WO2020088641A1 - 化合物a与化合物b联合在制备治疗痛风或高尿酸血症的药物中的用途 - Google Patents

化合物a与化合物b联合在制备治疗痛风或高尿酸血症的药物中的用途 Download PDF

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Publication number
WO2020088641A1
WO2020088641A1 PCT/CN2019/114980 CN2019114980W WO2020088641A1 WO 2020088641 A1 WO2020088641 A1 WO 2020088641A1 CN 2019114980 W CN2019114980 W CN 2019114980W WO 2020088641 A1 WO2020088641 A1 WO 2020088641A1
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Prior art keywords
compound
febuxostat
formula
uric acid
administered
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PCT/CN2019/114980
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English (en)
French (fr)
Inventor
陈建文
沈扬
宁睿
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江苏恒瑞医药股份有限公司
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Priority to JP2021523073A priority Critical patent/JP2022505976A/ja
Priority to AU2019370062A priority patent/AU2019370062A1/en
Priority to MX2021004811A priority patent/MX2021004811A/es
Priority to US17/288,742 priority patent/US20210393610A1/en
Priority to EP19877607.2A priority patent/EP3875087A4/en
Priority to CA3117761A priority patent/CA3117761A1/en
Priority to BR112021007084-2A priority patent/BR112021007084A2/pt
Priority to KR1020217015376A priority patent/KR20210089176A/ko
Priority to CN201980050251.1A priority patent/CN112512526B/zh
Publication of WO2020088641A1 publication Critical patent/WO2020088641A1/zh

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present disclosure belongs to the field of medicine, and relates to the use of compound A in combination with compound B selected from febuxostat and allopurinol in the preparation of a medicine for treating gout.
  • Hyperuricemia is a metabolic disease caused by impaired purine metabolism. Clinically, it is divided into two categories: primary and secondary. Primary hyperuricemia is mostly caused by congenital abnormalities of purine metabolism, often associated with obesity, glucose and lipid metabolism disorders, atherosclerosis, coronary heart disease and high Blood pressure and other aggregation occur, the latter is caused by certain systemic diseases or drugs. When the concentration of serum uric acid (sUA) is 6.8mg / dl, the saturation state of uric acid solubility is reached, and beyond this level is defined as hyperuricemia (HUA).
  • sUA serum uric acid
  • HUA serum uric acid
  • Febuxostat is a xanthine oxidase inhibitor (XOIs) and is commonly used in the treatment of gout.
  • XOIs xanthine oxidase inhibitor
  • the average half-life of the terminal elimination phase of febuxostat in the steady state ranged from 5 to 6 hours, and the steady state was basically reached after one administration.
  • 40% -70% of patients with febuxostat still cannot achieve the clinically recommended sUA level.
  • the American Rheumatology Association recommends the combination of uric acid excretion drug therapy.
  • Allopurinol can inhibit xanthine oxidase, so that hypoxanthine and xanthine can not be converted into uric acid, that is, the synthesis of uric acid is reduced, thereby reducing the concentration of uric acid in the blood, and reducing the deposition of urate in bones, joints and kidneys.
  • the Lesinurad 400 mg plus febuxostat group had a higher incidence of TEAE compared to febuxostat alone.
  • the incidence of renal-related adverse events of Recinald 400mg combined with febuxostat increased nearly twice (5.5% vs 10.1%), and serum creatinine increased ⁇ 1.5 times
  • the baseline increased to 10.1% (2.8% vs 10.1%), and serum creatinine increased ⁇ 2 times the baseline to 5.5% (0% vs 5.5%).
  • CN104470898A discloses that compounds of formula (I) and their pharmaceutically acceptable salts and esters are highly selective URAT1 inhibitors. By inhibiting URAT1, uric acid excretion can be increased and serum uric acid (sUA) levels can be significantly reduced.
  • the present disclosure provides a method for the combined treatment of gout or hyperuricemia with compound A and compound B, and shows good therapeutic effects, minor adverse reactions (easy recovery / resolution).
  • Compound A is selected from compounds of formula (I), or a pharmaceutically acceptable salt, or ester thereof, and compound B is selected from allopurinol and febuxostat.
  • the compound A and the compound B have a synergistic uric acid lowering effect.
  • the compound A is preferably a compound of formula (I-1).
  • the compound B is preferably febuxostat.
  • the pharmaceutically acceptable salt may be hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluorate, phosphate, acetate, propionate, succinate , Oxalate, malate, succinate, fumarate, maleate, tartrate, or trifluoroacetate, and may also be alkali metal ion salts of compounds such as sodium and potassium salts.
  • the ester may be a C 1-7 linear alkyl ester, a C 3-7 branched alkyl ester, a C 1-4 haloalkyl ester, a C 3-7 cycloalkyl ester, an aryl ester, a heterocyclic aryl group Ester etc.
  • the present disclosure provides the use of compound A in combination with compound B in the preparation of a medicament for treating gout or hyperuricemia.
  • the compound A and the compound B have a synergistic uric acid lowering effect.
  • Compound A is selected from compounds of formula (I), or a pharmaceutically acceptable salt, or ester thereof, and compound B is selected from allopurinol and febuxostat.
  • the compound A is preferably a compound of formula (I-1).
  • the compound B is preferably febuxostat.
  • the subject's serum uric acid level drops below 6 mg / dl.
  • the weight ratio of compound A to febuxostat is selected from 0.01-100: 1, preferably from 1:20, 1:19, 1:18, 1:17, 1:16, 1:15, 1:14, 1:13, 1:12, 1:11, 1:10, 1: 9, 1: 8, 2:15, 1: 7, 1: 6, 1: 5, 5:24, 2: 9, 1: 4, 4:15, 5:18, 2: 7, 3:10, 5:16, 1: 3, 5:14, 3: 8, 2: 5, 5:12, 3: 7, 4: 9, 1: 2, more preferably 1:16, 1: 8, 1: 4, 1: 2.
  • the weight ratio of compound A to allopurinol is selected from 0.01-100: 2, preferably from 0.01-1: 2, more preferably from 1: 180, 1: 170, 1: 160, 1: 150, 1: 140, 1: 130, 1: 120, 1: 110, 1: 100, 1:90, 1:80, 1:70, 1:60, 1:50, 1:40, 1:30, 1: 20, 1:10, 1: 5.
  • the amount of Compound A is selected from 1-100 mg, preferably 1-50 mg, more preferably 1-20 mg, most preferably about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, About 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg.
  • the amount of febuxostat is selected from 1-200 mg, preferably 10-120 mg, more preferably about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90mg, about 100mg, about 110mg, about 120mg.
  • the amount of allopurinol is selected from 50-900 mg, preferably 100-600 mg, more preferably 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg.
  • the route of administration is selected from oral administration, parenteral administration, and transdermal administration.
  • the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, and intramuscular injection, preferably oral administration.
  • both Compound A and Compound B are administered orally.
  • both Compound A and Compound B are administered in tablet form.
  • the administration frequency of Compound A may be once a day, twice a day, once every two days, and once every three days.
  • the administration frequency of Compound B may be once a day, twice a day, three times a day, once every two days, and once every three days.
  • Compound A is administered orally once a day
  • Compound B is administered once a day.
  • the compound of formula (I-1) is administered orally once daily and febuxostat is administered orally once daily.
  • the compound of formula (I-1) is administered orally once a day, 5 mg or 10 mg, and febuxostat is administered orally once a day, 20 mg, 40 mg, or 80 mg.
  • the compound of formula (I-1) is administered orally once a day, 5 mg or 10 mg, allopurinol is orally administered once or twice or three times a day, and the administered dose is 50 mg, 100 mg, 150 mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg.
  • the methods described in this disclosure include administering any suitable amount (effective amount) of Compound A to an individual in need.
  • about 1-100 mg of Compound A is administered.
  • about 1-50 mg of Compound A is administered.
  • about 1-20 mg of Compound A is administered.
  • the methods described in the present disclosure include administering to the individual in need any suitable amount (effective amount) of Compound B selected from febuxostat and allopurinol.
  • about 1-200 mg febuxostat is administered, preferably 10-120 mg, more preferably about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, About 100mg, about 110mg, about 120mg.
  • about 50-900 mg of allopurinol is administered, preferably about 100-600 mg, more preferably about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or about 600 mg.
  • about 1-20 mg of Compound A and about 20 mg of febuxostat are administered. In some embodiments, about 1-20 mg of Compound A and about 40 mg of febuxostat are administered. In some embodiments, about 1-20 mg of Compound A and about 80 mg of febuxostat are administered.
  • about 1-20 mg of Compound A and about 50-900 mg of allopurinol are administered. In some embodiments, about 1-20 mg of Compound A and about 100-600 mg of allopurinol are administered. In some embodiments, about 1-20 mg of Compound A and about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or about 600 mg of allopurinol are administered.
  • the present disclosure also provides a method of reducing the level of uric acid in one or more tissues, joints, organs, or blood of patients with elevated uric acid levels (eg, hyperuricemia or gout patients) by administering a therapeutically effective amount of Compound A.
  • the present disclosure provides a method for reducing uric acid levels in one or more tissues, joints, organs, or blood of a patient in need of lowering uric acid levels, including administering Compound A and Compound B to the patient.
  • the compound A and the compound B have a synergistic uric acid lowering effect.
  • Compound A and Compound B are administered simultaneously.
  • Compound A and Compound B are administered at different times.
  • Compound A is selected from compounds of formula (I), or a pharmaceutically acceptable salt, or ester thereof, and compound B is selected from allopurinol and febuxostat.
  • the compound A is preferably a compound of formula (I-1).
  • the compound B is preferably febuxostat.
  • about 10-120 mg febuxostat is administered. In some embodiments, about 20 mg of febuxostat is administered. In some embodiments, about 40 mg of febuxostat is administered. In some embodiments, about 80 mg of febuxostat is administered.
  • the present disclosure also provides methods for reducing uric acid levels in one or more tissues, joints, organs, or blood of a patient in need of lowering uric acid levels, including administering to the patient febuxostat and a compound of formula (I-1).
  • the febuxostat and the compound of formula (I-1) have a synergistic uric acid lowering effect.
  • febuxostat and the compound of formula (I-1) are administered simultaneously.
  • febuxostat and the compound of formula (I-1) are administered at different times.
  • about 10-120 mg febuxostat is administered.
  • about 20 mg of febuxostat is administered.
  • about 40 mg of febuxostat is administered.
  • about 80 mg of febuxostat is administered.
  • the present disclosure also provides a method for reducing uric acid levels in one or more tissues, joints, organs, or blood of a patient in need of lowering uric acid levels, including administering Compound A and Compound B to the patient.
  • Compound A and Compound B are administered simultaneously.
  • Compound A and Compound B are administered at different times.
  • about 1-50 mg of Compound A is administered.
  • about 1-20 mg of Compound A is administered.
  • about 1-20 mg of Compound A and about 10-120 mg of febuxostat are administered.
  • about 1-20 mg of Compound A and about 100-600 mg of allopurinol are administered.
  • the present disclosure also provides methods for reducing uric acid levels in one or more tissues, joints, organs, or blood of a patient in need of lowering uric acid levels, including administering to the patient febuxostat and a compound of formula (I-1).
  • febuxostat and the compound of formula (I-1) are administered simultaneously.
  • febuxostat and the compound of formula (I-1) are administered at different times.
  • about 1-50 mg of the compound of formula (I-1) is administered.
  • about 1-20 mg of the compound of formula (I-1) is administered.
  • the present disclosure also provides a method for reducing uric acid levels in one or more tissues, joints, organs, or blood of a patient in need of lowering uric acid levels, including administering to the patient allopurinol and a compound of formula (I-1).
  • allopurinol and the compound of formula (I-1) are administered simultaneously.
  • allopurinol and the compound of formula (I-1) are administered at different times.
  • about 1-50 mg of the compound of formula (I-1) is administered.
  • about 1-20 mg of the compound of formula (I-1) is administered.
  • a patient treated according to any method described in the present disclosure suffers from a disorder characterized by abnormally high uric acid content in one or more tissues or organs of the patient.
  • the disorder is characterized by excessive production of uric acid, low uric acid excretion, tumor lysis, blood disorder, or a combination thereof.
  • a patient in need of lowering serum uric acid levels and / or patients described in this disclosure suffers from gout, recurrent gout attacks, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, Lai Shi -Naphthalene syndrome, kelley-seegmiller syndrome, nephropathy, kidney stones, kidney failure, joint inflammation, arthritis, urinary calculi, lead poisoning, hyperparathyroidism, psoriasis or sarcoidosis.
  • the uric acid level of the individual receiving this treatment is reduced by at least about 10% (or> 10%).
  • the uric acid level is reduced by at least about 25% (or> 25%).
  • the uric acid level is reduced by at least about 50% (or> 50%).
  • the tissue or organ is blood.
  • the blood uric acid level of the individual receiving this treatment is reduced by at least about 1 mg / dl. In some embodiments, the blood uric acid level is reduced by at least about 1.5 mg / dl. In some embodiments, the blood uric acid level is reduced by at least about 2 mg / dl. In some embodiments, the blood uric acid level is reduced by at least about 2.5 mg / dl. In some embodiments, the blood uric acid level is reduced by at least about 3 mg / dl. In some embodiments, the blood uric acid level is reduced by at least about 3.5 mg / dl.
  • the blood uric acid level is reduced by at least about 4 mg / dl. In some embodiments, the blood uric acid level is reduced by at least about 4.5 mg / dl. In some embodiments, the blood uric acid level is reduced by at least about 5 mg / dl. In some embodiments, the blood uric acid level is reduced by at least about 5.5 mg / dl. In some embodiments, the blood uric acid level is reduced by at least about 6 mg / dl. In some embodiments, the blood uric acid level is reduced by more than about 6 mg / dl.
  • the blood uric acid level used in the present disclosure may refer to the uric acid level seen in whole blood or its constituent parts such as serum. The disclosure content of the serum uric acid level of the present disclosure should be understood as the disclosure content describing the blood uric acid level.
  • the blood uric acid level of the individual receiving this treatment drops to at least about 7 mg / dl (ie, to 7 mg / dl or less). In some embodiments, the blood uric acid level is reduced to at least about 6.5 mg / dl. In some embodiments, the blood uric acid level is reduced to at least about 6 mg / dl. In some embodiments, the blood uric acid level is reduced to at least about 5.5 mg / dl. In some embodiments, the blood uric acid level is reduced to at least about 5 mg / dl. In some embodiments, the blood uric acid level is reduced to at least about 4.5 mg / dl. In some embodiments, the blood uric acid level is reduced to at least about 4 mg / dl.
  • the present disclosure also provides a method for synergistically reducing serum uric acid levels, including administering Compound A and Compound B to a patient.
  • Compound A is selected from compounds of formula (I), or a pharmaceutically acceptable salt, or ester thereof, and compound B is selected from allopurinol and febuxostat.
  • the compound A is preferably a compound of formula (I-1).
  • the compound B is preferably febuxostat.
  • the present disclosure also describes a method of reducing a patient's serum uric acid level, which includes administering Compound A to a subject, and the patient has a serum uric acid level higher than 6.0 mg / dl before administration, and wherein the subject has a reduction after administration And lower than about 6.0mg / dl serum uric acid level.
  • the patient prior to treatment, has a serum uric acid level higher than 6.5 mg / dl, higher than 7.0 mg / dl, higher than 7.5 mg / dl, higher than 8.0 mg / dl or higher.
  • the compound A is selected from compounds of formula (I), or pharmaceutically acceptable salts, or esters thereof, preferably compounds of formula (I-1).
  • the method described in the present disclosure further comprises administering Compound B selected from febuxostat and allopurinol, said compound B is preferably febuxostat.
  • Compound A is administered in any suitable amount in the methods described in this disclosure. In some embodiments, about 1-50 mg of Compound A is administered. In some embodiments, about 1-20 mg of Compound A is administered. In some embodiments, Compound A is administered once a day. In some embodiments, Compound A is administered more than once per day. In some embodiments, Compound A is administered twice a day.
  • the compound A is selected from compounds of formula (I), or pharmaceutically acceptable salts, or esters thereof, preferably compounds of formula (I-1).
  • a method of treating or preventing hyperuricemia or gout comprises administering about 10-120 mg of febuxostat and the compound of formula (I-1).
  • the patient has received febuxostat treatment and the febuxostat treatment did not reduce serum uric acid levels to less than about 6 mg / ml, and is administered with febuxostat and the compound of formula (I-1) After that, the serum uric acid level fell below 6 mg / dl.
  • the present disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising Compound A, Compound B, and at least one pharmaceutically acceptable carrier.
  • the compound A is selected from compounds of formula (I), or pharmaceutically acceptable salts, or esters thereof, preferably compounds of formula (I-1).
  • the compound B is selected from febuxostat and allopurinol.
  • the composition contains about 1-50 mg of Compound A.
  • the composition contains about 1-20 mg of Compound A.
  • the composition comprises about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg of compound A.
  • the composition comprises about 10-120 mg febuxostat. In some embodiments, the composition contains about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg of febuxostat. . In some embodiments, the composition comprises about 50-900 mg allopurinol. In certain embodiments, about 100-600 mg of allopurinol is included in the composition. In some embodiments, about 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or about 600 mg allopurinol is included in the composition.
  • the compound A is preferably a compound of formula (I-1).
  • the compound B is preferably febuxostat.
  • Compound A and Compound B of the present disclosure have a synergistic effect when co-administered.
  • the compound A and the compound B of the present disclosure are used in combination with gout or hyperuricemia and have a synergistic effect.
  • Compound A and Compound B of the present disclosure have a synergistic effect on the reduction of serum uric acid when administered jointly.
  • the compound A and compound B of the present disclosure have a synergistic effect on the reduction of serum uric acid when administered jointly, and the concentration of sUA after administration has a certain decrease compared with the compound A alone, which has a synergistic pharmacodynamic uric acid lowering effect.
  • the compound A and the compound B of the present disclosure have a synergistic effect on the reduction of serum uric acid when administered jointly, and the concentration of sUA after administration has a certain decrease relative to the compound A alone, with a maximum decrease of 30-70%.
  • the compound A is selected from compounds of formula (I), or pharmaceutically acceptable salts, or esters thereof, preferably compounds of formula (I-1).
  • the compound B is selected from febuxostat and allopurinol, preferably febuxostat.
  • compound A and compound B refer to compound A, compound B itself or a pharmaceutical composition containing compound A or compound B.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof, or an ester thereof or the compound of formula (I-1) refers to the compound itself or a pharmaceutical composition containing the compound in a pharmaceutically acceptable form.
  • Febuxostat or allopurinol refers to any pharmaceutically acceptable form of the pharmaceutical composition containing febuxostat or allopurinol or to the febuxostat or allopurinol molecule itself.
  • the present disclosure regarding "combination” is a mode of administration, which refers to the administration of at least one dose of Compound A and at least one dose of Compound B within a certain period of time, where both substances exhibit pharmacological effects.
  • the time period may be within one administration cycle, within 1 week, or within 24 hours, more preferably within 12 hours.
  • Compound A and Compound B can be administered simultaneously or sequentially. This period includes treatments in which Compound A and Compound B are administered by the same route of administration or different routes of administration.
  • the combined administration method of the present disclosure is selected from simultaneous administration, independently formulated and co-administered, or independently formulated and sequentially administered.
  • the combination of the present disclosure may refer to the simultaneous administration of Compound A and Compound B, and the "simultaneous" used in the present disclosure refers to the administration of Compound A and Compound B at least partially overlapping in time. Therefore, simultaneous administration includes a dosing regimen that continues after one drug is stopped after the other drug is stopped.
  • an effective amount refers to an amount of medicine effective in treating a disease or condition in a mammal.
  • the dose refers to the daily dose.
  • Figure 1 colchicine, febuxostat, and compound of formula (I-1) after administration and combined administration of sUA concentration and relative baseline change percentage (Mean ⁇ SD);
  • Figure 2 Percent change (Mean ⁇ SD) of sUA from baseline D3-0h at various time points after multiple consecutive administrations of the compound of formula (I-1) and in combination with febuxostat.
  • Example 1 Drug interaction study of compound of formula (I-1), febuxostat and colchicine in patients with gout (single center, single arm, open, self-control)
  • Compound tablets of formula (I-1) 5mg / tablet, provided by Jiangsu Hengrui Pharmaceutical Co., Ltd .;
  • Febuxostat 80mg / tablet, provided by Jiangsu Hengrui Pharmaceutical Co., Ltd .;
  • Colchicine tablets 0.5mg / tablet, provided by Jiangsu Hengrui Pharmaceutical Co., Ltd .;
  • Subjects were screened during the screening period from D-21 to D-15, and those who passed the screening were given 0.5 mg colchicine once daily (qd) orally on an empty stomach (D-14 to D16). If the subject was receiving urate-lowering therapy (including allopurinol, febuxostat, benzbromarone, probenecid, etc.) at the time of screening, the drug should be stopped for at least 2 weeks before D1 day.
  • urate-lowering therapy including allopurinol, febuxostat, benzbromarone, probenecid, etc.
  • the subject was admitted to the Phase I clinical trial ward at D-2, and again conducted medical history inquiry, physical examination, vital signs examination, 12-lead electrocardiogram (ECG) examination, blood pregnancy examination (female childbearing age) [such as D-2 screening If the period exceeds 20 days, blood, urine routine, CK ⁇ CK-MB, blood biochemical (including serum creatinine and uric acid) examinations are also required].
  • ECG electrocardiogram
  • D3 to D6 were given orally in the morning with 240 ml of water on an empty stomach. After 1 hour, they were given a standard meal.
  • D-1, D1, D7 and D8 were given orally in the morning with 240 ml of water on an empty stomach. After 4h, eat the standard meal. After taking blood on D2, you can eat the standard meal and finish it within 20 minutes.
  • D3 ⁇ 8 daily drinking water is not less than 2L.
  • D9 can be discharged after completing relevant examinations and operations. He was hospitalized for a total of 10 days. D16 ⁇ 23 returned to the Phase I clinical trial ward for follow-up. Throughout the study, avoid strenuous exercise and prolonged bed rest. See Table 1 for drug administration.
  • Colchicine tablets D-14 ⁇ D16 0.5mg qd taken orally on an empty stomach;
  • Synovial fluid contains uric acid crystals
  • the inflammation reaches its heaviest within 1 day;
  • Body mass index (body weight / height squared) is between 18.5 and 30 (including both ends);
  • PK parameters of plasma compounds of formula (I-1), febuxostat (ruiyang) and colchicine are included in formula (I-1), febuxostat (ruiyang) and colchicine.
  • Safety indicators any adverse events (including gout attacks), physical examination, vital signs (heart rate, breathing, blood pressure, body temperature), laboratory tests (blood routine, urine routine, blood biochemistry, CK / CK-MB), 12-lead ECG and other inspections.
  • Fig. 1 and Fig. 2 show the serum uric acid (sUA) concentration and relative baseline change percentage after administration and combination of febuxostat and compound of formula (I-1) respectively.
  • febuxostat When gout patients are combined with febuxostat and the compound of formula (I-1), febuxostat has basically no effect on the steady-state exposure level of the compound of formula (I-1), but the compound of formula (I-1) causes febuxostat
  • the total exposure of statin (AUC 0-last and C max ) decreased slightly, and AUC 0-last and C max decreased by 11.46% and 13.58%, respectively, with no statistical difference (P> 0.05).
  • the concentration of sUA at each time point after administration is relatively -1)
  • the average maximum decrease occurs at 12h after co-administration
  • the maximum decrease percentage of sUA is 41.171%.
  • the above data indicate that after the combination of febuxostat and the compound of formula (I-1), the The uric acid lowering effect is significantly increased than when it is used alone, and it has a synergistic uric acid lowering effect on pharmacodynamics, so that the serum uric acid concentration of gout patients is significantly reduced.

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Abstract

本公开涉及化合物A与化合物B联合在制备治疗痛风或高尿酸血症的药物中的用途。具体而言，化合物A选自式(I)化合物、或其可药用盐、或其酯，化合物B选自别嘌呤醇、非布司他。尤其是式(I-1)化合物联合非布司他治疗痛风或高尿酸血症的方法，显示了良好的治疗效果

Description

化合物A与化合物B联合在制备治疗痛风或高尿酸血症的药物中的用途 技术领域
本公开属于医药领域，涉及化合物A与选自非布司他、别嘌呤醇的化合物B联合在制备治疗痛风的药物中的用途。
背景技术
高尿酸血症(HUA)是嘌呤代谢障碍引起的代谢性疾病。临床上分为原发性和继发性两大类，原发性高尿酸血症多由先天性嘌呤代谢异常所致，常与肥胖、糖脂代谢紊乱、动脉粥样硬化、冠心病和高血压等聚集发生，后者则由某些系统性疾病或药物引起。当血清尿酸(sUA)浓度为6.8mg/dl时，达到了尿酸溶解度的饱和状态，超过该水平则定义为高尿酸血症(HUA)。
部分高尿酸血症患者随着血尿酸水平的升高，过饱和状态的尿酸钠微小结晶析出，沉积于关节、滑膜、肌腱、肾及结缔组织等组织或器官(中枢神经系统除外)，形成痛风结石，引发急、慢性炎症和组织损伤，出现关节炎、尿路结石及肾脏疾病等多系统损害。约5％～12％的高尿酸血症者最终发展为痛风。
自20世纪80年代，随着我国人民生活水平提高，饮食习惯发生了改变，HUA患病率显著增加，沿海及发达地区达到5～23.5％。此外，HUA呈现年轻化趋势。除了急性发作外，痛风的其他症状包括骨质侵蚀和皮下痛风结节形成。多项研究证实长期持续降低血清尿酸(sUA)可以减少痛风发作和痛风结节的数量，并且使得痛风结节缩小。
非布司他属于黄嘌呤氧化酶抑制剂(XOIs)，是治疗痛风常用的药物。非布司他稳态终末消除相半衰期平均值范围为5～6h，给药1次基本可达稳态。但是用非布司他仍有40％-70％患者无法达到临床推荐的sUA水平，对于XOIs治疗不能达到推荐的sUA水平的患者，美国风湿协会建议联合促尿酸排泄的药物治疗。
别嘌呤醇可抑制黄嘌呤氧化酶，使次黄嘌呤及黄嘌呤不能转化为尿酸，即尿酸合成减少，进而降低血中尿酸浓度，减少尿酸盐在骨、关节及肾脏的沉着。
雷西纳德与非布司他联用的CRYSTAL III期临床数据表明(ARTHRITIS&RHEUMATOLOGY.Vol.69,No.9,September 2017,pp 1903–1913)，治疗6个月以后，单用非布司他组达到sUA<5.0mg/dl的患者为46.8％，Lesinurad 200mg加非布司他组为56.6％，Lesinurad 400mg加非布司他为76.1％，使用Lesinurad 400mg组的达标患者明显增多(P<0.0001)，而使用Lesinurad 200mg组(P＝0.13)与单用非布司他组的差异无统计学意义。但是Lesinurad 400mg加非布司他组与单用非布司他相比TEAE发生率增加。与非布司他单用 相比，雷西纳德400mg与非布司他联用的肾相关不良事件的发生率增加至将近两倍(5.5％v.s.10.1％)，血清肌酐升高≥1.5倍基线，升高至10.1％(2.8％v.s.10.1％)，血清肌酐升高≥2倍基线，升高至5.5％(0％v.s.5.5％)。
CN104470898A公开了式(I)化合物及其可药用盐、酯是高选择性URAT1抑制剂，通过抑制URAT1可以增加尿酸的排泄量而显著降低血清尿酸(sUA)水平。
Figure PCTCN2019114980-appb-000001
发明内容
本公开提供了化合物A与化合物B联合治疗痛风或高尿酸血症的方法，并显示了良好的治疗效果、轻微的不良反应(容易恢复/解决)。化合物A选自式(I)化合物、或其可药用盐、或其酯，化合物B选自别嘌呤醇、非布司他。所述的化合物A与化合物B具有协同降尿酸作用。所述的化合物A优选式(I-1)化合物。所述的化合物B优选非布司他。
Figure PCTCN2019114980-appb-000002
所述可药用盐可以是盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐，也可以是化合物的碱金属离子盐如钠盐、钾盐。所述酯可以是C 1-7直链烷基酯、C 3-7支链烷基酯、C 1-4卤代烷基酯、C 3-7环烷基酯、芳基酯、杂环芳基酯等。
本公开提供了化合物A联合化合物B在制备治疗痛风或高尿酸血症的药物中的用途。所述的化合物A与化合物B具有协同降尿酸作用。化合物A选自式(I)化合物、或其可药用盐、或其酯，化合物B选自别嘌呤醇、非布司他。所述的化合物A优选式(I-1)化合物。所述的化合物B优选非布司他。
在一些实施方案中，在施用化合物A和化合物B之后，受试者的血清尿酸水平降至低于6mg/dl。
在一些实施方案中，化合物A和非布司他的重量比例选自0.01-100:1，优选自1:20、1:19、1:18、1:17、1:16、1:15、1:14、1:13、1:12、1:11、1:10、1:9、1:8、2:15、1:7、1:6、1:5、5:24、 2:9、1:4、4:15、5:18、2:7、3:10、5:16、1:3、5:14、3:8、2:5、5:12、3:7、4:9、1:2，更优选自1:16、1:8、1:4、1:2。
在一些实施方案中，化合物A和别嘌呤醇的重量比例选自0.01-100:2，优选自0.01-1:2，更优选自1:180、1:170、1:160、1:150、1:140、1:130、1:120、1:110、1:100、1:90、1:80、1:70、1:60、1:50、1:40、1:30、1:20、1:10、1:5。
在一些实施方案中，化合物A的用量选自1-100mg，优选1-50mg，更优选1-20mg，最优选约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约11mg、约12mg、约13mg、约14mg、约15mg、约16mg、约17mg、约18mg、约19mg或约20mg。
在一些实施方案中，非布司他的用量选自1-200mg，优选10-120mg，更优选约10mg、约20mg、约30mg、约40mg、约50mg、约60mg、约70mg、约80mg、约90mg、约100mg、约110mg、约120mg。
在一些实施方案中，别嘌呤醇的用量选自50-900mg，优选100-600mg，更优选100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg。
给药途径选自经口给药、胃肠外给药、经皮给药，所述胃肠外给药包括但不限于静脉注射、皮下注射、肌肉注射，优选经口给药。在一些实施方案中，化合物A和化合物B均为口服给药。在一些实施方案中，化合物A和化合物B均以片剂形式给药。
化合物A的给药频次可以是一日一次、一日两次、两日一次、三日一次。化合物B的给药频次可以是一日一次、一日两次、一日三次、两日一次、三日一次。在一些实施方案中，化合物A每日口服给药一次，化合物B每日给药一次。在一些实施方案中，式(I-1)化合物每日口服给药一次，非布司他每日口服给药一次。在一些实施方案中，式(I-1)化合物每日口服给药一次，5mg或10mg，非布司他每日口服给药一次，20mg、40mg或80mg。本公开的优选实施方案中，式(I-1)化合物每日口服给药一次，5mg或10mg，别嘌呤醇每日口服给药一次或两次或三次，给药剂量50mg、100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg。
在一些实施方案中，本公开所述的方法包括向有需要的个体施用任何适量(有效量)的化合物A。在一些实施方案中，施用约1-100mg化合物A。在一些实施方案中，施用约1-50mg化合物A。在一些实施方案中，施用约1-20mg化合物A。在一些实施方案中，施用约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约11mg、约12mg、约13mg、约14mg、约15mg、约16mg、约17mg、约18mg、约19mg或约20mg化合物A。
在一些实施方案中，本公开所述的方法包括向有需要的个体施用任何适量(有效量)的选自非布司他、别嘌呤醇的化合物B。在一些实施方案中，施用约1-200mg非布司他，优选 10-120mg，更优选约10mg、约20mg、约30mg、约40mg、约50mg、约60mg、约70mg、约80mg、约90mg、约100mg、约110mg、约120mg。在一些实施方案中，施用约50-900mg别嘌呤醇，优选约100-600mg，更优选约100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg或约600mg。
在一些实施方案中，施用约1-20mg化合物A和约20mg的非布司他。在一些实施方案中，施用约1-20mg化合物A和约40mg非布司他。在一些实施方案中，施用约1-20mg化合物A和约80mg非布司他。
在一些实施方案中，施用约1-20mg化合物A和约50-900mg的别嘌呤醇。在一些实施方案中，施用约1-20mg化合物A和约100-600mg的别嘌呤醇。在一些实施方案中，施用约1-20mg化合物A和约100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg或约600mg的别嘌呤醇。
本公开还提供了通过施用治疗有效量的化合物A来降低尿酸水平升高的患者(例如高尿酸血症或痛风患者)的一个或多个组织、关节、器官或者血液中尿酸水平的方法。
本公开提供了用于降低需要降低尿酸水平的患者的一个或多个组织、关节、器官或者血液中尿酸水平的方法，包括向患者施用化合物A和化合物B。所述的化合物A和化合物B具有协同降尿酸作用。在一些实施方案中，同时施用化合物A和化合物B。在一些实施方案中，在不同时间施用化合物A和化合物B。化合物A选自式(I)化合物、或其可药用盐、或其酯，化合物B选自别嘌呤醇、非布司他。所述的化合物A优选式(I-1)化合物。所述的化合物B优选非布司他。在一些实施方案中，施用约10-120mg非布司他。在一些实施方案中，施用约20mg的非布司他。在一些实施方案中，施用约40mg的非布司他。在一些实施方案中，施用约80mg的非布司他。
本公开还提供了用于降低需要降低尿酸水平的患者的一个或多个组织、关节、器官或者血液中尿酸水平的方法，包括向患者施用非布司他和式(I-1)化合物。所述的非布司他和式(I-1)化合物具有协同降尿酸作用。在一些实施方案中，同时施用非布司他和式(I-1)化合物。在一些实施方案中，在不同时间施用非布司他和式(I-1)化合物。在一些实施方案中，施用约10-120mg非布司他。在一些实施方案中，施用约20mg的非布司他。在一些实施方案中，施用约40mg的非布司他。在一些实施方案中，施用约80mg的非布司他。
本公开还提供了用于降低需要降低尿酸水平的患者的一个或多个组织、关节、器官或者血液中尿酸水平的方法，包括向患者施用化合物A和化合物B。在一些实施方案中，同时施用化合物A和化合物B。在一些实施方案中，在不同时间施用化合物A和化合物B。。在一些实施方案中，施用约1-50mg化合物A。在一些实施方案中，施用约1-20mg的化合物A。 在一些实施方案中，施用约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约11mg、约12mg、约13mg、约14mg、约15mg、约16mg、约17mg、约18mg、约19mg或约20mg的化合物A。在一些实施方案中，施用约1-20mg的化合物A和约10-120mg的非布司他。在一些实施方案中，施用约1-20mg的化合物A和约100-600mg的别嘌呤醇。
本公开还提供了用于降低需要降低尿酸水平的患者的一个或多个组织、关节、器官或者血液中尿酸水平的方法，包括向患者施用非布司他和式(I-1)化合物。在一些实施方案中，同时施用非布司他和式(I-1)化合物。在一些实施方案中，在不同时间施用非布司他和式(I-1)化合物。在一些实施方案中，施用约1-50mg式(I-1)化合物。在一些实施方案中，施用约1-20mg的式(I-1)化合物。在一些实施方案中，施用约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约11mg、约12mg、约13mg、约14mg、约15mg、约16mg、约17mg、约18mg、约19mg或约20mg的式(I-1)化合物。在一些实施方案中，施用约1-20mg的式(I-1)化合物和约10-120mg的非布司他。
本公开还提供了用于降低需要降低尿酸水平的患者的一个或多个组织、关节、器官或者血液中尿酸水平的方法，包括向患者施用别嘌呤醇和式(I-1)化合物。在一些实施方案中，同时施用别嘌呤醇和式(I-1)化合物。在一些实施方案中，在不同时间施用别嘌呤醇和式(I-1)化合物。在一些实施方案中，施用约1-50mg式(I-1)化合物。在一些实施方案中，施用约1-20mg的式(I-1)化合物。在一些实施方案中，施用约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约11mg、约12mg、约13mg、约14mg、约15mg、约16mg、约17mg、约18mg、约19mg或约20mg的式(I-1)化合物。在一些实施方案中，施用约1-20mg的式(I-1)化合物和约100-600mg的别嘌呤醇。
在一些实施方案中，施用约1-50mg的化合物A。在一些实施方案中，施用约1-20mg的化合物A。在一些实施方案中，根据本公开描述的任何方法治疗的患者患有以患者的一个或多个组织或器官中的异常高尿酸含量为特征的病症。在一些实施方案中，病症的特征为尿酸过量产生、低尿酸排泄、肿瘤溶解、血液病症或其组合。在一些实施方案中，需要降低血清尿酸水平和/或本公开描述的患者患有痛风、复发性痛风发作、痛风性关节炎、高尿酸血症、高血压、心血管疾病、冠心病、莱施-萘恩综合征、kelley-seegmiller综合征、肾病、肾结石、肾衰竭、关节炎症、关节炎、尿路结石症、铅中毒、甲状旁腺功能亢进、银屑病或结节病。在一些实施方案中，在本公开所述的治疗后，接受这种治疗的个体的尿酸水平降低了至少约10％(或>10％)。在一些实施方案中，尿酸水平降低了至少约25％(或>25％)。在一些实施方案中，尿酸水平降低了至少约50％(或>50％)。在一些实施方案中，组织或器官是血液。
在一些实施方案中，在本公开所述的治疗后，接受这种治疗的个体的血尿酸水平降低了 至少约1mg/dl。在一些实施方案中，血尿酸水平降低了至少约1.5mg/dl。在一些实施方案中，血尿酸水平降低了至少约2mg/dl。在一些实施方案中，血尿酸水平降低了至少约2.5mg/dl。在一些实施方案中，血尿酸水平降低了至少约3mg/dl。在一些实施方案中，血尿酸水平降低了至少约3.5mg/dl。在一些实施方案中，血尿酸水平降低了至少约4mg/dl。在一些实施方案中，血尿酸水平降低了至少约4.5mg/dl。在一些实施方案中，血尿酸水平降低了至少约5mg/dl。在一些实施方案中，血尿酸水平降低了至少约5.5mg/dl。在一些实施方案中，血尿酸水平降低了至少约6mg/dl。在一些实施方案中，血尿酸水平降低了超过约6mg/dl。本公开使用的血尿酸水平可指在全血或其组成部分如血清中所见的尿酸水平。本公开对血清尿酸水平的公开内容应当被理解为描述血液尿酸水平的公开内容。
在一些实施方案中，在本公开描述的治疗后，接受这种治疗的个体的血尿酸水平至少降至约7mg/dl(即，降至7mg/dl或更低)。在一些实施方案中，血尿酸水平至少降至约6.5mg/dl。在一些实施方案中，血尿酸水平至少降至约6mg/dl。在一些实施方案中，血尿酸水平至少降至约5.5mg/dl。在一些实施方案中，血尿酸水平至少降至约5mg/dl。在一些实施方案中，血尿酸水平至少降至约4.5mg/dl。在一些实施方案中，血尿酸水平至少降至约4mg/dl。
本公开还提供了用于协同降低血清尿酸水平的方法，包括向患者施用化合物A和化合物B。化合物A选自式(I)化合物、或其可药用盐、或其酯，化合物B选自别嘌呤醇、非布司他。所述的化合物A优选式(I-1)化合物。所述的化合物B优选非布司他。
本公开还描述了降低患者的血清尿酸水平的方法，包括向受试者施用化合物A，并且在施用之前患者具有高于6.0mg/dl的血清尿酸水平，并且其中在施用之后受试者具有降低的且低于约6.0mg/dl的血清尿酸水平。在一些实施方案中，在治疗之前，患者具有高于6.5mg/dl、高于7.0mg/dl、高于7.5mg/dl、高于8.0mg/dl或更高的血清尿酸水平。所述的化合物A选自式(I)化合物、或其可药用盐、或其酯，优选式(I-1)化合物。在一些实施方案中，本公开所述的方法进一步包括施用选自非布司他、别嘌呤醇的化合物B，所述的化合物B优选非布司他。
在本公开描述的方法中以任何合适的量施用化合物A。在一些实施方案中，施用约1-50mg的化合物A。在一些实施方案中，施用约1-20mg的化合物A。在一些实施方案中，每天施用化合物A一次。在一些实施方案中，每天施用化合物A多于一次。在一些实施方案中，每天施用化合物A两次。所述的化合物A选自式(I)化合物、或其可药用盐、或其酯，优选式(I-1)化合物。
在一些实施方案中，治疗或预防高尿酸血症或痛风的方法包括施用约10-120mg的非布司他和式(I-1)化合物。在一些实施方案中，患者已接受非布司他治疗并且该非布司他治疗未 使血清尿酸水平降至低于约6mg/ml，并且在施用非布司他和式(I-1)化合物之后，血清尿酸水平降至低于6mg/dl。
本公开还提供了一种药物组合物，其包含化合物A、化合物B和至少一种药学上可接受的载体。所述的化合物A选自式(I)化合物、或其可药用盐、或其酯，优选式(I-1)化合物。所述的化合物B选自非布司他、别嘌呤醇。在一些实施方案中，该组合物包含约1-50mg化合物A。在一些实施方案中，该组合物包含约1-20mg化合物A。在一些实施方案中，该组合物包含约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约11mg、约12mg、约13mg、约14mg、约15mg、约16mg、约17mg、约18mg、约19mg或约20mg的化合物A。在一些实施方案中，该组合物包含约10-120mg非布司他。在一些实施方案中，组合物中包含约10mg、约20mg、约30mg、约40mg、约50mg、约60mg、约70mg、约80mg、约90mg、约100mg、约110mg、约120mg的非布司他。在一些实施方案中，该组合物包含约50-900mg别嘌呤醇。在某些实施方案中，组合物中包含约100-600mg别嘌呤醇。在一些实施方案中，组合物中包含约100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg或约600mg别嘌呤醇。所述的化合物A优选式(I-1)化合物。所述的化合物B优选非布司他。
本公开的化合物A与化合物B联合施用时，具有协同作用。本公开的化合物A与化合物B联合用于痛风或高尿酸血症，具有协同作用。本公开的化合物A与化合物B联合施用时，对血清尿酸的降低有协同作用。本公开的化合物A与化合物B联合施用时，对血清尿酸的降低有协同作用，给药后sUA的浓度相对于单用通化合物A时有一定的下降，具有药效动力学上的协同降尿酸作用。本公开的化合物A与化合物B联合施用时，对血清尿酸的降低有协同作用，给药后sUA的浓度相对于单用化合物A时有一定的下降，最大降幅为30-70％。所述的化合物A选自式(I)化合物、或其可药用盐、或其酯，优选式(I-1)化合物。所述的化合物B选自非布司他、别嘌呤醇，优选非布司他。
发明详述
本公开中，化合物A、化合物B指化合物A、化合物B本身或者指包含化合物A或化合物B的药物组合物。式(I)化合物、或其可药用盐、或其酯或式(I-1)化合物指的是化合物本身或者包含化合物的可药用形式的药物组合物。非布司他或别嘌呤醇是指包含非布司他或别嘌呤醇的任何一种可药用形式的药物组合物或者指非布司他或别嘌呤醇分子本身。
本公开关于“联合”是一种给药方式，是指在一定时间期限内给予至少一种剂量的化合物A和至少一种剂量的化合物B，其中两种物质都显示药理学作用。所述的时间期限可以是一个给药周期内，1周内，或24小时以内，更优选12小时以内。可以同时或依次给予化合物A和化合物B。这种期限包括这样的治疗，其中通过相同给药途径或不同给药途径给予化 合物A和化合物B。本公开所述联合的给药方式选自同时给药、独立地配制并共给药或独立地配制并相继给药。
本公开的联合可以指同时给与化合物A和化合物B，所述“同时”用于本公开指化合物A和化合物B的施用至少部分在时间上重叠。因此，同时施用包括一种药物的施用在停止另外一种药物的施用后仍继续的给药方案。
术语“有效量”指在哺乳动物中有效治疗疾病或病症的药物量。
本公开中，除非特别说明，否则所述的剂量指每日剂量。
本公开中“约”表示包含误差在±5％的方案。
尿酸单位mg/dl和umol/l的换算：mg/dl×59.5＝μmol/l；μmol/l×0.0168＝mg/dl。
附图说明：
图1：秋水仙碱、非布司他、式(I-1)化合物分别给药及联合给药用后sUA浓度及相对基线变化百分比(Mean±SD)；
图2：式(I-1)化合物连续多次给药及与非布司他联用后各时间点sUA相对基线D3-0h变化百分比(Mean±SD)。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制本公开的范围。
实施例1：式(I-1)化合物、非布司他和秋水仙碱在痛风患者中的药物相互作用研究(单中心、单臂、开放、自身对照)
试验药品：
式(I-1)化合物片：5mg/片，由江苏恒瑞医药股份有限公司提供；
非布司他片(瑞扬)：80mg/片，由江苏恒瑞医药股份有限公司提供；
秋水仙碱片：0.5mg/片，由江苏恒瑞医药股份有限公司提供；
研究目的：
主要目的：评价痛风患者口服式(I-1)化合物、非布司他和秋水仙碱的药物代谢动力学(PK)
的相互作用。
次要目的：评价痛风患者口服式(I-1)化合物、非布司他和秋水仙碱的安全性、耐受性以及
药物效应动力学(PD)的相互作用。
研究过程：
受试者于D–21～D–15进行筛选期检查，筛选合格者给予0.5mg秋水仙碱每日一次(qd)空腹口服(D–14～D16)。如该受试者筛选时正在接受降尿酸治疗(包括别嘌呤醇、非布司他、苯溴马隆、丙磺舒等)，应在D1天前至少停药洗脱2周。受试者于D–2入住I期临床试验病房，再次进行病史询问、体格检查、生命体征检查、12导联心电图(ECG)检查、血妊娠检查(育龄期女性)[如D-2距筛选期超过20天，还需进行血、尿常规、CK\CK-MB、血生化(包括血清肌酐和尿酸)检查]。
受试者住院期间每日晚餐后禁食10h以上不禁水，D3～D6早晨空腹240ml水口服给药，1h后进食标准餐，D–1、D1、D7和D8早晨空腹240ml水口服给药，4h后再进食标准餐，D2空腹采血后即可进食标准餐，20分钟内吃完。除服药前和服药后1h禁水外，其它时间按需饮水，D3～8每日饮水不少于2L。D9完成相关检查和操作后可出院，共住院10日，D16～23返回I期临床试验病房进行随访。整个研究期间，避免剧烈运动和长时间卧床。给药情况详见表1。
表1、给药情况
D-21～D-1 D1 D2 D3～D7 D8 D9 D10～D23
秋水仙碱0.5mg qd(D-14～D16)
Figure PCTCN2019114980-appb-000003
秋水仙碱片：D-14～D16 0.5mg qd空腹口服；
非布司他片：D1和D8 80mg qd空腹口服；
式(I-1)化合物片：D3～D8 10mg qd空腹口服。
入选标准：
1.年龄在18～65(含两端值)岁的男性和非哺乳期、非妊娠期女性；
2.根据美国风湿病学会急性原发性痛风关节炎分类标准诊断为痛风(符合下面3项中的任何一项)：
1)痛风石确诊包含尿酸结晶；
2)关节液中含有尿酸结晶；
3)病史符合下列标准中至少6项：
i.至少1次急性关节炎发作；
ii.炎症在1天之内达到最重；
iii.单关节炎；
iv.关节发红；
v.第一趾关节疼痛或肿胀；
vi.单侧第一趾关节痛风发作；
vii.单侧跗关节痛风发作；
viii.痛风石；
ix.高尿酸血症；
x.X线摄片显示单侧关节肿胀；
xi.X线摄片检查示不伴侵蚀的骨皮质下囊肿；
xii.痛风发作期间关节腔液微生物培养阴性；
3.体重指数(体重/身高的平方)在18.5～30(含两端值)；
4. 8mg/dl(480μmol/l)≤筛选时sUA≤10mg/dl(600μmol/l)；
主要观察指标
血浆式(I-1)化合物、非布司他(瑞扬)和秋水仙碱的PK参数。
次要观察指标
1.sUA水平；
2.安全性指标：任何不良事件(包括痛风发作)、体格检查、生命体征(心率、呼吸、血压、体温)、实验室检查(血常规、尿常规、血生化、CK/CK-MB)、12导联ECG等检查。
试验结果：
表2、非布司他、式(I-1)化合物与秋水仙碱的PK相互作用
Figure PCTCN2019114980-appb-000004
Figure PCTCN2019114980-appb-000005
表3、非布司他和式(I-1)化合物PK相互作用
Figure PCTCN2019114980-appb-000006
非布司他、式(I-1)化合物分别给药及联用后血清尿酸(sUA)浓度及相对基线变化百分比见图1和图2。
表4、受试者所有不良事件严重程度分析(SS)
Figure PCTCN2019114980-appb-000007
Figure PCTCN2019114980-appb-000008
结论：
式(I-1)化合物、非布司他和秋水仙碱的药代动力学相互作用：非布司他与秋水仙碱联合用药时，对痛风患者体内秋水仙碱的主要PK参数的影响不大，表现为非布司他对秋水仙碱AUC ss基本没有影响，但秋水仙碱C ss,max有轻微下降，降低幅度为9.92％，无统计学差异(P>0.05)；式(I-1)化合物与秋水仙碱联合用药时，引起痛风患者体内秋水仙碱的总体暴露量水平(AUC ss和C ss,max)下降，下降幅度分别为9.84％和12.12％，但无统计学差异(P>0.05)。痛风患者联用非布司他和式(I-1)化合物时，非布司他对式(I-1)化合物稳态暴露水平基本没有影响，但是式(I-1)化合物会引起非布司他总体暴露量(AUC 0-last和C max)轻微降低，AUC 0-last和C max分别降低11.46％和13.58％，均无统计学差异(P>0.05)。
式(I-1)化合物、非布司他和秋水仙碱的药效动力学相互作用：秋水仙碱达稳态后，单次给予非布司他，血清尿酸(sUA)浓度相对于单用秋水仙碱时有所下降，平均最大降幅为22.144％；式(I-1)化合物连续给药后，血清sUA浓度相对基线(式(I-1)化合物给药前(D3-0h)持续下降，平均最大降幅为60.883％；非布司他与式(I-1)化合物联合给药时，对血清尿酸的降低有协同作用，给药后各时间点sUA的浓度相对于单用式(I-1)化合物时有一定下降，平均最大降幅出现在联合给药后12h，sUA最大下降百分比为41.171％。以上数据均表明， 非布司他与式(I-1)化合物联合用药后，相比单独使用时降尿酸效果显著增加，具有药效动力学上的协同降尿酸作用，使得痛风患者血清尿酸浓度明显降低。
整个研究过程中，无严重不良事件发生，共6例患者发生轻度不良事件，研究过程中恢复/解决。

Claims (13)

  1. 化合物A与化合物B联合在制备治疗痛风或高尿酸血症的药物中的用途，其中化合物A选自式(I)化合物、或其可药用盐、或其酯，优选式(I-1)化合物，化合物B选自别嘌呤醇、非布司他，
    Figure PCTCN2019114980-appb-100001
  2. 如权利要求1所述的用途，其特征在于，所述的化合物A与化合物B具有协同降尿酸作用。
  3. 如权利要求1所述的用途，其特征在于，所述的化合物A与非布司他的重量比例选自0.01-100:1，优选自1:20、1:19、1:18、1:17、1:16、1:15、1:14、1:13、1:12、1:11、1:10、1:9、1:8、2:15、1:7、1:6、1:5、5:24、2:9、1:4、4:15、5:18、2:7、3:10、5:16、1:3、5:14、3:8、2:5、5:12、3:7、4:9、1:2，更优选自1:16、1:8、1:4、1:2。
  4. 如权利要求1所述的用途，其特征在于，所述的化合物A与别嘌呤醇的重量比例选自0.01-100:2，优选自0.01-1:2，更优选自1:180、1:170、1:160、1:150、1:140、1:130、1:120、1:110、1:100、1:90、1:80、1:70、1:60、1:50、1:40、1:30、1:20、1:10、1:5。
  5. 如权利要求1所述的用途，其特征在于，所述的化合物A的用量选自1-100mg，优选1-50mg，更优选1-20mg，最优选约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约11mg、约12mg、约13mg、约14mg、约15mg、约16mg、约17mg、约18mg、约19mg或约20mg。
  6. 如权利要求1所述的用途，其特征在于，所述的非布司他的用量选自1-200mg，优选10-120mg，更优选约10mg、约20mg、约30mg、约40mg、约50mg、约60mg、约70mg、约80mg、约90mg、约100mg、约110mg、约120mg。
  7. 如权利要求1所述的用途，其特征在于，所述的别嘌呤醇的用量选自50-900mg，优选100-600mg，更优选100mg、150mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg。
  8. 如权利要求1所述的用途，其特征在于，化合物A和化合物B均为口服给药，优选化合物A和化合物B均以片剂形式给药。
  9. 式(I-1)化合物与非布司他联合在制备治疗高尿酸血症或痛风的药物中的用途。
  10. 如权利要求9所述的用途，其特征在于，式(I-1)化合物的用量选自5mg/qd、10mg/qd，非布司他的用量选自20mg/qd、40mg/qd、80mg/qd。
  11. 如权利要求9所述的用途，其特征在于，式(I-1)化合物的用量选自5mg/qd、10mg/qd，非布司他的用量选自20mg/qd、40mg/qd、80mg/qd，式(I-1)化合物与非布司他均为每日给药一次，以片剂形式给药。
  12. 一种药物组合物，包含
    选自式(I)化合物、或其可药用盐、或其酯的化合物A；
    选自非布司他、别嘌呤醇的化合物B；
    至少一种药学上可接受的载体；
    其中化合物A优选式(I-1)化合物，化合物B优选非布司他。
  13. 如权利要求12所述的药物组合物，其特征在于，所述式(I-1)化合物的含量为5mg或10mg，所述非布司他的含量选自20mg、40mg、80mg，所述别嘌呤醇的含量选自100-600mg。
PCT/CN2019/114980 2018-11-02 2019-11-01 化合物a与化合物b联合在制备治疗痛风或高尿酸血症的药物中的用途 WO2020088641A1 (zh)

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JP2021523073A JP2022505976A (ja) 2018-11-02 2019-11-01 痛風または高尿酸血症の治療のための薬剤の調製における化合物ａおよび化合物ｂの併用
AU2019370062A AU2019370062A1 (en) 2018-11-02 2019-11-01 Joint use of compound a and compound B in preparation of medications for treatment of gout or hyperuricemia
MX2021004811A MX2021004811A (es) 2018-11-02 2019-11-01 Uso conjunto de un compuesto a y un compuesto b en la preparacion de medicamentos para el tratamiento de gota o hiperuricemia.
US17/288,742 US20210393610A1 (en) 2018-11-02 2019-11-01 Compositions and methods for treating gout and hyperuricemia
EP19877607.2A EP3875087A4 (en) 2018-11-02 2019-11-01 JOINT USE OF COMPOUND A AND COMPOUND B IN THE PREPARATION OF MEDICINAL PRODUCTS FOR THE TREATMENT OF GOUT OR HYPERURICAEMIA
CA3117761A CA3117761A1 (en) 2018-11-02 2019-11-01 Joint use of compound a and compound b in preparation of medications for treatment of gout or hyperuricemia
BR112021007084-2A BR112021007084A2 (pt) 2018-11-02 2019-11-01 uso conjunto de composto a e composto b na preparação de medicamentos para tratamento de gota ou hiperuricemia
KR1020217015376A KR20210089176A (ko) 2018-11-02 2019-11-01 통풍 또는 고요산혈증의 치료를 위한 의약품의 제조에서의 화합물 a 및 화합물 b의 공동 용도
CN201980050251.1A CN112512526B (zh) 2018-11-02 2019-11-01 化合物a与化合物b联合在制备治疗痛风或高尿酸血症的药物中的用途

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