Pharmaceutical composition of sulfamide compound

Abstract

The invention belongs to the field of medical chemistry, and relates to a pharmaceutical composition of an internal sulfonamide compound, in particular to a pharmaceutical composition of a compound shown as a formula I or pharmaceutically acceptable salt thereof and medical application of the pharmaceutical composition. # imgabs0 #

Description

Technical Field

[0001] The present application belongs to the field of medicinal chemistry and relates to a drug combination of an internal sulfonamide compound, and specifically to a drug combination of a compound of formula I or a pharmaceutically acceptable salt thereof and its medical use. Background Art

[0002] IDH (isocitrate dehydrogenase) stands for isocitrate dehydrogenase. It is the most important key enzyme in the tricarboxylic acid cycle in cells. It can catalyze the oxidative decarboxylation of isocitrate to produce 2-oxoglutarate (i.e., α-ketoglutarate). IDH has two different subtypes, one of which uses NAD(+) as an electron acceptor and the other uses NADP(+) as an electron acceptor. Five IDHs have been reported, three of which are NAD(+)-dependent isocitrate dehydrogenases, which are located in the mitochondrial matrix; the other two are NADP(+)-dependent isocitrate dehydrogenases, one located in the mitochondria and the other in the cytoplasm.

[0003] Studies have found that IDH mutations exist in many tumors (such as gliomas, sarcomas, acute myeloid leukemia, etc.), and the mutation site is the arginine residue located in the catalytic center (IDH1 / R132H, IDH2 / R140Q, IDH2 / R172K). In 2009, Bleeker et al. tested IDH1 mutations in 672 tumors of different origins and 84 different tumor cell lines and found that this mutation specifically occurred in brain gliomas [Bleeker et al., 2009. IDH1 mutations atresidue

[0004] p.R132 (IDH1 (R132)) occurs frequently in high-grade gliomas but not in other solid tumors. Hum Mutat. 30: 7-11.]. However, subsequent literature reports show that IDH1 mutations also exist in acute myeloid leukemia, prostate cancer, paraganglioma, etc. [Green et al., 2010, Somatic mutations of IDH1 and IDH2 in the leukemic transformation of myeloproliferative neoplasms. N Engl J Med. 362: 369-370.]. Bleeker et al. found that R132H accounted for 86.9% of IDH1 mutation cases, and other types such as R132C, R132G, R132L, R132V, and R132S accounted for a smaller proportion [Bleeker et al., 2009].

[0005] WO2017162157 discloses a series of compounds as IDH1 inhibitors, and specifically discloses a compound of formula I with the following structure:

[0006] DETAILED DESCRIPTION OF THE INVENTION

[0008] The present application provides a pharmaceutical combination comprising a compound of formula I or a pharmaceutically acceptable salt thereof and azacitidine.

[0009]

[0010] In another aspect, the present application provides a pharmaceutical combination for treating a blood tumor in a patient, comprising a compound of formula I or a pharmaceutically acceptable salt thereof and azacitidine.

[0011] On the other hand, in some embodiments of the present application, the drug combination is used to treat a patient's blood tumor. In some embodiments of the present application, in the drug combination, the compound of formula I or a pharmaceutically acceptable salt thereof and azacitidine are each in the form of a pharmaceutical composition.

[0012] In some embodiments of the present application, in the drug combination, the compound of formula I or a pharmaceutically acceptable salt thereof and azacitidine are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially or intermittently.

[0013] In some embodiments of the present application, in the drug combination, the compound of formula I or a pharmaceutically acceptable salt thereof and azacitidine are each administered in a single dose or multiple doses.

[0014] In some embodiments of the present application, the drug combination is packaged in the same medicine box, which also includes instructions for using the compound of Formula I or a pharmaceutically acceptable salt thereof and azacitidine in combination to treat a patient's blood tumor.

[0015] In some embodiments of the present application, the pharmaceutical combination comprises: a pharmaceutical composition of a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of azacitidine.

[0016] In some embodiments of the present application, the drug combination is packaged in the same medicine box, which also includes instructions for the combined use of a pharmaceutical composition of a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of azacitidine to treat a patient's blood tumor.

[0017] In some embodiments of the present application, in the drug combination, the compound of formula I or a pharmaceutically acceptable salt thereof and azacitidine are separately packaged in respective medicine boxes, and the medicine box also includes instructions for the combined use of the compound of formula I or a pharmaceutically acceptable salt thereof and azacitidine to treat blood tumors in patients.

[0018] The present application provides a medicine kit, which includes the drug combination of the present application and instructions for using the compound of formula I or a pharmaceutically acceptable salt thereof in combination with azacitidine to treat blood tumors.

[0019] In another aspect, the present application provides use of the above-mentioned drug combination in the preparation of a drug for treating a blood tumor in a patient.

[0020] On the other hand, the present application provides use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a patient's blood tumor in combination with azacitidine.

[0021] On the other hand, the present application provides use of a pharmaceutical composition of a compound of Formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a patient's blood tumor in combination with azacitidine.

[0022] In another aspect, the present application provides use of the drug combination as described above in treating a blood tumor in a patient.

[0023] On the other hand, the present application provides use of a compound of formula I or a pharmaceutically acceptable salt thereof in combination with azacitidine for treating a patient's blood tumor.

[0024] On the other hand, the present application provides use of a pharmaceutical composition of a compound of Formula I or a pharmaceutically acceptable salt thereof in combination with azacitidine in treating a patient's blood tumor.

[0025] In another aspect, the present application provides a method for treating a blood tumor in a patient, the method comprising administering to the patient a therapeutically effective amount of the drug combination as described above.

[0026] On the other hand, the present application provides a method for treating a blood tumor in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof; in combination with administering a therapeutically effective amount of azacitidine.

[0027] On the other hand, the present application provides a method for treating a blood tumor in a patient, the method comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition of a compound of Formula I or a pharmaceutically acceptable salt thereof; in combination with administering a therapeutically effective amount of azacitidine.

[0028] On the other hand, the present application provides a combination comprising a compound of formula I or a pharmaceutically acceptable salt thereof and azacitidine. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof and azacitidine are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially or intermittently.

[0029] On the other hand, the present application provides a use of a therapeutically effective amount of a combination in the preparation of a medicament for treating a patient's blood tumor, wherein the combination comprises a compound of formula I or a pharmaceutically acceptable salt thereof and azacitidine.

[0030] In some embodiments of the present application, the pharmaceutical combination contains 100-1000 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as the compound of formula I.

[0031] In some embodiments of the present application, the drug combination contains 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg of a compound of formula I, or a range formed by any of the above values, or a pharmaceutical composition thereof.

[0032] In some embodiments of the present application, the drug combination contains 100-900 mg, 200-900 mg, 200-800 mg, 200-600 mg, 400-900 mg or 400-600 mg of the compound of formula I or its pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0033] In some embodiments of the present application, the pharmaceutical combination contains 400-600 mg or 400-900 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as the compound of formula I.

[0034] In some embodiments of the present application, the pharmaceutical combination contains 400 mg, 600 mg or 900 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as the compound of formula I.

[0035] In some embodiments of the present application, the pharmaceutical combination contains 400-600 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as the compound of formula I.

[0036] In some embodiments of the present application, the pharmaceutical combination contains 400 mg or 600 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as the compound of formula I.

[0037] In some embodiments of the present application, in the pharmaceutical combination, the pharmaceutical composition of the compound of formula I or its pharmaceutically acceptable salt is in the form of a single dose or multiple doses. In some embodiments of the present application, in the pharmaceutical combination, the composition of the compound of formula I or its pharmaceutically acceptable salt is in the form of multiple doses.

[0038] In some embodiments of the present application, the content of the compound of formula I or its pharmaceutically acceptable salt in the drug combination is a daily dose.

[0039] In some embodiments of the present application, the content of the compound of formula I or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is a once-daily dose.

[0040] In some embodiments of the present application, in the pharmaceutical combination, the content of the compound of formula I or a pharmaceutically acceptable salt thereof is a dose once a day, and each dose is a single dose or multiple doses, usually multiple doses.

[0041] In some embodiments of the present application, the pharmaceutical combination contains a single dose of 50 mg and / or 200 mg of a compound of formula I or a pharmaceutical composition of a pharmaceutically acceptable salt thereof, calculated as a compound of formula I. Alternatively, the pharmaceutical combination is in the form of a single-dose formulation, containing 50 mg and / or 200 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as a compound of formula I.

[0042] In some embodiments of the present application, the pharmaceutical combination contains a single dose of 200 mg of a compound of formula I or a pharmaceutical composition of a pharmaceutically acceptable salt thereof, calculated as a compound of formula I. Alternatively, the pharmaceutical combination is in the form of a single-dose preparation, containing 200 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as a compound of formula I.

[0043] In some embodiments of the present application, the drug combination contains 50-150 mg / m 2 50-100 mg / m 2 or 75–100 mg / m 2 Azacitidine, or a pharmaceutical composition thereof.

[0044] In some embodiments of the present application, the drug combination contains 50 mg / m 2 , 75mg / m 2 or 100 mg / m 2 Azacitidine, or a pharmaceutical composition thereof.

[0045] In some embodiments of the present application, the drug combination contains 75 mg / m 2 Azacitidine, or a pharmaceutical composition thereof.

[0046] In some embodiments of the present application, in the drug combination, the pharmaceutical composition of azacitidine is in the form of a single dose or multiple doses.

[0047] In some embodiments of the present application, in the drug combination, the pharmaceutical composition of azacitidine is in the form of multiple doses.

[0048] In some embodiments of the present application, in the drug combination, the pharmaceutical composition of azacitidine is a daily dose.

[0049] In some embodiments of the present application, in the drug combination, the pharmaceutical composition of azacitidine is a once-daily dose.

[0050] In some embodiments of the present application, the pharmaceutical combination contains a single dose of 100 mg of azacitidine. Alternatively, the pharmaceutical combination is in the form of a single-dose preparation, and the pharmaceutical combination contains 100 mg of azacitidine or a pharmaceutical composition thereof.

[0051] In some embodiments of the present application, the drug combination contains 100-1000 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, calculated as the compound of formula I, and 50-150 mg / m2 of the subject's body surface area. 2 of azacitidine.

[0052] In some embodiments of the present application, the drug combination contains 400-600 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, calculated as the compound of formula I, and 75-100 mg / m2 of the subject's body surface area. 2 of azacitidine.

[0053] In some embodiments of the present application, the drug combination contains a daily dose of 400 mg or 600 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, and 75 mg / m2 of the compound of formula I or a pharmaceutically acceptable salt thereof, based on the body surface area of ​​the subject. 2 or 100 mg / m 2 daily dose of azacitidine.

[0054] In some embodiments of the present application, the drug combination contains a daily dose of 400 mg or 600 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, and 75 mg / m2 of the compound of formula I or a pharmaceutically acceptable salt thereof, based on the body surface area of ​​the subject. 2 daily dose of azacitidine.

[0055] In some embodiments of the present application, one treatment cycle is every 2-6 weeks. In some embodiments of the present application, one treatment cycle is every 28 days.

[0056] In some embodiments of the present application, the pharmaceutical combination contains: a single dose of 50 mg and / or 200 mg of a pharmaceutical composition of a compound of Formula I or a pharmaceutically acceptable salt thereof, and a single dose of 100 mg of azacitidine. Alternatively, the pharmaceutical combination is in the form of a single-dose preparation, and the pharmaceutical combination contains: 50 mg and / or 200 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and 100 mg of azacitidine or a pharmaceutical composition thereof, calculated as a compound of Formula I.

[0057] In some embodiments of the present application, the pharmaceutical combination contains: a single dose of 200 mg of a compound of Formula I or a pharmaceutical composition of a pharmaceutically acceptable salt thereof, and a single dose of 100 mg of azacitidine. Alternatively, the pharmaceutical combination is in the form of a single-dose preparation, and the pharmaceutical combination contains: 200 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and 100 mg of azacitidine or a pharmaceutical composition thereof, calculated as a compound of Formula I.

[0058] In some embodiments of the present application, the drug combination is a preparation suitable for administration in a single treatment cycle (e.g., a treatment cycle of 28 days), comprising: a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof with a total dose of 11.2 g to 16.8 g based on the compound of formula I, and a total dose of 350 mg / m2 based on the body surface area of ​​the subject. 2 ~700 mg / m 2 A pharmaceutical composition of azacitidine.

[0059] In some embodiments of the present application, the drug combination is a preparation suitable for administration in a single treatment cycle (e.g., a treatment cycle of 28 days), comprising: a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof with a total dose of 11.2 g to 16.8 g based on the compound of formula I, and a total dose of 525 mg / m2 based on the body surface area of ​​the subject. 2 ~700 mg / m 2 A pharmaceutical composition of azacitidine.

[0060] In some embodiments of the present application, the drug combination is a preparation suitable for administration in a single treatment cycle (e.g., a treatment cycle of 28 days), comprising: a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof with a total dose of 11.2 g or 16.8 g based on the compound of formula I, and a total dose of 525 mg / m2 based on the body surface area of ​​the subject. 2 or 700 mg / m 2 A pharmaceutical composition of azacitidine.

[0061] In some embodiments of the present application, the drug combination is a preparation suitable for administration in a single treatment cycle (e.g., a treatment cycle of 28 days), comprising: a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof with a total dose of 11.2 g or 16.8 g based on the compound of formula I, and a total dose of 525 mg / m2 based on the body surface area of ​​the subject. 2 A pharmaceutical composition of azacitidine.

[0062] In some embodiments of the present application, in the drug combination, the compound of formula I or a pharmaceutically acceptable salt thereof, and azacitidine can be in the form of a pharmaceutical composition separately or together.

[0063] On the other hand, the present application also provides a kit, which contains (a) a first pharmaceutical composition containing the compound of formula I described in the present application or a pharmaceutically acceptable salt thereof; and (b) a second pharmaceutical composition containing azacitidine.

[0064] On the other hand, the present application also provides a kit of pharmaceutical compositions for treating blood tumors in patients, which contains (a) a first pharmaceutical composition containing a compound of formula I described in the present application or a pharmaceutically acceptable salt thereof; and (b) a second pharmaceutical composition containing azacitidine.

[0065] In some embodiments of the present application, in the drug combination, the compound of formula I or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 50 mg or 200 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, and the azacitidine is prepared into a unit preparation containing 100 mg of azacitidine.

[0066] In some embodiments of the present application, in the drug combination, the compound of formula I or a pharmaceutically acceptable salt thereof is prepared into a unit preparation containing 200 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, and the azacitidine is prepared into a unit preparation containing 100 mg of azacitidine.

[0067] On the other hand, the present application also provides a method for treating a patient's blood tumor, which comprises administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, and azacitidine to an individual in need thereof, for example, administering a therapeutically effective amount of the drug combination described above in the present application to an individual in need thereof.

[0068] On the other hand, the present application also provides a combination therapy for treating an individual with a blood tumor, the combination therapy comprising administering to the individual a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of azacitidine.

[0069] On the other hand, the present application also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in combination with azacitidine in the preparation of a medicament for treating a patient's blood tumor, for example, the use of the above-mentioned drug combination of the present application in the preparation of a medicament for treating a patient's blood tumor. In some embodiments of the present application, the drug combination is any of the drug combinations described above in the present application.

[0070] On the other hand, the present application also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in combination with azacitidine for treating a patient's blood tumor, for example, the use of the above-mentioned drug combination of the present application for treating a patient's blood tumor.

[0071] In some embodiments of the present application, in the method, combination therapy or use, the definitions of the compound of formula I or a pharmaceutically acceptable salt thereof, and azacitidine are the same as those of the compound of formula I or a pharmaceutically acceptable salt thereof, and azacitidine in the drug combination described above, such as content, dosage, form of existence, packaging form, etc.

[0072] In some embodiments of the present application, in the method, combination therapy or use, the compound of formula I or a pharmaceutically acceptable salt thereof, and azacitidine are each in the form of a pharmaceutical composition and can be administered simultaneously, separately, concurrently, sequentially or intermittently.

[0073] In some embodiments of the present application, in the method, combination therapy or use, the compound of formula I or a pharmaceutically acceptable salt thereof and azacitidine have the same or different treatment cycles. In some specific embodiments of the present application, in the method, combination therapy or use, the compound of formula I or a pharmaceutically acceptable salt thereof and azacitidine have the same treatment cycle, for example, one treatment cycle is every 1 week, every 2 weeks, every 3 weeks or every 4 weeks. Preferably, one treatment cycle is every 4 weeks.

[0074] In some embodiments of the present application, in the method, combination therapy or use, the content of the compound of formula I or its pharmaceutically acceptable salt in the drug combination is a daily dose, which is administered in the following manner: the compound of formula I or its pharmaceutically acceptable salt is administered once a day.

[0075] In some embodiments of the present application, in the method, combination therapy or use, the content of the compound of formula I or its pharmaceutically acceptable salt in the drug combination is a daily dose, wherein the compound of formula I or its pharmaceutically acceptable salt is administered in a single dose or multiple doses, usually in multiple doses; further, the compound of formula I or its pharmaceutically acceptable salt is administered once a day in multiple doses.

[0076] In some embodiments of the present application, in the method, combination therapy or use, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 400 mg; or, a daily dose of 600 mg; or, a daily dose of 800 mg.

[0077] In some embodiments of the present application, in the method, combination therapy or use, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 400 mg; or, a daily dose of 600 mg.

[0078] In some embodiments of the present application, in the method, combination therapy or use, the compound of formula I or its pharmaceutically acceptable salt in the drug combination is administered in multiple doses, and the multiple doses are composed of a single dose of 50 mg and / or 200 mg of the compound of formula I or its pharmaceutically acceptable salt. The multiple doses are preferably composed of a single dose of 200 mg of the compound of formula I or its pharmaceutically acceptable salt. In some embodiments of the present application, in the method, combination therapy or use, the compound of formula I or its pharmaceutically acceptable salt is administered in a continuous daily administration manner.

[0079] In some embodiments of the present application, in the method, combination therapy or use, the content of the compound of formula I or its pharmaceutically acceptable salt in the drug combination is the dosage per treatment cycle (e.g., a treatment cycle of 28 days), which is administered in the following manner: the compound of formula I or its pharmaceutically acceptable salt is administered every day during the treatment cycle. Wherein, the compound of formula I or its pharmaceutically acceptable salt is packaged in a single aliquot or multiple aliquots (e.g., 2 aliquots, 4 aliquots, 7 aliquots, 14 aliquots, 28 aliquots or more aliquots).

[0080] In some embodiments of the present application, in the method, combination therapy or use, the content of azacitidine in the drug combination is a daily dose, which is administered in the following manner: azacitidine is administered once a day.

[0081] In some embodiments of the present application, in the method, combination therapy or use, the content of azacitidine in the drug combination is a daily dose, wherein azacitidine is administered in a single dose or multiple doses, usually in multiple doses; further, wherein azacitidine is administered once a day in multiple doses.

[0082] In some embodiments of the present application, in the method, combination therapy or use, the azacitidine is administered in the following manner: based on the body surface area of ​​the subject, the daily dose is 50 mg / m 2 Alternatively, a daily dose of 75 mg / m 2 Alternatively, a daily dose of 100 mg / m 2 ; or daily dose of 150 mg / m 2 mg.

[0083] In some embodiments of the present application, in the method, combination therapy or use, the azacitidine is administered in the following manner: based on the body surface area of ​​the subject, the daily dose is 75 mg / m 2 Alternatively, a daily dose of 100 mg / m 2 .

[0084] In some embodiments of the present application, in the method, combination therapy or use, the azacitidine is administered in the following manner: based on the body surface area of ​​the subject, the daily dose is 75 mg / m 2 .

[0085] In some embodiments of the present application, in the method, combination therapy or use, the azacitidine in the drug combination is administered in multiple doses, and the multiple doses consist of a pharmaceutical composition with a single dose of 100 mg of azacitidine. In some embodiments of the present application, in the method, combination therapy or use, the azacitidine is administered in a continuous daily administration manner.

[0086] In some embodiments of the present application, in the method, combination therapy or use, the content of azacitidine in the drug combination is a dose per treatment cycle (e.g., a treatment cycle of 28 days), which is administered in the following manner: azacitidine is administered every day on days 1 to 7 of each cycle, and azacitidine is stopped on days 8 to 28. Wherein, azacitidine is packaged in a single aliquot or multiple aliquots (e.g., 2 aliquots, 4 aliquots, 7 aliquots, 14 aliquots, 28 aliquots or more).

[0087] In some embodiments of the present application, in the method, combination therapy or use, 28 days is a treatment cycle, and the total dose of the pharmaceutical composition containing the compound of formula I or its pharmaceutically acceptable salt administered on days 1 to 28 of each treatment cycle is 11.2 g to 16.8 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula I or its pharmaceutically acceptable salt is selected from 11.2 g or 16.8 g.

[0088] In some embodiments of the present application, in the method, combination therapy or use, 28 days is a treatment cycle, and a total dose of 350 mg / m2 of azacitidine is administered on days 1 to 7 of each treatment cycle. 2 ~700 mg / m 2 In some embodiments, the total dose of azacitidine is selected from 525 mg / m 2 or 700 mg / m 2 In some regimens, the total dose of azacitidine is preferably 525 mg / m 2 .

[0089] In some embodiments of the present application, in the method, combination therapy or use, 28 days is a treatment cycle; the pharmaceutical composition containing the compound of formula I or a pharmaceutically acceptable salt thereof is administered once a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula I or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 11.2 g or 16.8 g; and azacitidine is administered once a day on days 1 to 7 of each treatment cycle, and the administration is stopped on days 8 to 28, and the total dose of azacitidine administered in each treatment cycle is 525 mg / m 2 or 700 mg / m 2 .

[0090] In the regimen of the present application, the above treatment cycles are repeated as long as the disease remains under control and the dosing regimen is clinically tolerated.

[0091] A compound of formula I or a pharmaceutically acceptable salt thereof

[0092] In some embodiments of the present application, the compound of formula I described in the present application can be obtained by referring to the preparation method in WO2017162157.

[0093]

[0094] The compound of formula I of the present application can be administered in the form of its free base, or in the form of its pharmaceutically acceptable salt, hydrate and prodrug, which is converted into the compound of formula I in vivo. For example, the pharmaceutically acceptable salt of the compound of formula I is within the scope of the present application, and the salt can be produced from various organic acids and inorganic acids according to methods known in the art.

[0095] As used herein, the compound of formula I is its free base.

[0096] As used in the present application, the compound of formula I is in the form of a hydrate and is administered in the form of a hydrate, wherein each molecule of the free base contains 0.5 to 3 water molecules; preferably, each molecule of the free base contains 1 water molecule, as shown in the following compound of formula II:

[0097]

[0098] As used herein, the compound of formula II is in crystalline form.

[0099] Or as used herein, the compound of formula II is in the form of an amorphous solid.

[0100] The dosage of the compound of formula I or its pharmaceutically acceptable salt involved in this application, unless otherwise specified, is based on the molecular weight (in C 28 H 23 ClF3N5O4S).

[0101] In some schemes of the present application, the compound of formula II described in the present application can be obtained by referring to the preparation method in WO2019057142.

[0102] As used herein, isomers of the compound of formula I are also included within the scope of the present application, for example, racemates of the compound of formula I, enantiomers of the compound of formula I, tautomers of the compound of formula I, diastereomers of the compound of formula I or mixtures of the above isomers.

[0103] Pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof

[0104] In some embodiments of the present application, the compound of formula I or a pharmaceutically acceptable salt thereof is a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments of the present application, the pharmaceutical composition contains a single dose of 50 mg or 200 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, calculated as the compound of formula I. Alternatively, the pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof is prepared as a unit preparation containing 50 mg or 200 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, calculated as the compound of formula I.

[0106] The method of administration can be determined comprehensively based on the activity, toxicity and patient tolerance of the drug.

[0107] In some embodiments of the present application, the pharmaceutical composition includes but is not limited to preparations suitable for oral, parenteral, and topical administration; in some embodiments, the pharmaceutical composition is a preparation suitable for oral administration; in some embodiments, the pharmaceutical composition is a solid preparation suitable for oral administration; in some embodiments, the pharmaceutical composition includes but is not limited to tablets and capsules.

[0108] In some embodiments of the present application, the pharmaceutical composition is a solid pharmaceutical composition.

[0109] In some embodiments of the present application, the pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition containing the compound of formula I or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments of the present application, the pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof is a tablet containing the compound of formula I or a pharmaceutically acceptable salt thereof.

[0111] The pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof of the present application may further contain a pharmaceutically acceptable carrier and / or excipient.

[0112] The pharmaceutical composition of the compound of formula I or its pharmaceutically acceptable salt can be prepared by methods well known in the art, such as conventional mixing, dissolving, granulating, making sugar-coated pills, grinding, emulsifying, freeze-drying, etc.

[0113] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.

[0114] Azacitidine

[0115] As used in this application, azacitidine is chemically known as 5-azacytidine, which has a structure shown in the following formula III compound:

[0116]

[0117] In some embodiments of the present application, the pharmaceutical composition of azacitidine further contains a pharmaceutically acceptable excipient. Preferably, the pharmaceutically acceptable excipient includes a filler, an absorbent, a wetting agent, a binder, a disintegrant, a lubricant, water for injection, and the like.

[0118] In some embodiments of the present application, the azacitidine is in the form of an injectable preparation.

[0119] The present application adopts any commercially available form to administer azacitidine, including but not limited to azacitidine for injection produced by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

[0120] In some embodiments of the present application, the azacitidine pharmaceutical composition is a single dose of 100 mg of azacitidine for injection.

[0121] Hematologic malignancies

[0122] In some embodiments of the present application, the blood tumor is selected from Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML).

[0123] In some embodiments of the present application, the blood tumor is acute myeloid leukemia.

[0124] In some embodiments of the present application, the blood tumor is an advanced blood tumor.

[0125] In some embodiments of the present application, the blood tumor is a blood tumor with IDH1 R132 gene mutation.

[0126] In some embodiments of the present application, the IDH1 R132 gene mutation includes but is not limited to one or more mutations of R132C, R132G, R132H, R132L and R132S.

[0127] In some embodiments of the present application, the hematological tumor is a refractory and / or relapsed hematological tumor.

[0128] In some embodiments of the present application, the blood tumor is acute myeloid leukemia carrying an IDH1 R132 gene mutation or myelodysplastic syndrome carrying an IDH1 R132 gene mutation.

[0129] In some embodiments of the present application, the myelodysplastic syndrome is refractory and / or relapsed myelodysplastic syndrome.

[0130] In some embodiments of the present application, the acute myeloid leukemia is refractory and / or relapsed acute myeloid leukemia.

[0131] In some embodiments of the present application, the acute myeloid leukemia is treatment-naive acute myeloid leukemia.

[0132] In some embodiments of the present application, the acute myeloid leukemia is an acute myeloid leukemia that is not suitable for standard induction chemotherapy.

[0133] In some embodiments of the present application, the acute myeloid leukemia is treatment-naive acute myeloid leukemia carrying an IDH1 R132 gene mutation.

[0134] In some embodiments of the present application, the acute myeloid leukemia is treatment-naive acute myeloid leukemia that is not suitable for standard induction chemotherapy.

[0135] In some embodiments of the present application, the acute myeloid leukemia is an acute myeloid leukemia with an IDH1 R132 gene mutation that is unsuitable for standard induction chemotherapy.

[0136] In some embodiments of the present application, the myelodysplastic syndrome is a higher-risk myelodysplastic syndrome.

[0137] In some embodiments of the present application, the myelodysplastic syndrome is a higher-risk refractory and / or relapsed myelodysplastic syndrome.

[0138] In some embodiments of the present application, the myelodysplastic syndrome is untreated higher-risk myelodysplastic syndrome.

[0139] In some embodiments of the present application, the myelodysplastic syndrome is an untreated higher-risk myelodysplastic syndrome for which azacitidine treatment is indicated.

[0140] In some embodiments of the present application, the relapsed acute myeloid leukemia refers to the reappearance of leukemia cells in the peripheral blood after complete remission, or the primitive cells in the bone marrow ≥5%, or the appearance of leukemia cell infiltration outside the marrow.

[0141] In some schemes of the present application, the refractory acute myeloid leukemia refers to newly diagnosed cases that have failed to respond to two courses of standard treatment, or relapsed within 12 months after complete remission after consolidation and intensive treatment, or relapsed after 12 months but was ineffective after conventional chemotherapy, or relapsed 2 or more times, or extramedullary leukemia persists.

[0142] In some embodiments of the present application, the newly treated acute myeloid leukemia that is not suitable for standard induction chemotherapy refers to patients who are not suitable for standard induction chemotherapy due to age, comorbidities, physical condition, and / or adverse risk factors. In some embodiments of the present application, the standard chemotherapy regimen includes cytarabine and anthracycline or anthraquinone drugs.

[0143] In some embodiments of the present application, the higher-risk myelodysplastic syndrome refers to an International Prognostic Scoring System (IPSS-R) assessment of >3.5 points.

[0144] In some schemes of the present application, the higher-risk myelodysplastic syndrome includes newly treated myelodysplastic syndrome with an IPSS-R assessment of >3.5 points, and / or relapsed / refractory myelodysplastic syndrome. In some schemes of the present application, the newly treated myelodysplastic syndrome refers to patients who have not received treatment with past methylating drugs or other drugs, are allowed to receive treatment with erythropoietic factors and / or myeloid cell growth factors, have indications for azacitidine treatment, and are not suitable for intensive chemotherapy or allogeneic hematopoietic stem cell transplantation. In some schemes of the present application, the relapsed myelodysplastic syndrome refers to patients who have achieved complete remission, partial remission, or hematological improvement according to the efficacy evaluation criteria revised in 2006 by the International Working Group (IWG 2006), and at least one of the following occurs: ① Bone marrow primitive cells return to pre-treatment levels, ② Neutrophils or platelets decrease by more than 50% compared with the best efficacy, ③ Hemoglobin decreases by more than 15g / L compared with the best efficacy or is dependent on blood transfusion.

[0145] In some schemes of the present application, each efficacy evaluation time is the date at the end of each treatment cycle, and the specific evaluation date will be advanced or postponed for several days according to the actual situation of the patient. In some schemes of the present application, the efficacy evaluation time is the first 6 cycles of treatment, and an efficacy evaluation is performed at the end of each treatment cycle (4 weeks ± 3 days), and after 6 cycles, an efficacy evaluation is performed at the end of every 2 treatment cycles (8 weeks ± 7 days).

[0146] In some embodiments of the present application, the refractory myelodysplastic syndrome refers to disease stabilization, failure, or disease progression after adequate treatment (eg, at least 4 cycles of demethylating drugs or other drug treatment) according to the IWG 2006 efficacy evaluation criteria.

[0147] In some embodiments of the present application, the blood tumor optionally includes a combination of any two or more of the above-mentioned types of blood tumors.

[0148] The azacitidine described in the present application is azacitidine for injection, and the administration method is subcutaneous injection.

[0149] The dosage of subcutaneous azacitidine described in the present application is calculated based on the patient's body surface area, and the body surface area calculation formula is: body surface area BSA (㎡) = 0.00616×height (cm) + 0.01286×body weight (kg) - 0.1529.

[0150] The dosage of subcutaneous azacitidine in the present application can be adjusted in subsequent treatment cycles. For example, if no beneficial effect is observed after two treatment cycles and no toxicity other than nausea and vomiting occurs, the dosage can be increased, for example, from the daily dose of 75 mg / m2 in the first treatment cycle to 2 Increase to 100 mg / m daily2 The administration method of the subsequent treatment cycle is the same as that of the first treatment cycle.

[0151] Mode of administration

[0152] The following contents do not limit the administration method of the drug combination of the present application.

[0153] The components of the drug combination of the present application can be administered independently or partially or all of them together in various suitable routes, including but not limited to, oral or parenteral (through intravenous, intramuscular, topical or subcutaneous routes). In some embodiments, the components of the drug combination of the present application can be administered independently or partially or all of them together orally or by injection, such as intravenous injection or subcutaneous injection.

[0154] The components of the pharmaceutical combination of the present application can be in suitable dosage forms independently, or some or all of them can be in suitable dosage forms together, including but not limited to tablets, lozenges, pills, capsules (such as hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and sustained-release preparations for oral or parenteral administration.

[0155] Technical Effects

[0156] The drug combination of the present application has good safety and anti-tumor activity, and the patients have good tolerance during treatment. It also provides a better disease control rate (DCR) and objective response rate (ORR), a longer duration of disease response (DOR), and a longer survival period (such as median survival, progression-free survival or overall survival) among the treated patients.

[0157] The objective response rate (ORR) was calculated as the proportion of patients with a best response of complete remission (CR), complete remission with incomplete blood count recovery (CRi), complete remission with incomplete platelet recovery (CRp), morphologic leukemia-free status (MLFS), or partial remission (PR).

[0158] The drug combination of the present application has better therapeutic effects than any drug in the combination administered alone, including but not limited to higher DCR, ORR, longer DOR and survival (such as median survival, progression-free survival or overall survival).

[0159] The drug combination of the present application has clinical benefits after failure of treatment with the compound of Formula I or a pharmaceutically acceptable salt thereof alone, including but not limited to higher DCR, ORR, longer DOR and survival (e.g., median survival, progression-free survival or overall survival).

[0160] Definition and Description

[0161] Unless otherwise specified, the terms used in this application have the following meanings. A particular term should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this application, it is intended to refer to the corresponding commodity or its active ingredient.

[0162] Herein, unless otherwise specified, the terms "comprise, comprises and comprising" or equivalents are open-ended expressions, meaning that in addition to the listed elements, components and steps, other unspecified elements, components and steps may also be included.

[0163] All patents, patent applications and other identified publications are expressly incorporated herein by reference for the purposes of description and disclosure. Any citation of these publications herein does not constitute an admission that the publication becomes part of the common general knowledge in the art.

[0164] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0165] The term "pharmaceutically acceptable salt" includes salts formed between a base ion and a free acid or between an acid ion and a free base.

[0166] As used in this application, the content of the compound of formula I or a pharmaceutically acceptable salt thereof is calculated as the free base form, for example, the dosage, dose, or content in a pharmaceutical composition.

[0167] As used herein, the compound in the drug combination of the present application can form an acid addition salt if it has, for example, at least one basic center. If necessary, a corresponding acid addition salt with an additional basic center can also be formed. A compound with at least one acidic group (e.g., COOH) can also form a salt with a base. If the compound, for example, contains both a carboxyl group and an amino group, a corresponding inner salt can also be formed.

[0168] The term "patient", "subject" or "individual" refers to mammals, such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats and transgenic non-human animals. In some embodiments, the patient, subject or individual is a human.

[0169] The term "pharmaceutical composition" refers to a mixture of one or more compounds or salts thereof of the present application and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds or salts thereof of the present application to a patient.

[0170] The term "treatment" generally refers to obtaining a desired pharmacological and / or physiological effect, including partial or complete stabilization or cure of a disease and / or effects resulting from a disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its development; or (b) alleviating the symptoms of the disease, i.e., causing regression of the disease or symptoms.

[0171] The term "effective amount" means the amount of the compound of the present application that (i) treats a particular disease, condition or disorder, or (ii) alleviates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder. The amount of the compound of the present application that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0172] The term "single dose" refers to the smallest packaging unit containing a certain amount of medicine. For example, if a box of medicine contains seven capsules, each capsule is a single dose; or each bottle of injection is a single dose.

[0173] The complete remission (CR), complete remission with incomplete blood cell count recovery (CRi), complete remission with incomplete platelet recovery (CRp), morphological leukemia-free state (MLFS) or partial remission (PR) described in the present invention refer to the proposed modified version of the International Working Group Efficacy Evaluation Criteria for Acute Myeloid Leukemia or the International Working Group Efficacy Evaluation Criteria for Myelodysplastic Syndrome.

[0174] All patents, patent applications and other identified publications are expressly incorporated herein by reference for the purposes of description and disclosure. Any citation of these publications herein does not constitute an admission that the publication becomes part of the common general knowledge in the art. DETAILED DESCRIPTION

[0175] The present invention is described in more detail by specific examples. The following examples are provided for illustrative purposes and should not be construed to limit the present invention in any way.

[0176] Example 1 Clinical Trial on Hematological Tumors

[0177] The purpose of this study is to evaluate the safety and efficacy of the compound of formula I alone or in combination with azacitidine for injection in patients with acute myeloid leukemia and myelodysplastic syndrome.

[0178] 1.1 Trial drugs and dosing regimen

[0179] 1.1.1 Trial drugs:

[0180] Tablets of the compound of formula I, with specifications of 50 mg / tablet or 200 mg / tablet, are provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

[0181] Azacitidine for injection, specification 100 mg / bottle, provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

[0182] 1.1.2 Dosage regimen:

[0183] Tablets of the compound of formula I: daily dose is 400 mg or 600 mg, taken orally on an empty stomach, once a day, and continuous administration for 28 days constitutes one treatment cycle.

[0184] Azacitidine for injection: 28 days for one treatment cycle, 75 mg / m2 subcutaneously injected daily on days 1 to 7 of each cycle 2 Azacitidine.

[0185] 1.2 Inclusion criteria

[0186] 1) Patients voluntarily participated in this study, signed informed consent, and had good compliance;

[0187] 2) Male or female; expected survival period ≥ 3 months;

[0188] 3) Patients with acute myeloid leukemia and / or myelodysplastic syndrome with IDH1 R132 mutation in bone marrow puncture fluid or peripheral blood;

[0189] 4) The serum / urine pregnancy test was negative within 7 days before the first dose, and the patient must be non-breastfeeding; women of childbearing age agree to use contraceptive measures (such as intrauterine devices, contraceptive pills or condoms) during the study and within 6 months after the end of the study; men agree to use contraceptive measures during the study and within 6 months after the end of the study;

[0190] 5)Major organs function well.

[0191] 1.3 Evaluation methods and indicators

[0192] Safety evaluation criteria: The NCI-CTC AE 5.0 standard was used to judge the severity of adverse events.

[0193] Effectiveness evaluation criteria: Acute myeloid leukemia uses the AML 2003 IWG efficacy evaluation criteria, and myelodysplastic syndrome uses the MDS IWG 2006 evaluation criteria.

[0194] 1.4 Test results

[0195] A total of 12 evaluable patients were enrolled in the combination of the compound of formula I of the present application with azacitidine, including 7 patients in the 400 mg dose group and 5 patients in the 600 mg dose group. The CR rate of AML in the 400 mg dose group was 43% (3 / 7), and the CR rate of AML in the 600 mg dose group was 100% (5 / 5).

[0196] Representative patient efficacy data of the combined azacitidine group are shown in Table 1. The drug combination of the present application showed good tolerability and safety, overall adverse events were controllable, and had significant clinical benefits.

[0197] Table 1 Efficacy data of patients in the combined group

[0198]

Claims

1. A pharmaceutical combination comprising a compound of formula I or a pharmaceutically acceptable salt thereof and azacitidine, 2. The pharmaceutical combination according to claim 1, wherein the compound of formula I or a pharmaceutically acceptable salt thereof and azacitidine are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially or intermittently.

3. The pharmaceutical combination according to claim 1 or 2, which contains 100-1000 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as the compound of formula I; further, it contains 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, or a range formed by any of the above values ​​of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; further, it contains 400 mg or 600 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, calculated as the compound of formula I; Optionally, the drug combination contains 50-150 mg / m 2 50-100 mg / m 2 or 75–100 mg / m 2 Azacitidine, or a pharmaceutical composition thereof; further comprising 50 mg / m 2 , 75mg / m 2 or 100 mg / m 2 Azacitidine, or a pharmaceutical composition thereof.

4. The pharmaceutical combination according to any one of claims 1 to 3, wherein the pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof is in a single dose or multiple dose form; Optionally, a pharmaceutical composition wherein a single dose is 50 mg and / or 200 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, calculated as the compound of formula I.

5. The pharmaceutical combination according to any one of claims 1 to 4, comprising a daily dose of 400 mg or 600 mg of the compound of formula I or a pharmaceutically acceptable salt thereof, calculated as the compound of formula I, and 75 mg / m2 of the compound of formula I, calculated as the body surface area of ​​the subject. 2 or 100 mg / m 2 daily dose of azacitidine.

6. A drug kit comprising the pharmaceutical combination of any one of claims 1 to 5, and instructions for using a compound of formula I or a pharmaceutically acceptable salt thereof in combination with azacitidine to treat a blood tumor in a patient.

7. Use of the pharmaceutical combination according to any one of claims 1 to 5 or the pharmaceutical kit according to claim 6 in the preparation of a medicament for treating a blood tumor in a patient, wherein the blood tumor is selected from myelodysplastic syndrome and acute myeloid leukemia; Optionally, the blood tumor is a blood tumor with an IDH1 R132 gene mutation.

8. The use according to claim 7, wherein the myelodysplastic syndrome is refractory and / or relapsed myelodysplastic syndrome; or, the myelodysplastic syndrome is a higher-risk myelodysplastic syndrome; or, the myelodysplastic syndrome is an untreated higher-risk myelodysplastic syndrome; Optionally, the acute myeloid leukemia is refractory and / or relapsed acute myeloid leukemia; or, the acute myeloid leukemia is treatment-naive acute myeloid leukemia; or, the acute myeloid leukemia is treatment-naive acute myeloid leukemia carrying an IDH1 R132 gene mutation; or, the acute myeloid leukemia is treatment-naive acute myeloid leukemia that is not suitable for standard induction chemotherapy; or, the acute myeloid leukemia is treatment-naive acute myeloid leukemia that is not suitable for standard induction chemotherapy carrying an IDH1 R132 gene mutation.

9. The use according to claim 7, wherein the compound of formula I or a pharmaceutically acceptable salt thereof and azacitidine have the same treatment cycle; preferably, one treatment cycle is every 1 week, every 2 weeks, every 3 weeks or every 4 weeks; more preferably, one treatment cycle is every 4 weeks.

10. The use according to claim 7, wherein 28 days is one treatment cycle; the pharmaceutical composition containing the compound of formula I or a pharmaceutically acceptable salt thereof is administered once a day for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of formula I or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 11.2 g or 16.8 g; and azacitidine is administered once a day on days 1 to 7 of each treatment cycle, and administration is stopped on days 8 to 28, and the total dose of azacitidine administered in each treatment cycle is 525 mg / m 2 or 700 mg / m 2 .

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