CN104119321B - The 2-maleate and its polymorph of indolinone derivative - Google Patents
The 2-maleate and its polymorph of indolinone derivative Download PDFInfo
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- CN104119321B CN104119321B CN201310153347.5A CN201310153347A CN104119321B CN 104119321 B CN104119321 B CN 104119321B CN 201310153347 A CN201310153347 A CN 201310153347A CN 104119321 B CN104119321 B CN 104119321B
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- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical class C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 title abstract description 4
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 39
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 27
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 27
- 239000011976 maleic acid Substances 0.000 claims description 27
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 27
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 abstract description 2
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 abstract description 2
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- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 abstract 1
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- YSMMOVBWZRIVPM-UHFFFAOYSA-N indol-2-ylidenemethanone Chemical class C1=CC=CC2=NC(=C=O)C=C21 YSMMOVBWZRIVPM-UHFFFAOYSA-N 0.000 abstract 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
The 2-maleate and its polymorph of indolinone derivative.The invention belongs to field of medicine and chemical technology, and in particular to N（5‑（（Z）(5 fluorine, 2 carbonyl indoles 3 is sub-) methyl）The base of 2,4 dimethyl, 1 hydrogen pyrroles 3）‑3‑（The base of 4 methyl piperazine 1）Propionamide 2-maleate（Compound I）And its polymorph.The invention further relates to the preparation method of compound I polymorphs, the Pharmaceutical composition of inclusion compound I and its polymorph, and the compound I and its polymorph pharmaceutical applications.The compound I of present invention polymorph has good crystallinity and physically and/or chemically stability.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to N- (5- ((Z) - (5-fluoro-2-carbonyl indole-3-methylene) methyl) -2, 4-dimethyl-1 hydrogen-pyrrole-3-yl) -3- (4-methylpiperazin-1-yl) propionamide dimaleate (compound I), a polymorphic substance thereof, a preparation method, a pharmaceutical composition containing the compound I and the polymorphic substance thereof, and pharmaceutical application of the compound I and the polymorphic substance thereof.
Background
Cancer is still the leading cause of human death worldwide. Statistically, 1200 million people are diagnosed with cancer and 960 million people die of cancer worldwide each year. Accounting for 13% of all deaths. The number of cancer attacks and deaths worldwide will continue to rise, and if no intervention is taken, 2600 million new cases and up to 1700 million deaths are expected worldwide in 2030. The first few cancers with mortality include lung cancer, gastric cancer, liver cancer, colorectal cancer, etc.
Tyrosine kinase is a kinase which catalyzes gamma-phosphate on ATP to transfer to protein tyrosine residue, can catalyze phosphorylation of various substrate protein tyrosine residues, and has important functions in cell growth, proliferation and differentiation. Most of the protein tyrosine kinases discovered to date are oncogene products belonging to oncogenic RNA viruses, and can also be produced from vertebrate proto-oncogenes. The tyrosine kinase inhibitor can be used as competitive inhibitor for combining Adenosine Triphosphate (ATP) and tyrosine kinase, can also be used as tyrosine analogue, blocks the activity of tyrosine kinase, inhibits cell proliferation, and can be developed into antitumor drugs.
The small molecular tyrosine kinase inhibitor has been widely applied clinically as a targeted antitumor drug, can be used for various solid tumors and blood tumors, and makes great contribution to the clinical treatment of the tumors. WO0160814, WO2008067756, WO2008138184, WO2008138232, WO2007085188, WO2005058309, WO2006002422 and the like disclose pyrrole substituted indolinone structure type derivatives having tyrosine kinase inhibitory activity. Among the drugs with the structure type, the marketed Sunitinib developed by the pfeiffer company belongs to a multi-target tyrosine kinase inhibitor, has a strong anti-angiogenesis effect, and can inhibit the proliferation of tumor cells. Since FDA approval in the united states at 1 month 2006, clinical efficacy is definite and is currently on the market in more than 60 countries for the treatment of gastrointestinal stromal tumors and progressive renal cell carcinoma that are treated with imatinib and whose disease is still progressing or is intolerant of this drug.
WO2011153814a1 discloses N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1-hydro-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propanamide compounds and methods for their preparation, and the compounds have potential for development as antitumor drugs. However, the solubility of this compound is very low and there is a need to find forms with superior physical and/or chemical properties to meet drug delivery applications.
Disclosure of Invention
The inventor successfully prepares the dimaleate form and various crystal forms of N- (5- ((Z) - (5-fluoro-2-carbonyl indole-3-methylene) methyl) -2, 4-dimethyl-1 hydrogen-pyrrole-3-yl) -3- (4-methylpiperazin-1-yl) propionamide through a large number of experiments, and proves that the N- (5- ((Z) - (5-fluoro-2-carbonyl indole-3-methylene) propionamide has better solubility in phosphate solution with the pH value of about 6.8 and is beneficial to absorption in vivo; and has better stability, facilitating packaging and storage, thereby completing the present invention.
In a first aspect, the present invention provides a compound of formula I:
the compound is named as N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1H-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide dimaleate and is also named as compound I in the invention.
A compound according to the first aspect of the invention which is a polymorph.
(1) The compound according to the first aspect of the present invention, characterized in that said crystalline form has an X-ray powder diffraction, expressed in terms of 2 Θ angles, using Cu-ka radiation, with characteristic absorption peaks at about the following positions: 5.5 +/-0.20 degrees, 8.3 +/-0.20 degrees, 13.8 +/-0.20 degrees, 16.6 +/-0.20 degrees, 22.2 +/-0.20 degrees, 25.1 +/-0.20 degrees, 26.3 +/-0.20 degrees and 27.9 +/-0.20 degrees;
preferably, it has characteristic absorption peaks at about the following positions: 5.5 +/-0.20 degrees, 6.5 +/-0.20 degrees, 8.3 +/-0.20 degrees, 9.8 +/-0.20 degrees, 11.0 +/-0.20 degrees, 13.0 +/-0.20 degrees, 13.8 +/-0.20 degrees, 16.6 +/-0.20 degrees, 18.3 +/-0.20 degrees, 22.2 +/-0.20 degrees, 22.8 +/-0.20 degrees, 23.5 +/-0.20 degrees, 25.1 +/-0.20 degrees, 26.3 +/-0.20 degrees, 27.9 +/-0.20 degrees and 28.7 +/-0.20 degrees;
in an embodiment of the invention, it has an X-ray powder diffraction pattern substantially as shown in figure 1.
The compound according to the first aspect of the present invention is characterized in that a differential scanning calorimetry analysis shows that the crystalline form has an endothermic peak at 194 to 220 ℃ confirming that the compound starts to melt.
In a particular embodiment of the invention, it is form a.
In a specific embodiment of the present invention, thermogravimetric analysis of the form a shows that the form a loses about 8.5% weight at 40-170 ℃, but does not have a corresponding change in heat, is not a solvate or hydrate, and loses weight indicating the presence of a free solvent; weight loss continued at 200 ℃ and compound I melted.
(2) The compound according to the first aspect of the present invention, characterized in that said crystalline form has characteristic absorption peaks at about the following positions, using Cu-Ka radiation, X-ray powder diffraction expressed in 2 Θ angles: 6.4 +/-0.2 degrees, 9.7 +/-0.20 degrees, 12.4 +/-0.20 degrees, 13.0 +/-0.20 degrees, 16.3 +/-0.20 degrees, 22.9 +/-0.20 degrees, 24.3 +/-0.2 degrees, 25.2 +/-0.2 degrees and 26.2 +/-0.20 degrees;
preferably, it has characteristic absorption peaks at about the following positions: 6.4 +/-0.20 degrees, 7.5 +/-0.20 degrees, 8.8 +/-0.20 degrees, 9.7 +/-0.20 degrees, 12.4 +/-0.20 degrees, 13.0 +/-0.20 degrees, 16.3 +/-0.20 degrees, 17.4 +/-0.20 degrees, 18.0 +/-0.20 degrees, 18.8 +/-0.20 degrees, 19.6 +/-0.20 degrees, 21.8 +/-0.20 degrees, 22.9 +/-0.20 degrees, 24.3 +/-0.20 degrees, 25.2 +/-0.20 degrees, 26.2 +/-0.20 degrees, 26.9 +/-0.20 degrees and 33.0 +/-0.20 degrees;
in an embodiment of the invention, it has an X-ray powder diffraction pattern substantially as shown in figure 4.
The compound according to the first aspect of the present invention is characterized in that a differential scanning calorimetry analysis shows that the crystal form has an endothermic peak at 274 ℃ of 188-.
In a particular embodiment of the invention, it is form B.
In a specific embodiment of the invention, thermogravimetric analysis of form B shows that the form is about 0.56% weight loss as a solvent-free anhydrate.
(3) The compound according to the first aspect of the present invention, characterized in that said crystalline form has an X-ray powder diffraction, expressed in terms of 2 Θ angles, using Cu-ka radiation, with characteristic absorption peaks at about the following positions: 2.8 +/-0.20 degrees, 5.6 +/-0.20 degrees, 8.4 +/-0.20 degrees, 16.4 +/-0.20 degrees, 22.5 +/-0.20 degrees, 25.4 +/-0.20 degrees, 26.6 +/-0.20 degrees and 28.2 +/-0.20 degrees;
preferably, it has characteristic absorption peaks at about the following positions: 2.8 +/-0.20 degrees, 5.6 +/-0.20 degrees, 8.4 +/-0.20 degrees, 11.2 +/-0.20 degrees, 16.4 +/-0.20 degrees, 19.5 +/-0.20 degrees, 22.5 +/-0.20 degrees, 24.0 +/-0.20 degrees, 25.4 +/-0.20 degrees, 26.6 +/-0.20 degrees and 28.2 +/-0.20 degrees;
in an embodiment of the invention, it has an X-ray powder diffraction pattern substantially as shown in figure 7.
The compound according to the first aspect of the present invention is characterized in that the crystal form has two endothermic peaks at 150 to 185 ℃ and 209 to 230 ℃ as shown by differential scanning calorimetry. The first endotherm is due to the loss of DMF from the solvate and the second endotherm indicates that Compound I starts to melt.
In a particular embodiment of the invention, it is form C.
In a specific embodiment of the invention, thermogravimetric analysis of form C shows that the form is about 12.1% weight loss as a N, N-Dimethylformamide (DMF) solvate, containing about 1N, N-dimethylformamide molecule.
(4) The compound according to the first aspect of the present invention, characterized in that said crystalline form has characteristic absorption peaks at about the following positions, using Cu-Ka radiation, X-ray powder diffraction expressed in 2 Θ angles: 5.6 +/-0.20 degrees, 8.4 +/-0.20 degrees, 14.0 +/-0.20 degrees, 22.5 +/-0.20 degrees, 23.8 +/-0.20 degrees, 25.4 +/-0.20 degrees, 26.5 +/-0.20 degrees and 28.3 +/-0.20 degrees;
preferably, it has characteristic absorption peaks at about the following positions: 5.6 +/-0.20 degrees, 8.4 +/-0.20 degrees, 9.0 +/-0.20 degrees, 14.0 +/-0.20 degrees, 14.7 +/-0.20 degrees, 15.6 +/-0.20 degrees, 16.6 +/-0.20 degrees, 18.1 +/-0.20 degrees, 22.5 +/-0.20 degrees, 23.8 +/-0.20 degrees, 24.6 +/-0.20 degrees, 25.4 +/-0.20 degrees, 26.5 +/-0.20 degrees, 28.3 +/-0.20 degrees and 29.5 +/-0.20 degrees;
in an embodiment of the invention, it has an X-ray powder diffraction pattern substantially as shown in figure 10.
The compound according to the first aspect of the present invention is characterized in that the crystal form has two endothermic peaks at 182-201 ℃ and 202-225 ℃ as shown by differential scanning calorimetry. The first endotherm is due to the loss of DMSO in the solvate, the second endotherm indicates that compound I starts to melt.
In a particular embodiment of the invention, it is form D.
In a specific embodiment of the invention, thermogravimetric analysis of form D shows that the form is about 11.8% weight loss as a dimethyl sulfoxide (DMSO) solvate, containing about 1 molecule of dimethylsulfone.
The second aspect of the present invention also relates to a process for the preparation of a compound according to any one of the first aspects of the present invention:
(1) a process for producing a compound of the first aspect (3) of the present invention:
reacting N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1-hydro-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide with maleic acid in N, N-Dimethylformamide (DMF) with stirring to give the compound of item (3) of the first aspect of the present invention; wherein the molar ratio of N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1 h-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide to maleic acid is 1: 2;
(2) a process for producing a compound of the first aspect (4) of the present invention:
reacting N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1-hydro-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide with maleic acid in dimethylsulfoxide with stirring to obtain the compound of item (4) of the first aspect of the present invention; wherein the molar ratio of N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1 h-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide to maleic acid is 1: 2;
(3) a process for producing a compound of the first aspect (1) of the present invention:
reacting N- (5- ((Z) - (5-fluoro-2-carbonylindol-3-ylidene) methyl) -2, 4-dimethyl-1 h-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide with maleic acid in tetrahydrofuran, tetrahydrofuran/water, acetone, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, ethanol, isopropanol, N-butanol, dioxane with stirring to give the compound of item (1) of the first aspect of the present invention; wherein the molar ratio of N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1 h-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide to maleic acid is 1: 2;
(4) a process for producing a compound of the first aspect (2) of the present invention:
reacting N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1-hydro-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide with maleic acid in water, DMF/water, N-Dimethylacetamide (DMAC)/water, methanol, ethylene glycol, acetonitrile with stirring to give a compound of item (2) of the first aspect of the present invention; wherein the molar ratio of N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1 h-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide to maleic acid is 1: 2; the mixed solvent of DMF, DMAC and water only needs to contain water with the content not being 0, wherein the preferable ratio is 1: 0.5-20;
or,
beating the compound of the first aspect of the present invention in the item (3) or (4) in water, stirring, filtering and drying to obtain the compound of the first aspect of the present invention in the item (2);
or,
drying the compound of the first aspect (3) or (4) at 150 to 200 ℃ to obtain the compound of the first aspect (2).
In the present invention, N- (5- ((Z) - (5-fluoro-2-carbonylindol-3-ylidene) methyl) -2, 4-dimethyl-1-hydro-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide is prepared by a person of ordinary skill in the art according to the prior art, in an exemplary method, N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1-hydro-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide may be prepared as described in reference WO2011153814a 1.
A third aspect of the invention relates to a pharmaceutical composition comprising a compound according to any one of the first aspects of the invention, and optionally one or more pharmaceutically acceptable carriers or excipients.
The fourth aspect of the present invention relates to the use of a compound according to any one of the first aspect of the present invention in the manufacture of a medicament for the prevention and/or treatment of a disease or condition associated with receptor tyrosine kinases in a mammal (including a human).
In the present invention, the disease or disorder associated with receptor tyrosine kinases refers to proliferation and migration of tumors or tumor cells driven by receptor tyrosine kinases mediated by receptor tyrosine kinases;
in the present invention, the receptor tyrosine kinase mediated tumor or receptor tyrosine kinase driven tumor cell proliferation and migration refers to 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 vulva, and non-solid tumors such as leukemia, multiple myeloma or lymphoma, etc.
The invention also relates to the use of a compound according to any one of the first aspect of the invention in the manufacture of a medicament for use as an inhibitor of receptor tyrosine kinases.
The present invention also relates to a method for the prevention and/or treatment of a disease or condition associated with receptor tyrosine kinases in a mammal (including a human being) comprising the step of administering to a mammal in need thereof a prophylactically and/or therapeutically effective amount of a compound according to any one of the first aspect of the present invention.
The present invention is further described in detail 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.
In the present invention, the polymorph refers to a crystal of a substance formed by molecules or ions arranged in different ways; in a specific embodiment of the present invention, the polymorphic form of compound I refers to form a, form B, form C, form D of compound I.
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" or "pharmaceutical 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.
Compound I, or a polymorph of compound I, of the present invention can be prepared into suitable pharmaceutical compositions using known pharmaceutical carriers by those skilled in the art. 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 upon addition of a pharmaceutical vehicle prior to injection).
As used herein, the term "therapeutically and/or prophylactically effective amount" is the amount of a drug or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other person.
When used for the above-mentioned treatment and/or prevention, the total daily amount of compound I of the present invention, or a polymorph of compound I and the pharmaceutical composition, is to be determined 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.
Drawings
Figure 1 is an X-ray powder diffraction pattern of compound I form a of example 2.
Figure 2 is a differential scanning calorimetry analysis of form a of compound I of example 2.
Figure 3 is a thermogravimetric analysis profile of compound I form a of example 2.
Figure 4 is an X-ray powder diffraction pattern of compound I form B of example 8.
Figure 5 is a differential scanning calorimetry analysis of form B of compound I of example 8.
Figure 6 is a thermogravimetric analysis of form B of compound I of example 8.
Figure 7 is an X-ray powder diffraction pattern of compound I form C of example 6.
FIG. 8 is a differential scanning calorimetry analysis plot of form C of Compound I of example 6
Figure 9 is a thermogravimetric analysis of form C of compound I of example 6.
Figure 10 is an X-ray powder diffraction pattern of compound I form D of example 7.
FIG. 11 is a differential scanning calorimetry analysis plot of form D of Compound I of example 7
Figure 12 is a thermogravimetric analysis profile of compound I form D of example 7.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
It will be clear to those skilled in the art that, in the following, the materials and methods of operation used in the present invention are well known in the art, if not specifically described; the temperature is expressed in degrees centigrade (DEG C), and the operation is performed at room temperature or normal temperature (generally 10 to 30 ℃).
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) X-ray powder diffractometer
The instrument model is as follows: PANALYTIC EMPyrean X-ray powder diffraction analyzer
The test method comprises the following steps: filling the ground sample (100mg) in a groove of a glass plate, hanging the plane of the glass plate and the surface of the glass plate to be flush by using a glass slide, placing the sample in a PANalytic Empyrean X-ray powder diffraction analyzer, using a 40kV and 40mA copper X-ray source, wherein the scanning range is 3-45 degrees (2 theta), the scanning speed is 4 degrees/minute, and the scanning time is 6 minutes. The scan error is typically ± 0.2 degrees (2 θ).
(3) TGA/DSC1 synchronous thermal analyzer
The instrument model is as follows: METTLER TGA/DSC 1.
The test method comprises the following steps: samples weighing 10mg were placed in a closed aluminum pan with small pinholes, equilibrated at 30 ℃ and then heated to 250 ℃ at a scan rate of 10 ℃/min. Dry nitrogen was used as purge gas.
N- (5- ((Z) - (5-fluoro-2-carbonylindol-3-ylidene) methyl) -2, 4-dimethyl-1 h-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide may be prepared according to the method described in WO2011153814a1, as shown in example 1 below.
Example 1: n- (5- ((Z) - (5-fluoro-2-carbonylindol-3-ylidene) methyl) -2, 4-dimethyl-1-hydro-pyrrole-3-
Preparation of yl) -3- (4-methylpiperazin-1-yl) propionamide:
a.N- { 5- [ 5-fluoro-2-oxo-1, 2-dihydro-indol- (3Z) -ylidenemethyl]-2, 4-dimethyl-1H-pyrrole-
Synthesis of 3-yl } -3-bromo-propionamide:
3-Bromopropionic acid (338 mg,1.2 eq) was dissolved in 5ml of N, N-Dimethylformamide (DMF) and stirred at room temperature until dissolved; 4- (4, 6-dimethoxytriazin-2-yl) -4-methylmorpholine hydrochloride (DMTMM) (618 mg,1.2 eq) was added thereto, and the mixture was stirred at room temperature for 20min, and then (3Z) - [ (3, 5-dimethyl-4-amino-1-hydropyrrol-2-yl) ylidenemethyl ] -5-fluoroindol-2-one (501mg,1.0eq) was added thereto, and the mixture was stirred at room temperature for 2h, and after completion of the reaction by TLC, the reaction mixture was added to 200ml of ethyl acetate, and a solid was precipitated, filtered, washed with ethyl acetate, and dried to obtain 548mg of the objective product (73% yield).
N- { 5- [ 5-fluoro-2-oxo-1, 2-dihydro-indol- (3Z) -ylidenemethyl]-2, 4-dimethyl-1H-pyrrole-
Synthesis of 3-yl } -3- (4-methylpiperazin-1-yl) propionamide:
dissolving N- { 5- [ 5-fluoro-2-oxo-1, 2-dihydro-indol- (3Z) -ylidenemethyl ] -2, 4-dimethyl-1H-pyrrol-3-yl } -3-bromo-propionamide (548 mg,1.0eq) in 4ml DMF, stirring at room temperature until the solution is dissolved, adding 4-methylpiperazine (850mg, 4.0eq) into the solution, heating the solution to 50 ℃ for reaction for 4 hours, detecting by TLC that the reaction is finished, adding the reaction solution into 200ml ethyl acetate, separating out a solid, filtering, washing by ethyl acetate, drying, and carrying out column chromatography to obtain N- (5- ((Z) - (5-fluoro-2-carbonylindol-3-ylidene) methyl) -2, 4-dimethyl-1H-pyrrol-3-yl) -3- (4- Methylpiperazin-1-yl) propionamide.
1H-NMR(600MHz,DMSO,ppm)：2.182.21(S,6H),2.54(t,3H),2.75(s,3H),2.813.16(br,8H),2.86(t,2H),6.17(s,4H),6.86(d,1H),7.63（s,1H),9.16(s,1H),10.74(s,1H),13.56(s,1H)。
Example 2: preparation of form a of compound I:
1g N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1H-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide was mixed with 20ml of water and stirred for 10 minutes, 1g of a tetrahydrofuran solution of maleic acid was added dropwise, stirred for 5 to 10 hours, filtered with suction, and dried under vacuum at 40 ℃ to obtain 1.39g of an orange solid with a yield of 90%, which was examined by X-ray powder diffraction and whose XRPD pattern was shown in FIG. 1, and whose DSC and DSC patterns were shown in FIGS. 2 and 3, respectively;
1H-NMR(600MHz,DMSO,ppm)：2.182.21(S,6H),2.54(t,3H),2.75(s,3H),2.813.16(br,8H),2.86(t,2H),6.17(s,4H),6.86(d,1H),6.877.66(dd,2H),7.63（s,1H),9.16(s,1H),10.74(s,1H),13.56(s,1H)。
example 3: preparation of form a of compound I:
10g N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1H-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propanamide was mixed with 100ml of ethyl acetate and stirred for 20 minutes, 8g of maleic acid was added, stirred for 3 to 6 hours, filtered with suction, and dried under vacuum at 50 ℃ to give 12.4g of an orange solid in a yield of 80.2%, which was examined by X-ray powder diffraction and had an XRPD pattern substantially in accordance with that of FIG. 1.
Example 4: preparation of form a of compound I:
2g N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1H-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propanamide was mixed with 20ml of n-butanol and stirred for 10 minutes, 2g of maleic acid was added, stirred for 30 to 40 hours, filtered with suction, and dried under vacuum at 40 ℃ to give 2.0g of an orange solid in a yield of 64.5%, which was detected by X-ray powder diffraction and the XRPD pattern of which was substantially in accordance with that of FIG. 1.
Example 5: preparation of form a of compound I:
1g N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1-hydro-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propanamide was mixed with 20ml dioxane and stirred for 10 minutes, 1g maleic acid was added, stirred for 5 to 10 hours, suction filtered, and dried under vacuum at 40 ℃ to give 1.39g of an orange solid with a yield of 90%, which was checked by X-ray powder diffraction and its XRPD pattern was substantially in accordance with that of FIG. 1.
Example 6: preparation of form C of compound I:
mixing 20ml DMF (N, N-dimethylformamide) and 1g N- (5- ((Z) - (5-fluoro-2-carbonylindol-3-ylidene) methyl) -2, 4-dimethyl-1H-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide at room temperature, stirring, adding 1g maleic acid, immediately dissolving out, precipitating solid after ten minutes, continuing stirring for 2 hours, filtering, drying at 60 ℃ under vacuum for 6 hours to obtain 1.0g (brick red) colored crystalline powder with a yield of 64.9%, subjecting the obtained product to X-ray powder diffraction detection, wherein the XRPD pattern is shown in FIG. 7, and the DSC and TGA patterns are respectively shown in FIGS. 8, and TGA, 9 is shown in the figure;
1H-NMR(600MHz,DMSO,ppm)：2.182.21(S,6H),2.54(t,3H),2.75(s,3H),2.812.90（s，6H）3.16(br,8H),2.86(t,2H),6.17(s,4H),6.86(d,1H),6.877.66(dd,2H),7.63（s,1H),8.02（s，1H）9.16(s,1H),10.74(s,1H),13.56(s,1H)。
example 7: preparation of form D of compound I:
mixing 20ml of DMSO (dimethyl sulfoxide) and 1g N- (5- ((Z) - (5-fluoro-2-carbonylindol-3-ylidene) methyl) -2, 4-dimethyl-1H-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide at room temperature, stirring, adding 1g of maleic acid, immediately dissolving, precipitating a solid after ten minutes, continuing stirring for 2 hours, filtering, drying at 60 ℃ in vacuo for 8 hours to obtain 1.1g of crystalline powder with a yield of 71.4%, subjecting the obtained product to X-ray powder diffraction detection, wherein the XRPD pattern is shown in FIG. 10, and the DSC and TGA patterns are respectively shown in FIGS. 11 and 12 by differential scanning calorimetry and thermogravimetric analysis;
1H-NMR(600MHz,DMSO,ppm)：2.182.21(S,6H),2.50（S，6H）2.54(t,3H),2.75(s,3H),2.813.16(br,8H),2.86(t,2H),6.17(s,4H),6.86(d,1H),6.877.66(dd,2H),7.63（s,1H),9.16(s,1H),10.74(s,1H),13.56(s,1H)。
example 8: preparation of form B of compound I (form C slurried in water to prepare form B):
mixing 20ml DMF (N, N-dimethylformamide) and 1g N- (5- ((Z) - (5-fluoro-2-carbonylindol-3-ylidene) methyl) -2, 4-dimethyl-1H-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide at room temperature, stirring, adding 1g maleic acid, immediately dissolving to clear, precipitating solid after ten minutes, continuing stirring for 2 hours, filtering, stirring the obtained filter cake in 20ml water for 2 hours to obtain 1.24g brick red crystalline powder with yield of 80.0% and purity of 99.3%, subjecting the obtained product to X-ray powder diffraction detection with XRPD pattern shown in FIG. 4, differential scanning calorimetry and thermogravimetric analysis, DSC and TGA spectra are shown in figure 5 and figure 6 respectively;
1H-NMR(600MHz,DMSO,ppm)：2.182.21(S,6H),2.54(t,3H),2.75(s,3H),2.813.16(br,8H),2.86(t,2H),6.17(s,4H),6.86(d,1H),6.877.66(dd,2H),7.63（s,1H),9.16(s,1H),10.74(s,1H),13.56(s,1H)。
example 9: preparation of form B of compound I:
20ml of water and 1g N- (5- ((Z) - (5-fluoro-2-carbonylindol-3-ylidene) methyl) -2, 4-dimethyl-1-hydro-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propanamide were mixed at room temperature, 1g of maleic acid was added, and after stirring for 5 hours, suction filtration and vacuum drying at 40 ℃ for 15 hours gave 1.4g of brick red crystalline powder in a yield of 90.9%, and the product obtained was subjected to X-ray powder diffraction detection and its XRPD pattern was substantially in accordance with that of FIG. 4.
Example 10: preparation of form B of compound I (form D slurried in water to prepare form B):
at room temperature, 20ml of DMSO (dimethyl sulfoxide) and 1g N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1H-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide are mixed, stirred, 1g of maleic acid is added, the mixture is immediately dissolved and cleared, the temperature is reduced, a solid is separated out after 15 minutes, the mixture is continuously stirred for 2 hours, filtered, the obtained filter cake is stirred and pulped in 30ml of water for 4 hours to obtain 1.35g of brick red crystalline powder with the yield of 87.0%, and the obtained product is subjected to X-ray powder diffraction detection, wherein the XRPD pattern is basically consistent with that of figure 4.
Example 11: preparation of form B of compound I:
20ml of methanol and 1g N- (5- ((Z) - (5-fluoro-2-carbonylindol-3-ylidene) methyl) -2, 4-dimethyl-1-hydro-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide were mixed at room temperature, 1g of maleic acid was added, and after stirring for 5 hours, suction filtration and vacuum drying at 40 ℃ for 15 hours gave 1.1g of brick-red crystalline powder with a yield of 71.5%, and the obtained product was subjected to X-ray powder diffraction detection and its XRPD pattern was substantially in accordance with that of FIG. 4.
Example 12: preparation of form B of compound I:
20ml of water, 10ml of DMF and 1g N- (5- ((Z) - (5-fluoro-2-carbonylindol-3-ylidene) methyl) -2, 4-dimethyl-1-hydro-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide were mixed at room temperature, 0.9g of maleic acid was added, and after stirring for 5 hours, suction filtration and vacuum drying at 40 ℃ for 15 hours gave 1.2g of a brick-red crystalline powder with a yield of 78.0%, and the product obtained was subjected to X-ray powder diffraction examination and its XRPD pattern was substantially in accordance with that of FIG. 4.
Example 13: preparation of form B of compound I:
and heating the crystal form C prepared in the example 6 to 180 ℃ in an oven under the protection of nitrogen, keeping the temperature for 5min, naturally cooling to room temperature, and detecting the obtained crystal form through powder X-ray diffraction, wherein the XRPD pattern of the crystal form C is basically consistent with that of the crystal form C shown in the figure 4.
Example 14: solubility test
Two KH are prepared2PO4NaOH buffers (pH: pH =6.8, pH =2.5, respectively) 0.2mL of each buffer and 2mg of N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1-hydro-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide from example 1 and form A, B of Compound I, C. d (prepared in example 2, example 8, example 6 and example 7, respectively) was slowly stirred for 24 hours or more, and the incompletely dissolved solid was filtered through a 0.22 μm microporous membrane, and the solubility was measured by the HPLC method (the HPLC method can be referred to the method in appendix V D of second part of the chinese pharmacopoeia 2010), and the solubility data are shown in table 1.
Table 1 results of solubility test of compound of example 1, compound I form A, B, C, D in phosphate buffer at ph2.5, ph6.8
| Compound (I) | Solubility (. mu.g/ml), pH2.5 | Solubility (. mu.g/ml), pH6.8 |
| Compound obtained in example 1 | 4.82 | 3.13 |
| Crystalline form A of Compound I | 29.18 | 31.74 |
| Crystal form B of compound I | 21.65 | 35.75 |
| Crystalline form C of Compound I | 22.10 | 39.74 |
| Crystalline form D of Compound I | 14.45 | 31.66 |
It can be seen that the solubility of each of the crystalline forms of N- (5- ((Z) - (5-fluoro-2-carbonylindol-3-ylidene) methyl) -2, 4-dimethyl-1 h-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide dimaleate is higher than the solubility of the free base.
Example 15: stability test
Samples of compound I form A, B, C, D (prepared as described in examples 2, 8, 6, and 7, respectively) were collected in duplicate, one portion was wrapped with aluminum foil paper, and left at room temperature in the dark for 48 hours, and the other portion was placed in a light stabilization box at 25 ℃ under 4500lx illumination for 48 hours, and the stability of the different forms was examined, and the results are shown in table 2.
Two samples of the compound I crystal form A, B, C, D were taken, one was placed at 60 ℃ for 7 days, the other was placed at 40 ℃/75% R.H. for 7 days, and the stability of the different crystal forms was examined, the results are shown in Table 2.
The specific stability investigation method can refer to the method in appendix XIX C of the second part of the Chinese pharmacopoeia 2010 edition; the purity of the sample can be measured by HPLC, which is described in appendix V D of the second part of the pharmacopoeia 2010. The detection of the crystal forms was carried out in the same manner as in the examples.
Table 2 stability test results of compound I crystal form A/B/C/D under illumination, constant temperature and constant humidity conditions
It can be seen that the stability of various crystal forms of N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1 h-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide dimaleate is better, wherein the crystal form B is more stable, and the crystal form A, C, D can be degraded to generate impurities or generate crystal transformation under high temperature or high temperature and high humidity conditions.
Although specific embodiments of the invention have been described in detail, those skilled in the art will appreciate. Various modifications and substitutions of those details may be made in light of the overall teachings of the disclosure, and such changes are intended to be within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.
Claims (30)
1. A compound of formula I
It is a polymorph, wherein the polymorph uses Cu-ka radiation, X-ray powder diffraction, expressed in degrees 2 Θ, having characteristic absorption peaks at the following positions: 5.5 +/-0.20 degrees, 8.3 +/-0.20 degrees, 13.8 +/-0.20 degrees, 16.6 +/-0.20 degrees, 22.2 +/-0.20 degrees, 25.1 +/-0.20 degrees, 26.3 +/-0.20 degrees and 27.9 +/-0.20 degrees.
2. The compound of claim 1, wherein the polymorph exhibits an X-ray powder diffraction pattern using Cu-ka radiation, expressed in terms of 2 Θ angles, having characteristic absorption peaks at the following positions: 5.5 +/-0.20 degrees, 6.5 +/-0.20 degrees, 8.3 +/-0.20 degrees, 9.8 +/-0.20 degrees, 11.0 +/-0.20 degrees, 13.0 +/-0.20 degrees, 13.8 +/-0.20 degrees, 16.6 +/-0.20 degrees, 18.3 +/-0.20 degrees, 22.2 +/-0.20 degrees, 22.8 +/-0.20 degrees, 23.5 +/-0.20 degrees, 25.1 +/-0.20 degrees, 26.3 +/-0.20 degrees, 27.9 +/-0.20 degrees and 28.7 +/-0.20 degrees.
3. The compound of claim 1, wherein the polymorph exhibits an X-ray powder diffraction pattern, expressed in terms of 2 Θ angles, using Cu-ka radiation, substantially as shown in figure 1.
4. A compound according to any one of claims 1 to 3, having an endothermic peak at 194 to 220 ℃ as shown by differential scanning calorimetry.
5. A compound of the formula I,
it is a polymorph, wherein the polymorph has characteristic absorption peaks at the following positions by X-ray powder diffraction expressed in degrees 2 Θ using Cu-Ka radiation: 6.4 +/-0.2 degrees, 9.7 +/-0.20 degrees, 12.4 +/-0.20 degrees, 13.0 +/-0.20 degrees, 16.3 +/-0.20 degrees, 22.9 +/-0.20 degrees, 24.3 +/-0.2 degrees, 25.2 +/-0.2 degrees and 26.2 +/-0.20 degrees.
6. The compound of claim 5, wherein the polymorph exhibits an X-ray powder diffraction pattern expressed in degrees 2 θ using Cu-Ka radiation having characteristic absorption peaks at: 6.4 +/-0.20 degrees, 7.5 +/-0.20 degrees, 8.8 +/-0.20 degrees, 9.7 +/-0.20 degrees, 12.4 +/-0.20 degrees, 13.0 +/-0.20 degrees, 16.3 +/-0.20 degrees, 17.4 +/-0.20 degrees, 18.0 +/-0.20 degrees, 18.8 +/-0.20 degrees, 19.6 +/-0.20 degrees, 21.8 +/-0.20 degrees, 22.9 +/-0.20 degrees, 24.3 +/-0.20 degrees, 25.2 +/-0.20 degrees, 26.2 +/-0.20 degrees, 26.9 +/-0.20 degrees and 33.0 +/-0.20 degrees.
7. The compound of claim 5, wherein the polymorph exhibits an X-ray powder diffraction pattern, expressed in terms of 2 θ using Cu-Ka radiation, substantially as shown in figure 4.
8. A compound according to any one of claims 5 to 7, wherein differential scanning calorimetry shows that the polymorph has an endothermic peak at 274 ℃.
9. A compound of the formula I,
it is a polymorph, wherein the polymorph uses Cu-ka radiation, X-ray powder diffraction, expressed in degrees 2 Θ, having characteristic absorption peaks at the following positions: 2.8 +/-0.20 degrees, 5.6 +/-0.20 degrees, 8.4 +/-0.20 degrees, 16.4 +/-0.20 degrees, 22.5 +/-0.20 degrees, 25.4 +/-0.20 degrees, 26.6 +/-0.20 degrees and 28.2 +/-0.20 degrees.
10. The compound of claim 9, wherein the polymorph exhibits an X-ray powder diffraction, expressed in terms of 2 Θ angles, using Cu-Ka radiation, having characteristic absorption peaks at the following positions: 2.8 +/-0.20 degrees, 5.6 +/-0.20 degrees, 8.4 +/-0.20 degrees, 11.2 +/-0.20 degrees, 16.4 +/-0.20 degrees, 19.5 +/-0.20 degrees, 22.5 +/-0.20 degrees, 24.0 +/-0.20 degrees, 25.4 +/-0.20 degrees, 26.6 +/-0.20 degrees and 28.2 +/-0.20 degrees.
11. The compound of claim 9, wherein the polymorph exhibits an X-ray powder diffraction pattern, expressed in terms of 2 Θ angles, using Cu-Ka radiation, substantially as shown in figure 7.
12. A compound according to any one of claims 9 to 11, having two endothermic peaks at 150 to 185 ℃ and 209 to 230 ℃ as shown by differential scanning calorimetry.
13. A compound of the formula I,
it is a polymorph, wherein the polymorph has characteristic absorption peaks at the following positions by X-ray powder diffraction expressed in degrees 2 Θ using Cu-Ka radiation: 5.6 +/-0.20 degrees, 8.4 +/-0.20 degrees, 14.0 +/-0.20 degrees, 22.5 +/-0.20 degrees, 23.8 +/-0.20 degrees, 25.4 +/-0.20 degrees, 26.5 +/-0.20 degrees and 28.3 +/-0.20 degrees.
14. The compound of claim 13, wherein the polymorph exhibits an X-ray powder diffraction pattern expressed in degrees 2 Θ using Cu-Ka radiation having characteristic absorption peaks at the following positions: 5.6 +/-0.20 degrees, 8.4 +/-0.20 degrees, 9.0 +/-0.20 degrees, 14.0 +/-0.20 degrees, 14.7 +/-0.20 degrees, 15.6 +/-0.20 degrees, 16.6 +/-0.20 degrees, 18.1 +/-0.20 degrees, 22.5 +/-0.20 degrees, 23.8 +/-0.20 degrees, 24.6 +/-0.20 degrees, 25.4 +/-0.20 degrees, 26.5 +/-0.20 degrees, 28.3 +/-0.20 degrees and 29.5 +/-0.20 degrees.
15. The compound of claim 13, wherein the polymorph exhibits an X-ray powder diffraction pattern, expressed in terms of 2 Θ angles, using Cu-Ka radiation, substantially as shown in figure 10.
16. A compound according to any one of claims 13 to 15, having two endothermic peaks at 182 to 201 ℃ and 202 to 225 ℃ as shown by differential scanning calorimetry.
17. A process for the preparation of a compound according to any one of claims 9 to 12:
reacting N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1 h-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide with maleic acid in N, N-dimethylformamide with stirring to give a compound according to any one of claims 9 to 12; wherein the molar ratio of N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1H-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide to maleic acid is 1: 2.
18. A process for the preparation of a compound according to any one of claims 13 to 16:
reacting N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1 h-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide with maleic acid in dimethylsulfoxide with stirring to give a compound according to any one of claims 13 to 16; wherein the molar ratio of N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1H-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide to maleic acid is 1: 2.
19. A process for the preparation of a compound according to any one of claims 1 to 4:
reacting N- (5- ((Z) - (5-fluoro-2-carbonylindol-3-ylidene) methyl) -2, 4-dimethyl-1 h-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide with maleic acid in tetrahydrofuran, tetrahydrofuran/water, acetone, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, ethanol, isopropanol, N-butanol, dioxane with stirring to give a compound according to any one of claims 1 to 4; wherein the molar ratio of N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1H-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide to maleic acid is 1: 2.
20. A process for the preparation of a compound according to any one of claims 5 to 8:
reacting N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1 h-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide with maleic acid in water, N-dimethylformamide/water, N-dimethylacetamide/water, methanol, ethylene glycol or acetonitrile with stirring to give a compound according to any one of claims 5 to 8; wherein the molar ratio of N- (5- ((Z) - (5-fluoro-2-carbonylindole-3-ylidene) methyl) -2, 4-dimethyl-1 h-pyrrol-3-yl) -3- (4-methylpiperazin-1-yl) propionamide to maleic acid is 1: 2; the mixed solvent of the N, N-dimethylformamide or the N, N-dimethylacetamide and water only needs to contain water in an amount of not 0; or,
beating the compound of any one of claims 9-16 in water with stirring, filtering and drying to obtain the compound of any one of claims 5-8;
or,
drying the compound of any one of claims 9 to 16 at 150 to 200 ℃ to obtain the compound of any one of claims 5 to 8.
21. The production method according to claim 20, wherein the ratio of the N, N-dimethylformamide or N, N-dimethylacetamide to water in the mixed solvent of the N, N-dimethylformamide or N, N-dimethylacetamide and water is 1:0.5 to 20.
22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, and optionally one or more pharmaceutically acceptable carriers or excipients.
23. Use of a compound according to any one of claims 1 to 16 in the manufacture of a medicament for the prophylaxis and/or treatment of a disease or condition associated with receptor tyrosine kinases in a mammal.
24. The use of claim 23, wherein the mammal is a human.
25. The use of claim 23 or 24, wherein the disease or condition associated with receptor tyrosine kinases is proliferation and migration of tumors or tumor cells driven by receptor tyrosine kinases mediated by receptor tyrosine kinases.
26. The use of claim 25 wherein the receptor tyrosine kinase mediated proliferation and migration of tumors or tumor cells driven by receptor tyrosine kinases is a cancer sensitive to erbB receptor tyrosine kinases.
27. The use of claim 26 wherein the erbB receptor tyrosine kinase sensitive cancer is a tumor that is highly expressed by EGFR or Her2 and that is EGF driven, including solid tumors and non-solid tumors.
28. The use of claim 27, wherein the solid tumor is selected from the group consisting of cancers of the bile duct, bone, bladder, brain/central nervous system, breast, colorectal, endometrial, gastric, head and neck, liver, lung, neurons, esophagus, ovary, pancreas, prostate, kidney, skin, testis, thyroid, uterus and vulva.
29. The use of claim 28, wherein the cancer of the lung is non-small cell lung cancer.
30. The use of claim 27, wherein the non-solid tumor is selected from the group consisting of leukemia, multiple myeloma, and lymphoma.
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