CN105566305B

CN105566305B - The polymorph and its preparation method and application of 4- (substituted anilinic) quinazoline derivant xylenesulfonate

Info

Publication number: CN105566305B
Application number: CN201610092050.6A
Authority: CN
Inventors: 王晶翼; 范传文; 冷传新; 张进; 林栋�; 王丙忠; 王会成
Original assignee: Qilu Pharmaceutical Co Ltd
Current assignee: QILU PHARMACEUTICAL (HAINAN) CO Ltd
Priority date: 2012-03-06
Filing date: 2012-03-06
Publication date: 2018-08-14
Anticipated expiration: 2032-03-06
Also published as: CN103304544B; CN105566305A; CN103304544A; WO2013131465A1

Abstract

The polymorph and its preparation method and application of 4 (substituted anilinic) quinazoline derivant xylenesulfonates, the present invention relates to the polymorphs as 4 amine xylenesulfonate (compound I) of tyrosine kinase inhibitor N (4 (3 fluorine benzyloxy) 3 chlorphenyls) 6 (5 ((2 (methyl sulfoxide base) ethylamino) methyl) 2 furyls) quinazoline.Specifically, the present invention relates to crystal form A, B, C and D of compound I.The invention further relates to the preparation methods of the polymorph of compound I, including its pharmaceutical composition and their pharmaceutical applications.The polymorph of the compounds of this invention I is effective tyrosine kinase inhibitor.

Description

Polymorphic substance of 4- (substituted anilino) quinazoline derivative xylene sulfonate and preparation method and application thereof

This application is a divisional application of the invention patent application 201210055636.7.

Technical Field

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a novel N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- ((2- (methylsulfonyl) ethylamino) methyl) -2-furyl) -quinazoline-4-aminoxylenesulfonate (compound I) polymorph with antitumor activity and a preparation method thereof, and application of the compound I polymorph in treatment or adjuvant treatment of tumors mediated by receptor tyrosine kinases of mammals (including human beings) or proliferation and migration of tumor cells driven by the receptor tyrosine kinases.

Background

Tumors are one of the major diseases that severely threaten human life and quality of life, and according to WHO statistics, about 690 million patients dying from tumors every year worldwide. Due to the change of living environment and life habit, the incidence and mortality of tumors are gradually increasing in recent years under the action of adverse environment and some adverse factors.

In recent years, efforts have been made to inhibit cell signal transduction pathways to develop novel target anti-tumor drugs. The signal transduction inhibitor can reduce the survival and proliferation signals of the tumor and promote apoptosis, but not through the cytotoxic effect, so that the selectivity is higher and the toxic and side effects are smaller. At present, more than ten kinds of signal transduction inhibitors are applied to clinical treatment of tumors, mainly tyrosine kinase inhibitor antitumor drugs, wherein the development of compounds with 4- (substituted anilino) quinazoline structure types is relatively mature, such as small molecule inhibitors Gefitinib (Gefitinib), Erlotinib (Erlotinib) and Lapatinib (Lapatinib) aiming at EGFR tyrosine kinase targets.

Gefitinib (Gefitinib), marketed under the trade name Iressa (Iressa), an EGFR tyrosine kinase inhibitor developed by AstraZeneca, which is the epidermal growth factor receptor tyrosine kinase inhibitor that first entered clinical studies, was marketed in japan in 2002 and in the united states the next year for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) that had previously received chemotherapy. Erlotinib (Erlotinib), tradename Tarceva (Tarceva), an EGFR tyrosine kinase inhibitor developed by OSI, assigned to Genentech and rotkish. Marketed in 2004 in the united states for the treatment of NSCLC and pancreatic cancer. Belongs to a first generation aniline quinazoline micromolecule inhibitor for treating NSCLC, is the only EGFR tyrosine kinase inhibitor which is proved to have survival advantage on advanced non-small cell lung cancer at present, is effective on various non-small cell lung cancer patients, has good tolerance, does not have bone marrow inhibition and neurotoxicity, can obviously prolong the life cycle, and improves the life quality of the patients. Lapatinib (Lapatinib), tradename Tycerb, is a dual inhibitor of EGFR and HER2 developed by GlaxoSmithKline, which has a stronger inhibitory effect on signaling of tumor proliferation and survival than single receptor inhibitors. FDA approved this product for marketing in the united states in 2007 for the indication of treatment with capecitabine in patients with advanced or metastatic breast cancer who overexpress HER2 and have previously received chemotherapy such as anthracyclines, taxanes and trastuzumab.

Furthermore, patent application publication nos. WO 96/33977, WO 97/30035, WO 98/13354, WO 00/55141, WO02/41882, WO 03/82290 and EP 837063 and the like disclose that certain quinazoline derivatives carrying an anilino substituent at the 4-position and a substituent at the 6-and/or 7-position have receptor tyrosine kinase activity.

The small molecular tyrosine kinase inhibitor is used as a new targeted antitumor drug, opens a new window for treating and preventing tumors, has slight side effect and good tolerance. Although more than 10 small molecule tyrosine kinase inhibitors have contributed greatly to the clinical treatment of tumors, there is still a need to find additional compounds with better in vivo activity and/or improved pharmacological properties than the existing tyrosine kinase inhibitors. Therefore, the development of new improved or more efficient tyrosine kinase inhibitors and the deeper understanding of the relationship between the drugs and known target proteins and the mechanism of the drugs for exerting antitumor effect have important significance for the clinical treatment of tumors.

CN102030742A investigates the use of 4- (substituted anilino) quinazoline derivatives as drugs for the treatment or co-treatment of tumors mediated by receptor tyrosine kinases or the proliferation and migration of tumor cells driven by receptor tyrosine kinases in mammals, including humans.

Disclosure of Invention

The present invention identifies polymorphs of N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- ((2- (methylsulfonyl) ethylamino) methyl) -2-furanyl) -quinazolin-4-amine xylenesulfonate (compound I) that are useful as tyrosine kinase inhibitors of the EGFR family.

The inventor finds that the compound I has high tyrosine kinase inhibition effect through research. We have found that certain forms of compound I are crystalline materials with advantageous properties.

To this end, a first aspect of the present invention provides a polymorph of N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- ((2- (methylsulphonidenyl) ethylamino) methyl) -2-furyl) -quinazolin-4-amine ditosylate salt (Compound I).

The inventors of the present invention have surprisingly found that compound I may exist in more than one polymorph. The inventors abbreviated these polymorphs as forms A, B, C and D. The polymorphic substance of the compound I has certain solubility in water, and is beneficial to absorption in vivo; and has better stability, which is beneficial to package and storage.

In one embodiment, form a of compound I has characteristic peaks at 4.6 ° ± 0.2 °, 9.2 ° ± 0.2 °, 11.5 ° ± 0.2 °, 12.6 ° ± 0.2 °, 15.1 ° ± 0.2 °, 19.7 ° ± 0.2 °, 24.9 ° ± 0.2 °, 27.2 ° ± 0.2 ° on an X-ray powder diffraction pattern expressed in terms of 2 θ radiation using Cu-K α.

In a further embodiment, form a of compound I has an X-ray powder diffraction pattern, expressed in terms of 2 Θ angles, using Cu-K α radiation having characteristic peaks at 4.6 ° ± 0.2 °, 9.2 ° ± 0.2 °, 11.5 ° ± 0.2 °, 12.6 ° ± 0.2 °, 14.5 ° ± 0.2 °, 15.1 ° ± 0.2 °, 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 °.

In a further embodiment, said compound I form a has an X-ray powder diffraction pattern substantially as shown in figure 2.

In one embodiment, differential scanning calorimetry analysis of form a of compound I shows that the form decomposes by melting at 240.82-255.59 ℃.

In another embodiment, form B of Compound I, when irradiated with Cu-K α, exhibits an X-ray powder diffraction pattern at 2 θ angles having characteristic peaks at 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 ° ± 0.2 °.

In a further embodiment, form B of Compound I, when irradiated with Cu-K α, exhibits an X-ray powder diffraction pattern at 2 θ angles having characteristic peaks at 4.6 ° ± 0.2 °, 8.3 ° ± 0.2 °, 9.1 ° ± 0.2 °, 12.0 ° ± 0.2 °, 13.9 ° ± 0.2 °, 15.0 ° ± 0.2 °, 15.8 ° ± 0.2 °, 17.6 ° ± 0.2 °, 18.7 ° ± 0.2 °, 19.7 ° ± 0.2 °, 20.8 ° ± 0.2 °, 22.2 ° ± 0.2 °, 22.8 ° ± 0.2 °, 26.0 ° ± 0.2 °.

In a further embodiment, said form B of compound I has an X-ray powder diffraction pattern substantially as shown in figure 4.

In one embodiment, differential scanning calorimetry analysis of form B of compound I shows that the form decomposes by melting at 239.11-254.49 ℃.

In yet another embodiment, form C of compound I has an X-ray powder diffraction pattern, expressed in terms of 2 Θ angles, using Cu-K α radiation, having characteristic peaks 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 ° ± 0.2 °.

In a further embodiment, form C of Compound I has an X-ray powder diffraction pattern using Cu-K α radiation having characteristic peaks 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 ° ± 0.2 ° expressed in terms of 2 θ.

In a further embodiment, said form C of compound I has an X-ray powder diffraction pattern substantially as shown in figure 6.

In yet another embodiment, form D of compound I has an X-ray powder diffraction pattern, expressed in terms of 2 Θ angles, using Cu-K α radiation having characteristic peaks at 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 ° ± 0.2 °.

In a further embodiment, form D of compound I has an X-ray powder diffraction pattern, expressed in terms of 2 Θ angles, using Cu-K α radiation having characteristic peaks at 4.4 ° ± 0.2 °, 8.3 ° ± 0.2 °, 14.8 ° ± 0.2 °, 18.7 ° ± 0.2 °, 19.4 ° ± 0.2 °, 21.0 ° ± 0.2 °, 21.7 ° ± 0.2 °, 22.2 ° ± 0.2 °, 23.0 ° ± 0.2 °, 25.1 ° ± 0.2 °, 25.6 ° ± 0.2 °.

In a further embodiment, said form D of compound I has an X-ray powder diffraction pattern substantially as shown in figure 7.

In a second aspect, the present invention provides a process for the preparation of a polymorph of compound I according to the first aspect of the present invention, said process comprising:

reacting N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- ((2- (methylsulfonyl) ethylamino) methyl) -2-furanyl) -quinazolin-4-amine (compound II) with p-toluenesulfonic acid in a solvent to give compound I;

dissolving the compound I in a proper solvent system under the heating condition, cooling and crystallizing, filtering and airing to obtain a crystal form C or D of the compound I; and

drying the crystal form C of the compound I at a certain temperature to obtain a crystal form A of the compound I; or

And drying the crystal form D of the compound I at a certain temperature to obtain the crystal form B of the compound I.

The preparation of the polymorphic form of compound I is described in detail below.

(1) A process for the preparation of compound I comprising the steps of:

dissolving N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- ((2- (methylsulfonyl) ethylamino) methyl) -2-furyl) -quinazoline-4-amine (compound II) in ethanol, adding p-toluenesulfonic acid into the system, separating out a solid, and filtering to obtain a compound I.

(2) A process for preparing form C of compound I comprising the steps of:

dissolving the compound I in tetrahydrofuran and a water system under the condition of heating reflux, cooling, crystallizing, filtering and airing to obtain the crystal form C of the compound I.

Wherein the ratio (volume) of the tetrahydrofuran to the water is 20: 1-1: 10, preferably 20: 1-4: 1.

(3) A process for preparing form D of compound I comprising the steps of:

dissolving the compound I in an ethanol and water system under the condition of heating reflux, cooling for crystallization, filtering, and airing to obtain the compound I crystal form D.

Wherein the ratio (volume) of the ethanol to the water is 20: 1-1: 1, preferably 20: 1-4: 1.

(4) A process for preparing form a of compound I comprising the steps of:

and drying the crystal form C of the compound I at the temperature of 60-150 ℃ to obtain the crystal form A of the compound I.

(5) A process for preparing form B of compound I comprising the steps of:

and drying the crystal form D of the compound I at the temperature of 60-150 ℃ to obtain a crystal form B of the compound I.

The relationship between the four polymorphs described above is as follows:

wherein, the crystal form of the compound I crystal form C, D is stable under the normal temperature condition, and the crystal form is unstable under the high temperature condition; the compound I crystal form A, B is stable at normal temperature and high temperature after being formed.

In the preparation method of the second aspect of the present 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 according to document CN 102030742A.

A third aspect of the present invention relates to a pharmaceutical composition comprising a polymorph of compound I according to any one of the first aspects of the present invention, optionally together with one or more pharmaceutically acceptable carriers or excipients.

The fourth aspect of the present invention relates to the use of a polymorph of compound I according to any one of the first aspect of the present invention in the manufacture of a medicament for the treatment and/or prevention of a disease or condition associated with receptor tyrosine kinases in a mammal (including a human).

The fourth aspect of the present invention also relates to the use of a polymorph of compound I according to any one of the first aspect of the present invention for the preparation of a medicament for the therapeutic or adjunctive treatment and/or prevention of receptor tyrosine kinase mediated tumor or receptor tyrosine kinase driven proliferation and migration of tumor cells in mammals, including humans.

According to the present invention, it is fully expected that polymorphs of compound I of the present invention may be useful in the treatment of 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/central nervous system, breast, colorectal, endometrial, gastric, head and neck, liver, lung (especially non-small cell lung cancer), neuronal, esophageal, ovarian, pancreatic, prostate, kidney, skin, testicular, thyroid, uterine and vulval cancers and non-solid tumors such as leukemia, multiple myeloma or lymphoma and the like. To this end, the tumors or cancers involved in the above-mentioned "diseases or disorders associated with receptor tyrosine kinases" and "tumors mediated by receptor tyrosine kinases" or "proliferation and migration of tumor cells driven by receptor tyrosine kinases" of the present invention may include erbB receptor tyrosine kinase sensitive cancers as described above, such as tumors with high expression of EGFR or Her2 and EGF drive, including solid tumors such as bile duct, bone, bladder, brain/central nervous system, breast, colorectal, endometrial, gastric, head and neck, liver, lung (especially non-small cell lung cancer), neuronal, esophageal, ovarian, pancreatic, prostate, kidney, skin, testicular, thyroid, uterine and vulva, and non-solid tumors such as leukemia, multiple myeloma or lymphoma, etc.

A fifth aspect of the present invention relates to a method for the treatment and/or prophylaxis of diseases or conditions associated with receptor tyrosine kinases in a mammal in need thereof, which method comprises administering to a mammal in need thereof a therapeutically effective amount of a polymorph of compound I according to any one of the first aspects of the present invention.

The fifth aspect of the present invention also relates to a method for the therapeutic or co-therapeutic treatment and/or prevention of receptor tyrosine kinase mediated tumor or receptor tyrosine kinase driven proliferation and migration of tumor cells in a mammal (including a human) in need thereof, which comprises administering to the mammal in need thereof a therapeutically effective amount of a polymorph of compound I according to any one of the first aspect of the present invention.

The fifth aspect of the present invention further relates to a method for the treatment and/or prevention of tumors or cancers in a mammal (including a human being) in need thereof, the method comprising administering to a mammal in need thereof a therapeutically effective amount of a polymorph of compound I according to any one of the first aspect of the invention, wherein said 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 cancers of the bile duct, bone, bladder, brain/central nervous system, breast, colorectal, endometrial, stomach, head and neck, liver, lung (especially non-small cell lung cancer), neurons, esophagus, ovary, pancreas, prostate, kidney, skin, testis, thyroid, uterus and vulva, and non-solid tumors such as leukemia, multiple myeloma or lymphoma, etc.

A sixth aspect of the present invention relates to a polymorph of compound I according to any one of the first aspect of the present invention for use as a medicament for the treatment and/or prevention of diseases or conditions associated with receptor tyrosine kinases in mammals, including humans.

The sixth aspect of the present invention also relates to a polymorph of compound I according to any one of the first aspect of the present invention for use as a medicament for the therapeutic or co-therapeutic treatment and/or prevention of receptor tyrosine kinase mediated tumor or receptor tyrosine kinase driven proliferation and migration of tumor cells in mammals, including humans.

According to the present invention, it is fully contemplated that polymorphs of compound I of the present invention may be used as medicaments for the treatment of erbB receptor tyrosine kinase sensitive cancers, such as EGFR or Her2 high expression and EGF driven tumors, cancers including solid tumors such as bile duct, bone, bladder, brain/central nervous system, breast, colorectal, endometrial, gastric, head and neck, liver, lung (especially non-small cell lung cancer), neuronal, esophageal, ovarian, pancreatic, prostate, renal, skin, testicular, thyroid, uterine and vulva, etc., and non-solid tumors such as leukemia, multiple myeloma or lymphoma, etc. To this end, the tumors or cancers involved in the above-mentioned "diseases or disorders associated with receptor tyrosine kinases" and "tumors mediated by receptor tyrosine kinases" or "proliferation and migration of tumor cells driven by receptor tyrosine kinases" of the present invention may include erbB receptor tyrosine kinase sensitive cancers as described above, such as tumors with high expression of EGFR or Her2 and EGF drive, including solid tumors such as bile duct, bone, bladder, brain/central nervous system, breast, colorectal, endometrial, gastric, head and neck, liver, lung (especially non-small cell lung cancer), neuronal, esophageal, ovarian, pancreatic, prostate, kidney, skin, testicular, thyroid, uterine and vulva, and non-solid tumors such as leukemia, multiple myeloma or lymphoma, etc.

The invention is further described below.

All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.

The polymorphic substance of the compound I of the invention has an X-ray powder diffraction characteristic peak expressed by a 2 theta angle, wherein +/-0.2 DEG is an allowable measurement error range.

The polymorph of compound I of the present invention can be used in combination with other active ingredients, as long as it does not produce other adverse effects, such as allergic reactions.

The active compounds represented by the polymorphic forms of compound I of the present invention may be used as the sole anticancer agent or may be used in combination with one or more other antineoplastic agents. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.

The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The actual dosage levels of each active ingredient in the pharmaceutical compositions of this invention can be varied so that the resulting amount of active compound is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration. Dosage levels will be selected with regard to the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is common practice in the art to start doses of the compounds at levels below those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

When used for the above-mentioned treatment and/or prophylaxis or other treatment and/or prophylaxis, a therapeutically and/or prophylactically effective amount of one of the polymorphic forms of compound I of the invention may be employed in pure form or, where present, in the form of a pharmaceutically acceptable ester or prodrug. Alternatively, the compounds may be administered in a pharmaceutical composition comprising the compound of interest together with one or more pharmaceutically acceptable excipients. The phrase "therapeutically and/or prophylactically effective amount" of a polymorph of compound I of the present invention refers to a sufficient amount of the compound to treat a disorder at a reasonable effect/risk ratio applicable to any medical treatment and/or prophylaxis. It will be appreciated, however, that the total daily amount of the polymorphic forms and compositions of compound I of the present invention will be decided by the attending physician within the scope of sound medical judgment. For any particular patient, the specific therapeutically effective dose level will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound employed; the duration of treatment; drugs used in combination or concomitantly with the specific compound employed; and similar factors known in the medical arts. For example, it is common in the art to start doses of the compound at levels below those required to achieve the desired therapeutic effect and to gradually increase the dose until the desired effect is achieved. In general, the dosage of the polymorphic forms of compound I of the present invention for use in mammals, particularly humans, may be between 0.001 to 1000mg/kg body weight/day, such as between 0.01 to 100mg/kg body weight/day, such as between 0.01 to 10mg/kg body weight/day.

Pharmaceutical compositions containing an effective amount of a polymorph of compound I of the present invention may be prepared using pharmaceutical carriers familiar to those skilled in the art. The present invention therefore also provides pharmaceutical compositions comprising a polymorph of compound I of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specifically formulated for oral administration, for parenteral injection or for rectal administration in solid or liquid form.

The pharmaceutical compositions can be formulated in a variety of dosage forms for ease of administration, for example, oral formulations (e.g., tablets, capsules, solutions or suspensions); injectable formulations (e.g., injectable solutions or suspensions, or injectable dry powders, which are ready to use by the addition of water for injection prior to injection). The carrier in the pharmaceutical composition comprises: binders for oral formulations (e.g., starch, typically corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone), diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycerol), lubricants (e.g., silicon dioxide, talc, stearic acid or salts thereof, typically magnesium or calcium stearate, and/or polyethylene glycol), and, if desired, disintegrating agents, such as starch, agar, alginic acid or salts thereof, typically sodium alginate, and/or effervescent mixtures, solubilizing agents, stabilizers, suspending agents, pigments, flavoring agents, and the like, preservatives, solvents, stabilizers, and the like for injectable formulations; bases for topical formulations, diluents, lubricants, preservatives, and the like. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.

More specifically, the pharmaceutical compositions of the present invention may be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (e.g., by powders, ointments, or drops), bucally to humans and other mammals, or as an oral or nasal spray. The term "parenteral" as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

Compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous or nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), vegetable oils (such as olive oil), injectable organic esters such as ethyl oleate, and suitable mixtures thereof.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of substances delaying absorption, for example, aluminum monostearate and gelatin.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

In some cases, to prolong the effect of a 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 crystalline or amorphous material which is poorly water soluble. Thus, the rate of absorption of the drug is dependent on its rate of dissolution, which in turn may be dependent on crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms can be prepared by forming a microencapsulated matrix of the drug in a biodegradable polymer such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include polyorthoesters (poly (orthoesters)) and polyanhydrides (polyanhydrides). Injectable depot formulations may also be prepared by embedding the drug in liposomes or microemulsions which are compatible with body tissues.

The injectable formulations can be sterilized, for example, by filtration through a bacterial filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium immediately prior to use.

The polymorphic form of compound I of the present invention or compositions thereof may be administered orally or parenterally. The oral administration can be tablet, capsule, coating agent, and intestinal tract external preparation such as injection and suppository. These formulations are prepared according to methods familiar to those skilled in the art. The adjuvants used for the manufacture of tablets, capsules, coatings are the customary adjuvants, such as starch, gelatin, gum arabic, silica, polyethylene glycol, solvents for liquid dosage forms, such as water, ethanol, propylene glycol, vegetable oils (e.g. corn oil, peanut oil, olive oil, etc.). The formulations containing the polymorphic forms of compound I of the present invention may also contain other adjuvants such as surfactants, lubricants, disintegrants, preservatives, flavoring agents and coloring agents. The dosage of the polymorphic forms of compound I of the present invention in tablets, capsules, coatings, injections and suppositories is calculated as the amount of compound present in the unit dosage form. The polymorph of Compound I of the present invention is generally present in an amount of 1 to 5000mg in a unit dosage form, preferably 10 to 500mg in a unit dosage form, more preferably 20 to 300mg in a unit dosage form. In particular, the present invention may provide solid dosage forms for oral administration including capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: 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 glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) humectants such as cetyl alcohol and glycerol monostearate; h) adsorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, buffers may also be included in the dosage forms.

Solid compositions of a similar type, using excipients such as lactose and high molecular weight polyethylene glycols and the like, can also be used as fillers in soft and hard capsules.

Solid dosage forms of tablets, dragees (dragees), capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. These solid dosage forms may optionally contain opacifying agents and may also be of such a composition that they release the active ingredient(s) only, or preferentially, at a site in the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. If appropriate, the active compounds can also be formulated in microencapsulated form with one or more of the abovementioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms may contain, in addition to the active compound, inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Oral compositions may contain, in addition to inert diluents, adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

Compositions for rectal or vaginal administration are preferably suppositories. Suppositories may be prepared by mixing the polymorphic forms of compound I of the invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax, which is solid at room temperature but liquid at body temperature and therefore will melt in the rectal or vaginal cavity and release the active compound.

Polymorphic forms of compound I of the present invention and compositions thereof are also contemplated for topical administration. Dosage forms for topical administration of polymorphic forms of compound I of the present invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives, buffers, or propellants. Ophthalmic formulations, ocular ointments, powders, and solutions are also contemplated within the scope of the invention.

Polymorphs of compound I of the present invention may also be administered in the form of liposomes. As is well known in the art, liposomes are typically made with phospholipids or other lipid materials. Liposomes are formed from single or multiple layers of hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The compositions of the present invention in liposome form may contain, in addition to the compound of the present invention, stabilizers, preservatives, excipients and 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, e.g., Prescott, ed., Methods in Cell Biology, Volume XIV, academic press, New York, n.y. (1976), p 33.

The inventor surprisingly found that the polymorphic substance of the compound I shows inhibitory activity on EGFR and Her2 tyrosine kinase, and simultaneously has inhibitory effect on cell strains with high expression of EGFR and Her2 tyrosine kinase, so that the polymorphic substance of the compound I can be used for diseases mediated by EGFR and Her2 receptor tyrosine kinase alone or partially, mainly through inhibiting one or more EGFR family tyrosine kinase and generating antiproliferative, anti-migration and proapoptotic effects through inhibiting the activity of the kinase. In particular, the polymorphic substance of the compound I can be used for preventing and treating tumors sensitive to one or more erbB receptor tyrosine kinases, especially tumors with high expression of EGFR or Her2 and EGF drive, through the inhibition effect on EGFR and Her2 tyrosine kinases. Including solid tumors such as cancers of the bile duct, bone, bladder, brain/central nervous system, breast, colorectal, endometrial, stomach, head and neck, liver, lung (especially non-small cell lung cancer), neurons, esophagus, ovary, pancreas, prostate, kidney, skin, testis, thyroid, uterus and vulva, non-solid tumors such as leukemia, multiple myeloma or lymphoma.

Description of the drawings:

FIG. 1X-ray powder diffraction pattern of amorphous form of Compound I.

Figure 2X-ray powder diffraction pattern of compound I form a.

Figure 3 differential scanning calorimetry trace of form a of compound I.

Figure 4X-ray powder diffraction pattern of compound I form B.

Figure 5 differential scanning calorimetry pattern of form B of compound I.

Figure 6X-ray powder diffraction pattern of compound I form C.

Figure 7X-ray powder diffraction pattern of compound I form D.

Figure 8 is the relationship between compound I crystalline form A, B, C, D.

Detailed Description

The present invention is further illustrated by the following specific preparation examples and biological test examples, but it should be understood that these examples and test examples are for illustrative purposes only in more detail and are not to be construed as limiting the present invention in any way. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. It will be apparent to those skilled in the art that the materials and methods of operation used in the present invention are well known in the art, unless otherwise specified.

The detection instrument used in the invention:

(1) nuclear magnetic resonance spectroscopy

The instrument model is as follows: varian INOVA-400 NMR spectrometer.

And (3) testing conditions are as follows: solvent DMSO-d₆。

(2) High resolution mass spectrometry

The instrument model is as follows: Q-Tof micro mass spectrometer.

And (3) testing conditions are as follows: ESI.

(3) X-ray powder diffractometer

Radiation source Cu target K α radiation.

Sample treatment: after the sample is ground, it is placed in a standard sample holder for measurement.

(4) Differential scanning calorimetry

The instrument model is as follows: NETZSCH thermal analyzer.

And (3) testing conditions are as follows: 10 ℃/min at 50 ℃.

Compound II can be prepared according to the procedure described in CN102030742A, as shown in example 1.

Example 1: n- (4- (3-Fluorobenzyloxy) -3-chlorophenyl) -6- (5- ((2- (methylsulfonyl) ethylamino) methyl) methane Preparation of yl) -2-furyl) -quinazolin-4-amine (compound II):

preparation of Boc protected 2-mercaptoethylamine:

adding 35.3g of di-tert-butyl dicarbonate, 20.4g of 2-mercaptoethylamine hydrochloride and 200ml of dichloromethane into a reaction bottle, adding 25ml of triethylamine in batches under an ice bath condition, stirring at room temperature for reaction overnight, adding excessive 0.5M hydrochloric acid solution for washing, washing an organic layer with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, and evaporating the solvent to obtain 8g of Boc-protected 2-mercaptoethylamine (oily liquid), wherein the yield is 87%.

Preparation of Boc protected 2-methylthioethylamine:

under the conditions of ice bath and nitrogen protection, adding 4.8g of NaH into 28g of anhydrous tetrahydrofuran (250ml) solution of 2-mercaptoethylamine protected by Boc in batches, heating to room temperature for reaction for 1h, dropwise adding 12ml of tetrahydrofuran solution of methyl iodide under the condition of ice bath, reacting at room temperature for about 1h after dropwise adding, adding saturated sodium carbonate solution for quenching reaction, pouring the reaction solution into water, extracting with ethyl acetate, washing an organic phase with saturated sodium chloride solution, drying with anhydrous sodium sulfate, and evaporating the solvent to obtain oily liquid. Column chromatography gave Boc protected 2-methylthioethylamine 14.2g, 47% yield.

Preparation of Boc protected 2-methylsulfonylethylamine:

under the ice bath condition, 14.0g of Boc protected 2-methylthioethylamine is dissolved in methanol, an aqueous solution of sodium periodate is dripped, the mixture is stirred at room temperature and reacts overnight after the addition, the filtration is carried out, dichloromethane is used for washing a filter cake, the organic solvent in the filtrate is evaporated under reduced pressure, a saturated sodium chloride solution is added, ethyl acetate is used for extraction, anhydrous magnesium sulfate is used for drying, the filtration is carried out, the solvent is evaporated under reduced pressure, and 13.2g (oily matter) of Boc protected 2-methylthioethylamine is obtained, and the yield is 87%.

Preparation of Boc protected 2-methylsulfonylethylamine hydrochloride:

dissolving 12g of Boc protected 2-methylsulfonylethylamine in anhydrous ether, introducing hydrochloric acid gas, detecting the completion of the raw material reaction by TLC, and evaporating under reduced pressure to remove the solvent to obtain 6.8g of Boc protected 2-methylsulfonylethylamine hydrochloride (oily substance) with the yield of 82%.

e.N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- ((2- (methylsulfonyl) ethylamino) methyl) -2- Preparation of furyl) -quinazolin-4-amine:

dissolving 12g of compound 5- (4- (4- (3-fluorobenzyloxy) -3-chloroanilino) -6-quinazolinyl) furan-2-formaldehyde p-toluenesulfonate in a dichloromethane/methanol (3:1) mixed solution, adding 12ml of triethylamine, stirring for reaction for 10min, adding 6.0g of 2-methylsulfoxide ethylamine hydrochloride, stirring for reaction at room temperature, detecting the reaction of raw materials by TLC, adding 2.0g of sodium borohydride in batches under ice bath, detecting the reaction by TLC, adding a proper amount of dichloromethane, washing with a saturated ammonium chloride solution, washing with a saturated sodium chloride solution, drying with anhydrous sodium sulfate, and performing column chromatography to obtain 7.3g of a yellow solid, namely N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- ((2- (methylsulfenyl) ethylamino) methyl) -2-furyl) -quinazolin-4-amine (compound II) in 69% yield.

¹H-NMR(600MHz,DMSO-d₆,δppm)：9.92(s,1H),9.044(s,1H),8.92(s,1H),8.41(t,1H,J＝6.6Hz),7.93(d,1H,J＝7.8Hz),7.64(dd,1H,J＝2.4Hz,J＝9Hz),7.50(d,1H,J＝7.8Hz),7.48(d,1H,J＝9.6Hz),7.36(d,1H,J＝9Hz),7.25(d,1H,J＝3.0Hz),7.22(dd,1H,J＝2.4Hz,J＝9Hz),7.11(d,1H,J＝7.2Hz),7.25(d,1H,J＝3.0Hz),5.32(s,2H),4.47(s,2H),3.51(t,2H,J＝7.2Hz),2.67(t,2H,J＝7.2Hz),2.29(s,3H)。

MS(m/z):[M-H]563.1389。

Example 2: n- (4- (3-Fluorobenzyloxy) -3-chlorophenyl) -6- (5- ((2- (methylsulfonyl) ethylamino) methyl) methane Preparation of the radical) -2-furyl) -quinazolin-4-aminedixylenesulfonate (Compound I)

Referring to the preparation method of CN102030742A, 2g (3.54mmol) of compound II was added to 10ml of tetrahydrofuran, stirred and dissolved, and 1.83g (10.6mmol) of ethanol solution of p-toluenesulfonic acid was added to precipitate a yellow solid quickly, which was then subjected to suction filtration and air drying to obtain 3.01g N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) -6- (5- ((2- (methylsulfonyl) ethylamino) methyl) -2-furyl) -quinazolin-4-aminoxylenesulfonate (yellow solid) with a yield of 93.5%.

The product is amorphous by X-ray powder diffraction, and the X-RPD pattern is shown in figure 1.

MS(m/z):[M-H]907.1713。

Nuclear magnetic resonance spectroscopy:¹H. COSY spectrum (600MHz, DMSO-d)₆)

And (3) testing results:

TABLE 1 nuclear magnetic resonance¹H. COSY spectral data Listing

Example 3: n- (4- (3-Fluorobenzyloxy) -3-chlorophenyl) -6- (5- ((2- (methylsulfonyl) ethylamino) methyl) methane Preparation of crystalline form C of the salt of phenyl-2-furyl) -quinazolin-4-aminoxylenesulfonic acid (Compound I)

Adding 2g of the compound I into a mixed system of 40ml of tetrahydrofuran and 5ml of water, refluxing and dissolving, cooling and crystallizing, filtering, and drying in the air to obtain 1.6g of yellow crystalline powder with the yield of 80%. The obtained product is subjected to X-ray powder diffraction, the result shows that the product is the compound I crystal form C, and an X-RPD map is shown in figure 6.

Example 4: n- (4- (3-Fluorobenzyloxy) -3-chlorophenyl) -6- (5- ((2- (methylsulfonyl) ethylamino) methyl) methane Preparation of crystalline form A of the salt of phenyl-2-furyl) -quinazolin-4-aminoxylenesulfonate (Compound I)

Drying the crystal form C2 g of the compound I for 1 hour at the temperature of 80 ℃ to obtain yellow crystalline powder, and performing X-ray powder diffraction on the obtained product, wherein the result shows that the product is the crystal form A of the compound I, and an X-RPD map is shown in figure 2; DSC detection data show that the crystal form A is subjected to melting decomposition at 240.82-255.59 ℃, and a Differential Scanning Calorimetry (DSC) pattern is shown in figure 3.

Example 5: n- (4- (3-Fluorobenzyloxy) -3-chlorophenyl) -6- (5- ((2- (methylsulfonyl) ethylamino) methyl) methane Preparation of crystalline form D of the salt of phenyl-2-furyl) -quinazolin-4-aminoxylenesulfonic acid (Compound I)

Adding 2g of the compound I into a mixed system of 40ml of ethanol and 6ml of water, refluxing for dissolution, cooling for crystallization, performing suction filtration and air drying to obtain 1.7g of yellow crystalline powder, wherein the yield is 85%, performing X-ray powder diffraction on the obtained product, and the result shows that the product is a compound I crystal form D, and an X-RPD map is shown in figure 7.

Example 6: n- (4- (3-)Fluorobenzyloxy) -3-chlorophenyl) -6- (5- ((2- (methylsulfonyl) ethylamino) methyl Preparation of crystalline form B of the salt of phenyl-2-furyl) -quinazolin-4-aminoxylenesulfonic acid (Compound I)

Drying the crystal form D2 g of the compound I for 1 hour at the temperature of 80 ℃ to obtain yellow crystalline powder, and performing X-ray powder diffraction on the obtained product, wherein the result shows that the product is the crystal form B of the compound I, and an X-RPD map is shown in figure 4; DSC detection data show that the crystal form B is melted and decomposed at 239.11-254.49 ℃; the DSC pattern is shown in figure 5.

(Note: since Compound I form C, D is converted to Compound I form A, B at high temperature (above 60 ℃ C.), no DSC run was performed.)

The invention researches the stability of amorphous substance and crystal form A, B, C, D of compound I, and the humidity is 60% +/-10% at the temperature of 25 +/-2 ℃; stability was examined for 6 months at 40. + -. 2 ℃ and 75%. + -. 5% humidity. Test results show that the amorphous compound I is obviously degraded, which indicates that the amorphous compound I has poor stability; the largest simple substance and total impurities of the crystal form A, B, C, D are not obviously increased, and the examined sample is analyzed and tested by X-ray powder diffraction and other analysis and test methods to verify that the crystal form A, B, C, D of the compound I is stable. The test results are shown in Table 2.

TABLE 2 stability test results for amorphous form of Compound I, form A, B, C, D

The solubility of compound II, amorphous compound I and crystal form A, B, C, D is studied. A compound to be detected is taken and placed in a 250ml iodometric flask, water is added, strong shaking is carried out at 25 +/-2 ℃ for 30 seconds at intervals of 5 minutes, and the dissolution condition within 30 minutes is observed. The test results are shown in Table 3.

TABLE 3 solubility test results of Compound II, amorphous Compound I, and crystalline form A, B, C, D in water

Compound (I)	Solute/solvent	Phenomenon(s)	Solubility in water
				Example 1 Compound II	10mg/99ml	Is not completely dissolved	Insoluble matter
Example 2 amorphous Material	0.1g/100ml	Dissolution	Slightly soluble
				Form A obtained in example 4	0.1g/100ml	Dissolution	Slightly soluble
Form B obtained in example 6	0.1g/100ml	Dissolution	Slightly soluble
				Form I of crystal form C obtained in example 3	0.1g/100ml	Dissolution	Slightly soluble
Form I of crystal form D obtained in example 5	0.1g/100ml	Dissolution	Slightly soluble

The results show that: the compound II is insoluble in water, and the amorphous compound I and the crystal form A, B, C, D are slightly soluble in water, which shows that the crystal form A, B, C, D is more favorable for dissolving the medicine in vivo than the compound II.

Biological experiments

The following experiments may be used to determine the effect of the compounds of the invention on erbB tyrosine kinase activity and as inhibitors of N87 cells and BT474 cells in vitro.

A) Protein tyrosine kinase phosphorylation assay

In vitro Kinase assays were detected using the HTScan EGF receptor Kinase Assay Kit (#7909) and HTScan HER2/ErbB2Kinase Assay Kit (#7058) from Cell Signaling Technology. The method detects the inhibition effect of the compound to be detected on the phosphorylation of the EGFR or Her2 receptor tyrosine kinase on the substrate peptide in vitro by referring to the kit instructions. Incubating ATP, substrate peptide and a compound to be detected in a kinase reaction buffer solution at room temperature, adding a stop solution to stop the reaction after a certain period of incubation, transferring a sample into a 96-well plate coated with streptavidin, washing the plate, detecting the phosphorylation level of the substrate peptide by using an anti-substrate phosphorylation antibody marked by HRP, developing the phosphorylation level by using TMB, and stopping the reaction by using 2M sulfuric acid. Detecting the absorption wavelength of 450nm, and calculating IC₅₀Value (. mu.M). The results are shown in Table 4.

B) Inhibition of cell proliferation

The tests were carried out with reference to the method described in Rusnakek et al, Cell Prolif, 2007, 40, 580-594. The cell proliferation inhibition test adopts human breast cancer cells BT474 and human gastric cancer cell lines NCI-N87, the BT474 expresses Her2 receptors in a high way, and the N87 expresses EGFR and Her2 receptors in a high way.

In Dulbecco's Modified Eagle's Medium (DMEM) containing 10% fetal bovine serum, 2mM glutamine and non-essential amino acids, 5% CO at 37 ℃₂Cells were cultured in a cell incubator and harvested from cell culture flasks using trypsin/ethylenediaminetetraacetic acid (EDTA). The cells were added to a 96-well cell culture plate at 4000/well (0.1ml medium) overnight for adherence, 0.1ml of a dilution of the test compound was added to give a final DMSO concentration of 0.25%, and the cell culture plate was incubated at 37 ℃ with 5% CO₂Incubate under conditions for 72 h. Then, the change in cell morphology was observed under a microscope, and 50. mu.l of trichloroacetic acid (TCA) was added to each well to fix the cells. Standing for 5min, standing for 1h in a refrigerator at 4 deg.C, washing each hole of the culture plate with deionized water for 5 times to remove TCA, spin-drying, and air-drying until no wet mark exists. Adding 0.4% (mass/volume) SRB100 μ l to each well, standing at room temperature for 10min, discarding the liquid in each well, washing with 1% acetic acid for 5 times, air drying, extracting with 10.5 pH 10mM Tris base (Tris hydroxymethyl aminomethane) 150 μ l, and detecting the absorption wavelength at 540 nm. Result IC₅₀The values (. mu.M) are shown in Table 4.

Table 4 analysis of inhibitory activity of crystalline form A, B, C, D of compound I of the invention against EGFR and Her2

Note: "+ + + + +" refers to IC₅₀The value is < 0.025. mu.M; "+ + + +" refers to IC₅₀The value is 0.025-0.10. mu.M.

In an important 'cell proliferation inhibition test' for evaluating the biological activity of the compound, the crystal form A, B, C, D of the compound I has better biological activity.

The results show that the crystalline form A, B, C, D of compound I of the present invention is a potent tyrosine kinase inhibitor.

Claims

1. A polymorph of compound I, characterized in that said polymorph is form B or form C, wherein form B, when irradiated with Cu-K α, has an X-ray powder diffraction pattern expressed in degrees 2 θ having characteristic peaks at 4.6 ° ± 0.2 °, 8.3 ° ± 0.2 °, 9.1 ° ± 0.2 °, 12.0 ° ± 0.2 °, 13.9 ° ± 0.2 °, 15.0 ° ± 0.2 °, 15.8 ° ± 0.2 °, 17.6 ° ± 0.2 °, 18.7 ° ± 0.2 °, 19.7 ° ± 0.2 °, 20.8 ° ± 0.2 °, 22.2 ° ± 0.2 °, 22.8 ° ± 0.2 °, 26.0 ° ± 0.2 °, 2C, when irradiated with Cu-K α °, 2 ° and an X-ray powder diffraction pattern expressed in degrees 2 θ having characteristic peaks at 4.4 ° ± 0.2 ° ± 0.2.2 ° ± 0.2 ° 2.2 °, 2 ° ± 0.2 ° ± 0.2.2 ° ± 0.2 ° 19 ° ± 0.2 °;

2. the polymorph of claim 1, wherein form B has an X-ray powder diffraction pattern substantially as shown in figure 4.

3. The polymorph of claim 1, wherein form B undergoes melt decomposition at a temperature of 239.11-254.49 ℃.

4. The polymorph of claim 1, wherein form B has a differential scanning calorimetry pattern as shown in figure 5.

5. The polymorph of claim 1, wherein form C has an X-ray powder diffraction pattern substantially as shown in figure 6.

6. A process for the preparation of the polymorph of any one of claims 1 to 5, comprising the steps of:

(1) preparation of compound I form C comprising the steps of:

dissolving a compound I in a tetrahydrofuran/water system under the condition of heating reflux, cooling, crystallizing, filtering and airing to obtain a crystal form C of the compound I; or,

(2) preparation of compound I form B comprising the steps of:

dissolving a compound I in an ethanol/water system under the condition of heating reflux, cooling, crystallizing, filtering and airing to obtain a compound I crystal form D, and drying the compound I crystal form D at 60-150 ℃ to obtain a compound I crystal form B.

7. A pharmaceutical composition comprising the polymorph of any one of claims 1 to 5, and optionally one or more pharmaceutically acceptable excipients.

8. Use of a polymorph according to any one of claims 1 to 5 in the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition associated with receptor tyrosine kinases in a mammal.

9. Use of the polymorph of any one of claims 1 to 5 for the preparation of a medicament for the therapeutic or adjunctive treatment and/or prevention of receptor tyrosine kinase mediated tumor or receptor tyrosine kinase driven proliferation and migration of tumor cells in a mammal.

10. Use according to claim 8 or 9, wherein the mammal is a human.

11. Use according to claim 8 or 9 wherein the disease or condition associated with a receptor tyrosine kinase, a tumour mediated by a receptor tyrosine kinase or proliferation and migration of tumour cells driven by a receptor tyrosine kinase is an erbB receptor tyrosine kinase sensitive cancer.

12. The use of claim 11 wherein the erbB receptor tyrosine kinase sensitive cancer is a tumor that is highly expressed by EGFR or Her2 and that is EGF driven.

13. The use of claim 12, wherein the EGFR or Her2 high expression and EGF driven tumor is a solid tumor.

14. The use according to claim 13, wherein the solid tumor is selected from the group consisting of cancer of the bile duct, bone, bladder, central nervous system, breast, colorectal, stomach, head, neck, liver, lung, neurons, esophagus, ovary, pancreas, prostate, kidney, skin, testis, thyroid, uterus, vulva.

15. Use according to claim 14, wherein the central nervous system is the brain.

16. The use of claim 12, wherein the EGFR or Her2 high expression and EGF driven tumor is a non-solid tumor.

17. Use according to claim 16, wherein the non-solid tumour is selected from leukaemia, multiple myeloma and lymphoma.