WO2015092720A1 - Métabolites de sonidegib (lde225) - Google Patents

Métabolites de sonidegib (lde225) Download PDF

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Publication number
WO2015092720A1
WO2015092720A1 PCT/IB2014/067042 IB2014067042W WO2015092720A1 WO 2015092720 A1 WO2015092720 A1 WO 2015092720A1 IB 2014067042 W IB2014067042 W IB 2014067042W WO 2015092720 A1 WO2015092720 A1 WO 2015092720A1
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compound
morpholino
pharmaceutically acceptable
substituted
patient
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PCT/IB2014/067042
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English (en)
Inventor
Andreas Fredenhagen
Matthias Kittelmann
Stefan Peukert
Fabian Kurt EGGIMANN
Juergen KUEHNOEL
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Novartis Ag
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Publication of WO2015092720A1 publication Critical patent/WO2015092720A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C07C65/34—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

Definitions

  • metabolites of N-(6-((2i?,6 ⁇ S)-2,6-dimethylmorpholino)pyridin-3-yl)- 2-methyl-4'-(trifluoromethoxy)-[l, -biphenyl]-3-carboxamide that modulate the activity of the Hedgehog signaling pathway and that are useful in the treatment of diseases related to activity of Hedgehog signaling pathway including, for example, cancers of the brain, muscle, skin, and prostate; medulloblastoma; pancreatic adenocarcinomas; and small-cell lung carcinomas.
  • the Hedgehog signaling pathway is essential for numerous processes such as the control of cell proliferation, differentiation, and tissue patterning.
  • the aberrant activity of the Hedgehog signaling pathway may have pathological consequences.
  • activation of the Hedgehog pathway in adult tissues can result in specific types of cancer that include, but are not limited to, cancers of the brain, muscle, skin, and prostate; medulloblastoma; pancreatic adenocarcinomas; and small-cell lung carcinomas.
  • Enhanced activation of the Hedgehog signaling pathway contributes to the pathology and/or symptomology of a number of diseases. Accordingly, molecules that modulate the activity of the Hedgehog signaling pathway are useful as therapeutic agents in the treatment of such diseases.
  • R 1 is C0 2 H, CONH 2 , CONH(3-pyndyl), or CO(2-pyndonyl),
  • C0 2 H is optionally glycosylated
  • 2-pyridonyl is substituted one or more times with Ci_3-alkyl, NH 2 , or morpholino, wherein morpholino is optionally substituted one or more times with Ci-3-alkyl, or a pharmaceutically acceptable salt thereof.
  • R 1 is CONH(3-pyridyl) or CO(2-pyridonyl), wherein 3-pyridyl and 2-pyridonyl are substituted with morpholino, wherein morpholino is substituted one or more times with Ci-3-alkyl
  • R 1 is CONH(3-pyridyl), wherein 3-pyridyl is substituted with a ring-opened form of morpholino, wherein the ring-opened form of morpholino substituted with Ci-3-alkyl
  • provided herein are one or more compounds of Formula (I), or pharmaceutically acceptable salts thereof, in substantially isolated form.
  • pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • a method of modulating the Hedgehog pathway in a cell comprising contacting the cell with a compound of Formula (I).
  • provided herein is a method of treating cancer in a patient, comprising administering to said patient a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • provided herein are uses of the compounds of Formula (I), or pharmaceutically acceptable salts thereof, in the preparation of a medicament for use in a method of treating one or more of the diseases described herein.
  • compositions comprising a compound of Table A, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • provided herein is a method of modulating the Hedgehog pathway in a cell, comprising contacting the cell with a compound of Table A.
  • provided herein is a method of treating cancer in a patient, comprising administering to said patient a therapeutically effective amount of a compound of Table A, or a pharmaceutically acceptable salt thereof.
  • Figure 1 shows the structures of sonidegib and metabolites of Formula (I).
  • Figures 2a - 2c show the mean concentration-time profiles of total radioactivity in blood and plasma, and sonidegib and its main circulating metabolite (M48) in plasma after a single oral dose of 800 mg 14 C-sondegib (A). Cumulative excretion of radioactivity in urine (B) and feces (C) after a single oral dose of 800 mg 14 C-sonidegib.
  • Figures 3a - 3c shows the metabolite profiles in plasma, urine and feces after a single oral dose of 800 mg 14 C-sonidegib.
  • Plasma pool from all 6 subjects at 16 h A
  • urine pool from all 6 subjects across the 0-144 h interval B
  • feces pools from 5 subjects (Subject 00003 omitted) across the 0-144 h interval C; y-axis zoomed 50-fold and the 144-504 h interval (D).
  • Figures 4a and 4b show the biotransformation pathways of sonidegib in human subjects following a single oral dose.
  • Hedgehog signaling pathway inhibitor N-(6-((2i?,6 ⁇ S)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4'- (trifluoromethoxy)-[l,l '-biphenyl]-3-carboxamide.
  • These metabolites modulate the activity the Hedgehog signaling pathway and are useful, for example, in the treatment of diseases associated with expression or activity of the Hedgehog signaling pathway.
  • R 1 is C0 2 H, CONH 2 , CONH(3-pyndyl), or CO(2-pyndonyl),
  • C0 2 H is optionally glycosylated
  • 2-pyridonyl is substituted one or more times with Ci_3-alkyl, NH 2 , or morpholino, wherein morpholino is optionally substituted one or more times with Ci-3-alkyl, or a pharmaceutically acceptable salt thereof.
  • R 1 is CONH(3-pyridyl) or CO(2-pyridonyl), wherein 3-pyridyl and 2-pyridonyl are substituted with morpholino, wherein morpholino is substituted one or more times with Ci-3-alkyl,
  • R 1 is CONH(3-pyridyl), wherein 3-pyridyl is substituted with a ring-opened form of morpholino, wherein the ring-opened form of morpholino substituted with Ci-3-alkyl,
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • Provided herein also are one or more compounds of Formula (I), or pharmaceutically acceptable salts thereof, in substantially isolated form.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Table A, or a pharmaceutically acceptable salt thereof, and at least one
  • the metabolites of Formula (I) are substantially isolated.
  • substantially isolated refers to a compound that is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, for example, a composition enriched in the compound of the invention.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the metabolite.
  • the present invention also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • the metabolites are asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis.
  • ring opened morpholino as used herein is meant to include acyclic chemical moieties that feature all or parts of a morpholine ring. Examples of such moieties include, but are not limited to:
  • R is H or Ci-6-alkyl
  • Patched loss-of-function refers to an aberrant modification or mutation of a Ptc gene, or a decreased level of expression of the gene, which results in a phenotype which resembles contacting a cell with a Hedgehog protein, e.g., aberrant activation of a Hedgehog pathway.
  • the loss-of-function may include a loss of the ability of the Ptc gene product to regulate the level of expression of Gli genes, e.g., Glil, Gli2, and Gli3.
  • Gli gain-of-function refers to an aberrant modification or mutation of a Gli gene, or an increased level of expression of the gene, which results in a phenotype which resembles contacting a cell with a Hedgehog protein, e.g., aberrant activation of a Hedgehog pathway.
  • “Smoothened gain-of-function” refers to an aberrant modification or mutation of a Smo gene, or an increased level of expression of the gene, which results in a phenotype which resembles contacting a cell with a Hedgehog protein, e.g., aberrant activation of a Hedgehog pathway.
  • contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
  • "contacting" a cell with a compound of Formula (I) includes the administration of a compound of the present invention to an individual or patient, such as a human, having a Hedgehog signaling pathway, as well as, for example, introducing a compound of Formula (I) into a sample containing a cellular or purified preparation containing the Hedgehog signaling pathway.
  • the term "individual”, “patient”, or “subject”, used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the phrase "therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
  • the term "treating" or “treatment” refers to one or more of: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder; and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • the present invention makes available methods and compounds for inhibiting activation of the Hedgehog signaling pathway, e.g., to inhibit aberrant growth states resulting from phenotypes such as Ptc loss-of-function, Hedgehog gain-of-function, smoothened gain-of- function or Gli gain-of-function, comprising contacting the cell with a compound of Formula (I), in a sufficient amount to agonize a normal Ptc activity, antagonize a normal Hedgehog activity, antagonize smoothened activity, or antagonize Gli activity e.g., to reverse or control the aberrant growth state.
  • phenotypes such as Ptc loss-of-function, Hedgehog gain-of-function, smoothened gain-of- function or Gli gain-of-function
  • Hedgehog signaling are sufficient to initiate cancer formation and are required for tumor survival.
  • cancers include, but are not limited to, prostate cancer including prostate regeneration, neoplasia and metastasis, breast cancer",
  • medulloblastoma basal cell carcinoma, pancreatic cancer, digestive tract tumours, and in small- cell lung cancer.
  • a method for preventing or treating any of the diseases or disorders described above in a subject in need of such treatment comprises administering to said subject a therapeutically effective amount (See, "Administration and Pharmaceutical Compositions", infra) of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • a therapeutically effective amount See, "Administration and Pharmaceutical Compositions", infra
  • the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.
  • a method of inhibiting the Hedgehog pathway in a cell comprising contacting the cell with a compound of Formula (I).
  • the cell has a phenotype of Ptc loss-of-function, Hedgehog gain-of-function, smoothened gain-of-function, or Gli gain-of-function.
  • a method of treating cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound of Formula (I) including Table A, or a pharmaceutically acceptable salt thereof.
  • said cancer is selected from pancreatic cancer, prostate cancer, medulloblastoma, basal cell carcinoma, solid tumor, myelofibrosis, and small-cell lung cancer, malignant
  • Compounds of Formula (I) can modulate activity of the Hedgehog signaling pathway.
  • modulate is meant to refer to an ability to increase or decrease the activity of the Hedgehog signaling pathway.
  • compounds of Formula (I) can be used in methods of modulating the Hedgehog singaling pathway by contacting a cell with any one or more of the compounds or compositions described herein.
  • compounds of Formula (I) can act as inhibitors of the Hedgehog signaling pathway.
  • compounds of Formula (I) can act to stimulate the activity of the Hedgehog signaling pathway.
  • the compounds of Formula (I) can be used to modulate activity of the Hedgehog signaling pathway in an individual in need of modulation of the receptor by administering a modulating amount of a compound of the invention.
  • the methods provided herein include the use of compounds of Formula (I), which agonize Ptc inhibition of Hedgehog signaling, such as by inhibiting activation of smoothened or downstream components of the signal pathway, in the regulation of repair and/or functional performance of a wide range of cells, tissues and organs, including normal cells, tissues, and organs, as well as those having the phenotype of Ptc loss-of- function, Hedgehog gain-of- function, smoothened gain-of-function or Gli gain-of-function.
  • compounds of Formula (I) which agonize Ptc inhibition of Hedgehog signaling, such as by inhibiting activation of smoothened or downstream components of the signal pathway, in the regulation of repair and/or functional performance of a wide range of cells, tissues and organs, including normal cells, tissues, and organs, as well as those having the phenotype of Ptc loss-of- function, Hedgehog gain-of- function, smoothened gain-of-function or Gli gain-of-function.
  • the subject method has therapeutic and cosmetic applications ranging from regulation of neural tissues, bone and cartilage formation and repair, regulation of spermatogenesis, regulation of smooth muscle, regulation of lung, liver and other organs arising from the primitive gut, regulation of hematopoietic function, regulation of skin and hair growth, etc.
  • the subject methods can be performed on cells which are provided in culture (in vitro), or on cells in a whole animal (in vivo).
  • the subject method can be to treat epithelial cells having a phenotype of Ptc loss-of-function, Hedgehog gain-of-function, smoothened gain-of-function or Gli gain-of-function.
  • the subject method can be used in treating or preventing basal cell carcinoma or other Hedgehog pathway-related disorders.
  • the subject treatments using a compound of Formula (I), patched agonists, smoothened antagonists, or downstream Hedgehog pathway protein antagonists can be effective for both human and animal subjects.
  • Animal subjects to which the compounds of Formula (I) are applicable extend to both domestic animals and livestock, raised either as pets or for commercial purposes. Examples are dogs, cats, cattle, horses, sheep, hogs, and goats.
  • the compounds of Formula (I) can be administered in the form of pharmaceutical compositions.
  • These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.
  • Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary ⁇ e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral or parenteral.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • Coated condoms, gloves and the like may also be useful.
  • compositions which contain, as the active ingredient, one or more of the compounds of Formula (I) above in combination with one or more pharmaceutically acceptable carriers (excipients).
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1000 mg (1 g), more usually about 100 to about 500 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the
  • the tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. .
  • liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible as well as elixirs and similar pharmaceutical vehicles.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.
  • the therapeutic dosage of the compounds of the present invention can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound of Formula (I) in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the compounds of Formula (I) can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 ⁇ g/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • compositions provided herein can further include one or more additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed hereinabove.
  • additional pharmaceutical agents such as a chemotherapeutic, steroid, anti-inflammatory compound, or immunosuppressant, examples of which are listed hereinabove.
  • the reactions for preparing compounds of Formula (I) can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the
  • reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of compounds of Formula (I) can involve the protection and deprotection of various chemical groups. Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., ⁇ ⁇ or 13 C), infrared spectroscopy,
  • spectrophotometry e.g., UV- visible
  • mass spectrometry or by chromatography such as high performance liquid chromatography (HPLC), thin layer chromatography or LC-MS.
  • HPLC high performance liquid chromatography
  • LC-MS LC-MS
  • Compounds of Formula (I) can be prepared according to numerous preparatory routes known in the literature. Example synthetic methods for preparing Compounds of Formula (I) are provided in the Exemplification section below.
  • a compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid.
  • a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the free acid form of the compound with a
  • salt forms of the compounds of Formula (I) can be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds of Formula (I) can be prepared from the corresponding base addition salt or acid addition salt from, respectively.
  • a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like).
  • a suitable base e.g., ammonium hydroxide solution, sodium hydroxide, and the like.
  • a compound of the invention in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).
  • Compounds of Formula (I) can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of Formula (I), dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities.
  • the diastereomers can be separated by chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • the present invention further includes isotopically-labeled compounds of Formula (I).
  • An "isotopically” or “radio-labeled” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature ⁇ i.e., naturally occurring).
  • Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 2 H (also written as D for deuterium), 3 H (also written as T for tritium), U C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 18 F, 35 S, 36 C1, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I,
  • radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro metalloprotease labeling and competition assays, compounds that incorporate 3 H, 14 C, 82 Br, 125 I ,
  • a “radio-labeled” or “labeled compound” is a compound that has incorporated at least one radionuclide.
  • the radionuclide is selected from the group consisting of 3 H, 14 C, 125 1 , 35 S and 82 Br.
  • the present invention can further include synthetic methods for incorporating radioisotopes into compounds of Formula (I). Synthetic methods for incorporating radio-isotopes into organic compounds are well known in the art, and a person of ordinary skill in the art will readily recognize the methods applicable for the compounds of invention.
  • a labeled compound of the invention can be used in a screening assay to identify/evaluate compounds.
  • kits useful for example, in the treatment or prevention of Hedgehog signaling pathway-associated diseases or disorders, such as cancer, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention.
  • kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • Example 1 was prepared according to a literature procedure (ACS Med. Chem. Lett. 2010, 1, 130-134) using a Suzuki-coupling with Pd(PPh 3 ) 4 as catalyst and Na 2 CC>3 as a base in a dioxane/water mixture as solvent in a sealed tube at 130 °C overnight.
  • the reaction mixture was diluted with EtOAc and water.
  • the aqueous layer was extracted with EtOAc.
  • the combined organic layer was washed with brine and concentrated to give the crude product which was then purified by preparative HPLC.
  • Step 1 2-methyl-4'-(trifluoromethoxy)-[l, -biphenyl]-3-carbonyl chloride
  • Step 1 N-(6-fluoropyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)-[l, -biphenyl]-3-carboxamide
  • Step 2 N-(6-((2-hydroxypropyl)amino)pyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)-[ 1 , 1 '- biphenyl]-3-carboxamide
  • the compound was prepared by electrochemical oxidation: A Harvard syringe pump (702212B, Harvard Apparatus Holliston, MA) with a Hamilton 5ml syringe was attached to the flow cell ( ⁇ -prepcell with magic diamond electrode) controlled by a Roxy potentiostat (Antec, Leyden, Netherlands).
  • the collected reaction mixture was lyophilized and purified by semiprep RP-HPLC on a Waters Acquity UPLC HSS T3 (1.8 ⁇ ; 3.0 x 150 mm) column.
  • the pure fraction was lyophilized and submitted without weighing to NMR and HR-MS analysis.
  • Isolute H-MN (Separtis AG, Grellingen, Switzerland) was added to the organic phase and the solvent was removed under reduced pressure.
  • the Isolute H-MN was filled into a liquid chromatography precolumn attached to a column (50 x 200 mm) filled with Lichroprep RP-18 (40 - 63 ⁇ ) and the products were eluted with a gradient of increasing acetonitrile concentration in water in the presence of 0.05 % TFA.
  • Method 1 Column Kromasil CN 21 x 250 mm; gradient of 50 - 95 % of acetonitrile in aqueous 0.05 % formic acid.
  • Method 2 Column Waters Sunfire CI 8 19 x 250 mm; gradient of 10 - 45 % of methanol in aqueous 0.4 % isopropylamine, pH 8.
  • Method 3 Waters Sunfire CI 8 19 x 250 mm; gradient of 50 - 95 % of acetonitrile in aqueous 0.05 % formic acid. The organic solvent was removed from the product containing fractions under reduced pressure in a rotary evaporator and afterwards water by lyophilization.
  • Example 6 Preparation of l-(iV-(5-(2-methyl-4'-(trifluoromethoxy)-[l,l'-biphenyl]-3- ylcarboxamido)pyridin-2-yl)formamido)propan-2-yl acetate (Metabolite Mia)
  • the reaction mixture was defrosted, extracted by mixing with 400 mL of isopropanol for one hour and centrifuged. The supernatant was filtered and adsorbed on the column by premixing it with 9 volumes of the aqueous mobile phase with the aid of 2 pumps pumping at a flow ratio of 10 : 90.
  • the acylglucuonide was purified by two RP-18 liquid chromatography runs using a gradient from 10 to 100 % B (v/v) of methanol as mobile phase B and a 0.05 % ammonium formate solution as mobile phase A. The solvent was removed from the product containing fractions in a rotary evaporator and subsequent by lyophilization. 265 mg of acylglucuronide with a purity of > 99 % (LC/fullDAD) was obtained.
  • Example 11 Pharmacokinetics of radioactivity, sonidegib, and its main circulating metabolite (M48)
  • PK data on total radioactivity in blood and plasma and on sonidegib and M48 (amide hydrolysis product) in plasma, derived from quantitative LC -MS/MS analyses, are summarized in Table 1.
  • the median Tmax was similar for radioactivity in blood (2 h) and plasma (3 h) and for sonidegib in plasma (2 h).
  • M48 showed a much longer Tmax (60 h), indicating a slow formation of this metabolite.
  • Sonidegib maximum concentration (Cmax) and AUCmf were 76.6% ⁇ 4.40% and 34.9% ⁇ 6.55% of plasma radioactivity Cmax and AUCinf, respectively.
  • Mean concentration-time profiles of total radioactivity, sonidegib, and M48 are shown in Figure 2.
  • Cmax maximum observed concentration
  • Tmax time to reach Cmax
  • AUCi as t area under the concentration-time curve from time zero to the time of the last measurable concentration
  • AUCinf area under the concentration-time curve from time zero to infinity with extrapolation of the terminal phase
  • T1/2 elimination half-life associated with the terminal slope
  • CL/F apparent total plasma clearance
  • Vss/F apparent volume of distribution at steady state
  • Vz/F apparent terminal volume of distribution
  • F absolute bioavailability.
  • Nanogram-equivalents (ng-eq; nanomoles multiplied by molecular weight of parent compound) were used in place of ng to calculate Cmax (ng-eq/mL) and AUC (h ng-eq/mL) of radioactivity in blood and plasma.
  • the acyl glucuronide M47e was detected in plasma and urine.
  • Acyl glucuronides are known to undergo hydrolysis to the aglycone and isomerization by intramolecular acyl migration, both catalyzed by base.
  • the degree of substitution in the a-position of the acyl function seems to correlate inversely with the reactivity of the acyl glucuronide. Therefore, M47e is expected to be relatively stable towards hydrolysis and isomerization. Indeed, data from a series of pretrials suggest negligible hydrolysis or isomerization of M47e during blood/plasma and urine sampling, sample handling (performed at decreased temperatures), storage in a deep- frozen state, and sample preparation for metabolite profiling. In line with these data, no isomers of M47e were detected in plasma or urine.
  • Sonidegib metabolites in plasma based on metabolite profiles in pooled samples from all 6 subjects (Table 2), unchanged sonidegib was the major circulating radiolabeled component, accounting for 36.4% of the AUCo- 5 o4h of radioactivity.
  • the most prominent metabolite was the amide hydrolysis product M48, accounting for approximately 15.4% of the AUCo-504h of radioactivity.
  • the acyl glucuronide M47e accounted for most of the radioactivity in the urine (0.908% of dose in urine 0-504 h). Other metabolites were present in traces only. Unchanged sonidegib was not detected in urine.
  • Metabolite profiles in feces were analyzed in two fractions (0-144 h and 144-504 h), both pooled across 5 of the 6 subjects.
  • the 0-144 h and 144-504 h fecal pools accounted for 90.4% and 1.61% of the administered radioactivity, respectively (Table 2).
  • the two 14 C-chromatograms were similar ( Figure 3).
  • UCaii area under the curve from time zero to the last available data point; n.d., not detected; RA, radioactivity.
  • M41 is not a product of amide hydrolysis but coeluted with M48. M41 in plasma is minor compared to M48, as indicated by comparison with quantitative data from LC-MS/MS analysis. M41 was detected in plasma and feces only.
  • Mean urinary excretion accounted for 0.386% ⁇ 0.176% of the dose up to 96 h and 1.95% ⁇ 0.760% of the dose when extrapolated to infinity (mean ⁇ SD of across all 6 subjects), whereas mean fecal excretion accounted for 86.3% ⁇ 10.4% of the dose up to 96 h and 93.4% ⁇ 1.87% of the dose when extrapolated to infinity (mean ⁇ SD of 5 subjects; Table 3).
  • ECG electrocardiogram
  • Subjects were not permitted to use known cytochrome P450 inhibitors or inducers, prescription drugs, or smoke within 4 weeks of dosing; take vitamins, supplements and herbal remedies within 2 weeks of dosing; be treated with investigational drugs within 60 days of dosing (or 10 times Ti /2 ); donate blood and/or plasma (> 100 mL) within 8 weeks of dosing; intake grapefruit, pomegranate, star fruit, Seville oranges, or St John's wort (or juices and products containing these items) within 7 days prior to dosing and throughout the study; or consume alcohol within 48 h of dosing throughout the first 3 weeks of the study. Subjects were not allowed to participate in any other investigational drug or device study during treatment or follow up. Subjects were expected to comply with dietary and fluid restrictions, and undergo multiple blood draws and medical visits as required by the protocol. Subjects were also required to have a regular defecation pattern (producing stools at least every second day).
  • the 14 C label was located at the central carboxamide moiety of the molecule ( Figure 1).
  • the radiochemical purity of the study drug was 98.0%, as confirmed by high-performance liquid chromatography (HPLC) with radioactivity detection.
  • the chosen dose of 800 mg was expected to be safe and tolerable based on data from a phase I study in adults with advanced solid tumors.
  • Subjects were monitored in-house from days 1-22 and required to return to the center for a 24-hour visit on a weekly (days 28-29, 35-36, 42-43) and bi-weekly schedule (days 56-57, 70-71, 84-85 and 98-99), followed by a study completion visit with safety assessments.
  • Plasma samples were collected over a 14- week period. Blood samples were drawn at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, and 24 h, and every 24 h until 504 h post-dose (days 1- 22), weekly on days 28-29, 35-36, 42-43, and bi-weekly on days 56-57, 70- 71, 84-85, and 98-99 (scheduled times). The blood was cooled to the temperature of ice-water immediately after sampling. Plasma samples were obtained from whole blood by centrifugation at approximately 4°C within 30 minutes of the collection. The plasma was kept on ice until aliquoting. Aliquots of blood and plasma were frozen at ⁇ -70°C.
  • Blood samples were used for total radioactivity (whole blood), and plasma samples were used for total radioactivity, PK, and metabolism analyses. Additional blood samples were taken for laboratory analyses.
  • Urine samples were collected pre-dose (day -1 to day 1), during the post-dose in- house period (days 1- 22; 24-hperiods), and during the 24-h visits (days 29-99). During each time interval, urine samples were pooled and stored at a reduced temperature. Immediately after each collection period, urine samples were mixed thoroughly, weighed, aliquoted, and then frozen at ⁇ -70°C. Fecal samples were collected individually pre-dose (within 48 h of dosing), during the post-dose in- house period (days 1-22), and during the 24-h visits (days 29-99). Fecal samples were pooled per 24-h time interval and stored at a reduced temperature prior to processing. Each 24-h pool was diluted with 3-4 volumes of water, weighed, thoroughly homogenized, aliquoted, and then frozen at ⁇ -70°C
  • Radioactivity measurements Total radioactivity in whole blood, plasma, urine, and feces was determined for all collection time points or collection intervals individually for all subjects by accelerator mass spectrometry (AMS) at Accium Biosciences, Inc. (Seattle, WA, USA) using a 1.5SDH Compact AMS System. The AMS method was chosen based on its analytical sensitivity and the low dose of radioactivity administered (74 kBq, 2 ⁇ ). Before the AMS measurement, the samples were combusted to C0 2 which was then reduced to graphite by methods similar to those described previously (A high-throughput method for the conversion of C02 obtained from biochemical samples to graphite in septa-sealed vials for quantification of 14C via accelerator mass spectrometry. Anal Chem 75:2192-2196). The total carbon content of the samples was either assumed to correspond to a standard value (blood, plasma) or was determined by AMS after addition of an 13 C-enriched carbon standard (urine, feces)
  • LSC liquid scintillation counting
  • the detection was performed on an API 5000TM triple quadrupole mass spectrometer from AB/Sciex (Foster City, CA, USA) equipped with a turbo ion spray source operated in the negative ion mode.
  • Sonidegib and its metabolite (M48) were quantified over the range from 0.500 ng/mL (LLOQ) to 100 ng/mL (ULOQ) using 0.050 mL of human plasma.
  • Metabolite profile analysis Plasma pools across all 6 subjects were analyzed at 4, 16, 120, and 504 h post-dose. Metabolite profiles in urine and feces were determined in pools across 6 (urine) or 5 (feces) subjects and across the two time intervals 0-144 and 144-504 h. One subject's samples were omitted from the fecal pool (see mass balance of radioactivity results section). Plasma pools were acidified to a pH of 6.0-6.5 before sample preparation by adding 3.0 ⁇ of a 50% (vol/vol) aqueous acetic acid solution per mL of plasma to stabilize the acyl glucuronide metabolite M47e. Acidified plasma pools and fecal pools were prepared by protein precipitation/extraction with methanol.
  • the reconstituted samples were divided into two halves, one of which was spiked with a solution containing unlabeled reference compounds for sonidegib, M47e, and M48 to serve as retention time markers.
  • Corresponding spiked and unspiked samples were fractionated by HPLC immediately adjacent to one another to minimize differences in retention times between the two runs.
  • the reference compounds were monitored by UV-detection (230 nm).
  • Fractions collected after injection of the spiked samples were used for 14 C-determination by AMS to obtain 14 C- chromatograms.
  • Fractions collected after injection of the unspiked samples were used for characterization of metabolite structures and metabolite correlation by LC-MS/MS.
  • HPLC HPLC was performed on a Shimadzu Prominence system (Columbia, MD, USA) using a Waters Symmetry C18 column (4.6 x 150 mm, 3.5 ⁇ particles, Milford, MA, USA), protected by a pre-column (3 x 20 mm) of the same stationary phase. The pre-column and column were held at 40°C. The components were eluted with a gradient of mobile phase A (5 mM ammonium formate + 0.1% (vol/vol) formic acid in water) vs. mobile phase B (5 mM ammonium formate + 0.1% (vol/vol) formic acid in acetonitrile/water 9: 1 (vol/vol)).
  • mobile phase A 5 mM ammonium formate + 0.1% (vol/vol) formic acid in water
  • mobile phase B 5 mM ammonium formate + 0.1% (vol/vol) formic acid in acetonitrile/water 9: 1 (vol/vol)
  • the mobile phase B was maintained at 20% from 0 and 3 minutes, increased to 45% at 8 minutes and maintained at 45% from 8 to 18 minutes, increased to 65% at 55 minutes and to 100% at 60 minutes, and maintained at 100% from 60 to 75 minutes.
  • the total flow rate was 1 mL/min.
  • the column effluent was collected in 0.25-minute fractions between 0 and 65 minutes and then in 1 -minute fractions up to 75 minutes.
  • Metabolite structure characterization Metabolite structures were characterized by LC- MS/MS analysis of selected plasma, urine, and fecal samples, prepared in a similar way as described above for metabolite profiling. In addition, selected HPLC fractions, obtained as described above, were subjected to LC-MS/MS analysis to confirm the correlation between metabolites observed by LC-MS/MS and peaks in the C-chromatograms. The instrumentation consisted of a Waters Acquity series HPLC coupled to a Waters Synapt G2-S quadrupole-time- of-flight tandem mass spectrometer. The chromatographic conditions were as described for metabolite profiling.
  • H/D hydrogen/deuterium
  • PK parameters of total radioactivity in blood and plasma, and of sonidegib and M48 in plasma were analyzed using noncompartmental methods with Phoenix WinNonlin ® , version 6.2 (Pharsight, Mountain View, CA, USA). Absorption, expressed as a percentage of the dose, was determined based on radioactivity in urine and metabolites in feces. Details are provided in the discussion.
  • Mass balance calculations the cumulative excretion of radioactivity in urine and feces during the continuous sampling phase (0-504 h) was calculated by summing up the percentages of dose excreted during the 24-hour collection intervals. The further excretion of radioactivity during the discontinuous sampling phase (days 22-99) and the excretion after the last sampling period up to infinity was estimated based on the AUC of the excretion rate. Excretion rates were calculated as percentage of dose excreted during 24-hour collection intervals, divided by 24 h, and were assigned to the mid-times of the respective collection intervals.
  • Peaks in the 14 C-chromatograms were integrated using the Radiostar software from Berthold Technologies (Bad Wildbad, Germany). Concentrations of individual radiolabeled components in plasma and amounts of individual radiolabeled components in excreta were calculated from the relative peak areas and the concentrations (plasma) or amounts (urine, feces) of total 14 C-labeled components in the respective original sample pools. Safety Assessments
  • CCAE Common Terminology Criteria for Adverse Events
  • the biological activity of the compounds of Formula (I) can be assessed, for example, using the procedures found in Examples 14 and 15.
  • Manassas, VA can be cultured in DMEM/F12 medium (Gibco/Invitrogen, Carlsbad, CA) supplemented with 5% heat inactivated horse serum and 2.5% FBS (Gibco/Invitrogen, Carlsbad, CA ), 50 unit/mL penicillin and 50 p g/rriL of streptomycin (Gibco/Invitrogen, Carlsbad, CA) at 37°C with 5% C0 2 in air atmosphere.
  • TM3 cells can be transfected with pTA-8xGli-Luc reporter plasmid.
  • a stably transfected clone termed TMHh-12 can be selected.
  • 8000 TMHh-12 cells can be plated into each wells in 384-well plates with 50% DMEM/F12 medium supplemented with 2% FBS.
  • Hedgehog pathway can be activated by adding recombinant mouse Shh protein (expressed in E.coli, 8 p g/mL) or by adding Smo agonists.
  • the testing compounds then can be added into plates with different concentrations.
  • the firefly luciferase luciferase activities can be assayed with the Bright-Gl oTM Luciferase Assay System (Promega, Madison, WI).
  • the IC 50 can be measured when the effect of the compound reduces the luminescence signal by 50%.
  • Toxicity of these compounds can be evaluated in TM3 cells using CellTiter Glo assays or by TM3-Luc cell line (a TM3 cell stably transfected with a constitutive luciferase expression vector).
  • TM3-Luc cell line a TM3 cell stably transfected with a constitutive luciferase expression vector.
  • a cytotoxicity assay can be performed to compare the effects of a compound of Formula (I) on medulloblastoma cells (Daoy cells), basal cell carcinoma cells (TE354.T cells), and control cells (human normal fibroblast) according to the following procedure:
  • Daoy cells (medulloblastoma cell line) can be purchased from ATCC, and cultured in Minimum essential medium (Eagle) with 2 mM L-glutamine and Earle's BSS adjusted to contain 1.5 g/L sodium bicarbonate, 0.1 mM non-essential amino acids, and 1.0 mM sodium pyruvate and 10% FBS at 37°C with 5% C02 in an air atmosphere.
  • Minimum essential medium Eagle
  • 2 mM L-glutamine and Earle's BSS adjusted to contain 1.5 g/L sodium bicarbonate, 0.1 mM non-essential amino acids, and 1.0 mM sodium pyruvate and 10% FBS at 37°C with 5% C02 in an air atmosphere.
  • TE354.T cells (from ATCC) can be cultured in Dulbecco's modified Eagle's medium with 4 mM L-glutamine fetal bovine serum andl0% of FBS.
  • Each of the above cell lines can be independently seeded into 96-well plates
  • the cell viability can be evaluated with Cell Titer-Glo Luminescent Cell Viability Assay Kit (Promega) following the manufacturer's protocol. The cell viability can be directly measured by luminescent signaling and EC50s can be measured when the signal is inhibited 50%.

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Abstract

L'invention concerne des métabolites de N-(6-((2R,6S)-2,6-diméthylmorpholino)pyridin-3-yl)- 2-methyl-4'-(trifluoromethoxy)-[1,1'-biphényl]-3-carboxamide (Sonidegib, LDE225) qui modulent l'activité de la voie de signalisation Hedgehog et qui sont utiles dans le traitement de maladies associées à l'activité de la voie de signalisation Hedgehog, telles que, par exemple, les cancers du cerveau, du muscle, de la peau et de la prostate; le médulloblastome; les adénocarcinomes pancréatiques; et les carcinomes pulmonaires à petites cellules.
PCT/IB2014/067042 2013-12-19 2014-12-17 Métabolites de sonidegib (lde225) WO2015092720A1 (fr)

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
CN105330658A (zh) * 2015-12-09 2016-02-17 苏州明锐医药科技有限公司 索尼吉布的制备方法
WO2017163258A1 (fr) * 2016-03-22 2017-09-28 Msn Laboratories Private Limited Procédé de préparation de n-[6-(cis-2,6-diméthylmorpholin-4-yl)pyridine-3-yl]-2- méthyl-4'-(trifluorométhoxy) [1,1'-biphényl]-3-carboxamide et de ses polymorphes
CN109293649A (zh) * 2018-11-12 2019-02-01 新发药业有限公司 一种索尼吉布中间体及索尼吉布的制备方法
CN113072460A (zh) * 2021-03-31 2021-07-06 西南大学 一种吗啉衍生物氧化开环的方法及其产品

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WO2007131201A2 (fr) * 2006-05-05 2007-11-15 Irm Llc Composés et compositions modulant le mécanisme d'action de la hedgehog
WO2010033481A1 (fr) * 2008-09-17 2010-03-25 Novartis Ag Sels de n-[6-cis-(2,6-diméthylmorpholin-4-yl)pyridin-3-yl)-2-méthyl-4'-(trifluorométhoxy)-[1,1’-biphényl]-3-carboxamide

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WO2007131201A2 (fr) * 2006-05-05 2007-11-15 Irm Llc Composés et compositions modulant le mécanisme d'action de la hedgehog
WO2010033481A1 (fr) * 2008-09-17 2010-03-25 Novartis Ag Sels de n-[6-cis-(2,6-diméthylmorpholin-4-yl)pyridin-3-yl)-2-méthyl-4'-(trifluorométhoxy)-[1,1’-biphényl]-3-carboxamide

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"Simultaneous AMS determination of 14C content and total carbon mass in biological samples", NUCLEAR INSTRUMENTS AND METHODS IN PHYSICS RESEARCH SECTION B, vol. 268, pages 1307 - 1308
SHIFENG PAN ET AL: "Discovery of NVP-LDE225, a Potent and Selective Smoothened Antagonist", ACS MEDICINAL CHEMISTRY LETTERS, vol. 1, no. 3, 10 June 2010 (2010-06-10), pages 130 - 134, XP055117479, ISSN: 1948-5875, DOI: 10.1021/ml1000307 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105330658A (zh) * 2015-12-09 2016-02-17 苏州明锐医药科技有限公司 索尼吉布的制备方法
WO2017163258A1 (fr) * 2016-03-22 2017-09-28 Msn Laboratories Private Limited Procédé de préparation de n-[6-(cis-2,6-diméthylmorpholin-4-yl)pyridine-3-yl]-2- méthyl-4'-(trifluorométhoxy) [1,1'-biphényl]-3-carboxamide et de ses polymorphes
CN109293649A (zh) * 2018-11-12 2019-02-01 新发药业有限公司 一种索尼吉布中间体及索尼吉布的制备方法
CN109293649B (zh) * 2018-11-12 2020-05-08 新发药业有限公司 一种索尼吉布中间体及索尼吉布的制备方法
CN113072460A (zh) * 2021-03-31 2021-07-06 西南大学 一种吗啉衍生物氧化开环的方法及其产品

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