WO2022237456A1 - Utilisation de composés d'acide 4-arylaminoquinazoline hydroxamique dans la préparation d'un médicament contre la douleur - Google Patents

Utilisation de composés d'acide 4-arylaminoquinazoline hydroxamique dans la préparation d'un médicament contre la douleur Download PDF

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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
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methyl
amino
quinazolinyl
hydroxy
phenoxy
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PCT/CN2022/087341
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English (en)
Chinese (zh)
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陈小新
张兰
刘苗
张倩茹
陈谋
龙超峰
姚于勤
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广东众生药业股份有限公司
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Priority to CN202280033602.XA priority Critical patent/CN117412752A/zh
Publication of WO2022237456A1 publication Critical patent/WO2022237456A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—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

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Abstract

L'invention concerne l'utilisation d'une série de composés d'acide 4-arylaminoquinazoline hydroxamique dans la préparation d'un médicament pour le traitement de maladies à douleur neuropathique, et plus précisément, l'utilisation d'un composé tel que représenté par la formule III-2, un tautomère de celui-ci ou un sel pharmaceutiquement acceptable de celui-ci dans la préparation d'un médicament pour le traitement de maladies à douleur neuropathique.
PCT/CN2022/087341 2021-05-12 2022-04-18 Utilisation de composés d'acide 4-arylaminoquinazoline hydroxamique dans la préparation d'un médicament contre la douleur WO2022237456A1 (fr)

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CN101142195A (zh) * 2005-01-07 2008-03-12 伊斯特芬博士实验室有限公司 用于治疗cns紊乱、疼痛、中风、上瘾和癫痫症的取代2－氨基－喹唑啉－4－氰基化合物及其制备方法和其作为媒介的应用
US20090111772A1 (en) * 2007-09-10 2009-04-30 Xiong Cai Formulation of quinazoline based egfr inhibitors containing a zinc binding moiety
CN105669567A (zh) * 2015-12-28 2016-06-15 上海应用技术学院 一种酪氨酸激酶抑制剂及其制备方法和用途
WO2016146074A1 (fr) * 2015-03-18 2016-09-22 广东众生药业股份有限公司 Inhibiteur de l'histone désacétylase, son procédé de préparation et son utilisation

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CN101142195A (zh) * 2005-01-07 2008-03-12 伊斯特芬博士实验室有限公司 用于治疗cns紊乱、疼痛、中风、上瘾和癫痫症的取代2－氨基－喹唑啉－4－氰基化合物及其制备方法和其作为媒介的应用
US20090111772A1 (en) * 2007-09-10 2009-04-30 Xiong Cai Formulation of quinazoline based egfr inhibitors containing a zinc binding moiety
WO2016146074A1 (fr) * 2015-03-18 2016-09-22 广东众生药业股份有限公司 Inhibiteur de l'histone désacétylase, son procédé de préparation et son utilisation
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