WO2016066115A1 - 取代杂环衍生物、其制备方法和用途 - Google Patents

取代杂环衍生物、其制备方法和用途 Download PDF

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WO2016066115A1
WO2016066115A1 PCT/CN2015/093140 CN2015093140W WO2016066115A1 WO 2016066115 A1 WO2016066115 A1 WO 2016066115A1 CN 2015093140 W CN2015093140 W CN 2015093140W WO 2016066115 A1 WO2016066115 A1 WO 2016066115A1
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pain
compound
group
pharmaceutically acceptable
solvate
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PCT/CN2015/093140
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French (fr)
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邱彦
任杰
李宇航
杨隆河
朱程刚
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厦门大学
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Priority claimed from CN201410604001.7A external-priority patent/CN104352488B/zh
Priority claimed from CN201410603721.1A external-priority patent/CN104356082B/zh
Application filed by 厦门大学 filed Critical 厦门大学
Priority to CN201580059446.4A priority Critical patent/CN107074788B/zh
Priority to US15/522,985 priority patent/US10174015B2/en
Publication of WO2016066115A1 publication Critical patent/WO2016066115A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the invention belongs to the field of medicinal chemical industry and relates to substituted heterocyclic derivatives, in particular to a kind of substituted heterocyclic derivatives which can inhibit the activity of endogenous cannabinoid hydrolase NAAA and/or FAAH enzyme.
  • the invention also relates to processes for the preparation of such compounds, to pharmaceutical compositions containing such compounds, and to the pharmaceutical use of such compounds.
  • THC Tetrahydrocannabinol
  • CB 1 or CB 2 cannabinoid receptor 1/2
  • AEA N-arachidonoylethanolamine
  • O-arachidonoylethanolamine O-arachidonoylethanolamine
  • N-arachidonoyopopamine act on cannabinoids.
  • Endogenous cannabinoids of the receptor Like lipid transmitters such as prostaglandins, these endocannabinoids do not accumulate in the body, but are synthesized locally on demand, and are regulated by enzymes and receptors, which can be metabolized by their specific hydrolases. Fatty acids and ethanolamines, glycerol and other substances, thereby reducing the role of such substances in the body.
  • AEA is the first endogenous cannabinoid found (Devane WA, Hanus L, Breuer A, et al., Science, 1992, 258:1946-1949; Di Marzo V, De Petrocellis L., Curr Med Chem, 2010, 17: 1430-1449; Gasperi V, Dainese E, Oddi S, et al., Curr Med Chem, 2013, 20: 64-78.), mainly stimulating CB 1 receptor, producing cannabis extracts such as THC Similar pharmacological functions.
  • AEA has a wide distribution in the body, and the presence of AEA can be detected in organs such as the central nervous system, liver, lung, and gastrointestinal tract.
  • AEA can produce a variety of pharmacological effects such as anti-inflammatory and analgesic by directly activating endogenous cannabinoid receptor (CB). Furthermore, AEA has been reported to transient receptor potential channel subfamily V member 1, TRPV1 (Bouaboula M, Hilairet S, Marchand J, et al., Eur J Pharmacol, 2005, 517: 174-181; Mechoulam R, Ben-Shabat S, Hanus L, et al., Biochem Pharmacol, 1995, 50: 83-90; Sugiura T, Kondo S, Sukagawa A, et al., Biochem Biophys Res Commun, 1995, 215:89-97.), G protein coupled receptor 55 (GPR55) (Sugiura T, Waku K., Journal of Biochemistry, 2002, 132: 7-12; Sigel E, Baur R, Racz I, et Al., Proc Natl Acad Sci USA, 2011, 108: 18150-18155; Guin
  • fatty acylethanolamine lipids such as N-Oleoylethanolamide (OEA), N-palmitoylethanolamide (PEA), although not directly acting on cannabinoid receptors.
  • OEA N-Oleoylethanolamide
  • PEA N-palmitoylethanolamide
  • PEA and OEA produce analgesic, anti-inflammatory and appetite-suppressing effects by acting on peroxisome proliferator-activated receptor alpha (PPAR-alpha) (Fu J, Gaetani S, Oveisi F, et al., Nature, 2003, 425 :90-93.).
  • PEA has a wide distribution in the body, and PEA can exert analgesic and anti-inflammatory effects on various targets such as the central nervous system and sensory nervous system and immune cells.
  • PEA can activate the receptor-alpha (PPAR- ⁇ ) by agonizing the nuclear receptor peroxisome proliferator, or partially agonize the GPG55 receptor and GPR119 receptor, and produce various pharmacological effects such as anti-inflammatory and analgesic effects (Mol Pharmacol, 2005, 67, 15-19).
  • N-stearoylethanolamine promotes apoptosis in tumor cells (Maccarrone M, Pauselli R, Di Rienzo M, et al., Biochem J, 2002, 366: 137-144) and appetite suppression (Terrazzino S, Berto F, Dalle) Carbonare M, et al., FASEB J, 2004, 18: 1580-1582); Oleamide (OA) has the effect of regulating sleep (Huitron-Resendiz S, Gombart L, Cravatt BF, et al., Exp Neurol, 2001, 172: 235-243).
  • AEA can be deactivated by hydrolysis of a specific fatty acid amide hydrolase (FAAH) to arachidonic acid and ethanolamine.
  • FAAH fatty acid amide hydrolase
  • FAAH was cloned in 1996 and belongs to the amidase signature family. It is the first family protein found in mammals, which exists in the inner membrane of cells and has a transmembrane-bound alpha helix.
  • the FAAH protein consists of 579 amino acids, and the FAAH crystal structure has been obtained.
  • the AEA active center of the hydrolyzed substrate consists of three typical amino acids Ser-Ser-Lys (Ser241-Ser217-Lys142).
  • pH alkaline pH alkaline
  • OEA fatty acid acylethanolamine substrate compounds
  • OA fatty acid amides
  • McKinney MK Cravatt BF., Annu Rev Biochem, 2005, 74:411-432
  • Fezza F De Simone C, Amadio D, et al., Subcell Biochem, 2008, 49: 101-132
  • relative hydrolytic activity Be weak Be weak.
  • FAAH inhibitors have a certain role in antidepressant, anti-anxiety, anti-neuropathic pain and the like. Some FAAH inhibitors have entered clinical research in the treatment of depression, arthritic pain and the like. FAAH inhibitors can be classified into four broad categories depending on the structure: early AEA substrate analogs, alpha-ketone heterocycles, carbamates, and aromatic ureas.
  • this enzyme is quite different from the known AEA hydrolase FAAH: (1) this enzyme has the strongest hydrolysis activity under acidic pH conditions (pH 4.5), while the FAAH enzyme is hydrolyzed under alkaline conditions. Strong (pH 9.0) (Linsenbardt DN, Boehm SL, 2nd., Neuroscience, 2009, 164: 424-434); (2) the activity of this enzyme on PEA is much greater than that of AEA; (3) The enzyme is not sensitive to the serine inhibitors PMSF and MAFP which have a good inhibitory effect on FAAH.
  • NAAA enzyme was the most active in the lungs in various tissues of rats, and gradually decreased in the tissues of the spleen, thymus, small intestine, etc., and finally purified in the lung tissue (Ueda N, Yamanaka K, Yamamoto S., J Biol Chem, 2001, 276: 35552-35557).
  • the cDNA sequence of this enzyme was successfully cloned from rat, mouse and human cells, and the enzyme was named N-Acylethanolamine-hydrolyzing Acid Amidase (NAAA). Tsuboi K, Sun YX, Okamoto Y, et al., J Biol Chem, 2005, 280: 11082-11092).
  • NAAA is primarily expressed in lysosomes (Tsuboi K, Zhao LY, Okamoto Y, et al., Biochim Biophys Acta, 2007, 1771: 623-632).
  • NAAA contains 362 amino acids (rat and mouse) and 359 amino acid (human) sequences with molecular weights of 40.3 Kda (rat) and 40.1 kDa (mouse and human), respectively.
  • the homology of rat and mouse was 90.1%
  • the homology of rat and human was 76.5%
  • mouse and human was 76.7%.
  • the human NAAA gene is located on the 4q21.1 chromosome.
  • NAAA has no homology with FAAH, but has some homology with acid ceramidases, classified as a family of choloylglycine hydrolase, which is selective for the hydrolysis of amides ( Tsuboi K, Sun YX, Okamoto Y, et al., J Biol Chem, 2005, 280: 11082-11092).
  • Topical administration of the structural analog ARN077 significantly inhibited carrageenan-induced inflammatory pain and neuropathic pain caused by sciatic nerve ligation.
  • ARN077 1%, 20 ⁇ L, epidermal administration
  • gabapentin 50 mg/kg, orally
  • Endogenous cannabinoid hydrolase inhibitors have less side effects on the central nervous system than opioids, antiepileptics, antidepressants, and local anesthetics. They are less addictive; compared to ibuprofen and sedatives.
  • COX inhibitor-type anti-inflammatory analgesics such as oxime and aspirin do not cause gastrointestinal bleeding and severe cardiovascular events, and have better drug safety. (Biochem J, 2004, 380, 749-756; Journal of Medicinal Chemistry, 2008, 51, 7327-7343; PAIN, 2013, 154, 326-327).
  • a first aspect of the invention relates to a compound of formula I, a pharmaceutically acceptable salt, hydrate or solvate thereof,
  • X is selected from: C, N, O;
  • Y is selected from: C, N;
  • A is selected from the group consisting of: R 12 , OR 6 , N R 7 R 8 or CR 9 R 10 R 11 ;
  • R 12 is -(CH 2 ) n R 13 ;
  • R 13 is selected from the group consisting of: H, C 1 - 10 linear or branched alkyl, phenyl, thienyl, furyl, C 4-6 cycloalkyl, biphenyl, phenoxyphenyl, benzyloxybenzene , phenylethoxyphenyl, piperidinyl, N-benzylpiperidinyl, naphthyl, anthracenyl, uracilyl, optionally substituted by 1 or 2 substituents selected from Halogen, methyl, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, nitro, trifluoromethyl, cyano, C 1-6 alkyl mono- or polysubstituted by halogen A C 1-6 alkoxy group which is mono- or polysubstituted by halogen.
  • n is an integer selected from 0 to 10;
  • Each R' is independently H or various substituted or unsubstituted linear alkyl, branched alkyl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, linear chain selected from 20 C atoms. Heteroalkyl, branched heteroalkyl, heterocycloalkyl, heteroalkenyl, heteroalkynyl, heterocyclyl or aryl.
  • the compound of the first aspect of the invention a pharmaceutically acceptable salt, hydrate or solvate thereof, which may be as shown in Formula Ia,
  • X is O or N
  • Y is N
  • n is an integer selected from 0 to 7;
  • R 13 is selected from the group consisting of: H, C 1 - 10 linear or branched alkyl, phenyl, thienyl, furyl, C 4-6 cycloalkyl, biphenyl, phenoxyphenyl, benzyloxybenzene , phenylethoxyphenyl, piperidinyl, N-benzylpiperidinyl, naphthyl, anthracenyl, uracilyl, optionally substituted by 1 or 2 substituents selected from Halogen, methyl, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, nitro, trifluoromethyl, cyano, C 1-6 alkyl mono- or polysubstituted by halogen A C 1-6 alkoxy group which is mono- or polysubstituted by halogen.
  • a second aspect of the invention relates to a process for the preparation of a compound of formula Ia, a pharmaceutically acceptable salt, hydrate or solvate thereof, comprising:
  • a compound of formula II is reacted with a compound of formula III at a suitable temperature to provide a compound of formula Ia.
  • a suitable solution is a solution containing n-butyl lithium, and a suitable temperature is -78 ° C to 0 ° C.
  • a third aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of the formula I or formula Ia according to any one of the first aspects of the invention, a pharmaceutically acceptable salt, hydrate or solvate thereof, And pharmaceutically acceptable excipients.
  • a fourth aspect of the invention relates to a method of treating or reducing the severity of a disease or condition,
  • the method comprises administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of Formula I or Formula Ia, a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of the first aspects of the invention.
  • the disease or condition is pain.
  • a fifth aspect of the invention relates to a compound of formula I or formula Ia, a pharmaceutically acceptable salt, hydrate or solvate thereof, according to any one of the first aspects of the invention, for use in the treatment of a disease or condition or amelioration Use in a medicament for the severity of the disease or condition, the disease or condition being pain.
  • a sixth aspect of the invention relates to a compound of the above formula I or formula Ia, a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of a disease or condition or for alleviating the severity of said disease or condition,
  • the disease or condition is pain.
  • the pain includes, but is not limited to, neuropathic pain (including but not limited to central nervous pain, peripheral neuropathic pain), inflammatory pain (including but not limited to osteoarthritis pain, fibromuscular pain syndrome, Inflammatory pain of rheumatism and rheumatoid arthritis, inflammatory pain of endometriosis, inflammatory toothache, ankylosing spondylitis pain, gouty arthritis pain, visceral inflammatory pain), mixed pain (including But not limited to low back pain, shoulder pain, burning mouth syndrome, complex local pain syndrome, migraine, from collective headache, tension headache syndrome, facial pain).
  • neuropathic pain including but not limited to central nervous pain, peripheral neuropathic pain
  • inflammatory pain including but not limited to osteoarthritis pain, fibromuscular pain syndrome, Inflammatory pain of rheumatism and rheumatoid arthritis, inflammatory pain of endometriosis, inflammatory toothache, ankylosing spondylitis pain, gouty arthritis pain, vis
  • the peripheral neuropathic pain includes, but is not limited to, neuralgia after herpes infection, pain caused by diabetic peripheral neuropathy, tumor-induced nerve compression and exudation, lumbar spine surgery failure syndrome, lumbar disc herniation-induced neuropathic pain, postpartum nerve Pain, trigeminal neuralgia, chemotherapy-induced multiple neuropathic pain, nerves from disease, root nerve pain after radiotherapy.
  • the central neuropathic pain includes, but is not limited to, compression pain caused by spinal sclerosis, multiple sclerosis-related pain, Parkinson's-related pain, dementia-related pain, post-stroke pain, and post-spinal pain.
  • the visceral inflammatory pain includes, but is not limited to, appendicitis, gastritis, pancreatitis, prostatitis, myocarditis, interstitial cystitis, pain caused by gallbladder kidney stones, irritable bowel syndrome, chronic pelvic pain syndrome.
  • alkyl refers to a saturated straight or branched monovalent hydrocarbon group, preferably having from 1 to 12 carbon atoms, more preferably from 1 to 10, 1 to 8, from 1 to 6, or 1-3 carbon atoms.
  • Typical examples of “alkyl” include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, tert-amyl, neopentyl, hexyl , heptyl, octyl, etc.
  • alkenyl include, but are not limited to, ethenyl, propenyl, allyl, buten-1-yl, buten-2-yl, penten-1-yl, penten-2-yl, 1 , 3-pentadienyl, hexene-1-yl, hexen-2-yl, 1,3-hexadienyl, heptenyl, octenyl and the like.
  • alkynyl refers to an acetylenically unsaturated, straight-chain or branched monovalent hydrocarbon radical containing at least one carbon-carbon triple bond (-C ⁇ C-) having from 2 to 12 carbon atoms, preferably having 2 -10, 2-8, 2-6, 2-4 or 2-3 carbon atoms.
  • Typical examples of “alkynyl” include, but are not limited to, ethynyl, propynyl, propargyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl and the like.
  • amino as used herein means -NH 2.
  • hydroxy as used herein means -OH.
  • cyano as used herein means -CN.
  • cycloalkyl as used herein, means a saturated cyclic hydrocarbon group having from 3 to 12 carbon atoms and having a single or bicyclic ring or a plurality of fused rings, including fused and bridged ring systems, preferably having 3 -10, 3-8, 5-8, 4-6 or 5-6 carbon atoms, particularly preferably 4-6 carbon atoms.
  • cycloalkyl include, but are not limited to, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl, 2- Methylcyclopentyl, 2-methylcyclooctyl and the like.
  • heterocycloalkyl refers to a cycloalkyl group, as defined herein, containing one, two or more heteroatoms independently selected from N, O and S.
  • heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperazinyl, thiazinyl, piperidinyl and morpholinyl, and the like.
  • heteroalkyl means that a certain C atom in the "alkyl", “alkenyl” or “alkynyl” group is hetero atom N, Substituted by O or S, these hetero atom-containing groups contain at least one C atom and one hetero atom. Any hydrogen atom on one of these groups may be substituted by a halogen, especially a fluoro group, a chloro group, or may be substituted by another group.
  • aryl refers to any monovalent, bicyclic or fused ring system monovalent substituent having an aromatic character to the electronic distribution of the entire ring system and combinations thereof.
  • Typical structures include: benzene ring, thiophene, furan, pyrrole, thiazole, pyrazole, imidazole, pyridine, pyran, pyrimidine, pyrazine, quinoline, isoquinoline, indole, indole or the above aromatic group in any form Fused and so on. Any hydrogen atom on one of these groups may be substituted by a halogen atom, especially a fluoro group, a chloro group, or may be substituted by another group.
  • alkoxy refers to the group -OR 14 , wherein R 14 is alkyl or cycloalkyl as defined herein.
  • Typical examples of “alkoxy” include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, n-Hexyloxy, 1,2-dimethylbutoxy, cyclohexyloxy, cyclopropyloxy and the like.
  • halogen as used herein means fluoro, chloro, bromo or iodo. Preferred halogen groups are fluorine, chlorine or bromine.
  • the groups defined by the various terms herein above may also be optionally mono- or polysubstituted by -CN, -OH, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy or halogen.
  • X may be O or N.
  • X is O.
  • X is N.
  • Y in the formula Ia of the invention may be N.
  • n is 0 or 1.
  • n may be 0 or 1
  • n 4, 5, 6 or 7.
  • n is 5, 6 or 7.
  • n may be 5, may be 6, or may be 7.
  • R 4 is H or (CH 3 ) 2 NCH 2 -.
  • R 13 is selected from the group consisting of: H, C 1 - 10 linear or branched alkyl, phenyl, thienyl, furyl, C 4-6 cycloalkyl , biphenyl, phenoxyphenyl, benzyloxyphenyl, phenylethoxyphenyl, piperidinyl, N-benzylpiperidinyl, naphthyl, anthryl, uracil, Optionally substituted with 1 or 2 substituents selected from the group consisting of halogen, methyl, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, nitro, trifluoromethyl, cyano , C 1-6 alkyl substituted by halogen or mono-substituted, mono- or polysubstituted by halogen, C 1-6 alkoxy group.
  • R 13 is selected from the group consisting of: H, C 1 -8 straight or branched alkyl, phenyl, thienyl, furyl, cyclohexyl, biphenyl , phenoxyphenyl, benzyloxyphenyl, phenylethoxyphenyl, piperidinyl, N-benzylpiperidinyl, naphthyl, anthryl, uracil, optionally 1 or 2 substituents selected from the group consisting of halogen, methyl, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitro, trifluoromethyl, cyano, halogen A substituted or polysubstituted C 1-4 alkyl group, a C 1-4 alkoxy group mono- or polysubstituted by a halogen.
  • R 13 is selected from the group consisting of H, a straight or branched alkyl group having 8 carbon atoms,
  • R 13 is selected from the group consisting of H, a linear alkyl group having 8 carbon atoms,
  • R13 is selected from the group consisting of H, a straight or branched alkyl group having 8 carbon atoms,
  • the compound of formula Ia a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:
  • X is O or N
  • Y is N
  • n is an integer selected from 0 to 7;
  • R13 is selected from the group consisting of: H, C1-8 straight or branched alkyl, phenyl, thienyl, furyl, cyclohexyl, biphenyl, phenoxyphenyl, benzyloxyphenyl, phenylethoxy Phenyl, piperidinyl, N-benzylpiperidinyl, naphthyl, anthracenyl, uracilyl, optionally substituted by 1 or 2 substituents selected from halogen, methyl, hydroxy , C1-4 alkyl, C1-4 alkoxy, hydroxy, nitro, trifluoromethyl, cyano, C1-4 alkyl mono- or polysubstituted by halogen, C1 mono- or polysubstituted by halogen -4 alkoxy group.
  • X is O or N
  • Y is N
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • R13 is selected from the group consisting of H, a linear or branched alkyl group having 8 carbon atoms,
  • X is O or N
  • Y is N
  • n 4, 5, 6 or 7;
  • R13 is selected from the group consisting of H, a linear alkyl group having 8 carbon atoms,
  • X is O or N
  • Y is N
  • n 4, 5, 6 or 7;
  • R13 is selected from the group consisting of H, a linear alkyl group having 8 carbon atoms,
  • X is O
  • Y is N
  • n 4, 5, 6 or 7;
  • R13 is selected from the group consisting of H, a linear alkyl group having 8 carbon atoms,
  • X is O
  • Y is N
  • n 4, 5, 6 or 7;
  • R13 is selected from the group consisting of H, a linear alkyl group having 8 carbon atoms,
  • X is O
  • Y is N
  • n 0 or 1
  • R4 is H, methyl, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy, nitro, trifluoromethyl, cyano or (CH3)2NCH2-;
  • R13 is selected from the group consisting of H, a linear or branched alkyl group having 8 carbon atoms,
  • X is O
  • Y is N
  • n 0 or 1
  • R4 is H or (CH3)2NCH2-;
  • R13 is selected from the group consisting of H, a linear or branched alkyl group having 8 carbon atoms,
  • the compound of Formula I or Formula Ia, a pharmaceutically acceptable salt, hydrate or solvate thereof is selected from the group consisting of:
  • the compounds of formula Ia of the invention can be synthesized by the following synthetic routes:
  • X, Y, R4, R13, n are as defined herein.
  • n, R 13 are as defined herein.
  • n, R13 are as defined herein.
  • the synthesis of the compound of formula Ia of the present invention is carried out as follows: slowly adding a positive solution to a solution containing oxazolidinone (44 mg, 0.5 mmol) in tetrahydrofuran (THF) at -78 °C A solution of butyl lithium in hexane (0.55 mmol, 0.2 mL). After stirring at this temperature for 10 min, a solution of the acid chloride in tetrahydrofuran (0.55 mmol, 1 mL) was added dropwise. The reaction solution was stirred at -78 ° C for 0.5 h, slowly warmed to room temperature over 4 h, and stirred at room temperature for 1 h.
  • the compound of the formula I or formula Ia of the present invention achieves the treatment of pain by inhibiting endogenous cannabinoid hydrolase activity.
  • the endogenous cannabinoid hydrolase described herein includes Fatty Acid Amide Hydrolase (FAAH) and N-acylethanolamide hydrolyzing acid amidase (NAAA).
  • FAAH Fatty Acid Amide Hydrolase
  • NAAA N-acylethanolamide hydrolyzing acid amidase
  • Inhibiting endogenous cannabinoid hydrolase activity as described herein means selectively inhibiting the activity of NAAA or selectively inhibiting the activity of FAAH or simultaneously inhibiting the activity of NAAA and FAAH.
  • pharmaceutically acceptable salt refers to those salts, prodrugs or solutions of any of the compounds described above, which are within the scope of the correct medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, stimulating strain response, etc., consistent with a reasonable benefit/risk ratio.
  • selectively inhibiting the activity of NAAA means that the compound inhibits the hydrolysis of the substrate by NAAA in a body at a dose (e.g., an effective amount), but does not inhibit FAAH in the body. Hydrolysis of the substrate.
  • selectively inhibiting the activity of FAAH means that the compound inhibits hydrolysis of the substrate by FAAH in a certain amount (e.g., an effective amount) of administration, but does not inhibit NAAA in the body. Hydrolysis of the substrate.
  • spontaneous inhibition of the activity of NAAA and FAAH means that the compound inhibits the hydrolysis of the substrate by FAAH in a certain amount (e.g., an effective amount) of the administered concentration, and can also inhibit Hydrolysis of the substrate by NAAA in the body.
  • compositions of formula I or formula Ia according to the invention may be used either as such or in the form of their pharmaceutically acceptable salts or hydrates or solvates.
  • Pharmaceutically acceptable salts of a compound of Formula I or Formula Ia include salts with pharmaceutically acceptable inorganic or organic acids, or with pharmaceutically acceptable inorganic or organic bases. Examples of suitable acid addition salts include with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid.
  • citric acid pamoic acid
  • malonic acid hydroxymaleic acid
  • phenylacetic acid glutamic acid
  • benzoic acid salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzene a salt formed from a sulfonic acid, a hydroxynaphthoic acid, hydroiodic acid, malic acid, citric acid or the like.
  • suitable base addition salts include sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B.
  • Diamine, N-methylglucamine and procaine isoforms Into the salt When reference is made herein to a compound of the invention, it includes a compound of formula I or formula Ia, and pharmaceutically acceptable salts or hydrates or solvates thereof.
  • the pharmaceutical composition comprises at least one compound of the formula I or formula Ia according to the invention together with a conventional pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition can be administered by, for example, oral or parenteral routes.
  • the pharmaceutical compositions of the present invention can be prepared in a variety of dosage forms including, but not limited to, tablets, capsules, solutions, suspensions, granules or injections, etc., by conventional methods in the art, for example, by oral or parenteral routes.
  • the dosage and method of use of the compounds of the invention depend on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and the diagnosis and treatment. Subjective judgment of the physician.
  • a preferred use dose is between 0.01 and 100 mg/kg body weight per day.
  • the compound of the formula I or formula Ia of the present invention achieves the treatment of pain by inhibiting endogenous cannabinoid hydrolase activity.
  • the compound of formula I or formula Ia of the present invention is capable of inhibiting the activity of NAAA and/or FAAH, can significantly inhibit the action of central nervous pain in mice, significantly inhibits the action of peritoneal inflammatory pain in mice, and significantly inhibits nitric acid.
  • Glycerol-induced headache in rats significantly inhibited osteoarthritic pain in rats.
  • the compound of the formula I or the formula Ia of the present invention has good stability, half-life of more than 24 hours under acid and alkaline conditions, and half-life in rat plasma is more than 120 minutes, and the stability far exceeds the reported one.
  • ⁇ -butyrolactone NAAA inhibitor ⁇ -butyrolactone NAAA inhibitor rat plasma half-life is less than 15 minutes.
  • the compound of formula I or formula Ia of the present invention has a metabolic half-life of 60-300 minutes in rats, and the stability far exceeds the reported ⁇ -butyrolactone NAAA inhibitor ( ⁇ -butyrolactone NAAA inhibitor). The metabolic half-life in rats is less than 5 minutes).
  • the compound of Formula I or Formula Ia of the present invention has a low inhibition rate of hERG potassium channel, and has better cardiac safety than the commercially available antipyretic analgesic drug COX2 selective inhibitor celecoxib.
  • Figure 1 shows the effects of Compounds 2, 9, 14, 24, 30 and the positive drug gabapentin on SNI neuropathic pain for 1 h.
  • Figure 2 is the effect of Compounds 2, 9, 14, 24, 30 and the positive drug gabapentin on SNI neuropathic pain for 4 h.
  • Figure 3 is the effect of Compounds 2, 9, 14, 24, 30 and the positive drug gabapentin on SNI neuropathic pain for 10 h.
  • Figure 4 is a graph showing the effects of compounds 2, 9, 14, 24, 30 and the positive drug indomethacin on acetic acid-induced inflammatory abdominal pain.
  • Figure 5 is a graph showing the effects of compounds 2, 9, 14, 24, 30 and the positive drug indomethacin on nitroglycerin-induced headache in rats.
  • Figure 6A shows the effect of different concentrations of Compound 2, 9 on RAW264.7 cells after 24 h incubation.
  • Figure 6B shows the effect of different concentrations of Compound 2, 9 on RAW264.7 cells after 48 h incubation.
  • the product is obtained as a product 16 (65 mg; yield: 48%, white amorphous powder) .
  • the product is obtained as a product 17 (86 mg; yield: 53%, white amorphous powder) .
  • reaction product 20 (76 mg; yield: 49%, white amorphous powder) .
  • the product is obtained as a product 22 (77 mg; yield: 50%, white amorphous powder) .
  • the product is obtained as a product 25 (27 mg; yield: 46%, white Shaped powder).
  • reaction product afforded product 46 (15 mg; yield: 26%, white amorphous powder ).
  • the compound to be evaluated or the test compound or test compound used in the experimental examples of the present invention are the compounds 1-46 prepared in the examples of the present invention.
  • the endogenous cannabinoid hydrolase used in this experimental example is Fatty Acid Amide Hydrolase (FAAH) and N-acylethanolamide hydrolyzing acid (N-acylethanolamide hydrolyzing acid).
  • Amidase, NAAA was prepared according to the method described in the literature (PMCID: PMC3423427, PMC3723234, PMC2692831, PMC3382457).
  • the preparation method is as follows: by constructing a plasmid carrying the complete NAAA/FAAH gene (pCDNA3.1/NAAA or pCDNA3.1/FAAH), the plasmid carrying the Cytomegalovirus (CMV) promoter and the Neomycin selection gene, and transferring into the above plasmid using a lipid medium.
  • CMV Cytomegalovirus
  • HEK-293 cells To HEK-293 cells, a stable and highly expressed NAAA/FAAH-expressing cell line was obtained using G418 screening and Western-blot detection.
  • HEK-293 recombinant cells were cultured and collected, washed 2 to 3 times with PBS, sonicated in 20 mM Tris-HCl containing 0.32 M sucrose, repeatedly frozen and thawed twice, centrifuged at 800 g for 15 min at 4 ° C, and the supernatant was collected ( That is, the desired protein), the protein concentration was measured by the BCA method, and the protein concentration was uniformly diluted to 1 mg/mL, and stored in a refrigerator at -80 ° C for use after storage.
  • the configuration procedure of the PBS solution used in this experimental example was: 8 g NaCl, 0.2 g KCl, 1.44 g Na 2 HPO 4 , 0.24 g KH 2 PO 4 , dissolved in 1 L ultrapure water, sterilized by damp heat, and stored at 4 ° C. .
  • buffer containing the enzymatically hydrolyzed substrate (substrate is 17 enoylethanolamine containing 17 carbon chain lengths, 17:1 FAE for short) (buffer composition is 50 mM disodium hydrogen phosphate, 0.1%) Triton X-100, 3 mM DTT, 150 ⁇ L) 170 ⁇ L, 17:1 FAE concentration was 5 ⁇ M, reacted at 37 ° C for 30 min, and then added 200 ⁇ L of methanol solution containing internal standard (internal standard heptadecanoic acid, concentration 1 nmol) to terminate the reaction. .
  • LC-MS Liquid chromatography-mass spectrometry
  • NAAA the concentration at which NAAA activity was inhibited to half of the uninhibited level
  • IC 50 (FAAH) indicates a concentration at which FAAH activity is inhibited to half of the uninhibited level
  • >100 ⁇ M indicates that the IC 50 of the compound to the corresponding enzyme is greater than 100 ⁇ M, and it is considered that the enzyme is not inhibited.
  • the compound to be evaluated or the test compound or test compound used in the present experimental examples are the compounds 1-46 prepared in the examples of the present invention. All the injectable drugs in this experimental example, including the compound to be evaluated or the test compound or test compound, and the positive control drug, were dissolved in a mixed solvent of PEG400: Tween 80: physiological saline (volume ratio: 5:5:90). The concentration is 5 mg/mL.
  • the mouse neuropathic pain model (SNI) caused by sciatic nerve branch selection injury is a medically common animal model for studying neuropathic pain.
  • the present invention uses this model to evaluate the therapeutic effect of neuropathic pain in a compound, which may represent neuropathic pain in peripheral nerves including, but not limited to, postherpetic infection, pain caused by diabetic peripheral neuropathy, tumor-induced neurological compression, and Exudation, lumbar spine surgery failure syndrome, lumbar disc herniation-induced neuropathic pain, postpartum neuralgia, trigeminal neuralgia, chemotherapy-induced multiple neuropathic pain, neurological disease after treatment, root nerve pain.
  • C57BL/6 mice purchased from Shanghai Slack Laboratory Animals Co., Ltd.
  • sodium pentobarbital 40 mg/kg
  • scalpels were used in the knee joints. Longitudinal cutting about 1cm, blunt separation of muscle tissue, exposure of the sciatic nerve. Carefully cut the sacral nerve trunk and the common peroneal nerve branch, then suture the wound and place the mouse in a clean observation cage.
  • the sham operation group only exposed the sciatic nerve and did not cut off the phrenic nerve and the common peroneal nerve branch.
  • the dynamic plantar tactile instrument (Ugo basile, product number 37450, Italy) was used to stimulate the edge of the sole of the foot, and the data was automatically collected to obtain the threshold of mechanical stimulation of the mouse.
  • the compound to be evaluated was administered intraperitoneally (10 mg/kg) 1 h before the test. Gabapentin The dose administered was 100 mg/kg. All injectable drugs were dissolved in a mixed solvent of PEG400: Tween 80: physiological saline (volume ratio: 5:5:90) at a concentration of 5 mg/mL.
  • the analgesic effect of the compound on neuropathic pain was evaluated by comparing the different administration times and the threshold changes of the different administration groups (the amount of force when the mouse paws were withdrawn).
  • a typical model of visceral pain caused by inflammation which is commonly used in medicine, is used to evaluate the therapeutic effect of inflammatory visceral pain of a compound.
  • the model may represent general visceral pain including but not limited to: appendicitis, gastritis, pancreatitis, prostatitis, myocarditis, interstitial cystitis, pain induced by gallbladder and kidney stones; irritable bowel syndrome; chronic pelvic pain syndrome.
  • mice purchased from Shanghai Slack Laboratory Animals Co., Ltd. from the Experimental Animal Center of Xiamen University
  • the mice were selected to freely ingest food and water in the experimental environment for one week. Fasted for 24 h before administration.
  • One hour before the administration of acetic acid the mice were intraperitoneally injected with the compound to be evaluated (10 mg/kg), the positive control drug indomethacin was administered at a dose of 20 mg/kg, and the blank control was physiological saline.
  • the mice were intraperitoneally injected with acetic acid (50 ⁇ L, acetic acid in physiological saline at a concentration of 5%), and then placed in an observation cage, and the behavior of the mice was recorded with a video camera for the next 20 minutes. Pain behavioral analysis counts the number of times the mouse has writhed during the above time.
  • the nitroglycerin-induced rat headache model is a medically common model for studying inflammatory pain.
  • the present invention employs this model to evaluate the therapeutic effect of a headache of a compound.
  • the model can represent mixed pain including, but not limited to, migraine, from collective headache, tension headache syndrome, facial pain, low back pain, shoulder pain, burning mouth syndrome, and complex local pain syndrome.
  • Wistar rats purchased from Shanghai Slack Laboratory Animals Co., Ltd.
  • the rats were intraperitoneally injected with the compound to be evaluated (10 mg/kg), and the positive control drug was a blank control for physiological saline.
  • Nitroglycerin (10 mg/kg, nitroglycerin dissolved in physiological saline at a concentration of 5%) was injected into the rat epidermis, and then placed in an observation cage, and the behavior of the rats was recorded with a video camera for the next 60 minutes. Pain behavioral analysis counts the number of times the rat scratches the head.
  • the detection compounds 2, 9, and 14 all showed significant inhibition of nitroglycerin-induced headache in rats.
  • the effective compound of the present invention has a better effect than the positive control drug indomethacin.
  • a typical model of inflammatory pain commonly studied in medicine is used to evaluate the therapeutic effect of the inflammatory pain of the compound to be evaluated.
  • Rats in each group were injected with 0.1 mL of Freund's complete adjuvant into the left hind toe to induce the rat model of adjuvant arthritis.
  • multiple arthritis score (5 grade score: 0 points no redness; 4 points including all the paws including the ankle joint redness and swelling. According to the remaining 3 limbs without adjuvant injection
  • the cumulative score of the lesion is up to 12 points).
  • the model may represent inflammatory pain including, but not limited to, osteoarthritis pain and fibromyalgia syndrome, inflammatory pain of rheumatism and rheumatoid arthritis, inflammatory pain of endometriosis, inflammatory toothache, Ankylosing spondylitis pain, gouty arthritis pain.
  • the detection compounds 2, 9, and 14 (10 mg/Kg) all showed significant effects of inhibiting osteoarthritic pain, and the effective compound of the present invention was superior to the positive control drug indomethacin (10 mg). /Kg).
  • the PBS solution used in this experimental example was prepared by: 8 g NaCl, 0.2 g KCl, 1.44 g Na 2 HPO 4 , 0.24 g KH 2 PO 4 , dissolved in 1 L ultrapure water, sterilized by damp heat, and stored at 4 ° C. .
  • a plurality of tubes of rat plasma were dispensed, and a volume of one-quarter volume of PBS was added to dilute and mix. 1.5 ml of diluted rat plasma was taken, and the test compound (compounds 2, 8, 9, 11, 31, 41) was added to make the final concentration of the compound 2 ⁇ M, and the plasma sample containing the compound was placed in a 37 ° C incubator.
  • Rats were randomly divided into 5 groups of 10 rats each using 50 SD rats (purchased from Shanghai Slack Laboratory Animals Co., Ltd.). After anesthesia with ether, fix it on the operating table, shave the hair of the neck operation site, disinfect with 75% alcohol, make a longitudinal skin incision about 1.5 cm in the neck, and bluntly separate the muscle tissue around the trachea. And vascular nerves, bluntly separating the carotid artery.
  • the distal end of the heart was ligated, and the proximal end of the heart was clamped with an artery clamp. The distance between the two ends was about 1 cm.
  • the proximal end of the ligature was placed close to the thin line and the small end of the artery was inserted from the small opening to the proximal end.
  • the arterial clip is used to clamp the arterial port with the abutment and send the arterial catheter to the ventricle. After the catheter enters the ventricle, the catheter is ligated with a thin wire.
  • the jugular vein was cannulated using the same intubation method as the artery.
  • the tubules filled with heparin sodium are taken out from the artery and the vein, and the skin from the lower ear of the rat is taken out to the skin on the north side of the rat neck, and the thin catheter is fixed, and the muscle of the surgical site of the rat is sutured.
  • Blood was taken from the catheter drawn from the carotid artery at 2, 5, 10, 20, 30, 60, 240, 360, 720 minutes, each time taking 200 ⁇ L of blood, and the whole blood was placed in a commercially available heparin sodium blood collection tube (Jiangxi Needles In Medical Equipment Co., Ltd., centrifuged at 1800g for 15 minutes, and the upper layer of plasma was added to a pre-cooled 150 ⁇ L methanol stop solution (containing internal standard E8, 1 nmol/sample), vortexed and then centrifuged at 12000 g for 10 minutes at 4 °C. The supernatant was transferred to a sample vial and the target compound was detected using LC-MS/MS and the standard curve was taken to calculate the compound content.
  • the metabolic half-life of the effective compound of the present invention in rats is 60-300 minutes, and the stability far exceeds the reported ⁇ -butyrolactone NAAA inhibitor ( ⁇ -butyrolactone NAAA inhibition).
  • the metabolic half-life of rats in rats is less than 5 minutes).
  • the PBS solution used in this experimental example was prepared by: 8 g NaCl, 0.2 g KCl, 1.44 g Na 2 HPO 4 , 0.24 g KH 2 PO 4 , dissolved in 1 L ultrapure water, sterilized by damp heat, and stored at 4 ° C. .
  • RAW264.7 cells purchased from American Type Culture Collection, ATCC, Beijing
  • the density was about 80%-90%
  • the cell suspension was prepared by scraping with a cell scraper.
  • the cells were accurately seeded in a 96-well culture plate at 100 ⁇ L per well, and the total number of cells was kept constant, about 20,000 cells/well, and the culture solution was added (the culture solution contained 10% fetal bovine serum (PAA), 1%).
  • PAA double-antibody
  • DMEM Gibco, Shanghai
  • the edge wells around the experimental wells were filled with an equal amount of PBS, but the cells were not seeded.
  • the old culture solution was aspirated, and 100 ⁇ L of different concentrations of Compound 2 and 9 (concentrations of 3, 10, 30, and 100 ⁇ M, respectively) diluted with the culture solution were added to the plate, and the control group was added with an equal amount of DMSO. Control, three parallels per well. Incubate the plates in the incubator for a period of 24 or 48 hours. 10 ⁇ L of CCK8 solution was added to each well. The plates were incubated for 1.5 hours in an incubator.
  • the absorbance OD value at 450 nm was measured by a microplate reader, and the OD value was proportional to the number of living cells.
  • the survival rate of the cells was obtained by comparing the OD values of the respective groups with the OD values of the blank groups.
  • Cell viability ⁇ 100% [OD value (administration group) - OD value (blank group)] / [OD value (control group) - OD value (blank group)] ⁇ 100%.
  • the fertilized egg (a gift from the zebrafish research group of the College of Life Sciences of Xiamen University) was placed in the newly configured zebrafish embryo culture medium.
  • the fresh culture medium was replaced every day and cultured in an incubator at 28.5 ° C.
  • the pure incubator was placed in the incubator. Water to ensure a certain humidity in the culture environment.
  • the zebrafish embryo culture solution was formulated as: 5 mM NaCl, 0.17 mM KCl, 0.33 mM CaCl 2 , 0.33 mM MgSO 4 , 10-5% Methylene Blue.
  • the culture solution is placed in pure water.
  • a 1 L culture solution is required to have NaCl: 292.2 mg, KCl: 12.68 mg, CaCl 2 : 36.63 mg, MgSO 4 : 39.72 mg, and methylene blue: 0.1 ⁇ L.
  • test substance was divided into 7 groups, including 5 experimental groups containing different concentrations of drugs (the test drugs were prepared with different concentrations of zebrafish embryo culture solution) at concentrations of 10 mg/L, 3 mg/L, and 1 mg, respectively. /L, 0.3 mg/L, 0.1 mg/L), 1 cosolvent control group (DMSO) and 1 blank control group.
  • the positive control drug was treated with the OTC antipyretic analgesic drug ibuprofen at the same concentration as above.
  • Experiments were carried out on 96-well cell culture plates, three in each experimental group, each with 10 fish eggs in parallel.
  • the drug-containing culture solution prepares the drug-containing culture solution, add the drug-containing culture solution to the 96-well plate in advance, and then expose each fertilized egg (refer to the experimental method in OECD212 file, select the fertilized egg that develops normally within 2 hours after fertilization, and expose it to the naked eye.
  • the fish eggs are normally fertilized, the whitened fish eggs have died, discarded, and after the fertilized eggs are picked, the normal development of the fertilized egg cells has begun to split under the microscope. Independently placed in different holes, the fertilized eggs will be The cells were cultured in different concentrations of the drug-containing experimental solution, and observed and photographed with an inverted microscope to record the embryo development in different periods. include:
  • the zebrafish fertilized egg culture method is the same as described above.
  • the experiment was divided into 7 groups, including 5 experimental groups containing different concentrations of drugs (the test drugs were prepared with different concentrations of zebrafish embryo culture), the concentrations were: 100mg/L, 10mg/L, 1mg/L, 0.1 mg/L, 0.01 mg/L), 1 cosolvent control group (DMSO) and 1 blank control group.
  • the fertilized eggs are cultured in an incubator at 28.5 ° C to ensure a certain humidity in the culture environment.
  • Prepare the culture medium containing the test drug add the drug-containing culture solution to the 96-well plate in advance, and then expose each fertilized egg (refer to the experimental method in OECD No.
  • the experimental results showed that the zebrafish in the solvent control group and the blank group developed normally.
  • the zebrafish embryos exposed to 10 mg/L ibuprofen had a hatching rate of 0 at 72 h and a mortality rate of 100%, and the hatching rate of the ibuprofen group was decreased with increasing dose at 72 h; the same dose of compound 2, compound 9, zebrafish
  • the hatching rate of the embryos was 93.3%, and the hatching rate had little effect when the dose was less than 10 mg/L (Table 5).
  • CHO-hERG cells purchased from ATCC were cultured in culture flasks, and the cell density was increased to 60-80%, and the culture solution (Glutamax DMEM/F12 medium (Gibco, Shanghai) containing 10% fetal bovine serum) was removed. Wash once with 7mL PBS, then add 3mLDetachin cell digestive juice digestion, after digestion is complete, add 7mL culture solution to neutralize, centrifuge, aspirate the supernatant, add 5mL culture solution and resuspend to ensure cell density is 2 ⁇ 5 ⁇ 10 6 /mL.
  • the culture solution Glutamax DMEM/F12 medium (Gibco, Shanghai) containing 10% fetal bovine serum
  • the intracellular fluid and the extracellular fluid were prepared as follows.
  • a compound solution was prepared by dissolving a certain amount of the compound in an extracellular solution at the following concentration. 2 ⁇ L of the mother liquor of the compound was added to 998 ⁇ L of the extracellular fluid, and serial dilutions were performed in an extracellular solution containing 0.2% DMSO to obtain a final concentration to be tested. The highest tested concentration of the test drug was 40 ⁇ M, which were respectively 40 ⁇ M, 8 ⁇ M, 1.6 ⁇ M, 0.32 ⁇ M, 0.064 ⁇ M, and 0.0128 ⁇ M.
  • Positive compound cisapride ( ⁇ ) highest test The test concentration was 3 ⁇ M, which were 6 ⁇ M, 0.6 ⁇ M, 0.12 ⁇ M, 0.024 ⁇ M, 0.0048 ⁇ M, and 0.00096 ⁇ M, respectively.
  • the DMSO content in the final test concentration did not exceed 0.2%, and this concentration of DMSO had no effect on the hERG potassium channel.
  • Single-cell high-impedance sealing and whole-cell patterning are all done automatically by the Qpatch HT high-throughput automated patch-clamp system (Sophion).
  • the cells are clamped at -80 mV, given 5
  • a 50-millisecond -50 mV preamplifier was applied, then repolarized to -50 mV for 5 seconds and back to -80 mV.
  • This voltage stimulation was applied every 15 seconds, and the extracellular fluid was recorded for 2 minutes after 2 minutes of recording, and then the administration process was started.
  • the concentration of the test drug was started from the lowest test concentration, and each test concentration was given for 2 minutes, after all the concentrations were continuously administered.
  • the positive control compound cisapride was administered. Test at least 3 cells (n ⁇ 3) for each concentration. Experimental data was analyzed using XLFit software.

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Abstract

提供具有可抑制内源性大麻素水解酶NAAA和/或FAAH酶活性的式I所示化合物、其可药用的盐、水合物或溶剂合物，以及该化合物的制备方法和用途。

Description

取代杂环衍生物、其制备方法和用途 技术领域
本发明属于医药化工领域，涉及取代杂环衍生物，尤其是涉及可抑制内源性大麻素水解酶NAAA和/或FAAH酶活性的一类取代杂环衍生物。本发明还涉及这类化合物的制备方法、含有这类化合物的药物组合物以及这类化合物的医药用途。
背景技术
四氢大麻酚(Tetrahydrocannabinol，简称THC)作用的受体为大麻素受体1或2(cannabinoid receptor 1/2，简称CB1或CB2)。该发现促使科学家对大麻素受体的内源性配体进行研究。目前已发现N-花生四烯酰乙醇胺(anandamide，N-arachidonoylethanolamine,AEA)、O-花生四烯酰乙醇胺(virodhamine，O-arachidonoylethanolamine)和花生四烯酰多巴胺(N-arachidonoyldopamine)等作用于大麻素受体的内源性大麻素。与前列腺素等脂类递质一样，这些内源性大麻素在体内并不蓄积，而是在局部按需合成，并且受到酶和受体的调控，能被其特异性的水解酶代谢成相应的脂肪酸和乙醇胺、甘油等物质，从而降低这类物质在体内的作用。
AEA是第一个被发现的内源性大麻素(Devane WA,Hanus L,Breuer A,et al.,Science,1992,258:1946-1949；Di Marzo V,De Petrocellis L.,Curr Med Chem,2010,17:1430-1449；Gasperi V,Dainese E,Oddi S,et al.,Curr Med Chem,2013,20:64-78.)，主要激动CB1受体，可产生与THC等大麻提取物相似的药理学功能。AEA在体内有着广泛的分布，在中枢神经系统、肝脏、肺、胃肠道等脏器中均可检测到AEA的存在。AEA可以通过直接激活内源性大麻素受体(CB)，产生抗炎，镇痛等多种药理作用。此外有报道，AEA对瞬时受体电位阳离子通道子类V成员1(transient receptor potential cation channel subfamily V member 1，TRPV1)(Bouaboula M,Hilairet S,Marchand J,et al.,Eur J Pharmacol,2005,517:174-181；Mechoulam R,Ben-Shabat S,Hanus L,et al.,Biochem Pharmacol,1995,50:83-90；Sugiura T,Kondo S,Sukagawa A,et al.,Biochem Biophys Res Commun,1995,215:89-97.)、G蛋白偶联受体55(GPR55)(Sugiura T,Waku K.,Journal of Biochemistry,2002,132:7-12；Sigel E,Baur R,Racz I,et al.,Proc Natl Acad Sci U S A,2011,108:18150-18155；Guindon J,Hohmann AG.,Cns&Neurological Disorders-Drug Targets,2009,8:403-421；Nomura DK,Long JZ,Niessen S,et al.,Cell,2010,140:49-61；Fowler CJ,Gustafsson SB,Chung SC,et al.,Current Topics in Medicinal Chemistry,2010,10:814-827.)、过氧化物酶体增殖物活化受体γ(PPAR-γ)(Arevalo-Martin A,Garcia-Ovejero D,Molina-Holgado E.,Neurobiology of Disease,2010,38:304-312；Scotter EL,Abood ME,Glass M.,British Journal of Pharmacology,2010,160:480-498；Cobellis G,Ricci G,Cacciola G,et al.,Biology of Reproduction,2010,82:451-458；Guida M,Ligresti A,De Filippis D,et al.,Endocrinology,2010,151: 921-928.)也有较弱的激动作用。AEA是目前研究最为广泛的内源性大麻素之一，AEA被认为是大麻素受体的部分激动剂。
除此之外，还有一部分脂肪酰基乙醇胺类脂质，例如：油酰乙醇胺(N-Oleoylethanolamide，OEA)、N-棕榈酰乙醇胺(N-palmitoylethanolamide，PEA)，虽不直接作用于大麻素受体，但是与AEA和2-AG(花生四烯酸甘油，2-arachidonoylglycerol)有着相似的结构以及在内分泌调节方面有类似的功能，被称为类内源性大麻素物质。PEA和OEA通过作用于过氧化物酶增殖体激活受体α(PPAR-α)产生镇痛抗炎和抑制食欲的作用(Fu J,Gaetani S,Oveisi F,et al.,Nature,2003,425:90-93.)。特别是PEA在体内有着广泛的分布，PEA可作用于中枢及感觉神经系统、免疫细胞等多个靶点而发挥镇痛抗炎作用。PEA可通过激动细胞核受体过氧化物酶体增殖物激活受体-α(PPAR-α)，也可部分激动GPG55受体和GPR119受体，产生抗炎、镇痛等多种药理作用(Mol Pharmacol，2005，67，15-19)。N-stearoylethanolamine(SEA)能够促进肿瘤细胞的凋亡(Maccarrone M,Pauselli R,Di Rienzo M,et al.,Biochem J,2002,366:137-144)以及抑制食欲(Terrazzino S,Berto F,Dalle Carbonare M,et al.,FASEB J,2004,18:1580-1582)；油酰胺(Oleamide，OA)具有调节睡眠等作用(Huitron-Resendiz S,Gombart L,Cravatt BF,et al.,Exp Neurol,2001,172:235-243)。
AEA能被特异性的脂肪酰胺水解酶(Fatty acid amide hydrolase，FAAH)水解成花生四烯酸和乙醇胺而失去活性。FAAH在1996年克隆获得，属于酰胺水解酶(amidase signature)家族，是第一个在哺乳动物中发现的此家族蛋白，存在于细胞内膜，并具有一段跨膜结合的α螺旋。FAAH蛋白由579个氨基酸构成，目前FAAH晶体结构已经获得。水解底物AEA活性中心由典型的Ser-Ser-Lys三个氨基酸构成(Ser241-Ser217-Lys142)。FAAH最佳水解条件是pH偏碱性(pH＝8～9)，在脂肪酸酰基乙醇胺类底物化合物中对AEA水解选择性较高，此外还可水解OEA、PEA、OA等其他多种脂肪酸酰胺(McKinney MK,Cravatt BF.,Annu Rev Biochem,2005,74:411-432；Fezza F,De Simone C,Amadio D,et al.,Subcell Biochem,2008,49:101-132)，但相对水解活性要弱。
在FAAH基因敲除鼠中，AEA水平在中枢和外周组织中显著升高(Cravatt BF,Demarest K,Patricelli MP,et al.,Proc Natl Acad Sci U S A,2001,98:9371-9376)。小分子化合物抑制FAAH活性也能显著提高AEA的水平，但动物表现出僵直、活动度降低、体温降低等大麻样副作用。目前，FAAH抑制剂在抗抑郁、抗焦虑、抗神经病理性疼痛等方面具有一定的作用。有些FAAH抑制剂在治疗抑郁、关节炎性疼痛等方面已经进入临床研究。FAAH抑制剂根据结构可以分为四大类：早期的AEA底物类似物、α-酮杂环类、氨基甲酸酯类和芳香脲类。
PEA的特异性水解酶脂肪酰基乙醇胺水解酶(N-acylethanolamine acid amidase，NAAA)于2005年才被发现与克隆(Tsuboi K,Sun YX,Okamoto Y,et al.,J Biol Chem,2005,280:11082-11092)。Natuo Ueda课题组于1999年在人成巨核细胞株(CMK)中发现一种具有水解AEA活性的大麻素水解酶(Ueda N,Yamanaka K,Terasawa Y,et al.,FEBS Lett,1999,454:267-270)。然而，这种酶与已知的AEA水解酶FAAH有很大的不同：(1)这种酶在酸性pH条件下(pH 4.5)水解活性最强，而FAAH酶是在碱性条件下水解较强(pH 9.0)(Linsenbardt DN,Boehm SL,2nd.，Neuroscience,2009,164:424-434)；(2)这种酶对PEA水解活性远远大于对AEA的水解活性；(3)这种酶对FAAH具有较好抑制作用的丝氨酸抑制剂PMSF和MAFP不敏感。随后，该课题组又在大鼠各个组织中发现NAAA酶在肺中活性最高，在脾、胸腺、小肠等组织中活性逐渐降低，并最终在肺组织中纯化出这种酶(Ueda N,Yamanaka K,Yamamoto S.,J Biol Chem,2001,276:35552-35557)。2005年，成功从大鼠、小鼠和人源细胞中克隆出这种酶的cDNA序列，并把这种酶命名为N-脂肪酰基乙醇胺水解酶(N-Acylethanolamine-hydrolyzing Acid Amidase，NAAA)(Tsuboi K,Sun YX,Okamoto Y,et al.,J Biol Chem,2005,280:11082-11092)。随后的研究发现NAAA主要在溶酶体中表达(Tsuboi K,Zhao LY,Okamoto Y,et al.,Biochim Biophys Acta,2007,1771:623-632)。NAAA包含362个氨基酸(大鼠和小鼠)及359个氨基酸(人)序列，分子量分别为40.3Kda(大鼠)及40.1kDa(小鼠和人)。这些氨基酸序列中，大鼠和小鼠的同源性达90.1％，大鼠和人的同源性达76.5％，小鼠和人的同源性达76.7％。人的NAAA基因位于4q21.1染色体上。NAAA与FAAH并没有同源性，然而却与酸性神经酰胺水解酶(acid ceramidases)具有一定的同源性，归类为胆酰甘氨酸水解酶(choloylglycine hydrolase)家族，对酰胺的水解具有选择性(Tsuboi K,Sun YX,Okamoto Y,et al.,J Biol Chem,2005,280:11082-11092)。
由于缺乏晶体结构，NAAA的催化水解域空间组成尚不完全清楚，特异性的抑制剂也较少。有限的研究显示，β-内酰胺类NAAA抑制剂S-OOPP(IC50＝420nM)局部给药能够抑制角叉菜胶诱导的大鼠肉芽肿白细胞及LPS诱导的RAW264.7细胞PEA含量下降，从而抑制白细胞的迁移以及炎性渗出，同时，对大鼠的脊柱损伤模型也表现出较好的治疗作用，该过程经由PPAR-α途径介导(Solorzano C,Zhu C,Battista N,et al.,Proc Natl Acad Sci U S A,2009,106:20966-20971)。结构类似物ARN077(IC50＝127nM)局部给药可明显抑制角叉菜胶诱导的炎性疼痛和坐骨神经结扎引发的神经病理性疼痛。在坐骨神经结扎模型中，ARN077(1％，20μL，表皮给药)比阳性对照药物加巴喷丁(50mg/kg，口服)对促诱发痛的镇痛效果更加明显(Sasso O,Moreno-Sanz G,Martucci C,et al.,Pain,2013,154:350-360)。该研究首次证明NAAA抑制剂具有镇痛的作用，但是该类结构的主要药效团四元内酯环不但本身结构不稳定，生物稳定性也极差，动物体内半衰期低于1min，使其不能应用于系统性给药。
相比阿片类、抗癫痫类、抗抑郁类以及局麻类镇痛药，内源性大麻素水解酶抑制剂对中枢神经系统副作用比较小，且无成瘾性；相比布洛芬、塞来昔布、阿斯匹林等COX抑制剂型抗炎镇痛药，不会引起肠胃出血及严重心血管事件，具有更好的药物安全性。(Biochem J，2004，380，749-756；Journal of Medicinal Chemistry，2008，51，7327-7343；PAIN，2013，154，326-327)。
本发明的目的在于提供新颖的更为稳定的内源性大麻素水解酶抑制剂及其制备方法和用途。
发明内容
发明人经过创造性的劳动和大量的试验，得到了一类新颖的化合物，这类化合物可以作为内源性大麻素水解酶抑制剂，能够用于治疗疼痛，包括但不限于神经性疼痛、炎性疼痛、混合型疼痛。发明人还惊奇地发现，这类化合物的稳定性出色，在大鼠体内代谢半衰期在60-300分钟，稳定性超过已报道的β-内酰胺类NAAA抑制剂。由此提供了下述发明：
本发明的第一方面涉及式I所示化合物、其可药用的盐、水合物或溶剂合物，
Figure PCTCN2015093140-appb-000001
其中，
X选自：C、N、O；
Y选自：C、N；
A选自：R12、OR6、N R7R8或CR9R10R11；
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11独立选自：-H、＝O、＝NOR’、卤素、卤代基、多卤代基、-(CH2)nCN、-(CH2)nNO2、-(CH2)nR’、-(CH2)nCOOR’、-(CH2)nCONR’2、-(CH2)nOR’、-(CH2)nSR’、-(CH2)nSOR’、-(CH2)nSO2R’、-(CH2)nNR’2、-(CH2)nNR’COR’或-(CH2)nNR’SO2R’；
R12为-(CH2)nR13；
R13选自：H、C1-10直链或支链烷基、苯基、噻吩基、呋喃基、C4-6环烷基、联苯基、苯氧基苯基、苄氧基苯基、苯基乙氧基苯基、哌啶基、N-苯甲基哌啶基、萘基、吲哚基、尿嘧啶基，其任选地被1或2个选自以下的取代基取代：卤素、甲基、羟基、C1-6烷基、C1-6烷氧基、羟基、硝基、三氟甲基、氰基、被卤素单取代或多取代的C1-6烷基、被卤素单取代或多取代的C1-6烷氧基。
n为选自0～10的整数；
各个R’独立为H或选自含有20个C原子以内的各种取代或未取代的直链烷基、支链烷基、环烷基、环杂烷基、烯基、炔基、直链杂烷基、支链杂烷基、杂环烷基、杂烯基、杂炔基、杂环基或芳香基。
在一个实施方案中，本发明第一方面所述的化合物、其可药用的盐、水合物或溶剂合物，其可以如式Ia所示，
Figure PCTCN2015093140-appb-000002
其中：
X为O或N；
Y为N；
n为选自0～7的整数；
R4为H、甲基、卤素、C1-6烷基、C1-6烷氧基、羟基、硝基、三氟甲基、氰基、CH3C(＝O)CH2-或(CH3)2NCH2-；
R13选自：H、C1-10直链或支链烷基、苯基、噻吩基、呋喃基、C4-6环烷基、联苯基、苯氧基苯基、苄氧基苯基、苯基乙氧基苯基、哌啶基、N-苯甲基哌啶基、萘基、吲哚基、尿嘧啶基，其任选地被1或2个选自以下的取代基取代：卤素、甲基、羟基、C1-6烷基、C1-6烷氧基、羟基、硝基、三氟甲基、氰基、被卤素单取代或多取代的C1-6烷基、被卤素单取代或多取代的C1-6烷氧基。
本发明的第二方面涉及制备式Ia所示化合物、其可药用的盐、水合物或溶剂合物的方法，包括：
在合适的溶液中，式II所示化合物与式III所示化合物在合适的温度条件下反应获得式Ia所示化合物，
Figure PCTCN2015093140-appb-000003
其中X、Y、R4、R13以及n的定义同上。其中合适的溶液为含有正丁锂的溶液，合适的温度为-78℃～0℃。
本发明的第三方面涉及药物组合物，其至少含有一种本发明第一方面任一项所述的式I或式Ia所示化合物、其可药用的盐、水合物或溶剂合物，和药学上可接受的辅料。
本发明的第四方面涉及治疗疾病或病症或减轻所述疾病或病症严重性的方法，所 述方法包括给予需要这种治疗的患者治疗有效量的至少一种本发明第一方面任一项所述的式I或式Ia所示化合物、其可药用的盐、水合物或溶剂合物，所述疾病或病症为疼痛。
本发明的第五方面涉及本发明第一方面任一项所述的式I或式Ia所示化合物、其可药用的盐、水合物或溶剂合物在制备用于治疗疾病或病症或减轻所述疾病或病症严重性的药物中的用途，所述疾病或病症为疼痛。
本发明的第六方面涉及上述式I或式Ia所示化合物、其可药用的盐、水合物或溶剂合物，该化合物用于治疗疾病或病症或减轻所述疾病或病症严重性，所述疾病或病症为疼痛。
本发明中，所述的疼痛包括但不限于神经性疼痛(包括但不限于中枢神经性疼痛、外周神经性疼痛)、炎性疼痛(包括但不仅限于骨关节炎疼痛、纤维肌疼痛综合症、风湿及类风湿性关节炎的炎性疼痛、子宫内膜移位症的炎性疼痛、炎性牙痛、强直性脊柱炎疼痛、痛风性关节炎疼痛、内脏炎性疼痛)、混合型疼痛(包括但不仅限于腰痛、肩膀痛、灼口综合症、复杂性局部疼痛综合症、偏头痛、从集性头痛、紧张性头痛综合症、面痛)。所述的外周神经性疼痛包括但不限于疱疹感染后神经痛、糖尿病周围神经病变引发的疼痛、肿瘤引起的神经压迫和渗出、腰椎手术失败综合症、腰椎间盘突出致神经性疼痛、产后神经痛、三叉神经痛、化疗诱发多发性神经疼痛、放疗后神经从疾病、根性神经疼痛。所述的中枢神经性疼痛包括但不限于脊柱硬化引起的压迫性疼痛、多发性硬化相关疼痛、帕金森症相关疼痛、痴呆症相关疼痛、中风后疼痛、脊髓损伤后疼痛。所述的内脏炎性疼痛包括但不仅限于：阑尾炎、胃炎、胰腺炎、前列腺炎、心肌炎、间质性膀胱炎、肝胆肾结石诱发的疼痛、肠易激惹综合症、慢性骨盆疼痛综合症。
取代基定义
本文中使用的术语“烷基”是指饱和的直链或支链一价烃基，优选具有1－12个碳原子，更优选具有1－10，1－8，1－6，1－4或1－3个碳原子。“烷基”的典型实例包括但不限于甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，正戊基，叔戊基，新戊基，己基，庚基，辛基等。
本文中使用的术语“烯基”是指含有至少一个碳碳双键(-C＝C-)的烯属不饱和直链或支链一价烃基，具有2－12个碳原子，优选具有2－10，2－8，2－6，2－4或2－3个碳原子。“烯基”的典型实例包括但不限于乙烯基，丙烯基，烯丙基，丁烯-1-基，丁烯-2-基，戊烯-1-基，戊烯-2-基，1,3-戊二烯基，己烯-1-基，己烯-2-基，1,3-己二烯基，庚烯基，辛烯基等。
本文中使用的术语“炔基”是指含有至少一个碳碳三键(-C≡C-)的炔属不饱和直链或支链一价烃基，具有2－12个碳原子，优选具有2－10，2－8，2－6，2－4或2－3个碳原子。“炔基”的典型实例包括但不限于乙炔基，丙炔基，炔丙基，丁炔基，戊炔基，己炔基，庚炔基，辛炔基等。
本文中使用的术语“氨基”意指-NH2。
本文中使用的术语“羟基”意指-OH。
本文中使用的术语“氰基”意指-CN。
本文中使用的术语“羧基”意指-C(O)OH。
本文中使用的术语“环烷基”意指具有3－12个碳原子并且具有单环或二环或多个稠合环(包括稠合和桥连环系)的饱和环状烃基，优选具有3－10，3－8，5－8，4－6或5－6个碳原子，特别优选具有4－6个碳原子。“环烷基”的典型实例包括但不限于单环结构，诸如环丙基，环丁基，环戊基，环己基、环庚基、环辛基，1-甲基环丙基，2-甲基环戊基，2-甲基环辛基等。
本文所用的术语“杂环烷基”意指包含一个、两个或多个独立地选自N，O和S的杂原子的如本文所定义的环烷基。“杂环烷基”的典型实例包括但不限于四氢呋喃基，四氢噻吩基，吡咯烷基，哌嗪基，噻嗪基，哌啶基和吗啉基等。
本发明所用术语“杂烷基”、“杂烯基”、“杂炔基”指的是：“烷基”、“烯基”、“炔基”中的某个C原子被杂原子N、O或S所取代，这些含杂原子基团至少含有一个C原子和一个杂原子。这些基团之一上的任何氢原子可被卤素，尤其是氟代基、氯代基所取代，也可以被其他基团所取代。
本发明所用术语“芳香基”指的是：对整个环系统的电子分布而言具有芳香特征的任何单环、双环或稠环系统的一价取代基以及这些的组合物。典型的结构包括：苯环、噻吩、呋喃、吡咯、噻唑、吡唑、咪唑、吡啶、吡喃、嘧啶、吡嗪、喹啉、异喹啉、吲哚、嘌呤或上述芳香基团以任何形式稠合等。这些基团之一上的任何氢原子可被卤原子，尤其是氟代基、氯代基所取代，也可以被其他基团所取代。
本文所用的术语“烷氧基”意指基团-OR14，其中R14为如本文所定义的烷基或环烷基。“烷氧基”的典型实例包括但不限于甲氧基，乙氧基，正丙氧基，异丙氧基，正丁氧基，叔丁氧基，仲丁氧基，正戊氧基，正己氧基，1,2-二甲基丁氧基，环己基氧基，环丙基氧基等。
本文所用的术语“卤素”意指氟，氯，溴或碘。优选的卤素基团为氟、氯或溴。
上述本文各个术语所限定的基团还可以任选地被-CN、-OH、-NH2、C1-4烷基、C1-4烷氧基或卤素单或多取代。
本文中使用的化合物名称与化学结构式不一致时，以化学结构式为准。
在一个优选的实施方案中，本发明的式Ia中，X可以为O，也可以为N。
在一个优选的实施方案中，本发明的式Ia中，X为O。
在一个优选的实施方案中，本发明的式Ia中，X为N。
在一个优选的实施方案中，本发明的式Ia中，Y可以为N。
在一个优选的实施方案中，本发明的式Ia中，n为0或1。
在另一个优选的实施方案中，本发明的式Ia中，n可以为0，也可以为1，
在一个优选的实施方案中，本发明的式Ia中，n为4、5、6或7。
在一个优选的实施方案中，本发明的式Ia中，n为5、6或7。
在另一个优选的实施方案中，本发明的式Ia中，n可以为5，也可以为6，还可以为7。
在一个优选的实施方案中，本发明的式Ia中，R4为H、甲基、卤素、C1-6烷基、C1-6烷氧基、羟基、硝基、三氟甲基、氰基、CH3C(＝O)CH2-或(CH3)2NCH2-。
在另一个优选的实施方案中，本发明的式Ia中，R4为H、甲基、卤素、C1-4烷基、C1-4烷氧基、羟基、硝基、三氟甲基、氰基、CH3C(＝O)CH2-或(CH3)2NCH2-。
在另一个优选的实施方案中，本发明的式Ia中，R4为H、甲基、卤素、羟基、硝基、三氟甲基、氰基、CH3C(＝O)CH2-或(CH3)2NCH2-。
在另一个优选的实施方案中，本发明的式Ia中，R4为H、甲基、卤素、CH3C(＝O)CH2-或(CH3)2NCH2-。
在另一个优选的实施方案中，本发明的式Ia中，R4为H、甲基、CH3C(＝O)CH2-或(CH3)2NCH2-。
在另一个优选的实施方案中，本发明的式Ia中，R4为H、甲基或CH3C(＝O)CH2。
在另一个优选的实施方案中，本发明的式Ia中，R4为H或(CH3)2NCH2-。
在一个优选的实施方案中，本发明的式Ia中，R13选自：H、C1-10直链或支链烷基、苯基、噻吩基、呋喃基、C4-6环烷基、联苯基、苯氧基苯基、苄氧基苯基、苯基乙氧基苯基、哌啶基、N-苯甲基哌啶基、萘基、吲哚基、尿嘧啶基，其任选地被1或2个选自以下的取代基取代：卤素、甲基、羟基、C1-6烷基、C1-6烷氧基、羟基、硝基、三氟甲基、氰基、被卤素单取代或多取代的C1-6烷基、被卤素单取代或多取代的C1-6烷氧基。
在另一个优选的实施方案中，本发明的式Ia中，R13选自：H、C1-8直链或支链烷基、苯基、噻吩基、呋喃基、环己基、联苯基、苯氧基苯基、苄氧基苯基、苯基乙氧基苯基、哌啶基、N-苯甲基哌啶基、萘基、吲哚基、尿嘧啶基，其任选地被1或2个选自以下的取代基取代：卤素、甲基、羟基、C1-4烷基、C1-4烷氧基、羟基、硝基、三氟甲基、氰基、被卤素单取代或多取代的C1-4烷基、被卤素单取代或多取代的C1-4烷氧基。
在另一个优选的实施方案中，本发明的式Ia中，R13选自以下取代基：H、含有8个碳原子的直链或支链烷基、
Figure PCTCN2015093140-appb-000004
在另一个优选的实施方案中，本发明的式Ia中，R13选自以下取代基：H、含有8个碳原子的直链烷基、
Figure PCTCN2015093140-appb-000005
Figure PCTCN2015093140-appb-000006
在另一个优选的实施方案中，本发明的式Ia中，R13选自以下取代基：H、含有8个碳原子的直链或支链烷基、
Figure PCTCN2015093140-appb-000007
在一个优选的实施方案中，式Ia所示化合物、其可药用的盐、水合物或溶剂合物，其中：
X为O或N；
Y为N；
n为选自0～7的整数；
R4为H、甲基、卤素、C1-4烷基、C1-4烷氧基、羟基、硝基、三氟甲基、氰基、CH3C(＝O)CH2-或(CH3)2NCH2-；
R13选自：H、C1-8直链或支链烷基、苯基、噻吩基、呋喃基、环己基、联苯基、苯氧基苯基、苄氧基苯基、苯基乙氧基苯基、哌啶基、N-苯甲基哌啶基、萘基、吲哚基、尿嘧啶基，其任选地被1或2个选自以下的取代基取代：卤素、甲基、羟基、C1-4烷基、C1-4烷氧基、羟基、硝基、三氟甲基、氰基、被卤素单取代或多取代的C1-4烷基、被卤素单取代或多取代的C1-4烷氧基。
在另一个优选的实施方案中，式Ia所示化合物、其可药用的盐、水合物或溶剂合物，其中：
X为O或N；
Y为N；
n为0、1、2、3、4、5、6或7；
R4为H、甲基、卤素、C1-4烷基、C1-4烷氧基、羟基、硝基、三氟甲基、氰基、CH3C(＝O)CH2-或(CH3)2NCH2-；
R13选自以下取代基：H、含有8个碳原子的直链或支链烷基、
Figure PCTCN2015093140-appb-000008
在另一个优选的实施方案中，式Ia所示化合物、其可药用的盐、水合物或溶剂合物，其中：
X为O或N；
Y为N；
n为4、5、6或7；
R4为H、甲基、卤素、C1-4烷基、C1-4烷氧基、羟基、硝基、三氟甲基、氰基或CH3C(＝O)CH2-；
R13选自以下取代基：H、含有8个碳原子的直链烷基、
Figure PCTCN2015093140-appb-000009
Figure PCTCN2015093140-appb-000010
在另一个优选的实施方案中，式Ia所示化合物、其可药用的盐、水合物或溶剂合物，其中：
X为O或N；
Y为N；
n为4、5、6或7；
R4为H、甲基或CH3C(＝O)CH2-；
R13选自以下取代基：H、含有8个碳原子的直链烷基、
Figure PCTCN2015093140-appb-000011
在另一个优选的实施方案中，式Ia所示化合物、其可药用的盐、水合物或溶剂合物，其中：
X为O；
Y为N；
n为4、5、6或7；
R4为H、甲基、卤素、C1-4烷基、C1-4烷氧基、羟基、硝基、三氟甲基、氰基或CH3C(＝O)CH2-；
R13选自以下取代基：H、含有8个碳原子的直链烷基、
Figure PCTCN2015093140-appb-000012
Figure PCTCN2015093140-appb-000013
在另一个优选的实施方案中，式Ia所示化合物、其可药用的盐、水合物或溶剂合物，其中：
X为O；
Y为N；
n为4、5、6或7；
R4为H、甲基或CH3C(＝O)CH2-；
R13选自以下取代基：H、含有8个碳原子的直链烷基、
Figure PCTCN2015093140-appb-000014
在另一个优选的实施方案中，式Ia所示化合物、其可药用的盐、水合物或溶剂合物，其中：
X为O；
Y为N；
n为0或1；
R4为H、甲基、卤素、C1-4烷基、C1-4烷氧基、羟基、硝基、三氟甲基、氰基或(CH3)2NCH2-；
R13选自以下取代基：H、含有8个碳原子的直链或支链烷基、
Figure PCTCN2015093140-appb-000015
Figure PCTCN2015093140-appb-000016
在另一个优选的实施方案中，式Ia所示化合物、其可药用的盐、水合物或溶剂合物，其中：
X为O；
Y为N；
n为0或1；
R4为H或(CH3)2NCH2-；
R13选自以下取代基：H、含有8个碳原子的直链或支链烷基、
Figure PCTCN2015093140-appb-000017
在另一个优选的实施方案中，式I或式Ia所示的化合物、其可药用的盐、水合物或溶剂合物，其选自以下化合物：
Figure PCTCN2015093140-appb-000018
Figure PCTCN2015093140-appb-000019
Figure PCTCN2015093140-appb-000020
Figure PCTCN2015093140-appb-000021
Figure PCTCN2015093140-appb-000022
在一个优选的实施方案中，本发明的式Ia化合物可以通过以下合成路线合成：
Figure PCTCN2015093140-appb-000023
其中，X、Y、R4、R13、n的定义如本文中所述。
当式Ia中X为O、Y为N、R4为CH3C(＝O)CH2-时，可以按照以下反应路线制备式Ia所示化合物：
Figure PCTCN2015093140-appb-000024
(a)(i)CbzCl,Et3N,EtOAc,(ii)BnBr,NaH,THF；
(b)DIBAl-H,THF,0℃；
(c)I2,PPh3,0℃；
(d)(i)SmI2,THF,-78℃,(ii)DMP,CH2Cl2,0℃；
(e)(i)H2,Pd/C,(ii)CDI or BTC.
其中：n、R13的定义如本文中所述。
当式Ia中X为O、Y为N、R4为(CH3)2NCH2-时，可以按照以下反应路线制备式Ia所示化合物：
Figure PCTCN2015093140-appb-000025
(a)(i)NaN3,DMF,(ii)PPh3,THF/H2O,(iii)Boc2O,Et3N；
(b)(i)H2,Pd/C,(ii)CDI or BTC；
(c)CH3I,Et3N,THF
其中：n、R13的定义如本文中所述。
在一个具体的实施方案中，本发明的式Ia化合物的合成方法如下：在–78℃条件下，向含有恶唑烷酮(44mg，0.5mmol)的四氢呋喃(THF)溶液中缓慢滴加含正丁基锂的己烷溶液(0.55mmol，0.2mL)。在此温度下搅拌10min之后，向反应溶液中滴加含酰氯的四氢呋喃溶液(0.55mmol，1mL)。反应液在–78℃条件下搅拌0.5h，在4h之内缓慢升温到室温，并在室温条件下搅拌1h。反应结束后，往反应液中滴加饱和NH4Cl溶液(5mL)，并用乙酸乙酯萃取水层，萃取3次，合并乙酸乙酯层，无水硫酸钠干燥，减压蒸去乙酸乙酯，残留物通过硅胶柱层析纯化，纯化溶剂为乙酸乙酯与石油醚的混合物，二者的体积比为乙酸乙酯︰石油醚＝1:5～1:1，可得到相应的化合物。
本发明的式I或式Ia所示化合物通过抑制内源性大麻素水解酶活性，实现疼痛的治疗。
本文所述的内源性大麻素水解酶包括脂肪酰胺水解酶(Fatty Acid Amide Hydrolase，FAAH)和N-酰基乙醇胺水解酶(N-acylethanolamide hydrolyzing acid amidase，NAAA)。
本文所述的抑制内源性大麻素水解酶活性是指选择性抑制NAAA的活性或选择性抑制FAAH的活性或同时抑制NAAA和FAAH的活性。
本文采用术语“药学上可接受的盐”指的是：所述任一项化合物的那些盐、前药或溶液，其在正确的医学判断范围内，适于用来与人和动物的组织接触，而无过分的毒性、刺激应变性响应等，与合理的利益/风险比相符合。
本文所用术语“选择性抑制NAAA的活性”指的是：所述化合物在一定量的(例如，有效量)给药浓度下，可抑制机体内NAAA对底物的水解，但不抑制机体内FAAH对底物的水解。
本文所用术语“选择性抑制FAAH的活性”指的是：所述化合物在一定量的(例如，有效量)给药浓度下，可抑制机体内FAAH对底物的水解，但不抑制机体内NAAA对底物的水解。
本文所用术语“同时抑制了NAAA和FAAH的活性”指的是：所述化合物在一定量的(例如，有效量)给药浓度下，即可抑制机体内FAAH对底物的水解，也可以抑制机体内NAAA对底物的水解。
本发明的式I或式Ia化合物既可以其本身也可以其可药用盐或水合物或溶剂化物的形式使用。式I或式Ia化合物的可药用盐包括与药学上可接受的无机酸或有机酸、或者与可药用的无机碱或有机碱形成的盐。合适的酸加成盐的例子包括与盐酸、氢溴酸、硫酸、磷酸、硝酸、高氯酸、富马酸、乙酸、丙酸、琥珀酸、羟基乙酸、甲酸、乳酸、马来酸、酒石酸、柠檬酸、扑酸、丙二酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、富马酸、甲苯磺酸、甲磺酸、萘-2-磺酸、苯磺酸、羟基萘甲酸、氢碘酸、苹果酸、鞣酸等形成的盐。合适的碱加成盐的例子包括与钠、锂、钾、镁、铝、钙、锌、N,N'-二苄基乙二胺、氯代普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因等形 成的盐。本文中涉及到本发明化合物时，包括式I或式Ia化合物及其可药用盐或水合物或溶剂化物。
根据本发明，药物组合物包含至少一种本发明式I或式Ia化合物与常规药用载体或赋形剂。该药物组合物可通过例如口服或非肠道等途径给药。本发明的药物组合物可按本领域常规方法制备成各种剂型，包括但不限于片剂、胶囊、溶液、悬浮液、颗粒剂或注射剂等，经例如口服或非肠道等途径给药。
另外需要指出，本发明化合物使用剂量和使用方法取决于诸多因素，包括患者的年龄、体重、性别、自然健康状况、营养状况、化合物的活性强度、服用时间、代谢速率、病症的严重程度以及诊治医师的主观判断。优选的使用剂量介于0.01－100mg/kg体重/天。
发明的有益效果
本发明的式I或式Ia所示化合物通过抑制内源性大麻素水解酶活性，实现疼痛的治疗。实验表明本发明的式I或式Ia所示化合物能够抑制NAAA和/或FAAH的活性，能够显著的抑制小鼠中枢神经性疼痛的作用，显著抑制小鼠腹腔炎性疼痛的作用，显著抑制硝酸甘油所致大鼠头痛，显著抑制大鼠骨关节炎性疼痛。
同时，本发明的式I或式Ia所示化合物的稳定性好，在酸、碱性条件下半衰期均大于24小时，在大鼠血浆中半衰期均大于120分钟，稳定性远远超过已报道的β-丁内酯类NAAA抑制剂(β-丁内酯类NAAA抑制剂大鼠血浆半衰期小于15分钟)。本发明的式I或式Ia所示化合物在大鼠体内代谢半衰期在60-300分钟，稳定性远远超过已报道的β-丁内酯类NAAA抑制剂(β-丁内酯类NAAA抑制剂大鼠体内代谢半衰期小于5分钟)。
此外，本发明的式I或式Ia所示化合物对hERG钾通道抑制率低，比市场常用解热镇痛药物COX2选择性抑制剂塞来昔布具有更好的心脏安全性。
附图说明
图1为化合物2、9、14、24、30与阳性药物加巴喷丁对SNI神经病理性疼痛给药1h后的作用。
图2为化合物2、9、14、24、30与阳性药物加巴喷丁对SNI神经病理性疼痛给药4h后的作用。
图3为化合物2、9、14、24、30与阳性药物加巴喷丁对SNI神经病理性疼痛给药10h后的作用。
图4为化合物2、9、14、24、30与阳性药物吲哚美辛对醋酸致炎性腹痛的作用。
图5为化合物2、9、14、24、30与阳性药物吲哚美辛对硝酸甘油致大鼠头痛的作用。
图6A为不同浓度的化合物2、9与RAW264.7细胞孵育24h后对细胞活力的影响。
图6B为不同浓度的化合物2、9与RAW264.7细胞孵育48h后对细胞活力的影响。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是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，均为可以通过市购获得的常规产品。
实施例：采用以下通用合成方法制备化合物1-46
在–78℃条件下，向含有恶唑烷酮(44mg，0.5mmol)的四氢呋喃(THF)溶液中缓慢滴加含正丁基锂的己烷溶液(0.55mmol，0.2mL)。在此温度下搅拌10min之后，向反应溶液中滴加含酰氯的四氢呋喃溶液(0.55mmol，1mL)。反应液在–78℃条件下搅拌0.5h，在4h之内缓慢升温到室温，并在室温条件下搅拌1h。反应结束后，往反应液中滴加饱和NH4Cl溶液(5mL)，并用乙酸乙酯萃取水层，萃取3次，合并乙酸乙酯层，无水硫酸钠干燥，减压蒸去乙酸乙酯，残留物通过硅胶柱层析纯化，纯化溶剂为乙酸乙酯与石油醚的混合物，二者的体积比为乙酸乙酯︰石油醚＝1:5～1:1，可得到相应的化合物。
棕榈酰恶唑烷酮(1)
Figure PCTCN2015093140-appb-000026
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5，酰氯为棕榈酰氯)，反应得到产物1(83mg；产率：51％，白色不定形粉末)。
IR(film)vmax:2914,2846,1765,1699,1386cm–1；1H NMR(400MHz,CDCl3)δ0.88(t,J＝7.2Hz,3H),1.26–1.32(m,24H),1.62–1.69(m,2H),2.91(t,J＝7.6Hz,2H),4.02(t,J＝8.0Hz,2H),4.41(t,J＝8.0Hz,2H)ppm；13C NMR(100MHz,CDCl3)δ14.0,22.6,24.2,29.1,29.3,29.4,29.5,29.6,29.6,31.8,35.0,42.5,61.9,153.5,173.5ppm；MS(ESI,m/z):326(M+H)+；Anal.calcd for C19H35NO3:C,70.11；H,10.84；N,4.30.Found:C,70.13；H,10.86；N,4.32.
苯己酰恶唑烷酮(2)
Figure PCTCN2015093140-appb-000027
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶4，酰氯为苯己酰氯)，反应得到产物2(41mg；产率：31％，白色不定形粉末)。
IR(film)vmax:2920,2858,1780,1700,1388,1225,1111,1039cm–1；1H NMR(400MHz,CDCl3)δ1.36–1.44(m,2H),1.61–1.73(m,4H),2.61(t,J＝7.6Hz,2H),2.90(t,J＝7.6Hz,2H),3.97(t,J＝8.4Hz,2H),4.36(t,J＝8.4Hz,2H),7.16–7.18(m,3H),7.24–7.28(m,2H)ppm；13C NMR(100MHz,CDCl3)δ24.0,28.6,31.1,34.9,35.6,42.4,61.9,125.5,128.2,128.3,142.4,153.4,173.3ppm；MS(ESI,m/z):262(M+H)+；HRMS(ESI)calcd for[C15H20NO3]+(M+H+):262.1438；found:262.1451；Anal.calcd for C15H19NO3:C,68.94；H,7.33；N,5.36.Found:C,68.70；H,7.31；N,5.38.
苯庚酰恶唑烷酮(3)
Figure PCTCN2015093140-appb-000028
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶4，酰氯为苯庚酰氯)，反应得到产物3(61mg；产率：44％，白色不定形粉末)。
IR(film)vmax:2918,2850,1781,1703,1386,1225,1039cm–1；1H NMR(400MHz,CDCl3)δ1.35–1.42(m,4H),1.58–1.69(m,4H),2.60(t,J＝7.6Hz,2H),2.90(t,J＝7.6Hz,2H),3.98(t,J＝8.4Hz,2H),4.36(t,J＝8.4Hz,2H),7.16–7.17(m,3H),7.24–7.28(m,2H)ppm；113C NMR(100MHz,CDCl3)δ24.1,28.9,28.9,31.2,35.0,35.8,42.4,61.9,125.5,128.1,128.3,142.6,153.5,173.4ppm；MS(ESI,m/z):276(M+H)+；Anal.calcd for C16H21NO3:C,69.79；H,7.69；N,5.09.Found:C,69.83；H,7.68；N,5.10.
苯辛酰恶唑烷酮(4)
Figure PCTCN2015093140-appb-000029
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶4，酰氯为苯辛酰氯)，反应得到产物4(61mg；产率：44％，白色不定形粉末)。
IR(film)vmax:2920,2848,1780,1703,1386,1225,1020cm–1；1H NMR(400MHz,CDCl3)δ1.35–1.42(m,4H),1.58–1.69(m,4H),2.60(t,J＝7.6Hz,2H),2.90(t,J＝7.6Hz,2H),3.98(t,J＝8.4Hz,2H),4.36(t,J＝8.4Hz,2H),7.16–7.17(m,3H),7.24–7.28(m,2H)ppm；113C NMR(100MHz,CDCl3)δ24.1,28.9,28.9,31.2,35.0,35.8,42.4,61.9,125.5,128.1,128.3,142.6,153.5,173.4ppm；MS(ESI,m/z):290(M+H)+；Anal.calcd for C17H23NO3:C,70.56；H,8.01；N,4.84.Found:C,70.61；H,7.99；N,4.85.
3–噻吩己酰恶唑烷酮(5)
Figure PCTCN2015093140-appb-000030
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶3，酰氯为3–噻吩己酰氯)；反应得到产物5(57mg；产率：43％，，白色不定形粉末)。
IR(film)vmax:2917,2849,1777,1697,1386,1222cm–1；1H NMR(400MHz,CDCl3)δ1.36–1.44(m,2H),1.62–1.73(m,4H),2.63(t,J＝7.6Hz,2H),2.90(t,J＝7.6Hz,2H),3.98(t,J＝8.0Hz,2H),3.37(t,J＝8.0Hz,2H),6.91–6.92(m,2H),7.21–7.23(m,1H)ppm；13C NMR(100MHz,CDCl3)δ23.9,28.6,29.9,30.1,34.9,42.4,61.9,119.8,125.0,128.1,142.7,153.4,173.3ppm；MS(ESI,m/z):268(M+H)+；Anal.calcd for C13H17NO3S:C,58.40；H,6.41.Found:C,58.57；H,6.40.
环己基己酰恶唑烷酮(6)
Figure PCTCN2015093140-appb-000031
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5，酰氯为环己基己酰氯)，反应得到产物6(57mg；产率：43％，白色不定形粉末)。
IR(film)vmax:2917,2849,1577,1541,1468,1384,1068,1023cm–1；1H NMR(400MHz,CDCl3)δ0.82–0.90(m,2H),1.15–1.23(m,6H),1.32–1.34(m,4H),1.63–1.70(m,7H),2.92(t,J＝7.6Hz,2H),4.03(t,J＝8.0Hz,2H),4.42(t,J＝8.0Hz,2H)ppm；13C NMR(100MHz,CDCl3)δ24.3,26.4,26.5,26.7,29.4,33.4,25.0,37.3,37.6,42.5,61.9,153.5,173.6ppm；MS(ESI,m/z):268(M+H)+；Anal.calcd for C15H25NO3:C,67.38；H,9.42；N,5.24.Found:C,67.15；H,9.41；N,5.25.
3–呋喃基己酰恶唑烷酮(7)
Figure PCTCN2015093140-appb-000032
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶3，酰氯为3-呋喃基己酰氯)，反应得到产物7(6.3mg；产率：5％，白色油状物)。
1H NMR(400MHz,CDCl3)δ1.34–1.43(m,2H),1.52–1.73(m,4H),2.61(t,J＝7.6Hz,2H),2.90(t,J＝7.6Hz,2H),3.98(t,J＝8.0Hz,2H),3.37(t,J＝8.0Hz,2H),6.25(br,1H),7.19(br,1H),7.33(t,J＝1.4Hz,1H)ppm；13C NMR(100MHz,CDCl3)δ24.3,24.0,28.6,31.1,34.9,42.4,61.9,110.9,124.8,138.7,142.6,153.4,173.3ppm；MS(ESI,m/z):252(M+H)+
3–氟基苯基己酰恶唑烷酮(8)
Figure PCTCN2015093140-appb-000033
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5，酰氯为3-氟基苯基己酰氯)，反应得到产物8(57mg；产率：51％，白色不定形粉末)。
IR(film)vmax:2918,2850,1779,1699,1617,1585,1387,1223,1044cm–1；1H NMR(400MHz,CDCl3)δ1.36–1.44(m,2H),1.61–1.74(m,4H),2.61(t,J＝7.6Hz,2H),2.92(t,J＝7.6Hz,2H),4.00(t,J＝8.4Hz,2H),4.40(t,J＝8.4Hz,2H),6.84–6.88(m,2H),6.94(d,J＝7.5Hz,1H),7.19–7.24(m,1H)ppm；13C NMR(100MHz,CDCl3)δ24.0,28.6,30.8,34.9,35.4,42.5,61.9,112.4,112.6,115.1,115.3,124.0,124.1,145.0,145.1,153.5,161.7,164.1,173.4ppm；MS(ESI,m/z):280(M+H)+；Anal.calcd for C15H18FNO3:C,64.50；H,6.50；N,5.01.Found:C,64.37；H,6.49；N,5.00.
3–氯基苯基己酰恶唑烷酮(9)
Figure PCTCN2015093140-appb-000034
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶3，酰氯为3–氯基苯基己酰氯)，反应得到产物9(57mg；产率：51％，白色不定形粉末)。
IR(film)vmax:2917,2849,1777,1692,1573,1537,1468,1383,1202,1066,1036cm–1；1H NMR(400MHz,CDCl3)δ1.35–1.43(m,2H),1.60–1.73(m,4H),2.59(t,J＝7.6Hz,2H),2.90(t,J＝7.6Hz,2H),3.99(t,J＝8.3Hz,2H),4.39(t,J＝8.3Hz,2H),7.04(d,J＝7.3Hz,1H),7.13–7.20(m,3H)ppm；13C NMR(100MHz,CDCl3)δ23.9,28.5,30.8,34.9,35.3,43.4,61.9,125.7,126.6,128.4,129.4,133.8,144.5,153.5,173.3ppm；MS(ESI,m/z):296(M+H)+；Anal.calcd for C15H18ClNO3:C,60.91；H,6.13；N,4.74.Found:C,60.77；H,6.15；N,4.73.
4–氯基苯基己酰恶唑烷酮(10)
Figure PCTCN2015093140-appb-000035
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶3，酰氯为4–氯基苯基己酰氯)，反应得到产物10(55mg；产率：49％，白色不定形粉末)。
IR(film)vmax:2917,2849,1782,1709,1579,1495,1384,1222,1091,1040cm–1；1H NMR(400MHz,CDCl3)δ1.35–1.42(m,2H),1.59–1.71(m,4H),2.58(t,J＝7.6Hz,2H),2.90(t,J＝7.6Hz,2H),4.00(t,J＝8.0Hz,2H),4.39(t,J＝8.0Hz,2H),7.09(d,J＝8.2 Hz,2H),7.23(d,J＝8.2Hz,2H)ppm；13C NMR(100MHz,CDCl3)δ224.0,24.4,28.5,31.0,34.9,42.4,61.9,128.3,129.7,140.9,153.5,173.4ppm；MS(ESI,m/z):296(M+H)+；Anal.calcd for C15H18ClNO3:C,60.91；H,6.13；N,4.74.Found:C,60.83；H,6.14；N,4.75.
5-丙酮基-3’–甲基苯基己酰恶唑烷酮(11)
Figure PCTCN2015093140-appb-000036
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶3，酰氯为3–甲基苯基己酰氯，将反应原料恶唑烷酮更换为5-丙酮基恶唑烷酮)，反应得到产物11(72mg；产率：52％，白色不定形粉末)。
IR(film)vmax:2955,2917,2849,1776,1701,1571,1541,1465,1384,1069cm–1；1H NMR(400MHz,CDCl3)δ1.36–1.44(m,2H),1.60–1.73(m,4H),2.32(s,1H),2.57(t,J＝7.6Hz,2H),2.91(t,J＝7.6Hz,2H),4.00(t,J＝8.2Hz,2H),4.38(t,J＝8.2Hz,2H),6.95–6.98(m,3H),7.16(dd,J＝7.3,7.3Hz,1H)ppm；13C NMR(100MHz,CDCl3)δ21.4,24.0,28.7,31.2,34.9,35.6,42.5,61.9,125.4,126.3,128.1,129.2,137.7,142.5,153.5,173.4ppm；MS(ESI,m/z):332(M+H)+；Anal.calcd for C19H25NO4。
5-丙酮基-4’–甲基苯基戊酰恶唑烷酮(12)
Figure PCTCN2015093140-appb-000037
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶3,酰氯为3–甲基苯基己酰氯，将反应原料恶唑烷酮更换为5-丙酮基恶唑烷酮)，反应得到产物12(76mg；产率：55％，白色不定形粉末)。
IR(film)vmax:2953,2917,2849,1776,1701,1579,1537,1468,1384,1069,1024cm–1；1H NMR(400MHz,CDCl3)δ1.35–1.43(m,2H),1.59–1.73(m,4H),2.31(s,1H),2.57(t,J＝7.7Hz,2H),2.90(t,J＝7.7Hz,2H),4.00(t,J＝7.8Hz,2H),4.38(t,J＝7.8Hz,2H),7.04–7.09(m,4H)ppm；13C NMR(100MHz,CDCl3)δ20.9,24.0,28.7,31.2,34.9,35.2,42.4,61.9,128.2,128.9,134.9,139.4,153.5,173.4ppm；MS(ESI,m/z):332(M+H)+；Anal.calcd for C19H25NO4。
3–联苯甲酰恶唑烷酮(13)
Figure PCTCN2015093140-appb-000038
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶2，酰氯为3-联苯甲酰氯)，反应得到产物13(81mg；产率：61％，白色不定形粉末)。
IR(film)vmax:2916,2848,1633,1565,1406,1107,1037cm–1；1H NMR(400MHz,CDCl3)δ4.19–4.20(m,2H),4.52(br,2H),7.36–7.38(m,1H),7.44(br,2H),7.50–7.52(m,1H),7.59–7.61(m,3H),7.77–7.78(br,1H),7.87(s,1H)ppm；13C NMR(100MHz,CDCl3)δ43.7,48.0,48.2,48.4,48.6,48.9,62.6,127.0,127.6,128.3,128.7,130.8,140.0,140.9,153.9,170.0ppm；MS(ESI,m/z):268(M+H)+；Anal.calcd for C16H13NO3:C,71.90；H,4.90；N,5.24.Found:C,71.74；H,4.89；N,5.25.
3–联苯乙酰恶唑烷酮(14)
Figure PCTCN2015093140-appb-000039
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶3，酰氯为3-联苯乙酰氯)，反应得到产物14(63mg；产率：45％，白色不定形粉末)。
IR(film)vmax:2916,2848,1776,1697,1598,1478,1387,1366,1223,1180,1109cm–1；1H NMR(400MHz,CDCl3)δ4.02(t,J＝8.0Hz,2H),4.35(s,2H),4.39(t,J＝8.0Hz,2H),7.31(d,J＝7.2Hz,1H),7.34(d,J＝7.2Hz,1H),7.38–7.44(m,3H),7.50(d,J＝7.6Hz,1H),7.55–7.60(m,1H)ppm；13C NMR(100MHz,CDCl3)δ41.1,42.7,61.9,126.0,127.2,127.3,128.6,128.6,128.7,128.9,134.0,140.8,141.5,153.5,171.2ppm；MS(ESI,m/z):282(M+H)+；Anal.calcd for C17H15NO3:C,72.58；H,5.37；N,4.98.Found:C,72.71；H,5.39；N,4.96.
4–联苯乙酰恶唑烷酮(15)
Figure PCTCN2015093140-appb-000040
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶3，酰氯为4-联苯乙酰氯)，反应得到产物15(65mg；产率：46％，白色不定形粉末)。
IR(film)vmax:2914,2844,1776,1697,1578,1386,1366,1025cm–1；1H NMR(400MHz,CDCl3)δ4.00(t,J＝8.4Hz,2H),4.31(s,2H),4.36(t,J＝8.4Hz,2H),7.33(t,J＝7.6Hz,1H),7.37–7.44(m,4H),7.54–7.58(m,4H)ppm；13C NMR(100MHz,CDCl3)δ40.7,42.6,61.9,127.0,127.2,128.7,130.1,132.5,140.0,140.7,153.4,171.1ppm；MS(ESI,m/z):282(M+H)+；Anal.calcd for C17H15NO3:C,72.58；H,5.37；N,4.98.Found:C, 72.67；H,5.38；N,4.97.
3–苯氧基苯甲酰恶唑烷酮(16)
Figure PCTCN2015093140-appb-000041
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶2，酰氯为3–苯氧基苯甲酰氯)，反应得到产物16(65mg；产率：48％，白色不定形粉末)。
IR(film)vmax:2917,2845,1783,1682,1577,1483,1436,1322,1200cm–1；1H NMR(400MHz,CDCl3)δ4.14(t,J＝8.0Hz,2H),4.46(t,J＝8.0Hz,2H),7.04(dd,J＝8.6,1.0Hz,2H),7.12(dd,J＝7.4,0.9Hz,1H),7.18(dddd,J＝7.2,7.2,2.0,2.0Hz,1H),7.26(br,1H),7.33–7.39(m,4H)ppm；13C NMR(100MHz,CDCl3)δ43.6,62.2,119.1,119.1,122.6,123.6,123.7,129.4,129.9,134.3,153.0,156.6,156.8,169.1ppm；MS(ESI,m/z):284(M+H)+；Anal.calcd for C16H13NO4:C,67.84；H,4.63；N,4.94.Found:C,68.01；H,4.64；N,4.93.
3–苯氧基苯乙酰恶唑烷酮(17)
Figure PCTCN2015093140-appb-000042
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶2，酰氯为3–苯氧基苯乙酰氯)，反应得到产物17(86mg；产率：53％，白色不定形粉末)。
IR(film)vmax:2914,2844,1777,1701,1583,1486,1387,1366,1269,1246,1211cm–1；1H NMR(400MHz,CDCl3)δ3.99(t,J＝8.0Hz,2H),4.24(s,1H),4.37(t,J＝8.0Hz,2H),6.89(d,J＝7.8Hz,1H),6.96(s,1H),7.01(dd,J＝8.4,8.4Hz,3H),7.09(dd,J＝7.8Hz,1H),7.25(d,J＝7.8Hz,1H),7.31(dd,J＝8.4,8.4Hz,2H)ppm；13C NMR(100MHz,CDCl3)δ40.9,42.6,61.9,117.4,118.9,120.1,123.2,124.5,129.7,135.3,153.4,156.9,157.2,170.8ppm；MS(ESI,m/z):298(M+H)+；Anal.calcd for C17H15NO4:C,68.68；H,5.09；N,4.71.Found:C,68.51；H,5.08；N,4.72.
4–苯氧基苯乙酰恶唑烷酮(18)
Figure PCTCN2015093140-appb-000043
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶2，酰氯为4–苯氧基苯乙酰氯)，反应得到产物18(88mg；产率：59％，白色不定形粉末)。
IR(film)vmax:2916,2848,1777,1577,1537,1486,1467,1385,1237,1108,1040cm–1；1H NMR(400MHz,CDCl3)δ4.02(t,J＝8.0Hz,2H),4.25(s,2H),4.39(t,J＝8.0 Hz,2H),6.95(d,J＝8.4Hz,2H),7.00(d,J＝7.6Hz,2H),7.09(t,J＝7.6Hz,1H),7.27(d,J＝8.4Hz,2H),7.32(t,J＝7.6Hz,2H)ppm；13C NMR(100MHz,CDCl3)δ40.3,42.6,62.0,118.8,118.9,123.3,128.2,129.7,131.0,153.4,156.4,157.0,171.3ppm；MS(ESI,m/z):298(M+H)+；Anal.calcd for C17H15NO4:C,68.68；H,5.09；N,4.71.Found:C,68.73；H,5.10；N,4.72.
3–苄氧基苯甲酰恶唑烷酮(19)
Figure PCTCN2015093140-appb-000044
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶2，酰氯为3–苄氧基苯甲酰氯)，反应得到产物19(82mg；产率：55％，白色不定形粉末)。
IR(film)vmax:2916,2849,1785,1679,1634,1579,1436,1383,1325,1244,1217,1196,1145,1098,1037cm–1；1H NMR(400MHz,CDCl3)δ4.16(t,J＝7.6Hz,2H),4.48(t,J＝7.6Hz,2H),5.08(s,2H),7.14–7.44(m,9H)ppm；13C NMR(100MHz,CDCl3)δ43.7,62.2,70.3,115.1,119.3,121.7,127.6,128.1,128.6,129.0,133.9,136.5,153.1,158.3,169.5ppm；MS(ESI,m/z):298(M+H)+；Anal.calcd for C17H15NO4:C,68.68；H,5.09；N,4.71.Found:C,68.81；H,5.11；N,4.71.
3–苄氧基苯乙酰恶唑烷酮(20)
Figure PCTCN2015093140-appb-000045
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶2，酰氯为3–苄氧基苯乙酰氯)，反应得到产物20(76mg；产率：49％，白色不定形粉末)。
IR(film)vmax:2916,2849,1777,1698,1583,1489,1449,1387,1365,1272,1224,1158,1109,1039cm–1；1H NMR(400MHz,CDCl3)δ3.97(t,J＝8.1Hz,2H),4.25(s,2H),4.35(t,J＝8.1Hz,2H),5.04(s,2H),6.88(d,J＝7.9Hz,1H),6.91(d,J＝7.9Hz,1H),6.96(s,1H),7.22(dd,J＝7.9,7.9Hz,1H),7.30(dd,J＝7.2,7.2Hz,1H),7.37(dd,J＝7.2,7.2Hz,2H),7.42(d,J＝7.2Hz,2H)ppm；13C NMR(100MHz,CDCl3)δ41.0,42.6,61.9,69.9,113.7,116.2,122.3,127.5,127.9,128.5,129.5,135.0,137.0,153.4,158.9,171.0ppm；MS(ESI,m/z):312(M+H)+；Anal.calcd for C18H17NO4:C,69.44；H,5.50；N,4.50.Found:C,69.20；H,5.49；N,4.51.
4–苄氧基苯甲酰恶唑烷酮(21)
Figure PCTCN2015093140-appb-000046
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶2，酰氯为4–苄氧基苯甲酰氯)，反应得到产物21(108mg；产率：73％，白色不定形粉末)。
IR(film)vmax:2916,2849,1774,1670,1607,1512,1378,1338,1249,1194,1108,1024cm–1；1H NMR(400MHz,CDCl3)δ4.14(t,J＝8.0Hz,2H),4.47(t,J＝8.0Hz,2H),5.11(s,2H),6.99(d,J＝8.8Hz,2H),7.34–7.43(m,5H),7.69(d,J＝8.8Hz,2H)ppm；13C NMR(100MHz,CDCl3)δ43.9,62.2,70.1,114.0,124.7,127.5,128.2,128.6,131.8,136.2,153.5,162.4,169.0ppm；MS(ESI,m/z):298(M+H)+；Anal.calcd for C17H15NO4:C,68.68；H,5.09；N,4.71.Found:C,68.90；H,5.11；N,4.69.
4–苄氧基苯乙酰恶唑烷酮(22)
Figure PCTCN2015093140-appb-000047
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶2，酰氯为4–苄氧基苯乙酰氯)，反应得到产物22(77mg；产率：50％，白色不定形粉末)。
IR(film)vmax:2916,2849,1777,1698,1607,1511,1387,1365,1240,1177,1111,1040,1016cm–1；1H NMR(400MHz,CDCl3)δ3.96(t,J＝8.0Hz,2H),4.20(s,2H),4.33(t,J＝8.0Hz,2H),5.03(s,2H),6.92(d,J＝8.4Hz,2H),7.22(d,J＝8.4Hz,2H),7.30(t,J＝7.2Hz,1H),7.35–7.42(m,4H)ppm；13C NMR(100MHz,CDCl3)δ40.1,42.6,61.9,69.9,114.8,125.8,127.4,127.9,128.5,130.7,136.9,153.4,157.9,171.5ppm；MS(ESI,m/z):312(M+H)+；Anal.calcd for C18H17NO4:C,69.44；H,5.50；N,4.50.Found:C,69.65；H,5.51；N,4.50.
5-N,N-二甲基甲氨基-4’–苯乙氧基苯甲酰恶唑烷酮(23)
Figure PCTCN2015093140-appb-000048
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶1，酰氯为4–苯乙氧基苯甲酰氯，将反应原料恶唑烷酮更换为5-N,N-二甲基甲氨基恶唑烷酮)，反应得到产物23(84 mg；产率：54％，白色不定形粉末)。
IR(film)vmax:2916,2849,1777,1672,1605,1508,1384,1324,1307,1254,1168,1094,1029cm–1；1H NMR(400MHz,CDCl3)δ3.11(t,J＝7.2Hz,2H),4.14(t,J＝8.0Hz,2H),4.22(t,J＝7.2Hz,2H),4.46(t,J＝8.0Hz,2H),6.90(d,J＝8.4Hz,2H),7.23–7.34(m,5H),7.67(d,J＝8.4Hz,2H)ppm；13C NMR(100MHz,CDCl3)δ35.6,43.9,62.2,68.8,113.7,124.4,126.6,128.5,129.0,131.8,137.8,153.5,162.5,169.0ppm；MS(ESI,m/z):312(M+H)+；Anal.calcd for C21H24N2O4:C,68.46；H,6.57；N,7.60；O,17.37；Found:C,68.23；H,6.44；N,7.78；O,17.45.
4–苄基环己酰恶唑烷酮(24)
Figure PCTCN2015093140-appb-000049
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5，酰氯为4–苄基环己酰氯)，反应得到产物24(84mg；产率：54％，白色不定形粉末)。
1H NMR(400MHz,CDCl3)δ1.53-1.68(m,6H),1.77-1.90(m,3H),2.61-2.63(m,2H),3.60-3.66(t,1H),3.99-4.03(t,J＝8.0Hz,2H),4.36-4.40(t,J＝8.0Hz,2H),7.11-7.19(m,3H),7.25-7.28(m,2H)ppm；13C NMR(100MHz,CDCl3)δ25.2,28.6,36.4,39.8,40.1,42.8,61.8,125.6,128.1,129.0,141.3,153.1,176.6ppm。
N–苄基哌啶-4-基酰恶唑烷酮(25)
Figure PCTCN2015093140-appb-000050
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶3，酰氯为N-苄基哌啶-4-基酰氯)，反应得到产物25(27mg；产率：46％，白色不定形粉末)。
1H NMR(400MHz,CDCl3)δ1.72-1.83(m,4H),2.64(m,1H),3.92-4.05(m,8H),4.39(t,J＝8.0Hz,2H),7.21-7.25(m,3H),7.28-7.30(m,2H)ppm；13C NMR(100MHz,CDCl3)δ27.9,28.3,34.7,38.6,42.6,42.8,60.3,125.7,128.4,130.6,140.7,153.1,176.6ppm；MS(ESI,m/z):289(M+H)+；Anal.calcd for C16H20N2O3:C,66.65；H,6.99；N,9.72；O,16.65。
苯己酰-5-甲基-恶唑烷酮(27)
Figure PCTCN2015093140-appb-000051
采用通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶4，酰氯为苯己酰氯，将反应原料恶唑烷酮更换为5-甲基恶唑烷酮)，反应得到产物27(57mg；产率：42％，白色不定形粉末)。
IR(film)vmax:2937,2872,1764,1725,1683,1363,1231,1058cm–1；1H NMR(400MHz,CDCl3)δ0.97(d,J＝5.6Hz,3H),1.32–1.40(m,2H),1.58–1.62(m,4H),2.63(t,J＝7.5Hz,2H),2.87(t,J＝7.5Hz,2H),4.05(m,1H),4.42(dd,J＝10.6,8.4Hz,2H),7.15–7.18(m,3H),7.24–7.29(m,2H)ppm；MS(ESI,m/z):276(M+H)+；C16H21NO3,C,69.79；H,7.69；N,5.09；O,17.43。
4-羟基苯己酰恶唑烷酮(31)
Figure PCTCN2015093140-appb-000052
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶2，酰氯为对羟基苯己酰氯)，反应得到产物31(53mg；产率：68％，白色不定形粉末)。
IR(film)vmax:3362,3130,2837,1764,1717,1538,1519,1267,1243,1075cm-1；1H NMR(400MHz,CDCl3)δ1.38(m,2H),1.62-1.68(m,4H),2.27(s,1H),2.54(t,J＝7.0Hz,2H),2.96(t,J＝7.0Hz,2H),4.07(t,J＝7.2Hz,2H),4.29(t,J＝7.2Hz,2H),6.82(d,J＝6.9Hz,2H),7.43(d,J＝6.9Hz,2H)ppm；13C NMR(100MHz,CDCl3)δ21.7,23.8,26.7,30.5,31.3,35.6,41.7,60.8,114.7,134.9,136.4,162.8,172.4ppm；MS(ESI,m/z):278(M+H)+；Anal.calcd for C15H19NO4:C,64.97；H,6.91；N,5.05；O,23.08。
3-甲基苯己酰恶唑烷酮(32)
Figure PCTCN2015093140-appb-000053
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5，酰氯为3-甲基苯己酰氯)，反应得到产物32(72mg；产率：52％，白色不定形粉末)。
IR(film)vmax:2955,2917,2849,1776,1701,1571,1541,1465,1384,1069cm-1；1H NMR(400MHz,CDCl3)δ1.36–1.44(m,2H),1.60–1.73(m,4H),2.32(s,3H),2.57(t,J＝7.6Hz,2H),2.91(t,J＝7.6Hz,2H),4.00(t,J＝8.2Hz,2H),4.38(t,J＝8.2Hz,2H),6.95-6.98(m,3H),7.16(dd,J＝7.3,7.3Hz,1H)ppm；13C NMR(100MHz,CDCl3)δ21.4,24.0,28.7,31.2,34.9,35.6,42.5,61.9,125.4,126.3,128.1,129.2,137.7,142.5,153.5,173.4ppm；MS(ESI,m/z):276(M+H)+；Anal.calcd for C16H21NO3:C,69.79；H,7.69；N,5.09.Found:C,69.61；H,7.67；N,5.10.
4-甲基苯己酰恶唑烷酮(33)
Figure PCTCN2015093140-appb-000054
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5，酰氯为对甲基苯己酰氯)，反应得到产物33(148mg；产率：72％，白色不定形粉末)。
IR(film)vmax:3034,2921,2850,1700,1458,1405cm-1；1H NMR(400MHz,CDCl3)δ1.34–1.41(m,2H),1.58–1.70(m,4H),2.31(s,3H),2.34(t,J＝7.6Hz,2H),2.56(t,J＝7.6Hz,2H),7.05(d,J＝8.4Hz,2H),7.08(d,J＝8.4Hz,2H)ppm；13C NMR(100MHz,CDCl3)δ20.9,24.5,28.6,31.1,34.0,35.2,128.2,128.9,135.0,139.3,153.5,180.4ppm；MS(ESI,m/z):207(M+H)+；Anal.calcd for C13H18O2:C,75.69；H,8.80.Found:C,75.78；H,8.82.
哌啶-3-基己酰恶唑烷酮(34)
Figure PCTCN2015093140-appb-000055
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶3，酰氯为哌啶-3-基己酰氯)，反应得到产物34(26mg；产率：36％，白色不定形粉末)。
IR(film)vmax:3314,3017,1577,1541,1468,1023cm-1；1H NMR(400MHz,CDCl3)δ0.82–0.90(m,2H),1.15–1.23(m,6H),1.63–1.70(m,5H),2.92(t,J＝7.6Hz,2H),3.39(t,J＝7.2Hz,2H),3.54(t,J＝7.2Hz,2H),4.03(t,J＝8.0Hz,2H),4.42(t,J＝8.0Hz,2H)ppm；13C NMR(100MHz,CDCl3)δ24.3,26.4,29.4,33.4,25.0,37.3,37.6,42.5,42.7,46.6,61.9,153.5,173.6ppm；MS(ESI,m/z):269(M+H)+；Anal.calcd for C14H24N2O3:C,62.66；H,9.01；N,10.44,O,17.89.
苯戊酰恶唑烷酮(35)
Figure PCTCN2015093140-appb-000056
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5，酰氯为苯戊酰氯)，反应得到产物35(69mg；产率：56％，白色不定形粉末)。
IR(film)vmax:2924,2858,1780,1700,1497,1478,1453,1388,1225,1111,1040cm-1；1H NMR(400MHz,CDCl3)δ1.69-1.71(m,4H),2.64(t,J＝7.2Hz,2H),2.94(t,J＝7.2Hz,2H),3.98(t,J＝8.4Hz,2H),4.37(t,J＝8.4Hz,2H),7.17-7.19(m,3H),7.25-7.29(m,2H)ppm；13C NMR(100MHz,CDCl3)δ23.8,30.7,34.8,35.5,42.4,61.9,125.7,128.2,128.3,142.1,153.5,173.3ppm；MS(ESI,m/z):248(M+H)+；Anal.calcd for  C14H17NO3:C,68.00；H,6.93；N,5.66.Found:C,68.20；H,6.91；N,5.67.
3–氯基苯戊酰恶唑烷酮(36)
Figure PCTCN2015093140-appb-000057
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶4，酰氯为3–氯基苯戊酰氯)，反应得到产物36(32mg；产率：43％，白色不定形粉末)。
IR(film)vmax:2917,2849,1777,1692,1573,1537,1468,1383,1202,1066,1036cm–1；1H NMR(400MHz,CDCl3)δ1.35–1.43(m,2H),1.60–1.73(m,2H),2.59(t,J＝7.6Hz,2H),2.90(t,J＝7.6Hz,2H),3.99(t,J＝8.3Hz,2H),4.39(t,J＝8.3Hz,2H),7.04(d,J＝7.3Hz,1H),7.13–7.20(m,3H)ppm；13C NMR(100MHz,CDCl3)δ23.9,30.8,34.9,35.3,43.4,61.9,125.7,126.6,128.4,129.4,133.8,144.5,153.5,173.3ppm；MS(ESI,m/z):282(M+H)+；Anal.calcd for C14H16ClNO3:C,59.68；H,5.72；Cl,12.58；N,4.97；O,17.04。
4–氟基苯戊酰恶唑烷酮(37)
Figure PCTCN2015093140-appb-000058
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶4，酰氯为4–氟基苯戊酰氯)，反应得到产物37(73mg；产率：62％，白色不定形粉末)。
IR(film)vmax:2926,2852,1774,1709,1371,1045cm–1；1H NMR(400MHz,CDCl3)δ1.35–1.42(m,2H),1.64(m,2H),2.58(t,J＝7.6Hz,2H),2.90(t,J＝7.6Hz,2H),4.04(t,J＝8.0Hz,2H),4.35(t,J＝8.0Hz,2H),7.07(d,J＝8.2Hz,2H),7.23(d,J＝8.2Hz,2H)ppm；13C NMR(100MHz,CDCl3)δ23.8,24.3,31.4,34.6,42.5,62.6,128.3,128.7,140.9,153.5,173.4ppm；MS(ESI,m/z):266(M+H)+；Anal.calcd for C14H16FNO3:C,63.39；H,6.08；F,7.16；N,5.28；O,18.09.
2,4–二氯基苯庚酰恶唑烷酮(38)
Figure PCTCN2015093140-appb-000059
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶3，酰氯为2,4–二氯基苯庚酰氯)，反应得到产物38(7.6mg；产率：14％，白色不定形粉末)。
IR(film)vmax:2928,2860,1784,1706,1617,1223,1067,986cm-1；1H NMR(400MHz,CDCl3)δ1.36–1.48(m,2H),1.65–1.78(m,6H),2.67(t,J＝7.6Hz,2H),2.91(t,J＝7.6Hz,2H),4.04(t,J＝8.4Hz,2H),4.42(t,J＝8.4Hz,2H),6.88-6.92(m,3H)ppm； 13C NMR(100MHz,CDCl3)δ24.2,24.6,28.6,30.5,35.1,35.4,42.5,61.9,112.4,112.6,116.7,124.3,124.6,145.1,153.5,173.4ppm；MS(ESI,m/z):344:346(3:2,M+H)+；Anal.calcd for C16H19Cl2NO3:C,55.83；H,5.56；Cl,20.60；N,4.07；O,13.94.
3,4-二羟基苯己酰恶唑烷酮(39)
Figure PCTCN2015093140-appb-000060
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶1，酰氯为3,4-二羟基苯己酰氯)，反应得到产物39(47mg；产率：36％，白色不定形粉末)。
IR(film)vmax:3130,3017,2939,1785,1724,1242,1085cm-1；1H NMR(400MHz,CDCl3)δ1.35(m,2H),1.68-1.74(m,4H),2.76(t,J＝7.6Hz,2H),2.87(t,J＝7.6Hz,2H),4.03(t,J＝8.4Hz,2H),4.39(t,J＝8.4Hz,2H),6.90(s,1H),7.07(d,1H),7.46(d,1H)ppm；13C NMR(100MHz,CDCl3)δ24.2,28.3,31.4,33.7,36.4,42.5,61.3,105.3,114.8,124.7,148.4,153.5,158.5,159.7,173.4ppm；MS(ESI,m/z):294(M+H)+；Anal.calcd for C15H19NO5:C,61.42；H,6.53；N,4.78；O,27.27.
棕榈酰咪唑烷酮(40)
Figure PCTCN2015093140-appb-000061
采用类似通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5，酰氯为棕榈酰氯，将反应原料恶唑烷酮更换为咪唑烷酮)，反应得到产物40(37mg；产率：54％，白色不定形粉末)。
IR(film)vmax:3312,3017,1768,1715,1388cm-1；1H NMR(400MHz,CDCl3)δ0.88(t,J＝7.2Hz,3H),1.26-1.32(m,24H),1.62-1.69(m,2H),2.93(t,J＝7.6Hz,2H),4.05(t,J＝8.0Hz,2H),4.38(t,J＝8.0Hz,2H)ppm；13C NMR(100MHz,CDCl3)δ14.0,22.7,24.1,28.6,29.3,29.4,29.5,29.6,29.6,31.8,35.0,40.3,45.2,153.2,174.8ppm；MS(ESI,m/z):325(M+H)+；Anal.calcd for C19H36N2O2:C,70.32；H,11.18；N,8.63；O,9.86。
4–苯氧基苯甲酰恶唑烷酮(41)
Figure PCTCN2015093140-appb-000062
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶3，酰氯为4–苯氧基苯甲酰氯)，反应得到产物41(78mg；产率：55％，白色不定形粉末)。
IR(film)vmax:2915,2844,1779,1681,1575,1482,1445,1382,1322cm-1；1H NMR(400MHz,CDCl3)δ4.17(t,J＝8.0Hz,2H),4.50(t,J＝8.0Hz,2H),6.97(ddd,J＝8.4,2.8,2.0Hz,2H),7.08(dd,J＝8.4,0.8Hz,2H),7.19(dd,J＝7.6Hz,1H),7.37-7.42(ddd,J＝8.4,7.6,2.0Hz 2H),7.67(ddd,J＝8.4,2.8,2.0Hz,2H)ppm；13C NMR(100MHz,CDCl3)δ43.9,62.2,116.7,120.3,124.6,126.4,130.0,131.7,153.4,155.5,161.7,168.9ppm；MS(ESI,m/z):284(M+H)+；Anal.calcd for C16H13NO4:C,67.84；H,4.63；N,4.94.Found:C,67.75；H,4.63；N,4.95.
3’氯-4–苯氧基苯甲酰恶唑烷酮(42)
Figure PCTCN2015093140-appb-000063
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶3，酰氯为3’氯-4–苯氧基苯甲酰氯)，反应得到产物42(36mg；产率：42％，白色不定形粉末)。
IR(film)vmax:2935,2768,1765,1673,1571cm-1；1H NMR(400MHz,CDCl3)δ4.11(t,J＝8.0Hz,2H),4.43(t,J＝8.0Hz,2H),6.89(d,J＝72.0Hz,1H),6.97(ddd,J＝8.4,2.8,2.0Hz,2H),7.08(dd,J＝8.4,0.8Hz,2H),7.11(dd,J＝7.6,2.0Hz 1H),7.47-7.50(m,2H)ppm；13C NMR(100MHz,CDCl3)δ42.5,60.4,116.7,119.7,124.6,126.4,127.6,130.3,132.7,136.4,145.3,153.4,157.6,161.7,168.9ppm；MS(ESI,m/z):318:320(3:1,M+H)+；Anal.calcd for C16H12ClNO4:C,60.48；H,3.81；Cl,11.16；N,4.41；O,20.14。
3-吲哚基-正己酰恶唑烷酮(43)
Figure PCTCN2015093140-appb-000064
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶2，酰氯为3-吲哚基正己酰氯)，反应得到产物43(14mg；产率：27％，白色不定形粉末)。
1H NMR(400MHz,CDCl3)δ1.35(m,2H),1.62-1.65(m,4H),2.47(t,J＝6.8Hz,2H),2.92(t,J＝7.0Hz,2H),4.73(m,2H),7.26(m,2H),7.56(d,J＝6.6Hz,1H),8.30(d,J＝6.6Hz,1H),8.33(s,1H)ppm；MS(ESI,m/z):301(M+H)+,C17H20N2O3。
尿嘧啶-1-基正己酰恶唑烷酮(44)
Figure PCTCN2015093140-appb-000065
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶1，酰氯为尿嘧啶-1-基-正己酰氯)，反应得到产物44(18mg；产率：38％，白色不定形粉末)。
1H NMR(400MHz,CDCl3)δ1.37(m,2H),1.61-1.65(m,4H),2.47(t,J＝6.8Hz,2H),2.90(t,J＝7.0Hz,2H),5.80(d,J＝8.4Hz,1H),8.21(d,J＝8.4Hz,1H),11.72(br,1H)ppm；MS(ESI,m/z):296(M+H)+,C13H17N3O5。
2-萘基己酰恶唑烷酮(45)
Figure PCTCN2015093140-appb-000066
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶5，酰氯为2-萘基己酰氯)，反应得到产物45(27mg；产率：32％，白色不定形粉末)。
1H NMR(400MHz,CDCl3)δ1.36(m,2H),1.60-1.64(m,4H),2.45(t,J＝6.8Hz,2H),2.91(t,J＝7.0Hz,2H),7.18-7.29(m,7H)ppm；MS(ESI,m/z):312(M+H)+,C19H21NO3。
7-氟2-萘基己酰恶唑烷酮(46)
Figure PCTCN2015093140-appb-000067
依通用合成方法1(纯化溶剂：乙酸乙酯∶石油醚＝1∶4，酰氯为7-氟2-萘基己酰氯)，反应得到产物46(15mg；产率：26％，白色不定形粉末)。
1H NMR(400MHz,CDCl3)δ1.36(m,2H),1.60-1.64(m,4H),2.47(t,J＝6.8Hz,2H),2.87(t,J＝7.0Hz,2H),7.20-7.31(m,6H)ppm；MS(ESI,m/z):330(M+H)+,C19H20FNO3。
本发明的实验例中用到的待评价化合物或待测化合物或受试化合物为本发明实施例制备的化合物1-46。
实验例1内源性大麻素水解酶活性检测方法
本实验例中用到的内源性大麻素水解酶为脂肪酰胺水解酶(Fatty Acid Amide Hydrolase，FAAH)和N-酰基乙醇胺水解酶(N-acylethanolamide hydrolyzing acid  amidase，NAAA)，根据文献中记载的方法(PMCID:PMC3423427，PMC3723234，PMC2692831，PMC3382457)制备得到。制备方法如下：通过构建携带完整NAAA/FAAH基因的质粒(pCDNA3.1/NAAA或pCDNA3.1/FAAH)，该质粒带有Cytomegalovirus(CMV)启动因子和Neomycin筛选基因，使用脂介质转入上述质粒至HEK-293细胞内，使用G418筛选和Western-blot检测方法获得稳定且高表达NAAA/FAAH的细胞株。培养并收集HEK-293重组细胞，用PBS洗涤2～3次，在含0.32M蔗糖的20mM Tris-HCl中超声处理，反复冻融两次后，于4℃，800g离心15min，收集上清(即为所需蛋白)，用BCA法测蛋白浓度，将蛋白浓度统一稀释至1mg/mL，分装后保存于-80℃冰箱备用。
本实验例中用到的PBS溶液的配置过程为：8g NaCl，0.2g KCl，1.44g Na2HPO4，0.24g KH2PO4，溶解于1L超纯水中，湿热灭菌，4℃保存。
将30μL(1mg/mL)内源性大麻素水解酶加入进样瓶中，再加入2μL DMSO(空白对照组)或不同浓度的待测化合物(本发明实施例制备的化合物1-46)于37℃反应10min。再加入含有酶水解底物(底物为含有一个烯双键，含17个碳链长度的17烯酰基乙醇胺，简称17:1FAE)的缓冲液(缓冲液组成为50mM磷酸氢二钠，0.1％Triton X-100,3mM DTT，150μL)170μL，17:1FAE的浓度为5μM，于37℃反应30min，后加入含有内标(内标为十七烷酸，浓度为1nmol)的甲醇溶液200μL终止反应。液质联用(LC-MS)检测17:1FAE的水解产物17:1FA(即含有一个烯双键的17烯酸)的产量，用Graphpad Prism 5作图。以此测定得到待测化合物对内源性大麻素水解酶的IC50值。
采用上述方法，检测本发明制备的化合物1-46对NAAA和FAAH的抑制作用，结果如表1所示，其中IC50(NAAA)表示抑制NAAA活性至未抑制水平一半时的浓度，IC50(FAAH)表示抑制FAAH活性至未抑制水平一半时的浓度，“>100μM”表示化合物对相应的酶的IC50大于100μM，认为未对该酶有抑制作用。
表1
Figure PCTCN2015093140-appb-000068
Figure PCTCN2015093140-appb-000069
Figure PCTCN2015093140-appb-000070
Figure PCTCN2015093140-appb-000071
Figure PCTCN2015093140-appb-000072
Figure PCTCN2015093140-appb-000073
实验例2：疼痛实验
本实验例中用到的待评价化合物或待测化合物或受试化合物为本发明实施例制备的化合物1-46。本实验例中所有注射药物，包括待评价化合物或或待测化合物或受试化合物，以及阳性对照药物，均溶于PEG400：Tween 80：生理盐水(体积比为5:5:90)混合溶剂中，浓度为5mg/mL。
1.神经性疼痛实验例
坐骨神经分支选择损伤导致的小鼠神经性疼痛模型(SNI)是医学上常见的研究神经性疼痛的动物模型。本发明采用此模型对化合物的神经性疼痛的治疗效果进行评价，该模型可代表对于外周神经性疼痛包括但不限于疱疹感染后神经痛、糖尿病周围神经病变引发的疼痛、肿瘤引起的神经压迫和渗出、腰椎手术失败综合症、腰椎间盘突出致神经性疼痛、产后神经痛、三叉神经痛、化疗诱发多发性神经疼痛、放疗后神经从疾病、根性神经疼痛的治疗作用。
C57BL/6小鼠(购自上海斯莱克实验动物有限责任公司)腹腔注射戊巴比妥钠(40mg/kg)麻醉，将膝关节到臀部一块备皮消毒，固定后在膝关节部位用手术刀纵向切割1cm左右，钝性分离肌肉组织，暴露坐骨神经。小心将坐骨神经干的胫神经和腓总神经分支切断，之后缝合伤口，将小鼠放在干净的观察笼内。假手术组只暴露坐骨神经，不切断胫神经和腓总神经分支。实验前一天及术后24h后每天用动态足底触觉仪(意大利ugo basile公司，产品编号37450)刺激小鼠足底边缘，自动采集数据，获得小鼠对机械刺激的阈值。待评价化合物于测试前1h腹腔注射给药(10mg/kg)。阳性对照药物加巴喷丁 给药剂量为100mg/kg。所有注射药物均溶于PEG400：Tween 80：生理盐水(体积比为5:5:90)混合溶剂中，浓度为5mg/mL。通过比较不同给药时间及不同给药组的阈值变化(小鼠鼠爪撤回时的作用力大小)来评价化合物对神经病理性疼痛的镇痛效果。
采用上述方法，检测待评价化合物在SNI模型中的镇痛作用，结果如图1～3所示。由图1、2可知，化合物2、9、14均表现出显著的抑制中枢神经性疼痛的作用，而化合物24、30则未表现出抑制中枢神经性疼痛的作用。与阳性对照药物加巴喷丁相对比，在给药后1h，化合物2、9、14的作用不如对照药物，但给药后4h，上述化合物仍持续具有较强烈的抑制中枢神经性疼痛的作用，而对照药物加巴喷丁的作用逐渐消失。图3显示，化合物2在10h仍具有持续镇痛作用，作用持续时间远远大于对照药物。
2.腹腔炎性疼痛实验例
采用医学上常用的研究炎症所致内脏疼痛的典型模型对化合物的炎性内脏疼痛的治疗效果进行评价。该模型可代表一般内脏疼痛包括但不仅限于：阑尾炎、胃炎、胰腺炎、前列腺炎、心肌炎、间质性膀胱炎、肝胆肾结石诱发的疼痛；肠易激惹综合症；慢性骨盆疼痛综合症。
选择实验昆明小鼠(由厦门大学实验动物中心购自上海斯莱克实验动物有限责任公司)在实验环境中自由摄取食物和水分，适应一周。给药前禁食24h。在给予醋酸前1h，小鼠腹腔注射待评价化合物(10mg/kg)，阳性对照药物吲哚美辛给药剂量为20mg/kg，空白对照为生理盐水。于小鼠腹腔注射醋酸(50μL，醋酸溶于生理盐水，浓度为5％)，随后放入观察笼，用摄像机记录随后20分钟内小鼠的行为。疼痛行为学分析统计上述时间内小鼠发生扭体的次数。
由图4可知，化合物2、9、14均表现出显著的抑制腹腔炎性疼痛的作用，而化合物24、30则未表现出抑制腹腔炎性疼痛的作用。与阳性对照药物吲哚美辛相对比，本发明所涉及有效化合物在二分之一的剂量即可达到吲哚美辛的作用。
3.头痛实验例
硝酸甘油诱导的大鼠头痛模型是医学上常见的研究炎性疼痛的模型。本发明采用此模型对化合物的头痛的治疗效果进行评价。该模型可代表混合型疼痛包括但不仅限于：偏头痛、从集性头痛、紧张性头痛综合症、面痛、腰痛、肩膀痛、灼口综合症、复杂性局部疼痛综合症。
选择250g左右实验Wistar大鼠(购自上海斯莱克实验动物有限责任公司)在实验环境中自由摄取食物和水分，适应一周。给药前禁食24h。在给以硝酸甘油前1h，大鼠腹腔注射待评价化合物(10mg/kg)，阳性对照药物为空白对照为生理盐水。于大鼠颈部表皮处注射硝酸甘油(10mg/kg，硝酸甘油溶于生理盐水，浓度为5％)，随后放入观察笼，用摄像机记录随后60分钟内大鼠的行为。疼痛行为学分析统计大鼠挠头的次数。
采用上述方法，检测化合物2、9、14均表现出显著的抑制硝酸甘油所致大鼠头痛的 作用，而化合物24、30则未表现出抑制大鼠头痛的作用(参见附图5)。本发明所涉及有效化合物的作用效果优于阳性对照药物吲哚美辛。
4.佐剂诱导的骨关节炎性疼痛实验例
采用医学上常见的研究炎性疼痛的典型模型对待评价化合物的炎性疼痛的治疗效果进行评价。各组大鼠均于左后足趾皮内注射0.1mL弗氏完全佐剂诱发大鼠佐剂性关节炎模型,足容积法测原发侧及继发侧足肿胀度(肿胀度＝致炎后容积—致炎前容积),并进行多发性关节炎评分(5级评分：0分无红肿；4分包括踝关节在内的全部足爪红肿。根据未注射佐剂的其余3个肢体的病变程度累计积分,最高为12分)。致炎前及致炎后6h,12h,18h及24h用足趾容积测量仪检测大鼠致炎侧足容积,并计算其肿胀度。该模型可代表炎性疼痛包括但不仅限于：骨关节炎疼痛和纤维肌疼痛综合症、风湿及类风湿性关节炎的炎性疼痛、子宫内膜移位症的炎性疼痛、炎性牙痛、强直性脊柱炎疼痛、痛风性关节炎疼痛。
采用上述方法，检测化合物2、9、14(10mg/Kg)均表现出显著的抑制骨关节炎性疼痛的作用，本发明所涉及有效化合物的作用效果优于阳性对照药物吲哚美辛(10mg/Kg)。
各组大鼠原发性足肿胀度的比较参见表2。
表2
Figure PCTCN2015093140-appb-000074
注：与正常对照组比较，aP<0.01；与佐剂性关节炎模型组比较，bP<0.05；cP<0.01。
实验例3：稳定性实验
本实验例中用到的PBS溶液的配置方法为：8g NaCl，0.2g KCl，1.44g Na2HPO4，0.24g KH2PO4，溶解于1L超纯水中，湿热灭菌，4℃保存。
1.大鼠血浆条件下稳定性实验
取若干管已分装好的大鼠血浆，加入血浆体积四分之一体积的PBS溶液进行稀释混匀。取1.5毫升稀释好的大鼠血浆，加入待测化合物(化合物2、8、9、11、31、41)， 使化合物的终浓度为2μM，将含有化合物的血浆样品置于37℃恒温箱中孵育，于不同的时间点(0、10、30、60、120、240、360、720、1440分钟)分别取出50μL血浆样品加入150μL预冷的甲醇(含内标化合物E8，结构为
Figure PCTCN2015093140-appb-000075
命名为1-(2-Biphenyl-4-yl)ethyl-carbonyl pyrrolidine，1nmol/个样品)中，每个时间点做三个平行。后将样品涡旋混匀，于4℃、12000g离心10分钟，将上清液转移到进样瓶中。使用LC-MS/MS检测不同时间点峰面积，使用
Figure PCTCN2015093140-appb-000076
version 1.4.1.软件分析色谱峰，带入标准曲线中计算目标化合物的含量。
2.酸性、碱性条件下稳定性实验
取若干配置好的PBS，使用稀盐酸将其pH之调整至pH 5.0，或使用饱和氢氧化钠将其pH之调整至pH＝7.4，加入待测化合物(化合物2、8、9、11、31、41)，使待测化合物的终浓度为1μM，后将含有待测化合物的样品置于37℃恒温摇床中孵育，于不同的时间点(0min、10min、30min、1h、2h、4h、6h、12h、24h)分别取出50μL样品加入150μL预冷的甲醇(含内标E8，1nmol/个样品)中，每个时间点做三个平行。涡旋混匀后，将样品转移至进样瓶中，使用LC-MS/MS检测不同时间点的峰面积，使用
Figure PCTCN2015093140-appb-000077
version 1.4.1.软件分析色谱峰，带入标准曲线中计算目标化合物的含量。
由表3可知，本发明所涉及有效化合物在酸、碱性条件下半衰期均大于24小时，大鼠血浆中半衰期均大于120分钟，稳定性远远超过已报道的β-丁内酯类NAAA抑制剂(β-丁内酯类NAAA抑制剂大鼠血浆半衰期小于15分钟)。
3.大鼠体内药物代谢实验
使用50只SD大鼠(购自上海斯莱克实验动物有限责任公司)，将大鼠随机分为5组，每组10只。乙醚麻醉后仰卧固定在手术台上，剃去颈部手术部位的毛，用75％的酒精消毒后，在颈部作一长约1.5厘米的纵形皮肤切口，钝性分离气管周围的肌肉组织及血管神经，钝性分离颈动脉。结扎远心端，近心端用动脉夹夹住，两者间间距约1厘米，紧贴细线结扎处近心端用眼科剪剪一小口将动脉导管由小口向近心端插入，松开动脉夹，用无齿镊夹住动脉口同时将动脉导管向心室方向送，待导管入心室后，用细线将导管血管结扎。使用和动脉同样的插管方法，对颈静脉进行插管。插管完成后，用充满肝素钠的细管从动脉和静脉引出，从大鼠耳下皮肤穿过到大鼠颈部北侧皮肤引出，并将细导管固定好，缝合大鼠手术部位的肌肉和皮肤，并不时往联通动脉和静脉的细导管中推入含肝素钠的生理盐水，以防导管因凝血而堵塞，并将放置在温暖、干净的鼠笼中，准备好水和食物，等待大鼠自然苏醒。
大鼠苏醒活动正常后，进行化合物大鼠体内代谢稳定性实验。所有注射药物(包括待测化合物和对照药物)均溶于PEG400：Tween 80：生理盐水(体积比为5:5:90)混 合溶剂中，浓度为5mg/mL。从颈静脉引出的导管中以30mg/Kg剂量给药，缓慢推入，给药完毕后开始计时。分别于2、5、10、20、30、60、240、360、720分钟从颈动脉引出的导管中取血，每次取血200μL，将全血置于商购肝素钠采血管(江西精致医疗器材有限公司)中，1800g离心15分钟，取上层血浆加入预冷的150μL甲醇终止液(含内标E8，1nmol/个样品)，涡旋混匀后于4℃、12000g离心10分钟。将上清液转移到进样瓶中使用LC-MS/MS检测目标化合物，带入标准曲线计算化合物含量。
如表3所示，本发明所涉及有效化合物在大鼠体内代谢半衰期在60-300分钟，稳定性远远超过已报道的β-丁内酯类NAAA抑制剂(β-丁内酯类NAAA抑制剂大鼠体内代谢半衰期小于5分钟)。
表3
Figure PCTCN2015093140-appb-000078
实验例4：细胞毒性实验
本实验例中用到的PBS溶液的配置方法为：8g NaCl，0.2g KCl，1.44g Na2HPO4，0.24g KH2PO4，溶解于1L超纯水中，湿热灭菌，4℃保存。
取生长状态良好的RAW264.7细胞(购自American Type Culture Collection，ATCC，北京)，密度达到80％-90％左右，用细胞刮刀刮下制成细胞悬液。经计数后，精确地将细胞接种于96孔培养板内，每孔100μL，细胞总数保持一致，约20000个/孔，加入培养液(培养液为含有10％胎牛血清(PAA)、1％双抗(PAA)的DMEM(Gibco，上海)培养液)的量也要一致。将培养板放在培养箱内预培养24小时(37℃，5％CO2)。为防止实验组培养液的蒸发，实验孔四周的边缘孔用等量的PBS填充，但不接种细胞。细胞铺板12小时后，吸去旧培养液，向培养板加入100μL用培养液稀释的不同浓度的化合物2、9(浓度分别为3、10、30、100μM)，对照组加入等量的DMSO作为对照，每孔三个平行。将培养板在培养箱孵育一段时间，24或48小时。向每孔加入10μL CCK8溶液。将培养板在培养箱内孵育1.5小时。用酶标仪测定在450nm处的吸光度OD值，OD值与活细胞数量成正比。将各组OD值与空白组的OD值相比得到细胞的存活率。 细胞活力×100％＝【OD值(给药组)-OD值(空白组)】/【OD值(对照组)-OD值(空白组)】×100％。
实验结果显示，除100μM高浓度化合物9外，其他不同浓度的化合物2、9与细胞孵育24h(参见附图6A)和48h(参见附图6B)后对细胞活力完全没有影响。
实验例5：斑马鱼胚胎早期发育毒性实验
将受精卵(厦门大学生命科学学院斑马鱼研究组惠赠)置于新配置的斑马鱼胚胎培养液中培养，每天需更换新鲜的培养液，于28.5℃的培养箱中培养，培养箱中放置纯水，保证培养环境一定的湿度。斑马鱼胚胎培养液配方为：5mM NaCl,0.17mM KCl,0.33mM CaCl2,0.33mM MgSO4,10-5％Methylene Blue。培养液用纯水配置，例如配置1L的培养液需NaCl：292.2mg、KCl：12.68mg、CaCl2：36.63mg、MgSO4：39.72mg、亚甲基蓝：0.1μL。
每个测试物分为7组，包括5个含不同浓度药物的实验组(受试药物用斑马鱼胚胎培养液配制成不同浓度的溶液)，浓度分别为：10mg/L、3mg/L、1mg/L、0.3mg/L、0.1mg/L)，1个助溶剂对照组(DMSO)和1个空白对照组。阳性对照药物采用OTC解热镇痛药物布洛芬，浓度同上所述。采96孔细胞培养板进行实验，每个实验组三个平行，每个平行10个鱼卵。
配制含药培养液，事先将含药培养液加入96孔板中，然后将每个受精卵(参照OECD212号文件中的实验方法，挑选受精后2h内发育正常的受精卵进行暴露，肉眼可见透明的鱼卵即为正常受精，发白的鱼卵已死亡，弃去，挑完受精卵后在显微镜下观察可见正常发育的受精卵细胞已经开始分裂)独立的放置在不同的孔中，将受精卵置于不同浓度的含药实验溶液中培养，观察并用倒置显微镜拍照记录不同时期胚胎发育的状况。包括：
I、形态学观察，观察并拍照2h、4h、8h、12h，24h、48h、72h、96h受精卵发育情况(卵黄是否凝结、眼点、心包囊水肿情况、有无血流和尾部发育状况等)；
II、统计72h受精卵孵化数和死亡数，计算孵化率(hatching rate)和致死率(mortality)；
III、测量72h孵化出的幼鱼的体长(倒置显微镜拍照后测量)；
IV、72h后胚胎畸形情况(畸形表现：没有黑色素的形成，卵黄囊病，脊柱弯曲，眼睛缺陷，尾部缺陷，心率降低，孵化率降低等)
V、记录受精后72h和96h幼鱼的心跳(次数/min)(记录方法：显微镜下可清晰的观察到幼鱼的心跳，计时30s，记录幼鱼心跳的次数)
实验结果显示，浓度为1mg/L时，化合物2和化合物9这两组72h孵化率分别高达96.67％、90％，而布洛芬组仅为56.67％，在0.3mg/L和0.1mg/L下，化合物2和化合物9这两72h孵化率均显著高于布洛芬组，死亡率明显低于布洛芬组(见表4)。以 上研究结果表明，在剂量小于3mg/L时，化合物2、化合物9对斑马鱼胚胎发育的毒性显著低于布洛芬。
表4、化合物2、9与布洛芬对斑马鱼孵育、心跳、体长等参数影响
Figure PCTCN2015093140-appb-000079
Figure PCTCN2015093140-appb-000080
实验例6：斑马鱼胚胎发育短期急性毒性实验
斑马鱼受精卵培养方法同上所述。实验分为7组，包括5个含不同浓度药物的实验组(受试药物用斑马鱼胚胎培养液配制成不同浓度的溶液)，浓度分别为：100mg/L、10mg/L、1mg/L、0.1mg/L、0.01mg/L)，1个助溶剂对照组(DMSO)和1个空白对照组。将受精卵置于28.5℃的培养箱中培养，保证培养环境一定的湿度。配制含受试药物培养液，事先将含药培养液加入96孔板中，然后将每个受精卵(参照OECD 212号文件中的实验方法，挑选受精后24小时发育正常的受精卵进行暴露，肉眼可见透明的鱼卵即为正常受精，发白的鱼卵已死亡，弃去，挑完受精卵后在显微镜下观察可见正常发育的受精卵细胞已经开始分裂)独立的放置在不同的孔中，将受精卵置于不同浓度的含 药实验溶液中培养，观察并用倒置显微镜拍照记录不同时期胚胎发育的状况。包括：
I、形态学观察，观察并拍照48h、72h、96h受精卵发育情况(卵黄是否凝结、眼点、心包囊水肿情况、有无血流和尾部发育状况等)；
II、统计72h受精卵孵化数和死亡数，计算孵化率(hatching rate)和致死率(mortality)；
III、测量72h孵化出的幼鱼的体长(倒置显微镜拍照后测量)；
IV、72h后胚胎畸形情况(畸形表现：没有黑色素的形成，卵黄囊病，脊柱弯曲，眼睛缺陷，尾部缺陷，心率降低，孵化率降低等)
V、记录受精后72h和96h幼鱼的心跳(次数/min)(记录方法：显微镜下可清晰的观察到幼鱼的心跳，计时30s，记录幼鱼心跳的次数)
实验结果显示，溶剂对照组和空白组斑马鱼发育正常。暴露于10mg/L布洛芬的斑马鱼胚胎72h孵化率为0，死亡率为100％，并且布洛芬组72h的孵化率随剂量的增高而降低；同等剂量化合物2、化合物9，斑马鱼胚胎的孵化率均为93.3％，剂量低于10mg/L时对其孵化率几乎没有影响(表5)。仅当F96浓度大于10mg/L才会对斑马鱼胚胎的72h孵化率和死亡率才会有显著的影响；而布洛芬在较小浓度0.01mg/L时就会影响斑马鱼72h孵化率，1mg/L时就使斑马鱼的孵化率降低一半左右，并且随着布洛芬浓度的增大影响更加显著。
表5、化合物2、9与布洛芬对斑马鱼孵育、心跳、体长等参数影响
Figure PCTCN2015093140-appb-000081
Figure PCTCN2015093140-appb-000082
Figure PCTCN2015093140-appb-000083
进一步观察斑马鱼胚胎发育的整个过程发现，100mg/L，48h时化合物2和化合物9这两组斑马鱼胚胎并未出现死亡现象，但胚胎出现心包囊水肿、无心跳、无血流且尾部不发育等现象；而同等剂量布洛芬组斑马鱼胚胎则全部死亡。10mg/L，48h时化合物2、9组斑马鱼胚胎发育基本正常；而布洛芬组斑马鱼则出现心包囊水肿、无心跳、无血流和尾部不发育的现象。布洛芬组在1mg/L、72h时发育迟缓，孵化率仅为56.7％，部分斑马鱼的心包囊出现轻度水肿现象。同等剂量化合物2、9则无任何影响。
实验例7：化合物2、9、34与COX2选择性抑制剂塞来昔布对hERG钾通道作用实验
CHO-hERG细胞(购于ATCC)培养于培养瓶中，待细胞密度生长到60～80％，移走培养液(含10％胎牛血清的Glutamax DMEM/F12培养基(Gibco,上海))，用7mLPBS洗一遍，然后加入3mLDetachin细胞消化液消化，待消化完全后加入7mL培养液中和，离心，吸去上清液，加入5mL培养液重悬，以确保细胞密度为2～5×106/mL。
细胞内液和细胞外液按下表组成配制。
Figure PCTCN2015093140-appb-000084
按下述浓度取一定量化合物溶解于细胞外液，配制化合物母液。取2μL化合物母液加入998μL细胞外液，在含0.2％DMSO的细胞外液中依次进行5倍连续稀释得到需要测试的最终浓度。受试药物最高测试浓度为40μM，依次分别为40μM，8μM，1.6μM，0.32μM，0.064μM，0.0128μM共6个浓度。阳性化合物cisapride(西沙比利)最高测 试浓度为3μM，依次分别为3μM，0.6μM，0.12μM，0.024μM，0.0048μM，0.00096μM共6个浓度。最终测试浓度中的DMSO含量不超过0.2％，此浓度的DMSO对hERG钾通道没有影响。
单细胞高阻抗封接和全细胞模式形成过程全部由Qpatch HT高通量全自动膜片钳系统(Sophion)自动完成，在获得全细胞记录模式后，细胞钳制在-80毫伏，在给予5秒的+20毫伏去极化刺激前，先给予50毫秒的-50毫伏前置电压，然后复极化到-50毫伏维持5秒，再回到-80毫伏。每15秒施加此电压刺激，记录2分钟后给予细胞外液记录2分钟，然后开始给药过程，受试药物浓度从最低测试浓度开始，每个测试浓度给予2分钟，连续给完所有浓度后，给予阳性对照化合物西沙比利。每个浓度至少测试3个细胞(n≥3)。实验数据使用XLFit软件进行分析。
实验结果显示西沙比利对hERG钾通道的半数抑制浓度为0.1μM，塞来昔布对hERG钾通道的半数抑制浓度为6.4μM，而化合物2、9、34在实施评价的最大浓度40μM时对hERG钾通道的最大抑制率分别为38.30％、31.42％、44.67％(表6)。这表明化合物2、9、34在高浓度时对hERG钾通道抑制率低，比市场常用解热镇痛药物COX2选择性抑制剂塞来昔布具有更好的心脏安全性。
表6化合物2、9、34和塞来昔布、西沙比利对hERG钾通道的抑制作用。
Figure PCTCN2015093140-appb-000085
尽管本发明的具体实施方式已经得到详细的描述，本领域技术人员将会理解。根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。

Claims (22)

  1. 式I所示化合物、其可药用的盐、水合物或溶剂合物，
    Figure PCTCN2015093140-appb-100001
    其中，
    X选自：C、N、O；
    Y选自：C、N；
    A选自：R12、OR6、N R7R8或CR9R10R11；
    R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11独立选自：-H、＝O、＝NOR’、卤素、卤代基、多卤代基、-(CH2)nCN、-(CH2)nNO2、-(CH2)nR’、-(CH2)nCOOR’、-(CH2)nCONR’2、-(CH2)nOR’、-(CH2)nSR’、-(CH2)nSOR’、-(CH2)nSO2R’、-(CH2)nNR’2、-(CH2)nNR’COR’或-(CH2)nNR’SO2R’；
    R12为-(CH2)nR13；
    R13选自：H、C1-10直链或支链烷基、苯基、噻吩基、呋喃基、C4-6环烷基、联苯基、苯氧基苯基、苄氧基苯基、苯基乙氧基苯基、哌啶基、N-苯甲基哌啶基、萘基、吲哚基、尿嘧啶基，其任选地被1或2个选自以下的取代基取代：卤素、甲基、羟基、C1-6烷基、C1-6烷氧基、羟基、硝基、三氟甲基、氰基、被卤素单取代或多取代的C1-6烷基、被卤素单取代或多取代的C1-6烷氧基。
    n为选自0～10的整数；
    各个R’独立为H或选自含有20个C原子以内的各种取代或未取代的直链烷基、支链烷基、环烷基、环杂烷基、烯基、炔基、直链杂烷基、支链杂烷基、杂环烷基、杂烯基、杂炔基、杂环基或芳香基。
  2. 式Ia所示化合物、其可药用的盐、水合物或溶剂合物，
    Figure PCTCN2015093140-appb-100002
    其中：
    X为O或N；
    Y为N；
    n为选自0～7的整数；
    R4为H、甲基、卤素、C1-6烷基、C1-6烷氧基、羟基、硝基、三氟甲基、氰基、CH3C(＝O)CH2-或(CH3)2NCH2-；
    R13选自：H、C1-10直链或支链烷基、苯基、噻吩基、呋喃基、C4-6环烷基、联苯基、苯氧基苯基、苄氧基苯基、苯基乙氧基苯基、哌啶基、N-苯甲基哌啶基、萘基、吲哚基、尿嘧啶基，其任选地被1或2个选自以下的取代基取代：卤素、甲基、羟基、C1-6烷基、C1-6烷氧基、羟基、硝基、三氟甲基、氰基、被卤素单取代或多取代的C1-6烷基、被卤素单取代或多取代的C1-6烷氧基。
  3. 权利要求2的式Ia所示化合物、其可药用的盐、水合物或溶剂合物，其中：
    X为O或N；
    Y为N；
    n为选自0～7的整数；
    R4为H、甲基、卤素、C1-4烷基、C1-4烷氧基、羟基、硝基、三氟甲基、氰基、CH3C(＝O)CH2-或(CH3)2NCH2-；
    R13选自：H、C1-8直链或支链烷基、苯基、噻吩基、呋喃基、环己基、联苯基、苯氧基苯基、苄氧基苯基、苯基乙氧基苯基、哌啶基、N-苯甲基哌啶基、萘基、吲哚基、尿嘧啶基，其任选地被1或2个选自以下的取代基取代：卤素、甲基、羟基、C1-4烷基、C1-4烷氧基、羟基、硝基、三氟甲基、氰基、被卤素单取代或多取代的C1-4烷基、被卤素单取代或多取代的C1-4烷氧基。
  4. 权利要求2的式Ia所示化合物、其可药用的盐、水合物或溶剂合物，其中：
    X为O或N；
    Y为N；
    n为0、1、2、3、4、5、6或7；
    R4为H、甲基、卤素、C1-4烷基、C1-4烷氧基、羟基、硝基、三氟甲基、氰基、CH3C(＝O)CH2-或(CH3)2NCH2-；
    R13选自以下取代基：H、含有8个碳原子的直链或支链烷基、
    Figure PCTCN2015093140-appb-100003
    Figure PCTCN2015093140-appb-100004
  5. 权利要求2的式Ia所示化合物、其可药用的盐、水合物或溶剂合物，其中：
    X为O或N；
    Y为N；
    n为4、5、6或7；
    R4为H、甲基、卤素、C1-4烷基、C1-4烷氧基、羟基、硝基、三氟甲基、氰基或CH3C(＝O)CH2-；
    R13选自以下取代基：H、含有8个碳原子的直链烷基、
    Figure PCTCN2015093140-appb-100005
  6. 权利要求2的式Ia所示化合物、其可药用的盐、水合物或溶剂合物，其中：
    X为O或N；
    Y为N；
    n为4、5、6或7；
    R4为H、甲基或CH3C(＝O)CH2-；
    R13选自以下取代基：H、含有8个碳原子的直链烷基、
    Figure PCTCN2015093140-appb-100006
  7. 权利要求2的式Ia所示化合物、其可药用的盐、水合物或溶剂合物，其中：
    X为O；
    Y为N；
    n为4、5、6或7；
    R4为H、甲基、卤素、C1-4烷基、C1-4烷氧基、羟基、硝基、三氟甲基、氰基或CH3C(＝O)CH2-；
    R13选自以下取代基：H、含有8个碳原子的直链烷基、
    Figure PCTCN2015093140-appb-100007
  8. 权利要求2的式Ia所示化合物、其可药用的盐、水合物或溶剂合物，其中：
    X为O；
    Y为N；
    n为4、5、6或7；
    R4为H、甲基或CH3C(＝O)CH2-；
    R13选自以下取代基：H、含有8个碳原子的直链烷基、
    Figure PCTCN2015093140-appb-100008
  9. 权利要求2的式Ia所示化合物、其可药用的盐、水合物或溶剂合物，其中：
    X为O；
    Y为N；
    n为0或1；
    R4为H、甲基、卤素、C1-4烷基、C1-4烷氧基、羟基、硝基、三氟甲基、氰基或(CH3)2NCH2-；
    R13选自以下取代基：H、含有8个碳原子的直链或支链烷基、
    Figure PCTCN2015093140-appb-100009
  10. 权利要求2的式Ia所示化合物、其可药用的盐、水合物或溶剂合物，其中：
    X为O；
    Y为N；
    n为0或1；
    R4为H或(CH3)2NCH2-；
    R13选自以下取代基：H、含有8个碳原子的直链或支链烷基、
    Figure PCTCN2015093140-appb-100010
  11. 权利要求1-4任一项的化合物、其可药用的盐、水合物或溶剂合物，其选自以下化合物：
    Figure PCTCN2015093140-appb-100011
    Figure PCTCN2015093140-appb-100012
    Figure PCTCN2015093140-appb-100013
    Figure PCTCN2015093140-appb-100014
    Figure PCTCN2015093140-appb-100015
  12. 制备权利要求2-11任一项的式Ia所示化合物、其可药用的盐、水合物或溶剂合物的方法，包括：
    在溶液中，式II所示化合物与式III所示化合物反应获得式Ia所示化合物，
    Figure PCTCN2015093140-appb-100016
    其中X、Y、R4、R13以及n的定义如权利要求2所述。
  13. 权利要求12的制备方法，其中所述的溶液为含有正丁锂的溶液，反应温度为-78℃～0℃。
  14. 药物组合物，其至少含有一种权利要求1-12任一项所述的化合物、其可药用的盐、水合物或溶剂合物，和药学上可接受的辅料。
  15. 治疗疾病或病症或减轻所述疾病或病症严重性的方法，所述方法包括给予需要这种治疗的患者治疗有效量的至少一种权利要求1-12任一项的化合物、其可药用的盐、水合物或溶剂合物。
  16. 权利要求1-12任一项的化合物、其可药用的盐、水合物或溶剂合物在制备用于治疗疾病或病症或减轻所述疾病或病症严重性的药物中的用途。
  17. 权利要求1-12任一项的化合物、其可药用的盐、水合物或溶剂合物，用于治疗疾病或病症或减轻所述疾病或病症严重性。
  18. 权利要求15的方法、权利要求16的用途或权利要求17的化合物、其可药用的盐、水合物或溶剂合物，其中所述疾病或病症为疼痛。
  19. 权利要求18的方法、用途或化合物、其可药用的盐、水合物或溶剂合物，其中所述的疼痛包括但不限于神经性疼痛(包括但不限于中枢神经性疼痛、外周神经性疼痛)、炎性疼痛(包括但不仅限于骨关节炎疼痛、纤维肌疼痛综合症、风湿及类风湿性关节炎的炎性疼痛、子宫内膜移位症的炎性疼痛、炎性牙痛、强直性脊柱炎疼痛、痛风性关节炎疼痛、内脏炎性疼痛)、混合型疼痛(包括但不仅限于腰痛、肩膀痛、灼口综合症、复杂性局部疼痛综合症、偏头痛、从集性头痛、紧张性头痛综合症、面痛)。
  20. 权利要求19的方法、用途或化合物、其可药用的盐、水合物或溶剂合物，其中所述的外周神经性疼痛包括但不限于疱疹感染后神经痛、糖尿病周围神经病变引发的疼痛、肿瘤引起的神经压迫和渗出、腰椎手术失败综合症、腰椎间盘突出致神经性疼痛、产后神经痛、三叉神经痛、化疗诱发多发性神经疼痛、放疗后神经从疾病、根性神经疼痛。
  21. 权利要求19的方法、用途或化合物、其可药用的盐、水合物或溶剂合物，其中所述的中枢神经性疼痛包括但不限于脊柱硬化引起的压迫性疼痛、多发性硬化相关疼痛、帕金森症相关疼痛、痴呆症相关疼痛、中风后疼痛、脊髓损伤后疼痛。
  22. 权利要求19的方法、用途或化合物、其可药用的盐、水合物或溶剂合物，其中所述的内脏炎性疼痛包括但不仅限于：阑尾炎、胃炎、胰腺炎、前列腺炎、心肌炎、间质性膀胱炎、肝胆肾结石诱发的疼痛、肠易激惹综合症、慢性骨盆疼痛综合症。
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