US20150072019A1 - Fgfr inhibitor for use in the treatment of hypophosphatemic disorders - Google Patents

Fgfr inhibitor for use in the treatment of hypophosphatemic disorders Download PDF

Info

Publication number
US20150072019A1
US20150072019A1 US14/388,978 US201314388978A US2015072019A1 US 20150072019 A1 US20150072019 A1 US 20150072019A1 US 201314388978 A US201314388978 A US 201314388978A US 2015072019 A1 US2015072019 A1 US 2015072019A1
Authority
US
United States
Prior art keywords
piperazin
dimethoxy
dichloro
urea
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US14/388,978
Other languages
English (en)
Inventor
Michaela Kneissel
Vito Gaugnano
Diana Graus Porta
Simon Wöhrle
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Novartis AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis AG filed Critical Novartis AG
Priority to US14/388,978 priority Critical patent/US20150072019A1/en
Assigned to NOVARTIS PHARMA AG reassignment NOVARTIS PHARMA AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KNEISSEL, MICHAELA, GRAUS PORTA, DIANA, WÖHRLE, Simon, GUAGNANO, VITO
Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NOVARTIS PHARMA AG
Publication of US20150072019A1 publication Critical patent/US20150072019A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/42—Phosphorus; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • 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
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

Definitions

  • the present invention relates generally to 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl ⁇ -1-methyl-urea or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition comprising 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl ⁇ -1-methyl-urea or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of the fibroblast growth factor receptor mediated disorders.
  • FGF fibroblast growth factor
  • signaling receptors are associated with multiple biological activities (proliferation, survival, apoptosis, differentiation, motility) that govern key processes (development, angiogenesis, and metabolism) for the growth and maintenance of organisms from worms to humans. 22 distinct FGFs have been identified, all sharing a conserved 120-aminoacids core domain with 15-65% sequence identity.
  • FGF23 is a critical, bone-derived mediator of phosphate homeostasis, which functions in the kidney to regulate vitamin D biosynthesis and renal absorption of phosphate.
  • FGF23 signaling controls expression of the vitamin D metabolizing enzymes CYP27B1 and CYP24A1, resulting in decreased biosynthesis and elevated turnover of the active vitamin D metabolite 1,25-dihydroxyvitamin D3 (1,25[OH]2D3).
  • FGF23 impairs expression of the sodium-phosphate co-transporters NPT2A and NPT2C in the brush border membrane of proximal tubular cells, which mediate the re-absorption of urinary phosphate.
  • Excess levels or augmented function of FGF23 result in hypophosphatemia along with impaired biosynthesis of 1,25(OH)2D3(vitamin D) and are associated with several hereditary hypophosphatemia disorders with skeletal abnormalities as a consequence of impaired bone mineralization, including X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets (ADHR), and autosomal recessive hypophosphatemic rickets (ARHR).
  • XLH X-linked hypophosphatemic rickets
  • ADHR autosomal dominant hypophosphatemic rickets
  • ARHR autosomal recessive hypophosphatemic rickets
  • secretion of FGF23 by tumor cells has been identified to cause hypophosphatemia resulting in tumor-induced osteomalacia (TIO). Elevated levels of FGF23 are also commonly observed in post-renal transplantation patients leading to servere hypophosphatemia.
  • FGF23 plays a role in several other hypophosphatemic syndromes such as epidermal nevus syndrome, osteoglophonic dysplasia and McCune-Albright syndrome which have been associated with increased FGF23 levels.
  • XLH and other FGF23-mediated hypophosphatemia diseases such as ADHR and ARHR commonly manifest clinically in early childhood with short stature and bowing deformities of the legs.
  • the present invention thus provides 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl ⁇ -1-methyl-urea or a pharmaceutically acceptable salt, N-oxide or solvate thereof for use in the treatment of X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), tumor-induced osteomalacia, post-renal transplant hypophosphatemia, epidermal nevus syndrome, osteoglophonic dysplasia or McCune-Albright syndrome.
  • XLH X-linked hypophosphatemic rickets
  • ADHR autosomal dominant hypophosphatemic rickets
  • ARHR autosomal recessive hypophosphatemic rickets
  • the compound, its pharmaceutically acceptable salt or solvate can be used in the treatment of X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR) or tumor-induced osteomalacia, post-renal transplant hypophosphatemia,
  • XLH X-linked hypophosphatemic rickets
  • ADHR autosomal dominant hypophosphatemic rickets
  • ARHR autosomal recessive hypophosphatemic rickets
  • tumor-induced osteomalacia post-renal transplant hypophosphatemia
  • the 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl ⁇ -1-methyl-urea or a pharmaceutically acceptable salt or solvate is administered to a patient in more than one dose.
  • the treatment should preferably last at least 8 weeks, optionally with an interruption.
  • the time between two consecutive doses of the compound can be more than 24 hours, optionally 48 hours.
  • the compound of formula I can be further used in the treatment in combination with another FGFR inhibitor, phosphate, calcium, osteopontin (OPN), parathyroid hormone or its analogue (PTH), and/or vitamin D or vitamin D analogue, preferably in combination with phosphate, calcium and/or vitamin D or vitamin D analogue, particularly vitamin D or vitamin D analogue.
  • another FGFR inhibitor phosphate, calcium, osteopontin (OPN), parathyroid hormone or its analogue (PTH), and/or vitamin D or vitamin D analogue, preferably in combination with phosphate, calcium and/or vitamin D or vitamin D analogue, particularly vitamin D or vitamin D analogue.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl ⁇ -1-methyl-urea or a pharmaceutically acceptable salt, N-oxide or solvate thereof for use as defined above.
  • Another aspect of the invention is 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl ⁇ -1-methyl-urea or a pharmaceutically acceptable salt, N-oxide or solvate thereof for use in increasing cortical bone volume or thickness when compared to a control or cortical bone volume or thickness before the beginning of the treatment.
  • Yet another aspect of the invention is 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl ⁇ -1-methyl-urea or a pharmaceutically acceptable salt, N-oxide or solvate thereof for use in gaining body weight in a patient that shows increased activity of FGF23 compared to control.
  • Further aspect of the invention is 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl ⁇ -1-methyl-urea or a pharmaceutically acceptable salt, N-oxide or solvate thereof for use in inhibiting FGF23 expression in bone or inhibiting FGF23 activity in bone.
  • FIG. 1 FGFR inhibitor treatment induces 1,25(OH)2D3 biosynthesis and alleviates hypocalcemia and hypophosphatemia in Hyp mice.
  • Regulation of the renal FGF23 target genes Cyp27b1 (A) and Cyp24a1 (B) upon FGFR inhibition for 7 h in vivo is shown. Data are shown as relative levels to the wild-type vehicle control group (relative expression of 100).
  • C Serum 1,25(OH)2D3 levels of wild-type and Hyp mice treated as described in A and B were determined by radio receptor assay. Calcium (E) and phosphate (F) levels at 24 h post-administration in wild-type and Hyp mice treated with a single oral dose of BGJ398 (50mg/kg) or vehicle.
  • Phosphate and calcium levels were determined from serum. Data are given as average with SEM (n ⁇ 6). Data were compared by unpaired Student's t test; *p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001; n. s.: not significant.
  • FIG. 2 FGFR inhibitor treatment modulates renal FGF23 target gene expression and alleviates hypocalcemia and hypophosphatemia in Dmp1-null mice.
  • Regulation of the renal FGF23 target genes Cyp27b1 (A) and Cyp24a1 (B) upon FGFR inhibition in vivo Data are shown as relative levels to the wild-type vehicle control group (relative expression of 100) and are given as average with standard errors of the mean (SEM) (n ⁇ 6). Effect of pharmacological FGFR inhibition on serum calcium (C) and phosphate (D) levels in wild-type and Dmp1-null mice. Data are shown as average with SEM (n ⁇ 6). Data were compared by unpaired Student's t test; *p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001; n. s.: not significant.
  • FIG. 3 shows FGFR-dependent signaling regulates FGF23 expression in bone.
  • FIG. 4 shows that FGFR inhibitor treatment leads to a persistent increase of calcium and phosphate serum levels. Determination of Calcium (A) and phosphate (B) levels from serum in Wild-type or Hyp mice 48 h after administration of the compound of formula I. (C) Compound concetration in the kidney after 7 h and 24 h of treatment.
  • FIG. 5 Long-term FGFR inhibition enhances body weight and tail length development and restores mineral ion homeostasis in Hyp mice.
  • Wild-type or Hyp mice were treated with the FGFR inhibitor BGJ398 (50 mg/kg) or vehicle 3qw for 56 days and body weight (A) and tail length (C) development was monitored.
  • Calcium (E) and phosphate (F) and levels at the end of the 8 week treatment were determined from serum 24 h after the last administration. Data are shown as average with SEM (n ⁇ 6). Data were compared by unpaired Student's t test; *p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001; n. s.: not significant.
  • FIG. 6 Serum levels of FGF23, parathyroid hormone (PTH) and 1,25(OH)2D3 after long-term FGFR inhibition with BGJ398.
  • Wild-type or Hyp mice were treated with the FGFR inhibitor BGJ398 (50 mg/kg) or vehicle 3qw for 56 days and FGF23 (A), PTH (B) and 1,25(OH)2D3 (C) levels were determined from serum at 24 h after the last dosing. Data are shown as average with SEM (n ⁇ 4). Data were compared by unpaired Student's t test; *p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001; n. s.: not significant.
  • FIG. 7 Long-term FGFR inhibition enhances growth of long bones in Hyp mice. Radiographs of femur (A) and tibia (B) from wild-type or Hyp mice treated with the FGFR inhibitor BGJ398 (50 mg/kg) or vehicle 3qw for 56 days. Quantification of femoral (C) and tibial (D) length. Data are shown as average with SEM (n ⁇ 6). Data were compared by unpaired Student's t test; *p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001; n. s.: not significant.
  • FIG. 8 Long-term FGFR inhibition improves cortex integrity in femoral bone of Hyp mice.
  • A Micro-CT scans of femoral cortex (sub growth plate area) from wild-type or Hyp mice treated with the FGFR inhibitor BGJ398 (50 mg/kg) or vehicle 3qw for 56 days. Quantification of relative cortical bone volume (B) and average cortex thickness (C). Data are shown as average with SEM (n ⁇ 6). Data were compared by unpaired Student's t test; *p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001; n. s.: not significant.
  • FIG. 9 shows Goldner staining of tibial sections from wild-type or Hyp mice treated with the FGFR inhibitor BGJ398 (50 mg/kg) or vehicle 3qw for 56 days
  • A Mineralized tissue is indicated by white arrows, unmineralized osteoid is indicated by black arrows,
  • B Osteoid surface/bone surface and osteoid width (C) determined by histomorphometry in the tibial epiphysis of wild-type or Hyp mice treated with BGJ398 (50 mg/kg) or vehicle 3qw for 56 days.
  • Data are shown as average with SEM (n ⁇ 6). Data were compared by unpaired Student's t test; *p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001.
  • the fibroblast growth factor 23 (FGF23) is known. It is considered a member of the fibroblast growth factor family with broad biological activities.
  • the sequence of the protein and/or the coding sequence of the protein can be retrieved from publicly available databases known in the art.
  • Human FGF23 is also known in the art as ADHR; HYPF; HPDR2; PHPTC.
  • FGF23 is the disease-causing factor in several hypophosphatemic conditions.
  • the compound can be especially useful for the treatment of X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets (ADHR) or autosomal recessive hypophosphatemic rickets (ARHR), post-renal transplant hypophosphatemia, particularly X-linked hypophosphatemic rickets (XLH) and autosomal dominant hypophosphatemic rickets (ADHR) or autosomal recessive hypophosphatemic rickets (ARHR).
  • XLH X-linked hypophosphatemic rickets
  • ADHR autosomal dominant hypophosphatemic rickets
  • ARHR autosomal recessive hypophosphatemic rickets
  • the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • “treat”, “treating” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • “treat”, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • “treat”, “treating” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • pharmaceutically acceptable salts refers to salts that retain the biological effectiveness and properties of the compound when used according to this invention and, which typically are not biologically or otherwise undesirable.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, propionate, stearate, succinate, subsalicylate, tartrate, tosylate, trifluoroacetate salt or the like.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • the pharmaceutically acceptable salt is monophosphoric acid salt (or phosphate) of the compound 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl ⁇ -1-methyl-urea, which can optionally be in anhydrous crystalline form.
  • the salt of the compound is any salt or form disclosed in WO2011/071821.
  • 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl ⁇ -1-methyl-urea is in its free base form.
  • solvate refers to a molecular complex of the compound with one or more solvent molecules.
  • solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the compound, e.g., water, ethanol, and the like.
  • N-Oxide of compound 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl ⁇ -1-methyl-urea has the following formula II
  • BGJ398 or a pharmaceutically acceptable salt, N-oxide or solvate is administered to a patient in need thereof in more than one therapeutically effective dose.
  • a therapeutically effective dose refers to an amount of the BGJ398 that will elicit the biological or medical response of a subject, for example, reduction or inhibition of kinase activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.
  • the subject can be any mammal, incuding human.
  • the therapeutically effective dose can be about 1-250 mg of BGJ398 for a subject of about 50-70 kg, or about 1-150 mg, for example at dose of 125 mg, or about 0.5-100 mg, or about 1-50 mg, or about 1-25 mg, or about 1-10 mg of BGJ398.
  • the therapeutically effective dosage of the compound, whether alone or in the pharmaceutical composition, or in a combination with other active ingredients as explained hereinafter, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease or the severity thereof being treated.
  • in another aspect of the invention is 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl ⁇ -1-methyl-urea or a pharmaceutically acceptable Salt, N-oxide or solvate thereof for use in increasing cortical bone volume or thickness when compared to a control or cortical bone volume or thickness before the beginning of the treatment.
  • the experiments that were conducted clearly show that the cortical bone volume increases from pathological values to indistinguishable with normal values when the subject is treated with BGJ398.
  • cortex thickness was significantly increased.
  • control refers to a value of FGF23 activity or expression in an individual, a number of subjects or population without the respective disease.
  • one embodiment of the invention is 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl ⁇ -1-methyl-urea or a pharmaceutically acceptable salt, N-oxide or solvate thereof for use in inhibiting FGF23 expression in bone or inhibiting FGF23 activity in bone.
  • “Expression” refers to the nucleic acids or amino acids generated when a gene is transcribed and translated.
  • transcriptional activity can be assessed by any appropriate method, including for example, detecting the quantity of mRNA transcribed from the FGF23 gene or the quantity of cDNA produced from the reverse transcription of the mRNA transcribed from the gene or the quantity of the polypeptide or protein encoded by the gene.
  • any one of gene copy number, transcription, or translation can be determined using known techniques.
  • an amplification method such as PCR may be useful.
  • the dose can be administered intermittently in order to minimize the undesired secondary effect which may be harmful to the subject.
  • Doses can be administered consecutively without interruptions, or starting first with a number of doses to achieve a steady state concentration in a patient in a need thereof and then modifying the time between the doses.
  • the dosing can be adapted immediately after the first dose.
  • the time between two consecutive doses of the compound can be more than 24 hours, optionally 48 hours or even a week.
  • the dose is given repeatedly, optionally again with one, two, or three days between two consecutive doses, or only after a relapse.
  • the compound 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl ⁇ -1-methyl-urea can be used in the treatment in combination with another FGFR inhibitor, phosphate, calcium, osteopontin (OPN), parathyroid hormone or its analogue (PTH), and/or vitamin D or vitamin D analogue, preferably in combination with phosphate, calcium and/or vitamin D or vitamin D analogue, particularly vitamin D or vitamin D analogue.
  • OPN osteopontin
  • PTH parathyroid hormone or its analogue
  • vitamin D or vitamin D analogue preferably in combination with phosphate, calcium and/or vitamin D or vitamin D analogue, particularly vitamin D or vitamin D analogue.
  • the BGJ389 may be used in combination to advantage to bring about additive or even synergistic effects, but also to reduce the need of using higher doses of BGJ389 and consecutively to limit the risk of adverse effects.
  • Phosphate can be used in any form which when taken orally or parenterally increases blood level of inorganic phosphorus (P), which may e.g. be measured in serum by ultraviolet method using for example kits from RANDOX Laboratories LTD, UK, and a clinical chemistry analyzer such as the HITACHI 717 analyzer (Roche Diagnostics).
  • Calcium can also be in any form which eventually leads to, when taken, increased blood level of total calcium that may e.g.
  • Osteopontin referred to as secreted phosphoprotein 1, bone sialoprotein I or early T-lymphocyte activation 1, which is known. It is considered an extracellular structural protein involved in bone remodeling.
  • Human osteopontin is known in the art as SPP1.
  • Parathyroid hormone (PTH) or parathormone is known. It is considered a hormone involved in the regulation of the calcium level in blood.
  • PTH analogue is a molecule that at least in part retains the activity of PTH and structurally resembles the complete PTH by being only shorter or has modified or additional substituents linked to the PTH backbone structure.
  • Vitamin D is a known hormone responsible for calcium homeostasis and important for healthy bone phenotype. Its analogue is a structurally similar compound in that it mimics the chemical structure of Vitamin D and elicits similar pharmacological effect.
  • An example of Vitamin D analogue is calcipotriol.
  • 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl ⁇ -1-methyl-urea, or a pharmaceutically acceptable salt, N-oxide or solvate thereof is formulated in a pharmaceutical composition which in turn can be used in any treatment as explained above.
  • the pharmaceutical composition would normally comprise 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1- ⁇ 6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimid-4-yl ⁇ -1-methyl-urea or a pharmaceutically acceptable salt, N-oxide or solvate thereof and one or more pharmaceutically acceptable excipients.
  • the amount of the compound in the pharmaceutical composition is preferably therapeutically effective.
  • FGFR inhibitor phosphate, calcium, osteopontin (OPN), parathyroid hormone or its analogue (PTH), and/or vitamin D or vitamin D analogue, preferably in combination with phosphate, calcium and/or vitamin D or vitamin D analogue, particularly vitamin D or vitamin D analogue are added in the pharmaceutical composition according to the present invention.
  • the pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and topical administration, etc.
  • the pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions).
  • compositions can be subjected to conventional pharmaceutical operations such as compacting, tabletting, filtering, lyophilization, sterilization or the like.
  • Excipient can be any conventional inert diluent, lubricating agent, buffering agent, binder, disintegration agent, sweetening agent, flavoring agent, as well as adjuvants, such as preservative, stabilizer, wetting agent, emulsifer, solvents, dispersion media, coating, surfactant, antioxidant, preservative (e.g. antibacterial agents, antifungal agents), isotonic agent, absorption delaying agent, salt, preservative, drug stabilizer, dye, and the like and combinations thereof.
  • preservative e.g. antibacterial agents, antifungal agents
  • FGFR inhibitor treatment induces 1,25(OH)2D3 biosynthesis and alleviates hypocalcemia and hypophosphatemia in Hyp mice.
  • Wild-type C57BL/6 and Hyp (B6.Cg-PhexHyp/J) mice were obtained from The Jackson Laboratory.
  • Dmp1-null mice were generated by Feng et al. (J. Dent. Res. 2003; 82:776-780.). All mice were kept in cages under standard laboratory conditions. Mice were fed on a standard rodent diet with water ad libitum.
  • Kidneys were sampled, total RNA was isolated. For RNA isolation from mouse tibial and femoral bones, epiphyses were cut off and bone marrow was removed by centrifugation at 4° C. Tissue was homogenized using a Precellyis 24 bead homogenizer and RNA was extracted with TRIzol reagent. RNA was purified subsequently by chloroform extraction, isopropanol precipitation and RNeasy Mini kit. For kidney RNA, approximately 60 mg of tissue was homogenized in 1.5 ml RTL buffer (Qiagen) with a rotor-stator homogenizer and RNA was purified with the RNeasy Mini kit. Random hexamer primed cDNA was synthesized with 0.5-2 ⁇ g RNA and MultiScribe MuLV reverse transcriptase.
  • Gene expression was analyzed by quantitative real-time PCR (qPCR).
  • TaqMan Probe-Based Gene Expression assays were used for expression analysis of mouse Cyp27b1 (Mm01165919), Cyp24a1 (Mm00487244) and Gapdh (4352339E).
  • Sequences of primers and FAM/TAMRA-labeled probes (Microsynth) for the detection of mouse Fgf23 were 5′-TTTGGATCGCTTCACTTCAG (forward), 5′-GTGATGCTTCTGCGACAAGT (reverse) and 5′-CGCCAGTGGACGCTGGAGAA (probe).
  • Quantitative real-time PCR was performed in an iQ5 Real-Time PCR Detection System using a qPCR core kit for probe assay and an equivalent of 40 or 80 ng RNA of each sample. The data were normalized to Gapdh expression.
  • Serum was separated from whole blood using clot activator centrifugation tubes. 100 ⁇ l of serum were used for determination of phosphate and calcium levels using the VetScan diagnostic profiling system. Serum concentrations of 1,25(OH)2D3 were determined using a radio receptor assay kit. FGF23 serum levels were analyzed by an ELISA detecting intact FGF23 (Kainos).
  • FGF23 exerts its hypophosphatemic functions in part by transcriptional regulation of the 1,25(OH)2D3-metabolizing enzymes CYP27B1 and CYP24A1 in the kidney.
  • Cyp27b1 and Cyp24a1 expression and 1,25(OH)2D3 serum levels in Hyp mice were not significantly different compared to wild-type mice ( FIGS. 1A , B and C), potentially owing to adaption processes and in line with previous reports.
  • FIG. 1 regulation of the renal FGF23 target genes Cyp27b1 (A) and Cyp24a1 ( FIG. 1B ) upon FGFR inhibition in vivo is depicted.
  • C Serum 1,25(OH)2D3 levels of wild-type and Hyp mice treated as described in A and B were determined by radio receptor assay.
  • Calcium ( FIG. 1E ) and ( FIG. 1F ) phosphate levels at 24 h post-administration in wild-type and Hyp mice treated with a single oral dose of BGJ398 (50 mg/kg) or vehicle are shown. All together this shows that FGFR inhibitor treatment induces 1,25(OH)2D3 biosynthesis and alleviates hypocalcemia and hypophosphatemia in Hyp mice. The results further indicate that pharmacological inhibition of FGFR is sufficient to counteract aberrant FGF23 signaling in Hyp mice.
  • FGFR inhibitor treatment modulates renal FGF23 target gene expression and alleviates hypocalcemia and hypophosphatemia in Dmp1-null mice.
  • Regulation of the renal FGF23 target genes Cyp27b1 ( FIG. 2A ) and Cyp24a1 ( FIG. 2B ) upon FGFR inhibition in vivo is shown on FIG. 2 .
  • Cyp27b1 and Cyp24a1 expression were also observed in Dmp1-null mice.
  • SEM standard errors of the mean
  • mice received a single oral dose of the FGFR inhibitor BGJ398 (50 mg/kg) or vehicle and were studied 24 h post-administration. Phosphate and calcium levels were determined from serum. As for Hyp mice, pharmacological FGFR inhibition led to increased serum calcium and phosphate levels in Dmp1-null mice ( FIGS. 2C and D, respectively). Data in FIG. 2 are shown as average with SEM (n ⁇ 6). Data were compared by unpaired Student's t test; *p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001; n. s.: not significant.
  • FIG. 3 shows FGFR-dependent signaling regulates FGF23 expression in bone.
  • BGJ398 FGFR inhibitor-treated Hyp mice.
  • Mice received a single oral dose of the FGFR inhibitor BGJ398 (50 mg/kg) or vehicle and were studied 7 h post-administration.
  • FGF23 bone mRNA ( FIG. 3A ) and serum ( FIG. 3B ) levels in wild-type and Hyp mice treated with BGJ398 were determined.
  • FIG. 2A The transcriptional repression of FGF23 resulted in undetectable serum FGF23 levels in wild-type mice, while the pathological high FGF23 levels in Hyp mice were reduced by approximately 50% ( FIG. 3B ).
  • mRNA expression is shown on the figure as relative levels to the wild-type vehicle control group (relative levels of 100) and are given as average with SEM (n ⁇ 7). FGF23 mRNA expression values were normalized to Gapdh mRNA copies. Data were compared by unpaired Student's t test; *p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001.
  • FIG. 4 clearly shows that FGFR inhibitor treatment leads to a persistent increase of calcium and phosphate serum levels.
  • wild-type or Hyp mice received a single oral dose of the FGFR inhibitor BGJ398 or vehicle and were studied 48 h after administration of the compound.
  • Calcium ( FIG. 4A ) and phosphate ( FIG. 4B ) levels were determined from serum. Data are shown as average with SEM (n ⁇ 3). Data were compared by unpaired Student's t test; *p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001; n. s.: not significant.
  • C BGJ398 concentrations in kidney at 7 h and 24 h post-administration. Values are given as average with SEM (n ⁇ 5).
  • FIG. 5 shows body weight ( FIG. 5A ) and tail length ( FIG. 5C ) development as monitored.
  • FIG. 5B and tail length gain ( FIG. 5D ) over the course of the treatment are depicted in FIG. 5 as well.
  • Data are shown as average with SEM (n ⁇ 6). Data were compared by unpaired Student's t test; *p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001; n. s.: not significant.
  • Hyp mice Compared to wild-type littermates, Hyp mice displayed a reduced body weight at 5 weeks of age, when the treatments were started. During the course of treatment, pharmacological FGFR inhibition in Hyp mice led to a stronger increase in body weight compared to the vehicle control group ( FIG. 5A ). Overall, the total body weight gain in BGJ398-treated Hyp mice was similar to vehicle-treated wild-type mice ( FIG. 5B ). A shorter tail is a pronounced feature of the hypophosphatemic rickets phenotype of Hyp mice, reflecting the impaired bone formation. Therefore, we monitored the tail length development during the 8 weeks of treatment and found that BGJ398-treated Hyp mice displayed a much stronger increase in tail length compared to control Hyp mice ( FIG. 5C ).
  • FIG. 6 shows serum levels of FGF23, parathyroid hormone (PTH) and 1,25(OH)2D3 after long-term FGFR inhibition with BGJ398.
  • Wild-type or Hyp mice were treated again with the FGFR inhibitor BGJ398 (50 mg/kg) or vehicle 3qw for 56 days and FGF23 ( FIG. 6A ), parathyroid hormone (PTH) ( FIG. 6B ) and 1,25(OH)2D3 ( FIG. 6C ) levels were determined from serum at 24 h after the last dosing.
  • PTH values were determined by separating the serum from whole blood using clot activator centrifugation tubes (Sarstedt).
  • FIGS. 7A and B Radiographs of femur ( FIG. 7A ) and tibia ( FIG. 7B ) from wild-type or Hyp mice treated with the FGFR inhibitor BGJ398 (50 mg/kg) or vehicle 3qw for 56 days. Quantification of femoral ( FIG. 7C ) and tibial ( FIG. 7D ) length. Data are shown as average with SEM (n ⁇ 6). Data were compared by unpaired Student's t test; *p ⁇ 0.05; **p ⁇ 0.01; ***p ⁇ 0.001; n. s.: not significant.
  • FGFR inhibition improves cortex integrity in femoral bone of Hyp mice.
  • ⁇ CT microcomputed tomography
  • FIG. 8B Compared to wild-type mice, vehicle-treated Hyp mice displayed reduced relative bone volume in the cortical bone area ( FIG. 8B ) and a decreased average cortex thickness ( FIG. 8C ). In contrast, cortex of BGJ398-treated Hyp mice appeared intact ( FIG. 8A ), relative cortical bone volume was indistinguishable from wild-type mice ( FIG. 8B ) and cortex thickness was significantly increased compared to vehicle-treated Hyp mice ( FIG. 8C ).
  • FIG. 9A left panels
  • FIG. 9B right panels
  • enhanced mineralization in the epiphyseal bone area adjacent to the growth plate as well as the formation of primary spongiosa in the metaphyseal sub-growth plate area, which was almost absent in vehicle-treated Hyp mice.
  • histomorphometric analysis revealed an attenuation of the increased OS/BS ratio in Hyp mice in upon FGFR inhibition ( FIG. 9B ) and a strong reduction of osteoid width within the epiphyseal, metaphyseal and cortical bone compartments ( FIG. 9C ).
  • our data indicate that pharmacological inhibition of FGFRs is sufficient to inhibit aberrant FGF23-signaling and to alleviate the hypophosphatemic rickets phenotype of XLH and potentially other FGF23-related hypophosphatemia diseases, such as ARHR.
  • the complete normalization of phosphate and calcium levels in Hyp mice upon continuous dosing of the FGFR inhibitor BGJ398 and the re-organization of the growth plate area in rickets-resembling bone are promising, since this constitutes a prerequisite for a potential reversion of the hypophosphatemic rickets phenotype.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Endocrinology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Obesity (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Nutrition Science (AREA)
  • Toxicology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US14/388,978 2012-03-30 2013-03-29 Fgfr inhibitor for use in the treatment of hypophosphatemic disorders Abandoned US20150072019A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/388,978 US20150072019A1 (en) 2012-03-30 2013-03-29 Fgfr inhibitor for use in the treatment of hypophosphatemic disorders

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201261617889P 2012-03-30 2012-03-30
US14/388,978 US20150072019A1 (en) 2012-03-30 2013-03-29 Fgfr inhibitor for use in the treatment of hypophosphatemic disorders
PCT/EP2013/056811 WO2013144339A1 (en) 2012-03-30 2013-03-29 Fgfr inhibitor for use in the treatment of hypophosphatemic disorders

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2013/056811 A-371-Of-International WO2013144339A1 (en) 2012-03-30 2013-03-29 Fgfr inhibitor for use in the treatment of hypophosphatemic disorders

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/272,633 Continuation US10028955B2 (en) 2012-03-30 2016-09-22 FGFR inhibitor for use in the treatment of hypophosphatemic disorders

Publications (1)

Publication Number Publication Date
US20150072019A1 true US20150072019A1 (en) 2015-03-12

Family

ID=47998482

Family Applications (3)

Application Number Title Priority Date Filing Date
US14/388,978 Abandoned US20150072019A1 (en) 2012-03-30 2013-03-29 Fgfr inhibitor for use in the treatment of hypophosphatemic disorders
US15/272,633 Active US10028955B2 (en) 2012-03-30 2016-09-22 FGFR inhibitor for use in the treatment of hypophosphatemic disorders
US16/005,966 Abandoned US20210308132A1 (en) 2012-03-30 2018-06-12 Fgfr inhibitor for use in the treatment of hypophosphatemic disorders

Family Applications After (2)

Application Number Title Priority Date Filing Date
US15/272,633 Active US10028955B2 (en) 2012-03-30 2016-09-22 FGFR inhibitor for use in the treatment of hypophosphatemic disorders
US16/005,966 Abandoned US20210308132A1 (en) 2012-03-30 2018-06-12 Fgfr inhibitor for use in the treatment of hypophosphatemic disorders

Country Status (11)

Country Link
US (3) US20150072019A1 (ru)
EP (1) EP2830626B1 (ru)
JP (1) JP6190871B2 (ru)
KR (1) KR102126092B1 (ru)
CN (2) CN109718239B (ru)
AU (1) AU2013241664B2 (ru)
CA (1) CA2866229C (ru)
IN (1) IN2014DN08969A (ru)
MX (1) MX354783B (ru)
RU (1) RU2643326C2 (ru)
WO (1) WO2013144339A1 (ru)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018128510A1 (ko) * 2017-01-06 2018-07-12 주식회사 레모넥스 전이성 난소암, 자궁내막암 또는 유방암의 예방 또는 치료용 조성물
CN110402143A (zh) * 2017-01-06 2019-11-01 雷莫内克斯生物制药有限公司 预防或治疗转移性卵巢癌、子宫内膜癌或乳腺癌的组合物

Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8754114B2 (en) 2010-12-22 2014-06-17 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
ES2704744T3 (es) 2012-06-13 2019-03-19 Incyte Holdings Corp Compuestos tricíclicos sustituidos como inhibidores de FGFR
WO2014026125A1 (en) 2012-08-10 2014-02-13 Incyte Corporation Pyrazine derivatives as fgfr inhibitors
US9266892B2 (en) 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
CN109776525B (zh) 2013-04-19 2022-01-21 因赛特控股公司 作为fgfr抑制剂的双环杂环
EA028614B1 (ru) * 2014-05-22 2017-12-29 Общество С Ограниченной Ответственностью "Русские Фармацевтические Технологии" Селективные ингибиторы, нарушающие взаимодействие рецептора фактора роста фибробластов и frs2, для профилактики и лечения рака
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9580423B2 (en) 2015-02-20 2017-02-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
AU2016219822B2 (en) 2015-02-20 2020-07-09 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
MA41551A (fr) 2015-02-20 2017-12-26 Incyte Corp Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4
WO2016189472A1 (en) * 2015-05-28 2016-12-01 Novartis Ag Fgfr inhibitor for use in the treatment of the phosphaturic mesenchymal tumor
EP3324970A4 (en) * 2015-07-20 2019-03-06 Taipei Medical University CHLORINE-SUBSTITUTED AZAARYL COMPOUNDS
CA2991846A1 (en) * 2015-07-24 2017-02-02 Anne VASLIN-CHESSEX Fgfr expression and susceptibility to an fgfr inhibitor
WO2018189906A1 (ja) 2017-04-14 2018-10-18 堺ディスプレイプロダクト株式会社 有機ｅｌ表示装置の製造方法及び製造装置
AR111960A1 (es) 2017-05-26 2019-09-04 Incyte Corp Formas cristalinas de un inhibidor de fgfr y procesos para su preparación
BR112020022392A2 (pt) 2018-05-04 2021-02-02 Incyte Corporation formas sólidas de um inibidor de fgfr e processos para preparação das mesmas
MX2020011639A (es) 2018-05-04 2021-02-15 Incyte Corp Sales de un inhibidor de receptores de factor de crecimiento de fibroblastos (fgfr).
WO2020185532A1 (en) 2019-03-08 2020-09-17 Incyte Corporation Methods of treating cancer with an fgfr inhibitor
EP3942045A1 (en) 2019-03-21 2022-01-26 Onxeo A dbait molecule in combination with kinase inhibitor for the treatment of cancer
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
IL291901A (en) 2019-10-14 2022-06-01 Incyte Corp Bicyclyl heterocycles as fgr suppressors
WO2021076728A1 (en) 2019-10-16 2021-04-22 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
EP4054579A1 (en) 2019-11-08 2022-09-14 Institut National de la Santé et de la Recherche Médicale (INSERM) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
WO2021113479A1 (en) 2019-12-04 2021-06-10 Incyte Corporation Tricyclic heterocycles as fgfr inhibitors
KR20220131900A (ko) 2019-12-04 2022-09-29 인사이트 코포레이션 Fgfr 억제제의 유도체
CA3176713A1 (en) * 2019-12-09 2021-06-17 Cedars-Sinai Medical Center Use of fgfr inhibitors for treatment of idiopathic short stature
WO2021146424A1 (en) 2020-01-15 2021-07-22 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
WO2021148581A1 (en) 2020-01-22 2021-07-29 Onxeo Novel dbait molecule and its use
CA3215903A1 (en) 2021-04-12 2022-10-20 Incyte Corporation Combination therapy comprising an fgfr inhibitor and a nectin-4 targeting agent
EP4352059A1 (en) 2021-06-09 2024-04-17 Incyte Corporation Tricyclic heterocycles as fgfr inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006000420A1 (en) * 2004-06-24 2006-01-05 Novartis Ag Pyrimidine urea derivatives as kinase inhibitors
US20110045511A1 (en) * 2008-04-29 2011-02-24 Diana Graus Porta Methods of monitoring the modulation of the kinase activity of fibroblast growth factor receptor and uses of said method
WO2011071821A1 (en) * 2009-12-07 2011-06-16 Novartis Ag Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof.

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1269960C (zh) 2000-12-26 2006-08-16 中外制药株式会社 降低血磷水平的人fgf23蛋白质突变体
EP1882475A1 (en) * 2006-07-26 2008-01-30 Novartis AG Method of treating disorders mediated by the fibroblast growth factor receptor
IN2012DN03180A (ru) * 2009-10-30 2015-09-25 Novartis Ag
JP2013514986A (ja) * 2009-12-18 2013-05-02 ノバルティス アーゲー 血液癌の処置方法
WO2013088191A1 (en) 2011-12-12 2013-06-20 Institut National De La Sante Et De La Recherche Medicale (Inserm) Antagonist of the fibroblast growth factor receptor 3 (fgfr3) for use in the treatment or the prevention of skeletal disorders linked with abnormal activation of fgfr3

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006000420A1 (en) * 2004-06-24 2006-01-05 Novartis Ag Pyrimidine urea derivatives as kinase inhibitors
US20110045511A1 (en) * 2008-04-29 2011-02-24 Diana Graus Porta Methods of monitoring the modulation of the kinase activity of fibroblast growth factor receptor and uses of said method
WO2011071821A1 (en) * 2009-12-07 2011-06-16 Novartis Ag Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof.

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
K. Chow et al., Engineering of Pharmaceutical Materials: an Industrial Perspective, 97 J. Pharmaceutical Sciences, 2855 (2008) *
K. R. Morris et al., An Integrated Approach to the Selection of Optimal Salt Form for a New Drug Candidate, 105 INT'L. J. PHARM. 209 (1994) *
P.L. Gould, Salt Selection for Basic Drugs, 33 INT. J. THERAPEUTICS 201, 217 (1986) *
R.J. Bastin et al., Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities, 4 ORGANIC PROCESS RES. DEV. 427 (2000) *
S. Badaway et al., Salt Selection for Pharmaceutical Compounds, in Preformulation in SOLID DOSAGE FORM DEV. 63 (M. Adeyeye ed., 2008) *
S. H. Neau, Pharmaceutical Salts, in WATER-INSOLUBLE DRUG FORMULATION 417, 429 (R. Liu ed., CRC Press, 2008) *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018128510A1 (ko) * 2017-01-06 2018-07-12 주식회사 레모넥스 전이성 난소암, 자궁내막암 또는 유방암의 예방 또는 치료용 조성물
CN110402143A (zh) * 2017-01-06 2019-11-01 雷莫内克斯生物制药有限公司 预防或治疗转移性卵巢癌、子宫内膜癌或乳腺癌的组合物
US11779582B2 (en) 2017-01-06 2023-10-10 Lemonex Inc. Composition for preventing or treating metastatic ovarian cancer, endometrial cancer or breast cancer

Also Published As

Publication number Publication date
AU2013241664B2 (en) 2016-05-19
RU2643326C2 (ru) 2018-01-31
CA2866229C (en) 2020-09-15
CN109718239B (zh) 2024-09-10
KR102126092B1 (ko) 2020-06-24
CN109718239A (zh) 2019-05-07
MX354783B (es) 2018-03-21
US20170007606A1 (en) 2017-01-12
US20210308132A1 (en) 2021-10-07
US10028955B2 (en) 2018-07-24
CA2866229A1 (en) 2013-10-03
EP2830626A1 (en) 2015-02-04
CN104321058A (zh) 2015-01-28
WO2013144339A1 (en) 2013-10-03
JP2015511621A (ja) 2015-04-20
IN2014DN08969A (ru) 2015-05-22
MX2014011841A (es) 2015-02-10
EP2830626B1 (en) 2019-01-02
KR20140145133A (ko) 2014-12-22
AU2013241664A1 (en) 2014-10-02
RU2014143517A (ru) 2016-05-27
JP6190871B2 (ja) 2017-08-30

Similar Documents

Publication Publication Date Title
US10028955B2 (en) FGFR inhibitor for use in the treatment of hypophosphatemic disorders
De Baaij et al. Magnesium in man: implications for health and disease
Kedlaya et al. Sclerostin inhibition reverses skeletal fragility in an Lrp5-deficient mouse model of OPPG syndrome
CN108135177A (zh) 用于治疗癌症的方法
Bastepe et al. Pseudohypoparathyroidism: new insights into an old disease
Andrukhova et al. Klotho lacks an FGF23‐independent role in mineral homeostasis
EP2428210A1 (en) Use of serum amyloid A gene in diagnosis and treatment of glaucoma and identification of anti-glaucoma agents
Alexander et al. Effects of parathyroid hormone on renal tubular calcium and phosphate handling
Dong et al. The extraglycemic effect of SGLT-2is on mineral and bone metabolism and bone fracture
Barzon et al. Comment—is there a role for low doses of mitotane (o, p′-DDD) as adjuvant therapy in adrenocortical carcinoma?
US20230190748A1 (en) Compositions for treatment of aged diseases
Nie et al. 1, 25-Dihydroxyvitamin D enhances alveolar fluid clearance by upregulating the expression of epithelial sodium channels
AU2012308097B2 (en) Treatment of bone diseases
WO2018210449A1 (en) Prevention and treatment of fibroblast growth factor 23 (fgf23)-associated disorders including chronic kidney disease (ckd)
Rabb et al. Possible molecular basis for changes in potassium handling in acute renal failure
JP2009511426A (ja) ミネラルおよび骨格代謝の調節
Zimering et al. Persistent tumor-induced osteomalacia confirmed by elevated postoperative levels of serum fibroblast growth factor-23 and 5-year follow-up of bone density changes
LU100168B1 (en) Prevention of Bone and Mineral Disorders by Restoring Calcium and Phosphate Homeostasis in Patients Suffering from Chronic Kidney Disease
US20220062299A1 (en) Use of glucocorticoid steroids in preventing and treating conditions of muscle wasting, aging and metabolic disorder
Fricke et al. Developmental fluoxetine exposure affects adolescent and adult bone depending on the dose and period of exposure
野田寛 Studies of potential applications of peptide ligands for the parathyroid hormone/parathyroid hormone-related protein type 1 receptor for therapeutic options of bone and calcium metabolic diseases
Tiosano Bone and Mineral Metabolism
Stratakis Carney complex and related syndromes and their genetic loci—author’s response
Benabbas Role of the H+-Activated Ovarian Cancer G Protein-Coupled Receptor 1 (OGR1) in the Renal Handling of Calcium and Magnesium
Bogers et al. Expression of renal distal tubule transporters TRPM6

Legal Events

Date Code Title Description
AS Assignment

Owner name: NOVARTIS PHARMA AG, SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:KNEISSEL, MICHAELA;GUAGNANO, VITO;GRAUS PORTA, DIANA;AND OTHERS;SIGNING DATES FROM 20131120 TO 20140430;REEL/FRAME:033841/0116

Owner name: NOVARTIS AG, SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:NOVARTIS PHARMA AG;REEL/FRAME:033841/0265

Effective date: 20140509

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION