Use of 4-arylaminoquinazoline hydroxamic acids in the preparation of medicaments for the treatment of pain

Abstract

The application discloses application of a series of 4-arylamino quinazoline hydroxamic acid compounds in preparation of medicines for treating neuropathic pain diseases, and particularly discloses application of a compound shown in formula III-2, a tautomer of the compound or a pharmaceutically acceptable salt of the compound in preparation of medicines for treating neuropathic pain diseases.

Description

Technical Field

[0001] This invention relates to the use of a series of 4-arylaminoquinazoline isohydroxamic acid compounds in the preparation of drugs for treating neuropathic pain, especially diabetic and chemotherapy-induced neuropathic pain. Background Technology

[0002] Neuropathic pain is pathological pain caused by damage or lesions to the peripheral or central nervous system. It includes pain caused by herpes zoster, peripheral neuropathy such as trigeminal neuralgia, and pathological pain such as diabetic neuropathic pain and pain induced by chemotherapy drugs. The main characteristics of this pain are anomalous pain (i.e., pain caused by harmless stimuli) and hyperalgesia (i.e., a pain response to increased stimuli).

[0003] Epigenetics has become a hot topic, with increasing research focus on its application in pain management. It is a heritable modification process that primarily includes DNA methylation, histone modifications, chromosomal remodeling, and RNA interference. Histone acetylation is an important mode of gene expression regulation among histone modifications. It is considered more unstable than both DNA methylation and histone methylation, representing a rapidly changing intracellular modification that promotes gene expression in response to environmental stimuli. Histone acetyltransferases catalyze the addition of acetyl groups to histones, promoting gene expression. Conversely, histone deacetylases catalyze the removal of acetyl groups from histones, thus reducing gene expression.

[0004] Currently, 11 deacetylases have been discovered and are classified into different groups based on their structure. Class I HDACs include 1, 2, 3, and 8; Class IIa HDACs include 4, 5, 7, and 9; Class IIb HDACs include 6 and 10; and Class IV is HDAC11. Different subtypes have different structures, different tissue distributions, different effects on pain, and vastly different regulatory physiological functions. Studies have shown that HDAC1 and HDAC2 play important roles in cancer pain, synaptic plasticity, and inflammatory pain. Therefore, the role of HDAC1 and HDAC2 in neuropathic pain within Class I HDACs has become a focus of our attention.

[0005] HDAC6, a class IIb HDAC, is mainly found in the cytoplasm of cells and has unique structure and function. It has two catalytic deacetylase domains and a zinc finger ubiquitin-binding domain. In the cytoplasm, it binds to various non-histone substrates, such as α-tubulin, ubiquitin, and heat shock protein 90 (HSP90), thereby regulating them. Therefore, HDAC6 is a key regulator for maintaining the balance between neuroprotection and neurodegeneration. Later, it was found that HDAC6 is involved in the regulation of neuropathic pain. Krukowski and Van et al. (Krukowski K, Ma J, Golonzhka O, et al. HDAC6 inhibition effectively reverses chemotherapy-induced peripheral neuropathy[J]. Pain, 2017, 158(6): 1126-1137. and Van Helleputte L, Kater M, Cook DP, et al. Inhibition of histone deacetylase 6 (HDAC6) protects against vincristine-induced peripheral neuropathies and inhibits tumor growth[J]. Neurobiol Dis, 2018, 111: 59-69.) found that antagonizing HDAC6 can improve chemotherapy-induced neuropathic pain.

[0006] In the experiments of Krukowski and Van et al., chemotherapy drugs disrupt neuronal axonal transport and microtubule dynamics, leading to chemotherapy-induced neurotoxicity and neuropathic pain. Acetylation 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-histone proteins, including α-tubulin, and is an important enzyme regulating α-tubulin acetylation levels. Therefore, inhibiting HDAC6 can increase α-tubulin acetylation levels in peripheral nerves, thereby increasing neuronal axonal transport capacity, improving microtubule stability, and alleviating chemotherapy-induced neuropathic pain.

[0007] Quinazolines are compounds formed by the fusion of a benzene ring and a pyrimidine ring. In medicine, quinazoline compounds have been found to have analgesic and anti-inflammatory activities.

[0008] Chinese patent CN200680001768.4, filed by Dr. Eastfin Laboratories Ltd. on January 9, 2006, discloses a substituted quinazoline compound and its use in the preparation of medicaments for treating pain, particularly neuropathic pain, as well as stroke, drug addiction and epilepsy.

[0009]

[0010] Chinese patent CN200480011981.4, applied for by Wotech Pharmaceuticals Co., Ltd. on March 3, 2004, discloses a substituted quinazoline compound and a method for using it to treat diseases such as neuropathic or inflammatory pain.

[0011]

[0012] US Patent US2009111772, filed by CAI XIONG et al. on 2008.09.10, discloses an HDAC inhibitor on 2009.04.30, which can be used to treat diseases with histone deacetylase (HDAC) dysregulation, including discogenic pain.

[0013]

[0014] Chinese Patent CN201680015470.2, filed by Guangdong Zhong Sheng Pharmaceutical Co., Ltd. on March 17, 2016, and disclosed on December 1, 2017, a series of 4-arylaminoquinazoline isohydroxamic acid compounds. This series of compounds exhibits histone deacetylase inhibitory activity, particularly high selective activity against HDAC6, HADC1, and HADC2, while showing lower selective inhibitory activity against other HDACs, demonstrating excellent efficacy in tumor treatment. Its selective inhibition of HDACs can reduce side effects caused by low selectivity during drug use. In subsequent research, the inventors were pleasantly surprised to find that this series of compounds also possesses a certain analgesic effect on neuropathic pain, especially for diabetic neuropathic pain and chemotherapy-induced neuropathic pain, providing new insights into the treatment of diabetes and cancer or chemotherapy-induced pain. Summary of the Invention

[0015] One object of the present invention is to provide the use of the compound of formula (I), its tautomers, or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating neuropathic pain.

[0016]

[0017] Wherein, R1 is one or more substituents;

[0018] R1, R2, and R3 are each independently hydrogen, halogen, and carbon. 1-10 Alkyl groups, oxygen-containing ether chains, nitrogen-containing alkane chains, R4O-, R4OC(O)-, R4C(O)O-, -NH2, -NO2, hydroxyamino, R4R5N-, R4CONH-, R4NHCO-, guanidino, urea, trifluoromethyl, C 1-10 alkylsulfonyl, substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclic groups;

[0019] R4 is C 1-10 Alkyl or benzyl groups;

[0020] R5 is hydrogen or C. 1-10 Alkyl groups;

[0021] Linker is a key, or -(CH2). n -、-(CH2) n O-, -O(CH2) n -、-O(CH2) n C(O)-、-C(O)(CH2) n O-, -OC(O)(CH2) n -、-(CH2) n C(O)O-、-(CH2) n C(O)NH-, -C(O)NH(CH2) n -、-(CH2) n SO2-, -SO2(CH2) n - or a substituted benzenesulfonyl group, a substituted phenyl group, a phenyl group, or a heterocyclic group, where n is an integer from 1 to 10;

[0022] Preferably, the substituted phenyl group has 1 to 4 substituents on its benzene ring, and the substituents are halogen, -OH, -NO2, cyano, alkoxy, C... 1-4 alkyl or amino groups;

[0023] Preferably, the heterocyclic group is a saturated or unsaturated five-membered or six-membered heterocyclic group containing one or more heteroatoms; the heteroatoms are selected from nitrogen, oxygen, or sulfur.

[0024] Preferably, the halogen is fluorine, chlorine, bromine, or iodine.

[0025] In the above-mentioned groups, the C 1-10 Alkyl groups are straight-chain, branched, or cyclic saturated hydrocarbons containing 1-10 carbon atoms. 1-10 Alkyl groups can be substituted (e.g., pyrrolidine-1-yl-C) 2-10 Alkyl, morpholin-1-yl-C 2-10 Alkyl or piperazine-1-C 2-10Alkyl) or unsubstituted; preferably, the present invention uses C 1-10 The alkyl group is methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, octyl, nonyl, or decyl;

[0026] Preferably, the R4O- used in this invention is benzyloxy, pyrrolidone-1-yl-C 2-10 Alkoxy, morpholin-1-yl-C 2-10 Alkyl or piperazine-1-C 2-10 Alkoxy;

[0027] Preferably, the R4OC(O)- used in this invention is ethaneoxycarbonyl, propaneoxycarbonyl, butaneoxycarbonyl, isobutaneoxycarbonyl, pentaneoxycarbonyl, hexaneoxycarbonyl, heptaneoxycarbonyl, octaneoxycarbonyl, nonaneoxycarbonyl, or decaneoxycarbonyl.

[0028] The R4C(O)O- used in this invention is ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate, pentyl acetate, hexyl acetate, heptyl acetate, octyl acetate, nonyl acetate, or decyl acetate;

[0029] Preferably, R4R5N- used in this 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.

[0030] Preferably, the R4CONH- used in this invention is acetamido, propionamido, butyramido, isobutyramido, pentamido, hexamido, heptaamido, octamido, nonamido, or decamido.

[0031] The C 1-10 The alkyl sulfonyl group is C as defined above. 1-10 The alkyl group is linked to a sulfonyl group, and is also linked to formula (I) via the sulfonyl group; preferably, the present invention uses C 1-10 The alkyl sulfonyl group is methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, pentanesulfonyl, hexanesulfonyl, heptasulfonyl, octanesulfonyl, nonanylsulfonyl, or decylsulfonyl.

[0032] Preferably, the present invention provides the use of the compound of formula (II), its tautomers, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating neuropathic pain.

[0033]

[0034] Among them, R2 and R3 are independently hydrogen, halogen, and C, respectively. 1-10 Alkyl groups, oxygen-containing ether chains, nitrogen-containing alkane chains, R4O-, R4OC(O)-, R4C(O)O-, -NH2, -NO2, hydroxyamino, R4NHR5, R4CONH-, R4NHCO-, guanidino, urea, trifluoromethyl, C 1-10 The alkylsulfonyl group, substituted benzenesulfonyl group, substituted phenyl group, phenyl group, or heterocyclic group, wherein R4 is C. 1-10 Alkyl or benzyl, R5 is hydrogen or C 1-10 Alkyl groups; preferably, R2 and R3 are each independently hydrogen or C. 1-6 Alkyl group; more preferably, R2 and R3 are each independently hydrogen or C. 1-4 Alkyl group; most preferably, R2 and R3 are each independently hydrogen or methyl;

[0035] Linker is a bond; -(CH2) n -、-(CH2) n O-, -O(CH2) n -、-O(CH2) n C(O)-、-C(O)(CH2) n O-, -OC(O)(CH2) n -、-(CH2) n C(O)O-、-(CH2) n C(O)NH-, -C(O)NH(CH2) n -、-(CH2) n SO2, -sulfonyl SO2-, or substituted benzenesulfonyl, substituted phenyl, phenyl or heterocyclic group, where n is an integer from 1 to 10;

[0036] Preferably, the substituted phenyl group has 1 to 4 substituents on its benzene ring, and the substituents are halogen, -OH, -NO2, cyano, alkoxy, C... 1-4 alkyl or amino groups;

[0037] Preferably, the heterocyclic group is a saturated or unsaturated five-membered or six-membered heterocyclic group containing one or more heteroatoms, wherein the heteroatoms are selected from nitrogen, oxygen or sulfur;

[0038] Preferably, the halogen is fluorine, chlorine, bromine, or iodine;

[0039] Preferably, the linker is -(CH2). n -, where n is an integer from 1 to 10; or -(CH2) m C6H4-, -C6H4(CH2) m-, where m is an integer from 0 to 5; or a saturated or unsaturated five-membered or six-membered heterocyclic group containing one or two heteroatoms selected from nitrogen; more preferably, the Linker is -(CH2). n -, where n is an integer from 1 to 5; or -(CH2) m Benzene-, where 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;

[0040] Furthermore, the present invention is based on the use of compounds of the following formula in the preparation of medicaments for treating neuropathic pain:

[0041] (II-1)N-Hydroxy-2-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)acetamide

[0042]

[0043] (II-2)N-Hydroxy-4-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)butyramide

[0044]

[0045] (II-3)N-hydroxy-5-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pentanamide

[0046]

[0047] (II-4)N-hydroxy-6-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)hexanoamide

[0048]

[0049] (II-5)N-Hydroxy-4-((4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)methyl)benzamide

[0050]

[0051] (II-6)N-hydroxy-4-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)benzamide

[0052]

[0053] (II-7)N-hydroxy-6-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)nicotinamide

[0054]

[0055] (II-8)N-hydroxy-5-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyridineamide

[0056]

[0057] (II-9)N-hydroxy-2-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrimidin-5-amide

[0058]

[0059] (II-10)N-hydroxy-5-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrimidine-2-amide

[0060]

[0061] (II-11)N-hydroxy-5-(4-(methyl(2-methyl-4-quinazolinyl)amino)phenoxypyrazine-2-amide

[0062]

[0063] (II-12)N-hydroxy-2-(4-(methyl(4-quinazolinyl)amino)phenoxy)acetamide

[0064]

[0065] (II-13)N-hydroxy-4-(4-(methyl(4-quinazolinyl)amino)phenoxy)butyramide

[0066]

[0067] (II-14)N-hydroxy-5-(4-(methyl(4-quinazolinyl)amino)phenoxy)pentanamide

[0068]

[0069] (II-15)N-hydroxy-6-(4-(methyl(4-quinazolinyl)amino)phenoxy)hexanoamide

[0070]

[0071] (II-16)N-hydroxy-4-((4-(methyl(4-quinazolinyl)amino)phenoxy)methyl)benzamide

[0072]

[0073] (II-17)N-hydroxy-4-(4-(methyl(4-quinazolinyl)amino)phenoxy)benzamide

[0074]

[0075] (II-18)N-hydroxy-6-(4-(methyl(4-quinazolinyl)amino)phenoxy)nicotinamide

[0076]

[0077] (II-19)N-hydroxy-5-(4-(methyl(4-quinazolinyl)amino)phenoxypyridine amide

[0078]

[0079] (II-20)N-hydroxy-2-(4-(methyl(4-quinazolinyl)amino)phenoxy)pyrimidin-5-carboxamide

[0080]

[0081] (II-21)N-hydroxy-5-(4-(methyl(4-quinazolinyl)amino)phenoxy)pyrimidin-2-carboxamide

[0082]

[0083] (II-22)N-hydroxy-5-(4-(methyl(4-quinazolinyl)amino)phenoxy)pyrazine-2-carboxamide

[0084]

[0085] (II-23)N-hydroxy-2-(4-((2-methyl-4-quinazolinyl)amino)phenoxy)acetamide

[0086]

[0087] (II-24)N-Hydroxy-3-(4-((2-methyl-4-quinazolinyl)amino)phenoxy)propionamide

[0088]

[0089] (II-25)N-hydroxy-4-(4-((2-methyl-4-quinazolinyl)amino)phenoxy)butyramide

[0090]

[0091] (II-26)N-hydroxy-5-(4-((2-methyl-4-quinazolinyl)amino)phenoxy)pentanamide

[0092]

[0093] (II-27)N-hydroxy-6-(4-((2-methyl-4-quinazolinyl)amino)phenoxy)hexanoamide

[0094]

[0095] Preferably, the present invention provides the use of the compound of formula (III), its tautomers, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating neuropathic pain.

[0096]

[0097] Among them, R1, R2, and R3 are each independently hydrogen, halogen, and carbon. 1-10 Alkyl groups, oxygen-containing ether chains, nitrogen-containing alkane chains, R4O-, R4OC(O)-, R4C(O)O-, -NH2, -NO2, hydroxyamino, R4NHR5, R4CONH-, R4NHCO-, guanidino, urea, trifluoromethyl, C 1-10 The alkylsulfonyl group, substituted benzenesulfonyl group, substituted phenyl group, phenyl group, or heterocyclic group, wherein R4 is C. 1-10 Alkyl or benzyl, R5 is hydrogen or C 1-10 Alkyl group; preferably, R1 is hydrogen or C 1-6 alkoxy group; more preferably, R1 is hydrogen or C 1-4 Alkyl group; most preferably, R1 is hydrogen or methoxy group; preferably, R2 and R3 are independently hydrogen or C. 1-6 Alkyl; more preferably, R2 and R3 are independently hydrogen or C. 1-4 Alkyl group; most preferably, R2 and R3 are independently hydrogen or methyl.

[0098] Linker is a bond; -(CH2) n -、-(CH2) n O-, -O(CH2) n -、-O(CH2) n C(O)-、-C(O)(CH2) n O-, -OC(O)(CH2) n -、-(CH2) n C(O)O-、-(CH2) n C(O)NH-, -C(O)NH(CH2) n -、-(CH2) n SO2-, -SO2(CH2) n - or a substituted benzenesulfonyl group, a substituted phenyl group, a phenyl group, or a heterocyclic group, where n is an integer from 1 to 10;

[0099] Preferably, the substituted phenyl group has 1 to 4 substituents on its benzene ring, and the substituents are halogen, -OH, -NO2, cyano, alkoxy, C... 1-4 alkyl or amino groups;

[0100] Preferably, the heterocyclic group is a saturated or unsaturated five-membered or six-membered heterocyclic group containing one or more heteroatoms; the heteroatoms are selected from nitrogen, oxygen, or sulfur.

[0101] Preferably, the halogen is fluorine, chlorine, bromine, or iodine.

[0102] Preferably, the linker is -(CH2). n O-, -O(CH2) n -, where n is an integer from 1 to 10; more preferably, the Linker is -(CH2). n O-, where n is an integer from 1 to 10; most preferably, the Linker is -(CH2). n O-, where n is an integer from 1 to 5;

[0103] Furthermore, this invention relates to the use of compounds selected from the following formula in the preparation of medicaments for treating neuropathic pain:

[0104] (III-1)N-hydroxy-2-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)acetamide

[0105]

[0106] (III-2)N-hydroxy-4-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)butyramide

[0107]

[0108] (III-3)N-hydroxy-5-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pentanamide

[0109]

[0110] (III-4)N-hydroxy-6-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)hexanoamide

[0111]

[0112] (III-5)N-hydroxy-4-((2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)methyl)benzamide

[0113]

[0114] (III-6)N-hydroxy-4-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)benzamide

[0115]

[0116] (III-7)N-hydroxy-6-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)nicotinamide

[0117] (III-8)N-hydroxy-5-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyridineamide

[0118]

[0119] (III-9)N-hydroxy-2-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrimidin-5-carboxamide

[0120]

[0121] (III-10)N-hydroxy-5-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrimidin-2-carboxamide

[0122]

[0123] (III-11)N-hydroxy-5-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrazine-2-carboxamide

[0124]

[0125] (III-12)N-hydroxy-2-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)acetamide

[0126]

[0127] (III-13)N-hydroxy-4-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)butyramide

[0128]

[0129] (III-14)N-hydroxy-5-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pentanamide

[0130]

[0131] (III-15)N-hydroxy-6-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)hexanoamide

[0132]

[0133] (III-16)N-hydroxy-4-((3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)methyl)benzamide

[0134]

[0135] (III-17)N-hydroxy-4-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)benzamide

[0136]

[0137] (III-18)N-hydroxy-6-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)nicotinamide

[0138]

[0139] (III-19)N-hydroxy-5-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyridineamide

[0140]

[0141] (III-20)N-hydroxy-2-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrimidin-5-carboxamide

[0142]

[0143] (III-21)N-hydroxy-5-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrimidin-2-carboxamide

[0144]

[0145] (III-22)N-hydroxy-5-(3-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)pyrazine-2-carboxamide

[0146]

[0147] Preferably, the present invention provides the use of the compound of formula (IV), its tautomers, or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating neuropathic pain.

[0148]

[0149] Wherein, R2 is independently hydrogen, halogen, or C. 1-10 Alkyl groups, oxygen-containing ether chains, nitrogen-containing alkane chains, R4O-, R4OC(O)-, R4C(O)O-, -NH2, -NO2, hydroxyamino, R4-O-CH2-, R4-O-CH2-O-CH2-, R4NHR5, R4CONH-, R4NHCO-, guanidino, ureoyl, trifluoromethyl, C 1-10 The alkylsulfonyl group, substituted benzenesulfonyl group, substituted phenyl group, phenyl group, or heterocyclic group, wherein R4 is C. 1-10 Alkyl or benzyl, R5 is hydrogen or C 1-10 Alkyl group; preferably, R2 is independently hydrogen or C. 1-6 alkyl;

[0150] Furthermore, this invention relates to the use of compounds selected from the following formula in the preparation of medicaments for treating neuropathic pain:

[0151] (IV-1)4-(5-(ethyl(2-methyl-4-quinazolinyl)amino)-2-methoxyphenyl)-N-hydroxybutyramide

[0152]

[0153] (IV-2)N-hydroxy-4-(2-methoxy-5-((2-methyl-4-quinazolinyl)(propyl)amino)phenoxy)butyramide

[0154]

[0155] (IV-3)4-(5-(butyl(2-methyl-4-quinazolinyl)amino)-2-methoxyphenyl)-N-hydroxybutyramide

[0156]

[0157] (IV-4)N-hydroxy-4-(2-methoxy-5-((2-methyl-4-quinazolinyl)(pentyl)amino)phenoxy)butyramide

[0158]

[0159] (IV-5)N-hydroxy-4-(2-methoxy-5-((methoxymethyl)(2-methyl-4-quinazolinyl)amino)phenoxy)butyramide

[0160]

[0161] (IV-6)N-hydroxy-4-(2-methoxy-5-(((methoxymethoxy)methyl)(2-methyl-4-quinazolinyl)amino)phenoxy)butyramide

[0162]

[0163] According to another aspect of the invention, there is also a pharmaceutical composition for use in the preparation of a medicament for treating neuropathic pain, the pharmaceutical composition comprising all of the compounds described above, their tautomers or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients.

[0164] The dosage form of the pharmaceutical composition may be tablets, suppositories, dispersible tablets, enteric-coated tablets, chewable tablets, orally disintegrating tablets, capsules, sugar-coated tablets, granules, dry powder, oral solutions, small injection needles, lyophilized powder for injection, or large-volume infusions.

[0165] 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, encapsulating agents, or colorants.

[0166] The use of the compounds or compositions according to the present invention in the preparation of medicaments for treating neuropathic pain, wherein the neuropathic pain is selected from chronic back pain, postherpetic neuralgia, diabetic neuropathic pain, myofibromyalgia, and chemotherapy-induced neuropathic pain; specifically, the aforementioned neuropathic pain is selected from diabetic neuropathic limb pain and chemotherapy-induced limb pain.

[0167] Furthermore, according to the application described in this invention, the compound is compound III-2 as shown in the following formula, and the pain is diabetic neuropathic pain and chemotherapy-induced neuropathic pain.

[0168]

[0169] Related definitions

[0170] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0171] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0172] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound having specific substituents discovered in this invention with a relatively non-toxic acid or base. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a neutral form of such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, tannates, citrates, trifluoroacetate, and similar acids; as well as salts of amino acids (such as arginine) 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 thus can be converted into either a base or an acid addition salt.

[0173] Preferably, the preparation method of the above-mentioned pharmaceutically acceptable salt is as follows: the salt is contacted with a base or acid in a conventional manner, and then the parent compound is separated, thereby regenerating the neutral form of the compound. The parent form of the compound differs from its various salt forms in certain physical properties, such as different solubilities in polar solvents.

[0174] The "pharmaceutically acceptable salts" described herein are derivatives of the compounds of this invention, obtained by modifying the parent compound through salt formation with an acid or a base. Examples of pharmaceutically acceptable salts include, but are not limited to: bases such as inorganic or organic acid salts of amines, anions such as alkali metal or organic salts of carboxylic acids, etc. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, such as salts formed from non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids, wherein the inorganic or organic acids are selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edemacid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucohepose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxy, hydroxynaphthalene, hydroxyethanesulfonic acid, lactic acid, lactose, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, dihydroxynaphthalic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, aminosulfonic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, tartaric acid, and p-toluenesulfonic acid.

[0175] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both. Generally, non-aqueous media such as ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

[0176] In addition to the salt form, the compounds provided by this invention also exist in prodrug form. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to transform into the compounds of this invention. Furthermore, prodrugs can also be converted into the compounds of this invention in the in vivo environment by chemical or biochemical methods.

[0177] Some compounds of this invention can exist in either a solvated or a solvent-based form, including hydrated forms. Generally, the solvent-based and solvated forms are equally effective and are both included within the scope of this invention.

[0178] Some compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Therefore, racemates, diastereomers, geometric isomers, and single isomers are all included within the scope of the compounds of the present invention.

[0179] Unless otherwise stated, wedge keys and dashed keys are used in this invention. The absolute configuration of the center of a solid is represented by... The relative configuration of a stereocenter is indicated. When the compounds described herein contain alkene double bonds or other geometrically asymmetric centers, they include E and Z geometric isomers unless otherwise specified. Similarly, all their tautomers are included within the scope of this invention.

[0180] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention relates to all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this 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 this invention.

[0181] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, by separating the resulting diastereomeric mixture and cleaving the auxiliary group to provide a pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0182] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). All isotopic variations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0183] The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of the active substance of the present invention without interfering with the biological activity of the active substance and without toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, ointment bases, lotion bases, and ointment bases. These bases include suspending agents, thickeners, transdermal penetration enhancers, etc. The use of such substances to assist in the preparation of formulations is well known to those skilled in the art of cosmetics or topical pharmaceuticals. For further information on carriers, see Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0184] For pharmaceuticals or pharmacologically active agents, the term "effective amount" or "therapeutic effective amount" refers to a sufficient quantity of a drug or agent that is non-toxic but achieves the desired effect. For the oral dosage forms of this invention, the "effective amount" of one active substance in the composition refers to the amount required to achieve the desired effect, or the amount required to achieve the desired effect when the active ingredient is used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. A suitable effective amount in any given case can be determined by those skilled in the art through routine testing.

[0185] The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat a target disorder, disease, or symptom.

[0186] "Optional" or "optionally" means that the event or condition described below may occur but is not required to occur, and the description includes both the scenario in which said event or condition occurs and the scenario in which said event or condition does not occur.

[0187] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, provided that the valence state 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 replaced. Ketone substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents can be arbitrary on a chemically feasible basis.

[0188] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Therefore, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the option of R is independent in each case. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0189] Unless otherwise specified, "ring" means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloynyl, heterocycloynyl, aryl, or heteroaryl. The term "ring" includes monocyclic, tandem, spirocyclic, fused, or bridged rings. The number of atoms on a ring is generally defined as the elemental number of the ring; for example, "5- to 7-membered ring" refers to a ring with 5 to 7 atoms arranged in a ring. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms. Thus, "5- to 7-membered ring" includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term "5- to 7-membered heterocyclic alkyl ring" includes piperazinyl and piperidinyl, but not phenyl. The term "ring" also includes ring systems containing at least one ring, each of which independently meets the above definition.

[0190] Examples of heterocyclic compounds include, but are not limited to: pyridinyl, pyrroloyl, pyrimidinyl, imidazolyl, pyridazinyl, triazinyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolyl, 2H-pyrroloyl, tetrazolyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl.

[0191] Unless otherwise specified, the term "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group, which may be monosubstituted (e.g., -CH2F) or polysubstituted (e.g., -CF3), and may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (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), etc.

[0192] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0193] All solvents used in this invention are commercially available and can be used without further purification.

[0194] This invention uses the following abbreviations: Pen. represents pentoxifylline; INT-747 represents 6-ethylchenodeoxycholic acid; aq represents water; HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate; EDC represents N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents equivalent; CDI represents carbonyl diimidazole; DCM represents dichloromethane; PE represents petroleum ether; DIAD represents diazobiscarboxylic acid. Isopropyl ester; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; CBz represents benzyloxycarbonyl, an amine protecting group; BOC represents tert-butylcarbonyl, an amine protecting group; HOAc represents acetic acid; NaCNBH3 represents sodium cyanoborohydride; rt represents room temperature; O / N represents overnight; THF represents tetrahydrofuran; Boc2O represents di-tert-butyldicarbonate; TFA represents trifluoroacetic acid; DIPEA represents diisopropylethyl Amine; SOCl2 represents thionyl chloride; CS2 represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI represents N-fluoro-N-(benzenesulfonyl)benzenesulfonamide; NCS represents 1-chloropyrrolidine-2,5-dione; n-Bu4NF represents tetrabutylammonium fluoride; iPrOH represents 2-propanol; mp represents melting point; LDA represents lithium diisopropylamino; TMSCF3 represents trifluoromethyltrimethylsilane; Ti(Oi-Pr)4 represents tetraisopropyl titanate; MSCl represents methanesulfonyl chloride; DMAP represents N,N-dimethyl- 4-Aminopyridine; TEA represents triethylamine; BnBr represents benzyl bromide; DIEA represents diisopropylethylamine; BH3DMS represents borane dimethyl sulfide; DMP represents dimethinol periodide; TBAF represents tetrabutylamine fluoride; HOBT represents 1-hydroxybenzotriazole; AIBN represents azobisisobutyronitrile; NBS represents N-bromosuccinimide; RT buffer represents reverse transcription buffer; dNTP represents deoxyribonucleoside triphosphate; PBS represents phosphate buffer; CMCNa represents sodium carboxymethyl cellulose; STZ represents streptozotocin.

[0195] Compounds are processed manually or Software naming conventions are used; commercially available compounds use supplier catalog names. Attached Figure Description

[0196] Figure 1 The mechanical stimulation threshold for paw withdrawal in rats was compared with that of the model control group 1; where * represents p<0.05 compared with the model control group 1.

[0197] Figure 2 Weight change curves for each group of animals.

[0198] Figure 3 Statistical graph of mechanical paw withdrawal pain threshold in each group of animals (Mean±SEM), * represents p<0.05 vs model, ** represents p<0.01 vs model. Detailed Implementation

[0199] All compounds in this invention were prepared according to the preparation method disclosed in CN201680015470.2.

[0200] Example 1: Pharmacodynamic study of a rat STZ-induced diabetic peripheral neuropathy pain model

[0201] Experimental Objective: To investigate the behavior of peripheral neuropathic pain caused by diabetic peripheral neuropathy using an STZ-induced type 1 diabetic rat model in SD rats, and to evaluate the therapeutic effect of the test product in the diabetic neuropathic pain animal model by observing changes in rat sensitivity to mechanical stimulation.

[0202] Experimental model: STZ-induced type 1 diabetes animal model in SD rats

[0203] Experimental animals: SD rats (Speford (Beijing) Biotechnology Co., Ltd.)

[0204] Experimental reagents:

[0205] 1. Gabapentin (Shanghai Haohong Biomedical Technology Co., Ltd.);

[0206] 2.0.5% CMCNa (Sigma-Aldrich (Shanghai) Trading Co., Ltd.);

[0207] 3.0.9% Sodium Chloride Injection (Sichuan Kelun Pharmaceutical Co., Ltd.);

[0208] 4. Sodium pentobarbital (Merck);

[0209] 5. Streptozotocin (Sigma-Aldrich (Shanghai) Trading Co., Ltd.);

[0210] 6. Test compound III-2

[0211] Experimental methods:

[0212] 1. Preparation and storage of STZ solution

[0213] Solution A: Weigh 1.471g of sodium citrate into a 50mL sterile centrifuge tube, and use a 50mL syringe to draw 50.0mL of physiological saline into the centrifuge tube and dissolve it evenly;

[0214] Solution B: Weigh 0.995g of citric acid into a 50mL sterile centrifuge tube, and use a 50mL syringe to draw 50.0mL of physiological saline into the centrifuge tube and dissolve it evenly;

[0215] Citrate buffer: Mix solution A and solution B at a 1:1 ratio, and adjust the pH to 4.5 with solution A or solution B. Filter the solution through a 0.22μm disposable syringe filter in a clean bench for sterilization. Dispense into 50mL tubes, label them, and store at -20℃ for later use.

[0216] Streptozotocin (STZ) solution: Before modeling, weigh 240 mg of streptozotocin per tube and place it in a 50 mL sterile centrifuge tube wrapped in aluminum foil. Place the tube in an ice box and add 40 mL of aliquoted citrate buffer just before use. Mix well to prepare a 6 mg / mL streptozotocin (STZ) solution. Use within 15 minutes. Discard any unused portion.

[0217] 2. STZ-induced diabetic animal model

[0218] Rats were intraperitoneally injected with STZ at a dose of 65 mg / kg, as a single injection. Animals were fasted for at least 12 hours before injection. On the day of injection, the drinking water of the rats was replaced with a 10% sucrose solution (to prevent hypoglycemia in rats).

[0219] 3. Grouping

[0220] This study includes Experiment I and Experiment II. Experiment I includes one model control group, one positive control group and one test sample group. Experiment II includes one model control group and one test sample group.

[0221] Grouping method: Type I diabetic SD rats with diabetic neuropathic pain were selected and randomly grouped according to their mechanical stimulation withdrawal threshold.

[0222] Table 1 Animal Grouping Table 1

[0223]

[0224] Table 2 Animal Grouping Table 2

[0225]

[0226] Note: The first letter of the animal number represents the experimental stage, the first digit represents the group (1, 2 and 3 represent the model control group, positive control group and test sample group, respectively); the second letter represents the sex (M is male), and the last 3 digits represent the animal serial number.

[0227] 4. Administration

[0228] Experiment I: The model control group was given the solvent, while the other groups were given different doses of the drug. Since the animals in the 75 mg / kg dose group (Bid) of the test product developed severe diarrhea as a toxic side effect on the 3rd day of administration, the administration frequency was changed to once a day on the 3rd and 4th days. Furthermore, 4 animals in this group died on the 4th day of administration, so administration was stopped on the 5th day. For details, please refer to Table 3 below.

[0229] Experiment II: The model control group received the solvent, while the drug treatment group received the test drug twice daily for 5 days. See Table 4 below for details.

[0230] Table 3 Dosage Design Table 1

[0231]

[0232] Note: The day of model establishment is defined as D0, grouping is on D27, and drug administration begins on D28. Qd: once a day, Bid: twice a day.

[0233] Table 4 Dosage Design Table 2

[0234]

[0235] Note: The day of model establishment is defined as D0, grouping is on day 37, and drug administration begins on day 38, Bid: twice a day.

[0236] 5. Testing

[0237] Mechanical stimulation threshold for foot withdrawal

[0238] Testing time: STZ was tested once before modeling, once before grouping, once on days 1, 4 and 8 after administration to animals in Experiment I, and once on days 1 and 5 after administration to animals in Experiment II.

[0239] Methods: Animals were placed in the test box for 30 minutes each day for three consecutive days before the test. Before each test, the animals were placed in the test box for 15 minutes to adapt. Each animal was tested 3 times and the average value was taken. There was at least a 5-minute interval between each test.

[0240] 6. Experimental Results

[0241] The mechanical irritation withdrawal threshold of rats began to decrease on day 14 after STZ injection, and decreased to 50% on day 21. On day 25, the mechanical irritation withdrawal threshold of the animals was basically the same as that on day 21, indicating that the mechanical irritation withdrawal threshold of the animals had basically been reduced to the lowest level at this time. Therefore, this experiment chose to start drug intervention on day 28.

[0242] like Figure 1As shown in Tables 5 and 6, the results of Experiment I showed that after drug intervention, the mechanical withdrawal threshold of rats treated with the positive control drug gabapentin (150 mg / kg, Qd) was significantly increased, with a statistically significant difference compared to the model control group (P<0.05). The test compound III-2 75 mg / kg (bid, 2d, qd, 2d) group showed a significant increase in the mechanical withdrawal threshold of rats after the first administration (D28), with a statistically significant difference compared to the model control group (P<0.05). Furthermore, 3 days after drug withdrawal (D34), the mechanical withdrawal threshold of rats remained at the level at the time of administration, with a statistically significant difference compared to the model control group (P<0.05). The results of Experiment II showed that the test compound III-2 15 mg / kg (bid, 5d) group also showed a significant increase in the mechanical withdrawal threshold of rats after the first administration (D38), with a statistically significant difference compared to the model control group (P<0.05).

[0243] Table 5. Mechanical stimulation threshold for foot withdrawal in rats (g)

[0244]

[0245] Note: * indicates p<0.05, compared with the model control group 1; all data in PRE to D31 in the table are from 8 animals (n=8), data in the model group and positive drug group on day D34 are from 8 animals, and data in the test sample group are from 3 animals; pre represents before modeling, the day of modeling is D0, D14 represents the 14th day after modeling, and so on.

[0246] Table 6. Mechanical stimulation-induced foot withdrawal threshold 2 (g) in rats

[0247]

[0248] Note: * indicates p<0.05, compared with the model control group 1; all data in each group in the table are from 5 animals (n=5); pre represents before modeling, the day of modeling is D0, D14 represents the 14th day after modeling, and so on.

[0249] In summary, compound III-2 significantly increased the mechanical withdrawal threshold in SD rats with diabetic neuropathic pain at doses of 75 mg / kg (bid, 2d, qd, 2d) and 15 mg / kg (bid, 5d), indicating that the compound has a good analgesic effect at these doses.

[0250] Example 2: Pharmacodynamic study of a paclitaxel-induced pain model in rats

[0251] Experimental objective: To evaluate whether the test product has a therapeutic and relieving effect on paw pain in rats using a paclitaxel-induced pain model.

[0252] Experimental model: Paclitaxel-induced pain model in rats

[0253] Laboratory animals: SD rats (Chengdu Dashuo Laboratory Animal Co., Ltd.)

[0254] Experimental reagents:

[0255] 1. Paclitaxel Injection (Yangtze River Pharmaceutical Group Co., Ltd.);

[0256] 2.0.5% CMC-Na (Chengdu Kelong Chemical Reagent Factory);

[0257] 3.0.9% Sodium Chloride Injection (Sichuan Kelun Pharmaceutical Co., Ltd.);

[0258] 4. Test compound III-2

[0259] Experimental methods:

[0260] 1. Preparation of test sample / reference standard

[0261] Preparation of solvent reference standard: Add an appropriate amount of CMC-Na to purified water, vortex and mix well to prepare a 0.5% CMC-Na (w / v) solvent reagent solution.

[0262] Preparation of the test sample: Weigh an appropriate amount of the drug, add 0.5% CMC-Na, and mix by sonication and vortexing. Obtain a suspension with a final concentration of 0.3 mg / mL.

[0263] 2. Paclitaxel-induced pain model in rats

[0264] Forty-five Sprague Dawley (SD) rats were purchased and acclimatized for 7 days. Forty rats were then selected to undergo modeling by intraperitoneal injection (ip) of 2 mg / kg paclitaxel solution. The injection was administered every other day for four consecutive days. The remaining five rats were injected intraperitoneally with saline as a normal control group. On the fourth day after modeling, the mechanical pain threshold (baseline) of the 40 model animals and the 5 saline group animals was measured using the von Frey up-down method. Twenty successful model animals were then selected for drug administration.

[0265] 3. Grouping

[0266] Twenty rats selected for the model were randomly divided into two groups of 10 each. Five rats that received intraperitoneal injections of saline served as the normal control group. The administration of drugs was carried out according to the table below:

[0267]

[0268] 4. Weight measurement

[0269] Weight should be measured every 2 days during the medication period.

[0270] 5. Mechanical pain threshold measurement

[0271] The mechanical pain threshold of rats was measured using the von Frey up-and-down method 1 hour after the first dose on days 1, 4, and 7, and 3 days after drug withdrawal, and the mechanical paw withdrawal pain threshold (50% PWT) was calculated.

[0272] 6. Data Analysis

[0273] The nonparametric Mann-Whitney test was used, and P < 0.05 was defined as statistically significant.

[0274] 7. Experimental Results

[0275] Weight: See details on weight changes. Figure 2 During the administration period, the body weight of all groups increased.

[0276] Mechanical threshold: Statistics on mechanical foot withdrawal pain threshold can be found in [link to relevant documentation]. Figure 3 During the administration period, the 50% PWT in the normal group was significantly higher than that in the model group (p<0.01). In the compound III-2 3mg / kg group, the 50% PWT was significantly higher than that in the model group 1 hour after the first dose on days 4 and 7 (p<0.01, p<0.05). On day 3 after drug withdrawal (D10), the 50% PWT in the normal group was significantly higher than that in the model group (p<0.01), and the 50% PWT in the compound III-2 3mg / kg group was significantly higher than that in the model group (p<0.05).

[0277] 8. Conclusion

[0278] In the examples, compound III-2 was administered at a dose of 3 mg / kg for 7 consecutive days, twice daily, which significantly relieved paclitaxel-induced paw pain in rats. Compared with the normal group and the model group, there was no significant decrease in body weight, indicating that the compound has good analgesic effect and safety at this dose.

[0279] The inventors then selected 10 rats from the remaining 20 model animals in Part 2 and administered the HDAC inhibitor Voronostat (SAHA) at the same dose (3 mg / kg) and dosing cycle and frequency (Bid, 7 days) as compound III-2. The results showed that the weight of the animals in the Voronostat group did not decrease significantly. However, there was no significant difference in 50% PWT between the Voronostat group and the model group at 1 hour after the first dose on days 4 and 7, and on day 3 after drug withdrawal (D10). This indicates that under the same dosage conditions, Voronostat did not significantly relieve paclitaxel-induced paw pain in rats.

Claims

1. The application of compounds of formula (III-2) in the preparation of drugs for treating neuropathic pain. The compound of formula (III-2) is named (III-2)N-hydroxy-4-(2-methoxy-5-(methyl(2-methyl-4-quinazolinyl)amino)phenoxy)butyramide; the structural formula of the compound of formula (III-2) is: 。 2. The use of a pharmaceutical composition in the preparation of a medicament for treating neuropathic pain, said pharmaceutical composition comprising a compound of formula (III-2) according to claim 1, and pharmaceutically acceptable excipients; said medicament being a suppository, dispersible tablet, enteric-coated tablet, chewable tablet, orally disintegrating tablet, capsule, sugar-coated tablet, granule, dry powder, oral solution, small injection needle, lyophilized powder for injection, or large-volume parenteral solution; said pharmaceutically acceptable excipients comprising one or more of the following: diluents, solubilizers, disintegrants, suspending agents, lubricants, binders, fillers, flavoring agents, antioxidants, surfactants, preservatives, encapsulating agents, or pigments.

3. The application according to any one of claims 1-2, characterized in that, The neuropathic pain is selected from chronic back pain, postherpetic neuralgia, diabetic neuropathic pain, fibromyalgia, and chemotherapy-induced neuropathic pain.

4. The application according to claim 3, characterized in that, The neuropathic pain is selected from diabetic neuropathic limb pain or chemotherapy-induced limb pain.

5. The application according to claim 1, characterized in that, The neuropathic pain mentioned refers to diabetic neuropathic pain or neuropathic pain induced by chemotherapy drugs.

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