WO2009094211A1 - Composés de quinazoline et méthodes de traitement du cancer - Google Patents

Composés de quinazoline et méthodes de traitement du cancer Download PDF

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Publication number
WO2009094211A1
WO2009094211A1 PCT/US2009/000477 US2009000477W WO2009094211A1 WO 2009094211 A1 WO2009094211 A1 WO 2009094211A1 US 2009000477 W US2009000477 W US 2009000477W WO 2009094211 A1 WO2009094211 A1 WO 2009094211A1
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Prior art keywords
compound
cancer
therapeutic agent
patient
deuterium
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PCT/US2009/000477
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English (en)
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Roger Tung
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Concert Pharmaceuticals Inc.
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Publication of WO2009094211A1 publication Critical patent/WO2009094211A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • This invention relates to novel quinazolines, their derivatives, pharmaceutically acceptable salts, solvates, and hydrates 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 angiogenesis and vascular endothelial growth factor receptor (VEGF) kinases.
  • VEGF vascular endothelial growth factor receptor
  • Cediranib also known as 4-(4-fluoro-2 -methyl- lH-indol-5-yloxy)-6-methoxy- 7-(3-(l -pyrrolidinyl)propoxy)quinazoline, RecentinTM, and AZD2171, acts as an angiogenesis inhibitor through inhibition of vascular endothelial growth factor
  • VEGF vascular endothelial growth factor
  • AML acute myeloid leukemia
  • ameliorate and “treat” are used interchangeably and include both therapeutic and prophylactic treatment. Both terms mean decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease.
  • 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 3340 times greater than the natural abundance of deuterium, which is 0.015%' (i.e., at least 50.1% incorporation of deuterium).
  • isotopic enrichment factor as used herein 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 incorporation), 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).
  • the term "isotopologue” refers to a species that differs from a specific compound of this invention only in the isotopic composition thereof.
  • 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, solvates or hydrates 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.
  • the 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.
  • a “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.
  • a “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
  • hydrate means a compound which further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • solvate means a compound which further includes a stoichiometric or non-stoichiometric amount of solvent such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, or the like, bound by non-covalent intermolecular forces.
  • solvent such as water, acetone, ethanol, methanol, dichloromethane, 2-propanol, or the like.
  • the compounds of the present invention may contain an asymmetric carbon atom, for example, as the result of deuterium substitution or otherwise. As such, compounds of this invention can exist as either individual enantiomers, or mixtures of the two enantiomers.
  • a compound of the present invention will include both racemic mixtures, and also individual respective stereoisomers that are substantially free from another possible stereoisomer.
  • substantially free of other stereoisomers 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, or less than "X"% of other stereoisomers (wherein X is a number between 0 and 100, inclusive) are present.
  • stable compounds refers to compounds which possess stability sufficient to allow for their manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents).
  • variable D refers to deuterium.
  • Stepoisomer refers to both enantiomers and diastereomers.
  • Tet refers to both enantiomers and diastereomers.
  • Tet refers to tertiary.
  • US refers to the United States of America.
  • FDA refers to Food and Drug Administration.
  • a 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.
  • R 1 is selected from -CH 3 , -CH 2 D, -CHD 2 and -CD 3 ;
  • R 2 is n-propylene, wherein 1-6 hydrogen atoms are optionally replaced with deuterium;
  • RR 33 iiss ppyyrrolidin-1-yl, wherein 1-8 hydrogen atoms are optionally replaced with deuterium; and at least one of R', R 2 or R 3 comprises a deuterium atom.
  • R 1 is selected from -CH 3 and -CD 3 ;
  • R 2 is selected from -(CH 2 ) 3 -, -(CD 2 ) 3 -, -CD 2 CH 2 CD 2 -, -CD 2 CH 2 CH 2 -, and -CH 2 CH 2 CD 2 -; or c) R , 3 is selected from and
  • a compound of Formula I has the features set forth in two or more of a) through c), above.
  • the compound is selected from any one of the compounds (Cmpd) set forth in Table 1 (below):
  • the compound is selected from any one of
  • any atom not designated as deuterium in any of the embodiments set forth above is present at its natural isotopic abundance.
  • Such methods can be carried out utilizing corresponding deuterated and optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure.
  • Conversion of intermediate 12 to the amine 13 can be carried out by stepwise treatment with HNO 3 followed by NaBH 4 and NiCl 2 . Esterification of 13 in the presence of MeOH followed by condensation with formamide affords the quinazolinone 14. Deprotection of the benzyl ether of 14 with TFA gives the free alcohol 15 which can be readily converted to the acetyl ester 16 using acetic anhydride. Treatment of 16 with thionyl chloride to yield intermediate 17 is followed by deprotection of the acetyl ester in the presence of ammonia/MeOH to afford intermediate 18.
  • the chloride is then treated with appropriately deuterated pyrrolidine 22, such as commercially available pyrrolidine-2,2,3,3,4,4,5,5-d 8 in toluene using the procedure from Syn Comm, 2006, 36: 47-354, to afford the appropriately deuterated intermediate 23.
  • appropriately deuterated pyrrolidine 22 such as commercially available pyrrolidine-2,2,3,3,4,4,5,5-d 8 in toluene using the procedure from Syn Comm, 2006, 36: 47-354, to afford the appropriately deuterated intermediate 23.
  • compositions [43] The invention also provides pyrogen-free compositions comprising an effective amount of a compound of Formula I (e.g., including any of the formulae herein), or a pharmaceutically acceptable salt, solvate, or hydrate of said compound; and an acceptable carrier.
  • a composition of this invention is formulated for pharmaceutical use ("a pharmaceutical composition"), wherein the carrier is a pharmaceutically acceptable carrier.
  • 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.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphate
  • the solubility and bioavailability of the compounds of the present invention in pharmaceutical compositions may be enhanced by methods well-known in the art.
  • One method includes the use of lipid excipients in the formulation. See “Oral Lipid-Based Formulations: Enhancing the Bioavailability of Poorly Water- Soluble Drugs (Drugs and the Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare, 2007; and “Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples," Kishor M. Wasan, ed. Wiley-Interscience, 2006.
  • 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's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA (17th ed. 1985).
  • 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.
  • 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.
  • the compound is administered orally.
  • 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.
  • carriers that are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
  • 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.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
  • the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • 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.
  • Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.
  • the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.
  • the pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention.
  • Application of the subject therapeutics may be local, so as to be administered at the site of interest.
  • Various techniques can be used for providing the subject compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access.
  • 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 coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
  • Coatings for invasive devices are to be included within the definition of pharmaceutically acceptable carrier, adjuvant or vehicle, as those terms are used herein.
  • 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.
  • the invention provides a method of impregnating an implantable drug release device comprising the step of contacting said drug release device with a compound or composition of this invention.
  • Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non-degradable, diffusible polymer capsules and biodegradable polymer wafers.
  • the invention provides an implantable medical device coated with a compound or a composition comprising a compound of this invention, such that said compound is therapeutically active.
  • the invention provides an implantable drug release device impregnated with or containing a compound or a composition comprising a compound of this invention, such that said compound is released from said device and is therapeutically active.
  • a composition of this invention may be painted onto the organ, or a composition of this invention may be applied in any other convenient way.
  • a composition of this invention further comprises a second therapeutic agent.
  • the second therapeutic agent 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 cediranib.
  • the second therapeutic agent is an agent useful in the treatment or prevention of cancer.
  • the second therapeutic agent is selected from 5- fluorouracil, leucovorin, oxaliplatin, capecitabine, paclitaxel, carboplatin, bevacizumab, lomustine, docetaxel, AZD0530, gefitinib, irinotecan, fulvestrant, prednisone, pemetrexed, gemcitabine, cyclophosphamide, doxorubicin, filgrastim, pegfilgrastim, cisplatin and cetuximab.
  • the invention provides separate dosage forms of a compound of this invention and one or more of any of the above-described second therapeutic agents, wherein the compound and second therapeutic agent are associated with one another.
  • the term "associated with one another" as used herein means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or simultaneously).
  • the compound of the present invention is present in an effective amount.
  • the term “associated with one another” means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or simultaneously).
  • an effective amount refers to an amount which, when administered in a proper dosing regimen, is sufficient to reduce or ameliorate the severity, duration or progression of the disorder being treated, prevent the advancement of the disorder being treated, cause the regression of the disorder being treated, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy.
  • an effective amount of a compound of this invention can range from 5-5000 mg per square meter body area of the animal, i.e. approximately 0.1-100 mg/kg.
  • a unit dose in the range for example, 1-100 mg/kg, preferably 1-50 mg/kg is envisaged and this normally provides a therapeutically-effective dose.
  • a unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg of active ingredient.
  • a daily dose in the range of 1-50 mg/kg is employed.
  • Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the patient, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician. For example, guidance for selecting an effective dose can be determined by reference to the prescribing information for cediranib.
  • 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. Preferably, 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.
  • the invention provides a method of modulating the activity of a VEGF receptor tyrosine kinase in a cell, comprising contacting a cell with one or more compounds of Formula I herein.
  • the invention provides a method of treating a patient suffering from, or susceptible to, a disease that is beneficially treated by cediranib comprising the step of administering to said patient an effective amount of a compound or a composition of this invention.
  • the method of this invention is used to treat a patient suffering from or susceptible to a disease or condition selected from cancer.
  • the method of this invention is used to treat a patient suffering from or susceptible to a disease or condition selected from colorectal cancer and metastatic colorectal cancer, glioblastoma multiforme, non- small cell lung cancer, breast and metastatic breast cancer, head and neck cancer, renal cell carcinoma, liver cancer, ovarian cancer, metastatic prostate cancer, solid tumors, gastrointestinal stromal cancer (GIST), acute myeloid leukemia, malignant melanoma, malignant mesothelioma, myelodysplasia, and lymphoma.
  • GIST gastrointestinal stromal cancer
  • any of the above methods of treatment comprises the further step of co-administering to the patient one or more second therapeutic agents.
  • the choice of second therapeutic agent may be made from any second therapeutic agent known to be useful for co-administration with cediranib. The choice of second therapeutic agent is also dependent upon the particular disease or condition to be treated.
  • the combination therapies of this invention include coadministering a compound of Formula I and a second therapeutic agent for treatment of the following conditions (with the particular second therapeutic agent indicated in parentheses following the indication): metastatic colorectal cancer (5-fluorouracil, leucovorin, oxaliplatin, capecitabine, bevacizumab, irinotecan, cisplatin, gemcitabine), glioblastoma multiforme (lomustine), non-small cell lung cancer (5- fluorouracil, leucovorin, oxaliplatin, paclitaxel, carboplatin, gemcitabine, gefitinib, pemetrexed, gemcitabine), breast and metastatic breast cancer (fulvestrant, cyclophosphamide, doxorubicin, docetaxe
  • 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, hi such combination therapy treatment, 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 patient does not preclude the separate administration of that same therapeutic agent, any other second therapeutic agent or any compound of this invention to said patient at another time during a course of treatment.
  • 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.
  • 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 patient of a disease, disorder or symptom set forth above.
  • Another aspect of the invention is a compound of Formula I for use in the treatment or prevention in a patient of a disease, disorder or symptom thereof delineated herein.
  • a disease or condition selected from colorectal cancer and metastatic colorectal cancer, glioblastoma multiforme, non-small cell lung cancer, breast and metastatic breast cancer, head and neck cancer, renal cell carcinoma, liver cancer, ovarian cancer, metastatic prostate cancer, solid tumors, gastrointestinal stromal cancer (GIST), acute myeloid leukemia, malignant melanoma, malignant mesothelioma, myelodysplasia, and lymphoma.
  • kits comprise (a) a pharmaceutical composition comprising a compound of Formula I or a salt, hydrate, or solvate thereof, wherein said pharmaceutical composition is in a container; and (b) instructions describing a method of using the pharmaceutical composition to treat the disease of condition.
  • the container may be any vessel or other sealed or sealable apparatus that can hold said pharmaceutical composition. Examples include bottles, ampules, divided or multi-chambered holders bottles, wherein each division or chamber comprises a single dose of said composition, a divided foil packet wherein each division comprises a single dose of said composition, or a dispenser that dispenses single doses of said composition.
  • the container can be in any conventional shape or form as known in the art which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule.
  • a pharmaceutically acceptable material for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule.
  • the container employed can depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle, which is in turn
  • kits of this invention may also comprise a device to administer or to measure out a unit dose of the pharmaceutical composition.
  • a device to administer or to measure out a unit dose of the pharmaceutical composition may include an inhaler if said composition is an inhalable composition; a syringe and needle if said composition is an injectable composition; a syringe, spoon, pump, or a vessel with or without volume markings if said composition is an oral liquid composition; or any other measuring or delivery device appropriate to the dosage formulation of the composition present in the kit.
  • kits of this invention may comprise in a separate vessel of container a pharmaceutical composition comprising a second therapeutic agent, such as one of those listed above for use for co-administration with a compound of this invention.
  • reaction mixture was concentrated in vacuo and 1 ,4-dioxane (20 mL) was then added. To that solution was added NH 4 OH dropwise until the solution became basic, and the resulting solution was stirred for 1 h. The resulting mixture was concentrated in vacuo then acidified with IM HCl to a pH of 8.0. The mixture was filtered and the solid dried to afford 0.80 g (89%) of the product 32.
  • Example 4 Synthesis of S-ffPyrrolidin-dsVl-ylVpropan-dftVl-ol (37).
  • Intermediate 37 was prepared as outlined in Scheme 6 above using appropriately deuterated starting materials. Details of the synthesis are as follows.
  • Example 5 Synthesis of 4-(4-Fluoro-2-methyl-lH-indol-5-yloxy)-6- (methoxy-d3)-7-(3-(pyrrolidin-l-yl)-propoxy)quinazoline (100).
  • Compound 100 was prepared as outlined in Scheme 7 below. Details of the synthesis are set forth below.
  • Example 7 Synthesis of 4-(4-Fluoro-2-methyl-lH-indol-5-yloxy)-6- (methoxy-d3)-7-(3-((pyrrolidin-ds)-l-yl)-fpropoxy-d ⁇ ))quinazoline (109).
  • Compound 109 was prepared as generally outlined in Scheme 7 above using appropriately deuterated starting materials. Details of the synthesis are set forth below.
  • 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. The incubation mixtures are prepared according to Table 2:
  • SUPERSOMESTM Assay Various human cytochrome P450-specific SUPERSOMESTM are purchased from Gentest (Woburn, MA, USA). A l.O mL reaction mixture containing 25 pmole of SUPERSOMESTM, 2.OmM NADPH, 3.OmM MgCl, and l ⁇ M of a compound of Formula I in 10OmM potassium phosphate buffer (pH 7.4) is incubated at 37 0 C in triplicate. Positive controls contain 1 ⁇ M of Compound 1 instead of a compound of formula I. Negative controls use Control Insect Cell Cytosol (insect cell microsomes that lack any human metabolic enzyme) purchased from GenTest (Woburn, MA, USA).
  • Aliquots (50 ⁇ L) are removed from each sample and placed in wells of a multi-well plate at various time points (e.g., 0, 2, 5, 7, 12, 20, and 30 minutes) and to each aliquot is added 50 ⁇ L of ice cold acetonitrile with 3 ⁇ M haloperidol as an internal standard to stop the reaction.

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Abstract

La présente invention concerne de nouvelles quinazolines, leurs dérivés, sels, solvates et hydrates pharmaceutiquement acceptables. La présente invention concerne également des compositions contenant un composé selon cette invention et l'utilisation de telles compositions dans des méthodes de traitement de maladies et de pathologies dont le traitement bénéficie de l’administration d’un inhibiteur de l’angiogenèse et des kinases du récepteur du facteur de croissance de l’endothélium vasculaire (VEGF).
PCT/US2009/000477 2008-01-22 2009-01-22 Composés de quinazoline et méthodes de traitement du cancer WO2009094211A1 (fr)

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US10568965B2 (en) 2009-06-09 2020-02-25 Auspex Pharmaceuticals, Inc. Aminopyrimidine inhibitors of tyrosine kinase
US9353122B2 (en) 2013-02-15 2016-05-31 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9877970B2 (en) 2013-02-15 2018-01-30 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US10398703B2 (en) 2013-02-15 2019-09-03 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US10966987B2 (en) 2013-02-15 2021-04-06 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
US9827248B2 (en) 2013-02-15 2017-11-28 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
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US9861634B2 (en) 2013-02-20 2018-01-09 Kala Pharmaceuticals, Inc. Therapeutic compounds and uses thereof
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US10160765B2 (en) 2013-11-01 2018-12-25 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
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