CN117412962A

CN117412962A - Methods of treating disorders with phthalazinone derivatives

Info

Publication number: CN117412962A
Application number: CN202280039501.3A
Authority: CN
Inventors: 李原植; 鲁珢振; 李铭宰; 洪民主; 宋昇姬
Original assignee: Edith Inc
Current assignee: Edith Inc
Priority date: 2021-06-02
Filing date: 2022-06-02
Publication date: 2024-01-16

Abstract

The present invention relates to methods of treating a condition (e.g., breast, ovarian or pancreatic cancer) with a derivative having a poly (ADP-ribose) polymerase inhibitor or a pharmaceutical composition thereof.

Description

Methods of treating disorders with phthalazinone derivatives

RELATED APPLICATIONS

The present application claims the benefit and priority of U.S. S. N.63/196,036 filed on month 2 of 2021 and U.S. S. N.63/331,371 filed on month 4 of 2022, the respective contents of which are incorporated herein by reference in their entirety.

Technical Field

The present invention relates to compounds and compositions comprising phthalazinone derivatives capable of inhibiting poly (ADP-ribose) polymerase activity and methods of use thereof.

Background

The poly (ADP-ribose) polymerase (PARP) family has many fundamental functions in cellular processes, including regulation of transcription, apoptosis, and DNA damage reactions. PARP inhibitors target the enzyme Poly ADP Ribose Polymerase (PARP) and are being studied in several types of malignancies. PARP is a protein involved in repairing single-strand breaks in DNA, and inhibitors of this enzyme prevent DNA repair and allow accumulation of single-strand breaks. During DNA replication, these single strand breaks result in double strand breaks when the DNA helices unwind.

Patients with tumors that have mutations in certain homologous recombination repair enzymes (e.g., mutations in BRCA1, BRCA2, and PALB 2) are unable to repair these double strand breaks, thereby allowing the affected cells to enter apoptosis. PARP inhibitors are most promising in the treatment of many types of cancers that have relatively high rates of these types of mutations in homologous recombination repair enzymes in these malignancies. In particular, PARP inhibitors have become the mainstay for the treatment of patients with BRCA mutant breast cancer and ovarian cancer, given the limited options of treatment for diseases, including endocrine therapy and chemotherapy, which are beneficial treatments for patients with BRCA mutant breast cancer. Thus, a safe and effective PARP inhibitor is a promising solution for the unmet medical need for anticancer agents.

Disclosure of Invention

The invention provides phthalazinone derivatives and compositions comprising such compounds, and methods of using such compounds and compositions in the treatment of conditions, such as cancer (such as ovarian, breast and pancreatic cancer). Each of these different aspects may be more particularly described by the various embodiments described in this application, which may be equally applicable to the different aspects.

In one aspect, provided herein is a method of treating cancer having a BRCA1 mutation, a BRCA2 mutation, an ATM mutation, or a homologous recombination repair mutation in a subject in need thereof, comprising administering to the subject about 2mg to about 300mg of a compound of formula 1

Or a pharmaceutically acceptable salt thereof.

In one aspect, provided herein is a method of treating cancer having a BRCA1 mutation, a BRCA2 mutation, an ATM mutation, or a homologous recombination repair mutation in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising:

(i) About 2mg to about 300mg of a compound of formula I:

or a pharmaceutically acceptable salt thereof; a kind of electronic device with high-pressure air-conditioning system

(ii) At least one pharmaceutically acceptable excipient.

In another aspect, provided herein is a method of obtaining a clinical benefit in a subject having ovarian cancer, comprising administering to the subject from about 2mg to about 300mg of a compound of formula I:

or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a method of obtaining clinical benefit in a subject having breast cancer comprising administering to the subject from about 2mg to about 300mg of a compound of formula I:

or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein is a method of obtaining a clinical benefit in a subject having pancreatic cancer comprising administering to the subject from about 2mg to about 300mg of a compound of formula I:

or a pharmaceutically acceptable salt thereof.

Brief description of the drawings

Fig. 1 illustrates an exemplary phase 1 clinical trial study design for treating a subject with an advanced cancerous solid tumor.

Figure 2 illustrates the pharmacodynamics of the compound of formula 1.

Figure 3 illustrates objective response rates for a range of concentrations of the compound of formula 1 used in phase 1 clinical trials.

Figure 4 illustrates the clinical benefit rates of a range of concentrations of the compound of formula 1 for use in phase 1 clinical trials.

Figure 5 illustrates the results of different concentrations of the compound of formula 1 for patients with BRCA mutant breast or ovarian cancer in phase 1 clinical trials.

Figure 6 illustrates the results of different concentrations of the compound of formula 1 for patients with BRCA wild-type breast cancer, ovarian cancer or other cancers in phase 1 clinical trials.

Figure 7 illustrates an exemplary phase 1b/2a clinical trial study design for treating a subject having cancer, such as breast, ovarian or pancreatic cancer, with compound 1.

Figure 8 illustrates a waterfall plot of the change in tumor size in ovarian cancer patients receiving a specific dose of a compound of formula 1, wherein the tumor under study has a specific BRCA1 or BRCA2 mutation.

Fig. 9 illustrates a waterfall plot of the change in tumor size in pancreatic cancer patients receiving a specific dose of a compound of formula 1, wherein the tumor under study has a specific BRCA2 or ATM mutation.

Figure 10 illustrates a waterfall plot of the change in tumor size in platinum-group-resistant ovarian cancer patients receiving a specific dose of a compound of formula 1, wherein the tumor under study has a specific BRCA2 mutation.

Detailed Description

The present invention provides a method of treating a disorder (e.g., cancer having a BRCA1 mutation, a BRCA2 mutation, an ATM mutation, or a homologous recombination repair mutation) in a subject in need thereof. Examples of cancers with such mutations include, but are not limited to, breast cancer, ovarian cancer, small cell lung cancer, biliary tract cancer, urothelial cancer, and pancreatic cancer. Examples of other homologous recombination repair mutations include, but are not limited to, the following: PALB2, XRCC1, CTPS, RPA, RPA1, RPA2, RPA3, XPD, ERCC1, XPF, MMS19, RAD51B, RAD51C, RAD D, DMC1, XRCC2, XRCC3, RAD52, RAD54, RAD50, MRE11, NBS1, WRN, BLM, ku70, ku80, ATR, chk1, chk2, FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, RAD1, RAD9, FEN-1, mus81, eme1, DDS1, and BARD. Preferably, the method comprises administering the active ingredient of formula 1 in an amount of about 2mg to about 300 mg. The present invention also provides methods comprising administering a pharmaceutical composition comprising a compound of formula 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In accordance with the present invention, the pharmaceutical composition preferably has a pH of about 2.6 to about 6.74 when measured in a 1% (w/v) aqueous suspension.

As provided in more detail in the examples, the experimental results show that the compound of formula I as described herein (i.e. compound 1) demonstrates anti-cancer activity in a subject suffering from cancer, which may have certain mutations, such as BRCA1, BRCA2, ATM or homologous recombination repair mutations. In particular, the compounds of formula 1 as described herein demonstrate anti-cancer activity in subjects suffering from breast, ovarian or pancreatic cancer.

I. Methods of use and methods of treatment

The methods of the present invention include the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I described herein, for providing clinical benefits including, but not limited to, preventing, treating, or ameliorating a disease, disorder, or condition. In certain embodiments, the disease is ovarian cancer with a BRCA1 mutation, a BRCA2 mutation, an ATM mutation, or a homologous recombination repair mutation. In certain embodiments, the disease is breast cancer with BRCA1 mutations, BRCA2 mutations, ATM or homologous recombination repair mutations. In some embodiments, the cancer is platinum-resistant ovarian cancer. In certain embodiments, the disease is cancer having homologous recombination repair mutations. In some embodiments, the disease is pancreatic cancer with BRCA1 mutations, BRCA2 mutations, ATM or homologous recombination repair mutations. In some embodiments, the disease is a cancer having BRCA1 mutations. In some embodiments, the disease is a cancer having BRCA2 mutations. In some embodiments, the disease is cancer with mutations in ATM. In some embodiments, the disease is cancer having homologous recombination repair mutations.

In one embodiment, provided herein is a method of treating cancer having a BRCA1 mutation, a BRCA2 mutation, an ATM mutation, or a homologous recombination repair mutation in a subject in need thereof, comprising administering to the subject about 2mg to about 300mg of a compound of formula 1

Or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating cancer having a BRCA1 mutation, a BRCA2 mutation, an ATM mutation, or a homologous recombination repair mutation in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising:

(i) About 2mg to about 300mg of a compound of formula I:

(ii) At least one pharmaceutically acceptable excipient.

In various embodiments, a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, is administered once, twice, three times, four times, or five times daily. In certain embodiments, the pharmaceutical composition is administered once daily. In certain embodiments, the pharmaceutical composition is administered twice daily.

In another embodiment, provided herein is a method of treating cancer having a BRCA1 mutation, a BRCA2 mutation homologous recombination repair mutation in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising as an active ingredient a compound of formula 1 or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient, wherein the pH of the composition, measured in a 1% w/v aqueous suspension, is from about 2.6 to about 6.74:

In another embodiment, provided herein is a method of treating cancer having a BRCA1 mutation, a BRCA2 mutation, an ATM mutation, or a homologous recombination repair mutation in a subject in need thereof, comprising administering to the subject a solid oral dosage form comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient; and at least one excipient selected from the group consisting of: diluents, binders, disintegrants, lubricants, and any combination thereof.

In another aspect, provided herein is a method of treating cancer having a BRCA1 mutation, a BRCA2 mutation, an ATM mutation, or a homologous recombination repair mutation in a subject in need thereof, comprising administering to the subject a stable solid oral dosage form comprising as an active ingredient a compound of formula 1 or a pharmaceutically acceptable salt thereof; wherein the oral dosage form maintains at least 99% by weight of the compound of formula I after storage at 75% relative humidity for at least 1 month at 20 ℃):

in any of the methods of the present application, the cancer is ovarian, breast or pancreatic cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is platinum-resistant ovarian cancer.

In any of the methods herein, the method comprises administering to the subject about 2mg, 5mg, 10mg, 20mg, 40mg, 80mg, 120mg, 160mg, or 240mg of the compound or a pharmaceutically acceptable salt thereof, preferably about 40mg, 80mg, 120mg, 160mg, or 240mg of the compound or a pharmaceutically acceptable salt thereof, and most preferably about 80mg of the compound or a pharmaceutically acceptable salt thereof. In certain embodiments, comprising administering to the subject about 160mg or about 240mg of the compound or a pharmaceutically acceptable salt thereof.

In some embodiments, the methods described herein comprise administering about 40mg of a compound or pharmaceutically acceptable salt thereof to a subject. In some embodiments, the methods described herein comprise administering about 80mg of a compound or pharmaceutically acceptable salt thereof to a subject. In some embodiments, the methods described herein comprise administering about 120mg of a compound or pharmaceutically acceptable salt thereof to a subject.

In some embodiments, the active ingredient is the hydrochloride salt of the compound of formula 1. In some embodiments, the pharmaceutically acceptable excipient is a diluent, binder, disintegrant, lubricant, or any combination thereof.

In certain embodiments, the composition comprises from about 40 to about 90wt% diluent, based on the total weight of the composition; about 0.1 to about 30wt% of a binder, based on the total weight of the composition; about 1 to about 40wt% of a disintegrant, based on the total weight of the composition; and from about 0.5 to about 40wt% of a lubricant, based on the total weight of the composition.

In certain embodiments, the diluent is selected from the group consisting of: hydrated lactose, anhydrous lactose, mannitol, sorbitol, microcrystalline cellulose, hydrated dibasic calcium phosphate, or any combination thereof; the binder is selected from the group consisting of: hydroxypropyl cellulose (HPC), povidone, or any combination thereof; the disintegrant is selected from the group consisting of: carboxymethyl cellulose, crospovidone, croscarmellose sodium, sodium starch glycolate, carboxymethyl cellulose (CMC), CMC-Ca, low-substituted hydroxypropyl cellulose, corn starch, and potassium polacrilin, or any combination thereof; and the lubricant is selected from the group consisting of: colloidal silica, magnesium stearate, sodium stearyl fumarate, talc, stearic acid or any combination thereof. In some embodiments, the diluent is selected from the group consisting of: hydrated lactose, anhydrous lactose, and microcrystalline cellulose. In some embodiments, the diluent is lactose hydrate. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the binder is hydroxypropyl cellulose. In some embodiments, the binder is povidone.

In some embodiments, the disintegrant is selected from the group consisting of: low substituted hydroxypropyl cellulose, corn starch, potassium polycosanol and carboxymethyl cellulose. In some embodiments, the disintegrant is carboxymethylcellulose. In some embodiments, the lubricant is selected from the group consisting of colloidal silica and magnesium stearate.

In some embodiments, the pharmaceutical composition further comprises a pH controlling agent. In some embodiments, the pH control agent has a pH of about 1 to about 5. In some embodiments, the pH control agent is selected from the group consisting of: citric acid, fumaric acid, maleic acid, or any combination thereof. In some embodiments, the pH controlling agent is fumaric acid. In some embodiments, the pharmaceutical composition further comprises a superdisintegrant. In some embodiments, the composition comprises from about 0.01 to about 20wt% super-disintegrant, based on the total weight of the composition. In embodiments, the superdisintegrant is selected from the group consisting of: crospovidone, croscarmellose sodium, sodium starch glycolate, or any combination thereof.

In certain embodiments, the composition comprises from about 10mg to about 240mg of active ingredient per unit dose. In certain embodiments, the composition comprises about 80mg of active ingredient per unit dose.

In certain embodiments, the composition is in solid form. In embodiments, the solid form is selected from the group consisting of: tablets, wet granules, dry granules, microparticles or capsules. In embodiments, the solid form is a tablet. In embodiments, the solid form is a film coated tablet. In embodiments, the solid form is an enteric coated tablet. In embodiments, the composition comprises 0.50wt% or less of impurities of the active ingredient after storage for 1 month at 20 ℃ and 75% relative humidity.

In certain embodiments, the solid dosage form is a tablet. In some embodiments, the compound is present in a solid oral dosage form about 3 months after formulation of the solid oral dosage form. In some embodiments, the solid oral dosage form comprises a diluent, a binder, a disintegrant, and a lubricant. In some embodiments, the solid oral dosage form comprises from about 40 to about 90wt% diluent, based on the total weight of the solid oral dosage form; about 0.1 to about 30wt% of a binder, based on the total weight of the solid oral dosage form; about 1 to about 40 weight percent of a disintegrant, based on the total weight of the solid oral dosage form; and from about 0.5 to about 40wt% of a lubricant, based on the total weight of the solid oral dosage form.

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the ovarian cancer is platinum-resistant ovarian cancer.

or a pharmaceutically acceptable salt thereof.

In one embodiment, provided herein are compounds of formula I

Or a pharmaceutically acceptable salt thereof, for use in treating cancer having a BRCA1 mutation, a BRCA2 mutation, an ATM mutation, or a homologous recombination repair mutation in a subject, wherein the use comprises administering from about 2mg to about 300mg of the compound to the subject once daily.

In one embodiment, provided herein are compounds of formula I

Or a pharmaceutically acceptable salt thereof, for use in treating cancer having a BRCA1 mutation, a BRCA2 mutation, an ATM mutation, or a homologous recombination repair mutation in a subject, wherein the use comprises administering from about 2mg to about 300mg of the compound to the subject twice daily.

In any of the above methods, the cancer is ovarian cancer, breast cancer or pancreatic cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is platinum-resistant ovarian cancer.

In any of the above methods, the method comprises administering to the subject about 2mg, 5mg, 10mg, 20mg, 40mg, 80mg, 120mg, 160mg, or 240mg of the compound or a pharmaceutically acceptable salt thereof, preferably about 40mg, 80mg, 120mg, 160mg, or 240mg of the compound or a pharmaceutically acceptable salt thereof, and most preferably about 80mg of the compound or a pharmaceutically acceptable salt thereof. In certain embodiments, comprising administering to the subject about 160mg or about 240mg of the compound or a pharmaceutically acceptable salt thereof.

In various embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered once, twice, three times, four times, or five times daily. In certain embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered once daily. In certain embodiments, the compound of formula I, or a pharmaceutically acceptable salt thereof, is administered twice daily.

II compounds

The methods of the invention include providing a clinical benefit in a subject in need thereof, preventing and/or treating a disease, disorder or condition (e.g., a disease, disorder or condition associated with ovarian, breast or pancreatic cancer, e.g., having a BRCA1 mutation, BRCA2 mutation, ATM mutation, or homologous recombination repair mutation), comprising administering a compound (e.g., a compound of formula 1) to the subject.

In certain embodiments, the compound is a compound of formula 1:

or a pharmaceutically acceptable salt thereof.

The compound of formula 1 has IUPAC (international union of pure and applied chemistry) nomenclature, 4- [3- (3- [ (cyclopropylamino) methyl ] azetidine-1-carbonyl) -4-fluorobenzyl ] phthalazin-1 (2H) -one. Formula 1 or a pharmaceutically acceptable salt thereof may be obtained by following any method known to one of ordinary skill in the art. Suitable methods of preparation are disclosed, for example, in U.S. patent No. 9,682,973, which is incorporated by reference herein in its entirety.

Crystalline forms of phthalazinone compounds are also disclosed in U.S. patent application Ser. No. 16/858,158, 24, 2020, which is incorporated herein by reference in its entirety.

In some embodiments, the hydrochloride salt of formula 1 is in a crystalline form that exhibits an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ±0.2° of 13.7 °, 15.9 ° and 24.1 ° (hereinafter referred to as "crystalline form a"). In some embodiments, the XRPD pattern that crystalline form a may exhibit comprises peaks at three or more, and preferably four or more 2θ±0.2° values selected from the group consisting of: 9.1 °, 11.9 °, 13.2 °, 13.7 °, 15.9 °, 16.8 °, 18.1 °, 23.2 °, 24.1 °, 25.5 °, and 26.6 °. In particular, crystalline form a may exhibit XRPD patterns comprising peaks at 2θ±0.2° values of 9.1 °, 13.2 °, 13.7 °, 15.9 °, 16.8 °, 24.1 ° and 26.6 °. More particularly, crystalline form a may exhibit XRPD patterns comprising peaks at 2θ±0.2° values of 9.1 °, 11.9 °, 13.2 °, 13.7 °, 15.9 °, 16.8 °, 18.1 °, 23.2 °, 24.1 °, 25.5 ° and 26.6 °. XRPD patterns may be obtained using any method known to those skilled in the art, including by irradiation with a Cu-ka light source, e.g., a D8 Advance (Bruker ASX, germany) analyzer. The Cu-K alpha light source may have Is a wavelength of (c).

III dosage forms and compositions

In one aspect, the invention provides dosage forms or compositions suitable for providing clinical benefits including, but not limited to, preventing and/or treating a disease, disorder, or condition described herein (e.g., ovarian, breast, or pancreatic cancer with BRCA1 mutation, BRCA2 mutation, ATM mutation, or homologous recombination repair mutation) in a subject in need thereof, comprising administering a compound (e.g., a compound of formula 1) to the subject.

The present invention provides pharmaceutical compositions containing a compound described herein (e.g., compound 1) or a pharmaceutically acceptable salt thereof as an active ingredient and one or more pharmaceutically acceptable excipients including, but not limited to, any one or more of the following: carrier, diluent, binder, disintegrant and lubricant. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents.

The pharmaceutical composition of the present invention may comprise from about 0.1 to about 70wt% and preferably from about 1 to 40wt% of compound 1 or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. The pharmaceutical composition of the present invention comprises, in total, from about 1 to about 400mg, and preferably from about 2 to about 240mg, of compound 1 or a pharmaceutically acceptable salt thereof per unit dose. Other embodiments of the pharmaceutical composition comprise 2mg, 5mg, 10mg, 20mg, 40mg, 80mg, 120mg, 160mg or 240mg of compound 1 or a pharmaceutically acceptable salt thereof. The amounts mentioned are based on the free base form of compound 1.

In one embodiment, the composition of the invention has a preferred threshold of total impurities in the pharmaceutical composition after stability testing. The pharmaceutical composition of the present invention has a total impurity content of 1.50% or less, preferably 1.0% or less, more preferably 0.80% or less and still more preferably 0.40% or less, as measured by HPLC, by total weight of the pharmaceutical composition after storage at a temperature of 25 ℃ to 70 ℃ (e.g., 25 ℃, 40 ℃, 50 ℃,60 ℃ or 70 ℃) and a Relative Humidity (RH) of 60% to 75% (e.g., 60% or 75%) for about 1 week to 12 months (e.g., 1 week, 2 weeks, 4 weeks, 1 month, 3 months, 6 months or 12 months). For example, the total impurity content of the active ingredient may be 1.0% or less after storage of the composition of the present invention at 50 ℃ and 75% relative humidity for 1 month.

In another embodiment, the compositions of the invention have a preferred threshold of M1 impurities in the pharmaceutical composition after stability testing. The content of M1 impurity of the active ingredient measured by HPLC after the pharmaceutical composition of the present invention is stored at a temperature of 25 ℃ to 70 ℃ (e.g., 25 ℃, 40 ℃, 50 ℃,60 ℃ or 70 ℃) and a Relative Humidity (RH) of 60% to 75% (e.g., 60% or 75%) for about 1 week to 12 months (e.g., 1 week, 2 weeks, 4 weeks, 1 month, 3 months, 6 months or 12 months), based on the total weight of the pharmaceutical composition, is 0.50% or less, preferably 0.4% or less, more preferably 0.20% or less. For example, the M1 impurity content of the active ingredient may be 0.50% or less after storage of the composition of the present invention at 50℃and 75% relative humidity for 1 month.

The pharmaceutical composition of the invention has at least one pharmaceutically acceptable excipient. The type and amount of excipients may be suitably selected such that the pharmaceutical composition of the present invention meets a pH of about 2.6 to about 6.74, as measured in a 1% w/v aqueous suspension prepared according to example 3 of the present invention. In addition, excipients may improve the processing characteristics of the formulation, such as flowability and/or aggregation, to allow for better compression of the pharmaceutical composition. The excipient is also preferably selected in view of the dissolution rate of the pharmaceutical composition.

In one embodiment, the pharmaceutical composition of the invention comprises one or more pharmaceutically acceptable excipients including, but not limited to, any one or more of the following: carrier, diluent, binder, disintegrant and lubricant.

Diluents may include, but are not limited to, the following: lactose, such as anhydrous lactose or hydrated lactose (e.g., flowlac 100); microcrystalline cellulose (e.g., avicel pH-101 or Pharmacel 101); hydrated dibasic calcium phosphate (e.g., carboxymethylcellulose, EMCOMPRESS); mannitol, such as D-mannitol (e.g., mannogem EZ); sorbitol, such as D-sorbitol (e.g., XTAB 200S); refined sugars such as compressible sugar, dextrates, dextrins or dextrose; powdered cellulose; or any combination thereof. Preferably, the diluent of the present invention may be hydrated lactose, anhydrous lactose, mannitol, sorbitol, microcrystalline cellulose, hydrated dibasic calcium phosphate, or any combination thereof, more preferably hydrated lactose, mannitol, sorbitol, microcrystalline cellulose, or any combination thereof, and most preferably hydrated lactose, microcrystalline cellulose, or any combination thereof.

In some embodiments, the diluent is lactose hydrate. In some embodiments, the diluent is lactose anhydrous. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is hydrated dibasic calcium phosphate. In some embodiments, the diluent is mannitol. In some embodiments, the diluent is sorbitol. In some embodiments, the diluent is refined sugar. In some embodiments, the diluent is powdered cellulose.

The diluent may be included in an amount of about 40 to about 90wt%, preferably about 70 to about 90wt%, based on the total weight of the composition.

In some embodiments, the pharmaceutical compositions of the present invention comprise from about 40 to about 90wt% of a diluent, based on the total weight of the composition; about 0.1 to about 30wt% of a binder, based on the total weight of the composition; about 1 to about 40wt% of a disintegrant, based on the total weight of the composition; and from about 0.5 to about 40wt% of a lubricant, based on the total weight of the composition.

In some embodiments, the diluent is selected from the group consisting of: hydrated lactose, anhydrous lactose, mannitol, sorbitol, microcrystalline cellulose, hydrated dibasic calcium phosphate, or any combination thereof; the binder is selected from the group consisting of: hydroxypropyl cellulose (HPC), povidone, or any combination thereof; the disintegrant is selected from the group consisting of: carboxymethyl cellulose, crospovidone, croscarmellose sodium, sodium starch glycolate, carboxymethyl cellulose (CMC), CMC-Ca, low-substituted hydroxypropyl cellulose, corn starch, and potassium polacrilin, or any combination thereof; and the lubricant is selected from the group consisting of: colloidal silica, magnesium stearate, sodium stearyl fumarate, talc, stearic acid or any combination thereof.

The binder may include, but is not limited to, the following: hydroxypropyl cellulose (e.g., HPC-L or HPC-EXF), povidone (e.g., K-30); hydroxyethyl cellulose; hydroxypropyl methylcellulose (e.g., METHOCEL); sucrose; dextrose; corn syrup; a polysaccharide; or any combination thereof. Preferably, the binder of the present invention may be hydroxypropyl cellulose, povidone, or any combination thereof, and more preferably is hydroxypropyl cellulose.

In some embodiments, the binder is hydroxypropyl cellulose. In some embodiments, the binder is povidone. In some embodiments, the binder is hydroxyethylcellulose. In some embodiments, the binder is sucrose. In some embodiments, the binder is dextrose. In some embodiments, the binder is corn syrup. In some embodiments, the binder is a polysaccharide.

The binder may be included in an amount of about 0.1 to about 30wt%, preferably about 0.5 to about 20wt%, based on the total weight of the composition.

Disintegrants may include (but are not limited to) the following: carboxymethyl cellulose (CMC; referred to as carboxymethyl cellulose, e.g., NS-300); carboxymethylcellulose calcium (CMC-Ca); sodium carboxymethyl cellulose (CMC-Na); low substituted hydroxypropyl cellulose (e.g., LH-11, LH-21, LH-31 grade, etc., having a hydroxypropoxy content of 11%); corn starch; potassium polycleirine; pregelatinized starch; clay; an alginate; a gum; or any combination thereof. Preferably, the disintegrant of the present invention may be CMC, CMC-Ca, CMC-Na, low substituted hydroxypropyl cellulose, corn starch, potassium polycosanol, or any combination thereof, and more preferably CMC.

In some embodiments, the disintegrant is carboxymethyl cellulose. In some embodiments, the disintegrant is calcium carboxymethyl cellulose. In some embodiments, the disintegrant is sodium carboxymethyl cellulose. In some embodiments, the disintegrant is low substituted hydroxypropyl cellulose. In some embodiments, the disintegrant is corn starch. In some embodiments, the disintegrant is potassium polycosanol. In some embodiments, the disintegrant is pregelatinized starch. In some embodiments, the disintegrant is clay. In some embodiments, the disintegrant is an alginate. In some embodiments, the disintegrant is a gum.

The disintegrant may be included in an amount of about 1 to about 40wt%, preferably about 3 to about 20wt%, based on the total weight of the composition.

Lubricants may include, but are not limited to, the following: colloidal silica; talc; stearic acid, magnesium stearate, calcium stearate; sodium stearyl fumarate (e.g., pruv); or any combination thereof. Preferably, the lubricant of the present invention may be colloidal silica, magnesium stearate, sodium stearyl fumarate, talc, stearic acid or any combination thereof, and more preferably colloidal silica, magnesium stearate or any combination thereof.

In some embodiments, the lubricant is colloidal silica. In some embodiments, the lubricant is talc. In some embodiments, the lubricant is stearic acid, magnesium stearate, calcium stearate. In some embodiments, the lubricant is sodium stearyl fumarate.

The lubricant may be included in an amount of about 0.5 to about 40wt%, preferably about 1 to about 20wt%, based on the total weight of the composition.

In another embodiment, the pharmaceutical composition of the present invention may further comprise a pH controlling agent. When the pH of the pharmaceutical composition is in the range of about 2.6 to 6.74 without any pH control agent, as measured in a 1% w/v aqueous suspension prepared according to example 3 of the present invention, no additional pH control agent will be required. When the pH of the pharmaceutical composition is outside this range without any pH control agent, the pH control agent may be appropriately added to adjust the pH of the pharmaceutical composition within this pH range. In an exemplary embodiment, when the pharmaceutical composition comprises CMC as disintegrant (test sample 2), the pH in the 1% w/v aqueous suspension prepared according to example 3 of the present invention is about 4.3, which means that no additional pH controlling agent will need to be used. On the other hand, when the pharmaceutical composition contains potassium polycleiside as a disintegrant, the pH is about 7.97 and the content of impurities increases, thereby becoming unstable (test sample 9). In this case, additional use of a pH controlling agent would be required to bring it within the desired pH range. It was also found that the impurity content increased when CMC-Na (test sample 11) was used, and that the additional use of a pH controlling agent increased the stability of the pharmaceutical composition.

Any pH control agent or combination of pH agents known in the art may be used so long as the desired pH range is achieved.

In a preferred embodiment, the pH control agent used in the present invention may be a pH control agent having a pH of about 1 to about 5, preferably about 1.5 to about 3, and more preferably about 2 to about 2.5. In this application, the pH of a pH controlling agent is defined as the pH of a solution or suspension obtained when the pH controlling agent is dissolved or suspended in water at a concentration of 1% w/v at room temperature.

The pH control agents may include (but are not limited to) the following: acidic substances such as tartaric acid, citric acid, lactic acid, fumaric acid, maleic acid, ascorbic acid, acetic acid or acidic amino acids (e.g. glutamic acid or aspartic acid); inorganic salts of acidic substances (e.g., alkali metal salts, alkaline earth metal salts, ammonium, etc.); salts of acidic substances with organic bases (e.g., basic amino acids such as lysine, arginine, meglumine, etc.); and hydrates thereof, solvates thereof, or any combination thereof. Preferably, the pH controlling agent may be citric acid, fumaric acid, maleic acid, or any combination thereof.

The pH controlling agent may be included in an amount of about 0.01 to about 20wt% and preferably about 0.05 to about 10wt%, based on the total weight of the composition.

In another embodiment, the pharmaceutical composition of the present invention may further comprise a super-disintegrant. Superdisintegrants may include (but are not limited to) the following: crospovidone; croscarmellose sodium; sodium starch glycolate; natural, modified or pregelatinized starch; an effervescent disintegration system; or any combination thereof. Preferably, the superdisintegrant may be crospovidone, croscarmellose sodium, sodium starch glycolate, or any combination thereof.

In some embodiments, the superdisintegrant is crospovidone. In some embodiments, the superdisintegrant is croscarmellose sodium. In some embodiments, the superdisintegrant is sodium starch glycolate. In some embodiments, the super-disintegrant is a native, modified, or pregelatinized starch. In some embodiments, the superdisintegrant is an effervescent disintegration system.

The superdisintegrants may be included in an amount of about 0.01 to about 20wt%, preferably about 1 to about 10wt%, more preferably about 1 to about 5wt%, based on the total weight of the composition.

The function or effect of the excipients described above is not absolute, and in some cases, one excipient may have at least two functions. For example, some disintegrants may also act as binders and fillers. The various functions or roles of the excipients can be determined as known in the art.

Oral administration is the route of administration of the compounds according to the invention. Administration may be via capsules or tablets or similar dosage forms. In the manufacture of pharmaceutical compositions comprising at least one compound described herein, the active ingredient is typically diluted with an excipient and/or sealed within such a carrier, which may be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be in the form of a solid, semi-solid, or liquid material (as described above), which acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may take the form: tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

The pharmaceutical compositions of the present invention may be in the form of solid oral dosage forms or solid formulations such as tablets, granules, microparticles, capsules, pills and the like. The solid formulation may preferably be a tablet, for example a tablet coated with a film coating agent. In some embodiments, the pharmaceutical composition may be formulated as a tablet. In some embodiments, a tablet comprising a pharmaceutical composition as described herein may be coated with a film coating. In some embodiments, a tablet comprising a pharmaceutical composition as described herein may be coated with an enteric coating.

Tablets containing the pharmaceutical composition of the invention may also be coated with a film. For example, films are used for enteric coatings. In some embodiments, the film comprises a cellulosic polymer (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, or any combinations thereof). An exemplary film coating may be a film coating comprising hydroxypropyl methylcellulose (hydroxyPropylmethylcellulose)For example->White 03B28796。

In one embodiment, provided herein is a pharmaceutical composition comprising an active ingredient of formula 1 below, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, wherein the composition has a pH of about 2.6 to about 6.74 when measured in a 1% w/v aqueous suspension.

< 1>

In some embodiments, the active pharmaceutical ingredient may be the hydrochloride salt of formula 1.

In another embodiment, the pharmaceutically acceptable excipient may be a diluent, a binder, a disintegrant, a lubricant, or any combination thereof.

In some embodiments, the composition comprises from about 40 to about 90wt% diluent, based on the total weight of the composition; about 0.1 to about 30wt% of a binder, based on the total weight of the composition; about 1 to about 40wt% of a disintegrant, based on the total weight of the composition; and from about 0.5 to about 40wt% of a lubricant, based on the total weight of the composition.

In one embodiment, provided herein is a solid oral dosage form comprising a compound of formula I:

or a pharmaceutically acceptable salt thereof; and at least one excipient selected from the group consisting of: diluents, binders, disintegrants, lubricants, and any combination thereof.

In one embodiment, provided herein is a stable solid oral dosage form comprising a pharmaceutically acceptable excipient and a compound of formula I:

Or a pharmaceutically acceptable salt thereof, wherein the oral dosage form maintains at least 99% by weight of the compound of formula I after storage at 75% relative humidity for at least 1 month at 20 ℃.

In one embodiment, the solid oral dosage form is a tablet.

In one embodiment, the solid oral dosage form comprises from about 40 to about 90wt% diluent, based on the total weight of the composition; about 0.1 to about 30wt% of a binder, based on the total weight of the composition; about 1 to about 40wt% of a disintegrant, based on the total weight of the composition; and from about 0.5 to about 40wt% of a lubricant, based on the total weight of the composition.

In one embodiment, provided herein is a method for preparing a pharmaceutical composition having a pH of about 2.6 to about 6.74 measured in a 1% w/v aqueous suspension comprising: (a) Mixing a compound of the following formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient with at least one pharmaceutically acceptable excipient to obtain a blend

< 1>

And (b) directly compressing the blend.

In one embodiment, provided herein is a product obtained from the methods described herein.

As provided in more detail in the examples, the experimental results show that when the pH of the composition comprising the active pharmaceutical ingredient of formula 1 or a pharmaceutically acceptable salt thereof is adjusted to be within a predetermined range, the degradation amount of the active ingredient of formula 1 is significantly lower during long-term storage. The resulting pharmaceutical composition has improved stability over the expected normal shelf life of the composition.

The pH of the pharmaceutical composition was measured by preparing an aqueous suspension of the composition in a 1% w/v (weight/volume) aqueous suspension prepared at room temperature according to example 3. Methods for measuring pH are well known to those skilled in the art of pharmaceutical compositions. For example, the pH of a subject matter was measured by dissolving the matter in water at a concentration of 1% w/v to obtain an aqueous suspension prepared according to example 3 and then measuring the pH of the suspension. The pH can be determined by using any standard technique.

The pH of the pharmaceutical composition of the present invention may be from about 2.6 to about 6.74, preferably from about 2.9 to about 6.5, more preferably from about 2.95 to about 4.95. In some embodiments, the pH of the pharmaceutical composition is between about 2 and about 8 (e.g., between about 2 and about 7.5, between about 2 and about 7, between about 2 and about 6.5, between about 2 and 6, between about 2 and about 5.5, between about 2 and about 5, between about 2 and about 4.5, between about 2.5 and about 7.5, between about 2.5 and about 7, between about 2.5 and about 6.5, between about 2.5 and about 5.5, between about 2.5 and about 4.5), or any particular value within this range, as measured by preparing an aqueous suspension of the composition in a 1% w/v (weight/volume) aqueous suspension. In some embodiments, the pH of the pharmaceutical composition is preferably between about 3 and about 8 (e.g., between about 3 and about 7.5, between about 3 and about 7, between about 3 and about 6.5, between about 3 and about 6, between about 3 and about 5.5, between about 3 and about 5) when measured by preparing an aqueous suspension of the composition in a 1% w/v (weight/volume) aqueous suspension. The pH of the pharmaceutical composition of the present invention may be in any of the above specific ranges, i.e. the pH value is preceded by the word "about".

IV method of manufacture

The pharmaceutical compositions of the present invention may be prepared by any known method or process, such as grinding, mixing or blending, granulating, drying, molding (tableting), film coating, crystallizing, and the like.

Accordingly, the present invention also provides a process for preparing a pharmaceutical composition having a pH of 2.6 to 6.74 measured in a 1% w/v aqueous suspension comprising:

(a) Mixing a compound of the following formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient with at least one pharmaceutically acceptable excipient to obtain a blend;

< 1>

(b) The blend is directly compressed.

In one embodiment, the present invention provides a direct compression process for preparing a pharmaceutical composition comprising the steps of:

(a) Pre-blending the active ingredient with some or most of the excipients in a mixer to obtain a pre-blend;

(b) Optionally dry sieving the preblend through a screen to separate the adherent particles and improve content uniformity;

(c) Mixing the pre-blend in step (a) or (b) with the remaining excipients in a mixer to obtain a final blend;

(d) Compressing and tableting the final blend in step (c) in a tablet press to produce a tablet core; a kind of electronic device with high-pressure air-conditioning system

(e) Optionally, film coating the tablet cores of step (d).

According to one particular embodiment, the active ingredient, diluent, binder, disintegrant, and lubricant are pre-blended in a diffusion mixer, sieved in a manual sieve or screen mill, and pre-blended again in a diffusion mixer to prepare a blended intermediate composition. The additional lubricant is separately screened in a manual screen or screen mill and then blended with the blended intermediate in a diffusion mixer to prepare the blend. The blend is subjected to direct compression in a rotary tablet machine to obtain tablets (plain tablets), followed by the addition of film coating agents to prepare film coated tablets.

The particles of the pharmaceutical composition according to the invention may be prepared by any method known to the person skilled in the art. Preferred methods for granulating the active ingredient with excipients include wet granulation (such as high shear wet granulation or fluid bed wet granulation), and dry granulation, also known as rolling.

In the wet granulation process, the granulation liquid is a solvent alone or a formulation of one or more binders in a solvent or solvent mixture. Suitable binders are described above. Examples are hypromellose, hydroxypropyl cellulose, povidone and copovidone. Suitable solvents are, for example, purified water, ethanol, methanol, isopropanol, acetone, preferably purified water, including mixtures thereof. The solvent is a volatile component that is not retained in the final product. One or more active ingredients and other excipients, in particular one or more diluents and one or more disintegrants (usually in addition to a lubricant) are pre-mixed with a granulation liquid and granulated, for example using a high shear granulator. The wet granulation step is typically followed by one or more drying and sieving steps. For example, a drying oven or a fluid bed dryer may then be used for drying.

The dried granules were sieved through a suitable screen. After optionally adding other excipients, in particular disintegrants, binders, fillers and/or lubricants, the mixture is blended in a suitable blender, for example a free-fall blender, followed by the addition of one or more lubricants (e.g. magnesium stearate), and finally blended in the blender.

In a particular embodiment, the present invention provides a wet granulation process for preparing a pharmaceutical composition comprising the steps of:

(a) Pre-blending the active ingredient and some or most of the excipients including binders in a mixer to obtain a pre-blend;

(b) Granulating the pre-blend of step (a) by adding a granulation liquid, preferably purified water;

(c) Drying the granules of step (b) in a fluid bed dryer or drying oven;

(d) Optionally dry sieving the dried granules of step (c);

(e) Mixing the dried granules of step (d) with the remaining excipients of lubricants, glidants and the like in a mixer to obtain a final mixture;

(f) Tabletting the final mixture of step (e) by compressing the final mixture on a suitable tabletting machine to produce tablet cores; a kind of electronic device with high-pressure air-conditioning system

(g) Optionally subjecting the tablet cores of step (f) to a film-coating.

In another embodiment, the present invention provides a dry granulation process for preparing a pharmaceutical composition comprising the steps of:

(a) Mixing the active ingredient with all or a portion of the excipient in a mixer;

(b) Compacting the mixture of step (a) on a suitable roller press;

(c) Changing the ribbon obtained during step (b) into particles, preferably small particles, by a suitable grinding or sieving step;

(d) Optionally mixing the granules of step (c) with the remaining excipients in a mixer to obtain a final mixture;

(e) Tabletting the granules or the final mixture of step (c) by compressing the granules or the final mixture of step (d) on a suitable tabletting machine to produce tablet cores; a kind of electronic device with high-pressure air-conditioning system

(f) Optionally subjecting the tablet cores of step (e) to a film-coating.

The invention also provides a pharmaceutical composition, such as a tablet, obtainable by the following process.

Granules and microgranules can be prepared by granulation (e.g., wet granulation or dry granulation) based on the same method as for tablets. Alternatively, it can be prepared by spraying a coating liquid comprising the active ingredient and excipients (in particular binders such as sucrose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc.) on the sugar spheres to coat the spheres. Thus, the particles may be wet or dry particles.

Capsules are manufactured by filling capsules made of gelatin (e.g., hydroxypropyl methylcellulose) with granules or microparticles, or with active ingredients together with excipients (e.g., lactose, sucrose, dextrose, starch, sucrose, microcrystalline cellulose, powdered licorice, mannitol, sodium bicarbonate, calcium phosphate, calcium sulfate, etc.).

V. definition

The term "active pharmaceutical ingredient of formula 1" or "compound of formula 1" may also be referred to as "compound 1" or "compound of the invention". Similarly, "salt of the active pharmaceutical ingredient of formula 1" may also be referred to as "salt of compound 1" or "salt of the compound of the invention". For example, the active pharmaceutical ingredient of formula 1 in the form of the hydrochloride salt may be referred to as "the hydrochloride salt of compound 1" or "the hydrochloride salt of the compound of the invention".

The "pharmaceutically acceptable salts" herein may be prepared by any suitable method available in the art, for example by treating the active pharmaceutical ingredient of formula 1 in free base form with a mineral acid. Examples of suitable inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, and the like, or with organic acids such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyronic acid (such as glucuronic acid or galacturonic acid), alpha hydroxy acids (such as citric acid or tartaric acid), amino acids (such as aspartic acid or glutamic acid), aromatic acids (such as benzoic acid or cinnamic acid), sulfonic acids (such as p-toluenesulfonic acid or ethanesulfonic acid), or the like. The hydrochloride salt of the active pharmaceutical ingredient of formula 1 is most preferred.

As used herein, a "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions described herein include, but are not limited to, ion exchangers; alumina; aluminum stearate; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; a partial glyceride mixture of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; a cellulose-based material; polyethylene glycol; sodium carboxymethyl cellulose; a polyacrylate; a wax; polyethylene-polyoxypropylene-block polymers; polyethylene glycol; lanolin.

The terms "stable" and "stability" in this application mean that the pharmaceutical composition is stable, for example, in terms of heat, light, temperature and/or humidity. For example, the pharmaceutical composition of the present invention is stable when the amount of total impurities of the active ingredient contained in the pharmaceutical composition or the amount of M1 impurities ("M1 impurities") is a specific percentage or less after the pharmaceutical composition is stored under specific conditions. The M1 impurity is any inactive form of the active ingredient, such as a synthetic intermediate, metabolic intermediate, by-product or degradation product of the active ingredient.

The total impurities measured by HPLC can be defined as a relative retention time ("RRT") relative to the peak of compound 1 of about 0.11 to 2.10, more particularly about 0.90, about 1.12, about 1.35, or about 1.38. The M1 impurity may be defined as having an RRT of about 0.90 relative to the peak of compound 1. As is well known in the art, RRT values in HPLC can have experimental errors of ±10% of the indicated values. Therefore, the values described above should be interpreted in view of experimental errors.

As used herein, a "subject" contemplated to be administered includes, but is not limited to, a human (i.e., a male or female of any age group, such as a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young, middle-aged, or elderly)). In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably in this application.

As used herein and unless otherwise indicated, the term "treating" encompasses concurrent behavior of a subject with a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition or delays or slows progression of the disease, disorder, or condition ("therapeutic treatment"), and also encompasses behavior that occurs before the subject begins to suffer from the indicated disease, disorder, or condition ("prophylactic treatment").

As used herein and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or delay or minimize one or more symptoms associated with a disease, disorder or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent alone or in combination with other therapies that provides a therapeutic benefit in the treatment of a disease, disorder or condition. The term "therapeutically effective amount" may encompass an amount that improves overall therapy, reduces or avoids symptoms or etiologies of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

As used in this application, "about" will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If there are applications of terms that are not apparent to one of ordinary skill in the art, the term "about" will mean that a particular term is up to plus or minus 10% in view of the context in which it is used. For pH values, the term "about" will mean a pH value of up to plus or minus 0.5%.

As used herein, "assay" refers to a procedure for determining a particular indicated stability of a drug substance content. For example, the assay may be a chromatographic method (e.g., HPLC) involving the use of a reference standard.

As used herein, "crystalline" refers to a solid having a highly regular chemical structure, i.e., a long range order of structure in the lattice. The molecules are arranged in a regular periodic fashion in the 3-dimensional space of the lattice. In particular, the crystalline forms may be produced in one or more single crystalline forms.

As used herein, an "excipient" is a pharmaceutically acceptable inactive ingredient that is commonly used in the preparation of pharmaceutical formulations. Examples of suitable excipients can be found in Shrekey et al, handbook of Pharmaceutical Excipients, eighth edition, write (Pharmaceutical Press 2017), which is incorporated herein by reference in its entirety. Excipients can be categorized by their functional characteristics such as diluents, binders, disintegrants, superdisintegrants, lubricants, pH controlling agents, glidants, fillers, stabilizers, antioxidants and film-coating agents. However, as is well known in the art, depending on the time and manner in which the excipient is used, a particular excipient may be categorized into more than one of the functional groups previously listed, e.g., the excipient may be categorized as a disintegrant in one formulation and as a binder in another formulation. In some cases, a particular excipient may be multifunctional, i.e., classified as belonging to more than one functional group within the same formulation. General considerations in formulating and/or manufacturing pharmaceutical composition agents can be found, for example, in Remington's Pharmaceutical Sciences, sixteenth edition, e.w. martin (Mack Publishing co., easton, pa., 1980) and remington: the Science and Practice of Pharmacy, 21 st edition (Lippincott Williams & Wilkins, 2005), all of which are incorporated herein by reference in their entirety.

As used herein, a "binder" is an excipient that imparts enhanced cohesive or tensile strength (e.g., hardness) to a pharmaceutical composition. Examples of binders include dicalcium phosphate, sucrose, corn starch, microcrystalline cellulose and modified cellulose (e.g., hydroxymethyl cellulose).

As used herein, a "diluent" is an excipient that increases the volume of a pharmaceutical composition. Examples of diluents include lactose, sorbitol, cellulose, calcium phosphate, starch, sugar (e.g., mannitol, sucrose, or the like) or any combination thereof.

As used herein, a "disintegrant" is an excipient that hydrates a pharmaceutical composition and aids in the dispersion of a tablet. Examples of disintegrants include croscarmellose sodium and/or sodium starch glycolate.

As used herein, a "lubricant" is an excipient added to a pharmaceutical composition that is compressed into a tablet. The lubricant aids in compressing the granules into tablets and extruding the tablets of the pharmaceutical composition from a die press. Examples of lubricants include magnesium stearate, stearic acid (stearin), hydrogenated oil, sodium stearyl fumarate, or any combination thereof.

As used herein, "compound 1" refers to a compound of formula I as described herein.

Examples

In order that the invention described in this application may be more fully understood, the following examples are set forth. The examples described in this application are provided to illustrate aspects of the invention and embodiments thereof provided in this application and should not be construed to limit the scope thereof in any way.

Abbreviations (abbreviations)

BRT is below reporting threshold

BOR optimal overall reaction

Clinical benefit rate of CBR

CMC carboxymethyl cellulose

CMC-Ca carboxymethyl cellulose calcium

HDPE high density polyethylene

HPLC high performance liquid chromatography

HPC hydroxypropyl cellulose

ND is not measured

ORR objective response Rate

QD once daily

RH relative humidity

UV ultraviolet

Example 1. Clinical study of compound 1 in patients with advanced solid cancerous tumors (stage 1 a).

Phase I clinical studies were conducted to determine the recommended dose of compound 1 monotherapy and to explore the safety, tolerability, pharmacokinetics, pharmacodynamics and anticancer efficacy of compound 1 in patients with advanced solid tumors who progressed after trial of standard of care therapies and for whom no effective therapies were present. This study consisted of a conventional 3+3 dose escalation design as shown in figure 1. Phase I studies were performed in a conventional 3+3 design, starting from the lowest dose level (2 mg) until the maximum tolerated dose ("MTD") was determined. Dose limiting toxicity ("DLT") and pharmacokinetics were assessed during the first period.

During the period 1 DLT assessment period following study product administration, no subjects experiencing DLT were present in those subjects including those at level 1 (2 mg QD), level 2 (5 mg QD), level 3 (10 mg QD), level 4 (20 mg QD), level 5 (20 mg QD), level 6 (40 mg QD), level 7 (80 mg QD), level 8 (120 mg QD), level 9 (160 mg QD) and level 10 (240 mg QD), and MTD was not determined. Thus, for a continuous daily regimen of administration for 3 weeks, the MTD of oral administration of compound 1 is expected to exceed 240 mg/day.

Pharmacodynamics of the compound of formula 1 was examined using standardized enzyme-linked immunosorbent assay (ELISA) with peripheral blood mononuclear cells ("PBMC") and PAR levels analysis in tumors. For PAR measurements in PBMCs and tumors, the results of measurements of dose levels and time points of treatment and tumor response with PAR inhibition are presented. The results are provided in table 1 and illustrated in fig. 2. The compound of formula 1 shows >90% PAR inhibition in pharmacodynamic analysis of tumor biopsy samples using a dose starting at 10 mg.

TABLE 1 pharmacodynamic data for compounds of formula 1

* BLQ: below the limit of quantification (LLOQ: 390.6pg/mg tumor)

Assessment of tumor response

According to the response assessment criteria for solid tumors, version 1.1 (RECIST, v 1.1), compound 1 was evaluated for anti-cancer activity in the relevant patient population based on objective response rate (orr=complete response [ CR ] + partial response [ PR ]) and clinical benefit rate (cbr=complete response [ CR ] + partial response [ PR ] + stable disease [ SD ]). Thus, the term "clinical benefit" shall mean providing any one of the following responses after treatment of the disease: completely reacting; partial reaction; or to stabilize the disease. Table 2 presents data following administration of compound 1 in selected patients, wherein Objective Response Rate (ORR) and Clinical Benefit Rate (CBR) were determined by Best Overall Response (BOR) in the overall response assessed during the period of phase 1. This data is graphically illustrated in fig. 3 (ORR) and fig. 4 (CBR).

TABLE 2 objective response rate and clinical benefit rate according to RECIST version 1.1

The compounds of formula 1 were found to be equally effective against BRCA mutant breast cancer and ovarian cancer, and against BRCA wild-type breast cancer, ovarian cancer, and other cancers (i.e., not containing BRCA mutations but possibly other mutations). Table 3 provides data for BRCA mutant breast or ovarian cancer patients, which is also illustrated in FIG. 5. Table 4 provides data for BRCA wild-type breast cancer, ovarian cancer, and other cancer patients illustrated in fig. 6.

TABLE 3 BRCA mutant breast or ovarian cancer patients

TABLE 4 wild type BRCA breast cancer, ovarian cancer or other cancer patients

Example 2. Clinical study of Compound 1 in patients with advanced solid cancerous tumors (stage 1b/2 a).

This is an open-label, multicenter, stage 1b/2a basket assay to investigate the safety and anti-cancer activity of compound 1 monotherapy in patients with homologous recombination to repair mutable solid tumors. The main objective was to assess the safety and tolerability of compound 1 to determine the recommended phase 2a dose in patients with homologous recombination to repair a mutant solid tumor.

The study consisted of two parts: compound 1 dose for determining recommended phase 2 dose phase 1 dose selection phase 1 trial, open label, non-randomized phase 2a trial to confirm and assess safety and efficacy of recommended phase 2 doses. FIG. 7 illustrates a protocol for this phase 1b/2a clinical study.

The initial dose for phase 1 trial was 80mg to 240mg (i.e., 80mg, 120mg, 160mg and 240 mg), which had safety and tolerability assessments in phase 1, which were incremented after safety and tolerability assessments. The following are exemplary results for four groups studied: 12 patients with breast cancer (group 1), 4 patients with ovarian cancer (group 2), 3 patients with pancreatic cancer (group 6) and 2 patients with platinum-group resistant ovarian cancer (group 7). Patients in these groups received at least one dose of the compound prior to assessment.

Assessment of tumor response

The anticancer activity of compound 1 in the relevant patient population was assessed based on objective response rate (orr=complete response [ CR ] + partial response [ PR ]) and clinical benefit rate (cbr=complete response [ CR ] + partial response [ PR ] + stable disease [ SD ]) according to the response assessment criteria for solid tumors in the relevant patient population, version 1.1 (RECIST, v 1.1). In addition, the study assessed duration of response (DOR), time To Response (TTR), time To Progression (TTP), progression Free Survival (PFS), and total survival (OS) in patients.

The ORR and CBR were determined by the Best Overall Response (BOR) among the overall responses assessed during the period of phase 1b, which is presented in table 5.

TABLE 5 results for group 1 (breast), group 2 (ovary), and group 6 (pancreas) and group 7 (platinum-resistant ovary)

* For tumor response, the tumor response assessment following compound 1 administration was assessed according to RECIST v 1.1.

As used in table 5 above, complete response is defined as the disappearance of all signs of disease; the partial response is defined by the World Health Organization (WHO) as a reduction of more than 50% in the sum of the products of the vertical diameters of all measurable lesions or by RECIST as a reduction of 30% in the sum of the longest diameters of lesions; progressive disease is to indicate any new lesion that increases by more than 25% according to the sum of the products of the vertical diameters of all measurable lesions of WHO, or by 20% according to the sum of the longest diameters of RECIST; and stable disease refers to tumor shrinkage or growth that does not meet any of the foregoing criteria.

In addition, waterfall plots of the change in tumor size from baseline following administration of compound 1 in selected group 1, group 2, group 6 and group 7 patients are shown in fig. 8 (group 2-ovaries), fig. 9 (group 6-pancreas) and fig. 10 (group 7-platinum-resistant ovaries). These figures demonstrate the change in tumors with germline BRCA1 (gBRCA 1), germline BRCA2 (gBRCA 2), germline ATM (gATM), somatic BRCA1 (sBRCA 1) or somatic ATM (sATM) mutations.

Example 3 stability of tablets of test samples 1 to 9 against different pH

The hydrochloride salts of the compounds of the present invention and excipients were mixed and tableted according to the compositions listed in table 6 below to prepare uncoated plain tablets. Each tablet was placed in triple distilled water so that the concentration of the tablet was 1% w/v (weight/volume), and stirred at room temperature using a magnetic stirring bar at 1,200rpm for five (5) minutes to form an aqueous suspension (referred to as "1% w/v aqueous suspension"). After allowing the suspension to stand for five (5) minutes, the pH of the suspension was measured at room temperature using an S20 Seveneasy pH meter manufactured by Mettler Toledo. The pH of each tablet prepared in test samples 1 to 9 was measured, and the results are presented in table 6 below.

In addition, the stability of each of the tablets prepared in examples 1 to 9 was evaluated. Each tablet was stored at 50 ℃ for 2 and 4 weeks together with a desiccant (silica gel) sealed in HDPE bottles at 75% RH (relative humidity), and then the content (%) of M1 impurity and the content (%) of total impurity in each tablet were determined by HPLC.

UV using a C18 column (4.6 mm. Times.15 cm;5 μm) _max HPLC analysis was performed on a detector set at 280nm or near 280nm, and the mobile phase was either a mixture of purified water and formic acid or a mixture of methanol and formic acid. The M1 impurity content (%) and the total impurity content (%) were analyzed on the initial date (day 0), 2 weeks and 4 weeks. The impurity content (%) was calculated in the following manner.

The results are presented in table 6 below.

Table 6.

ND: not measured

The low levels of impurities after prolonged storage show that the hydrochloride salts of the compounds of the present invention, pharmaceutical compositions having a pH in the range of about pH 2.6 to pH 6.48 (test samples 1 to 8), exhibit significant stability. In particular, the best stability was found around pH 3.0 (test sample 3 and test sample 7). On the other hand, when the pH was higher than 7.0, the amount of impurities rapidly increased and the stability was lowered (test sample 9).

The compounds of the present invention were thus demonstrated to be stable over a range of about pH 2.6 to pH 6.48.

Example 4 stability of tablets of test samples 2 and 10 to 21 based on different excipients

Based on the preparation methods described in test samples 1 to 9, the hydrochloride salt of the compound of the present invention and each additive were mixed and tableted according to the compositions shown in tables 7 and 8 below to prepare uncoated plain tablets.

The pH of each tablet prepared in test samples 2 and 10 to 21 was measured as described in example 3, and the results are presented in tables 7 and 8 below.

The stability of each of the tablets prepared in test samples 2 and 10 to 21 containing different excipients was evaluated. After each tablet was stored at 75% RH for 1 week at 50 ℃ in an open state, the content (%) of impurity (M1) in each tablet was measured according to the HPLC method described in example 3. The results are shown in tables 7 and 8.

TABLE 7 test samples 2 and 10 to 17

BRT (below reporting threshold)

The above results confirm that the tablets of test sample 2, 10 and 12 to 17 show excellent stability, while the tablet of test sample 11 has lower stability. In test sample 11, CMC-Na was used as a disintegrant, wherein this ingredient was determined to increase the pH of the whole tablet, thereby decreasing the stability of the active ingredient.

TABLE 8 test samples 18 to 21

ND: not measured

Test sample 21 provides the best stability results. Although test samples 18 through 20 were less stable with increased M1 impurity compared to test sample 21, test samples 18 and 19 (and 21) still exhibited less than 0.50% levels of M1 impurity required. With the exception of test sample 20.

Example 5 stability of tablets of test samples 22 to 33 based on different excipients

Based on the preparation methods described in test samples 1 to 9, the hydrochloride salt of the compound of the present invention and each additive were mixed and tableted according to the compositions shown in table 9 below to prepare uncoated plain tablets.

The pH of each tablet prepared in test samples 22 to 33 was measured as described in example 3, and the results are presented in table 9 below.

The stability of each of the tablets prepared in test samples 22 to 33 containing different excipients was evaluated. After each tablet was stored at 50 ℃ for 2 and 4 weeks without controlling RH, the content (%) of M1 impurity and the content (%) of total impurity in each tablet were measured according to the HPLC method described in example 3. Table 9 shows the results.

Table 9. Test samples 22 to 33.

ND: not measured

The above results show improved stability of the compositions of the present invention at pH 2.8 to 6.55. In fact, the remaining test samples were stable except for test sample 28. In particular, test samples (i.e., test samples 23, 25, 27, 29, 31, and 33) using a pH control agent to bring the pH to about 3 exhibited significantly improved stability.

Example 6 stability of film coated tablets based on different excipients of samples 34 to 36 were tested

Based on the preparation methods described in test samples 1 to 9, the hydrochloride of the compound of the present invention and each additive were mixed according to the compositions shown in the following table 10, and tabletted to prepare tablets (plain tablets), usingFilm-coated tablets of test samples 34 to 36 were prepared by coating film-coating.

The stability of each of the tablets prepared in test samples 34 to 36 was evaluated. The tablets were stored in a sealed state at 40 ℃ in Alu-Alu packages at 75% RH for 3 months and 6 months, after which the M1 impurity content (%) and the total impurity content (%) in each tablet were determined by HPLC according to example 3. Table 10 shows the results.

Table 10 test samples 34 to 36.

The stability of a film coated pharmaceutical composition comprising an active pharmaceutical ingredient of formula 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient was confirmed when the composition had a pH in the range of about 2.6 to about 6.74, measured in a 1% w/v aqueous suspension prepared according to example 3.

Equivalents and scope

In the claims, articles such as "a/an" and "the" may mean one or more than one unless indicated to the contrary or otherwise apparent from the context. Unless indicated to the contrary or otherwise apparent from the context, a claim or description that includes an "or" between one or more members of a group is considered to be satisfied if one, more than one, or all of the group members are present in, used in, or otherwise relevant to a given product or process. The invention includes embodiments in which exactly one member of the set is present in, used in, or otherwise associated with a given product or process. The present invention includes embodiments in which more than one or all of the group members are present in, used in, or otherwise associated with a given product or process.

Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, strips, and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim that depends from another claim may be modified to include one or more limitations found in any other claim that depends from the same base claim. If an element is presented in a list, such as in Markush group format, each subgroup of the element is also disclosed, and any element may be removed from the group. It should be understood that, in general, certain embodiments of the invention or aspects of the invention consist of or consist essentially of the particular elements and/or features if such elements and/or features are referred to as being included. For the sake of simplicity, those embodiments have not been specifically set forth in the present application in terms of words. It should also be noted that the terms "comprising" and "including" are intended to be open ended and permit the inclusion of additional elements or steps. If a range is given, the endpoint is included. Furthermore, unless indicated otherwise or otherwise evident from the context and understanding of one of ordinary skill in the art, values expressed as ranges may, in different embodiments of the invention, employ any particular value or subrange within the stated range, up to one tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

This application mentions various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated by reference into this application. If a conflict exists between any of the incorporated references and the present specification, the present specification shall control. In addition, any particular embodiment of the invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are considered to be known to those of ordinary skill in the art, they may be excluded even if the exclusion is not explicitly set forth in the present application. Any particular embodiment of the invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described in the present application. The scope of the embodiments of the invention described in this application is not intended to be limited to the above description, but rather it is set forth in the appended claims. It will be understood by those skilled in the art that various changes and modifications may be made to the present description without departing from the spirit or scope of the invention as defined in the following claims.

Claims

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, for use in treating cancer having a BRCA1 mutation, a BRCA2 mutation, an ATM mutation, or a homologous recombination repair mutation in a subject, wherein the use comprises administering from about 2mg to about 300mg of the compound to the subject.

2. The compound for use according to claim 1, wherein the cancer is ovarian, breast or pancreatic cancer.

3. The compound for use according to claim 2, wherein the cancer is platinum-group-resistant ovarian cancer.

4. A pharmaceutical composition comprising:

(i) About 2mg to about 300mg of a compound of formula I:

(ii) At least one pharmaceutically acceptable excipient for use in treating a cancer having a BRCA1 mutation, a BRCA2 mutation, an ATM mutation, or a homologous recombination repair mutation in a subject, wherein the use comprises administering the pharmaceutical composition to the subject.

5. The pharmaceutical composition for use according to claim 4, wherein the composition has a pH of about 2.6 to about 6.74 measured in a 1% w/v aqueous suspension.

6. The pharmaceutical composition for use according to claim 4, wherein the cancer is ovarian, breast or pancreatic cancer.

7. The pharmaceutical composition for use according to claim 6, wherein the cancer is platinum-group resistant ovarian cancer.

8. A compound or pharmaceutical composition for use according to any one of claims 1 to 7, wherein the use comprises administering to the subject about 2mg, 5mg, 10mg, 20mg, 40mg, 80mg, 120mg, 160mg or 240mg of the compound or a pharmaceutically acceptable salt thereof.

9. The compound or pharmaceutical composition for use according to claim 8, wherein the use comprises administering about 40mg, 80mg, 120mg, 160mg or 240mg of the compound or a pharmaceutically acceptable salt thereof to the subject.

10. A compound or pharmaceutical composition for use according to any one of claims 1 to 7, wherein the cancer has BRCA1 mutations.

11. A compound or pharmaceutical composition for use according to any one of claims 1 to 7, wherein the cancer has BRCA2 mutations.

12. A compound or pharmaceutical composition for use according to any one of claims 1 to 7, wherein the cancer has an ATM mutation.

13. A compound or pharmaceutical composition for use according to any one of claims 1 to 7, wherein the cancer has a homologous recombination repair mutation.

14. A compound of formula I:

or a pharmaceutically acceptable salt thereof, for use in obtaining a clinical benefit in a subject having ovarian cancer, wherein the use comprises administering to the subject from about 2mg to about 300mg of the compound.

15. The compound for use according to claim 14, wherein the ovarian cancer is platinum-group resistant ovarian cancer.

16. A compound of formula I:

or a pharmaceutically acceptable salt thereof, for use in obtaining clinical benefit in a subject having breast cancer, comprising administering to the subject from about 2mg to about 300mg of the compound.

17. A compound of formula I:

or a pharmaceutically acceptable salt thereof, for use in obtaining a clinical benefit in a subject having pancreatic cancer, comprising administering to the subject from about 2mg to about 300mg of the compound.

18. The compound for use according to any one of claims 14 to 17, wherein said use comprises administering about 2mg, 5mg, 10mg, 20mg, 40mg, 80mg, 120mg, 160mg or 240mg of the compound or a pharmaceutically acceptable salt thereof to the subject.

19. The compound for use according to claim 18, wherein said use comprises administering about 40mg, 80mg, 120mg, 160mg or 240mg of said compound or a pharmaceutically acceptable salt thereof to the subject.

20. A compound for use according to any one of claims 14 to 17, wherein the cancer has BRCA1 mutations.

21. A compound for use according to any one of claims 14 to 17, wherein the cancer has BRCA2 mutations.

22. A compound for use according to any one of claims 14 to 17, wherein the cancer has an ATM mutation.

23. A compound for use according to any one of claims 14 to 17, wherein the cancer has a homologous recombination repair mutation.

24. A compound for use according to any one of claims 14 to 17, wherein the composition further comprises a pharmaceutically acceptable excipient, and wherein the pH of the composition measured in a 1% w/v aqueous suspension is from about 2.6 to about 6.74.

25. A compound of formula I:

26. A compound of formula I:

27. The compound for use according to claim 25 or 26, wherein the cancer is ovarian cancer, breast cancer, pancreatic cancer or platinum-group-resistant ovarian cancer.

28. The compound for use according to claim 25 or 26, wherein said use comprises administering to said subject about 2mg, 5mg, 10mg, 20mg, 40mg, 80mg, 120mg, 160mg or 240mg of said compound or a pharmaceutically acceptable salt thereof.