WO2010019701A2 - Dérivés de diaryl urée - Google Patents

Dérivés de diaryl urée Download PDF

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Publication number
WO2010019701A2
WO2010019701A2 PCT/US2009/053595 US2009053595W WO2010019701A2 WO 2010019701 A2 WO2010019701 A2 WO 2010019701A2 US 2009053595 W US2009053595 W US 2009053595W WO 2010019701 A2 WO2010019701 A2 WO 2010019701A2
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composition
compound
disease
condition
conjunction
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PCT/US2009/053595
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WO2010019701A3 (fr
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Julie Liu
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Concert Pharmaceuticals, Inc.
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Publication of WO2010019701A2 publication Critical patent/WO2010019701A2/fr
Publication of WO2010019701A3 publication Critical patent/WO2010019701A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to novel diaryl urea compounds, their derivatives, and pharmaceutically acceptable salts thereof. More specifically, this invention relates to novel diaryl urea compounds that are derivatives of sorafenib. 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 multikinase inhibitors, such as sorafenib.
  • Sorafenib also known as 4-[4-[3-[4-Chloro-3-
  • Sorafenib is currently approved for the treatment of patients with renal cell carcinoma and for the treatment of patients with hepatocellular carcinoma. Sorafenib is also in clinical trials for the treatment of various cancers including non- small cell lung, lung, small cell lung, breast, ovarian, fallopian tube, peritoneal cavity, pancreatic, bladder, metastatic prostate, thyroid, uterine, gastrointestinal stromal, metastatic melanoma, prostate adenocarcinoma, soft tissue sarcoma, mesothelioma, glioblastoma multiforme, acute myeloid leukemia, non-Hodgkin's lymphoma, multiple myeloma, glioblastoma, lymphoma, anaplastic astrocytoma, solid tumor, colorectal, squamous cell head and neck carcinoma, and oligodendroglioma, Sorafenib is also under clinical evaluation for pulmonary hypertension.
  • Sorafenib is metabolized primarily in the liver via oxidation or glucuronidation.
  • Adverse events reported In at least 10% of patients treated with sorafenib include, but are not limited to, hypertension, fatigue, weight loss, rash, hand-foot skin reaction, alopecia, pruritis, diarrhea, nausea, vomiting, constipation, hemorrhage, sensory neuropathy, joint pain, and headache. (See product label: http://www.fda.gov/eder/foi/label/2005/0219231bl.pdf),
  • Figure 1 depicts chromatograms from the phosphate-buffered saline (PBS) side of a dialysis of a) Compound 1 14 with human plasma; and b) sorafenib with human plasma.
  • PBS phosphate-buffered saline
  • treat includes both therapeutic treatment and prophylactic treatment (reducing the likelihood of development) means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease
  • a disease or disorder delineated herein e.g., a disease or disorder delineated herein
  • lessen the severity of the disease or improve the symptoms associated with the disease e.g., a disease or disorder delineated herein
  • Disease means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.
  • Disease means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.
  • isotopic enrichment factor means the ratio between the isotopic abundance the naturally occurring abundance of a specified isotope.
  • a compound of this invention has an isotopic enrichment factor for each deuterium present at a site designated as a potential site of deuteration on the compound of at least 3500 (52.5% deuterium incorporation), 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).
  • the isotopic enrichment factor of each deuterium present at a site designated as a site of deuteration is independent of other deuterated sites. For example, if there are two sites of deuteration on a compound one site could be deuterated at 52.5% while the other could be dettterated at 75%. The resulting compound would be considered to be a compound wherein the isotopic enrichment factor is at least 3500 (52.5%).
  • isotopologue refers to a species that differs from a specific compound of this invention only in the isotopic composition thereof. Isotopotogues can differ in the level of isotopic enrichment at one or more positions and/or in the positions(s) of isotopic enrichment.
  • compound when referring to compounds of the invention, refers to a collection of molecules having an identical chemical structure, except that there may be isotopic variation among the constituent atoms of the molecules.
  • 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. However, as set forth above the relative amount of such isotopologues in toto will be less than 49.9% of the compound.
  • the relative amount of such isotopologues in tola 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. 119] 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. According to another embodiment, 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.
  • 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 couiiterion 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-toluetiesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fiimaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, melhanesulfooic 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
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogetiphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succiaate, suberate, sebacate, fiimarate, nialeate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobcnzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, pheny
  • pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobrornic acid, and especially those formed with organic acids such as maleic acid, f22J
  • 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).
  • D refers to deuterium.
  • Tet and “t-” each refer to tertiary.
  • US refers to the United States of America.
  • FDA refers to Food and Drug Administration.
  • NDA refers to New Drug Application
  • variable may be referred to generally (e.g., "each R") or may be referred to specifically (e.g., R 1 , R", 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.
  • X is selected from N and N + -O " ;
  • R 1 is selected from CHj, CH 2 D, CHD 2 and CD 3 ; each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 is independently selected from H and D; and at least one R group comprises a deuterium atom.
  • R 1 is selected from CH 2 D, and CHD 2 .
  • Other embodiments of Formula I include a compound wherein: a) X is N: b) R 2 , R 10 and R 1 ' are the same; c) R 3 , R 4 , R s and R 9 are the same; d) R 5 , R 6 and R 7 are the same; or e) R 1 is selected from CH 3 and CD 3 .
  • a compound of Formula I includes two or more of the features set forth in a) through e), above.
  • R 2 , R 10 and R 11 are the same; X is N and R 3 , R 4 , R 8 and R 9 are the same; X is N and R 5 , R 6 and R 7 are the same; X is N and R 1 is selected from CH 3 and CD 3 ; X is N, R 2 , R 10 and R 11 are the same and R 3 , R 4 , R 8 and R 9 are the same; X is N, R 2 , R 10 and R 1 ' are the same and R 5 , R 6 and R 7 are the same; X is N, R 2 , R 10 and R 11 are the same and and R 1 Is selected from CH 3 and CD 3 ; X is N, R 3 , R 4 , R 8 and R 9 are the same and R 5 , R 6 and R 7 are the same; X is N, R 3 , R 4 , R 8 and R 9 are the same and R 1 is selected from CH 3 and CD 3 ; X is N, R 3 , R 4 , R 8
  • X is N, R 2 , R 10 and R 11 are the same, R 3 , R 4 , R s and R 9 are the same and R 1 Is selected from CH 3 and CD 3 ;
  • X is N, R a , R l ⁇ and R ⁇ are the same, R 5 , R 6 and R 7 are the same and R ! is selected from CH 3 and CD 3 ; and
  • X is N, R 3 , R 4 , R 8 and R 9 are the same, R 5 , R 6 and R 7 are the same and R ! is selected from CH 3 and CD- 5 .
  • R 1 is selected from CH 3 and CDs , R 5 and R 7 are the same; R 2 , R 10 and R ⁇ are the same; and R 3 , R 4 , R 8 and R 9 are the same,
  • R 5 and R 7 are deuterium; R 6 is hydrogen; and X is N.
  • X is N
  • any atom not designated as deuterium in any of the embodiments set forth above is present at its natural isotopic abundance.
  • f35J The synthesis of compounds of Formula I can be readily achieved by synthetic chemists of ordinary skill. Relevant procedures and intermediates are disclosed, for instance in PCT publications WO 2000041698 and WO 2000042012; and in Sorbera, LA et al, Drags Fut, 2002, 27(12):1141; and Bankston, D et al., Org Process Res Dev, 2002, 6(6): 777.
  • 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.
  • Certain intermediates can be used with or without purification (e.g., filtration, distillation, sublimation, crystallization, trituration, solid phase extraction, and chromatography).
  • N-oxide forms of a compound of Formula I are synthesized by oxidizing the pyridine ring nitrogen using an oxidant such as meta-chloroperoxybenzoic acid (m-
  • 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 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, d ⁇ s ⁇ dium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial
  • 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 transdermal ⁇ y (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.
  • 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.
  • 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 usefal for containing such suspensions, which may beneficially increase the rate of compound absorption,
  • carriers that are commonly used include lactose and com starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • 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 non-aqueous 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 (lyopMllzed) 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.
  • suitable dispersing or wetting agents such as, for example, Tween 80
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic pareiiterally-acceptable diluent or solvent, for example, as a solution in 1,3- butanediol.
  • Suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution, in addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or d ⁇ glycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutical Iy- 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,
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • These compositioiis 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.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • the pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation.
  • 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 5 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 arc 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 drag 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 drag 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 sorafenib.
  • the second therapeutic agent is an agent useful in the treatment or prevention of a disease or condition selected from cancer, viral infections, inflammatory skin, eye and/or car diseases, diabetic neuropathy, pulmonary hypertension, arterial restenosis and transplant rejection.
  • the second therapeutic agent is selected from doxorubicin, dacarbazine, temozolomide, anastrozole, gemcitabinc, topotecan, bicalutamide, RADOOl, AMG 386, taxotere, bevacizumab, temsirolimus, erlotinib, tipifarnib, perifosine, pemetrexed, cetuximab, recombinant IL-21, paclitaxcl, irinotecaii hydrochloride, everolimus, abraxane, mitoxantrone, prednisone, eioposide, and carboplatin.
  • 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.
  • 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).
  • the compound of the present invention is present in an effective amount
  • the term "effective amount” refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat (therapeutically or prophylactically) the target disorder. For example, and effective amount is sufficient to reduce or ameliorate the severity, deration 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.
  • the interrelationship of dosages for animals and humans is described in Freireich et al., (1966) Cancer Chemother. Rep 50: 219. Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N. Y., 1970, 537. 47»
  • an effective amount of a compound of this invention can range from about 0.5 to 6000 mg per treatment. In more specific embodiments the range is from about 5 to 3000 mg, or 10 to 1200 ing, or most specifically from about 50 to 600 mg per treatment. Treatment typically is administered from about twice daily to once per week.
  • 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 Sorafenib.
  • 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 monotherapeut ⁇ c 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, Tarascoii 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 inhibiting multiple kinases in a cell, comprising contacting a cell with one or more compounds of Formula I herein or pharmaceutically acceptable salts thereof, (78]
  • the invention provides a method of treating a disease that is beneficially treated by sorafenib comprising the step of administering to a patient in need thereof an effective amount of a compound or a composition of this invention.
  • Such diseases are well known in the art and are disclosed in, but not limited to the following patents and published applications: WO 2005000284, WO 2007068383, WO 2007068381 , WO 2007053573, WO 2007054302, and WO 2007054215,
  • diseases include, but are not limited to, cancer, viral infections, inflammatory skin, eye and/or ear diseases, diabetic neuropathy, pulmonary hypertension, arterial restenosis and transplant rejection.
  • the method of this invention is used to treat a disease or condition selected from renal cell carcinoma and other cancers including liver, non-small cell lung, lung, breast, ovarian, fallopian tube, peritoneal cavity, pancreatic, bladder, prostate metastatic, thyroid, uterine, gastrointestinal stromal, metastatic melanoma, prostate adenocarcinoma, soft tissue sarcoma, mesothelioma, glioblastoma multiforme, acute myeloid leukemia, non-Hodgkin's lymphoma, multiple myeloma, glioblastoma, lymphoma, anaplastic astrocytoma, squamous cell head and neck carcinoma, oligodendroglioma, solid tumor, and colorectal cancers, and pulmonary hypertension.
  • a disease or condition selected from renal cell carcinoma and other cancers including liver, non-small cell lung, lung, breast, ovarian, fallopian tube, peritoneal cavity, pan
  • the method of this invention is used to treat renal cell carcinoma
  • Methods delineated herein also include those wherein the patient is identified as in need of a particular stated treatment. Identifying a patient in need of such treatment can be in the judgment of a patient or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).
  • 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 sorafenib.
  • the choice of second therapeutic agent is also dependent upon the particular disease or condition to be treated. Examples of second therapeutic agents that may be employed in the methods of this invention are those set forth above for use in combination compositions comprising a compound of this invention and a second therapeutic agent,
  • the combination therapies of this invention include treatment of the following conditions by co-administering to a patient in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof and the particular second therapeutic agent indicated in parentheses; renal cell carcinoma (AMG 386, recombinant IL-21, perifosine, and RADOOl); hepatocellular carcinoma (doxorubicin); breast cancer (anastrozole); bladder cancer (gemcitabine, and carboplatin); pancreatic cancer (gemcitabine); small cell lung cancer (topotccan); non-small cell lung cancer (pemetrexed, carboplatin, gemcitabine, cisplatin, and etoposide); prostate adenocarcinoma (bicalutamide); kidney cancer (RADOOl, bevacizumab, and temsirolimus); prostate cancer (taxotere, mitoxantrone, and prednisone); brain and central nervous system tumors (erlotinib, tip
  • 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. Alternatively, the additional agent may be administered prior to, consecutively with, or following the administration of a compound of this invention. In 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.
  • Other potential advantages including without limitation improved dosing regimens and/or reduced drug cost
  • 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.
  • the composition is for use in treating a disease or condition selected from cancer, viral infections, inflammatory skin, eye and/or ear diseases, diabetic neuropathy, pulmonary hypertension, arterial restenosis and transplant rejection.
  • a disease or condition selected from cancer, viral infections, inflammatory skin, eye and/or ear diseases, diabetic neuropathy, pulmonary hypertension, arterial restenosis and transplant rejection.
  • the composition is for use in treating renal cell carcinoma, liver cancer, non-small cell lung cancer, other lung cancers, breast cancer, ovarian cancer, fallopian tube cancer, peritoneal cavity cancer, pancreatic cancer, bladder cancer, metastatic prostate cancer, thyroid cancer, uterine cancer, gastrointestinal stromal cancer, metastatic melanoma, prostate adenocarcinoma, soft tissue sarcoma, mesothelioma, glioblastoma multiforme, acute myeloid leukemia, n ⁇ n-H ⁇ dgkin's lymphoma, multiple myeloma, glioblasto
  • the composition is for use in treating renal cell carcinoma; and the composition is used in conjunction with a second therapeutic reagent selected from AMG 386, recombinant IL-21, perifosine, and RADOOl ,
  • composition is for use in treating hepatocellular carcinoma; and the composition is used in conjunction with doxorubicin;
  • composition is for use in treating breast cancer; and the composition is used in conjunction with anastrozole.
  • the composition is for use in treating bladder cancer; and the composition is used in conjunction with a second therapeutic reagent selected from gemcitabine and carboplatin.
  • composition is for use in treating pancreatic cancer; and the composition is used in conjunction with gemcitabine,
  • the composition is for use in treating small cell lung cancer; and the composition is used in conjunction with topotecan.
  • the composition is for use in treating non-small cell lung cancer; and the composition is used in conjunction with a second therapeutic reagent selected from pemetrexed, carboplatin, gemcitabine, cisplatin, and etoposide.
  • a second therapeutic reagent selected from pemetrexed, carboplatin, gemcitabine, cisplatin, and etoposide.
  • the composition is for use in treating prostate adenocarcinoma; and the composition is used in conjunction with bicalutamide.
  • the composition is for use in treating kidney cancer; and the composition is used in conjunction with a second therapeutic reagent selected from RADOOl, bevacizumab, and temsirolimus.
  • the composition is for use in treating prostate cancer; and the composition is used in conjunction with a second therapeutic reagent selected from taxotere, mitoxantrone, and prednisone.
  • the composition is for use in treating brain and central nervous system tumors; and the composition is used in conjunction with a second therapeutic reagent selected from erlotinib, tipifaraib, and temsirolimus.
  • a second therapeutic reagent selected from erlotinib, tipifaraib, and temsirolimus.
  • the composition is for use in treating colorectal cancer; and the composition is used in conjunction with a second therapeutic reagent selected from cetuximab, and irinotecan hydrochloride.
  • the composition is for use in treating intraocular melanoma; and the composition is used in conjunction with a second therapeutic reagent selected from paclitaxel, and carboplatin.
  • composition is for use in treating solid tumors; composition is used in conjunction with a second therapeutic reagent selected from temsirolimus, erlotinib, and bevacizumab.
  • the composition is for use in treating melanoma; and the composition is used in conjunction with a second therapeutic reagent selected from temsirolimus, abraxane, carboplatin, dacarbazine, and temozolomide.
  • a second therapeutic reagent selected from temsirolimus, abraxane, carboplatin, dacarbazine, and temozolomide.
  • composition is for use in treating lymphoma or multiple myeloma; and the composition is used in conjunction with everolimus.
  • kits for use to treat renal cell carcinoma and other cancers including liver, non-small cell lung, lung, breast, ovarian, fallopian tube, peritoneal cavity, pancreatic, bladder, prostate metastatic, thyroid, uterine, gastrointestinal stromal, metastatic melanoma, prostate adenocarcinoma, soft tissue sarcoma, mesothelioma, glioblastoma multiforme, acute myeloid leukemia, non- Hodgkin's lymphoma, multiple myeloma, glioblastoma, lymphoma, anaplastic astrocytoma, squamous cell head and neck carcinoma, oligodendroglioma, solid tumor, and colorectal cancers, as well as for pulmonary hypertension.
  • renal cell carcinoma and other cancers including liver, non-small cell lung, lung, breast, ovarian, fallopian tube, peritoneal cavity, pancreatic, bladder, prostate metastatic, thyroid, uterine,
  • kits comprise (a) a pharmaceutical composition comprising a compound of Formula I or a salt thereof, wherein said pharmaceutical composition is in a container; and (b) instructions describing a method of using the pharmaceutical composition to treat renal cell carcinoma and other cancers including liver, non-small cell lung, lung, breast, ovarian, fallopian tube, peritoneal cavity, pancreatic, bladder, prostate metastatic, thyroid, uterine, gastrointestinal stromal, metastatic melanoma, prostate adenocarcinoma, soft tissue sarcoma, mesothelioma, glioblastoma multiforme, acute myeloid leukemia, non-Hodgkin's lymphoma, multiple myeloma, glioblastoma, lymphoma, anaplastic astrocytoma, squamous cell head and neck carcinoma, oligodendroglioma, solid tumor, and colorectal cancers, as well as for pulmonary hypertension.
  • a pharmaceutical composition compris
  • the container may be any vessel or other sealed or scalable 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 closes for pressing out of the pack according to a therapeutic schedule.
  • kits of this invention may also comprise a device to administer or to measure out a unit dose of the pharmaceutical composition.
  • Such device 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.
  • the combined organic layers were dried (Na 2 SO 4 ) and concentrated to dryness.
  • the unpiirified material thus obtained was subjected to two more cycles of heating to 160 0 C, cooling, washing and drying. The second heating was for 48 h. The third heating was for 16 h.
  • the unpurified material obtained after the third cycle was added to a microwave tube, followed by D 2 O (1 niL), and DCl (35 wt% in D 2 O, 0.32 niL, 7,24 mmol) under N 2 .
  • the mixture was heated by microwave irradiation at 200 0 C for 2 h 5 minutes (min) and then submitted to the work-up procedure described above.
  • Microsomes The metabolic stability of compounds of the invention is tested using pooled liver microsomal incubations. Full scan LC-MS analysis is then performed to detect major metabolites. Samples of the test compounds, exposed to pooled human liver microsomes, are analyzed using HPLC-MS (or MS/MS) detection. For determining metabolic stability, multiple reaction monitoring (MRM) is used to measure the disappearance of the test compounds. For metabolite detection, Ql full scans are used as survey scans to detect the major metabolites. [120] Experimental Procedures. Human liver microsomes ("HLM"; 20 mg/mL) were obtained from Xenotech, LLC (Lenexa, KS).
  • ⁇ -nicotinamide adenine dinucleotidc phosphate, reduced form (NADPH), magnesium chloride (MgCl 2 ), and dimethyl sulfoxide (DMSO) were purchased from Sigma- Aldrich, [121]
  • Stock solutions of Compound 114 and sorafenib (7.5 mM) were separately prepared in DMSO.
  • the 7.5 mM stock solutions were diluted to 50 ⁇ M in acet ⁇ nltrile (ACN).
  • the 20 mg/mL human liver microsomes were diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7,4, containing 3 mM MgCl 2 .
  • the diluted microsomes (375 ⁇ L) were added to wells of a 96-well deep-well polypropylene plate in triplicate. Ten ⁇ L of the 50 ⁇ M test compound solution was added to the microsomes and the mixture was pre-warmed for 10 minutes. Reactions were initiated by addition of 125 ⁇ L of pre-warmed NADPH solution (8 mM NADPH in 0.1M potassium phosphate buffer, pH 7.4, containing 3 mM MgCl 2 ). The final reaction volume was 0.5 ⁇ iL and contains 0.5 mg/mL human liver microsomes, 1 ⁇ M test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mM MgCIa.
  • reaction mixtures were incubated at 37°C ? and 50 ⁇ L aliquots were removed at O 5 5, 10, 20, and 30 minutes and added to shallow-well 96-well plates which contain 50 ⁇ L of ice-cold ACN with internal standard to stop the reactions.
  • the plates were stored at 4 0 C for 20 minutes after which 100 ⁇ L of water was added to the wells of the plate before centrifugation to pellet precipitated proteins.
  • Supematants were transferred to another 96-well plate and analyzed for amounts of parent remaining by LC-MS/MS using an Applied Bio- systems API 4000 mass spectrometer.
  • Example 4 Comparison of Plasma Protein Binding of Compound 114 and Sorafenlb.
  • Compound 1 14 and sorafenib were each analyzed for their ability to be bound by plasma proteins using the assay described in Banker, MJ et al, J Pharm Sci 2003, 92:967.
  • the compound to be tested was added to human plasma and the mixture was then dialyzed in a REDTM Device (Pierce) against PBS according to the manufacturer's instructions. Following dialysis, an aliquot from both the plasma side and the PBS side of the dialysis were collected.
  • the plasma was diluted with an equal volume of fresh plasma and the plasma was diluted with an equal volume of PBS.
  • Three volumes of methanol with haloperidol IS were added to each sample to precipitate the proteins and release the teat compounds.
  • the supematants were analyzed by LC/MS/MS using either an Agilent 6410 mass spectrometer coupled with an Agilent 1200 HPLC and a CTC PAL chilled autosampler, all controlled by
  • MassHunter software (Agilent), or an AB ⁇ 2000 mass spectrometer coupled with an Agilent 1100 HPLC and a CTC PAL chilled autosampler, all controlled by Analyst software (ABI). After separation on a Cl 8 reverse phase HPLC column (Agilent, Waters, or equivalent) using an acetonitrile-water gradient system, peaks were analyzed by mass spectrometry (MS) using ESI ionization in MRM mode. 1125] Chromatograms from the PBS side of each dialysis representing unbound compound are shown in Figure 1. As can be seen from Figure 1, Compound 114 can be detected in the PBS side, but sorafenib cannot (see arrow labelled "peak location" in Figure 1).

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Abstract

La présente invention porte sur des nouveaux composés de diaryl urée, leurs dérivés et des sels pharmaceutiquement acceptables de ceux-ci. Plus spécifiquement, l'invention porte sur de nouveaux composés de diaryl urée qui sont des dérivés de sorafenib. L’invention porte également sur des compositions comprenant un composé de cette invention et sur l'utilisation de telles compositions dans des méthodes de traitement de maladies et de pathologies qui sont traitées avantageusement par l'administration d'inhibiteurs de multikinase, tels que le sorafenib.
PCT/US2009/053595 2008-08-14 2009-08-12 Dérivés de diaryl urée WO2010019701A2 (fr)

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WO2010135579A1 (fr) * 2009-05-22 2010-11-25 Concert Pharmaceuticals, Inc. Dérivés fluorés de diaryl urée
US10568965B2 (en) 2009-06-09 2020-02-25 Auspex Pharmaceuticals, Inc. Aminopyrimidine inhibitors of tyrosine kinase
CN102803221B (zh) * 2010-03-18 2014-09-10 苏州泽璟生物制药有限公司 氘代的ω-二苯基脲及衍生物以及包含该化合物的药物组合物
EP2548868A1 (fr) * 2010-03-18 2013-01-23 Suzhou Zelgen Biopharmaceutical Co., Ltd. Méthode et procédés de préparation et de production de -diphénylurée deutérée
CN102803221A (zh) * 2010-03-18 2012-11-28 苏州泽璟生物制药有限公司 氘代的ω-二苯基脲及其衍生物以及包含这些化合物的药物组合物
JP2013522244A (ja) * 2010-03-18 2013-06-13 ▲蘇▼州▲澤▼▲ジン▼生物制▲薬▼有限公司 フッソ含有重水素化ジフェニル尿素の製造方法
JP2013522243A (ja) * 2010-03-18 2013-06-13 ▲蘇▼州▲澤▼▲ジン▼生物制▲薬▼有限公司 重水素化ω−ジフェニル尿素の合成及び生産の方法並びにプロセス
WO2011113370A1 (fr) * 2010-03-18 2011-09-22 苏州泽璟生物制药有限公司 Oméga-diphénylurée substituée par un deutérium et ses dérivés, et compositions pharmaceutiques les contenant
JP2015091845A (ja) * 2010-03-18 2015-05-14 ▲蘇▼州▲澤▼▲ジン▼生物制▲薬▼有限公司 ４−（４−（３−（４−クロロ−３−（トリフルオロメチル）フェニル）ウレイド）−フェノキシ）−Ｎ−（１’，１’，１’−トリデューテロメチル）ピコリンアミドのｐ−トルエンスルホン酸塩（ＣＭ４３０７・ＴｓＯＨ）、ＣＭ４３０７・ＴｓＯＨの製造方法、及びＣＭ４３０７・ＴｓＯＨを含有する医薬的組成物
EP2548868A4 (fr) * 2010-03-18 2015-07-08 Suzhou Zelgen Biopharmaceutical Co Ltd Méthode et procédés de préparation et de production de -diphénylurée deutérée
WO2011113203A1 (fr) * 2010-03-18 2011-09-22 苏州泽璟生物制药有限公司 Oméga-diphénylurée substituée par du deutérium et ses dérivés et compositions pharmaceutiques comprenant les composés
US9145390B2 (en) 2011-03-03 2015-09-29 Concert Pharmaceuticals, Inc. Derivatives of pyrazole-substituted amino-heteroaryl compounds
US9707218B2 (en) 2011-03-03 2017-07-18 Concert Pharmaceuticals, Inc. Derivatives of pyrazole-substituted amino-heteroaryl compounds
CN105348186A (zh) * 2015-10-15 2016-02-24 青岛海洋生物医药研究院股份有限公司 氘代双芳基脲类化合物及其制备方法和在制备抗肿瘤的药物中的应用
CN105348186B (zh) * 2015-10-15 2018-05-22 青岛海洋生物医药研究院股份有限公司 氘代双芳基脲类化合物及其制备方法和在制备抗肿瘤的药物中的应用

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