WO2013192512A1 - Dérivés de composés amino-hétéroaryle substitués par un pyrazole - Google Patents

Dérivés de composés amino-hétéroaryle substitués par un pyrazole Download PDF

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Publication number
WO2013192512A1
WO2013192512A1 PCT/US2013/047028 US2013047028W WO2013192512A1 WO 2013192512 A1 WO2013192512 A1 WO 2013192512A1 US 2013047028 W US2013047028 W US 2013047028W WO 2013192512 A1 WO2013192512 A1 WO 2013192512A1
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compound
deuterium
hydrogen
cancer
cds
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PCT/US2013/047028
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English (en)
Inventor
Bhaumik PANDYA
Craig E. Masse
Ian Robert Silverman
Roger Tung
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Concert Pharmaceuticals, Inc.
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Publication of WO2013192512A1 publication Critical patent/WO2013192512A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • 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

Definitions

  • ADME limitation that affects many medicines is the formation of toxic or biologically reactive metabolites.
  • some patients receiving the drug may experience toxicities, or the safe dosing of such drugs may be limited such that patients receive a suboptimal amount of the active agent.
  • modifying dosing intervals or formulation approaches can help to reduce clinical adverse effects, but often the formation of such undesirable metabolites is intrinsic to the metabolism of the compound.
  • a metabolic inhibitor will be co-administered with a drug that is cleared too rapidly. Such is the case with the protease inhibitor class of drugs that are used to treat HIV infection.
  • ritonavir an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for their metabolism (see Kempf, D.J. et al., Antimicrobial agents and chemotherapy, 1997, 41(3): 654-60).
  • Ritonavir causes adverse effects and adds to the pill burden for HIV patients who must already take a combination of different drugs.
  • the CYP2D6 inhibitor quinidine has been added to dextromethorphan for the purpose of reducing rapid CYP2D6 metabolism of dextromethorphan in a treatment of pseudobulbar affect.
  • a potentially attractive strategy for improving a drug's metabolic properties is deuterium modification.
  • Deuterium is a safe, stable, nonradioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability.
  • the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.
  • Crizotinib also known as 3-[l(R)-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[l- (4-piperidinyl)-lH-pyrazol-4-yl]pyridin-2-amine is known to inhibit hepatocyte growth factor receptor (c-met/HGFR) kinase and also to block the tyrosine kinase of anaplastic lympohoma kinase (ALK).
  • a percentage of non- small cell lung cancer patients carry the echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4- ALK) fusion gene.
  • EML4- ALK echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase
  • Crizotinib currently is recommended for approval for non- small cell lung cancer (NSCLC) and is undergoing Phase I/II clinical trials for solid tumor cancer and for lymphoma.
  • This invention relates to novel pyrazole-substituted amino-heteroaryl compounds, and pharmaceutically acceptable salts thereof.
  • This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering an inhibitor of anaplastic lymphoma kinase (ALK) and hepatocyte growth factor receptor (c-met/HGFR) kinase.
  • ALK anaplastic lymphoma kinase
  • c-met/HGFR hepatocyte growth factor receptor
  • Figure 1A shows IC 50 shift assessment plots for crizotinib.
  • Figure 1C shows IC 50 shift assessment plot for Compound 211.
  • Disease means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • a position is designated specifically as “H” or “hydrogen”
  • the position is understood to have hydrogen at its natural abundance isotopic composition.
  • a position is designated specifically as “D” or “deuterium”
  • the position is understood to have deuterium at an abundance that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 45% incorporation of deuterium).
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a compound of this invention has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5%) deuterium incorporation).
  • a compound represented by a particular chemical structure containing indicated deuterium atoms will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure.
  • the relative amount of such isotopologues in a compound of this invention will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound.
  • the relative amount of such isotopologues in toto will be less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues in toto will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, or less than 0.5%> of the compound.
  • the invention also provides salts of the compounds of the invention.
  • a salt of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.
  • a salt of a provided compound is a pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention.
  • pharmaceutically acceptable counterion is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.
  • Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para- toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids.
  • inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylprop
  • subject as used herein includes a human or a non-human animal, such as mouse, rat, guinea pig, dog, cat, horse, cow, pig, monkey (e.g., rhesus), chimpanzee, or baboon.
  • the subject is a non-human animal.
  • the subject is a human.
  • the compounds of the present invention may contain an asymmetric carbon atom, for example, as the result of deuterium substitution or otherwise.
  • compounds of this invention can exist as either individual enantiomers, or mixtures of the two enantiomers.
  • a compound of the present invention may exist as either a racemic mixture or a scalemic mixture, or as individual respective stereoisomers that are substantially free from another possible stereoisomer.
  • substantially free of other stereoisomers as used herein means less than 25% of other stereoisomers, preferably less than 10% of other stereoisomers, more preferably less than 5% of other stereoisomers and most preferably less than 2% of other stereoisomers are present.
  • Substituted with deuterium refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.
  • variable may be referred to generally (e.g., "each R") or may be referred to specifically (e.g., R 1 , R 2 , R 3 , etc.). Unless otherwise indicated, when a variable is referred to generally, it is meant to include all specific embodiments of that particular variable.
  • the present invention rovides a compound of Formula I:
  • R 1 and R 2 are each independently selected from CI, CH 3 and CD 3 ;
  • R 3 is CH 3 or CD 3 ;
  • X la , X lb , X 2a , X 2b , X 3a , X 3b , X 4a , X 4b , and X 5 are each independently selected from hydrogen and deuterium;
  • Y 1 is hydrogen or deuterium
  • Y 2 is hydrogen or deuterium; provided that when each of R 1 and R 2 are CI, each of X la , X lb , X 2a , X 2b , X 3a , X 3b , X 4a , X 4b , and X 5 is hydrogen and each of Y 1 and Y 2 is hydrogen, then R 3 is CD 3 .
  • each of R 1 and R 2 are CI, each of X la , X lb , X 2a , X 2b , X 3a , X 3b , X 4a , X 4b , and X 5 is hydrogen and Y 1 is hydrogen, then R 3 is CD 3 .
  • each of R 1 and R 2 are CI, each of X la , X lb , X 2a , X 2b , X 3a , X 3b , X 4a , and X 4b is hydrogen and each of Y 1 and Y 2 is hydrogen, then R 3 is CD 3 .
  • each of X la , X lb , X 2a , X 2b , X 3a , X 3b , X 4a , and X 4b is hydrogen
  • Y 1 is hydrogen
  • X 5 is deuterium
  • R 3 is CD 3 .
  • each of X la , X lb , X 2a , X 2b , X 3a , X 3b , X 4a , and X 4b is hydrogen
  • Y 1 is hydrogen
  • Y 2 is deuterium
  • R 3 is CD 3 .
  • each of X la , X lb , X 2a , X 2b , X 3a , X 3b , X 4a , and X 4b is hydrogen
  • Y 1 is hydrogen
  • X 5 and Y 2 are each deuterium
  • R 3 is CD 3 .
  • each of X la , X lb , X 2a , X 2b , X 3a , X 3b , X 4a , X 4b , and X 5 is hydrogen and each of Y 1 and Y 2 is hydrogen, then R 3 is CD 3 .
  • X la and X lb are the same, X 2a and X 2b are the same, X 3a and X 3b are the same, and X 4a and X 4b are the same.
  • R 1 and R 2 are independently selected from CI and CD 3 .
  • R 1 and R 2 are the same and are each CI.
  • R 1 and R 2 are the same and are each CD 3 .
  • X la , X lb , X 2a and X 2b are the same, X 3a , X 3b , X 4a and X 4b are the same and R 1 and R 2 are independently selected from CI and CD 3 .
  • each of X la , X lb , X 2a and X 2b is hydrogen; and each of X 3a , X 3b , X 4a and X 4b is deuterium.
  • each of X la , X lb , X 2a and X 2b is deuterium; and each of X 3a , X 3b , X 4a and X 4b is hydrogen.
  • each of X la , X lb , X 2a , X 2b , X 3a , X 3b , X 4a and X 4b is deuterium.
  • each of X la , X lb , X 2a , X 2b , X 3a , X 3b , X 4a and X 4b is hydrogen.
  • R 1 and R 2 are the same and are each CI.
  • R 1 and R 2 are the same and are each CD 3 .
  • each of X la , X lb , X 2a , X 2b , X 3a , X 3b , X 4a and X 4b is hydrogen
  • R 1 and R 2 are the same and are selected from CI
  • CD 3 and R 3 is CH 3 .
  • R 1 and R 2 are each CI.
  • R 1 and R 2 are each CD 3 .
  • each of X la , X lb , X 2a , X 2b , X 3a , X 3b , X 4a and X 4b is hydrogen
  • R 1 and R 2 are the same and are selected from CI
  • CD 3 and R 3 is CD 3 .
  • R 1 and R 2 are each CI.
  • R 1 and R 2 are each CD 3 .
  • each of X la , X lb , X 2a , X 2b , X 3a , X 3b , X 4a and X 4b is deuterium; R 1 and R 2 are the same and are selected from CI and CD 3 and R 3 is CD 3 . In one aspect, R 1 and R 2 are each CI. In one aspect, R 1 and R 2 are each CD 3 .
  • each of X la , X lb , X 2a and X 2b is deuterium
  • each of X 3a , X 3b , X 4a and X 4b is hydrogen
  • R 1 and R 2 are the same and are selected from CI
  • CD 3 and R 3 is CH 3 .
  • R 1 and R 2 are each CI.
  • R 1 and R 2 are each CD 3 .
  • the invention also provides pharmaceutical compositions comprising an effective amount of a compound of Formula I (e.g., including any of the formulae herein), or a pharmaceutically acceptable salt of said compound; and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier e.g., including any of the formulae herein
  • the carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.
  • Another known method of enhancing bioavailability is the use of an amorphous form of a compound of this invention optionally formulated with a poloxamer, such as LUTROLTM and PLURONICTM (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See United States patent 7,014,866; and United States patent publications 20060094744 and 20060079502.
  • compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch or iontophoretic techniques).
  • Other formulations may conveniently be presented in unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed. 2000).
  • Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients.
  • ingredients such as the carrier that constitutes one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc.
  • Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.
  • compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.
  • compositions suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit- dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • compositions of this invention may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, e.g.: Rabinowitz JD and Zaffaroni AC, US Patent 6,803,031, assigned to Alexza Molecular Delivery Corporation.
  • the compounds of this invention may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters.
  • an implantable medical device such as prostheses, artificial valves, vascular grafts, stents, or catheters.
  • Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in US Patents 6,099,562; 5,886,026; and 5,304,121.
  • the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
  • the invention provides a method of coating an implantable medical device comprising the step of contacting said device with the coating composition described above. It will be obvious to those skilled in the art that the coating of the device will occur prior to implantation into a mammal.
  • a composition of this invention further comprises a second therapeutic agent or a combination of second therapeutic agents.
  • the second therapeutic agent(s) may be selected from any compound or therapeutic agent known to have or that demonstrates advantageous properties when administered with a compound having the same mechanism of action as crizotinib.
  • Such agents include those indicated as being useful in combination with crizotinib, including but not limited to, those described in US 2011003805, and CN101836991.
  • the second therapeutic agent(s) is an agent useful in the treatment or prevention of a cancer, more specifically of prostate cancer, osteosarcomas, lung cancer, particularly non-small cell lung cancer, breast cancer, endometrial cancer, glioblastoma, colorectal cancer, ovarian cancer, pancreatic cancer, kidney cancer, small intestinal cancer, esophageal cancer or gastric cancer.
  • a cancer more specifically of prostate cancer, osteosarcomas, lung cancer, particularly non-small cell lung cancer, breast cancer, endometrial cancer, glioblastoma, colorectal cancer, ovarian cancer, pancreatic cancer, kidney cancer, small intestinal cancer, esophageal cancer or gastric cancer.
  • erlotinib is compound A, D D (A).
  • the deuterated form of erlotinib is compound
  • the deuterated form of sorafenib is compound C
  • the kinase inhibitor is erlotinib or sorafenib. In one aspect the kinase inhibitor is a deuterated form of erlotinib (as disclosed in the above-referenced patent applications) or a deuterated form of sorafenib (as disclosed in the above-referenced patent application).
  • the combination is with erlotinib or compound B, and sorafenib or compound C.
  • the combination is erlotinib and sorafenib.
  • the combination is a deuterated form of erlotinib and a deuterated form of sorafenib.
  • the combination is a deuterated form of erlotinib and sorafenib.
  • the combination is erlotinib and a deuterated form of sorafenib.
  • the compound of the present invention is present in an effective amount.
  • effective amount refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat the target disorder.
  • an effective amount of a compound of this invention can range from 25 mg to 500 mg per treatment. Treatment is typically administered one to two times daily. In more specific embodiments the effective amount can be one of the following amounts or ranges:
  • an effective amount of the second therapeutic agent is between about 20% and 100% of the dosage normally utilized in a monotherapy regime using just that agent.
  • an effective amount is between about 70% and 100% of the normal monotherapeutic dose.
  • the normal monotherapeutic dosages of these second therapeutic agents are well known in the art. See, e.g., Wells et al, eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), each of which references are incorporated herein by reference in their entirety.
  • the invention provides a method of treating a disease that is beneficially treated by inhibiting ALK and c-met/HGFR, e.g., crizotinib, in a subject in need thereof, comprising the step of administering to the subject an effective amount of a compound or a composition of this invention.
  • the subject is a patient in need of such treatment.
  • diseases are well known in the art and are disclosed in, but not limited to published application WO 2006/021884.
  • Such diseases include, but are not limited to, cancer, in particular, lung cancer, non-small cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colorectal cancer, colon cancer, gastric cancer, breast cancer, endometrial cancer, carcinoma of the fallopian tubes, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, esophageal cancer, small intestinal cancer, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, cancer of the urethra, cancer of the penis, cancer of the prostate, chronic or acute leukemia, lymphoma, sarcoma of soft tissue, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system
  • the invention provides a method of treating abnormal cell growth in a mammal.
  • the method of this invention is used to treat a disease or condition selected from lymphoma, neuroblastoma, solid tumors and non-small cell lung cancer in a subject in need thereof.
  • Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).
  • the combination therapies of this invention include coadministering a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a second therapeutic agent to a subject in need thereof for treatment of the following conditions (with the particular second therapeutic agent indicated in parentheses following the indication: non-small cell lung cancer (PF-00299804).
  • co-administered means that the second therapeutic agent may be administered together with a compound of this invention as part of a single dosage form (such as a composition of this invention comprising a compound of the invention and an second therapeutic agent as described above) or as separate, multiple dosage forms.
  • the additional agent may be administered prior to, consecutively with, or following the administration of a compound of this invention.
  • both the compounds of this invention and the second therapeutic agent(s) are administered by conventional methods.
  • composition of this invention comprising both a compound of the invention and a second therapeutic agent, to a subject does not preclude the separate administration of that same therapeutic agent, any other second therapeutic agent or any compound of this invention to said subject at another time during a course of treatment.
  • Effective amounts of these second therapeutic agents are well known to those skilled in the art and guidance for dosing may be found in patents and published patent applications referenced herein, as well as in Wells et al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000), and other medical texts. However, it is well within the skilled artisan's purview to determine the second therapeutic agent's optimal effective-amount range.
  • the effective amount of the compound of this invention is less than its effective amount would be where the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is less than its effective amount would be where the compound of this invention is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art.
  • the invention provides the use of a compound of Formula I alone or together with one or more of the above-described second therapeutic agents in the manufacture of a medicament, either as a single composition or as separate dosage forms, for treatment or prevention in a subject of a disease, disorder or symptom set forth above.
  • Another aspect of the invention is a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention in a subject of a disease, disorder or symptom thereof delineated herein.
  • Compound 215 was prepared using a procedure similar to the one disclosed in Example 1 above.
  • Compound 214 was prepared using a procedure similar to the one disclosed in Example 1 above. Without further purification of the reaction product, an 1H NMR was taken (disclosed below) that suggests that 214 is the major component of the mixture.
  • tert-butyl 2,2,6, 6-tetradeutero-4-((methylsulfonyl)oxy)piperidine- 1 - carboxylate 17c Alcohol 16c (0.78 g, 3.81 mmol) and N-methylmorpholine (0.46 mL) were dissolved in dicholoromethane (10 mL) and then cooled to 0C with an ice bath. Methanesulfonyl chloride (0.3 mL) was then added by syringe as a single portion. After 10 minutes the bath was removed and the reaction was warmed to ambient temperature for 2h at which point the reaction was deemed complete by TLC.
  • tert-butyl,2,2,6,6-tetradeutero-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-pyrazol-l-yl) piperidine-l-carboxylate 15c Pyrazole iodide 18c (0.45 g, 1.2 mmol) was dissolved in tetrahydrofuran (5 mL) and then cooled to 0 °C. A solution of isopropyl magnesium chloride in 2-methyl-THF (0.74 mL, 2.4M) was then added dropwise.
  • Piperidine-pyrazole boroxalanes such as 15a, 15b and 15d-h may be prepared from the corresponding 4-hydroxypiperidines as described for compound 15c in Example 10 above.
  • compound 15a may be prepared as described in Example 10 from commercially available tert-butyl 4-hydroxypiperidine-l-carboxylate (CAS 109384- 19-2).
  • Compound 15b may be prepared as described in Example 10 from compound 16e.
  • Compound 15d may be prepared as described in Example 10 from compound 16d.
  • Compound 15e may be prepared as described in Example 10 from compound 16c.
  • Compound 15f may be prepared as described in Example 10 from compound 16f.
  • Compound 15g may be prepared as described in Example 10 from compound 16g.
  • Compound 15h may be prepared as described in Example 10 from compound 16h.
  • Microsomal Assay Human liver microsomes (20 mg/mL) are obtained from Xenotech, LLC (Lenexa, KS). ⁇ -nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCl 2 ), and dimethyl sulfoxide (DMSO) are purchased from Sigma- Aldrich.
  • Testosterone (final concentration 50 mM) was added and the reactions were initiated by addition 2 mM NADPH. These reactions were incubated for another 10 min and then stopped by the addition of acetonitrile with internal standard. The plates were centrifuged to pellet precipitated protein, and supernatants were analyzed by LC-MS/MS for amounts of 6P-OH-testosterone formed. [00191] The same assay was run another two times, each time with a different representative test compound instead of crizotinib: the test compounds in the two runs were, respectively, Compound 212 and Compound 211.

Abstract

Cette invention concerne de nouveaux composés amino-hétéroaryle substitués par un pyrazole de Formule (I) et des sels pharmaceutiquement acceptables de ceux-ci. Des compositions comprenant un composé selon l'invention sont décrites ainsi que l'utilisation de ces compositions dans des méthodes destinées à traiter des maladies et des affections qui sont traitées avec succès par administration de la kinase du lymphome anaplasique (ALK).
PCT/US2013/047028 2012-06-22 2013-06-21 Dérivés de composés amino-hétéroaryle substitués par un pyrazole WO2013192512A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10053477B2 (en) 2014-07-04 2018-08-21 Qilu Pharmaceutical Co., Ltd. Spirocyclic aryl phosphorus oxide and aryl phosphorus sulfide

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060046991A1 (en) * 2004-08-26 2006-03-02 Agouron Pharmaceuticals, Inc. Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors
CN101967140A (zh) * 2010-09-14 2011-02-09 郑州泰基鸿诺药物科技有限公司 氘代克里唑蒂尼及其衍生物、制备方法和应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060046991A1 (en) * 2004-08-26 2006-03-02 Agouron Pharmaceuticals, Inc. Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors
CN101967140A (zh) * 2010-09-14 2011-02-09 郑州泰基鸿诺药物科技有限公司 氘代克里唑蒂尼及其衍生物、制备方法和应用

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10053477B2 (en) 2014-07-04 2018-08-21 Qilu Pharmaceutical Co., Ltd. Spirocyclic aryl phosphorus oxide and aryl phosphorus sulfide

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