Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
  • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
  • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• the present invention relates to new crystalline forms of (S,E)-4-(dimethylamino)-N- (3-(4-(2-hydroxy-l-phenylethylamino)-6-phenylfuro[2,3-d]pyrimidin -5-yl)phenyl)but-2- enamide (ABT-101) free base, to pharmaceutical compositions and capsules comprising the same, and to methods of using the crystalline forms in the treatment of cancer.
• Epidermal growth factor receptor is a subfamily of four closely related receptor tyrosine kinases: EGFR, HER2, HER3, and HER4. Binding of EGF ligand to the extracellular domain of EGFR leads to activation of the intracellular protein-tyrosine kinase activity. As a result, autophosphorylation of several tyrosine residues in the C-terminal domain of EGFR occurs. (Kamath, S. Buolamwini, J. K., Med. Res. Rev. 2006, 26, 569-594).
• NSCLC Non-Small Cell Lung cancer
• the invention is based on the discovery that certain crystalline forms of (S, E)- 4- (dimethylamino)-N-(3-(4-(2-hydroxy-l-phenylethylamino)-6-phenylfuro[2,3-d]pyrimidin -5- yl)phenyl)but-2-enamide (ABT-101) free base, which exhibit unexpected stability and improved pharmacokinetic properties.
• the present invention provides a crystalline form of (S, E)-4- (dimethylamino)-N-(3-(4-(2-hydroxy-l-phenylethylamino)-6-phenylfuro[2,3-d]pyrimidin -5- yl)phenyl)but-2-enamide (ABT-101) free base characterized by an X-ray powder diffraction pattern comprising peaks at 2 ⁇ values of 4.8 ° ⁇ 0.2 ° , 9.5 ° ⁇ 0.2 ° , 10.2 ° ⁇ 0.2 ° , 12.5 ° ⁇ 0.2 ° , 15.0 ° ⁇ 0.2 ° , 18.4 ° ⁇ 0.2 ° and 20.8 ° ⁇ 0.2 ° .
• the crystalline form provided herein is characterized by an X-ray powder diffraction pattern further comprising a peak at 2 ⁇ value of 8.7° ⁇ 0.2°.
• the crystalline form provided herein is characterized by an X-ray powder diffraction pattern further comprising a peak at 2 ⁇ value of 19.4° ⁇ 0.2°.
• the crystalline form provided herein is characterized by an X-ray powder diffraction pattern further comprising a peak at 2 ⁇ value of 23.1° ⁇ 0.2°.
• the crystalline form provided herein has a melting point temperature of 170 to
• the crystalline form provided herein has an enthalpy of melting of 75 to 85 °C.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising the crystalline form provided herein and a pharmaceutically acceptable carrier or excipient.
• the present invention provides a capsule comprising the pharmaceutical composition provided herein. Further, the capsule provided herein comprises from 0.1 to 200 mg of said crystalline form.
• the capsule provided herein comprises from 25 to 100 mg of said crystalline form.
• the capsule provided herein comprises from 50 to 100 mg of said crystalline form.
• the present invention provides a method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the crystalline form provided herein.
• the crystalline form provided herein is a EGFR inhibitor, a HER2 inhibitor or a tumor-agnostic inhibitor.
• the cancer is peritoneal cancer, small intestine cancer, non-small cell lung cancer (NSCLC), neuroendocrine cancer, salivary gland, bladder cancer, breast cancer, cervix cancer, bile duct cancer, esophageal cancer, stomach cancer, early gastric cancer, colorectal cancer, prostate cancer, ovarian cancer, head and neck cancer, endometrial cancer, kidney cancer, melanoma cancer, sarcoma cancer, pancreatic cancer, small cell lung cancer (SCLC), leukemia cancer, brain cancer or thyroid cancer .
• NSCLC non-small cell lung cancer
• SCLC small cell lung cancer
• the effect of the present invention is that the specific crystalline form of ABT-101 free base can exhibit unexpected stability and improved pharmacokinetic properties compared to other forms or salt thereof, thereby allowing said compound more suitable for drug development and satisfying the requirements for bioavailability and drug efficacy.
• Figure 1 illustrates a DSC curve for crystalline of ABT-101 free base
• Figure 2a and 2b illustrate DSC thermograms for the obtained crystalline forms of ABT-101 free base
• Figure 3 illustrates a XRPD pattern for a crystalline form of ABT-101 free base (01BP-063-184);
• Figure 4 illustrates XRPD patterns for crystalline forms of ABT-101 free base
• Figure 5 illustrates the comparison of amorphous free form (00BP-081-154) and crystalline free form (01BP-063-120) of ABT-101.
• crystalline may refer to having a regularly repeating arrangement of molecules or external face planes. Crystalline forms may differ with respect to thermodynamic stability, physical parameters , X-ray structure and preparation processes.
• amorphous may refer to a form of a compound, or a salt or molecular complex of a compound, that lacks long range crystalline order where the x-ray diffraction pattern lacks Bragg reflections.
• solid form may refer to a crystalline solid form or phase, including crystalline free base, crystalline salt, or a cocrystal, as well as an amorphous phase, including an amorphous dispersion.
• treating means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
• treatment refers to the act of treating as “treating as defined immediately above.
• effective amount or “therapeutically effective amount” refers to that amount of a compound or combination of compounds that is sufficient to effect the intended application including, but not limited to, disease treatment.
• a therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g., the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art.
• the term also applies to a dose that will induce a particular response in target cells (e.g., the reduction of platelet adhesion and/or cell migration).
• the specific dose will vary depending on the particular compounds chosen, the dosing regimens to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.
• the present invention provides a crystalline form of (S, E)- 4- (dimethylamino)-N-(3-(4-(2-hydroxy-l-phenylethylamino)-6-phenylfuro[2,3-d]pyrimidin -5- yl)phenyl)but-2-enamide (ABT-101, represented by Formula I) free base.
• Said crystalline form is characterized by an X-ray powder diffraction pattern comprising peaks at 2 ⁇ values of 4.8 ⁇ 0.2 ° , 9.5 ⁇ 0.2 ° , 10.2 ⁇ 0.2 ° , 12.5 ⁇ 0.2 ° , I5.0 ⁇ 0.2f 18.4 ⁇ 0.2 ° and 20.8 ⁇ 0.2 ° .
• the crystalline form provided herein is characterized by an X-ray powder diffraction pattern further comprising a peaks at 2 ⁇ value of 8.7 ⁇ 0.2 ° .
• the crystalline form provided herein is characterized by an X-ray powder diffraction patern further comprising a peaks at 2 ⁇ value of 19.4 ⁇ 0,2 ° ,
• the crystalline form provided herein is characterized by an X-ray powder diffraction pattern further comprising a peaks at 2 ⁇ value of 23.1 ⁇ 0.2 ° .
• said crystalline form is characterized by an X-ray powder diffraction pattern comprising peaks selected from the group consisting of 4.8 ⁇ 0.2 ° , 8.7 ⁇ 0.2 ° , 9, 5 ⁇ 0.2 ° , 10.2 ⁇ 0.2 ° , 12.5 ⁇ 0.2 ° , 15.0 ⁇ 0.2 ° , 18.4 ⁇ 0.2 ° , 19.4 ⁇ 0.2 ° , 20.8 ⁇ 0.2 ° and 23.1 ⁇ 0.2 ° , with peak positions measured in 2.
• an X-ray powder diffraction (XPRD) patern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation or instrument used).
• intensities in an X-ray powder diffraction pattern may vary depending on measurement conditions and sample preparation.
• persons skilled in the art of X-ray powder diffraction will realize that the relative intensities of peaks may vary- according to the orientation of the sample under test and based on the type and settings of the instrument used.
• the skilled person will also realize that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer, the sample's surface planarity, and the zero calibration of the diffractometer.
• the crystalline form provided herein has a melting point temperature of 170 to 195°C; more particularly, said melting point temperature is, for example, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194 or 195°C.
• the crystalline form provided herein has an enthalpy of melting of 75 to 85 °C; more particularly, said enthalpy of melting is, for example, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 or 85°C.
• the melting point temperature and enthalpy of melting characterizing the crystalline form of the present invention are analyzed by differential scanning calorimetry (DSC), including modulated differential scanning calorimetry or temperature-modulated differential scanning calorimetry.
• DSC differential scanning calorimetry
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising the crystalline form provided herein and a pharmaceutically acceptable carrier or excipient. More specifically, said pharmaceutical composition is a EGFR inhibitor, a HER2 inhibitor or a tumor-agnostic inhibitor.
• the pharmaceutical compositions contain a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, permeation enhancers, solubilizers, or adjuvants.
• the concentration of the crystalline form of ABT-101 free base provided in the pharmaceutical compositions of the invention is independently less than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, or 0.001%, w/w, w/v, or v/v, relative to the total mass or volume of the pharmaceutical composition.
• the concentration of the crystalline form of ABT-101 free base provided in the pharmaceutical compositions of the invention is independently greater than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, or 0.001%, w/w, w/v, or v/v, relative to the total mass or volume of the pharmaceutical composition.
• suitable fillers for use in the pharmaceutical composition disclosed herein include, but are not limited to, lactose monohydrate, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
• lubricants for use in the pharmaceutical composition disclosed herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium stearyl fumarate, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof.
• Additional lubricants include, for example, a silica gel, a coagulated aerosol of synthetic silica, silicified microcrystalline cellulose, or mixtures thereof.
• disintegrants examples include, but are not limited to, croscarmellose sodium, alginic acid, calcium carbonate, microcrystalline cellulose, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof
• the present invention provides a capsule comprising said pharmaceutical composition.
• the capsule provided herein comprises from 0.1 to 200 mg of the crystalline form of ABT-101 free base; more particularly, the amount of said crystalline form is, for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 mg.
• the capsule provided herein comprises from 25 to 100 mg of the crystalline form of ABT-101 free base; more particularly, the amount of said crystalline form is, for example, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg. More preferably, the capsule provided herein comprises from 50 to 100 mg of the crystalline form of ABT-101 free base; more particularly, the amount of said crystalline form is, for example, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg.
• compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, sachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil emulsion.
• Pharmaceutical compositions of the invention also include powder for reconstitution, powders for oral consumptions, bottles (such as powder or liquid in bottle), orally dissolving films, lozenges, pastes, tubes, gums, and packs.
• Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient(s) into association with the carrier, which constitutes one or more necessary ingredients.
• the compositions are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
• the present invention provides a method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of the crystalline form of ABT- 101 free base.
• the crystalline form of ABT-101 free base administered is a EGFR inhibitor, a HER2 inhibitor or a tumor-agnostic inhibitor.
• the crystalline form of ABT-101 free base is administered in a single dose.
• a single dose of the crystalline form of ABT-101 free base may also be used for treatment of an acute condition.
• the crystalline form of ABT-101 free base is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day.
• the crystalline form of ABT-101 free base is administered about once per day to about 6 times per day.
• the administration of the crystalline form of ABT-101 free base continues for less than about 7 days.
• the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.
• the crystalline form of ABT-101 free base are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the crystalline form of ABT-101 free base are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In selected embodiments, the crystalline form of ABT-101 free base is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.
• an effective dosage of the crystalline form of ABT-101 free base is in the range of about 1 mg to about 500 mg, about 10 mg to about 300 mg, about 20 mg to about 250 mg, about 25 mg to about 200 mg, about 10 mg to about 200 mg, about 20 mg to about 150 mg, about 30 mg to about 120 mg, about 10 mg to about 90 mg, about 20 mg to about 80 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, about 48 mg to about 52 mg, about 50 mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg, about 150 mg to about 250 mg, about 160 mg to about 240 mg, about 170 mg to about 230 mg, about 180 mg to about 220 mg, about 190 mg to about 210 mg, about 195 mg to about 205 mg, or about 198 to about 202 mg.
• an effective dosage of the crystalline form of ABT-101 free base is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg.
• an effective dosage of the crystalline form of ABT-101 free base is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg.
• the cancer is peritoneal cancer, small intestine cancer, non-small cell lung cancer (NSCLC), neuroendocrine cancer, salivary gland, bladder cancer, breast cancer, cervix cancer, bile duct cancer, esophageal cancer, stomach cancer, early gastric cancer, colorectal cancer, prostate cancer, ovarian cancer, head and neck cancer, endometrial cancer, kidney cancer, melanoma cancer, sarcoma cancer, pancreatic cancer, small cell lung cancer (SCLC), leukemia cancer, brain cancer or thyroid cancer.
• NSCLC non-small cell lung cancer
• SCLC small cell lung cancer
• X-ray Powder Diffraction XPRD data shown as follows is collected according to the following measurement parameters:.
• Anode Cu; Generator voltage: 30 kV;
• Scan type Coupled Two Theta/Theta
• Anti-scanning screen 0.5 mm;
• Step size 0.03 deg/step
• DSC measurements in the present invention are carried out using a TA Q20, Thermal Analysis Instruments. Sample weight of 3.0-15.0 mg was placed in a hermetically sealed aluminum pan. The sample was equilibrated tol00° C. and then ramped to 200° C. at a scan rate of 5°C/min. Dry nitrogen was used as the purge gas.
• ABT-101 compound is obtained through the process as follows:
• the fallowing purification was executed by re-crystallization with hot Acetone at 53-58 °C. After the mixture was cooled to 0 ⁇ 5 °C to yield ABT-101 crystals, solvent was then centrifuged followed by washing of ABT-101 crystals with Acetone to generate ABT-101.
• the free base form of ABT-101 compared with the glycollate form, succinate form and hydrochloride form, exhibits improved “weight loss before melting”, “hygroscopicity”, “crystal form change post DVS”, “solubility”, and “stability”.
• compositions thereof are shown in Table 6.
• ABT-101 capsules described above are tested following the program shown in Table 7; wherein: “S” stands for stability test; “M” stands for microbial limit test (MLT); “(-)” stands for optional, sample only pulled and tested when needed.
• the crystalline forms of ABT-101 free base can exhibit unexpected stability and improved pharmacokinetic properties compared to other forms or salt thereof, thereby allowing said compound more suitable for drug development and satisfying the requirements for bioavailability and drug efficacy.
• the specific embodiments of the present invention have been disclosed, but it is not intended to limit the present invention. Those with ordinary knowledge in the technical field to which the present invention belongs are capable of understanding. And in the case of deviating from the principle and spirit of the present invention, various changes and modifications can be made to it, so the scope of protection of the present invention should be based on those defined in the scope of the accompanying patent application.

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