-1,6-dihydro-pyridazin
yl)-benzonitrile or a pharmaceucally acceptable salt and/or solvate thereof for the use for the
treatment of renal cell carcinoma (RCC).
NZ 722879 B2
A 6-oxo-1,6-dihydro-pyridazine derivative for the use for the
treatment of renal cell carcinoma (RCC)
FIELD OF THE INVENTION
This invention relates to 3-(1-{3-[5-(1-methyl-piperidin—4-ylmethoxy)-pyrimidin-
2-yl]—benzy|}—6—oxo-1,6-dihydro-pyridazinyl)—benzonitrile or a
pharmaceutically acceptable salt and/or solvate f for the use for the
’IO treatment of renal cell carcinoma (RCC), preferably for the use for the
treatment of ary renal cell carcinoma (pRCC).
BACKGROUND OF THE INVENTION
The invention had the object of finding novel pharmaceutical compositions having
valuable properties, in particular those which can be used for the preparation of
medicaments.
Moreover, aim of this invention are new compositions for the tion and
treatment of hepatocellular carcinoma.
It has been found that 3-(1-{3—[5—(1-methyl-piperidin-4—ylmethoxy)-pyrimidin
yl]-benzyl}oxo-1,6-dihydro-pyridazinyl)—benzonitrile according to the
invention or a pharmaceutically acceptable salt and/or solvate thereof has very
valuable cological ties while being well tolerated.
Renal cell carcinoma (RCC) is the most common type of kidney cancer in
adults. It accounts for approximately 3% of adult malignancies and 90-95% of
neoplasms arising from the kidney. Renal cell carcinoma (RCC, formerly
known as hypernephroma) is a kidney cancer that originates in the lining of the
proximal convoluted tubule, the very small tubes in the kidney that transport
GF rular filtrate) from the glomerulus to the descending limb of the
nephron. RCC is the most common type of kidney cancer in adults,
responsible for approximately 80% of cases. It has been described as being
initial treatment is most
among the most lethal of all the urological cancers.
commonly a radical or partial ctomy and remains the mainstay of
curative treatment. Where the tumor is confined to the renal parenchyma, the
-year al rate is , but this is lowered considerably where
metastases have spread. A special type of RCC is pRCC (papillary renal cell
carcinoma).
Activation of the c-Met pathway occurs in a range of malignancies, including
RCC. Published studies indicate that c-Met is associated with poor pathologic
features and sis in RCC and especially in papillary renal cell carcinoma
(pRCC).
RCC is curable only in patients presenting with able, early-stage
disease. Advanced local or metastatic disease carries an approximate 15% 5-
of metastatic RCC is
year survival rate. However, the natural history
heterogeneous, and aggressive palliative ent is recommended,
especially for patients with a solitary metastatic site and good performance
status. se rates to cytokine therapy remain generally less than 25%,
and complete responses are rare. To improve these results, combinations of
biologics with and without cytotoxic chemotherapy are being investigated.
Here we demonstrate that the Met kinase inhibitor 3-(1-{3-[5—(1—methyl-
dinylmethoxy)—pyrimidInyl]—benzyl}—6-oxo-1 ,6-dlhyd ro—pyridazin-S-y|)-. .
benzonitrile or a pharmaceutically acceptable salt and/or solvate thereof is
active in RCC, preferably in pRCC.
PRIOR ART
3—[5—(1-Methyl-piperidinylmethoxy)-pyrimidinyl]—benzyl}-6—oxo—1 ,6-
dihydro-pyridazin—3-yl)-benzonitrile has been described in
A1.
3-(1-{3-[5-(1-Methyl-piperidinylmethoxy)-pyrimidinyl]-benzyl}oxo-1,6-
dihydro-pyridazinyl)-benzonitrile hydrochloride hydrate has been described
in WO 07074 A1.
SUMMARY OF THE INVENTION
The present ion particularly provides for aspects and embodiments as
set out in the clauses below:
1. Use of 3-(1-{3-[5-(1-methyl-piperidinylmethoxy)-pyrimidinyl]-benzyl}
6-dihydro-pyridazinyl)-benzonitrile hydrochloride hydrate for the
manufacture of a medicament for the treatment of renal cell carcinoma
(RCC).
2. The use according to clause 1, wherein, the 3-(1-{3-[5-(1-methyl-piperidin
ylmethoxy)-pyrimidinyl]-benzyl}oxo-1,6-dihydro-pyridazinyl)-
benzonitrile hydrochloride hydrate is 3-(1-{3-[5-(1-methyl-piperidin
ylmethoxy)-pyrimidinyl]-benzyl}oxo-1,6-dihydro-pyridazinyl)-
benzonitrile hydrochloride monohydrate.
3. The use according to clause 1 or 2, wherein the treatment comprises
administration of an amount of 100 mg to 800 mg of the compound to a
t per day.
4. The use according to any one of clauses 1 to 3, wherein the treatment
ses oral administration of the nd.
. The use according to any one of clauses 1 to 4, wherein renal cell
oma (RCC) is papillary renal cell carcinoma (pRCC).
Moreover, the invention relates to 3-(1-{3-[5-(1-methyl-piperidinylmethoxy)-
pyrimidinyl]-benzyl}oxo-1,6-dihydro-pyridazinyl)-benzonitrile or a
pharmaceutically acceptable salt and/or solvate thereof for the use for the
treatment of renal cell carcinoma (RCC), preferably for the use for the
treatment of papillary renal cell carcinoma (pRCC).
- 3a -
Moreover, the invention relates to 3-(1-{3-[5-(1-methyl-piperidinylmethoxy)-
pyrimidinyl]-benzyl}oxo-1,6-dihydro-pyridazinyl)-benzonitrile
hydrochloride hydrate for the use for the treatment of renal cell oma
(RCC), preferably for the use for the treatment of papillary renal cell carcinoma
(pRCC).
Moreover, the invention relates to 3-(1-{3-[5-(1-methyl-piperidinylmethoxy)-
pyrimidinyl]-benzyl}oxo-1,6-dihydro-pyridazinyl)-benzonitrile or a
pharmaceutically able salt and/or solvate thereof, wherein the
nd is administered to a patient in an amount of 100 mg to 800 mg per
day.
Moreover, the invention relates to 3-(1-{3-[5-(1-methyl-piperidinylmethoxy)-
pyrimidinyl]-benzyl}oxo-1,6-dihydro-pyridazinyl)-benzonitrile or a
pharmaceutically acceptable salt and/or solvate thereof, wherein the
nd is administered orally.
Moreover, the invention relates to the use of 3-(1-{3-[5-(1-methyl-piperidin
oxy)-pyrimidinyl]-benzyl}oxo-1,6-dihydro-pyridazinyl)-
benzonitrile or a pharmaceutically acceptable salt and/or solvate thereof for
the manufacture of a medicament for the treatment of renal cell carcinoma
(RCC), preferably for the use for the treatment of papillary renal cell carcinoma
. Moreover, the invention relates to the use. of 3—(1-{3-[5-(1-methyl-
piperidinylmethoxy)—pyrimidinyl]—benzy|}—6—oxo—1,6-dihydro—pyridazinyl)—
benzonitrile hydrochloride hydrate for the manufacture of a medicament for the
treatment of renal cell carcinoma (RCC), preferably for the use for the
treatment of papillary renal cell carcinoma (pRCC).
Moreover, the invention relates to the use as described above,
n 3—(1-{3-[5—(1—methyl—piperidin—4-ylmethoxy)—pyrimidinyl]—benzyl}
oxo-1,6-dihydro-pyridazinyI)-benzonitrile or a ceutically acceptable
salt and/or solvate thereof or
3-(1-{3-[5-(1-methy|—piperidin-4—yI-methoxy)-pyrimidin-2—yI]-benzyl}oxo-1 ,6-
dihydro-pyridazinyl)—benzonitrile hydrochloride hydrate,
wherein the compound is administered to a patient in an amount of 100 mg to
800 mg per day, preferably in an amount of 200 mg to 700 mg per week,
particularly preferably in an amount of 250 mg to 350 mg per day.
er, the ion s to the use as described above,
wherein 3-(1—{3—[5-(1-methy|—piperidin-4—ylmethoxy)—pyrimidinyl]—benzyI}
oxo-1,6—dihydro-pyridazin—3-yl)-benzonitrile or a pharmaceutically acceptable
salt and/or solvate thereof or
3—(1-{3—[5-(1—methyI—piperidinylmethoxy)—pyrimidin—2-yl]—benzy|}oxo—1 ,6—
dihydro-pyridaziny|)-benzonitrile hydrochloride hydrate
wherein the compound is administered orally.
The therapy with 3-(1-{3-[5—(1—methy|—piperidin-4—ylmethoxy)-pyrimidin—2—y|]-
benzyl}oxo—1,6-dihydro—pyridazin—3—yl)-benzonitrile or a pharmaceutically
acceptable salt and/or solvate thereof or
3-(1-{3-[5-(1-methy|—piperidin—4-ylmethoxy)—pyrimidinyl]—benzyl}—6—oxo-1 ,6—
dihydro-pyridazin-3—yl)-benzonitrile hydrochloride e may include
optionally further treatment with radiation. The invention relates rmore to
of 3-(1-{3-[5-(1-
a new therapy form sing the start of the administration
methyl—piperidin—4—ylmethoxy)-pyrimidinyI]—benzyI}—6-oxo-1,6—dihydro-
pyridazinyI)-benzonitrile or a pharmaceutically acceptable salt and/or solvate
thereof prior to radiotherapy for the treatment of renal cell carcinoma (RCC),
preferably for the use for the ent of papillary renal cell carcinoma
(pRCC).
The invention also s to the optically active forms (stereoisomers),
and solvates
enantiomers, the racemates, the diastereomers and the hydrates
of the compound.
The invention also relates to the solvates of the salts of the compound e.g.
mono- or dihydrate of the hydrochloride.
1O The term solvates of the compound is taken to mean adductions of inert
solvent molecules onto the compounds which form owing to their mutual
attractive force. Solvates are, for example, mono- or dihydrates or alcoholates.
The expression "effective amount” denotes the amount of a medicament or of
in a tissue, system, animal or
a pharmaceutical active ingredient which causes
human a biological or medical se which is sought or desired, for
example, by a researcher or ian.
In addition, the expression "therapeutically ive amount” denotes an
amount which, compared with a corresponding subject who has not received
this amount, has the following consequence:
improved treatment, g, prevention or elimination of a e, syndrome,
condition, complaint, disorder or side-effects or also the reduction in the
advance of a disease, complaint or disorder.
The expression "therapeutically effective amount” also encompasses the
amounts which are effective for increasing normal physiological function.
The said compounds according to the ion can be used in their final non—
salt form. On the other hand, the t ion also encompasses the use
of these compounds in the form of their pharmaceutically acceptable salts,
which can be derived from various organic and inorganic acids and bases by
procedures known in the art. Pharmaceutically acceptable salt forms of 3-(1—
{3~[5—(1-methyl-piperidinylmethoxy)-pyrimidin—2-yl]-benzy|}—6—oxo-1 ,6—
WO 04042 2014/003365
dihydro-pyridazinyl)—benzonitrile and N—((S)—2,3-dihydroxy—propyl)—3—(2—
fluoro-4—iodo-phenylamino)-isonicotinamide are for the most part prepared by
conventional methods.
If a compound contains a carboxyl group, one of its suitable salts can be
formed by ng the compound with a le base to give the
corresponding base-addition salt. Such bases are, for example, alkali metal
hydroxides, including potassium hydroxide, sodium hydroxide and lithium
hydroxide; alkaline earth metal ides, such as barium hydroxide and
1O calcium hydroxide; alkali metal alkoxides, for example potassium ethoxide and
sodium propoxide; and various organic bases, such as piperidine,
diethanolamine and N-methylglutamine. The aluminium salts of the
compounds are likewise included. In the case of certain compounds acid-addi-
tion salts can be formed by treating these compounds with pharmaceutically
acceptable organic and nic acids, for example hydrogen halides, such as
hydrogen chloride, hydrogen bromide or hydrogen , other mineral acids
and corresponding salts thereof, such as sulfate, nitrate or ate and the
like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,
toluenesulfonate and esulfonate, and other organic acids and
corresponding salts thereof, such as acetate, trifluoroacetate, tartrate, maleate,
succinate, citrate, benzoate, salicylate, ascorbate and the like. Accordingly,
pharmaceutically acceptable acid—addition salts of the compounds e the
following: e, adipate, alginate, arginate, aspartate, benzoate, benzene-
sulfonate (besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,
camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentane-
nate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecyl-
sulfate, ethanesulfonate, fumarate, galacterate (from mucic acid), galacturo-
nate, glucoheptanoate, gluconate, glutamate, glycerophosphate, hemi—
succinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,
hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, , isethionate, iso-
te, lactate, lactobionate, , maleate, malonate, mandelate,
metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphos—
phate, 2—naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,
pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,
phosphonate, phthalate, but this does not ent a restriction.
Furthermore, the base salts of the nds according to the invention
include aluminium, ammonium, calcium, copper, iron(lll), iron(ll), lithium,
magnesium, manganese(lll), manganese(ll), potassium, sodium and zinc
salts, but this is not intended to represent a restriction. Of the above—men—
tioned salts, preference is given to ammonium; the alkali metal salts sodium
1O and potassium, and the alkaline earth metal salts calcium and magnesium.
Salts of the compounds which are derived from pharmaceutically acceptable
organic xic bases include salts of primary, secondary and tertiary
amines, tuted , also including naturally occurring substituted
amines, cyclic amines, and basic ion ger resins, for example arginine,
betaine, caffeine, chloroprocaine, choline, N,N'—dibenzylethylenediamine
(benzathine), dicyclohexylamine, dieth'anolamine, diethylamine, 2-diethyl-
aminoethanol, 2-dimethylaminoethanol, lamine, nediamine,
N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,
hydrabamine, isopropylamine, ine, lysine, meglumine, N-methyl-D-
glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine,
purines, theobromine, triethanolamine, triethylamine, trimethylamine, pyl-
amine and ydroxymethyl)methylamine (tromethamine), but this is not
intended to represent a restriction.
Compounds of the present invention which contain basic nitrogen-containing
groups can be quaternised using agents such as (C1-C4)alkyl halides,
example methyl, ethyl, isopropyl and utyl chloride, bromide and iodide;
di(C1—C4)alkyl sulfates, for example dimethyl, diethyl and diamyl sulfate; (C10—
C1e)alkyl halides, for example decyl, dodecyl, lauryl, yl and stearyl
chloride, bromide and iodide; and aryl(C1-C4)alkyl halides, for example benZyl
chloride and hyl bromide. Both water— and oil-soluble compounds
according to the invention can be prepared using such salts.
W0 2015/104042
- 8 _
The above—mentioned pharmaceutical salts which are preferred include
acetate, oroacetate, besylate, citrate, fumarate, gluconate, hemisuccinate,
hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine,
e, oleate, onate, pivalate, sodium phosphate, stearate, e,
sulfosalicylate, tartrate, late, tosylate and tromethamine, but this is not
intended to represent a restriction.
Particular preference is given to hydrochloride, dihydrochloride, hydrobromide,
maleate, mesylate, phosphate, sulfate and succinate.
The acid—addition salts of basic compounds are prepared by bringing the free
base form into contact with a sufficient amount of the desired acid, causing the
formation of the salt in a conventional manner. The free base can be
regenerated by bringing the salt form into contact with a base and isolating the
free base in a conventional manner. The free base forms differ in a certain
respect from the corresponding salt forms thereof with respect to certain
al properties, such as lity in polar solvents; for the purposes of the
invention, however, the salts otherwise correspond to the respective free base
forms thereof.
As mentioned, the pharmaceutically able base-addition salts of the
compounds are formed with metals or amines, such as alkali metals and
alkaline earth metals or organic amines. Preferred metals are sodium,
potassium, magnesium and calcium. Preferred organic amines are N,N’-
dibenzylethylenediamine, chloroprocaine, choline, nolamine,
ethylenediamine, N-methyl-D-glucamine and procaine.
The base—addition salts of acidic compounds according to the invention are
prepared by bringing the free acid form into contact with a sufficient amount of
the desired base, causing the formation of the salt in a conventional manner.
The free acid can be rated by bringing the salt form into contact with an
acid and isolating the free acid in a conventional manner. The free acid forms
W0 2015/104042
- g _
differ in a certain t from the corresponding salt forms thereof with
respect to n physical properties, such as lity in polar solvents; for
the purposes of the invention, however, the salts othen/vise correspond to the
respective free acid forms thereof.
With regard to that stated above, it can be seen that the expression "phar-
maceutically acceptable salt” in the present connection is taken to mean an
active ingredient which comprises a compound in the form of one of its salts, in
particular if this salt form imparts improved pharmacokinetic properties on the
active ingredient compared with the free form of the active ingredient or any
other salt form of the active ingredient used earlier. The pharmaceutically
acceptable salt form of the active ingredient can also provide this active
ingredient for the first time with a desired pharmacokinetic ty which it did
not have r and can even have a positive influence on the
pharmacodynamics of this active ingredient with respect to its therapeutic
cy in the body.
The invention furthermore relates to medicaments comprising at least one
compound and/or pharmaceutically acceptable salts, es, tautomers and
stereoisomers thereof, including mixtures thereof in all ratios, and optionally
excipients and/or nts.
Pharmaceutical formulations can be administered in the form of dosage units
which comprise a ermined amount of active ingredient per dosage unit.
Such a unit can comprise, for example, 0.5 mg to 1 9, preferably 1 mg to
700 mg, particularly preferably 5 mg to 100 mg, of a nd according to
the invention, depending on the condition treated, the method of administration
and the age, weight and condition of the patient, or pharmaceutical
formulations can be administered in the form of dosage units which comprise a
predetermined amount of active ingredient per dosage unit. Preferred dosage
unit formulations are those which comprise a daily dose or part—dose, as
indicated above, or a corresponding fraction thereof of an active ingredient.
rmore, pharmaceutical formulations of this type can be prepared using a
process which is generally known in the pharmaceutical art.
Pharmaceutical formulations can be adapted for administration via any desired
suitable method, for example by oral (including buccal or sublingual), rectal,
nasal, topical (including , sublingual or transdermal), vaginal or
parenteral ding aneous, intramuscular, intravenous or intradermal)
methods. Such formulations can be prepared using all processes known in the
pharmaceutical art by, for example, combining the active ingredient with the
ent(s) or adjuvant(s).
Pharmaceutical formulations adapted for oral administration can be adminis-
tered as separate units, such as, for example, capsules or tablets; powders or
granules; solutions or sions in aqueous or non-aqueous liquids; edible
foams or foam foods; or oil-in-water liquid emulsions or water-in—oil liquid
emulsions.
Thus, for example, in the case of oral administration in the form of a tablet or
capsule, the active—ingredient component can be ed with an oral, non—
toxic and pharmaceutically acceptable inert excipient, such as, for example,
ethanol, ol, water and the like. Powders are ed by comminuting
the compound to a suitable fine size and mixing it with a pharmaceutical
excipient comminuted in a similar manner, such as, for example, an edible
carbohydrate, such as, for example, starch or mannitol. A flavour, preservative,
dispersant and dye may likewise be present.
Capsules are produced by preparing a powder mixture as described above
and filling shaped gelatine shells ith. Glidants and lubricants, such as,
for example, highly se silicic acid, talc, magnesium stearate, calcium
stearate or polyethylene glycol in solid form, can be added to the powder
mixture before the filling operation. A disintegrant or solubiliser, such as, for
example, agar-agar, calcium carbonate or sodium ate, may likewise be
added in order to improve the availability of the medicament after the capsule
has been taken.
In addition, if desired or necessary, suitable binders, lubricants and disin-
Suitable
ts as well as dyes can se be incorporated into the mixture.
binders include , gelatine, natural sugars, such as, for example, glucose
l and synthetic rubber,
or beta-lactose, sweeteners made from maize,
such as, for example, acacia, tragacanth or sodium alginate, carboxymethyl-
cellulose, polyethylene glycol, waxes, and the like. The lubricants used in
these dosage forms include sodium oleate, sodium stearate, magnesium
stearate, sodium benzoate, sodium acetate, sodium chloride and the like. The
egrants include, without being restricted thereto, starch, methylcellulose,
and the like. The s are formulated by, for
agar, bentonite, xanthan gum
example, ing a powder e, granulating or dry-pressing the mixture,
adding a ant and a disintegrant and pressing the entire mixture to give
tablets. A powder mixture is prepared by mixing the compound comminuted in
and optionally
a suitable manner with a diluent or a base, as described above,
with a binder, such as, for example, carboxymethylcellulose, an te,
gelatine or polyvinylpyrrolidone, a dissolution retardant, such as, for e,
paraffin, an absorption accelerator, such as, for example, a quaternary salt,
and/or an absorbant, such as, for example, bentonite, kaolin or dicalcium
phosphate. The powder mixture can be granulated by wetting it with a binder,
such as, for example, syrup, starch paste, acadia mucilage or ons of
cellulose or polymer materials and pressing. it through a sieve. As an
alternative to granulation, the powder mixture can be run h a tabletting
machine, giving lumps of iform shape, which are broken up to form
granules. The granules can be lubricated by addition of stearic acid, a stearate
salt, talc or mineral oil in order to prevent sticking to the tablet casting moulds.
The lubricated mixture is then pressed to give tablets. The compounds
according to the invention can also be combined with a free-flowing inert
excipient and then pressed directly to give tablets without carrying out the
granulation or dry-pressing steps. A transparent or opaque protective layer
consisting of a shellac sealing layer, a layer of sugar or polymer material and a
gloss layer of wax may be present. Dyes can be added to these coatings
order to be able to differentiate between different dosage units.
Oral liquids, such as, for e, solution, syrups and elixirs, can be prepared
in the form of dosage units so that a given quantity ses a ecified
amount of the compound. Syrups can be prepared by dissolving the compound
in an aqueous solution with a suitable r, while s are prepared using
can be formulated by dispersion of
a non-toxic alcoholic vehicle. Suspensions
the compound in a non-toxic vehicle. Solubilisers and emulsifiers, such as, for
example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,
preservatives, flavour ves, such as, for example, peppermint oil or l
ners or saccharin, or other artificial sweeteners and the like, can
likewise be added.
The dosage unit formulations for oral administration can, if desired, be en-
capsulated in microcapsules. The formulation can also be prepared in such a
extended or retarded, such as, for example, by coating
way that the release is
and the like.
or embedding of particulate material in polymers, wax
The compounds and salts, solvates, tautomers and stereoisomers thereof can
also be administered in the form of liposome delivery s, such as, for
example, small unilamellar vesicles, large unilamellar vesicles and
multilamellar vesicles. Liposomes can be formed from various phospholipids,
such as, for example, terol, stearylamine or phosphatidylcholines.
The compounds and the salts, solvates, tautomers and stereoisomers thereof
individual carriers to
can also be delivered using onal dies as
which the compound molecules are coupled. The compounds can also be
coupled to soluble polymers as targeted medicament carriers. Such polymers
may encompass polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl—
methacrylamidophenol, polyhydroxyethylaspartamidophenol or polyethylene
W0 2015/104042
_ 13 _
oxide polylysine, substituted by palmitoyl radicals. The compounds may
which are
furthermore be coupled to a class of biodegradable rs
suitable for achieving controlled e of a medicament, for example
polylactic acid, psilon-caprolactone, polyhydroxybutyric acid, poly-
orthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates and
crosslinked or amphipathic block copolymers of hydrogelsf
Pharmaceutical formulations adapted for transdermal administration can be
1O administered as ndent plasters for extended, close contact with the
epidermis of the recipient. Thus, for example, the active ingredient can be
delivered from the plaster by iontophoresis, as described in general terms in
Pharmaceutical Research, 3(6), 318 (1986).
Pharmaceutical compounds adapted for topical administration can be for-
mulated as ointments, creams, suspensions, lotions, powders, solutions,
pastes, gels, sprays, ls or oils.
Pharmaceutical formulations adapted for rectal stration can be ad-
ministered in the form of suppositories or enemas.
Pharmaceutical formulations d for nasal administration in which the
carrier substance is a solid comprise a coarse powder having a particle size,
for example, in the range 20-500 microns, which is administered in the manner
in which snuff is taken, i.e. by rapid inhalation via the nasal passages from a
container containing the powder held close to the nose. Suitable formulations
for administration as nasal spray or nose drops with a liquid as carrier
substance encompass active-ingredient solutions in water or oil.
Pharmaceutical ations adapted for administration by inhalation encom—
which can be ted by various types
pass finely particulate dusts or mists,
of pressurised dispensers with aerosols, nebulisers or insufflators.
2014/003365
Pharmaceutical formulations d for parenteral administration include
solutions comprising antioxidants,
aqueous and non—aqueous sterile injection
buffers, bacteriostatics and s, by means of which the formulation is
rendered isotonic with the blood of the recipient to be treated; and aqueous
and non-aqueous sterile suspensions, which may comprise suspension media
and thickeners. The formulations can be administered in —dose or
multidose containers, for example sealed es and vials, and stored in
freeze-dried (Iyophilised) state, so that only the addition of the sterile carrier
1O liquid, for example water for injection purposes, immediately before use is
in accordance with
necessary. Injection solutions and suspensions prepared
the recipe can be prepared from sterile powders, granules and s.
It goes without saying that, in addition to the above particularly mentioned
constituents, the formulations may also comprise other agents usual in the art
with respect to the particular type of formulation; thus, for example, for—
mulations which are suitable for oral administration may comprise flavours.
A therapeutically effective amount of a compound depends on a number of
factors, including, for example, the age and weight of the animal, the precise
ion that requires ent, and its severity, the nature of the formulation
and the method of administration, and is ultimately determined by the treating
doctor or vet. r, an effective amount of a compound according to the
invention is generally in the range from 0.1 to 100 mg/kg of body weight of the
recipient (mammal) per day and ularly lly in the range from 1 to
mg/kg of body weight per day. Thus, the actual amount per day for an adult
mammal weighing 70 kg is usually between 70 and 700 mg, where this amount
can be administered as a single dose per day or usually in a series of part—
doses (such as, for example, two, three, four, five or six) per day, so that the
total daily dose is the same. An effective amount of a salt, solvate, tautomer
and stereoisomer thereof can be determined as the fraction of the ive
amount of the compound according to the invention per se. It can be assumed
that similar doses are suitable for the treatment of other conditions mentioned
above.
The anti-cancer treatment defined herein may be applied as a sole therapy or
may involve, in addition to the composition of the invention, conventional
surgery or radiotherapy.
"Treating" as used herein, means an alleviation, in whole or in part, of
symptoms associated with a disorder or disease, or g, or halting of
r progression or ing of those symptoms, or prevention or
prophylaxis of the disease or disorder in a subject at risk for developing the
disease or disorder.
The term "effective amount" in connection with a compound can mean an
amount capable of alleviating, in whole or in part, symptoms associated with a
disorder or disease, or slowing or halting further progression or worsening of
those symptoms, or preventing or ing prophylaxis for the disease or
disorder in a subject having or at risk for ping a disease disclosed
herein, such as cancer,
The term “therapeutically ive” or “therapeutically effective amount” refers
to an amount of a drug effective to treat a e or disorder in a mammal. In
the case of cancer, the therapeutically effective amount of the drug may
reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to
some extent and preferably stop) cancer cell ration into peripheral organs;
inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit,
to some extent, tumor growth; and/or relieve to some extent one or more of the
symptoms associated with the cancer. To the extent the drug may prevent
growth and/or kill ng cancer cells, it may be cytostatic and/or cytotoxic.
For cancer y, efficacy can, for example, be measured by assessing the
time to disease progression (TTP) and/or determining the response rate (RR).
W0 2015/104042
_ 15 _
3-(1—{3-[5-(1—methyl—piperidin—4-ylmethoxy)—pyrimidin-2—yl]-benzyl}—6-oxo-1 ,6-
dihydro-pyridazinyl)-benzonitrile hydrochloride hydrate is suitable as
pharmaceutical active ingredient for mammals, especially for humans, in the
treatment of renal cell carcinoma (RCC), preferably for the use for the
treatment of papillary renal cell carcinoma (pRCC).
mental
Evaluation of 3-(1-{3-[5-(1—methyl—piperidin—4—ylmethoxy)—pyrimidin-2—yl]-
benzyl}—6-oxo-1,6-dihydro—pyridazinyl)-benzonitrile hydrochloride hydrate in
preclinical RCC models. To this end several t—derived tumor models
were obtained:
786-0 (ATCC CRL-1932) Human Primary renal cell adenocarcinoma
A-498 (ATCC HTB—44) Human Papillary, epidermoid kidney carcinoma
Caki—1 (ATCC HTB-46) Human Kidney carcinoma
CAKl-2 (DSM ACC 54) Human Kidney carcinoma
G-401 (ATCC CRL 1441) Human a rhabdoid tumor of the kidney
G—402 (ATCC CRL 1440) Human Kidney Leiomyoblastoma
SK-NEP-1 (ATCC HTB-48) Human Ewing sarcoma
SN12A1 (NCl vial 0502750) Human renal carcinoma
786-0: The renal carcinoma cell line 786-0 was established from a primary
renal cell adenocarcinoma of a 58 year old male ian patient. The cells
y both microvilli and omes, and can be grown in soft agar.
Previous studies have shown that the 786-0 cell line harbors an inactivating
mutation in the von-Hippel Lindau (VHL) gene.
A-498: The kidney oma A-498 was established from the kidney
IEF of AST,
carcinoma of a 52—year-old man in 1973 med as human with
MDH, NP.
Caki-1: The Caki-1 cell line was established in 1971 from a metastatic site
(skin) in a 49-year—old ian male with clear cell carcinoma of the kidney.
Caki—1 is a human clear cell renal cell carcinoma ) line that displays
epithelial morphology and grows in adherent culture. When grown on transwell
the apical
filters, these cells form a polarized monolayer with microvilli on
e and display characteristic features of the proximal tubule epithelium. In
addition, the Caki-1 cells are also a useful model to study renal cancer. They
inhibitor of
are more sensitive to 5-fluorouracii and sorafenib (multi-kinase
VEGFR8 1-3, PDGFR-b and Raf—1) than the Caki—2 cells. The Caki-1 cells
and are
express wildtype von Hippei-Lindau (VHL) tumor-suppressor protein
known to form tumors in immunocompromised mice.
Caki-2: This cell line derived from a 69 year old Caucasian male with a kidney
carcinoma. The cells contain microfilaments and multilaminar bodies. They
also exhibit microvilli. Recent evaluation (K. Pulkkanen and J. en,
personal communication) of nude mouse tumors formed by this line in
orthotopic and 5.0. implantations were consistent with cystic papillary renal cell
carcinoma according to the criteria of Kovacs et ai..
(5-401: Derived from a tumour of a 3 month old male Caucasian. Highiy
transformed and grows in soft agar. Highly undifferentiated. G401 was
originally described as a cell line derived from a Wilms tumour. Due to a
3O change in the fication of such tumours, the cell line was examined by
Garvin et al., 1993 and found to be more appropriately classified as derived
from a rhabdoid tumour of the kidney.
(3-402: This cell line was established from a tumour of a 9 month old female
Caucasian. Highly transformed and grows in soft agar. The tumors formed by
W0 2015/104042
_ 18 _
classified as derived from
this cell line in immune compromised mice were
human Caucasian renal leiomyoblastoma of the kidney.
SK—NEP-1: By gene expression profiling it was demonstrated that SK-NEP-1, a
is instead
cell line previously thought to ent anaplastic Wilms tumor,
EWS-
related to Ewing a. RT-PCR med that SK-NEP—1 expresses
FL|1 gene fusion transcripts characteristic of Ewing sarcoma, and
sequencing demonstrated the g of exon 7 of EWS with exon 5 of FLl1 for
these transcripts.
: This tumor cell line derived from a tumor tissue that was obtained
in a 43-year—
from a primary renal tumor subsequent to a radical nephrectomy
old male. The tumor was diagnosed as a renal" cell carcinoma with extensive
invasion of perinephric fat.
After reproducing the growth of these tumor models in immune—compromised
mice 3-(1-{3-[5-(1—methyl-piperidinylmethoxy)-pyrimidinyl]-benzyl}-6—oxo-
1,6-dihydro—pyridazinyl)—benzonitrile hydrochloride hydrate was evaluated in
models with acceptable take rate.
Patent
Claims (6)
1. Use of 3-(1-{3-[5-(1-methyl-piperidinylmethoxy)-pyrimidinyl]- benzyl}oxo-1,6-dihydro-pyridazinyl)-benzonitrile hydrochloride hydrate for the manufacture of a medicament for the treatment of renal cell carcinoma (RCC).
2. The use according to claim 1, wherein, the 3-[5-(1-methylpiperidinylmethoxy )-pyrimidinyl]-benzyl}oxo-1,6-dihydropyridazinyl )-benzonitrile hydrochloride hydrate is 3-(1-{3-[5-(1- methyl-piperidinylmethoxy)-pyrimidinyl]-benzyl}oxo-1,6- dihydro-pyridazinyl)-benzonitrile hydrochloride monohydrate.
3. The use ing to claim 1 or 2, wherein the treatment comprises administration of an amount of 100 mg to 800 mg of the compound to a patient per day.
4. The use according to any one of claims 1 to 3, wherein the treatment comprises oral administration of the compound.
5. The use according to any one of claims 1 to 4, wherein renal cell carcinoma (RCC) is papillary renal cell oma (pRCC).
6. A use according to claim 1 substantially as herein bed or exemplified.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP14000036 | 2014-01-07 | ||
EP14000036.5 | 2014-01-07 | ||
PCT/EP2014/003365 WO2015104042A1 (en) | 2014-01-07 | 2014-12-16 | A 6-oxo-1,6-dihydro-pyridazine derivative for the use for the treatment of renal cell carcinoma (rcc) |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ722879A NZ722879A (en) | 2021-08-27 |
NZ722879B2 true NZ722879B2 (en) | 2021-11-30 |
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