WO2023083296A1 - 用于降低尿酸水平的化合物 - Google Patents

用于降低尿酸水平的化合物 Download PDF

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WO2023083296A1
WO2023083296A1 PCT/CN2022/131336 CN2022131336W WO2023083296A1 WO 2023083296 A1 WO2023083296 A1 WO 2023083296A1 CN 2022131336 W CN2022131336 W CN 2022131336W WO 2023083296 A1 WO2023083296 A1 WO 2023083296A1
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uric acid
compound
use according
individual
hyperuricemia
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PCT/CN2022/131336
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English (en)
French (fr)
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李元念
陈瑾瑜
朱清华
朱倩
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恒翼生物医药(上海)股份有限公司
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Priority to US18/709,820 priority Critical patent/US20250000865A1/en
Publication of WO2023083296A1 publication Critical patent/WO2023083296A1/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
    • A61K31/495—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
    • A61K31/33—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
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

  • the present application relates to the field of disease treatment, in particular, the present application relates to PDE4 inhibitors (for example, 4-[1-(3-chlorophenyl)-7-methoxy-2,4-dioxo-pyrimido[5 , 4-c] quinoline-3-yl] cyclohexanecarboxylic acid or a pharmaceutically acceptable salt thereof) in preparation for reducing uric acid levels in individuals, preventing uric acid levels from increasing, treating, preventing or alleviating in individuals with Use in medicine for a disease, disorder or condition associated with elevated levels of uric acid (eg, gout, hyperuricemia).
  • PDE4 inhibitors for example, 4-[1-(3-chlorophenyl)-7-methoxy-2,4-dioxo-pyrimido[5 , 4-c] quinoline-3-yl] cyclohexanecarboxylic acid or a pharmaceutically acceptable salt thereof
  • Hyperuricemia is caused by excessive production or insufficient excretion of uric acid and is considered a predisposing factor for several diseases that seriously affect quality of life.
  • hyperuricemia is considered a predisposing factor for gout, the most common form of inflammatory arthritis, which is characterized by severe joint pain and tenderness caused by the accumulation of urate crystals.
  • Uric acid drugs and xanthine oxidase inhibitors are commonly used to lower uric acid levels and treat gout.
  • Xanthine oxidase inhibitors eg, allopurinol or febuxostat
  • uricosuric drugs inhibit uric acid uptake from the kidney back into the blood via the URAT1 transporter.
  • Benzbromarone is a uricosuric drug and is known to be very effective in lowering serum uric acid (sUA). It has been found that therapy with benzbromarone can induce sUA reduction after even a single dose, continue to induce sUA reduction after multiple doses, and long-term treatment can achieve sUA target levels of ⁇ 6 mg/dL. Unfortunately, like many other drugs, benzbromarone may cause side effects of hepatotoxicity and acute liver failure.
  • PDE4 inhibitors can be used to reduce uric acid levels, prevent uric acid levels from increasing, and treat, prevent or alleviate diseases, disorders or conditions associated with uric acid levels in individuals.
  • the application provides a use of a PDE4 inhibitor for the manufacture of a medicament for reducing uric acid levels in an individual. In another aspect, the application provides a use of a PDE4 inhibitor for the manufacture of a medicament for preventing elevated uric acid levels in an individual. In another aspect, the present application provides the use of a PDE4 inhibitor for the manufacture of a medicament for treating, preventing or alleviating a disease, disorder or condition associated with elevated levels of uric acid in an individual.
  • the application provides the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for reducing uric acid levels or preventing uric acid levels in individuals
  • the application provides a compound as represented by formula (I) or a pharmaceutically acceptable salt thereof in preparation for treating, preventing or alleviating diseases and disorders associated with elevated levels of uric acid in an individual use in medicines or conditions.
  • the diseases, disorders or conditions described herein associated with elevated levels of uric acid are selected from the group consisting of gout, hyperuricemia, higher levels not reaching levels commonly diagnosed as hyperuricemia Uric acid levels, kidney dysfunction, urolithiasis, kidney stones, kidney failure, diabetes, diabetes-related conditions, insulin resistance, metabolic syndrome, high blood pressure, hypothyroidism, hyperparathyroidism, obesity, inflammation, Muscle cramps, local swelling, inflammation, joint pain, myocardial infarction, arthritis, tumor lysis syndrome, cognitive impairment, lead poisoning, psoriasis, sarcoidosis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, cardiac Vascular disease, atherosclerosis, and blood, bone marrow, or solid organ transplantation.
  • the disease, disorder or condition described herein associated with elevated levels of uric acid is gout or hyperuricemia. In certain embodiments, the disease, disorder or condition described herein associated with elevated levels of uric acid is gout. In certain embodiments, the disease, disorder or condition described herein associated with elevated levels of uric acid is hyperuricemia. In certain embodiments, the hyperuricemia described in the present application is primary hyperuricemia or secondary hyperuricemia. In certain embodiments, the secondary hyperuricemia described herein includes drug-related hyperuricemia or hyperuricemia associated with various medical conditions.
  • the uric acid level described herein is the uric acid level in a bodily fluid. In certain embodiments, the uric acid level described herein is the uric acid level in blood. In certain embodiments, the uric acid levels described herein are serum uric acid levels.
  • the individual is further administered one or more additional urate-lowering drugs.
  • the additional urate-lowering drug is selected from the group consisting of xanthine oxidase inhibitors, uricosuric agents, urate transporter-1 inhibitors, uricase, and statins.
  • the additional uric acid-lowering drug is selected from the group consisting of allopurinol, febuxostat, lecienade, benzbromarone, roflumilast, apremilast, bicarbonate Sodium, Potassium Sodium Bicitrate, Potassium Sodium Citrate, NSAIDs, Corticosteroids, and Colchicine.
  • the individual described herein is a mammal. In certain embodiments, the individual described herein is a human. In certain embodiments, prior to administering the medicament to the individual, the individual had two fasting serum uric acid levels greater than 420 ⁇ mol/L on two different days.
  • the agents described herein are administered orally, subcutaneously, intravenously, intramuscularly, or intraperitoneally.
  • the medicament comprises no more than 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg of a PDE4 inhibitor.
  • the drug includes no more than 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg or 50 mg of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof .
  • the agent is administered to the individual once a day, twice a day, or three times a day.
  • Fig. 1 shows the changes of uric acid levels of subjects in the 6mg single-dose group and 10mg single-dose group (Fig. 1A), 20mg single-dose group and 30mg single-dose group (Fig. 1B) of compound I.
  • Fig. 2 is a diagram showing the change of uric acid levels of subjects in the 10 mg multiple dose group and the 20 mg multiple dose group of compound I.
  • Figure 3 shows the results of changes in uric acid from baseline after compound I was administered once a day for 7 days at two different doses (10 mg and 20 mg), and four different doses of compound I (6 mg) using the PK/PD model , 15mg, 30mg and 40mg) the predicted results of uric acid changes compared with the baseline after 7 days of continuous administration once a day.
  • the prediction is based on the data of 54 healthy subjects, with the typical values of population PK parameters and PD parameters.
  • sUA denotes serum uric acid.
  • Figure 4 is from the reference Jacob Leander, Journal of Pharmacokinetics and Pharmacodynamics https://doi.org/10.1007/s10928-021-09747-y, showing Recinard (12mg), febuxostat (80mg) and The prediction results of the change of uric acid from the baseline after the combination of the two combined with multiple doses.
  • the prediction is based on 12 clinical trial data of 434 subjects (including healthy subjects, patients with hyperuricemia and patients with renal impairment).
  • sUA denotes serum uric acid.
  • Phosphodiesterases comprise a superfamily of enzymes responsible for the hydrolysis and inactivation of the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Eleven distinct PDE families (PDE1 to PDE11 ) have been identified to date that differ in substrate preference, catalytic activity, sensitivity to endogenous activators and inhibitors, and encoding genes.
  • the PDE4 isozyme family exhibits high affinity for cAMP but only weak affinity for cGMP. Increased cAMP levels resulting from PDE4 inhibition were associated with suppressed cellular activation in a variety of inflammatory and immune cells, including lymphocytes, macrophages, basophils, neutrophils, and eosinophils.
  • a variety of PDE4 inhibitors with different chemical structures have been disclosed in the prior art for the treatment and prevention of chronic and acute inflammatory diseases.
  • PDE4 inhibitors can be used to reduce uric acid levels, prevent uric acid levels from increasing, and treat, prevent or alleviate diseases, disorders or conditions associated with uric acid levels in individuals.
  • the application provides a use of a PDE4 inhibitor for the manufacture of a medicament for reducing uric acid levels in an individual.
  • the present application provides a use of a PDE4 inhibitor in the preparation of a medicament for preventing elevated uric acid levels.
  • the present application provides the use of a PDE4 inhibitor for the manufacture of a medicament for treating, preventing or alleviating a disease, disorder or condition associated with elevated levels of uric acid in an individual.
  • PDE4 inhibitor refers to an agent that can directly or indirectly lead to a decrease in the level or activity of PDE4.
  • the PDE4 inhibitor is a PDE4 selective inhibitor, for example, if the inhibitory activity of an agent against PDE enzymes in the PDE superfamily other than PDE4 is 1-fold lower than the inhibitory activity against PDE4, 5 times, 10 times, 20 times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times, 200 times, 300 times, 400 times, 500 times or more times, Then the reagent can be considered as a PDE4 selective inhibitor.
  • the inhibitory activity of a reagent on PDE4 can be tested by assay methods known in the art, for example, using commercially available PDE4 kits. For example, use the TR-FRET-based phosphodiesterase assay kit from "Molecular Devices" to test whether a certain reagent is indeed a direct inhibitor of the PDE4 enzyme.
  • the PDE4 inhibitors described herein have the chemical structure shown below:
  • R 1 is hydrogen or (C 1 -C 6 )alkyl optionally substituted 1, 2, 3 times by halogen (eg, fluorine, chlorine, bromine, iodine) or cyano (-CN).
  • R 1 is hydrogen.
  • R is methyl , ethyl, propyl, butyl (eg, tert-butyl), pentyl, or hexyl.
  • the application provides the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for reducing uric acid levels in an individual
  • the present application provides the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing the increase of uric acid level in an individual.
  • the application provides a compound as represented by formula (I) or a pharmaceutically acceptable salt thereof in preparation for treating, preventing or alleviating diseases and disorders associated with elevated levels of uric acid in an individual use in medicines or conditions.
  • racemate refers to a mixture of two or more optical isomers with different optical properties.
  • a compound with one chiral center can have two optical isomers, one with the R-configured chiral center and the other with the S-configured chiral center.
  • its racemate includes both the optical isomer of R configuration and the optical isomer of S configuration.
  • different optical isomers may exist in equal molar amounts (ie, optical activity cancels out), or may exist in unequal molar amounts.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • a compound having the structure shown in formula (I) but the hydrogen atom is replaced by deuterium or tritium, or the carbon atom is replaced by 13 C or 14 C rich carbon, all of these are within the scope of the present invention.
  • pharmaceutically acceptable salt refers to a salt prepared from a pharmaceutically acceptable inorganic or organic acid and base.
  • Compound I can react with various inorganic acids and organic acids to form pharmaceutically acceptable acid addition salts, such as but not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, Citric Acid, Tartaric Acid and Benzoic Acid.
  • Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, for example, sodium, potassium, lithium, ammonium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, those of primary, secondary, and tertiary amines.
  • Specific examples of such amines include, for example, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, tromethamine , lysine, arginine, histidine, caffeine, procaine, choline, betaine and ethylenediamine.
  • Such pharmaceutically acceptable salts and common methods for their preparation are well known in the art. See, e.g., P.
  • the pharmaceutically acceptable salt of Compound I described in the present application is an acid salt of Compound I.
  • the pharmaceutically acceptable salt of Compound I described herein is Compound I hydrochloride.
  • “individual” includes humans and non-human animals.
  • Non-human animals include all vertebrates, eg, mammals and non-mammals (eg, non-human primates, mice, rats, cats, rabbits, sheep, dogs, cows, chickens, amphibians, and reptiles).
  • vertebrates eg, mammals and non-mammals (eg, non-human primates, mice, rats, cats, rabbits, sheep, dogs, cows, chickens, amphibians, and reptiles).
  • the terms “patient”, “subject” or “individual” are used interchangeably in this application.
  • the individual described herein is a mammal. In another embodiment, the individual described herein is a human. In another embodiment, an individual described herein is a human exhibiting one or more symptoms characteristic of a condition in need of treatment. In certain embodiments, the individual exhibits elevated levels of uric acid.
  • “elevated uric acid level” means that the level of uric acid in the biological sample from the individual is found to be higher than its corresponding reference level by comparing the uric acid level in the biological sample from the individual with its corresponding reference level.
  • "comparing” as used herein refers to the comparison of corresponding parameters or values, for example, comparing an absolute quantity with an absolute reference quantity, comparing a concentration with a reference concentration, or comparing an intensity signal obtained from a tested sample with a reference The intensity signals of the same type of samples are compared. Comparisons can be made manually or computer-assisted.
  • the value of the determined quantity can be compared with the value of a suitable reference stored in a database by a computer program.
  • the computer program can further evaluate the results of the comparison and automatically provide the desired evaluation in a suitable output format.
  • Individuals suffering from a disease, disorder or condition associated with elevated levels of uric acid can be identified by comparing uric acid levels in a biological sample from an individual to their corresponding reference levels, and can also be treated with a PDE4 inhibitor (e.g., Compound I or or a pharmaceutically acceptable salt thereof) to monitor the individual's response to treatment.
  • a PDE4 inhibitor e.g., Compound I or or a pharmaceutically acceptable salt thereof
  • the term "reference level” refers to the threshold level for including or excluding the individual from the elevated uric acid level, or refers to the threshold level for receiving a PDE4 inhibitor (for example, Compound I or a pharmaceutically acceptable salt thereof).
  • a threshold level in an individual is monitored for the individual's response to treatment.
  • an individual may be considered to have an elevated uric acid level if the uric acid level in a test sample is higher than its corresponding reference level.
  • the level of uric acid in the test sample is at least 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 3, 4, 5, 6, 7, 8, 9, 10 times or more times.
  • a PDE4 inhibitor e.g., compound I or a pharmaceutically acceptable salt thereof
  • a PDE4 inhibitor can prevent an increase in uric acid levels in said individual.
  • the level of uric acid in a biological sample obtained after treatment with a PDE4 inhibitor is at least 10%, 20% lower than the corresponding uric acid level before treatment , 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100%.
  • the reference level of uric acid levels can be derived from one or more reference samples, wherein the reference level is obtained from an experiment performed in parallel with the experiment detecting the sample of interest.
  • reference levels may be obtained in a database comprising a collection of data, standards or levels from one or more reference samples or disease reference samples.
  • sets of data, standards or levels are normalized so that they can be used for comparison purposes with data from one or more samples. "Normalization" is the process of transforming measured raw data into data that can be directly compared with other standardized data. Normalization is used to overcome analytical method-specific errors caused by different factors in different analytical methods, such as differences in sample loading, differences in binding efficiencies, differences in detection sensitivity, and other types of errors.
  • reference level can choose the reference level according to the desired sensitivity and specificity.
  • Means for determining suitable reference levels are known to those skilled in the art, for example reference levels may be determined from data collected in clinical studies.
  • reference levels for uric acid levels are 400 ⁇ mol/L, 410 ⁇ mol/L, 420 ⁇ mol/L, 430 ⁇ mol/L, 440 ⁇ mol/L, 450 ⁇ mol/L or higher.
  • an individual is considered to have an elevated uric acid level if the uric acid level (eg, serum uric acid level) is greater than 420 ⁇ mol/L.
  • an individual is considered to have an elevated uric acid level if the uric acid level (eg, serum uric acid level) on two different occasions is greater than 420 ⁇ mol/L. In certain embodiments, an individual is considered to have an elevated uric acid level if the serum uric acid level is greater than 420 ⁇ mol/L on two fastings on different days.
  • the uric acid level eg, serum uric acid level
  • uric acid in biological samples eg, serum
  • biological samples eg, serum
  • biological sample refers to a biological composition obtained or derived from a subject of interest comprising cells and/or other molecular entities to be characterized and/or identified, for example based on Characterized and/or identified by physical, biochemical, chemical and/or physiological characteristics.
  • Biological samples include, but are not limited to, cells, tissues, organs and/or biological fluids of a subject obtained by any method known to those of skill in the art.
  • the biological sample is a fluid sample.
  • the fluid sample is whole blood, plasma, serum, mucus (including nasal discharge and sputum), peritoneal fluid, pleural fluid, pleural fluid, saliva, urine, synovial fluid, cerebrospinal fluid (CSF), Thoracentesis, abdominal fluid, ascites, or pericardial effusion.
  • the biological sample is tissue or cells obtained from the subject's heart, liver, spleen, lung, kidney, skin, or blood vessels.
  • the uric acid level described herein is the uric acid level in a fluid sample from an individual. In certain embodiments, the level of uric acid described herein is the level of uric acid in blood from an individual. In certain embodiments, the uric acid level described herein is the uric acid level in serum from an individual.
  • treatment includes preventing or alleviating a disease, disorder or condition, reducing the occurrence of a disease, disorder or condition or speed of development, reducing the risk of developing a disease, disorder or condition, preventing or delaying the development of symptoms associated with a disease, disorder or condition, reducing or terminating symptoms associated with a disease, disorder or condition, producing Complete or partial reversal of a disease, disorder or condition, cure of a disease, disorder or condition, or a combination of the above.
  • the diseases, disorders or conditions described herein associated with elevated levels of uric acid are selected from the group consisting of gout, hyperuricemia, higher levels not reaching levels commonly diagnosed as hyperuricemia Uric acid levels, kidney dysfunction, urolithiasis, kidney stones, kidney failure, diabetes, diabetes-related conditions, insulin resistance, metabolic syndrome, high blood pressure, hypothyroidism, hyperparathyroidism, obesity, inflammation, Muscle cramps, local swelling, inflammation, joint pain, myocardial infarction, arthritis, tumor lysis syndrome, cognitive impairment, lead poisoning, psoriasis, sarcoidosis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, cardiac Vascular disease, atherosclerosis, and blood, bone marrow, or solid organ transplantation.
  • the disease, disorder or condition described herein associated with elevated levels of uric acid is gout. In certain embodiments, the disease, disorder or condition described herein associated with elevated levels of uric acid is hyperuricemia. In certain embodiments, the hyperuricemia is primary hyperuricemia or secondary hyperuricemia. In certain embodiments, the secondary hyperuricemia comprises drug-related hyperuricemia or hyperuricemia associated with various medical conditions.
  • the present application provides a medicament comprising a PDE4 inhibitor (eg, Compound I or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier.
  • a PDE4 inhibitor eg, Compound I or a pharmaceutically acceptable salt thereof
  • pharmaceutically acceptable carrier refers to a carrier that is generally chemically and/or physically compatible with the other ingredients in the formulation and physiologically compatible with its recipients.
  • the pharmaceutically acceptable carrier used in the pharmaceutical composition disclosed in the present invention may include, for example, pharmaceutically acceptable liquid, gel or solid carrier, aqueous phase vehicle, non-aqueous phase vehicle, antimicrobial substance, etc. Osmotic substances, buffers, antioxidants, anesthetics, suspending/dispersing agents, chelating agents, diluents, adjuvants, adjuvants or non-toxic auxiliary substances, other components known in the art or multiple combinations of the above.
  • Suitable components may include, for example, antioxidants, fillers, binders, disintegrants, buffers, preservatives, lubricants, flavorants, thickeners, colorants, emulsifiers or stabilizers such as Sugars and cyclodextrins.
  • Suitable antioxidants may include, for example, methionine, ascorbic acid, EDTA, sodium thiosulfate, platinum, catalase, citric acid, cysteine, mercaptoglycerol, thioglycolic acid, mercaptosorbitol, butyl methyl Anisole, Butylated Hydroxytoluene and/or Propyl Gallate.
  • a pharmaceutical composition comprising a PDE4 inhibitor (e.g., Compound I or a pharmaceutically acceptable salt thereof) reduces the PDE4 Oxidation of an Inhibitor (eg, Compound I or a pharmaceutically acceptable salt thereof).
  • a PDE4 inhibitor e.g., Compound I or a pharmaceutically acceptable salt thereof
  • the present invention further provides various methods for preventing oxidation of said PDE4 inhibitor (for example, Compound I or a pharmaceutically acceptable salt thereof), prolonging its shelf life and/or increasing its activity, for example, by incorporating the PDE4 inhibitor provided in the present invention This is achieved by mixing an inhibitor (eg, Compound I or a pharmaceutically acceptable salt thereof) with one or more antioxidants (eg, methionine).
  • compositions of the present application may be formulated in unit dosage form containing a predetermined amount of active ingredient per unit dose.
  • predetermined amounts or unit doses may contain from 0.5 mg to 1 g (e.g., no more than 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg) of a PDE4 inhibitor (for example, compound I or a pharmaceutically acceptable salt thereof), depending on the disease to be treated, the route of administration and the age, weight and general condition of the patient.
  • Typical unit dosage forms are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient.
  • Such pharmaceutical compositions can be prepared by any of the methods well known in the art of pharmacy.
  • the unit dosage form of the pharmaceutical composition may comprise a PDE4 inhibitor (e.g., Compound 1 or a pharmaceutically acceptable salt thereof) in an amount greater than 1 mg of a PDE4 inhibitor (e.g., Compound 1 or a pharmaceutically acceptable salt thereof). acceptable salt).
  • the pharmaceutical composition may comprise a PDE4 inhibitor (e.g., Compound I or a pharmaceutically acceptable salt thereof) in an amount of 1 to 100 mg, or 1 to 50 mg, or 10 to 50 mg, or 30 to 50 mg.
  • the pharmaceutical composition may comprise a PDE4 inhibitor (eg, Compound I or a pharmaceutically acceptable salt thereof) in an amount of 1 to 20 mg, or 5 to 15 mg, or 10 to 20 mg, or 20 to 30mg.
  • compositions may be adapted for administration by any suitable route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or Parenteral (including subcutaneous, intramuscular, intraperitoneal, intravenous or intradermal) routes.
  • Such pharmaceutical compositions can be prepared by any methods known in the art of pharmacy, for example, by bringing into association the active ingredient with carriers or excipients.
  • certain routes of administration are preferred over others.
  • compositions suitable for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions, each containing an aqueous or non-aqueous liquid; edible foams or whips; Oil-in-liquid emulsion or water-in-oil liquid emulsion.
  • the active pharmaceutical ingredient can be mixed with an oral, non-toxic pharmaceutically acceptable inert carrier (such as ethanol, glycerol, water, etc.).
  • powders are prepared by comminuting the compound to a suitable fine size and mixing with a suitable pharmaceutical carrier, such as an edible carbohydrate, eg, starch or mannitol. Flavoring, preservative, dispersing and coloring agents may also be present.
  • Capsules may be prepared by preparing a mixture of powder, liquid or suspension and encapsulating with gelatin or some other suitable shell material.
  • Glidants and lubricants such as silica gel, talc, magnesium stearate, calcium stearate or solid polyethylene glycol, may be added to the mixture prior to encapsulation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate, may also be added to enhance the availability of the drug after ingestion of the capsule.
  • suitable binders, lubricants, disintegrants and colorants may also be incorporated into the mixture, if desired or necessary.
  • Suitable binders include starch, gelatin, natural sugars (such as glucose or beta-lactose, corn sweeteners), natural and synthetic gums (such as acacia, tragacanth, or sodium alginate), carboxymethyl Base cellulose, polyethylene glycol, wax, etc.
  • Lubricants used in these dosage forms include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding lubricants and disintegrants, and compressing into tablets.
  • Powder mixtures can be prepared by mixing the suitably finely divided compound with a diluent or base as previously described.
  • Optional ingredients include binders, such as carboxymethylcellulose, alginate, gelatin, or polyvinylpyrrolidone; solution retardants, such as paraffin; resorption accelerators, such as quaternary salts; and/or Adsorbents such as bentonite, kaolin, or dicalcium phosphate.
  • the powder mixture can be wet granulated with a binder such as syrup, starch paste, mucilage arabic or a solution of cellulosic or polymeric material and compressed through a screen.
  • a binder such as syrup, starch paste, mucilage arabic or a solution of cellulosic or polymeric material
  • the powder mixture can be passed through a tablet machine, as a result, incompletely formed lumps are broken into granules.
  • the granules may be lubricated by the addition of stearic acid, stearates, talc or mineral oil to prevent sticking of the granules to the tableting dies.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be mixed with a free-flowing inert carrier and compressed directly into tablets without going through the granulation or compression steps.
  • a clear or opaque protective coating consisting of a shellac barrier, sugar or polymer coating and a wax polish can be
  • unit dosage form formulations for oral administration can be microencapsulated.
  • the formulations can also be prepared so as to provide prolonged or sustained release, for example by coating or embedding the particulate material in polymers, waxes or the like.
  • Oral fluids such as solutions, syrups or elixirs can be prepared in unit dosage form so that a given quantity contains a predetermined amount of the compound.
  • Syrups for example, can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions are usually formulated by dispersing the compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether, preservatives, flavor additives, such as peppermint oil, or natural sweeteners, saccharin, or other artificial sweeteners may also be added wait.
  • Suitable packaging for the preparation of pharmaceutical solutions may be all approved containers for parenteral use, such as plastic and glass containers, ready-to-use syringes, and the like.
  • the container is a hermetically sealed glass container, such as a vial or ampoule.
  • An airtight glass vial is an example of a hermetically sealed glass container.
  • a sterile injectable solution is provided in a sealed glass container, the solution comprising Compound I or a pharmaceutically acceptable salt thereof in a physiologically acceptable solvent, and for stability it has suitable pH.
  • Acid salts of compounds of the invention may be more soluble in aqueous solutions than their free base counterparts, but when the acid salts are added to aqueous solutions, the pH of the solutions is too low to be suitable for administration.
  • a solution formulation having a pH above pH 4.5 can be mixed with a diluent having a pH above 7 prior to administration such that the pH of the administered combination formulation is pH 4.5 or higher.
  • the diluent comprises a pharmaceutically acceptable base, such as sodium hydroxide, and the pH of the combination formulation administered is between pH 5.0 and 7.0.
  • One or more other ingredients such as co-solvents, tonicity modifiers, stabilizers, and preservatives, such as those previously listed, may be added to the solution prior to passing the solution through the sterile filter.
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • compositions suitable for topical administration in the mouth include lozenges, pastilles and mouthwashes.
  • compositions suitable for nasal administration include coarse powders having a particle size of, for example, 20 to 500 microns.
  • the powder is administered by inhalation, ie, by rapid inhalation through the nasal passages from a container containing the powder near the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops include aqueous or oily solutions of the active ingredient.
  • compositions suitable for administration by inhalation include fine particle dusts or mists, which may be produced by various types of metered dose pressurized aerosols, nebulizers or inhalers.
  • compositions of the present invention may also be used in the form of suppositories for rectal administration of the compounds of the present invention.
  • Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient include, for example, cocoa butter and polyethylene glycols.
  • Pharmaceutical compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions suitable for parenteral administration include aqueous and anhydrous sterile injectable solutions which may contain antioxidants, buffers, bactericides and solutes to render the formulation isotonic with the blood of the intended recipient; aqueous and anhydrous Aqueous sterile suspensions may contain suspending and thickening agents.
  • the formulations can be presented in unit dosage form or in multi-dose containers, such as hermetically sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use .
  • Immediate injectable solutions and suspensions can be prepared from sterile powders, granules and tablets.
  • formulations of the present invention may include other agents conventional in the art as appropriate to the intended formulation type.
  • formulations suitable for oral administration may include flavoring or coloring agents.
  • the pharmaceutical composition described herein further comprises one or more additional urate-lowering drugs.
  • “Uric acid-lowering drugs” can be drugs that reduce uric acid synthesis, or drugs that promote uric acid excretion.
  • “Urate-lowering drugs” can be uric acid-lowering drugs that have been approved for marketing by drug regulatory authorities (for example, the United States Food and Drug Administration (USFDA), China National Medical Products Administration (NMPA), European Medicines Agency (EMA)) , It can also be a drug that has been proven to reduce uric acid levels in preclinical studies or clinical studies, but has not been approved for marketing by the drug regulatory department.
  • USFDA United States Food and Drug Administration
  • NMPA China National Medical Products Administration
  • EMA European Medicines Agency
  • the additional urate-lowering drug is selected from the group consisting of xanthine oxidase inhibitors, uricosuric agents, urate transporter-1 inhibitors, uricase, and statins.
  • the additional uric acid-lowering drug is selected from the group consisting of allopurinol, febuxostat, lecienade, benzbromarone, roflumilast, apremilast, bicarbonate Sodium, Potassium Sodium Bicitrate, Potassium Sodium Citrate, NSAIDs, Corticosteroids, and Colchicine.
  • the present application provides a method of reducing uric acid levels, comprising administering a PDE4 inhibitor (eg, Compound I or a pharmaceutically acceptable salt thereof) to an individual in need thereof.
  • a PDE4 inhibitor eg, Compound I or a pharmaceutically acceptable salt thereof
  • the present application also provides a method for preventing elevated uric acid levels, comprising administering a PDE4 inhibitor (eg, compound I or a pharmaceutically acceptable salt thereof) to an individual in need.
  • the present application also provides a method of treating, preventing or alleviating a disease, disorder or condition associated with elevated levels of uric acid in an individual, comprising, comprising administering a PDE4 inhibitor (e.g., compound I or a pharmaceutically acceptable salt thereof).
  • the disease, disorder or condition associated with elevated uric acid levels described herein is selected from the group consisting of gout, hyperuricemia, hyperuricemia not reaching levels commonly diagnosed as hyperuricemia High uric acid levels, kidney dysfunction, urolithiasis, kidney stones, kidney failure, diabetes, diabetes-related conditions, insulin resistance, metabolic syndrome, high blood pressure, hypothyroidism, hyperparathyroidism, obesity, inflammation , muscle cramps, localized swelling, inflammation, joint pain, myocardial infarction, arthritis, tumor lysis syndrome, cognitive impairment, lead poisoning, psoriasis, sarcoidosis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, Cardiovascular disease, atherosclerosis, and blood, bone marrow, or solid organ transplantation.
  • the disease, disorder or condition described herein associated with elevated levels of uric acid is gout. In certain embodiments, the disease, disorder or condition described herein associated with elevated levels of uric acid is hyperuricemia. In certain embodiments, the hyperuricemia is primary hyperuricemia or secondary hyperuricemia. In certain embodiments, the secondary hyperuricemia comprises drug-related hyperuricemia or hyperuricemia associated with various medical conditions.
  • the methods of treatment described herein comprise administering a PDE4 inhibitor (e.g., Compound I) or a pharmaceutically acceptable salt thereof, e.g., 6 mg, 6.5 mg, 7 mg, to the individual at a dose of 6 mg to 40 mg , 7.5mg, 8mg, 9mg, 9.5mg, 10mg, 10.5mg, 11mg, 11.5mg, 12mg, 12.5mg, 13mg, 13.5mg, 14mg, 14.5mg, 15mg, 15.5mg, 16mg, 16.5mg, 17mg, 17.5mg , 18mg, 18.5mg, 19mg, 19.5mg, 20mg, 20.5mg, 21mg, 21.5mg, 22mg, 22.5mg, 23mg, 23.5mg, 24mg, 24.5mg, 25mg, 25.5mg, 26mg, 26.5mg, 27mg, 27.5mg , 28m
  • the clinician can determine the dosage and/or daily (for example, once a day, twice a day, three times a day, etc.) or each period (once a week, twice a week, etc.) , three times a week, etc.) dosing frequency.
  • dose and/or daily for example, once a day, twice a day, three times a day, etc.
  • each period once a week, twice a week, etc.
  • dosing frequency for any particular individual may depend on factors such as, but not limited to, age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug The combination and severity of the particular disease being treated.
  • the PDE4 inhibitors described herein can also be administered in combination with additional urate-lowering drugs.
  • the additional urate-lowering drug is selected from the group consisting of xanthine oxidase inhibitors, uricosuric agents, urate transporter-1 inhibitors, uricase, and statins.
  • the additional uric acid-lowering drug is selected from the group consisting of allopurinol, febuxostat, lecienade, benzbromarone, roflumilast, apremilast, bicarbonate Sodium, Potassium Sodium Bicitrate, Potassium Sodium Citrate, NSAIDs, Corticosteroids, and Colchicine.
  • the PDE4 inhibitor described in the application for example, Compound I or its pharmaceutically acceptable salt
  • additional urate-lowering drugs such drug combination can be administered together or separately, and when administered separately When used, they can be administered simultaneously or sequentially in any order.
  • the amount of compound or drug and the relative timing of administration are selected to achieve the desired therapeutic effect.
  • the combined administration of the PDE4 inhibitor described in the application (for example, Compound I or its pharmaceutically acceptable salt) and additional urate-lowering drugs can be administered in combination in the following manner: (1) a single drug comprising two compounds combination, or (2) separate pharmaceutical compositions each comprising a compound.
  • the combination agents may be administered separately in an orderly fashion, wherein one therapeutic agent is administered first, followed by the other, or vice versa. Such sequential administration may be at short or long intervals.
  • the uric acid level change of the experimenter of compound I single-dose group and multiple dose group is shown in Figure 1A (6mg single dose and 10mg single dose), Figure 1B (20mg single dose and 30mg single dose), Figure 2 (10mg multiple dose and 20 mg multiple dose), the results are also shown in Table 1.1, Table 1.2, Table 1.3 and Table 2.1, and Table 2.2, Table 2.3 and Table 2.4.
  • Table 1.1, Table 1.2 and Table 1.3 have shown the change of the uric acid level numerical value of the experimenter of single dose group (6mg, 10mg, 20mg and 30mg) before and after receiving Compound I treatment
  • Table 2.1, Table 2.2, Table 2.3 and Table 2.4 shows the changes in the uric acid level values of the subjects in the multi-dose groups (10 mg and 20 mg) before and after receiving Compound I treatment.
  • Example 2 the inventors based on the results of uric acid changes from the baseline after 7 days of continuous administration of Compound I with two different doses (10mg and 20mg) per day, using the PK/PD model for Compound I. Another four different doses (6mg, 15mg, 30mg and 40mg) were administered once a day for 7 consecutive days to predict the uric acid-lowering effect. Please refer to Figure 3 for specific results.
  • Recinard and febuxostat disclosed in the literature (see the literature Jacob Leander, Journal of Pharmacokinetics and Pharmacodynamics https://doi.org/10.1007/s10928-021-09747-y, And Fig.
  • This example aims to compare the effect of compound I and other urate-lowering drugs on reducing uric acid levels.
  • the animal experiment design scheme is shown below.
  • Compound I is expected to be as effective or better at lowering uric acid levels than other urate-lowering drugs.

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Abstract

本申请提供了PDE4抑制剂(例如，如式(I)所示的化合物)或其药学上可接受的盐)在制备用于在个体中降低尿酸水平，预防尿酸水平升高，治疗、预防或缓解个体中与尿酸水平升高相关的疾病、病症或状况(例如，痛风、高尿酸血症)的药物中的用途。

Description

用于降低尿酸水平的化合物 技术领域
本申请涉及疾病治疗领域，具体地，本申请涉及PDE4抑制剂(例如，4-[1-(3-氯苯基)-7-甲氧基-2，4-二氧代-嘧啶并[5，4-c]喹啉-3-基]环己烷甲酸或其药学上可接受的盐)在制备用于在个体中降低尿酸水平，预防尿酸水平升高，治疗、预防或缓解个体中与尿酸水平升高相关的疾病、病症或状况(例如，痛风、高尿酸血症)的药物中的用途。
背景技术
高尿酸血症是由尿酸过量产生或排泄不足引起的，并且被认为是几种严重影响生活质量的疾病的诱发因素。例如，高尿酸血症被认为是痛风(炎症性关节炎的最常见形式)的诱发因素，其特征为由尿酸盐结晶积累引起的关节严重疼痛和压痛。
通常使用促尿酸排泄药和黄嘌呤氧化酶抑制剂来降低尿酸水平并治疗痛风。黄嘌呤氧化酶抑制剂(如别嘌呤醇或非布司他)可以减少尿酸的形成，而促尿酸排泄药可抑制尿酸经由URAT1转运蛋白从肾被吸收回血液。苯溴马隆(Benzbromarone)为促尿酸排泄药物，并且已知其在降低血清尿酸(sUA)方面非常有效。已经发现，使用苯溴马隆的疗法可以在甚至单次剂量后促使sUA降低，并在多次剂量后继续促使sUA降低，并且长期治疗可以使sUA达到＜6mg/dL的目标水平。遗憾的是，与许多其他药物一样，苯溴马隆可能会引起肝毒性和急性肝衰竭的副作用。
本领域仍需要毒性降低的高效降尿酸药物。
发明内容
本申请的发明人意想不到地发现，PDE4抑制剂可以用于降低尿酸水平、预防尿酸水平升高，治疗、预防或缓解个体中与尿酸水平升高相关的疾病、病症或状况。
在一个方面，本申请提供了PDE4抑制剂在制备用于在个体中降低尿酸水平的药物中的用途。在另一个方面，本申请提供了PDE4抑制剂在制备用于在个体中预防尿酸水平升高的药物中的用途。在另一个方面，本申请提供了PDE4抑制剂在制备用于在个体中治疗、预防或缓解个体中与尿酸水平升高相关的疾病、病症或状况的药物中的用途。
在另一个方面，本申请提供了如式(I)所示的化合物或其药学上可接受的盐在制备用于在个体中降低尿酸水平或预防尿酸水平升高的药物中的用途
Figure PCTCN2022131336-appb-000001
在另一个方面，本申请提供了如式(I)所示的化合物或其药学上可接受的盐在制备用于在个体中治疗、预防或缓解个体中与尿酸水平升高相关的疾病、病症或状况的药物中的用途。
在某些实施方式中，本申请所述的与尿酸水平升高相关的疾病、病症或状况选自下组：痛风、高尿酸血症、未达到通常确诊为高尿酸血症的水平的较高尿酸水平、肾功能障碍、尿石病、肾结石、肾衰竭、糖尿病、糖尿病相关的病况、胰岛素抗性、代谢综合征、高血压、甲状腺功能减退、甲状旁腺功能亢进、肥胖症、炎症、肌肉痉挛、局部肿胀、炎症、关节疼痛、心肌梗塞、关节炎、肿瘤溶解综合征、认知障碍、铅中毒、牛皮癣、结节病、非酒精性脂肪性肝病、非酒精性脂肪性肝炎、心血管疾病、动脉粥样硬化、以及血液、骨髓或实体器官的移植。在某些实施方式中，本申请所述的与尿酸水平升高相关的疾病、病症或状况为痛风或者高尿酸血症。在某些实施方式中，本申请所述的与尿酸水平升高相关的疾病、病症或状况为痛风。在某些实施方式中，本申请所述的与尿酸水平升高相关的疾病、病症或状况为高尿酸血症。在某些实施方式中，本申请所述的高尿酸血症为原发性高尿酸血症或者继发性高尿酸血症。在某些实施方式中，本申请所述的继 发性高尿血酸血症包括与药物有关的高尿酸血症或与各种不同的医学状况有关的高尿酸血症。
在某些实施方式中，本申请所述的尿酸水平为体液中的尿酸水平。在某些实施方式中，本申请所述的尿酸水平为血液中的尿酸水平。在某些实施方式中，本申请所述的尿酸水平为血清尿酸水平。
在某些实施方式中，所述个体进一步被给予一种或多种额外的降尿酸药物。在某些实施方式中，所述额外的降尿酸药物选自下组：黄嘌呤氧化酶抑制剂、排尿酸剂、尿酸盐转运体-1抑制剂、尿酸酶和抑制素。在某些实施方式中，所述额外的降尿酸药物选自下组：别嘌醇、非布司他、雷西纳德、苯溴马隆、罗氟斯特、阿普斯特、碳酸氢钠、枸橼酸氢钾钠、枸橼酸钾钠、非甾体抗炎药、糖皮质激素和秋水仙碱。
在某些实施方式中，本申请所述的个体为哺乳动物。在某些实施方式中，本申请所述的个体为人类。在某些实施方式中，在向所述个体施用所述药物之前，所述个体非同日2次空腹的血清尿酸水平高于420μmol/L。
在某些实施方式中，本申请所述药物通过口服、皮下、静脉内、肌肉内或腹膜内途径施用。在某些实施方式中，所述药物包括不超过5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg或50mg的PDE4抑制剂。在某些实施方式中，所述药物包括不超过5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg或50mg的如式(I)所示的化合物或其药学上可接受的盐。在某些实施方式中，每天一次、每天两次或每天三次向所述个体施用所述药物。
附图说明
图1表示化合物I的6mg单剂量组和10mg单剂量组(图1A)、20mg单剂量组和30mg单剂量组(图1B)的受试者的尿酸水平变化图。
图2表示化合物I的10mg多剂量组和20mg多剂量组的受试者的尿酸水平变化图。
图3显示了化合物I以二个不同剂量(10mg和20mg)每天给药1次连续 给药7天后尿酸较基线变化的结果，以及使用PK/PD模型对于化合物I以另外四个不同剂量(6mg、15mg、30mg以及40mg)每天给药1次连续给药7天后尿酸较基线变化的预测结果。该预测是基于54名健康受试者数据，以群体PK参数和PD参数典型值进行的预测。sUA表示血清尿酸。
图4来源于参考文献Jacob Leander，Journal of Pharmacokinetics and Pharmacodynamics https：//doi.org/10.1007/s10928-021-09747-y，显示了雷西纳德(12mg)、非布司他(80mg)以及二者联合多剂量给药后尿酸较基线变化的预测结果。该预测是基于434名受试者(包括健康受试者、高尿酸血症患者和肾受损患者)的12个临床试验数据进行的预测。sUA表示血清尿酸。
具体实施方式磷酸二酯酶(PDE)包括负责第二信使环腺苷酸(cAMP)和环鸟苷酸(cGMP)的水解和灭活的酶的超家族。迄今已经鉴定出十一个不同的PDE家族(PDE1至PDE11)，它们在底物优选性、催化活性、对内源性激活剂和抑制剂的敏感性、和编码基因上有差异。
PDE4同工酶家族对cAMP呈现出高亲和性，但对cGMP只呈现出弱亲和性。由PDE4抑制引起的cAMP水平提高与多种炎性和免疫细胞中的细胞激活抑制有关，这些细胞包括淋巴细胞、巨噬细胞、嗜碱细胞、中性粒细胞和嗜酸性细胞。现有技术中已公开了多种不同化学结构的PDE4抑制剂用于治疗和预防慢性和急性炎性疾病。
本申请的发明人意想不到地发现，PDE4抑制剂可以用于降低尿酸水平、预防尿酸水平升高，治疗、预防或缓解个体中与尿酸水平升高相关的疾病、病症或状况。
1.PDE4抑制剂的制药用途
在一个方面，本申请提供了PDE4抑制剂在制备用于在个体中降低尿酸水平的药物中的用途。在另一个方面，本申请提供了PDE4抑制剂在制备用于预防尿酸水平升高的药物中的用途。在另一个方面，本申请提供了PDE4抑制剂在制备用于在个体中治疗、预防或缓解个体中与尿酸水平升高相关的疾病、病症或状况的药物中的用途。
在本申请中，“PDE4抑制剂”是指能够直接或间接导致PDE4的水平或活性 降低的试剂。在某些实施方式中，PDE4抑制剂为PDE4选择性抑制剂，例如，如果某一试剂对PDE超家族里的除了PDE4之外的其他PDE酶的抑制活性比对PDE4的抑制活性低1倍、5倍、10倍、20倍、30倍、40倍、50倍、60倍、70倍、80倍、90倍、100倍、200倍、300倍、400倍、500倍或更多倍时，则可认为该试剂为PDE4选择性抑制剂。可以通过本领域公知的测定方法来测试某一试剂对PDE4的抑制活性，例如，使用市售的PDE4试剂盒。例如，使用来自“Molecular Devices”的基于TR-FRET的磷酸二酯酶试验试剂盒来测试某一试剂是否确实是PDE4酶的直接抑制剂。
在某些实施方式中，本申请所述的PDE4抑制剂具有如下所示的化学结构：
Figure PCTCN2022131336-appb-000002
其中R 1为氢或任选地被卤素(例如，氟、氯、溴、碘)或氰基(-CN)取代1、2、3次的(C 1-C 6)烷基。在某些实施方式中，R 1为氢。在某些实施方式中，R 1为甲基、乙基、丙基、丁基(例如，叔丁基)、戊基或己基。
在另一个方面，本申请提供了如式(I)所示的化合物或其药学上可接受的盐在制备用于在个体中降低尿酸水平的药物中的用途
Figure PCTCN2022131336-appb-000003
在另一个方面，本申请提供了如式(I)所示的化合物或其药学上可接受的盐在制备用于在个体中预防尿酸水平升高的药物中的用途。在另一个方面，本申请提供了如式(I)所示的化合物或其药学上 可接受的盐在制备用于在个体中治疗、预防或缓解个体中与尿酸水平升高相关的疾病、病症或状况的药物中的用途。
在本申请中，如式(I)所示的化合物是指具有如下所示结构的化合物：
Figure PCTCN2022131336-appb-000004
其化学名称为4-[1-(3-氯苯基)-7-甲氧基-2，4-二氧代-嘧啶并[5，4-c]喹啉-3-基]环己烷甲酸。在本申请中，“如式(I)所示的化合物”也被称为“化合物I”。
化合物I是对映异构体，其化学结构分别如下式(Ia)和式(Ib)所示：
Figure PCTCN2022131336-appb-000005
其化学名称分别为反式-4-[1-(3-氯苯基)-7-甲氧基-2，4-二氧代-嘧啶并[5，4-c]喹啉-3-基]环己烷甲酸(在本申请中也称为“化合物Ia”)、顺式-4-[1-(3-氯苯基)-7-甲氧基-2，4-二氧代-嘧啶并[5，4-c]喹啉-3-基]环己烷甲酸(在本申请中也称为“化合物Ib”)。在某些实施方式中，化合物I为化合物Ia。在某些实施方式中，化合物I为化合物Ib。在某些实施方式中，化合物I为包含化合物Ia和化合物Ib的外消旋体。
在本申请中，“外消旋体”是指，具有两种或两种以上的具有不同旋光性质的光学异构体的混合物。例如，具有一个手性中心的化合物可以具有两种光学异 构体，一种具有R构型的手性中心，另一种具有S构型的手性中心。对于该化合物而言，其外消旋体既包括R构型的光学异构体也包括S构型的光学异构体。在本申请所述的外消旋体中，不同的光学异构体可以以相等的摩尔量存在(即旋光性抵消)，也可以以不等的摩尔量存在。
在本申请中，除非另有说明，否则本申请所描述的结构也意指包括差别仅在于存在一个或多个同位素富集的原子的化合物。例如，具有式(I)所示结构的化合物，但氢原子被氘或氚替代，或碳原子被富含 13C或 14C的碳取代，这些都在本发明的范围内。
在本申请中，“药学上可接受的盐”是指由药学上可接受的无机酸或有机酸和碱制备的盐。例如，化合物I可与多种无机酸和有机酸反应形成药学上可接受的酸加成盐，例如但不限于盐酸、氢溴酸、氢碘酸、硫酸、磷酸、甲酸、乙酸、丙酸、柠檬酸、酒石酸和苯甲酸。药学上可接受的碱加成盐可以从无机碱和有机碱制备。从无机碱衍生的盐，例如包括钠盐、钾盐、锂盐、铵盐、钙盐和镁盐。从有机碱衍生的盐包括但不限于伯、仲和叔胺的盐。此类胺的具体实例包括，例如，异丙胺、三甲胺、二乙胺、三(异丙基)胺、三(正丙基)胺、乙醇胺、2-二甲基氨基乙醇、氨丁三醇、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱和乙二胺。这种药学上可接受的盐和制备它们的常用方法是本领域众所周知的。参见，例如，P.Stahl等人，HANDBOOK OF PHARMACEUTICAL SALTS：PROPERTIES，SELECTION AND USE(VCHA/Wiley-VCH，2002)；S.M.Berge，等人，“Pharmaceutical Salts”，Journal of Pharmaceutical Sciences，第66卷，No.1，1977年1月。
在某些实施方式中，本申请所述的化合物I的药学上可接受的盐为化合物I的酸式盐。在某些实施方式中，本申请所述的化合物I的药学上可接受的盐为化合物I的盐酸盐。
在本申请中，“个体”包括人类和非人类动物。非人类动物包括所有脊椎动物，例如，哺乳动物和非哺乳动物(例如，非人类灵长类、小鼠、大鼠、猫、兔子、绵羊、狗、牛、鸡、两栖动物和爬行动物)。除另有说明外，否则术语“患者”、“受试者”或“个体”在本申请中可互换使用。
在一个实施方式中，本申请中所述的个体为哺乳动物。在另一个实施方式中，本申请中所述的个体为人类。在另一个实施方式中，本申请所述的个体是表现出需要治疗的病症的一种或多种症状特征的人。在某些实施方式中，所述个体表现出尿酸水平升高。
在本申请中，“尿酸水平升高”是指通过比较来自个体的生物样品中的尿酸水平与其相应的参考水平发现，来自所述个体的生物样品中的尿酸水平高于其相应的参考水平。应当理解，本文所用的“比较”是指相应参数或值的比较，例如，将绝对量与绝对参考量进行比较，将浓度与参考浓度进行比较，或从检测的样品中获得的强度信号同参考样品的同类型的强度信号进行比较。可以通过手动或计算机辅助进行比较。对于计算机辅助进行的比较，可以将所确定的量的值与通过计算机程序存储在数据库中的合适参考的值进行比较。该计算机程序可以进一步评估比较的结果，并以合适的输出格式自动提供期望的评估。通过比较来自个体的生物样品中的尿酸水平与其相应的参考水平，可以识别出患有与尿酸水平升高相关的疾病、病症或状况的个体，还可以在接受PDE4抑制剂(例如，化合物I或其药学上可接受的盐)治疗的个体中监测所述个体对治疗的应答。
在本申请中，术语“参考水平”是指将个体纳入或排除尿酸水平升高的阈值水平，或是指用于在接受PDE4抑制剂(例如，化合物I或其药学上可接受的盐)的个体中监测所述个体对治疗的应答的阈值水平。
例如，对于在个体中降低尿酸水平的方法，如果检测样品中的尿酸水平高于其相应的参考水平，则该个体可被认为具有尿酸水平升高。在一些实施方式中，检测样品中尿酸水平至少是其相应参考水平的1、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2、3、4、5、6、7、8、9、10倍或更多倍。
又例如，对于在个体中预防尿酸水平升高的方法，如果检测样品中的尿酸水平相比其接受PDE4抑制剂(例如，化合物I或其药学上可接受的盐)治疗前的相应的尿酸水平更低或者没有按照原来的进展进一步升高，则认为PDE4抑制剂(例如，化合物I或其药学上可接受的盐)可以在所述个体中预防尿酸水平升高。在一些实施方式中，在进行PDE4抑制剂(例如，化合物I或其药学上可接受的盐)治疗后获得的生物样品中的尿酸水平至少比治疗之前的相应尿酸水平低至少 10％、20％、30％、40％、50％、60％、70％、80％、90％、95％、99％或100％。
尿酸水平的参考水平可以源自一个或多个参考样品，其中参考水平获自与检测目的样品的实验平行进行的实验。或者，可以在数据库中获得参考水平，该数据库包括来自一个或多个参考样品或疾病参考样品的数据、标准或水平的集合。在一些实施方式中，此类数据、标准或水平的集合被标准化，以便可用于与来自一个或多个样品的数据进行比较的目的。“标准化”是将测量原始数据转换为可以直接与其他标准化数据进行比较的数据的过程。标准化被用于克服因不同的分析方法里因素不同而导致的、分析方法特异性的误差，例如上样量的不同、结合效率的不同、检测灵敏度的不同和其他各类的误差。
本领域技术人员可以根据期望的灵敏度和特异性来选择参考水平。确定合适的参考水平的手段是本领域技术人员已知的，例如参考水平可以从临床研究中收集的数据来确定。例如，尿酸水平的参考水平为400μmol/L、410μmol/L、420μmol/L、430μmol/L、440μmol/L、450μmol/L或更高。在某些实施方式中，如果个体的尿酸水平(例如，血清尿酸水平)高于420μmol/L，则被认为具有尿酸水平升高。在某些实施方式中，如果个体非同日2次的尿酸水平(例如，血清尿酸水平)高于420μmol/L，则被认为具有尿酸水平升高。在某些实施方式中，如果个体非同日2次空腹的血清尿酸水平高于420μmol/L，则被认为具有尿酸水平升高。
本领域技术人员也可以通过本领域的常规方法来测定生物样品(例如，血清)中的尿酸水平。例如，伏安法、色谱法、毛细血管电泳法、同位素稀释质谱法、表面等离子体共振法等。
在本申请中，术语“生物样品”或“样品”是指获自或源自目标受试者的生物组合物，其包含待表征和/或待鉴定的细胞和/或其他分子实体，例如基于物理、生化、化学和/或生理特征来表征和/或鉴定。生物样品包括但不限于通过本领域技术人员已知的任何方法获得的受试者的细胞、组织、器官和/或生物流体。在一些实施方式中，生物样品是流体样品。在一些实施方式中，流体样品是全血、血浆、血清、粘液(包括鼻腔排泄物和痰)、腹膜液、胸膜液、胸腔液、唾液、尿液、滑液、脑脊髓液(CSF)、胸腔穿刺液、腹部流体、腹水或心包积液。在 一些实施方式中，生物学样品是获自受试者的心脏、肝、脾、肺、肾、皮肤或血管的组织或细胞。
在某些实施方式中，本申请所述的尿酸水平为来自个体的流体样品中的尿酸水平。在某些实施方式中，本申请所述的尿酸水平为来自个体的血液中的尿酸水平。在某些实施方式中，本申请所述尿酸水平为来自个体的血清中的尿酸水平。
在本申请中，对某种疾病、病症或状况的“治疗”、“疗法”、“预防”或“缓解”包括预防或减轻某种疾病、病症或状况，降低某种疾病、病症或状况发生或发展的速度，降低发展出某种疾病、病症或状况的风险，预防或延迟与某种疾病、病症或状况相关的症状发展，减少或终止与某种疾病、病症或状况相关的症状，产生某种疾病、病症或状况的完全或部分的逆转，治愈某种疾病、病症或状况，或以上的组合。
在某些实施方式中，本申请所述的与尿酸水平升高相关的疾病、病症或状况选自下组：痛风、高尿酸血症、未达到通常确诊为高尿酸血症的水平的较高尿酸水平、肾功能障碍、尿石病、肾结石、肾衰竭、糖尿病、糖尿病相关的病况、胰岛素抗性、代谢综合征、高血压、甲状腺功能减退、甲状旁腺功能亢进、肥胖症、炎症、肌肉痉挛、局部肿胀、炎症、关节疼痛、心肌梗塞、关节炎、肿瘤溶解综合征、认知障碍、铅中毒、牛皮癣、结节病、非酒精性脂肪性肝病、非酒精性脂肪性肝炎、心血管疾病、动脉粥样硬化、以及血液、骨髓或实体器官的移植。
在某些实施方式中，本申请所述的与尿酸水平升高相关的疾病、病症或状况为痛风。在某些实施方式中，本申请所述的与尿酸水平升高相关的疾病、病症或状况为高尿酸血症。在某些实施方式中，高尿酸血症为原发性高尿酸血症或者继发性高尿酸血症。在某些实施方式中，所述继发性高尿血酸血症包括与药物有关的高尿酸血症或与各种不同的医学状况有关的高尿酸血症。
2.药物
在另一方面，本申请提供了包含PDE4抑制剂(例如，化合物I或其药学上可接受的盐)和药学上可接受的载体的药物。
在本申请中，“药学上可接受的载体”是指总的来说在化学上和/或在物理上与制剂中的其他配料相兼容，并在生理上与其接收者相兼容的载体。
用于本发明中公开的药物组合物的药学上可接受的载体可包括，例如，药学上可接受的液体、凝胶或固体载剂、水相溶媒、非水相溶媒、抗微生物物质、等渗物质、缓冲液、抗氧化剂、麻醉剂、悬浮剂/分散剂、螯合剂、稀释剂、佐剂、辅料或无毒辅助物质，其他本领域公知的组分或以上的多种组合。
适用的组分可包括，例如，抗氧剂、填充剂、粘合剂、崩解剂、缓冲液、防腐剂、润滑剂、搅味剂、增稠剂、着色剂、乳化剂或稳定剂例如糖和环糊精。适用的抗氧剂可包括，例如，甲硫氨酸、抗坏血酸、EDTA、硫代硫酸钠、铂、过氧化氢酶、柠檬酸、半胱氨酸、巯基甘油、巯基乙酸、巯基山梨醇、丁基甲基茴香醚、丁基化羟基甲苯和/或没食子酸丙酯。如本发明所公开，在包含PDE4抑制剂(例如，化合物I或其药学上可接受的盐)的药物组合物中包括一种或多种抗氧剂如甲硫氨酸，可降低所述PDE4抑制剂(例如，化合物I或其药学上可接受的盐)的氧化。本发明进一步提供多种防止所述PDE4抑制剂(例如，化合物I或其药学上可接受的盐)氧化、延长其保质期和/或提高其活性的方法，例如，通过将本发明中提供的PDE4抑制剂(例如，化合物I或其药学上可接受的盐)与一种或多种抗氧剂(例如，甲硫氨酸)混合来实现。
本申请中的药物组合物可以制成含有预定量的活性成分/单位剂量的单位剂型。作为非限制性实例，这样的预定量或单位剂量可以含有0.5mg-1g(例如，不超过5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、60mg、70mg、80mg、90mg或100mg)的PDE4抑制剂(例如，化合物I或其药学上可接受的盐)，这取决于待治疗的疾病、给药途径和患者的年龄、体重和一般状况。典型的单位剂型是含有日剂量或亚剂量或其适当分数的活性成分的剂型。可以通过制药领域中公知的任一种方法来制备这样的药物组合物。
在一个实施方式中，药物组合物的单位剂型可以包含PDE4抑制剂(例如，化合物I或其药学上可接受的盐)，其量为大于1mg的PDE4抑制剂(例如，化合物I或其药学上可接受的盐)。在另一个实施方式中，所述药物组合物可以包含PDE4抑制剂(例如，化合物I或其药学上可接受的盐)，其量为1至100mg、或1至50mg、或10至50mg、或30至50mg。在其他实施方式中，所述药物组合物可以包含PDE4抑制剂(例如，化合物I或其药学上可接受的盐)，其量为1至20mg、或5至15mg、或10至20mg、或20至30mg。
可以将药物组合物进行改变以适于通过任何合适途径来给药，例如，通过口服(包括含服或舌下)、直肠、鼻、局部(包括含服、舌下或经皮)、阴道或胃肠外(包括皮下、肌肉内、腹膜内、静脉内或皮内)途径。可以通过制药领域已知的任何方法来制备这样的药物组合物，例如，通过使活性成分与载体或赋形剂缔合。举例来说，并且不是用来限制本发明，对于认为使用本发明的化合物是有用的特定病症和障碍来说，特定的给药途径与其他相比是更优先的。
适于口服给药的药物组合物可以呈现为离散单位，如胶囊或片剂；粉末或颗粒；溶液或混悬剂，它们各自含有水性或非水性液体；可食泡沫或搅打物；或水包油型液体乳剂或油包水型液体乳剂。例如，对于片剂或胶囊形式的口服给药，可以将活性药物成分与口服的、无毒药学可接受的惰性载体(如乙醇、甘油、水等)混合。通常，通过将化合物粉碎成合适的微细尺寸并与合适的药物载体(如可食用的碳水化合物，例如，淀粉或甘露醇)混合来制备粉末。也可以存在调味剂、防腐剂、分散剂和着色剂。
可以通过制备粉末、液体或混悬液的混合物并用明胶或其他一些适合的外壳材料包囊来制备胶囊。在包囊前，可以将助流剂和润滑剂例如硅胶、滑石粉、硬脂酸镁、硬脂酸钙或固体聚乙二醇加入混合物中。还可以加入崩解剂或增溶剂，如琼脂、碳酸钙或碳酸钠，以提高在摄入胶囊后药物的利用度。此外，期望或需要时，还可以将合适的粘合剂、润滑剂、崩解剂和着色剂掺入混合物中。合适的粘合剂的实例包括淀粉、明胶、天然糖类(如葡萄糖或β-乳糖、玉米甜昧剂)、天然和合成胶(如阿拉伯胶、西黄蓍胶或海藻酸钠)、羧甲基纤维素、聚乙二醇、蜡等。
这些剂型中使用的润滑剂包括，例如，油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括但不限于，淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。
例如，通过制备粉末混合物、制粒或重压法(slugging)、添加润滑剂和崩解剂、压制成片剂来配制片剂。可以通过将适当粉碎的化合物与如上所述的稀释剂或基质混合来制得粉末混合物。任选的成分包括粘合剂，如羧甲基纤维素、海藻酸盐、明胶或聚乙烯吡咯烷酮；溶液缓凝剂(solution retardant)，如石蜡；再吸 收加速剂，如季盐；和/或吸附剂，如膨润土、高岭土或磷酸二钙。粉末混合物可以用粘合剂湿法制粒，粘合剂例如是糖浆、淀粉糊、阿拉伯胶粘液或纤维素或聚合材料的溶液，并压制通过筛网。作为制粒的可替换方案，可以将粉末混合物通过压片机，结果，未完全形成的块状物粉碎成颗粒。可以通过加入硬脂酸、硬脂酸盐、滑石粉或矿物油，将颗粒润滑以防止颗粒粘着在形成片剂的模具上。然后将润滑的混合物压制成片剂。本发明的化合物还可以与自由流动的惰性载体混合并直接压制成片剂，而不必通过制粒或重压步骤。可以提供由虫胶隔离层、糖衣或聚合物包衣和蜡抛光层组成的透明或不透明的保护涂层。可以将染料加入这些涂层中，以区别不同的单位剂量。
在适当的情况下，用于口服给药的单位剂型制剂可以是微囊化的。还可以制得制剂以使其延长或持续释放，例如通过将颗粒材料涂覆或包埋于聚合物、蜡等中。
可以以单位剂型形式制备口服液体，例如溶液、糖浆或酏剂，使得给定的量含有预定量的化合物。例如，可以通过将化合物溶解于适当调味的水溶液中制得糖浆，而通过使用无毒醇媒介物制得酏剂。通常通过将化合物分散于无毒媒介物中来配制混悬液。还可以加入增溶剂和乳化剂，例如乙氧基化异硬脂醇和聚氧乙烯山梨糖醇醚，防腐剂；风味添加剂，例如薄荷油，或天然甜味剂，糖精，或其他人造甜味剂等。
用于药物溶液制剂的合适包装可以是所有批准的可用于胃肠外使用的容器，如塑料和玻璃容器、即用型注射器等。在一个实施方式中，容器是密封的玻璃容器，如小瓶或安瓿。气密性玻璃小瓶是密封玻璃容器的一个实例。根据本发明的一个实施方式，在密封的玻璃容器中提供了无菌可注射溶液，该溶液包含在生理学可接受的溶剂中的化合物I或其药学上可接受的盐，并且为了稳定性其具有合适的pH。本发明化合物的酸式盐在水溶液中的溶解度可能大于它们的游离碱对应物，但将该酸式盐加入水溶液中时，溶液的pH太低，使得不适于给药。因此，pH在pH4.5以上的溶液制剂可以在给药前与pH高于7的稀释液混合，使得所给药的组合制剂的pH为pH 4.5或更高。在一个实施方式中，稀释液包含药学上可接受的碱，如氢氧化钠，并且所给药的组合制剂的pH在pH 5.0～7.0之间。在将溶液通过灭菌过滤器之前，可以将一种或多种其他成分加入溶液中，这些成 分例如是共溶剂、张力调节剂、稳定剂和防腐剂，例如之前所列举的种类。
适于局部给药的药物组合物可以配制成膏剂、霜剂、混悬液、洗液、粉末、溶液、糊剂、凝胶、喷雾剂、气溶胶或油。
适于在口中局部给药的药物组合物包括锭剂(lozenges)、糖锭剂(pastilles)和漱口剂。
适于鼻给药的药物组合物(其中载体是固体)包括具有例如20～500微米粒径的粗粉。以采用吸入的方式来给药粉末，即，通过从靠近鼻子的装有粉末的容器，通过鼻通道快速吸入。其中载体是液体的、作为鼻喷雾剂或作为滴鼻剂来给药的合适制剂包括活性成分的水性溶液或油性溶液。
适于通过吸入给药的药物组合物包括细颗粒粉尘或细雾，这可以通过各种类型的计量剂量的加压气雾剂、喷雾器或吸入器来产生。
此外，本发明的组合物还可以栓剂的形式用于直肠给药本发明的化合物。可以通过将药物与合适的非刺激性赋形剂混合来制备这种组合物，该赋形剂在常温下是固体的，但在直肠温度下是液体的，并因此将在直肠中熔化，以释放药物。例如，这样的材料包括可可脂和聚乙二醇。适于直肠给药的药物组合物可以作为栓剂或作为灌肠剂存在。
适于胃肠外给药的药物组合物包括含水和无水无菌注射液，其可以含有抗氧化剂、缓冲剂、杀菌剂和使得制剂与预期的接受者的血液等渗的溶质；含水和无水无菌混悬液，其可以包含助悬剂和增稠剂。可以在单位剂型或多剂量的容器中提供制剂，这些容器例如为密封的安瓿和小瓶，并且可以贮存于冷冻干燥(冻干)条件下，临用前只需要加入无菌液体载体，例如注射用水。
即时注射液和混悬液可以从无菌粉末、颗粒和片剂制得。
除了以上特别提及的成分，本发明制剂可以包括适于目标制剂类型的本领域常规的其他试剂。例如，适于口服给药的制剂可以包括调味剂或着色剂。
在另一方面，本申请所述的药物组合物进一步包含一种或多种额外的降尿酸药物。“降尿酸药物”可以是减少尿酸合成的药物，也可以是促进尿酸排泄的药物。“降尿酸药物”可以是已被药品监督管理部门(例如，美国食品和药品管理 局(USFDA)、中国国家药品监督管理局(NMPA)、欧洲药品管理局(EMA))批准上市的降尿酸药物，也可以是在临床前研究或临床研究中被证明可以降低尿酸水平、但尚未被药品监督管理部门批准上市的药物。在某些实施方式中，所述额外的降尿酸药物选自下组：黄嘌呤氧化酶抑制剂、排尿酸剂、尿酸盐转运体-1抑制剂、尿酸酶和抑制素。在某些实施方式中，所述额外的降尿酸药物选自下组：别嘌醇、非布司他、雷西纳德、苯溴马隆、罗氟斯特、阿普斯特、碳酸氢钠、枸橼酸氢钾钠、枸橼酸钾钠、非甾体抗炎药、糖皮质激素和秋水仙碱。
3.PDE4抑制剂或其药物组合物的治疗方法
在另一个方面，本申请提供了一种降低尿酸水平的方法，包括向有需要的个体施用PDE4抑制剂(例如，化合物I或其药学上可接受的盐)。在另一个方面，本申请还提供了一种预防尿酸水平升高的方法，包括向有需要的个体施用PDE4抑制剂(例如，化合物I或其药学上可接受的盐)。在另一个方面，本申请还提供了一种治疗、预防或缓解个体中与尿酸水平升高相关的疾病、病症或状况的方法，包括，包括向有需要的个体施用PDE4抑制剂(例如，化合物I或其药学上可接受的盐)。
在某些实施方式中，本申请中所述的与尿酸水平升高相关的疾病、病症或状况选自下组：痛风、高尿酸血症、未达到通常确诊为高尿酸血症的水平的较高尿酸水平、肾功能障碍、尿石病、肾结石、肾衰竭、糖尿病、糖尿病相关的病况、胰岛素抗性、代谢综合征、高血压、甲状腺功能减退、甲状旁腺功能亢进、肥胖症、炎症、肌肉痉挛、局部肿胀、炎症、关节疼痛、心肌梗塞、关节炎、肿瘤溶解综合征、认知障碍、铅中毒、牛皮癣、结节病、非酒精性脂肪性肝病、非酒精性脂肪性肝炎、心血管疾病、动脉粥样硬化、以及血液、骨髓或实体器官的移植。
在某些实施方式中，本申请所述的与尿酸水平升高相关的疾病、病症或状况为痛风。在某些实施方式中，本申请所述的与尿酸水平升高相关的疾病、病症或状况为高尿酸血症。在某些实施方式中，高尿酸血症为原发性高尿酸血症或者继发性高尿酸血症。在某些实施方式中，所述继发性高尿血酸血症包括与药物有关的高尿酸血症或与各种不同的医学状况有关的高尿酸血症。
在某些实施方式中，本申请所述的治疗方法包括以6mg～40mg的剂量向个 体施用PDE4抑制剂(例如，化合物I)或其药学上可接受的盐，例如，6mg、6.5mg、7mg、7.5mg、8mg、9mg、9.5mg、10mg、10.5mg、11mg、11.5mg、12mg、12.5mg、13mg、13.5mg、14mg、14.5mg、15mg、15.5mg、16mg、16.5mg、17mg、17.5mg、18mg、18.5mg、19mg、19.5mg、20mg、20.5mg、21mg、21.5mg、22mg、22.5mg、23mg、23.5mg、24mg、24.5mg、25mg、25.5mg、26mg、26.5mg、27mg、27.5mg、28mg、28.5mg、29mg、29.5mg、30mg、35mg、40mg等。
临床医生可以根据被治疗的个体具体的临床状况来确定每天或每个时期的剂量和/或每天(例如，每天一次，每天两次，每天三次等)或每个时期(一周一次，一周两次，一周三次等)的给药频率。因此，应理解，任何特定个体的具体剂量水平和给药频率可取决于多种因素，例如但不限于年龄、体重、总体健康、性别、饮食、给药时间、给药途径、排泄率、药物组合以及接受治疗的特定疾病的严重程度。
在某些实施方式中，本申请所述的PDE4抑制剂(例如，化合物I或其药学上可接受的盐)也可以与额外的降尿酸药物组合施用。在某些实施方式中，所述额外的降尿酸药物选自下组：黄嘌呤氧化酶抑制剂、排尿酸剂、尿酸盐转运体-1抑制剂、尿酸酶和抑制素。在某些实施方式中，所述额外的降尿酸药物选自下组：别嘌醇、非布司他、雷西纳德、苯溴马隆、罗氟斯特、阿普斯特、碳酸氢钠、枸橼酸氢钾钠、枸橼酸钾钠、非甾体抗炎药、糖皮质激素和秋水仙碱。
当本申请所述的PDE4抑制剂(例如，化合物I或其药学上可接受的盐)与额外的降尿酸药物组合施用时，这样的药物组合可以一起给药或分开给药，当分开给药时，可以同时或以任何次序按序进行给药。选择化合物或药物的用量以及给药的相对时间，以获得所需的治疗效果。本申请所述的PDE4抑制剂(例如，化合物I或其药学上可接受的盐)与额外的降尿酸药物的组合给药可以伴随以下方式来组合给药：(1)包含两种化合物的单一组合物，或(2)各自包含一种化合物的分开的药物组合物。或者，可以以有序的方式分开给药组合药剂，其中首先给药一种治疗剂，随后给药另一种，或反之。这样的按序给药可以间隔短或间隔长。
实施例
实施例1化合物I的合成及其PDE4抑制活性实验
关于化合物I的合成方法及其PDE4抑制活性实验，请参考中国专利CN111808098B实施例(说明书第10页第[0082]-第14页第[0114]段)的相关描述。
实施例2化合物I的临床试验
2.1临床试验方案设计
Figure PCTCN2022131336-appb-000006
Figure PCTCN2022131336-appb-000007
Figure PCTCN2022131336-appb-000008
Figure PCTCN2022131336-appb-000009
Figure PCTCN2022131336-appb-000010
Figure PCTCN2022131336-appb-000011
2.2临床试验结果
化合物I的单剂量组和多剂量组的受试者的尿酸水平变化如图1A(6mg单剂量和10mg单剂量)、图1B(20mg单剂量和30mg单剂量)、图2(10mg多剂量和20mg多剂量)所示，其结果也示于表1.1、表1.2、表1.3和表2.1，以及表2.2、表2.3和表2.4中。其中表1.1、表1.2和表1.3显示了单剂量组(6mg、10mg、20mg和30mg)的受试者在接受化合物I治疗前后的尿酸水平数值的变化，表2.1、表2.2、表2.3和表2.4显示了多剂量组(10mg和20mg)的受试者在接受化合物I治疗前后的尿酸水平数值的变化。根据相关数据显示，单剂量组给药后：第二天即显示出明显的尿酸水平降低，并且显示出一定的剂量依赖性；在随后的几天(第4天和第6天)的检测显示，给药组的尿酸水平逐渐恢复；多剂量组给药后：第二天即显示出明显的尿酸水平降低，并且显示出一定的剂量依赖性；在随后的几天(第4-6天)的检测显示，给药组的尿酸水平显示了持续性的降低。这些临床试验结果表明，化合物I显著地(p＜0.05)降低了受试者的尿 酸水平，有潜力成为降低尿酸水平或预防尿酸水平升高，或者治疗、预防或缓解个体中与尿酸水平升高相关的疾病、病症或状况的候选药物。
Figure PCTCN2022131336-appb-000012
Figure PCTCN2022131336-appb-000013
Figure PCTCN2022131336-appb-000014
Figure PCTCN2022131336-appb-000015
Figure PCTCN2022131336-appb-000016
Figure PCTCN2022131336-appb-000017
Figure PCTCN2022131336-appb-000018
Figure PCTCN2022131336-appb-000019
Figure PCTCN2022131336-appb-000020
Figure PCTCN2022131336-appb-000021
实施例3化合物I与其他降尿酸药物的对比
根据实施例2的临床试验数据，发明人基于化合物I以二个不同剂量(10mg和20mg)每天给药1次连续给药7天后尿酸较基线变化的结果，使用PK/PD模型对于化合物I以另外四个不同剂量(6mg、15mg、30mg以及40mg)每天给药1次连续给药7天的降尿酸作用进行了预测，具体结果请参见图3。与文献中披露的雷西纳德和非布司他的单药和联用数据(参见文献Jacob Leander，Journal of Pharmacokinetics and Pharmacodynamics https：//doi.org/10.1007/s10928-021-09747-y，以及图4)相比，化合物I在相同或更低的剂量表现出了优于雷西纳德和非布司他单药的降尿酸水平的效果，甚至取得了与雷西纳德和非布司他联用类似的降尿酸水平的效果。
实施例4化合物I与其他降尿酸药物的对比试验
本实施例旨在比较化合物I与其他降尿酸药物在降低尿酸水平方面的效果。动物试验设计方案如下所示。
Figure PCTCN2022131336-appb-000022
Figure PCTCN2022131336-appb-000023
预计与其他降尿酸药物，化合物I在降低尿酸水平方面的效果相当或者更好。

Claims (17)

  1. 如式(I)所示的化合物或其药学上可接受的盐在制备用于在个体中降低尿酸水平或预防尿酸水平升高的药物中的用途
    Figure PCTCN2022131336-appb-100001
  2. 如式(I)所示的化合物或其药学上可接受的盐在制备用于在个体中治疗、预防或缓解个体中与尿酸水平升高相关的疾病、病症或状况的药物中的用途
    Figure PCTCN2022131336-appb-100002
  3. 根据权利要求1或2所述的用途，其中所述如式(I)所示的化合物具有如下式(Ia)或式(Ib)所示的结构：
    Figure PCTCN2022131336-appb-100003
  4. 根据权利要求3所述的用途，其中所述如式(I)所示的化合物具有如下式(Ia)所示的结构：
    Figure PCTCN2022131336-appb-100004
  5. 根据权利要求1或2所述的用途，其中所述的与尿酸水平升高相关的疾病、病症或状况选自下组：痛风、高尿酸血症、未达到通常确诊为高尿酸血症的水平的较高尿酸水平、肾功能障碍、尿石病、肾结石、肾衰竭、糖尿病、糖尿病相关的病况、胰岛素抗性、代谢综合征、高血压、甲状腺功能减退、甲状旁腺功能亢进、肥胖症、炎症、肌肉痉挛、局部肿胀、炎症、关节疼痛、心肌梗塞、关节炎、肿瘤溶解综合征、认知障碍、铅中毒、牛皮癣、结节病、非酒精性脂肪性肝病、非酒精性脂肪性肝炎、心血管疾病、动脉粥样硬化、以及血液、骨髓或实体器官的移植。
  6. 根据权利要求5所述的用途，其中所述高尿酸血症为原发性高尿酸血症或者继发性高尿酸血症。
  7. 根据权利要求6所述的用途，其中所述继发性高尿血酸血症包括与药物有关的高尿酸血症或与各种不同的医学状况有关的高尿酸血症。
  8. 根据权利要求1或2所述的用途，其中所述尿酸水平为血清尿酸水平。
  9. 根据权利要求1或2所述的用途，其中所述个体进一步被给予一种或多种额外的降尿酸药物。
  10. 根据权利要求9所述的用途，其中所述额外的降尿酸药物选自下组：黄嘌呤氧化酶抑制剂、排尿酸剂、尿酸盐转运体-1抑制剂、尿酸酶和抑制素。
  11. 根据权利要求9所述的用途，其中所述额外的降尿酸药物选自下组：别嘌醇、非布司他、雷西纳德、苯溴马隆、罗氟斯特、阿普斯特、碳酸氢钠、枸橼酸氢钾钠、枸橼酸钾钠、非甾体抗炎药、糖皮质激素和秋水仙碱。
  12. 根据权利要求1或2所述的用途，其中所述个体为哺乳动物。
  13. 根据权利要求12所述的用途，其中所述个体为人类。
  14. 根据权利要求1或2所述的用途，其中在向所述个体施用所述药物之前，所述个体非同日2次空腹的血清尿酸水平高于420μmol/L。
  15. 根据权利要求1或2所述的用途，其中所述药物通过口服、皮下、静脉内、肌肉内或腹膜内途径施用。
  16. 根据权利要求1或2所述的用途，其中所述药物包括不超过5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg或50mg的如式(I)所示的化合物或其药学上可接受的盐。
  17. 根据权利要求1或2所述的用途，其中每天一次、每天两次或每天三次向所述个体施用所述药物。
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