WO2013131465A1 - Polymorphes de n-(4-(3-fluorobenzyloxy)-3-chlorophényl)-6-(5-((2-(méthylsulfinyl)éthylamino)méthyl)-2-furannyl)-quinazolin-4-aminoxylène-sulfonate et leur procédé de préparation et leurs utilisations - Google Patents

Polymorphes de n-(4-(3-fluorobenzyloxy)-3-chlorophényl)-6-(5-((2-(méthylsulfinyl)éthylamino)méthyl)-2-furannyl)-quinazolin-4-aminoxylène-sulfonate et leur procédé de préparation et leurs utilisations Download PDF

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WO2013131465A1
WO2013131465A1 PCT/CN2013/072169 CN2013072169W WO2013131465A1 WO 2013131465 A1 WO2013131465 A1 WO 2013131465A1 CN 2013072169 W CN2013072169 W CN 2013072169W WO 2013131465 A1 WO2013131465 A1 WO 2013131465A1
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compound
polymorph
ray powder
powder diffraction
tyrosine kinase
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PCT/CN2013/072169
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English (en)
Chinese (zh)
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王晶翼
范传文
冷传新
张进
林栋�
王丙忠
王会成
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齐鲁制药有限公司
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Publication of WO2013131465A1 publication Critical patent/WO2013131465A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the field of medicine and chemical industry, and particularly relates to a novel anti-tumor activity N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-((2-( ⁇ )) Polyphenylenesulfonyl)ethylamino)hydrazino)-2-furyl)-quinazolin-4-amine diindolene sulfonate (Compound I) polymorph and its preparation method, and The use of a crystalline form as a medicament for the treatment or adjuvant treatment of proliferation and migration of tumor cells driven by a receptor tyrosine kinase-mediated tumor or receptor tyrosine kinase in a mammal, including humans. Background technique
  • Tumors are one of the major diseases that seriously threaten human life and quality of life. According to WHO statistics, about 6.9 million patients die from cancer every year in the world. Due to the changes in living environment and living habits, the incidence and mortality of tumors have gradually increased in recent years due to adverse environmental and some unfavorable factors.
  • Gefitinib trade name Iressa (Iressa), an EGFR tyrosine kinase inhibitor developed by AstraZeneca, was the first epidermal growth factor receptor tyrosine kinase inhibitor to enter clinical studies. Listed in Japan, listed in the US the following year, used for treatment To advanced or metastatic non-small cell lung cancer (NSCLC) who received chemotherapy.
  • NSCLC metastatic non-small cell lung cancer
  • Erlotinib trade name Tarceva
  • OSI metastatic non-small cell lung cancer
  • Lapatinib trade name Tycerb
  • Tycerb is a dual inhibitor of EGFR and HER2 developed by GlaxoSmithKline Inc., which inhibits tumor cell proliferation and survival signaling more than a single receptor inhibitor.
  • the US FDA approved the market in 2007, with indications for combination with capecitabine for the treatment of advanced or metastatic breast cancer that overexpresses HER2 and previously received chemotherapy such as anthracyclines, taxanes, and trastuzumab. patient.
  • Patent Application Publication Nos. WO 96/33977, WO 97/30035, WO 98/13354, WO 00/55141, WO 02/41882, WO 03/82290, and EP 837 063, etc. disclose carrying an anilino group at the 4-position.
  • the substituents and certain quinazoline derivatives carrying a substituent at the 6- and/or 7-position have receptor tyrosine kinase activity.
  • the present invention defines N-(4-(3-fluorobenzylchlorophenyl)-6-(5-((2-(indenylethylidene)-2-furanyl)-quinazoline-4- a polymorph of an amine diterpene sulfonate (Compound I) which can be used as
  • Compound I has a high tyrosine kinase inhibitory action. We have found that certain forms of Compound I are crystalline materials with a favorable shield.
  • the first aspect of the invention provides ⁇ -(4-(3-fluorobenzyl fL&)-3-chlorobenzene
  • the inventors of the present invention have surprisingly found that Compound I can exist in more than one polymorph.
  • the inventors have abbreviated these polymorphs as the crystal forms ⁇ , ⁇ , ⁇ and 0.
  • the polymorph of Compound I has a certain solubility in water, which is beneficial to absorption in the body; and has better stability, which is favorable for packaging and storage.
  • the Compound I crystalline form is Cu, using Cu- ⁇ radiation, and the X-ray powder diffraction pattern expressed in terms of 2 ⁇ angle is at 4.6° ⁇ 0.2. , 9.2° ⁇ 0.2. , 11.5° ⁇ 0.2°, 12.6 Q ⁇ 0.2. , 15 ⁇ 1 ⁇ ⁇ 0 ⁇ 2 ⁇ , 19.7 Q ⁇ 0 ⁇ 2 ⁇ , 24.9 Q ⁇ 0 ⁇ 2 ⁇ , 27.2 Q ⁇ 0 ⁇ 2 ⁇ There are characteristic peaks.
  • the compound I is in crystalline form, using Cu- ⁇ radiation, and the X-ray powder diffraction pattern expressed in terms of 2 ⁇ angle is 4.6 ° ⁇ 0 ⁇ 2 ⁇ , 9.2 ° ⁇ 0 ⁇ 2 ⁇ , 11.5° ⁇ 0.2°, 12.6 Q ⁇ 0.2. , 14.5° ⁇ 0.2°, 15.1 Q ⁇ 0.2. , 15.7 ° ⁇ 0.2 °, 16.0 ° ⁇ 0.2 °, 19.1. ⁇ 0.2°, 19.7° ⁇ 0 ⁇ 2 ⁇ , 20.0. ⁇ 0.2 °, 21.9.
  • the Compound I Form A has substantially the same pattern as
  • differential scanning calorimetry of Form A of Compound I shows that the crystal form melts at 240.82 to 255.59 °C.
  • the Compound I Form B using Cu- ⁇ radiation, has an X-ray powder diffraction pattern at a ⁇ angle of 4.6° ⁇ 0 ⁇ 2 ⁇ , 8.3 ° ⁇ 0 ⁇ 2 ⁇ , 12.0° ⁇ 0.2°, 15 ⁇ 8 ⁇ ⁇ 0 ⁇ 2 ⁇ , 19 ⁇ 7 ⁇ ⁇ 0 ⁇ 2 ⁇ , 20 ⁇ 8 ⁇ ⁇ 0 ⁇ 2 ⁇ , 22.8. There is a characteristic peak at ⁇ 0 ⁇ 2 ⁇ .
  • the Compound I crystalline form is Cu, using Cu- ⁇ radiation, and the X-ray powder diffraction pattern at 2 ⁇ angle is at 4.6. ⁇ 0.2. , 8 ⁇ 3. ⁇ 0 ⁇ 2 ⁇ , 9.1. ⁇ 0.2 °, 12.0. ⁇ 0.2. , 13.9 Q ⁇ 0.2. , 15.0 Q ⁇ 0.2. , 15.8 Q ⁇ 0.2. , 17.6. ⁇ 0.2. , 18 ⁇ 7 ⁇ ⁇ 0 ⁇ 2 ⁇ , 19.7 Q ⁇ 0.2. , 20 ⁇ 8 ⁇ 0 ⁇ 2 ⁇ , 22 ⁇ 2 ⁇ ⁇ 0 ⁇ 2 ⁇ , 22 ⁇ 8 ⁇ 0 ⁇ 2 ⁇ , 26.0° ⁇ 0.2. There are characteristic peaks.
  • the Form I of the Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 4.
  • differential scanning calorimetry of Form B of Compound I shows that the crystal form melts and decomposes at 239.11 to 254.49 °C.
  • the Compound C Form C using Cu- ⁇ radiation, has an X-ray powder diffraction pattern at a angle of 2 ⁇ at 4.4° ⁇ 0 ⁇ 2 ⁇ , 9.5 ° ⁇ 0 ⁇ 2 ⁇ , 12.7° ⁇ 0.2°, 14 ⁇ 9 ⁇ ⁇ 0 ⁇ 2 ⁇ , 19 ⁇ 8 ⁇ ⁇ 0 ⁇ 2 ⁇ , 23 ⁇ 7 ⁇ ⁇ 0 ⁇ 2 ⁇ , 26.8. There is a characteristic peak at ⁇ 0 ⁇ 2 ⁇ .
  • the Compound I Form C using Cu- ⁇ radiation, has an X-ray powder diffraction pattern at a angle of 2 ⁇ at 4.4° ⁇ 0 ⁇ 2 ⁇ , 9.5 ° ⁇ 0 ⁇ 2 ⁇ , 12.7° ⁇ 0.2°, 14.9 ° ⁇ 0.2. , 16.1. ⁇ 0.2. , 17.1. ⁇ 0.2. , 19.4° ⁇ 0.2. , 19.8. ⁇ 0.2. , 20 ⁇ 9 ⁇ ⁇ 0 ⁇ 2 ⁇ , 21 ⁇ 4. ⁇ 0 ⁇ 2 ⁇ , 23 ⁇ 7° ⁇ 0 ⁇ 2 ⁇ , 26.8. There is a characteristic peak at ⁇ 0 ⁇ 2 ⁇ .
  • the Compound C Form C has an X-ray powder diffraction pattern substantially as shown in Figure 6.
  • the Compound I crystal form D using Cu- ⁇ radiation, has an X-ray powder diffraction pattern at a ⁇ angle of 4.4° ⁇ 0 ⁇ 2 ⁇ , 8.3 ° ⁇ 0 ⁇ 2 ⁇ , 14.8° ⁇ 0.2°, 19 ⁇ 4 ⁇ ⁇ 0 ⁇ 2 ⁇ , 21 ⁇ 0 ⁇ ⁇ 0 ⁇ 2 ⁇ , 21 ⁇ 7 ⁇ ⁇ 0 ⁇ 2 ⁇ , 25.1. There is a characteristic peak at ⁇ 0 ⁇ 2 ⁇ .
  • the Compound I Form D using Cu- ⁇ radiation, has an X-ray powder diffraction pattern at a angle of 2 ⁇ at 4.4° ⁇ 0 ⁇ 2 ⁇ , 8.3 ° ⁇ 0 ⁇ 2 ⁇ , 14.8° ⁇ 0.2°, 18.7G ⁇ 0.2. , 19.4G ⁇ 0.2. , 21.0c ⁇ 0.2 o, 21.7c ⁇ 0.2 o, 22.2c ⁇ 0.2 o, 23 ⁇ 0 ⁇ Disabled 0 ⁇ 2 ⁇ , 25.1. Earth 0 ⁇ 2 ⁇ , 25.6. There is a characteristic peak at 0. 2 ⁇ .
  • Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 7.
  • Compound I is dissolved in a suitable solvent system under heating conditions, cooled and crystallized, filtered, and air-dried to obtain crystal form C of compound I.
  • Compound I is slurried in a suitable solvent system, filtered, and air-dried to give Form C of Compound I.
  • the solvent system comprises: tetrahydrofuran/water, 1,4-dioxane/water, ethylene glycol dioxime/water, and the ratio of the solvent to water (volume) is 20:1 ⁇ 1: 10, preferably 20:1 ⁇ 4:1;
  • Compound I is dissolved in a suitable solvent system under heating conditions, cooled and crystallized, filtered, and air-dried to obtain crystal form D of compound I.
  • the compound I is slurried in a suitable solvent system, filtered, and air-dried to obtain the hydrazone D of the compound I.
  • the solvent system comprises: ethanol/water, methanol/water, isopropanol/water, N,N-dimercaptoamide, and the ratio of the alcohol/water is 20:1 to 1 :10, preferably 20:1 ⁇ 4:1;
  • the crystal form D of the compound I is dried at 60 to 150 ° C to obtain a crystal form B of the compound I.
  • the relationship between the above four types is as follows:
  • the crystal form of Compound I (:, D is stable under normal temperature conditions, and the crystal form is unstable under high temperature conditions; the crystal form of Compound I crystal form A and B is formed under normal temperature and high temperature conditions. stable.
  • the compound II in an exemplary method, can be prepared by referring to the document CN102030742A.
  • a third aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a polymorph of Compound I according to any one of the first aspects of the invention, and optionally one or more pharmaceutically acceptable carriers or forms Agent.
  • a fourth aspect of the invention relates to the polymorph of the compound I according to any one of the first aspects of the invention for use in the preparation and/or prevention of mammalian (including human) and receptor tyrosine Use in medicines for related diseases or conditions.
  • a fourth aspect of the invention relates to the polymorph of the compound I according to any one of the first aspects of the invention for use in the treatment or adjunctive treatment and/or prevention of a receptor tyrosine kinase in a mammal, including a human Use in drugs that mediate the proliferation and migration of tumors or tumor cells driven by receptor tyrosine kinases.
  • the polymorph of Compound I of the present invention can be used to treat erbB receptor tyrosine kinase-sensitive cancers, such as EGFR or Her2 high expression and EGF driven tumors, including solid tumors such as bile ducts, bone, bladder , brain/central nervous system, breast, colorectal, endometrium, stomach, head and neck, liver, lung (especially non-small cell lung cancer), neurons, esophagus, ovary, pancreas, prostate, kidney, skin, testicles, Cancers such as the squamous gland, uterus, and vulva, and non-solid tumors such as leukemia, multiple myeloma, or lymphoma.
  • cancers such as the squamous gland, uterus, and vulva
  • non-solid tumors such as leukemia, multiple myeloma, or lymphoma.
  • the tumor or cancer involved may include the above-mentioned erbB receptor tyrosine kinase-sensitive cancer, such as EGFR or Her2 high expression and EGF-driven tumors, including solid tumors such as bile duct, bone, bladder, brain/central nervous system, breast , colorectal, endometrium, stomach, head and neck, liver, lung (especially non-small cell lung cancer), neurons, esophagus, ovary, pancreas, prostate, kidney, skin, testes, verrucous, uterus and vulva Cancer, and non-solid tumors such as leukemia, multiple myeloma or lymphoma.
  • erbB receptor tyrosine kinase-sensitive cancer such as EGFR or Her2 high expression and EGF-driven tumors
  • solid tumors such as bile duct, bone, bladder, brain/central nervous system, breast , colorectal, endometrium, stomach, head and neck, liver, lung (especially
  • a fifth aspect of the invention relates to a method of treating and/or preventing a disease or condition associated with a receptor tyrosine kinase in a mammal in need thereof, the method comprising administering to the mammal in need thereof a therapeutically effective amount of the present invention
  • a polymorph of the compound I according to any one of the first aspects of the invention.
  • a fifth aspect of the invention also relates to a method of treating or adjunctively treating and/or preventing a mammalian (including human) tumor mediated by a receptor tyrosine kinase or driven by a receptor tyrosine kinase in a mammal in need thereof
  • a method of proliferation and migration of a tumor cell comprising administering to a mammal in need thereof a therapeutically effective amount of the compound I of any one of the first aspects of the invention Polymorph.
  • a fifth aspect of the invention further relates to a method of treating and/or preventing a tumor or cancer in a mammal, including a human, in a mammal in need thereof, the method comprising administering to the mammal in need thereof a therapeutically effective amount of the invention
  • the tumor or cancer comprises an erbB receptor tyrosine kinase-sensitive cancer, such as EGFR or Her2 high expression and EGF driven tumors, including solid tumors such as Bile duct, bone, bladder, brain/central nervous system, breast, colorectal, endometrium, stomach, head and neck, liver, lung (especially non-small cell lung cancer), neurons, esophagus, ovary, pancreas, prostate, kidney , cancers of the skin, testes, verrucous glands, uterus and vulva, and non-solid tumors such as leukemia, multiple myeloma or lymphoma.
  • a sixth aspect of the invention relates to the polymorph of the compound I according to any one of the first aspects of the invention, which is useful for the treatment and/or prevention of mammalian (including human) and receptor tyrosine A drug for a kinase-related disease or condition.
  • a sixth aspect of the invention relates to the polymorph of the compound I according to any one of the first aspects of the invention, which is useful as a therapeutic or adjunctive treatment and/or prevention of mammals (including humans) A drug that mediated by a tyrosine kinase-mediated tumor or proliferation and migration of tumor cells driven by a receptor tyrosine kinase.
  • the polymorph of Compound I of the present invention can be used as a medicament for the treatment of erbB receptor tyrosine kinase-sensitive cancers, such as EGFR or Her2 high expression and EGF driven tumors, including entities.
  • Tumors such as bile duct, bone, bladder, brain/central nervous system, breast, colorectal, endometrium, stomach, head and neck, liver, lung (especially non-small cell lung cancer), neurons, esophagus, ovary, pancreas, prostate , spleen, skin, testes, verrucous, uterus and vulva, and non-solid tumors such as leukemia, multiple myeloma or lymphoma.
  • the tumor or cancer involved may include the above-described erbB receptor tyrosine kinase-sensitive cancer, such as EGFR or Her2 high expression and EGF-driven tumors, including entities Tumors such as bile duct, bone, bladder, brain/central nervous system, breast, colorectal, endometrium, stomach, head and neck, liver, lung (especially non-small cell lung cancer), neurons, esophagus, ovary, pancreas, prostate Cancers such as kidneys, skin, testes, verrucous glands, uterus and vulva, and non-solid tumors such as leukemia, multiple myeloma or lymphoma.
  • the invention may include the above-described erbB receptor tyrosine kinase-sensitive cancer, such as EGFR or Her2 high expression and EGF-driven tumors, including entities Tumors such as bile duct, bone, bladder, brain/central nervous system, breast, colorectal, endometri
  • the polymorph of the compound I of the present invention has an X-ray powder diffraction characteristic peak expressed by a angle of 2 ,, where " ⁇ 0.2,” is an allowable measurement error range.
  • the polymorph of the compound I of the present invention can be used in combination with other active ingredients as long as it does not cause other adverse effects such as an allergic reaction.
  • the active compound represented by the polymorph of the compound I of the present invention can be used as the sole anticancer drug or can be used in combination with one or more other antitumor drugs. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
  • composition as used herein is meant to include a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from the specified combination of the specified ingredients.
  • each active ingredient in the pharmaceutical compositions of the present invention can be varied so that the resulting amount of active compound is effective to provide the desired therapeutic response to the particular patient, composition, and mode of administration.
  • the dosage level will be selected based on the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and past medical history of the patient to be treated. However, it is the practice in the art that the dosage of the compound be started from a level lower than that required to achieve the desired therapeutic effect, and the dosage is gradually increased until the desired effect is obtained.
  • a therapeutically and/or prophylactically effective amount of a polymorph of a compound of the invention I may be applied in pure form, or as a pharmaceutically acceptable ester or The prodrug form (in the presence of these forms) is applied.
  • the compound can be administered in a pharmaceutical composition comprising the compound of interest and one or more pharmaceutically acceptable excipients.
  • therapeutic and/or prophylactically effective amount of a polymorph of Compound I of the present invention refers to a sufficient amount of a compound to treat the disorder at a reasonable effect/risk ratio suitable for any medical treatment and/or prevention.
  • the total daily usage of the polymorphs and compositions of Compound I of the present invention will be determined by the attending physician within the scope of sound medical judgment.
  • the particular therapeutically effective dosage level for any particular patient will depend on a number of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition employed; Patient's age, weight, general health, sex and diet; time of administration, route of administration and excretion rate of the particular compound employed; duration of treatment; drug used in combination with or concurrent with the particular compound employed; Similar factors are known in the medical field.
  • the dosage of the compound be started from a level lower than that required to achieve the desired therapeutic effect, and the dosage is gradually increased until the desired effect is obtained.
  • the polymorph of the compound I of the present invention can be used in mammals, especially humans, at a dose of from 0.001 to 1000 mg/k body weight per day, for example from 0.01 to 100 mg/k body weight per day, for example At 0.01 ⁇ 10 mg / k body weight / day.
  • compositions containing an effective amount of a polymorph of Compound I of the present invention can be prepared using pharmaceutical carriers well known to those skilled in the art.
  • the invention therefore also provides a pharmaceutical composition comprising a polymorph of Compound I of the invention formulated together with one or more non-toxic pharmaceutically acceptable carriers.
  • the pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form for parenteral injection or for rectal administration.
  • the pharmaceutical composition can be formulated into a plurality of dosage forms for ease of administration, for example, oral preparations (such as tablets, capsules, solutions or suspensions); injectable preparations (such as injectable solutions or suspensions) , or an injectable dry powder, which can be used immediately before injection.
  • oral preparations such as tablets, capsules, solutions or suspensions
  • injectable preparations such as injectable solutions or suspensions
  • injectable dry powder which can be used immediately before injection.
  • the carrier in the pharmaceutical composition includes: an adhesive for oral preparation (such as starch, usually corn, small) Wheat or rice starch, gelatin, decyl cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone, diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or Glycerin), a lubricant (such as silica, talc, stearic acid or a salt thereof, usually magnesium stearate or calcium stearate, and/or polyethylene glycol), and if necessary, a disintegrant , such as starch, agar, alginic acid or a salt thereof, usually sodium alginate, and / or effervescent mixture, cosolvents, stabilizers, suspending agents, pigments, flavors, etc., preservatives for injectable preparations, Solvents, stabilizers, etc.; base shields, thinners, lubricants
  • compositions of the present invention can be administered orally, rectally, parenterally, intracereally, intravaginally, intraperitoneally, topically (e.g., by powder, ointment or drops), orally to humans and other mammals. Or as an oral spray or nasal spray.
  • parenteral refers to administrations which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injections and infusions.
  • compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for the preparation of sterile injectable solutions or dispersions.
  • suitable aqueous or nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, etc.), vegetable oils (such as olive oil), injectable organic esters such as oleic acid. Ethyl esters and suitable mixtures thereof.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • the action of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid and the like. It is also desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of materials which delay absorption, such as aluminum monostearate and gelatin.
  • Suspensions may contain suspending agents in addition to the active compound, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite , agar and tragacanth or a mixture of these substances.
  • suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite , agar and tragacanth or a mixture of these substances.
  • the rate of absorption of the drug depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form.
  • delayed absorption of the parenterally administered drug form is accomplished by dissolving or suspend
  • the injectable depot form can be prepared by forming a microcapsule matrix of the drug in a biodegradable polymer such as polylacide-polygly colide.
  • a biodegradable polymer such as polylacide-polygly colide.
  • the rate of drug release can be controlled based on the ratio of drug to polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Injectable depot formulations are also prepared by embedding the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable preparation can be sterilized, for example, by filtration with a bacteriophage or by incorporating a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterilized form before use. Injectable medium.
  • the polymorph of the compound I of the present invention or a composition thereof may be administered orally or parenterally.
  • Oral administration may be a tablet, a capsule, a coating, an enteral preparation, an injection, a suppository, and the like.
  • These formulations are prepared according to methods familiar to those skilled in the art.
  • the excipients used in the manufacture of tablets, capsules, and coatings are conventional excipients such as starch, gelatin, gum arabic, silica, polyethylene glycol, solvents used in liquid dosage forms such as water, ethanol, propylene glycol, vegetable oils (eg Corn oil, peanut oil, olive oil, etc.).
  • the dosage of the polymorph of the compound of the invention I in tablets, capsules, coatings, injections and suppositories is calculated as the amount of the compound present in the unit dosage form.
  • the content of the unit dosage form of the polymorph I of the compound of the present invention is 1 ⁇ 5000mg
  • the preferred unit dosage form contains 10 ⁇ 500mg
  • the unit dosage form contains 20 ⁇ 300mg o
  • the present invention can provide for Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound can be And at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and
  • a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone , sucrose and gum arabic; c) humectants such as glycerin; d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarders such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glyceryl monostearate; h) adsorbents such as kaolin and bentonite and i) lubricants such as talc, calcium stearate, stearic acid Magnesium, solid polyethylene glycol, sodium lauryl 3 ⁇ 4 and mixtures thereof
  • compositions of a similar type may be employed as fillers in soft and hard gelatin using excipients such as lactose and high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other materials well known in the art of pharmaceutical preparations. These solid dosage forms may optionally contain opacifying agents, and may be formulated such that they are only or preferentially released in a certain portion of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used include polymeric materials and waxes. If appropriate, the active compound may also be formulated in microquine form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage form may contain, in addition to the active compound, an inert diluent commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid.
  • Benzyl ester propylene glycol, 1,3-butanediol, dimercaptoamide, oils (especially cottonseed oil, peanut oil, corn oil, apple oil, olive oil, castor oil and sesame oil), glycerin, tetrahydrofurfuryl alcohol (tetrahydrofurfuryl alcohol), fatty acid esters of polyethylene glycol and sorbitan, and mixtures thereof.
  • the oral compositions may contain, in addition to the inert diluent, excipients such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and flavoring agents.
  • compositions for rectal or vaginal administration are preferably suppositories.
  • Suppositories can be made by the invention
  • the polymorph of Compound I is prepared by mixing with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or suppository wax, which is solid at room temperature but liquid at body temperature, thus It can be melted in the rectal or vaginal cavity to release the active compound.
  • Polymorphs of Compound I of the present invention and compositions thereof are also contemplated for topical administration.
  • Dosage forms for the topical administration of the polymorph of the compound of the invention I include powders, sprays, ointments and inhalants.
  • the active compound is admixed under sterile conditions with apharmaceutically acceptable carrier and any of the required preservatives, buffers or propellants.
  • Ophthalmic formulations, ophthalmic ointments, powders and solutions are also contemplated as being within the scope of the invention.
  • the polymorph of Compound I of the present invention may also be administered in the form of a liposome.
  • liposomes are typically made from phospholipids or other lipid materials. Liposomes are formed from single or multiple layers of hydrated liquid crystal dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the composition of the present invention in the form of a liposome may contain, in addition to the compound of the present invention, a stabilizer, a preservative, an excipient or the like.
  • Preferred lipids are natural and synthetic phospholipids and phosphatidylcholines (lecithins), which may be used alone or together. Methods of forming liposomes are well known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p33.
  • the present inventors have surprisingly found that the polymorph of Compound I exhibits an inhibitory activity against both EGFR and Her2 tyrosine kinases, and at the same time, has an inhibitory effect on cell lines with high expression of EGFR and Her2 tyrosine kinase, therefore,
  • the polymorph of the inventive compound I can be used for EGFR and Her2 receptor tyrosine kinases alone or in part to mediated diseases, primarily by inhibiting one or more EGFR family tyrosine kinases and by inhibiting kinase activity Proliferation, anti-migration, and pro-apoptotic effects.
  • the polymorph of the compound I of the present invention can be used for the prevention and treatment of one or more erbB receptor tyrosine kinase-sensitive tumors by inhibiting EGFR and Her2 tyrosine kinase, in particular EGFR or Her2 high expression and EGF driven tumors.
  • solid tumors such as bile duct, bone, bladder, brain/central nervous system, breast, colorectal, endometrium, stomach, head and neck, liver, lung (especially non-small cell lung cancer), neurons, esophagus, egg Cancers of the nest, pancreas, prostate, kidney, skin, testes, verrucous, uterus and vulva, non-solid tumors such as leukemia, multiple myeloma or lymphoma.
  • solid tumors such as bile duct, bone, bladder, brain/central nervous system, breast, colorectal, endometrium, stomach, head and neck, liver, lung (especially non-small cell lung cancer), neurons, esophagus, egg Cancers of the nest, pancreas, prostate, kidney, skin, testes, verrucous, uterus and vulva, non-solid tumors such as leukemia, multiple myeloma or lymphoma.
  • the present invention provides a general and/or specific description of the materials and test methods used in the tests. While many of the materials and methods of operation used to accomplish the objectives of the present invention are well known in the art, the present invention is still described in detail herein. It will be apparent to those skilled in the art that, hereinafter, the materials and methods of operation of the present invention are well known in the art unless otherwise specified.
  • Instrument model Varian INOVA-400 nuclear magnetic resonance instrument.
  • Test conditions Solvent DMSO-d 6 .
  • Radiation source Cu target ⁇ radiation.
  • Sample Handling After the sample has been finely ground, it is placed in a standard sample holder for measurement.
  • Test conditions 50 ° C 10 ° C / min.
  • Compound II can be prepared according to the method described in CN102030742A, as shown in Example 1.
  • the compound 5-(4-(4-(3-fluorobenzylchloroanilino)-6-quinazolinyl)furan-2-indole-p-toluenesulfonate 12 was dissolved in dichloromethane/methanol (3 In the mixed solution of 1), 12 ml of triethylamine was added to stir the reaction for 10 min, and 6.0 g of 2-sulfoximine ethylamine hydrochloride was added. The reaction was stirred at room temperature, and the reaction of the starting materials was confirmed by TLC, and sodium borohydride was added in portions under ice bath.
  • Example 6 N-(4-(3-fluorobenzylchlorophenyl)-6-(5-((2-(methylethylideneamino)methyl)-2-furanyl)-quinazoline
  • 4-Aminexylenesulfonate (Compound I) Form B The compound I crystal form 028 was dried at 80" for 1 hour to obtain a yellow crystalline powder, and the obtained product was subjected to X-ray powder diffraction. The results showed that the product was Compound B Form B, and the XRPD pattern is shown in Figure 4. The DSC data showed that Form B was at 239.11 ⁇ 254.49 °C. Melt decomposition; DSC spectrum is shown in Figure 5.
  • Example 7 N-(4-(3-Fluorobenzyl 3 ⁇ 4 ⁇ )-3-chlorophenyl)-6-(5-((2-(methylethylideneamino)methyl)-2-furanyl) - Preparation of quinazoline-4-amine xylene sulfonate (Compound I) Form A.
  • Compound I crystal form C 28 is dried at 60 ° C for 2 hours to obtain a yellow crystalline powder. The product was subjected to X-ray powder diffraction, and the result showed that the product was Compound I crystal form A.
  • Example 8 N-(4-(3-fluorobenzyl 3 ⁇ 4 ⁇ )-3-chlorophenyl)-6-(5-( Preparation of (2-(methylethylideneamino)methyl)-2-furanyl)-quinazolin-4-amine-xylenesulfonate (Compound I) Form A
  • Compound I crystal form C 2 g After drying at 150 ° C for 1 hour, a yellow crystalline powder was obtained, and the obtained product was subjected to X-ray powder diffraction, and it was found that the product was Compound I crystal form A.
  • Example 9 N-(4-(3) -fluorobenzyl 3 ⁇ 4 ⁇ )-3-chlorophenyl)-6-(5-((2-(methylethylideneamino)methyl)-2-furanyl)-quinazolin-4-amine xylene
  • sulfonate (Compound I) Form B
  • the compound I crystal form 028 was dried at 60 ° C for 2 hours to obtain a yellow crystalline powder, and the obtained product was subjected to X-ray powder diffraction, and the product was confirmed to be the product.
  • Compound Form I B is
  • Example 10 N-(4-(3-fluorobenzyl-3-chlorophenyl)-6-(5-((2-(methylethylidenemethyl))-2-furanyl) - Preparation of quinazoline-4-amine xylene sulfonate (Compound I) Form B.
  • Compound D crystal form D 2 g is dried at 150 ° C for 1 hour to obtain a yellow crystalline powder.
  • the product was subjected to X-ray powder diffraction, and the result showed that the product was Compound B crystal form B.
  • Example 11 N-(4-(3-fluorobenzyl 3 ⁇ 4 -3-chlorophenyl)-6-(5-(( Preparation of 2-(methylethylidenemethyl)-2-furanyl)-quinazolin-4-amine xylene sulfonate (Compound I) Form C
  • Compound 12g was added to 30ml 1,4-dioxane In a mixed system of six rings and 5 ml of water, reflux Dissolved, cooled and crystallized, suction filtered, dried to obtain 1.2 g of yellow crystalline powder, yield 60%.
  • Example 14 N-( 4-(3-fluorobenzyl L3 ⁇ 4 ⁇ )-3-chlorophenyl)-6-(5-((2-(methylsulfoxide)) Preparation of crystalline form of methyl 2-(2-furyl)-quinazolin-4-amine-xylene sulfonate (Compound I).
  • Compound I 2g was added to a mixed system of 10 ml of decyl alcohol and 2 ml of water, and dissolved under reflux.
  • Example 15 N -(4-(3-fluorobenzyl L3 ⁇ 4 ⁇ )-3-chlorophenyl)-6-(5-((2-(methylsulfoxide)ethylmethyl)-2-furanyl)-quinazoline Preparation of morpholin-4-amine xylene sulfonate (Compound I) Form D.
  • Example 17 N-(4-(3-fluorobenzylchlorophenyl)-6- Preparation of (5-((2-(indolylsulfonyl)ethylmethyl)-2-furanyl)-quinazolin-4-amine-xylenesulfonate (Compound I) Form D
  • Compound 12g After adding 40 ml of ethanol and 6 ml of water, the mixture was beaten for 4 hours, filtered by suction, and air-dried to obtain 1.5 g of a yellow crystalline powder in a yield of 75%. The obtained product was subjected to X-ray powder diffraction, and the product was found to be Compound I Form D.
  • In vitro kinase assays were performed using Cell Signaling Technolog's HTScan EGF Receptor Kinase Assay Kit (#7909) and HTScan HER2/ErbB2 Kinase Assay Kit (#7058). The procedure is described in the kit, which detects the inhibitory effect of the test compound on the phosphorylation of the substrate peptide by EGFR or Her2 receptor tyrosine kinase in vitro. Incubate ATP and substrate peptides and the test compound in kinase reaction buffer at room temperature. After incubation for a while, stop the reaction by adding stop solution and transfer the sample to streptavidin-coated 96-well plate, wash and use.
  • HRP-labeled anti-substrate phosphorylation antibody detects phosphorylation levels on substrate peptides, TMB color development, 2M acid stopped the reaction. The 450 nm absorption wavelength was measured and IC 5 was calculated. Value ( ⁇ ). The results are shown in Table 2.
  • the test was carried out in accordance with the method described in Rusnak et al, Cell Prolif, 2007, 40, 580-594.
  • the cell proliferation inhibition assay used human breast cancer cell line BT474 and human gastric cancer cell line NCI-N87. BT474 highly expressed Her2 receptor, and N87 highly expressed EGFR and Her2 receptor.
  • DMEM Dulbecco's Modified Eagle Medium
  • EDTA trypsin / ethylene Aminotetraacetic acid
  • TCA trichloroacetic acid

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Abstract

L'invention concerne les polymorphes de N-(4-(3-fluorobenzyloxy)-3-chlorophényl)-6-(5-((2-(méthylsulfinyl)éthylamino)méthyl)-2-furannyl)-quinazolin-4-aminoxylène-sulfonate (composé I) utilisés comme inhibiteurs de la tyrosine kinase. En particulier, L'invention concerne les formes cristallines A, B, C et D du composé I. L'invention concerne également un procédé de préparation des polymorphes du composé I et comprend ses compositions pharmaceutiques et leurs utilisations pharmaceutiques. Les polymorphes du composé I de l'invention sont des inhibiteurs efficaces de la tyrosine kinase.
PCT/CN2013/072169 2012-03-06 2013-03-05 Polymorphes de n-(4-(3-fluorobenzyloxy)-3-chlorophényl)-6-(5-((2-(méthylsulfinyl)éthylamino)méthyl)-2-furannyl)-quinazolin-4-aminoxylène-sulfonate et leur procédé de préparation et leurs utilisations WO2013131465A1 (fr)

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CN105646461B (zh) * 2014-11-28 2019-04-23 齐鲁制药有限公司 S构型4-(取代苯胺基)喹唑啉衍生物及其制备方法和用途
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CN104610364B (zh) * 2015-01-30 2017-03-29 江苏康缘药业股份有限公司 含磷取代的喹唑啉衍生物的新晶型及其制备方法和应用
CN104558042B (zh) * 2015-01-30 2017-03-29 江苏康缘药业股份有限公司 含磷取代的喹唑啉衍生物的新晶型及其制备方法和应用
CN105237573B (zh) * 2015-11-11 2017-10-24 江苏康缘药业股份有限公司 二对甲苯磺酸缘生替尼的制备方法

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CN1440403A (zh) * 2000-06-30 2003-09-03 葛兰素集团有限公司 喹唑啉二甲苯磺酸盐化合物
CN102030742A (zh) * 2009-09-28 2011-04-27 齐鲁制药有限公司 作为酪氨酸激酶抑制剂的4-(取代苯胺基)喹唑啉衍生物

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EP2166859A4 (fr) * 2007-06-11 2011-09-07 Smithkline Beecham Cork Ltd Composés à base de sel de quinazoline
US20090215802A1 (en) * 2007-09-13 2009-08-27 Protia, Llc Deuterium-enriched lapatinib
WO2009140144A1 (fr) * 2008-05-15 2009-11-19 Teva Pharmaceutical Industries Ltd. Formes du lapatinib cristallin et leurs procédés de préparation

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CN1440403A (zh) * 2000-06-30 2003-09-03 葛兰素集团有限公司 喹唑啉二甲苯磺酸盐化合物
CN102030742A (zh) * 2009-09-28 2011-04-27 齐鲁制药有限公司 作为酪氨酸激酶抑制剂的4-(取代苯胺基)喹唑啉衍生物

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