EP4021912A1 - Prodrugs of the tyrosine kinase inhibitor for treating cancer - Google Patents
Prodrugs of the tyrosine kinase inhibitor for treating cancerInfo
- Publication number
- EP4021912A1 EP4021912A1 EP20857153.9A EP20857153A EP4021912A1 EP 4021912 A1 EP4021912 A1 EP 4021912A1 EP 20857153 A EP20857153 A EP 20857153A EP 4021912 A1 EP4021912 A1 EP 4021912A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- compound
- mmol
- axitinib
- mixture
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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- 229940002612 prodrug Drugs 0.000 title claims description 34
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- 239000005483 tyrosine kinase inhibitor Substances 0.000 title description 7
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- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
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- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
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- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002829 nitrogen Chemical class 0.000 description 1
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- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- CQYBNXGHMBNGCG-RNJXMRFFSA-N octahydroindole-2-carboxylic acid Chemical compound C1CCC[C@H]2N[C@H](C(=O)O)C[C@@H]21 CQYBNXGHMBNGCG-RNJXMRFFSA-N 0.000 description 1
- 125000004930 octahydroisoquinolinyl group Chemical group C1(NCCC2CCCC=C12)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
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- 125000005954 phenoxathiinyl group Chemical group 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
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- 229910052698 phosphorus Inorganic materials 0.000 description 1
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- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000004928 piperidonyl group Chemical group 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
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- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- DFVFTMTWCUHJBL-BQBZGAKWSA-N statine Chemical compound CC(C)C[C@H](N)[C@@H](O)CC(O)=O DFVFTMTWCUHJBL-BQBZGAKWSA-N 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- NPDBDJFLKKQMCM-UHFFFAOYSA-N tert-butylglycine Chemical compound CC(C)(C)C(N)C(O)=O NPDBDJFLKKQMCM-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
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- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- DZLNHFMRPBPULJ-UHFFFAOYSA-N thioproline Chemical compound OC(=O)C1CSCN1 DZLNHFMRPBPULJ-UHFFFAOYSA-N 0.000 description 1
- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical class C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- BJBUEDPLEOHJGE-IMJSIDKUSA-N trans-3-hydroxy-L-proline Chemical compound O[C@H]1CC[NH2+][C@@H]1C([O-])=O BJBUEDPLEOHJGE-IMJSIDKUSA-N 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- JLGLQAWTXXGVEM-UHFFFAOYSA-N triethylene glycol monomethyl ether Chemical compound COCCOCCOCCO JLGLQAWTXXGVEM-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229960004441 tyrosine Drugs 0.000 description 1
- 235000002374 tyrosine Nutrition 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present disclosure relates to prodrugs of N-methyl-2-((3-((1E)-2-(2- pyridinyl)ethenyl)-1H -indazol-6-yl)thio)benzamide and compositions thereof that are tyrosine kinase inhibitors (TKIs), and uses thereof to treat disease states or conditions mediated by tyrosine kinases, such as cancers.
- TKIs tyrosine kinase inhibitors
- Axitinib (chemical name: N-methyl-2-((3-((1E)-2-(2-pyridinyl)ethenyl)-1H- indazol-6-yl)thio)benzamide; trade name: Inlyta®) is a small molecule tyrosine kinase inhibitor (TKI) used for treating cancer (see, for example, International PCT Application Publication no. W02001002369; the compound's structure is shown below). Axitinib has been shown to significantly inhibit growth of breast cancer in animal xenograft models (Wilmes, L.J. et al., Magn. Reson. Imaging, 2007, 25(3):319- 327).
- TKI tyrosine kinase inhibitor
- RCC renal cell carcinoma
- Axitinib was approved for treatment of RCC by the U.S. Food and Drug Administration after showing a modest increase in progression-free survival.
- Axitinib is used as a targeted anti-cancer therapy since it targets and binds to the vascular endothelial growth factor receptors (VEGFR) on the inside of cancer cells.
- VEGFR vascular endothelial growth factor receptors
- axitinib blocks an important pathway that promotes angiogenesis (the formation of new blood vessels by tumors) (Escudier, B. and Gore, M., "Axitinib for the Management of Metastatic Renal Cell Carcinoma", Drugs in R&D, 2011, 11(2): 113-126).
- axitinib is also used off-label for the treatment of thyroid cancer (differentiated, advanced).
- axitinib in the treatment of cancer is its side effects. Many different adverse effects have been reported, including diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia, hand-foot syndrome, weight decrease, vomiting, asthenia, and constipation, with the most common side effects occurring in more than 20% of patients (FDA Prescribing Information, January 30, 2012).
- PK pharmacokinetics
- axitinib PK a large variability in axitinib PK was evident from the estimated residual standard deviation of 50.9% for oral administration and 34.2% for intravenous administration of axitinib, which could not be reduced by introduction of inter-occasion variability in the model. [0009] The exact causes for this variability in axitinib PK are yet to be elucidated. Axitinib is known to be heavily metabolized (Smith, B. J. et al., Drug Metab. Dispos., 2014, 42:918-931; and Zientek, M. A, et al., Drug Meta. Dispos., 2016, 44(1): 102—114).
- axitinib is primarily metabolized by CYP3A4/5, it has been speculated that one major source of variability may be differences in CYP3A4/5 expression and/or activity in the liver and intestine (a 10- to 40-fold variability in expression of CYP3A4/5 has been reported in healthy subjects). Since axitinib is a low extraction drug, the metabolic clearance of axitinib may be particularly sensitive to variable levels of hepatic and intestinal metabolizing enzymes.
- axitinib solubility is pH-dependent, with solubility declining with increasing pH, changes in pH values in stomach and duodenum may lead to variable dissolution of axitinib.
- a prodrug is a medication or compound that, after administration, is metabolized (i.e., converted within the body) into a pharmacologically active drug (see for example, Rautio, J. et al., "The expanding role of prodrugs in contemporary drug design and development", Nat. Rev.
- Inactive prodrugs are pharmacologically inactive medications that are metabolized into an active form within the body.
- a corresponding prodrug may be used to improve how a medicine is absorbed, distributed, metabolized, and/or excreted (ADME) (for example, see Malhotra, B., et al., "The design and development of fesoterodine as a prodrug of 5 -hydroxymethyl tolterodine (5-HMT), the active metabolite of tolterodine", Curr. Med. Chem., 2009, 16 (33): 4481-9; and Stella, V.J., et al, "Prodrugs. Do they have advantages in clinical practice?", Drugs, 1985, 29 (5): 455-73).
- ADME excreted
- a prodrug may be used to improve how selectively a drug interacts with cells or processes that are not its intended target. This can reduce adverse or unintended effects of a drug, which is especially important for treatments like chemotherapy that often have severe unintended and undesirable side effects.
- tenofovir alafenamide TAF
- TAF tenofovir alafenamide
- axitinib derivatives and/or prodrugs pharmaceutical compositions and uses thereof to inhibit or modulate the activity of tyrosine kinase and to treat disease states or conditions mediated by tyrosine kinases, such as cancers.
- a proper prodrug strategy with axitinib would be able to modulate the pharmacokinetic profile of the drug, through changing the course and/or rate of metabolic pathways of the drug.
- protection of the ring nitrogen atoms in axitinib may modify the electron density of the system and thus modulate the rate of oxidation and subsequently modulate the metabolism of the compound.
- a protection is introduced to the pyrazole nitrogen, it may avoid, at least to a certain extent, glucuronidation at this nitrogen.
- R 1 and R 2 are independently a hydrogen (H) or a protecting group (P); R 3 , which may be present or absent, is a protecting group, and when R 3 is present, the nitrogen atom is positively charged and a counterion is also present; provided that the compound of Formula I is not axitinib.
- R 1 and R 2 are a protecting group (P)
- the protecting groups may be the same or different.
- compounds provided herein are prodrugs of axitinib, i.e., are metabolized or converted in a subject to axitinib.
- a compound of Formula I is a compound of Formula II, or a pharmaceutically acceptable salt, ester, solvate, or polymorph thereof: where R 1 and R 2 are independently a hydrogen (H) or a protecting group (P), and when both R 1 and R 2 are a protecting group, the protecting groups may be the same or different.
- a compound of Formula I is a compound of Formula III, or a pharmaceutically acceptable salt, ester, solvate, or polymorph thereof: where R 3 is a protecting group (P), and is a counterion.
- a protecting group is selected from acyl group, alkylcarbonyl group, arylcarbonyl group, alkylthiocarbonyl group, arylthiocarbonyl group, alkylcarbamoyl group, arylcarbamoyl group, substituted or unsubstituted acetyl, substituted or unsubstituted aminoalkanoyl, substituted or unsubstituted a-aminoalkanoyl, acyl group derived from a natural or an unnatural amino acid with or without substitution, acyl group of a peptide residue, phosphonyl, phosphinyl, aminophophinyl, alkylaminophophinyl, sulfonyl, cycloalkane-carbonyl, heterocycloalkane-carbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroalkoxycarbonyl, heteroaryloxycarbonyl, and O
- a counterion is selected from, but not limited to, halide ion (F-, Cl-, Br-, and I-, sulfate ion, methanesulfonate ion, toluenesulfonate ion, oxalate ion, and other pharmaceutically accepted anionic moiety.
- the compound of Formula I is a compound shown in Table 1, or a pharmaceutically- acceptable salt, ester, chelator, hydrate, solvate, stereoisomer, or polymorphic form thereof.
- compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- pharmaceutical compositions comprising a compound of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- methods of inhibiting or modulating the activity of tyrosine kinases comprising administering to the subject an effective amount of a compound and/or a pharmaceutical composition described herein.
- Non-limiting examples of disease states or conditions mediated by tyrosine kinases that may be treated according to methods provided herein include various tumors and cancers.
- tumors and cancers that may be treated include, without limitation, renal cell carcinoma (RCC), breast cancer, thyroid cancer, and other solid tumors.
- compounds of Formula I, II or III and/or pharmaceutical compositions thereof are administered to modulate the pharmacokinetic profile of axitinib, e.g., to increase bioavailability, change duration of the effective plasma concentration, decrease the variability of plasma levels, reduce the side effects of axitinib, and/or improve the therapeutic effect in a subject, as compared to administration of axitinib itself.
- compounds of Formula I, II or III and/or pharmaceutical compositions thereof are administered to improve biodistribution, reduce the metabolism, and/or broaden the therapeutic application of axitinib in a subject, as compared to administration of axitinib itself.
- compounds of Formula I, II or III and/or pharmaceutical compositions thereof are administrated to increase or modulate the half- life of axitinib through modification of the PK profile, and thereby decrease dose frequency of the compound to a subject, as compared to administration of axitinib itself.
- methods of treating a disease state or condition mediated by tyrosine kinases in a subject in need thereof comprising administering an effective amount of a compound of Formula I, II or III or a pharmaceutical composition thereof to the subject, such that the disease state or condition is treated.
- a method of treating a tumor or a cancer in a subject in need thereof comprising administering an effective amount of a compound of Formula I, II or III or a pharmaceutical composition thereof to the subject, such that the tumor or the cancer is treated.
- the compounds and methods of the present invention are used alone in treating a disease state or condition mediated by tyrosine kinases in a subject.
- kits comprising one or more compound or pharmaceutical composition described herein.
- a kit may further comprise one or more additional therapeutic agents and/or instructions, for example, instructions for using the kit to treat a subject having disease states or conditions mediated by tyrosine kinases.
- FIG. 1 shows plasma axitinib concentration-time curves in mice after oral administration of axitinib, compounds 1, 5, and 10 to the animals at a mole-equivalent dose of 30 mg/kg for all compounds: -o-, compound 1 ; - ⁇ -, compound 2, -x- compound 10; and -D-, axitinib.
- FIG. 2 gives tumor volumes (mm 3 ) from the control group and all the treatment groups at the end of 19-day treatment: all the doses refer to a molar equivalent dose for axitinib; Gl, Control; G2, axitinib-10 mg/kg; G3, axitinib-30 mg/kg, G4, compound 1-10 mg/kg; G5, compound 1-30 mg/kg; G6, compound 5-10 mg/kg; G7, compound 5-30 mg/kg; G8, compound 10-10 mg/kg; G9, compound 10-30 mg/kg.
- FIG. 3 shows a bar-graph representing average tumor weights (g) from different animal groups (control group and all the treatment groups) at the end of 19-day treatment: all the doses refer to an molar equivalent dose for axitinib; G1, Control; G2, axitinib-10 mg/kg; G3, axitinib-30 mg/kg, G4, compound 1-10 mg/kg; G5, compound 1- 30 mg/kg; G6, compound 5-10 mg/kg; G7, compound 5-30 mg/kg; G8, compound 10-10 mg/kg; G9, compound 10-30 mg/kg.
- the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.
- substituted or “with substitution” refers to a parent compound or a moiety has at least one (1) substituent group.
- a “substituent” or a “substituent group” refers to a group selected from halogen (F, Cl, Br, or I), hydroxy, sulfhydryl, amino, nitro, carbonyl, carboxyl, alkyl, alkoxyl, alkylamino, aryl, aryloxyl, arylamino, acyl, thionyl, sulfonyl, phosphonyl, or other organic moiety as used and accepted in general organic chemistry.
- halogen F, Cl, Br, or I
- hydroxy, sulfhydryl amino, nitro, carbonyl, carboxyl, alkyl, alkoxyl, alkylamino, aryl, aryloxyl, arylamino, acyl, thionyl, sulfonyl, phosphonyl, or other organic moiety as used and accepted in general organic chemistry.
- alkyl refers to saturated hydrocarbons having from one to twelve carbon atoms, including linear, branched, and cyclic alkyl groups.
- alkyl groups include, without limitation, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, isopropyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
- alkyl includes both unsubstituted alkyl groups and substituted alkyl groups.
- C 1 -C n alkyl wherein n is an integer from 2 to 12, refers to an alkyl group having from 1 to the indicated "n" number of carbon atoms.
- Alkyl residues may be substituted or unsubstituted. In some embodiments, for example, alkyl may be substituted by hydroxyl, amino, carboxyl, carboxylic ester, amide, carbamate, or aminoalkyl.
- lower as in “lower aliphatic,” “lower alkyl,” “lower alkenyl,” and “lower alkylnyl”, as used herein means that the moiety has at least one (two for alkenyl and alkynyl) and equal to or less than 6 carbon atoms.
- cycloalkyl refers to a group comprising a saturated or partially unsaturated carbocyclic ring in a single, spiro (sharing one atom), or fused (sharing at least one bond) carbocyclic ring system having from three to fifteen ring members.
- cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-yl, cycloheptyl, bicyclo[4,3,0]nonanyl, norbornyl, and the like.
- the term cycloalkyl includes both unsubstituted cycloalkyl groups and substituted cycloalkyl groups.
- C 3 -C n cycloalkyl refers to a cycloalkyl group having from 3 to the indicated "n" number of carbon atoms in the ring structure. Unless the number of carbons is otherwise specified, "lower cycloalkyl” groups as herein used, have at least 3 and equal to or less than 8 carbon atoms in their ring structure.
- Cycloalkyl residues can be saturated or contain one or more double bonds within the ring system. In particular they can be saturated or contain one double bond within the ring system. In unsaturated cycloalkyl residues the double bonds can be present in any suitable positions.
- Monocycloalkyl residues are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl or cyclotetradecyl, which can also be substituted, for example by C 1-4 alkyl.
- substituted cycloalkyl residues are 4-methylcyclohexyl and 2,3-dimethylcyclopentyl.
- Examples of parent structures of bicyclic ring systems are norbornane, bicyclo [2.2.1] heptane, bicyclo[2.2.2]octane and bicyclo[3.2.1]octane.
- heterocycloalkyl refers to a group comprising a saturated or partially unsaturated carbocyclic ring in a single, spiro (sharing one atom), or fused (sharing at least one bond) carbocyclic ring system having from three to fifteen ring members, including one to six heteroatoms (e.g., N, O, S, P) or groups containing such heteroatoms (e.g., NH, NR X (R x is alkyl, acyl, aryl, heteroaryl or cycloalkyl), PO 2 , SO, SO 2 , and the like).
- heteroatoms e.g., N, O, S, P
- groups containing such heteroatoms e.g., NH, NR X (R x is alkyl, acyl, aryl, heteroaryl or cycloalkyl), PO 2 , SO, SO 2 , and the like.
- Heterocycloalkyl groups may be C-attached or heteroatom-attached (e.g., via a nitrogen atom) where such is possible.
- heterocycloalkyl groups include, without limitation, pyrrolidino, tetrahydrofuranyl, tetrahydrodithienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2- pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-
- heterocycloalkyl includes both unsubstituted heterocycloalkyl groups and substituted heterocycloalkyl groups.
- C 3 -C n heterocycloalkyl wherein n is an integer from 4 to 15, refers to a heterocycloalkyl group having from 3 to the indicated "n" number of atoms in the ring structure, including at least one hetero group or atom as defined above. Unless the number of carbons is otherwise specified, “lower heterocycloalkyl” groups as herein used, have at least 3 and equal to or less than 8 carbon atoms in their ring structure.
- aryl and aryl ring refer to aromatic groups having "4n+2".pi.(pi) electrons, wherein n is an integer from 1 to 3, in a conjugated monocyclic or polycyclic system (fused or not) and having six to fourteen ring atoms.
- a polycyclic ring system includes at least one aromatic ring.
- Aryl may be directly attached, or connected via a C 1 -C 3 alkyl group (also referred to as arylalkyl or aralkyl).
- aryl groups include, without limitation, phenyl, benzyl, phenetyl, 1-phenylethyl, tolyl, naphthyl, biphenyl, terphenyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, azulenyl, acenaphthylenyl, fluorenyl, phenanthemyl, anthracenyl, and the like.
- aryl includes both unsubstituted aryl groups and substituted aryl groups.
- C 6 - C n aryl wherein n is an integer from 6 to 15, refers to an aryl group having from 6 to the indicated "n" number of atoms in the ring structure, including at least one hetero group or atom as defined above.
- heteroaryl and “heteroaryl ring” refer to an aromatic groups having "4n+2".pi.(pi) electrons, wherein n is an integer from 1 to 3, in a conjugated monocyclic or polycyclic system (fused or not) and having five to fourteen ring members, including one to six heteroatoms (e.g. N, O, S) or groups containing such heteroatoms (e.g. NH, NR x (R x is alkyl, acyl, aryl, heteroaryl or cycloalkyl), SO, and the like).
- a polycyclic ring system includes at least one heteroaromatic ring.
- Heteroaryls may be directly attached, or connected via a C 1 -C 3 alkyl group (also referred to as heteroarylalkyl or heteroaralkyl). Heteroaryl groups may be C-attached or heteroatom-attached (e.g., via a nitrogen atom), where such is possible.
- heteroaryl groups include, without limitation, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl; isooxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrollyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, chromenyl, isochromenyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,
- heteroaryl includes both unsubstituted heteroaryl groups and substituted heteroaryl groups.
- C 5 - C n heteroaryl wherein n is an integer from 6 to 15, refers to a heteroaryl group having from 5 to the indicated "n" number of atoms in the ring stmcture, including at least one hetero group or atom as defined above.
- heterocycle or “heterocyclic” include heterocycloalkyl and heteroaryl groups.
- heterocycles include, without limitation, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3- b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazoliny
- amine refers to an unsubstituted or substituted moiety of the formula -NR a R b , in which R a and R b are each independently hydrogen, alkyl, aryl, or heterocyclyl, or R a and R b , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring.
- amino includes compounds or moieties in which a nitrogen atom is covalently bonded to at least one carbon or heteroatom.
- alkylamino and dialkylamino as used herein mean an amine group having respectively one and at least two C 1 -C 6 alkyl groups attached thereto.
- arylamino and diarylamino include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively.
- amide or “aminocarbonyl” include compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group.
- acylamino refers to an amino group directly attached to an acyl group as defined herein.
- alkylthio refers to an alkyl group, having a sulfhydryl group attached thereto. Suitable alkylthio groups include groups having 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms.
- alkylcarboxyl as used herein means an alkyl group having a carboxyl group attached thereto.
- alkoxy or “lower alkoxy” as used herein mean an alkyl group having an oxygen atom attached thereto.
- Representative alkoxy groups include groups having 1 to about 6 carbon atoms, e.g., methoxy, ethoxy, propoxy, tert-butoxy and the like.
- Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, pentoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy groups, and the like.
- alkoxy includes both unsubstituted or substituted alkoxy groups, etc., as well as perhalogenated alkyloxy groups.
- carbonyl or “carboxy” include compounds and moieties which contain a carbon connected with a double bond to an oxygen atom.
- moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.
- acyl refers to a carbonyl group that is attached through its carbon atom to a hydrogen (i.e., formyl), an aliphatic group (C1-C alkyl , C1-C alkenyl, C1-C alkynyl, e.g., acetyl), a cycloalkyl group (C3-C8cycloalkyl), a heterocyclic group (C3-C8 heterocycloalkyl and C5-C6 heteroaryl), an aromatic group (C6 aryl, e.g., benzoyl), and the like.
- Acyl groups may be unsubstituted or substituted acyl groups (e.g., salicyloyl).
- solvate refers to a physical association of a compound with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances, a solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. "Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include, without limitation, hydrates, ethanolates, methanolates, hemiethanolates, and the like.
- a "pharmaceutically acceptable salt” of a compound means a salt of a compound that is pharmaceutically acceptable. Desirable are salts of a compound that retain or improve the biological effectiveness and properties of the free acids and bases of the parent compound as defined herein or that take advantage of an intrinsically basic, acidic or charged functionality on the molecule and that are not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts are also described, for example, in Berge et al., “Pharmaceutical Salts", J. Pharm. Sci. 66, 1-19 (1977). Non- limiting examples of such salts include:
- (1) acid addition salts formed on a basic or positively charged functionality, by the addition of inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, carbonate forming agents, and the like; or formed with organic acids such as acetic acid, propionic acid, lactic acid, oxalic, glycolic acid, pivalic acid, t-butylacetic acid, b-hydroxybutyric acid, valeric acid, hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisul
- a metal ion including, an alkali metal ion (e.g., lithium, sodium, potassium), an alkaline earth ion (e.g., magnesium, calcium, barium), or other metal ions such as aluminum, zinc, iron and the like; or coordinates
- salts may be synthesized from a parent compound that contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base forms of compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Salts may be prepared in situ, during the final isolation or purification of a compound or by separately reacting a compound in its free acid or base form with the desired corresponding base or acid, and isolating the salt thus formed.
- pharmaceutically acceptable salts also include zwitterionic compounds containing a cationic group covalently bonded to an anionic group, as they are "internal salts".
- an effective amount refers to the amount or dose of a therapeutic agent, such as a compound, upon single or multiple dose administration to a subject, which provides the desired therapeutic, diagnostic, or prognostic effect in the subject.
- a therapeutic agent such as a compound
- An effective amount can be readily determined by an attending physician or diagnostician using known techniques and by observing results obtained under analogous circumstances.
- a number of factors are considered including, but not limited to: the size, age, and general health of the subject; the specific disease involved; the degree of or involvement or the severity of the disease or condition to be treated; the response of the individual subject; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication(s); and other relevant considerations.
- “Pharmaceutically acceptable” refers to drugs, medicaments, inert ingredients etc., which the term describes, suitable for use in contact with the cells or tissues of humans and animals without undue toxicity, incompatibility, instability, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. It generally refers to a compound or composition that is approved or approvable by a regulatory agency of the Federal or state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals and more particularly in humans.
- “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient, vehicle or carrier with which a compound is administered.
- the terms “Pharmaceutically acceptable vehicle” and “Pharmaceutically acceptable carrier” are used interchangeably herein.
- “Pharmaceutical composition” refers to a composition comprising a compound as described herein and at least one component comprising a pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or vehicle, such as a preserving agent, a filler, a disintegrating agent, a wetting agent, an emulsifying agent, a suspending agent, a sweetening agent, a flavoring agent, a perfuming agent, an antibacterial agent, an antifungal agent, a lubricating agent, a dispensing agent, and the like, depending on the nature of the mode of administration and dosage forms.
- a pharmaceutically acceptable carrier such as a preserving agent, a filler, a disintegrating agent, a wetting agent, an emulsifying agent, a suspending agent, a sweetening agent, a flavoring agent, a perfuming agent, an antibacterial agent, an antifungal agent, a lubricating agent, a dispensing agent, and the like
- Preventing or “prevention” is intended to refer to at least the reduction of likelihood of the risk of (or susceptibility to) acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a patient that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).
- Treating” or “treatment” of any disease or disorder refers, in some embodiments, to ameliorating at least one disease or disorder. In certain embodiments “treating” or “treatment” refers to ameliorating at least one physical parameter, which may or may not be discernible by the patient. In certain embodiments, “treating” or “treatment” refers to inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In some embodiments, “treating” or “treatment” refers to improving the quality of life or reducing the symptoms or side effects of a disease in a subject in need thereof.
- “Therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating or preventing a disease, is sufficient to effect such treatment or prevention of the disease.
- the “therapeutically effective amount” will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject having the disease to be treated or prevented.
- the term “therapeutically effective amount” refers to an amount of a compound or composition sufficient to prevent, treat, inhibit, reduce, ameliorate or eliminate one or more causes, symptoms, or complications of a disease such as cancers.
- subject includes animals, including mammals and humans, particularly humans.
- prodrug and equivalent expressions refer to agents which can be converted in vitro or in vivo directly or indirectly to an active form (see, e.g., R. B. Silverman, 1992, “The Organic Chemistry of Drug Design and Drug Action,” Academic Press, Chap. 8; Bundgaard, Hans; Editor. Neth. (1985), “Design of Prodrugs”. 360 pp. Elsevier, Amsterdam; Stella, V.; Borchardt, R.; Hageman, M.; Oliyai, R.; Maag, H.; Tilley, J. (Eds.) (2007), “Prodrugs: Challenges and Rewards, XVIII, 1470 p. Springer).
- Prodrugs can be used to alter the bio-distribution (e.g., to allow agents which would not typically enter the reactive site of a protease) or the pharmacokinetics for a particular agent.
- a wide variety of groups have been used to modify compounds to form prodrugs, for example, esters, ethers, phosphates, etc.
- the group is cleaved, enzymatically or non-enzymatically, reductively, oxidatively, or hydrolytically, or otherwise to reveal the active form.
- prodrug includes pharmaceutically acceptable salts thereof, or pharmaceutically acceptable solvates as well as crystalline forms of any of the foregoing. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the active form.
- esters refers to compounds that can be represented by the formula RCOOR (carboxylic ester) or the formula RSO3R' (sulfonate ester), usually respectively formed by the reaction between a carboxylic or a sulfonic acid and an alcohol usually with the elimination of water.
- amino acid generally refers to an organic compound comprising both a carboxylic acid group and an amine group.
- amino acid includes both "natural” and “unnatural” or “non-natural” amino acids.
- amino acid includes O-alkylated and N-alkylated amino acids, as well as amino acids having nitrogen or oxygen-containing side chains (such as Lys, Cys, or Ser) in which the nitrogen or oxygen atom has been acylated or alkylated.
- Amino acids may be pure L or D isomers or mixtures of L and D isomers, including (but not limited to) racemic mixtures.
- natural amino acid and equivalent expressions refer to L-amino acids commonly found in naturally- occurring proteins.
- natural amino acids include, without limitation, alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (lle), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gin), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), b-alanine (b-Ala), and g-aminobutyric acid (GABA).
- unnatural amino acid refers to any derivative of a natural amino acid including D forms, and a- and b-amino acid derivatives.
- the terms "unnatural amino acid” and “non-natural amino acid” are used interchangeably herein. It is noted that certain amino acids, e.g., hydroxyproline, that are classified as a non-natural amino acid herein, may be found in nature within a certain organism or a particular protein. Amino acids with many different protecting groups appropriate for immediate use in the solid phase synthesis of peptides are commercially available.
- non-natural amino acids and amino acid derivatives may be used according to the invention (common abbreviations in parentheses): 2-aminoadipic acid (Aad), 3-aminoadipic acid ( b-Aad), 2- aminobutyric acid (2-Abu), a,-dehydro-2-aminobutyric acid (8-AU), 1- aminocyclopropane-1 -carboxylic acid (ACPC), aminoisobutyric acid (Aib), 3- aminoisobutyric acid (b-Aib), 2-amino-thiazoline-4-carboxylic acid, 5-aminovaleric acid (5-Ava), 6-aminohexanoic acid (6-Ahx), 2-aminoheptanoic acid (Ahe), 8-aminooctanoic acid (8-Aoc), 11-aminoundecanoic acid (11-Aun), 12-aminododecanoic acid
- salts thereof are also encompassed, including pharmaceutically acceptable salts.
- pharmaceutically acceptable salts e.g., TFA salt, tetrazolium salt, sodium salt, potassium salt, etc.
- pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.
- salts may be prepared from pharmaceutically acceptable non toxic acids including inorganic and organic acids.
- Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include without limitation acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like.
- suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include without limitation metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.
- methods of increasing the therapeutic effectiveness of axitinib in a subject in need thereof comprising administering an effective amount of a compound of Formula I, II or III or a pharmaceutical composition thereof as described herein to the subject, such that the therapeutic effectiveness of axitinib is increased as compared to administration of axitinib itself.
- the compound is a prodrug of axitinib.
- one or more of the following is increased by administration of a compound, an axitinib prodrug, or a pharmaceutical composition provided herein: bioavailability of axitinib; AUC of axitinib in blood or plasma; C max of axitinib; T max of axitinib; t 1 ⁇ 2 of axitinib; therapeutic biodistribution of axitinib; therapeutic level of axitinib in a selected tissue; and/or bioabsorption of axitinib in a subject, as compared to administration of axitinib itself.
- one or more of the following is reduced by administration of a compound, an axitinib prodrug, or a pharmaceutical composition provided herein: metabolism of axitinib; and side effects of axitinib in a subject, as compared to administration of axitinib itself.
- a target pharmacokinetic parameter for axitinib in a subject comprising administering an effective amount of a compound, an axitinib prodrug, or a pharmaceutical composition thereof as described herein to the subject, such that the target pharmacokinetic parameter for axitinib is attained in the subject.
- target pharmacokinetic parameters include a target bioavailability, AUC in blood or plasma, C max , T max , bio- distribution, level in a selected tissue, half-life (t 1 ⁇ 2 ), bioabsorption, and amount or rate of metabolism.
- Pharmacokinetic parameters may be calculated using methods known in the art.
- a pharmaceutical composition comprising a compound of the invention, e.g., a compound of Formula I, II, or III, or a pharmaceutically acceptable salt, ester, solvate or polymorph thereof, and a pharmaceutically acceptable carrier.
- a pharmaceutical composition comprising a compound in Table 1, or a pharmaceutically acceptable salt, ester, solvate or polymorph thereof, and a pharmaceutically acceptable carrier.
- a pharmaceutical composition comprising a compound of Formula I, II, or III or a compound in Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- Example 1 Synthesis of N-methyl- -((1-pentoxycarbonyl-3-((1E)- -( - pyridiny)ethenyl)- 1H -indazol-6-yl)thio)benzamide (compound 1).
- Example 2 Synthesis of N-methyl-2-((1-oxododecyl-3-((1E)-2-(2- pyridiny)ethenyl)- 1H -indazol-6-yl)thio)benzamide (compound 2)
- axitinib 200 mg, 0.517 mmol, 1.0 eq.
- DMF 4 mL
- Laurie acid 126 mg, 0.621 mmol, 1.2 eq.
- diisopropylamine 110 mg, 0.776 mmol, 1.5 eq.
- HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, hexafluorophosphate azabenzotriazole tetramethyl uronium
- Example 3 Synthesis of N-methyl-2-((1-(N-(t-butoxycarbonyl)-L-valyl)-3- ((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide (compound 3).
- axitinib 150 mg, 0.388 mmol, 1.0 eq.
- DMF 4 mL
- Boc-Val-OSu N-Boc-L- valine N-succinimidyl ester
- triethylamine 117 mg, 1.16 mmol, 3.0 eq.
- Example 5 Synthesis of N-methyl-2-((1-((1-oxo-2,5,8,11-tetraoxadodec-1- yl)-L-valyl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide (compound 51
- Example 6 Synthesis of N-methyl-2-((1-(2,2,2-trifluoroethyloxycarbonyl)-3- ((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide (compound 6).
- Trifluoroethanol 500 mg, 4.98 mmol, 1.0 eq.
- THF 10 mL
- triethylamine 1.1 g, 9.96 mmol, 2.0 eq.
- the reaction mixture was warmed to rt, and stirred at rt overnight, until the starting material disappeared (monitored by TLC).
- Example 7 Synthesis of N-methyl-2-((1-((1S)-(1- methoxycarbonylethyl))amino)(phenoxy)phosphinyl-3-((1E)-2-(2-pyridinyl)ethenyl)- 1/7- indazol-6-yl)thio)benzamide (compound 7)
- Example 8 N-methyl-2-((1-pivaloyl-3-((1E)-2-(2-pyridinyl)ethenyl)-1H- indazol-6-yl)thio)benzamide (compound 8).
- axitinib 400 mg, 1.04 mmol, 1.0 eq.
- DCM 35 mL
- triethylamine 315.1 mg, 3.12 mmol, 3.0 eq.
- pivaloyl chloride 188 mg, 1.24 mmol, 1.2 eq.
- Example 9 N-methyl-2-((1-((1S)-(1-methoxycarbonylethyl))amino)(1- naphthoxy)phosphinyl-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide (compound 10).
- Example 10 Synthesis of N-methyl-2-((1-((1S)-(1- isopropoxycarbonylethyl))amino)(phenoxy)phosphinyl-3-((1E)-2-(2-pyridinyl)ethenyl)- 1H-ndazol-6-yl)thio)benzamide (compound 11).
- Axitinib 200 mg, 0.517 mmol, 1.0 eq.
- DMF 4 mL
- ((1S)-(1- isopropoxycarbonyl)ethyl)amino)(1-naphthoxy)phosphinyl chloride (201.9 mg, 0.569 mmol, 1.1 eq.)
- triethylamine 131.9 mg, 1.29 mmol, 2.5 eq.
- Example 12 N-methyl-2-(( 1-(N-(t-butoxycarbonyl)-L-phenylalanyl)-3-((1E)- 2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl )thio)benzamide (compound 13).
- axitinib 300 mg, 0.778 mmol, 1.0 eq.
- DMF 4 mL
- N-Boc-L-phenylalanine (247 mg, 0.934 mmol, 1.2 eq.)
- N,N-diisopropylethylamine 151 mg, 1.16 mmol, 1.5 eq.
- HATU 354 mg, 0.934 mmol, 1.2 eq.
- the mixture was stirred at rt overnight, followed by addition of water (20 mL) and ethyl acetate (30 mL).
- Example 13 N-methyl-2-((1-(N-(t-butoxycarbonyl)-L-histidyl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl )thio)benzamide (compound 14)
- axitinib 300 mg, 0.78 mmol, 1.0 eq.
- DMF 6 mL
- N(a)-(t-Boc)-L-histidine 219 mg, 0.86 mmol, 1.1 eq.
- DPPA 234 mg, 0.86 mmol, 1.1 eq.
- triethylamine 95 mg, 0.94 mmol, 1.2 eq.
- the mixture was stirred at rt overnight, followed by addition of water (20 mL) and ethyl acetate (30 mL).
- the mixture was transferred to a separatory funnel; and the organic layer was separated, washed with brine (3 x 30 mL), and concentrated.
- Example 14 Synthesis of N-methyl-2-((1-(4-fluorophenoxy)((1S)-(1- methoxycarbonylethyl))amino)phosphinyl-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6- yl)thio)benzamide (compound 15).
- axitinib 400 mg, 1.03 mmol, 1.0 eq.
- N,N- dimethylformamide (6 mL)
- (4-fluorophenoxy)((1S)-(1- methoxycarbonylethyl))amino)phosphinyl chloride 678.5 mg, 2.30 mmol, 2.2 eq.
- triethylamine 260.5 mg, 2.6 mmol, 2.5 eq.
- Example 16 Synthesis of N-methyl-2-((1-(4-chlorophenoxy)((1S)-(1- methoxycarbonylethyl))amino)phosphinyl-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide (compound 19).
- the mixture was concentrated; and the residual material was purified (silica-gel; pet-ether and ethyl acetate, from 100:0 to 50:50), providing (4-chlorophenoxy)((1S-1-methoxycarbonylethyl)amino)phosphinyl chloride (3.0 g, 42%).
- Axitinib 400 mg, 1.03 mmol, 1.0 eq.
- DMF (6 mL)
- (4-chlorophenoxy)((1S- 1-methoxycarbonylethyl)amino)phosphinyl chloride 702.5 mg, 2.30 mmol, 2.2 eq.
- triethylamine 260.5 mg, 2.6 mmol, 2.5 eq.
- the mixture was stirred at rt for 5 h, followed by addition of water (20 mL) and ethyl acetate (30 mL).
- the organic layer was separated, washed with brine (3 x 30 mL), and concentrated.
- Example 17 Synthesis of N-methyl-2-((1-ethoxycavbonyl-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl )thio)benzamide (compound 22)
- axitinib 400 mg, 1.03 mmol, 1.0 eq.
- DMF (12 mL)
- triethylamine 312.1 mg, 3.09 mmol, 3.0 eq.
- 1-dodecyl p-nitrophenyl carbonate 472 mg, 1.34 mmol, 1.3 eq.
- the latter mixture was stirred at rt for 3 h, followed by addition to the mixture of water (50 mL) and ethyl acetate (90 mL). The organic layer was separated, washed with brine (3 x 70 mL), and concentrated.
- Example 19 Synthesis of N-methyl-2-((1-(2-oxo-4H-1,3,2- benzodioxaphosphorin-2-yl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6- yl)thio)benzamide (compound 27)
- axitinib 300 mg, 0.776 mmol, TO eq.
- DMF (12 mL)
- DBU 141.7 mg, 0.931 mmol, E2 eq.
- the mixture was cooled to -20 °C, followed by addition, dropwise, of 2-oxo-4H-2-pentafluorophenoxy-l,3,2-benzodioxaphosphorin (327.9 mg, 0.931 mmol, E2 eq.) in DMF (1 mL).
- the mixture was stirred at -20 °C for 40 min, followed by addition of water (50 mL) and ethyl acetate (70 mL).
- Example 20 Synthesis of N-methyl-2-((1-(P(S)-((1S)-(1- isopropoxycarbonylethyl ))amino)(phenoxy)phosphinyl)-3-((1E)-2-(2-pyridinyl)ethenyl)- 1H-ndazol-6-yl)thio)benzamide (compound 39).
- axitinib 500 mg, 1.3 mmol, TO eq.
- DMF 13 mL
- N-(P(S)-(phenoxy)(pentafluorophenoxy)phosphinyl)-L-alanine isopropyl ester 704 mg, 1.6 mmol, 1.2 eq.
- the mixture was cooled to -50 °C, followed by addition of DBU (208 mg, 1.4 mmol, 1.1 eq.); and the mixture was stirred at -50 °C for 1 h.
- the reaction was quenched by addition of 4 mL of 0.5 M HC1 solution.
- Example 21 Synthesis of N-methyl-2-((1-(b-L-asparaginyl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide bis(trifluoroacetate) (compound 40) [00138] In a flask were mixed axitinib (500 mg, 1.3 mmol, E0 eq.), DMF (10 mL), N- (t-Boc)-L-aspartic acid 1-t-butyl ester (413 mg, 1.4 mmol, 1.1 eq.), and TEA (328 mg, 3.3 mmol, 2.5 eq.), followed by addition of DPPA (716 mg, 2.6 mmol, 2 eq.) dropwise.
- axitinib 500 mg, 1.3 mmol, E0 eq.
- DMF 10 mL
- Example 22 N-methyl-2-((1-(P(S)-(1S)-(1-methoxycarbonylethyl))amino)(1- naphthoxy)phosphinyl-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide (compound 41)
- Axitinib 500 mg, 1.3 mmol, 1.0 eq.
- N-(P(S)-(1- naphthoxy)(pentafluorophenoxy)phosphinyl)-L-alanine methyl ester 741 mg, 1.6 mmol, 1.2 eq.
- DMF 13 mL
- DBU 208 mg, 1.4 mmol, 1.1 eq.
- axitinib 300 mg, 0.778 mmol, 1.0 eq.
- DMF 5mL
- nicotinic acid 116 mg, 0.945 mmol, 1.2 eq.
- N,N-diisopropylethylamine 151 mg, 1.16 mmol, 1.5 eq.
- HATU 354 mg, 0.934 mmol, 1.2 eq.
- Example 24 Synthesis of N-acetyl-N-methyl-2-((1-acetyl-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl )thio)benzamide (compound 43).
- Axitinib (1 g, 2.59 mmol, 1.0 eq.), DCM (50 mL), and triethylamine (784.7 mg, 7.77 mmol, 3.0 eq.) were mixed in a flask, and cooled in an ice-water bath under nitrogen atmosphere. To the cold mixture was added dropwise acetyl chloride (405 mg, 5.18 mmol, 2.0 eq.). The cold bath was then removed; and the mixture was stirred at rt for 16 h, followed by addition of water (60 mL). The organic layer was separated, washed with brine (60 mL), and concentrated.
- N-methyl-2-((1-acetyl-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6- yl)thio)benzamide (1.1 g, 2.58 mmol, 1.0 eq.) and THE (35 mL) were placed in a flask. Under nitrogen atmosphere, the mixture was cooled in an ice-water bath, followed by addition to the mixture of Lithium bis(trimethylsilyl)amide (LiHMDS, 1.0 M solution in THE; 7.74 mL, 7.74 mmol, 3.0 eq.).
- LiHMDS Lithium bis(trimethylsilyl)amide
- the residual material was purified (silica-gel column; eluent, pet-ether and ethyl acetate from 100:0 to 90:10), providing 2-methoxyethyl p-nitrophenyl carbonate (7.2 g, 56.8%).
- Axitinib (450 mg, 1.16 mmol, 1.0 eq.), DMF (12 mL), and triethylamine (351.48 mg, 3.48 mmol, 3.0 eq.) were mixed and stirred in a flask, followed by addition of 2-methoxyethyl p-nitrophenyl carbonate (337.1 mg, 1.39 mmol, 1.2 eq.). The mixture was stirred at rt for 3 h, followed by addition of water (100 mL) and ethyl acetate (120 mL). The organic layer was separated, washed with brine (3 x 70 mL), and concentrated.
- Example 26 Synthesis of N-methyl-2-((1-(1-oco-2,5,8-trioxanayl)-3-((1E)- 2-(2-pyridinyl)ethenyl)-1H-indazo-6-yl)thio)benzamide (compound 45).
- Axitinib 450 mg, 1.16 mmol, 1.0 eq.
- DMF (12 mL)
- triethylamine 351.48 mg, 3.48 mmol, 3.0 eq.
- 2- (2-methoxyethoxy)ethyl p-nitrophenyl carbonate 396.2 mg, 1.39 mmol, 1.2 eq.
- the mixture was stirred at rt for 3 h, followed by addition of water (100 mL) and ethyl acetate (120 mL). The organic layer was separated, washed with brine (3 x 70 mL), and concentrated.
- Example 27 Synthesis of N-methyl-2-((1-(1-oxo-2,5,8,11,14- pentaoxapentadecyl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazoF6-yl)thio)benzamide (compound 46).
- Axitinib 400 mg, 1.03 mmol, 1.0 eq.
- DMF (12 mL)
- triethylamine 313.6 mg, 3.1 mmol, 3.0 eq.
- p-nitrophenyl 3,6,9, 12-tetraoxatridecyl carbonate 462.9 mg, 1.24 mmol, 1.2 eq.
- the mixture was stirred at rt overnight.
- Water (100 mL) and ethyl acetate (120 mL) were added to the reaction mixture. The organic layer was separated, washed with brine (3 x 70 mL), and concentrated.
- Example 28 Synthesis of N-methyl-2-((1-(2-(2- hvdroxyethoxy)ethoxycarbonyl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6- yl)thio)benzamide hydrochloride (compound 49).
- the reaction temperature was raised to rt; and the reaction continued at rt for 3 h, followed by washing the reaction mixture with saturated ammonium chloride solution (30 mL) and brine (30 mL) subsequently.
- the organic layer was concentrated, providing diethylene glycol mono-(tert- butyldimethylsilyl) ether (1.3 g, 89.4%).
- the residual material was purified on a silica-gel column (eluent: DCM-methanol, from 100:0 to 100:3), giving N-methyl-2-((1- (2-(2-(ter-butyldimethysilyloxy)ethoxy)ethoxycarbonyl)-3-((1E)-2-(2-pyridinyl)ethenyl)- 1H-indazol-6-yl)thio)benzamide (1.7 g, 81.0%).
- the above obtained product (1.0 g) was stirred in a solution of 1% hydrochloric acid in ethanol (60 mL) at rt for 2 h.
- Example 29 Synthesis of N-methyl-2-((1-(2-(2-(2-(2- hydrosxyethoxy)ethoxy)ethoxcarbonyl) -3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6- yl)thio)benzamide hydrochloride (compound 50).
- the mixture was absorbed on silica-gel, loaded onto a silica-gel column, and purified with eluent of a mixture pet-ether and ethyl acetate (from 100:0 to 100:20), giving p-nitrophenyl 10,10,11,11-tetramethyl-3, 6, 9-trioxa-10- siladodec-1-yl carbonate (1.6 g, 70.3%).
- Axitinib (1.2 g, 3.1 mmol, 1.0 eq.), DMF (30 mL), TEA (783 mg, 7.75 mmol, 2.5 eq.), and a solution of the carbonate obtained from the reaction above (1.6 g, 3.7 mmol, 1.2 eq.) in DMF (6 mL) were mixed in a flask. The mixture was stirred overnight, followed by addition of water (60 mL) and ethyl acetate (90 mL). The organic layer was separated, washed with brine (3 x 50 mL), and concentrated.
- Example 30 Synthesis of N-methyl-2-((1-(13-hvdroxy-1-oxo-2,5,8,11- tetraoxatridec- 1-yl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide hydrochloride (compound 51).
- Tetraethylene glycol (8 g, 41.18 mmol, 5.0 eq.), DCM (25 mL), DMAP (201 mg, 8.24 mmol, 0.2 eq.), and triethylamine (833.1 mg, 8.24 mmol, 1.0 eq.) were mixed in a flask and cooled to 0 °C in an ice-water bath, followed by addition of a solution of TBSC1 (1.24 g, 8.24 mmol, 1.0 eq.) in DCM (5 mL). The temperature of the reaction was raised to rt; and the mixture was stirred at rt for 5 h.
- the reaction mixture was then concentrated to dryness, and the residue was extracted with ethyl acetate and water (40 mL each). The organic layer was separated and concentrated. The residue was purified (silica-gel column; eluent, pet-ether and ethyl acetated from 100:0 to 100:10), providing p-nitrophenyl 13, 13,14, 14-tetramehtyl-3, 6,9, 12-trtraoxa-13- silapentadec-1-yl carbonate (1.6 g, 49.7%).
- the residual material was purified (silica-gel column; eluent, DCM- methanol from 100:0 to 100:3), providing N-methyl-2-((1-(13,13,14,14-tetramehtyl- 3,6,9, 12-trtraoxa-13-silapentadec-1-yl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6- yl)thio)benzamide (850 mg, 83.1 %), which was treated, under stirring, in a solution of hydrochloric acid in ethanol (1 mL cone. HC1 in 99 mL ethanol) for 3 h (TLC indicating completion of the reaction at this point).
- Example 31 Synthesis of N-methyl-2-((1-(indol-4-oxy)((1S)-1- methoxycarbonylethyl))amino)phosphinyl-3-((1E)--(2-pyridinyl)ethenyl)-1H-indazol-6- yl)thio)benzamide (compound 61).
- Axitinib 400 mg, 1.03 mmol, 1.0 eq.
- DMF (12 mL)
- N-(chloro(indol-4- oxy)phosphinyl)-L-alanine methyl ester (1.47 g, 4.65 mmol, 4.5 eq.)
- triethylamine 0.575 g, 5.69 mmol, 5.5 eq.
- water 50 mL
- ethyl acetate 70 mL
- the organic layer was separated, washed with brine (3 x 50 mL), and concentrated.
- Example 32 Synthesis of N-methyl-2-((1-((1S)-(9H-carbazol-4-oxy)(1- methoxycarbonylethyl))amino)phosphinyl-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6- yl)thio)benzamide (compound 66).
- Axitinib 400 mg, 1.03 mmol, 1.0 eq.
- DMF (12 mL)
- (4-carbazol-4- oxy)((1S)-(1-methoxycarbonylethyl)amino)phosphinyl chloride (1.89 g, 5.18 mmol, 5.0 eq.)
- triethylamine (0.63 g, 6.18 mmol, 6.0 eq.) were mixed in a flask and stirred at rt for 5 h, followed by addition of water (50 mL) and ethyl acetate (70 mL). The organic layer was separated, washed with brine (3 x 50 mL), and concentrated.
- Example 33 Synthesis of N-methyl-2-((1-((1S)-(naphth-2-oxy)(1- methoxycarbonylethyl))amino)phosphinyl-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6- yl)thio)benzamide (compound 90).
- Axitinib 200 mg, 0.518 mmol, 1.0 eq.
- DMF 4 mL
- N-(chloro(naphth-2- yl)phosphinyl)-L-alanine methyl ester 186.5 mg, 0.569 mmol, 1.1 eq.
- triethylamine 131.9 mg, 1.29 mmol, 2.5 eq.
- Example 34 Synthesis of N-methyl-2-((1-(1-oxo-2,5,8,11,14,17,20,23- octaoxatetracos-1-yl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide (compound 94)
- Heptaethylene glycol monomethyl ether 400 mg, 1.17 mmol, 1.0 eq.
- THF 5 mL
- triethylamine 177.59 g, 1.76 mmol, 1.5 eq.
- p-nitrophenyl chloroformate 258.69 mg, 1.29 mmol, 1.1 eq.
- the residual material was purified on a silica-gel column (eluent: pet-ether and ethyl acetate from 100:0 to 70:30), giving 3,6,9,12,15,18,21-heptaoxadocos-1-yl p-nitrophenyl carbonate (400 mg, 67.8%).
- Example 35 Synthesis of N-methyl-2-((1-((1S)-(2-methylbenzyloxy)(1- methoxycarbonylethyl))amino)phosphinyl-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6- yl)thio)benzamide (compound 95).
- phosphorus oxychloride (1.9 g, 12.3 mmol, 1.0 eq.) and DCM (50 mL) were placed in a flask and cooled to -78 °C, followed by addition, to the cold mixture, of 2-methylbenzyl alcohol (1.5 g, 12.3 mmol, 1.0 eq.) and a solution of triethylamine (1.2 g, 12.3 mmol, 1.0 eq.) in DCM (20 mL).
- the residual material was purified on a silica-gel column (eluent: pet-ether and ethyl acetate, from 100:0 to 35:65), giving N-((2-methylbenzyloxy)(pentefluorophenoxy)phosphinyl)-L-alanine methyl ester (2.8 g, 71.9%).
- axitinib 400 mg, 1.0 mmol, 1.0 eq.
- DMF 15 mL
- N-((2-methylbenzyloxy)(pentefluorophenoxy)phosphinyl)-L-alanine methyl ester 563 mg, 1.2 mmol, 1.2 eq.
- DBU 183 mg, 1.2 mmol, 1.2 eq.
- the mixture was stirred at rt for 0.5 h, and then treated with water (10 mL) and ethyl acetate (30 mL). The organic layer was separated, washed with brine (3 x 10 mL), and concentrated.
- Example 36 Synthesis of N-methyl-2-((1-((1S)-(naphthoxy)(1-(1S-1- phenylethoxycarbonyl)lethyl))amino)phosphinyl-3-((1E)-2-(2-pyridinyl)ethenyl)-1H- indazol-6-yl)thio)benzamide (compound 96).
- Axitinib 256.3 mg, 0.663 mmol, 1.0 eq.
- DMF (12 mL)
- DBU (121.2 mg, 0.796 mmol, 1.2 eq.) were mixed in a flask and cooled to -20 °C, followed by addition a solution of N-chloro(naphth-1-yloxy)(pentafluorophenoxy)phosphonyl-L- alanine (S)-1-phenylethyl ester (450 mg, 0.796 mmol, 1.2 eq.) in DMF (1 mL).
- Example 37 Synthesis of N-methyl-2-((1-((5-methyl-2-oxo-1,3-dioxol-4- yl)methoxycabonyl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6-yl)thio)benzamide (compound 97)
- the residue was purified (silica-gel column; eluent, pet-ether and ethyl acetate from 100:0 to 50:50), providing 5-methyl-2-oxo-l,3-dioxol-4-yl)methyl p-nitrophenyl carbonate (600 mg, 54%).
- Axitinib 400 mg, 1.04 mmol, 1.0 eq.
- DMF 6 mL
- triethylamine 157 mg, 1.56 mmol, 1.5 eq.
- the mixture was stirred at rt for 16 h, followed by addition of water (20 mL) and ethyl acetate (30 mL). The organic layer was separated, washed with brine (3 x 30 mL), and concentrated.
- the residual material was purified on a silica-gel column (eluent: per-ether and ethyl acetate from 100:0 to 80:20), providing 2- (tert-butyldimethylsilyloxy)ethanol (1.93 g, 82%).
- the mixture was concentrated; and the residual material was extracted between ethyl acetate and water (40 mL each). The organic layer was separated and concentrated to a residue. The residual material was purified (silica-gel column; eluent, pet-ether and ethyl acetate from 100:0 to 80:20), giving 2-(tert-butyldimethylsilyloxy)ethyl p-nitrophenyl carbonate (3 g, 81%).
- Axitinib 400 mg, 1.04 mmol, 1.0 eq.
- DMF 6 mL
- triethylamine 79 mg, 2.08 mmol, 2.0 eq.
- 2-(tert- butyldimethylsilyloxy)ethyl p-nitrophenyl carbonate 424 mg, 1.25 mmol, 1.2 eq.
- the mixture was stirred at rt for 16 h, followed by addition of water (20 mL) and ethyl acetate (30 mL).
- the organic layer was separated, washed with brine (3 x 30 mL), and concentrated.
- the residual material was purified (silica-gel column; eluent, DCM- methanol from 100:0 to 100:3), giving N-methyl-2-((1-(2-(tert- butyldimetylsilyoxyethoxycabonyl)-3-((1E)-2-(2-pyridinyl)ethenyl)-1H-indazol-6- yl)thio)benzamide (600 mg, 98%) as silyl-protected intermediate.
- the intermediate (600 mg) was stirred in ethanol (10 mL) containing concentrated HC1 (0.1 mL) at rt for 3 h.
- Test articles were prepared in suspension in a mixture of DMSO (5%) and 0.5%-CMC-Na (95%, v/v), at a concentration of 3 mg/mL axitinib-molar-equivalence for each test article.
- Male ICR mice 64, body weight ranging 18-22 g) were grouped randomly in 4 groups (16 animals per group).
- Test articles were administered to animals through oral-gavage, at a dose of molar-equivalent to 30 mg/kg of axitinib, after the animals were fasted for 12 h.
- Blood samples were collected from orbit to heparinized EP tube at time points of 0.25, 0.5, 1, 2, 4, 6, and 8 h following the administration of the dosing solution.
- Example 40 Pharmacokinetic studies (b).
- mice Male ICR mice (body weight: 18 to 22 g) were divided into 6 groups randomly with 6 animals per group, with blood sample collection from 6 animals at each time point for a total of 6 time points.
- Dosing solution of a test article was prepared by dissolving or suspending a compound in a solvent system as indicated in Table 2. For all the compounds, the concentration of dosing solution was 3 mg/mL of axitinib molar equivalent, and the dose was 30 mg/kg of axitinib molar equivalent. Animals were fasted for 12 h, and then given the test article in dosing media at a dosing volume calculated according to the above information.
- Plasma sample (20 mL) was mixed well with acetonitrile (220 mL). The sample was then centrifuged at 12,000 rpm and 4 °C. The supernatant was analyzed with an LC- MS/MS instrument, and the target analytes were axitinib and its corresponding prodrug molecules. Table 2 gives pharmacokinetic parameters for some test compounds following administration of the corresponding prodrugs to the animals.
- Example 41 Anti-tumor activity of selected compounds in an EN1903-3 HT-
- the HT29 model was created using male Balb/c Nude mice, 16-18 g body weight, (Balb/c Nude mice, SPF grade from Shanghai Qinlong Biotechnology Co., Ltd., Shanghai, China), as follows : a) HT29 cells were cultured and expanded until enough cells were obtained, then the cells were collected; b) HT29 cells were suspended in serum-free M5A culture media at a concentration of 3.0 x 10 7 cells/mL, total 15 mL; c) A total of 130 Balb/c nude mice were subcutaneously inoculated with 0.1 mL cell suspension per mouse (or 3.0 x 10 6 cells/mouse).
- each group was given a number as follows: G1, Control; G2, axitinib at 10 mg/kg; G3, axitinib at 30 mg/kg; G4, compound 1 at 10 mg/kg molar equivalent of axitinib; G5, compound 1 at 30 mg/kg of molar equivalent of axitinib; G6, compound 5 at 10 mg/kg molar equivalent of axitinib; G7, compound 5 at
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