WO2023051725A1 - Combinaison pharmaceutique et son utilisation - Google Patents

Combinaison pharmaceutique et son utilisation Download PDF

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Publication number
WO2023051725A1
WO2023051725A1 PCT/CN2022/122744 CN2022122744W WO2023051725A1 WO 2023051725 A1 WO2023051725 A1 WO 2023051725A1 CN 2022122744 W CN2022122744 W CN 2022122744W WO 2023051725 A1 WO2023051725 A1 WO 2023051725A1
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WIPO (PCT)
Prior art keywords
substance
breast cancer
pharmaceutically acceptable
solvate
acceptable salt
Prior art date
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PCT/CN2022/122744
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English (en)
Chinese (zh)
Inventor
李永国
隗维
叶未
Original Assignee
广州嘉越医药科技有限公司
上海嘉坦医药科技有限公司
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Publication of WO2023051725A1 publication Critical patent/WO2023051725A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a medicine combination and its application.
  • HR+/HER2- human epidermal growth factor receptor-2 negative breast cancer
  • HR+/HER2- breast cancer is the most common breast cancer, accounting for about 70% of all breast cancers.
  • early HR+/HER2- breast cancer can be radically cured by surgery, some patients still have recurrence or metastasis after postoperative adjuvant endocrine therapy or chemotherapy.
  • the pathogenic factors leading to the occurrence of HR+/HER2- breast cancer have been relatively clear.
  • Some advanced HR+/HER2- breast cancers are sensitive to first-line endocrine therapy and combination therapy of endocrine and CDK4/6 inhibitors. The survival rate and quality of life of patients are significantly improved. significantly improved.
  • Alpelisib a targeted drug targeting PI3K ⁇ , was approved by the FDA in 2019 in combination with Fulvestrant for the treatment of PIK3CA-mutated, postmenopausal, advanced or metastatic HR+/HER2- breast cancer that failed an endocrine therapy.
  • the technical problem to be solved by the present invention is that breast cancer resistant to endocrine therapy combined with CDK4/6 inhibitors lacks effective treatment means. Therefore, the present invention provides a drug combination and its application. Breast cancer resistant to CDK4/6 inhibitors.
  • the present invention provides a pharmaceutical combination comprising substance X and substance Y;
  • the substance X is a first therapeutic agent, a pharmaceutically acceptable salt thereof, a solvate thereof, and a solvate of a pharmaceutically acceptable salt thereof, and the first therapeutic agent is compound I, samotolisib, copanilisb, SHC014748M, pilaralisib, YZJ-0673, gedatolisib, omipalisib, bimiralisib, voxtalisib, AL58805, or HEC68498;
  • the substance Y is Fulvestrant, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof;
  • the first therapeutic agent is Compound I.
  • said pharmaceutical combination consists of said substance X and said substance Y.
  • the substance X and the substance Y may be administered simultaneously or separately.
  • the “simultaneous administration” includes simultaneous administration of substance X and substance Y in separate pharmaceutical compositions; or, "separate pharmaceutical composition comprising substance X" and “separate pharmaceutical composition comprising substance Y" are administered simultaneously.
  • Said “separate administration” such as “separate pharmaceutical composition comprising substance X” and “separate pharmaceutical composition comprising substance Y” are administered separately at different times, for example: “separate pharmaceutical composition comprising substance X” and "separate pharmaceutical composition comprising substance One of the separate pharmaceutical compositions of Y" is administered first and the other is administered subsequently.
  • the separate administrations may be close in time or distant in time.
  • the administration regimens (including administration route, administration dose, administration interval, etc.) of the substance X and substance Y may be the same or different, which can be adjusted by those skilled in the art as needed to provide the optimal treatment effect.
  • the substance X is administered orally.
  • the substance Y is administered by injection (eg, intravenous, subcutaneous, or intramuscular injection).
  • injection eg, intravenous, subcutaneous, or intramuscular injection.
  • said substance X is administered orally; and, said substance Y is administered by subcutaneous injection.
  • the Substance X is administered orally; and, the Substance Y is administered by subcutaneous injection; and the first therapeutic agent is Compound I.
  • the present invention provides a pharmaceutical composition A, which comprises substance X, substance Y and pharmaceutical excipients:
  • the substance X is a first therapeutic agent, a pharmaceutically acceptable salt thereof, a solvate thereof, and a solvate of a pharmaceutically acceptable salt thereof, and the first therapeutic agent is compound I, samotolisib, copanilisb, SHC014748M, pilaralisib, YZJ-0673, gedatolisib, omipalisib, bimiralisib, voxtalisib, AL58805, or HEC68498;
  • the substance Y is Fulvestrant, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition A consists of the substance X, the substance Y and pharmaceutical excipients.
  • the pharmaceutical composition A is a single pharmaceutical composition.
  • the pharmaceutical composition A can be made into various suitable dosage forms according to different administration methods, including gastrointestinal administration dosage forms (such as oral dosage forms) and parenteral administration dosage forms (such as injection dosage forms).
  • the pharmaceutical composition A is presented in an oral dosage form.
  • the pharmaceutical composition A is presented as an injectable dosage form.
  • the first therapeutic agent is Compound I.
  • the present invention also provides a pharmaceutical composition B, which comprises a first pharmaceutical composition and a second pharmaceutical composition;
  • the first pharmaceutical composition comprises substance X and a pharmaceutical excipient, and the substance X is a first therapeutic agent, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof,
  • the first therapeutic agent is compound I, samotolisib, copanilisb, SHC014748M, pilaralisib, YZJ-0673, gedatolisib, omipalisib, bimiralisib, voxtalisib, AL58805 or HEC68498; and,
  • the second pharmaceutical composition comprises substance Y and pharmaceutical excipients, and the substance Y is Fulvestrant, a pharmaceutically acceptable salt thereof, a solvate thereof, and a solvate of a pharmaceutically acceptable salt thereof.
  • the first pharmaceutical composition is a single pharmaceutical composition; the second pharmaceutical composition is a single pharmaceutical composition.
  • the pharmaceutical composition B consists of the first pharmaceutical composition and the second pharmaceutical composition.
  • the first therapeutic agent is Compound I.
  • the first pharmaceutical composition is presented in an oral dosage form.
  • the second pharmaceutical composition is presented as an injectable (eg, intravenous, subcutaneous, or intramuscular injection) dosage form.
  • injectable eg, intravenous, subcutaneous, or intramuscular injection
  • the first pharmaceutical composition is presented as an oral dosage form; and, the second pharmaceutical composition is presented as an injectable dosage form.
  • the first pharmaceutical composition is presented as an oral dosage form; and, the second pharmaceutical composition is presented as an injectable dosage form; and the first therapeutic agent is Compound I.
  • the present invention provides an application of a substance X in the preparation of a drug for treating breast cancer
  • the substance X is the first therapeutic agent, its pharmaceutically acceptable salt, its solvate, its pharmaceutically acceptable A solvate of a salt
  • the first therapeutic agent is compound I, samotolisib, copanilisb, SHC014748M, pilaralisib, YZJ-0673, gedatolisib, omipalisib, bimiralisib, voxtalisib, AL58805 or HEC68498, and the breast cancer is HR positive, HER2-negative, PIK3CA gene-altered breast cancer or breast cancer resistant to endocrine therapy combined with CDK4/6 inhibitor therapy.
  • the present invention provides a use of the pharmaceutical composition, pharmaceutical composition A or pharmaceutical composition B as described herein in the preparation of a medicament for treating breast cancer.
  • the present invention provides an application of a substance X in the preparation of a drug for treating breast cancer.
  • the substance X is a first therapeutic agent, a pharmaceutically acceptable salt thereof, a solvate thereof, a pharmaceutically acceptable
  • the solvate of the salt of said first therapeutic agent is compound I, samotolisib, copanilisb, SHC014748M, pilaralisib, YZJ-0673, gedatolisib, omipalisib, bimiralisib, voxtalisib, AL58805 or HEC68498, wherein said substance X and substance Y In combination, the substance Y is Fulvestrant, its pharmaceutically acceptable salt, its solvate, and its pharmaceutically acceptable salt's solvate.
  • the first therapeutic agent is Compound I.
  • the present invention provides an application of a substance Y in the preparation of a drug for treating breast cancer, the substance Y is Fulvestrant, a pharmaceutically acceptable salt thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof a solvate, wherein said substance Y is used in combination with substance X, said substance X being a first therapeutic agent, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof,
  • the first therapeutic agent is compound I, samotolisib, copanilisb, SHC014748M, pilaralisib, YZJ-0673, gedatolisib, omipalisib, bimiralisib, voxtalisib, AL58805 or HEC68498.
  • the first therapeutic agent is Compound I.
  • the present invention provides a method of treating breast cancer, comprising administering a therapeutically effective amount of a pharmaceutical combination, pharmaceutical composition A or pharmaceutical composition B as described herein to a patient in need thereof.
  • the breast cancer can be HR positive, HER2 negative, PIK3CA gene altered breast cancer.
  • the breast cancer can be advanced breast cancer with HR positive, HER2 negative and PIK3CA gene alteration.
  • the breast cancer may be breast cancer resistant to endocrine therapy combined with CDK4/6 inhibitor therapy.
  • the breast cancer may be breast cancer resistant to treatment with estradiol combined with Palbociclib.
  • administration regimens of substance X and substance Y can be the same or different, and can be adjusted by those skilled in the art as needed to provide the optimal therapeutic effect.
  • the substance X and the substance Y can be administered simultaneously or separately.
  • the substance X can be administered by any suitable route known in the art, including oral, injection (eg intravenous, intramuscular, subcutaneous) and the like.
  • the substance X is administered orally.
  • the substance Y is administered by subcutaneous injection.
  • said substance X is administered orally; and, said substance Y is administered by subcutaneous injection.
  • the Substance X is administered orally, the Substance Y is administered by subcutaneous injection, and the first therapeutic agent is Compound I.
  • the substance X can be administered according to the weight of the patient, a non-limiting example range can be 0.01-1 mg/kg (referring to a single dose), such as 0.01 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.15 mg/kg kg, 0.2mg/kg, 0.25mg/kg, 0.3mg/kg, 0.35mg/kg, 0.4mg/kg, 0.45mg/kg, 0.5mg/kg, 0.55mg/kg, 0.6mg/kg, 0.7mg/kg kg, 0.8mg/kg, 0.9mg/kg or 1mg/kg.
  • the dose of Compound I is 0.05-0.5 mg/kg, such as 0.2 mg/kg.
  • the above doses of the substance X may be administered according to the frequency of QD (once a day), QOD (one day apart) or QW (once a week).
  • the substance X is administered on a QD frequency.
  • the substance X is administered orally according to the dosage and frequency mentioned above.
  • the substance X is administered orally at 0.2 mg/kg, QD.
  • the substance X is administered orally at 0.2 mg/kg, QD, and the first therapeutic agent is compound I.
  • the substance X may also be administered to the patient in fixed doses, ie a fixed or predetermined amount of dose is given to the patient.
  • a non-limiting example of a fixed dose (referred to as a single dose) may range from 0.01 to 50 mg, such as 0.01 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47m
  • the above-mentioned fixed doses of the substance X may be administered at a frequency of QD (once a day), QOD (once a day) or QW (once a week).
  • the substance X is administered on a QD frequency.
  • the substance X is administered orally at a fixed dose and frequency as described above.
  • the substance Y can be administered by any suitable route in the art, including oral administration, injection (eg intravenous, intramuscular, subcutaneous) and the like.
  • the substance Y is administered by injection.
  • the substance Y can be administered according to the weight of the patient, a non-limiting example range can be 0.01-20 mg/kg (referring to a single dose), such as 0.1 mg/kg, 0.2 mg/kg, 0.25 mg/kg, 0.3 mg/kg kg, 0.35mg/kg, 0.4mg/kg, 0.45mg/kg, 0.5mg/kg, 0.55mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1mg/kg , 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 7mg/kg, 8mg/kg, 9mg/kg, 10mg/kg, 11mg/kg, 12mg/kg, 13mg/kg, 14mg /kg, 15mg/kg, 16mg/kg, 17mg/kg, 18mg/kg, 19mg/kg or 20mg/kg; preferably, the
  • the above doses of the substance Y may be administered at a frequency of QW (once a week), BIW (twice a week) or Q2W (once a fortnight).
  • the substance Y is administered at QW frequency at the doses described above.
  • the substance Y is administered by injection according to the above dosage and frequency.
  • the substance Y may also be administered to the patient in a fixed dose, ie a fixed or predetermined amount of dose is given to the patient.
  • a fixed dose ie a fixed or predetermined amount of dose is given to the patient.
  • fixed doses meaning single doses
  • the dose of substance Y is 1-10 mg, eg 5 mg.
  • the above-mentioned fixed dose of the substance Y may be administered with a frequency of QW (once a week), BIW (twice a week) or Q2W (once a fortnight).
  • the substance Y is administered at the QW frequency at the above fixed dose.
  • the substance Y is administered by injection (eg, intravenously, subcutaneously or intramuscularly) according to the above-mentioned fixed dose and frequency.
  • the substance Y is administered by injection in the fixed dose, QW, described above.
  • the substance Y is administered by injection at 5 mg, QW.
  • the substance X is administered orally; and, the substance Y is administered by injection (eg, intravenously, subcutaneously, or intramuscularly).
  • the substance X is administered orally at 0.05-0.5 mg/kg, QD; and the substance Y is administered at 1-10 mg, QW, by injection (eg, intravenously, subcutaneously or intramuscularly).
  • the substance X is administered orally at 0.2 mg/kg, QD; and the substance Y is administered at 5 mg, QW, by injection (eg, intravenously, subcutaneously, or intramuscularly).
  • the substance X is administered orally at 0.2 mg/kg, QD, and the first therapeutic agent is compound I; and, the substance Y is injected (eg, intravenously, subcutaneously, or intramuscularly) according to 5 mg, administered QW.
  • substance X and substance Y When substance X and substance Y are administered separately, they may be administered continuously according to the respective administration periods.
  • the dosing cycles of Substance X and Substance Y may begin at the same time or at different times.
  • Substance X and Substance Y can be administered consecutively in their respective dosing cycles starting on the same day; alternatively, Substance X can be administered starting on the second or third day or more after Substance Y is started, and then both Continuous administration according to the respective dosing cycle.
  • Item 1 A pharmaceutical combination comprising substance X and substance Y;
  • the substance X is a first therapeutic agent, a pharmaceutically acceptable salt thereof, a solvate thereof, and a solvate of a pharmaceutically acceptable salt thereof, and the first therapeutic agent is compound I, samotolisib, copanilisb, SHC014748M, pilaralisib, YZJ-0673, gedatolisib, omipalisib, bimiralisib, voxtalisib, AL58805, or HEC68498;
  • the substance Y is Fulvestrant, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof;
  • Item 2 The drug combination according to Item 1, wherein the first therapeutic agent is compound I.
  • Item 3 The pharmaceutical combination according to Item 1, wherein the substance X and the substance Y are administered simultaneously or separately;
  • said pharmaceutical combination consists of said substance X and said substance Y.
  • Item 4 The pharmaceutical combination according to at least one of items 1-3, wherein the substance X is administered orally;
  • said substance Y is administered by subcutaneous injection.
  • composition A comprising substance X, substance Y and pharmaceutical excipients,
  • the substance X is a first therapeutic agent, a pharmaceutically acceptable salt thereof, a solvate thereof, and a solvate of a pharmaceutically acceptable salt thereof, and the first therapeutic agent is compound I, samotolisib, copanilisb, SHC014748M, pilaralisib, YZJ-0673, gedatolisib, omipalisib, bimiralisib, voxtalisib, AL58805, or HEC68498;
  • the substance Y is Fulvestrant, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof.
  • Item 6 The pharmaceutical composition A according to Item 5, wherein the first therapeutic agent is compound I.
  • Item 7 The pharmaceutical composition A as described in Item 5 or 6, wherein the pharmaceutical composition A is presented in an oral dosage form or an injection dosage form;
  • the pharmaceutical composition A consists of the substance X, the substance Y and pharmaceutical excipients.
  • a pharmaceutical composition B comprising a first pharmaceutical composition and a second pharmaceutical composition
  • the first pharmaceutical composition comprises substance X and a pharmaceutical excipient, and the substance X is a first therapeutic agent, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof,
  • the first therapeutic agent is compound I, samotolisib, copanilisb, SHC014748M, pilaralisib, YZJ-0673, gedatolisib, omipalisib, bimiralisib, voxtalisib, AL58805 or HEC68498; and,
  • the second pharmaceutical composition comprises substance Y and pharmaceutical excipients, and the substance Y is Fulvestrant, a pharmaceutically acceptable salt thereof, a solvate thereof, and a solvate of a pharmaceutically acceptable salt thereof.
  • Item 10 The pharmaceutical composition B according to item 8 or 9, wherein the first pharmaceutical composition is presented in an oral dosage form;
  • the second pharmaceutical composition is presented in the form of injection.
  • Item 11 The pharmaceutical composition B according to Item 10, wherein the pharmaceutical composition B consists of the first pharmaceutical composition and the second pharmaceutical composition.
  • Item 12 A pharmaceutical combination according to at least one of Items 1-4, pharmaceutical composition A according to at least one of Items 5-7, or pharmaceutical composition B according to at least one of Items 8-11 Application in preparation of medicine for treating breast cancer.
  • a substance X in the preparation of a medicament for treating breast cancer, the substance X being a solvent for the first therapeutic agent, its pharmaceutically acceptable salt, its solvate, and its pharmaceutically acceptable salt compound
  • the first therapeutic agent is compound I, samotolisib, copanilisb, SHC014748M, pilaralisib, YZJ-0673, gedatolisib, omipalisib, bimiralisib, voxtalisib, AL58805 or HEC68498, characterized in that the substance X is combined with substance Y
  • the substance Y is Fulvestrant, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof.
  • Item 14 The use according to Item 13, wherein the first therapeutic agent is compound I.
  • Item 15 The use of a substance Y in the preparation of a medicament for treating breast cancer, the substance Y being fulvestrant, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, It is characterized in that the substance Y is used in combination with substance X, wherein the substance X is the first therapeutic agent, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof,
  • the first therapeutic agent is compound I, samotolisib, copanilisb, SHC014748M, pilaralisib, YZJ-0673, gedatolisib, omipalisib, bimiralisib, voxtalisib, AL58805 or HEC68498.
  • Item 16 The use according to Item 15, wherein the first therapeutic agent is compound I.
  • Item 17 The use according to at least one of Items 12-16, wherein the breast cancer is HR-positive, HER2-negative, and PIK3CA gene-altered breast cancer.
  • Item 18 The use according to at least one of Items 12-16, wherein the breast cancer is HR-positive, HER2-negative, and advanced breast cancer with PIK3CA gene alteration.
  • Item 19 The use according to at least one of Items 12-16, wherein the breast cancer is resistant to endocrine therapy combined with CDK4/6 inhibitor therapy.
  • Item 20 The application according to at least one of Items 12-16, wherein the breast cancer is breast cancer resistant to estradiol combined with Palbociclib treatment.
  • Item 21 Use according to at least one of Items 12-20, characterized in that the substance X and the substance Y are administered simultaneously or separately.
  • Item 22 The use according to at least one of Items 12-20, wherein the substance X is administered orally;
  • said substance Y is administered by subcutaneous injection.
  • Item 23 Use of a substance X in the preparation of a medicament for treating breast cancer, the substance X being the first therapeutic agent, a pharmaceutically acceptable salt thereof, a solvate thereof, and a solvate of a pharmaceutically acceptable salt thereof
  • the first therapeutic agent is compound I, samotolisib, copanilisb, SHC014748M, pilaralisib, YZJ-0673, gedatolisib, omipalisib, bimiralisib, voxtalisib, AL58805 or HEC68498, and the breast cancer is HR positive, HER2 negative, PIK3CA Genetically altered breast cancer or breast cancer resistant to endocrine therapy combined with CDK4/6 inhibitor therapy.
  • treatment refers to therapeutic therapy.
  • treatment means: (1) amelioration of one or more biological manifestations of the disease or condition, (2) interference with (a) one or more points in the biological cascade leading to or causing the condition or (b ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, Or (4) slowing the development of the disorder or one or more biological manifestations of the disorder.
  • the term "therapeutically effective amount” refers to an amount of a compound sufficient to effectively treat a disease or condition described herein when administered to a patient.
  • the amount of a compound that constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as necessary by those skilled in the art.
  • composition refers to a composition containing the specified active ingredients, which can be prepared in the same dosage form.
  • patient refers to any animal, preferably a mammal, and most preferably a human, that is about to or has received the administration of the compound or composition according to the embodiments of the present invention.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being most preferred.
  • pharmaceutical excipients refers to the excipients and additives used in the production of medicines and formulation of prescriptions, and refers to all substances contained in pharmaceutical preparations except active ingredients. See Pharmacopoeia of the People's Republic of China (2020 edition) four, or, Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).
  • pharmaceutically acceptable means that the acid or base (used to prepare the salt), solvent, excipient, etc. are generally non-toxic, safe and suitable for use by patients.
  • the "patient” is preferably a mammal, more preferably a human.
  • the term "pharmaceutically acceptable salt” refers to a salt of a compound prepared with a relatively non-toxic, pharmaceutically acceptable acid or base.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base either in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, diethanolamine salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid, either neat solution or in a suitable inert solvent.
  • a pharmaceutically acceptable acid includes inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate root, phosphorous acid, sulfuric acid, bisulfate, etc.
  • the pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (ie 4,4'-methylene-bis( 3-hydroxy-2-naphthoic acid)), amino acids (eg glutamic acid, arginine) and the like.
  • the compound When the compound contains relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt.
  • a base addition salt or an acid addition salt For details, see Berge et al., “Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention is to provide a drug combination comprising the first therapeutic agent and Fulvestrant, to treat breast cancer after endocrine therapy combined with CDK4/6 inhibitors to treat drug-resistant breast cancer, and to use the first therapeutic agent and Fulvestrant in combination better.
  • DMSO purchased from Sigma
  • FBS purchased from GIBCO
  • PRMI1640 purchased from GIBCO
  • trypsin purchased from GIBCO
  • MCF7 cells purchased from ATCC, HTB-22
  • 100 U/mL penicillin and 100 ⁇ g/mL streptomycin purchased from GIBCO
  • estrogen purchased from Sichuan Jinke Pharmaceutical Co., Ltd., estradiol benzoate injection
  • palbociclib purchased from Shanghai Yuanye Biotechnology Co., Ltd.
  • Fulvestrant Fulvestrant, purchased from Shanghai Yishi Chemical Co., Ltd.
  • CDK4/6 drug-resistant MCF7 tumors CDK4/6 drug-resistant MCF7 cells were cultured in vitro as a monolayer, and the culture conditions were 10% fetal bovine serum, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin in RPMI1640 medium cultured under the conditions of 37°C, 5% CO 2 , and 95% relative humidity, and passaged twice a week with trypsinization. When the cells were in the logarithmic growth phase, the digested cells were used for inoculation.
  • the CDX model was constructed by subcutaneous transplantation of MCF7 cells, and 100 mg/kg palbociclib was continuously administered until the tumor showed continuous growth, which was defined as P0.
  • a tumor that was passaged again was defined as P1
  • a tumor that was passed n times was defined as Pn.
  • the passaged tumors were continuously treated with 50 mg/kg or 100 mg/kg palbociclib until drug resistance occurred (there was no statistical difference between the palbociclib treatment group and the solvent control group in the animal model) before the tumor passage.
  • the tumor used in this experiment was P6.
  • mice BALB/c nude mice, female, 6-8 weeks (the age of mice at the time of tumor cell inoculation), weighing 17-23 g, purchased from Shanghai Family Planning Research Institute.
  • Tumor inoculation Before tumor inoculation, experimental mice were subcutaneously injected with estrogen at a dose of 0.04 mg, twice a day. Experimental mice need continuous injection of estrogen throughout the test period. Experimental mice were subcutaneously inoculated with about 30 mm 3 CDK4/6 inhibitor-resistant MCF7 tumors, and the tumor growth was observed regularly. When the average volume of the tumor was about 200mm 3 , the patients were randomly divided into groups according to the size of the tumor.
  • Experimental grouping The experiment was divided into solvent control group, test drug compound I (0.2mg/kg) group, test drug Fulvestrant (5mg/mouse) group, test drug Palbociclib (50mg/kg) group, Palbociclib (50mg/kg) combined with Fulvestrant (5mg/mouse) group, compound I (0.2mg/kg) combined with Fulvestrant (5mg/mouse) group, 5 rats in each group, and the specific administration data are shown in Table 1 below.
  • Disease model animals received different treatment regimens, and the tumor volume of the animals was measured every day until the end of the experiment.
  • Vehicle 1 1% DMSO+99% double distilled water (1% methylcellulose)
  • the experimental results are as follows: on the 21st day after administration, the average tumor volume of the vehicle control group was 959 mm 3 .
  • the average tumor volumes of the compound I administration group and the Fulvestrant administration group were 485 mm 3 and 929 mm 3 , and TGI were 61.05% and 3.85%, respectively.
  • Table 3 Evaluation of antitumor efficacy of each treatment group (calculated based on the tumor volume on day 21 after administration)
  • c. p-values are calculated based on tumor volume.
  • Example 2 Test the IC 50 of compound I combined with Fulvestrant in MCF7 tumor cell line by CTG method
  • CCG CellTiter-Glo
  • FBS fetal bovine serum
  • ExCell fetal bovine serum
  • trypsin-EDTA purchased from Gibco
  • DMSO purchased from Sigma
  • MEM medium purchased from Hyclone
  • NEAA purchased from Gibco
  • Fulvestrant fulvestrant, purchased from Shanghai Yishi Chemical Co., Ltd.
  • Human breast cancer cell MCF7 was cultured in a single layer in vitro.
  • the culture conditions were MEM medium plus 10% fetal bovine serum and 1% NEAA, cultured at 37°C, 5% CO 2 , and 95% relative humidity, and twice a week with 0.25% Trypsin-EDTA digestion and passage, when the cells are in the logarithmic growth phase, the digested cells are used for inoculation.
  • Cells in exponential growth phase were harvested and viable cell counts were performed with a Vi-Cell XR cell counter. Adjust the cell suspension to an appropriate concentration with the corresponding medium. Add 80 ⁇ L of cell suspension to each well in a 96-well cell culture plate, and the final cell concentration is 8000 cells/well.
  • a 10 mM stock solution of each test compound was dissolved in DMSO. A 5-fold serial dilution was prepared from the stock solution and DMSO. Then each was diluted 100-fold with MEM medium. In the 96-well cell culture plate, MCF7 tumor cells were added 10 ⁇ L of compound I 10 times solution in the form of 6X6, and then 10 ⁇ L of Fulvestrant 10 times solution was added respectively, so that compound I and Fulvestrant were combined to treat MCF7 tumor cells, each drug concentration was 3 For multiple wells, the concentration range of the test compound used in the final test can be found in the compound preparation method and sample loading design on the back page. The test compound was diluted, and the final concentration of DMSO in each well was 0.2%. Placed in a 37°C, 5% CO 2 incubator for 72 hours.
  • the inhibition rate of Compound I combined with Fulvestrant to inhibit the proliferation of MCF7 in vitro is shown in Table 4 below.
  • the inhibition of Fulvestrant single drug on MCF7 cells reached saturation at 8nM, and the maximum inhibition rate was 36.01%.
  • the increase of Compound I concentration made the inhibitory rate increased to 48.23% (Compound I was 0.32nM); 63.81% (Compound I was 1.6nM); 73.31% (Compound I is 8nM).

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Abstract

L'invention concerne une combinaison pharmaceutique et son utilisation. La combinaison pharmaceutique comprend une substance X et une substance Y. Lorsqu'une thérapie endocrinienne est utilisée en combinaison avec des inhibiteurs de CDK4/6 pour traiter un cancer du sein présentant une résistance aux médicaments, la combinaison pharmaceutique a un meilleur effet thérapeutique en combinaison avec un premier agent thérapeutique et du Fulvestrant.
PCT/CN2022/122744 2021-09-30 2022-09-29 Combinaison pharmaceutique et son utilisation WO2023051725A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106456776A (zh) * 2014-05-21 2017-02-22 豪夫迈·罗氏有限公司 用PI3K抑制剂Pictilisib治疗PR阳性腔性A乳腺癌的方法
WO2017101829A1 (fr) * 2015-12-16 2017-06-22 辰欣药业股份有限公司 Forme cristalline d'un analogue de pyrido[1,2-a]pyrimidone, son procédé de préparation et son intermédiaire
WO2020076432A1 (fr) * 2018-10-08 2020-04-16 Genentech, Inc. Méthodes de traitement du cancer avec des inhibiteurs de pi3k alpha et de la metformine
WO2021113219A1 (fr) * 2019-12-03 2021-06-10 Genentech, Inc. Polythérapies pour le traitement du cancer du sein
WO2021174195A2 (fr) * 2020-02-29 2021-09-02 The University Of Vermon Utilisation de thyromimétiques pour le traitement du cancer
WO2021180111A1 (fr) * 2020-03-10 2021-09-16 正大天晴药业集团股份有限公司 Combinaison pharmaceutique comprenant un composé pyridino[1,2-a]pyrimidinone

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106456776A (zh) * 2014-05-21 2017-02-22 豪夫迈·罗氏有限公司 用PI3K抑制剂Pictilisib治疗PR阳性腔性A乳腺癌的方法
WO2017101829A1 (fr) * 2015-12-16 2017-06-22 辰欣药业股份有限公司 Forme cristalline d'un analogue de pyrido[1,2-a]pyrimidone, son procédé de préparation et son intermédiaire
WO2020076432A1 (fr) * 2018-10-08 2020-04-16 Genentech, Inc. Méthodes de traitement du cancer avec des inhibiteurs de pi3k alpha et de la metformine
WO2021113219A1 (fr) * 2019-12-03 2021-06-10 Genentech, Inc. Polythérapies pour le traitement du cancer du sein
WO2021174195A2 (fr) * 2020-02-29 2021-09-02 The University Of Vermon Utilisation de thyromimétiques pour le traitement du cancer
WO2021180111A1 (fr) * 2020-03-10 2021-09-16 正大天晴药业集团股份有限公司 Combinaison pharmaceutique comprenant un composé pyridino[1,2-a]pyrimidinone

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