CN117412752A - Application of 4-arylaminoquinazoline hydroxamic acid compound in preparation of pain medicines - Google Patents

Application of 4-arylaminoquinazoline hydroxamic acid compound in preparation of pain medicines Download PDF

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Publication number
CN117412752A
CN117412752A CN202280033602.XA CN202280033602A CN117412752A CN 117412752 A CN117412752 A CN 117412752A CN 202280033602 A CN202280033602 A CN 202280033602A CN 117412752 A CN117412752 A CN 117412752A
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methyl
amino
quinazolinyl
phenoxy
hydroxy
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Chinese (zh)
Inventor
陈小新
张兰
刘苗
张倩茹
陈谋
龙超峰
姚于勤
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Guangdong Zhongsheng Pharmaceutical Co Ltd
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Guangdong Zhongsheng Pharmaceutical Co Ltd
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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

Abstract

The invention discloses application of a series of 4-arylaminoquinazoline hydroxamic acid compounds in preparing medicaments for treating neuropathic pain diseases, and particularly discloses application of a compound shown in a formula III-2, a tautomer thereof or pharmaceutically acceptable salt thereof in preparing medicaments for treating neuropathic pain diseases.

Description

Application of 4-arylaminoquinazoline hydroxamic acid compound in preparation of pain medicines Technical Field
The invention relates to application of a series of 4-arylaminoquinazoline hydroxamic acid compounds in preparing medicaments for treating neuropathic pain, in particular to neuropathic pain induced by diabetes and chemotherapy medicaments.
Background
Neuropathic pain is a pathological pain caused by injury or lesions of the peripheral or central nervous system. Including pain caused by shingles, peripheral neuropathy such as trigeminal neuralgia, and pathological pain such as diabetic neuropathic pain and chemotherapy drugs. The main characteristics of pain are allodynia (i.e., pain caused by innocuous stimuli) and hyperalgesia (i.e., pain response from increased stimuli).
Epigenetic inheritance has become a hotspot at present, and research on pain is also increasing. It is a genetic modification, mainly including DNA methylation, histone modification, chromosome remodeling, RNA interference, etc. Among them, histone acetylation is an important means of regulating gene expression among histone modifications, and is considered to be a modification which is more unstable than DNA methylation and histone methylation, and thus represents a transient and perpetual intracellular modification capable of promoting gene expression in response to environmental stimuli. Histone acetyltransferase, which catalyzes the addition of acetyl groups to histones to promote expression of genes. Conversely, histone deacetylases catalyze the removal of acetyl groups from histones, thus reducing gene expression.
The deacetylases found at present are 11 in total and are divided into different groups according to their structure. Class I HDACs include 1,2,3,8; IIa HDACs include 4,5,7,9; IIb HDACs include 6 and 10; class IV is HDAC11. Different subtypes have structures, different tissue distributions, and different effects on pain, and the physiological functions of regulation and control are also quite different. There are studies demonstrating that HDAC1, HDAC2 plays an important role in cancer pain, synaptic plasticity and inflammatory pain. Therefore, the role of HDAC1, HDAC2 in class I HDACs in neuropathic pain is an important point of our attention.
HDAC6 in class IIb HDACs is mainly present in the cytoplasm of cells, is structurally and functionally unique, has two catalytic deacetylase domains, and one zinc finger ubiquitin binding domain, and binds to a variety of non-histone substrates, such as α -tubulin, ubiquitin, heat shock protein 90 (HSP 90) and the like, in the cytoplasm, thereby modulating it, therefore, HDAC6 becomes a key regulator for maintaining balance between neuroprotection and neurodegeneration, and HDAC6 was found to be involved in the modulation of neuropathic pain. Krukowski and Van et al (Krukowski K, ma J, golon zhka O, et al, HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy [ J ]. Pan, 2017,158 (6): 1126-1137. And Van Helleputte L, kater M, cook DP, et al, inhibition of histone deacetylase 6 (HDAC 6) protects against vincristine-induced peripheral neuropathies and inhibits tumor growth [ J ]. Neurobiol Dis,2018, 111:59-69.) found that chemotherapy-induced neuropathic Pain could be ameliorated by antagonizing HDAC 6.
In the experiments of Krukowski and Van et al, tumor chemotherapeutic drugs disrupt the axonal transport and microtubule dynamics of neurons, resulting in neurotoxicity of the chemotherapeutic drugs, which causes neuropathic pain. Whereas the acetylation modification of α -tubulin is one of the key mechanisms regulating neuronal axonal transport and microtubule dynamics. Compared to other HDACs, HDAC6 is specific for non-histones including alpha-tubulin and is an important enzyme that regulates the level of alpha-tubulin acetylation. Thus, by inhibiting HDAC6, the level of α -tubulin acetylation in peripheral nerves can be increased, thereby increasing the transport capacity of neuronal axons, improving microtubule stability, and ameliorating chemotherapy-induced neuropathic pain.
Quinazoline is a compound formed by fusing benzene rings and pyrimidine rings, and quinazoline compounds have been found to have analgesic and anti-inflammatory activities in medicine.
Chinese patent CN200680001768.4, filed 2006.01.09 by easter doctor laboratories, discloses a substituted quinazoline compound and its use in the preparation of a medicament for the treatment of pain, in particular neuropathic pain, and stroke, drug addiction and epilepsy.
Chinese patent CN200480011981.4, filed by Wo Taike s pharmaceutical company, limited at 2004.03.03, discloses a substituted quinazoline compound and a method for its use in the treatment of neuropathic or inflammatory pain.
U.S. patent No. 2009111772, filed by CAI XIONG, equal to 2008.09.10, discloses an HDAC inhibitor and is useful for treating diseases associated with Histone Deacetylase (HDAC) disorders, including intervertebral disc-derived pain, in 2009.04.30.
Chinese patent CN201680015470.2, filed 2016.03.17 by guangdong pharmaceutical industry, limited, discloses a series of 4-arylaminoquinazoline hydroxamic acid compounds at 2017.12.01, which have histone deacetylase inhibitory activity, in particular, higher selective HDAC6, HADC1 and HADC2 activities, and lower selective inhibitory activity for the remaining HDACs, and are shown to have excellent effect in tumor treatment. The selective inhibition of the compounds on the HDACs can reduce side effects caused by low selectivity in the use of the drugs, and the inventor surprisingly discovers that the series of compounds have certain analgesic effect on neuropathic pain, especially on diabetic neuropathic pain and neuropathic pain induced by chemotherapy drugs, and provides a new thought for treating diabetes and cancer or chemotherapy pain caused by the diabetes and cancer.
Disclosure of Invention
The invention aims at providing the application of a compound shown in a formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof in preparing a medicament for treating neuropathic pain,
wherein R is 1 Is one or more substituents;
R 1 、R 2 and R is 3 Each independently is 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 R 5 N-、R 4 CONH-、R 4 NHCO-, guanidino-, ureido-, trifluoromethyl-, C 1-10 An alkylsulfonyl group, a substituted benzenesulfonyl group, a substituted phenyl group, a phenyl group or a heterocyclic group;
R 4 is C 1-10 Alkyl or benzyl;
R 5 is hydrogen or C 1-10 Alkyl of (a);
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 is a substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclyl group, wherein n is an integer from 1 to 10;
preferably, the benzene ring of the substituted phenyl contains 1 to 4 substituents, and the substituents of the substituted phenyl are halogen, -OH, -NO 2 Cyano, alkoxy, C 1-4 An alkyl or amino group of (a);
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 heteroatom is selected from nitrogen, oxygen or sulfur;
preferably, the halogen is fluorine, chlorine, bromine or iodine.
In the above groups, the C 1-10 Alkyl is a straight, branched or cyclic saturated hydrocarbon containing 1 to 10 carbon atoms, the C 1-10 The alkyl group may be substituted (for example, pyrrolidin-1-yl-C 2-10 Alkyl, morpholin-1-yl-C 2-10 Alkyl or piperazine-1-C 2-10 Alkyl) or unsubstituted; preferably, C employed in the present invention 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;
preferably, R employed in the present invention 4 O-is benzyloxy, pyrrolidin-1-yl-C 2-10 Alkoxy, morpholin-1-yl-C 2-10 Alkoxy or piperazine-1-C 2-10 An alkoxy group;
preferably, R employed in the present invention 4 OC (O) -isAn ethylenealkoxycarbonyl group, a propyloxycarbonyl group, a butylalkoxycarbonyl group, an isobutyloxycarbonyl group, a pentyloxycarbonyl group, a hexyloxycarbonyl group, a heptyloxycarbonyl group, an octyloxycarbonyl group, a nonyloxycarbonyl group or a decyloxycarbonyl group;
r used in the invention 4 C (O) O-is ethyl, propyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl;
preferably, R employed in the present invention 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;
Preferably, R employed in the present invention 4 CONH-is acetamido, propionamido, butyrylamino, isobutyrylamino, valerylamino, caproamido, heptanamido, octanoamido, nonanamido or decanoamido;
the C is 1-10 Is C as defined above 1-10 Alkyl is linked to sulfonyl and to formula (I) via sulfonyl; preferably, C employed in the present invention 1-10 Is methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, pentanesulfonyl, hexanesulfonyl, heptanesulfonyl, octanesulfonyl, nonanesulfonyl or decanesulfonyl.
Preferably, the present invention provides the use of a compound of formula (II), a tautomer thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of neuropathic pain,
wherein R is 2 、R 3 Each independently is 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 NHR 5 、R 4 CONH-、R 4 NHCO-, guanidino-, ureido-, trifluoromethyl-, C 1-10 Alkanesulfonyl, substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclyl radicals, wherein R 4 Is C 1-10 Alkyl or benzyl, R 5 Is hydrogen or C 1-10 Alkyl of (a); preferably, R 2 、R 3 Each independently is hydrogen or C 1-6 Alkyl of (a); more preferably, R 2 、R 3 Each independently is hydrogen or C 1-4 Alkyl of (a); most preferably, R 2 、R 3 Each independently is hydrogen or methyl;
linker is a key; - (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 is a substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclyl group, wherein n is an integer from 1 to 10;
preferably, the benzene ring of the substituted phenyl contains 1 to 4 substituents, and the substituents of the substituted phenyl are halogen, -OH, -NO 2 Cyano, alkoxy, C 1-4 An alkyl or amino group of (a);
preferably, the heterocyclyl is a saturated or unsaturated five-or six-membered heterocyclyl containing one or more heteroatoms selected from nitrogen, oxygen or sulfur;
preferably, the halogen is fluorine, chlorine, bromine or iodine;
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 selected from nitrogen; more preferably, linker is- (CH) 2 ) n -, wherein n is an integer from 1 to 5; or- (CH) 2 ) m Benzene-, wherein m is an integer from 0 to 5; or a saturated or unsaturated six-membered heterocyclic group containing 1 or 2 nitrogen atoms, preferably an unsaturated six-membered heterocyclic group containing 1 nitrogen atom;
Further, the present invention provides the use of a compound selected from the group consisting of the following formulas:
(II-1) N-hydroxy-2- (4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) acetamide
(II-2) N-hydroxy-4- (4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) butanamide
(II-3) N-hydroxy-5- (4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) valeramide
(II-4) N-hydroxy-6- (4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) hexanamide
(II-5) N-hydroxy-4- ((4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) methyl) benzamide
(II-6) N-hydroxy-4- (4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) benzamide
(II-7) N-hydroxy-6- (4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) nicotinamide
(II-8) N-hydroxy-5- (4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pyridine amide
(II-9) N-hydroxy-2- (4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pyrimidine-5-amide
(II-10) N-hydroxy-5- (4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pyrimidine-2-amide
(II-11) N-hydroxy-5- (4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy pyrazine-2-amide
(II-12) N-hydroxy-2- (4- (methyl (4-quinazolinyl) amino) phenoxy) acetamide
(II-13) N-hydroxy-4- (4- (methyl (4-quinazolinyl) amino) phenoxy) butanamide
(II-14) N-hydroxy-5- (4- (methyl (4-quinazolinyl) amino) phenoxy) pentanamide
(II-15) N-hydroxy-6- (4- (methyl (4-quinazolinyl) amino) phenoxy) hexanamide
(II-16) N-hydroxy-4- ((4- (methyl (4-quinazolinyl) amino) phenoxy) methyl) benzamide
(II-17) N-hydroxy-4- (4- (methyl (4-quinazolinyl) amino) phenoxy) benzamide
(II-18) N-hydroxy-6- (4- (methyl (4-quinazolinyl) amino) phenoxy) nicotinamide
(II-19) N-hydroxy-5- (4- (methyl (4-quinazolinyl) amino) phenoxy pyridine amide
(II-20) N-hydroxy-2- (4- (methyl (4-quinazolinyl) amino) phenoxy) pyrimidine-5-carboxamide
(II-21) N-hydroxy-5- (4- (methyl (4-quinazolinyl) amino) phenoxy) pyrimidine-2-carboxamide
(II-22) N-hydroxy-5- (4- (methyl (4-quinazolinyl) amino) phenoxy) pyrazine-2-carboxamide
(II-23) N-hydroxy-2- (4- ((2-methyl-4-quinazolinyl) amino) phenoxy) acetamide
(II-24) N-hydroxy-3- (4- ((2-methyl-4-quinazolinyl) amino) phenoxy) propanamide
(II-25) N-hydroxy-4- (4- ((2-methyl-4-quinazolinyl) amino) phenoxy) butanamide
(II-26) N-hydroxy-5- (4- ((2-methyl-4-quinazolinyl) amino) phenoxy) valeramide
(II-27) N-hydroxy-6- (4- ((2-methyl-4-quinazolinyl) amino) phenoxy) hexanamide
Preferably, the present invention provides the use of a compound of formula (III), a tautomer thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of neuropathic pain,
wherein R is 1 、R 2 、R 3 Each independently is 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 NHR 5 、R 4 CONH-、R 4 NHCO-, guanidino-, ureido-, trifluoromethyl-, C 1-10 Alkanesulfonyl, substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclyl radicals, wherein R 4 Is C 1-10 Alkyl or benzyl, R 5 Is hydrogen or C 1-10 Alkyl of (a); preferably, R 1 Is hydrogen or C 1-6 An alkoxy group; more preferably, R 1 Is hydrogen or C 1-4 An alkoxy group; most preferably, R 1 Is hydrogen or methoxy; preferably, R 2 、R 3 Independently hydrogen or C 1-6 An alkyl group; more preferably, R 2 、R 3 Independently hydrogen or C 1-4 An alkyl group; most preferably, R 2 、R 3 Independently hydrogen or methyl;
linker is a key; - (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 is a substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclyl group, wherein n is an integer from 1 to 10;
preferably, the benzene ring of the substituted phenyl contains 1 to 4 substituents, and the substituents of the substituted phenyl are halogen, -OH, -NO 2 Cyano, alkoxy, C 1-4 An alkyl or amino group of (a);
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 heteroatom is selected from nitrogen, oxygen or sulfur;
preferably, the halogen is fluorine, chlorine, bromine or iodine.
Preferably, linker is- (CH) 2 ) n O-、-O(CH 2 ) n -wherein n is an integer from 1 to 10; more preferably, linker is- (CH) 2 ) n O-, wherein n is an integer from 1 to 10; most preferably, linker is- (CH) 2 ) n O-, wherein n is an integer from 1 to 5;
further, the present invention relates to the use of a compound selected from the group consisting of the following formulae in the preparation of a medicament for the treatment of neuropathic pain:
(III-1) N-hydroxy-2- (2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) acetamide
(III-2) N-hydroxy-4- (2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) butanamide
(III-3) N-hydroxy-5- (2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pentanoic acid amide
(III-4) N-hydroxy-6- (2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) hexanamide
(III-5) N-hydroxy-4- ((2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) methyl) benzamide
(III-6) N-hydroxy-4- (2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) benzamide
(III-7) N-hydroxy-6- (2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) nicotinamide
(III-8) N-hydroxy-5- (2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) picolinamide
(III-9) N-hydroxy-2- (2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pyrimidine-5-carboxamide
(III-10) N-hydroxy-5- (2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pyrimidine-2-carboxamide
(III-11) N-hydroxy-5- (2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pyrazine-2-carboxamide
(III-12) N-hydroxy-2- (3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) acetamide
(III-13) N-hydroxy-4- (3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) butanamide
(III-14) N-hydroxy-5- (3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) valeramide
(III-15) N-hydroxy-6- (3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) hexanamide
(III-16) N-hydroxy-4- ((3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) methyl) benzamide
(III-17) N-hydroxy-4- (3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) benzamide
(III-18) N-hydroxy-6- (3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) nicotinamide
(III-19) N-hydroxy-5- (3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pyridine amide
(III-20) N-hydroxy-2- (3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pyrimidine-5-carboxamide
(III-21) N-hydroxy-5- (3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pyrimidine-2-carboxamide
(III-22) N-hydroxy-5- (3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pyrazine-2-carboxamide
Preferably, the present invention provides the use of a compound of formula (IV), a tautomer thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of neuropathic pain,
wherein R is 2 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 Alkanesulfonyl, substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclyl radicals, wherein R 4 Is C 1-10 Alkyl or benzyl, R 5 Is hydrogen or C 1-10 Alkyl of (a); preferably, R 2 Independently hydrogen or C 1-6 An alkyl group;
further, the present invention relates to the use of a compound selected from the group consisting of the following formulae in the preparation of a medicament for the treatment of neuropathic pain:
(IV-1) 4- (5- (ethyl (2-methyl-4-quinazolinyl) amino) -2-methoxyphenyl) -N-hydroxybutyramide
(IV-2) N-hydroxy-4- (2-methoxy-5- ((2-methyl-4-quinazolinyl) (propyl) amino) phenoxy) butanamide
(IV-3) 4- (5- (butyl (2-methyl-4-quinazolinyl) amino) -2-methoxyphenyl) -N-hydroxybutyramide
(IV-4) N-hydroxy-4- (2-methoxy-5- ((2-methyl-4-quinazolinyl) (pentyl) amino) phenoxy) butanamide
(IV-5) N-hydroxy-4- (2-methoxy-5- ((methoxymethyl) (2-methyl-4-quinazolinyl) amino) phenoxy) butanamide
(IV-6) N-hydroxy-4- (2-methoxy-5- (((methoxymethoxy) methyl) (2-methyl-4-quinazolinyl) amino) phenoxy) butanamide
According to another aspect of the present invention there is also provided the use of a pharmaceutical composition comprising all of the compounds described above, their tautomers or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients, in the manufacture of a medicament for the treatment of neuropathic pain.
The dosage form of the pharmaceutical composition can be tablets, suppositories, dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, sugar-coated agents, granules, dry powder, oral solution, small injection needles, freeze-dried injection needles or large transfusion.
Preferably, the pharmaceutically acceptable excipients include one or more of the following: diluents, solubilizers, disintegrants, suspending agents, lubricants, binders, fillers, flavoring agents, sweeteners, antioxidants, surfactants, preservatives, coating agents or pigments.
Use of a compound or composition according to the invention for the preparation of a medicament for the treatment of neuropathic pain selected from chronic back pain, post-herpetic neuralgia, diabetic neuropathic pain, myofibrotic pain, neuropathic pain induced with chemotherapeutics; in particular, the neuropathic pain is selected from diabetic neuropathic limb pain and chemotherapy-induced limb pain.
Further, according to the use of the present invention, the compound is compound III-2 shown in the following formula, and the pain is diabetic neuropathic pain and chemotherapy drug-induced neuropathic pain.
Correlation definition
The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a base in pure 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 the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of an acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts including acids 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, tannate, citrate, trifluoroacetate and the like; also included are salts of amino acids such as arginine and the like, 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 invention contain basic and acidic functionalities that can be converted to either base or acid addition salts.
Preferably, the preparation method of the pharmaceutically acceptable salt comprises the following steps: the salt is contacted with a base or acid in a conventional manner to isolate the parent compound, thereby regenerating the neutral form of the compound. The parent form of a compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.
The "pharmaceutically acceptable salts" as described herein are derivatives of the compounds of the invention, wherein the parent compound is modified by salt formation with an acid or by salt formation with a base. Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic 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 with non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic or 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, hydroiodic acid, hydroxy, 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, polygalactural, propionic acid, salicylic acid, stearic acid, sulfurous acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, and p-toluenesulfonic acid.
Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
In addition to salt forms, the compounds provided herein exist in prodrug forms. Prodrugs of the compounds referred to herein readily undergo chemical changes under physiological conditions to convert to the compounds of the present invention. In addition, prodrugs (prodrugs) can also be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
Certain compounds of the invention may exist in unsolvated forms or solvated forms, including hydrated forms. In general, solvated forms are equivalent in effect to unsolvated forms and are intended to be encompassed within the scope of the present invention.
Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Thus, racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the compounds of the present invention.
In the present invention, wedge-shaped keys and dotted keys are used, unless otherwise indicatedRepresenting the absolute configuration of a stereogenic center, usingRepresenting the relative configuration of a stereogenic center. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E, Z geometric isomers unless specified otherwise. Likewise, all tautomeric forms thereof are included within the scope of the invention.
The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention relates to all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.
Optically active (R) -and (S) -isomers and 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 may be prepared by asymmetric synthesis or derivatization with chiral auxiliary, by separating the resulting diastereomeric mixture and cleaving the auxiliary group to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is carried out by conventional methods well known in the art, and then the pure enantiomer is recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine).
The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example 3 H) Iodine-125% 125 I) Or C-14% 14 C) A. The invention relates to a method for producing a fibre-reinforced plastic composite All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of the active agent of the present invention, which does not interfere with the biological activity of the active agent and which does not have toxic or side effects to the host or patient. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. Such matrices include suspending agents, viscosity enhancers, transdermal enhancers, and the like. The preparation of formulations with the aid of said substances is known to the person skilled in the cosmetic or topical pharmaceutical arts. For additional information on the vector, reference may be made to Remington, the Science and Practice of Pharmacy,21st Ed., lippincott, williams & Wilkins (2005), the contents of which are incorporated herein by reference.
For a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For the purposes of the present oral dosage form, an "effective amount" of one active agent in a composition refers to the amount required to achieve the desired effect, or the amount required to achieve the desired effect when the active agent is combined with another active agent in the composition. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.
The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating a disorder, disease or condition of interest.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The term "substituted" refers to any one or more hydrogen atoms on a particular atom being substituted with a substituent, including heavy hydrogen and variants of hydrogen, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is a ketone group (i.e., =o), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on the aromatic group. The term "optionally substituted" means that the substituents may or may not be substituted, and the types and numbers of substituents may be arbitrary on the basis that they can be chemically achieved unless otherwise specified.
When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0 to 2R, the group may optionally be substituted with up to two R's, and the R's options in each case are independent. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds.
Unless otherwise specified, "ring" means a substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. The term ring includes monocyclic, bicyclic, spiro, and fused or bridged rings. The number of atoms on a ring is generally defined as the number of ring elements, for example, "5-7 membered ring" means a ring of 5-7 atoms arranged around the ring. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms. Thus, "5-7 membered ring" includes, for example, phenyl, pyridine, and piperidinyl; in another aspect, the term "5-7 membered heterocycloalkyl ring" includes piperazinyl and piperidinyl, but does not include phenyl. The term "ring" also includes ring systems comprising at least one ring, each of which independently meets the definition set forth above.
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.
Unless otherwise specified, the term "alkyl" is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (e.g. -CH 2 F) Or polysubstituted (e.g. -CF) 3 ) May be monovalent (e.g., methyl), divalent (e.g., methylene), or multivalent (e.g., 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 (e.g., n-pentyl, isopentyl, neopentyl), and the like.
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.
All solvents used in the present invention are commercially available and can be used without further purification.
The invention adopts the following abbreviations: pen is pentoxifylline; INT-747 is 6-ethyl chenodeoxycholic acid; aq represents water; HATU represents O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate; EDC represents 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 stands for diisopropyl azodicarboxylate; DMF represents N, N-dimethylformamide; DMSO represents dimethylsulfoxide; etOAc represents ethyl acetate; etOH stands for ethanol; meOH represents methanol; CBz represents benzyloxycarbonyl, an amine protecting group; BOC represents tert-butylcarbonyl, an amine protecting group; HOAc stands for acetic acid; naCNBH 3 Represents sodium cyanoborohydride; r.t. stands for room temperature; O/N stands for overnight; THF represents tetrahydrofuran; boc 2 O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl 2 Represents thionyl chloride; CS (circuit switching) 2 Represents carbon disulphide; tsOH represents p-toluenesulfonic acid; NFSI represents N-fluoro-N- (benzenesulfonyl) benzenesulfonamide; NCS represents 1-chloropyrrolidine-2, 5-dione; n-Bu 4 NF represents tetrabutylammonium fluoride; iPrOH stands for 2-propanol; mp represents the melting point; LDA represents lithium diisopropylamide; TMSCF (TMSCF) 3 Represents trifluoromethyl trimethylsilane; 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 stands for diisopropylethylamine; BH (BH) 3 DMS stands for borane dimethyl sulfide; DMP represents dessmartin periodate; TBAF represents tetrabutylammonium fluoride; HOBT represents 1-hydroxybenzotriazole; AIBN represents azobisisobutyronitrile; NBS represents N-bromosuccinimide; RT buffer represents reverse transcription buffer; dNTP stands for deoxidizationRibonucleoside triphosphates; PBS represents phosphate buffer; CMCNa represents sodium carboxymethyl cellulose; STZ stands for streptozotocin.
The compounds being prepared by hand or by handSoftware naming, commercial compounds are referred to by vendor catalog names.
Drawings
FIG. 1 is a mechanical stimulus foot-reduction threshold of rats compared to model control group 1; wherein, p <0.05 is represented, compared to model control group 1.
Figure 2 shows the body weight change profile for each group of animals.
Figure 3 is a statistical graph of mechanical paw withdrawal threshold (mean±sem) of animals for p <0.05 vs. model and p <0.01 vs. model.
Detailed Description
All compounds in the present disclosure were prepared by the preparation method disclosed in CN 201680015470.2.
Example 1: pharmacodynamic study of rat STZ diabetic peripheral neuropathic pain model
The purpose of the experiment is as follows: and (3) using an STZ-induced SD rat type I diabetes animal model to study behaviors such as peripheral neuropathic pain caused by diabetes peripheral neuropathy, and evaluating the therapeutic effect of a test sample in the diabetes neuropathic pain animal model through the change of mechanical stimulus sensitivity of the rat.
Experimental model: STZ-induced SD rat type I diabetes animal model
Experimental animals: SD rat (Si Bei Fu (Beijing) biotechnology Co., ltd.)
Experimental reagent:
1. gabapentin (Shanghai Haohong biomedical technologies Co., ltd.);
2.0.5% cmcna (sigma aldrich, shanghai) trade limited);
3.0.9% sodium chloride injection (Sichuan Korea pharmaceutical Co., ltd.);
4. sodium pentobarbital (merck);
5. streptozotocin (sigma aldrich, shanghai) trade limited;
6. test Compound III-2
The experimental method comprises the following steps:
preparation and storage of STZ solutions
And (3) solution A: 1.471g of sodium citrate is weighed and placed in a 50mL sterile centrifuge tube, 50.0mL of physiological saline is sucked by a 50mL syringe and placed in the centrifuge tube, and the solution is uniform;
and (2) liquid B: weighing 0.995g of citric acid, placing the citric acid into a 50mL sterile centrifuge tube, sucking 50.0mL of physiological saline by using a 50mL syringe, placing the saline into the centrifuge tube, and uniformly dissolving;
citrate buffer: mixing the solution A and the solution B according to a ratio of 1:1, regulating the pH value to 4.5 by using the solution A or the solution B, filtering and sterilizing by using a disposable needle-type filter with the thickness of 0.22 mu m in a clean workbench, sub-packaging into 50mL tubes, labeling, and preserving at the temperature of minus 20 ℃ for later use;
streptozotocin (STZ) solution: before molding, weighing 240 mg/tube of streptozotocin, placing in a 50mL sterile centrifuge tube wrapped by tinfoil paper, placing in an ice box, adding 40mL of a packaged citrate buffer before use, uniformly mixing to prepare 6mg/mL of Streptozotocin (STZ) solution, and directly discarding the solution after use within 15 minutes.
Animal model of STZ-induced diabetes
Rats were intraperitoneally injected with STZ,65mg/kg, and animals were fasted for more than 12 hours prior to single injection, and the day after injection was changed from drinking water to 10% sucrose solution (to prevent hypoglycemia in rats).
3. Grouping
The test comprises a test I and a test II, wherein the test I comprises 1 model control group, 1 positive control group and 1 test sample group, and the test II comprises 1 model control group and 1 test sample group.
The grouping method comprises the following steps: type I diabetic SD rats with diabetic neuropathic pain were selected and randomly grouped according to a mechanical stimulation paw withdrawal threshold.
Table 1 animals group table 1
Table 2 animals grouping table 2
Note that: the first letter of the animal number represents the test stage, and the first number represents the group (1, 2 and 3 represent the model control group, the positive control group and the test sample group, respectively); the second letter represents sex (M is male) and the last 3 digits represent animal serial number.
4. Administration of drugs
Test I: model control group was given vehicle, the other groups were given different doses of drug, and since the test 75mg/kg dose group (Bid) showed severe diarrhea side effects in animals on day 3 of administration, the frequency of administration was changed to once daily on days 3 and 4 days, and 4 animals in this group had died on day 4 of administration, and thus the administration was stopped on day 5, as detailed in table 3 below.
Test II: the model control group was given vehicle, and the administration group was given test drug 2 times daily for 5 days. Specific information is shown in Table 4 below.
Table 3 dose design table 1
Note that: the day of modeling was defined as D0, D27 day of grouping, D28 day of starting dosing, qd: once daily, bid: twice daily.
Table 4 dose design table 2
Note that: the day of modeling was defined as D0, D37 day group, D38 day start dosing, bid: twice daily.
5. Detection of
Mechanical stimulation foot-shrinking threshold
Detection time: 1 time before STZ molding, 1 time before grouping, 1 time after 1, 4 and 8 days after administration of test I animals, 1 time after 1, 5 days after administration of test II animals;
the method comprises the following steps: placing animals into a detection box for adaptation 3 days before detection, and adapting for 30min each day; in each detection, animals are put into a detection box for 15min, and then detection is carried out, wherein each animal is detected for 3 times, the average value is taken, and each detection is carried out at least 5 minutes.
6. Experimental results
The rat mechanical stimulation paw withdrawal threshold began to decrease at D14 after STZ injection, decreased to 50% at D21, and was essentially the same as D21 at D25, indicating that the animal mechanical stimulation paw withdrawal threshold had been essentially minimized at this time, so the trial option began to administer drug intervention at D28.
As shown in fig. 1 and tables 5 and 6, test I results show: after the drug is dried, the mechanical stimulation foot shrinkage threshold of the rats in the treatment group of the positive drug gabapentin (150 mg/kg, qd) is obviously increased, and compared with the model control group, the positive drug gabapentin has obvious statistical difference (P < 0.05); the test compound III-2 75mg/kg (bid, 2D, qd, 2D) group significantly increased the mechanical stimulation paw withdrawal threshold after the first administration (D28), with a statistical difference (P < 0.05) compared to the model control group, and the mechanical stimulation paw withdrawal threshold remained at the level of administration after 3 days of drug withdrawal (D34), with a significant statistical difference (P < 0.05) compared to the model control group. The results of test II show that: the test compound III-2 15mg/kg (bid, 5D) group also significantly increased the mechanical stimulation paw withdrawal threshold of the rats after the first administration (D38), with a significant statistical difference (P < 0.05) compared to the model control group.
TABLE 5 mechanical stimulation foot contraction threshold 1 (g) for rats
Note that: * Represents p <0.05, compared to model control group 1; all data of each of PRE-D31 groups in the table were from 8 animals (n=8), D34 day model group and positive drug group data were from 8 animals, and test group data were from 3 animals; pre represents before molding, the day of molding is D0, D14 represents the 14 th day after molding, and the rest are the same.
TABLE 6 mechanical stimulation foot contraction threshold 2 (g) for rats
Note that: * Represents p <0.05, compared to model control group 1; all data from each group in the table were from 5 animals (n=5); pre represents before molding, the day of molding is D0, D14 represents the 14 th day after molding, and the rest are the same.
In summary, compound III-2 significantly increased the mechanical stimulated paw withdrawal threshold in SD rats at 75mg/kg (bid, 2d, qd,2 d) and 15mg/kg (bid, 5 d), indicating that the compound had better analgesic effect at this dose.
Example 2: pharmacodynamic study of paclitaxel-induced rat pain model test
The purpose of the experiment is as follows: a paclitaxel-induced rat pain model is adopted, and whether the test sample has a therapeutic and relieving effect on the rat podalgia in the model is evaluated.
Experimental model: paclitaxel-induced rat pain model
Experimental animals: SD rat (Chengdu Daso laboratory animal Co., ltd.)
Experimental reagent:
1. paclitaxel injection (Yangzi river pharmaceutical Co., ltd.);
2.0.5% CMC-Na (Chengdu Kelong chemical reagent Co., ltd.);
3.0.9% sodium chloride injection (Sichuan Korea pharmaceutical Co., ltd.);
4. test Compound III-2
The experimental method comprises the following steps:
1. test article/reference article preparation
Preparing a solvent reference substance: adding a proper amount of CMC-Na into purified water, and mixing by vortex to prepare a solvent reagent 0.5% CMC-Na (w/v) solution.
Preparing a test sample: weighing a proper amount of medicine, adding CMC-Na with 0.5% concentration, ultrasonic treating, and mixing. A final concentration of 0.3mg/mL of suspension was obtained.
2. Paclitaxel-induced rat pain model
After 45 Sprague Dawley (SD) rats were purchased and fed adaptively for 7 days, 40 rats were selected for intraperitoneal injection (i.p.) to give 2mg/kg of paclitaxel injection for molding, 1 injection every other day, 4 continuous injections were performed, the remaining 5 rats were intraperitoneally injected with physiological saline as a normal control group, and on the 4 th day after molding was completed, the mechanical pain threshold (baseline) of the rats was measured by using von Frey up and down method for 40 molded animals and 5 physiological saline group animals, and 20 molded animals were screened for group administration.
3. Grouping
The 20 model rats selected into the group were randomly divided into 2 groups of 10 and 5 rats intraperitoneally injected with physiological saline as normal control groups, and were dosed as follows:
4. weight measurement
Body weight was measured every 2 days during dosing.
5. Mechanical pain threshold measurement
1 hour after 1 st, 4, 7 days, 1 st, the mechanical pain threshold of the rats was measured using von Frey up and down method 3 days after discontinuation, and the mechanical paw withdrawal threshold (50% pwt) was calculated.
6. Data analysis
P <0.05 was defined as statistically significant differences using the nonparametric Mann-Whitney test.
7. Experimental results
Weight of: body weight changes are shown in figure 2, and body weight of each group increased during the administration period.
Mechanical threshold: the mechanical paw withdrawal threshold statistics are shown in figure 3, during the dosing period, the normal group had significantly higher 50% PWT than the model group (p < 0.01), and the compound III-2, 3mg/kg group had significantly higher 50% PWT than the model group (p <0.01, p < 0.05) 1 hour after dosing on days 4, 7, 1; on day 3 after drug withdrawal (D10), both normal 50% PWT were significantly higher than in the model group (p < 0.01), and both compound III-2 3mg/kg 50% PWT were significantly higher than in the model group (p < 0.05).
8. Conclusion(s)
In the examples, compound III-2 was administered continuously at a dose of 3mg/kg for 7 days, 2 times daily, with significant relief of paclitaxel-induced paw pain in rats, and no significant weight loss relative to the normal and model groups, indicating that the compound had better analgesic effect and safety at this dose.
The inventors continued to screen 10 model rats from the remaining 20 model animals of section 2, dosed with HDAC inhibitor Vorinostat (SAHA) at the dose of compound III-2 (3 mg/kg) and dosing cycle and frequency (Bid, 7 days), and the experimental results showed no significant decrease in body weight in the Vorinostat group, but no significant difference in 50% pwt compared to the model group at the 4 th, 7 th day 1 hour post dose, and 3 rd day after drug withdrawal (D10), indicating that Vorinostat had no significant relief from paclitaxel-induced rat podalgia at the same dose.

Claims (10)

  1. The application of a compound shown in a formula (I), a tautomer thereof or a pharmaceutically acceptable salt thereof in preparing a medicament for treating neuropathic pain,
    wherein R is 1 Is a group of one or more substituents,
    R 1 、R 2 and R is 3 Each independently is 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 R 5 N-、R 4 CONH-、R 4 NHCO-, guanidino-, ureido-, trifluoromethyl-, C 1-10 An alkylsulfonyl group, a substituted benzenesulfonyl group, a substituted phenyl group, a phenyl group or a heterocyclic group;
    R 4 is C 1-10 Alkyl or benzyl;
    R 5 is hydrogen or C 1-10 Alkyl of (a);
    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 is a substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclyl group;
    wherein n is an integer from 1 to 10;
    preferably, the benzene ring of the substituted phenyl contains 1 to 4 substituents, and the substituents of the substituted phenyl are halogen, -OH, -NO 2 Cyano, alkoxy, C 1-4 Is selected from the group consisting of an alkyl or amino group,
    preferably, the heterocyclyl is a saturated or unsaturated five-or six-membered heterocyclyl containing one or more heteroatoms selected from nitrogen, oxygen or sulfur;
    preferably, the halogen is fluorine, chlorine, bromine or iodine,
    in the above groups, the C 1-10 Alkyl is a straight, branched or cyclic saturated hydrocarbon containing 1 to 10 carbon atoms, said C 1-10 Alkyl groups optionally substituted, e.g. pyrrolidin-1-yl-C 2-10 Alkyl, morpholin-1-yl-C 2-10 Alkyl or piperazine-1-C 2-10 An alkyl group; 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,
    preferably, said 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 An alkoxy group;
    preferably, said R 4 OC (O) -is an ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl or decyloxycarbonyl group,
    the R is 4 C (O) O-is ethyl, propyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl,
    preferably, said 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,
    Preferably, said R 4 CONH-is acetamido, propionamido, butyramideA group, isobutyrylamino, valerylamino, caproamido, heptanamido, octanoylamino, nonanamido or decanoylamino group;
    the C is 1-10 Is C as defined above 1-10 Alkyl is linked to sulfonyl and to formula (I) via sulfonyl; preferably, the C 1-10 Is methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, pentanesulfonyl, hexanesulfonyl, heptanesulfonyl, octanesulfonyl, nonanesulfonyl or decanesulfonyl.
  2. The application of a compound shown in a formula (II), a tautomer thereof or a pharmaceutically acceptable salt thereof in preparing a medicament for treating neuropathic pain,
    wherein R is 2 、R 3 Each independently is 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 NHR 5 、R 4 CONH-、R 4 NHCO-, guanidino-, ureido-, trifluoromethyl-, C 1-10 Alkanesulfonyl, substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclyl radicals, wherein R 4 Is C 1-10 Alkyl or benzyl, R 5 Is hydrogen or C 1-10 Alkyl of (a); preferably, R 2 、R 3 Each independently is hydrogen or C 1-6 Alkyl of (a); more preferably, R 2 、R 3 Each independently is hydrogen or C 1-4 Alkyl of (a); most preferably, R 2 、R 3 Each independently of the other is hydrogen or methyl,
    linker is a key; - (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 a substituted benzenesulfonyl group, a substituted phenyl group, a phenyl group or a heterocyclic group,
    preferably, the benzene ring of the substituted phenyl contains 1 to 4 substituents, and the substituents of the substituted phenyl are halogen, -OH, -NO 2 Cyano, alkoxy, C 1-4 Is selected from the group consisting of an alkyl or amino group,
    preferably, the heterocyclyl is a saturated or unsaturated five-or six-membered heterocyclyl containing one or more heteroatoms selected from nitrogen, oxygen or sulfur;
    preferably, the halogen is fluorine, chlorine, bromine or iodine,
    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 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 unsaturated six-membered heterocyclic group containing 1 or 2 nitrogen atoms, preferably containingUnsaturated six-membered heterocyclic group of 1 nitrogen atom.
  3. Use according to claim 1 or 2, characterized in that said compound is selected from the group consisting of:
    (II-1) N-hydroxy-2- (4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) acetamide
    (II-2) N-hydroxy-4- (4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) butanamide
    (II-3) N-hydroxy-5- (4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) valeramide
    (II-4) N-hydroxy-6- (4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) hexanamide
    (II-5) N-hydroxy-4- ((4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) methyl) benzamide
    (II-6) N-hydroxy-4- (4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) benzamide
    (II-7) N-hydroxy-6- (4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) nicotinamide
    (II-8) N-hydroxy-5- (4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pyridine amide
    (II-9) N-hydroxy-2- (4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pyrimidine-5-amide
    (II-10) N-hydroxy-5- (4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pyrimidine-2-amide
    (II-11) N-hydroxy-5- (4- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy pyrazine-2-amide
    (II-12) N-hydroxy-2- (4- (methyl (4-quinazolinyl) amino) phenoxy) acetamide
    (II-13) N-hydroxy-4- (4- (methyl (4-quinazolinyl) amino) phenoxy) butanamide
    (II-14) N-hydroxy-5- (4- (methyl (4-quinazolinyl) amino) phenoxy) pentanamide
    (II-15) N-hydroxy-6- (4- (methyl (4-quinazolinyl) amino) phenoxy) hexanamide
    (II-16) N-hydroxy-4- ((4- (methyl (4-quinazolinyl) amino) phenoxy) methyl) benzamide
    (II-17) N-hydroxy-4- (4- (methyl (4-quinazolinyl) amino) phenoxy) benzamide
    (II-18) N-hydroxy-6- (4- (methyl (4-quinazolinyl) amino) phenoxy) nicotinamide
    (II-19) N-hydroxy-5- (4- (methyl (4-quinazolinyl) amino) phenoxy pyridine amide
    (II-20) N-hydroxy-2- (4- (methyl (4-quinazolinyl) amino) phenoxy) pyrimidine-5-carboxamide
    (II-21) N-hydroxy-5- (4- (methyl (4-quinazolinyl) amino) phenoxy) pyrimidine-2-carboxamide
    (II-22) N-hydroxy-5- (4- (methyl (4-quinazolinyl) amino) phenoxy) pyrazine-2-carboxamide
    (II-23) N-hydroxy-2- (4- ((2-methyl-4-quinazolinyl) amino) phenoxy) acetamide
    (II-24) N-hydroxy-3- (4- ((2-methyl-4-quinazolinyl) amino) phenoxy) propanamide
    (II-25) N-hydroxy-4- (4- ((2-methyl-4-quinazolinyl) amino) phenoxy) butanamide
    (II-26) N-hydroxy-5- (4- ((2-methyl-4-quinazolinyl) amino) phenoxy) valeramide
    (II-27) N-hydroxy-6- (4- ((2-methyl-4-quinazolinyl) amino) phenoxy) hexanamide
  4. The application of a compound shown in a formula (III), a tautomer thereof or a pharmaceutically acceptable salt thereof in preparing a medicament for treating neuropathic pain,
    wherein R is 1 、R 2 、R 3 Each independently is 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 NHR 5 、R 4 CONH-、R 4 NHCO-, guanidino-, ureido-, trifluoromethyl-, C 1-10 Alkanesulfonyl, substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclyl radicals, wherein R 4 Is C 1-10 Alkyl or benzyl, R 5 Is hydrogen or C 1-10 Alkyl of (a); preferably, R 1 Is hydrogen or C 1-6 An alkoxy group; more preferably, R 1 Is hydrogen or C 1-4 An alkoxy group; most preferably, R 1 Is hydrogen or methoxy; preferably, R 2 、R 3 Independently hydrogen or C 1-6 An alkyl group; more preferably, R 2 、R 3 Independently hydrogen or C 1-4 An alkyl group; most preferably, R 2 、R 3 Independently of which is hydrogen or a methyl group,
    linker is a key; - (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 a substituted benzenesulfonyl group, a substituted phenyl group, a phenyl group or a heterocyclic group,
    preferably, the benzene ring of the substituted phenyl contains 1 to 4 substituents, and the substituents of the substituted phenyl are halogen, -OH, -NO 2 Cyano, alkoxy, C 1-4 Is selected from the group consisting of an alkyl or amino group,
    preferably, the heterocyclyl is a saturated or unsaturated five-or six-membered heterocyclyl containing one or more heteroatoms selected from nitrogen, oxygen or sulfur;
    Preferably, the halogen is fluorine, chlorine, bromine or iodine,
    preferably, linker is- (CH) 2 ) n O-、-O(CH 2 ) n -wherein n is an integer from 1 to 10; more preferably, linker is- (CH) 2 ) n O-, wherein n is an integer from 1 to 10; most preferably, linker is- (CH) 2 ) n O-, wherein n is an integer from 1 to 5.
  5. Use according to claim 1 or 3, characterized in that the compound is selected from the group consisting of:
    (III-1) N-hydroxy-2- (2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) acetamide
    (III-2) N-hydroxy-4- (2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) butanamide
    (III-3) N-hydroxy-5- (2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pentanoic acid amide
    (III-4) N-hydroxy-6- (2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) hexanamide
    (III-5) N-hydroxy-4- ((2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) methyl) benzamide
    (III-6) N-hydroxy-4- (2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) benzamide
    (III-7) N-hydroxy-6- (2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) nicotinamide
    (III-8) N-hydroxy-5- (2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) picolinamide
    (III-9) N-hydroxy-2- (2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pyrimidine-5-carboxamide
    (III-10) N-hydroxy-5- (2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pyrimidine-2-carboxamide
    (III-11) N-hydroxy-5- (2-methoxy-5- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pyrazine-2-carboxamide
    (III-12) N-hydroxy-2- (3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) acetamide
    (III-13) N-hydroxy-4- (3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) butanamide
    (III-14) N-hydroxy-5- (3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) valeramide
    (III-15) N-hydroxy-6- (3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) hexanamide
    (III-16) N-hydroxy-4- ((3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) methyl) benzamide
    (III-17) N-hydroxy-4- (3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) benzamide
    (III-18) N-hydroxy-6- (3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) nicotinamide
    (III-19) N-hydroxy-5- (3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pyridine amide
    (III-20) N-hydroxy-2- (3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pyrimidine-5-carboxamide
    (III-21) N-hydroxy-5- (3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pyrimidine-2-carboxamide
    (III-22) N-hydroxy-5- (3- (methyl (2-methyl-4-quinazolinyl) amino) phenoxy) pyrazine-2-carboxamide
  6. The application of a compound shown in a formula (IV), a tautomer thereof or a pharmaceutically acceptable salt thereof in preparing a medicament for treating neuropathic pain,
    wherein R is 2 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 Alkanesulfonyl, substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclyl radicals, wherein R 4 Is C 1-10 Alkyl or benzyl, R 5 Is hydrogen or C 1-10 Alkyl of (a); preferably, R 2 Independently hydrogen or C 1-6 An alkyl group.
  7. Use according to claim 1 or 6, characterized in that said compound is selected from the group consisting of:
    (IV-1) 4- (5- (ethyl (2-methyl-4-quinazolinyl) amino) -2-methoxyphenyl) -N-hydroxybutyramide
    (IV-2) N-hydroxy-4- (2-methoxy-5- ((2-methyl-4-quinazolinyl) (propyl) amino) phenoxy) butanamide
    (IV-3) 4- (5- (butyl (2-methyl-4-quinazolinyl) amino) -2-methoxyphenyl) -N-hydroxybutyramide
    (IV-4) N-hydroxy-4- (2-methoxy-5- ((2-methyl-4-quinazolinyl) (pentyl) amino) phenoxy) butanamide
    (IV-5) N-hydroxy-4- (2-methoxy-5- ((methoxymethyl) (2-methyl-4-quinazolinyl) amino) phenoxy) butanamide
    (IV-6) N-hydroxy-4- (2-methoxy-5- (((methoxymethoxy) methyl) (2-methyl-4-quinazolinyl) amino) phenoxy) butanamide
  8. Use of a pharmaceutical composition comprising a compound according to any one of claims 1-7, and a pharmaceutically acceptable adjuvant for the manufacture of a medicament for the treatment of neuropathic pain;
    preferably, the pharmaceutical composition is a tablet, a suppository, a dispersible tablet, an enteric coated tablet, a chewable tablet, an orally disintegrating tablet, a capsule, a sugar-coated agent, a granule, a dry powder, an oral solution, a small injection needle, a freeze-dried injection needle or a large infusion;
    preferably, the pharmaceutically acceptable excipients include one or more of the following: diluents, solubilizers, disintegrants, suspending agents, lubricants, binders, fillers, flavoring agents, sweeteners, antioxidants, surfactants, preservatives, coating agents or pigments.
  9. The use according to any one of claims 1 to 8, wherein said neuropathic pain is selected from chronic back pain, post-herpetic neuralgia, diabetic neuropathic pain, myofibrotic pain, neuropathic pain induced with chemotherapeutics; in particular, the neuropathic pain is selected from diabetic neuropathic limb pain and chemotherapy drug-induced limb pain.
  10. The use according to claim 9, wherein the compound is compound III-2 of the formula, the pain is diabetic neuropathic pain and chemotherapy-induced neuropathic pain,
CN202280033602.XA 2021-05-12 2022-04-18 Application of 4-arylaminoquinazoline hydroxamic acid compound in preparation of pain medicines Pending CN117412752A (en)

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