WO2022237456A1 - Use of 4-arylaminoquinazoline hydroxamic acid compounds in preparation of pain drug - Google Patents

Use of 4-arylaminoquinazoline hydroxamic acid compounds in preparation of pain drug Download PDF

Info

Publication number
WO2022237456A1
WO2022237456A1 PCT/CN2022/087341 CN2022087341W WO2022237456A1 WO 2022237456 A1 WO2022237456 A1 WO 2022237456A1 CN 2022087341 W CN2022087341 W CN 2022087341W WO 2022237456 A1 WO2022237456 A1 WO 2022237456A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
amino
quinazolinyl
hydroxy
phenoxy
Prior art date
Application number
PCT/CN2022/087341
Other languages
French (fr)
Chinese (zh)
Inventor
陈小新
张兰
刘苗
张倩茹
陈谋
龙超峰
姚于勤
Original Assignee
广东众生药业股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 广东众生药业股份有限公司 filed Critical 广东众生药业股份有限公司
Priority to CN202280033602.XA priority Critical patent/CN117412752A/en
Publication of WO2022237456A1 publication Critical patent/WO2022237456A1/en

Links

Images

Classifications

    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms

Definitions

  • the invention relates to the application of a series of 4-arylaminoquinazoline hydroxamic acid compounds in the preparation of drugs for treating neuropathic pain, especially neuropathic pain induced by diabetes and chemotherapy drugs.
  • Neuropathic pain is pathological pain caused by peripheral or central nervous system injury or disease. These include pain caused by herpes zoster, peripheral neuropathic diseases such as trigeminal neuralgia, and pathological pain such as diabetic neuropathic pain and chemotherapy drugs.
  • the main features of pain are allodynia (ie, pain caused by innocuous stimuli) and hyperalgesia (ie, pain response to increased stimuli).
  • Epigenetics has become a hot topic at present, and the research on pain is also increasing. It is a heritable modification, mainly including DNA methylation, histone modification, chromosomal remodeling, RNA interference, etc.
  • histone acetylation is an important way of regulating gene expression in histone modification, which is considered to be a more unstable modification than DNA methylation and histone methylation, and thus represents a modification in response to environmental stimuli. , a rapidly changing intracellular modification that promotes gene expression.
  • Histone acetyltransferase which catalyzes the addition of acetyl groups to histones to promote gene expression.
  • histone deacetylases catalyze the removal of acetyl groups from histones, thereby reducing gene expression.
  • Class I HDACs include 1, 2, 3, 8; IIa HDACs include 4, 5, 7, 9; IIb HDACs include 6 and 10; IV class is HDAC11.
  • Different subtypes have structures, different tissue distributions, different effects on pain, and different physiological functions of regulation. Studies have shown that HDAC1 and HDAC2 play an important role in cancer pain, synaptic plasticity and inflammatory pain. Therefore, the role of HDAC1 and HDAC2 in class I HDACs in neuropathic pain has become the focus of our attention.
  • HDAC6 in class IIb HDACs mainly exists in the cytoplasm of cells and is unique in structure and function. HDAC6 binds to a variety of non-histone substrates, such as ⁇ -tubulin, ubiquitin, heat shock protein 90 (HSP90), etc., thereby regulating them. Therefore, HDAC6 becomes a key regulator of the balance between neuroprotection and neurodegeneration , and later found that HDAC6 is involved in the regulation of neuropathic pain. Krukowski and Van et al. (Krukowski K, Ma J, Golonzhka O, et al. HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy [J]. Pain, 2017, 158(6): 1126-1137.
  • HDAC6 histone deacetylase 6
  • tumor chemotherapeutic drugs can disrupt the axonal transport and microtubule dynamics of neurons, resulting in neurotoxicity of chemotherapeutic drugs and neuropathic pain.
  • the acetylation modification of ⁇ -tubulin is one of the key mechanisms to regulate neuronal axonal transport and microtubule dynamics.
  • HDAC6 is specific to non-histone proteins including ⁇ -tubulin, and is an important enzyme that regulates the acetylation level of ⁇ -tubulin.
  • the acetylation level of ⁇ -tubulin in peripheral nerves can be increased, thereby increasing the transport capacity of neuron axons, improving the stability of microtubules, and improving the neuropathic pain induced by chemotherapy drugs.
  • Quinazoline is a compound formed by condensing a benzene ring and a pyrimidine ring. In medicine, quinazoline compounds have been found to have analgesic and anti-inflammatory activities.
  • Chinese patent CN200680001768.4 was applied by Dr. Estefan Laboratory Co., Ltd. on January 9, 2006. This patent discloses a substituted quinazoline compound and its use in the preparation and treatment of pain, especially neuralgia, stroke, poison Drug use in addiction and epilepsy.
  • Chinese patent CN200480011981.4 was applied by Votex Pharmaceutical Co., Ltd. on March 3, 2004. This patent discloses a substituted quinazoline compound and its method for treating diseases such as neuropathy or inflammatory pain.
  • HDAC histone deacetylase
  • One of the objects of the present invention is to provide the application of the compound represented by formula (I), its tautomer or its pharmaceutically acceptable salt in the preparation of medicine for treating neuropathic pain,
  • R 1 is one or more substituents
  • R 1 , R 2 and R 3 are each independently hydrogen, halogen, C 1-10 alkyl, oxygen-containing ether chain, nitrogen-containing alkyl chain, R 4 O-, R 4 OC(O)-, R 4 C (O)O-, -NH 2 , -NO 2 , hydroxylamino, R 4 R 5 N-, R 4 CONH-, R 4 NHCO-, guanidino, ureido, trifluoromethyl, C 1-10 Alkylsulfonyl, substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclic;
  • R 4 is C 1-10 alkyl or benzyl
  • R 5 is hydrogen or C 1-10 alkyl
  • Linker is a bond, or -(CH 2 ) n -, -(CH 2 ) n O-, -O(CH 2 ) n -, -O(CH 2 ) n C(O)-, -C(O) (CH 2 ) n O-, -OC(O)(CH 2 ) n -, -(CH 2 ) n C(O)O-, -(CH 2 ) n C(O)NH-, -C(O )NH(CH 2 ) n -, -(CH 2 ) n SO 2 -, -SO 2 (CH 2 ) n -, or a substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclic group, wherein n is an integer from 1 to 10;
  • the phenyl ring of the substituted phenyl group contains 1 to 4 substituents, and the substituents of the substituted phenyl group are halogen, -OH, -NO 2 , cyano, alkoxy, C 1-4 Alkyl or amino groups;
  • the heterocyclic group is a saturated or unsaturated five-membered heterocyclic group or six-membered heterocyclic group containing one or more heteroatoms; the heteroatom is selected from nitrogen, oxygen or sulfur;
  • said halogen is fluorine, chlorine, bromine or iodine.
  • the C 1-10 alkyl group is a straight chain, branched or cyclic saturated hydrocarbon containing 1-10 carbon atoms, and the C 1-10 alkyl group may be substituted (for example, it may be Pyrrolidin-1-yl-C 2-10 alkyl, morpholin-1-yl-C 2-10 alkyl or piperazine-1-C 2-10 alkyl) or unsubstituted;
  • the present invention The C 1-10 alkyl group used is methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, Cyclopentyl, hexyl, cyclohexyl, heptyl, octyl, nonyl or decyl;
  • R 4 O- used in the present invention is benzyloxy, pyrrolidin-1-yl-C 2-10 alkoxy, morpholin-1-yl-C 2-10 alkoxy or piperazine-1 -C 2-10 alkoxy;
  • R 4 OC(O)- used in the present invention is ethanoyloxycarbonyl, propaneoxycarbonyl, butanoyloxycarbonyl, isobutanoyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl , heptyloxycarbonyl, octaneoxycarbonyl, nonyloxycarbonyl or decanyloxycarbonyl;
  • R 4 C(O)O- used in the present invention is ethyl, propyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl;
  • R 4 R 5 N- used in the present invention is aminoethyl, 1-aminopropyl, 2-aminopropyl, 1-aminobutyl, 2-aminobutyl, 1-aminopentyl, 1- Aminohexyl, 1-aminoheptyl, 1-aminooctyl, 1-aminononyl, 1-aminodecyl, N-methylamino, N-ethylamino, N-propylamino, N-butylamino, N- Pentylamino, N-hexylamino, N-heptylamino, N-octylamino, N-nonylamino or N-decylamino;
  • R 4 CONH- used in the present invention is acetamide, propionamide, butyramide, isobutyramide, pentanoyl, hexanoyl, heptanyl, octanyl, nonylamide or decylamino Amide group;
  • the C 1-10 alkylsulfonyl group is a C 1-10 alkyl group as defined above connected to a sulfonyl group, and connected to formula (I) via a sulfonyl group; preferably, the C 1-10 alkyl group used in the present invention
  • the sulfonyl group is methylsulfonyl, ethylsulfonyl, propanesulfonyl, isopropylsulfonyl, butanesulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octanesulfonyl, nonylsulfonyl or decanylsulfonyl.
  • the present invention provides the application of the compound represented by formula (II), its tautomer or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating neuropathic pain,
  • R 2 and R 3 are each independently hydrogen, halogen, C 1-10 alkyl, oxygen-containing ether chain, nitrogen-containing alkane chain, R 4 O-, R 4 OC(O)-, R 4 C( O)O-, -NH 2 , -NO 2 , hydroxylamino, R 4 NHR 5 , R 4 CONH-, R 4 NHCO-, guanidino, ureido, trifluoromethyl, C 1-10 alkylsulfonyl , substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclic group, wherein R 4 is C 1-10 alkyl or benzyl, R 5 is hydrogen or C 1-10 alkyl; preferably, R 2 , R 3 are each independently hydrogen or C 1-6 alkyl; more preferably, R 2 , R 3 are each independently hydrogen or C 1-4 alkyl; most preferably, R 2 , R 3 are each is independently hydrogen or methyl;
  • Linker is a bond; -(CH 2 ) n -, -(CH 2 ) n O-, -O(CH 2 ) n -, -O(CH 2 ) n C(O)-, -C(O)(CH 2 ) n O-, -OC(O)(CH 2 ) n -, -(CH 2 ) n C(O)O-, -(CH 2 ) n C(O)NH-, -C(O)NH (CH 2 ) n -, -(CH 2 ) n SO 2 , -sulfonyl SO 2 -, or substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclic group, where n is an integer from 1 to 10;
  • the phenyl ring of the substituted phenyl group contains 1 to 4 substituents, and the substituents of the substituted phenyl group are halogen, -OH, -NO 2 , cyano, alkoxy, C 1-4 Alkyl or amino groups;
  • the heterocyclic group is a saturated or unsaturated five-membered heterocyclic group or six-membered heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen or sulfur;
  • said halogen is fluorine, chlorine, bromine or iodine
  • Linker is -(CH 2 ) n -, wherein n is an integer from 1 to 10; or -(CH 2 ) m C 6 H 4 -, -C 6 H 4 (CH 2 ) m -, wherein m is an integer from 0 to 5; or a saturated or unsaturated five-membered heterocyclic group or six-membered heterocyclic group containing 1 or 2 heteroatoms, the heteroatoms being selected from nitrogen; more preferably, Linker is -( CH 2 ) n -, where n is an integer from 1 to 5; or -(CH 2 ) mbenzene-, where m is an integer from 0 to 5; or saturated or unsaturated with 1 or 2 nitrogen atoms Six-membered heterocyclic group, preferably an unsaturated six-membered heterocyclic group containing 1 nitrogen atom;
  • the present invention is selected from the application of compounds of the following formulas in the preparation of drugs for the treatment of neuropathic pain:
  • the present invention provides the application of the compound represented by formula (III), its tautomer or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating neuropathic pain,
  • R 1 , R 2 , and R 3 are each independently hydrogen, halogen, C 1-10 alkyl, oxygen-containing ether chain, nitrogen-containing alkyl chain, R 4 O-, R 4 OC(O)-, R 4 C(O)O-, -NH 2 , -NO 2 , hydroxylamino, R 4 NHR 5 , R 4 CONH-, R 4 NHCO-, guanidino, ureido, trifluoromethyl, C 1-10 Alkylsulfonyl, substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclic group, wherein R 4 is C 1-10 alkyl or benzyl, R 5 is hydrogen or C 1-10 alkyl; preferably , R 1 is hydrogen or C 1-6 alkoxy; more preferably, R 1 is hydrogen or C 1-4 alkoxy; most preferably, R 1 is hydrogen or methoxy; preferably, R 2 , R 3 is independently hydrogen or C
  • Linker is a bond; -(CH 2 ) n -, -(CH 2 ) n O-, -O(CH 2 ) n -, -O(CH 2 ) n C(O)-, -C(O)(CH 2 ) n O-, -OC(O)(CH 2 ) n -, -(CH 2 ) n C(O)O-, -(CH 2 ) n C(O)NH-, -C(O)NH (CH 2 ) n -, -(CH 2 ) n SO 2 -, -SO 2 (CH 2 ) n -, or substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclic group, wherein n is 1 to an integer of 10;
  • the phenyl ring of the substituted phenyl group contains 1 to 4 substituents, and the substituents of the substituted phenyl group are halogen, -OH, -NO 2 , cyano, alkoxy, C 1-4 Alkyl or amino groups;
  • the heterocyclic group is a saturated or unsaturated five-membered heterocyclic group or six-membered heterocyclic group containing one or more heteroatoms; the heteroatom is selected from nitrogen, oxygen or sulfur;
  • said halogen is fluorine, chlorine, bromine or iodine.
  • the Linker is -(CH 2 ) n O-, -O(CH 2 ) n -, wherein n is an integer from 1 to 10; more preferably, the Linker is -(CH 2 ) n O-, wherein n is An integer of 1 to 10; most preferably, Linker is -(CH 2 ) n O-, wherein n is an integer of 1 to 5;
  • the present invention relates to the application of compounds selected from the following formulas in the preparation of drugs for the treatment of neuropathic pain:
  • the present invention provides the application of the compound represented by formula (IV), its tautomer or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating neuropathic pain,
  • R 2 is independently hydrogen, halogen, C 1-10 alkyl, oxygen-containing ether chain, nitrogen-containing alkyl chain, R 4 O-, R 4 OC(O)-, R 4 C(O)O- , -NH 2 , -NO 2 , Hydroxyamino, R 4 -O-CH 2 -, R 4 -O-CH 2 -O-CH 2 -, R 4 NHR 5 , R 4 CONH-, R 4 NHCO-, Guanidino, ureido, trifluoromethyl, C 1-10 alkylsulfonyl, substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclic group, wherein R is C 1-10 alkyl or benzyl , R 5 is hydrogen or C 1-10 alkyl; preferably, R 2 is independently hydrogen or C 1-6 alkyl;
  • the present invention relates to the application of compounds selected from the following formulas in the preparation of drugs for the treatment of neuropathic pain:
  • a pharmaceutical composition in the preparation of medicines for treating neuropathic pain comprising all the above-mentioned compounds, their tautomers or their pharmaceutically acceptable salt, and pharmaceutically acceptable excipients.
  • the dosage form of the pharmaceutical composition can be tablet, suppository, dispersible tablet, enteric-coated tablet, chewable tablet, orally disintegrating tablet, capsule, sugar-coated agent, granule, dry powder, oral solution, small needle for injection, injection Freeze-dried powder for injection or large infusion.
  • the pharmaceutically acceptable excipients include one or more of the following: diluents, solubilizers, disintegrants, suspending agents, lubricants, binders, fillers, flavoring agents, sweeteners agents, antioxidants, surfactants, preservatives, coatings or pigments.
  • neuropathic pain is selected from chronic back pain, postherpetic neuralgia, diabetic neuropathic pain, fibromyalgia, and chemotherapy drugs Induced neuropathic pain; specifically, the aforementioned neuropathic pain is selected from diabetic neuropathic limb pain and chemotherapy drug-induced limb pain.
  • the compound is the compound III-2 shown in the following formula, and the pain is diabetic neuropathic pain and chemotherapeutic drug-induced neuropathic pain.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, Hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, tannates, citrates, trifluoroacetates, etc.
  • organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzo
  • acids also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977 )).
  • Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into either base or acid addition salts.
  • the above pharmaceutically acceptable salts are prepared by contacting the salt with a base or acid in a conventional manner followed by isolation of the parent compound, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from its various salt forms by certain physical properties, such as solubility in polar solvents.
  • the "pharmaceutically acceptable salt” described herein belongs to the derivatives of the compounds of the present invention, wherein the parent compound is obtained by modifying the parent compound by forming a salt with an acid or forming a salt with a base.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, such as salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phosphoric
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • the compounds provided herein also exist in prodrug forms.
  • Prodrugs of the compounds referred to herein readily undergo chemical changes under physiological conditions to convert them into the compounds of the present invention.
  • prodrugs can also be converted to the compounds of the invention by chemical or biochemical methods in an in vivo environment.
  • Certain compounds of the present invention can exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to unsolvated forms and are within the scope of the present invention.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Accordingly, racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the compounds of the present invention.
  • wedge-shaped keys and dotted-line keys are used to represent the absolute configuration of a stereocenter.
  • use Indicates the relative configuration of a stereocenter.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, they include E, Z geometric isomers. Likewise, all tautomeric forms thereof are included within the scope of the present invention.
  • the compounds of the invention may exist in particular geometric or stereoisomeric forms.
  • the present invention relates to all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all such geometric or stereoisomeric All conformational forms are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, by separation of the resulting diastereomeric mixture and cleavage of the auxiliary group to provide pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a common method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention, without interfering with the biological activity of the active substance, and without toxic side effects to the host or patient.
  • Representative carriers include water, oils, vegetable and minerals, cream bases, lotion bases, ointment bases and the like. These bases include suspending agents, viscosity builders, skin penetration enhancers and the like. The preparation of preparations aided by such substances is well known to those skilled in the field of cosmetics or topical medicine. Additional information on carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
  • the term "effective amount” or “therapeutically effective amount” refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect.
  • the "effective amount” of an active substance in the composition refers to the amount needed to achieve the desired effect, or when the active ingredient is used in combination with another active substance in the composition to achieve Amount required for desired effect.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
  • active ingredient refers to a chemical entity that is effective in treating the disorder, disease or condition of interest.
  • substituted refers to the replacement of any one or more hydrogen atoms on a specified atom with a substituent, including deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable .
  • Keto substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically realizable basis.
  • any variable eg, R
  • R any variable
  • its definition is independent at each occurrence.
  • a group may optionally be substituted with up to two R, and the choice of R in each case is independent.
  • substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • ring means a substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl.
  • the so-called ring includes monocyclic, bicyclic, spiro, fused or bridged rings.
  • the number of atoms on a ring is usually defined as the number of ring members, for example, "5-7 membered ring” refers to 5-7 atoms arranged around it. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms.
  • 5-7 membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5-7 membered heterocycloalkyl ring” includes piperazinyl and piperidinyl, but excludes phenyl .
  • ring also includes ring systems comprising at least one ring, wherein each "ring” is independently defined above.
  • heterocyclic compounds include, but are not limited to: pyridyl, pyrrolyl, pyrimidinyl, imidazolyl, pyridazinyl, triazinyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolyl, 2H-pyrrolyl , tetrazolyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl.
  • alkyl is used to denote a linear or branched saturated hydrocarbon group, which may be monosubstituted (such as -CH 2 F) or polysubstituted (such as -CF 3 ), which may be monovalent ( Such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • alkyl groups examples include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
  • Pen. is pentoxifylline; INT-747 is 6-ethylchenodeoxycholic acid; aq stands for water; HATU stands for O-(7-azabenzotriazole-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride ; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents equivalent, equivalent; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents petroleum ether; DIAD represents diisopropyl azodicarboxylate; DMF Represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents
  • Figure 1 The paw withdrawal threshold of rats mechanically stimulated, compared with model control group 1; where, * represents p ⁇ 0.05, compared with model control group 1.
  • Fig. 2 The body weight change curves of animals in each group.
  • Figure 3 Statistical diagram of mechanical foot withdrawal pain threshold of animals in each group (Mean ⁇ SEM), * represents p ⁇ 0.05 vs model, ** represents p ⁇ 0.01 vs model.
  • Example 1 Pharmacodynamic study of rat STZ diabetic peripheral neuropathic pain model
  • CMCNa Sigma-Aldrich (Shanghai) Trading Co., Ltd.
  • Streptozotocin (Sigma-Aldrich (Shanghai) Trading Co., Ltd.);
  • Solution A Weigh 1.471g of sodium citrate and place it in a 50mL sterile centrifuge tube, draw 50.0mL of normal saline into the centrifuge tube with a 50mL syringe, and dissolve evenly;
  • Solution B Weigh 0.995g of citric acid and place it in a 50mL sterile centrifuge tube, draw 50.0mL of normal saline into the centrifuge tube with a 50mL syringe, and dissolve evenly;
  • Citrate buffer solution Mix liquid A and liquid B at a ratio of 1:1, adjust the pH to 4.5 with liquid A or liquid B after mixing, filter and sterilize with a 0.22 ⁇ m disposable syringe filter in a clean bench, and pack as 50mL per tube, label well, store at -20°C until use;
  • Streptozotocin (STZ) solution Weigh 240mg/tube of streptozotocin before modeling, put it in a 50mL sterile centrifuge tube wrapped with tinfoil, put it in an ice box, add aliquots before use Prepare 40mL of citrate buffer solution, mix well, and prepare 6mg/mL streptozotocin (STZ) solution, use it up within 15 minutes, and discard the unused one directly.
  • Rats were intraperitoneally injected with STZ, 65mg/kg, single injection, and the animals were fasted for more than 12 hours before the injection, and the drinking water of the rats was replaced with 10% sucrose solution on the day after the injection (to prevent hypoglycemia in the rats).
  • Test I includes a model control group, a positive control group and a test product group
  • test II includes a model control group and a test product group.
  • Type I diabetic SD rats with diabetic neuropathic pain were selected and randomly grouped according to the paw withdrawal threshold of mechanical stimulation.
  • the first letter of the animal number represents the test stage, the first number represents the group (1, 2 and 3 represent the model control group, the positive control group and the test product group respectively); the second letter represents the gender (M is male), The last 3 digits represent the serial number of the animal.
  • Test 1 the model control group was given vehicle, and all the other groups were given different doses of medicines. Because the test product 75mg/kg dose group (Bid) had severe diarrhea in animals on the 3rd day of administration, the animals had severe diarrhea on the 3rd day. On the first day and the fourth day, the administration frequency was changed to once a day, and 4 animals in this group died on the fourth day of administration, so the administration was stopped on the fifth day. For details, see Table 3 below.
  • Test II The vehicle was given to the model control group, and the drug to be tested was given to the treatment group.
  • the dosing frequency was 2 times a day for 5 consecutive days. For details, see Table 4 below.
  • the day of modeling was defined as D0, grouped on D27, and administered on D28, Qd: once a day, Bid: twice a day.
  • the day of modeling was defined as D0, grouping was performed on D37, and administration began on D38, Bid: twice a day.
  • Testing time 1 test before STZ modeling, 1 test before grouping, 1 test on the 1st, 4th, and 8th day after the administration of the animals in Test I, and 1 test on the 1st and 5th day after the administration of the animals in Test II;
  • Method Put the animals in the test box for 3 consecutive days before the test to adapt, and adapt to it for 30 minutes every day; each test, put the animal in the test box to adapt to it for 15 minutes before testing, and each animal was tested 3 times to get the average value , with at least 5 minutes between each test.
  • the mechanically stimulated paw withdrawal threshold of rats began to decrease on D14 days after STZ injection, and decreased to 50% on D21 days. has been reduced to a minimum, so this experiment chooses to start giving drug intervention on D28.
  • test I result shows: after drug intervention, the rat mechanical stimulation paw withdrawal threshold of positive drug gabapentin (150mg/kg, Qd) treatment group obviously raises, compares with model control group Ratio, there is significant statistical difference (P ⁇ 0.05);
  • the paw withdrawal threshold was significantly increased, compared with the model control group, there was a statistical difference (P ⁇ 0.05), and after 3 days of drug withdrawal (D34), the mechanically stimulated paw withdrawal threshold of the rats was still maintained at the same level as the drug administration.
  • test compound III-2 15mg/kg (bid, 5d) group can also significantly increase the paw withdrawal threshold of rats after the first administration (D38), compared with the model control group. There was a significant statistical difference (P ⁇ 0.05).
  • compound III-2 can make the mechanical stimulation of SD rat diabetic neuropathic pain animals under the dosage of 75mg/kg (bid, 2d, qd, 2d) and 15mg/kg (bid, 5d).
  • the paw withdrawal threshold was significantly increased, indicating that the compound has a better analgesic effect at this dose.
  • Embodiment 2 Pharmacodynamic study of paclitaxel-induced pain model test in rats
  • the purpose of the experiment To use the Paclitaxel-induced rat pain model to evaluate whether the test product has a therapeutic and alleviating effect on rat foot pain in this model.
  • Preparation of solvent reference substance Add appropriate amount of CMC-Na into purified water, vortex and mix to prepare 0.5% CMC-Na (w/v) solution of solvent reagent.
  • Preparation of the test product Weigh an appropriate amount of drug, add 0.5% CMC-Na for ultrasonication, vortex oscillation and mix. A suspension with a final concentration of 0.3 mg/mL was obtained.
  • mice After buying 45 Sprague Dawley (SD) rats and feeding them for 7 days, 40 rats were selected for intraperitoneal injection (i.p.) and given 2 mg/kg paclitaxel injection for modeling, once every other day for 4 consecutive injections, and the remaining 5 Rats were intraperitoneally injected with normal saline as the normal control group. On the 4th day after the completion of modeling, 40 model animals and 5 animals in the normal saline group were used to measure the mechanical pain threshold (baseline) of the rats using the von Frey up and down method. 20 model animals were included in the group for administration.
  • baseline mechanical pain threshold
  • the 20 model rats selected into the group were randomly divided into 2 groups, 10 in each group, and 5 rats intraperitoneally injected with normal saline were used as the normal control group, and the administration was performed according to the following table:
  • Body weight was measured every 2 days during the dosing period.
  • the von Frey up and down method was used to measure the mechanical pain threshold of the rats 3 days after drug withdrawal, and the mechanical pain threshold (50% PWT) was calculated.
  • Body weight body weight changes are shown in Figure 2. During the administration period, the body weight of each group increased.
  • Mechanical threshold The statistics of mechanical foot withdrawal pain threshold are shown in Figure 3.
  • the 50% PWT of the normal group was significantly higher than that of the model group (p ⁇ 0.01), and the compound III-2 3mg/kg group was on the 4th and 7th day of administration 1 hour after the first administration, the 50% PWT of the normal group was significantly higher than that of the model group (p ⁇ 0.01, p ⁇ 0.05); on the 3rd day (D10) after drug withdrawal, the 50% PWT of the normal group was significantly higher than that of the model group ( p ⁇ 0.01), compound III-2 3mg/kg 50%PWT were significantly higher than model group (p ⁇ 0.05).
  • compound III-2 was administered continuously for 7 days with a dose of 3 mg/kg, administered twice a day, and it had a significant alleviating effect on paclitaxel-induced rat foot pain, and compared with the normal group and the model group, the body weight had no significantly decreased, indicating that the compound has better analgesic effect and safety at this dose.
  • SAHA HDAC inhibitor

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Disclosed is the use of a series of 4-arylaminoquinazoline hydroxamic acid compounds in the preparation of a drug for treating neuropathic pain diseases, and specifically, the use of a compound as represented by formula III-2, a tautomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating neuropathic pain diseases.

Description

4-芳氨基喹唑啉异羟肟酸类化合物在制备疼痛药物方面的用途Use of 4-arylaminoquinazoline hydroxamic acid compounds in the preparation of pain medicine 技术领域technical field
本发明涉及一系列4-芳氨基喹唑啉异羟肟酸类化合物在制备治疗神经病理性疼痛症药物中的应用，尤其是糖尿病性和化疗药物诱导的神经病理性疼痛。The invention relates to the application of a series of 4-arylaminoquinazoline hydroxamic acid compounds in the preparation of drugs for treating neuropathic pain, especially neuropathic pain induced by diabetes and chemotherapy drugs.
背景技术Background technique
神经病理痛是由外周或中枢神经系统损伤或病变引起的病理性疼痛。包括带状疱疹引起的疼痛，三叉神经痛等外周神经病变疾病，以及如糖尿病神经病理性疼痛和化疗药物引起的病理性疼痛。疼痛的主要特征是异常性疼痛(即由无害刺激引起的疼痛)和痛觉过敏(即增加刺激所产生的疼痛反应)。Neuropathic pain is pathological pain caused by peripheral or central nervous system injury or disease. These include pain caused by herpes zoster, peripheral neuropathic diseases such as trigeminal neuralgia, and pathological pain such as diabetic neuropathic pain and chemotherapy drugs. The main features of pain are allodynia (ie, pain caused by innocuous stimuli) and hyperalgesia (ie, pain response to increased stimuli).
表观遗传目前已经成为热点，且在疼痛方面的研究也日益增多。它是一种可遗传的修饰，主要包括DNA甲基化，组蛋白修饰，染色体重塑，RNA干扰等。其中组蛋白乙酰化是组蛋白修饰中一种重要的调节基因表达的方式，它被认为是比DNA甲基化和组蛋白甲基化更不稳定的修饰，因此代表了一种应对环境刺激时，能够促进基因表达的一种瞬息万变的细胞内修饰。组蛋白乙酰转移酶，它催化组蛋白上加入乙酰基促进基因的表达。相反地，组蛋白去乙酰化酶催化乙酰基从组蛋白上离去，因此降低基因的表达。Epigenetics has become a hot topic at present, and the research on pain is also increasing. It is a heritable modification, mainly including DNA methylation, histone modification, chromosomal remodeling, RNA interference, etc. Among them, histone acetylation is an important way of regulating gene expression in histone modification, which is considered to be a more unstable modification than DNA methylation and histone methylation, and thus represents a modification in response to environmental stimuli. , a rapidly changing intracellular modification that promotes gene expression. Histone acetyltransferase, which catalyzes the addition of acetyl groups to histones to promote gene expression. Conversely, histone deacetylases catalyze the removal of acetyl groups from histones, thereby reducing gene expression.
目前发现的去乙酰化酶共11种，并根据他们的结构分为不同的组。I类HDACs包括1，2，3，8；IIa HDACs包括4，5，7，9；IIb HDACs包括6和10；IV类是HDAC11。不同的亚型具有结构，不同的组织分布，对于疼痛的影响不同，调控的生理功能也是千差万别。有研究证明HDAC1，HDAC2在癌症痛，突触可塑性及炎性痛中发挥了重要的作用。因此，I类HDACs中的HDAC1，HDAC2在神经病理痛中的作用成为我们关注的重点。A total of 11 sirtuins have been discovered so far, and they are divided into different groups according to their structures. Class I HDACs include 1, 2, 3, 8; IIa HDACs include 4, 5, 7, 9; IIb HDACs include 6 and 10; IV class is HDAC11. Different subtypes have structures, different tissue distributions, different effects on pain, and different physiological functions of regulation. Studies have shown that HDAC1 and HDAC2 play an important role in cancer pain, synaptic plasticity and inflammatory pain. Therefore, the role of HDAC1 and HDAC2 in class I HDACs in neuropathic pain has become the focus of our attention.
IIb类HDACs中的HDAC6主要存在于细胞细胞质中，在结构和功能上均具有独特性，其具有两个催化脱乙酰酶结构域，以及一个锌指泛素结合结构域，且在细胞质中与多种非组蛋白底物结合，如α-微管蛋白、泛素、热休克蛋白90(HSP90)等，从而对其进行调控，因此，HDAC6成为神经保护和神经变性之间维持平衡的关键调节因子，后又发现HDAC6参与神经病理性疼痛的调控。Krukowski和Van等(Krukowski K,Ma J,Golonzhka O,et al.HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy[J].Pain,2017,158(6):1126-1137.和Van Helleputte L,Kater M,Cook DP,et al.Inhibition of histone deacetylase 6(HDAC6)protects against vincristine-induced peripheral neuropathies and inhibits tumor growth[J].Neurobiol Dis,2018,111:59-69.)发现通过拮抗HDAC6能够改善化疗药物诱导的神经病理性疼痛。HDAC6 in class IIb HDACs mainly exists in the cytoplasm of cells and is unique in structure and function. HDAC6 binds to a variety of non-histone substrates, such as α-tubulin, ubiquitin, heat shock protein 90 (HSP90), etc., thereby regulating them. Therefore, HDAC6 becomes a key regulator of the balance between neuroprotection and neurodegeneration , and later found that HDAC6 is involved in the regulation of neuropathic pain. Krukowski and Van et al. (Krukowski K, Ma J, Golonzhka O, et al. HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy [J]. Pain, 2017, 158(6): 1126-1137. and Van Helleputte L, Kater M , Cook DP, et al. Inhibition of histone deacetylase 6 (HDAC6) protects against vincristine-induced peripheral neuropathies and inhibits tumor growth [J]. Neurobiol Dis, 2018, 111:59-69.) found that chemotherapy drugs can be improved by antagonizing HDAC6 Induced neuropathic pain.
在Krukowski和Van等的实验中，肿瘤化疗药物会破坏神经元的轴突运输和微管动力学，从而导致化疗药物的神经毒性，出现神经病理性疼痛。而α-微管蛋白的乙酰化修饰是调节神经元轴突运输和微管动力学的关键机制之一。与其他HDACs相比，HDAC6对包括α-微管蛋 白在内的非组蛋白具有特异性，是调节α-微管蛋白乙酰化水平的重要酶。因此通过抑制HDAC6，能够增加外周神经中的α-微管蛋白乙酰化水平，从而增加神经元轴突的运输能力，提高微管稳定性，改善化疗药物诱导的神经病理性疼痛。In the experiments of Krukowski and Van et al., tumor chemotherapeutic drugs can disrupt the axonal transport and microtubule dynamics of neurons, resulting in neurotoxicity of chemotherapeutic drugs and neuropathic pain. The acetylation modification of α-tubulin is one of the key mechanisms to regulate neuronal axonal transport and microtubule dynamics. Compared with other HDACs, HDAC6 is specific to non-histone proteins including α-tubulin, and is an important enzyme that regulates the acetylation level of α-tubulin. Therefore, by inhibiting HDAC6, the acetylation level of α-tubulin in peripheral nerves can be increased, thereby increasing the transport capacity of neuron axons, improving the stability of microtubules, and improving the neuropathic pain induced by chemotherapy drugs.
喹唑啉是由苯环与嘧啶环稠合而成的化合物，在医学上，喹唑啉类化合物已被发现具有止痛和消炎的活性。Quinazoline is a compound formed by condensing a benzene ring and a pyrimidine ring. In medicine, quinazoline compounds have been found to have analgesic and anti-inflammatory activities.
中国专利CN200680001768.4，由伊斯特芬博士实验室有限公司于2006.01.09申请，该专利公开了一种取代喹唑啉类化合物，以及其在制备治疗疼痛特别是神经疼痛，以及中风、毒瘾和癫痫症的药剂中的应用。Chinese patent CN200680001768.4 was applied by Dr. Estefan Laboratory Co., Ltd. on January 9, 2006. This patent discloses a substituted quinazoline compound and its use in the preparation and treatment of pain, especially neuralgia, stroke, poison Drug use in addiction and epilepsy.
Figure PCTCN2022087341-appb-000001
Figure PCTCN2022087341-appb-000001
中国专利CN200480011981.4，由沃泰克斯药物股份有限公司于2004.03.03申请，该专利公开了一种取代喹唑啉类化合物，以及其用于治疗神经病性或炎性疼痛等疾病的方法。Chinese patent CN200480011981.4 was applied by Votex Pharmaceutical Co., Ltd. on March 3, 2004. This patent discloses a substituted quinazoline compound and its method for treating diseases such as neuropathy or inflammatory pain.
Figure PCTCN2022087341-appb-000002
Figure PCTCN2022087341-appb-000002
美国专利US2009111772，由CAI XIONG等于2008.09.10申请，于2009.04.30公开了一种HDAC抑制剂，并可用于治疗与组蛋白脱乙酰基酶(HDAC)失调的疾病，包括椎间盘源性疼痛。US Patent US2009111772, filed by CAI XIONG on 2008.09.10, disclosed a HDAC inhibitor on 2009.04.30, and can be used to treat diseases related to histone deacetylase (HDAC) imbalance, including discogenic pain.
Figure PCTCN2022087341-appb-000003
Figure PCTCN2022087341-appb-000003
中国专利CN201680015470.2，由广东众生药业股份有限公司于2016.03.17申请，于2017.12.01公开了一系列4-芳氨基喹唑啉异羟肟酸类化合物，该系列化合物具有组蛋白去乙酰化酶抑制活性，尤其选择性HDAC6、HADC1和HADC2活性较高，对于其余HDACs选择性抑制活性较低，表现为在肿瘤治疗上具有优秀的效果。其对于HDACs的选择性抑制可减少药物使用中由于选择性低引起的副作用，发明人在后续进一步研究中惊喜地发现，该系列化合物对神经病理性疼痛具备一定的镇痛作用，尤其对于糖尿病性神经病理性疼痛和化疗 药物诱导的神经病理性疼痛，为糖尿病以及癌症或其引起化疗疼痛治疗提供新的思路。Chinese patent CN201680015470.2 was applied by Guangdong Zhongsheng Pharmaceutical Co., Ltd. on 2016.03.17 and disclosed a series of 4-arylaminoquinazoline hydroxamic acid compounds on 2017.12.01. The enzyme inhibitory activity, especially the selective HDAC6, HADC1 and HADC2 activity is high, and the selective inhibitory activity for the rest of HDACs is low, which shows that it has an excellent effect on tumor treatment. Its selective inhibition of HDACs can reduce the side effects caused by low selectivity in drug use. The inventors were pleasantly surprised to find that this series of compounds has certain analgesic effects on neuropathic pain, especially for diabetic neuropathy. Rational pain and chemotherapeutic drug-induced neuropathic pain provide new ideas for the treatment of diabetes and cancer or chemotherapy-induced pain.
发明内容Contents of the invention
本发明的目的之一在于提供式(I)所示化合物、其互变异构体或其药学上可接受的盐在制备治疗神经病理性疼痛药物中的应用，One of the objects of the present invention is to provide the application of the compound represented by formula (I), its tautomer or its pharmaceutically acceptable salt in the preparation of medicine for treating neuropathic pain,
Figure PCTCN2022087341-appb-000004
Figure PCTCN2022087341-appb-000004
其中，R 1为一个或多个取代基； Wherein, R 1 is one or more substituents;
R 1、R 2和R 3各自独立地是氢、卤素、C 1-10的烷基、含氧醚链、含氮烷链、R 4O-、R 4OC(O)-、R 4C(O)O-、-NH 2、-NO 2、羟氨基、R 4R 5N-、R 4CONH-、R 4NHCO-、胍基、脲基、三氟甲基、C 1-10的烷磺酰基、取代苯磺酰基、取代苯基、苯基或杂环基； R 1 , R 2 and R 3 are each independently hydrogen, halogen, C 1-10 alkyl, oxygen-containing ether chain, nitrogen-containing alkyl chain, R 4 O-, R 4 OC(O)-, R 4 C (O)O-, -NH 2 , -NO 2 , hydroxylamino, R 4 R 5 N-, R 4 CONH-, R 4 NHCO-, guanidino, ureido, trifluoromethyl, C 1-10 Alkylsulfonyl, substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclic;
R 4为C 1-10的烷基或苄基； R 4 is C 1-10 alkyl or benzyl;
R 5为氢或C 1-10的烷基； R 5 is hydrogen or C 1-10 alkyl;
Linker是键，或是-(CH 2) n-、-(CH 2) nO-、-O(CH 2) n-、-O(CH 2) nC(O)-、-C(O)(CH 2) nO-、-OC(O)(CH 2) n-、-(CH 2) nC(O)O-、-(CH 2) nC(O)NH-、-C(O)NH(CH 2) n-、-(CH 2) nSO 2-、-SO 2(CH 2) n-，或是取代苯磺酰基、取代苯基、苯基或杂环基，其中n为1至10的整数； Linker is a bond, or -(CH 2 ) n -, -(CH 2 ) n O-, -O(CH 2 ) n -, -O(CH 2 ) n C(O)-, -C(O) (CH 2 ) n O-, -OC(O)(CH 2 ) n -, -(CH 2 ) n C(O)O-, -(CH 2 ) n C(O)NH-, -C(O )NH(CH 2 ) n -, -(CH 2 ) n SO 2 -, -SO 2 (CH 2 ) n -, or a substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclic group, wherein n is an integer from 1 to 10;
优选地，所述取代苯基的苯环上含有1至4个取代基，所述取代苯基的取代基是卤素、-OH、-NO 2、氰基、烷氧基、C 1-4的烷基或氨基基团； Preferably, the phenyl ring of the substituted phenyl group contains 1 to 4 substituents, and the substituents of the substituted phenyl group are halogen, -OH, -NO 2 , cyano, alkoxy, C 1-4 Alkyl or amino groups;
优选地，所述杂环基是含一个或多个杂原子的饱和或不饱和的五元杂环基或六元杂环基；所述杂原子选自氮、氧或硫；Preferably, the heterocyclic group is a saturated or unsaturated five-membered heterocyclic group or six-membered heterocyclic group containing one or more heteroatoms; the heteroatom is selected from nitrogen, oxygen or sulfur;
优选地，所述卤素是氟、氯、溴或碘。Preferably, said halogen is fluorine, chlorine, bromine or iodine.
在上述基团中，所述C 1-10烷基是包含1-10个碳原子的直链、支链或环状的饱和烃，该C 1-10烷基可以被取代的(例如可以是吡咯烷-1-基-C 2-10烷基、吗啉-1-基-C 2-10烷基或哌嗪-1-C 2-10烷基)或者未被取代；优选地，本发明采用的C 1-10烷基是甲基、乙基、丙基、异丙基、环丙基、丁基、异丁基、仲-丁基、叔-丁基、环丁基、戊基、环戊基、己基、环己基、庚基、辛基、壬基或癸基； In the above groups, the C 1-10 alkyl group is a straight chain, branched or cyclic saturated hydrocarbon containing 1-10 carbon atoms, and the C 1-10 alkyl group may be substituted (for example, it may be Pyrrolidin-1-yl-C 2-10 alkyl, morpholin-1-yl-C 2-10 alkyl or piperazine-1-C 2-10 alkyl) or unsubstituted; Preferably, the present invention The C 1-10 alkyl group used is methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, Cyclopentyl, hexyl, cyclohexyl, heptyl, octyl, nonyl or decyl;
优选地，本发明采用的R 4O-是苄氧基、吡咯烷-1-基-C 2-10烷氧基、吗啉-1-基-C 2-10烷氧基或哌嗪-1-C 2-10烷氧基； Preferably, R 4 O- used in the present invention is benzyloxy, pyrrolidin-1-yl-C 2-10 alkoxy, morpholin-1-yl-C 2-10 alkoxy or piperazine-1 -C 2-10 alkoxy;
优选地，本发明采用的R 4OC(O)-是乙烷氧基羰基、丙烷氧基羰基、丁烷氧基羰基、异丁烷氧基羰基、戊烷氧基羰基、己烷氧基羰基、庚烷氧基羰基、辛烷氧基羰基、壬烷氧基羰基或癸烷氧基羰基； Preferably, R 4 OC(O)- used in the present invention is ethanoyloxycarbonyl, propaneoxycarbonyl, butanoyloxycarbonyl, isobutanoyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl , heptyloxycarbonyl, octaneoxycarbonyl, nonyloxycarbonyl or decanyloxycarbonyl;
本发明采用的R 4C(O)O-是乙酯、丙酯、丁酯、异丁酯、戊酯、己酯、庚酯、辛酯、壬酯或癸酯； R 4 C(O)O- used in the present invention is ethyl, propyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl;
优选地，本发明采用的R 4R 5N-是氨基乙基、1-氨基丙基、2-氨基丙基、1-氨基丁基、 2-氨基丁基、1-氨基戊基、1-氨基己基、1-氨基庚基、1-氨基辛基、1-氨基壬基、1-氨基癸基、N-甲氨基、N-乙胺基、N-丙氨基、N-丁氨基、N-戊氨基、N-己氨基、N-庚氨基、N-辛氨基、N-壬氨基或N-癸氨基； Preferably, R 4 R 5 N- used in the present invention is aminoethyl, 1-aminopropyl, 2-aminopropyl, 1-aminobutyl, 2-aminobutyl, 1-aminopentyl, 1- Aminohexyl, 1-aminoheptyl, 1-aminooctyl, 1-aminononyl, 1-aminodecyl, N-methylamino, N-ethylamino, N-propylamino, N-butylamino, N- Pentylamino, N-hexylamino, N-heptylamino, N-octylamino, N-nonylamino or N-decylamino;
优选地，本发明采用的R 4CONH-是乙酰胺基、丙酰胺基、丁酰胺基、异丁酰胺基、戊酰胺基、己酰胺基、庚酰胺基、辛酰胺基、壬酰胺基或癸酰胺基； Preferably, R 4 CONH- used in the present invention is acetamide, propionamide, butyramide, isobutyramide, pentanoyl, hexanoyl, heptanyl, octanyl, nonylamide or decylamino Amide group;
所述C 1-10的烷基磺酰基是如上定义的C 1-10烷基与磺酰基相连，并且经由磺酰基与式(I)连接；优选地，本发明采用的C 1-10的烷磺酰基是甲磺酰基、乙磺酰基、丙磺酰基、异丙磺酰基、丁磺酰基、戊磺酰基、己磺酰基、庚磺酰基、辛磺酰基、壬磺酰基或癸磺酰基。 The C 1-10 alkylsulfonyl group is a C 1-10 alkyl group as defined above connected to a sulfonyl group, and connected to formula (I) via a sulfonyl group; preferably, the C 1-10 alkyl group used in the present invention The sulfonyl group is methylsulfonyl, ethylsulfonyl, propanesulfonyl, isopropylsulfonyl, butanesulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl, octanesulfonyl, nonylsulfonyl or decanylsulfonyl.
优选地，本发明提供式(II)所示化合物、其互变异构体或其药学上可接受的盐在制备治疗神经病理性疼痛药物中的应用，Preferably, the present invention provides the application of the compound represented by formula (II), its tautomer or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating neuropathic pain,
Figure PCTCN2022087341-appb-000005
Figure PCTCN2022087341-appb-000005
其中，R 2、R 3各自独立地是氢、卤素、C 1-10的烷基、含氧醚链、含氮烷链、R 4O-、R 4OC(O)-、R 4C(O)O-、-NH 2、-NO 2、羟氨基、R 4NHR 5、R 4CONH-、R 4NHCO-、胍基、脲基、三氟甲基、C 1-10的烷磺酰基、取代苯磺酰基、取代苯基、苯基或杂环基，其中R 4为C 1-10的烷基或苄基，R 5为氢或C 1-10的烷基；优选地，R 2、R 3各自独立地是氢或C 1-6的烷基；更优选地，R 2、R 3各自独立地是氢或C 1-4的烷基；最优选地，R 2、R 3各自独立地是氢或甲基； Wherein, R 2 and R 3 are each independently hydrogen, halogen, C 1-10 alkyl, oxygen-containing ether chain, nitrogen-containing alkane chain, R 4 O-, R 4 OC(O)-, R 4 C( O)O-, -NH 2 , -NO 2 , hydroxylamino, R 4 NHR 5 , R 4 CONH-, R 4 NHCO-, guanidino, ureido, trifluoromethyl, C 1-10 alkylsulfonyl , substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclic group, wherein R 4 is C 1-10 alkyl or benzyl, R 5 is hydrogen or C 1-10 alkyl; preferably, R 2 , R 3 are each independently hydrogen or C 1-6 alkyl; more preferably, R 2 , R 3 are each independently hydrogen or C 1-4 alkyl; most preferably, R 2 , R 3 are each is independently hydrogen or methyl;
Linker是键；-(CH 2) n-、-(CH 2) nO-、-O(CH 2) n-、-O(CH 2) nC(O)-、-C(O)(CH 2) nO-、-OC(O)(CH 2) n-、-(CH 2) nC(O)O-、-(CH 2) nC(O)NH-、-C(O)NH(CH 2) n-、-(CH 2) nSO 2、-磺酰基SO 2-，或是取代苯磺酰基、取代苯基、苯基或杂环基，其中n为1至10的整数； Linker is a bond; -(CH 2 ) n -, -(CH 2 ) n O-, -O(CH 2 ) n -, -O(CH 2 ) n C(O)-, -C(O)(CH 2 ) n O-, -OC(O)(CH 2 ) n -, -(CH 2 ) n C(O)O-, -(CH 2 ) n C(O)NH-, -C(O)NH (CH 2 ) n -, -(CH 2 ) n SO 2 , -sulfonyl SO 2 -, or substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclic group, where n is an integer from 1 to 10;
优选地，所述取代苯基的苯环上含有1至4个取代基，所述取代苯基的取代基是卤素、-OH、-NO 2、氰基、烷氧基、C 1-4的烷基或氨基基团； Preferably, the phenyl ring of the substituted phenyl group contains 1 to 4 substituents, and the substituents of the substituted phenyl group are halogen, -OH, -NO 2 , cyano, alkoxy, C 1-4 Alkyl or amino groups;
优选地，所述杂环基是含一个或多个杂原子的饱和或不饱和的五元杂环基或六元杂环基，所述杂原子选自氮、氧或硫；Preferably, the heterocyclic group is a saturated or unsaturated five-membered heterocyclic group or six-membered heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen or sulfur;
优选地，所述卤素是氟、氯、溴或碘；Preferably, said halogen is fluorine, chlorine, bromine or iodine;
优选地，Linker是-(CH 2) n-，其中n为1至10的整数；或是-(CH 2) mC 6H 4-、-C 6H 4(CH 2) m-，其中m为0至5的整数；或是含1或2个杂原子的饱和或不饱和的五元杂环基或六元杂环基，所述杂原子选自氮；更优选地，Linker是-(CH 2) n-，其中n为1至5的整数；或是-(CH 2) m苯-，其中m为0至5的整数；或是含1或2个氮原子的饱和或不饱和的六元杂环基，优选含1个氮原子的不饱和的六元杂环基； Preferably, Linker is -(CH 2 ) n -, wherein n is an integer from 1 to 10; or -(CH 2 ) m C 6 H 4 -, -C 6 H 4 (CH 2 ) m -, wherein m is an integer from 0 to 5; or a saturated or unsaturated five-membered heterocyclic group or six-membered heterocyclic group containing 1 or 2 heteroatoms, the heteroatoms being selected from nitrogen; more preferably, Linker is -( CH 2 ) n -, where n is an integer from 1 to 5; or -(CH 2 ) mbenzene-, where m is an integer from 0 to 5; or saturated or unsaturated with 1 or 2 nitrogen atoms Six-membered heterocyclic group, preferably an unsaturated six-membered heterocyclic group containing 1 nitrogen atom;
进一步，本发明选自下式化合物在制备治疗神经病理性疼痛药物中应用：Further, the present invention is selected from the application of compounds of the following formulas in the preparation of drugs for the treatment of neuropathic pain:
(II-1)N-羟基-2-(4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)乙酰胺(II-1) N-Hydroxy-2-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)acetamide
Figure PCTCN2022087341-appb-000006
Figure PCTCN2022087341-appb-000006
(II-2)N-羟基-4-(4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)丁酰胺(II-2) N-Hydroxy-4-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)butanamide
Figure PCTCN2022087341-appb-000007
Figure PCTCN2022087341-appb-000007
(II-3)N-羟基-5-(4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)戊酰胺(II-3) N-Hydroxy-5-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pentanamide
Figure PCTCN2022087341-appb-000008
Figure PCTCN2022087341-appb-000008
(II-4)N-羟基-6-(4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)己酰胺(II-4) N-Hydroxy-6-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)caproamide
Figure PCTCN2022087341-appb-000009
Figure PCTCN2022087341-appb-000009
(II-5)N-羟基-4-((4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)甲基)苯甲酰胺(II-5) N-Hydroxy-4-((4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)methyl)benzamide
Figure PCTCN2022087341-appb-000010
Figure PCTCN2022087341-appb-000010
(II-6)N-羟基-4-(4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)苯甲酰胺(II-6) N-Hydroxy-4-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)benzamide
Figure PCTCN2022087341-appb-000011
Figure PCTCN2022087341-appb-000011
(II-7)N-羟基-6-(4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)烟酰胺(II-7) N-Hydroxy-6-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)nicotinamide
Figure PCTCN2022087341-appb-000012
Figure PCTCN2022087341-appb-000012
(II-8)N-羟基-5-(4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)吡啶酰胺(II-8) N-Hydroxy-5-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyridineamide
Figure PCTCN2022087341-appb-000013
Figure PCTCN2022087341-appb-000013
(II-9)N-羟基-2-(4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)嘧啶-5-酰胺(II-9) N-Hydroxy-2-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrimidine-5-amide
Figure PCTCN2022087341-appb-000014
Figure PCTCN2022087341-appb-000014
(II-10)N-羟基-5-(4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)嘧啶-2-酰胺(II-10) N-Hydroxy-5-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrimidine-2-amide
Figure PCTCN2022087341-appb-000015
Figure PCTCN2022087341-appb-000015
(II-11)N-羟基-5-(4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基吡嗪-2-酰胺(II-11) N-Hydroxy-5-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxypyrazine-2-amide
Figure PCTCN2022087341-appb-000016
Figure PCTCN2022087341-appb-000016
(II-12)N-羟基-2-(4-(甲基(4-喹唑啉基)氨基)苯氧基)乙酰胺(II-12) N-Hydroxy-2-(4-(methyl(4-quinazolinyl)amino)phenoxy)acetamide
Figure PCTCN2022087341-appb-000017
Figure PCTCN2022087341-appb-000017
(II-13)N-羟基-4-(4-(甲基(4-喹唑啉基)氨基)苯氧基)丁酰胺(II-13) N-Hydroxy-4-(4-(methyl(4-quinazolinyl)amino)phenoxy)butanamide
Figure PCTCN2022087341-appb-000018
Figure PCTCN2022087341-appb-000018
(II-14)N-羟基-5-(4-(甲基(4-喹唑啉基)氨基)苯氧基)戊酰胺(II-14) N-Hydroxy-5-(4-(methyl(4-quinazolinyl)amino)phenoxy)pentanamide
Figure PCTCN2022087341-appb-000019
Figure PCTCN2022087341-appb-000019
(II-15)N-羟基-6-(4-(甲基(4-喹唑啉基)氨基)苯氧基)己酰胺(II-15) N-Hydroxy-6-(4-(methyl(4-quinazolinyl)amino)phenoxy)hexanamide
Figure PCTCN2022087341-appb-000020
Figure PCTCN2022087341-appb-000020
(II-16)N-羟基-4-((4-(甲基(4-喹唑啉基)氨基)苯氧基)甲基)苯甲酰胺(II-16) N-Hydroxy-4-((4-(methyl(4-quinazolinyl)amino)phenoxy)methyl)benzamide
Figure PCTCN2022087341-appb-000021
Figure PCTCN2022087341-appb-000021
(II-17)N-羟基-4-(4-(甲基(4-喹唑啉基)氨基)苯氧基)苯甲酰胺(II-17) N-Hydroxy-4-(4-(methyl(4-quinazolinyl)amino)phenoxy)benzamide
Figure PCTCN2022087341-appb-000022
Figure PCTCN2022087341-appb-000022
(II-18)N-羟基-6-(4-(甲基(4-喹唑啉基)氨基)苯氧基)烟酰胺(II-18) N-Hydroxy-6-(4-(methyl(4-quinazolinyl)amino)phenoxy)nicotinamide
Figure PCTCN2022087341-appb-000023
Figure PCTCN2022087341-appb-000023
(II-19)N-羟基-5-(4-(甲基(4-喹唑啉基)氨基)苯氧基吡啶酰胺(II-19) N-Hydroxy-5-(4-(methyl(4-quinazolinyl)amino)phenoxypyridineamide
Figure PCTCN2022087341-appb-000024
Figure PCTCN2022087341-appb-000024
(II-20)N-羟基-2-(4-(甲基(4-喹唑啉基)氨基)苯氧基)嘧啶-5-甲酰胺(II-20) N-Hydroxy-2-(4-(methyl(4-quinazolinyl)amino)phenoxy)pyrimidine-5-carboxamide
Figure PCTCN2022087341-appb-000025
Figure PCTCN2022087341-appb-000025
(II-21)N-羟基-5-(4-(甲基(4-喹唑啉基)氨基)苯氧基)嘧啶-2-甲酰胺(II-21) N-Hydroxy-5-(4-(methyl(4-quinazolinyl)amino)phenoxy)pyrimidine-2-carboxamide
Figure PCTCN2022087341-appb-000026
Figure PCTCN2022087341-appb-000026
(II-22)N-羟基-5-(4-(甲基(4-喹唑啉基)氨基)苯氧基)吡嗪-2-甲酰胺(II-22) N-Hydroxy-5-(4-(methyl(4-quinazolinyl)amino)phenoxy)pyrazine-2-carboxamide
Figure PCTCN2022087341-appb-000027
Figure PCTCN2022087341-appb-000027
(II-23)N-羟基-2-(4-((2-甲基-4-喹唑啉基)氨基)苯氧基)乙酰胺(II-23) N-Hydroxy-2-(4-((2-methyl-4-quinazolinyl)amino)phenoxy)acetamide
Figure PCTCN2022087341-appb-000028
Figure PCTCN2022087341-appb-000028
(II-24)N-羟基-3-(4-((2-甲基-4-喹唑啉基)氨基)苯氧基)丙酰胺(II-24) N-Hydroxy-3-(4-((2-methyl-4-quinazolinyl)amino)phenoxy)propionamide
Figure PCTCN2022087341-appb-000029
Figure PCTCN2022087341-appb-000029
(II-25)N-羟基-4-(4-((2-甲基-4-喹唑啉基)氨基)苯氧基)丁酰胺(II-25) N-Hydroxy-4-(4-((2-methyl-4-quinazolinyl)amino)phenoxy)butanamide
Figure PCTCN2022087341-appb-000030
Figure PCTCN2022087341-appb-000030
(II-26)N-羟基-5-(4-((2-甲基-4-喹唑啉基)氨基)苯氧基)戊酰胺(II-26) N-Hydroxy-5-(4-((2-methyl-4-quinazolinyl)amino)phenoxy)pentanamide
Figure PCTCN2022087341-appb-000031
Figure PCTCN2022087341-appb-000031
(II-27)N-羟基-6-(4-((2-甲基-4-喹唑啉基)氨基)苯氧基)己酰胺(II-27) N-Hydroxy-6-(4-((2-methyl-4-quinazolinyl)amino)phenoxy)hexanamide
Figure PCTCN2022087341-appb-000032
Figure PCTCN2022087341-appb-000032
优选地，本发明提供式(III)所示化合物、其互变异构体或其药学上可接受的盐在制备治疗神经病理性疼痛药物中的应用，Preferably, the present invention provides the application of the compound represented by formula (III), its tautomer or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating neuropathic pain,
Figure PCTCN2022087341-appb-000033
Figure PCTCN2022087341-appb-000033
其中，R 1、R 2、R 3各自独立地是氢、卤素、C 1-10的烷基、含氧醚链、含氮烷链、R 4O-、R 4OC(O)-、R 4C(O)O-、-NH 2、-NO 2、羟氨基、R 4NHR 5、R 4CONH-、R 4NHCO-、胍基、脲基、三氟甲基、C 1-10的烷磺酰基、取代苯磺酰基、取代苯基、苯基或杂环基，其中R 4为C 1-10的烷基或苄基，R 5为氢或C 1-10的烷基；优选地，R 1是氢或C 1-6烷氧基；更优选地，R 1是氢或C 1-4烷氧基；最优选地，R 1是氢或甲氧基；优选地，R 2、R 3独立地是氢或C 1-6烷基；更优选地，R 2、R 3独立地是氢或C 1-4烷基；最优选地，R 2、R 3独立地是氢或甲基； Wherein, R 1 , R 2 , and R 3 are each independently hydrogen, halogen, C 1-10 alkyl, oxygen-containing ether chain, nitrogen-containing alkyl chain, R 4 O-, R 4 OC(O)-, R 4 C(O)O-, -NH 2 , -NO 2 , hydroxylamino, R 4 NHR 5 , R 4 CONH-, R 4 NHCO-, guanidino, ureido, trifluoromethyl, C 1-10 Alkylsulfonyl, substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclic group, wherein R 4 is C 1-10 alkyl or benzyl, R 5 is hydrogen or C 1-10 alkyl; preferably , R 1 is hydrogen or C 1-6 alkoxy; more preferably, R 1 is hydrogen or C 1-4 alkoxy; most preferably, R 1 is hydrogen or methoxy; preferably, R 2 , R 3 is independently hydrogen or C 1-6 alkyl; more preferably, R 2 and R 3 are independently hydrogen or C 1-4 alkyl; most preferably, R 2 and R 3 are independently hydrogen or methane base;
Linker是键；-(CH 2) n-、-(CH 2) nO-、-O(CH 2) n-、-O(CH 2) nC(O)-、-C(O)(CH 2) nO-、-OC(O)(CH 2) n-、-(CH 2) nC(O)O-、-(CH 2) nC(O)NH-、-C(O)NH(CH 2) n-、-(CH 2) nSO 2-、-SO 2(CH 2) n-， 或是取代苯磺酰基、取代苯基、苯基或杂环基，其中n为1至10的整数； Linker is a bond; -(CH 2 ) n -, -(CH 2 ) n O-, -O(CH 2 ) n -, -O(CH 2 ) n C(O)-, -C(O)(CH 2 ) n O-, -OC(O)(CH 2 ) n -, -(CH 2 ) n C(O)O-, -(CH 2 ) n C(O)NH-, -C(O)NH (CH 2 ) n -, -(CH 2 ) n SO 2 -, -SO 2 (CH 2 ) n -, or substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclic group, wherein n is 1 to an integer of 10;
优选地，所述取代苯基的苯环上含有1至4个取代基，所述取代苯基的取代基是卤素、-OH、-NO 2、氰基、烷氧基、C 1-4的烷基或氨基基团； Preferably, the phenyl ring of the substituted phenyl group contains 1 to 4 substituents, and the substituents of the substituted phenyl group are halogen, -OH, -NO 2 , cyano, alkoxy, C 1-4 Alkyl or amino groups;
优选地，所述杂环基是含一个或多个杂原子的饱和或不饱和的五元杂环基或六元杂环基；所述杂原子选自氮、氧或硫；Preferably, the heterocyclic group is a saturated or unsaturated five-membered heterocyclic group or six-membered heterocyclic group containing one or more heteroatoms; the heteroatom is selected from nitrogen, oxygen or sulfur;
优选地，所述的卤素是氟、氯、溴或碘。Preferably, said halogen is fluorine, chlorine, bromine or iodine.
优选地，Linker是-(CH 2) nO-、-O(CH 2) n-，其中n为1至10的整数；更优选地，Linker是-(CH 2) nO-，其中n为1至10的整数；最优选地，Linker是-(CH 2) nO-，其中n为1至5的整数； Preferably, the Linker is -(CH 2 ) n O-, -O(CH 2 ) n -, wherein n is an integer from 1 to 10; more preferably, the Linker is -(CH 2 ) n O-, wherein n is An integer of 1 to 10; most preferably, Linker is -(CH 2 ) n O-, wherein n is an integer of 1 to 5;
进一步，本发明涉及选自下式的化合物在制备治疗神经病理性疼痛药物中应用：Further, the present invention relates to the application of compounds selected from the following formulas in the preparation of drugs for the treatment of neuropathic pain:
(III-1)N-羟基-2-(2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)乙酰胺(III-1) N-Hydroxy-2-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)acetamide
Figure PCTCN2022087341-appb-000034
Figure PCTCN2022087341-appb-000034
(III-2)N-羟基-4-(2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)丁酰胺(III-2) N-Hydroxy-4-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)butanamide
Figure PCTCN2022087341-appb-000035
Figure PCTCN2022087341-appb-000035
(III-3)N-羟基-5-(2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)戊酰胺(III-3) N-Hydroxy-5-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pentanamide
Figure PCTCN2022087341-appb-000036
Figure PCTCN2022087341-appb-000036
(III-4)N-羟基-6-(2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)己酰胺(III-4) N-Hydroxy-6-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)caproamide
Figure PCTCN2022087341-appb-000037
Figure PCTCN2022087341-appb-000037
(III-5)N-羟基-4-((2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)甲基)苯甲酰胺(III-5) N-Hydroxy-4-((2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)methyl)benzamide
Figure PCTCN2022087341-appb-000038
Figure PCTCN2022087341-appb-000038
(III-6)N-羟基-4-(2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)苯甲酰胺(III-6) N-Hydroxy-4-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)benzamide
Figure PCTCN2022087341-appb-000039
Figure PCTCN2022087341-appb-000039
(III-7)N-羟基-6-(2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)烟酰胺(III-7) N-Hydroxy-6-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)nicotinamide
Figure PCTCN2022087341-appb-000040
Figure PCTCN2022087341-appb-000040
(III-8)N-羟基-5-(2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)吡啶酰胺(III-8) N-Hydroxy-5-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyridineamide
Figure PCTCN2022087341-appb-000041
Figure PCTCN2022087341-appb-000041
(III-9)N-羟基-2-(2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)嘧啶-5-甲酰胺(III-9) N-Hydroxy-2-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrimidine-5-carboxamide
Figure PCTCN2022087341-appb-000042
Figure PCTCN2022087341-appb-000042
(III-10)N-羟基-5-(2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)嘧啶-2-甲酰胺(III-10) N-Hydroxy-5-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrimidine-2-carboxamide
Figure PCTCN2022087341-appb-000043
Figure PCTCN2022087341-appb-000043
(III-11)N-羟基-5-(2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)吡嗪-2-甲酰胺(III-11) N-Hydroxy-5-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrazine-2-carboxamide
Figure PCTCN2022087341-appb-000044
Figure PCTCN2022087341-appb-000044
(III-12)N-羟基-2-(3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)乙酰胺(III-12) N-Hydroxy-2-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)acetamide
Figure PCTCN2022087341-appb-000045
Figure PCTCN2022087341-appb-000045
(III-13)N-羟基-4-(3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)丁酰胺(III-13) N-Hydroxy-4-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)butanamide
Figure PCTCN2022087341-appb-000046
Figure PCTCN2022087341-appb-000046
(III-14)N-羟基-5-(3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)戊酰胺(III-14) N-Hydroxy-5-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pentanamide
Figure PCTCN2022087341-appb-000047
Figure PCTCN2022087341-appb-000047
(III-15)N-羟基-6-(3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)己酰胺(III-15) N-Hydroxy-6-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)caproamide
Figure PCTCN2022087341-appb-000048
Figure PCTCN2022087341-appb-000048
(III-16)N-羟基-4-((3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)甲基)苯甲酰 胺(III-16) N-Hydroxy-4-((3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)methyl)benzamide
Figure PCTCN2022087341-appb-000049
Figure PCTCN2022087341-appb-000049
(III-17)N-羟基-4-(3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)苯甲酰胺(III-17) N-Hydroxy-4-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)benzamide
Figure PCTCN2022087341-appb-000050
Figure PCTCN2022087341-appb-000050
(III-18)N-羟基-6-(3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)烟酰胺(III-18) N-Hydroxy-6-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)nicotinamide
Figure PCTCN2022087341-appb-000051
Figure PCTCN2022087341-appb-000051
(III-19)N-羟基-5-(3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)吡啶酰胺(III-19) N-Hydroxy-5-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyridineamide
Figure PCTCN2022087341-appb-000052
Figure PCTCN2022087341-appb-000052
(III-20)N-羟基-2-(3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)嘧啶-5-甲酰胺(III-20) N-Hydroxy-2-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrimidine-5-carboxamide
Figure PCTCN2022087341-appb-000053
Figure PCTCN2022087341-appb-000053
(III-21)N-羟基-5-(3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)嘧啶-2-甲酰胺(III-21) N-Hydroxy-5-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrimidine-2-carboxamide
Figure PCTCN2022087341-appb-000054
Figure PCTCN2022087341-appb-000054
(III-22)N-羟基-5-(3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)吡嗪-2-甲酰胺(III-22) N-Hydroxy-5-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrazine-2-carboxamide
Figure PCTCN2022087341-appb-000055
Figure PCTCN2022087341-appb-000055
优选地，本发明提供式(IV)所示化合物、其互变异构体或其药学上可接受的盐在制备治疗神经病理性疼痛药物中的应用，Preferably, the present invention provides the application of the compound represented by formula (IV), its tautomer or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating neuropathic pain,
Figure PCTCN2022087341-appb-000056
Figure PCTCN2022087341-appb-000056
其中，R 2独立地是氢、卤素、C 1-10的烷基、含氧醚链、含氮烷链、R 4O-、R 4OC(O)-、R 4C(O)O-、-NH 2、-NO 2、羟氨基、R 4-O-CH 2-、R 4-O-CH 2-O-CH 2-、R 4NHR 5、R 4CONH-、R 4NHCO-、胍基、脲基、三氟甲基、C 1-10的烷磺酰基、取代苯磺酰基、取代苯基、苯基或杂环基，其中R 4为C 1-10的烷基或苄基，R 5为氢或C 1-10的烷基；优选地，R 2独立地是氢或C 1-6烷基； Wherein, R 2 is independently hydrogen, halogen, C 1-10 alkyl, oxygen-containing ether chain, nitrogen-containing alkyl chain, R 4 O-, R 4 OC(O)-, R 4 C(O)O- , -NH 2 , -NO 2 , Hydroxyamino, R 4 -O-CH 2 -, R 4 -O-CH 2 -O-CH 2 -, R 4 NHR 5 , R 4 CONH-, R 4 NHCO-, Guanidino, ureido, trifluoromethyl, C 1-10 alkylsulfonyl, substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclic group, wherein R is C 1-10 alkyl or benzyl , R 5 is hydrogen or C 1-10 alkyl; preferably, R 2 is independently hydrogen or C 1-6 alkyl;
进一步，本发明涉及选自下式的化合物在制备治疗神经病理性疼痛药物中应用：Further, the present invention relates to the application of compounds selected from the following formulas in the preparation of drugs for the treatment of neuropathic pain:
(IV-1)4-(5-(乙基(2-甲基-4-喹唑啉基)氨基)-2-甲氧基苯基)-N-羟基丁酰胺(IV-1) 4-(5-(Ethyl(2-methyl-4-quinazolinyl)amino)-2-methoxyphenyl)-N-hydroxybutyramide
Figure PCTCN2022087341-appb-000057
Figure PCTCN2022087341-appb-000057
(IV-2)N-羟基-4-(2-甲氧基-5-((2-甲基-4-喹唑啉基)(丙基)氨基)苯氧基)丁酰胺(IV-2) N-Hydroxy-4-(2-methoxy-5-((2-methyl-4-quinazolinyl)(propyl)amino)phenoxy)butanamide
Figure PCTCN2022087341-appb-000058
Figure PCTCN2022087341-appb-000058
(IV-3)4-(5-(丁基(2-甲基-4-喹唑啉基)氨基)-2-甲氧基苯基)-N-羟基丁酰胺(IV-3) 4-(5-(Butyl(2-methyl-4-quinazolinyl)amino)-2-methoxyphenyl)-N-hydroxybutyramide
Figure PCTCN2022087341-appb-000059
Figure PCTCN2022087341-appb-000059
(IV-4)N-羟基-4-(2-甲氧基-5-((2-甲基-4-喹唑啉基)(戊基)氨基)苯氧基)丁酰胺(IV-4) N-Hydroxy-4-(2-methoxy-5-((2-methyl-4-quinazolinyl)(pentyl)amino)phenoxy)butanamide
Figure PCTCN2022087341-appb-000060
Figure PCTCN2022087341-appb-000060
(IV-5)N-羟基-4-(2-甲氧基-5-((甲氧基甲基)(2-甲基-4-喹唑啉基)氨基)苯氧基)丁酰胺(IV-5) N-Hydroxy-4-(2-methoxy-5-((methoxymethyl)(2-methyl-4-quinazolinyl)amino)phenoxy)butanamide
Figure PCTCN2022087341-appb-000061
Figure PCTCN2022087341-appb-000061
(IV-6)N-羟基-4-(2-甲氧基-5-(((甲氧基甲氧基)甲基)(2-甲基-4-喹唑啉基)氨基)苯氧基)丁酰胺(IV-6) N-Hydroxy-4-(2-methoxy-5-(((methoxymethoxy)methyl)(2-methyl-4-quinazolinyl)amino)phenoxy base) butanamide
Figure PCTCN2022087341-appb-000062
Figure PCTCN2022087341-appb-000062
根据本发明的另一个方面还提供了一种药物组合物在制备治疗神经病理性疼痛药物中的应用，该药物组合物包含上述所有所述化合物、其互变异构体或其药学上可接受的盐，以及药学上可接受的辅料。According to another aspect of the present invention, there is also provided a pharmaceutical composition in the preparation of medicines for treating neuropathic pain, the pharmaceutical composition comprising all the above-mentioned compounds, their tautomers or their pharmaceutically acceptable salt, and pharmaceutically acceptable excipients.
所述药物组合物的剂型可以为片剂、栓剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖衣剂、颗粒剂、干粉剂、口服溶液剂、注射用小针、注射用冻干粉针或大输液。The dosage form of the pharmaceutical composition can be tablet, suppository, dispersible tablet, enteric-coated tablet, chewable tablet, orally disintegrating tablet, capsule, sugar-coated agent, granule, dry powder, oral solution, small needle for injection, injection Freeze-dried powder for injection or large infusion.
优选地，所述药学上可接受的辅料包括下述的一种或多种：稀释剂、增溶剂、崩解剂、 悬浮剂、润滑剂、粘合剂、填充剂、矫味剂、甜味剂、抗氧化剂、表面活性剂、防腐剂、包裹剂或色素。Preferably, the pharmaceutically acceptable excipients include one or more of the following: diluents, solubilizers, disintegrants, suspending agents, lubricants, binders, fillers, flavoring agents, sweeteners agents, antioxidants, surfactants, preservatives, coatings or pigments.
根据本发明所述的化合物或组合物在制备治疗神经病理性疼痛药物中的应用，所述神经病理性疼痛选自慢性背疼、疱疹后遗神经痛、糖尿病性神经病理性疼痛、肌纤维痛、与化疗药物诱导的神经病理性疼痛；具体地，上述神经病理性疼痛选自糖尿病性神经病理性肢体疼痛和化疗药物诱导的肢体疼痛。Application of the compound or composition according to the present invention in the preparation of a drug for treating neuropathic pain, wherein the neuropathic pain is selected from chronic back pain, postherpetic neuralgia, diabetic neuropathic pain, fibromyalgia, and chemotherapy drugs Induced neuropathic pain; specifically, the aforementioned neuropathic pain is selected from diabetic neuropathic limb pain and chemotherapy drug-induced limb pain.
进一步，根据本发明所述的应用，所述化合物为如下式所示化合物III-2，所述疼痛为糖尿病性神经病理性疼痛与化疗药物诱导的神经病理性疼痛。Further, according to the application of the present invention, the compound is the compound III-2 shown in the following formula, and the pain is diabetic neuropathic pain and chemotherapeutic drug-induced neuropathic pain.
Figure PCTCN2022087341-appb-000063
Figure PCTCN2022087341-appb-000063
相关定义related definition
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indeterminate or unclear if it is not specifically defined, but should be understood according to its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸、鞣酸盐、枸橼酸盐、三氟醋酸盐等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, Hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, tannates, citrates, trifluoroacetates, etc. acids; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977 )). Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into either base or acid addition salts.
优选地，上述药学上可接受的盐的制备方法为：以常规方式使盐与碱或酸接触，再分离 母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。Preferably, the above pharmaceutically acceptable salts are prepared by contacting the salt with a base or acid in a conventional manner followed by isolation of the parent compound, thereby regenerating the neutral form of the compound. The parent form of the compound differs from its various salt forms by certain physical properties, such as solubility in polar solvents.
本文所述的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物而获得。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。The "pharmaceutically acceptable salt" described herein belongs to the derivatives of the compounds of the present invention, wherein the parent compound is obtained by modifying the parent compound by forming a salt with an acid or forming a salt with a base. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, such as salts formed from non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturin, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannin, tartaric acid and p-toluenesulfonic acid.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所涉及的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物(前药)也可以在体内环境中通过化学或生化方法被转换到本发明的化合物。In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds referred to herein readily undergo chemical changes under physiological conditions to convert them into the compounds of the present invention. In addition, prodrugs (prodrugs) can also be converted to the compounds of the invention by chemical or biochemical methods in an in vivo environment.
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式效果相当，都包含在本发明的范围之内。Certain compounds of the present invention can exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are within the scope of the present invention.
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。因此，外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的化合物的范围之内。Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Accordingly, racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the compounds of the present invention.
除非另有说明，本发明中，用楔形键和虚线键
Figure PCTCN2022087341-appb-000064
表示一个立体中心的绝对构型，用
Figure PCTCN2022087341-appb-000065
表示一个立体中心的相对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，其所有的互变异构形式均包括在本发明的范围之内。 Unless otherwise specified, in the present invention, wedge-shaped keys and dotted-line keys are used
Figure PCTCN2022087341-appb-000064
To represent the absolute configuration of a stereocenter, use
Figure PCTCN2022087341-appb-000065
Indicates the relative configuration of a stereocenter. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, they include E, Z geometric isomers. Likewise, all tautomeric forms thereof are included within the scope of the present invention.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明涉及所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些几何或立体异构体形式都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the invention may exist in particular geometric or stereoisomeric forms. The present invention relates to all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers isomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all such geometric or stereoisomeric All conformational forms are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
可以通过手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，通过将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所 需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常用方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, by separation of the resulting diastereomeric mixture and cleavage of the auxiliary group to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a common method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质。代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。以所述物质辅助制备制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention, without interfering with the biological activity of the active substance, and without toxic side effects to the host or patient. Representative carriers include water, oils, vegetable and minerals, cream bases, lotion bases, ointment bases and the like. These bases include suspending agents, viscosity builders, skin penetration enhancers and the like. The preparation of preparations aided by such substances is well known to those skilled in the field of cosmetics or topical medicine. Additional information on carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指为了达到预期效果所需要的用量，或者所述活性成分与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。For a drug or a pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect. For the oral dosage form in the present invention, the "effective amount" of an active substance in the composition refers to the amount needed to achieve the desired effect, or when the active ingredient is used in combination with another active substance in the composition to achieve Amount required for desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that is effective in treating the disorder, disease or condition of interest.
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" refers to the replacement of any one or more hydrogen atoms on a specified atom with a substituent, including deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable . When a substituent is keto (ie =0), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically realizable basis.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R的选项都是独立的。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted with 0-2 R, said group may optionally be substituted with up to two R, and the choice of R in each case is independent. Also, combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另 有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括哌嗪基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。Unless otherwise specified, "ring" means a substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. The so-called ring includes monocyclic, bicyclic, spiro, fused or bridged rings. The number of atoms on a ring is usually defined as the number of ring members, for example, "5-7 membered ring" refers to 5-7 atoms arranged around it. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms. Thus, "5-7 membered ring" includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term "5-7 membered heterocycloalkyl ring" includes piperazinyl and piperidinyl, but excludes phenyl . The term "ring" also includes ring systems comprising at least one ring, wherein each "ring" is independently defined above.
杂环化合物的实例包括但不限于：吡啶基，吡咯基，嘧啶基、咪唑基、哒嗪基、三嗪基、哌嗪基、哌啶基、吡嗪基、吡唑基、2H-吡咯基、四唑基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基。Examples of heterocyclic compounds include, but are not limited to: pyridyl, pyrrolyl, pyrimidinyl, imidazolyl, pyridazinyl, triazinyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolyl, 2H-pyrrolyl , tetrazolyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl.
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基，其可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。 Unless otherwise specified, the term "alkyl" is used to denote a linear or branched saturated hydrocarbon group, which may be monosubstituted (such as -CH 2 F) or polysubstituted (such as -CF 3 ), which may be monovalent ( Such as methyl), divalent (such as methylene) or multivalent (such as methine). Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。All solvents used in the present invention are commercially available and used without further purification.
本发明采用下述缩略词：Pen.为己酮可可碱；INT-747为6-乙基鹅去氧胆酸；aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁基羰基，是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；TMSCF 3代表三氟甲基三甲基硅烷；Ti(Oi-Pr) 4代表钛酸四异丙酯；MSCl代表甲烷磺酰氯；DMAP代表N,N-二甲基-4-氨基吡啶；TEA代表三乙胺；BnBr代表苄溴；DIEA代表二异丙基乙胺；BH 3DMS代表硼烷二甲硫醚；DMP代表戴斯马丁过碘烷；TBAF代表四丁基氟化胺；HOBT代表1-羟基苯并三唑；AIBN代表偶氮二异丁腈；NBS代表N-溴代丁二酰亚胺；RT缓冲液代表逆转录缓冲液；dNTP代表脱氧核糖核苷三磷酸；PBS代表磷酸盐缓冲液；CMCNa代表羧甲基纤维素钠；STZ代表链脲佐霉素。 The present invention adopts the following abbreviations: Pen. is pentoxifylline; INT-747 is 6-ethylchenodeoxycholic acid; aq stands for water; HATU stands for O-(7-azabenzotriazole-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride ; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents equivalent, equivalent; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents petroleum ether; DIAD represents diisopropyl azodicarboxylate; DMF Represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; CBz represents benzyloxycarbonyl, which is an amine protecting group; BOC represents tert-butyl ylcarbonyl, is an amine protecting group; HOAc represents acetic acid; NaCNBH 3 represents sodium cyanoborohydride; rt represents room temperature; O/N represents overnight; THF represents tetrahydrofuran; Boc 2 O represents di-tert-butyl dicarbonate ; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl 2 stands for thionyl chloride; CS 2 stands for carbon disulfide; TsOH stands for p-toluenesulfonic acid; NFSI stands for N-fluoro-N-(benzenesulfonyl) Benzenesulfonamide; NCS stands for 1-chloropyrrolidine-2,5-dione; n-Bu 4 NF stands for tetrabutylammonium fluoride; iPrOH stands for 2-propanol; mp stands for melting point; LDA stands for diisopropylamine TMSCF 3 represents trifluoromethyltrimethylsilane; Ti(Oi-Pr) 4 represents tetraisopropyl titanate; MSCl represents methanesulfonyl chloride; DMAP represents N,N-dimethyl-4-aminopyridine ; TEA represents triethylamine; BnBr represents benzyl bromide; DIEA represents diisopropylethylamine; BH 3 DMS represents borane dimethyl sulfide; DMP represents Dess Martin periodane; TBAF represents tetrabutylammonium fluoride; HOBT stands for 1-hydroxybenzotriazole; AIBN stands for azobisisobutyronitrile; NBS stands for N-bromosuccinimide; RT buffer stands for reverse transcription buffer; dNTP stands for deoxyribonucleoside triphosphate; PBS stands for phosphate buffered saline; CMCNa stands for sodium carboxymethylcellulose; STZ stands for streptozotocin.
化合物经手工或者
Figure PCTCN2022087341-appb-000066
软件命名，市售化合物采用供应商目录名称。 Compounds were manually or
Figure PCTCN2022087341-appb-000066
The software is named, and the commercially available compounds adopt the supplier catalog name.
附图说明Description of drawings
图1大鼠机械刺激性缩足阈值，与模型对照组1比较；其中，*代表p<0.05，与模型对照组1比较。Figure 1 The paw withdrawal threshold of rats mechanically stimulated, compared with model control group 1; where, * represents p<0.05, compared with model control group 1.
图2各组动物体重变化曲线。Fig. 2 The body weight change curves of animals in each group.
图3各组动物机械缩足痛阈值统计图(Mean±SEM)，*代表p<0.05 vs model，**代表p<0.01 vs model。Figure 3 Statistical diagram of mechanical foot withdrawal pain threshold of animals in each group (Mean±SEM), * represents p<0.05 vs model, ** represents p<0.01 vs model.
具体实施方式Detailed ways
本方案发明内容中的所有化合物参照CN201680015470.2公开的制备方法制备所得。All the compounds in the content of the invention of this scheme are prepared according to the preparation method disclosed in CN201680015470.2.
实施例1：大鼠STZ糖尿病性外周神经病理性疼痛模型药效学研究Example 1: Pharmacodynamic study of rat STZ diabetic peripheral neuropathic pain model
实验目的：采用STZ诱导的SD大鼠I型糖尿病动物模型，研究糖尿病外周神经病变引起的周围神经病理性疼痛等行为，通过大鼠机械刺激敏感性变化，评价供试品在糖尿病性神经病理性疼痛动物模型中的治疗作用。Purpose of the experiment: To study the behaviors of peripheral neuropathic pain caused by diabetic peripheral neuropathy by using STZ-induced SD rat type I diabetes animal model, and to evaluate the effect of the test product on diabetic neuropathic pain animals through the change of mechanical stimulation sensitivity in rats. Treatment effect in the model.
实验模型：STZ诱导的SD大鼠I型糖尿病动物模型Experimental model: SD rat type I diabetes animal model induced by STZ
实验动物：SD大鼠(斯贝福(北京)生物技术有限公司)Experimental animals: SD rats (Speyford (Beijing) Biotechnology Co., Ltd.)
实验试剂：Experimental reagents:
1.加巴喷丁(上海皓鸿生物医药科技有限公司)；1. Gabapentin (Shanghai Haohong Biomedical Technology Co., Ltd.);
2. 0.5％CMCNa(西格玛奥德里奇(上海)贸易有限公司)；2. 0.5% CMCNa (Sigma-Aldrich (Shanghai) Trading Co., Ltd.);
3. 0.9％氯化钠注射液(四川科伦药业股份有限公司)；3. 0.9% Sodium Chloride Injection (Sichuan Kelun Pharmaceutical Co., Ltd.);
4.戊巴比妥钠(默克公司)；4. Sodium pentobarbital (Merck &Co.);
5.链脲佐霉素(西格玛奥德里奇(上海)贸易有限公司)；5. Streptozotocin (Sigma-Aldrich (Shanghai) Trading Co., Ltd.);
6.供试品化合物III-26. The test compound III-2
实验方法：experimental method:
1.STZ溶液的配制与存储1. Preparation and storage of STZ solution
A液：称取1.471g柠檬酸钠置于50mL无菌离心管中，用50mL注射器吸取50.0mL生理盐水置于离心管中，溶解均匀；Solution A: Weigh 1.471g of sodium citrate and place it in a 50mL sterile centrifuge tube, draw 50.0mL of normal saline into the centrifuge tube with a 50mL syringe, and dissolve evenly;
B液：称取0.995g柠檬酸置于50mL无菌离心管中，用50mL注射器吸取50.0mL生理盐水置于离心管中，溶解均匀；Solution B: Weigh 0.995g of citric acid and place it in a 50mL sterile centrifuge tube, draw 50.0mL of normal saline into the centrifuge tube with a 50mL syringe, and dissolve evenly;
柠檬酸盐缓冲液：将A液与B液按1:1混合，混匀后用A液或B液调pH至4.5，洁净工作台内0.22μm一次性针头式滤器过滤除菌，分装为50mL每管，贴好标签，-20℃保存待用；Citrate buffer solution: Mix liquid A and liquid B at a ratio of 1:1, adjust the pH to 4.5 with liquid A or liquid B after mixing, filter and sterilize with a 0.22 μm disposable syringe filter in a clean bench, and pack as 50mL per tube, label well, store at -20°C until use;
链脲佐菌素(STZ)溶液：造模前称取链脲佐菌素240mg/管，置于用锡箔纸包裹好的50mL无菌离心管中，放置于冰盒内，临用前加入分装好的柠檬酸盐缓冲液40mL，混匀，配制成6mg/mL的链脲佐菌素(STZ)溶液，15分钟内使用完，未使用完的直接废弃。Streptozotocin (STZ) solution: Weigh 240mg/tube of streptozotocin before modeling, put it in a 50mL sterile centrifuge tube wrapped with tinfoil, put it in an ice box, add aliquots before use Prepare 40mL of citrate buffer solution, mix well, and prepare 6mg/mL streptozotocin (STZ) solution, use it up within 15 minutes, and discard the unused one directly.
2.STZ诱导糖尿病动物模型2. STZ-induced diabetes animal model
大鼠腹腔注射STZ，65mg/kg，单次注射，注射前动物需禁食12h以上，注射后当天将大鼠饮用水换成10％蔗糖溶液(防止大鼠发生低血糖症)。Rats were intraperitoneally injected with STZ, 65mg/kg, single injection, and the animals were fasted for more than 12 hours before the injection, and the drinking water of the rats was replaced with 10% sucrose solution on the day after the injection (to prevent hypoglycemia in the rats).
3.分组3. Grouping
本试验包括试验I和试验II，试验I包括1个模型对照组，1个阳性对照组和1个供试品组，试验II包括1个模型对照组和1个供试品组。This test includes test I and test II. Test I includes a model control group, a positive control group and a test product group, and test II includes a model control group and a test product group.
分组方法：选取发生糖尿病性神经病理性疼痛的I型糖尿病SD大鼠，按机械刺激缩足阈 值随机分组。Grouping method: Type I diabetic SD rats with diabetic neuropathic pain were selected and randomly grouped according to the paw withdrawal threshold of mechanical stimulation.
表1动物分组表1Table 1 Animal grouping Table 1
Figure PCTCN2022087341-appb-000067
Figure PCTCN2022087341-appb-000067
表2动物分组表2Table 2 Animal Group Table 2
Figure PCTCN2022087341-appb-000068
Figure PCTCN2022087341-appb-000068
注：动物编号的首位字母代表试验阶段，首位数字代表组别(1、2和3分别代表模型对照组、阳性对照组和供试品组)；第二位字母代表性别(M为雄性)，后3位数字代表动物序列号。Note: the first letter of the animal number represents the test stage, the first number represents the group (1, 2 and 3 represent the model control group, the positive control group and the test product group respectively); the second letter represents the gender (M is male), The last 3 digits represent the serial number of the animal.
4.给药4. Administration
试验I：模型对照组给予溶媒，其余各组给予不同剂量的药物，由于供试品75mg/kg剂量组(Bid)，在给药第3天动物出现严重腹泻的毒副反应，因此在第3天和第4天将给药频率改为每天一次，且该组动物在给药第4天已有4只动物死亡，因此在第5天停止给药，具体信息详见下表3。Test 1: the model control group was given vehicle, and all the other groups were given different doses of medicines. Because the test product 75mg/kg dose group (Bid) had severe diarrhea in animals on the 3rd day of administration, the animals had severe diarrhea on the 3rd day. On the first day and the fourth day, the administration frequency was changed to once a day, and 4 animals in this group died on the fourth day of administration, so the administration was stopped on the fifth day. For details, see Table 3 below.
试验II：模型对照组给予溶媒，给药组给予供试品药物，给药频率为每天2次，持续给药5天。具体信息详见下表4。Test II: The vehicle was given to the model control group, and the drug to be tested was given to the treatment group. The dosing frequency was 2 times a day for 5 consecutive days. For details, see Table 4 below.
表3剂量设计表1Table 3 Dose Design Table 1
Figure PCTCN2022087341-appb-000069
Figure PCTCN2022087341-appb-000069
注：造模当天定义为D0，D27天分组，D28天开始给药，Qd：每天一次，Bid：每天两次。Note: The day of modeling was defined as D0, grouped on D27, and administered on D28, Qd: once a day, Bid: twice a day.
表4剂量设计表2Table 4 Dose Design Table 2
Figure PCTCN2022087341-appb-000070
Figure PCTCN2022087341-appb-000070
注：造模当天定义为D0，D37天分组，D38天开始给药，Bid：每天两次。Note: The day of modeling was defined as D0, grouping was performed on D37, and administration began on D38, Bid: twice a day.
5.检测5. Detection
机械刺激性缩足阈值mechanical stimulus paw withdrawal threshold
检测时间：STZ造模前检测1次，分组前检测1次，试验I动物给药后第1、4、8天检测1次，试验II动物给药后第1、5天检测1次；Testing time: 1 test before STZ modeling, 1 test before grouping, 1 test on the 1st, 4th, and 8th day after the administration of the animals in Test I, and 1 test on the 1st and 5th day after the administration of the animals in Test II;
方法：检测前连续3天将动物放入检测盒中适应，每天适应30min；每次检测时，动将动物放入检测盒中适应15min后进行检测，检测时每只动物检测3次取平均值，每次检测至少间隔5分钟。Method: Put the animals in the test box for 3 consecutive days before the test to adapt, and adapt to it for 30 minutes every day; each test, put the animal in the test box to adapt to it for 15 minutes before testing, and each animal was tested 3 times to get the average value , with at least 5 minutes between each test.
6.实验结果6. Experimental results
大鼠机械刺激性缩足阈值在STZ注射后D14天开始降低，在D21天降低至50％，D25天时动物机械刺激性缩足阈值与D21基本相同，说明此时动物机械刺激性缩足阈值基本已降至最低，因此本试验选择在D28天开始给予药物干预。The mechanically stimulated paw withdrawal threshold of rats began to decrease on D14 days after STZ injection, and decreased to 50% on D21 days. has been reduced to a minimum, so this experiment chooses to start giving drug intervention on D28.
如图1和表5和表6所示，试验I结果显示：药物干预后，阳性药物加巴喷丁(150mg/kg，Qd)治疗组大鼠机械刺激性缩足阈值明显升高，与模型对照组相比，有明显统计学差异(P<0.05)；供试品化合物III-2 75mg/kg(bid，2d，qd，2d)组在首次给药(D28)后，就能使大鼠机械刺激性缩足阈值显著升高，与模型对照组相比，有统计学差异(P<0.05)，且在停药3天(D34)后，大鼠机械刺激性缩足阈值仍维持在给药时的水平，与模型对照组比较，有明显统计学差异(P<0.05)。试验II结果显示：供试品化合物III-2 15mg/kg(bid，5d)组在首次给药(D38)后，也能使大鼠机械刺激性缩足阈值显著升高，与模型对照组相比，有明显统计学差异(P<0.05)。As shown in Figure 1 and Table 5 and Table 6, test I result shows: after drug intervention, the rat mechanical stimulation paw withdrawal threshold of positive drug gabapentin (150mg/kg, Qd) treatment group obviously raises, compares with model control group Ratio, there is significant statistical difference (P<0.05); The test compound III-2 75mg/kg (bid, 2d, qd, 2d) group after the first administration (D28), just can make rat mechanical stimulation The paw withdrawal threshold was significantly increased, compared with the model control group, there was a statistical difference (P<0.05), and after 3 days of drug withdrawal (D34), the mechanically stimulated paw withdrawal threshold of the rats was still maintained at the same level as the drug administration. Compared with the model control group, there was a significant statistical difference (P<0.05). The results of the test II show that the test compound III-2 15mg/kg (bid, 5d) group can also significantly increase the paw withdrawal threshold of rats after the first administration (D38), compared with the model control group. There was a significant statistical difference (P<0.05).
表5.大鼠机械刺激性缩足阈值1(g)Table 5. Rat Mechanical Stimulation Paw Withdrawal Threshold 1 (g)
Figure PCTCN2022087341-appb-000071
Figure PCTCN2022087341-appb-000071
注：*代表p<0.05，与模型对照组1比较；表中PRE～D31各组所有数据均来自8只动物(n＝8)，D34天模型组和阳性药组数据来自8只动物，供试品组数据来自3只动物；pre代表造模前，造模当天为D0，D14代表造模后第14天，其余类同。Note: * represents p<0.05, compared with model control group 1; in the table, all the data of each group from PRE to D31 come from 8 animals (n=8), and the data of the model group and positive drug group on D34 days come from 8 animals, for The data of the test group come from 3 animals; pre means before modeling, the day of modeling is D0, D14 means the 14th day after modeling, and the rest are similar.
表6.大鼠机械刺激性缩足阈值2(g)Table 6. Rat Mechanical Stimulation Paw Withdrawal Threshold 2 (g)
Figure PCTCN2022087341-appb-000072
Figure PCTCN2022087341-appb-000072
注：*代表p<0.05，与模型对照组1比较；表中各组所有数据均来自5只动物(n＝5)；pre代表造模前，造模当天为D0，D14代表造模后第14天，其余类同。Note: * represents p<0.05, compared with model control group 1; all data in each group in the table come from 5 animals (n=5); pre represents before modeling, D0 on the day of modeling, D14 represents the first day after modeling 14 days, the rest are similar.
综上所述，化合物III-2在75mg/kg(bid，2d，qd，2d)和15mg/kg(bid，5d)剂量下，均能使SD大鼠糖尿病性神经病理性疼痛动物的机械刺激性缩足阈值显著升高，说明该化合物在该剂量下具有较好的镇痛作用。In summary, compound III-2 can make the mechanical stimulation of SD rat diabetic neuropathic pain animals under the dosage of 75mg/kg (bid, 2d, qd, 2d) and 15mg/kg (bid, 5d). The paw withdrawal threshold was significantly increased, indicating that the compound has a better analgesic effect at this dose.
实施例2：紫杉醇诱导大鼠疼痛模型试验的药效学研究Embodiment 2: Pharmacodynamic study of paclitaxel-induced pain model test in rats
实验目的：采用紫杉醇诱导大鼠疼痛模型，评价供试品在该模型中对于大鼠足痛是否有治疗缓解作用。The purpose of the experiment: To use the Paclitaxel-induced rat pain model to evaluate whether the test product has a therapeutic and alleviating effect on rat foot pain in this model.
实验模型：紫杉醇诱导大鼠疼痛模型Experimental model: paclitaxel-induced pain model in rats
实验动物：SD大鼠(成都达硕实验动物有限公司)Experimental animal: SD rat (Chengdu Dashuo Experimental Animal Co., Ltd.)
实验试剂：Experimental reagents:
1.紫杉醇注射液(扬子江药业集团有限公司)；1. Paclitaxel injection (Yangzijiang Pharmaceutical Group Co., Ltd.);
2. 0.5％CMC-Na(成都市科龙化工试剂厂)；2. 0.5% CMC-Na (Chengdu Kelong Chemical Reagent Factory);
3. 0.9％氯化钠注射液(四川科伦药业股份有限公司)；3. 0.9% Sodium Chloride Injection (Sichuan Kelun Pharmaceutical Co., Ltd.);
4.供试品化合物III-24. Test compound III-2
实验方法：experimental method:
1.供试品/对照品配制1. Preparation of test substance/reference substance
溶媒对照品配制：取适量CMC-Na加入纯化水中，涡旋混匀配制成溶媒试剂0.5％CMC-Na(w/v)溶液。Preparation of solvent reference substance: Add appropriate amount of CMC-Na into purified water, vortex and mix to prepare 0.5% CMC-Na (w/v) solution of solvent reagent.
供试品配制：称取适量药物，加入0.5％CMC-Na超声、涡漩振荡混匀。获得终浓度为0.3mg/mL的混悬液。Preparation of the test product: Weigh an appropriate amount of drug, add 0.5% CMC-Na for ultrasonication, vortex oscillation and mix. A suspension with a final concentration of 0.3 mg/mL was obtained.
2.紫杉醇诱导大鼠疼痛模型2. Paclitaxel-induced pain model in rats
购入45只Sprague Dawley(SD)大鼠适应性饲养7天后，选取40只大鼠腹腔注射(i.p.)给予2mg/kg紫杉醇注射液造模，隔天注射1次，连续注射4次，剩余5只大鼠腹腔注射生理盐水做为正常对照组，造模完成后第4天，40只造模动物与5只生理盐水组动物使用von Frey上下法测量大鼠的机械痛阈(baseline)，筛选20只成模动物入组给药。After buying 45 Sprague Dawley (SD) rats and feeding them for 7 days, 40 rats were selected for intraperitoneal injection (i.p.) and given 2 mg/kg paclitaxel injection for modeling, once every other day for 4 consecutive injections, and the remaining 5 Rats were intraperitoneally injected with normal saline as the normal control group. On the 4th day after the completion of modeling, 40 model animals and 5 animals in the normal saline group were used to measure the mechanical pain threshold (baseline) of the rats using the von Frey up and down method. 20 model animals were included in the group for administration.
3.分组3. Grouping
筛选入组的20只成模大鼠，随机分成2组，每组10只，5只腹腔注射生理盐水的大鼠做为正常对照组，按下表进行给药：The 20 model rats selected into the group were randomly divided into 2 groups, 10 in each group, and 5 rats intraperitoneally injected with normal saline were used as the normal control group, and the administration was performed according to the following table:
Figure PCTCN2022087341-appb-000073
Figure PCTCN2022087341-appb-000073
4.体重测量4. Weight measurement
给药期间每2天测量一次体重。Body weight was measured every 2 days during the dosing period.
5.机械痛阈测量5. Mechanical Pain Threshold Measurement
给药第1、4、7天第1次给药后1小时，停药后3天使用von Frey上下法测量大鼠的机械痛阈，并计算出机械缩足痛阈值(50％PWT)。One hour after the first administration on the 1st, 4th, and 7th days of administration, the von Frey up and down method was used to measure the mechanical pain threshold of the rats 3 days after drug withdrawal, and the mechanical pain threshold (50% PWT) was calculated.
6.数据分析6. Data analysis
采用非参数Mann-Whitney检验，P<0.05定义为有统计学显著性差异。A non-parametric Mann-Whitney test was used, and P<0.05 was defined as a statistically significant difference.
7.实验结果7. Experimental results
体重：体重变化见图2，给药期间，各组体重均上升。Body weight: body weight changes are shown in Figure 2. During the administration period, the body weight of each group increased.
机械阈值：机械缩足痛阈值统计见图3，给药期间，正常组50％PWT均显著高于模型组(p<0.01)，化合物III-2 3mg/kg组在给药第4、7天第1次给药后1小时，50％PWT均显著高于模型组(p<0.01，p<0.05)；停药后第3天(D10)，正常组50％PWT均显著高于模型组(p<0.01)，化合物III-2 3mg/kg 50％PWT均显著高于模型组(p<0.05)。Mechanical threshold: The statistics of mechanical foot withdrawal pain threshold are shown in Figure 3. During the administration period, the 50% PWT of the normal group was significantly higher than that of the model group (p<0.01), and the compound III-2 3mg/kg group was on the 4th and 7th day of administration 1 hour after the first administration, the 50% PWT of the normal group was significantly higher than that of the model group (p<0.01, p<0.05); on the 3rd day (D10) after drug withdrawal, the 50% PWT of the normal group was significantly higher than that of the model group ( p<0.01), compound III-2 3mg/kg 50%PWT were significantly higher than model group (p<0.05).
8.结论8. Conclusion
在实施例中，化合物III-2以3mg/kg剂量连续给药7天，每天2次给药，对紫杉醇诱导的大鼠足痛有显著缓解作用，且相对于正常组及模型组，体重无明显下降，说明该化合物在该剂量下具有较好的镇痛作用及安全性。In the embodiment, compound III-2 was administered continuously for 7 days with a dose of 3 mg/kg, administered twice a day, and it had a significant alleviating effect on paclitaxel-induced rat foot pain, and compared with the normal group and the model group, the body weight had no significantly decreased, indicating that the compound has better analgesic effect and safety at this dose.
发明人继续从第2部分剩余的20只造模动物中筛选10只成模动物大鼠，以HDAC抑制剂Vorinostat(SAHA)，按照化合物III-2的剂量(3mg/kg)以及给药周期与频率(Bid，7天)进行给药，试验结果显示，Vorinostat组动物体重无明显下降，但在给药第4、7天第1次给药后1小时，以及停药后第3天(D10)，50％PWT与模型组相比并无显著性差异，表明同等剂量条件下，Vorinostat对紫杉醇诱导的大鼠足痛并无显著缓解作用。The inventor continued to screen 10 model animal rats from the remaining 20 model animals in Part 2, and used the HDAC inhibitor Vorinostat (SAHA), according to the dose of compound III-2 (3mg/kg) and the administration cycle and Frequency (Bid, 7 days) was administered, and the test results showed that the animal body weight of the Vorinostat group had no significant decline, but 1 hour after the first administration on the 4th and 7th days of administration, and the 3rd day after drug withdrawal (D10 ), 50% PWT compared with the model group had no significant difference, indicating that under the same dose conditions, Vorinostat had no significant relief effect on paclitaxel-induced rat foot pain.

Claims (10)

  1. 式(I)所示化合物、其互变异构体或其药学上可接受的盐在制备治疗神经病理性疼痛药物中的应用，Application of a compound represented by formula (I), its tautomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating neuropathic pain,
    Figure PCTCN2022087341-appb-100001
    Figure PCTCN2022087341-appb-100001
    其中，R 1为一个或多个取代基， Wherein, R 1 is one or more substituents,
    R 1、R 2和R 3各自独立地是氢、卤素、C 1-10的烷基、含氧醚链、含氮烷链、R 4O-、R 4OC(O)-、R 4C(O)O-、-NH 2、-NO 2、羟氨基、R 4R 5N-、R 4CONH-、R 4NHCO-、胍基、脲基、三氟甲基、C 1-10的烷基磺酰基、取代苯磺酰基、取代苯基、苯基或杂环基； R 1 , R 2 and R 3 are each independently hydrogen, halogen, C 1-10 alkyl, oxygen-containing ether chain, nitrogen-containing alkyl chain, R 4 O-, R 4 OC(O)-, R 4 C (O)O-, -NH 2 , -NO 2 , hydroxylamino, R 4 R 5 N-, R 4 CONH-, R 4 NHCO-, guanidino, ureido, trifluoromethyl, C 1-10 Alkylsulfonyl, substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclic;
    R 4为C 1-10的烷基或苄基； R 4 is C 1-10 alkyl or benzyl;
    R 5为氢或C 1-10的烷基； R 5 is hydrogen or C 1-10 alkyl;
    Linker是键，或者-(CH 2) n-、-(CH 2) nO-、-O(CH 2) n-、-O(CH 2) nC(O)-、-C(O)(CH 2) nO-、-OC(O)(CH 2) n-、-(CH 2) nC(O)O-、-(CH 2) nC(O)NH-、-C(O)NH(CH 2) n-、-(CH 2) nSO 2-、-SO 2(CH 2) n-，或是取代苯磺酰基、取代苯基、苯基或杂环基； Linker is a bond, or -(CH 2 ) n -, -(CH 2 ) n O-, -O(CH 2 ) n -, -O(CH 2 ) n C(O)-, -C(O)( CH 2 ) n O-, -OC(O)(CH 2 ) n -, -(CH 2 ) n C(O)O-, -(CH 2 ) n C(O)NH-, -C(O) NH(CH 2 ) n -, -(CH 2 ) n SO 2 -, -SO 2 (CH 2 ) n -, or substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclic group;
    其中，n为1至10的整数；Wherein, n is an integer from 1 to 10;
    优选地，所述取代苯基的苯环上含有1至4个取代基，所述取代苯基的取代基是卤素、-OH、-NO 2、氰基、烷氧基、C 1-4的烷基或氨基基团， Preferably, the phenyl ring of the substituted phenyl group contains 1 to 4 substituents, and the substituents of the substituted phenyl group are halogen, -OH, -NO 2 , cyano, alkoxy, C 1-4 Alkyl or amino groups,
    优选地，所述杂环基是含一个或多个杂原子的饱和或不饱和的五元杂环基或六元杂环基，所述杂原子选自氮、氧或硫；Preferably, the heterocyclic group is a saturated or unsaturated five-membered heterocyclic group or six-membered heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen or sulfur;
    优选地，所述卤素是氟、氯、溴或碘，Preferably, said halogen is fluorine, chlorine, bromine or iodine,
    在上述基团中，所述C 1-10烷基是包含1-10个碳原子的直链、支链或环状的饱和烃，所述C 1-10烷基任选地被取代，例如是吡咯烷-1-基-C 2-10烷基、吗啉-1-基-C 2-10烷基或哌嗪-1-C 2-10烷基；优选地，所述C 1-10烷基是甲基、乙基、丙基、异丙基、环丙基、丁基、异丁基、仲-丁基、叔-丁基、环丁基、戊基、环戊基、己基、环己基、庚基、辛基、壬基或癸基， In the above groups, the C 1-10 alkyl group is a straight chain, branched chain or cyclic saturated hydrocarbon containing 1-10 carbon atoms, and the C 1-10 alkyl group is optionally substituted, for example Is pyrrolidin-1-yl-C 2-10 alkyl, morpholin-1-yl-C 2-10 alkyl or piperazine-1-C 2-10 alkyl; preferably, the C 1-10 Alkyl is methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, octyl, nonyl or decyl,
    优选地，所述R 4O-是苄氧基、吡咯烷-1-基-C 2-10烷氧基、吗啉-1-基-C 2-10烷氧基或哌嗪-1-C 2-10烷氧基； Preferably, the R 4 O- is benzyloxy, pyrrolidin-1-yl-C 2-10 alkoxy, morpholin-1-yl-C 2-10 alkoxy or piperazine-1-C 2-10 alkoxy;
    优选地，所述R 4OC(O)-是乙烷氧基羰基、丙烷氧基羰基、丁烷氧基羰基、异丁烷氧基羰基、戊烷氧基羰基、己烷氧基羰基、庚烷氧基羰基、辛烷氧基羰基、壬烷氧基羰基或癸烷氧基羰基， Preferably, said R 4 OC(O)- is ethoxycarbonyl, propaneoxycarbonyl, butaneoxycarbonyl, isobutaneoxycarbonyl, pentaneoxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, heptyloxycarbonyl, Alkoxycarbonyl, octaneoxycarbonyl, nonyloxycarbonyl or decanyloxycarbonyl,
    所述R 4C(O)O-是乙酯、丙酯、丁酯、异丁酯、戊酯、己酯、庚酯、辛酯、壬酯或癸酯， The R 4 C(O)O- is ethyl ester, propyl ester, butyl ester, isobutyl ester, pentyl ester, hexyl ester, heptyl ester, octyl ester, nonyl ester or decyl ester,
    优选地，所述R 4R 5N-是氨基乙基、1-氨基丙基、2-氨基丙基、1-氨基丁基、2-氨基丁基、1-氨基戊基、1-氨基己基、1-氨基庚基、1-氨基辛基、1-氨基壬基、1-氨基癸基、N- 甲氨基、N-乙胺基、N-丙氨基、N-丁氨基、N-戊氨基、N-己氨基、N-庚氨基、N-辛氨基、N-壬氨基或N-癸氨基， Preferably, the R 4 R 5 N- is aminoethyl, 1-aminopropyl, 2-aminopropyl, 1-aminobutyl, 2-aminobutyl, 1-aminopentyl, 1-aminohexyl , 1-aminoheptyl, 1-aminooctyl, 1-aminononyl, 1-aminodecyl, N-methylamino, N-ethylamino, N-propylamino, N-butylamino, N-pentylamino , N-hexylamino, N-heptylamino, N-octylamino, N-nonylamino or N-decylamino,
    优选地，所述R 4CONH-是乙酰胺基、丙酰胺基、丁酰胺基、异丁酰胺基、戊酰胺基、己酰胺基、庚酰胺基、辛酰胺基、壬酰胺基或癸酰胺基； Preferably, the R 4 CONH- is acetamide, propionyl, butyramide, isobutyramide, pentylamide, caproylamide, heptylamide, octanylamide, nonylamide or decanylamide ;
    所述C 1-10的烷基磺酰基是如上定义的C 1-10烷基与磺酰基相连，并且经由磺酰基与式(I)连接；优选地，所述C 1-10的烷磺酰基是甲磺酰基、乙磺酰基、丙磺酰基、异丙磺酰基、丁磺酰基、戊磺酰基、己磺酰基、庚磺酰基、辛磺酰基、壬磺酰基或癸磺酰基。 The C 1-10 alkylsulfonyl group is a C 1-10 alkyl group as defined above connected to a sulfonyl group, and connected to formula (I) via a sulfonyl group; preferably, the C 1-10 alkylsulfonyl group is methylsulfonyl, ethylsulfonyl, propanesulfonyl, isopropylsulfonyl, butanesulfonyl, pentanesulfonyl, hexylsulfonyl, heptylsulfonyl, octanesulfonyl, nonylsulfonyl or decanesulfonyl.
  2. 式(II)所示化合物、其互变异构体或其药学上可接受的盐在制备治疗神经病理性疼痛药物中的应用，The application of the compound represented by formula (II), its tautomer or its pharmaceutically acceptable salt in the preparation of medicine for treating neuropathic pain,
    Figure PCTCN2022087341-appb-100002
    Figure PCTCN2022087341-appb-100002
    其中，R 2、R 3各自独立地是氢、卤素、C 1-10的烷基、含氧醚链、含氮烷链、R 4O-、R 4OC(O)-、R 4C(O)O-、-NH 2、-NO 2、羟氨基、R 4NHR 5、R 4CONH-、R 4NHCO-、胍基、脲基、三氟甲基、C 1-10的烷磺酰基、取代苯磺酰基、取代苯基、苯基或杂环基，其中R 4为C 1-10的烷基或苄基，R 5为氢或C 1-10的烷基；优选地，R 2、R 3各自独立地是氢或C 1-6的烷基；更优选地，R 2、R 3各自独立地是氢或C 1-4的烷基；最优选地，R 2、R 3各自独立地是氢或甲基， Wherein, R 2 and R 3 are each independently hydrogen, halogen, C 1-10 alkyl, oxygen-containing ether chain, nitrogen-containing alkane chain, R 4 O-, R 4 OC(O)-, R 4 C( O)O-, -NH 2 , -NO 2 , hydroxylamino, R 4 NHR 5 , R 4 CONH-, R 4 NHCO-, guanidino, ureido, trifluoromethyl, C 1-10 alkylsulfonyl , substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclic group, wherein R 4 is C 1-10 alkyl or benzyl, R 5 is hydrogen or C 1-10 alkyl; preferably, R 2 , R 3 are each independently hydrogen or C 1-6 alkyl; more preferably, R 2 , R 3 are each independently hydrogen or C 1-4 alkyl; most preferably, R 2 , R 3 are each are independently hydrogen or methyl,
    Linker是键；-(CH 2) n-、-(CH 2) nO-、-O(CH 2) n-、-O(CH 2) nC(O)-、-C(O)(CH 2) nO-、-OC(O)(CH 2) n-、-(CH 2) nC(O)O-、-(CH 2) nC(O)NH-、-C(O)NH(CH 2) n-、-(CH 2) nSO 2、-SO 2(CH 2) n-，其中n为1至10的整数；或是取代苯磺酰基、取代苯基、苯基或杂环基， Linker is a bond; -(CH 2 ) n -, -(CH 2 ) n O-, -O(CH 2 ) n -, -O(CH 2 ) n C(O)-, -C(O)(CH 2 ) n O-, -OC(O)(CH 2 ) n -, -(CH 2 ) n C(O)O-, -(CH 2 ) n C(O)NH-, -C(O)NH (CH 2 ) n -, -(CH 2 ) n SO 2 , -SO 2 (CH 2 ) n -, wherein n is an integer from 1 to 10; or substituted benzenesulfonyl, substituted phenyl, phenyl or hetero ring group,
    优选地，所述取代苯基的苯环上含有1至4个取代基，所述取代苯基的取代基是卤素、-OH、-NO 2、氰基、烷氧基、C 1-4的烷基或氨基基团， Preferably, the phenyl ring of the substituted phenyl group contains 1 to 4 substituents, and the substituents of the substituted phenyl group are halogen, -OH, -NO 2 , cyano, alkoxy, C 1-4 Alkyl or amino groups,
    优选地，所述杂环基是含一个或多个杂原子的饱和或不饱和的五元杂环基或六元杂环基，所述杂原子选自氮、氧或硫；Preferably, the heterocyclic group is a saturated or unsaturated five-membered heterocyclic group or six-membered heterocyclic group containing one or more heteroatoms selected from nitrogen, oxygen or sulfur;
    优选地，所述卤素是氟、氯、溴或碘，Preferably, said halogen is fluorine, chlorine, bromine or iodine,
    优选地，Linker是-(CH 2) n-，其中n为1至10的整数；或是-(CH 2) mC 6H 4-、-C 6H 4(CH 2) m-，其中m为0至5的整数；或是含1或2个杂原子的饱和或不饱和的五元杂环基或六元杂环基，所述杂原子选自氮；更优选地，Linker是-(CH 2) n-，其中n为1至5的整数；或是-(CH 2) mC 6H 4-，其中m为0至5的整数；或是含1或2个氮原子的饱和或不饱和的六元杂环基，优选含1个氮原子的不饱和的六元杂环基。 Preferably, Linker is -(CH 2 ) n -, wherein n is an integer from 1 to 10; or -(CH 2 ) m C 6 H 4 -, -C 6 H 4 (CH 2 ) m -, wherein m is an integer from 0 to 5; or a saturated or unsaturated five-membered heterocyclic group or six-membered heterocyclic group containing 1 or 2 heteroatoms, the heteroatoms being selected from nitrogen; more preferably, Linker is -( CH 2 ) n -, wherein n is an integer from 1 to 5; or -(CH 2 ) m C 6 H 4 -, wherein m is an integer from 0 to 5; or a saturated or An unsaturated six-membered heterocyclic group, preferably an unsaturated six-membered heterocyclic group containing one nitrogen atom.
  3. 根据权利要求1或2所述的应用，其特征在于，所述化合物选自于：The application according to claim 1 or 2, wherein the compound is selected from:
    (II-1)N-羟基-2-(4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)乙酰胺(II-1) N-Hydroxy-2-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)acetamide
    Figure PCTCN2022087341-appb-100003
    Figure PCTCN2022087341-appb-100003
    (II-2)N-羟基-4-(4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)丁酰胺(II-2) N-Hydroxy-4-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)butanamide
    Figure PCTCN2022087341-appb-100004
    Figure PCTCN2022087341-appb-100004
    (II-3)N-羟基-5-(4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)戊酰胺(II-3) N-Hydroxy-5-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pentanamide
    Figure PCTCN2022087341-appb-100005
    Figure PCTCN2022087341-appb-100005
    (II-4)N-羟基-6-(4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)己酰胺(II-4) N-Hydroxy-6-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)caproamide
    Figure PCTCN2022087341-appb-100006
    Figure PCTCN2022087341-appb-100006
    (II-5)N-羟基-4-((4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)甲基)苯甲酰胺(II-5) N-Hydroxy-4-((4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)methyl)benzamide
    Figure PCTCN2022087341-appb-100007
    Figure PCTCN2022087341-appb-100007
    (II-6)N-羟基-4-(4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)苯甲酰胺(II-6) N-Hydroxy-4-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)benzamide
    Figure PCTCN2022087341-appb-100008
    Figure PCTCN2022087341-appb-100008
    (II-7)N-羟基-6-(4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)烟酰胺(II-7) N-Hydroxy-6-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)nicotinamide
    Figure PCTCN2022087341-appb-100009
    Figure PCTCN2022087341-appb-100009
    (II-8)N-羟基-5-(4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)吡啶酰胺(II-8) N-Hydroxy-5-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyridineamide
    Figure PCTCN2022087341-appb-100010
    Figure PCTCN2022087341-appb-100010
    (II-9)N-羟基-2-(4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)嘧啶-5-酰胺(II-9) N-Hydroxy-2-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrimidine-5-amide
    Figure PCTCN2022087341-appb-100011
    Figure PCTCN2022087341-appb-100011
    (II-10)N-羟基-5-(4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)嘧啶-2-酰胺(II-10) N-Hydroxy-5-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrimidine-2-amide
    Figure PCTCN2022087341-appb-100012
    Figure PCTCN2022087341-appb-100012
    (II-11)N-羟基-5-(4-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基吡嗪-2-酰胺(II-11) N-Hydroxy-5-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxypyrazine-2-amide
    Figure PCTCN2022087341-appb-100013
    Figure PCTCN2022087341-appb-100013
    (II-12)N-羟基-2-(4-(甲基(4-喹唑啉基)氨基)苯氧基)乙酰胺(II-12) N-Hydroxy-2-(4-(methyl(4-quinazolinyl)amino)phenoxy)acetamide
    Figure PCTCN2022087341-appb-100014
    Figure PCTCN2022087341-appb-100014
    (II-13)N-羟基-4-(4-(甲基(4-喹唑啉基)氨基)苯氧基)丁酰胺(II-13) N-Hydroxy-4-(4-(methyl(4-quinazolinyl)amino)phenoxy)butanamide
    Figure PCTCN2022087341-appb-100015
    Figure PCTCN2022087341-appb-100015
    (II-14)N-羟基-5-(4-(甲基(4-喹唑啉基)氨基)苯氧基)戊酰胺(II-14) N-Hydroxy-5-(4-(methyl(4-quinazolinyl)amino)phenoxy)pentanamide
    Figure PCTCN2022087341-appb-100016
    Figure PCTCN2022087341-appb-100016
    (II-15)N-羟基-6-(4-(甲基(4-喹唑啉基)氨基)苯氧基)己酰胺(II-15) N-Hydroxy-6-(4-(methyl(4-quinazolinyl)amino)phenoxy)hexanamide
    Figure PCTCN2022087341-appb-100017
    Figure PCTCN2022087341-appb-100017
    (II-16)N-羟基-4-((4-(甲基(4-喹唑啉基)氨基)苯氧基)甲基)苯甲酰胺(II-16) N-Hydroxy-4-((4-(methyl(4-quinazolinyl)amino)phenoxy)methyl)benzamide
    Figure PCTCN2022087341-appb-100018
    Figure PCTCN2022087341-appb-100018
    (II-17)N-羟基-4-(4-(甲基(4-喹唑啉基)氨基)苯氧基)苯甲酰胺(II-17) N-Hydroxy-4-(4-(methyl(4-quinazolinyl)amino)phenoxy)benzamide
    Figure PCTCN2022087341-appb-100019
    Figure PCTCN2022087341-appb-100019
    (II-18)N-羟基-6-(4-(甲基(4-喹唑啉基)氨基)苯氧基)烟酰胺(II-18) N-Hydroxy-6-(4-(methyl(4-quinazolinyl)amino)phenoxy)nicotinamide
    Figure PCTCN2022087341-appb-100020
    Figure PCTCN2022087341-appb-100020
    (II-19)N-羟基-5-(4-(甲基(4-喹唑啉基)氨基)苯氧基吡啶酰胺(II-19) N-Hydroxy-5-(4-(methyl(4-quinazolinyl)amino)phenoxypyridineamide
    Figure PCTCN2022087341-appb-100021
    Figure PCTCN2022087341-appb-100021
    (II-20)N-羟基-2-(4-(甲基(4-喹唑啉基)氨基)苯氧基)嘧啶-5-甲酰胺(II-20) N-Hydroxy-2-(4-(methyl(4-quinazolinyl)amino)phenoxy)pyrimidine-5-carboxamide
    Figure PCTCN2022087341-appb-100022
    Figure PCTCN2022087341-appb-100022
    (II-21)N-羟基-5-(4-(甲基(4-喹唑啉基)氨基)苯氧基)嘧啶-2-甲酰胺(II-21) N-Hydroxy-5-(4-(methyl(4-quinazolinyl)amino)phenoxy)pyrimidine-2-carboxamide
    Figure PCTCN2022087341-appb-100023
    Figure PCTCN2022087341-appb-100023
    (II-22)N-羟基-5-(4-(甲基(4-喹唑啉基)氨基)苯氧基)吡嗪-2-甲酰胺(II-22) N-Hydroxy-5-(4-(methyl(4-quinazolinyl)amino)phenoxy)pyrazine-2-carboxamide
    Figure PCTCN2022087341-appb-100024
    Figure PCTCN2022087341-appb-100024
    (II-23)N-羟基-2-(4-((2-甲基-4-喹唑啉基)氨基)苯氧基)乙酰胺(II-23) N-Hydroxy-2-(4-((2-methyl-4-quinazolinyl)amino)phenoxy)acetamide
    Figure PCTCN2022087341-appb-100025
    Figure PCTCN2022087341-appb-100025
    (II-24)N-羟基-3-(4-((2-甲基-4-喹唑啉基)氨基)苯氧基)丙酰胺(II-24) N-Hydroxy-3-(4-((2-methyl-4-quinazolinyl)amino)phenoxy)propionamide
    Figure PCTCN2022087341-appb-100026
    Figure PCTCN2022087341-appb-100026
    (II-25)N-羟基-4-(4-((2-甲基-4-喹唑啉基)氨基)苯氧基)丁酰胺(II-25) N-Hydroxy-4-(4-((2-methyl-4-quinazolinyl)amino)phenoxy)butanamide
    Figure PCTCN2022087341-appb-100027
    Figure PCTCN2022087341-appb-100027
    (II-26)N-羟基-5-(4-((2-甲基-4-喹唑啉基)氨基)苯氧基)戊酰胺(II-26) N-Hydroxy-5-(4-((2-methyl-4-quinazolinyl)amino)phenoxy)pentanamide
    Figure PCTCN2022087341-appb-100028
    Figure PCTCN2022087341-appb-100028
    (II-27)N-羟基-6-(4-((2-甲基-4-喹唑啉基)氨基)苯氧基)己酰胺(II-27) N-Hydroxy-6-(4-((2-methyl-4-quinazolinyl)amino)phenoxy)hexanamide
    Figure PCTCN2022087341-appb-100029
    Figure PCTCN2022087341-appb-100029
  4. 式(III)所示化合物、其互变异构体或其药学上可接受的盐在制备治疗神经病理性疼痛药物中的应用，The application of the compound represented by formula (III), its tautomer or its pharmaceutically acceptable salt in the preparation of medicine for treating neuropathic pain,
    Figure PCTCN2022087341-appb-100030
    Figure PCTCN2022087341-appb-100030
    其中，R 1、R 2、R 3各自独立地是氢、卤素、C 1-10的烷基、含氧醚链、含氮烷链、R 4O-、R 4OC(O)-、R 4C(O)O-、-NH 2、-NO 2、羟氨基、R 4NHR 5、R 4CONH-、R 4NHCO-、胍基、脲基、三氟甲基、C 1-10的烷磺酰基、取代苯磺酰基、取代苯基、苯基或杂环基，其中R 4为C 1-10的烷基或苄基，R 5为氢或C 1-10的烷基；优选地，R 1是氢或C 1-6烷氧基；更优选地，R 1是氢或C 1-4烷氧基；最优选地，R 1是氢或甲氧基；优选地，R 2、R 3独立地是氢或C 1-6烷基；更优选地，R 2、R 3独立地是氢或C 1-4烷基；最优选地，R 2、R 3独立地是氢或甲基， Wherein, R 1 , R 2 , and R 3 are each independently hydrogen, halogen, C 1-10 alkyl, oxygen-containing ether chain, nitrogen-containing alkyl chain, R 4 O-, R 4 OC(O)-, R 4 C(O)O-, -NH 2 , -NO 2 , hydroxylamino, R 4 NHR 5 , R 4 CONH-, R 4 NHCO-, guanidino, ureido, trifluoromethyl, C 1-10 Alkylsulfonyl, substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclic group, wherein R 4 is C 1-10 alkyl or benzyl, R 5 is hydrogen or C 1-10 alkyl; preferably , R 1 is hydrogen or C 1-6 alkoxy; more preferably, R 1 is hydrogen or C 1-4 alkoxy; most preferably, R 1 is hydrogen or methoxy; preferably, R 2 , R 3 is independently hydrogen or C 1-6 alkyl; more preferably, R 2 and R 3 are independently hydrogen or C 1-4 alkyl; most preferably, R 2 and R 3 are independently hydrogen or methane base,
    Linker是键；-(CH 2) n-、-(CH 2) nO-、-O(CH 2) n-、-O(CH 2) nC(O)-、-C(O)(CH 2) nO-、-OC(O)(CH 2) n-、-(CH 2) nC(O)O-、-(CH 2) nC(O)NH-、-C(O)NH(CH 2) n-、-(CH 2) nSO 2-、-SO 2(CH 2) n-，其中n为1至10的整数；或是取代苯磺酰基、取代苯基、苯基或杂环基， Linker is a bond; -(CH 2 ) n -, -(CH 2 ) n O-, -O(CH 2 ) n -, -O(CH 2 ) n C(O)-, -C(O)(CH 2 ) n O-, -OC(O)(CH 2 ) n -, -(CH 2 ) n C(O)O-, -(CH 2 ) n C(O)NH-, -C(O)NH (CH 2 ) n -, -(CH 2 ) n SO 2 -, -SO 2 (CH 2 ) n -, wherein n is an integer from 1 to 10; or substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclyl,
    优选地，所述取代苯基的苯环上含有1至4个取代基，所述取代苯基的取代基是卤素、-OH、-NO 2、氰基、烷氧基、C 1-4的烷基或氨基基团， Preferably, the phenyl ring of the substituted phenyl group contains 1 to 4 substituents, and the substituents of the substituted phenyl group are halogen, -OH, -NO 2 , cyano, alkoxy, C 1-4 Alkyl or amino groups,
    优选地，所述杂环基是含一个或多个杂原子的饱和或不饱和的五元杂环基或六元杂环 基，所述杂原子选自氮、氧或硫；Preferably, the heterocyclic group is a saturated or unsaturated five-membered heterocyclic group or a six-membered heterocyclic group containing one or more heteroatoms, the heteroatoms being selected from nitrogen, oxygen or sulfur;
    优选地，所述卤素是氟、氯、溴或碘，Preferably, said halogen is fluorine, chlorine, bromine or iodine,
    优选地，Linker是-(CH 2) nO-、-O(CH 2) n-，其中n为1至10的整数；更优选地，Linker是-(CH 2) nO-，其中n为1至10的整数；最优选地，Linker是-(CH 2) nO-，其中n为1至5的整数。 Preferably, the Linker is -(CH 2 ) n O-, -O(CH 2 ) n -, wherein n is an integer from 1 to 10; more preferably, the Linker is -(CH 2 ) n O-, wherein n is An integer of 1 to 10; most preferably, the Linker is -(CH 2 ) n O—, where n is an integer of 1 to 5.
  5. 根据权利要求1或3所述的应用，其特征在于，所述化合物选自于：The application according to claim 1 or 3, wherein the compound is selected from:
    (III-1)N-羟基-2-(2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)乙酰胺(III-1) N-Hydroxy-2-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)acetamide
    Figure PCTCN2022087341-appb-100031
    Figure PCTCN2022087341-appb-100031
    (III-2)N-羟基-4-(2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)丁酰胺(III-2) N-Hydroxy-4-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)butanamide
    Figure PCTCN2022087341-appb-100032
    Figure PCTCN2022087341-appb-100032
    (III-3)N-羟基-5-(2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)戊酰胺(III-3) N-Hydroxy-5-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pentanamide
    Figure PCTCN2022087341-appb-100033
    Figure PCTCN2022087341-appb-100033
    (III-4)N-羟基-6-(2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)己酰胺(III-4) N-Hydroxy-6-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)caproamide
    Figure PCTCN2022087341-appb-100034
    Figure PCTCN2022087341-appb-100034
    (III-5)N-羟基-4-((2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)甲基)苯甲酰胺(III-5) N-Hydroxy-4-((2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)methyl)benzamide
    Figure PCTCN2022087341-appb-100035
    Figure PCTCN2022087341-appb-100035
    (III-6)N-羟基-4-(2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)苯甲酰 胺(III-6) N-Hydroxy-4-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)benzamide
    Figure PCTCN2022087341-appb-100036
    Figure PCTCN2022087341-appb-100036
    (III-7)N-羟基-6-(2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)烟酰胺(III-7) N-Hydroxy-6-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)nicotinamide
    Figure PCTCN2022087341-appb-100037
    Figure PCTCN2022087341-appb-100037
    (III-8)N-羟基-5-(2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)吡啶酰胺(III-8) N-Hydroxy-5-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyridineamide
    Figure PCTCN2022087341-appb-100038
    Figure PCTCN2022087341-appb-100038
    (III-9)N-羟基-2-(2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)嘧啶-5-甲酰胺(III-9) N-Hydroxy-2-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrimidine-5-carboxamide
    Figure PCTCN2022087341-appb-100039
    Figure PCTCN2022087341-appb-100039
    (III-10)N-羟基-5-(2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)嘧啶-2-甲酰胺(III-10) N-Hydroxy-5-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrimidine-2-carboxamide
    Figure PCTCN2022087341-appb-100040
    Figure PCTCN2022087341-appb-100040
    (III-11)N-羟基-5-(2-甲氧基-5-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)吡嗪 -2-甲酰胺(III-11) N-Hydroxy-5-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrazine-2-carboxamide
    Figure PCTCN2022087341-appb-100041
    Figure PCTCN2022087341-appb-100041
    (III-12)N-羟基-2-(3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)乙酰胺(III-12) N-Hydroxy-2-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)acetamide
    Figure PCTCN2022087341-appb-100042
    Figure PCTCN2022087341-appb-100042
    (III-13)N-羟基-4-(3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)丁酰胺(III-13) N-Hydroxy-4-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)butanamide
    Figure PCTCN2022087341-appb-100043
    Figure PCTCN2022087341-appb-100043
    (III-14)N-羟基-5-(3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)戊酰胺(III-14) N-Hydroxy-5-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pentanamide
    Figure PCTCN2022087341-appb-100044
    Figure PCTCN2022087341-appb-100044
    (III-15)N-羟基-6-(3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)己酰胺(III-15) N-Hydroxy-6-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)caproamide
    Figure PCTCN2022087341-appb-100045
    Figure PCTCN2022087341-appb-100045
    (III-16)N-羟基-4-((3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)甲基)苯甲酰胺(III-16) N-Hydroxy-4-((3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)methyl)benzamide
    Figure PCTCN2022087341-appb-100046
    Figure PCTCN2022087341-appb-100046
    (III-17)N-羟基-4-(3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)苯甲酰胺(III-17) N-Hydroxy-4-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)benzamide
    Figure PCTCN2022087341-appb-100047
    Figure PCTCN2022087341-appb-100047
    (III-18)N-羟基-6-(3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)烟酰胺(III-18) N-Hydroxy-6-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)nicotinamide
    Figure PCTCN2022087341-appb-100048
    Figure PCTCN2022087341-appb-100048
    (III-19)N-羟基-5-(3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)吡啶酰胺(III-19) N-Hydroxy-5-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyridineamide
    Figure PCTCN2022087341-appb-100049
    Figure PCTCN2022087341-appb-100049
    (III-20)N-羟基-2-(3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)嘧啶-5-甲酰胺(III-20) N-Hydroxy-2-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrimidine-5-carboxamide
    Figure PCTCN2022087341-appb-100050
    Figure PCTCN2022087341-appb-100050
    (III-21)N-羟基-5-(3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)嘧啶-2-甲酰胺(III-21) N-Hydroxy-5-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrimidine-2-carboxamide
    Figure PCTCN2022087341-appb-100051
    Figure PCTCN2022087341-appb-100051
    (III-22)N-羟基-5-(3-(甲基(2-甲基-4-喹唑啉基)氨基)苯氧基)吡嗪-2-甲酰胺(III-22) N-Hydroxy-5-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrazine-2-carboxamide
    Figure PCTCN2022087341-appb-100052
    Figure PCTCN2022087341-appb-100052
  6. 式(IV)所示化合物、其互变异构体或其药学上可接受的盐在制备治疗神经病理性疼痛药物中的应用，The application of the compound represented by formula (IV), its tautomer or its pharmaceutically acceptable salt in the preparation of medicine for treating neuropathic pain,
    Figure PCTCN2022087341-appb-100053
    Figure PCTCN2022087341-appb-100053
    其中，R 2独立地是氢、卤素、C 1-10的烷基、含氧醚链、含氮烷链、R 4O-、R 4OC(O)-、R 4C(O)O-、-NH 2、-NO 2、羟氨基、R 4-O-CH 2-、R 4-O-CH 2-O-CH 2-、R 4NHR 5、R 4CONH-、R 4NHCO-、胍基、脲基、三氟甲基、C 1-10的烷磺酰基、取代苯磺酰基、取代苯基、苯基或杂环基，其中R 4为C 1-10的烷基或苄基，R 5为氢或C 1-10的烷基；优选地，R 2独立地是氢或C 1-6烷基。 Wherein, R 2 is independently hydrogen, halogen, C 1-10 alkyl, oxygen-containing ether chain, nitrogen-containing alkyl chain, R 4 O-, R 4 OC(O)-, R 4 C(O)O- , -NH 2 , -NO 2 , Hydroxyamino, R 4 -O-CH 2 -, R 4 -O-CH 2 -O-CH 2 -, R 4 NHR 5 , R 4 CONH-, R 4 NHCO-, Guanidino, ureido, trifluoromethyl, C 1-10 alkylsulfonyl, substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclic group, wherein R is C 1-10 alkyl or benzyl , R 5 is hydrogen or C 1-10 alkyl; preferably, R 2 is independently hydrogen or C 1-6 alkyl.
  7. 根据权利要求1或6所述的应用，其特征在于，所述化合物选自于：The application according to claim 1 or 6, wherein the compound is selected from:
    (IV-1)4-(5-(乙基(2-甲基-4-喹唑啉基)氨基)-2-甲氧基苯基)-N-羟基丁酰胺(IV-1) 4-(5-(Ethyl(2-methyl-4-quinazolinyl)amino)-2-methoxyphenyl)-N-hydroxybutyramide
    Figure PCTCN2022087341-appb-100054
    Figure PCTCN2022087341-appb-100054
    (IV-2)N-羟基-4-(2-甲氧基-5-((2-甲基-4-喹唑啉基)(丙基)氨基)苯氧基)丁酰胺(IV-2) N-Hydroxy-4-(2-methoxy-5-((2-methyl-4-quinazolinyl)(propyl)amino)phenoxy)butanamide
    Figure PCTCN2022087341-appb-100055
    Figure PCTCN2022087341-appb-100055
    (IV-3)4-(5-(丁基(2-甲基-4-喹唑啉基)氨基)-2-甲氧基苯基)-N-羟基丁酰胺(IV-3) 4-(5-(Butyl(2-methyl-4-quinazolinyl)amino)-2-methoxyphenyl)-N-hydroxybutyramide
    Figure PCTCN2022087341-appb-100056
    Figure PCTCN2022087341-appb-100056
    (IV-4)N-羟基-4-(2-甲氧基-5-((2-甲基-4-喹唑啉基)(戊基)氨基)苯氧基)丁酰胺(IV-4) N-Hydroxy-4-(2-methoxy-5-((2-methyl-4-quinazolinyl)(pentyl)amino)phenoxy)butanamide
    Figure PCTCN2022087341-appb-100057
    Figure PCTCN2022087341-appb-100057
    (IV-5)N-羟基-4-(2-甲氧基-5-((甲氧基甲基)(2-甲基-4-喹唑啉基)氨基)苯氧基)丁酰胺(IV-5) N-Hydroxy-4-(2-methoxy-5-((methoxymethyl)(2-methyl-4-quinazolinyl)amino)phenoxy)butanamide
    Figure PCTCN2022087341-appb-100058
    Figure PCTCN2022087341-appb-100058
    (IV-6)N-羟基-4-(2-甲氧基-5-(((甲氧基甲氧基)甲基)(2-甲基-4-喹唑啉基)氨基)苯氧基)丁酰胺(IV-6) N-Hydroxy-4-(2-methoxy-5-(((methoxymethoxy)methyl)(2-methyl-4-quinazolinyl)amino)phenoxy base) butanamide
    Figure PCTCN2022087341-appb-100059
    Figure PCTCN2022087341-appb-100059
  8. 药物组合物在制备治疗神经病理性疼痛药物中的应用，所述药物组合物包含根据权利要求1-7任一项所述的化合物，以及药学上可接受的辅料；The application of a pharmaceutical composition in the preparation of a drug for the treatment of neuropathic pain, the pharmaceutical composition comprising the compound according to any one of claims 1-7, and pharmaceutically acceptable auxiliary materials;
    优选地，所述药物组合物为片剂、栓剂、分散片、肠溶片、咀嚼片、口崩片、胶囊、糖衣剂、颗粒剂、干粉剂、口服溶液剂、注射用小针、注射用冻干粉针或大输液；Preferably, the pharmaceutical composition is tablet, suppository, dispersible tablet, enteric-coated tablet, chewable tablet, orally disintegrating tablet, capsule, sugar-coated agent, granule, dry powder, oral solution, small needle for injection, injection Freeze-dried powder injection or large infusion;
    优选地，所述药学上可接受的辅料包括下述的一种或多种：稀释剂、增溶剂、崩解剂、悬浮剂、润滑剂、粘合剂、填充剂、矫味剂、甜味剂、抗氧化剂、表面活性剂、防腐剂、包裹剂或色素。Preferably, the pharmaceutically acceptable excipients include one or more of the following: diluents, solubilizers, disintegrants, suspending agents, lubricants, binders, fillers, flavoring agents, sweeteners agents, antioxidants, surfactants, preservatives, coatings or pigments.
  9. 根据权利要求1-8任意一项所述的应用，其特征在于，所述神经病理性疼痛选自慢性背疼、疱疹后遗神经痛、糖尿病性神经病理性疼痛、肌纤维痛、与化疗药物诱导的神经病理性疼痛；具体地，所述神经病理性疼痛选自糖尿病性神经病理性肢体疼痛和化疗药物诱导的肢体疼痛。The use according to any one of claims 1-8, wherein the neuropathic pain is selected from chronic back pain, postherpetic neuralgia, diabetic neuropathic pain, fibromyalgia, and neuropathy induced by chemotherapy drugs Rational pain; specifically, the neuropathic pain is selected from diabetic neuropathic limb pain and chemotherapy drug-induced limb pain.
  10. 根据权利要求9所述的应用，其特征在于，所述化合物为如下式所示化合物III-2，所述疼痛为糖尿病性神经病理性疼痛与化疗药物诱导的神经病理性疼痛，The application according to claim 9, characterized in that the compound is compound III-2 shown in the following formula, and the pain is diabetic neuropathic pain and chemotherapeutic drug-induced neuropathic pain,
    Figure PCTCN2022087341-appb-100060
    Figure PCTCN2022087341-appb-100060
PCT/CN2022/087341 2021-05-12 2022-04-18 Use of 4-arylaminoquinazoline hydroxamic acid compounds in preparation of pain drug WO2022237456A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280033602.XA CN117412752A (en) 2021-05-12 2022-04-18 Application of 4-arylaminoquinazoline hydroxamic acid compound in preparation of pain medicines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110514943 2021-05-12
CN202110514943.6 2021-05-12

Publications (1)

Publication Number Publication Date
WO2022237456A1 true WO2022237456A1 (en) 2022-11-17

Family

ID=84028812

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/087341 WO2022237456A1 (en) 2021-05-12 2022-04-18 Use of 4-arylaminoquinazoline hydroxamic acid compounds in preparation of pain drug

Country Status (2)

Country Link
CN (1) CN117412752A (en)
WO (1) WO2022237456A1 (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1784391A (en) * 2003-03-03 2006-06-07 沃泰克斯药物股份有限公司 Quinazolines useful as modulators of ion channels
CN101142195A (en) * 2005-01-07 2008-03-12 伊斯特芬博士实验室有限公司 Substituted 2-amino-quinazolin-4-on compoundsfor use in the treatment of C N S disorders, pain, stroke, addicition and epilepsy, their preparation and use as intermediates
US20090111772A1 (en) * 2007-09-10 2009-04-30 Xiong Cai Formulation of quinazoline based egfr inhibitors containing a zinc binding moiety
CN105669567A (en) * 2015-12-28 2016-06-15 上海应用技术学院 Tyrosine kinase inhibitor, preparation method and application thereof
WO2016146074A1 (en) * 2015-03-18 2016-09-22 广东众生药业股份有限公司 Histone deacetylase inhibitor, and preparation method and use thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1784391A (en) * 2003-03-03 2006-06-07 沃泰克斯药物股份有限公司 Quinazolines useful as modulators of ion channels
CN101142195A (en) * 2005-01-07 2008-03-12 伊斯特芬博士实验室有限公司 Substituted 2-amino-quinazolin-4-on compoundsfor use in the treatment of C N S disorders, pain, stroke, addicition and epilepsy, their preparation and use as intermediates
US20090111772A1 (en) * 2007-09-10 2009-04-30 Xiong Cai Formulation of quinazoline based egfr inhibitors containing a zinc binding moiety
WO2016146074A1 (en) * 2015-03-18 2016-09-22 广东众生药业股份有限公司 Histone deacetylase inhibitor, and preparation method and use thereof
CN105669567A (en) * 2015-12-28 2016-06-15 上海应用技术学院 Tyrosine kinase inhibitor, preparation method and application thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KRUKOWSKI, K. ET AL.: "HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy.", PAIN., vol. 158, no. 6, 1 June 2018 (2018-06-01) *
LAWRENCE VAN HELLEPUTTE, MANDY KATER, DANA P. COOK, CAROLINE EYKENS, ELISABETH ROSSAERT, WANDA HAECK, TOM JASPERS, NATASJA GEENS, : "Inhibition of histone deacetylase 6 (HDAC6) protects against vincristine-induced peripheral neuropathies and inhibits tumor growth", NEUROBIOLOGY OF DISEASE, ELSEVIER, AMSTERDAM, NL, vol. 111, 1 March 2018 (2018-03-01), AMSTERDAM, NL , pages 59 - 69, XP055465564, ISSN: 0969-9961, DOI: 10.1016/j.nbd.2017.11.011 *

Also Published As

Publication number Publication date
CN117412752A (en) 2024-01-16

Similar Documents

Publication Publication Date Title
US20240067600A1 (en) SMALL MOLECULE INHIBITORS OF THE MITOCHONDRIAL PERMEABILITY TRANSITION PORE (mtPTP)
Smith et al. Drugs in anaesthesia and intensive care
CA2641880C (en) Treatment of duchenne muscular dystrophy
US10590079B2 (en) Cyano-substituted indoles as LSD1 inhibitors
JP2019006834A (en) Toxic aldehyde-related diseases and treatment
US20170313719A1 (en) Thieno[2,3-D]pyrimidin-4-one Derivatives as NMDAR Modulators and Uses Related Thereto
US20140187579A1 (en) Tip60 inhibitors
EP1746099A1 (en) Mnk1 or Mnk2 inhibitors
EP2995617B1 (en) Benzoisothiazole compounds and use in preparation of antipsychotic drugs
ES2532210T3 (en) Methods for the concomitant treatment of theophylline and febuxostat
CN110290789B (en) Bicyclic inhibitors of histone deacetylase
JPWO2010053120A1 (en) Carbamate compound or salt thereof
BRPI1008727B1 (en) substituted azole derivative, monoamine oxidase b (maob) inhibitor and pharmaceutical composition containing the derivatives for the treatment of parkinson&#39;s disease
CA3026322C (en) Novel b-lactamase inhibitors
EP2681209B1 (en) Compounds and methods for the treatment of pain and other disorders
WO2022237456A1 (en) Use of 4-arylaminoquinazoline hydroxamic acid compounds in preparation of pain drug
WO2018045969A1 (en) Compound for activating adenosine monophosphate-activated protein kinase
US11084795B2 (en) CFTR regulators and methods of use thereof
US8530453B2 (en) Compounds and methods for the treatment of pain and other diseases
US20230051850A1 (en) Compositions and methods for reducing tactile dysfunction, anxiety, and social impairment
US9505743B2 (en) Matrix metalloproteinase inhibitors and methods for the treatment of pain and other diseases
BR112015025033B1 (en) Compound and its use as a pde-5 inhibitor, as well as a pharmaceutical preparation comprising said compound
WO2018081556A1 (en) Pharmaceutical combinations comprising a histone deacetylase inhibitor and epothilone and methods of use thereof
WO2022197993A1 (en) Inhibitors of the peptidyl-prolyl cis/trans isomerase (pin1) and uses thereof
WO2024050434A1 (en) ISOQUINOLINE COMPOUNDS AND THEIR USE IN TREATING AhR MEDIATED DISEASES

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22806426

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202280033602.X

Country of ref document: CN

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22806426

Country of ref document: EP

Kind code of ref document: A1