WO2019110006A1 - 抗疼痛化合物及其制备方法 - Google Patents

抗疼痛化合物及其制备方法 Download PDF

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WO2019110006A1
WO2019110006A1 PCT/CN2018/119785 CN2018119785W WO2019110006A1 WO 2019110006 A1 WO2019110006 A1 WO 2019110006A1 CN 2018119785 W CN2018119785 W CN 2018119785W WO 2019110006 A1 WO2019110006 A1 WO 2019110006A1
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group
dxl
compound
pharmaceutically acceptable
tautomer
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PCT/CN2018/119785
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English (en)
French (fr)
Inventor
李润涛
叶加
王欣
葛泽梅
梁莹莹
杜小雷
王丁
张贵民
姚景春
赵桂芳
Original Assignee
北京大学
鲁南制药集团股份有限公司
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Priority to BR112020011397-2A priority Critical patent/BR112020011397A2/pt
Priority to KR1020207019577A priority patent/KR20200096947A/ko
Priority to CN202211090920.8A priority patent/CN115611904A/zh
Priority to EP18886979.6A priority patent/EP3722299A4/en
Priority to JP2020530682A priority patent/JP2021505594A/ja
Priority to US16/770,533 priority patent/US11795174B2/en
Priority to CN202211090254.8A priority patent/CN115850287A/zh
Priority to CN202211090938.8A priority patent/CN116178378A/zh
Application filed by 北京大学, 鲁南制药集团股份有限公司 filed Critical 北京大学
Priority to CN202211090261.8A priority patent/CN116178377A/zh
Priority to RU2020122252A priority patent/RU2791108C2/ru
Priority to CN202211090249.7A priority patent/CN115785105A/zh
Priority to CN201880077143.9A priority patent/CN111417637B/zh
Publication of WO2019110006A1 publication Critical patent/WO2019110006A1/zh
Priority to JP2022093166A priority patent/JP2022130435A/ja

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    • 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]
    • 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
    • A61K31/499—Spiro-condensed pyrazines or piperazines
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/547—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame spiro-condensed or forming part of bridged ring systems
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/10—Spiro-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to novel compounds for treating neuropathic pain and/or neuropathic pain syndrome, and methods for their preparation and use.
  • Pain is a common disease, and pain is divided into three categories: physiological pain, inflammatory pain, and neuropathic pain (NPP).
  • NPP neuropathic pain
  • Neuropathic pain is a relatively common type of disease in the clinic.
  • IASP International Pain Society
  • Pain caused by damage or disease of the somatosensory system Neuropathic pain is caused by, for example, damage or dysfunction of the surrounding or central nervous system, and is a clinically intractable chronic pain that lacks effective treatment.
  • the diseases of neuropathic pain include, for example, diseases exhibiting symptoms of hyperalgesia or allodynia, such as post-herpetic neuralgia, trigeminal neuralgia, diabetic neuropathic pain, and postoperative persistent or post-traumatic pain.
  • hyperalgesia or allodynia diseases exhibiting symptoms of hyperalgesia or allodynia, such as post-herpetic neuralgia, trigeminal neuralgia, diabetic neuropathic pain, and postoperative persistent or post-traumatic pain.
  • neuropathic pain Although both belong to chronic pain, there is a fundamental difference between neuropathic pain and inflammatory pain.
  • Prior art treatments for neuropathic pain include the use of traditional analgesics such as non-steroidal anti-inflammatory drugs and opioids, as well as other drugs including anticonvulsants and tricyclic antidepressants (Max, MBAnn. Neurol, 35 (Suppl): S50-S53 (1994); Raja, SN et al, Neurology, 59: 1015 (2002); Galer, BS et al, Pain, 80: 533 (1999)).
  • these drugs do not adequately relieve pain or have undesirable side effects such as drug resistance and addiction risk.
  • the spiropiperazine quaternary ammonium salt compound is a structure of the quaternary ammonium nicotinic receptor agonist 1,1-dimethyl-4-phenylpiperazine iodide (DMPP) from the research group of Peking University Li Runtao. A class of compounds that have been modified. It has been reported that spiropiperazine quaternary ammonium compounds are studied for analgesic activity, and such compounds are not addictive (see Yue, CQ, Ye, J., Li, CL, Li, RT, Sun, Q., 2007. Antinociceptive effects of the novel spirocyclopiperazinium salt compound LXM-10in mice. Pharmacol Biochem Behav 86, 643-650).
  • DMPP quaternary ammonium nicotinic receptor agonist 1,1-dimethyl-4-phenylpiperazine iodide
  • Its analgesic mechanism may be related to agonistic cholinergic receptors (see: Zhao, X., Ye, J., Sun, Q., Xiong, Y., Li, R., Jiang, Y., 2011. Antinociceptive). Effect of spirocyclopiperazinium salt compound LXM-15via activating peripheral alpha7nAChR and M4mAChR in mice. Neuropharmacology 60, 446-452).
  • the present invention provides a compound represented by the following formula (I), or a stereoisomer, tautomer, derivative, prodrug or pharmaceutically acceptable salt thereof:
  • R 1 is selected from the group consisting of hydrogen, halogen, alkyl, cyano and haloalkyl.
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl and nitro, and R 1 , R 2 and R 3 are not simultaneously hydrogen;
  • R 2 and R 3 when one of R 2 and R 3 is a nitro group or a halogen, the other two of R 1 , R 2 and R 3 are not hydrogen at the same time.
  • halogen as used in the present invention means a fluorine, chlorine, bromine and iodine atom, preferably a fluorine, chlorine or bromine atom.
  • halo refers to fluoro, chloro, bromo or iodo.
  • alkyl as used in the present invention is a straight or branched alkyl group having 1 to 6 carbon atoms, more preferably a linear or branched alkyl group having 1 to 3 carbon atoms, particularly preferably a methyl group. , ethyl or propyl.
  • haloalkyl refers to an alkyl group as defined above substituted by one or more, preferably one to five, halogen atoms, as defined in the present application.
  • Haloalkyl includes monohaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, and the like, such as chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl. Base, perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl, and the like.
  • the halogenated alkyl group may preferably be a trihaloalkyl group, and more preferably a trifluoromethyl group.
  • nitro refers to a -NO 2 group.
  • cyano refers to a -CN group.
  • R 2 and R 3 are each independently selected from alkyl, haloalkyl and nitro, and R 1 is hydrogen.
  • R 2 and R 3 are each independently selected from methyl, ethyl, trifluoromethyl or nitro, and R 1 is hydrogen.
  • the compound of the present invention is represented by the following formula (II):
  • R 1 is selected from the group consisting of hydrogen, halogen, alkyl, cyano and haloalkyl.
  • R 2 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl and nitro, and R 1 and R 2 are not simultaneously hydrogen.
  • R 1 is selected from the group consisting of halogen, alkyl, cyano and haloalkyl
  • R 2 is selected from the group consisting of halogen, alkyl, haloalkyl and nitro.
  • R 1 is selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, cyano and trifluoromethane
  • R 2 is selected from the group consisting of fluorine, chlorine, bromine, methyl, and B.
  • Base trifluoromethane and nitro group.
  • R 1 and R 2 are both halogen.
  • the R 1 is selected from hydrogen, halogen or haloalkyl; and R 2 is selected from hydrogen or nitro.
  • R 1 is selected from alkyl, cyano, halo or haloalkyl, and R 2 is hydrogen.
  • R 1 is selected from halo or haloalkyl, and R 2 is hydrogen.
  • the alkyl group is selected from the group consisting of methyl, ethyl or propyl.
  • the haloalkyl group is a trifluoromethyl group.
  • Preferred compounds of the invention are selected from the group consisting of
  • the compounds of the present invention can be prepared according to conventional methods in the art, preferably in accordance with the following reaction scheme:
  • the invention provides a process for the preparation of a compound of formula (I), which process comprises the steps of:
  • the halogenated benzene reagent may be selected from the group consisting of trifluoromethyl-substituted bromobenzene, trifluoromethyl-substituted iodobenzene; difluoromethyl-substituted bromobenzene, difluoromethyl-substituted iodobenzene; Iodobenzene; nitro-substituted chlorobenzene, nitro-substituted bromobenzene, nitro-substituted iodobenzene, and the like.
  • the metal catalyst may be selected from the group consisting of palladium chloride, copper acetate, propylene iodide, ferric chloride, and the like; preferably, iodide iodide.
  • the ligand may be selected from different ⁇ -amino acids, o-hydroxybenzamide, binaphthol, and the like. Among them, the ligand is preferably dinaphthol.
  • the base may be selected from the group consisting of an organic base and an inorganic base such as pyridine, triethylamine, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, cesium carbonate, potassium phosphate, Sodium phosphate, etc.
  • the base is preferably potassium phosphate.
  • the solvent used is an alcohol, a ketone, a nitrile, a chlorinated hydrocarbon solvent, a benzene solvent, DMSO or DMF, wherein the alcohol solvent is, for example, methanol, ethanol or isopropanol.
  • a ketone solvent such as acetone, methyl ethyl ketone or the like
  • the nitrile solvent such as acetonitrile
  • the chlorinated hydrocarbon solvent such as dichloromethane, chloroform or the like
  • the benzene solvent such as benzene; Toluene, xylene, and the like.
  • Preferred solvents are methanol, ethanol, isopropanol, acetonitrile, acetone, toluene, benzene, DMSO, DMF, chloroform or dichloromethane, and a more preferred solvent is DMF.
  • the preferred reaction temperature is 100 °C.
  • the reaction time may be from 6 h to 48 h, preferably from 12 h to 32 h, more preferably 24 h.
  • the organic solvent is selected from an alcohol or an ester solvent, wherein the alcohol solvent is, for example, methanol, ethanol, isopropanol, ethylene glycol or the like; wherein the ester solvent is, for example, It is ethyl formate, ethyl acetate, methyl acetate, isopropyl acetate, and the like.
  • a preferred organic solvent is ethyl acetate.
  • the room temperature may be from 0 ° C to 40 ° C, preferably from 10 ° C to 30 ° C, more preferably from 15 ° C to 25 ° C.
  • the solvent used is an alcohol, a ketone, a nitrile, a chlorinated hydrocarbon solvent, a benzene solvent, DMSO or DMF, wherein the alcohol solvent such as methanol, ethanol, isopropanol, Ethylene glycol or the like, the ketone solvent such as acetone, methyl ethyl ketone or the like, the nitrile solvent such as acetonitrile or the like, the chlorinated hydrocarbon solvent such as dichloromethane, chloroform or the like, the benzene solvent
  • preferred solvents are methanol, ethanol, isopropanol, acetonitrile, acetone, toluene, benzene, DMSO, DMF, chloroform, dichloromethane or ethylene glycol, and more preferred solvents are Ethanol.
  • the objective product obtained by the above method can be purified and purified by a conventional method, for example, can be isolated and purified by a recrystallization method, and the solvent used for the recrystallization can be ethyl acetate-ethanol, acetone-ethanol, ethyl acetate-methanol, acetone-methanol. Acetone-water, methanol, ethanol or isopropanol, etc., preferably ethyl acetate-ethanol.
  • a pharmaceutical composition comprising a compound of the invention for use in the treatment of neuropathic pain and/or neuropathic pain syndrome, optionally further comprising a pharmaceutically acceptable carrier.
  • the active ingredient is included in the pharmaceutical composition in an amount ranging from 0.1 to 99%, as needed, and the remainder being a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention can be prepared into various desired pharmaceutical dosage forms according to conventional methods in the pharmaceutical field, such as oral preparations, injections, rectal administration preparations, topical administration preparations and the like, such as tablets, pills, dispersion powders. , capsules, granules, emulsions, solutions, suspensions, syrups, solid suppository formulations for vaginal or rectal administration, patches for topical application, and the like. It is preferably formulated into an injectable form, an oral dosage form or a transdermal topical administration, and a corresponding sustained release or controlled release dosage form is particularly preferred.
  • compositions of the invention and the various formulations of the compositions can be prepared according to conventional methods known in the pharmaceutical art.
  • a pharmaceutically acceptable carrier may be added as needed, including various suitable pharmaceutical adjuvants such as excipients, fillers, diluents, disintegrating agents, surfactants, wetting agents, preservatives, sweets. Flavors, pigments, etc.
  • the appropriate dosage form and administration dose are selected according to the type of the disease, the severity of the disease, and the condition of the patient, such as sex, age, body weight, etc., usually, the dosage is from 1 to 200 mg/kg body weight/day, preferably from 1 to 50 mg/kg body weight. / between days.
  • the present invention relates to compounds DXL-A-16, DXL-A-19, DXL-A-21, DXL-A-22, DXL-A-23, DXL-A-24, or stereoisomers thereof, Use of a tautomer, derivative, prodrug or pharmaceutically acceptable salt for the treatment of neuropathic pain and/or neuropathic pain syndrome.
  • the invention relates to compounds DXL-A-16, DXL-A-19, DXL-A-21, DXL-A-22, DXL-A-23, and DXL-A-24, or stereoisomers thereof
  • a tautomer, derivative, prodrug or pharmaceutically acceptable salt for the preparation of a medicament for use in anti-inflammatory.
  • Another object of the present invention is to provide a method of treating neuropathic pain and/or neuropathic pain syndrome comprising administering a therapeutically effective amount of a compound of formula (I), or a stereoisomer thereof, or a tautomer thereof.
  • Isomers, prodrugs or pharmaceutically acceptable salts are administered to patients in need of such treatment.
  • Another object of the present invention is to provide an anti-inflammatory method comprising administering a therapeutically effective amount of a compound of formula (I), or a stereoisomer, tautomer, prodrug thereof or pharmaceutically acceptable
  • the salt is administered to a patient in need of such treatment.
  • neuropathic pain is a pain caused or caused by a primary lesion or dysfunction in the central nervous system.
  • neuropathic pain syndrome includes postherpetic neuralgia (caused by herpes zoster), root avulsion, painful traumatic mononeuropathy, painful polyneuropathy (especially due to diabetes), central sexual pain syndrome (may be caused by almost any level of neurological damage), post-surgical pain syndrome (such as post-mastectomy syndrome, thoracotomy syndrome, hallucinatory pain), and complex regional pain syndrome (reflex) Sexual sympathetic dystrophy and burning pain).
  • neuropathic pain has typical symptoms, such as a feeling of dullness (spontaneous or induced burning pain, often with a superimposed part of the pain), but the pain may also be deep and dull.
  • Other sensations such as hyperesthesia, hyperalgesia, allodynia (pain due to innocuous irritations), and hyperalgesia (especially unpleasant, exaggerated pain reactions) may also occur.
  • pathological pain can be classified into “peripheral” (originating from the peripheral nervous system) and “central” (originating from the brain or spinal cord).
  • Central neuropathic pain is a pain that has a cause selected from the group consisting of brain lesions of the thalamus; infarction, such as thalamic infarction or brain stem infarction; brain tumor or abscess compression of the thalamus or brainstem; multiple sclerosis; camphor Surgery, such as thalamic incision in the case of muscle dysmotility; spinal cord lesions; spinal cord injury; spinal surgery, such as anterior lateral columnectomy; bloody lesions; anterior spinal artery syndrome; lateral medullary syndrome; disease.
  • infarction such as thalamic infarction or brain stem infarction
  • brain tumor or abscess compression of the thalamus or brainstem multiple sclerosis
  • camphor Surgery such as thalamic incision in the case of muscle dysmotility
  • spinal cord lesions spinal cord injury
  • spinal surgery such as anterior lateral columnectomy; bloody lesions; anterior spinal artery syndrome; lateral medullary syndrome; disease.
  • neuropathic pain is a central neuropathic pain syndrome.
  • central neuropathic pain syndrome is caused by spinal cord injury and/or spinal cord contusion.
  • neuropathic pain is a type of head pain syndrome caused by a central pain mechanism, such as migraine or migraine pain.
  • neuropathic pain is a peripheral neuropathic pain.
  • peripheral neuropathic pain is caused by chronic compression injury or sciatic nerve ligation.
  • the primary peripheral neuropathic pain comprises neuropathic pain selected from the group consisting of: and/or neuropathic pain selected from the group consisting of systemic diseases such as diabetic neuropathy; drug-induced lesions, such as those caused by chemotherapy Neuropathy; post-traumatic syndrome and compression syndrome; nerve root and ganglion lesions; neuropathy after HIV infection; neuralgia after herpes infection; nerve root tear; cranial neuropathy; cranial neuralgia, such as trigeminal Neuropathic pain; neuropathic pain; hallucinatory pain; compression of peripheral nerves, plexus and nerve roots; attachment of neoplastic peripheral neuropathy and ganglion lesions; complications of cancer treatment, such as chemotherapy, radiation, and surgery; Regional pain syndrome; type I lesions (formerly known as sympathetic reflex dystrophy); and type II lesions (roughly equivalent to burning pain).
  • systemic diseases such as diabetic neuropathy
  • drug-induced lesions such as those caused by chemotherapy Neuropathy
  • post-traumatic syndrome and compression syndrome such as those caused by chemotherapy Neuropathy
  • the compound of the formula (I) of the present invention or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof, has good therapeutic neuropathic pain and/or neuropathic pain syndrome and anti-inflammatory Role, and no addictive side effects.
  • the reagents and solvents are either commercially available chemically or analytically pure, and are used without treatment unless otherwise stated.
  • the petroleum ether is a fraction of 60-90 ° C
  • the anhydrous dioxane is dried by activated molecular sieves
  • the anhydrous THF is subjected to sodium treatment.
  • Raw materials and reagents are from domestic, Arcos, Saen, Inokkai and so on.
  • the starting material 2-26 (570mg, 2.22mmol) was dissolved in ethanol (15mL), followed by addition of NaHCO 3 (1.5g, 17.76mmol), stirred for ten minutes at room temperature (dissociation HCl), followed by addition of 1,4-dibromobutane (527 mg, 2.44 mmol), refluxing for 6 hours, and the reaction was completed. After filtration, the NaHCO 3 solid was removed, the filtrate was evaporated, and ethyl acetate (20 mL) was added and washed twice. Filtration gave a crude white product. Recrystallization from ethyl acetate/ethanol gave a white solid product (yield: &lt
  • the starting material 2-29 (600mg, 2.62mmol) was dissolved in ethanol (15mL), was added NaHCO 3 (1.76g, 20.96mmol), was added with stirring 1,4-dibromobutane (567mg, 2.62mmol). The reaction was refluxed for 6 hours, and the reaction was completed by TLC. NaHCO 3 was removed by filtration, and the solvent was evaporated to give a solid. The solid obtained was washed twice with ethyl acetate (20 mL) and filtered to give a solid. The solid was washed twice more with dichloromethane and filtered to give a crude solid. Recrystallization from ethyl acetate / methylene chloride afforded mp.
  • DXL-A-22 can also be prepared as follows:
  • DXL-A-24 can also be prepared as follows:
  • the preparation method was the same as the second preparation method of DXL-A-22 in Example 4 except that A was taken from 4-trifluoromethylbromobenzene to give a white solid product Ib, yield 70.7%.
  • the doses of 0.4, 1, 3, 4, 6, 9, 12 mg/kg of each compound when there is no significant difference in the efficacy of each compound administered at a low dose, the dose is increased, that is, 0.4 mg/kg.
  • the dose was adjusted to 1 mg/kg to repeat the test, and so on.
  • the dose of these compounds is 4 ⁇ mol. /kg.
  • ICR mice 18-22 g, male and female, were provided by the Experimental Animal Department of Peking University (license number: SCXK (Beijing) 2016-0010).
  • the analgesic effect of the compound of the present invention was measured by the following test.
  • the following examples relate to pharmaceutical experiments of the compounds of the present invention.
  • all the results of the pharmaceutical experiments were statistically processed, and the results were analyzed by SPSS 13.0 software; acetic acid writhing method, formalin test One-way analysis of variance was used for comparison between groups.
  • the hot plate test and xylene-induced ear swelling test were performed by repeated measures analysis of variance.
  • the significance test was P ⁇ 0.05.
  • the temperature of the hot plate was adjusted to 55 ° C, and the hind paw and the jumping reaction of the mouse were used as observation indexes, and the time from the occurrence of the above reaction to the copper plate was the latency time.
  • Three incubation periods were measured 30 min before dosing, and the average value was taken as the baseline threshold, or the baseline latency (BL), and the animals with latency longer than 15 s less than 5 s were removed.
  • the mice were randomly divided into groups of 8 rats.
  • a vehicle control group double distilled water
  • each sample group to be tested are shown in Table 1). All drugs were dissolved in physiological saline before administration and administered by gavage.
  • the incubation period of 2.0 h after administration was determined.
  • the Percentage of Pain Threshold Elevated Rate (PTE%) of the compound was calculated according to the following formula:
  • the experimental results are shown in Table 1 below.
  • the results of the compounds of the present invention were P ⁇ 0.05 compared to the vehicle group, wherein the compounds DXL-A-16, DXL-A-19, DXL-A-21, DXL-A-22, DXL-A- 23.
  • DXL-A-24, DXL-A-27, DXL-A-28, DXL-A-29 and DXL-A-32 were compared with the vehicle group P ⁇ 0.01.
  • mice male and female, were randomly divided into groups of 8 each.
  • a vehicle control group double distilled water
  • an ibuprofen control group each sample group to be tested (compounds and their doses are shown in Table 2). All drugs were dissolved in double distilled water before use, and administered by a given dose.
  • the mice were intraperitoneally injected with 0.6% acetic acid solution (10 ml/kg, ip), and the number of times the mouse writhing (abdominal depression, buttocks were elevated, and the body was elongated) was recorded within 5 to 20 minutes.
  • the body pain inhibition rate % is calculated according to the following formula.
  • Inhibition rate% (number of writhing in the control group - number of writhing in the test group) / number of writhing in the vehicle control group ⁇ 100
  • the analgesic effect of the compound of the present invention on acetic acid irritating pain is shown in Table 2.
  • the results of the compound of the present invention were P ⁇ 0.05 compared with the vehicle group, wherein the compound DXL-A-29 and DXL-A-30 were compared with the vehicle group P ⁇ 0.01. .
  • mice male and female, were randomly divided into groups of 8 each.
  • the vehicle control group double distilled water
  • each sample group to be tested the compound and its dosage are shown in Table 3. All drugs were dissolved in double distilled water before use, and administered by a given dose. Two hours after the administration, the mice were injected with a 2.5% formalin solution (20 ul) on the right hind paw. The time of sputum or bite (s) was recorded as an indicator of pain response. 0 to 5 min was phase I, and 10 to 60 min was II. Phase, a total of 60 minutes. The % inhibition of compound phase II pain in mice is calculated according to the following formula:
  • Inhibition rate% (media control group ⁇ or bite time - test group ⁇ or bite time) / vehicle control group ⁇ or bite time ⁇ 100
  • the effect of the compounds of the present invention on formalin-stimulated pain is shown in Table 3.
  • the results of the compounds of the present invention were P ⁇ 0.05 compared to the vehicle group, wherein the compounds DXL-A-05, DXL-A-10, DXL-A-16 , DXL-A-19, DXL-A-21, DXL-A-22, DXL-A-23, and DXL-A-24 were compared with the vehicle group P ⁇ 0.01.
  • ICR mice were randomized into groups of 8 animals, half male and half female.
  • a vehicle control group double distilled water
  • each sample group to be tested compounds and their doses are shown in Table 4
  • All drugs were dissolved in double distilled water before use, and administered by a given dose.
  • 50 uL of xylene was evenly applied to the inner and outer sides of the right ear of the mouse.
  • the left and right ears of the mouse were cut out, and circular ear pieces of the same size were punched and punched at the same position on the left and right sides, and weighed.
  • the inhibition rate of the compound on mouse ear swelling was calculated according to the formula.
  • Inhibition rate% (vehicle control ear swelling degree-test group ear swelling degree)/media control group ear swelling degree ⁇ 100
  • the effect of the compound of the present invention on xylene-induced ear swelling in mice is shown in Table 4.
  • the results of the compounds of the present invention were P ⁇ 0.05 compared with the vehicle group, wherein the compounds DXL-A-05, DXL-A-06, DXL-A-21, DXL-A-22, DXL-A-24 and DXL-A-29 were P ⁇ 0.01 compared to the vehicle group.
  • Rats were housed in a standard environment with a temperature of 22 ⁇ 0.5 ° C and a relative humidity of 55 ⁇ 5%, and a standard feed was fed for 12 h / 12 h light and dark cycles.
  • CCI Sciatic nerve chronic compression injury
  • the rats were anesthetized with sodium pentobarbital (60 mg/kg, ip), the right hind limb was removed from the surgical site, and the prone position was fixed. The longitudinal incision was made along the middle femur of the right hind limb of the rat. The muscle was bluntly separated, the sciatic nerve was exposed, and the sciatic nerve was bifurcated. The proximal end was ligated 4 times with a 4-0 silk thread, each interval of about 1 mm, and the degree of tightness was observed to slightly shake the right hind leg. After ligation, the muscles and skin were sutured in sequence, and the sham operation group only exposed the sciatic nerve, but did not ligature. Whether the modeling was successful was observed by observing whether the hind limbs of the postoperative hind limbs were close to the toe, slightly eversion, and often in the vacant state, and the mechanical stimulation threshold and the thermal stimulation contraction latency were measured.
  • the mechanical stimulation threshold and the thermal stimulation contraction latency were measured before operation.
  • the sham, vehicle (double distilled water, ig) and DXL-A-22 groups (2 mg/kg, Ig), DXL-A-24 group (1mg/kg, ig) and gabapentin group (100mg/kg, ig), all compounds and drugs were dissolved in double distilled water, administered at a dose of 1mL/100g, from postoperative The daily dosing was started on the first day, and the mechanical stimulation threshold and the thermal stimulation contraction latency were measured 2 h after the administration.
  • the rat mechanical stimulation threshold was measured using a von Frey electronic pain tester. The test was performed 5, 7, and 14 days after surgery. The rats were placed in a transparent plexiglass box (barbed wire with a gap of 1 mm 2 at the bottom) to adapt to the environment for 30 min. After the rats did not explore the action, the von Frey electronic pain tester was used to stimulate the middle position of the plantar side of the rat, and the pain was measured. The instrument recorded the maximum force (ie, MWT) that caused the paw withdrawal response in rats. The inhibition rate of the compound is calculated by the following formula:
  • % inhibition rate (test group MWT-solvent group MWT) / (sham operation group MWT-solvent group MWT) ⁇ 100 (2)
  • the thermal stimulation contraction latency was determined by hot plate method. The test was performed 5, 7, and 14 days after surgery. The hot plate temperature was 50.5 ° C, and the rats were shaken from the start of the hot plate test until the rats showed shaking and the lameness reaction stopped. This time was the rat PWL. The hot plate cut-off time is 14 s, and the percentage of analgesia (ie, MPE%) is calculated according to formula (3):
  • Results are expressed as mean ⁇ standard error (mean ⁇ SEM). Analysis was performed using SPSS 19.0 software. The comparison between the groups in the mechanical stimulation test and the comparison between the groups in the thermal stimulation test were performed by repeated measures analysis of variance. The significance test was P ⁇ 0.05.
  • ICR mice weighing 18g-22g, are male and female. Provided by the Experimental Animal Department of Peking University. Animals were housed in a standard environment: temperature 23 ⁇ 1 ° C, relative humidity 55 ⁇ 5%, light and dark cycle 12 h / 12 h, standard pellet feed.
  • mice were randomly divided into 5 groups, 8 in each group, half male and half female.
  • the vehicle control group double distilled water, ig
  • dexamethasone control group (2 mg/kg, ig)
  • compound DXL-A-22 group (1 mg/kg, ig)
  • compound DXL-A-24 group (1 mg) /kg, ig).
  • All drugs were dissolved in double distilled water before use, and administered by 0.1 mL/10 g. After administration for 1 h, 30 ⁇ L of xylene was evenly applied to the inner and outer sides of the right ear of the mice.
  • the left and right ears of the mice were cut out, and the punches (diameter 6 mm) were respectively placed in the same part of the left and right ears.
  • the round ears are weighed and the left and right ears are heavy.
  • the difference between the weight of the right ear and the weight of the left ear to which xylene was not applied (i.e., the degree of swelling) after application of xylene was used as an indicator of the degree of swelling.
  • the degree of swelling is calculated according to formula (1).
  • the anti-inflammatory effect intensity is expressed by the inhibition rate (%).
  • the inhibition rate (%) was calculated according to the formula (2).
  • Inflammation inhibition rate (%) (solvent control ear swelling degree - administration group ear swelling degree) / vehicle control ear swelling degree ⁇ 100% (2)
  • mice were fixed in a special holder, and the hind hind legs were exposed. Before the test, a line was drawn with a marker pen 0.5 cm below the ankle joint of the mouse as a marker for measuring the volume of the ankle. The right hind paw volume was measured as the baseline threshold 30 minutes before administration.
  • the mice were randomly divided into 5 groups, 8 in each group, half male and half female.
  • the vehicle control group double distilled water, ig
  • dexamethasone control group 0.5 mg/kg, ig
  • compound DXL-A-22 group (1 mg/kg, ig
  • DXL-A-24 group (1 mg/) Kg, ig. All drugs were dissolved in double distilled water before use and administered at 0.1 mL/10 g.
  • Inflammation inhibition rate (%) (vehicle control group foot swelling degree - administration group foot swelling degree) / vehicle control group foot swelling degree ⁇ 100% (4)
  • Results are expressed as mean ⁇ standard deviation (mean ⁇ SD). Analysis by SPSS 19.0 software, the comparison of xylene-induced ear swelling experiments in each group was analyzed by one-way analysis of variance; the comparison between the groups of carrageenan-induced paw swelling in mice was performed by repeated measures analysis of variance. The significance test was P ⁇ 0.05.
  • the compound of the present invention is a class of compounds having an obvious analgesic effect. It is expected to develop into a new generation of analgesic drugs.

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Abstract

本发明公开了通式（I）所表示的化合物，或其立体异构体、互变异构体、衍生物、前药或药学可接受的盐，以及所述化合物的制备方法和其在制备用于治疗神经病理性疼痛和/或神经病理性疼痛综合征的药物或者用于抗炎的药物中的应用：见（I）其中，R1选自氢、卤素、烷基、氰基和卤代烷基，R2和R3分别独立地选自氢、卤素、烷基、卤代烷基和硝基，并且R1、R2和R3不同时为氢；以及，当R2和R3之一为硝基或卤素时，R1、R2和R3中的其余两者不同时为氢。该类化合物具有良好的治疗神经病理性疼痛和/或神经病理性疼痛综合征以及抗炎的效果，并且没有成瘾性等副作用。

Description

抗疼痛化合物及其制备方法 技术领域
本发明涉及新的治疗神经病理性疼痛和/或神经病理性疼痛综合征的化合物，及其制备方法和应用。
背景技术
疼痛是一种常见疾病，疼痛分为三类：生理性疼痛、炎性疼痛和神经病理性疼痛(neuropathic pain，NPP)。
神经病理性疼痛是临床中较为常见的一类疾病，2008年国际疼痛学会(IASP)将其定义为：“由躯体感觉系统的损害或疾病导致的疼痛”。神经病理性疼痛是由于例如周围或中枢神经系统的损伤或功能障碍引起的，是一种临床缺乏有效治疗手段的顽固性慢性疼痛。神经病理性疼痛的疾病包括，例如表现出痛觉过敏或异常性疼痛的症状的疾病，如带状疱疹后神经痛、三叉神经痛、糖尿病性神经痛、及术后持续或创伤后疼痛等。作为世界性难题的神经病理性疼痛，全世界患病人数以百万计，严重影响患者的生活质量。
虽然同属于慢性疼痛，神经病理性疼痛与炎性疼痛存在本质上的差别。现有技术中神经病理性疼痛的治疗方法包括用传统镇痛药如非甾体抗炎药和阿片类物质，以及包括抗惊厥剂和三环抗抑郁药在内的其它药物(Max，M.B.Ann.Neurol，35(Suppl)：S50-S53(1994)；Raja，S.N.等，Neurology，59：1015(2002)；Galer，B.S.等，Pain，80：533(1999))。然而，这些药物不能充分缓解疼痛或者具有不良的副作用，例如，耐药性、成瘾风险。
螺环哌嗪季铵盐类化合物是由北京大学李润涛老师课题组，在季铵盐类烟碱受体激动剂1,1-二甲基-4-苯基哌嗪碘化物(DMPP)的结构上改造得到的一类化合物。目前已有报道，螺环哌嗪季铵盐类化合物在镇痛活性方面的研究，且此类化合物无成瘾性(请参见Yue,C.Q.，Ye,J.，Li,C.L.，Li,R.T.，Sun,Q.，2007.Antinociceptive effects of the novel spirocyclopiperazinium salt compound LXM-10in mice.Pharmacol Biochem Behav 86,643-650)。其镇痛机制可能与激动胆碱能受体有关(请参见：Zhao,X.，Ye,J.，Sun,Q.，Xiong,Y.，Li,R.，Jiang,Y.，2011.Antinociceptive effect of spirocyclopiperazinium salt compound LXM-15via activating peripheral alpha7nAChR and M4mAChR in mice.Neuropharmacology 60,446-452)。
但是，关于这类螺环哌嗪季铵盐类化合物的镇痛作用，现有技术的报道中仅公开了这些螺环哌嗪季铵盐类化合物(尤其是化合物LXM-10)在抑制生理性疼痛和炎性疼痛方面的效果(请参见例如WO2007/147346)，并未记载这些化合物在治疗神经病理性疼痛方面是否具有有效性。
因此，需要研发更有效地治疗神经病理性疼痛的药物。
发明内容
在一个方面，本发明的目的在于提供新的用于治疗神经病理性疼痛和/或神经病理性疼痛综合征的化合物，或其立体异构体、互变异构体、衍生物、前药或药学上可接受的盐。
在另一方面，本发明的目的在于提供了上述化合物的制备方法。
本发明提供了如下式(I)所表示的化合物，或其立体异构体、互变异构体、衍生物、前药或药学上可接受的盐：
Figure PCTCN2018119785-appb-000001
其中，R 1选自氢、卤素、烷基、氰基和卤代烷基，
R 2和R 3分别独立地选自氢、卤素、烷基、卤代烷基和硝基，并且R 1、R 2和R 3不同时为氢；
以及，当R 2和R 3之一为硝基或卤素时，R 1、R 2和R 3中的其余两者不同时为氢。
本发明所用的术语“卤素”是指氟、氯、溴和碘原子，优选为氟、氯或溴原子。
本发明所用的术语“卤代”是指氟代、氯代、溴代或碘代。
本发明所用的术语“烷基”为具有1-6个碳原子的直链或支链的烷基，更优选具有1-3个碳原子的直链或支链的烷基，特别优选甲基、乙基或丙基。
本发明所用的术语“卤代烷基”是指被一个或多个、优选一个到五个卤素原子取代的如上定义的烷基，所述卤素原子如本申请中定义的术语。卤代烷基包括单卤代烷基、二卤代烷基、三卤代烷基、全卤代烷基等，如氯代甲基、二氯甲基、二氟甲基、三氟甲基、2,2,2-三氟乙基、全氟乙基、2,2,2-三氟-1,1-二氯乙基等。其中，卤代烷基可优选三卤代烷基，更优选三氟甲基。
本发明所用的术语“硝基”是指-NO 2基团。
本发明所用的术语“氰基”是指-CN基团。
在本发明的式(I)的实施方式中，R 2和R 3分别独立地选自烷基、卤代烷基和硝基，R 1为氢。
在本发明的式(I)的实施方式中，R 2和R 3分别独立地选自甲基、乙基、三氟甲基或硝基，R 1为氢。
在本发明的实施方式中，本发明的化合物由下式(II)表示：
Figure PCTCN2018119785-appb-000002
其中，R 1选自氢、卤素、烷基、氰基和卤代烷基，
R 2选自氢、卤素、烷基、卤代烷基和硝基，并且R 1和R 2不同时为氢。
在本发明的式(II)的实施方式中，R 1选自卤素、烷基、氰基和卤代烷基，R 2选自卤素、烷基、卤代烷基和硝基。
在本发明的式(II)的实施方式中，R 1选自氟、氯、溴、甲基、乙基、氰基和三氟甲烷，R 2选自氟、氯、溴、甲基、乙基、三氟甲烷和硝基。
在本发明的式(II)的实施方式中，R 1和R 2同时为卤素。
在本发明的实施方式中，所述R 1选自氢、卤素或卤代烷基；R 2选自氢或硝基。
在本发明的式(II)的实施方式中，R 1选自烷基、氰基、卤素或卤代烷基，并且R 2为氢。
在本发明的式(II)的实施方式中，R 1选自卤素或卤代烷基，并且R 2为氢。
在本发明的式(II)的实施方式中，所述烷基选自甲基、乙基或丙基。
在本发明的式(II)的实施方式中，所述卤代烷基为三氟甲基。
优选的本发明化合物选自：
Figure PCTCN2018119785-appb-000003
进一步优选的本发明化合物选自：
Figure PCTCN2018119785-appb-000004
本发明化合物可按本领域的常规方法制备，优选按照以下的反应流程进行制备：
Figure PCTCN2018119785-appb-000005
在本发明的优选实施方式中，本发明提供了通式(I)化合物的制备方法，该方法包括以下步骤：
(1)将原料卤代苯试剂(A)、金属催化剂、配体、碱溶于溶剂中，然后加入1-Boc-哌嗪(B)，在氩气保护下反应，反应温度为40℃-140℃，得到中间体化合物(C)；
(2)向中间体化合物(C)中加入盐酸-有机溶剂，室温搅拌，得到脱保护中间体(D)；以及
(3)将脱保护中间体(D)溶于溶剂中，在NaHCO 3存在下与1,4-二溴丁烷反应，得到本发明通式(I)的化合物。
在上述方法中，卤代苯试剂可选自三氟甲基取代的溴苯，三氟甲基取代的碘苯；二氟甲基取代的溴苯，二氟甲基取代的碘苯；溴代碘苯；硝基取代的氯苯，硝基取代的溴苯，硝基取代的碘苯等。
在上述方法中，金属催化剂可选自氯化钯、醋酸铜、碘化亚酮、三氯化铁等；优选碘化亚酮。
在上述方法中，配体可选自不同的α-氨基酸、邻羟基苯甲酰胺、联二萘酚等。其中，配体优选联二萘酚。
在上述方法中，碱可选自有机碱和无机碱，如吡啶、三乙胺、氢氧化钾、氢氧化钠、碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠、碳酸铯、磷酸钾、磷酸钠等。其中，碱优选磷酸钾。
在上述方法的步骤(1)中，所用的溶剂为醇、酮、腈、氯代烃类溶剂，苯系溶剂，DMSO或DMF，其中，所述醇类溶剂例如是甲醇、乙醇、异丙醇、乙二醇等；所述酮类溶剂例如丙酮、甲乙酮等；所述腈类溶剂例如乙腈等；所述氯代烃溶剂例如二氯甲烷、三氯甲烷等；所述苯系溶剂例如苯、甲苯、二甲苯等。优选的溶剂是甲醇、乙醇、异丙醇、乙腈、丙酮、甲苯、苯、DMSO、DMF、三氯甲烷或二氯甲烷，更优选的溶剂是DMF。
在上述方法的步骤(1)中，优选的反应温度为100℃。
在上述方法的步骤(1)中，反应时间可为6h-48h，优选12h-32h，更优选24h。
在上述方法的步骤(2)中，有机溶剂选自醇或酯类溶剂，其中，所述醇类溶剂例如是甲醇、乙醇、异丙醇、乙二醇等；其中，所述酯类溶剂例如是甲酸乙酯、乙酸乙酯、乙酸甲酯、乙酸异丙酯等。优选的有机溶剂为乙酸乙酯。
在本发明中，室温可为0℃-40℃、优选10℃-30℃、更优选15℃-25℃.
在上述方法的步骤(3)中，所用的溶剂为醇、酮、腈、氯代烃类溶剂，苯系溶剂，DMSO或DMF，其中所述的醇类溶剂例如甲醇、乙醇、异丙醇、乙二醇等，所述的酮类溶剂例如丙酮、甲乙酮等，所述的腈类溶剂如乙腈等，所述的氯代烃溶剂例如二氯甲烷、三氯甲烷等，所述的苯系溶剂例如苯、甲苯、二甲 苯等，优选的溶剂是甲醇、乙醇、异丙醇、乙腈、丙酮、甲苯、苯、DMSO、DMF、三氯甲烷、二氯甲烷或乙二醇，更优选的溶剂是乙醇。
上述方法中所得的目的产物可通过常规方法精制和纯化，例如可以用重结晶方法分离纯化，重结晶所用的溶剂可以为乙酸乙酯-乙醇、丙酮-乙醇、乙酸乙酯-甲醇、丙酮-甲醇、丙酮-水、甲醇、乙醇或异丙醇等，优选乙酸乙酯-乙醇。
在又一方面，本发明的目的在于提供用于治疗神经病理性疼痛和/或神经病理性疼痛综合征的包括本发明的化合物的药物组合物，其中还可任选地含有药学上可接受的载体。根据需要，药物组合物中活性成分的含量在0.1-99％范围内，其余为药学上可接受的载体。
本发明的药物组合物可按照制药领域的常规方法制备成所需的各种不同的药物剂型，例如口服制剂、注射剂、直肠给药制剂、局部给药制剂等，例如片剂、丸剂、分散粉末、胶囊剂、颗粒剂、乳剂、溶液剂、悬浮液、糖浆、阴道或直肠给药的固体栓剂制剂、局部应用的贴剂等。优选被制成注射剂型、口服剂型或透皮局部给药的剂型，特别优选其相应的缓释或控释的剂型。
本发明的药物组合物和该组合物的各种制剂可按照制药领域已知的常规方法制备。
为了制备适用的剂型，可根据需要添加药用载体，包括各种适用的药用辅剂，例如赋形剂、填充剂、稀释剂、崩解剂、表面活性剂、湿润剂、防腐剂、甜味剂、色素等。
根据疾病的类型、严重的程度以及患者的状况，例如性别、年龄、体重等选用合适的剂型和施用剂量，通常成人施用剂量在1-200mg/kg体重/天，优选为1-50mg/kg体重/天之间。
在再一方面，本发明的目的在于提供了通式(I)化合物、或其立体异构体、互变异构体、衍生物、前药或药学上可接受的盐在治疗神经病理性疼痛和/或神经病理性疼痛综合征中的用途，包括将上述物质制成各种适于应用的药用剂型。
优选地，本发明涉及化合物DXL-A-16、DXL-A-19、DXL-A-21、DXL-A-22、DXL-A-23、DXL-A-24、或其立体异构体、互变异构体、衍生物、前药或药学上可接受的盐在治疗神经病理性疼痛和/或神经病理性疼痛综合征中的用途。
在另一方面，本发明的目的在于提供了通式(I)化合物、或其立体异构体、互变异构体、衍生物、前药或药学上可接受的盐在抗炎中的用途，包括将上述物质制成各种适于应用的药用剂型。
在另一方面，本发明的目的在于提供了通式(I)化合物、或其立体异构体、互变异构体、衍生物、前药或药学上可接受的盐在制备用于治疗神经病理性疼痛和/或神经病理性疼痛综合征的药物中的用途。
在另一方面，本发明的目的还在于提供了通式(I)化合物、或其立体异构体、互变异构体、衍生物、前药或药学上可接受的盐在制备用于抗炎的药物中的用途。
优选地，本发明涉及化合物DXL-A-16、DXL-A-19、DXL-A-21、DXL-A-22、DXL-A-23、和DXL-A-24、或其立体异构体、互变异构体、衍生物、前药或药学上可接受的盐在制备用于抗炎的药物中的用途。
本发明的另一目的是提供了一种治疗神经病理性疼痛和/或神经病理性疼痛综合征的方法，该方法包括将治疗有效量的通式(I)化合物，或其立体异构体、互变异构体、前药或药学上可接受的盐施用于需要这种治疗的患者。
本发明的另一目的是提供了一种抗炎方法，该方法包括将治疗有效量的通式(I)化合物，或其立体异构体、互变异构体、前药或药学上可接受的盐施用于需要这种治疗的患者。
根据本发明，神经病理性疼痛是一种由中枢神经系统中的原发性病灶或功能障碍引起或导致的疼痛。
例如，神经病理性疼痛综合征包括带状疱疹后遗神经痛(带状疱疹引起的)，根性撕脱伤，痛苦的创伤性单神经病变，痛苦的多发性神经病变(尤其是由于糖尿病)，中枢性疼痛综合征(可能由几乎任何级别的神经系统损害造成)，手术后疼痛综合征(如乳房切除术后综合征，开胸术后综合征，幻觉痛)，和复杂区域疼痛综合征(反射性交感神经营养不良症和灼痛)。
在一些情况中，神经病理性疼痛具有典型症状，如感觉迟钝(自发或诱发的烧灼痛，常常带有叠加的抽痛部分)，但疼痛也可能是深深的和隐隐作痛。其它的感觉(如感觉过敏、痛觉过敏、异常性疼痛(由于无害的刺激的疼痛)，及痛觉过敏(特别是不愉快的、夸张的疼痛反应))也可能发生。
根据本发明，的经病理性疼痛可分为“外周”(起源于外周神经系统)和“中央”(起源于大脑或脊髓)。
中央神经病理性疼痛是一种具有选自下列原因的疼痛：主要是丘脑的脑部病变；梗塞，例如丘脑梗塞或脑干梗塞；脑肿瘤或脓肿压迫丘脑或脑干；多发性硬化症；劈脑手术，例如在肌肉运动失调的情况下的丘脑切开术；脊髓病变；脊髓损伤；脊髓手术，例如脊髓前外侧柱切断术；血性病变；脊髓前动脉综合征；延髓外侧综合征；及脊髓空洞症。
根据本发明，神经病理性疼痛是一个中央神经病理性疼痛综合征。例如，中央神经病理性疼痛综合征是由脊髓损伤和/或脊髓挫伤引起的。
在一些情况中，神经病理性疼痛是一种的由中枢性疼痛机制引起的头部疼痛综合征，如偏头痛或偏头疼痛。
在一些情况中，神经病理性疼痛是一种外周神经病理性疼痛。例如，外周神经病理性疼痛是由慢性压迫损伤或坐骨神经结扎引起的。
根据本发明，主要的外周神经病理性疼痛包括选自以下类型的神经病理性疼痛和/或具有选自以下原因的神经病理性疼痛：系统性疾病，例如糖尿病神经病变；药物诱导的病变，例如因化疗引起的神经病变；创伤后综合征和卡压综合征；神经根和神经节病变；HIV感染后的神经病变；疱疹感染后的神经痛；神经根撕裂；颅神经病变；颅神经痛，例如三叉神经痛；神经性癌性疼痛；幻觉痛；周围神经、神经丛及神经根的压迫；附肿瘤性周围神经病变及神经节病变；癌症治疗的并发症，例如化疗，放射，和外科手术；复杂区域疼痛综合征；类型I病变(以前被称为交感神经反射性营养不良)；及类型II病变(大致相当于灼痛)。
本发明通式(I)化合物，或其立体异构体、互变异构体、前药或药学上可接受的盐具有良好的治疗神经病理性疼痛和/或神经病理性疼痛综合征以及抗炎的作用，且没有成瘾副作用。
具体实施方式
接着，将通过以下实施例对本发明进行详细说明。
本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过购买获得的常规产品。
试剂和溶剂均为市售化学纯或者分析纯，如无说明，均不经过处理直接使用。石油醚为60-90℃的馏分，无水二氧六环经过活化的分子筛干燥，无水THF经过钠处理。原料和试剂均来自国产，Arcos公司，萨恩公司，伊诺凯公司等。
柱层析：青岛海洋化工厂硅胶200-300目，显色剂，碘，或紫外灯下检测。
核磁共振仪：BrukerAVANCE III 400；高分辨质谱：Waters Xevo G2Q-TOF液质联用仪。
合成通法一(以化合物DXL-A-10合成为例)
Figure PCTCN2018119785-appb-000006
将间碘甲苯(2.18g，0.01mol)加入到有25mL异丙醇的100mL圆底烧瓶中，然后依次加入无水哌嗪(1.76g，0.02mol)，碘化亚铜(0.5g，25mmol)，磷酸钾(4.66g，17.5mmol)，乙二醇(1.5mL)，氩气保护下回流反应18小时，TLC(PE：EA＝20；1，DCM：MeOH＝10:1)检测反应完毕。过滤，减压除去溶剂，加入水20mL，氯仿萃取30mL三次，合并萃取液，用饱和食盐水，水洗涤，无水硫酸钠干燥。浓缩至干，柱层析(EA：MeOH：NH 3·H 2O＝25:3:2)得无色油状产物2-22 0.5g，收率23％。
1H NMR(400MHz,CDCl 3)：δ7.18(t,J＝7.7Hz,1H),6.74(dd,J＝17.8,8.7Hz,3H),3.14(s,8H),2.35(s,3H).
Figure PCTCN2018119785-appb-000007
50mL圆底瓶，加入18mL乙醇，依次加入原料3-1(0.5g,2.84mmol),1,4-二溴丁烷(0.6g，2.84mmol)，取NaHCO 3(1.67g，19.88mmol)研细，搅拌下加入到上述体系，80℃加热回流搅拌反应6小时，点板仍有原料，继续反应到18小时，反应完毕。过滤，除去碳酸氢钠固体，将滤液旋干得到白色固体粗品(0.93g)。 上述固体加入乙酸乙酯20mL，超声5分钟，过滤，除去乙酸乙酯，得固体粗品。然后乙酸乙酯/乙醇重结晶得到白色固体产物730mg，产率：83％。
合成通法二(以化合物DXL-A-08合成为例)
Figure PCTCN2018119785-appb-000008
在含有40mL 1,4-二氧六环的250mL圆底瓶中，依次加入原料2-23间溴苯甲酸甲酯(2.15g，10mmol)，BINAP(622mg，1mmol)，醋酸钯(45mg，0.2mmol)，碳酸铯(6.5g，20mmol)，2-24Boc-哌嗪(1.86g，10mmol)，氩气保护下，100℃回流反应18小时，TLC(PE：EA＝10:1)检测，反应完毕。硅藻土下过滤，除去固体。滤液旋干，柱层析(PE：EA＝10:1)得淡黄色油状产物720mg，产率23％。
Figure PCTCN2018119785-appb-000009
将原料2-25(720mg,2.25mmol)放入到50mL圆底瓶中，加入盐酸乙酸乙酯(2.8M)，搅拌反应5小时，TLC点板原料反应完毕。过滤，除去盐酸乙酸乙酯，用乙酸乙酯反复洗涤，点板显示只有一个产物点，得白色固体产物2-26,570mg，产率99％。
Figure PCTCN2018119785-appb-000010
将原料2-26(570mg，2.22mmol)溶于乙醇(15mL)，然后加入NaHCO 3(1.5g，17.76mmol)，室温搅拌十分钟(解离HCl)，然后加入1,4-二溴丁烷(527mg，2.44mmol)，回流反应6小时，点板反应完毕。过滤，除去NaHCO 3固体，旋干滤液，加入乙酸乙酯20mL，洗涤两遍。过滤得到白色粗品产物。乙酸乙酯/乙醇重结晶，得到白色固体产物160mg，产率20.3％。
合成通法三(以化合物DXL-A-26合成为例)
Figure PCTCN2018119785-appb-000011
将原料4-碘代苯甲醚2-27(2.34g，10mmol)，配体(430mg，1.5mmol)，CuI(580mg，2mmol)，K 3PO 4(5.32g，20mmol)溶于无水DMF(30mL)，然后加入Boc-哌嗪2-24(2.8g，15mmol)，氩气保护下，100℃条件下，反应24小时。TLC检测(PE：EA＝5:1)，原料反应完毕。用二氯甲烷50mL萃取三次，合并萃取液，依次用饱和氯化钠溶液，水，洗涤，无水硫酸钠干燥。柱层析(PE：EA＝5:1)得到黄色固体产物720mg。产率：24.6％。
Figure PCTCN2018119785-appb-000012
将原料2-28(720mg，2.46mmol)放入50mL圆底瓶中，加入盐酸乙酸乙酯(3.8M)，室温搅拌24小时，过滤，得到白色固体产物600mg，产率90％。
Figure PCTCN2018119785-appb-000013
将原料2-29(600mg，2.62mmol)溶于乙醇(15mL)，加入NaHCO 3(1.76g，20.96mmol)，搅拌下加入1,4-二溴丁烷(567mg，2.62mmol)。回流反应6小时，TLC检测反应完毕。过滤除去NaHCO 3，旋干溶剂得到固体。所得到的固体用乙酸乙酯(20mL)洗涤两次，过滤得到固体。该固体再用二氯甲烷加热洗涤两次，过滤得到固体粗品。用乙酸乙酯/二氯甲烷重结晶，得到白色固体产物800mg，产率93％。
实施例1 DXL-A-16的制备
8-(4-氟苯基)-8-氮-5-氮螺[4.5]癸烷溴化物
8-(4-fluorophenyl)-5,8-diazaspiro[4.5]decan-5-ium bromide
Figure PCTCN2018119785-appb-000014
采用通法三，白色固体，产率43％。 1H NMR(400MHz,D 2O)δ7.24(d,J＝9.0Hz,2H),6.94(d,J＝9.0Hz,2H),3.61–3.26(m,12H),2.10(s,4H).
13C NMR(101MHz,D 2O)δ159.26,156.89,145.41,119.27,119.19,116.03,115.81,62.66,59.01,45.69,21.08.
ES-HRMS:Calcd for C 14H 20BrFN 2[M-Br] +,235.31985,Found 235.16041.
实施例2 DXL-A-19的制备
8-(4-氰基苯基)-8-氮-5-氮螺[4.5]癸烷溴化物
8-(4-cyanophenyl)-5,8-diazaspiro[4.5]decan-5-ium bromide
Figure PCTCN2018119785-appb-000015
采用通法二，白色固体，产率37.1％。 1H NMR(400MHz,D 2O)δ7.54(d,J＝8.8Hz,2H),6.97(d,J＝8.9Hz,2H),3.54(dd,J＝17.0,9.7Hz,12H),2.11(s,4H).
13C NMR(101MHz,D 2O)δ152.22,133.92,120.55,115.30,100.85,62.52,58.55,42.79,21.03.
ES-HRMS:Calcd for C 15H 20BrN 3[M-Br] +,242.33885,Found 242.16511.
实施例3 DXL-A-21的制备
8-(3,4-二氟苯基)-8-氮-5-氮螺[4.5]癸烷溴化物
8-(3,4-difluorophenyl)-5,8-diazaspiro[4.5]decan-5-ium bromide
Figure PCTCN2018119785-appb-000016
采用通法三，白色固体，产率59.3％。 1H NMR(400MHz,D 2O)δ7.10(dd,J＝19.3,9.4Hz,1H),6.89(m,J＝13.1,6.8,2.7Hz,1H),6.72(d,J＝8.7Hz,1H),3.69–3.44(m,8H),3.38(s,4H),2.11(s,4H).
13C NMR(101MHz,D 2O)δ151.37,151.22,148.93,148.81,146.35,146.22,146.09,145.97,143.96,143.84,117.65,117.48,113.06,113.04,113.01,112.98,106.61,106.41,62.61,58.85,45.08,21.07.
ES-HRMS:Calcd for C 14H 19BrF 2N 2[M-Br] +,253.31032,Found 253.15087.
实施例4 DXL-A-22的制备
8-(4-溴苯基)-8-氮-5-氮螺[4.5]癸烷溴化物
8-(4-bromophenyl)-5,8-diazaspiro[4.5]decan-5-ium bromide
Figure PCTCN2018119785-appb-000017
采用通法三，白色固体，产率86.9％。 1H NMR(400MHz,D 2O)δ7.38(d,J＝8.9Hz,2H),6.89(d,J＝8.9Hz,2H),3.50(dd,J＝12.4,7.3Hz,8H),3.39(s,4H),2.10(s,4H).
13C NMR(101MHz,D 2O)δ148.30,132.21,118.64,113.20,62.56,58.83,44.37,21.13.
ES-HRMS:Calcd for C 14H 20Br 2N 2[M-Br] +,296.22545,Found 296.08329.
DXL-A-22还可按照以下方法制备：
1.中间体4-(4-溴代苯基)-1-Boc哌嗪(C)的制备
将原料4-溴碘代苯A(10mmol)、1,1’-二-2-萘酚(430mg，1.5mmol)、CuI(580mg，2mmol)和K 3PO 4(5.32g，20mmol)溶于无水DMF(30mL)，然后加入Boc-哌嗪B(2.8g，15mmol)，在氩气保护下，100℃的温度下反应24小时。TLC检测(PE:EA＝5:1)，原料反应完毕。用二氯甲烷萃取(50mL×3)三次，合并萃取液，依次用饱和氯化钠溶液和水洗涤，无水硫酸钠干燥。柱层析(PE:EA＝5:1)后得到黄色固体产物4-(4-溴代苯基)-1-Boc哌嗪C。
2.中间体1-(4-溴代苯基)哌嗪(D)的制备
将4-(4-溴代苯基)-1-Boc哌嗪C(2.46mmol)放入50mL圆底瓶中，加入盐酸-乙酸乙酯(3.8M)，室温搅拌24小时，过滤，得到白色固体脱保护中间体1-(4-溴代苯基)哌嗪(D)。
3.Ia的制备
将脱保护中间体1-(4-溴代苯基)哌嗪D(2.62mmol)溶于乙醇(15mL)，加入NaHCO 3(1.76g，20.96mmol)，搅拌下加入1,4-二溴丁烷(567mg，2.62mmol)。回流反应6小时，TLC检测反应完毕。过滤除去NaHCO 3，旋干溶剂得到固体。所得到的固体依次用乙酸乙酯、二氯甲烷洗涤，然后将所得的粗品用乙酸乙酯/二氯甲烷重结晶，得到白色固体产物Ia，产率86.9％。 1H NMR(400MHz,D 2O)δ7.38(d,J＝8.9Hz,2H),6.89(d,J＝8.9Hz,2H),3.50(dd,J＝12.4,7.3Hz,8H),3.39(s,4H),2.10(s,4H). 13C NMR(101MHz,D 2O)δ148.30,132.21,118.64,113.20,62.56,58.83,44.37,21.13.ES-HRMS:Calcd for C 14H 20Br 2N 2[M-Br] +,296.22545,Found 296.08329.。
实施例5 DXL-A-23的制备
8-(4-氯苯基)-8-氮-5-氮螺[4.5]癸烷溴化物
8-(4-chlorophenyl)-5,8-diazaspiro[4.5]decan-5-ium bromide
Figure PCTCN2018119785-appb-000018
采用通法三，白色固体，产率17.5％。 1H NMR(400MHz,D 2O)δ7.25(d,J＝8.8Hz,2H),6.95(d,J＝8.9Hz,2H),3.51(dd,J＝11.6,7.1Hz,8H),3.40(s,4H),2.10(s,4H).
13C NMR(101MHz,D 2O)δ147.75,129.23,125.89,118.38,62.56,58.85,44.63,21.08.
ES-HRMS:Calcd for C 14H 20BrClN 2[M-Br] +,251.77445,Found 251.13077.
实施例6 DXL-A-24的制备
8-(4-三氟甲基苯基)-8-氮-5-氮螺[4.5]癸烷溴化物
8-(4-(trifluoromethyl)phenyl)-5,8-diazaspiro[4.5]decan-5-ium bromide
Figure PCTCN2018119785-appb-000019
采用通法三，白色固体，产率70.7％。 1H NMR(400MHz,D 2O)δ7.54(d,J＝8.7Hz,2H),7.05(d,J＝8.6Hz,2H),3.52(d,J＝11.3Hz,12H),2.11(s,4H).
13C NMR(101MHz,D 2O)δ151.55,126.66,126.63,125.83,123.15,121.91,121.59,121.25,115.82,62.52, 58.68,43.62,21.02.
ES-HRMS:Calcd for C 15H 20BrF 3N 2[M-Br] +,285.32736,Found 285.15687.
DXL-A-24还可按照以下方法制备：
制备方法同实施例4中DXL-A-22的第二种制备方法，除了A取4-三氟甲基溴苯，得到白色固体产物Ib，产率70.7％。 1H NMR(400MHz,D 2O)δ7.54(d,J＝8.7Hz,2H),7.05(d,J＝8.6Hz,2H),3.52(d,J＝11.3Hz,12H),2.11(s,4H). 13C NMR(101MHz,D 2O)δ151.55,126.66,126.63,125.83,123.15,121.91,121.59,121.25,115.82,62.52,58.68,43.62,21.02.ES-HRMS:Calcd for C 15H 20BrF 3N 2[M-Br] +,285.32736,Found285.15687.
实施例7 DXL-A-27的制备
8-(3,5-二三氟甲基苯基)-8-氮-5-氮螺[4.5]癸烷溴化物
8-(3,5-bis(trifluoromethyl)phenyl)-5,8-diazaspiro[4.5]decan-5-ium bromide
Figure PCTCN2018119785-appb-000020
采用通法二，白色固体，产率75％。 1H NMR(400MHz,D 2O)δ7.52(s,1H),7.48(s,2H),3.62(s,12H),2.21(s,4H).
13C NMR(101MHz,D 2O)δ149.95,132.36,132.03,131.71,131.44,124.86,122.20,116.17,114.18,114.10,114.06,114.02,62.71,58.78,43.86,21.16.
ES-HRMS:Calcd for C 16H 19BrF 6N 2[M-Br] +,353.32533,Found 353.14369.
实施例8 DXL-A-28的制备
8-(3-硝基-5-三氟甲基苯基)-8-氮-5-氮螺[4.5]癸烷溴化物
8-(3-nitro-5-(trifluoromethyl)phenyl)-5,8-diazaspiro[4.5]decan-5-ium bromide
Figure PCTCN2018119785-appb-000021
采用通法二，黄色固体，产率43.2％。 1H NMR(400MHz,D 2O)δ7.88(d,J＝12.1Hz,2H),7.54(s,1H),3.59(t,J＝16.9Hz,12H),2.18(s,4H).
13C NMR(101MHz,D 2O)δ150.36,148.96,132.63,132.27,131.83,131.49,124.47,118.28,113.33,111.74,62.70,58.66,43.53,21.17.
ES-HRMS:Calcd for C 15H 19BrF 3N 3O 2[M-Br] +,330.32492,Found 330.14195.
实施例9 DXL-A-29的制备
8-(3-甲基-5-硝基苯基)-8-氮-5-氮螺[4.5]癸烷溴化物
8-(3-methyl-5-nitrophenyl)-5,8-diazaspiro[4.5]decan-5-ium bromide
Figure PCTCN2018119785-appb-000022
采用通法二，黄色固体，产率27.1％。 1H NMR(400MHz,D 2O)δ7.50(s,2H),7.20(s,1H),3.79–3.32(m,12H),2.34(s,3H),2.26(s,4H).
13C NMR(101MHz,D 2O)δ149.43,148.38,123.19,116.18,107.69,62.63,58.78,43.99,21.14,20.64.
ES-HRMS:Calcd for C 15H 22BrN 3O 2[M-Br] +,276.35353,Found 276.17033.
实施例10 DXL-A-30的制备
8-(3-硝基-4-甲基苯基)-8-氮-5-氮螺[4.5]癸烷溴化物
8-(4-methyl-3-nitrophenyl)-5,8-diazaspiro[4.5]decan-5-ium bromide
Figure PCTCN2018119785-appb-000023
采用通法二，黄色固体，产率18.2％。 1H NMR(400MHz,D 2O)δ7.31(s,1H),7.10(t,J＝6.6Hz,2H),3.67–3.49(m,8H),3.40(s,4H),2.19(s,4H),2.17(s,3H).
13C NMR(101MHz,D 2O)δ148.67,147.64,133.68,126.13,121.81,111.63,62.70,58.87,44.16,21.18,18.78.
ES-HRMS:Calcd for C 15H 22BrN 3O 2[M-Br] +,276.35353,Found 276.17085.
实施例11 DXL-A-32的制备
8-(3-硝基-4-氰基苯基)-8-氮-5-氮螺[4.5]癸烷溴化物
8-(4-cyano-3-nitrophenyl)-5,8-diazaspiro[4.5]decan-5-ium bromide
Figure PCTCN2018119785-appb-000024
采用通法二，黄色固体，产率32.6％。 1H NMR(400MHz,D 2O)δ7.58(dd,J＝10.9,5.5Hz,2H),7.14(dt,J＝33.4,16.7Hz,1H),3.73(s,4H),3.66–3.51(m,8H),2.16(s,4H).
13C NMR(101MHz,D 2O)δ152.27,136.61,118.50,117.34,110.52,94.25,62.60,58.29,42.14,21.05.
ES-HRMS:Calcd for C 15H 19BrN4O 2[M-Br] +,287.33641,Found 287.15134.
实施例12 DXL-A-05的制备
8-(3-氯苯)-8-氮-5-氮螺[4.5]癸烷溴化物
8-(3-chlorophenyl)-5,8-diazaspiro[4.5]decan-5-ium bromide
Figure PCTCN2018119785-appb-000025
采用通法三，白色固体，产率58.8％。 1H NMR(400MHz,D 2O)δ7.23(d,J＝8.1Hz,1H),7.01(d,J＝1.8Hz,1H),6.92(dd,J＝17.4,8.1Hz,2H),3.47(dd,J＝30.2,26.7Hz,12H),2.14(s,4H).
13C NMR(101MHz,D 2O)δ150.24,134.62,130.77,121.34,116.65,115.14,62.62,58.81,44.36,21.09.
ES-HRMS:Calcd for C 14H 20BrClN 2[M-Br] +,251.77445,Found 251.13082.
实施例13 DXL-A-06的制备
8-(3-三氟甲苯基)-8-氮-5-氮螺[4.5]癸烷溴化物
8-(3-(trifluoromethyl)phenyl)-5,8-diazaspiro[4.5]decan-5-ium bromide
Figure PCTCN2018119785-appb-000026
采用通法二，白色固体，产率23.7％。 1H NMR(400MHz,D 2O)δ7.46(t,J＝7.9Hz,1H),7.31(s,1H),7.26(t,J＝7.6Hz,2H),3.58(dd,J＝13.8,5.7Hz,12H),2.17(s,4H).
13C NMR(101MHz,D 2O)δ149.37,131.22,130.90,130.29,125.46,122.77,120.24,117.94,113.20,62.65,58.87,44.39,21.11.
ES-HRMS:Calcd for C 15H 20BrF 3N 2[M-Br] +,285.32736,Found 285.15715.
实施例14 DXL-A-10的制备
8-(3-甲苯基)-8-氮-5-氮螺[4.5]癸烷溴化物
8-(m-tolyl)-5,8-diazaspiro[4.5]decan-5-ium bromide
Figure PCTCN2018119785-appb-000027
采用通法一，白色固体，产率83％。 1H NMR(400MHz,D 2O)δ7.22(t,J＝7.8Hz,1H),6.90(s,1H),6.85(d,J＝6.8Hz,2H),3.62–3.49(m,8H),3.44(s,4H),2.24(s,3H),2.15(s,4H).
13C NMR(101MHz,D 2O)δ160.00,150.52,130.67,110.01,107.15,103.40,62.61,58.90,55.44,44.80,21.07.
ES-HRMS:Calcd for C 15H 23BrN 2[M-Br] +,231.35597,Found 231.18548.
实施例15 DXL-A-18的制备
8-(2-氟苯基)-8-氮-5-氮螺[4.5]癸烷溴化物
8-(2-fluorophenyl)-5,8-diazaspiro[4.5]decan-5-ium bromide
Figure PCTCN2018119785-appb-000028
采用通法三，白色片状晶体，产率91％。 1H NMR(400MHz D2O)δ7.15–6.98(m 4H)，3.63–3.43(m，8H),3.31(s,4H),2.11(s,4H).
13C NMR(101MHz,D 2O)δ156.72,154.51,137.09,137.00,125.09,125.05,125.02,119.84,116.47,116.27,62.82,59.20,45.73,21.03.
ES-HRMS:Calcd for C 14H 20BrFN 2[M-Br] +,235.31985,Found 235.16094.
效果实施例
化合物LXM-21、LXM-22的制备参见WO 2007/147346 A1，以引用的方式将其整体并入本文。
各化合物按照0.4、1、3、4、6、9、12mg/kg给药量，当低剂量给药各化合物的药效没有显著性差异时，再依次增加给药剂量，即0.4mg/kg给药量与对照相比无显著性差异时，再调整给药剂量至1mg/kg重复试验，以此类推。
由于化合物DXL-A-27、DXL-A-28、DXL-A-29、DXL-A-30、DXL-A-32的分子量与其它化合物的分子量差异较大，这些化合物的给药剂量采用4μmol/kg。
实验动物
ICR小鼠，18-22g，雌雄各半，由北京大学实验动物部提供(许可证号：SCXK(京)2016-0010)。
采用以下试验对本发明化合物的镇痛效果进行测定。
下述实施例涉及本发明化合物的药学实验，在下述实验中，对所有的药学实验结果都进行了统计学处理，实验结果用SPSS 13.0软件进行分析；醋酸扭体法、福尔马林实验中各组间的比较采用单因素方差分析；热板试验和二甲苯致鼠耳肿胀试验采用重复测定的方差分析，显著性检验标准为P<0.05。
效果实施例1 热板试验
将热板温度调至55℃，以小鼠舔后足、跳跃反应为观察指标，从小鼠置于铜板上到出现上述反应的时间为潜伏期(laiencytime)。给药前30min测定3次潜伏期，取平均值作为基础阈值，或称基础潜伏期(Baseline latency，BL)，去除潜伏期大于15s小于5s的动物，将小鼠随机分组，每组8只。设溶媒对照组(双蒸水)，各待测样品组(化合物及其剂量见表1)。所有药物临用前用生理盐水溶解，灌胃给予。测定给药后2.0h的潜伏期。化合物对小鼠痛阈提高率(Percentage of Pain Threshold Elevated Rate，PTE％)按以下公式计算：
PTE％＝(试验组潜伏期-溶媒对照组潜伏期)/溶媒对照组潜伏期×100
实验结果见下表1，本发明化合物的结果相比溶媒组P<0.05，其中化合物DXL-A-16、DXL-A-19、DXL-A-21、DXL-A-22、DXL-A-23、DXL-A-24、DXL-A-27、DXL-A-28、DXL-A-29和DXL-A-32相比溶媒组P<0.01。
表1 本发明的化合物的痛阈提高率
化合物 剂量 PTE％
溶媒对照(双蒸水) - 0
LXM-21 3mg/kg 4.78
LXM-22 3mg/kg 25.03
DXL-A-05 3mg/kg 19.5
DXL-A-06 3mg/kg 16.67
DXL-A-10 3mg/kg 11.18
DXL-A-16 1mg/kg 31.44
DXL-A-19 1mg/kg 34.34
DXL-A-21 1mg/kg 36.63
DXL-A-22 1mg/kg 52.57
DXL-A-23 1mg/kg 39.24
DXL-A-24 1mg/kg 48.64
DXL-A-27 4μmol/kg 49
DXL-A-28 4μmol/kg 36
DXL-A-29 4μmol/kg 36
DXL-A-30 4μmol/kg 21
DXL-A-32 4μmol/kg 38
效果实施例2 醋酸扭体实验
ICR小鼠，雌雄各半，随机分组，每组8只。设溶媒对照组(双蒸水)；布洛芬对照组；各待测样品组(化合物及其剂量见表2)。所有药物临用前用双蒸水溶解，按确定剂量灌胃给予。给药后2h，小鼠腹腔注射0.6％醋酸溶液(10ml/kg，i.p.)，记录5～20min内小鼠扭体(腹部凹陷，臀部高抬，身体拉长)的次数，化合物对小鼠扭体疼痛抑制率％按以下公式计算。
抑制率％＝(溶媒对照组扭体次数－试验组扭体次数)/溶媒对照组扭体次数×100
本发明的化合物对醋酸刺激性痛的镇痛作用见表2，本发明化合物的结果相比溶媒组P<0.05，其中化合物DXL-A-29和DXL-A-30相比溶媒组P<0.01。
表2 本发明化合物对醋酸刺激性痛的镇痛作用
化合物 剂量 抑制率(％)
溶媒对照(双蒸水) - 0
LXM-21 3mg/kg 32.45
LXM-22 3mg/kg 16.4
DXL-A-05 3mg/kg 22.49
DXL-A-06 3mg/kg 14.03
DXL-A-10 3mg/kg 29.82
DXL-A-16 1mg/kg -
DXL-A-18 1mg/kg 21.71
DXL-A-19 1mg/kg -
DXL-A-21 1mg/kg -
DXL-A-22 1mg/kg -
DXL-A-23 1mg/kg -
DXL-A-24 1mg/kg -
DXL-A-27 4μmol/kg -
DXL-A-28 4μmol/kg -
DXL-A-29 4μmol/kg 75.97
DXL-A-30 4μmol/kg 41.75
DXL-A-32 4μmol/kg -
布洛芬片 200mg/kg 49.08
注：符号“-”表示在该剂量下所得数据相比溶媒对照组没有显著性差异。
效果实施例3 福尔马林实验
ICR小鼠，雌雄各半，随机分组，每组8只。设溶媒对照组(双蒸水)；各待测样品组：化合物及其剂量见表3。所有药物临用前用双蒸水溶解，按确定剂量灌胃给予。给药后2h，小鼠右后足底注射2.5％福尔马林溶液20ul，记录小鼠舔或咬足时间(s)作为疼痛反应的指标，0～5min为I相，10～60min为II相，共观 察60min。化合物对小鼠II相疼痛抑制率％按以下公式计算：
抑制率％＝(溶媒对照组舔或咬足时间－试验组舔或咬足时间)/溶媒对照组舔或咬足时间×100
本发明化合物对福尔马林刺激痛的影响如表3所示，本发明化合物的结果相比溶媒组P<0.05，其中化合物DXL-A-05、DXL-A-10、DXL-A-16、DXL-A-19、DXL-A-21、DXL-A-22、DXL-A-23、和DXL-A-24相比溶媒组P<0.01。
表3 本发明化合物对福尔马林刺激痛的影响
Figure PCTCN2018119785-appb-000029
效果实施例4 二甲苯致鼠耳肿胀试验
ICR小鼠随机分组，每组8只，雌雄各半。设溶媒对照组(双蒸水)以及各待测样品组(化合物及其剂量见表4)。所有药物临用前用双蒸水溶解，按确定剂量灌胃给药。化合物给予后2h，于小鼠右耳内外侧均匀涂抹50uL二甲苯，30min后剪下小鼠左右耳，用打孔器分别在左右同一位置打下大小相同的圆形耳片，称重。化合物对小鼠耳肿胀的抑制率％按公式计算。
抑制率％＝(溶媒对照组耳肿胀度－试验组耳肿胀度)/溶媒对照组耳肿胀度×100
本发明化合物对二甲苯致小鼠耳肿胀的影响见表4，本发明化合物的结果相比溶媒组P<0.05，其中化合物DXL-A-05、DXL-A-06、DXL-A-21、DXL-A-22、DXL-A-24和DXL-A-29相比溶媒组P<0.01。
表4 本发明化合物对二甲苯致小鼠耳肿胀的影响
化合物 剂量 抑制率(％)
溶媒对照(双蒸水) - 0
LXM-21 3mg/kg 10.85
LXM-22 3mg/kg -
DXL-A-05 3mg/kg 30.81
DXL-A-06 3mg/kg 45.85
DXL-A-10 3mg/kg 27.37
DXL-A-16 1mg/kg -
DXL-A-18 1mg/kg -
DXL-A-19 1mg/kg -
DXL-A-21 1mg/kg 42.46
DXL-A-22 1mg/kg 46.97
DXL-A-23 1mg/kg -
DXL-A-24 1mg/kg 53.37
DXL-A-27 4μmol/kg 4.13
DXL-A-28 4μmol/kg 9.27
DXL-A-29 4μmol/kg 63.27
DXL-A-30 4μmol/kg -
DXL-A-32 4μmol/kg 20.37
注：符号“-”表示在该剂量下所得数据相比溶媒对照组没有显著性差异。
效果实施例5 化合物DXL-A-22和DXL-A-24抗神经病理性疼痛作用研究
材料和方法
1材料
1.1 动物
SD大鼠，体重180g-220g，雌雄各半，由北京大学实验动物部提供。大鼠在温度22±0.5℃和相对湿度55±5％的标准环境下饲养，12h/12h明暗周期，标准饲料喂养。
1.2 试剂
化合物DXL-A-22和化合物DXL-A-24，由北京大学化学生物学系合成提供；加巴喷丁(江苏恒瑞医药股份有限公司)
1.3 仪器
von Frey电子测痛仪(IITC 2390，USA)；热痛反应测量仪(LE 7406，USA)
2 方法
2.1 坐骨神经慢性压迫性损伤(CCI)模型
大鼠用戊巴比妥钠(60mg/kg，i.p.)麻醉，右后肢手术部位去毛，俯卧位固定，沿大鼠右后肢股骨中部纵向切口，钝性分离肌肉，暴露坐骨神经，在坐骨神经分叉处近端用4-0丝线松结扎4次，每次间隔约1mm，松紧程度以观察到右后腿稍微抖动为宜。结扎后依次缝合肌肉和皮肤，假手术组只暴露坐骨神经，但不结扎。通过观察术后大鼠术侧后肢是否出现足趾并拢、轻微外翻、经常处于腾空状态以及测定大鼠机械刺激缩足阈值和热刺激缩足潜伏期来判断是否造模成功。
术前测定大鼠机械刺激缩足阈值和热刺激缩足潜伏期，以此分组：设假手术组(sham)、溶媒组(双蒸水，i.g.)、DXL-A-22组(2mg/kg，i.g.)、DXL-A-24组(1mg/kg，i.g.)和加巴喷丁组(100mg/kg，i.g.)，所有化合物和药物均用双蒸水溶解，按1mL/100g灌胃给药，从术后第一天开始每天给药，给药后2h测机械刺激缩足阈值和热刺激缩足潜伏期。
2.2 机械刺激缩足阈值(MWT)测定
大鼠机械刺激缩足阈值(MWT)用von Frey电子测痛仪检测。术后5、7、14天测定。将大鼠置于透明有机玻璃箱(底部是空隙1mm 2的铁丝网)中适应环境30min，待大鼠没有探索动作后，用von Frey电子测痛仪刺激大鼠术侧足底中间位置，测痛仪记录引起大鼠缩足反应的最大作用力(即MWT)。化合物的抑制率按以下公式计算：
绝对提高率(即PTE％)：PTE％＝(试验组MWT－溶媒组MWT)/溶媒组MWT×100        (1)
相对提高率：抑制率％＝(试验组MWT－溶媒组MWT)/(假手术组MWT-溶媒组MWT)×100     (2)
2.3 热刺激缩足潜伏期(PWL)测定
用热板法测定热刺激缩足潜伏期(PWL)。术后5，7，14天测定。热板温度为50.5℃，从大鼠置于热板仪开始计时到大鼠出现抖、舔足反应停止计时，此时间即为大鼠PWL。热板切断时间为14s，按公式(3)计算镇痛百分率(即MPE％)：
MPE％＝(试验组PWL－溶媒组PWL)/(切断时间－溶媒组PWL)×100    (3)
2.4 统计处理
结果以均值±标准误(mean±SEM)表示。用SPSS 19.0软件进行分析，机械刺激试验的各组间比较与热刺激试验的各组间比较均采用重复测量的方差分析。显著性检验标准为P<0.05。
3 实验结果
3.1 DXL-A-22对CCI大鼠机械刺激缩足阈值(MWT)的影响(mean±SEM，n＝8)
Figure PCTCN2018119785-appb-000030
**与溶媒组相比P＜0.01
3.2 DXL-A-22对CCI大鼠热刺激缩足潜伏期(PWL)的影响(mean±SEM，n＝8)
Figure PCTCN2018119785-appb-000031
**与溶媒组相比P＜0.01
3.3 DXL-A-24对CCI大鼠机械刺激缩足阈值(MWT)的影响(mean±SEM，n＝8)
Figure PCTCN2018119785-appb-000032
**与溶媒组相比P＜0.01
3.4 DXL-A-24对CCI大鼠热刺激缩足潜伏期(PWL)的影响(mean±SEM，n＝8)
Figure PCTCN2018119785-appb-000033
**与溶媒组相比P＜0.01
效果实施例6 化合物DXL-A-22、DXL-A-24抗炎作用研究
1 材料
1.1 动物
ICR小鼠，体重18g-22g，雌雄各半。由北京大学实验动物部提供。动物饲养于标准环境：温度23±1℃，相对湿度55±5％，明暗周期12h/12h，标准颗粒饲料喂养。
1.2 试剂
化合物DXL-A-22和DXL-A-24由北京大学化学生物学系合成提供；醋酸地塞米松片(浙江仙琚制药股份有限公司，批号：120415)；二甲苯(北京化工厂，批号：20100513)；角叉菜胶(美国sigma adlrich公司，批号：015K0172)。
1.3 仪器
自制打孔器(直径6mm)。YLS-7B足趾容积测量仪，山东省医学科学院设备站。
2.方法
2.1 二甲苯致小鼠耳肿胀试验
将小鼠随机分5组，每组8只，雌雄各半。设溶媒对照组(双蒸水，i.g.)、地塞米松对照组(2mg/kg，i.g.)、化合物DXL-A-22组(1mg/kg，i.g.)、和化合物DXL-A-24组(1mg/kg，i.g.)。所有药物临用前用双蒸水溶解，按0.1mL/10g灌胃给药。给药1h后，于小鼠右耳内外侧各均匀涂抹30μL二甲苯致炎，0.5h后剪下小鼠左右耳，用打孔器(直径6mm)分别在左、右耳同一部位打下等大的圆形耳片，称重，求左、右耳片重。以涂抹二甲苯后右耳重量与未涂抹二甲苯的左耳重量之差(即肿胀度)作为肿胀程度指标。按公式(1)计算肿胀度。抗炎作用强度以抑制率(％)表示。按公式(2)计算抑制率(％)。
肿胀度＝右耳片重量－左耳片重量    (1)
炎症抑制率(％)＝(溶媒对照组耳肿胀度－给药组耳肿胀度)/溶媒对照组耳肿胀度×100％(2)
2.2 角叉菜胶致小鼠足肿胀试验
将小鼠固定于特制的固定器内，双后足外露，试验前用记号笔于小鼠踝关节下0.5cm处画线，作为足跖容积测量的标志。给药前30min测右后足容积作为基础阈值。将小鼠随机分5组，每组8只，雌雄各半。设溶媒对照组(双蒸水，i.g.)、地塞米松对照组(0.5mg/kg，i.g.)、化合物DXL-A-22组(1mg/kg，i.g.)、DXL-A-24组(1mg/kg，i.g.)。所有药物临用前用双蒸水溶解，按0.1mL/10g给药。灌胃给药后立即于小鼠右后足跖皮下注射5％角叉菜胶生理盐水溶液20μL，于注射后各时间点0.5h、1h、2h测足跖容积。以注射角叉菜胶后右足跖容积与注射前右足跖容积之差(肿胀度)作为肿胀程度指标。按公式(3)计算肿胀度。抗炎作用强度以抑制率(％)表示。按公式(4)计算抑制率(％)。
肿胀度＝注射后右足跖容积－注射前右足跖容积    (3)
炎症抑制率(％)＝(溶媒对照组足跖肿胀度-给药组足跖肿胀度)/溶媒对照组足跖肿胀度×100％  (4)
2.3 统计处理
结果以均值±标准差(mean±SD)表示。用SPSS 19.0软件进行分析，二甲苯致小鼠耳肿胀实验各组间的比较采用单因素方差分析；角叉菜胶致小鼠足跖肿胀实验各组间的比较采用重复测量的方差分析。显著性检验标准为P<0.05。
3.实验结果
3.1 化合物DXL-A-22和DXL-A-24对二甲苯致小鼠耳肿胀的影响(mean±SD，n＝8)
Figure PCTCN2018119785-appb-000034
与溶媒对照组比较， **P<0.01
3.2 化合物DXL-A-22和DXL-A-24对角叉菜胶致小鼠足肿胀的影响(mean±SD，n＝8)
Figure PCTCN2018119785-appb-000035
与同一时间的溶媒对照组比较， **P＜0.01
由以上结果我们可以推断，本发明的化合物是一类镇痛作用明显的化合物。有望开发成为新一代镇痛药物。

Claims (14)

  1. 由式(I)表示的化合物、或其立体异构体、互变异构体、衍生物、前药或药学上可接受的盐：
    Figure PCTCN2018119785-appb-100001
    其中，R 1选自氢、卤素、烷基、氰基和卤代烷基，
    R 2和R 3分别独立地选自氢、卤素、烷基、卤代烷基和硝基，并且R 1、R 2和R 3不同时为氢；
    以及，当R 2和R 3之一为硝基或卤素时，R 1、R 2和R 3中的其余两者不同时为氢。
  2. 如权利要求1所述的化合物、或其立体异构体、互变异构体、衍生物、前药或药学上可接受的盐，其中，所述化合物由式(II)表示：
    Figure PCTCN2018119785-appb-100002
    其中，R 1选自氢、卤素、烷基、氰基和卤代烷基，
    R 2选自氢、卤素、烷基、卤代烷基和硝基，并且R 1和R 2不同时为氢。
  3. 如权利要求2所述的化合物、或其立体异构体、互变异构体、衍生物、前药或药学上可接受的盐，其中，所述化合物由式(II)表示：
    Figure PCTCN2018119785-appb-100003
    其中，R 1选自氢、卤素或卤代烷基；R 2选自氢或硝基。
  4. 如权利要求2所述的化合物、或其立体异构体、互变异构体、衍生物、前药或药学上可接受的盐，其中，R 1选自烷基、氰基、卤素或卤代烷基，并且R 2为氢。
  5. 如权利要求2-4中任一项所述的化合物、或其立体异构体、互变异构体、衍生物、前药或药学上可接受的盐，其中，R 1选自卤素或卤代烷基，并且R 2为氢。
  6. 如权利要求2-5中任一项所述的化合物、或其立体异构体、互变异构体、衍生物、前药或药学上可接受的盐，其中，所述烷基选自甲基、乙基或丙基。
  7. 如权利要求2-6中任一项所述的化合物、或其立体异构体、互变异构体、衍生物、前药或药学上可接受的盐，其中，所述卤代烷基为三氟甲基。
  8. 如权利要求2-7中任一项所述的化合物、或其立体异构体、互变异构体、衍生物、前药或药学上可接受的盐，其中，所述化合物选自：
    Figure PCTCN2018119785-appb-100004
  9. 制备由式(I)表示的化合物的方法，所述方法包括：
    (1)将原料卤代苯试剂(A)、金属催化剂、配体、碱溶于溶剂中，然后加入1-Boc-哌嗪(B)，在氩气保护下反应，反应温度为40℃-140℃，得到中间体化合物(C)；
    (2)向所述中间体化合物(C)中加入盐酸-有机溶剂，室温下搅拌，得到脱保护的中间体(D)；以及
    (3)将所述脱保护的中间体(D)溶于溶剂中，在NaHCO 3存在下与1,4-二溴丁烷反应，得到所述的由式(I)表示的化合物，
    Figure PCTCN2018119785-appb-100005
    其中，在步骤(1)和步骤(3)中，所述溶剂为醇、酮、腈、氯代烃类溶剂、苯系溶剂、DMSO或DMF；所述金属催化剂选自氯化钯、醋酸铜、碘化亚酮或三氯化铁；
    所述配体为α-氨基酸、邻羟基苯甲酰胺或联二萘酚；
    在步骤(2)中，所述有机溶剂为醇或酯类溶剂。
  10. 药物组合物，所述药物组合物含有如权利要求1-8中任一项所述的化合物、或其立体异构体、互变异构体、衍生物、前药或药学上可接受的盐，以及任选地药学上可接受的载体。
  11. 如权利要求1-8中任一项所述的化合物、或其立体异构体、互变异构体、衍生物、前药或药学上可接受的盐在制备用于抗神经病理性疼痛的药物中的用途。
  12. 如权利要求1-8中任一项所述的化合物、或其立体异构体、互变异构体、衍生物、前药或药学上可接受的盐在制备用于抗炎的药物中的用途。
  13. 一种镇痛方法，所述方法包括将如权利要求1-8中任一项所述的化合物、或其立体异构体、互变异构体、衍生物、前药或药学上可接受的盐给予有需要的受试者。
  14. 一种抗炎方法，所述方法包括将如权利要求1-8中任一项所述的化合物、或其立体异构体、互变异构体、衍生物、前药或药学上可接受的盐给予有需要的受试者。
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