RU2810112C2 - Medical use of pyrrolopyrimidine compound and solid pharmaceutical composition of pyrrolopyrimidine compound - Google Patents

Abstract

FIELD: medicine; pharmaceuticals.

SUBSTANCE: invention relates to the treatment of myeloproliferative neoplasms. The following is disclosed: the use of a compound of formula II or a pharmaceutically acceptable salt thereof in the preparation of a medicinal product for the treatment of a myeloproliferative neoplasm, a solid pharmaceutical composition for the treatment of a myeloproliferative neoplasm containing a compound of formula II or a pharmaceutically acceptable salt thereof, and a diluent, a binder, a wetting agent and a disintegrant, and the use of such solid pharmaceutical composition in the preparation of a medicinal product for the treatment of myeloproliferative neoplasm.

EFFECT: use of the invention makes it possible to effectively treat myeloproliferative neoplasms.

15 cl, 9 tbl, 6 ex

Description

This application claims the benefit and priority of Chinese Patent Application No. 201811581815.8, filed with the China National Intellectual Property Administration on December 24, 2018, and Chinese Patent Application No. 201910679429.0, filed with the China National Intellectual Property Administration on July 26, 2019, which are incorporated herein by links in their entirety.

TECHNICAL FIELD

The present application relates to the field of medicinal chemistry and, specifically, to the therapeutic use and solid pharmaceutical composition of a pyrrolopyrimidine compound.

BACKGROUND ART

Janus kinase (JAK), which is found in cells and transmits cytokine stimulation signals through the JAK-STAT pathway, is a group of non-receptor tyrosine kinases (nRTKs). The JAK-STAT pathway transmits extracellular chemical signals across the cell membrane to the DNA gene promoter in the nucleus, which ultimately causes changes in DNA transcription and activity. The JAK-STAT pathway consists of three main components: 1) the receptor; 2) JAK; and 3) signal transducer and activator of transcription (STAT) protein. The receptor can be activated by interferons, interleukins, growth factors, or other chemical messengers, resulting in JAK autophosphorylation; the STAT protein binds to the phosphorylated receptor such that the STAT protein is phosphorylated by JAK; the phosphorylated STAT protein then dissociates from the receptor, dimerizes, and translocates into the nucleus to bind to specific sites on DNA and alter transcription (Scott, M. I, C. J. Godshall, et al., (2002) "Jaks, STATs, Cytokines, and Sepsis", Clin Diagn Lab Immunol 9(6): 1153-9).

The JAK family plays a role in cell proliferation and functional cytokine-dependent regulation of immune responses. There are currently four known members of the JAK family in mammals: JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase 2). The size of JAK proteins ranges from 120–140 kDa. The JAK protein contains 7 conserved JAK homology (JH) domains, one of which is a functional catalytic kinase domain, and another of which is a pseudokinase domain that effectively exerts regulatory function and/or acts as a docking site for STAT proteins ( Scott, Godshall, et al., 2002, supra).

Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell diseases characterized by excessive proliferation of relatively mature bone marrow cells of one or more lineages. Mainly, MPNs include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF).

SUMMARY

This application provides a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt for use in the treatment of a myeloproliferative neoplasm:

wherein each of R ¹ and R ² is independently selected from the group consisting of H, C _1-6 alkyl, C _1-6 alkyl acyl and C _1-6 alkylsulfonyl; each of R ³ and R ⁴ is independently selected from the group consisting of H, hydroxyl and oxo.

In yet another aspect, the present application provides a pharmaceutical composition for the treatment of a myeloproliferative neoplasm comprising a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt as described above.

In yet another aspect, the present application provides a method of treating a myeloproliferative neoplasm, comprising administering to a subject an effective amount of a compound of formula I, a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described above.

In yet another aspect, the present application provides the use of a compound of formula I, a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described above, in the preparation of a medicament for the treatment of a myeloproliferative neoplasm.

In yet another aspect, the present application provides the use of a compound of formula I, a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described above, in the treatment of a myeloproliferative neoplasm.

In yet another aspect, the present application provides a solid pharmaceutical composition comprising a compound of formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, and a diluent, a binder, a wetting agent and a disintegrant.

In yet another aspect, the present application provides a solid pharmaceutical composition, as described above, for use in the treatment of a JAK-mediated disease.

In yet another aspect, the present application provides the use of a solid pharmaceutical composition as described above in the preparation of a medicament for the treatment of a JAK-mediated disease.

In yet another aspect, the present application provides a method of treating a JAK-mediated disease, comprising administering to a subject an effective amount of a solid pharmaceutical composition as described above.

In yet another aspect, the present application provides the use of a solid pharmaceutical composition as described above in the treatment of a JAK-mediated disease.

DESCRIPTION OF THE INVENTION

This application provides a compound of formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt for use in the treatment of a myeloproliferative neoplasm:

wherein each of R ¹ and R ² is independently selected from the group consisting of H, C _1-6 alkyl, C _1-6 alkyl acyl and C _1-6 alkylsulfonyl; each of R ³ and R ⁴ is independently selected from the group consisting of H, hydroxyl and oxo.

In yet another aspect, the present application provides a pharmaceutical composition for the treatment of a myeloproliferative neoplasm comprising a compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt as described above.

In yet another aspect, the present application provides a method of treating a myeloproliferative neoplasm, comprising administering to a subject an effective amount of a compound of formula I, a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described above.

In yet another aspect, the present application provides the use of a compound of formula I, a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described above, in the preparation of a medicament for the treatment of a myeloproliferative neoplasm.

In yet another aspect, the present application provides the use of a compound of formula I, a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described above, in the treatment of a myeloproliferative neoplasm.

In some embodiments of the present application, the pharmaceutical composition contains a compound of formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, as described above.

In some embodiments of this application, R ¹ and R ² are each independently selected from the group consisting of H, methyl, ethyl, propyl, butyl, pentyl, hexyl, formyl, acetyl, propanoyl, butyryl, valeryl, hexanoyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl , butyl sulphonyl, pentylsulfonyl and hexylsulfonyl

In some embodiments of this application, R ¹ is H, and R ² is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, formyl, acetyl, propanoyl, butyryl, valeryl, hexanoyl, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butyl sulphonyl, pentylsulfonyl and hexylsulfonyl.

In some embodiments of the present application, the compound of formula I has the configuration shown in the following formulas:

In some embodiments of the present application, the compound of formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

In some embodiments of the present application, the compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, is preferably selected from the group consisting of:

In some embodiments of the present application, the hydrochloride salt of the compound of Formula I is preferred. In some embodiments of the present application, the monohydrochloride salt of the compound of Formula I is preferred. In some embodiments of the present application, the crystalline monohydrochloride salt of the compound of Formula I is preferred.

In some embodiments of the present application, the free base of the compound of Formula I is preferred. In some embodiments of the present application, the crystalline free base of the compound of Formula I is preferred.

In some embodiments of the present application, the compound of formula I is a compound of formula II:

Some embodiments of the present application provide a compound of formula II or a pharmaceutically acceptable salt thereof for use in the treatment of polycythemia vera.

Some embodiments of the present application provide a compound of formula II or a pharmaceutically acceptable salt thereof for use in the treatment of thrombocythemia.

Some embodiments of the present application provide a compound of formula II or a pharmaceutically acceptable salt thereof for use in the treatment of myelofibrosis.

Some embodiments of the present application provide a pharmaceutical composition for use in the treatment of polycythemia vera containing a compound of formula II or a pharmaceutically acceptable salt thereof, as described above.

Some embodiments of the present application provide a pharmaceutical composition for use in the treatment of thrombocythemia, containing a compound of formula II or a pharmaceutically acceptable salt thereof, as described above.

Some embodiments of the present application provide a pharmaceutical composition for use in the treatment of myelofibrosis containing a compound of formula II or a pharmaceutically acceptable salt thereof, as described above.

Some embodiments of the present application provide a method of treating polycythemia vera, comprising administering to a subject an effective amount of a compound of Formula II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described above.

Some embodiments of the present application provide a method of treating thrombocythemia, comprising administering to a subject an effective amount of a compound of Formula II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described above.

Some embodiments of the present application provide a method of treating myelofibrosis, comprising administering to a subject an effective amount of a compound of formula II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as described above.

Some embodiments of the present application provide the use of a compound of formula II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment of polycythemia vera.

Some embodiments of the present application provide the use of a compound of formula II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment of thrombocythemia.

Some embodiments of the present application provide the use of a compound of formula II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment of myelofibrosis.

Some embodiments of the present application provide the use of a compound of formula II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of polycythemia vera.

Some embodiments of the present application provide the use of a compound of formula II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of thrombocythemia.

Some embodiments of the present application provide the use of a compound of formula II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the treatment of myelofibrosis.

The pharmaceutical composition disclosed herein can be prepared by combining a compound disclosed herein with a suitable pharmaceutically acceptable excipient and can be formulated, for example, as a solid, semi-solid, liquid or gaseous composition such as a tablet, pill, capsule , powder, granule, ointment, emulsion, suspension, suppository, injection, inhalant, gel, microsphere and aerosol. The pharmaceutical composition disclosed herein can be prepared by methods well known in the art, such as conventional mixing, dissolution, granulation, panning, trituration, emulsification and lyophilization. Suitable excipients include, but are not limited to: binders, diluents, wetting agents, disintegrants, lubricants, lubricants, sweeteners or flavoring agents and the like.

In some embodiments of the present application, the pharmaceutical composition is a composition suitable for oral administration, including tablets, capsules, powders, granules, micropills, pastes, powder and the like, preferably tablets and capsules. The oral composition can be prepared by a conventional method using a pharmaceutically acceptable carrier well known in the art. The pharmaceutically acceptable carrier includes diluents, binders, wetting agents, disintegrants, lubricants and the like. Diluents include microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin, etc., or a mixture thereof; binders include hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, gelatin, polyvinylpyrrolidone, starch, sucrose, glucose, gelatin and the like, or a mixture thereof; wetting agents include magnesium stearate, talc, polyethylene glycol, sodium dodecyl sulfate, silica gel micropowder, talc and the like, or a mixture thereof; disintegrants include sodium carboxymethyl starch, dry starch, microcrystalline cellulose, hydroxyethyl methyl cellulose, sodium carboxy methyl cellulose, calcium carboxy methyl cellulose, croscarmellose sodium, low-substituted hydroxypropyl methyl cellulose, crospovidone, etc., or a mixture thereof; and lubricants include magnesium stearate, colloidal silicon dioxide, talc, polyethylene glycol, stearic acid, sodium stearoyl fumarate and the like, or a mixture thereof. Pharmaceutical excipients also include coloring agents, sweeteners, coating agents and the like.

In some embodiments of the present application, the pharmaceutical composition is in unit dosage form. In some embodiments, the pharmaceutical composition contains from 1 mg to 50 mg of a compound, or a stereoisomer or pharmaceutically acceptable salt thereof, disclosed herein. In some embodiments, the pharmaceutical composition contains 1 mg, 2 mg, 5 mg, 8 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg, 22 mg, 25 mg, 28 mg, 30 mg, 32 mg, 35 mg . , for example from 2 mg to 50 mg, from 10 mg to 40 mg, from 5 mg to 30 mg, from 5 mg to 20 mg, and so on

Solid pharmaceutical composition

The present application provides a solid pharmaceutical composition containing a compound of formula I or a compound of formula II, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a diluent, a binder, a wetting agent and a disintegrant.

In some embodiments of the application, the solid pharmaceutical composition contains a compound of formula I or a compound of formula II and a diluent, a binder, a wetting agent and a disintegrant.

In some embodiments of the present application, the solid pharmaceutical composition further contains a lubricant. In some embodiments of the present application, the amount of a compound of formula I or a compound of formula II is selected from 1-30 wt%, preferably 1-25 wt%, 1-20 wt%, 2-20 wt%, 2-15 wt%. , 2-10 wt%, 3-10 wt% or 2-8 wt%, more preferably 3-8 wt%, even more preferably 3.5-6 wt%; or in some embodiments, the amount of a compound of formula I or a compound of formula II is selected from the group consisting of 1 wt%, 1.2 wt%, 1.4 wt%, 1.6 wt%, 1.8 wt%. , 2% wt., 2.2% wt., 2.4% wt., 2.6% wt., 2.8% wt., 3% wt., 3.2% wt., 3.4% wt., 3.6% wt., 3.8% wt., 4% wt., 4.2% wt., 4.4% wt., 4.6% wt., 4.8% wt., 5% wt., 5.2% wt., 5.4% wt., 5.6% wt., 5.8% wt., 6% wt., 6.2% wt., 6.4% wt. ., 6.6% wt., 6.8% wt., 7% wt., 7.2% wt., 7.4% wt., 7.6% wt., 7.8% wt., 8 % wt., 8.2% wt., 8.4% wt., 8.6% wt., 8.8% wt., 9% wt., 9.2% wt., 9.4% wt. , 9.6% wt., 9.8% wt., 10% wt., 10.5% wt., 11% wt., 11.5% wt., 12% wt., 12.5% wt. , 13 wt%, 13.5 wt%, 14 wt%, 14.5 wt%, 15 wt%, 15.5 wt%, 16 wt%, 16.5 wt%, 17 % wt., 17.5% wt., 18% wt., 18.5% wt., 19% wt., 19.5% wt., 20% wt., 21% wt., 22% wt., 23 wt%, 24 wt%, 25 wt%, 26 wt%, 27 wt%, 28 wt%, 29 wt%, and 30 wt%, or any range determined by the endpoints of any of the above above values, or any value within the specified range.

In some embodiments of the present application, the diluent is selected from the group consisting of microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch and dextrin, or a mixture thereof; preferably microcrystalline cellulose, mannitol, lactose and pregelatinized starch or a mixture thereof; more preferably microcrystalline cellulose and mannitol or mixtures thereof.

In some embodiments of the present application, the amount of diluent is selected from 50-95 wt%, preferably 60-95 wt%, 65-95 wt%, 70-95 wt%, 75-95 wt%, 80-95 wt%. ., 80-90% by weight, or 85-95% by weight, more preferably 85-90% by weight; or in some embodiments, the amount of diluent is selected from the group consisting of 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 wt%, 80 wt%, 85 wt%, 90 wt%. ., and 95% by weight, or any range defined by the endpoints of any of the values listed above, or any value within the range specified.

In some embodiments of the present application, the binder is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMC-Na), ethylcellulose (EC), methylcellulose (MC), hydroxypropylcellulose (HPC), low-substituted hydroxypropylcellulose (L-HPC), gelatin, polyvinylpyrrolidone (PVP), partially hydrolyzed starch, starch, pregelatinized starch, sucrose, glucose, gelatin, polyethylene glycol (PEG) and polyvinyl alcohol, or mixtures thereof; preferably hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose (CMC-Na), ethylcellulose (EC), methylcellulose (MC), hydroxypropylcellulose (HPC), low-substituted hydroxypropylcellulose (L-HPC) and polyvinylpyrrolidone or mixtures thereof; more preferably hydroxypropylcellulose and polyvinylpyrrolidone or mixtures thereof.

In some embodiments of the present application, the amount of binder is selected from 1.0-10 wt%, preferably 1.0-8.0 wt%, 1.0-6.0 wt%, or 1.0-5.0 wt%, more preferably 2.0-4.0 wt%; or in some embodiments, the amount of binder is selected from the group consisting of 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3. 5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, 7.0 wt%, 7.5 wt%, 8.0 wt%, 8.5 wt%, 9.0 wt%, 9.5 wt%, and 10 wt%, or any range specified the endpoints of any of the values listed above, or any value in the range specified.

In some embodiments of the present application, the wetting agent is selected from the group consisting of sodium dodecylbenzenesulfonate, magnesium dodecylbenzenesulfonate, sodium tetradecylbenzenesulfonate, sodium hexadecylbenzenesulfonate, sodium octadecylbenzenesulfonate, sodium dodecylsulfonate, magnesium dodecylsulfonate, sodium tetradecylsulfonate, sodium hexadecylsulfonate, octadecylsulfonate sodium onate, sodium dodecyl sulfate, magnesium dodecyl sulfate, tetradecyl sulfate sodium, sodium hexadecyl sulfate, sodium octadecyl sulfate, sodium lauroyl sarcosine, sodium lactate, sodium palmitate, lauric acid isopropanolamide, lauric acid diethanolamide, tetradecyl lactate, hexadecyllactate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate a 85, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene sorbitol tetraoleoyl ether, polyoxyethylene stearate, polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil or mixtures thereof; preferably sodium dodecyl sulfonate, magnesium dodecyl sulfonate, sodium tetradecyl sulfonate, sodium dodecyl sulfate, magnesium dodecyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate and sodium lauroyl sarcosine or mixtures thereof; more preferably sodium dodecyl sulfate and magnesium dodecyl sulfate or mixtures thereof.

In some embodiments of the present application, the amount of wetting agent is selected from 0.01-5.0 wt%, preferably 0.01-4.0 wt%, 0.01-3.0 wt%, 0.02-2, 5 wt%, 0.02-2.0 wt%, more preferably 0.03-2.0 wt%, even more preferably 0.05-1.0 wt%, even more preferably 0.1- 0.5% mass; or in some embodiments, the amount of lubricant is selected from the group consisting of 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0. 06 wt%, 0.07 wt%, 0.08 wt%, 0.09 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 % wt., 0.5% wt., 0.6% wt., 0.7% wt., 0.8% wt., 0.9% wt., 1.0% wt., 1.1% wt., 1.2% wt., 1.3% wt., 1.4% wt., 1.5% wt., 1.6% wt., 1.7% wt., 1.8% wt. ., 1.9% wt., 2.0% wt., 2.1% wt., 2.2% wt., 2.3% wt., 2.4% wt., 2.5% wt. , 2.6% wt., 2.7% wt., 2.8% wt., 2.9% wt., 3.0% wt., 3.2% wt., 3.4% wt., 3.6 wt%, 3.8 wt%, 4.0 wt%, 4.2 wt%, 4.4 wt%, 4.6 wt%, 4.8 wt%, and 5.0% by weight, or any range defined by the endpoints of any of the values listed above, or any value within the range specified.

In some embodiments of the present application, the disintegrant is selected from the group consisting of sodium carboxymethyl starch, dry starch, microcrystalline cellulose, hydroxyethyl methyl cellulose, sodium carboxy methyl cellulose, calcium carboxy methyl cellulose, carmellose sodium, low-substituted hydroxypropyl methyl cellulose or crospovidone, sodium dodecyl sulfate and magnesium dodecyl sulfate, or mixtures thereof; preferably from sodium carboxymethyl starch and croscarmellose sodium or a mixture thereof.

In some embodiments of the present application, the amount of disintegrant is selected from 1.0-7.0 wt%, preferably 1.0-6.5 wt%, 1.0-6.5 wt%, 1.0-6.0 wt%, 1.5-5.5 wt%, 1.5-5.0 wt%, or 1.5-4.5 wt%, more preferably 2.0-4.0 wt%; or in some embodiments, the amount of disintegrant is selected from the group consisting of 1.0 wt%, 1.5 wt%, 2.0 wt%, 2.5 wt%, 3.0 wt%, 3.5 wt%, 4.0 wt%, 4.5 wt%, 5.0 wt%, 5.5 wt%, 6.0 wt%, 6.5 wt%, and 7.0 % by weight, or any range defined by the endpoints of any of the values listed above, or any value within a specified range.

In some embodiments of this application, the lubricant is selected from the group consisting of magnesium stearate, colloidal silica, talc, polyethylene glycol 4000, polyethylene glycol 6000, stearic acid, sodium stearyl fumarate and sodium dodecyl sulfate or a mixture thereof, preferably magnesium stearate and colloidal silica or their mixtures.

In some embodiments of the present application, the amount of lubricant is selected from 0.1-3 wt%, preferably 0.2-2.5 wt%, 0.3-2.0 wt%, or 0.4-1.5 wt%, more preferably 0.5-1 wt%; or in some embodiments, the amount of lubricant is selected from the group consisting of 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0. 6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1.0 wt%, 1.1 wt%, 1.2 wt%, 1.3 % wt., 1.4% wt., 1.5% wt., 1.6% wt., 1.7% wt., 1.8% wt., 1.9% wt., 2.0% wt., 2.1% wt., 2.2% wt., 2.3% wt., 2.4% wt., 2.5% wt., 2.6% wt., 2.7% wt. ., 2.8% by weight, 2.9% by weight, and 3.0% by weight, or any range defined by the endpoints of any of the values listed above, or any value within the range indicated.

In some embodiments of the present application, the solid pharmaceutical composition contains 50-95% by weight, microcrystalline cellulose, mannitol, lactose or pregelatinized starch, or a mixture thereof; preferably 60-95 wt%, 65-95 wt%, 70-95 wt%, 75-95 wt%, 80-95 wt%, 80-90 wt%, or 85-95 wt%. microcrystalline cellulose, mannitol, lactose or pregelatinized starch or a mixture thereof; more preferably 85-90% by weight, microcrystalline cellulose, mannitol, lactose, and pregelatinized starch or a mixture thereof; even more preferably 85-90% by weight, microcrystalline cellulose or mannitol or a mixture thereof. In some preferred embodiments, the diluent is a mixture of microcrystalline cellulose and mannitol, where the weight ratio of microcrystalline cellulose to mannitol is selected from 1:1 to 5:1, preferably 1:1 to 4:1, 1.2:1 to 3, 5:1 or 1.2:1 to 3:1, more preferably 1.5:1 to 2.5:1; or the weight ratio of microcrystalline cellulose to mannitol is selected from the group consisting of 1:1, 1.2:1, 1.5:1, 1.8:1, 1.9:1, 2:1, 2.2:1 , 2.5:1, 2.8:1, 3:1, 3.2:1, 3.5:1, 3.8:1, 4:1, 4.2:1, 4.5:1 , 4.8:1 and 5:1.

In some embodiments of the present application, based on the amount of the solid pharmaceutical composition, the diluent in the solid pharmaceutical composition is selected from 50-70 wt% microcrystalline cellulose and 20-40 wt% mannitol, preferably 52-68 wt% microcrystalline cellulose and 22-38 wt% mannitol, 54-66 wt% microcrystalline cellulose and 24-36 wt% mannitol, 54-64 wt% microcrystalline cellulose and 24-34 wt% mannitol, or 56- 62 wt% microcrystalline cellulose and 26-32 wt% mannitol, more preferably 56-60 wt% microcrystalline cellulose and 26-30 wt% mannitol, even more preferably 58.3 wt% microcrystalline cellulose and 29.4% wt., mannitol.

In some embodiments of the present application, the solid pharmaceutical composition contains 1.0-10 wt.%. HPMC, CMC, CMC-Na, EC, MS, NPC, L-HPC or PVP or mixtures thereof; preferably 1.0-8.0% wt., 1.0-6.0% wt., or 1.0-5.0% wt. HPMC, CMC, CMC-Na, EC, MS, NPC, L-HPC or PVP or mixtures thereof; more preferably 2.0-4.0% wt. HPMC, CMC, CMC-Na, EC, MS, NPC or L-HPC or mixtures thereof; even more preferably 2.0-4.0% wt. LDC or PVP or mixtures thereof.

In some embodiments of the present application, the solid pharmaceutical composition contains 0.01-5.0% by weight, sodium dodecyl sulfonate, magnesium dodecyl sulfonate, sodium tetradecyl sulfonate, sodium dodecyl sulfate, magnesium dodecyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate or sodium lauroyl sarcosine or a mixture thereof; preferably 0.01-4.0 wt%, 0.01-3.0 wt%, 0.02-2.5 wt%, or 0.02-2.0 wt% sodium dodecyl sulfonate, dodecyl sulfonate magnesium, sodium tetradecyl sulfonate, sodium dodecyl sulfate, magnesium dodecyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate or sodium lauroyl sarcosine or mixtures thereof; more preferably 0.03-2.0% by weight, sodium dodecyl sulfonate, magnesium dodecyl sulfonate, sodium tetradecyl sulfonate, sodium dodecyl sulfate, magnesium dodecyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate or sodium lauroyl sarcosine or mixtures thereof; even more preferably 0.03-2.0% by weight, sodium dodecyl sulfate or magnesium dodecyl sulfate or a mixture thereof; even more preferably 0.1-0.5% by weight, sodium dodecyl sulfate or magnesium dodecyl sulfate or mixtures thereof.

In some embodiments of the present application, the solid pharmaceutical composition contains 1.0-7.0 wt%. sodium carboxymethyl starch or croscarmellose sodium or mixtures thereof; preferably 1.0-6.5 wt%, 1.0-6.5 wt%, 1.0-6.0 wt%, 1.5-5.5 wt%, 1.5-5 .0% wt. or 1.5-4.5% by weight, sodium carboxymethyl starch or croscarmellose sodium or mixtures thereof; more preferably 2.0-4.0% by weight, sodium carboxymethyl starch or croscarmellose sodium or mixtures thereof.

In some embodiments of the present application, the solid pharmaceutical composition contains 0.1-3% by weight, magnesium stearate or colloidal silicon dioxide, or a mixture thereof; preferably 0.2-2.5% wt., 0.3-2.0% wt. or 0.4-1.5% by weight, magnesium stearate or colloidal silicon dioxide or mixtures thereof; more preferably 0.5-1% by weight, magnesium stearate or colloidal silicon dioxide or mixtures thereof.

In some embodiments of this application, the solid pharmaceutical composition disclosed herein contains:

A) 1-30% wt. compounds of formula I or compounds of formula II;

50-95% wt. microcrystalline cellulose, mannitol, lactose or pregelatinized starch or a mixture thereof;

1.0-10% wt. HPMC, CMC, CMC-Na, EC, MS, NPC, L-HPC or PVP or mixtures thereof;

0.01-5.0% wt. sodium dodecyl sulfonate, magnesium dodecyl sulfonate, sodium tetradecyl sulfonate, sodium dodecyl sulfate, magnesium dodecyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate or sodium lauroyl sarcosine or mixtures thereof;

1.0-7.0% wt. sodium carboxymethyl starch or croscarmellose sodium or mixtures thereof; And

perhaps 0.1-3% wt. magnesium stearate or colloidal silicon dioxide or mixtures thereof; or

B) 2-10% wt. compounds of formula I or compounds of formula II;

75-95% wt. microcrystalline cellulose or mannitol or a mixture thereof, where the weight ratio of microcrystalline cellulose to mannitol in the mixture is selected from 1.2:1 to 3.5:1;

1.0-6.0% wt. hydroxypropylcellulose or polyvinylpyrrolidone or mixtures thereof;

0.01-3.0% wt. sodium dodecyl sulfonate, magnesium dodecyl sulfonate, sodium tetradecyl sulfonate, sodium dodecyl sulfate, magnesium dodecyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate or sodium lauroyl sarcosine or mixtures thereof;

1.0-6.0% wt. sodium carboxymethyl starch or croscarmellose sodium or mixtures thereof; And

possibly 0.3-2.0% wt. magnesium stearate or colloidal silicon dioxide or mixtures thereof; or

C) 3-8% by weight, compounds of formula I or compounds of formula II;

85-90% by weight, microcrystalline cellulose or mannitol or a mixture thereof, where the weight ratio of microcrystalline cellulose to mannitol in the mixture is selected from 1.5:1 to 2.5:1;

2.0-4.0% wt., hydroxypropylcellulose or polyvinylpyrrolidone or mixtures thereof;

0.03-2.0% by weight, sodium dodecyl sulfate or magnesium dodecyl sulfate or a mixture thereof;

2.0-4.0% wt., sodium carboxymethyl starch or croscarmellose sodium or mixtures thereof; And

optionally 0.5-1% by weight, magnesium stearate or colloidal silicon dioxide or mixtures thereof; or

D) 3.0-5.0% by weight, compounds of formula I or compounds of formula II;

50-70% wt., microcrystalline cellulose;

20-40% wt., mannitol;

2.0-6.0% wt., hydroxypropylcellulose;

0.05-0.2% wt., sodium dodecyl sulfate;

2.0-6.0% wt., croscarmellose sodium; and, perhaps

0.5-2% wt., magnesium stearate; or

E) 3.4-4.6% by weight, compounds of formula I or compounds of formula II;

55-60% wt., microcrystalline cellulose;

26-32% wt., mannitol;

2.0-4.0% wt., hydroxypropylcellulose;

0.1-0.5% wt., sodium dodecyl sulfate;

2.0-4.0% wt., croscarmellose sodium; and, perhaps

0.5-1% wt., magnesium stearate; or

F) 4.2% by weight, compounds of formula I or compounds of formula II;

58.3% wt., microcrystalline cellulose;

29.4% wt., mannitol;

4.0% wt., hydroxypropylcellulose;

0.1% wt., sodium dodecyl sulfate

3.0% wt., croscarmellose sodium; and, perhaps

1.0% wt., magnesium stearate.

In some embodiments of the present application, the compound of formula I or the compound of formula II is present in the form of a free base or hydrochloride salt. In certain exemplary embodiments of the present application, the compound of formula I or the compound of formula II is present in free base form. In some embodiments of the present application, the compound of formula I or the compound of formula II is present in the form of a monohydrochloride salt.

In some embodiments of the present application, the solid pharmaceutical composition further comprises a coating agent. In some embodiments, the coating agent is formed from an aqueous film coating composition, wherein the aqueous film coating composition contains a film-forming polymer, water and/or alcohol as a carrier, and optionally one or more auxiliary agents, such as additives known in the field of film coatings. In some embodiments, the coating agent is selected from the group consisting of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, cellulose acetate phthalate, sodium ethyl cellulose sulfate, carboxymethyl cellulose, polyvinylpyrrolidone, zein, acrylic polymers (e.g., methacrylic acid/methacrylate copolymers such as methacrylic acid/methyl methacrylate) and polyvinyl alcohol. In some typical embodiments, the coating agent comprises polyvinyl alcohol.

In some embodiments of the present application, the dissolution rate of the solid pharmaceutical composition within 30 minutes is equal to at least 60% of the claimed amount. In some embodiments of the present application, the dissolution rate of the solid pharmaceutical composition within 30 minutes is at least 80% of the claimed amount. In some embodiments of this application, the dissolution rate of the solid pharmaceutical composition within 30 minutes in hydrochloric acid solution (pH 1.0), acetate buffer (pH 4.5), phosphate buffer (pH 6.8) or purified water is at least 80 % of the declared quantity, preferably at least 85% of the declared quantity. In some embodiments of the present application, the dissolution rate of the solid pharmaceutical composition within 30 minutes in purified water is at least 80% of the stated amount, preferably not less than 85% of the stated amount, more preferably not less than 90% of the stated amount. In some exemplary embodiments of the present application, the dissolution rate of the solid pharmaceutical composition within 15 minutes in purified water is at least 85% of the claimed amount.

In some embodiments of the present application, the dosage form of the solid pharmaceutical composition may be selected from the group consisting of powders, granules, tablets, capsules, pills, pellets, dispersions and powders for inhalation, preferably tablets and capsules, more preferably tablets.

In some embodiments of the present application, the solid pharmaceutical composition is a unit dose pharmaceutical composition, and the amount of a compound of formula I or a compound of formula II per unit dose is 5-20 mg. In some embodiments of the present application, the amount of a compound of formula I or a compound of formula II per unit dose is 5 mg, 8 mg, 10 mg, 12 mg, 15 mg, 18 mg or 20 mg, or any range defined by the endpoints of any of the above values, or any value in the specified range.

In yet another aspect, the present application provides a method for preparing a solid pharmaceutical composition of a compound of formula I or a compound of formula P. In the present application, wet granulation can be used to produce solid granules. During the wet granulation process, if necessary, additional excipients compatible with the compound of formula I or the compound of formula P can be added. Wet granulation can be carried out in a wet granulator (mixed granulation) or in a fluidized bed (fluidized bed granulation), preferably in a fluidized bed. layer. In wet granulation, a compound of formula I or a compound of formula II may be added to the premix as a solid additive along with other additives or formulated as a solution (suspension or clear solution) for granulation. Preferably, it is obtained in the form of a suspension, which is included in the granules at the granulation stage.

In some embodiments of the present application, a method for preparing a solid pharmaceutical composition of a compound of formula I or a compound of formula II includes:

1) mixing the diluent with the baking powder to obtain a mixture for further use; mixing a compound of formula I or a compound of formula II, a binder and a wetting agent with water to form a mixed solution;

2) spraying the mixed solution from step (1) onto the mixture from step (1), granulating and drying in a fluidized bed and calibrating the resulting mixture to obtain dried granules; And

3) it is possible to mix dried granules with a lubricant and tabletting;

wherein the mixed solution in step (1) is a suspension or a clear solution, preferably a suspension; and the diluent, binder, wetting agent, disintegrant and lubricant are as described above.

In some embodiments of the present application, in step (2), the inlet air temperature is selected from 35-90°C, preferably 45-85°C, more preferably 55-80°C. In some embodiments of the present application, in step (2), the spray pressure is selected from 400-1200 mbar (4-12×10 ⁴ Pa), preferably 500-1100 mbar (5-11×10 ⁴ Pa), more preferably 600-1000 mbar ( 6-10×10 ⁴ Pa). In some embodiments of the present application, in step (2), the temperature of the substance is selected from 20-40°C, preferably 25-35°C. In some embodiments of the present application, in step (2), the sieve mesh size is Φ 0.4-1.5 mm, preferably Φ 0.5-1.4 mm, more preferably Φ 0.6-1.2 mm.

In yet another aspect, the present application provides the use of a solid pharmaceutical composition of a compound of formula I or a compound of formula II in the preparation of a medicament for the treatment of a JAK-mediated disease.

In yet another aspect, the present application provides a solid pharmaceutical composition of a compound of formula I or a compound of formula II for use in the treatment of a JAK-mediated disease.

In yet another aspect, the present application provides the use of a solid pharmaceutical composition of a compound of formula I or a compound of formula II in the treatment of a JAK-mediated disease.

In yet another aspect, the present application provides a method of treating a JAK-mediated disease, comprising administering to a subject a therapeutically effective amount of a solid pharmaceutical composition of a compound of formula I or a compound of formula P.

In some embodiments of the present application, JAK-mediated disease includes, but is not limited to, tumors. In some embodiments, a tumor described herein is a lymphoma or leukemia. Lymphoma described herein includes, but is not limited to: Hodgkin's disease and non-Hodgkin's lymphoma, and non-Hodgkin's lymphoma includes, but is not limited to: B-cell lymphoma and T-cell lymphoma. Leukemia described herein includes, but is not limited to: acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia and chronic myelocytic leukemia.

In some embodiments of the present application, the JAK-mediated disease is a myeloproliferative neoplasm.

In some embodiments of the present application, myeloproliferative neoplasm includes polycythemia vera, thrombocythemia, and myelofibrosis. Polycythemia vera includes hydroxyurea and/or interferon-resistant and/or non-resistant polycythemia vera. Thrombocythemia includes essential thrombocythemia, and hydroxyurea and/or interferon-resistant and/or interferon-resistant essential thrombocythemia. Myelofibrosis includes primary myelofibrosis, post-polycythemia vera myelofibrosis (PPV-MF), and post-essential thrombocythemia myelofibrosis (PET-MF).

In some embodiments of the present application, the myeloproliferative neoplasm and diseases comprising it include low-risk, intermediate-risk and high-risk myeloproliferative neoplasms. For example, polycythemia vera may include low-risk and high-risk polycythemia vera; thrombocythemia may include very low risk, low risk, intermediate risk and high risk thrombocythemia; myelofibrosis may include low-risk, intermediate-risk and/or high-risk myelofibrosis. In some embodiments, polycythemia vera is intermediate-risk and/or high-risk polycythemia vera, thrombocythemia is intermediate-risk and/or high-risk thrombocythemia, myelofibrosis is intermediate-risk and/or high-risk myelofibrosis, and essential thrombocythemia is intermediate-risk essential thrombocythemia and /or high risk. For example, primary myelofibrosis, myelofibrosis following polycythemia vera, and myelofibrosis following essential thrombocythemia all belong to the corresponding intermediate- or high-risk myelofibrosis. In this application, for diagnostic criteria and risk stratification (eg, very low risk, low risk, intermediate risk, and high risk) of myeloproliferative neoplasm, reference can be made to the basic principles in this field. This can be assessed with reference to NCCN (US National Cancer Network) Myeloproliferative Neoplasms Revision 2.2019 guidelines, such as the Dynamic International Prognosis Score (DIPSS). In some embodiments, WHO 2016 and IWG-MRT (International Working Group on Research and Treatment of Myeloproliferative Neoplasms) are used as diagnostic criteria.

As used herein, myeloproliferative neoplasm includes mutant myeloproliferative neoplasms, and the mutant genes include, but are not limited to: JAK2 (eg JAK2 V617F), MPL, CALR, ASXL1/SRSF2/IDH1/21, JAK2 exon 12, TP53, SH2B3/IDH2/U2AF1/ SF3B1/EZH2/TP53, MPL W515L/K, CALR type 1/type 1-like, triple negative (no JAK2, MPL and CALR mutations), ASXL1, EZH2, IDH1/2, SRSF2, SF3B1, CALR/ASXL1, TP53 and U2AF1 Q157.

In some embodiments of the present application, the compound of formula I or the compound of formula II is administered in free base form. In some embodiments of the present application, the compound of formula I or the compound of formula II is administered in the form of a crystalline free base. In some embodiments of the present application, the crystalline free base of the compound of Formula II may be selected from Crystal Form A and Crystal Form B disclosed in WO 2017215630.

In some embodiments of the present application, the compound of formula II is administered in the form of a hydrochloride salt. In some embodiments of the present application, the hydrochloride salt of the compound of formula II may be selected from the hydrochloride salts disclosed in WO 2017101777.

A compound or a stereoisomer or pharmaceutically acceptable salt thereof disclosed herein can be administered through a variety of routes, including, but not limited to: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intralipid, intraarticular and intrathecal administration. In one specific embodiment, it is administered orally.

The amount of a compound, a stereoisomer or pharmaceutically acceptable salt thereof, or a solid pharmaceutical composition thereof disclosed herein may be determined based on the severity of the disease, the response, any treatment-related toxicity, and the age and health of the subject. For example, it can be determined from a complete blood count of the subject, which includes platelet count, neutrophil count, hemoglobin concentration, and so on. In some embodiments, the daily dosage for administration of a compound, a stereoisomer or pharmaceutically acceptable salt thereof, or a solid pharmaceutical composition thereof disclosed herein is from 1 mg to 100 mg. In some embodiments, the daily dosage for administration of a compound, a stereoisomer or pharmaceutically acceptable salt thereof, or a solid pharmaceutical composition thereof disclosed herein may be selected from the group consisting of 1 mg, 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 and 100 mg, or any range defined by the endpoints of any of the values listed above, or any value within a specified range, such as 1 mg to 90 mg, 5 mg to 80 mg, 10 mg to 70 mg, 15 mg to 60 mg, and 20 mg to 50 mg and so on. In certain specific embodiments, the daily dosage for administration of a compound, a stereoisomer or pharmaceutically acceptable salt thereof, or a solid pharmaceutical composition thereof disclosed herein may be selected from 1 mg to 50 mg, 5 mg to 50 mg, 5 to 45 mg, 5 to 40 mg, 10 to 35 mg, or 10 to 30 mg. In certain specific embodiments, the daily dosage for administration of a compound, a stereoisomer or pharmaceutically acceptable salt thereof, or a solid pharmaceutical composition thereof disclosed herein may be selected from the group consisting of 1 mg, 2 mg, 5 mg, 8 mg, 10 mg , 12 mg, 15 mg, 18 mg, 20 mg, 22 mg, 25 mg, 28 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 42 mg, 45 mg, 48 mg and 50 mg, or any range defined by the endpoints of any of the values listed above, or any value within a specified range, such as 2 mg to 50 mg, 10 mg to 40 mg, 5 mg to 30 mg and 5 mg to 20 mg, and so on.

The compound, stereoisomer or pharmaceutically acceptable salt thereof, or solid pharmaceutical composition thereof disclosed herein may be administered once or several times daily. In some embodiments, a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solid pharmaceutical composition thereof disclosed herein can be administered once or twice daily. The compound, or a stereoisomer or pharmaceutically acceptable salt thereof, can also be administered in unit dosage form. In one embodiment, it is administered in unit dosage form once or twice daily. In one embodiment, it is administered in a unit dosage form of an oral solid composition once or twice daily.

The route of administration may be determined depending on factors such as the activity and toxicity of the drug and the tolerance of the subject. In some embodiments, the compound or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is administered intermittently.

A compound, a stereoisomer or pharmaceutically acceptable salt thereof, or a solid pharmaceutical composition thereof disclosed herein can be administered intermittently. The intermittent regimen includes treatment periods and rest periods. During treatment periods, the compound, a stereoisomer or pharmaceutically acceptable salt thereof, or a solid pharmaceutical composition thereof may be administered once, twice or several times daily. An intermittent regimen may be prescribed based on disease severity, response, any treatment-related toxicity, and the age and health of the subject. For example, it can be prescribed based on the patient/subject's complete blood count, which includes platelet count, neutrophil count and hemoglobin concentration, etc.

Technical effects

The compound disclosed herein can effectively reduce the volume of the spleen of a subject. The compound disclosed herein has good therapeutic effect in myeloproliferative neoplasm and has excellent safety.

The solid pharmaceutical composition disclosed herein has excellent stability and dissolution properties and is suitable for clinical use. In addition, the solid pharmaceutical composition of the present application in the form of a tablet has the property of rapid release with a dissolution rate of not less than 80% of the declared amount within 30 minutes.

Definitions and description

Unless otherwise specified, the following terms as used in this application will have the following meanings. A specific term, unless otherwise specifically defined, should not be considered vague or unclear, but should be construed in accordance with its ordinary meaning in the field. The trade name refers to the corresponding commercial product or its active ingredient.

The term "pharmaceutically acceptable" is used herein for those compounds, substances, compositions and/or dosage forms that, within the bounds of sound medical judgment, are suitable for use in contact with tissues of humans and animals without undue toxicity, irritation, allergic reaction or other problems or complications and commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" includes salts formed by basic radicals and free acids, and salts formed by acid radicals and free bases, for example hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate , succinate, mesylate, benzenesulfonate and p-methylbenzenesulfonate, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, mesylate, p-methylbenzenesulfonate, sodium salt, potassium salt, ammonium salt and amino acid salt, and so on. In the present application, when forming a pharmaceutically acceptable salt, the free acid and the basic radical are in a molar ratio of about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1: 4, 1:5, 1:6, 1:7 or 1:8. In the present application, when forming a pharmaceutically acceptable salt, the free base and the acid radical are in a molar ratio of about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1: 4, 1:5, 1:6, 1:7 or 1:8.

As used herein, if a compound of formula I or a compound of formula II has, for example, at least one basic site, an acid addition salt may be formed. If required, it can also form an acid addition salt with additional basic sites. A compound with at least one acidic group (eg -COOH) can also form a salt with a base. A compound containing, for example, both a carboxyl and an amino group may also form an internal salt.

A compound disclosed herein may be asymmetric, such as having one or more stereoisomers. Unless otherwise noted, all stereoisomers, such as enantiomers and diastereoisomers, are included. The compound containing the asymmetric carbon atoms disclosed herein can be isolated in optically pure form or in racemic form. The optically pure form can be isolated from a racemic mixture or can be synthesized using a chiral raw material or a chiral reagent.

The term "subject" refers to a mammal. In some embodiments, the subject is a human.

The term "pharmaceutical composition" refers to a mixture consisting of one or more compounds or pharmaceutically acceptable salts thereof disclosed herein and pharmaceutically acceptable excipients. The pharmaceutical composition is intended to provide administration of the compound to a subject.

The terms “treat,” “receive treatment,” and “treatment” refer to the administration of a compound or pharmaceutical composition disclosed herein to ameliorate or eliminate a disease or one or more symptoms associated with a disease, and includes:

1) suppression of a disease or painful condition, that is, cessation of its development; And

2) alleviation of a disease or painful condition, that is, causing its regression.

The term "effective amount" refers to the amount of a compound disclosed herein for (1) treating a specific disease, condition or disorder; (2) alleviating, reducing or eliminating one or more symptoms of a particular disease, condition or disorder, or (3) preventing or delaying the onset of one or more symptoms of a particular disease, condition or disorder described herein. The amount of a compound disclosed herein that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal being treated, but can be determined according to normal practice by one of ordinary skill in the art, in in accordance with their knowledge and this description.

As used herein, a “pharmaceutically acceptable salt” includes, but is not limited to: acid addition salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; or acid addition salts of organic acids such as formic acid, acetic acid, trifluoroacetic acid, succinic acid, malic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid; or acid addition salts of acidic amino acids such as aspartic acid or glutamic acid. Solvates include, but are not limited to, hydrates.

In the present application, the amount of a compound of formula I or a compound of formula II in a pharmaceutical composition is determined based on the free base form.

The diluent described herein is also called excipient, and is mainly divided into water-soluble diluents, water-insoluble diluents, direct compression diluents and so on, including but not limited to: starch, sucrose, dextrin, lactose, pregelatinized starch, microcrystalline cellulose, inorganic salts and/or sugar alcohols. Lactose includes, but is not limited to: lactose anhydrous and lactose monohydrate or mixtures thereof.

According to sources, the binder described herein can be divided into natural binders and synthetic binders. Depending on the use of the binder, the binder may also be subdivided into binders that exhibit viscosity only in aqueous solutions or mucilages, binders that exhibit viscosity when dry, and binders that exhibit viscosity after dissolution or wetting with a non-aqueous solvent. Binders include, but are not limited to: starch slurry, cellulose derivatives, polyvidone, gelatin, polyethylene glycol, sucrose solutions and/or sodium alginate solutions.

The wetting agent described herein includes liquids and/or surfactants that have low surface tension and are miscible with water. Surfactants include anionic surfactants, cationic surfactants, zwitterionic surfactants and/or non-ionic surfactants. Anionic surfactants include, but are not limited to: alkylbenzene sulfonate salts, alkyl sulfonate ester salts, alkyl sulfonate salts, alkyl sulfate salts, fluorinated fatty acid salts, polysiloxanes and/or fatty alcohol sulfate salts. Cationic surfactants include, but are not limited to: quaternary ammonium compounds, alkylpyridinium salts and/or amine salts. Zwitterionic surfactants include, but are not limited to: lecithin, amino acids and/or betaines; Nonionic surfactants include, but are not limited to: alkyl polyglycosides (APGs), fatty acid glycerides, sorbitan fatty acid esters (Span), polysorbates (Tween), polyoxyethylenes and/or poloxamers.

Disintegrants described herein include, but are not limited to: starch and its derivatives, celluloses, surfactants, effervescent disintegrants, gums, alginates and/or ion exchange resins.

Broadly speaking, the lubricant described herein includes three excipients: lubricants (in the narrow sense), lubricants and release agents. The lubricant described herein includes, but is not limited to: stearates, colloidal silicon dioxide, talc, hydrogenated vegetable oil and/or polyethylene glycols.

Amount "% wt." of a particular component (including active substances or excipients) used herein refers to the percentage by weight of the component relative to the total weight of the solid pharmaceutical composition (the weight of the compound of formula I and the compound of formula II is calculated in free base form). The total weight of the solid pharmaceutical composition does not include the weight of coating agents.

The preparation of solid pharmaceutical compositions or corresponding dosage forms disclosed herein can be accomplished in accordance with methods well known in the art. Specifically, the production method may include the procedures of grinding, mixing, sieving, granulating, filling, tableting, and so on. The necessary steps and method or apparatus for carrying out specific procedures are selected based on expediency. For example, the grinding procedure can be carried out by means of a mortar, ball mill, roller press, impact mill, hammer mill and/or jet mill; the mixing procedure may be mixing with a stirrer, mixing with grinding and/or mixing with a sieve; the sifting procedure can be carried out using a shaker with a sieve and/or a vibrating sieve; or with reference to Pharmacy (6th or 7th Edition, People's Medical Publishing House), edited by Cui Fude et al.

The term "or a mixture thereof" means a mixture of two or more, for example, "a diluent selected from the group consisting of microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch and dextrin or a mixture thereof" means that the diluent is selected from the group consisting from microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch and dextrin or a mixture of two or more.

The term "claimed amount" in the field of pharmaceutical compositions refers to the content of a specific active substance in a unit dose of the composition.

The compound of formula I and the compound of formula II disclosed herein can be prepared with reference to the production methods in WO 2016095805 or WO 2017215627.

DETAILED DESCRIPTION

The present invention will be illustrated in more detail by means of specific examples. The following examples are offered for illustration purposes only and are not intended to limit the present invention in any way.

Example 1 (3R)-3-{3-amino-4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}-1H-pyrazol-1-yl}-3-cyclopentylpropionitrile (II)

The title compound was obtained with reference to WO 2016095805 or WO 2017215627.

Example 2 Tablets of the solid pharmaceutical composition (3R)-3-{3-amino-4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}-1H-pyrazol-1-yl}-3-cyclopentylpropionitrile ( II)

The compositions of 5 mg tablets and 20 mg solid pharmaceutical composition are shown in Table 1:

Procedures:

1) Mannitol, microcrystalline cellulose and croscarmellose sodium were mixed to obtain mixture A for further use;

Preparation of drug suspension: hydroxypropylcellulose was dissolved in purified water to obtain a 4% (w/w) hydroxypropylcellulose solution; dissolved sodium dodecyl sulfate; a compound of formula II was added and dispersed by stirring to obtain a drug suspension;

2) Fluidized bed granulation and drying: The drug suspension was applied to mixture A by spraying for fluidized bed granulation. Granulation parameters: inlet air temperature: 55-80°C, spray pressure: 600-1000 mbar (6-10×10 ⁴ Pa), substance temperature: 25-35°C. Drying began after spraying and ended when the temperature of the substance was above 45°C. The substance was calibrated in a mill through a sieve with a mesh size of Φ 0.6-1.2 mm and dried granules were obtained;

3) The dried granules and magnesium stearate were sequentially fed into a hopper mixer and mixed well to obtain a solid pharmaceutical composition for tabletting.

Example 3 Preparation of solid pharmaceutical compositions with compositions A-I

Solid pharmaceutical compositions with compositions A-I were prepared as 5 mg tablets with reference to the method of Example 2. The specific compositions were as follows:

Example 4. Study of the stability of solid pharmaceutical compositions

The stability of solid pharmaceutical compositions with the compositions disclosed above was examined according to the Guidelines for Stability Testing of Active Pharmaceutical Ingredients and Drugs, China. The 5 mg tablets and 20 mg solid pharmaceutical composition obtained in Example 2 were placed in an open state under illumination (6000 lux) and at high temperature (60° C.) and high humidity (RH75%). A suitable amount of sample was added to a water-acetonitrile (30:70) mixture to obtain a test solution containing approximately 0.5 mg of test sample per ml; octadecylsilane, chemically bonded to silica gel, was used as a filler; performed a linear gradient elution using a mixture of potassium dihydrogen phosphate buffer-acetonitrile (90:10) and acetonitrile as mobile phase A and mobile phase B, respectively; the flow rate was 1.0 ml per minute; detection wavelength was 220 nm; the column temperature was 30°C. The total impurity content was analyzed and the results were as follows:

Example 5: Investigation of dissolution properties

The dissolution characteristics of solid pharmaceutical compositions with the above compositions were examined in four media according to the second method for dissolution and release testing of Chapter 0931 of the Chinese Pharmacopoeia (Volume IV, 2015 Edition). The four media were hydrochloric acid solution (pH 1.0), acetate buffer (pH 4.5), phosphate buffer (pH 6.8) and purified water, respectively, with a volume of 900 ml. A control solution containing approximately 5.6 μg of compound of formula II per ml was prepared. The method and conditions were: paddle stirrer method, rotation speed: 50 rpm, medium temperature: 37°C ± 0.5°C, sampling time points: 5 min, 10 min, 15 min, 20 min, 30 min and 45 min. Octadecylsilane, chemically bonded to silica gel, was used as a filler; a mixture of potassium dihydrogen phosphate buffer and acetonitrile (70:30) was used as the mobile phase; the flow rate was 0.4 ml per minute; detection wavelength was 220 nm; the column temperature was 30°C. The results were as follows:

Example 6 Dosage and Compound

6.1 Mode

The drug used was the 5 mg tablet from Example 2.

Administration: oral administration on an empty stomach, once daily during preliminary testing. Consistently, for treatment groups, drug was administered orally every 12 hours, and subjects were fasted for 2 hours after administration. Treatment was provided over a 28-day cycle.

Eligible subjects should receive treatment for at least 1 cycle and be monitored for tolerability and monitored for preliminary efficacy. For subjects with investigator-assessed clinical benefit who agree to continue investigational treatment, treatment must be continued without charge until the disease progresses or the investigator determines that continuation of investigational treatment is not appropriate. Once eligibility was complete, the study was closed when subjects had received treatment for 6 consecutive cycles.

6.2 Selection criteria

1) Age at least 18 years; ECOG score: 0-2; expected survival more than 3 months;

2) Diagnosed with PMF, PV, ET, PPV-MF or PET-MF according to the PMF, PV and ET criteria published by the World Health Organization (WHO) in 2016, and the PPV-MF and PET-MF criteria recommended by the International Research Working Group and treatment of myeloproliferative neoplasms (IWG-MRT);

3) Subjects with intermediate-risk myelofibrosis-1 or the above patients on treatment according to the Dynamic International Prognosis Score (DIPSS).

4) Subjects with PV or ET, resistant or not resistant to hydroxyurea and/or interferons;

5) The results of basic hematological laboratory tests meet the following criteria:

Platelet count (PLT) > 100 × 10 ⁹ /L;

Absolute neutrophil count (ANC) > 1.5 × 10%;

Hemoglobin (Hgb) concentration > 75 g/L (without infusion of blood products such as whole blood suspensions, red blood cells, or the like, within four weeks);

6) The most prominent part of the subject's spleen is ≥ 5 cm from the lower edge

ribs;

7) Bone marrow government cells and peripheral blood blast cells <20%;

8) The results of basic laboratory tests of the liver and kidneys meet the following criteria:

Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 2.5 × upper limit of normal (ULN);

Serum creatinine ≤ 2.0 mg/dL (176.82 µmol/L);

Direct bilirubin ≤ 2 × ULN;

9) The results of the basic laboratory coagulation test meet the following criteria:

Prothrombin time (PT) or thrombin time (TT) is within the normal range of ±3 s;

Activated partial thromboplastin time (ARTTT) is within the normal range of ±10 s;

10) 2 weeks or more since other MPN treatment; 4 weeks or more since MPN surgery;

11) Female subjects must agree to take contraceptive measures (such as intrauterine devices, contraceptives, or condoms) throughout the study and for at least 6 months after the study; serologic pregnancy test results must be negative within 7 days prior to the study, and subjects must not be breastfeeding; male subjects must agree to use contraception throughout the study and for at least 6 months after the study;

12) Voluntary participation.

6.3 Exclusion criteria

Subjects who meet any of the following points will not be included in the study:

1) The presence of other malignant tumors within 5 years, with the exception of cured non-melanocytic tumor, skin cancer and carcinoma in situ;

2) Participation in clinical trials of other drugs within four weeks;

3) Factors affecting oral administration (such as swallowing disorder, gastrointestinal resection, chronic diarrhea and intestinal obstruction, and so on);

4) History of misuse of psychotropic drugs and difficulties in rehabilitation or presence of mental disorders;

5) Positive for HBsAg (hepatitis B virus surface antigen); positive for HBcAb (hepatitis B virus capsid antigen antibody) and having an HBV (hepatitis B virus) DNA test result ≥ ULN; positive for antibodies to HCV (hepatitis C virus); positive for antibodies to HIV (human immunodeficiency virus);

6) Immunodeficiency (acquired or congenital immunodeficiency diseases, or a history of organ transplantation);

7) In the presence of arterial/venous thrombosis events within 4 weeks, such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis and pulmonary embolism;

8) Receiving long-term (≥3 days) high-dose (≥10 mg prednisone equivalent dose) glucocorticoid or other immunosuppressive therapy within 28 days before the screening visit or increasing the dose;

9) Systemic active infections such as bacterial, fungal, parasitic or viral infections that require treatment and are of clinical significance. For those requiring antibiotics to treat acute bacterial infections, screening/selection should be delayed until antibiotic treatment is completed;

10) Significant cardiovascular disease, such as heart failure increasing to New York Heart Association (NYHA) score 2 or higher, unstable angina, myocardial ischemia or myocardial infarction within the last 3 months, arrhythmia (for women QTc > 470 ms , for men QTc > 450 ms) and heart failure stage I;

11) Hypertension (systolic blood pressure>150 mm Hg, diastolic blood pressure ≥ 100 mm Hg), which cannot be controlled with medication;

12) Other comorbidities that seriously affect the safety of the subject, or completion of the study, at the discretion of the investigator.

6.4 Blood sampling schedule

Blood samples were collected via a catheter in the upper limb vein of the subjects, and approximately 3 ml of venous blood was collected at each time point. Blood samples were collected into pre-treated blood collection tubes with sodium heparin to inhibit coagulation (no more than 0.5 h at room temperature), centrifuged at 4°C for 10 min (2500 g), separated to obtain plasma and stored at - 80°C for testing (at room temperature for no more than 2 hours).

6.5 Observations

Starting from the second cycle of continuous treatment:

1) A comprehensive physical examination was performed at each visit: weight, vital signs, physical examination of various organs;

2) Various clinical manifestations, symptoms and signs (including liver enlargement and spleen enlargement) were observed throughout the treatment period, and the subjects' comprehensive symptom tolerance was measured according to the Myeloproliferative Tumor General Symptom Rating Scale every 3 cycles;

3) At the end of the second cycle, MRI (magnetic resonance imaging) of the spleen was performed every 3 cycles starting from the third cycle, and if removed early.

4) At the end of the second cycle, every 3 cycles, starting from the third cycle, and in case of early removal, a bone marrow puncture smear and determination of the leukocyte formula of a peripheral blood smear were performed;

5) At the end of the second cycle, every 3 cycles starting from the third cycle, and in case of early removal, a bone marrow biopsy was performed for pathological cytological analysis and (silverophil) staining of the reticular fibers.

6.6 Results and evaluation

Claims (54)

1. Use of a compound of formula II or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a myeloproliferative neoplasm: 2. Solid pharmaceutical composition for the treatment of myeloproliferative neoplasm, containing a compound of formula II or a pharmaceutically acceptable salt thereof, and a diluent, a binder, a wetting agent and a disintegrant where the amount of compound of formula II is selected from 1-30% by weight, wherein the diluent is selected from the group consisting of microcrystalline cellulose, mannitol, lactose and pregelatinized starch or a mixture thereof, and the amount of diluent is selected from 50-95% by weight, wherein the binder is selected from the group consisting of hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose and polyvinylpyrrolidone or a mixture thereof, and the amount of binder is selected from 1.0-10% by weight, wherein the wetting agent is selected from the group consisting of sodium dodecyl sulfonate, magnesium dodecyl sulfonate, sodium tetradecyl sulfonate, sodium dodecyl sulfate, magnesium dodecyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate and sodium lauroyl sarcosine, and the amount of the wetting agent is selected from 0.01-5.0% mass., where the baking powder is chosen from a group consisting of sodium carboxymethyl starch, dry starch, microcrystalline cellulose, hydroxyethyl methyl cellulose, sodium carboxymethylolosis, calcium carboxymethyls, sodium cross -laid -established hydroxypropyllose or corpovidone, pre -dezylolis. sodium sulfate and magnesium milk sulfate or their mixture, and the amount of baking powder is chosen from 1.0 -7.0% wt. 3. Solid pharmaceutical composition according to claim 2, where the amount of the compound of formula II is selected from 1-25 wt%, 1-20 wt%, 2-20 wt%, 2-15 wt%, 2-10 wt%. ., 3-10% wt. or 2-8% wt., preferably 3-8% wt. and more preferably 3.5-6% wt. 4. Solid pharmaceutical composition according to claim 2 or 3, where the diluent is selected from the group consisting of microcrystalline cellulose and mannitol or a mixture thereof; and/or the amount of diluent is selected from 60-95 wt%, 65-95 wt%, 70-95 wt%, 75-95 wt%, 80-95 wt%, 80-90 wt%. or 85-95% by weight, preferably 85-90% by weight; or wherein the diluent is a mixture of microcrystalline cellulose and mannitol, wherein the weight ratio of microcrystalline cellulose to mannitol is selected from 1:1 to 5:1, preferably 1:1 to 4:1, 1.2:1 to 3.5:1 or 1.2:1 to 3:1, more preferably 1.5:1 to 2.5:1. 5. Solid pharmaceutical composition according to any one of paragraphs. 2-4, where the binder is selected from the group consisting of hydroxypropylcellulose and polyvinylpyrrolidone or a mixture thereof; and/or the amount of binder is selected from 1.0-8.0% wt., 1.0-6.0% wt. or 1.0-5.0% wt., more preferably 2.0-40% wt. 6. Solid pharmaceutical composition according to any one of paragraphs. 2-5, where the wetting agent is selected from the group consisting of sodium dodecyl sulfate and magnesium dodecyl sulfate or a mixture thereof; and/or the amount of wetting agent is selected from 0.01-4.0% wt., 0.01-3.0% wt., 0.02-2.5% wt. or 0.02-2.0% wt., preferably 0.03-2.0% wt., more preferably 0.05-1.0% wt., even more preferably 0.1-0.5% wt. 7. Solid pharmaceutical composition according to any one of paragraphs. 2-6, where the disintegrant is selected from the group consisting of sodium carboxymethyl starch and croscarmellose sodium or a mixture thereof; and/or the amount of leavening agent is selected from 1.0-6.5 wt%, 1.0-6.0 wt%, 1.5-5.5 wt%, 1.5-5.0 wt%. or 1.5-4.5% wt., more preferably 2.0-4.0% wt. 8. Solid pharmaceutical composition according to any one of paragraphs. 2-7, further containing a lubricant that is selected from the group consisting of magnesium stearate, colloidal silicon dioxide, talc, polyethylene glycol 4000, polyethylene glycol 6000, stearic acid, sodium stearyl fumarate and sodium dodecyl sulfate or a mixture thereof, preferably magnesium stearate and colloidal silicon dioxide or mixtures thereof; and/or the amount of lubricant is selected from 0.1-3% wt., preferably 0.2-2.5% wt., 0.3-2.0% wt. or 0.4-1.5% wt., more preferably 0.5-1% wt. 9. Solid pharmaceutical composition according to any one of paragraphs. 2-8, containing: 1-30% wt. compounds of formula II; 50-95% wt. microcrystalline cellulose, mannitol, lactose or pregelatinized starch or a mixture thereof; 1.0-10% wt. hydroxypropyl methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropylcellulose, L-HPC (low-substituted hydroxypropylcellulose) or polyvinylpyrrolidone or mixtures thereof; 0.01-5.0% wt. sodium dodecyl sulfonate, magnesium dodecyl sulfonate, sodium tetradecyl sulfonate, sodium dodecyl sulfate, magnesium dodecyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate or sodium lauroyl sarcosine or mixtures thereof; 1.0-7.0% wt. sodium carboxymethyl starch or croscarmellose sodium or mixtures thereof; And perhaps 0.1-3% wt. magnesium stearate or colloidal silicon dioxide or mixtures thereof; or 2-10% wt. compounds of formula II; 75-95% wt. microcrystalline cellulose or mannitol or a mixture thereof, where the weight ratio of microcrystalline cellulose to mannitol in the mixture is selected from 1.2:1 to 3.5:1; 1.0-6.0% wt. hydroxypropylcellulose or polyvinylpyrrolidone or mixtures thereof; 0.01-3.0% wt. sodium dodecyl sulfonate, magnesium dodecyl sulfonate, sodium tetradecyl sulfonate, sodium dodecyl sulfate, magnesium dodecyl sulfate, sodium tetradecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate or sodium lauroyl sarcosine or mixtures thereof; 1.0-6.0% wt. sodium carboxymethyl starch or croscarmellose sodium or mixtures thereof; And possibly 0.3-2.0% wt. magnesium stearate or colloidal silicon dioxide or mixtures thereof. 10. Solid pharmaceutical composition according to any one of paragraphs. 2-9, containing: 3.4-4.6% wt. compounds of formula II; 55-60% wt. microcrystalline cellulose; 26-32% wt. mannitol; 2.0-4.0% wt. hydroxypropylcellulose; 0.1-0.5% wt. sodium dodecyl sulfate; 2.0-4.0% wt. croscarmellose sodium; And perhaps 0.5-1% wt. magnesium stearate; or 4.2% wt. compounds of formula II; 58.3% wt. microcrystalline cellulose; 29.4% wt. mannitol; 4.0% wt. hydroxypropylcellulose; 0.1% wt. sodium dodecyl sulfate; 3.0% wt. croscarmellose sodium; And possibly 1.0% wt. Magnesium stearate. 11. Solid pharmaceutical composition according to any one of paragraphs. 2-10, wherein the dosage form of the solid pharmaceutical composition is selected from tablets and capsules. 12. Use of a solid pharmaceutical composition according to any one of paragraphs. 2-11 in obtaining a drug for the treatment of myeloproliferative neoplasm. 13. Use according to claim 1 or 12, wherein the myeloproliferative neoplasm is selected from polycythemia vera, thrombocythemia and myelofibrosis. 14. Application according to any one of paragraphs. 1, 12 and 13, where the daily dose is from 1 mg to 100 mg; preferably the daily dose may be selected from the group consisting of 1 mg, 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 and 100 mg, or any range defined by the endpoints of any of the values listed above, or any value within the range specified. 15. Application according to any one of paragraphs. 1 and 12-14, where one or more doses are administered daily, possibly in a single dose; preferably the unit dosage form is administered once or twice daily.