JP2020189888A - Quinolone analog and form of salt thereof - Google Patents

Abstract

To provide a crystal form of a tetracyclic quinolone compound or a salt of the tetracyclic quinolone compound and/or a crystal form of a solvate of the tetracyclic quinolone compound, a pharmaceutical composition containing the same, and a method for using the same.SOLUTION: In one embodiment, the invention provides a crystalline form of a tetracyclic quinolone compound or a pharmaceutically acceptable salt, ester and/or solvate thereof. In one embodiment, the crystalline form of the tetracyclic quinolone compound is Compound I or a pharmaceutically acceptable salt, ester and/or solvate thereof. In one embodiment, there is provided a composition comprising a crystalline form of the Compound I or the pharmaceutically acceptable salt, ester and/or solvate thereof as described herein. In one embodiment, there is provided a method of stabilizing a G-quadruple chain (G4) in the subject, wherein the method comprises administering a therapeutically effective amount of the crystalline form of the Compound I or the pharmaceutically acceptable salt, ester and/or solvate thereof as described herein to the subject.SELECTED DRAWING: Figure 1

Description

The present invention relates to a crystal form of a tetracyclic quinolone compound or a salt and / or solvate of a tetracyclic quinolone compound, a pharmaceutical composition containing the same, and a method for using the same.

It has been suggested that various tetracyclic quinolone compounds function by interacting with the tetracyclic region of nucleic acids and regulating the transcription of ribosomal RNA. See, for example, U.S. Pat. Nos. 7,928,100 and 8,853,234. Specifically, tetracyclic quinolone compounds can stabilize the G-quadruplex (G4) of DNA in cancer cells, thereby inducing synthetic lethality in cancer cells. Since treatment of cells with G4 stabilizers can result in the formation of DNA double-strand breaks (DSBs), the formation of DSBs induced by G4 stabilizing ligand / agent (eg, tetracyclic quinolone) treatment is non-homologous. It is even more pronounced in cells that are genetically defective or chemically inhibited in repair pathways that include both end binding (NHEJ) and homologous recombination repair (HRR). Furthermore, tetracyclic quinolone compounds selectively inhibit the synthesis of rRNA by PolI in the nucleolus, but do not inhibit the synthesis of mRNA by RNA polymerase II (PolII) and do not inhibit DNA replication or protein synthesis. It has been suggested that targeting RNA polymerase I (PolI) and activating p53 via the nuclear stress pathway can result in selective activation of p53 in tumor cells. The p53 protein normally functions as a tumor suppressor by self-destructing cancer cells. Activating p53 to kill cancer cells is a well-validated anti-cancer strategy that utilizes a number of approaches. Selective activation of p53 in tumor cells does not affect normal healthy cells, while it is an attractive way to treat, control and improve tumor cells. The aforementioned tetracyclic quinolones are disclosed in US Pat. Nos. 7,928,100 and 8,853,234, and the content of this publication is herein by reference in its entirety for any intended purpose. Incorporated into the book.
The crystallization of the active ingredient is important for pharmaceutical technology professionals, such as stability, solubility, bioavailability, particle size, bulk density, fluidity, polymorphic content, and other properties We understand that we provide the best way to control quality. Therefore, there is a need for crystal forms of tetracyclic quinolones and processes for producing such forms. These crystalline forms should be suitable for pharmaceutical use.

U.S. Pat. No. 7,928,100 U.S. Pat. No. 8,853,234

In one embodiment, the invention provides a crystalline form of a tetracyclic quinolone compound or a pharmaceutically acceptable salt, ester and / or solvate thereof. In one embodiment, the crystalline form of the tetracyclic quinolone compound is Compound I:
Or a pharmaceutically acceptable salt, ester and / or solvate thereof. In one embodiment, the crystalline form of compound I is the free base of compound I. In another embodiment, the crystalline form of Compound I is a salt or solvate of Compound I. In one embodiment, the crystalline form of Compound I is the acid salt of Compound I.

In some embodiments, the crystalline form of Compound I is an X-ray powder containing peaks at about 7.730 ± 0.3, 22.050 ± 0.3, and 24.550 ± 0.3 degrees in two theta. The diffraction (XRPD) pattern is shown. In a further embodiment, the crystalline form of Compound I further exhibits an XRPD peak at 2 theta at about 9.410 ± 0.3 and 27.700 ± 0.3 degrees. In another embodiment, the crystalline form of Compound I further exhibits an XRPD peak at 2 theta at about 17.950 ± 0.3 and 25.400 ± 0.3 degrees. In one embodiment, the crystalline form of Compound I is further about 11.230 ± 0.3, 11.630 ± 0.3, 16.900 ± 0.3, 18.580 ± 0.3, 23.300 ±. XRPD peaks are shown at 2 theta of 0.3 and 26.700 ± 0.3 degrees. In one embodiment, the crystalline form of Compound I is 7.730 ± 0.3, 9.410 ± 0.3, 11.230 ± 0.3, 11.630 ± 0.3, 16.900 ± 0. 3, 17.950 ± 0.3, 18.580 ± 0.3, 22.050 ± 0.3, 23.300 ± 0.3, 24.550 ± 0.3, 25.400 ± 0.3, An XRPD pattern containing three or more peaks selected from the two-seater group of 26.700 ± 0.3 and 27.700 ± 0.3 degrees is shown. In another embodiment, the crystalline form of Compound I shows an XRPD pattern that is substantially similar to FIG. In one embodiment, the crystalline form of Compound I shows a differential scanning calorimetry (DSC) thermogram with peak eigenvalues at about 215.41 ± 2.0 ° C.

In one embodiment, the crystalline form of compound I is polymorph A. In some embodiments, the crystalline form of compound I and / or the crystalline form of compound A of compound I has a purity of about 95%, about 97%, about 99%, or about 99.5% or higher.

In another embodiment, the crystalline form of Compound I exhibits an XRPD pattern that includes a peak at about 5.720 ± 0.3 degrees 2 theta. In another embodiment, the crystalline form of Compound I shows an XRPD pattern that is substantially similar to FIG. In one embodiment, the crystalline form of Compound I shows a DSC thermogram with peak eigenvalues at about 246.47 ± 2.0 ° C.

In one embodiment, the crystalline form of compound I is polymorph C. In some embodiments, the crystalline form of compound I and / or the crystalline form of compound I polymorph C has a purity of about 95%, about 97%, about 99%, or about 99.5% or higher.

In some embodiments, the crystalline form of Compound I exhibits an XRPD pattern that includes a peak at about 5.680 ± 0.2 degrees for 2 theta. In one embodiment, the crystalline form of Compound I is XRPD in two theta of about 12.200 ± 0.2, 12.600 ± 0.3, 25.360 ± 0.3 and 27.560 ± 0.3 degrees. Shows a peak. In one embodiment, the crystalline forms of Compound I are 5.680 ± 0.2, 12.200 ± 0.2, 12.600 ± 0.3, 25.360 ± 0.3 and 27.560 ± 0.3. Shows an XRPD pattern containing two or more peaks selected from the group consisting of. In another embodiment, the crystalline form of Compound I shows an XRPD pattern that is substantially similar to FIG. In one embodiment, the crystalline form of Compound I shows a DSC thermogram with peak eigenvalues at 231.99 ± 2.0 degrees.

In one embodiment, the crystalline form of compound I is polymorphic E. In some embodiments, the crystalline form of compound I and / or the crystalline form of compound E polymorph E has a purity of about 95%, about 97%, about 99%, or about 99.5% or higher.

In one embodiment, the crystalline form of Compound I exhibits an XRPD pattern containing peaks at about 5.000 ± 0.3 and 6.060 ± 0.4 degrees in two theta. In another embodiment, the crystalline form of Compound I shows an XRPD pattern that is substantially similar to FIG. In another embodiment, the crystalline form of Compound I shows a DSC thermogram with peak eigenvalues at about 222.11 ± 2.0 degrees.

In one embodiment, the crystalline form of compound I is polymorph G. In some embodiments, the crystalline form of compound I and / or the crystalline form of compound I polymorph G has a purity of about 95%, about 97%, about 99%, or about 99.5% or higher.

In one embodiment, the crystalline form of Compound I exhibits a purity greater than about 90%, 95%, 97%, 98%, 99% or 95% of Compound I.

In one embodiment, the crystalline form of Compound I is hydrochloride, maleate, fumarate, citrate, malate, acetate, sulfate, phosphate, L- (+)-tartrate, D-Glucronate, benzoate, succinate, ethanesulfonate, methanesulfonate, p-toluenesulfonate, malonate, benzenesulfonate, and 1-hydroxy-2-naphthoate A salt salt of compound I selected from the group consisting of. In one embodiment, the crystalline form of the salt of Compound I is selected from the group consisting of hydrochloride, maleate, fumarate, citrate, and L-malate.

In one embodiment, the crystalline form of Compound I is a solvate of Compound I. In some embodiments, the crystalline form of Compound I is the NMP (N-methylpyrrolidone) solvate of Compound I.

In one embodiment, the crystalline form of Compound I is the crystalline form of the HCl salt of Compound I. In some embodiments, the crystalline form of the HCl salt of Compound I has an X-ray powder diffraction pattern (XRDP) containing peaks at 2 theta at about 4.660 ± 0.3 and 24.540 ± 0.3 degrees. Shown. In one embodiment, the crystalline form of the HCl salt of Compound I is further about 19.260 ± 0.4, 20.160 ± 0.4, 24.920 ± 0.3 and 26.360 ± 0.5 degrees. It shows 1 or more XRPD peaks in 2 theta. In another embodiment, the crystalline form of the HCl salt of Compound I is further about 13.980 ± 0.4, 14.540 ± 0.3, 25.380 ± 0.3, and 28.940 ± 0.3. It shows an XRPD peak of 1 or more at 2 theta of degree. In another embodiment, the crystalline form of the HCl salt of Compound I shows an X-ray powder diffraction pattern that is substantially similar to FIG. In another embodiment, the crystalline form of the HCl salt of Compound I shows a differential scanning calorimetry (DSC) thermogram with peak eigenvalues at about 266.27 ± 2.0 ° C.

In one embodiment, the crystalline form of Compound I is the crystalline form of the maleate of Compound I. In some embodiments, the crystalline form of the maleate of Compound I contains peaks at about 7.400 ± 0.3, 18.440 ± 0.5 and 26.500 ± 0.4 degrees in two theta. The X-ray powder diffraction pattern (XRDP) is shown. In another embodiment, the crystalline form of the maleate of Compound I is further about 22.320 ± 0.4, 23.920 ± 0.3, 24.300 ± 0.4 and 25.240 ± 0.7. It shows 1 or more XRPD peaks in 2 theta of degree. In another embodiment, the crystalline form of the maleate of Compound I is further about 5.040 ± 0.3, 15.080 ± 0.3, 15.880 ± 0.4, 20.860 ± 0.4. , And an XRPD peak of 1 or more at 2 theta of 28.540 ± 0.3 degrees. In another embodiment, the crystalline form of the maleate of Compound I shows an X-ray powder diffraction pattern that is substantially similar to FIG. In another embodiment, the crystalline form of the maleate of Compound I shows a differential scanning calorimetry (DSC) thermogram with peak eigenvalues at about 217.32 ± 2.0 ° C.

In one embodiment, the crystalline form of Compound I is the crystalline form of the fumarate of Compound I. In some embodiments, the crystalline form of the fumarate of Compound I is an X-ray powder diffraction pattern (XRDP) containing peaks at 2 theta at about 6.360 ± 0.3 and 24.800 ± 0.3 degrees. Is shown. In another embodiment, the crystalline form of the fumarate of Compound I is further 1 or more in 2 theta at about 19.660 ± 0.3, 20.420 ± 0.3, and 26.860 ± 0.3 degrees. XRPD peak is shown. In another embodiment, the crystalline form of the fumarate of Compound I is further about 12.680 ± 0.3, 17.020 ± 0.2, 25.180 ± 0.2, and 28.280 ± 0.3. It shows an XRPD peak of 1 or more at 2 theta of degree. In another embodiment, the crystalline form of the fumarate of Compound I shows an X-ray powder diffraction pattern that is substantially similar to FIG. In another embodiment, the crystalline form of fumarate of Compound I shows a differential scanning calorimetry (DSC) thermogram with peak eigenvalues at about 222.40 ± 2.0 ° C.

In one embodiment, the crystalline form of Compound I is the crystalline form of the citrate of Compound I. In some embodiments, the crystalline form of the citrate of Compound I peaks at about 4.900 ± 0.3, 25.380 ± 0.3, and 27.500 ± 0.4 degrees in two theta. The X-ray powder diffraction pattern (XRDP) containing is shown. In another embodiment, the crystalline form of the citrate of Compound I is further about 15.360 ± 0.3, 18.100 ± 0.3, 19.300 ± 0.3, and 26.140 ± 0.4. It shows an XRPD peak of 1 or more at 2 theta of degree. In another embodiment, the crystalline form of the citrate of Compound I is further about 17.400 ± 0.3, 18.680 ± 0.4, 24.040 ± 0.4, and 26.740 ± 0.3. It shows an XRPD peak of 1 or more at 2 theta of degree. In another embodiment, the crystalline form of the citrate of Compound I shows an X-ray powder diffraction pattern that is substantially similar to FIG. In another embodiment, the crystalline form of the citrate of Compound I shows a differential scanning calorimetry (DSC) thermogram with peak eigenvalues at about 196.86 ± 2.0 ° C.

In one embodiment, the crystalline form of Compound I is the crystalline form of L-malate of Compound I. In some embodiments, the crystalline form of L-malate of Compound I is at about 6.580 ± 0.2, 6.780 ± 0.3, and 25.560 ± 0.4 degrees in two theta. The X-ray powder diffraction pattern (XRDP) including the peak is shown. In another embodiment, the crystalline form of L-malate of Compound I is further about 19.560 ± 0.4, 23.660 ± 0.4, 26.060 ± 0.7, and 26.960 ± 0. It shows 1 or more XRPD peaks in 2 theta at 7 degrees. In another embodiment, the crystalline form of L-malate of Compound I is further about 8.800 ± 0.3, 11.800 ± 0.3, 18.600 ± 0.3, 24.460 ± 0. It shows 1 or more XRPD peaks at 5 and 2 theta at 25.080 ± 0.3 degrees. In another embodiment, the crystalline form of L-malate of Compound I shows an X-ray powder diffraction pattern that is substantially similar to FIG. In another embodiment, the crystalline form of L-malate of Compound I shows a differential scanning calorimetry (DSC) thermogram with peak eigenvalues at about 209.67 ± 2.0 ° C.

In one embodiment, a composition comprising the crystalline form of Compound I or a pharmaceutically acceptable salt, ester and / or solvate thereof as described herein is provided. In another embodiment, a composition comprising a crystalline form of the free base of Compound I is provided. In one embodiment, a composition comprising a crystalline form of a salt or solvate of Compound I is provided. In one embodiment, a composition comprising a crystalline form of the acid salt of Compound I is provided. In one embodiment, a composition comprising one or more crystalline forms of Compound I as described herein is provided. In some embodiments, the compositions described herein comprise at least one pharmaceutically acceptable carrier.

In one embodiment, a method of stabilizing a G-quadruplex (G4) is provided in the subject, wherein the method comprises a therapeutically effective amount of Compound I or as described herein. It comprises administering to the subject the crystalline form of the pharmaceutically acceptable salt, ester and / or solvate thereof.

In one embodiment, a method of regulating the activity of p53 in a subject is provided, wherein the method is a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof, as described herein. Includes administration to a subject in crystalline form of an ester and / or solvate.

In one embodiment, a method of treating or ameliorating a cell proliferative disorder in a subject is provided, wherein the method is therapeutically effective as described herein for a subject in need thereof. It comprises administering an amount of Compound I or a pharmaceutically acceptable salt, ester and / or solvate thereof in crystalline form. In one embodiment, a method is provided for treating or ameliorating cancer.

In one embodiment, a method of treating or ameliorating cancer is provided, in which the method is a therapeutically effective amount of Compound I or pharmaceutical as described herein for a subject in need thereof. The cancers include hem cancer, colorectal cancer, breast cancer, lung cancer, liver cancer, ovarian cancer, cervical cancer, Ewing sarcoma, including administration of an acceptable crystalline form of the salt, ester and / or solvent. , Pancreatic cancer, lymph node cancer, colon cancer, prostate cancer, brain cancer, head and neck cancer, skin cancer, kidney cancer, and heart cancer. In one embodiment, the cancer treated or ameliorated by the method is a heme cancer selected from the group consisting of leukemia, lymphoma, myeloma, and multiple myeloma. In one embodiment, the cancer treated or ameliorated by the method is a cancer lacking homologous recombination (HR) -dependent double-strand break (DSB) repair, or a non-homologous end-binding (NHEJ) DSB repair. Is a deficient cancer. In another embodiment, the cancer treated or ameliorated by the method comprises cancer cells having a defect in breast cancer 1 (BRCA1), breast cancer 2 (BRCA2) and / or other members of the homologous recombination pathway. In another embodiment, the cancer cells are deficient in BRCA1 and / or BRCA2. In another embodiment, the cancer cells are homozygous for mutations in BRCA1 and / or BRCA2. In another embodiment, the cancer cell is heterozygous for mutations in BRCA1 and / or BRCA2.

In one embodiment, the method provided herein comprises administering one or more additional therapeutic agents. In some embodiments, the one or more therapeutic agents are anti-cancer agents or immunotherapeutic agents. In one embodiment, one or more therapeutically active agents are immunotherapeutic agents. In some embodiments, one or more immunotherapeutic agents include, but are not limited to, monoclonal antibodies, immune effector cells, adoptive cell transfer, immunotoxins, vaccines or cytokines.

In one embodiment, a method of reducing or inhibiting cell proliferation is provided in which the cell is contacted with a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt, ester and / or solvate thereof. including. In one embodiment, the cells are present in a cancer cell line or cancer in a subject. In one embodiment, the cancer cells in the method described above are hem cancer, colorectal cancer, breast cancer, lung cancer, liver cancer, ovarian cancer, cervical cancer, Ewing sarcoma, pancreatic cancer, lymph node cancer, colon cancer, prostate cancer. , Brain cancer, head and neck cancer, skin cancer, kidney cancer, and heart cancer. In some embodiments, the heme cancer cells in the methods described above are selected from the group consisting of leukemia, lymphoma, myeloma, and multiple myeloma. In one embodiment, the cancer cells in the method described above are cancer cells that are deficient in homologous recombination (HR) -dependent double-strand break (DSB) repair or non-homologous end joining (NHEJ) DSB repair. .. In one embodiment, the cancer cell is a cancer cell that has a defect in breast cancer 1 (BRCA1), breast cancer 2 (BRCA2) and / or other members of the homologous recombination pathway. In another embodiment, the cancer cells are deficient in BRCA1 and / or BRCA2. In another embodiment, the cancer cells are homozygous for mutations in BRCA1 and / or BRCA2. In another embodiment, the cancer cell is heterozygous for mutations in BRCA1 and / or BRCA2.

It is a graph which shows the X-ray powder diffraction (XRPD) pattern of the polymorph A of compound I (free base). It is a figure which shows the thermogram of the differential scanning calorimetry (DSC) of the polymorph A of compound I (free base). It is a figure which shows the thermogravimetric analysis (TGA) thermogravimetric analysis (TGA) of the polymorph A of compound I (free base). It is the figure which superposed the DSC of the polymorphic form A of compound I (free base), and the thermogram of TGA. It is a figure which shows the ¹ H NMR spectrum of the polymorphic form A of compound I (free base). (A) It is a photograph which shows the microscope image of the polymorph A of compound I (free base) using a cross-polarizing filter. (B) It is a photograph which shows the microscopic image of the polymorphic form A of compound I (free base) which does not use a polarizing filter. (A) It is a photograph which shows the microscope image of the polymorph A of compound I (free base) using a cross-polarizing filter. (B) It is a photograph which shows the microscopic image of the polymorphic form A of compound I (free base) which does not use a polarizing filter. It is a graph which shows the XRPD pattern of the polymorphic form C of compound I (free base). It is a figure which shows the thermogram of DSC of the polymorphic form C of compound I (free base). It is a figure which shows the ¹ H NMR spectrum of the polymorphic form C of compound I (free base). (A) It is a photograph which shows the microscope image of the polymorphic form C of compound I (free base) using a cross-polarizing filter. (B) It is a photograph which shows the microscope image of the polymorphic form C of compound I (free base) which does not use a polarizing filter. (A) It is a photograph which shows the microscope image of the polymorphic form C of compound I (free base) using a cross-polarizing filter. (B) It is a photograph which shows the microscope image of the polymorphic form C of compound I (free base) which does not use a polarizing filter. It is a graph which shows the XRPD pattern of the polymorphic form E of compound I (free base). It is a figure which shows the thermogram of DSC of the polymorphic form E of compound I (free base). It is a figure which shows the ¹ H NMR spectrum of the polymorphic form E of compound I (free base). (A) It is a photograph which shows the microscope image of the polymorphic form E of compound I (free base) using a cross-polarizing filter. (B) It is a photograph which shows the microscope image of the polymorphic form E of compound I (free base) which does not use a polarizing filter. (A) It is a photograph which shows the microscope image of the polymorphic form E of compound I (free base) using a cross-polarizing filter. (B) It is a photograph which shows the microscope image of the polymorphic form E of compound I (free base) which does not use a polarizing filter. It is a figure which shows the thermogravimetric analysis (TGA) thermogravimetric analysis (TGA) of the polymorphic form E of compound I (free base). It is a graph which shows the XRPD pattern of the polymorphic form G of compound I (free base). It is a figure which shows the thermogram of DSC of the polymorphic form G of compound I (free base). It is a figure which shows the ¹ H NMR spectrum of the polymorphic form G of compound I (free base). (A) It is a photograph which shows the microscope image of the polymorphic form G of compound I (free base) using a cross-polarizing filter. (B) It is a photograph which shows the microscope image of the polymorphic form G of compound I (free base) which does not use a polarizing filter. (A) It is a photograph which shows the microscope image of the polymorphic form G of compound I (free base) using a cross-polarizing filter. (B) It is a photograph which shows the microscope image of the polymorphic form G of compound I (free base) which does not use a polarizing filter. It is a figure which shows the solubility of various polymorphs of compound I (free base) in methanol and THF. It is a graph which shows the XRPD pattern of the HCl salt of compound I. It is a figure which shows the thermogram of DSC of the HCl salt of compound I. It is a figure which shows the ¹ H NMR spectrum of the HCl salt of compound I. It is a photograph which shows the microscope image of the HCl salt of compound I using a polarizing filter. It is a figure which shows the TGA thermogram of the HCl salt of compound I. It is a graph which shows the XRPD pattern of maleate of compound I. It is a figure which shows the DSC thermogram of the maleate of compound I. It is a figure which shows the ¹ H NMR spectrum of the maleate of compound I. It is a photograph which shows the microscopic image of the maleate of compound I using a polarizing filter. It is a figure which shows the TGA thermogram of the maleate of compound I. It is a graph which shows the XRPD pattern of the fumarate of compound I. It is a figure which shows the thermogram of DSC of the fumarate of compound I. It is a figure which shows the ¹ H NMR spectrum of the fumarate of compound I. It is a photograph which shows the microscopic image of the fumarate of compound I using a polarizing filter. It is a figure which shows the TGA thermogram of the fumarate of compound I. It is a graph which shows the XRPD pattern of the citrate of compound I. It is a figure which shows the DSC thermogram of the citrate of compound I. It is a figure which shows the ¹ H NMR spectrum of the citrate of compound I. It is a photograph which shows the microscopic image of the citrate of compound I using a polarizing filter. It is a figure which shows the TGA thermogram of the citrate of compound I. It is a graph which shows the XRPD pattern of L-malate of compound I. It is a figure which shows the thermogram of DSC of L-malate of compound I. It is a figure which shows the ¹ H NMR spectrum of the L-malate of compound I. It is a photograph which shows the microscopic image of L-malate of compound I using a polarizing filter. It is a figure which shows the thermogram of TGA of L-malate of compound I.

The present invention is the crystal form of a tetracyclic quinolone compound that stabilizes the G-quadruplex (G4) and / or inhibits PolI, as well as the crystal of a salt and / or solvate of the tetracyclic quinolone compound. Regarding the shape. These crystalline substances can be formulated into pharmaceutical compositions and can be used to treat diseases characterized by cell proliferation.

Definitions It should be understood that the terms used herein are for the purposes of describing a particular embodiment only and are not intended to be limiting.

Unless defined, the terminology and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Any methods and materials similar to or equivalent to those described herein can be used in the practice or testing of this application, but representative methods and materials are described herein. Has been done.

According to long-standing patent law practice, the terms "a", "an" and "the" refer to "one or more" when used in this application, including claims. Thus, for example, the reference to "a carrier" includes a mixture of one or more carriers, two or more carriers, and the like.

Unless instructed, it should be understood that all numbers representing the amounts of ingredients, reactions, conditions, etc. used herein and in the claims are in any case modified by the term "about". Thus, unless otherwise indicated, the numerical parameters mentioned herein and in the accompanying claims are approximations that can vary depending on the desired properties obtained by this application. In general, the term "about", when used herein when referring to measurable values such as quantities such as weight, time, dose, etc., implements the method in which such variations are disclosed. A variation of ± 15% or ± 10% in one example, ± 5% in another example, ± 1% in another example, and ± 0. In yet another example, as appropriate to do so. We will include a 1% variation.

The term "compound of the invention (s)" or "compound (s)" refers to 2- (4-methyl- [1,4] diazepan-1-yl) -5-oxo-5H-7-thia. -1,11b-diaza-benzo [c] fluorene-6-carboxylic acid (5-methyl-pyrazine-2-ylmethyl) -amide (Compound I) or its isomers, salts, esters, N-oxides or solvates Refers to the crystal form of an object. Alternatively, the term may refer to a salt or solvate of Compound I, or both forms. Crystal forms of Compound I described throughout this application, including a single isomer of Compound I, a mixture of any number of isomers of Compound I.

The terms "co-administration" or "co-administration" refer to (a) the crystalline form of Compound I, or the pharmaceutically acceptable salts, esters, solvates and / or prodrugs thereof of Compound I, and (b). ) Refers to administration in combination, i.e., in combination with one or more additional therapeutic agents and / or radiation therapy in a coordinated manner.

The term "isomer" refers to a compound having the same chemical formula but with a different steric chemical formula, structural formula or specific arrangement of atoms. Examples of isomers include steric variants, diastereomers, enantiomers, conformational isomers, rotational isomers, geometric isomers and atropisomers.

N-oxide, also known as amine oxide or amine-N-oxide, means a compound derived from a compound of the invention via oxidation of the amine group of the compound of the invention. N- oxides are usually functional group _R 3 ^N + ^-O - containing _(R 3 N = O or _{R 3} N → O and being described also).

Polymorphism can be characterized as the ability of compounds to crystallize into different crystalline forms while maintaining the same chemical formula. The crystalline polymorphs of a given drug substance are chemically identical to other crystalline polymorphs of the drug substance in that they contain the same atoms that bind to each other in the same way, but differ in their crystalline morphology. It can affect one or more physical properties such as stability, solubility, melting point, bulk density, fluidity, bioavailability and the like.

The term "composition" means one or more substances in physical form, for example solids, liquids, gases, or mixtures thereof. An example of a composition is a pharmaceutical composition, i.e., a composition involved in, prepared for, or used in a drug therapy.

The term "carboxylic acid" refers to organic acids characterized by one or more carboxyl groups, such as acetic acid and oxalic acid. A sulfonic acid is an organic acid having the general formula of R- (S (O) _2- OH) _n , where R is the organic moiety and n is an integer greater than zero, such as 1, 2 and 3. Point to. The term "polyhydroxy acid" refers to a carboxylic acid containing two or more hydroxyl groups. Examples of polyhydroxy acids include, but are not limited to, lactobionic acid, gluconic acid and galactose.

As used herein, "pharmaceutically acceptable" makes sense, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, etc. It means that it is commensurate with the benefit / risk ratio and is effective for its intended use within the scope of sound medical judgment.

A "salt" comprises a derivative of the activator, in which the activator is modified by making an acid or base addition salt thereof. Preferably, the salt is a pharmaceutically acceptable salt. Suitable salts include, but are not limited to, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts. Examples of the acid addition salt include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid and the like. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malonic acid, Mandelic acid, oxalic acid, picric acid, pyruvate, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bismethylene salicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, aspartic acid, Steeric acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamate, benzenesulfonic acid, p-toluenesulfonic acid, sulfate, nitrate, phosphate, perchlorate, borate, acetate, Examples thereof include benzoate, hydroxynaphthoate, glycerophosphate, ketoglutarate and the like. Base addition salts include ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazin, tris- ( Hydroxymethyl) -aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, efenamine, dehydroabiethylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, Basic amino acids such as, but not limited to, lysine and arginine dicyclohexylamine. Examples of metal salts include lithium salts, sodium salts, potassium salts, magnesium salts and the like. Examples of ammonium salts and alkylated ammonium salts include ammonium salts, methylammonium salts, dimethylammonium salts, trimethylammonium salts, ethylammonium salts, hydroxyethylammonium salts, diethylammonium salts, butylammonium salts, tetramethylammonium salts and the like. Can be mentioned. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like. Standard methods for the preparation of pharmaceutically acceptable salts and formulations thereof are well known in the art, for example, Remington: The Science and Practice of Pharmacy ”, A. Gennaro, ed., 20th edition, Lippincott, Williams. & Published in various references including Wilkins, Philadelphia, PA.

As used herein, a "solvate" is a solute ion with a complex or one or more solvent molecules formed by solvation (a molecule of the activator of the invention or a combination of a solvent molecule with an ion). Alternatively, it means an aggregate composed of molecules (activators of the present invention). In the present invention, the preferred solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, hexahydrates and the like. It should be understood by those skilled in the art that pharmaceutically acceptable salts of the compounds may be present in the form of solvates. Solvates are usually formed through hydration, which is part of the preparation of the compound, or through the natural absorption of water by the anhydrous compounds of the invention. Solvates containing hydrates may be in stoichiometric ratios, for example with 2, 3 or 4 salt molecules per solvate or per molecule of hydrate. For example, another possibility that two salt molecules are stoichiometrically related to 3, 5, 7 solvent or hydrate molecules. Solvents used for crystallization, such as alcohols, especially methanol and ethanol; aldehydes; ketones, especially acetone; esters, such as ethyl acetate, may be embedded in the crystal lattice. A pharmaceutically acceptable solvent is preferred.

The term "substantially similar" as used herein means an analytical spectrum that is very similar to the reference spectrum in both peak position and its intensity, such as the XRPD pattern, Raman spectroscopy. To do.

The terms "excipient", "carrier" and "vehicle" are used interchangeably throughout this application and mean substances to which the compounds of the invention are administered together.

"Therapeutically effective amount" means an amount in crystalline form that, when administered to a patient to treat a disease or other undesired medical condition, is sufficient to have a beneficial effect on the disease or condition. To do. The therapeutically effective amount will vary depending on the crystal form, disease or condition and its severity, as well as the age, weight, etc. of the patient being treated. Determining a therapeutically effective amount of a given crystalline form is within the normal skill of the technique and merely requires routine experimentation.

As used herein, the phrase "disease characterized by cell proliferation" or "condition characterized by cell proliferation" includes, but is not limited to, cancer, benign and malignant tumors. Examples of cancers and tumors include colorectal, mammary gland, lung, liver, pancreas, lymph nodes, colon, prostate, brain, head and neck, skin, kidney, blood and heart cancer or tumor growth (eg, leukemia, lymphoma, etc.) And cancer), but is not limited to these.

The terms "treat," "treat," or "treat" for a particular disease or disorder include prevention of the disease or disorder and / or reduction, amelioration, improvement, or reduction, amelioration, or improvement of the symptoms and / or condition of the disease or disorder. Includes invalidation. In general, the term, as used herein, refers to ameliorating, alleviating, alleviating and eliminating the symptoms of a disease or condition. Candidate molecules or compounds described herein may be present in therapeutically effective amounts in a formulation or drug, such as apoptosis of a particular cell (eg, a cancer cell), of a particular cell. An amount that can bring about biological effects such as reduced proliferation, or can, for example, ameliorate, alleviate, alleviate and eliminate the disease or condition. The term also reduces or stops the growth rate of cells (eg, slows or stops tumor growth), or reduces the number of cancer cells growing (eg, removes part or all of the tumor). That) can be pointed out. These terms reduce the titer of a microorganism in a system infected with the microorganism (ie, a cell, tissue or subject), reduce the number of symptoms or the effects of the symptoms associated with the microbial infection, and / or detect. It can also be applied to remove as much microorganisms as possible from the system. Examples of microorganisms include, but are not limited to, viruses, bacteria and fungi.

As used herein, the term "inhibiting" or "reducing" cell proliferation is provided in the methods and compositions of the present application when measured using methods known to those of skill in the art. The amount of cell proliferation compared to non-proliferating cells, eg, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%. You decide to delay, reduce, or, for example, stop.

As used herein, the term "apoptosis" refers to an endogenous cell self-destruction or suicide program. In response to evoked stimuli, cells undergo a cascade of events, including cell contraction, cell membrane blebbing, and chromatin enrichment and fragmentation. These events lead to the conversion of cells into clusters of membrane-bound particles (apoptotic bodies), which are then taken up by macrophages.

Crystalline Material In one embodiment, the invention provides a crystalline form of compound I (free base). In another embodiment, the crystalline form of the salt and / or solvate of Compound I of the present invention is provided. In one embodiment, the salt is a hydrochloric acid addition salt. In one embodiment, the salt is a sulfate addition salt. In one embodiment, the salt is a sulfonic acid addition salt. In one embodiment, the salt is a carboxylic acid addition salt. In one embodiment, the salt is a polyhydroxy acid addition salt.

Examples of crystalline salts include hydrochloride, maleate, fumarate, citrate, malate, sulfate, acetate, phosphate, L- (+)-tartrate, D-glucron. Included salts, benzoates, succinates, ethane sulfonates, methane sulfonates, p-toluene sulfonates, malonates, benzene sulfonates, and 1-hydroxy-2-naphthoate. However, it is not limited to these. In one embodiment, the ratio of compound I to acid in the crystalline salt is from about 1: 0.5 to about 1: 3.

Examples of crystalline solvates include, but are not limited to, NMP (N-methyl-2-pyrrolidone) solvates of Compound I.

In one embodiment, the crystalline form is characterized by a lattice spacing determined by X-ray powder diffraction (XRDP). The spectrum of XRDP is usually represented by a figure that plots the position of the peak, i.e., the intensity of the peak as opposed to the diffraction angle 2θ (2 theta) in degrees. Intensity is often given in parentheses along with the following abbreviations: very strong = vst; strong = st; moderate = m; weak = w; and very weak = vw. The characteristic peaks of a given XRDP can be selected according to the position of the peaks and their relative intensities to conveniently distinguish this crystal structure from others. The% intensity of the peak compared to the strongest peak may be expressed as I / Io.

Those skilled in the art will recognize that measurements of XRDP peak position and / or intensity for a given crystal form of the same compound will vary within error limits. The value of degree 2θ allows for an appropriate margin of error. The margin of error is usually represented by "±". For example, a degree 2θ of about "8.716 ± 0.3" indicates a range of about 8.716 + 0.3, ie from 9.016 to about 8.716-0.3, ie about 8.416. Depending on the sample preparation method, calibration method, etc. applied to the equipment, human operational variations, etc., those skilled in the art will have an appropriate error limit for XRDP of about ± 0.7; ± 0.6; ± 0.5. Recognize that it can be ± 0.4; ± 0.3; ± 0.2; ± 0.1; ± 0.05.

Additional details of the methods and instruments used to analyze the XRDP are given in the Examples section.

In one embodiment, the crystalline form is characterized by differential scanning calorimetry (DSC). The DSC thermogram is usually represented by a diagram that plots a standardized heat flow in watts / gram (W / g) against the temperature of the sample measured at ° C. DSC thermograms are usually evaluated for estimated start and end (end) temperatures, peak temperatures and heat of fusion. The peak eigenvalues of the DSC thermogram are often used as characteristic peaks to distinguish this crystal structure from others.

One of ordinary skill in the art recognizes that DSC thermogram measurements for a given crystal form of the same compound will vary within error limits. The value of the eigenvalue of a single peak expressed in ° C allows an appropriate margin of error. The margin of error is usually indicated by ±. For example, the eigenvalue of a single peak of about "53.09 ± 2.0 means the range of about 53.09 + 2, i.e. about 55.09 to 53.09-2, i.e. about 51.09. Depending on the sample preparation method, the calibration method applied to the instrument, and human operational variations, those skilled in the art will have appropriate error limits for the eigenvalues of a single peak ± 2.5; ± 2.0; ±. Recognize that 1.5; ± 1.0; ± 0.5; can be less than or equal to.

Additional details of the methods and instruments used in the analysis of the DSC thermogram are given in the Examples section.

In one embodiment, the crystalline form is characterized by Raman spectroscopy. The Raman spectrum is usually represented by a figure that plots the Raman intensity of the peak as opposed to the Raman shift of the peak. The "peak" of Raman spectroscopy is also known as the "absorption band". Intensity is often given in parentheses with the following abbreviations: strong = st; moderate = m; and weak = w. Characteristic peaks in a given Raman spectrum can be selected according to the position of the peaks and their relative intensities to conveniently distinguish this crystal structure from others.

One of ordinary skill in the art recognizes that Raman peak shift and / or intensity measurements for a given crystal form of the same compound will vary within error limits. The peak shift value represented by the reverse wave number (cm ^-1 ) is expected to have an appropriate margin of error. The margin of error is usually indicated by ±. For example, a Raman shift of about "1310 ± 10 means a range of about 1310 + 10, ie from about 1320 to 1310-10, ie about 1300. Sample preparation methods, instrumentation calibration methods and humans. In response to operational variations and the like, those skilled in the art will recognize that the appropriate margin of error for Raman shift can be ± 12; ± 10; ± 8; ± 5; ± 3; ± 1 or less.

Additional details of the methods and instruments used in Raman spectroscopy analysis are given in the Examples section.

In one embodiment, the crystalline form of compound I (free base). In some embodiments, the crystalline form of compound I (free base) shows a different polymorph. Examples of crystalline forms of compound I (free base) include, but are not limited to, polymorphs A, C, E and G as defined in the following sections.

In some embodiments, one form of the polymorph is more stable than the other. In one embodiment, the crystalline form of compound A (free base) polymorph A exhibits high stability. In some embodiments, various polymorphs of compound I (free base) are converted to other polymorphic forms under certain conditions. In some embodiments, the polymorphs C, E and / or G are converted to polymorph A under suitable conditions. In one embodiment, each of the polymorphs C, E and G is independently converted to polymorph A in solution at room temperature or high temperature. Polymorphic A is the most thermodynamically stable form, while other forms may be dynamically formed or preferred under certain conditions.

In one embodiment of the disclosure, the crystalline form of Compound I may be composed of a mixture of one or more forms of a polymorph of Compound I. In some embodiments, the crystalline form of Compound I may be composed of a substantially pure form of a polymorph of one type. In one embodiment, the crystalline form of Compound I is about 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.4% of Compound I. It may be composed of one polymorph that exceeds about 99.3%, about 99.2%, about 99.1%, or about 99.0%. In another embodiment, the crystalline form of Compound I is one that exceeds approximately 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, or 90% of Compound I. It may be composed of polymorphs. In some embodiments, the crystalline form of Compound I is approximately 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, or 40% of Compound I. It may be composed of one polymorph that exceeds.

In one embodiment of the disclosure, the crystalline form of Compound I is at least about 99.9%, about 99.8%, about 99.7%, about 99.6% of the polymorph A of Compound I (free base). About 99.5%, about 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99.0%, about 98%, about 97%, about 96%, about 95 It may be composed of%, about 94%, about 93%, about 92%, about 91%, about 90%, or about 85%.

In one embodiment of the present disclosure, the crystalline form of Compound I is about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%. , 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5% , 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15% , 16%, 17%, 18%, 18%, or 20% polymorph C, E or G, or a mixture thereof of compound I (free base) polyform A.

In one embodiment of the present disclosure, the crystalline form of compound I is about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%. , 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5% , 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15% , 16%, 17%, 18%, 18%, or 20% polymorphic form A of compound I (free base) containing polymorphic form A.

In one embodiment of the present disclosure, the crystalline form of compound I is about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%. , 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5% , 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15% , 16%, 17%, 18%, 18%, or 20% polymorphic form A of compound I (free base) containing polymorphic form A.

In one embodiment of the present disclosure, the crystalline form of compound I is about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%. , 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5% , 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15% , 16%, 17%, 18%, 18%, or 20% polymorph A of compound I (free base) containing polyform A.

In one embodiment, the disclosure provides a crystal form of compound I that is highly pure. In one embodiment of the disclosure, the purity of the crystalline form of Compound I is at least 99.9%, about 99.8%, about 99.7%, about 99.6%, about 99.5%, about 99.5% with respect to Compound I. 99.4%, about 99.3%, about 99.2%, about 99.1%, about 99.0%, about 98%, about 97%, about 96%, about 95%, about 94%, about It may be 93%, about 92%, about 91%, or about 90% pure.

Additional methods for characterizing the crystalline form are described in the Examples section of the application.

Polymorphic A
In one embodiment, the polymorph A of compound I (free base) is about ± 0.5; about ± 0.4; about ± 0.3; about ± 0.2; about ± 0.1; about ± 0. 0.05; XRDP with peaks at about 7.730, 22.050 and 24.550 degrees 2 theta with the following error limits. In another embodiment, the XRDP of the crystalline polymorph A of compound I (free base) is further about ± 0.5; about ± 0.4; about ± 0.3; about ± 0.2; about ± 0. 1; about ± 0.05; including peaks at about 9.410 and 27.700 degrees 2-seater with the following error limits: In a further embodiment, the crystalline form of compound A (free base) polymorph A is further about ± 0.5; about ± 0.4; about ± 0.3; about ± 0.2; about ± 0.1; Approximately ± 0.05; 2 theta peaks at approximately 17.950 and 25.400 degrees with the following error limits. In another embodiment, the crystalline form of compound A (free base) polymorph A is further about ± 0.5; about ± 0.4; about ± 0.3; about ± 0.2; about ± 0.1. At least one peak at about 11.230, 11.630, 16.900, 18.580, 23.300, and 26.700 degrees 2-seater with the following error limits: about ± 0.05; Including. In yet another embodiment, the crystalline form of compound I (free base) polymorph A shows an XRDP containing the peaks shown in Table 1 below.
In one specific embodiment, the crystalline form of compound I (free base) polymorph A shows an XRDP that is substantially similar to FIG.

In one embodiment, the crystalline form of compound I (free base) polymorph A is about ± 2.5, about ± 2.0, about ± 1.5, about ± 1.0, about ± 0.5 or less. Shows a DSC thermogram containing a sharp endothermic at about 215.41 ° C. with an error limit of. In another embodiment, the crystalline form of compound I (free base) polymorph A has the following peaks: exotherm at about 216.92 ± 2.0 ° C., endothermic at about 230.56 ± 2.0, A DSC thermogram containing one or more of heat generation at about 232.84 ± 2.0 and endotherm at about 241.56 ± 2.0 is shown. In one specific embodiment, the crystalline form of compound I (free base) polymorph A shows a DSC thermogram that is substantially similar to FIG.

In one embodiment, the crystalline form of compound I (free base) polymorph A shows a ^{1 1} H-NMR spectrum that is substantially similar to FIG. In another embodiment, the crystalline form of compound I (free base) polymorph A has a crystalline phase of fine acicular crystals that form loosely bound masses at the microscopic level, substantially similar to FIGS. 6A and 6B. You may have.

Polymorphic C
The polymorphic form C of compound I (free base) has an error of about ± 0.5, about ± 0.4, about ± 0.3, about ± 0.2, about ± 0.1, about ± 0.05 or less. XRDP with a peak at about 5.720 degrees 2 theta with a limit is shown. In another embodiment, the crystalline form of compound I (free base) polymorph C shows an XRDP containing the peaks shown in Table 2 below.
In one specific embodiment, the crystalline form of compound I (free base) polymorph C shows an XRDP that is substantially similar to FIG.

In one embodiment, the crystalline form of compound I (free base) polymorph C is about ± 2.5, about ± 2.0, about ± 1.5, about ± 1.0, about ± 0.5 or less. A DSC thermogram containing peak eigenvalues at about 246.47 ° C. with an error limit is shown. In one specific embodiment, the crystalline form of compound I (free base) polymorph C shows a DSC thermogram that is substantially similar to FIG.

In one embodiment, the crystalline form of compound I (free base) polymorph C shows a ¹ H-NMR spectrum that is substantially similar to FIG. In another embodiment, the crystalline form of compound I (free base) polymorph C may consist of agglomerates of acicular crystals at the microscopic level that are substantially similar to FIGS. 10A and 10B.

Polymorphic E
In one embodiment, the polymorph E of compound I (free base) is about ± 0.5; about ± 0.4; about ± 0.3; about ± 0.2; about ± 0.1; about ± 0. 05; XRDP with peaks at about 5.680 degrees 2 theta with the following error limits. In another embodiment, the XRDP in crystalline form of the polymorph E of compound I (free base) is further about ± 0.5; about ± 0.4; about ± 0.3; about ± 0.2; about ±. 0.1; about ± 0.05; containing at least one peak at about 12.200, 12.600, 25.360 and 27.560 degrees 2-seater with the following error limits: In yet another embodiment, the crystalline form of compound I (free base) polymorph E shows an XRDP containing the peaks shown in Table 3 below.
In one specific embodiment, the crystalline form of compound I (free base) polymorph E shows an XRDP that is substantially similar to FIG.

In one embodiment, the crystalline form of compound I (free base) polymorph E is about ± 2.5, about ± 2.0, about ± 1.5, about ± 1.0, about ± 0.5 or less. A DSC thermogram containing peak eigenvalues at about 231.99 ° C. with an error limit is shown. In one specific embodiment, the crystalline form of compound I (free base) polymorph E shows a DSC thermogram that is substantially similar to FIG.

In one embodiment, the crystalline form of compound I (free base) polymorph E shows a ¹ H-NMR spectrum that is substantially similar to FIG. In another embodiment, the crystalline form of compound I (free base) polymorph E may be substantially similar to FIGS. 14A and 14B.

Polymorphic G
In one embodiment, the polymorph G of compound I (free base) is about ± 0.5; about ± 0.4; about ± 0.3; about ± 0.2; about ± 0.1; about ± 0. 05; XRDP with peaks at about 5.000 and 6.060 degrees 2 theta with the following error limits. In another embodiment, the crystalline form of compound I (free base) polymorph G shows an XRDP containing the peaks shown in Table 4 below.
In one specific embodiment, the crystalline form of the polymorph G of compound I (free base) shows an XRDP that is substantially similar to FIG.

In one embodiment, the crystalline form of compound I (free base) polymorph G is about ± 2.5, about ± 2.0, about ± 1.5, about ± 1.0, about ± 0.5 or less. A DSC thermogram containing peak eigenvalues at about 222.11 ° C. with an error limit is shown. In one specific embodiment, the crystalline form of compound I (free base) polymorph G shows a DSC thermogram that is substantially similar to FIG.

In one embodiment, the crystalline form of compound I (free base) polymorph G shows a ¹ H-NMR spectrum that is substantially similar to FIG. In another embodiment, the crystalline form of the polymorph G of compound I (free base) may be substantially similar to FIGS. 19A and 19B.

HCl Salt of Compound In one embodiment, the crystalline form of the HCl salt of Compound I is about ± 0.5; about ± 0.4; about ± 0.3; about ± 0.2; about ± 0.1; about ±. 0.05; XRDP with peaks at about 4.660 and 24.540 degrees 2 theta with the following error limits. In another embodiment, the XRDP in crystalline form of the HCl salt of Compound I is further about ± 0.5; about ± 0.4; about ± 0.3; about ± 0.2; about ± 0.1; about ± 0.1; ± 0.05; Includes 1, 2, 3 or 4 peaks selected in 2 theta at about 19.260, 20.160, 24.920 and 26.360 degrees with the following error limits. In another embodiment, the XRDP in crystalline form of the HCl salt of Compound I is further about ± 0.5; about ± 0.4; about ± 0.3; about ± 0.2; about ± 0.1; about ± 0.1; ± 0.05; Includes 1, 2, or 3 peaks selected in 2 theta at about 13.980, 14.540, 25.380 and 28.940 degrees with the following error limits: In yet another embodiment, the crystalline form of the HCl salt of Compound I shows an XRDP containing the peaks shown in the table below.

In one specific embodiment, the crystalline form of the HCl salt of Compound I shows an XRDP that is substantially similar to FIG.

In one embodiment, the crystalline form of the HCl salt of Compound I is with error limits of about ± 2.5, about ± 2.0, about ± 1.5, about ± 1.0, about ± 0.5 or less. The DSC thermogram containing the peak eigenvalues is shown at about 266.27 ° C. In one specific embodiment, the crystalline form of the HCl salt of Compound I shows a DSC thermogram that is substantially similar to FIG. In one embodiment, the crystalline form of the HCl salt of Compound I has no clear melting point.

In one embodiment, the crystalline form of the HCl salt of Compound I shows a ¹ H-NMR spectrum that is substantially similar to FIG. In another embodiment, the crystalline form of the HCl salt of Compound I may consist of small needle-like crystals that form agglomerates at the microscopic level, substantially similar to FIG. 24. In one embodiment, the ratio of HCl to Compound I in the HCl salt of Compound I is about 1: 1.

Maleate of Compound I In one embodiment, the crystalline form of maleate of Compound I is about ± 0.5; about ± 0.4; about ± 0.3; about ± 0.2; about ± 0.1. XRDP with peaks at about 7.400, 18.440, and 26.500 degrees 2 theta with the following error limits: about ± 0.05. In another embodiment, the XRDP in crystalline form of the maleate of Compound I is further about ± 0.5; about ± 0.4; about ± 0.3; about ± 0.2; about ± 0.1; Approximately ± 0.05; including peaks 1, 2, 3 or 4 selected in 2-seater at approximately 22.320, 23.920, 24.300, and 25.240 degrees with the following error limits: .. In another embodiment, the XRDP in crystalline form of the maleate of Compound I is further about ± 0.5; about ± 0.4; about ± 0.3; about ± 0.2; about ± 0.1; Approximately ± 0.05; of 1, 2, 3 or 4 selected in 2 theta of approximately 5.040, 15.080, 15.880, 20.860 and 28.540 degrees with the following error limits: Includes peaks. In yet another embodiment, the crystalline form of the maleate of Compound I shows an XRDP containing the peaks shown in the table below.

In one specific embodiment, the crystalline form of the maleate of Compound I shows an XRDP that is substantially similar to FIG.

In one embodiment, the crystalline form of the maleate of Compound I is with an error limit of about ± 2.5, about ± 2.0, about ± 1.5, about ± 1.0, about ± 0.5 or less. The DSC thermogram containing the peak eigenvalues is shown at about 217.32 ° C. In one specific embodiment, the crystalline form of the maleate of Compound I shows a DSC thermogram that is substantially similar to FIG. 27.

In one embodiment, the crystalline form of the maleate of Compound I shows a ¹ H-NMR spectrum that is substantially similar to FIG. In another embodiment, the crystalline form of the maleate of Compound I may be substantially similar to FIG. 29, and may consist of small acicular crystals that form agglomerates at the microscopic level. In one embodiment, the ratio of maleic acid to compound I in the maleate of compound I is about 1: 1.

Fumarate of Compound I In one embodiment, the crystal form of fumarate of Compound I is about ± 0.5; about ± 0.4; about ± 0.3; about ± 0.2; about ± 0.1. Approximately ± 0.05; XRDP with peaks at approximately 6.360 and 24.800 degrees 2 theta with the following error limits. In another embodiment, the XRDP in crystalline form of the fumarate of Compound I is further about ± 0.5; about ± 0.4; about ± 0.3; about ± 0.2; about ± 0.1; Approximately ± 0.05; Containing at least 1, 2 or 3 peaks selected in 2 theta at approximately 19.660, 20.420 and 26.860 degrees with the following error limits. In another embodiment, the XRDP in crystalline form of the fumarate of Compound I is further about ± 0.5; about ± 0.4; about ± 0.3; about ± 0.2; about ± 0.1; Approximately ± 0.05; Containing at least 1, 2, 3 or 4 peaks selected in 2-seater at approximately 12.680, 17.020, 25.180 and 28.280 degrees with the following error limits: .. In yet another embodiment, the crystalline form of fumarate of Compound I shows an XRDP containing the peaks shown in the table below.

In one specific embodiment, the crystalline form of the fumarate of Compound I shows an XRDP that is substantially similar to FIG.

In one embodiment, the crystalline form of fumarate of Compound I is with error limits of about ± 2.5, about ± 2.0, about ± 1.5, about ± 1.0, about ± 0.5 or less. A DSC thermogram containing peak eigenvalues is shown at about 222.40 ° C. In one specific embodiment, the crystalline form of the fumarate of Compound I shows a DSC thermogram that is substantially similar to FIG.

In one embodiment, the crystalline form of the fumarate of Compound I shows a ¹ H-NMR spectrum that is substantially similar to FIG. In another embodiment, the crystal form of the fumarate of Compound I may be substantially similar to FIG. 34, and may consist of small acicular crystals that form agglomerates at the microscopic level. In one embodiment, the ratio of fumaric acid to compound I in the fumarate of compound I is about 1: 1.

Citrate of Compound I In one embodiment, the crystalline form of the citrate of Compound I is about ± 0.5; about ± 0.4; about ± 0.3; about ± 0.2; about ± 0. 1; about ± 0.05; XRDP with peaks at about 4.900, 25.380 and 27.500 degrees 2 theta with the following error limits. In another embodiment, the XRDP in crystalline form of the citrate of Compound I is further about ± 0.5; about ± 0.4; about ± 0.3; about ± 0.2; about ± 0.1; Approximately ± 0.05; Containing at least 1, 2, 3 or 4 peaks selected in 2 theta of approximately 15.360, 18.100, 19.300 and 26.140 degrees with the following error limits: .. In another embodiment, the XRDP in crystalline form of the citrate of Compound I is further about ± 0.5; about ± 0.4; about ± 0.3; about ± 0.2; about ± 0.1; Approximately ± 0.05; Containing at least 1, 2, 3 or 4 peaks selected in 2 theta of approximately 17.400, 18.680, 24.040 and 26.740 degrees with the following error limits: .. In yet another embodiment, the crystalline form of the citrate of Compound I shows an XRDP containing the peaks shown in the table below.

In one specific embodiment, the crystalline form of the citrate of Compound I shows an XRDP that is substantially similar to FIG. 36.

In one embodiment, the crystalline form of the citrate of Compound I is with an error limit of about ± 2.5, about ± 2.0, about ± 1.5, about ± 1.0, about ± 0.5 or less. The DSC thermogram containing the peak specific value is shown at about 196.86 ° C. In one specific embodiment, the crystalline form of the citrate of Compound I shows a DSC thermogram that is substantially similar to FIG. 37.

In one embodiment, the crystalline form of the citrate of Compound I shows a ¹ H-NMR spectrum that is substantially similar to FIG. 38. In another embodiment, the crystalline form of the citrate of Compound I may be substantially similar to FIG. 39, and may consist of small acicular crystals that form agglomerates at the microscopic level. In one embodiment, the ratio of citric acid to compound I in the citrate of compound I is about 1: 1.

L-Appleate of Compound I The crystal form of L-apple salt of Compound I is about ± 0.5; about ± 0.4; about ± 0.3; about ± 0.2; about ± 0.1; Approximately ± 0.05; XRDP with peaks at 2 theta of approximately 6.580, 6.780 and 25.560 degrees with the following error limits. In another embodiment, the XRDP in crystalline form of L-malate of Compound I is further about ± 0.7; about ± 0.6; about ± 0.5; about ± 0.4; about ± 0. 3; about ± 0.2; about ± 0.1; about ± 0.05; in two thetas of about 19.560, 23.660, 26.060, and 26.960 degrees with the following error limits: Includes 1, 2, 3 or 4 peaks selected. In another embodiment, the XRDP in crystalline form of L-malate of Compound I is further about ± 0.5; about ± 0.4; about ± 0.3; about ± 0.2; about ± 0. 1; about ± 0.05; 1, 2, 3, selected in two theta of about 8.800, 11.800, 18.600, 24.460 and 25.080 degrees with the following error limits: Includes 4 or 5 peaks. In yet another embodiment, the crystalline form of L-malate of Compound I shows an XRDP containing the peaks shown in the table below.

In one specific embodiment, the crystalline form of L-malate of Compound I shows an XRDP that is substantially similar to FIG. 41.

In one embodiment, the crystalline form of L-apple salt of Compound I has an error limit of about ± 2.5, about ± 2.0, about ± 1.5, about ± 1.0, about ± 0.5 or less. The DSC thermogram containing the peak eigenvalues is shown at about 209.67 ° C. In one specific embodiment, the crystalline form of L-malate of Compound I shows a DSC thermogram that is substantially similar to FIG. 42.

In one embodiment, the crystalline form of L-malate of Compound I shows a ¹ H-NMR spectrum substantially similar to FIG. 43. In another embodiment, the crystalline form of L-malate of Compound I may be substantially similar to FIG. 44, or may consist of small acicular crystals that form agglomerates at the microscopic level. In one embodiment, the ratio of L-malic acid to Compound I in L-malate of Compound I is about 1: 1.

Pharmaceutical Formulation In another embodiment, the invention is a therapeutically effective amount of the active ingredient in combination with a pharmaceutically acceptable excipient or carrier, such as Compound I or pharmaceutically acceptable as disclosed herein. Provided are a pharmaceutical composition comprising an acceptable crystalline form of the salt, ester and / or solvate thereof. Excipients are added to formulations for a variety of purposes.

Diluents may be added to the formulations of the present invention. Diluents may increase the bulk of the solid pharmaceutical composition and make the pharmaceutical dosage form containing the composition easier for the patient or caregiver. Diluters for solid compositions include, for example, crystalline cellulose (eg AVICEL), ultrafine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrin, dextrin, dextrin, calcium dibasic phosphate. Dihydrate, calcium tribasic phosphate, kaolin, magnesium carbonate, magnesium oxide, malt dextrin, mannitol, polymethacrylate (eg, EUDRAGIT (r)), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

For example, a solid pharmaceutical composition packed in a tablet-like dosage form may contain an excipient whose function comprises helping the active ingredient and other excipients to be combined together after compression. .. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (eg, carbopole), sodium carboxymethyl cellulose, dextrin, ethyl cellulose, gelatin, guar gum, tragacant rubber, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (eg, propyl cellulose). , KLUCEL), hydroxypropylmethylcellulose (eg, METHOCEL), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylate, povidone (eg, KOLLIDON, PLASSONE), pregelatinized starch, sodium alginate and starch.

The rate of dissolution of the compressed solid pharmaceutical composition in the patient's stomach may be increased by adding a disintegrant to the composition. Disintegrants include alginic acid, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose (eg AC-DI-SOL and PRIMELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (eg KOLLIDON and POLYPLASSONE), guar rubber, magnesium silicate. Examples include aluminum, methyl cellulose, crystalline cellulose, potassium polariline, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (eg EXPLOTAB), potato starch and starch.

A flow enhancer can be added to improve the fluidity of the uncompressed solid composition and improve the accuracy of dosing. Excipients that may function as fluidity accelerators include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and calcium tribasic phosphate.

When a tablet-like dosage form is made by compression of the powdered composition, the composition is subjected to pressure from a die. Some excipients and active ingredients tend to adhere to the surface of the die, which can cause the formation of small pits and other surface irregularities. Lubricant can be added to the composition to reduce adhesion and facilitate mold release of the product from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate. , Stearic acid, talc and zinc stearate.

Flavors and flavor enhancers make the dosage form palatable to the patient. General pharmaceutical flavoring agents and flavor enhancers that may be included in the compositions of the present invention include maltor, vanillin, ethylvanillin, menthol, citric acid, fumaric acid, ethylmaltor and tartaric acid. ..

Solid and liquid compositions may be colored with pharmaceutically acceptable colorants to improve their appearance and facilitate patient identification at product and unit dose levels.

In liquid form, the pharmaceutical composition may be prepared using the crystalline form of the invention and other solid excipients, wherein the ingredients are, for example, water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, etc. Alternatively, it is dissolved or suspended in a liquid carrier such as glycerin.

The liquid pharmaceutical composition may contain an emulsifier to uniformly disperse the active ingredient or other excipient that is not soluble in the liquid carrier throughout the composition. Emulsifiers that may be useful in the liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacant, tunomata, pectin, methylcellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.

The liquid pharmaceutical composition may also contain a viscosity enhancer to improve the mouthfeel of the product and coat the inner layer of the gastrointestinal tract. Such active agents include acacia, alginic acid, bentonite, carbomer, carboxymethyl cellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethyl cellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol. , Povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch, tragacant and xanthan rubber.

For example, sweeteners such as aspartame, lactose, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve taste.

For example, preservatives and chelators such as alcohol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole, and ethylenediaminetetraacetic acid may be added at safe levels to improve storage stability.

The liquid composition may also contain, for example, a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate. The choice of excipient and the amount used may be readily determined by the formulation scientist based on the experience and consideration of standard procedures and reference work in the field.

The solid composition of the present invention includes powders, granules, agglomerates and compressed compositions. Dosages include doses suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous) inhalation and ophthalmic administration. The most preferred administration in any given case will depend on the nature and severity of the condition being treated, but the most preferred route of the invention is oral. Dosages may be conveniently presented in unit dosage forms or may be prepared by any of the methods well known in pharmaceutical technology.

Dosage forms include liquid syrups, suspensions, aerosols and elixirs as well as solid dosage forms such as tablets, powders, capsules, suppositories, sachets, lozenges and candy.

The dosage form of the present invention may be a capsule containing the composition of the present invention, preferably a powdered or granulated solid composition, in a hard or soft exodermis. The exodermis may be made from gelatin and optionally contain plasticizers such as glycerin and sorbitol, as well as opalescent or colorants.

The composition for tableting or capsule filling may be prepared by a wet granulation method. In the wet granulation method, the active ingredient in powder form and some or all of the excipient are mixed, then further mixed in the presence of a liquid, usually water, which aggregates the powder into granules. The granules are sieved and / or milled, dried and then sieved and / or milled to the desired particle size. The granules may be tableted, or other excipients such as, for example, flow promoters and / or lubricants may be added prior to tableting.

The tableting composition may be prepared as usual by dry mixing. For example, the composition of the mixture of active ingredient and excipient may be compacted into slag or sheet and then crushed into compacted granules. The consolidated granules may then be compressed into tablets.

As an alternative to the wet granulation method, the mixed composition may be directly compressed into a consolidation dosage form using a direct compression method. Direct compression produces a more uniform tablet without granules. Excipients particularly well suited for direct compression tableting include crystalline cellulose, spray-dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression locks is known to those skilled in the art who have experience and skill in the particular formulation of direct compression locks.

Capsule filling of the present invention may include any of the above-mentioned mixtures and granules described with reference to tableting, but they are not subjected to the final tableting step.

Active ingredients and excipients may be formulated into compositions and dosage forms according to methods known in the art.

In one embodiment, the dosage form may be provided as a kit comprising a crystalline form of Compound I and a pharmaceutically acceptable excipient and carrier as another component. In some embodiments, the dosage form kit is used by physicians and patients prior to use by dissolving, suspending, or mixing the crystalline form of Compound I with pharmaceutically acceptable excipients and carriers. Allow oral or injectable solutions to be formulated. In one embodiment, the dosage form kit that provides the crystalline form of Compound I has improved stability of Compound I as compared to a pre-prepared liquid formulation of Compound I.

It is not necessary for the formulations of the invention to contain only one crystalline form of Compound I. The crystalline form of the present invention may be used in a pharmaceutical formulation or composition as a single component or as a mixture with other crystalline forms of Compound I. In one embodiment, the pharmaceutical formulation or composition of the invention is in the crystalline form of Compound I as described herein in 25-100% by weight or 50-100% by weight of the formulation or composition. Contains at least one.

Therapeutic Use The present invention also provides the treatment of diseases associated with cell proliferation. In one aspect, there is provided a method of selectively activating the p53 protein, which comprises contacting cells affected with a cell growth-related disease with the compound. In one embodiment, the method involves contacting cancer cells and / or tumor cells with the crystalline form of Compound I or a pharmaceutically acceptable salt, ester and / or solvate thereof as disclosed herein. including. In another embodiment, the method of contacting a cancer cell and / or a tumor cell with a crystalline form of Compound I or a pharmaceutically acceptable salt, ester and / or solvate thereof as disclosed herein is a cell. It may induce or prevent the progression of the disease.

Further disclosed are methods of treating cancer, cancer cells, tumors or tumor cells. Non-limiting examples of cancers that may be treated by the methods of the present disclosure include colonic rectal, mammary gland, lung, liver, pancreas, lymph nodes, colon, prostate, brain, head and neck, skin, ovary, cervix, thyroid. , Bladder, kidney, blood and heart cancers or cancer cells (eg, leukemia, lymphoma, and carcinoma). Non-limiting examples of tumors that may be treated by the methods of the present disclosure include colorectal, mammary gland, lung, liver, pancreas, lymph nodes, colon, prostate, brain, head and neck, skin, kidney, and blood and heart. Tumors and tumor cells (eg, leukemia, lymphoma, and carcinoma) can be mentioned.

The present invention also provides methods of treating, preventing, ameliorating and / or alleviating the progression of a disease or condition characterized by cell proliferation in a subject. More specifically, the methods of the invention involve administering to a subject an effective amount of a crystalline form of a quinolone compound described herein to treat a disease or condition characterized by cell proliferation. To do. The crystalline form can be administered in effective amounts that selectively activate the p53 protein in cancer cells and / or tumor cells, which may result in cell death or apoptosis. The terms "subject" and "patient" are used interchangeably throughout this application.

As used herein, administration can be achieved or practiced using any of a variety of methods known to those of skill in the art. The crystalline form is a conventional non-toxic, physiologically acceptable carrier or vehicle-containing dosage formulation, eg, subcutaneously, intravenously, parenterally, intraperitoneally, intradermally, intramuscularly. Administered topically, intrainally (eg, orally), rectum, intranasally, intratumorally, sublingually, intravaginally, by inhalation spray, by drug pump or via an implanted reservoir. be able to.

In addition, the currently disclosed crystalline forms can be administered to localized areas in need of treatment. This includes, for example, not for limited purposes, by topical infusion during surgery, by topical application, transdermal patches, by injection, by catheters, by suppositories, or by membranes, such as silicone membranes or fibers. It can be achieved by an implant, which can optionally be a porous, non-porous or gel-like substance.

The form in which the crystalline form is administered (eg, syrup, elixir, capsule, tablet, foam, emulsion, gel, etc.) will depend to some extent on the route by which it is administered. For example, for mucosal (eg, oral mucosa, rectal, intestinal mucosa, bronchial mucosa) administration, nasal drops, aerosols, inhalants, nebulizers, eye drops or suppositories can be used. The crystalline form can be used to coat bioimplantable material to enhance neurite outgrowth, nerve survival, or cell interaction with the implant surface. The crystalline forms disclosed herein can be used, for example, to control one or more symptoms or causes of diseases or conditions characterized by, for example, anti-cancer agents, analgesics, anti-inflammatory agents, anesthetics, and cell proliferation. Can be administered with other biologically active active agents such as the active agent of.

In one embodiment, the crystalline form of Compound I as disclosed herein, or the crystalline form of a pharmaceutically acceptable salt, ester and / or solvate of Compound I, is one or more therapeutically active. It can be administered in combination with certain drugs. In one embodiment, one or more therapeutically active agents are anti-cancer agents. In some embodiments, one or more therapeutically active anticancer agents include paclitaxel, vincristine, vincristine, etopocid, doxorubicin, herceptin, lapatinib, gefitinib, errotinib, tamoxyphene, flubestland, anastrazol, lectrozole, Exemestane, fadrosole, cyclophosphamide, taxotere, melfaran, chlorambucil, mechloretamine, chlorambucil, phenylalanine, mustard, cyclophosphamide, ifosfamide, carmustine (BCNU), romustine (CCNU), streptozotocin, busulphan, thiotepa , Dactinomycin (actinomycin D), doxorubicin (adriamycin), daunorubicin, idarubicin, mitoxantrone, plicamycin, mitomycin C, bleomycin, combinations thereof, etc., but are not limited thereto. In another embodiment, one or more therapeutically active antineoplastic agents include, but are not limited to, PARP (poly (DP-ribose) polymerase) inhibitors. Suitable PARP inhibitors include 4- (3- (1- (cyclopropanecarbonyl) piperazin-4-carbonyl) -4-fluorobenzyl) phthalazine-1 (2H) -one (olaparib, AZD2281, Ku-0059436). , 2-[(2R) -2-methylpyrrolidin-2-yl] -1H-benzimidazole-4-carboxamide (beniparib, ABT-888), (8S, 9R) -5-fluoro-8- (4-fluoro) Phenyl) -9- (1-methyl-1H-1,2,4-triazol-5-yl) -8,9-dihydro-2H-pyrido [4,3,2-de] phthalazine-3 (7H)- On (talazoparib, BMN 673), 4-iodo-3-nitrobenzamide (inipalib, BSI-201), 8-fluoro-5- (4-((methylamino) methyl) phenyl) -3,4-dihydro-2H -Azepino [5,4,3-cd] Indol-1 (6H) -Olynic acid (Lucaparib, AG-014699, PF-01376338), 2- [4-[(dimethylamino) methyl] phenyl] -5, 6-Dihydroimidazo [4,5,1-jk] [1,4] benzodiazepine-7 (4H) -one (AG14361), 3-aminobenzamide (IΝΟ-1001), 2- (2-fluoro-4- ( (S) -Pyrrolidine-2-yl) Phenyl) -3H-benzo [d] imidazole-4-carboxamide (A-966492), N- (5,6-dihydro-6-oxo-2-phenanthridinyl) -2-acetamide hydrochloride (PJ34, PJ34 HCl), MK-4827, 3,4-dihydro-4-oxo-3,4-dihydro-4-oxo-N-[(1S) -1-phenylethyl]- 2-Kynazolidine propanamide (ME0328), 5- (2-oxo-2-phenylethoxy) -1 (2H) -isoquinolinone (UPF-1069), 4-[[4-fluoro-3-[(4-4-fluoro-3-[(4-4-) Examples include, but are not limited to, methoxy-1-piperidinyl) carbonyl] phenyl] methyl] -1 (2H) -phthalazinone (AZD 2461). In another embodiment, one or more therapeutically active agents are immunotherapeutic agents. In some embodiments, the one or more immunotherapeutic agents include, but are not limited to, monoclonal antibodies, immune effector cells, adoptive cell transfer, immunotoxins, vaccines, cytokines and the like.

In another embodiment, the crystalline form of Compound I as disclosed herein, or the crystalline form of a pharmaceutically acceptable salt, ester and / or solvate of Compound I, is administered in combination with radiation therapy. can do.

In addition, administration can include administering to the subject multiple doses over a suitable period of time. Such dosing regimens can be determined according to routine methods during the review of this disclosure.

The crystalline form of the present invention is generally administered at a dose of about 0.01 mg / kg / dose to about 100 mg / kg / dose. Alternatively, the dose can be from about 0.1 mg / kg / dose to about 10 mg / kg / dose, or from about 1 mg / kg / dose to about 10 mg / kg / dose. Sustained-release formulations may be employed, or the dose may be administered as multiple divided doses as appropriate. When other methods are used (eg, intravenous administration), the crystalline form is at a rate of about 0.05 to about 10 mg / kg / hour, instead at a rate of about 0.1 to about 1 mg / kg / hour. Is administered to. Such rates are readily maintained when these crystalline forms are administered intravenously as discussed herein. Generally, topically administered formulations are administered at doses ranging from about 0.5 mg / kg / dose to about 10 mg / kg / dose. Alternatively, the topical formulation is administered at a dose of about 1 mg / kg / dose to about 7.5 mg / kg / dose, or even more about 1 mg / kg / dose to about 5 mg / kg / dose.

The range of about 0.1 to about 100 mg / kg is suitable for a single dose. Continuous administration is suitable in the range of about 0.05 to about 10 mg / kg.

The dose of the drug can also be given in milligrams per square meter of body surface area rather than body weight, as this method achieves a good correlation for specific metabolic and excretory functions. In addition, body surface area can be used as the common denominator of drug doses in various animal species as well as adults and children (Freireich, et al., (1966), Cancer Chemother Rep. 50, 219-244). Briefly, to express the mg / kg dose in a given animal as an equivalent mg / square meter dose, multiply the dose by the appropriate km factor. In an adult human, 100 mg / kg is equivalent to 100 mg / kg x 37 kg / square meter = 3700 mg / m ² .

Dosage forms of the invention may contain Compound I as disclosed herein, or a pharmaceutically acceptable salt, ester and / or solvate thereof in an amount of about 5 mg to about 500 mg. .. That is, the dosage form of the present invention is about 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 225 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 275 mg, 280 mg, 290 mg, 300 mg, 310 mg, Compounds in amounts of 320 mg, 325 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 375 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 425 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 475 mg, 480 mg, 490 mg, or 500 mg. I may be contained. In one embodiment, such doses may be in single doses or multiple times daily, eg, as daily doses in divided portions supplied twice, three or four times daily. Administered to the patient.

The dosage form of the present invention may be administered once an hour, once a day, once a week or once a month. The dosage form of the present invention may be administered twice daily or once daily. The dosage forms of the present invention may be administered with or without food.

It should be fully understood that the efficacy of an effective amount, and thus the dose, can vary as long as the crystalline form disclosed herein can take the form of a mimic or fragment thereof. However, those skilled in the art can easily evaluate the efficacy of the types of crystals currently envisioned by this application.

In the context of a progressive disease or condition characterized by cell proliferation, the crystalline form of the present application is generally administered on an ongoing basis. In certain situations, administration of the crystalline form disclosed herein can be initiated prior to the onset of symptoms of the disease as part of a strategy to delay or prevent the disease. In other situations, the crystalline forms disclosed herein are of the disease as part of a strategy to slow or overturn the disease process and / or as part of a strategy to improve cell function and reduce symptoms. It is administered after the onset of symptoms.

It will be well understood by those skilled in the art that the range of dosage depends on the particular crystalline form and its efficacy. The range of doses is wide enough to ameliorate neurodegenerative diseases or other diseases and their associated symptoms and / or produce the desired effect that cell survival is achieved, but unruly harmful. It is understood that it is not wide enough to cause serious side effects. However, the specific dose level for a particular patient, as well understood by those skilled in the art, is the specific crystalline activity employed; the age, weight, general condition, gender of the individual being treated. And diet; time and route of administration; rate of excretion; other drugs previously administered; and various factors including the severity of the particular disease being treated. Let's go. Dosage may also be adjusted by the individual physician in the event of complications. Unacceptable toxic effects are not expected when the crystalline forms disclosed herein are used in accordance with this application.

The effective amount of crystalline form disclosed herein includes an amount sufficient to cause a measurable biological reaction. The actual dose level of the active ingredient in the Therapeutic Crystal Form of the present application is to administer an amount of active Crystal Form that is effective in achieving the desired therapeutic response for a particular subject and / or application. Can change. Preferably, the lowest dose is administered and the dose is increased in the absence of dose limiting toxicity to the least effective amount. Evaluations of when and how such adjustments are made as well as determination and adjustment of therapeutically effective amounts are known to those of skill in the art.

Furthermore, regarding the method of this application, the preferred subject is a vertebrate subject. The preferred vertebrate is a warm-blooded animal; the preferred warm-blooded vertebrate is a mammal. It should be understood that the basic nature of this application is effective for all vertebrate subjects included in the term "subject", but the subject treated by the methods currently disclosed is preferably human. .. In this context, vertebrates are understood to be any vertebrate species for which treatment of neurodegenerative diseases is desirable. As used herein, the term "subject" includes both human and animal species. Therefore, therapeutic use by veterinarians is provided in accordance with this application.

As such, the application applies to mammals as well as humans that are important for endangerment such as the Siberian tiger; for example, animals raised on farms for human consumption. Economically important mammals such as; and / or provide treatment for mammals such as animals that are socially important to humans, such as pets or animals kept in zoos or farms. Examples of such animals include carnivorous animals such as cats and dogs; pigs, including pigs, wild boars and wild boars; cows, ungulates, sheep, giraffes, deer, goats, bison and camels. Ruminants and / or ungulates; and horses, but not limited to these. Also provided are poultry, more specifically domesticated, as well as endangered and / or zoo-reared species of birds, as they are also economically important to humans. It is the treatment of birds, including the treatment of poultry, i.e. poultry such as citrus, chicken, duck, geese, holo holo butterflies and the like. Accordingly, provided are also livestock treatments including, but not limited to, domesticated pigs, ruminants, ungulates, horses (including racehorses), poultry and the like.

The following examples further illustrate the invention, but should never be construed as limiting its scope.

Analytical Methods Various analytical methods as described below were applied to this crystalline form and its precursors to characterize their physiochemical properties.

Differential scanning calorimetry (DSC)
DSC data was collected on the DSC-system (DSC822e-Mettler Toledo) or TA Instruments Q2000. Generally, samples in the mass range of 1-5 mg were placed in a dry aluminum crucible and sealed with a perforated aluminum lid. In general, using a 20 mL / min nitrogen purge stream, the starting temperature was 20 ° C., the heating rate was 10 ° C./min, and the final temperature was 300 ° C.

Thermogravimetric analysis (TGA)
TGA data was collected with the TGA851e device. Generally, a sample in the mass range of approximately 10 mg was placed in a thin, dry aluminum oxide evaporating dish or aluminum evaporating dish. In general, sample dishes were scanned between −30 ° C. and about 350 ° C. at 5 ° C./min or 10 ° C./min using a nitrogen purge flow rate of 50 mL / min.

TGA analysis was also performed using a TA Instruments Discovery IR thermogravimetric analyzer. Temperature calibration was performed using nickel and Alumel ™. The sample was placed in an aluminum evaporating dish. The sample was sealed and sealed, the lid pierced and then inserted into a thermogravimetric furnace. The furnace was heated under nitrogen. Samples were analyzed from room temperature to 350 ° C. at a heating rate of 10 ° C./min. Thermograms were generated using Trios software v3.1.2.3591.

¹ H-Nuclear Magnetic Resonance Spectroscopy ( ¹ H NMR)
^{1 1} H NMR spectra were obtained using a Bruker AVANCE 400 MHz instrument in DMSO-d ₆ or CDCl ₃ with tetramethylsilane as an internal standard.

Hot Stage Optical Microscope (HSM)
An Olympus BX41 with a Di-Li 5MP camera and grab & massage software was used with the Hostage Mettler Toledo FP90 with an FP82 heating table. Samples were prepared with a brush on the subject holder. Observations were made with unpolarized or polarized light using two polarizing filters at 40, 100, 200, or 400 × magnification. The image was captured by software and transferred as a JPEG, but the scale is approximate and has not been verified.

X-ray powder diffraction (XRPD)
An XRPD pattern was obtained using MiniFlex (Rigaku Corporation) using a low background sample holder made of silicon (diameter 24 mm, recess 0.2 mm). The collection time was usually 75 minutes. Samples were irradiated using a 1.5406 angstrom radiation source of Cu Kα operated at 15 kV. The effective 2θ range was about 2-40 ° C and the sampling width was 0.02 ° C. The sample was ground in a mortar and pestle. The solid was placed in a sample holder prepared with lubricating oil and flattened with a glass disc.

HPLC Analysis The crystalline form of the invention (ie, salts and free bases) was analyzed by full region standardization (TAN).
HPLC conditions HPLC column: Phenomenex Luna8, 3 μm, C18, 4.6 × 50 mm
Flow rate: 1.0 mL / min Injection volume: 5 μL
Detection: DAD detector, recording at 240 nm Mobile phase: AH ₂ O + 0.05% CF ₃ COOH; B-CAN + 0.05% CF ₃ COOH
Gradient pump program

Example 1.2- (4-Methyl- [1,4] diazepan-1-yl) -5-oxo-5H-7-thia-1,11b-diaza-benzo [c] fluorene-6-carboxylic acid ( Solubility of 5-methyl-pyrazine-2-ylmethyl) -amide (Compound I, free base) of Compound I by then suspending Compound I in various solvents that are heated to a high temperature and then cooled to room temperature. Solubility was measured. The mother liquor was collected and the concentration of compound I was measured by HPLC.

Example 2. Preparation of Polyform E of Compound I (Free Base) Compound I (free base) was dissolved in a solvent mixture to form a solution, which was then concentrated in suspension. The suspension was then concentrated to dryness. The antisolvent was added to the suspension and it was concentrated until dry again. The formation of polymorph E was confirmed by XRPD analysis, and polyform E as a crystal was clarified (Fig. 11). The dry content was measured to be 99.97% w / w. ^{1 1} H NMR (FIG. 13) confirmed the structure of this material as the free base of the compound.

Example 3. Preparation of Compound I (Free Base) Polyform A Polyform E of Compound I (Free Base) as prepared in Example 2 was suspended in a solvent mixture. The suspension was heated and then cooled to room temperature. The suspension was filtered and the resulting filtered cake was dried to give polymorph A. The formation of polymorph A was confirmed by XRPD analysis, and polyform A as a crystal was clarified (Fig. 1). The dry content was measured to be 99.86% w / w. ^{1 1} H NMR (FIG. 5) confirmed the structure of this material as the free base of compound I.

The DSC thermogram (Fig. 2) shows a sharp endotherm at about 215 ° C, followed by an endotherm at about 217 ° C, an endotherm at about 231 ° C, an endotherm at about 233 ° C, and an endotherm at about 242 ° C. It was. Without being bound by theory, these events are consistent with the events of dissolution, subsequent recrystallization, another dissolution and recrystallization, and final dissolution. The TGA thermogram (FIG. 3) shows a weight loss of approximately 0.3% from room temperature to 300 ° C. FIG. 4 shows the superposition of DSC and TGA thermograms.

Example 4. Preparation of Polyform C of Compound I (Free Base) Suspension of Polyform A of Compound I in an organic solvent at high temperature, filtration, cooling the mother liquor to form a suspension, filtering it and white needles A crystalline solid was obtained. ^{1 1} H NMR (FIG. 9) confirmed the structure of this material as the free base of compound I.

XRPD analysis revealed polymorph C as a crystal as shown in FIG.

Example 5. Preparation of Polyform G of Compound I (Free Base) Polyform A of Compound I was suspended in another organic solvent at high temperature. The suspension was filtered and the mother liquor was evaporated to form a suspension, which was then filtered to give a slightly yellow solid. ^{1 1} H NMR (FIG. 18) confirmed the structure of this material as the free base of compound I.

XRPD analysis revealed polymorph G as a crystal as shown in FIG.

Example 6. Solubility and Stability Test of Polymorphic Form The solubility of compound I (free base) polymorphs A, C, E and G was determined by suspending approximately 25 mg of each polymorph in an organic solvent. The resulting mixture was stirred at room temperature or high temperature for 1 hour. The sample was filtered and the concentration was measured by HPLC. The remaining suspension was evaporated and the solids were analyzed by XRPD to confirm that the polymorphic morphology in the suspension was still the same polymorphic morphology used in the experiment.

The solubility of each polymorph is shown in FIG. Polyform A showed the lowest solubility and was identified as the most stable.

Example 7. Preparation of HCl Salt of Compound I Compound I was dissolved in a solvent mixture at elevated temperature and then HCl was added. The suspension was stirred overnight, then filtered and washed to give the HCl salt of compound I as a white powder (62% yield). The resulting salt was characterized by ^{1 1} H-NMR (FIG. 23), XRPD (FIG. 21) and TGA (FIG. 25). TGA has shown that the HCl salt of Compound I manifests a loss of up to 0.9 wt% at 140 ° C.

Example 8. Preparation of Maleate of Compound I Compound I was dissolved in a solvent mixture at elevated temperature, then maleic acid was added to the mixture. The resulting suspension was cooled, stirred, filtered and washed to give the maleate of Compound I as a white powder (86% yield). The resulting salt was characterized by ^{1 1} H NMR (FIG. 28), XRPD (FIG. 26) and TGA (FIG. 30). TGA showed that the maleate of Compound I manifested a loss of up to 2.9 wt% at 140 ° C. Without being bound by theory, this weight loss may be due to solvent loss.

Example 9. Preparation of fumarate of compound I Compound I was dissolved in a solvent mixture at high temperature and then fumaric acid was added to the mixture. The resulting suspension was cooled, stirred, filtered and washed to give the fumarate of Compound I as a white powder (104% yield). The resulting salt was characterized by ^{1 1} H NMR (FIG. 33), XRPD (FIG. 31) and TGA (FIG. 35). TGA has shown that the fumarate of Compound I exhibits a weight loss of up to 6.6 wt% at 140 ° C.

Example 10. Preparation of Citrate for Compound I Compound I was dissolved in a solvent mixture at elevated temperature, then citric acid was added to the mixture. The resulting suspension was cooled, stirred, filtered and washed to give compound I citrate as a white powder (93% yield). The resulting salt was characterized by ^{1 1} H NMR (FIG. 38), XRPD (FIG. 36) and TGA (FIG. 40). TGA has shown that the citrate of Compound I exhibits a weight loss of up to 5.2 wt% at 140 ° C.

Example 11. Preparation of L-malate of Compound I Compound I was dissolved in a solvent mixture at elevated temperature, then L-malic acid was added to the mixture. The resulting suspension was cooled, stirred, filtered and washed to give L-apple salt of Compound I as a white powder (59% yield). The resulting salt was characterized by ^{1 1} H NMR (FIG. 43), XRPD (FIG. 41) and TGA (FIG. 45). TGA showed that L-malate of Compound I showed a weight loss of up to 4.7 wt% at 140 ° C.

Example 12. Testing the solubility and stability of the acid salt of Compound I By suspending approximately 50 mg of each salt in 0.25 mL of water (x2, added in small portions), the HCl salt of Compound I, maleate, fumal The solubility of the acid salt, citrate and L-apple salt was determined. The mixture was stirred at 42 ° C. for 3 days and each solution was analyzed by HPLC for concentration and purity. The solubility and purity of each salt test after 3 days are shown in Table 11 below.
^* Samples dissolved during the 3-day stability test; NT = not examined

The stability of the acid salt was also investigated by storing the salt (solid form) at high temperatures of 45 ° C and 80 ° C. The results of the stability test are shown in Table 12 below.
NT = did not check

The patents and publications contained herein describe general workmanship in the art, for any purpose, as if each were specifically and individually directed to be incorporated by reference. To the same extent as is incorporated herein by reference in its entirety. If there is a contradiction between the cited document and the present specification, the present specification should control it. Specific terminology is adopted in describing embodiments of the present application for clarity. However, the present invention is not intended to be limited to the specific terminology so selected. Nothing in this specification should be considered limiting the scope of the invention. The examples presented are all representative and non-limiting. The above embodiments may be modified or modified without departing from the present invention, as will be fully understood by those skilled in the art in view of the above teachings. Therefore, it should be understood that within the scope of the claims and their equivalents, the present invention may be practiced outside of those specifically described.
For example, the following items can be mentioned as an example of the embodiment of the present invention.
(Item 1)
Compound I:
Or the crystalline form of the pharmaceutically acceptable salt, ester and / or solvate.
(Item 2)
The crystal form according to item 1, which is a crystal form of compound I.
(Item 3)
Item 2. The crystal form according to Item 2, which shows an X-ray powder diffraction pattern (XRDP) including a peak at 2 theta of about 7.730 ± 0.3, 22.050 ± 0.3 and 24.550 ± 0.3 degrees. ..
(Item 4)
The crystal form according to item 3, wherein the X-ray powder diffraction pattern further contains a peak at about 9.410 ± 0.3 and 27.700 ± 0.3 degrees in 2 theta.
(Item 5)
The crystal form according to item 2 or 3, wherein the X-ray powder diffraction pattern further contains a peak at about 17.950 ± 0.3 and 25.400 ± 0.3 degrees in a 2-seater.
(Item 6)
The X-ray powder diffraction pattern further extends to about 11.230 ± 0.3, 11.630 ± 0.3, 16.900 ± 0.3, 18.580 ± 0.3, 23.300 ± 0.3 and 26. The crystal form according to any one of items 2 to 5, which comprises one or more peaks selected from peaks at 700 ± 0.3 degrees in two theta.
(Item 7)
7.730 ± 0.3, 9.410 ± 0.3, 11.230 ± 0.3, 11.630 ± 0.3, 16.900 ± 0.3, 17.950 ± 0.3, 18. 580 ± 0.3, 22.050 ± 0.3, 23.300 ± 0.3, 24.550 ± 0.3, 25.400 ± 0.3, 26.700 ± 0.3 and 27.700 ± The crystal form according to item 2, which shows an X-ray powder diffraction pattern containing three or more peaks selected from the group consisting of two theta of 0.3 degrees.
(Item 8)
The crystal form according to any one of items 2 to 7, which shows a differential scanning calorimetry (DSC) thermogram having a peak eigenvalue at about 215.41 ± 2.0 ° C.
(Item 9)
The crystal form according to any one of items 2 to 8, which is a polymorph A having an X-ray powder diffraction pattern substantially similar to that of FIG. 1.
(Item 10)
The crystalline form according to any one of items 3 to 9, which has a purity of about 95% or more.
(Item 11)
The crystalline form according to item 10, which exhibits a purity of about 97% or more.
(Item 12)
The crystalline form according to item 11, which exhibits a purity of about 99% or about 99.5% or more.
(Item 13)
The crystal form according to item 2, which shows an X-ray powder diffraction pattern including a peak in a 2-seater of about 5.720 ± 0.3 degrees.
(Item 14)
The crystal form according to item 2 or 13, which shows a differential scanning calorimetry (DSC) thermogram having a peak eigenvalue at about 246.47 ± 2.0 ° C.
(Item 15)
The crystal form according to item 13 or 14, which is a polymorphic form C showing an X-ray powder diffraction pattern substantially similar to that of FIG. 7.
(Item 16)
The crystalline form according to any one of items 13 to 15, which has a purity of about 95% or more.
(Item 17)
The crystalline form according to item 16, which exhibits a purity of about 97% or more.
(Item 18)
The crystalline form according to item 17, which exhibits a purity of about 99% or about 99.5% or more.
(Item 19)
The crystal form according to item 2, which shows an X-ray powder diffraction pattern including a peak at about 5.680 ± 0.2 degrees in 2 theta.
(Item 20)
Items in which the X-ray powder diffraction pattern further contains peaks at about 12.200 ± 0.2, 12.600 ± 0.3, 25.360 ± 0.3 and 27.560 ± 0.3 degrees in two theta. The crystalline form according to 19.
(Item 21)
Two or more peaks selected from the group consisting of 5.680 ± 0.2, 12.200 ± 0.2, 12.600 ± 0.3, 25.360 ± 0.3 and 27.560 ± 0.3 Item 2. The crystal form according to item 2, 19 or 20, which shows an X-ray powder diffraction pattern including.
(Item 22)
The crystal form according to item 2 or 19-21, showing a differential scanning calorimetry (DSC) thermogram having a peak eigenvalue at about 231.99 ± 2.0 ° C.
(Item 23)
The crystal form according to any one of items 19 to 22, which is a polymorphe E showing an X-ray powder diffraction pattern substantially similar to FIG. 11.
(Item 24)
The crystalline form according to any one of items 19 to 23, which has a purity of about 95% or more.
(Item 25)
The crystalline form according to item 24, which exhibits a purity of about 97% or more.
(Item 26)
The crystalline form according to item 25, which exhibits a purity of about 99% or about 99.5% or more.
(Item 27)
The crystal form according to item 2, which shows an X-ray powder diffraction pattern including a peak at 2 theta of about 5.000 ± 0.3 and 6.060 ± 0.4 degrees.
(Item 28)
The crystal form according to item 2 or 27, which shows a differential scanning calorimetry (DSC) thermogram having a peak eigenvalue at about 222.11 ± 2.0 ° C.
(Item 29)
The crystal form according to item 27 or 28, which is a polymorph G showing an X-ray powder diffraction pattern substantially similar to FIG.
(Item 30)
The crystalline form according to any one of items 27 to 29, which has a purity of about 95% or more.
(Item 31)
The crystalline form according to item 30, which exhibits a purity of about 97% or more.
(Item 32)
The crystalline form according to item 32, which exhibits a purity of about 99% or about 99.5% or more.
(Item 33)
The salts are hydrochloride, maleate, fumarate, citrate, malate, acetate, sulfate, phosphate, L- (+)-tartrate, D-glucronate, benzoic acid. Items selected from the group consisting of salts, succinates, ethane sulfonates, methane sulfonates, p-toluene sulfonates, malonates, benzene sulfonates, and 1-hydroxy-2-naphthoate. The crystal form according to 1.
(Item 34)
The crystalline form according to item 1 or 19, wherein the salt is selected from the group consisting of hydrochloride, maleate, fumarate, citrate, and L-malate.
(Item 35)
34. The crystalline form of item 34, which is the crystalline form of the HCl salt of compound I.
(Item 36)
Item 35. The crystal form according to item 35, which shows an X-ray powder diffraction pattern (XRDP) including a peak at 2 theta of about 4.660 ± 0.3 and 24.540 ± 0.3 degrees.
(Item 37)
The X-ray powder diffraction pattern is further 1 or more in 2 theta of about 19.260 ± 0.4, 20.160 ± 0.4, 24.920 ± 0.3, and 26.360 ± 0.35 degrees. The crystal form according to item 36, which includes a peak.
(Item 38)
The X-ray powder diffraction pattern is further 1 or more in 2 theta of about 13.980 ± 0.4, 14.540 ± 0.3, 25.380 ± 0.3, and 28.940 ± 0.3 degrees. 35. The crystalline form according to item 35 or 36, which comprises a peak.
(Item 39)
The crystal form according to any one of items 35 to 38, which shows a differential scanning calorimetry (DSC) thermogram having a peak eigenvalue at about 266.27 ± 2.0 ° C.
(Item 40)
The crystal form according to any one of items 35 to 39, which shows an X-ray powder diffraction pattern substantially similar to FIG. 21.
(Item 41)
34. The crystalline form of item 34, which is the crystalline form of the maleate of Compound I.
(Item 42)
Item 4. The crystal according to item 41 showing an X-ray powder diffraction pattern (XRDP) containing a peak at about 7.400 ± 0.3, 18.440 ± 0.5, and 26.500 ± 0.4 degrees in a 2-seater. form.
(Item 43)
The X-ray powder diffraction pattern is further 1 or more in 2 theta of about 22.320 ± 0.4, 23.920 ± 0.3, 24.300 ± 0.4, and 25.240 ± 0.7 degrees. 42. The crystalline form according to item 42, which comprises a peak of.
(Item 44)
The X-ray powder diffraction pattern further includes about 5.040 ± 0.3, 15.080 ± 0.3, 15.880 ± 0.4, 20.860 ± 0.4, and 28.540 ± 0.3. The crystalline form according to item 41 or 42, which comprises one or more peaks at a degree of 2 theta.
(Item 45)
The crystal form according to any one of items 41 to 44, which shows a differential scanning calorimetry (DSC) thermogram having a peak eigenvalue at 217.32 ± 2.0 ° C.
(Item 46)
The crystal form according to items 41 to 45 showing an X-ray powder diffraction pattern substantially similar to FIG. 26.
(Item 47)
34. The crystalline form of item 34, which is the crystalline form of the fumarate of Compound I.
(Item 48)
Item 4. The crystal form according to item 47, which shows an X-ray powder diffraction pattern (XRDP) including a peak at about 6.360 ± 0.3 and 24.800 ± 0.3 degrees in 2 theta.
(Item 49)
Item 48, wherein the X-ray powder diffraction pattern further comprises one or more peaks in two theta of about 19.660 ± 0.3, 20.420 ± 0.3, and 26.860 ± 0.3 degrees. Crystal form.
(Item 50)
The X-ray powder diffraction pattern is further 1 or more in 2 theta of about 12.680 ± 0.3, 17.020 ± 0.2, 25.180 ± 0.2, and 28.280 ± 0.3 degrees. 47 or 48 of the crystal form comprising the peak of.
(Item 51)
The crystal form according to any one of items 47 to 50, which shows a differential scanning calorimetry (DSC) thermogram having a peak eigenvalue at about 222.40 ± 2.0 ° C.
(Item 52)
The crystal form according to any one of items 47 to 51, which shows an X-ray powder diffraction pattern substantially similar to FIG. 31.
(Item 53)
The crystal form according to item 34, which is a crystal form of the citrate of Compound I.
(Item 54)
The crystal of item 53 showing an X-ray powder diffraction pattern (XRDP) containing peaks at about 4.900 ± 0.3, 25.380 ± 0.3, and 27.500 ± 0.4 degrees 2-seater. form.
(Item 55)
The X-ray powder diffraction pattern is further 1 or more in 2 theta of about 15.360 ± 0.3, 18.100 ± 0.3, 19.300 ± 0.3, and 26.140 ± 0.4 degrees. 54. The crystalline form according to item 54, which comprises a peak of.
(Item 56)
The X-ray powder diffraction pattern is further 1 or more in 2 theta of about 17.400 ± 0.3, 18.680 ± 0.4, 24.040 ± 0.4, and 26.740 ± 0.3 degrees. 53 or 54 of item 53 or 54 comprising a peak of.
(Item 57)
The crystal form according to any one of items 53 to 56, which shows a differential scanning calorimetry (DSC) thermogram having a peak eigenvalue at about 196.86 ± 2.0 ° C.
(Item 58)
The crystal form according to any one of items 53 to 57, which shows an X-ray powder diffraction pattern substantially similar to FIG. 36.
(Item 59)
34. The crystalline form of item 34, which is the crystalline form of L-malate of Compound I.
(Item 60)
The crystal according to item 59 showing an X-ray powder diffraction pattern (XRDP) containing peaks at about 6.580 ± 0.2, 6.780 ± 0.3, and 25.560 ± 0.4 degrees 2-seater. form.
(Item 61)
The X-ray powder diffraction pattern is further 1 or more in 2 theta of about 19.560 ± 0.4, 23.660 ± 0.4, 26.060 ± 0.7, and 26.960 ± 0.7 degrees. The crystalline form according to item 60, which comprises the peak of.
(Item 62)
The X-ray powder diffraction pattern further includes about 8.800 ± 0.3, 11.800 ± 0.3, 18.600 ± 0.3, 24.460 ± 0.5, and 25.080 ± 0.3. The crystalline form according to item 59 or 60, which comprises one or more peaks in two theta degrees.
(Item 63)
The crystal form according to any one of items 59 to 62, which shows a differential scanning calorimetry (DSC) thermogram having a peak eigenvalue at about 209.67 ± 2.0 ° C.
(Item 64)
The crystal form according to any one of items 59 to 63, which shows an X-ray powder diffraction pattern substantially similar to FIG. 41.
(Item 65)
A composition comprising the crystalline form according to any one of items 1 to 64.
(Item 66)
65. The composition of item 65, wherein the composition comprises at least one pharmaceutically acceptable carrier.
(Item 67)
A method for stabilizing a G-quadruplex (G4) in a subject, wherein the crystalline form according to any one of items 1 to 64 in a therapeutically effective amount is administered to the subject. The method described above.
(Item 68)
A method of regulating the activity of p53 in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of the crystalline form according to any one of items 1-34.
(Item 69)
A method for treating or ameliorating a cell proliferative disease in a subject, wherein the method administers a therapeutically effective amount of the crystalline form according to any one of items 1 to 64 to the subject in need thereof. The method described above, comprising:
(Item 70)
69. The method of item 69, wherein the cell proliferative disorder is cancer.
(Item 71)
The cancers are hem cancer, colorectal cancer, breast cancer, lung cancer, liver cancer, ovarian cancer, cervical cancer, Ewing sarcoma, pancreatic cancer, lymph node cancer, colon cancer, prostate cancer, brain cancer, head and neck cancer, and skin. The method of item 70 selected from the group consisting of cancer, kidney cancer, and heart cancer.
(Item 72)
Item 71. The method of item 71, wherein the heme cancer is selected from the group consisting of leukemia, lymphoma, myeloma, and multiple myeloma.
(Item 73)
The method according to item 70, wherein the cancer is a cancer lacking homologous recombination (HR) -dependent double-strand break (DSB) repair or a cancer lacking non-homologous end binding (NHEJ) DSB repair.
(Item 74)
The method of item 70, wherein the cancer comprises cancer cells having a defect in breast cancer 1 (BRCA1), breast cancer 2 (BRCA2) and / or other members of the homologous recombination pathway.
(Item 75)
The method according to item 74, wherein the cancer cells are deficient in BRCA1 and / or BRCA2.
(Item 76)
The method of item 75, wherein the cancer cells are homozygous for mutations in BRCA1 and / or BRCA2.
(Item 77)
The method of item 75, wherein the cancer cells are heterozygous for mutations in BRCA1 and / or BRCA2.
(Item 78)
The method of any one of items 69-74, wherein the method further comprises co-administering one or more additional therapeutic agents and / or radiation therapy.
(Item 79)
The method of item 78, wherein the one or more additional therapeutic agents are anti-cancer agents or immunotherapeutic agents.
(Item 80)
A method of reducing or inhibiting cell proliferation, wherein the method comprises contacting the cells with a therapeutically effective amount of the crystalline form according to any one of items 1-34.
(Item 81)
The method of item 80, wherein the cells are present in a cancer cell line or cancer in a subject.
(Item 82)
The cancer cells are hem cancer, colonic rectal cancer, breast cancer, lung cancer, liver cancer, pancreatic cancer, lymph node cancer, colon cancer, prostate cancer, brain tumor, head and neck cancer, skin cancer, ovarian cancer, cervical cancer, 81. The method of item 81 selected from the group consisting of Ewing sarcoma, kidney cancer, and heart cancer.
(Item 83)
82. The method of item 82, wherein the heme cancer cells are selected from the group consisting of leukemia, lymphoma, myeloma, and multiple myeloma.
(Item 84)
Item 8. The method according to item 81, wherein the cancer cells have a defect in homologous recombination (HR) -dependent double-strand break (DSB) repair or non-homologous end binding (NHEJ) DSB repair.
81. The method of item 81, wherein said cancer comprises cancer cells having a defect in breast cancer 1 (BRCA1), breast cancer 2 (BRCA2) and / or other members of the homologous recombination pathway.
(Item 86)
85. The method of item 85, wherein the cancer cells are deficient in BRCA1 and / or BRCA2.
(Item 87)
86. The method of item 86, wherein the cancer cells are homozygous for mutations in BRCA1 and / or BRCA2.
(Item 88)
86. The method of item 86, wherein the cancer cells are heterozygous for mutations in BRCA1 and / or BRCA2.

Claims (1)

The invention described in the specification.