US20140179736A1 - Method of Treating Cancer and Bone Cancer Pain - Google Patents

Method of Treating Cancer and Bone Cancer Pain Download PDF

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US20140179736A1
US20140179736A1 US14/115,236 US201214115236A US2014179736A1 US 20140179736 A1 US20140179736 A1 US 20140179736A1 US 201214115236 A US201214115236 A US 201214115236A US 2014179736 A1 US2014179736 A1 US 2014179736A1
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bone
compound
cancer
pain
formula
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Gisela Schwab
Dana T. Aftab
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Exelixis Inc
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Exelixis Inc
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Assigned to EXELIXIS, INC. reassignment EXELIXIS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AFTAB, DANA T., SCHWAB, GISELA
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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
    • A61K31/495—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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • This invention is directed to the treatment of cancer, particularly to cancers where bone disease is common. These cancers include breast cancer, melanoma, renal cell carcinoma, and thyroid cancer, as well as others, using a compound of Formula I as disclosed herein.
  • the compound of Formula I can be used to treat the pain associated with bone metastases.
  • imaging technologies including magnetic resonance imaging, among other methods.
  • CRPC Castration-Resistant Prostate Cancer
  • Metastasis to bone is a complex process involving interactions between the cancer cell and components of the bone microenvironment including osteoblasts, osteoclasts, and endothelial cells.
  • Bone metastases cause local disruption of normal bone remodeling, and lesions generally show a propensity for either osteoblastic (bone-forming) or osteolytic (bone-resorbing) activity.
  • osteoblastic bone-forming
  • osteolytic bone-resorbing
  • prostate cancer bone metastases are often osteoblastic, with abnormal deposition of unstructured bone accompanied by increased skeletal fractures, spinal cord compression, and severe bone pain.
  • the receptor tyrosine kinase MET plays important roles in cell motility, proliferation, and survival, and has been shown to be a key factor in tumor angiogenesis, invasiveness, and metastasis. Prominent expression of MET has been observed in primary and metastatic prostate carcinomas, with evidence for higher levels of expression in bone metastases compared to lymph node metastases or primary tumors.
  • MET signaling can influence osteoblast and osteoclast function. Strong immunohistochemical staining of MET has been observed in osteoblasts in developing bone, while both HGF and MET are expressed by osteoblasts and osteoclasts in vitro and regulate cellular responses such as proliferation, migration and differentiation. Secretion of HGF by osteoblasts has been proposed as a key factor in osteoblast/osteoclast coupling and is thought to promote the development of bone metastases by tumor cells that express MET.
  • VEGF Vascular endothelial growth factor
  • endothelial cells are widely accepted as key mediators in the process of tumor angiogenesis.
  • elevated VEGF in either plasma or urine is associated with shorter overall survival.
  • VEGF may also play a role in activating the MET pathway in tumor cells by binding to neuropilin-1, which is frequently upregulated in prostate cancer and appears to activate MET in a co-receptor complex.
  • Agents targeting the VEGF signaling pathway have demonstrated some activity in patients with CRPC, as well as breast cancer, melanoma, renal cell carcinoma, and thyroid cancer.
  • VEGF signaling pathway is strongly implicated in bone formation and remodeling.
  • Both osteoblasts and osteoclasts express VEGF and VEGF receptors, which appear to be involved in autocrine and/or paracrine feedback mechanisms regulating cell proliferation, migration, differentiation and survival [62-66].
  • VEGF and VEGF receptors which appear to be involved in autocrine and/or paracrine feedback mechanisms regulating cell proliferation, migration, differentiation and survival [62-66].
  • angiogenesis and VEGF signaling in osteoblasts are both important in bone development and repair.
  • a need remains for methods of treating cancer in human patients with breast cancer, melanoma, renal cell carcinoma, and thyroid cancer, and the bone metastases associated with these forms of cancer.
  • a need also remains for a method of treating bone cancer or pain associated with bone metastases in individuals in need of such treatment.
  • the present invention is directed to a method for treating bone cancer associated with breast cancer, melanoma, renal cell carcinoma, lung cancer, and thyroid cancer.
  • the method comprises administering a therapeutically effective amount of a compound that modulates both MET and VEGF signaling to a patient in need of such treatment.
  • the bone cancer is bone metastases associated with breast cancer, melanoma, renal cell carcinoma, and thyroid cancer.
  • the present invention is directed to a method for treating bone metastases, lung cancer, breast cancer, melanoma, renal cell carcinoma, or thyroid cancer, or bone metastases associated with breast cancer, melanoma, renal cell carcinoma, or thyroid cancer, comprising administering a therapeutically effective amount of a compound that modulates both MET and VEGF signaling to a patient in need of such treatment.
  • the bone cancer or metastases is osteoblastic bone cancer or bone metastases.
  • the dual acting MET/VEGF inhibitor is a compound of Formula I:
  • R 1 is halo
  • R 2 is halo
  • R 3 is (C 1 -C 6 )alkyl
  • R 4 is (C 1 -C 6 )alkyl
  • Q is CH or N.
  • the compound of Formula I is compound 1:
  • Compound 1 is known as N-(4- ⁇ [6,7-bis(methyloxy)quinolin-4-yl]oxy ⁇ phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.
  • the invention provides a method for treating bone metastases associated with lung cancer, breast cancer, melanoma, renal cell carcinoma, or thyroid cancer, comprising administering a therapeutically effective amount of a pharmaceutical formulation to a patient in need of such treatment comprising Compound of Formula I or the malate salt of Compound of Formula I or another pharmaceutically acceptable salt of Compound of Formula I, to a patient in need of such treatment.
  • the invention provides a method for reducing or stabilizing metastatic bone lesions associated with lung cancer, breast cancer, melanoma, renal cell carcinoma, or thyroid cancer, comprising administering a therapeutically effective amount of a pharmaceutical formulation to a patient in need of such treatment comprising Compound of Formula I or the malate salt of Compound of Formula I or another pharmaceutically acceptable salt of Compound of Formula I, to a patient in need of such treatment.
  • the invention provides a method for reducing bone pain due to metastatic bone lesions associated with lung cancer, breast cancer, melanoma, renal cell carcinoma, or thyroid cancer, comprising administering a therapeutically effective amount of a pharmaceutical formulation to a patient in need of such treatment comprising Compound of Formula I or the malate salt of Compound of Formula I or another pharmaceutically acceptable salt of Compound of Formula I, to a patient in need of such treatment.
  • the invention provides a method for treating or minimizing bone pain due to metastatic bone lesions associated with lung cancer, breast cancer, melanoma, renal cell carcinoma, or thyroid cancer, comprising administering a therapeutically effective amount of a pharmaceutical formulation to a patient in need of such treatment comprising Compound of Formula I or the malate salt of Compound of Formula I or another pharmaceutically acceptable salt of Compound of Formula I, to a patient in need of such treatment.
  • the invention provides a method for preventing bone metastases associated with lung cancer, breast cancer, melanoma, renal cell carcinoma, or thyroid cancer, comprising administering a therapeutically effective amount of a pharmaceutical formulation to a patient in need of such treatment comprising Compound of Formula I or the malate salt of Compound of Formula I or another pharmaceutically acceptable salt of Compound of Formula I, to a patient in need of such treatment.
  • the invention provides a method for preventing bone metastases in patients with lung cancer, breast cancer, melanoma, renal cell carcinoma, or thyroid cancer, who have not yet advanced to metastatic disease, comprising administering a therapeutically effective amount of a pharmaceutical formulation to a patient in need of such treatment comprising Compound of Formula I or the malate salt of Compound of Formula I or another pharmaceutically acceptable salt of Compound of Formula I, to a patient in need of such treatment.
  • the invention provides a method for extending the overall survival in patients with lung cancer, breast cancer, melanoma, renal cell carcinoma, or thyroid cancer, comprising administering a therapeutically effective amount of a pharmaceutical formulation to a patient in need of such treatment comprising Compound of Formula I or the malate salt of Compound of Formula I or another pharmaceutically acceptable salt of Compound of Formula I, to a patient in need of such treatment.
  • the invention provides a method for treating bone cancer pain in an individual comprising administering to the individual an effective amount of a Compound of Formula I or the malate salt of Compound of Formula I or another pharmaceutically acceptable salt of Compound of Formula I, to a patient in need of such treatment.
  • the Compound of Formula I is Compound 1.
  • the bone cancer pain can originate from bone cancer, osteosarcoma, as well as from cancer metastasized to bone.
  • the bone cancer pain can be from the list including but not limited to bone metastases from lung cancer, breast cancer, sarcoma, or renal cancer.
  • the ability of the compound of Formula I to treat, ameliorate, or reduce the severity of bone metastases can be determined both qualitatively and quantitatively using various physiological markers, such as circulating biomarkers of bone turnover (ie bALP, CTx, and NTx), circulating tumor cell (CTC) counts, and imaging technologies.
  • the imaging technologies include positron emission tomography (PET) or computerized tomography (CT) and magnetic resonance imaging. By using these imaging techniques, it is possible to monitor and quantify the reduction in tumor size and the reduction in the number and size of bone lesions in response to treatment with the compound of Formula I.
  • shrinkage of soft tissue and visceral lesions has been observed to result when the compound of Formula I is administered to patients with CRPC.
  • administration of the compound of Formula I leads to increases in hemoglobin concentration in patients CRPC patients with anemia.
  • FIGS. 1A-C show the bone scan ( FIG. 1A ), bone scan response ( FIG. 1B ), and CT scan data ( FIG. 1C ) for Patient 1 having CRPC.
  • FIGS. 2A-C show the bone scan ( FIG. 2A ), bone scan response ( FIG. 2B ), and CT scan data ( FIG. 2C ) for Patient 2 having CRPC.
  • FIGS. 3A-B show the bone scan ( FIG. 3A ), bone scan response ( FIG. 3B ) for Patient 3 having CRPC.
  • FIGS. 4A and B shows the bone scan ( FIG. 4A ), bone scan response ( FIG. 4B ) for a Patient having renal cell carcinoma with bone metastases.
  • FIGS. 5A and 5B shows the bone scan ( FIG. 5A ), bone scan response ( FIG. 5B ) for a Patient having melanoma with bone metastases.
  • FIG. 6 shows a CT scan of a bone metastasis from a patient with differentiated thyroid cancer before ( FIG. 6A ) and after ( FIG. 6B ) treatment.
  • a substituent “R” may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.
  • a substituent “R” may reside on any atom of the fused ring system, assuming replacement of a depicted hydrogen (for example the —NH— in the formula above), implied hydrogen (for example as in the formula above, where the hydrogens are not shown but understood to be present), or expressly defined hydrogen (for example where in the formula above, “Z” equals ⁇ CH—) from one of the ring atoms, so long as a stable structure is formed.
  • the “R” group may reside on either the 5-membered or the 6-membered ring of the fused ring system.
  • a group “R” is depicted as existing on a ring system containing saturated carbons, as for example in the formula:
  • Halogen or “halo” refers to fluorine, chlorine, bromine or iodine.
  • Yield for each of the reactions described herein is expressed as a percentage of the theoretical yield.
  • Patient for the purposes of the present invention includes humans and other animals, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In another embodiment the patient is a mammal, and in another embodiment the patient is human.
  • a “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17 th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference or S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977; 66:1-19 both of which are incorporated herein by reference.
  • Examples of pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, malic acid, citric acid, benzoic acid, cinnamic acid, 3-(4-hydroxybenzoyl)benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid
  • “Prodrug” refers to compounds that are transformed (typically rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. Common examples include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety.
  • Examples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, alkyl esters (for example with between about one and about six carbons) the alkyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl.
  • Examples of pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (for example with between about one and about six carbons).
  • Amides and esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.
  • “Therapeutically effective amount” is an amount of a compound of the invention, that when administered to a patient, ameliorates a symptom of the disease.
  • a therapeutically effective amount is intended to include an amount of a compound alone or in combination with other active ingredients effective to modulate c-Met, and/or VEGFR2, or effective to treat or prevent cancer.
  • the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the age of the patient to be treated, and the like. The therapeutically effective amount can be determined by one of ordinary skill in the art having regard to their knowledge and to this disclosure.
  • Treating” or “treatment” of a disease, disorder, or syndrome includes (i) preventing the disease, disorder, or syndrome from occurring in a human, i.e. causing the clinical symptoms of the disease, disorder, or syndrome not to develop in an animal that may be exposed to or predisposed to the disease, disorder, or syndrome but does not yet experience or display symptoms of the disease, disorder, or syndrome; (ii) inhibiting the disease, disorder, or syndrome, i.e., arresting its development; and (iii) relieving the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome.
  • adjustments for systemic versus localized delivery, age, body weight, general health, sex, diet, time of administration, drug interaction and the severity of the condition may be necessary, and will be ascertainable with routine experience.
  • R 1 is halo
  • R 2 is halo
  • Q is CH or N.
  • the compound of Formula I is Compound 1:
  • WO 2005/030140 discloses Compound 1 and describes how it is made (Example 12, 37, 38, and 48) and also discloses the therapeutic activity of this compound to inhibit, regulate and/or modulate the signal transduction of kinases, (Assays, Table 4, entry 289).
  • Example 48 is on paragraph [0353] in WO 2005/030140.
  • the compound of Formula I, Ia, or Compound 1, or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition, wherein the pharmaceutical composition additionally comprises a pharmaceutically acceptable carrier, excipient, or diluent.
  • the Compound of Formula I is Compound 1.
  • the compound of Formula I, Formula Ia, and Compound I, as described herein, includes both the recited compounds as well as individual isomers and mixtures of isomers.
  • the compound of Formula I includes the pharmaceutically acceptable salts, hydrates, and/or solvates of the recited compounds and any individual isomers or mixture of isomers thereof.
  • the compound of Formula I, Ia, or Compound 1 can be the malate salt.
  • the malate salt of the Compound of Formula I and of Compound 1 is disclosed in PCT/US2010/021194 and 61/325,095.
  • the compound of Formula I, Ia, or 1 can be the (D)-malate salt.
  • the compound of Formula I, Ia, or 1 can be malate salt.
  • the compound of Formula I, Ia, or 1 can be the (L)-malate salt.
  • Compound 1 can be (D)-malate salt.
  • Compound 1 can be the (L)-malate salt.
  • the malate salt of Compound 1 is in the crystalline N-1 form of the (L) malate salt and/or the (D) malate salt of the Compound 1 as disclosed in U.S. patent Application Ser. No. 61/325,095. Also see WO 2008/083319 for the properties of crystalline enantiomers, including the N-1 and/or the N-2 crystalline forms of the malate salt of Compound 1. Methods of making and characterizing such forms are fully described in PCT/US10/21194, which is incorporated herein by reference in its entirety.
  • the invention is directed to a method for ameliorating the symptoms of bone metastases, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula I in any of the embodiments disclosed herein.
  • the Compound of Formula I is Compound 1.
  • the invention is directed to a method for treating pain associated with bone metastases, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula I in any of the embodiments disclosed herein.
  • the Compound of Formula I is Compound 1.
  • the compound of Formula I is administered post-taxotere treatment.
  • the Compound of Formula I is Compound 1.
  • the compound of Formula I is as effective or more effective than mitoxantrone plus prednisone.
  • the Compound of Formula I is Compound 1.
  • the Compound of Formula I, Ia, or Compound 1 or a pharmaceutically acceptable salt thereof is administered orally once daily as a tablet or capsule.
  • Compound 1 is administered orally as its free base or malate salt as a capsule or tablet.
  • Compound 1 is administered orally once daily as its free base or as the malate salt as a capsule or tablet containing up to 100 mg of Compound 1.
  • Compound 1 is administered orally once daily as its free base or as the malate salt as a capsule or tablet containing 100 mg of Compound 1.
  • Compound 1 is administered orally once daily as its free base or as the malate salt as a capsule or tablet containing 95 mg of Compound 1.
  • Compound 1 is administered orally once daily as its free base or as the malate salt as a capsule or tablet containing 90 mg of Compound 1.
  • Compound 1 is administered orally once daily as its free base or as the malate salt as a capsule or tablet containing 85 mg of Compound 1.
  • Compound 1 is administered orally once daily as its free base or as the malate salt as a capsule or tablet containing 80 mg of Compound 1.
  • Compound 1 is administered orally once daily as its free base or as the malate salt as a capsule or tablet containing 75 mg of Compound 1.
  • Compound 1 is administered orally once daily as its free base or as the malate salt as a capsule or tablet containing 70 mg of Compound 1.
  • Compound 1 is administered orally once daily as its free base or as the malate salt as a capsule or tablet containing 65 mg of Compound 1.
  • Compound 1 is administered orally once daily as its free base or as the malate salt as a capsule or tablet containing 60 mg of Compound 1.
  • Compound 1 is administered orally once daily as its free base or as the malate salt as a capsule or tablet containing 55 mg of Compound 1.
  • Compound 1 is administered orally once daily as its free base or as the malate salt as a capsule or tablet containing 50 mg of Compound 1.
  • Compound 1 is administered orally once daily as its free base or as the malate salt as a capsule or tablet containing 45 mg of Compound 1.
  • Compound 1 is administered orally once daily as its free base or as the malate salt as a capsule or tablet containing 40 mg of Compound 1.
  • Compound 1 is administered orally once daily as its free base or as the malate salt as a capsule or tablet containing 30 mg of Compound 1.
  • Compound 1 is administered orally once daily as its free base or as the malate salt as a capsule or tablet containing 25 mg of Compound 1.
  • Compound 1 is administered orally once daily as its free base or as the malate salt as a capsule or tablet containing 20 mg of Compound 1.
  • Compound 1 is administered orally once daily as its free base or as the malate salt as a capsule or tablet containing 15 mg of Compound 1.
  • Compound 1 is administered orally once daily as its free base or as the malate salt as a capsule or tablet containing 10 mg of Compound 1.
  • Compound 1 is administered orally once daily as its free base or as the malate salt as a capsule or tablet containing 5 mg of Compound 1.
  • Compound 1 is administered as its free base or malate salt orally once daily as a tablet as provided in the following table.
  • Compound 1 is administered orally as its free base or malate salt once daily as a tablet as provided in the following table.
  • Compound 1 is administered orally as its free base or malate salt once daily as a tablet as provided in the following table.
  • Theoretical Quantity (mg/unit Ingredient dose) Compound 1 100.0 Microcrystalline Cellulose PH- 155.4 102 Lactose Anhydrous 60M 77.7 Hydroxypropyl Cellulose, EXF 12.0 Croscarmellose Sodium 24 Colloidal Silicon Dioxide 1.2 Magnesium Stearate (Non- 3.0 Bovine) Opadry Yellow 16.0 Total 416
  • any of the tablet formulations provided above can be adjusted according to the dose of Compound 1 desired.
  • the amount of each of the formulation ingredients can be proportionally adjusted to provide a table formulation containing various amounts of Compound 1 as provided in the previous paragraphs.
  • the formulations can contain 20, 40, 60, or 80 mg of Compound 1.
  • Administration of the compound of Formula I, Formula Ia, or Compound 1, or a pharmaceutically acceptable salt thereof, in pure form or in an appropriate pharmaceutical composition can be carried out via any of the accepted modes of administration or agents for serving similar utilities.
  • administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin dosages (which can be in capsules or tablets), powders, solutions, suspensions, or aerosols, or the like, specifically in unit dosage forms suitable for simple administration of precise dosages.
  • compositions will include a conventional pharmaceutical carrier or excipient and a compound of Formula I as the/an active agent, and, in addition, may include carriers and adjuvants, etc.
  • Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • a pharmaceutical composition of the compound of Formula I may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.
  • compositions depend on various factors such as the mode of drug administration (e.g., for oral administration, compositions in the form of tablets, pills or capsules) and the bioavailability of the drug substance.
  • pharmaceutical compositions have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size.
  • U.S. Pat. No. 4,107,288 describes a pharmaceutical composition having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules.
  • 5,145,684 describes the production of a pharmaceutical composition in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical composition that exhibits remarkably high bioavailability.
  • compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • One specific route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or
  • fillers or extenders as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid
  • binders as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia
  • humectants as for example, glycerol
  • disintegrating agents as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate
  • solution retarders as for example paraffin
  • absorption accelerators as for example, quaternary
  • Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., the compound of Formula I, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols
  • Suspensions in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
  • compositions for rectal administration are, for example, suppositories that can be prepared by mixing the compound of Formula I with, for example, suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.
  • Dosage forms for topical administration of the compound of Formula I include ointments, powders, sprays, and inhalants.
  • the active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required.
  • Ophthalmic compositions, eye ointments, powders, and solutions are also contemplated as being within the scope of this disclosure.
  • Compressed gases may be used to disperse the compound of Formula I in aerosol form.
  • Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
  • the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of Formula I, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient.
  • the composition will be between about 5% and about 75% by weight of a compound(s) of Formula I, Formula Ia, or Compound 1, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.
  • composition to be administered will, in any event, contain a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this disclosure.
  • the compounds of this disclosure are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy.
  • the compound of Formula I, Formula Ia, or Compound 1 can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example.
  • the specific dosage used can vary.
  • the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used.
  • the determination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.
  • the compound of Formula I, Formula Ia, or Compound 1 can be administered to the patient concurrently with other cancer treatments.
  • treatments include other cancer chemotherapeutics, hormone replacement therapy, radiation therapy, or immunotherapy, among others.
  • the choice of other therapy will depend on a number of factors including the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy.
  • a reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (10.0 kg) and acetonitrile (64.0 L). The resulting mixture was heated to approximately 65° C. and phosphorus oxychloride (POCl 3 , 50.0 kg) was added. After the addition of POCl 3 , the temperature of the reaction mixture was raised to approximately 80° C. The reaction was deemed complete (approximately 9.0 hours) when less than 2 percent of the starting material remained (in process high-performance liquid chromotography [HPLC] analysis). The reaction mixture was cooled to approximately 10° C.
  • phosphorus oxychloride POCl 3 , 50.0 kg
  • a reactor was sequentially charged with 4-chloro-6,7-dimethoxy-quinoline (8.0 kg), 4 nitrophenol (7.0 kg), 4 dimethylaminopyridine (0.9 kg), and 2,6-lutidine (40.0 kg).
  • the reactor contents were heated to approximately 147° C.
  • the reaction was complete (less than 5% starting material remaining as determined by in process HPLC analysis, approximately 20 hours)
  • the reactor contents were allowed to cool to approximately 25° C.
  • Methanol (26.0 kg) was added, followed by potassium carbonate (3.0 kg) dissolved in water (50.0 kg).
  • the reactor contents were stirred for approximately 2 hours.
  • the resulting solid precipitate was filtered, washed with water (67.0 kg), and dried at 25° C. for approximately 12 hours to afford the title compound (4.0 kg).
  • Triethylamine (8.0 kg) was added to a cooled (approximately 4° C.) solution of commercially available cyclopropane-1,1-dicarboxylic acid (10.0 kg) in THF (63.0 kg) at a rate such that the batch temperature did not exceed 10° C.
  • the solution was stirred for approximately 30 minutes, and then thionyl chloride (9.0 kg) was added, keeping the batch temperature below 10° C.
  • a solution of 4-fluoroaniline (9.0 kg) in THF (25.0 kg) was added at a rate such that the batch temperature did not exceed 10° C.
  • the mixture was stirred for approximately 4 hours and then diluted with isopropyl acetate (87.0 kg).
  • Oxalyl chloride (1.0 kg) was added to a solution of 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (2.0 kg) in a mixture of THF (11 kg) and N,N-dimethylformamide (DMF; 0.02 kg) at a rate such that the batch temperature did not exceed 30° C. This solution was used in the next step without further processing.
  • a reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60° C. and phosphorus oxychloride (POCl 3 , 130.6 kg) was added. After the addition of POCl 3 , the temperature of the reaction mixture was raised to approximately 77° C. The reaction was deemed complete (approximately 13 hours) when less than 3 percent of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2 to 7° C.
  • phosphorus oxychloride POCl 3 , 130.6 kg
  • the crude product was collected by filtration and washed with a mixture of water (88 kg) and DMA (82.1 kg), followed by water (175 kg). The product was dried on a filter drier for 53 hours. The LOD showed less than 1 percent weight/weight (w/w).
  • Triethylamine (19.5 kg) was added to a cooled (approximately 5° C.) solution of cyclopropane-1,1-dicarboxylic acid (24.7 kg) in THF (89.6 kg) at a rate such that the batch temperature did not exceed 5° C.
  • the solution was stirred for approximately 1.3 hours, and then thionyl chloride (23.1 kg) was added, keeping the batch temperature below 10° C. When the addition was complete, the solution was stirred for approximately 4 hours keeping the temperature below 10° C.
  • a solution of 4-fluoroaniline (18.0 kg) in THF (33.1 kg) was then added at a rate such that the batch temperature did not exceed 10° C.
  • the mixture was stirred for approximately 10 hours, after which the reaction was deemed complete.
  • the reaction mixture was then diluted with isopropyl acetate (218.1 kg). This solution was washed sequentially with aqueous sodium hydroxide (10.4 kg, 50% dissolved in 119 L of water), further diluted with water (415 L), then with water (100 L), and finally with aqueous sodium chloride (20.0 kg dissolved in 100 L of water).
  • the organic solution was concentrated by vacuum distillation (100 L residual volume) below 40° C., followed by the addition of n-heptane (171.4 kg), which resulted in the precipitation of solid.
  • the solid was recovered by filtration and washed with n-Heptane (102.4 kg), resulting in wet crude, 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (29.0 kg).
  • the crude, 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid was dissolved in methanol (139.7 kg) at approximately 25° C., followed by the addition of water (320 L), resulting in slurry which was recovered by filtration, washed sequentially with water (20 L) and n-heptane (103.1 kg), and then dried on the filter at approximately 25° C. under nitrogen to afford the title compound (25.4 kg).
  • Oxalyl chloride (12.6 kg) was added to a solution of 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (22.8 kg) in a mixture of THF (96.1 kg) and N,N-dimethylformamide (DMF; 0.23 kg) at a rate such that the batch temperature did not exceed 25° C. This solution was used in the next step without further processing.
  • a reactor was charged with 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (35 kg), DMF (344 g), and THF (175 kg). The reaction mixture was adjusted to 12 to 17° C., and then to the reaction mixture was charged 19.9 kg of oxalyl chloride over a period of 1 hour. The reaction mixture was left stirring at 12 to 17° C. for 3 to 8 hours. This solution was used in the next step without further processing.
  • the product was recovered by filtration, washed with a pre-made solution of THF (68.6 kg) and water (256 L), and dried first on a filter under nitrogen at approximately 25° C. and then dried at approximately 45° C. under vacuum to afford the title compound (41.0 kg, 38.1 kg, calculated based on LOD).
  • the reaction temperature was then adjusted to 30 to 25° C., and the mixture was agitated. The agitation was stopped and the phases of the mixture were allowed to separate. The lower aqueous phase was removed and discarded. Water (804 kg) was added to the remaining upper organic phase. The reaction was left stirring at 15 to 25° C. for a minimum of 16 hours.
  • the product was filtered and washed with a mixture of water (179 kg) and THF (157.9 kg) in two portions.
  • the crude product was dried under a vacuum for at least two hours.
  • the dried product was then taken up in THF (285.1 kg).
  • the resulting suspension was transferred to reaction vessel and agitated until the suspension became a clear (dissolved) solution, which required heating to 30 to 35° C. for approximately 30 minutes.
  • Water (456 kg) was then added to the solution, as well as SDAG-1 (20 kg) ethanol (ethanol denatured with methanol over two hours).
  • the mixture was agitated at 15-25° C. for at least 16 hours.
  • the product was filtered and washed with a mixture of water (143 kg) and THF (126.7 kg) in two portions.
  • the product was dried at a maximum temperature set point of 40° C.
  • reaction temperature during acid chloride formation was adjusted to 10 to 15° C.
  • the recrystallization temperature was changed from 15 to 25° C. to 45 to 50° C. for 1 hour and then cooled to 15 to 25° C. over 2 hours.
  • Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (13.3 kg), L-malic acid (4.96 kg), methyl ethyl ketone (MEK; 188.6 kg), and water (37.3 kg) were charged to a reactor, and the mixture was heated to reflux (approximately 74° C.) for approximately 2 hours. The reactor temperature was reduced to 50 to 55° C., and the reactor contents were filtered.
  • Cyclopropane-1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (47.9 kg), L-malic acid (17.2), 658.2 kg methyl ethyl ketone, and 129.1 kg water (37.3 kg) were charged to a reactor, and the mixture was heated 50 to 55° C. for approximately 1 to 3 hours, and then at 55 to 60° C. for an additional 4 to 5 hours. The mixture was clarified by filtration through a 1 ⁇ m cartridge. The reactor temperature was adjusted to 20 to 25° C. and vacuum distilled with a vacuum at 150-200 mm Hg with a maximum jacket temperature of 55° C. to the volume range of 558-731 L.
  • the vacuum distillation was performed two more times with the charge of 380 kg and 380.2 kg methyl ethyl ketone, respectively.
  • the volume of the batch was adjusted to 18 volume/weight (v/w) of cyclopropane-,1-dicarboxylic acid [4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide by charging methyl ethyl ketone (159.9 kg) to give a total volume of 880 L.
  • An additional vacuum distillation was carried out by adjusting methyl ethyl ketone (245.7 kg). The reaction mixture was left with moderate agitation at 20 to 25° C. for at least 24 hours.
  • the product was filtered and washed with methyl ethyl ketone (415.1 kg) in three portions.
  • the product was dried under a vacuum with the jacket temperature set point at 45° C.
  • HGF and MET signaling pathways appear to play important roles in osteoblast and osteoclast function. Strong immunohistochemical staining of MET has been observed in both cell types in developing bone. HGF and MET are expressed by osteoblasts and osteoclasts in vitro and mediate cellular responses such as proliferation, migration, and expression of ALP. Secretion of HGF by osteoblasts has been proposed as a key factor in osteoblast/osteoclast coupling, and in the development of bone metastases by tumor cells that express MET. Osteoblasts and osteoclasts also express VEGF and its receptors, and VEGF signaling in these cells is involved in potential autocrine and/or paracrine feedback mechanisms regulating cell migration, differentiation, and survival.
  • Compound 1 is an orally bioavailable multitargeted tyrosine kinase inhibitor with potent activity against MET and VEGFR2.
  • Compound 1 suppresses MET and VEGFR2 signaling, rapidly induces apoptosis of endothelial cells and tumor cells, and causes tumor regression in xenograft tumor models.
  • Compound 1 also significantly reduces tumor invasiveness and metastasis and substantially improves overall survival in a murine pancreatic neuroendocrine tumor model.
  • Compound 1 was generally well-tolerated, with fatigue, diarrhea, anorexia, rash, and palmar-plantar erythrodysesthesia being the most commonly observed adverse events.
  • Compound 1 is an orally bioavailable multitargeted tyrosine kinase inhibitor with potent activity against MET and VEGFR2.
  • Compound 1 suppresses MET and VEGFR2 signaling, rapidly induces apoptosis of endothelial cells and tumor cells, and causes tumor regression in xenograft tumor models.
  • Compound 1 also significantly reduces tumor invasiveness and metastasis and substantially improves overall survival in a murine pancreatic neuroendocrine tumor model.
  • Compound 1 was generally well-tolerated, with fatigue, diarrhea, anorexia, rash, and palmar-plantar erythrodysesthesia being the most commonly observed adverse events.
  • Patient 1 was diagnosed with localized prostate cancer in 1993 and treated with radical prostatectomy (Gleason score unavailable; PSA, 0.99 ng/mL).
  • PSA radical prostatectomy
  • PSA 0.99 ng/mL
  • combined androgen blockade (CAB) with leuprolide and bicalutamide was initiated for rising PSA (3.5 ng/mL).
  • diethystillbestrol (DES) was administered briefly.
  • 6 cycles of docetaxel were given for new lung metastases. Rising PSA was unresponsive to antiandrogen withdrawal. Androgen ablation therapy was continued until clinical progression.
  • bone metastasis to the spine associated with impingement on the spinal cord and back pain was treated with radiation therapy (37.5 Gy).
  • Bone scan showed uptake of radiotracer in the left iliac wing, left sacroiliac joint, femoral head, and the pubic symphysis.
  • Biopsy of the left pubic ramus confirmed metastatic adenocarcinoma with mixed lytic and blastic lesions.
  • CAB with leuprolide and bicalutamide and radiation therapy (8 Gy) to the left pubic ramus and acetabulum resulted in bone pain relief and PSA normalization.
  • Rising PSA in November 2009 (16 ng/mL) was unresponsive to antiandrogen withdrawal.
  • a CT scan revealed retroperitoneal lymph node enlargement and liver metastases (PSA, 28.1 ng/mL). Further progression of disease was marked by recurrent bone pain, new lung and hepatic metastases.
  • a repeat bone scan showed new foci, and a CT scan showed an increase in the retroperitoneal, para-aortic, and bilateral common iliac adenopathy. Rising PSA in April 2010 (2.8 ng/mL) and increasing bone pain were unresponsive to antiandrogen withdrawal.
  • Patient 1 started Compound 1 on Feb. 12, 2010. Four weeks later, significant reduction in bone pain was reported. At Week 6, bone scan showed a dramatic decrease in radiotracer uptake by bone metastases ( FIG. 1A ). A CT scan showed a partial response (PR) with a 33% decrease in measurable target lesions ( FIG. 1C ). At Week 12, near complete resolution of bone lesions and a 44% decrease in target lesions was observed and was stable through Week 18. Corresponding with the bone scan response, after an initial rise, serum tALP levels decreased from 689 U/L at baseline to 159 U/L at Week 18 ( FIG. 1B and Table 1). In addition, there was an increase in hemoglobin of 1.4 g/dL at Week 2 compared with baseline (Table 1). PSA decreased from 430 ng/mL at baseline to 93.5 ng/mL at Week 18 ( FIG. 1B and Table 1). The patient was on open-label treatment through Week 18 when he withdrew after developing Grade 3 diarrhea.
  • Patient 2 started Compound 1 on Mar. 31, 2010. At Week 4, reduction in bone pain was reported. At Week 6, bone scan showed a slight flair in radiotracer uptake by bone lesions ( FIG. 2A ), and a CT scan showed a 13% decrease in target lesions ( FIG. 2C ). At Week 12, a substantial reduction of radiotracer uptake ( FIG. 2A ) and a 20% decrease in measurable disease were observed (Table 1). After randomization to placebo at Week 12 the patient developed severe bone pain and sacral nerve root impingement. Radiation to the spine was administered, and the patient crossed over to open-label Compound 1 treatment at Week 15. Serum tALP levels were within the normal range (101-144 U/L) ( FIG. 2B ).
  • Hemoglobin increased by 1.8 g/dL at Week 12 compared with baseline (Table 1).
  • PSA peaked at close to 6-fold of baseline by Week 16, but then decreased to 2-fold of baseline by Week 18 subsequent to crossing over to Compound 1 from placebo ( FIG. 2B and Table 1).
  • the patient continues on Compound 1 treatment as of September 2010.
  • Patient 3 started Compound 1 on Apr. 26, 2010. After three weeks a complete resolution of pain was reported. At Week 6, bone scan showed a dramatic reduction in radiotracer uptake ( FIG. 3A ), and a CT scan showed a PR with a 43% decrease in measurable target lesions. At Week 12 a complete resolution of bone lesions on bone scan ( FIG. 3A ) and a 51% decrease in measurable disease were observed (Table 1 and FIG. 3B )). After an initial rise, serum tALP levels steadily decreased, with tALP at 869 U/L at baseline and 197 U/L at Week 18 ( FIG. 3B and Table 1). Hemoglobin increased 2.2 g/dL at Week 2 compared with baseline (Table 1). PSA decreased from 2.4 ng/mL at screening to 1.2 ng/mL at Week 18 ( FIG. 3B and Table 1). The patient continues on Compound 1 treatment as of September 2010.
  • Uptake of radiotracer in bone depends on both local blood flow and osteoblastic activity, both of which may be pathologically modulated by the tumor cells associated with the bone lesion. Resolving uptake may therefore be attributable to either interruption of local blood flow, direct modulation of osteoblastic activity, a direct effect on the tumor cells in bone, or a combination of these processes.
  • decreased uptake on bone scan in men with CRPC has only been rarely noted with VEGF/VEGFR targeted therapy, despite numerous trials with such agents.
  • observations of decreased uptake on bone scan in CRPC patients have only been reported rarely for abiraterone, which targets the cancer cells directly, and for dasatinib, which targets both cancer cells and osteoclasts.
  • targeting angiogenesis alone, or selectively targeting the tumor cells and/or osteoclasts has not resulted in effects similar to those observed in the patients treated with Compound 1.
  • Compound 1 an inhibitor of tumor growth, metastasis and angiogenesis, simultaneously targets MET and VEGFR2, key kinases involved in the development and progression of many cancers.
  • Prominent expression of MET has been observed in primary and metastatic prostate carcinomas, with evidence for higher levels of expression in bone metastases.
  • Overexpression of hepatocyte growth factor (HGF), the ligand for MET has also been observed in prostate carcinoma, and increased plasma levels of HGF are associated with decreased overall survival in CRPC.
  • HGF hepatocyte growth factor
  • MET hepatocyte growth factor
  • both HGF and MET are regulated by the androgen signaling pathway in prostate cancer, where upregulation of MET signaling is associated with the transition to androgen-independent tumor growth.
  • both the MET and VEGFR signaling pathways also appear to play important roles in the function of osteoblasts and osteoclasts—cells in the bone microenvironment that are often dysregulated during the establishment and progression of bone metastases.
  • Bone metastases cause local disruption of normal bone remodeling, with lesions generally showing a propensity for an osteoblastic (bone-forming) phenotype on imaging. These lesions often lead to increased skeletal fractures, spinal cord compression, and severe bone pain. Osteoblastic lesions are typically visualized in CRPC patients by bone scan, which detects rapid incorporation of 99 mTc-labeled methylene-diphosphonate radiotracer into newly forming bone. In addition, increased blood levels of ALP and CTx, markers for osteoblast and osteoclast activity, respectively, are often observed in CRPC patients with bone metastases, and are associated with shorter overall survival.
  • CT x Cross-linked C-terminal telopeptides of type-1 collagen

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9717720B2 (en) 2011-02-10 2017-08-01 Exelixis, Inc. Processes for preparing quinoline compounds and pharmaceutical compositions containing such compounds
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US10501418B2 (en) 2014-02-14 2019-12-10 Exelixis, Inc. Crystalline solid forms of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, processes for making, and methods of use
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US11124481B2 (en) 2014-07-31 2021-09-21 Exelixis, Inc. Method of preparing fluorine-18 labeled Cabozantinib and its analogs
US11141413B2 (en) 2016-04-15 2021-10-12 Exelixis, Inc. Method of treating renal cell carcinoma using N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate
US11161817B2 (en) 2017-09-28 2021-11-02 Chongqing Pharmaceutical Industrial Research Institute Co. Ltd. Quinoline derivative and use thereof as tyrosine kinase inhibitor
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US11564915B2 (en) 2013-04-04 2023-01-31 Exelixis, Inc. Cabozantinib dosage form and use in the treatment of cancer
US11612597B2 (en) 2010-09-27 2023-03-28 Exelixis, Inc. Method of treating cancer

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104788372B (zh) * 2014-07-25 2018-01-30 上海圣考医药科技有限公司 一种氘代卡博替尼衍生物、其制备方法、应用及其中间体
DK3630726T3 (da) 2017-05-26 2022-03-07 Exelixis Inc Krystallinske faste former af salte af n-{4-[(6,7-dimethoxyquinolin-4-yl) oxy]phenyl}-n'-(4-fluorphenyl) cyclopropan-1,1-dicarboxamid, processer til fremstilling og fremgangsmåder til anvendelse
AU2018279834B2 (en) * 2017-06-09 2024-05-23 Exelixis, Inc. Liquid dosage forms to treat cancer
CR20200358A (es) 2018-01-26 2021-02-22 Exelixis Inc Compuestos para el tratamiento de trastornos dependientes de cinasas
CN109620143A (zh) * 2018-11-22 2019-04-16 张程程 调节骨转移中破骨细胞活化机制的测定方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090170896A1 (en) * 2003-09-26 2009-07-02 Exelixis, Inc. c-Met modulators and methods of use
US20090274693A1 (en) * 2008-05-05 2009-11-05 Gilmer Tona M Method of Treating Cancer using a cMet and AXL Inhibitor and an ErbB Inhibitor
WO2012044572A1 (en) * 2010-09-27 2012-04-05 Exelixis, Inc. Dual inhibitors of met and vegf for the treatment of castration- resistant prostate cancer and osteoblastic bone metastases
US20120252840A1 (en) * 2011-04-04 2012-10-04 Exelixis, Inc. Method of Treating Cancer

Family Cites Families (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7632486B1 (en) 1998-08-21 2009-12-15 Etsuro Ogata Method for diagnosing bone metastasis of malignant tumor
JP5368701B2 (ja) 2004-07-02 2013-12-18 エクセリクシス、インコーポレイテッド ｃ−Ｍｅｔモジュレーター及び使用方法
WO2006108059A1 (en) 2005-04-06 2006-10-12 Exelixis, Inc. C-met modulators and methods of use
CA2671982C (en) 2006-12-14 2016-01-26 Exelixis, Inc. Methods of using mek inhibitors
AR075084A1 (es) 2008-09-26 2011-03-09 Smithkline Beecham Corp Metodo de preparacion de quinolinil -oxidifenil - ciclopropanodicarboxamidas e intermediarios correspondientes
US20110229469A1 (en) * 2008-10-01 2011-09-22 Ludwig Institute For Cancer Research Methods for the treatment of cancer
KR20110084455A (ko) 2008-11-13 2011-07-22 엑셀리시스, 인코포레이티드 퀴놀린 유도체를 제조하는 방법
US20130030172A1 (en) 2008-12-04 2013-01-31 Exelixis, Inc. Methods of Preparing Quinoline Derivatives
EP2387563B2 (en) 2009-01-16 2022-04-27 Exelixis, Inc. Malate salt of n- (4- { [ 6, 7-bis (methyloxy) quinolin-4-yl]oxy}phenyl-n' - (4 -fluorophenyl) cyclopropane-1,1-dicarboxamide, and crystalline forms thereof for the treatment of cancer
WO2011009095A1 (en) 2009-07-17 2011-01-20 Exelixis, Inc. Crystalline forms of n-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]-quin0lin-4-yl}oxy)phenyl]-n'-(4-fluorophenyl)cyclopropane-1, 1-dicarboxamide
UA108618C2 (uk) 2009-08-07 2015-05-25 Застосування c-met-модуляторів в комбінації з темозоломідом та/або променевою терапією для лікування раку
CN102933551A (zh) 2010-03-12 2013-02-13 埃克塞里艾克西斯公司 N-[3-氟-4-({6-(甲氧基)-7-[(3-吗啉-4-基丙基)氧基]-喹啉-4-基}氧基)苯基]-n’-(4-氟苯基)环丙烷-1,1-二甲酰胺的水合结晶形式
US20120070368A1 (en) 2010-04-16 2012-03-22 Exelixis, Inc. Methods of Using C-Met Modulators
US20140186407A9 (en) 2010-07-16 2014-07-03 Exelixis Inc. C-Met Modulator Pharmaceutical Compositions
KR20190042768A (ko) * 2010-07-16 2019-04-24 엑셀리시스, 인코포레이티드 C-met 조절제 약제학적 조성물
JP2012042811A (ja) * 2010-08-20 2012-03-01 Sony Corp ズームレンズ及び撮像装置
JP2013540759A (ja) 2010-09-27 2013-11-07 エクセリクシス， インク． 去勢抵抗性前立腺癌および造骨性転移の治療のためのｍｅｔおよびｖｅｇｆの二元阻害薬
WO2012044577A1 (en) * 2010-09-27 2012-04-05 Exelixis, Inc. Dual inhibitors of met and vegf for the treatment of castration resistant prostate cancer and osteoblastic bone metastases
WO2012064967A2 (en) * 2010-11-10 2012-05-18 Cedars-Sinai Medical Center Cancer cell-derived receptor activator of the nf-kb ligand drives bone and soft tissue metastases
CN103327979A (zh) 2010-11-22 2013-09-25 葛兰素史密斯克莱知识产权（第2号）有限公司 治疗癌症的方法
KR20210010671A (ko) 2011-02-10 2021-01-27 엑셀리시스, 인코포레이티드 퀴놀린 화합물들의 제조 방법들 및 상기 화합물들을 함유하는 약학 조성물들
CN103717221A (zh) 2011-05-02 2014-04-09 埃克塞里艾克西斯公司 治疗癌症和骨癌疼痛的方法
TW201306842A (zh) 2011-06-15 2013-02-16 Exelixis Inc 使用ｐｉ３ｋ／ｍｔｏｒ吡啶並嘧啶酮抑制劑及苯達莫司汀及／或利妥昔單抗治療惡性血液疾病之組合療法
BR112014006702A2 (pt) 2011-09-22 2017-06-13 Exelixis Inc método para tratar osteoporose
TWI642650B (zh) 2011-10-20 2018-12-01 艾克塞里克斯公司 用於製備喹啉衍生物之方法
EA201490944A1 (ru) 2011-11-08 2014-10-30 Экселиксис, Инк. Двойной ингибитор met и vegf для лечения рака
WO2013166296A1 (en) 2012-05-02 2013-11-07 Exelixis, Inc. A dual met - vegf modulator for treating osteolytic bone metastases
WO2015164869A1 (en) 2014-04-25 2015-10-29 Exelixis, Inc. Method of treating lung adenocarcinoma
JP6452498B2 (ja) * 2015-03-03 2019-01-16 キヤノン株式会社 液体吐出ヘッドの検査装置、及び液体吐出ヘッド
CN109069499A (zh) 2016-04-15 2018-12-21 埃克塞里艾克西斯公司 使用 n-(4-(6,7-二甲氧基喹啉-4-基氧基)苯基)-n’-(4-氟苯基)环丙烷-1,1-二甲酰胺,(2s)-羟基丁二酸盐治疗肾细胞癌的方法
US20190262330A1 (en) 2017-12-21 2019-08-29 Exelixis, Inc. Method of Treating Hepatocellular Carcinoma Using N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090170896A1 (en) * 2003-09-26 2009-07-02 Exelixis, Inc. c-Met modulators and methods of use
US8067436B2 (en) * 2003-09-26 2011-11-29 Exelixis, Inc. c-Met modulators and methods of use
US8497284B2 (en) * 2003-09-26 2013-07-30 Exelixis, Inc. C-met modulators and method of use
US20090274693A1 (en) * 2008-05-05 2009-11-05 Gilmer Tona M Method of Treating Cancer using a cMet and AXL Inhibitor and an ErbB Inhibitor
WO2012044572A1 (en) * 2010-09-27 2012-04-05 Exelixis, Inc. Dual inhibitors of met and vegf for the treatment of castration- resistant prostate cancer and osteoblastic bone metastases
US20120252840A1 (en) * 2011-04-04 2012-10-04 Exelixis, Inc. Method of Treating Cancer

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
GORDON ET AL. Journal of Clinical Oncology, May 2011, vol. 29, no. 15 Suppl., Abstract #3010 *
KURZROCK ET AL. Journal of Clinical Oncology, July 1, 2011, vol. 29, no. 19, pages 2660-2666 *
LEE ET AL. Clin. Cancer Res., 2013, vol. 19, no. 11, pages 3088-3094 *
NATIONAL CANCER INSTITUTE (http://www.cancer.gov/drugdictionary?cdrid=461103 (accessed 4/27/2015) *
NECHUSHTAN ET AL. 22nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, November 16-19, 2010, Berlin, Germany *
VAISHAMPAYAN, Curr. Oncol. Rep., 2013, vol. 15, pages 76-82 *

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10548888B2 (en) 2010-07-16 2020-02-04 Exelixis C-Met modulator pharmaceutical compositions
US11123338B2 (en) 2010-07-16 2021-09-21 Exelixis, Inc. C-met modulator pharmaceutical compositions
US10034873B2 (en) 2010-07-16 2018-07-31 Exelixis, Inc. C-met modulator pharmaceutical compositions
US10039757B2 (en) 2010-07-16 2018-08-07 Exelixis, Inc. C-Met modulator pharmaceutical compositions
US11612597B2 (en) 2010-09-27 2023-03-28 Exelixis, Inc. Method of treating cancer
US11969419B2 (en) 2010-09-27 2024-04-30 Exelixis, Inc. Method of treating cancer
US10543206B2 (en) 2011-02-10 2020-01-28 Exelixis, Inc. Processes for preparing quinoline compounds and pharmaceutical compositions containing such compounds
US9717720B2 (en) 2011-02-10 2017-08-01 Exelixis, Inc. Processes for preparing quinoline compounds and pharmaceutical compositions containing such compounds
US11298349B2 (en) 2011-02-10 2022-04-12 Exelixis, Inc. Processes for preparing quinoline compounds and pharmaceutical compositions containing such compounds
US10123999B2 (en) 2011-02-10 2018-11-13 Exelixis, Inc. Processes for preparing quinoline compounds and pharmaceutical compositions containing such compounds
US11116759B2 (en) 2011-04-04 2021-09-14 Exelixis, Inc. Method of treating cancer
US11504363B2 (en) 2011-05-02 2022-11-22 Exelixis, Inc. Method of treating cancer and bone cancer pain
US10166225B2 (en) 2011-09-22 2019-01-01 Exelixis, Inc. Method for treating osteoporosis
US9969692B2 (en) 2011-10-20 2018-05-15 Exelixis, Inc. Process for preparing quinoline derivatives
US9861624B2 (en) 2012-05-02 2018-01-09 Exelixis, Inc. Method of treating cancer
US10273211B2 (en) 2013-03-15 2019-04-30 Exelixis, Inc. Metabolites of N-{4-([6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
US11564915B2 (en) 2013-04-04 2023-01-31 Exelixis, Inc. Cabozantinib dosage form and use in the treatment of cancer
US10851061B2 (en) 2014-02-14 2020-12-01 Exelixis, Inc. Crystalline solid forms of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, processes for making, and methods of use
US10501418B2 (en) 2014-02-14 2019-12-10 Exelixis, Inc. Crystalline solid forms of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, processes for making, and methods of use
US11760726B2 (en) 2014-02-14 2023-09-19 Exelixis, Inc. Crystalline solid forms of N-{4-[(6,7-Dimethoxyquinolin-4-yl)oxy]phenyl} -n'-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, processes for making, and methods of use
US11724986B2 (en) 2014-02-14 2023-08-15 Exelixis, Inc. Crystalline solid forms of N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide, processes for making, and methods of use
US10159666B2 (en) 2014-03-17 2018-12-25 Exelixis, Inc. Dosing of cabozantinib formulations
US11124481B2 (en) 2014-07-31 2021-09-21 Exelixis, Inc. Method of preparing fluorine-18 labeled Cabozantinib and its analogs
US11065240B2 (en) 2014-08-05 2021-07-20 Exelixis, Inc. Drug combinations to treat multiple myeloma
US11141413B2 (en) 2016-04-15 2021-10-12 Exelixis, Inc. Method of treating renal cell carcinoma using N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate
US11161817B2 (en) 2017-09-28 2021-11-02 Chongqing Pharmaceutical Industrial Research Institute Co. Ltd. Quinoline derivative and use thereof as tyrosine kinase inhibitor
WO2021242753A1 (en) * 2020-05-26 2021-12-02 The Regents Of The University Of Michigan Mitochondrial targeting compounds for the treatment of associated diseases

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