WO2013131465A1 - Polymorphs of n-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-((2-(methylsulfinyl)ethylamino)methyl)-2-furanyl)-quinazoline-4-aminexylene sulfonate and preparation method and uses thereof - Google Patents

Polymorphs of n-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-((2-(methylsulfinyl)ethylamino)methyl)-2-furanyl)-quinazoline-4-aminexylene sulfonate and preparation method and uses thereof 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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WIPO (PCT)
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compound
polymorph
ray powder
powder diffraction
tyrosine kinase
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PCT/CN2013/072169
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French (fr)
Chinese (zh)
Inventor
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/en

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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

Abstract

The invention relates to the polymorphs of N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-((2-(methylsulfinyl)ethylamino)methyl)-2-furanyl)-quinazoline-4-aminexylene sulfonate (compound I) used as tyrosine kinase inhibitors. In particular, the invention relates to the crystal forms A, B, C and D of compound I. The invention also relates to a preparation method for the polymorphs of compound I, and comprises its pharmaceutical compositions and their pharmaceutical uses. The polymorphs of compound I of the invention are efficient tyrosine kinase inhibitors.

Description

N- (4- (3-氟苄氧基) -3-氯苯基) -6- (5- ( (2- (甲基亚砜基）乙 基氨基）甲基) -2-呋喃基) -喹唑啉 -4-胺二甲苯磺酸盐  N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-((2-(methylsulfoxide)ethylamino)methyl)-2-furanyl) -quinazoline-4-amine xylene sulfonate
的多晶型物及其制备方法和用途 技术领域  Polymorph and preparation method and use thereof
本发明属于医药化工领域， 具体涉及一种新的具有抗肿瘤活性的 N-(4-(3-氟苄氧基) -3-氯苯基 )-6-(5-((2-(曱基亚砜基）乙基氨基)曱基) -2-呋 喃基) -喹唑啉 -4-胺二曱苯磺酸盐 (化合物 I)多晶型物及其制备方法， 以及 化合物 I 的多晶型物在作为用于治疗或辅助治疗哺乳动物 (包括人)由受 体酪氨酸激酶介导的肿瘤或受体酪氨酸激酶驱动的肿瘤细胞的增殖和迁 移的药物方面的应用。 背景技术  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-(曱)) 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
肿瘤是严重威胁人类生命和生活质量的主要疾病之一， 据 WHO统 计， 全世界每年死于肿瘤的患者约 690万。 由于生存环境和生活习性的 改变， 在不良环境和一些不利因素的作用下， 肿瘤的发病率和死亡率近 年呈逐步上升趋势。  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.
近年来， 人们致力于抑制细胞信号转导途径以开发新型靶点抗肿瘤 药物。 信号转导抑制剂下调肿瘤的生存和增殖信号， 促进细胞凋亡， 而 不是通过细胞毒作用， 因此选择性较高、 毒副作用较小。 目前已有十几 种信号转导抑制剂应用于临床治疗肿瘤， 主要为酪氨酸激酶抑制剂类抗 肿瘤药物， 其中 4- (取代苯胺基)喹唑啉结构类型的化合物开发的比较成 熟， 如针对 EGFR酪氨酸激酶靶点的小分子抑制剂吉非替尼 (Gefitinib)、 埃罗替尼 (Erlotinib)和拉帕替尼 (Lapatinib)等。  In recent years, efforts have been made to inhibit cell signal transduction pathways to develop novel target antitumor drugs. Signal transduction inhibitors down-regulate tumor survival and proliferation signals, promote apoptosis, and not through cytotoxicity, so they have higher selectivity and less toxic side effects. At present, there are more than ten kinds of signal transduction inhibitors used in clinical treatment of tumors, mainly tyrosine kinase inhibitor anti-tumor drugs, among which 4-(substituted anilino) quinazoline structure type compounds are relatively mature. For example, Gefitinib, Erlotinib and Lapatinib, which are small molecule inhibitors against EGFR tyrosine kinase targets.
吉非替尼 (Gefitinib) , 商品名 Iressa (易瑞沙）， AstraZeneca开发的 EGFR酪氨酸激酶抑制剂， 是最早进入临床研究的表皮生长因子受体酪 氨酸激酶抑制剂， 于 2002年在日本上市， 次年在美国上市， 用于治疗既 往接受过化疗的晚期或转移性非小细胞肺癌（NSCLC)。 埃罗替尼 (Erlotinib), 商品名 Tarceva (特罗凯)， OSI公司开发的 EGFR酪氨酸激酶 抑制剂， 受让于 Genentech和罗氏公司。 2004年在美国上市， 用于治疗 NSCLC和胰腺癌。 属于第一代治疗 NSCLC的苯胺喹唑啉类小分子抑制 剂， 也是目前唯一被证实的对晚期非小细胞肺癌具有生存优势的 EGFR 酪氨酸激酶抑制剂， 对各类非小细胞肺癌患者均有效， 且耐受性好， 无 骨髓抑制和神经毒性， 能显著延长生存期， 改善患者生活质量。 拉帕替 尼 (Lapatinib), 商品名 Tycerb, 是 GlaxoSmithKline公司开发的 EGFR和 HER2的双重抑制剂，其对肿瘤增殖和生存的信号传导的抑制作用强于单 一受体抑制剂。 2007年美国 FDA批准该品上市， 适应症为与卡培他滨联 合治疗过度表达 HER2和先前曾接收过化疗如蒽环类、紫杉烷类和曲妥珠 单抗的晚期或转移性乳腺癌患者。 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. Erlotinib, trade name Tarceva, EGFR tyrosine kinase inhibitor developed by OSI, accepted by Genentech and Roche. Launched in the United States in 2004 for the treatment of NSCLC and pancreatic cancer. It belongs to the first generation of aniline quinazoline small molecule inhibitors for the treatment of NSCLC. It is also the only confirmed EGFR tyrosine kinase inhibitor with superior survival for advanced non-small cell lung cancer. Effective, well tolerated, without myelosuppression and neurotoxicity, can significantly prolong survival and improve patients' quality of life. Lapatinib, trade name 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.
此外， 专利申请公开号 WO 96/33977、 WO 97/30035, WO 98/13354、 WO 00/55141、 WO 02/41882、 WO 03/82290和 EP 837 063等公开了在 4- 位上携带苯胺基取代基和在 6-和 /或 7-位上携带取代基的某些喹唑啉衍生 物， 具有受体酪氨酸激酶活性。  In addition, 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.
'J、分子酪氨酸激酶抑制剂作为新的靶向抗肿瘤药物， 为肿瘤的治疗 和预防打开了一扇新窗口， 而且其副作用轻微， 有良好的耐受性。 虽然 目前已有 10多个小分子酪氨酸激酶抑制剂为临床肿瘤治疗作出了很大贡 献， 但仍然需要发现一些较之现有的酪氨酸激酶抑制剂具有更好的体内 活性和 /或改良的药理学特性的另外的化合物。 因此开发新的改进的或更 高效的酪氨酸激酶抑制剂， 更深入地了解该类药物与已知靶蛋白之间的 关系以及其发挥抗肿瘤作用的机理对肿瘤临床治疗具有重要的意义。  'J, a molecular tyrosine kinase inhibitor as a new targeted anti-tumor drug, opened a new window for the treatment and prevention of tumors, and its side effects are mild and well tolerated. Although more than 10 small molecule tyrosine kinase inhibitors have been contributing to clinical tumor therapy, there is still a need to find some better in vivo activity and/or properties than existing tyrosine kinase inhibitors. Additional compounds with improved pharmacological properties. Therefore, the development of new improved or more efficient tyrosine kinase inhibitors, a deeper understanding of the relationship between this class of drugs and known target proteins and its mechanism of exerting anti-tumor effects are of great significance for the clinical treatment of tumors.
CN102030742A研究了 4- (取代苯胺基)喹唑啉衍生物作为用于治疗或 辅助治疗哺乳动物 (包括人)由受体酪氨酸激酶介导的肿瘤或受体酪氨酸 激酶驱动的肿瘤细胞的增殖和迁移的药物方面的应用。 发明内容 CN102030742A Study of 4-(substituted anilino)quinazoline derivatives as tumor cells for tumor therapy or receptor tyrosine kinase mediated by receptor tyrosine kinases for the treatment or adjuvant treatment of mammals, including humans, The application of drugs for proliferation and migration. Summary of the invention
本发明确定了 N-(4-(3-氟苄 氯苯基 )-6-(5-((2-(曱基亚 乙 基 曱基) -2-呋喃基) -喹唑啉 -4-胺二曱苯磺酸盐 (化合物 I)的多晶型 物， 其可用作  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
Figure imgf000004_0001
Figure imgf000004_0001
Ι0 Ι 0
本发明人经过研究发现， 化合物 I具有很高的酪氨酸激酶抑制作用。 我们已发现化合物 I的某些形式， 是具有有利性盾的晶体物质。  The present inventors have found through research that 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.
为此， 本发明第一方面提供了 Ν-(4-(3-氟苄 fL&)-3-氯苯  To this end, the first aspect of the invention provides Ν-(4-(3-fluorobenzyl fL&)-3-chlorobenzene
基) -6-(5-((2- (甲基亚砜基)乙基 曱基) -2-呋喃基) -喹唑啉 -4-胺二曱苯 磺酸盐 (化合物 I)的多晶型物。 -6-(5-((2-(Methylsulfoxide)ethyl)-yl)-2-furanyl)-quinazolin-4-amine diterpene sulfonate (Compound I) Crystal form.
本发明的发明人令人惊奇地发现化合物 I可以以一种以上的多晶型 物存在。 发明人将这些多晶型物简称为晶型 Α、 Β、 < 和0。 化合物 I的 多晶型物在水中有一定的溶解性， 有利于体内吸收； 并且具有更好的稳 定性， 有利于包装和贮存。  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 Α, Β, < 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.
在一个实施方案中， 所述的化合物 I晶型 Α, 使用 Cu-Κα辐射， 以 2Θ角度表示的 X-射线粉末衍射图语在 4.6° 士 0.2。， 9.2° 士 0.2。， 11.5° 士 0.2°, 12.6Q ± 0.2。， 15·1ο ± 0·2ο， 19.7Q ± 0·2ο， 24.9Q ± 0·2ο， 27.2Q ± 0·2ο 处有特征峰。 In one embodiment, the Compound I crystalline form is Cu, using Cu-Κα radiation, and the X-ray powder diffraction pattern expressed in terms of 2 Θ angle is at 4.6° ± 0.2. , 9.2° ± 0.2. , 11.5° ± 0.2°, 12.6 Q ± 0.2. , 15·1 ο ± 0·2 ο , 19.7 Q ± 0·2 ο , 24.9 Q ± 0·2 ο , 27.2 Q ± 0·2 ο There are characteristic peaks.
在进一步的实施方案中，所述的化合物 I晶型 Α,使用 Cu-Κα辐射， 以 2Θ角度表示的 X-射线粉末衍射图谱在 4.6°士 0·2ο， 9.2°士 0·2ο， 11.5°士 0.2°, 12.6Q ± 0.2。， 14.5°± 0.2°, 15.1Q ± 0.2。， 15.7°± 0.2°, 16.0°± 0.2°, 19.1。士 0.2°, 19.7° ± 0·2ο， 20.0。士 0.2°, 21.9。士 0.2°, 22.9°± 0.2°, 24.0° ± 0·2ο， 24.3°± 0.2°, 24.9°± 0.2°, 27.2。 ± 0·2ο处有特征峰。 在更进一步的实施方案中， 所述的化合物 I晶型 A具有基本如同图In a further embodiment, the compound I is in crystalline form, using Cu-Κα radiation, and the X-ray powder diffraction pattern expressed in terms of 2 Θ angle is 4.6 ° ± 0 · 2 ο , 9.2 ° ± 0 · 2 ο , 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 ο , 20.0. ± 0.2 °, 21.9. ± 0.2 °, 22.9 ° ± 0.2 °, 24.0 ° ± 0 · 2 ο , 24.3 ° ± 0.2 °, 24.9 ° ± 0.2 °, 27.2. There is a characteristic peak at ± 0·2 ο . In still further embodiments, the Compound I Form A has substantially the same pattern as
2所示出的 X 线粉末衍射图谱。 2 shows the X-ray powder diffraction pattern.
在一个实施方案中， 所述的化合物 I晶型 A的差示扫描量热分析显 示， 该晶型在 240.82~255.59°C熔融分解。  In one embodiment, differential scanning calorimetry of Form A of Compound I shows that the crystal form melts at 240.82 to 255.59 °C.
在另一个实施方案中， 所述的化合物 I晶型 B， 使用 Cu-Κα辐射， 以 2Θ角度表示的 X-射线粉末衍射图谱在 4.6°士 0·2ο， 8.3°士 0·2ο， 12.0°士 0.2°, 15·8ο±0·2ο， 19·7ο±0·2ο， 20·8ο±0·2ο， 22.8。 ± 0·2ο处有特征峰。 In another embodiment, the Compound I Form B, using Cu-Κα radiation, has an X-ray powder diffraction pattern at a Θ angle of 4.6° ± 0·2 ο , 8.3 ° ± 0·2 ο , 12.0°±0.2°, 15·8 ο ±0·2 ο , 19·7 ο ±0·2 ο , 20·8 ο ±0·2 ο , 22.8. There is a characteristic peak at ± 0·2 ο .
在进一步的实施方案中，所述的化合物 I晶型 Β,使用 Cu-Κα辐射， 以 2Θ角度表示的 X-射线粉末衍射图谱在 4.6。 ±0.2。， 8·3。±0·2ο， 9.1。士 0.2°, 12.0。 ±0.2。， 13.9Q±0.2。， 15.0Q±0.2。， 15.8Q±0.2。， 17.6。 ±0.2。， 18·7ο±0·2ο， 19.7Q±0.2。， 20·8ο±0·2ο， 22·2ο±0·2ο， 22·8ο±0·2ο， 26.0° 士 0.2。处有特征峰。 In a further embodiment, the Compound I crystalline form is Cu, using Cu-Κα radiation, and the X-ray powder diffraction pattern at 2 Θ angle is at 4.6. ±0.2. , 8·3. ±0·2 ο , 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 ο ±0·2 ο , 19.7 Q ±0.2. , 20·8ο±0·2 ο , 22·2 ο ±0·2 ο , 22·8ο±0·2 ο , 26.0° ± 0.2. There are characteristic peaks.
在更进一步的实施方案中， 所述的化合物 I晶型 Β具有基本如同图 4所示出的 X 线粉末衍射图谱。  In still further embodiments, the Form I of the Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 4.
在一个实施方案中， 所述的化合物 I晶型 B的差示扫描量热分析显 示， 该晶型在 239.11~254.49°C熔融分解。  In one embodiment, differential scanning calorimetry of Form B of Compound I shows that the crystal form melts and decomposes at 239.11 to 254.49 °C.
在又一个实施方案中， 所述的化合物 I晶型 C， 使用 Cu-Κα辐射， 以 2Θ角度表示的 X-射线粉末衍射图谱在 4.4°士 0·2ο， 9.5°士 0·2ο， 12.7°士 0.2°, 14·9ο±0·2ο， 19·8ο±0·2ο， 23·7ο±0·2ο， 26.8。 ± 0·2ο处有特征峰。 In still another embodiment, the Compound C Form C, using Cu-Κα radiation, has an X-ray powder diffraction pattern at a angle of 2 在 at 4.4° ± 0·2 ο , 9.5 ° ± 0·2 ο , 12.7°±0.2°, 14·9 ο ±0·2 ο , 19·8 ο ±0·2 ο , 23·7 ο ±0·2 ο , 26.8. There is a characteristic peak at ± 0·2 ο .
在进一步的实施方案中，所述的化合物 I晶型 C,使用 Cu-Κα辐射， 以 2Θ角度表示的 X-射线粉末衍射图谱在 4.4°士 0·2ο， 9.5°士 0·2ο， 12.7°士 0.2°, 14.9° ±0.2。， 16.1。 ±0.2。， 17.1。 ±0.2。， 19.4° ±0.2。， 19.8。 ±0.2。， 20·9ο±0·2ο， 21·4。±0·2ο， 23·7°±0·2ο， 26.8。 ± 0·2ο处有特征峰。 In a further embodiment, the Compound I Form C, using Cu-Κα radiation, has an X-ray powder diffraction pattern at a angle of 2 在 at 4.4° ± 0·2 ο , 9.5 ° ± 0·2 ο , 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 ο ±0·2 ο , 21·4. ±0·2 ο , 23·7°±0·2 ο , 26.8. There is a characteristic peak at ± 0·2 ο .
在更进一步的实施方案中， 所述的化合物 I晶型 C具有基本如同图 6所示出的 X 线粉末衍射图谱。  In still further embodiments, the Compound C Form C has an X-ray powder diffraction pattern substantially as shown in Figure 6.
在又一个实施方案中， 所述的化合物 I晶型 D， 使用 Cu-Κα辐射， 以 2Θ角度表示的 X-射线粉末衍射图谱在 4.4°士 0·2ο， 8.3°士 0·2ο， 14.8°士 0.2°, 19·4ο±0·2ο， 21·0ο±0·2ο， 21·7ο±0·2ο， 25.1。 ± 0·2ο处有特征峰。 在进一步的实施方案中，所述的化合物 I晶型 D,使用 Cu-Κα辐射， 以 2Θ角度表示的 X-射线粉末衍射图谱在 4.4°士 0·2ο， 8.3°士 0·2ο， 14.8°士 0.2°, 18.7G±0.2。， 19.4G±0.2。， 21.0c±0.2o， 21.7c±0.2o， 22.2c±0.2o， 23·0ο士 0·2ο， 25.1。土 0·2ο， 25.6。士 0·2ο处有特征峰。 In still another embodiment, the Compound I crystal form D, using Cu-Κα radiation, has an X-ray powder diffraction pattern at a Θ angle of 4.4° ± 0·2 ο , 8.3 ° ± 0·2 ο , 14.8°士 0.2°, 19·4 ο ±0·2 ο , 21·0 ο ±0·2 ο , 21·7 ο ±0·2 ο , 25.1. There is a characteristic peak at ± 0·2 ο . In a further embodiment, the Compound I Form D, using Cu-Κα radiation, has an X-ray powder diffraction pattern at a angle of 2 在 at 4.4° ± 0·2 ο , 8.3 ° ± 0·2 ο , 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 ο Disabled 0 · 2 ο, 25.1. Earth 0·2 ο , 25.6. There is a characteristic peak at 0. 2 ο .
在更进一步的实施方案中， 所述的化合物 I晶型 D具有基本如同图 7所示出的 X 线粉末衍射图谱。  In still further embodiments, the Form I of Compound I has an X-ray powder diffraction pattern substantially as shown in Figure 7.
本发明第二方面提供了本发明第一方面所述化合物 I多晶型物的制 备方法， 所述方法包括：  According to a second aspect of the present invention, there is provided a process for the preparation of a polymorph of the compound I according to the first aspect of the invention, the method comprising:
使 N-(4_(3-氟苄氧基) _3_氯苯基 )-6_(5-((2_ (曱基亚砜基）乙基氨基)曱 基) -2-呋喃基) -喹唑啉 -4-胺 (化合物 II)与对曱苯磺酸在溶剂中反应， 得到 化合物 I； N-( 4 _( 3 -fluorobenzyloxy) _ 3 _ chlorophenyl)- 6 _( 5 -(( 2 _(mercaptosulfonyl)ethylamino)indolyl)-2-furanyl - quinazolin-4-amine (compound II) and p-toluenesulfonic acid in a solvent to obtain a compound I;
Figure imgf000006_0001
将化合物 I在加热条件下溶于适当的溶剂体系， 降温析晶， 过滤， 晾干， 得化合物 I的晶型 C，
Figure imgf000006_0001
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.
或  Or
将化合物 I在适当的溶剂体系中打浆， 过滤， 晾干， 得化合物 I的 晶型 C，  Compound I is slurried in a suitable solvent system, filtered, and air-dried to give Form C of Compound I.
所述的溶剂体系包括： 四氢呋喃 /水、 1,4-二氧六环 /水、 乙二醇二曱 醚 /水， 所述的溶剂和水的配比 (体积)为 20:1 ~ 1:10， 优选 20:1~4:1； 将化合物 I在加热条件下溶于适当的溶剂体系， 降温析晶， 过滤， 晾干， 得化合物 I的晶型 D，  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.
或 将化合物 I在适当的溶剂体系中打浆， 过滤， 晾干， 得化合物 I的 曰曰曰型 D， Or The compound I is slurried in a suitable solvent system, filtered, and air-dried to obtain the hydrazone D of the compound I.
所述的溶剂体系包括： 乙醇 /水、 曱醇 /水、 异丙醇 /水、 N，N-二曱基 曱酰胺， 所述醇类 /水的配比 (体积)为 20:1 ~ 1:10， 优选 20:1 ~ 4:1；  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;
将化合物 I晶型 C在 60 ~ 150°C下烘干，得到化合物 I的晶型 A; 或 者  Drying Compound C Form C at 60 ~ 150 ° C to obtain Form A of Compound I; or
将化合物 I晶型 D在 60 ~ 150°C下烘干， 得到化合物 I的晶型 B。 上述该四 型物之间的关系如下所示:  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:
Figure imgf000007_0001
其中， 化合物 I晶型（：、 D在常温条件下晶型是稳定的， 在高温条 件下晶型是不稳定的； 化合物 I晶型 A、 B形成后在常温、 高温条件下 晶型均是稳定的。
Figure imgf000007_0001
Among them, 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.
在本发明第二方面的制备方法中， 其中所述的化合物 II是本领域技 术人员根据已有技术可以制备的， 在一个示例性的方法中， 化合物 II可 以参照文献 CN102030742A制备。  In the production method of the second aspect of the invention, wherein the compound II is prepared by a person skilled in the art according to the prior art, in an exemplary method, the compound II can be prepared by referring to the document CN102030742A.
本发明第三方面涉及一种药物组合物， 其包含本发明第一方面任 一项所述的化合物 I的多晶型物，以及任选的一种或多种药学可接受的 载体或赋形剂。  A third aspect of the invention relates to 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.
本发明第四方面涉及本发明第一方面任一项所述的化合物 I的多 晶型物在制备用于治疗和 /或预防哺乳动物（包括人)与受体酪氨趣 相关的疾病或病症的药物中的用途。 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.
本发明第四方面还涉及本发明第一方面任一项所述的化合物 I的 多晶型物在制备用于治疗或辅助治疗和 /或预防哺乳动物（包括人）由受 体酪氨酸激酶介导的肿瘤或由受体酪氨酸激酶驱动的肿瘤细胞的增殖和 迁移的药物中的用途。  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.
根据本发明， 完全可以预期本发明化合物 I的多晶型物可用于治疗 erbB受体酪氨酸激酶敏感癌症， 如 EGFR或 Her2高表达及 EGF驱动 的肿瘤， 包括实体肿瘤如胆管、 骨、 膀胱、 脑 /中枢神经系统、 乳房、 结 直肠、 子宫内膜、 胃、 头和颈、 肝、 肺 (尤其是非小细胞肺癌)、 神经元、 食道、 卵巢、 胰腺、 前列腺、 肾脏、 皮肤、 睾丸、 曱状腺、 子宫和外阴 等的癌症， 和非实体肿瘤如白血病、 多发性骨髓瘤或淋巴瘤等。 为此， 本发明上述"与受体酪氨酸激酶相关的疾病或病症 "以及"由受体酪氨酸 激酶介导的肿瘤"或"由受体酪氨酸激酶驱动的肿瘤细胞的增殖和迁移" 所涉及的肿瘤或癌症可以包括上述 erbB受体酪氨酸激酶敏感癌症， 如 EGFR或 Her2高表达及 EGF驱动的肿瘤， 包括实体肿瘤如胆管、 骨、 膀胱、 脑 /中枢神经系统、 乳房、 结直肠、 子宫内膜、 胃、 头和颈、 肝、 肺 (尤其是非小细胞肺癌)、 神经元、 食道、 卵巢、 胰腺、 前列腺、 肾脏、 皮肤、 睾丸、 曱状腺、 子宫和外阴等的癌症， 和非实体肿瘤如白血病、 多发性骨髓瘤或淋巴瘤等。  In accordance with the present invention, it is fully contemplated that 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. To this end, the above-mentioned "disease or condition associated with receptor tyrosine kinase" and "tumor mediated by receptor tyrosine kinase" or "proliferation of tumor cells driven by receptor tyrosine kinase" of the present invention Migration "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.
本发明第五方面涉及一种在有需要的哺乳动物中治疗和 /或预防 与受体酪氨酸激酶相关的疾病或病症的方法，该方法包括给有需要的哺 乳动物施用治疗有效量的本发明第一方面任一项所述的化合物 I的多 晶型物。  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.
本发明第五方面还涉及一种在有需要的哺乳动物中治疗或辅助治 疗和 /或预防哺乳动物（包括人）由受体酪氨酸激酶介导的肿瘤或由受体 酪氨酸激酶驱动的肿瘤细胞的增殖和迁移的方法，该方法包括给有需要 的哺乳动物施用治疗有效量的本发明第一方面任一项所述的化合物 I 的多晶型物。 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, the method 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.
本发明第五方面进一步涉及一种在有需要的哺乳动物中治疗和 / 或预防哺乳动物（包括人)的肿瘤或癌症的方法， 该方法包括给有需要 的哺乳动物施用治疗有效量的本发明第一方面任一项所述的化合物 I 的多晶型物， 所述的肿瘤或癌症包括 erbB受体酪氨酸激酶敏感癌症， 如 EGFR或 Her2高表达及 EGF驱动的肿瘤，包括实体肿瘤如胆管、骨、 膀胱、 脑 /中枢神经系统、 乳房、 结直肠、 子宫内膜、 胃、 头和颈、 肝、 肺 (尤其是非小细胞肺癌)、 神经元、 食道、 卵巢、 胰腺、 前列腺、 肾脏、 皮肤、 睾丸、 曱状腺、 子宫和外阴等的癌症， 和非实体肿瘤如白血病、 多发性骨髓瘤或淋巴瘤等。  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 A polymorph of Compound I according to any one of the preceding claims, wherein 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.
本发明第六方面涉及本发明第一方面任一项所述的化合物 I的多 晶型物，所述多晶型物用作治疗和 /或预防哺乳动物（包括人)与受体酪氨 酸激酶相关的疾病或病症的药物。  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.
本发明第六方面还涉及本发明第一方面任一项所述的化合物 I的 多晶型物， 所述多晶型物用作治疗或辅助治疗和 /或预防哺乳动物（包括 人）由受体酪氨酸激酶介导的肿瘤或由受体酪氨酸激酶驱动的肿瘤细胞 的增殖和迁移的药物。  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.
根据本发明， 完全可以预期本发明化合物 I的多晶型物可以用作药 物，所述药物可以治疗 erbB受体酪氨酸激酶敏感癌症，如 EGFR或 Her2 高表达及 EGF驱动的肿瘤， 包括实体肿瘤如胆管、 骨、 膀胱、 脑 /中枢 神经系统、 乳房、 结直肠、 子宫内膜、 胃、 头和颈、 肝、 肺 (尤其是非小 细胞肺癌)、 神经元、 食道、 卵巢、 胰腺、 前列腺、 賢脏、 皮肤、 睾丸、 曱状腺、 子宫和外阴等的癌症， 和非实体肿瘤如白血病、 多发性骨髓瘤 或淋巴瘤等。 为此， 本发明上述"与受体酪氨酸激酶相关的疾病或病症" 以及"由受体酪氨酸激酶介导的肿瘤，，或 "由受体酪氨酸激酶驱动的肿瘤 细胞的增殖和迁移，，所涉及的肿瘤或癌症可以包括上述 erbB受体酪氨酸 激酶敏感癌症， 如 EGFR或 Her2高表达及 EGF驱动的肿瘤， 包括实体 肿瘤如胆管、 骨、 膀胱、 脑 /中枢神经系统、 乳房、 结直肠、 子宫内膜、 胃、 头和颈、肝、肺 (尤其是非小细胞肺癌)、神经元、食道、 卵巢、胰腺、 前列腺、 肾脏、 皮肤、 睾丸、 曱状腺、 子宫和外阴等的癌症， 和非实体 肿瘤如白血病、 多发性骨髓瘤或淋巴瘤等。 下面对本发明作进一步的描述。 In accordance with the present invention, it is fully contemplated that 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. To this end, the above-mentioned "disease or condition associated with receptor tyrosine kinase" and "tumor mediated by receptor tyrosine kinase," or "proliferation of tumor cells driven by receptor tyrosine kinase" of the present invention And migration, 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 is further described below.
本发明所引述的所有文献， 它们的全部内容通过引用并入本文， 并且如果这些文献所表达的含义与本发明不一致时， 以本发明的表述 为准。 此外， 本发明使用的各种术语和短语具有本领域技术人员公知 的一般含义， 即便如此， 本发明仍然希望在此对这些术语和短语作更 详尽的说明和解释， 提及的术语和短语如有与公知含义不一致的， 以 本发明所表述的含义为准。  All documents cited in the present invention are hereby incorporated by reference in their entirety, and if the meanings expressed by these documents are inconsistent with the present invention, the expression of the present invention shall prevail. Moreover, the various terms and phrases used in the present invention have the ordinary meanings well known to those skilled in the art, and even though the present invention is intended to provide a more detailed description and explanation of the terms and phrases herein, such terms and phrases are Inconsistent with the well-known meaning, the meaning expressed in the present invention shall prevail.
本发明的化合物 I的多晶型物以 2Θ角度表示的 X-射线粉末衍射 特征峰， 其中" ±0.2。，，为允许的测量误差范围。  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.
本发明的化合物 I的多晶型物可以与其它活性成分组合使用， 只要 它不产生其他不利作用， 例如过敏反应。  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.
本发明化合物 I的多晶型物所示的活性化合物可作为唯一的抗癌药 物使用， 或者可以与一种或多种其他抗肿瘤药物联合使用。 联合治疗通 过将各个治疗组分同时、 顺序或隔开给药来实现。  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.
本文所用的术语"组合物 "意指包括包含指定量的各指定成分的产 品， 以及直接或间接从指定量的各指定成分的组合产生的任何产品。  The term "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.
可改变本发明药物组合物中各活性成分的实际剂量水平， 以便所 得的活性化合物量能有效针对具体患者、 组合物和给药方式得到所需 的治疗反应。 剂量水平须根据具体化合物的活性、 给药途径、 所治疗 病况的严重程度以及待治疗患者的病况和既往病史来选定。 但是， 本 领域的做法是， 化合物的剂量从低于为得到所需治疗效果而要求的水 平开始， 逐渐增加剂量， 直到得到所需的效果。 当用于上述治疗和 /或预防或其他治疗和 /或预防时， 治疗和 /或预 防有效量的一种本发明化合物 I的多晶型物可以以纯形式应用， 或者 以药学可接受的酯或前药形式 (在存在这些形式的情况下)应用。 或者， 所述化合物可以以含有该目的化合物与一种或多种药物可接受赋形剂 的药物组合物给药。 词语"治疗和 /或预防有效量 "的本发明化合物 I的 多晶型物指以适用于任何医学治疗和 /或预防的合理效果 /风险比治疗 障碍的足够量的化合物。 但应认识到， 本发明化合物 I的多晶型物和 组合物的总日用量须由主诊医师在可靠的医学判断范围内作出决定。 对于任何具体的患者，具体的治疗有效剂量水平须根据多种因素而定， 所述因素包括所治疗的障碍和该障碍的严重程度； 所采用的具体化合 物的活性； 所采用的具体组合物； 患者的年龄、 体重、 一般健康状况、 性别和饮食； 所采用的具体化合物的给药时间、 给药途径和排泄率； 治疗持续时间； 与所采用的具体化合物组合使用或同时使用的药物； 及医疗领域公知的类似因素。 例如， 本领域的做法是， 化合物的剂量 从低于为得到所需治疗效果而要求的水平开始， 逐渐增加剂量， 直到 得到所需的效果。 一般说来， 本发明化合物 I的多晶型物用于哺乳动 物特别是人的剂量可以介于 0.001 ~ 1000 mg/k 体重 /天， 例如介于 0.01 ~ 100 mg/k 体重 /天， 例如介于 0.01 ~ 10 mg/k 体重 /天。 The actual dosage level of 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. When used in the above treatment and/or prophylaxis or other treatment and/or prophylaxis, 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. Alternatively, the compound can be administered in a pharmaceutical composition comprising the compound of interest and one or more pharmaceutically acceptable excipients. The phrase "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. It will be appreciated, however, that 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. For example, 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. In general, 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.
运用本领域技术人员熟悉的药物载体可以制备成含有效剂量的本发 明化合物 I的多晶型物的药物组合物。因此本发明还提供包含与一种或 多种无毒药物可接受载体配制在一起的本发明化合物 I的多晶型物的 药物组合物。 所述药物组合物可特别专门配制成以固体或液体形式供 口服给药、 供胃肠外注射或供直肠给药。  Pharmaceutical 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.
所述的药物组合物可配制成许多剂型，便于给药，例如，口服制剂 (如 片剂、胶嚢剂、溶液或混悬液)；可注射的制剂（如可注射的溶液或混悬液， 或者是可注射的干燥粉末， 在注射前加入注射水可立即使用）。 所述的药 物组合物中载体包括： 口服制剂使用的粘合剂 (如淀粉， 通常是玉米、 小 麦或米淀粉、明胶、曱基纤维素、羧曱基纤维素钠和 /或聚乙烯吡咯烷酮)， 稀释剂 (如乳糖、 右旋糖、 蔗糖、 甘露醇、 山梨醇、 纤维素， 和 /或甘油)， 润滑剂 (如二氧化硅、滑石、硬脂酸或其盐，通常是硬脂酸镁或硬脂酸钙， 和 /或聚乙二醇)， 以及如果需要， 还含有崩解剂， 如淀粉、 琼脂、 海藻酸 或其盐， 通常是海藻酸钠， 和 /或泡腾混合物， 助溶剂、稳定剂、 悬浮剂、 色素、 矫味剂等， 可注射的制剂使用的防腐剂、 溶剂、 稳定剂等； 局部 制剂用的基盾、 稀释剂、 润滑剂、 防腐剂等。 药物制剂可以经口服或胃 肠外方式 (例如静脉内、皮下、 J^ 内或局部)给药， 如果某些药物在胃部 条件下是不稳定的， 可以将其配制成肠衣片剂。 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. 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, preservatives, etc. for topical preparations. The pharmaceutical preparations can be administered orally or parenterally (e.g., intravenously, subcutaneously, internally or topically), and if certain drugs are unstable under gastric conditions, they can be formulated into enteric coated tablets.
更具体地说， 本发明的药物组合物可通过口服、 直肠、 胃肠外、 池内、 阴道内、 腹膜内、 局部 (如通过散剂、 软膏剂或滴剂）、 口颊给 予人类和其他哺乳动物， 或者作为口腔喷雾剂或鼻腔喷雾剂给予。 本 文所用术语"胃肠外 "指包括静脉内、 肌肉内、 腹膜内、 胸骨内、 皮下 和关节内注射和输液的给药方式。  More specifically, the pharmaceutical 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. The term "parenteral" as used herein, refers to administrations which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injections and infusions.
适合于胃肠外注射的组合物可包括生理上可接受的无菌含水或非 水溶液剂、 分散剂、 混悬剂或乳剂， 及供重构成无菌可注射溶液剂或 分散剂的无菌散剂。 合适的含水或非水载体、 稀释剂、 溶剂或媒介物 的实例包括水、 乙醇、 多元醇 (丙二醇、聚乙二醇、甘油等)、植物油 (如 橄榄油）、 可注射有机酯如油酸乙酯及它们的合适混合物。  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. . Examples of 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.
这些组合物也可含有辅料， 如防腐剂、 湿润剂、 乳化剂和分散剂。 通过各种抗细菌剂和抗真菌剂， 例如尼泊金酯类、 三氯叔丁醇、 苯酚、 山梨酸等， 可确保防止微生物的作用。 还期望包括等渗剂， 例如糖类、 氯化钠等。 通过使用能延迟吸收的物质， 例如单硬脂酸铝和明胶， 可 达到可注射药物形式的延长吸收。  These compositions may also contain 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.
混悬剂中除活性化合物外还可含有悬浮剂， 例如乙氧基化异十八 醇、 聚氧乙烯山梨醇和聚氧乙烯失水山梨糖醇酯、 微晶纤维素、 偏氢 氧化铝、 膨润土、 琼脂和黄蓍胶或者这些物质的混合物等。 在一些情况下， 为延长药物的作用， 期望减慢皮下或肌内注射药 物的吸收。 这可通过使用水溶性差的晶体或无定形物质的液体混悬剂 来实现。 这样， 药物的吸收速度取决于其溶解速度， 而溶解速度又可 取决于晶体大小和晶型。 或者， 胃肠外给药的药物形式的延迟吸收通 过将该药物溶解于或悬浮于油媒介物中来实现。 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. In some cases, in order to prolong the action of the drug, it is desirable to slow the absorption of the drug by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of poorly water-soluble crystals or amorphous materials. Thus, the rate of absorption of the drug depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
可注射贮库制剂形式可通过在生物可降解聚合物如聚丙交酯-聚 乙交酯 (poly lactide-polygly colide)中形成药物的微胶嚢基质来制备。可 根据药物与聚合物之比和所采用的具体聚合物的性质， 对药物释放速 度加以控制。 其他生物可降解聚合物的实例包括聚原酸酯类 (poly(orthoesters))和聚酐类（poly(anhydrides))。 可注射贮库制剂也可 通过将药物包埋于能与身体组织相容的脂质体或微乳中来制备。  The injectable depot form can be prepared by forming a microcapsule matrix of the drug in 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.
可注射制剂可例如通过用滤菌器过滤或通过掺入无菌固体组合物 形式的灭菌剂来灭菌， 所述固体组合物可在临用前溶解或分散于无菌 水或其他无菌可注射介质。  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.
本发明化合物 I的多晶型物或其组合物可用口服方法或非胃肠道给 药方式。 口服给药可以是片剂、 胶嚢剂、 包衣剂， 肠道外用药制剂有注 射剂和栓剂等。这些制剂是按照本领域的技术人员所熟悉的方法制备的。 为了制造片剂、 胶嚢剂、 包衣剂所用的辅料是常规用的辅料， 例如淀粉、 明胶、 阿拉伯胶， 硅石， 聚乙二醇， 液体剂型所用的溶剂如水、 乙醇、 丙二醇、 植物油 (如玉米油、 花生油、 橄榄油等)。 含有本发明化合物 I 的多晶型物的制剂中还有其它辅料， 例如表面活性剂， 润滑剂， 崩解剂， 防腐剂， 矫味剂和色素等。 在片剂、 胶嚢剂、 包衣剂、 注射剂和栓剂中 含有本发明化合物 I的多晶型物的剂量是以单元剂型中存在的化合物量 计算的。 在单元剂型中本发明化合物 I 的多晶型物的一般含量为 1 ~ 5000mg,优选的单元剂型含有 10 ~ 500mg,更优选的单元剂型含有 20 ~ 300mgo 具体地说， 本发明可以提供的供口服给药的固体剂型包括胶嚢 剂、 片剂、 丸剂、 散剂和颗粒剂。 在此类固体剂型中， 活性化合物可 与至少一种惰性的药物可接受赋形剂或载体如柠檬酸钠或磷酸二钙和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.). There are other adjuvants in the formulation containing the polymorph of the compound I of the present invention, such as surfactants, lubricants, disintegrants, preservatives, flavoring agents and pigments. 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. Usually 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, more preferably the unit dosage form contains 20 ~ 300mg o In particular, the present invention can provide for Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound can be And at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and
/或以下物质混合： a)填充剂或增量剂如淀粉、 乳糖、 蔗糖、 葡萄糖、 甘露糖醇和硅酸； b)粘合剂如羧甲基纤维素、 海藻酸盐、 明胶、 聚乙 烯吡咯烷酮、 蔗糖和阿拉伯树胶； c)保湿剂如甘油； d)崩解剂如琼脂、 碳酸钙、 马铃薯或木薯淀粉、 海藻酸、 某些硅酸盐和碳酸钠； e)溶液 阻滞剂如石蜡； f)吸收加速剂如季铵化合物； g)湿润剂如鯨蜡醇和甘油 单硬脂酸酯； h)吸附剂如高岭土和膨润土以及 i)润滑剂如滑石粉、 硬 脂酸钙、硬脂酸镁、 固体聚乙二醇、 十二烷基¾酸钠和它们的混合物。 在胶嚢剂、 片剂和丸剂的情况下， 所述剂型中也可包含緩冲剂。 / or a mixture of: 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. In the case of capsules, tablets and pills, buffers may also be included in the dosage form.
相似类型的固体组合物使用赋形剂例如乳糖及高分子量聚乙二醇 等， 也可用作软胶嚢和硬胶嚢中的填充物。  Solid 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.
片剂、 糖衣丸剂（dragees)、 胶嚢剂、 丸剂和颗粒剂的固体剂型可 与包衣和壳料如肠溶衣材和医药制剂领域公知的其他衣材一起制备。 这些固体剂型可任选含有遮光剂， 且其组成还可使其只是或优先地在 肠道的某个部位任选以延迟方式释放活性成分。 可以使用的包埋组合 物的实例包括高分子物质和蜡类。 如果适合， 活性化合物也可与一种 或多种上述赋形剂配成微嚢形式。  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.
供口服给药的液体剂型包括药学可接受的乳剂、溶液剂、混悬剂、 糖浆剂和酏剂。 液体剂型除含有活性化合物外还可含有本领域常用的 惰性稀释剂， 例如水或其他溶剂， 增溶剂和乳化剂例如乙醇、 异丙醇、 碳酸乙酯、 乙酸乙酯、 苄醇、 苯曱酸苄酯、 丙二醇、 1,3-丁二醇、 二 曱基曱酰胺、 油类 (特别是棉籽油、花生油、 玉米油、胚茅油、橄榄油、 蓖麻油和芝麻油）、 甘油、 四氢糠醇 (tetrahydrofurfuryl alcohol)、 聚乙 二醇和脱水山梨糖醇的脂肪酸酯及它们的混合物。 口服组合物除包含 惰性稀释剂外还可包含辅料， 例如湿润剂、 乳化剂和悬浮剂、甜味剂、 矫味剂和香味剂。  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.
供直肠或阴道给药的组合物优选是栓剂。 栓剂可通过将本发明化 合物 I的多晶型物与合适的非刺激性赋形剂或载体例如可可脂、 聚乙 二醇或栓剂蜡混合来制备， 它们在室温下为固体， 但在体温下则为液 体， 因此可在直肠腔或阴道腔内熔化而释放出活性化合物。 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.
本发明的化合物 I的多晶型物及其组合物还考虑用于局部给药。 供局部给予本发明化合物 I的多晶型物的剂量形式包括散剂、喷雾剂、 软膏剂和吸入剂。 在无菌条件下将活性化合物与药学可接受的载体和 任何所需的防腐剂、 緩冲剂或推进剂混合。 眼用制剂、 眼软膏剂、 散 剂和溶液剂也被考虑在本发明范围内。  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.
本发明化合物 I的多晶型物也可以脂质体形式给药。 如本领域所 公知， 脂质体通常用磷脂或其他脂类物质制得。 脂质体由分散于含水 介质中的单层或多层水化液晶所形成。 任何能够形成脂质体的无毒、 生理上可接受和可代谢的脂质均可使用。 脂质体形式的本发明组合物 除含有本发明化合物外， 还可含有稳定剂、 防腐剂、 赋形剂等。 优选 的脂类是天然和合成的磷脂和磷脂酰胆碱 (卵磷脂）， 它们可单独或者 一起使用。形成脂质体的方法是本领域公知的。参见例如 Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p33。  The polymorph of Compound I of the present invention may also be administered in the form of a liposome. As is known in the art, 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.
本发明人惊奇地发现， 化合物 I的多晶型物对 EGFR和 Her2酪氨 酸激酶都显示了抑制活性， 同时， 对 EGFR和 Her2酪氨酸激酶高表达 的细胞株有抑制作用， 因此， 本发明化合物 I的多晶型物可用于 EGFR 和 Her2受体酪氨酸激酶单独或部分介导的疾病，主要通过抑制一种或多 种 EGFR家族酪氨酸激酶，并通过抑制激酶的活性产生抗增殖、抗迁移、 促凋亡作用。 具体地说， 本发明化合物 I的多晶型物可通过对 EGFR和 Her2酪氨酸激酶的抑制作用， 用于预防和治疗一种或多种 erbB受体酪 氨酸激酶敏感的肿瘤，尤其是 EGFR或 Her2高表达及 EGF驱动的肿瘤。 包括实体肿瘤如胆管、 骨、 膀胱、 脑 /中枢神经系统、 乳房、 结直肠、 子 宫内膜、 胃、 头和颈、 肝、 肺 (尤其是非小细胞肺癌)、 神经元、 食道、 卵 巢、 胰腺、 前列腺、 肾脏、 皮肤、 睾丸、 曱状腺、 子宫和外阴的癌症， 非实体肿瘤如白血病、 多发性骨髓瘤或淋巴瘤。 附图说明： 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. In particular, 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. Includes 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. BRIEF DESCRIPTION OF THE DRAWINGS:
图 1 化合物 I无定形物的 X-射线粉末衍射图谱。  Figure 1 X-ray powder diffraction pattern of Compound I amorphous.
图 1 化合物 I晶型 A的 X-射线粉末衍射图谱。  Figure 1 X-ray powder diffraction pattern of Compound I Form A.
图 3 化合物 I晶型 A的差示扫描量热图谱。  Figure 3. Differential scanning calorimetry of Compound I Form A.
图 4 化合物 I晶型 B的 X-射线粉末衍射图谱。  Figure 4 X-ray powder diffraction pattern of Compound I Form B.
图 5 化合物 I晶型 B的差示扫描量热图谱。  Figure 5. Differential scanning calorimetry of Compound B Form B.
图 6 化合物 I晶型 C的 X-射线粉末衍射图谱。  Figure 6. X-ray powder diffraction pattern of Compound I Form C.
图 7 化合物 I晶型 D的 X-射线粉末衍射图谱。 具体实施方式：  Figure 7 X-ray powder diffraction pattern of Compound I Form D. detailed description:
下面通过具体的制备实施例和生物学试验例进一步说明本发明， 但是， 应当理解为， 这些实施例和试验例仅仅是用于更详细具体地说 明之用， 而不应理解为用于以任何形式限制本发明。  The invention is further illustrated by the following specific examples of preparation and biological examples, but it should be understood that these examples and test examples are only used in more detail and are not to be construed as Forms restrict the invention.
本发明对试验中所使用到的材料以及试验方法进行一般性和 /或 具体的描述。 虽然为实现本发明目的所使用的许多材料和操作方法是 本领域公知的， 但是本发明仍然在此作尽可能详细描述。 本领域技术 人员清楚， 在下文中， 如果未特别说明， 本发明所用材料和操作方法 是本领域公知的。  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.
本发明所用的检测仪器：  Detection instrument used in the present invention:
(1)核磁共振语  (1) Nuclear magnetic resonance
仪器型号： Varian INOVA-400核磁共振仪。  Instrument model: Varian INOVA-400 nuclear magnetic resonance instrument.
测试条件： 溶剂 DMSO-d6。 Test conditions: Solvent DMSO-d 6 .
(2)高分辨质谱  (2) High resolution mass spectrometry
仪器型号： Q-Tof micro质语仪。 测试条件： ESI。 Instrument model: Q-Tof micro grammar instrument. Test conditions: ESI.
(3) X-射线粉末衍射仪  (3) X-ray powder diffractometer
辐射源： Cu靶 Κα辐射。  Radiation source: Cu target Κα radiation.
样品处理： 样品研细后， 置于标准样品架中测定。  Sample Handling: After the sample has been finely ground, it is placed in a standard sample holder for measurement.
(4)差示扫描量热分析  (4) Differential scanning calorimetry
仪器型号： NETZSCH热分析仪。  Instrument model: NETZSCH thermal analyzer.
测试条件： 50 °C 10°C/min。 按照 CN102030742A中描述的方法可以制备化合物 II， 如实施例 1 所示。  Test conditions: 50 ° C 10 ° C / min. Compound II can be prepared according to the method described in CN102030742A, as shown in Example 1.
实施例 1: N-(4-(3-氟苄 氯苯基 )-6-(5-((2- (甲基亚 乙基氨 基)甲基) -2-呋喃基) -喹唑啉 -4-胺 (化合物 II)的制备：  Example 1: N-(4-(3-fluorobenzylchlorophenyl)-6-(5-((2-(methylethylideneamino)methyl)-2-furanyl)-quinazoline- Preparation of 4-amine (Compound II):
a. Boc保护的 2-巯基乙胺的制备：  a. Preparation of Boc protected 2-mercaptoethylamine:
二乙胺  Diethylamine
uQ/^ N H2- HCI ^二 ^ HS^^NHBocu Q /^ NH 2- HCI ^二^ HS ^^NHBoc
HS 二碳酸二叔丁酯 HS di-tert-butyl dicarbonate
在反应瓶中加入二碳酸二叔丁酯 35.3g、 2-巯基乙胺盐酸盐 20.4g和 200ml二氯曱烷， 并在冰浴条件下分批加入三乙胺 25ml， 室温搅拌反应 过夜， 加入过量 0.5M的盐酸溶液洗涤， 有机层用饱和氯化钠溶液洗涤， 无水 υ酸钠干燥， 蒸干溶剂得 Boc保护的 2-巯基乙胺 8g (油状液体)， 产 率 87%。  35.3 g of di-tert-butyl dicarbonate, 20.4 g of 2-mercaptoethylamine hydrochloride and 200 ml of dichloromethane were added to the reaction flask, and 25 ml of triethylamine was added in portions under ice-cooling, and the reaction was stirred at room temperature overnight. After washing with an excess of 0.5 M hydrochloric acid solution, the organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness.
b. Boc保护的 2-甲硫基乙胺的制备：  b. Preparation of Boc protected 2-methylthioethylamine:
HS/^NHBoc NaH>. \s/^NHBoc HS /^NHBoc NaH >. \ s /^NHBoc
CH3I CH 3 I
冰浴、氮气保护条件下，将 NaH 4.8g分批加入 Boc保护的 2-巯基乙 胺 28g的无水四氢呋喃 (250ml)溶液中， 升至室温反应 lh， 冰浴条件下滴 加 12ml碘曱烷的四氢呋喃溶液， 滴毕后室温反应约 lh， 加入饱和碳酸 钠溶液淬灭反应， 将反应液倾入水中， 乙酸乙酯萃取， 有机相用饱和氯 化钠溶液洗涤，无水硫酸钠干燥，蒸干溶剂得油状液体。柱层析得到 Boc 保护的 2-曱¾基乙胺 14.2g， 产率 47%。 Under ice-cooling and nitrogen protection, 4.8 g of NaH was added in portions to a solution of Boc-protected 2-mercaptoethylamine in 28 g of anhydrous tetrahydrofuran (250 ml), and the mixture was warmed to room temperature for 1 hour, and 12 ml of iodonane was added dropwise under ice bath. The tetrahydrofuran solution is reacted at room temperature for about 1 hour after the dropwise addition. The reaction is quenched by adding saturated sodium carbonate solution, and the reaction solution is poured into water, extracted with ethyl acetate, and the organic phase is saturated with chlorine. The sodium solution was washed, dried over anhydrous sodium sulfate, and evaporated to dryness. Column chromatography gave 14.2 g of Boc-protected 2-indole-ethylamine, yield 47%.
c Boc保护的 2-甲亚砜基乙胺的制备：  Preparation of c-Boc protected 2-methylsulfoxide ethylamine:
\〜 闘 oc ^ 高碘酸钠 ， 、〜 闘 oc S 0  \~ 闘 oc ^ sodium periodate, ~ 闘 oc S 0
冰浴条件下， 将 Boc保护的 2-曱¾基乙胺 14.0g溶于曱醇中， 滴加 高碘酸钠的水溶液， 加毕后室温搅拌反应过夜， 过滤， 二氯曱烷洗涤滤 饼， 减压蒸除滤液中的有机溶剂， 加入饱和氯化钠溶液， 乙酸乙酯萃取， 无水硫酸镁干燥， 过滤减压蒸除溶剂得 Boc保护的 2-甲亚砜基乙胺 13.2g (油状物）， 产率 87%。  Under ice-cooling conditions, 14.0 g of Boc-protected 2-indole-ethylamine was dissolved in decyl alcohol, and an aqueous solution of sodium periodate was added dropwise. After the addition, the reaction was stirred at room temperature overnight, filtered, and the filter cake was washed with dichloromethane. The organic solvent in the filtrate was evaporated under reduced pressure, and a saturated aqueous sodium chloride solution was added, and ethyl acetate was evaporated. Oil), yield 87%.
d. Boc保护的 2-甲亚 乙胺盐酸盐的制备：  d. Preparation of Boc-protected 2-methylethylamine hydrochloride:
O O
I I I I
S v HCI N H3 ¾' S v HCI NH 3 3⁄4'
O  O
将 Boc保护的 2-曱亚砜基乙胺 12g溶于无水乙醚中，通入盐酸气体， TLC检测原料反应完毕，减压蒸除溶剂得 Boc保护的 2-曱亚砜基乙胺盐 酸盐 6.8g (油状物）， 产率 82%。  12 g of Boc-protected 2-indolylsulfonylethylamine was dissolved in anhydrous diethyl ether, and hydrochloric acid gas was passed through. The reaction of the starting material was determined by TLC, and the solvent was evaporated under reduced pressure to give Boc-protected 2-indolesulfonylethylamine hydrochloride. Salt 6.8 g (oil), yield 82%.
e. N-(4-(3-氟苄氣基) -3-氯苯基 )-6-(5-((2- (甲基亚砜基）乙基氨基）甲 基) -2-呋喃基) -喹唑啉 -4-胺的制备：  e. N-(4-(3-Fluorobenzyl)-3-chlorophenyl)-6-(5-((2-(methylsulfoxide)ethylamino)methyl)-2-furan Preparation of - quinazoline-4-amine:
Figure imgf000018_0001
将化合物 5-(4-(4-(3-氟苄 氯苯胺基) -6-喹唑啉基)呋喃 -2-曱酪 对曱苯磺酸盐 12 溶于二氯曱烷 /甲醇 (3:1)的混合溶液中， 加入 12ml三 乙胺搅拌反应 10min， 加入 2-曱亚砜乙胺盐酸盐 6.0g， 室温搅拌反应， TLC检测原料反应完毕，冰浴下分批加入硼氢化钠 2.0g， TLC检测反应 完毕， 加入适量二氯甲烷， 饱和氯化铵溶液洗涤， 饱和氯化钠溶液洗涤， 无水硫酸钠干燥， 柱层析得黄色固体 7.3g， 即为 N-(4-(3-氟苄氧基) -3-氯 苯基) -6-(5-((2- (曱基亚砜基)乙基氨基)曱基) -2-呋喃基) -喹唑啉 -4-胺 (化合 物 11)， 产率 69%。
Figure imgf000018_0001
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. After the reaction was completed by TLC, the mixture was washed with saturated ammonium chloride solution, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then purified by column chromatography to give 7.3 g of a yellow solid, which is N-(4- (3-fluorobenzyloxy)-3-chlorophenyl)-6-(5-((2-(indolylsulfonyl)ethylamino)indolyl)-2-furanyl)-quinazoline- 4-amine (Compound 11), yield 69%.
^ NMR (600MHz, DMSO-d6, δρριη): 9.92 (s, IH), 9.044 (s, IH), 8.92 (s, 1H)， 8.41 (t, 1Η, /= 6.6 Hz), 7.93 (d， 1Η, /= 7.8 Hz), 7.64 (dd， 1H， J = 2.4 Hz, / = 9 Hz), 7.50 (d， 1H， J = 7.8 Hz), 7.48 (d， 1H， J = 9.6 Hz), 7.36 (d， 1H， / = 9 Hz), 7.25 (d， 1Η, /= 3.0 Hz), 7.22 (dd， 1H， /= 2.4 Hz, J = 9 Hz), 7.11 (d， IH, J= 7.2 Hz), 7.25 (d， 1Η, /= 3.0 Hz), 5.32 (s, 2H), 4.47 (s, 2H), 3.51 (t, 2H, /= 7.2 Hz), 2.67 (t, 2H, J= 7.2 Hz), 2.29 (s, 3H)。 ^ NMR (600MHz, DMSO-d 6 , δρριη): 9.92 (s, IH), 9.044 (s, IH), 8.92 (s, 1H), 8.41 (t, 1Η, /= 6.6 Hz), 7.93 (d, 1Η, /= 7.8 Hz), 7.64 (dd, 1H, J = 2.4 Hz, / = 9 Hz), 7.50 (d, 1H, J = 7.8 Hz), 7.48 (d, 1H, J = 9.6 Hz), 7.36 (d, 1H, / = 9 Hz), 7.25 (d, 1Η, /= 3.0 Hz), 7.22 (dd, 1H, /= 2.4 Hz, J = 9 Hz), 7.11 (d, IH, J= 7.2 Hz) ), 7.25 (d, 1Η, /= 3.0 Hz), 5.32 (s, 2H), 4.47 (s, 2H), 3.51 (t, 2H, /= 7.2 Hz), 2.67 (t, 2H, J= 7.2 Hz) ), 2.29 (s, 3H).
MS (m/z): [M-H] 563.1389。 实施例 2: N-(4-(3-氟苄 氯苯基 )-6-(5-((2- (甲基亚 乙基氨 基)甲基) -2-呋喃基) -喹唑啉 -4-胺二甲苯磺酸盐 (化合物 I)的制备  MS (m/z): [M-H] 563.1389. Example 2: N-(4-(3-fluorobenzylchlorophenyl)-6-(5-((2-(methylethylideneamino)methyl)-2-furanyl)-quinazoline- Preparation of 4-amine xylene sulfonate (Compound I)
参照 CN102030742A 的制备方法， 将化合物 II 2g(3.54mmol)加入 10ml四氢呋喃中，搅拌溶解，加入对曱苯磺酸 1.83g(10.6mmol)的乙醇溶 液， 迅速析出黄色固体， 抽滤， 晾干， 得 3.01g N-(4-(3-氟苄氧基) -3-氯苯 基) -6-(5-((2-(甲基亚砜基）乙基氨基)曱基) -2-呋喃基) -喹唑啉 -4-胺二曱苯 磺酸盐 (黄色固体)， 收率 93.5%。  Referring to the preparation method of CN102030742A, 2 g of compound II (3.54 mmol) was added to 10 ml of tetrahydrofuran, stirred and dissolved, and 1.83 g (10.6 mmol) of p-toluenesulfonic acid was added to a solution of ethanol, and a yellow solid was quickly precipitated, suction-filtered, and dried to obtain 3.01g N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-(5-((2-(methylsulfoxide)ethylamino)indolyl)-2-furan - quinazoline-4-amine diterpene benzene sulfonate (yellow solid), yield 93.5%.
X-射线粉末衍射表明该产物为无定形物， XRPD图谱见图 1所示。  X-ray powder diffraction indicated that the product was amorphous and the XRPD pattern is shown in Figure 1.
MS (m/z): [M-H] 907.1713。  MS (m/z): [M-H] 907.1713.
核磁共振谱： 、 COSY谱 (600MHz, DMSO-d6) Nuclear Magnetic Resonance Spectroscopy: , COSY Spectrum (600MHz, DMSO-d 6 )
测试结果：
Figure imgf000020_0001
Test Results:
Figure imgf000020_0001
c d  c d
表 1核磁共振 ¾、 COSY谱数据列表 序号 6H(ppm) 质子数 多重性 (J/Hz) COSY a 2.27 6 s 1Table 1 Nuclear Magnetic Resonance 3⁄4, COSY Spectrum Data List No. 6 H (ppm) Proton Number Multiplicity (J/Hz) COSY a 2.27 6 s 1
1 2.63 3 s 11 2.63 3 s 1
2 3.08 3.26 2 m 12 3.08 3.26 2 m 1
3 3.50 2 m 13 3.50 2 m 1
4 4.48 2 s 14 4.48 2 s 1
23 5.30 2 s 123 5.30 2 s 1
8 6.87 1 d 4.0 H-7 c c， 7.10 4 AA'BB' H-d H-d'8 6.87 1 d 4.0 H-7 c c, 7.10 4 AA'BB' H-d H-d'
27 7.18 1 dt 127 7.18 1 dt 1
7 7.26 1 d 4.0 H-87 7.26 1 d 4.0 H-8
21 7.31 1 d 8.8 121 7.31 1 d 8.8 1
25 7.30-7.35 1 1 125 7.30-7.35 1 1 1
29 7.30-7.35 1 1 129 7.30-7.35 1 1 1
28 7.47 1 dt 1 d d' 7.51 AA'BB' H-c H-c'28 7.47 1 dt 1 d d' 7.51 AA'BB' H-c H-c'
22 7.62 1 dd 8.8 2.8 122 7.62 1 dd 8.8 2.8 1
18 7.84 1 d 2.8 118 7.84 1 d 2.8 1
11 7.93 1 d 8.8 H-1011 7.93 1 d 8.8 H-10
10 8.44 1 dd 8.8 1.2 H-1110 8.44 1 dd 8.8 1.2 H-11
13 8.91 1 s 113 8.91 1 s 1
16 9.06 1 d 1.2 116 9.06 1 d 1.2 1
NH 9.3 11.4 2 br 1 实施例 3: N-(4-(3-氟苄 t^)-3-氯苯基 )-6-(5-((2- (甲基亚 乙基氨 基)甲基) -2-呋喃基) -喹唑啉 -4-胺二甲苯磺酸盐 (化合物 I)晶型 C的制备 将化合物 I 2g加入 40ml四氢呋喃和 5ml水的混合体系中， 回流溶 解， 降温析晶， 抽滤， 晾干， 得 1.6g黄色结晶性粉末， 收率 80%。 将得 到的产物进行 X-射线粉末衍射， 结果表明该产物为化合物 I晶型 C， XRPD图谱见图 6所示。 实施例 4: N-(4-(3-氟苄 ¾^)-3-氯苯基 )-6-(5-((2- (甲基亚 乙基氨 基)甲基) -2-呋喃基) -喹唑啉 -4-胺二甲苯磺酸盐 (化合物 I)晶型 A的制备 将化合物 I晶型€28在80" 条件下烘干 1小时，得黄色结晶性粉末， 将得到的产物进行 X-射线粉末衍射，结果表明该产物为化合物 I晶型 A, XRPD图谱见图 2所示； DSC检测数据显示晶型 A在 240.82 ~ 255.59°C 熔融分解， 差示扫描量热 (DSC)图语见图 3所示。 实施例 5: N-(4-(3-氟苄 L¾^)-3-氯苯基 )-6-(5-((2- (甲基亚 乙基氨 基)甲基) -2-呋喃基) -喹唑啉 -4-胺二甲苯磺酸盐 (化合物 I)晶型 D的制备 将化合物 I 2g加入 40ml乙醇和 6ml水的混合体系中， 回流溶解， 降温析晶， 抽滤， 晾干， 得 1.7g黄色结晶性粉末， 收率 85%， 将得到的 产物进行 X-射线粉末衍射， 结果表明该产物为化合物 I晶型 D， XRPD 图谱见图 7所示。 实施例 6: N-(4-(3-氟苄 氯苯基 )-6-(5-((2- (甲基亚 乙基氨 基)甲基) -2-呋喃基) -喹唑啉 -4-胺二甲苯磺酸盐 (化合物 I)晶型 B的制备 将化合物 I晶型 028在80" 条件下烘干 1小时，得黄色结晶性粉末， 将得到的产物进行 X-射线粉末衍射，结果表明该产物为化合物 I晶型 B， XRPD图谱见图 4所示； DSC检测数据显示晶型 B在 239.11 ~ 254.49°C 熔融分解； DSC图谱见图 5所示。 实施例 7: N-(4-(3-氟苄 ¾^)-3-氯苯基 )-6-(5-((2- (甲基亚 乙基氨 基)甲基) -2-呋喃基) -喹唑啉 -4-胺二甲苯磺酸盐 (化合物 I)晶型 A的制备 将化合物 I晶型 C 28在 60°C条件下烘干 2小时，得黄色结晶性粉末， 将得到的产物进行 X-射线粉末衍射，结果表明该产物为化合物 I晶型 A。 实施例 8: N-(4-(3-氟苄 ¾^)-3-氯苯基 )-6-(5-((2- (甲基亚 乙基氨 基)甲基) -2-呋喃基) -喹唑啉 -4-胺二甲苯磺酸盐 (化合物 I)晶型 A的制备 将化合物 I晶型 C 2g在 150°C条件下烘干 1小时， 得黄色结晶性粉 末， 将得到的产物进行 X-射线粉末衍射， 结果表明该产物为化合物 I晶 型 A。 实施例 9: N-(4-(3-氟苄 ¾^)-3-氯苯基 )-6-(5-((2- (甲基亚 乙基氨 基)甲基) -2-呋喃基) -喹唑啉 -4-胺二甲苯磺酸盐 (化合物 I)晶型 B的制备 将化合物 I晶型 028在 60°C条件下烘干 2小时,得黄色结晶性粉末， 将得到的产物进行 X-射线粉末衍射，结果表明该产物为化合物 I晶型 B。 实施例 10: N-(4-(3-氟苄 ^ 3-氯苯基 )-6-(5-((2- (甲基亚 乙基 甲基) -2-呋喃基) -喹唑啉 -4-胺二甲苯磺酸盐 (化合物 I)晶型 B的制备 将化合物 I晶型 D 2g在 150°C条件下烘干 1小时， 得黄色结晶性粉 末， 将得到的产物进行 X-射线粉末衍射， 结果表明该产物为化合物 I晶 型 B。 实施例 11: N-(4-(3-氟苄 ¾ -3-氯苯基 )-6-(5-((2- (甲基亚 乙基 甲基) -2-呋喃基) -喹唑啉 -4-胺二甲苯磺酸盐 (化合物 I)晶型 C的制备 将化合物 12g加入 30ml 1,4-二氧六环和 5ml水的混合体系中， 回流 溶解， 降温析晶， 抽滤， 晾干， 得 1.2g黄色结晶性粉末， 收率 60%。 将 得到的产物进行 X-射线粉末衍射， 结果表明该产物为化合物 I晶型（：。 实施例 12: N-(4-(3-氟苄 ^ 3-氯苯基 )-6-(5-((2- (甲基亚 乙基 曱基) -2-呋喃基) -喹唑啉 -4-胺二曱苯磺酸盐 (化合物 I)晶型 C的制备 将化合物 I 2g加入 40ml 乙二醇二曱醚和 5ml水的混合体系中， 打 浆 4小时， 抽滤， 晾干， 得 1.6g黄色结晶性粉末， 收率 80%。 将得到的 产物进行 X-射线粉末衍射， 结果表明该产物为化合物 I晶型（：。 实施例 13: N-(4-(3-氟苄 ¾^)-3-氯苯基 )-6-(5-((2- (甲基亚砜基）乙基 甲基) -2-呋喃基) -喹唑啉 -4-胺二甲苯磺酸盐 (化合物 I)晶型 C的制备 将化合物 I 2g加入 40ml 四氢呋喃和 5ml水的混合体系中， 打浆 4 小时， 抽滤， 晾干， 得 1.7g黄色结晶性粉末， 收率 85%。 将得到的产物 进行 X-射线粉末衍射， 结果表明该产物为化合物 I晶型（：。 实施例 14: N-(4-(3-氟苄 L¾^)-3-氯苯基 )-6-(5-((2- (甲基亚砜基）乙基 甲基) -2-呋喃基) -喹唑啉 -4-胺二甲苯磺酸盐 (化合物 I)晶型 D的制备 将化合物 I 2g加入 10ml曱醇和 2ml水的混合体系中， 回流溶解， 降温析晶， 抽滤， 晾干， 得 1.6g黄色结晶性粉末， 收率 80%， 将得到的 产物进行 X-射线粉末衍射， 结果表明该产物为化合物 I晶型 D。 实施例 15: N-(4-(3-氟苄 L¾^)-3-氯苯基 )-6-(5-((2- (甲基亚砜基）乙基 甲基) -2-呋喃基) -喹唑啉 -4-胺二甲苯磺酸盐 (化合物 I)晶型 D的制备 将化合物 I 2g加入 100ml异丙醇和 20ml水的混合体系中， 回流溶 解， 降温析晶， 抽滤， 晾干， 得 1.5g黄色结晶性粉末， 收率 75%， 将得 到的产物进行 X-射线粉末衍射， 结果表明该产物为化合物 I晶型 D。 实施例 16: N-(4-(3-氟苄 氯苯基 )-6-(5-((2- (甲基亚 乙基 甲基) -2-呋喃基) -喹唑啉 -4-胺二甲苯磺酸盐 (化合物 I)晶型 D的制备 将化合物 I 2g加入 8ml N，N-二甲基甲酰胺中，加热溶解，降温析晶， 抽滤， 晾干， 得 l g黄色结晶性粉末， 收率 50%， 将得到的产物进行 X- 射线粉末衍射， 结果表明该产物为化合物 I晶型 D。 实施例 17: N-(4-(3-氟苄 氯苯基 )-6-(5-((2- (曱基亚砜基）乙基 甲基) -2-呋喃基) -喹唑啉 -4-胺二甲苯磺酸盐 (化合物 I)晶型 D的制备 将化合物 12g加入 40ml乙醇和 6ml水的混合体系中， 打浆 4小时， 抽滤， 晾干， 得 1.5g黄色结晶性粉末， 收率 75%， 将得到的产物进行 X-射线粉末衍射， 结果表明该产物为化合物 I晶型 D。 NH 9.3 11.4 2 br 1 Example 3: N-(4-(3-Fluorobenzyl t^)-3-chlorophenyl)-6-(5-((2-(methylethylideneamino)methyl)-2-furanyl) - Preparation of quinazoline-4-amine xylene sulfonate (Compound I) Form C. Add 2 g of compound I to a mixed system of 40 ml of tetrahydrofuran and 5 ml of water, dissolve under reflux, cool down and crystallize, suction filtration, and dry. 1.6 g of a yellow crystalline powder was obtained in a yield of 80%. The obtained product was subjected to X-ray powder diffraction, and it was found that the product was Compound C crystal form C, and the XRPD pattern is shown in Fig. 6. Example 4: N- (4-(3-Fluorobenzyl 3⁄4^)-3-chlorophenyl)-6-(5-((2-(methylethylideneamino)methyl)-2-furanyl)-quinazoline- Preparation of 4-Aminexylenesulfonate (Compound I) Form A The compound I crystal form 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 show that the product is Form I of Compound I, and the XRPD pattern is shown in Figure 2. The DSC data show that Form A melts at 240.82 ~ 255.59 °C, and the differential scanning calorimetry (DSC) pattern is shown in Figure 3. Example 5: N-(4-(3-fluorobenzyl L3⁄4^)-3-chlorophenyl)-6-(5-((2-(methylethylamino))) Preparation of 2-(2-furyl)-quinazolin-4-amine-xylene sulfonate (Compound I) Form D. Compound I 2g was added to a mixed system of 40 ml of ethanol and 6 ml of water, and dissolved under reflux to reduce temperature. Crystal, suction filtration, drying, 1.7 g of yellow crystalline powder, yield 85%, the product was subjected to X-ray powder diffraction, the result showed that the product was Compound I crystal form D, the XRPD spectrum is shown in Fig. 7. Example 6: N-(4-(3-fluorobenzylchlorophenyl)-6-(5-((2-(methylethylideneamino)methyl)-2-furanyl)-quinazoline Preparation of 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 Preparation of 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. 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%. The obtained product was subjected to X-ray powder diffraction, and it was confirmed that the product was a crystal form of Compound I (: Example 12: N-(4-(3-fluorobenzyl) 3-chlorophenyl)-6-(5- Preparation of (2-(methylethylidene)-2-furanyl)-quinazolin-4-amine diterpene benzenesulfonate (Compound I) Form C Compound I 2g was added to 40 ml of ethylene In a mixed system of an alcohol dioxime ether and 5 ml of water, it was beaten for 4 hours, suction filtered, and air-dried to obtain 1.6 g of a yellow crystalline powder in a yield of 80%. The obtained product was subjected to X-ray powder diffraction, and the product was confirmed to be the product. Is the crystalline form of Compound I (: Example 13: N-(4-(3-fluorobenzyl 3⁄4^)-3-chlorophenyl)-6-(5-((2-(methyl sulfoxide)) Preparation of crystalline form of methyl 2-(2-furyl)-quinazolin-4-amine-xylene sulfonate (Compound I) Form C of compound I was added to a mixed system of 40 ml of tetrahydrofuran and 5 ml of water, and beaten for 4 hours. After suction filtration and drying, 1.7 g of a yellow crystalline powder was obtained in a yield of 85%. The obtained product was subjected to X-ray powder diffraction, and the product was found to be the crystal form of Compound I (: 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. The product was cooled to crystallize, suction filtered, and dried to obtain 1.6 g of a yellow crystalline powder in a yield of 80%. The obtained product was subjected to X-ray powder diffraction, and the product was found to be Compound I crystal form D. 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. Add 2 g of compound I to a mixed system of 100 ml of isopropanol and 20 ml of water, dissolve at reflux, cool down and crystallize, suction filtration, and dry to obtain 1.5. g Yellow crystalline powder, yield 75%, and the obtained product was subjected to X-ray powder diffraction, and it was found that the product was Compound D crystal form D. Example 16: N-(4-(3-fluorobenzylchlorophenyl)-6-(5-((2-(methylethylidenemethyl)-2-furanyl)-quinazoline-4- Preparation of Aminoxylene sulfonate (Compound I) Form D. 2 g of the compound I was added to 8 ml of N,N-dimethylformamide, dissolved by heating, cooled and decrystallized, suction filtered, and dried to obtain lg yellow crystallinity. The powder was obtained in a yield of 50%, and the obtained product was subjected to X-ray powder diffraction. The product was found to be Compound D crystal 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.
(注： 由于化合物 I晶型（：、 D高温 (60°C以上)会转化为化合物 I晶型 A、 B， 因此未进行 DSC检测。 ；） 本发明对化合物 I无定形物、 晶型 A、 B、 C、 D的稳定性进行了研究， 于温度 25±2°C， 湿度 60%±10%； 温度 40±2°C， 湿度 75%±5%条件下对稳 定性考察 6个月。 试验结果显示， 化合物 I无定形物有明显的降解， 说明 化合物 I无定形物稳定性较差； 晶型 A、 B、 C. D最大单质和总杂质均未 见明显增加， 并将上述考察后的样品经 X-射线粉末衍射等分析测试方法 化合物 I晶型 A、 B、 C. D均稳定。 试验结果见表 2。 (Note: Since the compound I crystal form (:, D high temperature (above 60 ° C) will be converted to the compound I crystal form A, B, the DSC test is not performed.) The amorphous form of the compound I, the crystal form A The stability of B, C, and D was studied at a temperature of 25 ± 2 ° C, humidity of 60% ± 10%; temperature of 40 ± 2 ° C, humidity of 75% ± 5% for 6 months. The test results show that the amorphous substance of compound I has obvious degradation, indicating that the stability of compound I amorphous is poor; the maximum elemental and total impurities of crystal forms A, B and C. D have not increased significantly, and the above investigation will be carried out. After the sample was analyzed by X-ray powder diffraction and the like, the crystal forms A, B, and C. D of the compound I were all stable. The test results are shown in Table 2.
表 2化合物 I无定形物、 晶型 A、 B、 C. D的稳定性试验结果 Table 2 Stability test results of compound I amorphous form, crystal form A, B, C. D
Figure imgf000025_0001
本发明对化合物 II、 化合物 I无定形物、 晶型 A、 B、 C. D的溶解 度进行了研究。 取拟检测化合物， 置 250ml 的碘量瓶中， 加水， 于 25°C士 2°C， 每间隔 5分钟强力振摇 30秒钟， 观察 30分钟内的溶解情况。 试验结果见表 3。 表 3化合物 II、 化合物 I无定形物、 晶型 A、 B、 C. D
Figure imgf000025_0001
The solubility of Compound II, Compound I amorphous, Form A, B, C. D was investigated in the present invention. The test compound was taken, placed in a 250 ml iodine measuring flask, and water was added thereto. The mixture was shaken at 25 ° C for 2 seconds at 25 ° C for 30 minutes, and the dissolution was observed within 30 minutes. The test results are shown in Table 3. Table 3 Compound II, Compound I amorphous, crystalline form A, B, C. D
Figure imgf000026_0001
结果表明： 化合物 II在水中不溶， 化合物 I无定形物、 晶型 A、 B、 C. D在水中微溶， 说明晶型 、 B、 C. D比化合物 II更有利于药物在 体内的溶出。 生物学实验
Figure imgf000026_0001
The results showed that: Compound II was insoluble in water, and the compound I amorphous substance, crystal form A, B, C. D was slightly soluble in water, indicating that the crystal form, B, C. D is more favorable for the dissolution of the drug in the body than the compound II. Biological experiment
可以使用以下实验来测定本发明所述化合物对 erbB酪氨酸激酶的 活性作用以及在体外作为 N87细胞和 BT474细胞抑制剂的作用。  The following experiments can be used to determine the effect of the compounds of the invention on erbB tyrosine kinase activity and in vitro as N87 cells and BT474 cell inhibitors.
A)蛋白酪氨酸激酶磷酸化测定  A) Protein tyrosine kinase phosphorylation assay
体外激酶分析用 Cell Signaling Technolog 公司的 HTScan EGF Receptor Kinase Assay Kit(#7909)和 HTScan HER2/ErbB2 Kinase Assay Kit(#7058) ^测。操作步骤参照试剂盒说明书， 该方法在体外检测待测化 合物对 EGFR或 Her2受体酪氨酸激酶对底物肽磷酸化的抑制作用。 室 温下激酶反应緩冲液中温育 ATP和底物肽以及待测化合物， 孵育一段时 间后，加入终止液终止反应并将样品转移到链霉亲和素包被的 96孔板中， 洗板并用 HRP标记的抗底物磷酸化抗体检测底物肽上的磷酸化水平，用 TMB显色， 2M 酸中止反应。检测 450 nm吸收波长，计算 IC5。值 (μΜ)。 结果见表 2所示。 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 (μΜ). The results are shown in Table 2.
Β)细胞增值抑制  Β) cell proliferation inhibition
参考 Rusnak等， Cell Prolif, 2007， 40， 580-594中描述的方法进行 试验。 细胞增殖抑制试验采用人乳腺癌细胞 BT474 和人胃癌细胞系 NCI-N87, BT474高表达 Her2受体， N87高表达 EGFR和 Her2受体。  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.
在含 10%胎牛血清、 2 mM谷氨酰胺和非必需氨基酸的 Dulbecco改 良 Eagle培养基 (DMEM)中， 在 37°C、 5%C02细胞培养箱中培养细胞， 应用胰蛋白酶 /乙二胺四乙酸 (EDTA)从细胞培养瓶中收获细胞。 细胞以 4000/孔 (0.1ml培养基)加入 96孔细胞培养板贴壁过夜， 加入 0.1ml待测 化合物的稀释液， DMSO的最终浓度为 0.25%， 将细胞培养板在 37°C， 5%的 C02条件下温育 72h。 然后在显微镜下观察细胞形态的变化， 然后 每孔加入 50% (盾量 /体积)的三氯乙酸 (TCA)50 l固定细胞。 TCA的终浓 度为 10%， 静置 5min后在 4°C冰箱中放置 1 h， 培养板各孔用去离子水 冲洗 5遍， 以去除 TCA, 甩干， 空气干燥至无湿迹。 每孔加 0.4% (盾量 / 体积)的 SRBlOO l, 室温放置 lOmin, 弃去各孔内液体后用 1%乙酸沖洗 5遍，空气干燥后用 pH为 10.5，10mM Tris base (三羟曱基氨基曱烷 )150μ1 萃取， 检测 540nm的吸收波长。 结果 IC5。值 (μΜ)见表 4所示。 In Dulbecco's Modified Eagle Medium (DMEM) containing 10% fetal calf serum, 2 mM glutamine and non-essential amino acids, cells were cultured in a 5% CO 2 incubator at 37 ° C using trypsin / ethylene Aminotetraacetic acid (EDTA) harvests cells from cell culture flasks. The cells were added to a 96-well cell culture plate at 4000/well (0.1 ml medium) overnight, and 0.1 ml of a dilution of the test compound was added. The final concentration of DMSO was 0.25%, and the cell culture plate was at 37 ° C, 5%. Incubate for 72 h under C0 2 conditions. The morphology of the cells was then observed under a microscope, and then 50% (shield/volume) of trichloroacetic acid (TCA) 50 l was added to each well to fix the cells. The final concentration of TCA was 10%. After standing for 5 min, it was placed in a refrigerator at 4 °C for 1 h. The wells of the plates were rinsed 5 times with deionized water to remove TCA, dried, and air dried to no trace. Add 0.4% (shield/volume) of SRBlOO l per well, leave lOmin at room temperature, discard the liquid in each well and rinse with 5% acetic acid for 5 times. After air drying, use pH 10.5, 10 mM Tris base (trihydroxy sulfhydryl group). Amino decane) 150 μl extraction, detecting the absorption wavelength of 540 nm. The result is IC 5 . The values (μΜ) are shown in Table 4.
表 4本发明化合物 I的晶型 A、 B、 C. D  Table 4 Crystal Forms A, B, C. D of Compound I of the Invention
对 EGFR和 Her2的抑制活性分析  Analysis of inhibitory activity against EGFR and Her2
Figure imgf000027_0001
Figure imgf000027_0001
注： "++++"指 IC50值 < 0.025μΜ; "+++"指 IC50值为 0.025-0.10μΜ。 在作为评价化合物生物学活性的一个重要的"细胞增殖抑制试验，，中 可以看到， 本发明化合物 I的晶型 A、 B、 C. D均具有较好的生物学活 性。 Note: "++++" means IC 50 value <0.025μΜ;"+++" means IC 50 value is 0.025-0.10μΜ. In an important "cell proliferation inhibition test" for evaluating the biological activity of a compound, it can be seen that the crystal forms A, B, and C. D of the compound I of the present invention have a good biological activity.
结果表明， 本发明的化合物 I的晶型 A、 B、 C、 D都是有效的酪氨 酸激酶抑制剂。  The results show that the crystalline forms A, B, C and D of the compound I of the present invention are all potent tyrosine kinase inhibitors.

Claims

Figure imgf000029_0001
化合物
Figure imgf000029_0001
Compound
Figure imgf000029_0002
Figure imgf000029_0002
I  I
2、 根据权利要求 1所述的化合物 I的多晶型物， 其中所述多晶型物 包括： 晶型 A、 晶型 B、 晶型 C和晶型 D。 2. The polymorph of Compound I according to Claim 1, wherein said polymorph comprises: Form A, Form B, Form C and Form D.
3、 根据权利要求 1所述的化合物 I的多晶型物， 其中化合物 I晶型 A, 使用 Cu-Κα辐射， 以 2Θ角度表示的 X-射线粉末衍射图谱在 4.6。 士 0.2°, 9.2Q±0.2。， 11.5Q±0.2。， 12·6ο±0·2ο， 15.1Q±0.2。， 19.7Q±0.2。， 24.9°士 0·2ο， 27.2。士 0·2ο处有特征峰。 3. A polymorph of Compound I according to claim 1, wherein Compound I Form A, using Cu-Κα radiation, has an X-ray powder diffraction pattern at 2 Θ angle of 4.6. ± 0.2 °, 9.2 Q ± 0.2. , 11.5 Q ±0.2. , 12·6 ο ±0·2 ο , 15.1 Q ±0.2. , 19.7 Q ±0.2. 24.9°士0·2 ο , 27.2. There is a characteristic peak at 0. 2 ο .
4、 根据权利要求 1所述的的化合物 I的多晶型物， 其中化合物 I晶 型 Α，使用 Cu-Κα辐射，以 2Θ角度表示的 X-射线粉末衍射图语在 4.6。士 0.2°, 9.2Q±0.2o, 11.5Q±0.2o, 12.6Q±0.2o, 14.5°± 0.2°, 15·1ο±0·2ο, 15.7。士 0.2°, 16.0。士 0.2°, 19.1。士 0.2°, 19.7° ± 0.2。， 20.0。士 0.2°, 21.9。士 0.2°, 22.9°± 0.2°, 24.0° ± 0.2°, 24.3°± 0.2°, 24.9°± 0.2°, 27.2。 ± 0.2。处有特征 峰。 4. A polymorph of Compound I according to claim 1, wherein the Compound I crystalline form is Cu, using Cu-Κα radiation, the X-ray powder diffraction pattern expressed in terms of 2 Θ angle is at 4.6. ± 0.2 °, 9.2 Q ± 0.2 o , 11.5 Q ± 0.2 o , 12.6 Q ± 0.2 o , 14.5 ° ± 0.2 °, 15·1 ο ± 0·2 ο , 15.7. ± 0.2 °, 16.0. ± 0.2 °, 19.1. ± 0.2 °, 19.7 ° ± 0.2. , 20.0. ± 0.2 °, 21.9. ± 0.2 °, 22.9 ° ± 0.2 °, 24.0 ° ± 0.2 °, 24.3 ° ± 0.2 °, 24.9 ° ± 0.2 °, 27.2. ± 0.2. There are characteristic peaks.
5、 根据权利要求 2或 3或 4所述的化合物 I的多晶型物， 其中化合 物 I晶型 Α的差示扫描量热分析显示， 该晶型在 240.82 ~255.59°C熔融 分解。 6、 根据权利要求 2所述的化合物 I的多晶型物， 其中化合物 I晶型 B, 使用 Cu-Κα辐射， 以 2Θ角度表示的 X-射线粉末衍射图谱在 4.5. A polymorph of Compound I according to claim 2 or 3 or 4, wherein differential scanning calorimetry of Form I of Compound I shows that the crystal form melts and decomposes at 240.82 to 255.59 °C. 6. The polymorph of compound I according to claim 2, wherein the compound I crystal form B, using Cu-Κα radiation, has an X-ray powder diffraction pattern at a 2 Θ angle of 4.
6。 士 0.2°, 8.3Q±0.2。， 12·0ο±0·2ο， 15.8Q±0.2。， 19.7Q±0.2。， 20.8Q±0.2。， 22.8°士 0.2。处有特征峰。 6. ± 0.2 °, 8.3 Q ± 0.2. , 12·0 ο ±0·2 ο , 15.8 Q ±0.2. , 19.7 Q ±0.2. , 20.8 Q ±0.2. , 22.8 ° ± 0.2. There are characteristic peaks.
7、 根据权利要求 1所述的化合物 I的多晶型物， 其中化合物 I晶型7. The polymorph of compound I according to claim 1, wherein the compound I crystal form
B, 使用 Cu-Κα辐射， 以 2Θ角度表示的 X-射线粉末衍射图谱在 4.6。 士 0.2°, 8.3Q±0.2。， 9.1Q±0.2。， 12.0Q ± 0·2ο， 13.9Q ± 0·2ο， 15.0Q ± 0·2ο， 15·8ο±0·2ο， 17·6ο±0·2ο， 18.7Q±0.2。， 19·7ο±0·2ο， 20.8Q±0.2。， 22.2° ±0·2ο， 22·8ο±0·2ο， 26.0。 ± 0.2。处有特征峰。 B, using Cu-Κα radiation, the X-ray powder diffraction pattern at 2 Θ angle is at 4.6. ± 0.2 °, 8.3 Q ± 0.2. , 9.1 Q ±0.2. , 12.0 Q ± 0·2 ο , 13.9 Q ± 0·2 ο , 15.0 Q ± 0·2 ο , 15·8 ο ±0·2 ο , 17·6 ο ±0·2 ο , 18.7 Q ±0.2. , 19·7 ο ±0·2 ο , 20.8 Q ±0.2. , 22.2° ±0·2 ο , 22·8 ο ±0·2 ο , 26.0. ± 0.2. There are characteristic peaks.
8、 根据权利要求 2或 6或 7所述的化合物 I的多晶型物， 其中化合 物 I晶型 Β的差示扫描量热分析显示， 该晶型在 239.11 ~254.49°C熔融 分解。 8. A polymorph of Compound I according to claim 2 or 6 or 7, wherein differential scanning calorimetry of Form I of Compound I shows that the crystal form melts and decomposes at 239.11 to 254.49 °C.
9、 根据权利要求 1所述的化合物 I的多晶型物， 其中化合物 I晶型9. The polymorph of compound I according to claim 1, wherein the compound I crystal form
C, 使用 Cu-Κα辐射， 以 2Θ角度表示的 X-射线粉末衍射图谱在 4.4。 士 0.2°, 9.5Q±0.2。， 12.7。 ±0.2。， 14.9Q±0.2。， 19.8Q±0.2。， 23.7Q±0.2。， 26.8°士 0.2。处有特征峰。 C, using Cu-Κα radiation, the X-ray powder diffraction pattern expressed at 2Θ angle is 4.4. ± 0.2 °, 9.5 Q ± 0.2. , 12.7. ±0.2. , 14.9 Q ±0.2. , 19.8 Q ± 0.2. , 23.7 Q ±0.2. , 26.8 ° ± 0.2. There are characteristic peaks.
10、 根据权利要求 1所述的化合物 I的多晶型物， 其中化合物 I晶型 C, 使用 Cu-Κα辐射， 以 2Θ角度表示的 X-射线粉末衍射图谱在 4.4。 士 0.2°, 9.5c±0.2o， 12.7c±0.2o， 14.9c±0.2o， 16.1c±0.2o，
Figure imgf000030_0001
10. The polymorph of Compound I according to claim 1, wherein Compound C Form C, using Cu-Κα radiation, has an X-ray powder diffraction pattern at 2 Θ angle of 4.4. ± 0.2 °, 9.5 c ± 0.2 o , 12.7 c ± 0.2 o , 14.9 c ± 0.2 o , 16.1 c ± 0.2 o ,
Figure imgf000030_0001
19·4ο±0·2ο， 19·8ο±0·2ο， 20.9Q±0.2。， 21·4ο±0·2ο， 23.7Q±0.2。， 26.8° 士 0.2。处有特征峰。 19·4 ο ±0·2 ο , 19·8 ο ±0·2 ο , 20.9 Q ±0.2. , 21·4 ο ±0·2 ο , 23.7 Q ±0.2. , 26.8° ± 0.2. There are characteristic peaks.
11、 根据权利要求 2所述的化合物 I的多晶型物， 其中化合物 I晶型 D, 使用 Cu-Κα辐射， 以 2Θ角度表示的 X-射线粉末衍射图谱在 4.4。 ± 0.2°,
Figure imgf000031_0001
^^士。. 。， 25.1°士 0·2ο处有特征峰。 11. A polymorph of Compound I according to claim 2, wherein Compound I Form D, using Cu-Κα radiation, has an X-ray powder diffraction pattern at 2 Θ angle of 4.4. ± 0.2°,
Figure imgf000031_0001
^^士. . . . , 25.1°士0·2 ο There are characteristic peaks.
12、 根据权利要求 2所述的化合物 I的多晶型物， 其中化合物 I晶型 D, 使用 Cu-Κα辐射， 以 2Θ角度表示的 X-射线粉末衍射图谱在 4.4。 士
Figure imgf000031_0002
12. A polymorph of Compound I according to claim 2, wherein Compound I Form D, using Cu-Κα radiation, has an X-ray powder diffraction pattern at Θ angle of 4.4. Shishi
Figure imgf000031_0002
21·7ο ± 0·2ο， 22·2ο ± 0·2ο， 23·0ο ± 0·2ο， 25·1ο ± 0·2ο， 25·60 ± 0.2。处有特 征峰。 21·7 ο ± 0·2 ο , 22·2 ο ± 0·2 ο , 23·0 ο ± 0·2 ο , 25·1 ο ± 0·2 ο , 25·6 0 ± 0.2. There are characteristic peaks.
13、 根据权利要求 1至 12任一项所述的化合物 I的多晶型物的制备 方法， 包括如下步骤： 13. A method of preparing a polymorph of Compound I according to any one of claims 1 to 12, comprising the steps of:
(1)化合物 I晶型 C的制备， 其包括以下步骤：  (1) Preparation of Compound I Form C, which comprises the following steps:
将化合物 I在加热回流条件下溶于溶剂体系中， 降温析晶， 过滤， 晾干， 得化合物 I晶型 C, 或  Compound I is dissolved in a solvent system under heating and refluxing conditions, cooled and crystallized, filtered, and air-dried to obtain Compound I crystal form C, or
将化合物 I在溶剂体系中打浆， 过滤， 晾干， 得化合物 I晶型 C， 所述的溶剂体系包括： 四氢呋喃 /水、 1,4-二氧六环 /水、 乙二醇二曱 醚 /水； 所述的溶剂和水的配比 (体积)为 20:1 ~ 1:10， 优选 20:1 ~ 4:1； 或者，  Compound I is slurried in a solvent system, filtered, and air-dried to obtain Compound I Form C. The solvent system includes: tetrahydrofuran/water, 1,4-dioxane/water, ethylene glycol dioxime/ Water; the ratio of the solvent to water (volume) is 20:1 ~ 1:10, preferably 20:1 ~ 4:1; or
(2)化合物 I晶型 D的制备， 其包括以下步骤：  (2) Preparation of Compound I Form D, which comprises the following steps:
将化合物 I在加热回流条件下溶于溶剂体系中， 降温析晶， 过滤， 晾干， 得化合物 I晶型 D， 或，  Compound I is dissolved in a solvent system under heating and refluxing conditions, cooled and crystallized, filtered, and air-dried to obtain Compound I crystal form D, or
将化合物 I在溶剂体系中打浆， 过滤， 晾干， 得化合物 I晶型 D; 所述的溶剂体系包括： 乙醇 /水、 曱醇 /水、 异丙醇 /水、 N，N-二曱基 曱酰胺， 所述醇类 /水的配比 (体积)为 20:1 ~ 1:10， 优选 20:1 ~ 4:1；  Compound I is slurried in a solvent system, filtered, and air-dried to obtain Compound I Form D; the solvent system includes: ethanol/water, methanol/water, isopropanol/water, N,N-didecyl曱 amide, the alcohol / water ratio (volume) is 20:1 ~ 1:10, preferably 20:1 ~ 4:1;
或者， (3)化合物 I晶型 A的制备， 其包括以下步骤： or, (3) Preparation of Compound I Form A, which comprises the steps of:
将化合物 I晶型 C在 60 ~ 150°C下烘干， 得化合物 I晶型 A;  Drying Compound C Form C at 60 ~ 150 ° C to obtain Compound I Form A;
或者，  Or,
(4)化合物 I晶型 B的制备， 其包括以下步骤：  (4) Preparation of Compound I Form B, which comprises the following steps:
将化合物 I晶型 D在 60 ~ 150°C下烘干， 得化合物 I晶型 B。  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.
14、 一种药物组合物， 其包含权利要求 1至 12任一项所述的化合物 I的多晶型物， 以及任选的一种或多种药学可接受的载体或赋形剂。 A pharmaceutical composition comprising the polymorph of Compound I according to any one of claims 1 to 12, and optionally one or more pharmaceutically acceptable carriers or excipients.
15、 权利要求 1至 12任一项所述的化合物 I的多晶型物在制备用于 治疗和 /或预防哺乳动物（包括人)与受体酪氨酸激酶相关的疾病或病症 的药物中的用途。 15. A polymorph of Compound I according to any one of claims 1 to 12 in the manufacture of a medicament for the treatment and/or prevention of a disease or condition associated with a receptor tyrosine kinase in a mammal, including a human. the use of.
16、 权利要求 1至 12任一项所述的化合物 I的多晶型物在制备用于 治疗或辅助治疗和 /或预防哺乳动物（包括人）由受体酪氨酸激酶介导的 肿瘤或由受体酪氨酸激酶驱动的肿瘤细胞的增殖和迁移的药物中的用 途； 其中所述的与受体酪氨酸激酶相关的疾病或病症、 由受体酪氨酸激 酶介导的肿瘤、 或由受体酪氨酸激酶驱动的肿瘤细胞的增殖和迁移包括 erbB受体酪氨酸激酶敏感癌症， 如 EGFR或 Her2高表达及 EGF驱动 的肿瘤， 包括实体肿瘤如胆管、 骨、 膀胱、 脑 /中枢神经系统、 乳房、 结 直肠、 子宫内膜、 胃、 头和颈、 肝、 肺、 神经元、 食道、 卵巢、 胰腺、 前列腺、 腎脏、 皮肤、 睾丸、 曱状腺、 子宫和外阴等的癌症， 和非实体 肿瘤如白血病、 多发性骨髓瘤或淋巴瘤。 16. The polymorph of Compound I according to any one of claims 1 to 12 for use in the preparation of a therapeutic or adjunctive treatment and/or prevention of a tumor mediated by a receptor tyrosine kinase in a mammal, including a human or Use in a drug for proliferation and migration of tumor cells driven by a receptor tyrosine kinase; wherein the disease or disorder associated with a receptor tyrosine kinase, a tumor mediated by a receptor tyrosine kinase, Or proliferation and migration of tumor cells driven by receptor tyrosine kinases including erbB receptor tyrosine kinase-sensitive cancers, such as EGFR or Her2 high expression and EGF-driven tumors, including solid tumors such as bile duct, bone, bladder, brain / CNS, breast, colorectal, endometrium, stomach, head and neck, liver, lung, neurons, esophagus, ovary, pancreas, prostate, kidney, skin, testes, squamous glands, uterus and vulva Cancer, and non-solid tumors such as leukemia, multiple myeloma or lymphoma.
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