WO2021155781A1 - Composé de benzène sulfonamide contenant un hétérocycle à cinq chaînons, son procédé de préparation et son utilisation - Google Patents

Composé de benzène sulfonamide contenant un hétérocycle à cinq chaînons, son procédé de préparation et son utilisation Download PDF

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WO2021155781A1
WO2021155781A1 PCT/CN2021/074831 CN2021074831W WO2021155781A1 WO 2021155781 A1 WO2021155781 A1 WO 2021155781A1 CN 2021074831 W CN2021074831 W CN 2021074831W WO 2021155781 A1 WO2021155781 A1 WO 2021155781A1
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substituted
formyl
sulfamoylphenyl
alkyl
aminothiazole
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PCT/CN2021/074831
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English (en)
Chinese (zh)
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何新华
周涛
杨朝福
李爱玲
陈亮
李涛
韩秋影
王静
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中国人民解放军军事科学院军事医学研究院
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Publication of WO2021155781A1 publication Critical patent/WO2021155781A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention belongs to the field of pharmacy, and specifically relates to a five-membered heterocyclic ring-containing benzenesulfonamide compound or a pharmaceutically acceptable salt thereof, and a preparation method thereof, and a pharmaceutical composition containing the compound, and the preparation method Glaucoma, high altitude hypoxia, epilepsy, cancer, leukemia, obesity, arthritis and other medicines.
  • CA S Human Carbonic Anhydrases
  • CA I and CA II are related to glaucoma, high altitude hypoxia, epilepsy, etc.
  • CA inhibitors have been used clinically for decades as diuretics and drugs for the treatment of glaucoma, epilepsy and acute mountain diseases.
  • AAZ acetazolamide
  • AMS acetazolamide
  • Acetazolamide's mechanism of action is to enhance respiratory drive, diuresis and reduce renal metabolic acidosis.
  • acetazolamide has obvious side effects, such as numbness of the limbs, general malaise, temporary myopia, gastrointestinal symptoms, etc., which limit its application in long-term treatment.
  • the currently marketed drugs include acetazolamide, formazolamide, diclofenamide, esozolomide, dorzolamide, brinzolamide, but they have problems such as poor water solubility, eye irritation, and short action time.
  • an object of the present invention is to provide the enantiomers, diastereomers, racemates and mixtures of the five-membered heterocyclic benzenesulfonamide compounds represented by formula I , And its pharmaceutically acceptable salts, crystalline hydrates and solvates.
  • Y is a carbon atom or a nitrogen atom
  • at least one of Z and W is
  • the substituent G is selected from NR1R2, OR3 or a substituted or unsubstituted five-membered, six-membered or seven-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O, the other of Z and W does not exist ,
  • hydrogen atom C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl group, is C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl substituted with 1 to 3 halogen atoms , Halogen atom, C6, C7, C8, C9, C10, C11,
  • the substituents in the substituted five-membered, six-membered or seven-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O are selected from C1, C2, C3, C4, C5, C6, C7, C8 , C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl, hydroxy substituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C10 , C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl, C5, C6, C7, C8, C9, C10, C5, C6, C7, C8, C9, C10, C18, C19 or C20 C11, C12, C13, C14 or C15 substituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C
  • R1, R2, and R3 are each independently:
  • the substituents in, C12, C13, C14, C15, C16, C17, C18, C19 or C20 aryl groups are selected from containing 1 to 3 C1, C2, C3, C4, C5, C6, C7, C8, C9, C10 , C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkyl, halogen atom, C7 to C20 aralkyloxy and C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 alkoxy,
  • the substituents in the six-membered or seven-membered heterocyclic group are selected from C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18 , C19 or C20 alkyl, hydroxy substituted C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19 or C20 And C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19
  • the halogen atom is selected from fluorine, chlorine, bromine and iodine.
  • At least one of Z and W is wherein the substituent G is selected from NR1R2, OR3 or a substituted or unsubstituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O, the other of Z and W does not exist, or is a hydrogen atom, C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl group, C1, C2, C3, C4, C5, C6, C7, C8, C9 or substituted by 1 to 3 halogen atoms C10 alkyl group, halogen atom, C6, C7, C8, C9 or C10 aryl group;
  • the substituents in the substituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O are selected from C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkane C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl group, hydroxyl substituted C1, C2, C3, C4, C5, C6, C10, C5 to C10 heterocyclic heteroaryl containing 1 to 3 heteroatoms selected from N or O Substituted C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl groups and C2 to C10 alkoxyalkyl groups;
  • R1, R2, and R3 are each independently:
  • a substituted or unsubstituted C6, C7, C8, C9 or C10 aryl group wherein the substituent in the substituted C6, C7, C8, C9 or C10 aryl group is selected from containing 1 to 3 C1, C2, C3, C4, C5 , C6, C7, C8, C9 or C10 alkyl, halogen atom, C7, C8, C9 or C10 aralkyloxy and C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkane Oxy,
  • a substituted or unsubstituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O wherein the substituted six-membered ring group containing 1 to 3 heteroatoms selected from N and O is a substituent Alkyl selected from C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10, hydroxy substituted C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl And C2 to C10 alkoxyalkyl groups,
  • At least one of Z and W is wherein the substituent G is selected from NR1R2, OR3 or a substituted or unsubstituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O, the other of Z and W does not exist, or is a hydrogen atom, C1, C2, C3, C4, C5 or C6 alkyl group, C1, C2, C3, C4, C5 or C6 alkyl group substituted by 1 to 3 halogen atoms, halogen atom, C6, C7, C8, C9 or C10 aryl group;
  • the substituents in the substituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O are selected from C1, C2, C3, C4, C5 or C6 alkyl, hydroxy substituted C1, C2 , C3, C4, C5 or C6 alkyl and C2, C3, C4, C5 or C6 alkoxyalkyl;
  • R1, R2, and R3 are each independently:
  • a substituted or unsubstituted C6, C7, C8, C9 or C10 aryl group wherein the substituent in the substituted C6, C7, C8, C9 or C10 aryl group is selected from alkane containing 1 to 3 C1, C2, C3 or C4 Group, halogen atom, C7, C8, C9 or C10 aralkyloxy and C1 to C3 alkoxy,
  • the substituted or unsubstituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O, and the substitution in the substituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O is selected from C1, C2, C3, C4, C5 or C6 alkyl, hydroxy substituted C1, C2, C3, C4, C5 or C6 alkyl and C2, C3, C4, C5 or C6 alkoxyalkyl base,
  • At least one of Z and W is wherein the substituent G is selected from NR1R2, OR3 or a substituted or unsubstituted six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O, the other of Z and W does not exist, or is a hydrogen atom, Methyl, ethyl, propyl, butyl, Cl, Br, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, phenyl or naphthalene base;
  • the substituent in the substituted six-membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O is selected from methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxy Propyl, hydroxybutyl, methoxymethyl, methoxyethyl, methoxypropyl, C5, C6, C7, C8, C9, C10 containing 1 or 2 heteroatoms selected from N or O , C11, C12, C13, C14 or C15 benzoheterocyclic aryl substituted methyl group, containing 1 or 2 heteroatoms selected from N or O C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 or C15 benzoheterocyclic aryl substituted ethyl group and C5, C6, C7, C8, C9, C10, C11, C12, C13 containing 1 or 2 heteroatoms selected from N or O , C14 or C
  • R1, R2, and R3 are each independently:
  • a substituted or unsubstituted phenyl or naphthyl group wherein the substituent in the substituted phenyl or naphthyl group is selected from the group consisting of 1 to 3 selected from methyl, ethyl, propyl, butyl, fluorine, chlorine, bromine, Phenoxy, benzyloxy, phenethoxy, phenylpropoxy, phenbutoxy, naphthyloxy, naphthylmethoxy, naphthylethoxy, naphthylpropoxy, naphthylbutoxy, methoxy Group, ethoxy and propoxy substituents,
  • the substituted or unsubstituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O, and the substitution in the substituted six-membered heterocyclic group containing 1 to 3 heteroatoms selected from N and O is selected from methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxymethyl, ethoxymethyl and propoxymethyl, methyl Oxyethyl, ethoxyethyl and propoxyethyl, methoxypropyl, ethoxypropyl and propoxypropyl,
  • the five-membered heterocyclic ring-containing benzenesulfonamide compound of formula I is selected from the following compounds:
  • an object of the present invention is to provide a five-membered heterocyclic ring-containing benzenesulfonamide compound represented by formula I, its enantiomers, diastereomers, racemates, and The mixture, and the preparation method of its pharmaceutically acceptable salt, crystalline hydrate and solvate, the method is selected from one of the following methods:
  • p-carboxybenzenesulfonamide is used as a raw material, through amide condensation, alkaline hydrolysis, amide condensation or ester condensation, the target product contains a five-membered heterocyclic benzenesulfonamide compound.
  • the specific reaction conditions of each step of the alkaline hydrolysis, amide condensation or ester condensation can be carried out according to the conventional design in the art.
  • the amide or ester condensation reaction can refer to the literature (Bioorganic&Medicinal Chemistry Letters, 2007, 17(5) :1355-1357)
  • the alkali hydrolysis can refer to the literature (Organic Letters, 2012, 14(20): 5370-5373).
  • Another aspect of the present invention is to provide a five-membered heterocyclic ring-containing benzenesulfonamide compound represented by formula I, its enantiomers, diastereomers, racemates and mixtures thereof, and their pharmaceutically Use of acceptable salts, crystalline hydrates and solvates in the preparation of CA inhibitors.
  • Another aspect of the present invention is to provide a five-membered heterocyclic ring-containing benzenesulfonamide compound represented by formula I, its enantiomers, diastereomers, racemates and mixtures thereof, and their pharmaceutically
  • the fourth aspect of the present invention is to provide a five-membered heterocyclic ring-containing benzenesulfonamide compound represented by formula I, its enantiomers, diastereomers, racemates and mixtures thereof, and their pharmaceuticals
  • the above-acceptable salt, crystalline hydrate and solvate as the active ingredient of the pharmaceutical composition the pharmaceutical composition comprises a therapeutically effective amount of the five-membered heterocyclic benzene sulfonamide compound shown in formula I and its enantiomers Isomers, diastereomers, racemates and mixtures thereof, as well as their pharmaceutically acceptable salts, crystalline hydrates and solvates, and pharmaceutical excipients.
  • the term "effective amount” may refer to an effective amount for the dosage and time period required to achieve the desired effect. This effective amount may vary depending on certain factors, such as the type of disease or the condition of the disease during treatment, the structure of the specific target organ to be administered, the size of the patient, or the severity of the disease or symptom. Those with ordinary knowledge in the art can empirically determine the effective amount of a specific compound without undue experimentation.
  • pharmaceutical excipients refer to various excipients conventionally used in medicines, such as excipients, controlled release agents, stabilizers, etc., which belong to the conventional knowledge of those skilled in the art.
  • compositions may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, sunscreens, glidants, processing aids Agents, coloring agents, sweeteners, flavoring agents, flavoring agents or other known additives to enable the pharmaceutical composition to be manufactured or used in an acceptable form.
  • the "pharmaceutically acceptable salt” is a conventional non-toxic salt formed by the reaction of a compound of formula I with an inorganic acid or an organic acid.
  • the conventional non-toxic salt can be prepared by reacting a compound of formula I with an inorganic acid or an organic acid.
  • the inorganic acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, aminosulfonic acid, phosphoric acid, etc.
  • the Organic acids include citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalene disulfonic acid, maleic acid, malic acid, malonic acid Acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzene Sulfonic acid, 2-acetoxybenzoic acid and isethionic acid
  • the pharmaceutical composition according to the present invention can be in the following dosage forms: tablets, such as but not limited to ordinary tablets, immediate-release tablets, sustained-release tablets, controlled-release tablets, film-coated tablets, sugar-coated tablets, buccal tablets, sublingual tablets Tablets, bioadhesive tablets, etc.; capsules, such as but not limited to hard capsules, soft capsules, etc.; injections, such as but not limited to sterile or bacteriostatic-containing aqueous injections, oily injections, freeze-dried powder injections, and microspheres for injection Etc.; sprays, such as but not limited to oral sprays, nasal sprays, topical skin sprays, etc.; aerosols, such as but not limited to lung inhalation aerosols, topical skin aerosols, etc.; nasal drops, such as But not limited to nasal drops, nasal drops, gels, etc.; powder mists, such as but not limited to cavity powder mist, nasal powder mist, topical skin powder mist, etc.; other human cavities such
  • pharmaceutical excipient refers to any preparation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic or side effects to the host or patient.
  • Representative carriers include water, oil, vegetables, and minerals. , Ointment base, lotion base, ointment base, etc. These bases include suspending agents, tackifiers, penetration enhancers and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine. For other information about the carrier, you can refer to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), and the content of this document is incorporated herein by reference.
  • the preparation process of the compound of the invention is simple, the raw materials are easily obtained, and the yield is high.
  • the synthetic method for preparing the five-membered heterocyclic-containing benzenesulfonamide derivatives shown in formula I provided by the present invention is scientific and reasonable, and has the characteristics of simple operation, low cost, easy reaction control and the like.
  • As a carbonic anhydrase inhibitor the compound of the present invention shows good development potential. Compared with the commonly used carbonic anhydrase (CA) inhibitor acetazamide, the inhibitory ability of acetazamide is unbalanced, and the ability to inhibit CA I is relatively weak.
  • CA carbonic anhydrase
  • IC 50 is at the micromolar level, and has a strong ability to inhibit CA II, and the IC 50 is at the nanomolar level. Therefore, the effect caused by its inhibition of CA II is easily compromised by CA I.
  • the compound of the present invention has stronger inhibitory activity on CA I, showing that it has a strong inhibitory ability on both CA I and CAII, and the IC 50 is equal.
  • the nanomolar level is expected to avoid the loss of efficacy in the body caused by the imbalance of acetazolamide.
  • the organic layer was washed with brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the raw material product was purified by column chromatography (DCM/MT60:1-30:1) to obtain a white solid compound with a yield of 69%.
  • Example 3 Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 51%.
  • Example 3 Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 42%.
  • Example 3 Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 47%.
  • Example 3 Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 42%.
  • Example 3 Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 43%.
  • Example 3 Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 48%.
  • Example 3 Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 57%.
  • Example 3 Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 72%.
  • Example 3 Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 73%.
  • Example 3 Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3, a white solid, with a yield of 85%.
  • Example 3 Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 51%.
  • Example 3 Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 68%.
  • Example 3 Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 70%.
  • Example 3 Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 64%.
  • Example 3 Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 54%.
  • Example 3 Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 63%.
  • Example 3 Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 56%.
  • Example 3 Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 61%.
  • Example 3 Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 54%.
  • Example 3 Except for replacing the corresponding reaction starting materials, the target compound was prepared according to the method of Example 3 as a white solid with a yield of 56%.
  • Test Example 1 Inhibition test of compound on carbonic anhydrase
  • test concentration of the compound is 30.0000, 10.0000, 3.3333, 1.1111, 0.3704, 0.1235, 0.0412, 0.0137, 0.0046, 0.0015, 0.0000uM/L, CAI, II enzyme solution and compound mixture are incubated at 25°C for 15 minutes, and then added to The phthalic acid was reacted for 60 minutes, the absorbance value was recorded, and the curve was drawn with the concentration of the inhibitor as the abscissa, IC 50 was calculated, and Ki was calculated using the Chenge-Prusoff equation. The results are shown in Table 1.
  • Acetazolamide is the only drug approved by the US Food and Drug Administration (FDA) for the treatment and prevention of high altitude hypoxia.
  • FDA US Food and Drug Administration
  • the preferred representative compounds of the present invention and acetazolamide are used for comparative efficacy studies.
  • C57 mice were randomly divided into groups according to their body weight, 10 mice in each group.
  • the test compound was prepared into a suspension solution with sodium carboxymethyl cellulose and administered by gavage for three consecutive days. After the last administration, the mice were placed in the grinding mill. Open the glass bottle, conduct the airtight hypoxia experiment, use soda lime to absorb the carbon dioxide in the sealed glass bottle during the experiment.
  • the results showed that, with acetazolamide, representative compounds can better extend the survival time of mice, show stronger anti-hypoxia effects (Table 2), and have the potential to develop into stronger anti-altitude hypoxia drugs.
  • CA inhibitors have been widely used clinically as diuretics and drugs for the treatment of glaucoma, epilepsy, macular edema and acute mountain diseases (Supuran CT. Nature Reviews Drug Discovery, 2008, 7, 168-181; Min Jingyu, etc., carbonic anhydrase inhibitors) The mechanism and progress of the treatment of macular edema, New Advances in Ophthalmology, 2016, 36(7):684-687). Studies have shown that the new carbonic anhydrase inhibitor compound of the present invention has good medical applications and can be used as a new type of potent and low-toxic CAI/II inhibitor.

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Abstract

La présente invention concerne un composé de benzène sulfonamide contenant un hétérocycle à cinq chaînons représenté par la formule (I), et un énantiomère, un diastéréoisomère, et un racémate de celui-ci et un mélange de ceux-ci, et un sel pharmaceutiquement acceptable, un hydrate cristallin et un solvate de celui-ci, ainsi qu'une utilisation d'un tel composé dans la préparation d'un inhibiteur de CA, et une composition pharmaceutique contenant un tel composé. Le composé selon la présente invention possède un bon potentiel de développement en tant qu'inhibiteur d'anhydrase carbonique. En comparaison avec l'inhibiteur de l'anhydrase carbonique (CA) couramment utilisé, l'acétazolamide diamox, dans la pratique clinique, le composé selon la présente invention a une activité inhibitrice plus forte sur CAI, et présente une forte capacité inhibitrice à la fois sur CAI et CAII, atteignant un IC50 de niveaux nanomolaires, et devrait permettre d'éviter la perte d'efficacité in vivo causée par le déséquilibre de l'acétazolamide diamox.
PCT/CN2021/074831 2020-02-04 2021-02-02 Composé de benzène sulfonamide contenant un hétérocycle à cinq chaînons, son procédé de préparation et son utilisation WO2021155781A1 (fr)

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