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WO2025232711A1 - Nouveau composé pyrazolone contenant du deutérium, composition pharmaceutique et utilisation associées - Google Patents

Nouveau composé pyrazolone contenant du deutérium, composition pharmaceutique et utilisation associées

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Publication number
WO2025232711A1
WO2025232711A1 PCT/CN2025/092791 CN2025092791W WO2025232711A1 WO 2025232711 A1 WO2025232711 A1 WO 2025232711A1 CN 2025092791 W CN2025092791 W CN 2025092791W WO 2025232711 A1 WO2025232711 A1 WO 2025232711A1
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WO
WIPO (PCT)
Prior art keywords
substituents
deuterium
unsubstituted
dsc207
compound
Prior art date
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Pending
Application number
PCT/CN2025/092791
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English (en)
Chinese (zh)
Inventor
张哲峰
孟月垒
侯雯
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nanjing Zhihe Medicine Technology Co Ltd
Original Assignee
Nanjing Zhihe Medicine Technology Co Ltd
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Filing date
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Publication of WO2025232711A1 publication Critical patent/WO2025232711A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • A61K31/41—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
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to, but is not limited to, the field of pharmaceutical chemistry, and particularly to a novel deuterium-containing pyrazolinone compound, tautomer, stereoisomer, prodrug, pharmaceutically acceptable salt thereof, pharmaceutical composition thereof, and uses thereof.
  • Neurodegenerative diseases are a group of neurological disorders characterized by the progressive loss of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). These chronic, progressive neurological illnesses affect the lives of millions worldwide. Since 1990, the total number of disabilities, illnesses, and premature deaths (disability-adjusted life years) caused by neurological diseases has increased by 18%. These diseases primarily include Alzheimer's disease, Parkinson's disease, Huntington's disease, various types of spinocerebellar ataxia, multiple sclerosis, cerebellar atrophy, and amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • the inventors have developed a novel deuterium-containing pyrazolone compound that exhibits better protection against L-glutamate-induced PC12 cell damage, better improvement in ischemic stroke, easier crossing of the blood-brain barrier, and longer retention time in brain tissue and cerebrospinal fluid. Unexpectedly, it has a short half-life, which effectively avoids accumulation in vivo and reduces hepatotoxic side effects.
  • this invention provides a novel deuterium-containing pyrazolinone compound, tautomer, stereoisomer, prodrug, and pharmaceutically acceptable salt thereof, as shown in (I) and/or (II):
  • R 1 is selected from hydrogen, deuterium, C1-C8 alkyl substituted or unsubstituted with one or more substituents, phenyl substituted or unsubstituted with one or more substituents, or pyridyl substituted or unsubstituted with one or more substituents, wherein the substituents are selected from deuterium or halogens;
  • R 2 is selected from hydrogen, deuterium, C1-C8 alkyl substituted or unsubstituted with one or more substituents, phenyl substituted or unsubstituted with one or more substituents, or pyridyl substituted or unsubstituted with one or more substituents, wherein the substituents are selected from deuterium or halogens;
  • R3 is selected from hydrogen or deuterium
  • R 4 is selected from cyclohexyl groups substituted or unsubstituted with one or more substituents, benzyl groups substituted or unsubstituted with one or more substituents, naphthyl groups substituted or unsubstituted with one or more substituents, heterocyclic groups substituted or unsubstituted with one or more substituents, or... in,
  • R X1 is selected from halogens, or C1-C8 alkyl groups substituted or unsubstituted by one or more substituents, wherein the substituents are selected from deuterium or halogens;
  • R X2 is selected from halogens, or C1-C8 alkyl groups substituted or unsubstituted by one or more substituents, wherein the substituents are selected from deuterium or halogens;
  • RX3 is selected from halogens, C1-C8 alkyl groups substituted or unsubstituted with one or more substituents, and C1-C8 alkoxy groups substituted or unsubstituted with one or more substituents.
  • R X4 is selected from C1-C8 alkyl groups substituted or unsubstituted by one or more substituents, or C1-C8 alkoxy groups substituted or unsubstituted by one or more substituents, wherein the substituents are selected from deuterium or halogens;
  • At least one of R1 , R2 , R3 and R4 is deuterium or is replaced by deuterium.
  • the present invention provides a novel deuterium-containing pyrazolinone compound, tautomer, stereoisomer, prodrug, and pharmaceutically acceptable salt thereof as shown in formula (III) and/or formula (IV):
  • R1 is selected from hydrogen, deuterium, C1-C8 alkyl substituted or unsubstituted with one or more substituents, phenyl substituted or unsubstituted with one or more substituents, or pyridyl substituted or unsubstituted with one or more substituents, wherein the substituents are selected from deuterium or halogens; preferably, R1 is selected from methyl, trideuterated methyl, phenyl, or propyl.
  • R2 is selected from hydrogen, deuterium, C1-C8 alkyl substituted or unsubstituted with one or more substituents, phenyl substituted or unsubstituted with one or more substituents, or pyridyl substituted or unsubstituted with one or more substituents, wherein the substituents are selected from deuterium or halogens; preferably, R2 is selected from hydrogen, deuterium, or isobutyl.
  • R3 is selected from hydrogen or deuterium
  • R4 is selected from cyclohexyl groups substituted or unsubstituted with one or more substituents, benzyl groups substituted or unsubstituted with one or more substituents, naphthyl groups substituted or unsubstituted with one or more substituents, heterocyclic groups substituted or unsubstituted with one or more substituents, or...
  • the substituent is selected from deuterium or halogen; preferably, R4 is selected from cyclohexyl, benzyl, naphthyl, pyridyl, benzothiophene, or in,
  • R X1 is selected from halogens, or C1-C8 alkyl groups substituted or unsubstituted by one or more substituents, wherein the substituents are selected from deuterium or halogens; preferably, R X1 is selected from chloro, methyl, or trideuterated methyl.
  • RX2 is selected from halogens, or C1-C8 alkyl groups substituted or unsubstituted by one or more substituents, wherein the substituents are selected from deuterium or halogens; preferably, RX2 is selected from methyl or trideuterated methyl.
  • RX3 is selected from halogens, C1-C8 alkyl groups substituted or unsubstituted with one or more substituents, and C1-C8 alkoxy groups substituted or unsubstituted with one or more substituents.
  • R X4 is selected from C1-C8 alkyl groups substituted or unsubstituted by one or more substituents, or C1-C8 alkoxy groups substituted or unsubstituted by one or more substituents, wherein the substituents are selected from deuterium or halogens;
  • RX3 is selected from chlorine, methoxy, ethoxy, hydroxymethyl, -CDHOH, -CD2OH , ethoxyacyl, or
  • R4 in equations (I)-(IV) above is selected from... in,
  • R X1 is selected from halogens, or C1-C8 alkyl groups substituted or unsubstituted by one or more substituents, wherein the substituents are selected from deuterium or halogens; preferably, R X1 is selected from chloro, methyl, or trideuterated methyl.
  • RX2 is selected from halogens, or C1-C8 alkyl groups substituted or unsubstituted by one or more substituents, wherein the substituents are selected from deuterium or halogens; preferably, RX2 is selected from methyl or trideuterated methyl.
  • RX3 is selected from halogens, C1-C8 alkyl groups substituted or unsubstituted with one or more substituents, and C1-C8 alkoxy groups substituted or unsubstituted with one or more substituents.
  • R X4 is selected from C1-C8 alkyl groups substituted or unsubstituted by one or more substituents, or C1-C8 alkoxy groups substituted or unsubstituted by one or more substituents, wherein the substituents are selected from deuterium or halogens;
  • RX3 is selected from chlorine, methoxy, ethoxy, hydroxymethyl, -CDHOH, -CD2OH , ethoxyacyl, or
  • At least one of R1 , R2 , R3 and R4 is deuterium or is replaced by deuterium.
  • novel deuterium-containing pyrazolone compounds, tautomers, stereoisomers, prodrugs, and pharmaceutically acceptable salts provided by the present invention are selected from the following compounds:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned novel deuterium-containing pyrazolone compound, tautomer, stereoisomer, prodrug, and pharmaceutically acceptable salt thereof.
  • This invention discloses a pharmaceutical composition
  • a pharmaceutical composition comprising the compounds, tautomers, stereoisomers, prodrugs and their pharmaceutically acceptable salts described in this invention as active ingredients or main active ingredients, supplemented by a pharmaceutically acceptable carrier.
  • the present invention provides the use of the above-mentioned novel deuterium-containing pyrazolone compounds, tautomers, stereoisomers, prodrugs and their pharmaceutically acceptable salts or the above-mentioned pharmaceutical compositions in the preparation of neuroprotective drugs.
  • the present invention provides the use of the above-mentioned novel deuterium-containing pyrazolone compounds, tautomers, stereoisomers, prodrugs and their pharmaceutically acceptable salts or the above-mentioned pharmaceutical compositions in the preparation of medicaments for the prevention or treatment of cardiovascular and cerebrovascular diseases.
  • This invention provides the use of the above-mentioned pharmaceutical composition in the preparation of neuroprotective drugs, wherein the neuroprotective drugs are drugs for treating neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, cerebellar ataxia, different types of spinocerebellar ataxia, spinal muscular atrophy, cerebral ischemia, and primary lateral sclerosis.
  • neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, cerebellar ataxia, different types of spinocerebellar ataxia, spinal muscular atrophy, cerebral ischemia, and primary lateral sclerosis.
  • This invention provides the use of the above-mentioned pharmaceutical composition in the preparation of drugs for the prevention or treatment of cardiovascular and cerebrovascular diseases
  • the drugs for the prevention or treatment of cardiovascular and cerebrovascular diseases are drugs for the treatment of cardiovascular and cerebrovascular diseases, including hypertension, coronary heart disease, stroke, diabetic heart failure, heart failure, diastolic heart failure, systolic heart failure, postoperative volume overload, idiopathic edema, pulmonary hypertension, pulmonary arterial hypertension, acute decompensated heart failure, heart failure, acute renal failure, and nephrotic syndrome.
  • novel compounds of the present invention can be formulated as pharmaceutical compositions and administered to patients via a variety of suitable routes of administration, including systemic (e.g., oral or parenteral), intravenous, intramuscular, transdermal, or subcutaneous routes.
  • systemic e.g., oral or parenteral
  • intravenous e.g., intramuscular, transdermal, or subcutaneous routes.
  • the inventors have developed a novel deuterium-containing pyrazolone compound that exhibits better protection against L-glutamate-induced PC12 cell damage, better improvement in ischemic stroke, easier crossing of the blood-brain barrier, and longer retention time in brain tissue and cerebrospinal fluid. Unexpectedly, it has a short half-life, which effectively avoids accumulation in vivo and reduces hepatotoxic side effects.
  • Some compounds of this invention can exist in either a solvated or a solvent-based form, such as hydrates or ethanolates. Generally, the solvent-based and the solvent-based forms are equivalent and are both included within the scope of this invention.
  • pharmaceutical acceptable refers to compounds, materials, compositions, and/or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent.
  • base addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include aluminum, sodium, potassium, calcium, manganese, iron, ammonium, organic amine, or magnesium salts, or similar salts.
  • acid addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as
  • alkyl refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups. Alkyl groups can be substituted or unsubstituted. When substituted, the substituent is preferably one or more, more preferably one to three, and most preferably one or two.
  • alkenyl refers to an aliphatic hydrocarbon group containing an unsaturated carbon-carbon double bond, including straight-chain and branched groups.
  • the alkyl group can be substituted or unsubstituted. There can be one or more carbon-carbon double bonds.
  • cycloalkyl refers to a monocyclic or fused-ring group consisting entirely of carbon atoms (a "fused" ring means that each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system), wherein one or more rings do not have a fully connected ⁇ -electron system.
  • cycloalkyl groups include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane, and cyclohepttriene. Cycloalkyl groups can be substituted or unsubstituted.
  • aryl refers to an all-carbon monocyclic or fused polycyclic group with 1 to 12 carbon atoms and a fully conjugated ⁇ -electron system.
  • Non-limiting examples of aryl groups include phenyl, naphthyl, and anthracene.
  • Aryl groups can be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two, or three, and even more preferably one or two.
  • aryl hydrocarbon group refers to a hydrocarbon group that has been replaced by an aryl group.
  • heteroaryl refers to a monocyclic or fused cyclic group of multiple atoms containing one, two, three, or four cyclic heteroatoms selected from N, O, or S, with the remaining cyclic atoms being C, and possessing a fully conjugated ⁇ -electron system.
  • unsubstituted heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, quinoline, isoquinoline, purine, tetrazolium, triazine, and carbazole.
  • alkoxy refers to an alkyl group bonded to an oxygen atom, where the alkyl group can be straight-chain, branched, or cycloalkyl.
  • hydroxyl group refers to the -OH group.
  • amino refers to the -NH2 group.
  • carboxyl group refers to the -COOH group.
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of this invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient.
  • Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, transdermal penetration enhancers, etc.
  • stereoisomer refers to compounds that have the same chemical composition but different spatial arrangements of atoms or groups.
  • C1-C8 means that the group can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 8 carbon atoms.
  • ZJT-2-SM (880 mg, 10 mmol, 1 eq) was cooled to -78 °C, and then bis(trimethylsilyl)aminolithium (1.0 mol/L tetrahydrofuran) (11 mL, 11 mmol, 1.1 eq) was added, and the reaction was continued for 10 min. Then acetyl chloride-3d (815 mg, 10 mL, 1.0 eq) was added, and the system was kept at -78 °C, and the reaction was continued for 2 h. Liquid chromatography monitoring showed that the reaction was complete.
  • DSC207-01-1 (25.0 g, 170.0 mmol, 1 eq) was added to toluene (250 ml), the system was cooled to -10 °C, and then phosphorus oxychloride (31.3 g, 20.4 mmol, 1.2 eq) was added. After the addition was complete, the system was heated to 90 °C and reacted for 16 hours.
  • DSC207-01-5 (4.0 g, 14.9 mmol, 1 eq) was added to DCM (40 mL), and the system was cooled to -10 °C.
  • m-CPBA (5.13 g, 29.7 mmol, 2 eq) was added in portions, and the reaction was allowed to proceed for another 30 min after each addition. Thin-layer chromatography showed that the reaction was complete.
  • the system was heated to 25 °C and poured into a sodium sulfite aqueous solution (50 mL). The mixture was separated, and the aqueous phase was extracted with DCM (50 mL ⁇ 3). The organic phases were combined, dried over sodium sulfate, and concentrated to obtain the crude product.
  • DSC207-03-1 (7.0 g, 42.1 mmol, 1 eq) was added to DCM (70 mL), and the system was cooled to -10 °C.
  • m-CPBA (8.7 g, 50.5 mmol, 1.2 eq) was added in portions, and the reaction was allowed to proceed at room temperature for 8 hours after the addition was complete. Thin-layer chromatography showed that the reaction was complete.
  • the system was heated to 25 °C and poured into an aqueous sodium sulfite solution (50 mL). The mixture was separated, and the aqueous phase was extracted with DCM (50 mL ⁇ 3). The organic phases were combined, dried over sodium sulfate, and concentrated to give 7.0 g of a white solid (yield: 91.3%).
  • DSC207-03-2 (5.0 g, 27.4 mmol, 1 eq) was added to toluene (25 mL), and the system was cooled to -10 °C. Phosphorus oxychloride (5.0 g, 32.9 mmol, 1.2 eq) was then added. After the addition was complete, the system was heated to 90 °C and reacted for 16 hours. Thin-layer chromatography showed that the reaction was complete. The mixture was concentrated, and the residue was dissolved in DCM (20 mL). The pH was adjusted to 8-9 with sodium bicarbonate aqueous solution. The mixture was separated, and the aqueous phase was extracted with DCM (50 mL ⁇ 3).
  • the system was poured into water, the pH was adjusted to 3-4 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate (15 mL ⁇ 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product.
  • DSC207-03-4 (1.0 g, 3.8 mmol, 1 eq) was added to methanol (10 mL), the system was cooled to -10 °C, sodium borohydride-4d (0.64 g, 15.2 mmol, 4 eq) was added, and after the addition was complete, the mixture was allowed to rise to room temperature and react for 4 hours.
  • ZJT-2 (1.47 g, 14.5 mmol, 1.45 eq) was added to DMSO (30 mL), the system was cooled to -10 °C, and then potassium carbonate (2.75 g, 20.0 mmol, 2 eq) was added. After the addition was complete, the mixture was stirred at room temperature for 10 minutes, and then DSC207-03-3 (2.0 g, 10.0 mmol, 1 eq) was added. After the addition was complete, the mixture was reacted at room temperature for 3 hours.
  • DSC207-05-1 (1.0 g, 3.8 mmol, 1 eq) was added to methanol (10 mL), the system was cooled to -10 °C, sodium borohydride-4d (0.64 g, 15.2 mmol, 4 eq) was added, and after the addition was complete, the mixture was allowed to rise to room temperature and react for 4 hours.
  • DSC207-06-2 (3.0 g, 12.2 mmol, 1 eq) was added to acetic anhydride (30 mL), and the system was heated to 130 °C and reacted for 5 hours. Thin-layer chromatography showed that the reaction was complete. The system was cooled to room temperature and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain 2.0 g of the target substance (yield: 57.3%).
  • DSC207-09-1 (988 mg, 3.74 mmol, 1 eq) was added to methanol (10 mL), the system was cooled to -10 °C, sodium borohydride (566 mg, 15 mmol, 4 eq) was added, and after the addition was complete, the mixture was brought to room temperature and reacted for 4 hours.
  • ZJT-3 (6.0 g, 58.2 mmol, 1.45 eq) was added to DMSO (120 mL), the system was cooled to -10 °C, and then potassium carbonate (11.1 g, 80.0 mmol, 2.0 eq) was added. After the addition was complete, the mixture was stirred at room temperature for 10 minutes, and then DSC207-01-2 (6.6 g, 40.0 mmol, 1 eq) was added. After the addition was complete, the mixture was reacted at room temperature for 3 hours.
  • DSC207-10-2 (3.0 g, 12.1 mmol, 1 eq) was added to acetic anhydride (30 mL), and the system was heated to 130 °C and reacted for 5 hours. Thin-layer chromatography showed that the reaction was complete. The system was cooled to room temperature and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain 2.1 g of the target analyte (yield: 60.1%).
  • DSC207-11-1 (4.22 g, 34.0 mmol, 1 eq) was added to toluene (50 mL), and the system was cooled to -10 °C.
  • Phosphorus oxychloride (6.25 g, 40.8 mmol, 1.2 eq) was then added. After the addition was complete, the system was heated to 90 °C and reacted for 16 hours. Thin-layer chromatography showed that the reaction was complete. The mixture was concentrated, and the residue was dissolved in DCM (20 mL). The pH was adjusted to 8-9 with sodium bicarbonate aqueous solution. The mixture was separated, and the aqueous phase was extracted with DCM (50 mL ⁇ 3).
  • ZJT-2 (1.47 g, 14.5 mmol, 1.45 eq) was added to DMSO (30 mL), and the system was cooled to -10 °C. Potassium carbonate (2.75 g, 20 mmol, 2 eq) was then added. After the addition was complete, the mixture was stirred at room temperature for ten minutes. DSC207-11-2 (1.43 g, 10.0 mmol, 1 eq) was then added, and the mixture was allowed to react at room temperature for 3 hours. Thin-layer chromatography showed that the reaction was complete. The system was poured into water, and the pH was adjusted to 3-4 with 1 N hydrochloric acid. Extraction was performed with ethyl acetate (20 mL ⁇ 3).
  • DSC207-11-4 (1.0 g, 4.18 mmol, 1 eq) was added to toluene (25 mL), and the system was cooled to -10 °C. Phosphorus oxychloride (0.77 g, 5.02 mmol, 2 eq) was then added. After the addition was complete, the system was heated to 90 °C and reacted for 16 hours. Thin-layer chromatography showed that the reaction was complete. The mixture was concentrated, and the residue was dissolved in DCM (20 mL). The pH was adjusted to 8-9 with sodium bicarbonate aqueous solution. The mixture was separated, and the aqueous phase was extracted with DCM (30 mL ⁇ 3).
  • DSC207-11-5 (0.5 g, 2.07 mmol, 1 eq) and (2.41 g, 10 mmol, 1 eq) were added to ethanol (25 mL).
  • the system was cooled to -10 °C, and sodium ethoxide (0.16 g, 2.35 mmol, 1.1 eq) and (748.5 mg, 11 mmol, 1.1 eq) were added.
  • the reaction was allowed to proceed for another 50 minutes. Thin-layer chromatography showed that the reaction was complete.
  • the system was poured into 1 N hydrochloric acid aqueous solution (35 mL), and the aqueous phase was extracted with ethyl acetate (50 mL ⁇ 3).
  • the compound DSC207-16-SM (16.0 g, 105.2 mmol) was dissolved in ethanol (250 mL). The system was cooled to 0 °C, and 2 drops of sulfuric acid were added. After the addition was complete, the system was allowed to react at room temperature for 3 hours. Thin-layer chromatography showed that the reaction was essentially complete. The system was concentrated, and the residue was poured into water and extracted with ethyl acetate (150 mL ⁇ 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give 14.4 g of the target compound (yield: 76.5%).
  • DSC207-16-2 (5.38 g, 27.44 mmol, 1 eq) was added to toluene (50 mL), and the system was cooled to -10 °C. Phosphorus oxychloride (5.1 g, 32.93 mmol, 1.2 eq) was then added. After the addition was complete, the system was heated to 90 °C and reacted for 16 hours. Thin-layer chromatography showed that the reaction was complete. The mixture was concentrated, and the residue was dissolved in DCM (25 mL). The pH was adjusted to 8-9 with sodium bicarbonate aqueous solution. The mixture was separated, and the aqueous phase was extracted with DCM (50 mL ⁇ 3).
  • ZJT-2 (1.47 g, 14.5 mmol, 1.45 eq) was added to DMSO (50 mL), and the system was cooled to -10 °C. Potassium carbonate (2.75 g, 20.0 mmol, 2 eq) was then added. After the addition was complete, the mixture was stirred at room temperature for ten minutes. DSC207-16-3 (2.15 g, 10.0 mmol, 1 eq) was then added, and the mixture was allowed to react at room temperature for 3 hours. Thin-layer chromatography showed that the reaction was complete. The system was poured into water, and the pH was adjusted to 3-4 with 1 N hydrochloric acid.
  • DSC207-03-4 (1.0 g, 3.81 mmol, 1 eq) was added to DCM (10 mL), and the system was cooled to -10 °C.
  • Diisobutylaluminum hydride (DIBAL-H, 1 mol/L in DCM) (4.2 mL, 4.2 mmol, 1.1 eq) was added, and the mixture was allowed to react at room temperature for 4 hours. Thin-layer chromatography showed that the reaction was complete.
  • the system was poured into an aqueous solution (50 mL), and the aqueous phase was extracted with DCM (40 mL ⁇ 3). The organic phases were combined, dried over sodium sulfate, concentrated, and the residue was purified by column chromatography to give 521 mg of the target analyte (yield: 58.9%).
  • DSC207-16 (1.0 g, 3.58 mmol, 1 eq) was added to DCM (30 mL), and the system was cooled to -10 °C.
  • DIBAL-H (1 mol/L in DCM) (4.14 mL, 4.14 mmol, 1.1 eq) was added, and the mixture was allowed to react at room temperature for 4 hours. Thin-layer chromatography showed that the reaction was complete. The system was poured into an aqueous solution (50 mL), and the aqueous phase was extracted with DCM (30 mL ⁇ 3).
  • DSC207-02-2 (4.42 g, 34 mmol, 1 eq) was added to toluene (25 ml), the system was cooled to -10 °C, and then phosphorus oxychloride (6.25 g, 40.8 mmol, 1.2 eq) was added. After the addition was complete, the system was heated to 90 °C and reacted for 16 hours.
  • PC-12 Rat adrenal pheochromocytoma cells
  • PC-12Adh National Model and Characteristic Experimental Cell Resource Bank/Chinese Academy of Sciences Cell Bank Stem Cell Bank, catalog number SCSP-5259
  • the cell culture incubator was maintained at 37°C with 5% CO2 .
  • Culture medium RPMI 1640, Gibco
  • Preparation of modeling agent solution (L-glutamic acid): Weigh an appropriate amount of L-glutamic acid powder, dissolve it in RPMI 1640 complete culture medium (containing 10% FBS) to a concentration of 10 mmol/L, sonicate for 15 min, and then sonicate in a 37°C water bath for 15 min until completely dissolved. Prepare fresh before use.
  • test solution series Dissolve an appropriate amount of sample in DMSO to 100 mmol/L as a stock solution and store at -20°C for later use. Immediately before use, dilute the above-prepared modeling agent solution (final L-glutamic acid concentration 10 mmol/L) 1000 times with RPMI 1640 whole medium (containing 10% FBS) to 100 ⁇ mol/L. After thorough mixing, take an appropriate amount and dilute it 1/2 with the above-prepared modeling agent solution to 50 ⁇ mol/L. Then, continue to dilute 1/2 to obtain test solution series concentrations (25, 12.5, 6.25, 3.125, 1.6, 0.8, 0.4, 0.2 ⁇ mol/L).
  • PC12 cells in the logarithmic growth phase cultured in vitro were used for experiments.
  • the experiment included a blank control group, a model group, a control compound group (X1901), and a test substance group.
  • the control group was given 100 ⁇ L/well of RPMI 1640 complete medium (containing 10% FBS), the model group was given 100 ⁇ L/well of the above-prepared modeling agent solution, and the test substance group was given 100 ⁇ L/well of a series of concentrations of the test substance solution prepared above (0.2, 0.4, 0.8, 1.6, 3.125, 6.25, 12.5, 25, 50, 100 ⁇ mmol/L, a total of 10 concentration groups). Each group had 5 replicates. After adding all solutions, the cells were immediately incubated at 37°C in a 5% CO2 incubator. After 24 hours of incubation, the viability of PC12 cells was detected using the CCK-8 assay.
  • the EC50 (50% effective concentration) of the corresponding test substance was calculated using GraphPad Prism 6.0 software.
  • the compounds of the present invention have very strong protective activity against L-glutamate-induced PC12 cell damage, especially DSC207-L01, DSC207-L02, DSC207-L03, DSC207-L04 and DSC207-L05, among which compound DSC207-L05 has the strongest protective activity, which is about 7.5 times that of the comparative compound X1901.
  • Example 20 Pharmacological efficacy test in a rat model of cerebral ischemia-reperfusion.
  • Rats were fasted for 12-14 hours before surgery, but had free access to water. Before surgery, all groups of animals were anesthetized with isoflurane, preserving spontaneous respiration. They were fixed in a supine position on a rat board, with hair removed from the midline of the neck and disinfected with 75% alcohol. A surgical incision was made on the ventral side of the neck midline, separating the muscle and fascia along the inner edge of the sternocleidomastoid muscle. The right common carotid artery, external carotid artery, and internal carotid artery were then separated.
  • Drug administration The drugs for each group were administered intravenously 0.5 hours after cerebral infarction in the animals.
  • the sham-operated group and the model group were given the same volume of blank solvent (8% propylene glycol + 92% physiological saline). Grouping and detailed drug administration information are shown in Table 2.
  • Zea-Longa scoring criteria No neurological deficits: 0 points; Inability to fully extend the forepaw on the paralyzed side: 1 point; Turning in circles towards the paralyzed side while walking: 2 points; Leaning towards the paralyzed side while walking: 3 points; Inability to walk automatically, with signs of loss of consciousness: 4 points.
  • Infarct area ratio Total infarct area ⁇ Total area of whole brain slices ⁇ 100%;
  • Infarction improvement rate (Infarction area ratio in the model group - Infarction area ratio in the treatment group) ⁇ Infarction area ratio in the model group ⁇ 100%
  • test substance groups (DSC207-01, DSC207-02, DSC207-03, DSC207-04, and DSC207-05) all effectively improved the Zea-Longa score and balance beam time of MCAO rats compared with the positive drug group (Xenbisin) and the control group (X1901). They also significantly improved the difference in blood flow between the left and right sides of the brain in MCAO rats, significantly reduced the cerebral infarction area, and increased the cerebral infarction improvement rate in rats. Among them, DSC207-05 showed the best performance.
  • Example 21 Distribution of drug in brain and spinal cord tissues in rats via gavage
  • the number of animals included in the group was 36, and their weight was approximately 200 ⁇ 20g at the start of the experiment.
  • mice Male SD rats were randomly divided into four groups according to body weight: a control group (X1901 group), a DSC207-02 group, a DSC207-03 group, and a DSC207-05 group, with nine rats in each group. Animals were fasted for 12-14 hours before administration, but water was allowed. On the day of the experiment, the animals were administered the drug by gavage at a dose of 13.40 mg/kg (5 mL/kg, 5% DMSO + 95% 0.5% MC solution). Three animals from each group were euthanized at 10 min, 60 min, and 3 h after the single oral gavage administration. Brain and spinal cord tissue samples were collected (care was taken to remove blood with filter paper and remove blood vessels as much as possible) and stored at -80°C for later analysis.
  • a control group X1901 group
  • DSC207-02 group Male SD rats were randomly divided into four groups according to body weight: a control group (X1901 group), a DSC207-02 group, a DSC207-03 group
  • the experimental animals were observed in their general condition. This included: changes in the rats' food and water intake, weight changes, any abnormalities in coat color, behavior and mental state, any abnormal secretions from the eyes, ears, mouth, and nose, and any abnormalities in urination and defecation. Any abnormalities were immediately recorded, and the causes were analyzed.
  • Plasma protein precipitation-LC/MS/MS method was used to detect the original drug content in brain tissue and spinal cord.
  • mice Eighteen male SD rats were divided into 6 groups of 3 rats each. Animals were fasted for 12-14 hours before administration, but water was allowed.
  • the control group (X1901 group), DSC207-01 group, DSC207-02 group, DSC207-03 group, DSC207-04 group, and DSC207-05 group were all administered the drug via tail vein injection.
  • the drugs were administered sequentially according to the animals' body weight at a dose of 5 mg/kg (administration volume of 5 mL/kg).
  • Plasma collection Within 0.5 h before a single intravenous injection (0 h), and at 0.083 h, 0.25 h, 0.50 h, 1.0 h, 3.0 h, 6.0 h, 9.0 h, and 24.0 h after administration, 200 ⁇ L of blood was collected from the orbital vein of rats and placed in EDTA-K2 anticoagulant tubes. The tubes were then placed in an ice bath and centrifuged at 4000 rpm for 10 min. The plasma was transferred to 1.5 mL centrifuge tubes and stored at -80°C for analysis. Animals were fed 4 h after administration, but water was not restricted throughout the process.

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Abstract

L'invention concerne un nouveau composé pyrazolone contenant du deutérium, une composition pharmaceutique et son utilisation. Le nouveau composé pyrazolone contenant du deutérium est tel que représenté par la formule (I) et/ou la formule (II), la définition de chaque substituant étant détaillée dans la description. Le composé peut être utilisé dans la préparation d'un médicament pour la prévention ou le traitement de maladies neurodégénératives et de maladies cardiovasculaires et cérébrovasculaires.
PCT/CN2025/092791 2024-05-06 2025-05-06 Nouveau composé pyrazolone contenant du deutérium, composition pharmaceutique et utilisation associées Pending WO2025232711A1 (fr)

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