WO2017114225A1 - 稠合三环γ-氨基酸衍生物及其制备方法和在医药上的应用 - Google Patents

稠合三环γ-氨基酸衍生物及其制备方法和在医药上的应用 Download PDF

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WO2017114225A1
WO2017114225A1 PCT/CN2016/110946 CN2016110946W WO2017114225A1 WO 2017114225 A1 WO2017114225 A1 WO 2017114225A1 CN 2016110946 W CN2016110946 W CN 2016110946W WO 2017114225 A1 WO2017114225 A1 WO 2017114225A1
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group
alkyl
substituted
compound
acid
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PCT/CN2016/110946
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French (fr)
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李瑶
石宗军
徐波
李升�
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四川海思科制药有限公司
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Priority to CN201680042081.9A priority Critical patent/CN107848952B/zh
Publication of WO2017114225A1 publication Critical patent/WO2017114225A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/28—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/32—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a fused tricyclic ⁇ -amino acid derivative represented by the formula (I), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.
  • Pharmaceutical compositions and uses in the field of analgesia are particularly useful.
  • the voltage-gated calcium channel is composed of an ⁇ 1 subunit and an auxiliary protein ⁇ 2 ⁇ , ⁇ , and ⁇ subunits.
  • the ⁇ 2 ⁇ protein regulates calcium channel density and calcium channel voltage-dependent kinetics (Felix et al (199 7) J. Neuroscience 17:6884-6891; Klugbauer et al (1999) J. Neuroscience 19:684-691; Hobom et Al (2000) Eur. J. Neuroscience 12: 1217-1226; and Qin et al (2002) Mol. Pharmacol. 62: 485-496).
  • Compounds that exhibit high affinity binding to the voltage-dependent calcium channel subunit ⁇ 2 ⁇ have been shown to be effective in the treatment of pain, such as pregabalin and gabapentin.
  • the ⁇ 2 ⁇ protein has four subtypes, each of which is encoded by a different gene.
  • ⁇ 2 ⁇ subtype 1 and subtype 2 showed high affinity with pregabalin, while ⁇ 2 ⁇ subtype 3 and subtype 4 showed no significant drug binding.
  • WO2002085839 describes bicyclic amino acid analogs and derivatives, prodrugs thereof and pharmaceutically acceptable salts and solvates thereof for treating diseases such as epilepsy, neurodegenerative disorders, pain and the like, wherein R 1 and R 2 are each independently selected from hydrogen, a C 1-6 linear or branched alkyl group, a C 3-6 cycloalkyl group, a phenyl group or a benzyl group, and in the formula (XVII), R 1 and R 2 are simultaneously hydrogen, and the invention and the compound of the invention
  • R 1 and R 2 are simultaneously hydrogen, and the invention and the compound of the invention
  • the structural differences are large and it is not considered that the specific description in this patent is part of the present invention, and the compounds of the formula are as follows:
  • WO2004031124 describes an amino acid derivative of the formula wherein the invention is as an intermediate, wherein n is selected from 0, 1 or 2, R 1 , R 1a , R 2 , R 2a , R 3 , R 3a And R 4 and R 4a are each independently selected from hydrogen, C 1-6 straight or branched alkyl, or R 1 and R 2 , or R 2 and R 3 are bonded to form optionally 1 or 2 C 1-
  • the 6- alkyl-substituted C 3-7 cycloalkyl group has a large difference in structure from the compound of the present invention, and it is not considered that the specific description in this patent is a part of the present invention, and the compound of the formula is as follows:
  • WO2009041453 describes fused ring gamma-amino acid derivatives or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 2 ', R 4 , R 5 , R 6 , R 7 , R 8 , R 8 ' Each independently selected from hydrogen, halogen, C 1-6 alkyl or R 2 and R 2 ' together with the carbon atom to which they are bonded form a C 3-7 cycloalkyl group, R 3 is hydrogen, halogen, C 1-6 alkane Group, C 1-6 alkyl halide group, hydroxy C 1-6 alkyl group, sulfanyl C 1-6 alkyl group, C 1-6 alkoxy C 1-6 alkyl group, C 2-6 alkenyl group , C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylsulfanyl, C 1-6 alkylsulfanyl C 1-6 alkyl, C 2-7 acylthio C 1-6 alky
  • WO2010079668 describes the pain treatable fused ring ⁇ - amino acid derivative or a pharmaceutically acceptable salt thereof, wherein R 1, R 5 are each independently selected from hydrogen or C 1-6 alkyl, R 2, R 3, R 4 , and R 4 ' are each independently selected from a hydrogen atom, a C 1-6 alkyl group or a C 3-6 cycloalkyl group, or R 4 and R 4 ' combine to form a C 3-6 cycloalkyl group, and R 6 is selected from hydrogen, C 1-6 alkyl or amino protecting group, R 7 is selected from hydrogen, C 1-6 alkyl or carboxy protecting group, and R 8 and R 8 ' are the same or different and are each independently selected from hydrogen, halogen, C 1- a 6 alkylthio group, a C 1-6 alkoxy group or a C 1-6 sulfanyl group, or R 8 and R 8 ' together with a carbon atom to which they are bonded form a C 3-6 cycloalkyl group,
  • the object of the present invention is to provide a fused tricyclic ⁇ -amino acid derivative having novel structure and good medicinal effect, or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts thereof, eutectic or Prodrugs, pharmaceutical compositions thereof and their use in the field of analgesia.
  • the present invention relates to a compound of the formula (I), or all stereoisomers, solvates, prodrug metabolites, pharmaceutically acceptable salts or co-crystals thereof:
  • R 1 , R 2 , R 2′ , R 3 , R 4 , R 4′ or R 5 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, cyano, C 1-6 alkyl, C a 1-6 alkoxy group, a C 1-6 sulfanyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a 3 to 6 membered carbocyclic group or a 3 to 6 membered heterocyclic group, said alkyl group Or alkoxy, sulfanyl, alkenyl, alkynyl, carbocyclyl or heterocyclyl optionally further from 0 to 6 selected from F, Cl, Br, I, hydroxy, C 1-6 alkyl or Substituted to a 6-membered carbocyclic group containing 1 to 2 heteroatoms selected from N, O or S;
  • R 1 and R 2 , R 2 and R 2 ′ , R 2 and R 3 , R 3 and R 4 , R 4 and R 4 ′ , R 4 and R 5 may be bonded to any atom to which they are bonded. form a double bond, the double bond optionally is further substituted with 0 to 2 substituents selected from F, Cl, Br, I, C 1-6 alkyl, substituted with 1-3 halo or C 1-6 alkyl 3 Substituted to a 6-membered carbocyclic group, said halogen is selected from F, Cl or Br;
  • R 2 and R 2′ , R 3 and R 4 , R 4 and R 4′ , R 4 and R 5 together with a carbon atom to which they are attached form a 3 to 6 membered carbocyclic group, said carbon
  • the ring group is optionally further substituted with from 0 to 6 selected from the group consisting of F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 thioalkyl;
  • R 6 is selected from H, C 1-6 alkyl or amino protecting group
  • R 7 is selected from H, C 1-6 alkyl or a carboxy protecting group.
  • Preferred embodiments of the invention include a compound of the formula (I), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs thereof:
  • R 1 , R 2 , R 2 ' , R 3 , R 4 , R 4 ' or R 5 are each independently selected from the group consisting of H, F, Cl, Br, hydroxy, C 1-6 alkyl, C 1-4 alkoxy a group, C 1-4 sulfanyl, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 6 membered carbocyclyl or 3 to 6 membered heterocyclic, preferably R 1 , R 2 , R 2' , R 3 , R 4 , R 4' or R 5 are each independently selected from the group consisting of H, F, Cl, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, a C 2-4 alkynyl group or a 3 to 6 membered carbocyclic group, more preferably, R 1 , R 2 , R 2 ' , R 3 , R 4 , R 4 ' or R 5 are each independently selected from H, F,
  • R 1 and R 2 , R 2 and R 2 ′ , R 2 and R 3 , R 3 and R 4 , R 4 and R 4 ′ , R 4 and R 5 may be bonded to any atom to which they are bonded. form a double bond, the double bond optionally is further substituted with 0 to 2 substituents selected from F, Cl, Br, I, C 1-6 alkyl, substituted with 1-3 halo or C 1-6 alkyl 3 Substituted to a 6-membered carbocyclic group, preferably further substituted with 0 to 2 selected from F, Cl, Br or C 1-4 alkyl, said halogen selected from F, Cl or Br;
  • the cyclo group is optionally further substituted by 0 to 6 selected from F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 thioalkyl, preferably further 0 to 4 substituents selected from F, Cl, Br, C 1-4 alkyl, C 1-4 alkoxy or C 1-4 thioalkyl, more preferably further from 0 to 4 selected from F, Cl or C Substituted by 1-4 alkyl;
  • R 6 is selected from H, C 1-4 alkyl or an amino protecting group
  • R 7 is selected from H, C 1-4 alkyl or a carboxy protecting group.
  • Preferred embodiments of the invention include a compound of the formula (I), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs thereof:
  • R 1 , R 2 , R 2 ' , R 3 , R 4 , R 4 ' or R 5 are each independently selected from the group consisting of H, F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, isopropyl , n-Butyl, sec-butyl, neobutyl, tert-butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CHFCH 3 , CHFCH 2 F, hydroxymethyl, hydroxyethyl, methoxy Base, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl Base or cyclohexyl;
  • R 1 and R 2 , R 2 and R 2 ′ , R 2 and R 3 , R 3 and R 4 , R 4 and R 4 ′ , R 4 and R 5 may be bonded to any atom to which they are bonded.
  • Forming a double bond the double bond optionally further being 0 to 2 selected from the group consisting of F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, new Substituted by butyl, tert-butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CHFCH 3 , CHFCH 2 F, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
  • R 2 and R 2′ , R 3 and R 4 , R 4 and R 4′ , R 4 and R 5 together with a carbon atom to which they are attached form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, Cyclohexyl, fluorocyclopropyl, 2,2-difluorocyclopropyl, fluorocyclobutyl, fluorocyclopentyl, cyclobutyl-2-alkenyl, cyclopentyl-2-alkenyl, Cyclohexyl-2-alkenyl;
  • R 6 is selected from the group consisting of H, methyl, ethyl, and t-butyl;
  • R 7 is selected from the group consisting of H, methyl, ethyl, and t-butyl.
  • Preferred embodiments of the invention include compounds of the formula (Ia) or (Ib), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs thereof:
  • R 1 , R 2 , R 2′ , R 3 , R 4 , R 4′ or R 5 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 sulfanyl, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 6 membered carbocyclic or 3 to 6 membered heterocyclic, preferably R 1 , R 2 , R 3 , R 4 or R 5 are each independently selected from the group consisting of H, F, Cl, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2 - 4 alkynyl or a 3 to 6 membered carbocyclic group, more preferably, R 1 , R 2 , R 3 , R 4 or R 5 are each independently selected from H, F, hydroxy, C 1-4 alkyl, C 1 a 4 -alkoxy group,
  • R 1 and R 2 , R 2 and R 2 ′ , R 2 and R 3 , R 3 and R 4 , R 4 and R 4 ′ , R 4 and R 5 may be bonded to any atom to which they are bonded. form a double bond, the double bond optionally is further substituted with 0 to 2 substituents selected from F, Cl, Br, I, C 1-6 alkyl, substituted with 1-3 halo or C 1-6 alkyl 3 Substituted to a 6-membered carbocyclic group, said halogen is selected from F, Cl or Br;
  • the cyclo group is optionally further substituted by 0 to 6 selected from F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy or C 1-6 thioalkyl, preferably further 0 to 4 substituents selected from F, Cl, Br, C 1-4 alkyl, C 1-4 alkoxy or C 1-4 thioalkyl, more preferably further from 0 to 4 selected from F, Cl or C Substituted by 1-4 alkyl;
  • R 6 is selected from H, C 1-6 alkyl or amino protecting group, preferably H or C 1-6 alkyl;
  • R 7 is selected from H, C 1-6 alkyl or a carboxy protecting group, preferably H or C 1-6 alkyl.
  • Preferred embodiments of the invention include compounds of the formula (Ia) or (Ib), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs thereof:
  • R 1 , R 2 , R 2 ' , R 3 , R 4 , R 4 ' or R 5 are each independently selected from the group consisting of H, F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, isopropyl , n-Butyl, sec-butyl, neobutyl, tert-butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CHFCH 3 , CHFCH 2 F, hydroxymethyl, hydroxyethyl, methoxy Base, ethoxy, propoxy, isopropoxy, methylthio, thio, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl Base or cyclohexyl;
  • R 1 and R 2 , R 2 and R 2 ′ , R 2 and R 3 , R 3 and R 4 , R 4 and R 4 ′ , R 4 and R 5 may be bonded to any atom to which they are bonded.
  • Forming a double bond the double bond optionally further being 0 to 2 selected from the group consisting of F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, new Substituted by butyl, tert-butyl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CHFCH 3 , CHFCH 2 F, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
  • R 2 and R 2′ , R 3 and R 4 , R 4 and R 4′ , R 4 and R 5 together with a carbon atom to which they are attached form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, Cyclohexyl, fluorocyclopropyl, 2,2-difluorocyclopropyl, fluorocyclobutyl, fluorocyclopentyl, cyclobutyl-2-alkenyl, cyclopentyl-2-alkenyl, Cyclohexyl-2-alkenyl;
  • R 6 is selected from the group consisting of H, methyl, ethyl, and t-butyl;
  • R 7 is selected from the group consisting of H, methyl, ethyl, and t-butyl.
  • Preferred embodiments of the invention include compounds of the formula (I), (Ia) or (Ib), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or former medicine:
  • R 1 , R 2 , R 2 ' are each independently selected from H, or R 1 and R 2 , R 2 and R 2′ are bonded to each other to form a double bond, and the double bond is optional. Further substituted by 0 to 2 selected from F, Cl, C 1-6 alkyl or 3 to 6 membered carbocyclic groups;
  • R 3 , R 4 , R 4' or R 5 are each independently selected from the group consisting of H, F, Cl, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2 - a 6 alkynyl group, a 3 to 6 membered carbocyclic group or a 3 to 6 membered heterocyclic group, the alkyl group, alkoxy group, alkenyl group, alkynyl group, carbocyclic group or heterocyclic group optionally further being 0 to 6 Substituted from F, Cl, Br, hydroxy, C 1-6 alkyl or a 3 to 6 membered carbocyclic group containing from 1 to 2 heteroatoms selected from N, O or S;
  • R 4 and any of R 4 ' , R 4 and R 5 are bonded together with the atoms to which they are attached to form a double bond, which is optionally further 0 to 2 selected from F, Cl, C 1 Substituted by a -6 alkyl group or a 3 to 6 membered carbocyclic group;
  • R 4 and R 4 ' may form a 3 to 6 membered carbocyclic ring together with the carbon atom to which they are attached, and the carbocyclic ring is optionally further 0 to 6 selected from the group consisting of F, Cl, Br, I, C 1- Substituted by a 6 alkyl group, a C 1-6 alkoxy group or a C 1-6 sulfanyl group;
  • R 6 is selected from H or C 1-6 alkyl
  • R 7 is selected from H or C 1-6 alkyl.
  • Preferred embodiments of the invention include compounds of the formula (I), (Ia) or (Ib), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or former medicine:
  • R 1 , R 2 , R 2 ' are each independently selected from H;
  • R 3 , R 4 , R 4' or R 5 are each independently selected from H, F, Cl, hydroxy or C 1-4 alkyl;
  • R 4 and any of R 4 ' , R 4 and R 5 are bonded together with the atoms to which they are attached to form a double bond, which is optionally further selected from 0 to 2 selected from F, Cl, C 1 Substituted with a -4 alkyl group or a 3 to 6 membered carbocyclic group;
  • R 4 and R 4 ' may form a 3 to 6 membered carbocyclic ring together with the carbon atom to which they are attached, and the carbocyclic ring is optionally further 0 to 6 selected from the group consisting of F, Cl, Br, I, C 1- Substituted by a 4- alkyl or C 1-4 alkoxy group;
  • R 6 is selected from H or C 1-4 alkyl
  • R 7 is selected from H or C 1-4 alkyl.
  • Preferred embodiments of the invention include compounds of the formula (I), (Ia) or (Ib), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or former medicine:
  • R 3 , R 4 , R 4 ' or R 5 are each independently selected from the group consisting of H, F, Cl, hydroxy, methyl, ethyl, n-propyl, isopropyl, t-butyl;
  • R 4 and any of R 4 ' , R 4 and R 5 are bonded together with the atoms to which they are attached to form a double bond, which is optionally further selected from 0 to 2 selected from F, Cl, methyl. Substituted with ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
  • R 4 and R 4 ' together with the carbon atom to which they are attached form a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a fluorocyclopropyl group, a 2,2-difluorocyclopropyl group, a fluorine group.
  • R 6 is selected from the group consisting of H, methyl, ethyl, and t-butyl;
  • R 7 is selected from the group consisting of H, methyl, ethyl, and t-butyl.
  • the invention relates to a compound selected from, but not limited to:
  • the present invention relates to an intermediate for preparing a compound represented by the formula (I), (Ia) or (Ib) or a stereoisomer thereof, which is selected from a compound represented by the following formula (II) or Stereoisomers:
  • R a or R b are each independently selected from a hydroxyl group or a C 1-4 alkyl group, and the alkyl group is optionally further substituted with 0 to 2 selected from a nitro group or -COOR x ;
  • R c , R d , R d ' or R e are each independently selected from H, F, Cl, hydroxy or C 1-4 alkyl, said alkyl optionally further being from 0 to 2 selected from F, hydroxy , -OMs, or -COOR x replaced;
  • R d and R d ' may form a 3 to 6 membered carbocyclic ring together with the carbon atom to which they are attached, said carbon ring optionally further being 0 to 6 selected from the group consisting of F, Cl, Br, I, C 1- Substituted by a 4- alkyl or C 1-4 alkoxy group;
  • R x is selected from H or C 1-4 alkyl.
  • Preferred embodiments of the invention include compounds of the formula (II), or all stereoisomers thereof:
  • R a or R b are each independently selected from hydroxy, methyl, ethyl, n-propyl, n-butyl or sec-butyl, said methyl, ethyl, n-propyl, n-butyl or sec-butyl Optionally further substituted by 0 to 2 selected from the group consisting of nitro, -COOH, -COOMe, -COOEt or -COOtBu;
  • R a , R b together with the carbon atom to which they are attached or
  • R c , R d , R d ' or R e are each independently selected from H, F, Cl, hydroxy, methyl, -CH 2 OH, -CH 2 COOEt, ethyl, -CH 2 CH 2 OH, -CH 2 CH 2 OMs, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl;
  • R d and R d ' together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluorocyclopropyl, 2,2-difluorocyclopropyl, fluoro Cyclobutyl, fluorocyclopentyl, cyclobutyl-2-alkenyl, cyclopentyl-2-alkenyl or cyclohexyl-2-alkenyl;
  • R x is selected from H, methyl, ethyl or tert-butyl.
  • the invention relates to a compound selected from, but not limited to:
  • the present invention relates to a pharmaceutically acceptable salt of a compound of the formula (I), (Ia) or (Ib), which is p-toluenesulfonate.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (I), (Ia) or (Ib) or all stereoisomers, solvates, metabolites thereof, A pharmaceutically acceptable salt, eutectic or prodrug, and one or more pharmaceutically acceptable carriers and/or excipients.
  • the present invention relates to a compound of the formula (I), (Ia) or (Ib), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs thereof Or a composition thereof, for use in the preparation of a medicament for the treatment and/or prevention of pain, preferably for the treatment of post-herpetic neuralgia, trigeminal neuralgia, migraine, pain associated with osteoarthritis or articular rheumatism, lower back Pain, sciatica, toothache, pain caused by burns, pain caused by diabetic neuropathy, pain caused by chemotherapy-induced neuropathy, HIV-related neuralgia, AIDS-related neuralgia, cancer-related nerves Use in pain or non-neural pain, acute or chronic tension headache, post-operative pain, fibromyalgia, epilepsy, generalized anxiety disorder or restless legs syndrome.
  • the present invention relates to a method of treating and/or preventing pain comprising administering to a mammal a therapeutically effective amount of a pharmaceutical composition of the present invention or a compound of the present invention or a stereoisomer, solvate or metabolite thereof a pharmaceutically acceptable salt, eutectic or prodrug.
  • the pain includes: post-herpetic neuralgia, trigeminal neuralgia, migraine, pain associated with osteoarthritis or articular rheumatism, lower back pain, sciatica, toothache, caused by burns Pain, pain caused by diabetic neuropathy, pain caused by chemotherapy-induced neuropathy, HIV-related neuralgia, AIDS-related neuralgia, cancer-related neuralgia or non-neuralgia, acute or chronic stress sexual headache, postoperative pain, fibromyalgia.
  • the mammal is a human.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopic conditions, and the carbons involved in the groups and compounds of the present invention.
  • Hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C and 14 C, and the hydrogen isotopes include helium (H), helium (D, Also known as heavy hydrogen), ⁇ (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • Alkyl means a straight or branched saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, further preferably An alkyl group of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl And various branched isomers thereof; the alkyl group may optionally be further selected from 0 to 6 selected from the group consisting of F, Cl, Br, I, hydroxy, thiol, nitro, cyano, amino, alkylamino, Amido, alkenyl, alkynyl, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, 3 to 8 membered carbocyclic, 3 to 8 membered heterocyclic, 3 to Substituted by a substituent of an 8-membered carbocyclic oxy group, a 3 to 8 membered heterocyclyloxy group, a carboxy
  • Alkoxy means -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropane Oxyl and cyclobutoxy.
  • the alkyl group may be further optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, decyl, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxy Substituents such as an alkyl group, an alkoxy group, a carbocyclic group, a heterocyclic group, a carbocyclic oxy group, a heterocyclic oxy group, a carboxyl group or a carboxylate group are substituted.
  • the alkoxy groups present herein are defined in accordance with this definition.
  • Thioalkyl means an -S-alkyl group. Non-limiting examples include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, n-hexylthio, cyclopropane Sulfur and cyclobutylthio.
  • the alkyl group may be further optionally further selected from 0 to 5 selected from the group consisting of F, Cl, Br, I, hydroxy, decyl, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxy Substituents such as an alkyl group, an alkoxy group, a carbocyclic group, a heterocyclic group, a carbocyclic oxy group, a heterocyclic oxy group, a carboxyl group or a carboxylate group are substituted.
  • the thioalkyl group present herein is defined in accordance with this definition.
  • Amino means -NH 2 .
  • Carboxyl means -COOH.
  • Alkenyl means an alkyl group having from 1 to 3 carbon-carbon double bonds, a linear or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably An alkenyl group of 2 to 8 carbon atoms, further preferably an alkenyl group of 2 to 6 carbon atoms.
  • Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, Hepten-2-yl, hepten-3-yl, hept-4-yl, oct-3-yl, nonen-3-yl, nonen-4-yl and undecen-3-yl.
  • the alkenyl group may be further optionally 0 to 6 selected from the group consisting of F, Cl, Br, I, alkyl, alkoxy, linear alkenyl, linear alkynyl, amino, nitro, cyano, fluorenyl Substituted by a substituent of an amide group, a carbocyclic group or a heterocyclic group.
  • Alkynyl means an alkynyl group having from 1 to 3 carbon-carbon triple bonds, a linear or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably An alkynyl group of 2 to 8 carbon atoms, further preferably an alkynyl group of 2 to 6 carbon atoms.
  • Non-limiting examples include ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl Butyrynyl-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyne-4- Base, octyn-3-yl, decyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4-yl.
  • the alkynyl group may be further optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, alkyl, alkoxy, linear alkenyl, linear alkynyl, amino, nitro, cyano, fluorenyl Substituted by a substituent of an amide group, a carbocyclic group or a heterocyclic group.
  • Carbocyclyl means a saturated or unsaturated non-aromatic ring, and the non-aromatic ring may be a 3 to 8 membered monocyclic ring, a 4 to 12 membered fused ring or a 10 to 15 membered tricyclic ring system, and a carbocyclic group may be attached.
  • the definition of carbocyclic groups appearing herein is consistent with this definition.
  • Heterocyclyl means a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3 to 8 membered monocyclic ring, a 4 to 12 membered bicyclic ring or 10 to 15 a tricyclic ring system, and comprising 1 to 3 hetero atoms selected from N, O or S, preferably a 3 to 8 membered heterocyclic group, and optionally substituted N, S in the ring of the heterocyclic group may be oxidized into various Oxidation state.
  • the heterocyclic group may be attached to a hetero atom or a carbon atom, and the heterocyclic group may be bonded to a bridged or spiro ring, and non-limiting examples include epoxyethyl, azacyclopropyl, oxetanyl, aza.
  • the heterocyclic groups appearing herein are defined in accordance with this definition.
  • amino protecting group refers to a group for amino protection which is suitable for protecting an amino group such that the amino group does not undergo a chemical reaction, but the group is easily removed after completion of the desired chemical reaction in other portions of the molecule.
  • Non-limiting examples include, but are not limited to, formyl, acetyl, phenyl, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, propoxycarbonyl, tert-butoxy Carbonyl, benzyloxycarbonyl, phenoxycarbonyl, 9-fluorenylmethyloxycarbonyl, adamantyloxycarbonyl, benzyloxycarbonyl, benzylcarbonyl, benzyl, benzyl, trityl Base, phthaloyl group.
  • Carboxy protecting group refers to a group for the protection of a carboxy group which is suitable for protecting a carboxyl group such that the carboxyl group does not undergo a chemical reaction, but the group is easily removed after completion of the desired chemical reaction in other portions of the molecule.
  • Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl , n-hexyl, trichloroethyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, p-methoxybenzyl, p-tert-butylbenzyl, acetoxymethyl, propionyloxy Base, butyryloxymethyl, isobutyryloxymethyl, pentoxymethyl, pivaloyloxymethyl, acetoxyethyl, acetoxypropyl, acetoxybutyl, propyl Acyloxyethyl, propionyloxypropyl, butyryloxyethyl, isobutyryloxyethyl,
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” means that the compound of the invention retains the biological effectiveness and properties of the free acid or free base, and the free acid is passed through with a non-toxic inorganic base or An organic base, a salt obtained by reacting a free base with a non-toxic inorganic or organic acid.
  • Non-limiting implementation of the inorganic base Examples include Al, Ca, Li, Mg, K, Na, and Zn; non-limiting examples of the organic base include ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropyl Amine, tetramethylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, beet Alkali, phthalicillin, ethylenediamine, glucosamine, N-methylmethylglucamine, theobromine, triethanolamine, tromethamine, hydrazine, piperazine, piperidine, N-ethylpiperidine and poly Amine resin; non-limiting examples of the inorganic acid and organic acid include sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid,
  • “Pharmaceutical composition” means a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof and other chemical components, wherein “other chemical components” means pharmaceutically acceptable Accepted carriers, excipients, and/or one or more additional therapeutic agents.
  • Carrier means a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
  • Excipient means an inert substance that is added to a pharmaceutical composition to facilitate administration of the compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, bonding Agent and disintegrant.
  • Prodrug means a compound of the invention that can be converted to biological activity by metabolism in vivo.
  • the prodrugs of the present invention are prepared by modifying an amino group or a carboxyl group in the compound of the present invention, and the modification can be carried out by a conventional operation or in vivo to obtain a parent compound.
  • a prodrug of the invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.
  • Cyctic crystal refers to a crystal in which an active pharmaceutical ingredient (API) and a eutectic former (CCF) are combined by hydrogen bonding or other non-covalent bonds, wherein the pure state of API and CCF is at room temperature. Solid, and there is a fixed stoichiometric ratio between the components. Eutectic is a multi-component crystal that contains both a binary eutectic formed between two neutral solids and a multi-component eutectic formed by a neutral solid with a salt or solvate.
  • API active pharmaceutical ingredient
  • CCF eutectic former
  • Non-limiting examples include alanine, valine, leucine, isoleucine, valine, phenylalanine, tryptophan, methionine, glycine, serine, threonine, cysteine, Tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, aspartic acid, glutamic acid, pyroglutamic acid, sulfuric acid, phosphoric acid, nitric acid, hydrogen Bromo acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonate Acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinyl sulfonic acid, formic acid, fumaric acid, citric acid, gluconic acid, glucuronic acid, glutamic acid, Glycolic acid, isethionic acid, lactic acid
  • Animal is meant to include mammals, such as humans, companion animals, zoo animals, and domestic animals, preferably humans, horses, or dogs.
  • Stepoisomer refers to isomers resulting from the spatial arrangement of atoms in a molecule, including cis and trans isomers, enantiomers and conformational isomers.
  • heterocyclic group optionally substituted by an alkyl group means that the alkyl group may be, but not necessarily, the description includes the case where the heterocyclic group is substituted by an alkyl group, and the heterocyclic group thereof is not substituted with an alkyl group.
  • IC 50 inhibitor measured half inhibitory concentration: Inhibition of calcium channels and gabapentin binding test required by the test compound concentration of 50%.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD). ), the internal standard is tetramethylsilane (TMS);
  • HPLC HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm, 3.5 ⁇ M);
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm-0.20mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. -0.5mm;
  • the known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from Titan Technology, An Naiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Suiyuan Chemical Technology, Belling Technology, etc. the company;
  • the nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume;
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume;
  • the hydrogenation reaction is usually evacuated, filled with hydrogen, and operated three times;
  • reaction is carried out under a nitrogen atmosphere
  • the solution means an aqueous solution
  • reaction temperature is room temperature, and the most suitable reaction temperature at room temperature is 20 ° C - 30 ° C;
  • PhSO 3 H benzenesulfonic acid.
  • 1,3-cyclopentadiene (1A) (6.6 g, 0.1 mol), cyclohexane (350 mL), nitrogen-purified, triethylamine (3.5 g, 35 mmol), and heated under reflux.
  • a solution of 4-chlorobutyryl chloride (4.9 g, 35.0 mmol) in cyclohexane (25 mL) was added dropwise. After cooling to room temperature, the reaction solution was suction filtered, washed with cyclohexane (20 mL ⁇ 3), and the filtrate was washed successively with saturated ammonium chloride (150 mL ⁇ 3) and water (150 mL ⁇ 3).
  • Step 4 2-((1r,1aR,1a 1 r,3as,5aS)-1-(aminomethyl)octahydro-1H-cyclobutane [cd]penten-1-yl)acetic acid (compound) 1)
  • Step Five 2 - ((1s, 1aR , 1a 1 r, 3as, 5aS) -1- ( aminomethyl) cyclobutane octahydro -1H- [cd] pentalene-en-1-yl) acetic acid (Compound 2)
  • 1,3-cyclopentadiene (1A) (26.4 g, 0.4 mol) and cyclohexane (1200 mL) were added to the reaction flask, and the mixture was purged with nitrogen.
  • Triethylamine (24.2 g, 0.24 mol) was added and heated to reflux.
  • 4-Bromobutyryl chloride (44.4 g, 0.24 mol) in cyclohexane solution (50 mL, 25 mL / h) was added dropwise, and the reaction was refluxed for 4 hours, and the reaction mixture was filtered with hexane (100 mL ⁇ 3).
  • EtOAc EtOAc 5R,7S)-7-(2-bromoethyl)spiro[bicyclo[3.2.0]hept-6,2'-[1,3]dioxol]-3-ol (4D-1) and ⁇ )-(1S,5R,7S)-7-(2-Bromoethyl)spiro[bicyclo[3.2.0]hept-6,2'-[1,3]dioxol]-3-ol ( A mixture of 4D-2) (30 g) was used directly for the next reaction.
  • dichloromethane 300 mL
  • 2M aqueous sodium thiosulfate solution 500 mL
  • 2M aqueous sodium thiosulfate solution 500 mL
  • 2M sodium hydroxide solution 500 mL ⁇ 2
  • water 500 mL ⁇ 2
  • Ester (v/v) 10:1) to give a pale yellow oily liquid ( ⁇ )-(1S,5R,7S)-7-(2-bromoethyl)spiro[bicyclo[3.2.0]hept-6,2 '-[1,3]dioxol-2-one (4E-1) (15g, yield: 50.4%) and light yellow oily liquid ( ⁇ )-(1S,5R,7S)-7-( 2-Bromoethyl)spiro[bicyclo[3.2.0]hept-6,2'-[1,3]dioxol-3-one (4E-2) (3.7 g, yield: 12.4%) .
  • Step 6 2-((1aR,1a 1 r,3as,5aS)-octahydrospiro[cyclobutane [cd]pentene-1,2'-[1,3]dioxolane-3a -base) ethyl acetate (4G)
  • Step 7 2-((1aR,1a 1 r,3as,5aS)-octahydrospiro[cyclobutane [cd]pentene-1,2'-[1,3]dioxolane-3a -base)ethanol (4H)
  • the reaction flask was added lithium tetrahydroaluminate (0.014g, 0.38mmol) and tetrahydrofuran (2 mL), ice-bath cooled solution of 2 - ((1aR, 1a 1 r, 3as, 5aS) - octahydro-spiro [cyclobutane [ Cd]pentaene-1,2'-[1,3]dioxolan]-3a-yl)acetate (4G) (0.1 g, 0.38 mmol) in tetrahydrofuran (1 mL).
  • Step 8 2-((1aR,1a 1 r,3as,5aS)-octahydrospiro[cyclobutane [cd]pentene-1,2'-[1,3]dioxolane-3a -yl)ethyl methanesulfonate (4I)
  • the ninth step (1aR, 1a 1 r, 3as, 5aS)-3a-ethyl octahydrospiro [cyclobutane [cd] pentylene-1,2'-[1,3]dioxolane] 4J)(1aR,1a 1 r,3as,5aS)-3a-ethyloctahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolane]
  • Step 10 (1aR, 1a 1 r, 3as, 5aS)-3a-ethyl octahydro-1 hydrogen-cyclobutane [cd]penten-1-one (4K)
  • Step 13 2-((1r,1aR,1a 1 r,3as,5aS)-1-(aminomethyl)-3a-ethyloctahydro-1H-cyclobutane [cd]pentene-1 -yl)tert-butyl acetate (4N)
  • Triphenylmethylphosphonium bromide (10.7 g, 30 mmol) and tetrahydrofuran (60 mL) were added to the reaction flask, and the mixture was filtered under nitrogen, and then cooled to 0 ° C, and potassium t-butoxide (3.4 g, 30 mmol) was added portionwise, and stirred at room temperature 30 In minutes, add ( ⁇ )-(1aR,1a 1 R,3aR,5aS)-hexahydrospiro[cyclobutane [cd]pentene-1,2'-[1,3]dioxole to the ice water bath.
  • Step 5 ( ⁇ )-2-((1R,1aR,1a 1 R,3aR,5aS)-3-methylene-1-(nitromethyl)octahydro-1H-cyclobutane [cd] Tert-butyl pentylene-1-yl)acetate (6F)
  • Step 6 ( ⁇ )-2-((1R,1aR,1a 1 R,3aR,5aS)-1-(aminomethyl)-3-methylene octahydro-1H-cyclobutane [cd] pent Tert-butyl-1-yl)acetate (6G)
  • Step 7 ( ⁇ )-2-((1R,1aR,1a 1 R,3aR,5aS)-1-(aminomethyl)-3-methylene octahydro-1H-cyclobutane [cd] pent Phenylene-1-yl)acetic acid (compound 6)
  • EtOAc EtOAc
  • EtOAc ether / ethyl acetate
  • v / v 100: 1 to give a yellow solid ( ⁇ ) - (1aR, 1a 1 R, 3aR, 5aS) -3,3- difluoro-cyclobutane-octahydro -1H- [cd Pentylene-1-one (8C) (1.7 g, yield: 71%).
  • the third step ( ⁇ )-2-((1aR,1a 1 R,3aR,5aS)-3,3-difluorooctahydro-1H-cyclobutane [cd]pentene-1-ylidene)acetic acid Tert-butyl ester (8D)
  • Step 5 ( ⁇ )-2-((1R,1aR,1a 1 R,3aR,5aS)-1-(aminomethyl)-3,3-difluorooctahydro-1H-cyclobutane [cd] Tert-butyl pentylene-1-yl)acetate (8F)
  • the third step ( ⁇ )-2-((1aS,1a 1 R,3aR,5aS)-1a,1a 1 ,2,3,3a,5a-hexahydrospiro[cyclobutene[cd]pentene- 1,2'-[1,3]dioxol-4-yl)ethane-1-ol (9D)
  • Step 5 ( ⁇ )-(1aS,1a 1 R,3aR,5aS)-4-ethyl-1a,1a 1 ,2,3,3a,5a-hexahydrospiro[cyclobutene[cd]pentene -1,2'-[1,3]dioxolane](9F)
  • Step 7 ( ⁇ )-2-((1aS,1a 1 R,3aR,5aS)-4-ethyl-1a,1a 1 ,2,3,3a,5a-hexahydro-1H-cyclobutan[cd Tert-butyl pentylene-1-phenyl)acetate (9H)
  • Step 8 ( ⁇ )-2-((1R,1aS,1a 1 R,3aR,5aS)-4-ethyl-1-(nitromethyl)-1a,1a 1 ,2,3,3a, 5a-hexahydro-1H-cyclobutyl [cd]penten-1-yl)acetic acid tert-butyl ester (9I)
  • Step 9 ( ⁇ )-2-((1R,1aS,1a 1 R,3aR,5aS)-1-(aminomethyl)-4-ethyl-1a,1a 1 ,2,3,3a,5a - hexahydro-1H-cyclobutyl [cd]penten-1-yl)acetic acid tert-butyl ester (9J)
  • Step 10 ( ⁇ )-2-((1R,1aS,1a 1 R,3aR,5aS)-1-(aminomethyl)-4-ethyl-1a,1a1,2,3,3a,5a- Hexahydro-1H-cyclobut[cd]penten-1-yl)acetic acid (compound 9)
  • the rat cerebral cortex was harvested in 10 volumes (w/v) ice-cold 0.32 M sucrose/5 mM Tris-acetic acid (pH 7.4), homogenized, and the synaptic plasma membrane was prepared by sucrose density gradient centrifugation and stored in Tris-acetic acid ( pH 7.4) buffer, before use Resuspend in 10 mM HEPES (pH 7.4) buffer.
  • Test compounds were dissolved in 1% DMSO and diluted to a gradient concentration (1 nM - 1000 nM), added to synaptic plasma membrane suspension (approximately 0.05-0.1 mg total protein) along with 20 nM [3H] gabapentin, and incubated at 25 ° C for 30 minutes.
  • the reaction system was vacuum filtered to a Whatman GFB filter, and the filter was washed three times with 5 mL of 100 mM ice-cold sodium chloride solution, and the radioactivity of the filter was measured by the liquid flash number. Non-specific binding was blocked with 100 M gabapentin. The inhibition rate of the binding of the radiolabeled gabapentin to the synaptic plasma membrane was calculated and the IC50 of the compound was calculated.
  • the compounds of the present invention have a good competitive binding ability to the calcium channel protein Cav ⁇ 2 ⁇ .
  • test compound Male Sprague-Dawley rats (purchased from Vitallihua Experimental Animal Co., Ltd.) 180-240 g, fasting water supply overnight, 3 rats orally administered 10 mg/kg, and 3 rats intravenously injected 5 mg/kg.
  • the test compound was formulated into a 1.0 mg/mL suspension in a 0.5% methylcellulose (MC) solution, before administration and 30 minutes after administration and 1, 2, 4, 6, 200 ⁇ L of blood was collected at 8, 12 and 24 hours; in the intravenous administration group, the compound was formulated into a 1.0 mg/mL solution in physiological saline, before administration and at 5, 15 and 30 minutes and 1, 2, 4 after administration.
  • MC methylcellulose
  • Blood was collected at 8, 12 and 24 hours, and the samples collected were all antibiotics of heparin.
  • the blood sample was centrifuged at 5,500 rpm for 10 minutes, and plasma was collected and stored at -20 °C.
  • Take 10 ⁇ L of rat plasma at each time point add 500 ⁇ L of acetonitrile solution containing internal standard, mix, vortex for 10 minutes, centrifuge at 3700 rpm for 18 minutes, take 50 ⁇ L of the supernatant and mix with 100 ⁇ L of water, vortex and mix for 10 minutes.
  • 5 ⁇ L of the mixed solution was subjected to LC-MS/MS analysis to determine the blood concentration of the original drug.
  • the main pharmacokinetic parameters were analyzed using the WinNonlin 6.3 software non-compartmental model. The test results are shown in Table 2.

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Abstract

本发明涉及一种稠合三环γ-氨基酸衍生物及其在医药上的应用，具体而言涉及如通（I）所示的稠合环γ-氨基酸衍生物，或者其立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或共晶，包含其的药物组合物以及本发明化合物或组合物在镇痛领域的用途，其中，通式（I）中各取代基的定义与说明书的定义相同

Description

稠合三环γ-氨基酸衍生物及其制备方法和在医药上的应用 技术领域
本发明涉及一种通式(I)所示的稠合三环γ-氨基酸衍生物，或者其立体异构体、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其药物组合物以及在镇痛领域的用途。
背景技术
电压门控钙通道由α1亚单位和辅助蛋白α2δ、β、γ亚基共同构成。α2δ蛋白可以调节钙通道的密度及钙通道电压依赖性动力学(Felix et al(199 7)J.Neuroscience 17:6884-6891；Klugbauer et al(1999)J.Neuroscience 19:684-691；Hobom et al(2000)Eur.J.Neuroscience 12:1217-1226；and Qin et al(2002)Mol.Pharmacol.62:485-496)。已经证实，对电压依赖性钙通道亚基α2δ表现出高亲合力结合的化合物可有效治疗疼痛，例如普瑞巴林和加巴喷丁。在哺乳动物中，α2δ蛋白有4个亚型，每个亚型均由不同的基因编码。α2δ亚型1和亚型2与普瑞巴林表现出高亲和力，而α2δ亚型3和亚型4无显著的药物结合力。
然而，对于加巴喷丁，其较大程度改善糖尿病周围神经病变患者病痛的比例约为60％(Acta Neurol.Scand.101:359-371,2000)，对于普瑞巴林，虽然其耐受性优于加巴喷丁，但其安全性更低，且有滥用或者使患者产生依赖的可能(Am J Health Syst Pharm.2007；64(14):1475-1482)。
鉴于加巴喷丁和普瑞巴林的局限性，需要开发新的具有更好药效的化合物。
WO2002085839描述了可治疗癫痫、神经变性障碍、疼痛等疾病的二环氨基酸类似物及其衍生物、前药以及可药用盐和溶剂合物，其中R1、R2各自独立地选自氢、C1-6直链或支链烷基、C3-6环烷基、苯基或苯甲基，且式(XVII)中，R1、R2同时为氢，该发明与本发明的化合物结构差异较大，不认为此专利中具体描述是本发明的一部分，其通式化合物如下：
Figure PCTCN2016110946-appb-000001
Figure PCTCN2016110946-appb-000002
WO2004031124说明书中记载了其发明发合物作为中间体可制得的下式氨基酸衍生物，其中n选自0、1或2，R1、R1a、R2、R2a、R3、R3a、R4和R4a各自独立地选自氢、C1-6直链或支链烷基，或者R1和R2、或R2和R3结合形成任选被1或2个C1-6烷基取代的C3-7环烷基，该发明与本发明的化合物结构差异较大，不认为此专利中具体描述是本发明的一部分，其通式化合物如下：
Figure PCTCN2016110946-appb-000003
WO2009041453描述了可治疗疼痛的稠合环γ-氨基酸衍生物或其药用盐，其中R1、R2、R2'、R4、R5、R6、R7、R8、R8'各自独立地选自氢、卤素、C1-6烷基或者R2和R2'与它们结合的碳原子一起形成C3-7环烷基，R3为氢、卤素、C1-6烷基、C1-6烷基卤基 团、羟基C1-6烷基、硫烷基C1-6烷基、C1-6烷氧基C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷基硫烷基、C1-6烷基硫烷基C1-6烷基、C2-7酰基硫代C1-6烷基、C2-7酰氧基C1-6烷基或C3-7环烷基，该发明与本发明的化合物结构差异较大，不认为此专利中具体描述是本发明的一部分，其通式化合物如下：
Figure PCTCN2016110946-appb-000004
WO2010079668描述了可治疗疼痛的稠合环γ-氨基酸衍生物或其药用盐，其中R1、R5各自独立地选自氢或C1-6烷基，R2、R3、R4和R4'各自独立地选自氢原子、C1-6烷基或C3-6环烷基，或者R4和R4'相结合形成C3-6环烷基，R6选自氢、C1-6烷基或氨基保护基，R7选自氢、C1-6烷基或羧基保护基，R8和R8'相同或不同，各自独立地选自氢、卤素、C1-6烷基硫基、C1-6烷氧基或C1-6硫烷基，或者R8和R8'与它们结合的碳原子一起形成C3-6环烷基，该发明与本发明的化合物结构差异较大，不认为此专利中具体描述是本发明的一部分，其通式化合物如下：
Figure PCTCN2016110946-appb-000005
发明内容
本发明的目的是提供一种结构新颖、药效好的稠合三环γ-氨基酸衍生物，或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药，其药物组合物以及其在镇痛领域的用途。
本发明涉及一种通式(I)所示的化合物，或者其所有的立体异构体、溶剂化物、前药代谢产物、药学上可接受的盐或共晶：
Figure PCTCN2016110946-appb-000006
其中：
R1、R2、R2’、R3、R4、R4’或R5各自独立地选自H、F、Cl、Br、I、羟基、氰基、C1-6烷基、C1-6烷氧基、C1-6硫烷基、C2-6烯基、C2-6炔基、3至6元碳环基或者3至6元杂环基，所述的烷基、烷氧基、硫烷基、烯基、炔基、碳环基或者杂环基任选进一步被0至6个选自F、Cl、Br、I、羟基、C1-6烷基或者3至6元碳环基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子；
作为选择，R1与R2、R2与R2’、R2与R3、R3与R4、R4与R4’、R4与R5任意一组相结合与其相连的原子一起形成双键，所述的双键任选进一步被0至2个选自F、Cl、Br、I、C1-6烷基、被1至3个卤素取代的C1-6烷基或者3至6元碳环基所取代，所述的卤素选自F、Cl或者Br；
作为选择，R2与R2’、R3与R4、R4与R4’、R4与R5任意一组与其连接的碳原子一起形成3至6元碳环基，所述的碳环基任选进一步被0至6个选自F、Cl、Br、I、C1-6烷基、C1-6烷氧基或者C1-6硫烷基所取代；
R6选自H、C1-6烷基或者氨基保护基；
R7选自H、C1-6烷基或者羧基保护基。
本发明优选方案，包括通式(I)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药：
其中：
R1、R2、R2’、R3、R4、R4’或R5各自独立地选自H、F、Cl、Br、羟基、C1-6烷基、C1-4烷氧基、C1-4硫烷基、C2-6烯基、C2-6炔基、3至6元碳环基或者3至6元杂环基，优选地，R1、R2、R2’、R3、R4、R4’或R5各自独立地选自H、F、Cl、羟基、C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基或者3至6元碳环基，更优选地，R1、R2、R2’、R3、R4、R4’或R5各自独立地选自H、F、羟基、C1-4烷基、C1-4烷氧基、C2-4烯基或者3至6元碳环基，所述的烷基、烷氧基、硫烷基、烯基、炔基、碳环基或者杂环基任选进一步被0至6个选自F、Cl、Br、I、羟基、C1-6烷基或者3至6元碳环基所取代，优选进一步被0至4个选自F、Cl、Br、羟基或者C1-4烷基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子；
作为选择，R1与R2、R2与R2’、R2与R3、R3与R4、R4与R4’、R4与R5任意一组相结合与其相连的原子一起形成双键，所述的双键任选进一步被0至2个选自F、Cl、Br、I、C1-6烷基、被1至3个卤素取代的C1-6烷基或者3至6元碳环基所取代，优选进一步被0至2个选自F、Cl、Br或者C1-4烷基所取代，所述的卤素选自F、Cl或者Br；
作为选择，R2与R2’、R3与R4、R4与R4’、R4与R5任意一组与其连接的碳原子一起形成3至6元碳环基，所述的碳环基任选进一步被0至6个选自F、Cl、Br、I、C1-6烷基、C1-6烷氧基或者C1-6硫烷基所取代，优选进一步被0至4个选自F、Cl、Br、C1-4烷基、C1-4烷氧基或者C1-4硫烷基所取代，更优选进一步被0至4个选自F、Cl或者C1-4烷基所取代；
R6选自H、C1-4烷基或者氨基保护基；
R7选自H、C1-4烷基或者羧基保护基。
本发明优选方案，包括通式(I)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药：
其中：
R1、R2、R2’、R3、R4、R4’或R5各自独立地选自H、F、Cl、Br、羟基、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、CH2F、CHF2、CF3、CH2CH2F、CHFCH3、CHFCH2F、羟基甲基、羟基乙基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、乙硫基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、环丙基、环丁基、环戊基或者环己基；
作为选择，R1与R2、R2与R2’、R2与R3、R3与R4、R4与R4’、R4与R5任意一组相结合与其相连的原子一起形成双键，所述的双键任选进一步被0至2个选自F、Cl、Br、I、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、CH2F、CHF2、CF3、CH2CH2F、CHFCH3、CHFCH2F、环丙基、环丁基、环戊基或者环己基所取代；
作为选择，R2与R2’、R3与R4、R4与R4’、R4与R5任意一组与其连接的碳原子一起形成环丙基、环丁基、环戊基、环己基、氟代环丙基、2,2-二氟代环丙基、氟代环丁基、氟代环戊基、环丁基-2-烯基、环戊基-2-烯基、环己基-2-烯基；
R6选自H、甲基、乙基、叔丁基；
R7选自H、甲基、乙基、叔丁基。
本发明优选方案，包括通式(Ia)或者(Ib)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药：
Figure PCTCN2016110946-appb-000007
或者
Figure PCTCN2016110946-appb-000008
其中：
R1、R2、R2’、R3、R4、R4’或R5各自独立地选自H、F、Cl、Br、I、羟基、氰基、C1-6烷基、C1-6烷氧基、C1-6硫烷基、C2-6烯基、C2-6炔基、3至6元碳环基或者3至6元杂环基，优选地，R1、R2、R3、R4或R5各自独立地选自H、F、Cl、羟基、C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基或者3至6元碳环基，更优选地，R1、R2、R3、R4或R5各自独立地选自H、F、羟基、C1-4烷基、C1-4烷氧基、C2-4烯基或者3至6元碳环基，所述的烷基、烷氧基、硫烷基、烯基、炔基、碳环基或者杂环基任选进一步被0至6个选自F、Cl、Br、I、羟基、C1-6烷基或者3至6元碳环基所取代，优选进一步被0至4个选自F、Cl、Br、羟基或者C1-4烷基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子；
作为选择，R1与R2、R2与R2’、R2与R3、R3与R4、R4与R4’、R4与R5任意一组相结合与其相连的原子一起形成双键，所述的双键任选进一步被0至2个选自F、Cl、Br、I、C1-6烷基、被1至3个卤素取代的C1-6烷基或者3至6元碳环基所取代，所述的卤素选自F、Cl或者Br；
作为选择，R2与R2’、R3与R4、R4与R4’、R4与R5任意一组与其连接的碳原子一起形成3至6元碳环基，所述的碳环基任选进一步被0至6个选自F、Cl、Br、I、C1-6烷基、C1-6烷氧基或者C1-6硫烷基所取代，优选进一步被0至4个选自F、Cl、Br、C1-4烷基、C1-4烷氧基或者C1-4硫烷基所取代，更优选进一步被0至4个选自F、Cl或者C1-4烷基所取代；
R6选自H、C1-6烷基或者氨基保护基，优选H或者C1-6烷基；
R7选自H、C1-6烷基或者羧基保护基，优选H或者C1-6烷基。
本发明优选方案，包括通式(Ia)或者(Ib)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药：
其中：
R1、R2、R2’、R3、R4、R4’或R5各自独立地选自H、F、Cl、Br、羟基、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、CH2F、CHF2、CF3、CH2CH2F、CHFCH3、CHFCH2F、羟基甲基、羟基乙基、甲氧基、乙氧基、丙氧基、异丙氧基、甲硫基、已硫基、乙烯基、丙烯基、烯丙基、乙炔基、丙炔基、环丙基、环丁基、环戊基或者环己基；
作为选择，R1与R2、R2与R2’、R2与R3、R3与R4、R4与R4’、R4与R5任意一组相 结合与其相连的原子一起形成双键，所述的双键任选进一步被0至2个选自F、Cl、Br、I、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、CH2F、CHF2、CF3、CH2CH2F、CHFCH3、CHFCH2F、环丙基、环丁基、环戊基或者环己基所取代；
作为选择，R2与R2’、R3与R4、R4与R4’、R4与R5任意一组与其连接的碳原子一起形成环丙基、环丁基、环戊基、环己基、氟代环丙基、2,2-二氟代环丙基、氟代环丁基、氟代环戊基、环丁基-2-烯基、环戊基-2-烯基、环己基-2-烯基；
R6选自H、甲基、乙基、叔丁基；
R7选自H、甲基、乙基、叔丁基。
本发明优选方案，包括通式(I)、(Ia)或者(Ib)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药：
其中：
R1、R2、R2’各自独立地选自H，或者R1与R2、R2与R2’任意一组相结合与其相连的原子一起形成双键，所述的双键任选进一步被0至2个选自F、Cl、C1-6烷基或者3至6元碳环基所取代；
R3、R4、R4’或R5各自独立地选自H、F、Cl、羟基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、3至6元碳环基或者3至6元杂环基，所述的烷基、烷氧基、烯基、炔基、碳环基或者杂环基任选进一步被0至6个选自F、Cl、Br、羟基、C1-6烷基或者3至6元碳环基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子；
作为选择，R4与R4’、R4与R5任意一组相结合与其相连的原子一起形成双键，所述的双键任选进一步被0至2个选自F、Cl、C1-6烷基或者3至6元碳环基所取代；
作为选择，R4与R4’可与其相连的碳原子一起形成3至6元碳环，所述的碳环任选进一步被0至6个选自F、Cl、Br、I、C1-6烷基、C1-6烷氧基或者C1-6硫烷基所取代；
R6选自H或者C1-6烷基；
R7选自H或者C1-6烷基。
本发明优选方案，包括通式(I)、(Ia)或者(Ib)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药：
其中：
R1、R2、R2’各自独立地选自H；
R3、R4、R4’或R5各自独立地选自H、F、Cl、羟基或者C1-4烷基；
作为选择，R4与R4’、R4与R5任意一组相结合与其相连的原子一起形成双键，所述 的双键任选进一步被0至2个选自F、Cl、C1-4烷基或者3至6元碳环基所取代；
作为选择，R4与R4’可与其相连的碳原子一起形成3至6元碳环，所述的碳环任选进一步被0至6个选自F、Cl、Br、I、C1-4烷基或者C1-4烷氧基所取代；
R6选自H或者C1-4烷基；
R7选自H或者C1-4烷基。
本发明优选方案，包括通式(I)、(Ia)或者(Ib)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药：
其中：
R3、R4、R4’或R5各自独立地选自H、F、Cl、羟基、甲基、乙基、正丙基、异丙基、叔丁基；
作为选择，R4与R4’、R4与R5任意一组相结合与其相连的原子一起形成双键，所述的双键任选进一步被0至2个选自F、Cl、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环丙基、环丁基、环戊基或者环己基所取代；
作为选择，R4与R4’可与其相连的碳原子一起形成环丙基、环丁基、环戊基、环己基、氟代环丙基、2,2-二氟代环丙基、氟代环丁基、氟代环戊基、环丁基-2-烯基、环戊基-2-烯基、环己基-2-烯基；
R6选自H、甲基、乙基、叔丁基；
R7选自H、甲基、乙基、叔丁基。
本发明优选方案，本发明涉及化合物选自，但不限于：
Figure PCTCN2016110946-appb-000009
Figure PCTCN2016110946-appb-000010
本发明涉及一种制备通式(I)、(Ia)或(Ib)所示的化合物或其立体异构体的中间体，该中间体选自如下通式(II)所示的化合物或其立体异构体：
Figure PCTCN2016110946-appb-000011
其中：
Ra或Rb各自独立地选自羟基或者C1-4烷基，所述的烷基任选进一步被0至2个选自硝基或者-COORx所取代；
作为选择，Ra与Rb相结合与其相连的原子一起形成双键、C＝O或者Ra、Rb与其相连的碳原子一起形成3至6元杂环基，所述的双键任选进一步被0至2个选自F、C1-4烷基、硝基或者-COORx所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子，且任选被0至2个＝O所取代；
Rc、Rd、Rd’或Re各自独立地选自H、F、Cl、羟基或者C1-4烷基，所述的烷基任选进一步被0至2个选自F、羟基、-OMs、或者-COORx所取代；
作为选择，Rd与Rd’、Rd与Re任意一组相结合与其相连的原子一起形成双键或者C＝O，所述的双键任选进一步被0至2个选自F、C1-4烷基或者-COORx所取代；
作为选择，Rd与Rd’可与其相连的碳原子一起形成3至6元碳环，所述的碳环任选进一步被0至6个选自F、Cl、Br、I、C1-4烷基或者C1-4烷氧基所取代；
Rx选自H或者C1-4烷基。
本发明优选方案，包括通式(II)所示的化合物，或者其所有的立体异构体：
其中：
Ra或Rb各自独立地选自羟基、甲基、乙基、正丙基、正丁基或者仲丁基，所述的甲基、乙基、正丙基、正丁基或者仲丁基任选进一步被0至2个选自硝基、-COOH、-COOMe、-COOEt或者-COOtBu所取代；
作为选择，Ra与Rb相结合与其相连的原子一起形成双键或者C＝O，所述的双键任选进一步被0至2个选自F、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、硝基、-COOEt或者-COOtBu所取代；
作为选择，Ra、Rb与其相连的碳原子一起形成
Figure PCTCN2016110946-appb-000012
或者
Figure PCTCN2016110946-appb-000013
Rc、Rd、Rd’或Re各自独立地选自H、F、Cl、羟基、甲基、-CH2OH、-CH2COOEt、乙基、-CH2CH2OH、-CH2CH2OMs、正丙基、异丙基、正丁基、仲丁基或者叔丁基；
作为选择，Rd与Rd’、Rd与Re任意一组相结合与其相连的原子一起形成双键或者C＝O，所述的双键任选进一步被0至2个选自F、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、-CH2COOH或者-CH2COOEt所取代；
作为选择，Rd与Rd’可与其相连的碳原子一起形成环丙基、环丁基、环戊基、环己基、氟代环丙基、2,2-二氟代环丙基、氟代环丁基、氟代环戊基、环丁基-2-烯基、环戊基-2-烯基或者环己基-2-烯基；
Rx选自H、甲基、乙基或者叔丁基。
本发明优选方案，本发明涉及化合物选自，但不限于：
Figure PCTCN2016110946-appb-000014
Figure PCTCN2016110946-appb-000015
本发明涉及通式(I)、(Ia)或者(Ib)所示化合物药学上可接受的盐，所述的盐为对甲苯磺酸盐。
本发明涉及一种药物组合物，所述的药物组合物包括通式通式(I)、(Ia)或者(Ib)所述的化合物或其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药，和一种或者多种药学上可接受的载体和/或赋形剂。
本发明涉及一种通式(I)、(Ia)或者(Ib)所示的化合物，或者其所有的立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药或者其组合物，在制备治疗和/或预防疼痛药物中的用途，所述用途优选：治疗疱疹后神经痛、三叉神经痛、偏头痛、与骨关节炎或关节风湿病相关的疼痛、下背疼痛、坐骨神经痛、牙痛、由烧伤引起的疼痛、由糖尿病性神经病引起的疼痛、由化疗诱导的神经病变引起的疼痛、与HIV相关的神经痛、与AIDS相关的神经痛、与癌症相关的神经痛或非神经痛、急性或慢性紧张性头痛、手术后疼痛、纤维肌痛、癫痫、广泛性焦虑症或者不宁腿综合征中的用途。
本发明涉及一种治疗和/或预防疼痛的方法，所述方法包括给予哺乳动物治疗有效量的本发明的药物组合物或者本发明所述的化合物或其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药。
根据本发明所述的方法，所述的疼痛包括：疱疹后神经痛、三叉神经痛、偏头痛、与骨关节炎或关节风湿病相关的疼痛、下背疼痛、坐骨神经痛、牙痛、由烧伤引起的疼痛、由糖尿病性神经病引起的疼痛、由化疗诱导的神经病变引起的疼痛、与HIV相关的神经痛、与AIDS相关的神经痛、与癌症相关的神经痛或非神经痛、急性或慢性紧张性头痛、手术后疼痛、纤维肌痛。
其中所述哺乳动物为人。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素包括17F和19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基，优选为1至8个碳原子的烷基，更优选为1至6个碳原子的烷基，进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；所述的烷基可以任选进一步被0至6个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、C1-6烷基、C1-6羟基烷基、C1-6烷氧基、3至8元碳环基、3至8元杂环基、3至8元碳环基氧基、3至8元杂环基氧基、羧基或者羧酸酯基的取代基所取代，本文中出现的烷基，其定义与本定义一致。
“烷氧基”是指-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷基可以任选进一步被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的烷氧基，其定义与本定义一致。
“硫烷基”是指-S-烷基。非限制性实施例包括甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、仲丁硫基、叔丁硫基、正戊硫基、正己硫基、环丙硫基和环丁硫基。所述的烷基可以任选进一步被0至5个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、烷基氨基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的硫烷基，其定义与本定义一致。
“氨基”是指-NH2。
“氰基”是指
Figure PCTCN2016110946-appb-000016
“羟基”是指-OH。
“巯基”是指-SH。
“羧基”是指-COOH。
“烯基”是指含有1至3个碳-碳双键，由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基，优选2至12个碳原子的烯基，更优选2至8个碳原子的烯基，进一步优选2至6个碳原子的烯基。非限制性实施例包括乙烯基、丙烯-2-基、丁烯-2-基、戊烯-2-基、戊烯-4-基、己烯-2-基、己烯-3-基、庚烯-2-基、庚烯-3-基、庚烯-4-基、辛烯-3-基、壬烯-3-基、癸烯-4-基和十一烯-3-基。所述的烯基可以任选进一步被0至6个选自F、Cl、Br、I、烷基、烷氧基、直链烯基、直链炔基、氨基、硝基、氰基、巯基、酰胺基、碳环基或者杂环基的取代基所取代。
“炔基”是指含有1至3个碳-碳叁键，由2至20个碳原子组成的直链或者支链不饱和脂肪族烃基，优选2至12个碳原子的炔基，更优选2至8个碳原子的炔基，进一步优选2至6个碳原子的炔基。非限制性实施例包括乙炔基、丙炔-1-基、丙炔-2-基、丁炔-1-基、丁炔-2-基、丁炔-3-基、3,3-二甲基丁炔-2-基、戊炔-1-基、戊炔-2-基、己炔-1-基、1-庚炔-1-基、庚炔-3-基、庚炔-4-基、辛炔-3-基、壬炔-3-基、癸炔-4-基、十一炔-3-基、十二炔-4-基。所述的炔基可以任选进一步被0至4个选自F、Cl、Br、I、烷基、烷氧基、直链烯基、直链炔基、氨基、硝基、氰基、巯基、酰胺基、碳环基或者杂环基的取代基所取代。
“碳环基”是指饱和或者不饱和的非芳香环，非芳香环可以是3至8元的单环、4至12元稠合环或者10至15元三环体系，碳环基可以连接有桥环或者螺环，非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基和环十二烷基、环丁烯、环戊烯、环己烯、
Figure PCTCN2016110946-appb-000017
所述的碳环基可以任选进一步被0至8个选自F、Cl、Br、I、＝O、羟基、巯基、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基所取代。本文中出现的碳环基，其定义与本定义一致。
“杂环基”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，且包含1至3个选自N、O或S的杂原子，优选3至8元杂环基，杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂环基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、 1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。所述的杂环基可以任选进一步被0至5个选自F、Cl、Br、I、＝O、羟基、巯基、硝基、氰基、氨基、烷基氨基、酰胺基、烯基、炔基、烷基、羟基烷基、烷氧基、碳环基、杂环基、碳环基氧基、杂环基氧基、羧基或者羧酸酯基的取代基所取代。本文中出现的杂环基，其定义与本定义一致。
“氨基保护基”是指是指用于氨基保护的基团，该基团适用于保护氨基，使氨基不进行化学反应，但是在分子的其它部分完成所需化学反应之后该基团容易除去。非限制性实施例包括但不限于甲酰基、乙酰基、苯基酰基、甲氧基羰基、乙氧基羰基、2,2,2-三氯乙氧羰基、丙氧基羰基、叔丁氧基羰基、苄基氧基羰基、苯氧基羰基、9-芴基甲基氧基羰基、金刚烷基氧基羰基、苄基氧基羰基、苄基羰基、苄基、苯甲基、三苯甲基、邻苯二甲酰基。
“羧基保护基”是指用于羧基保护的基团，该基团适用于保护羧基，使羧基不进行化学反应，但是在分子的其它部分完成所需化学反应之后该基团容易除去。非限制性实施例包括但不限于指甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基、三氯乙基、苄基、对硝基苄基、邻硝基苄基、对甲氧基苄基、对叔丁基苄基、乙酰氧基甲基、丙酰氧基甲基、丁酰氧基甲基、异丁酰氧基甲基、戊氧基甲基、新戊酰氧基甲基、乙酰氧基乙基、乙酰氧基丙基、乙酰氧基丁基、丙酰氧基乙基、丙酰氧基丙基、丁酰氧基乙基、异丁酰氧基乙基、新戊酰氧基乙基、己酰氧基乙基、异丁酰氧基甲基、乙基丁酰氧基甲基、二甲基丁酰氧基甲基、戊酰氧基乙基、甲氧基羰氧基甲基、乙氧基羰氧基甲基、丙氧基羰氧基乙基、异丙氧基羰氧基乙基、叔丁氧基羰氧基甲基、甲氧基羰氧基乙基、乙氧基羰氧基乙基、异丙氧基羰氧基乙基、叔丁基二甲基甲硅烷基、三甲基甲硅烷基、甲氧基甲基、乙氧基甲基、丙氧基甲基、异丙氧基甲基、(2-甲基硫代)-乙基、3-甲基-2-丁烯基、5-茚满基和3-2-苯并[C]呋喃酮亚基。
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。所述的无机碱的非限制性实施 例包括Al、Ca、Li、Mg、K、Na和Zn；所述的有机碱的非限制性实施例包括氨、异丙基胺、三甲基胺、二乙胺、三乙胺、三丙基胺、四甲基胺、二乙醇胺、乙醇胺、二甲基乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己基胺、咖啡碱、普鲁卡因、胆碱、甜菜碱、苯明青霉素、乙二胺、葡萄糖胺、N-甲基甲基葡糖胺、可可碱、三乙醇胺、氨丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶和聚胺树脂；所述的无机酸和有机酸的非限制性实施例包括硫酸、磷酸、硝酸、氢溴酸、盐酸、甲酸、乙酸、丙酸、苯磺酸、苯甲酸、苯乙酸、水杨酸、褐藻酸、氨茴酸、樟脑酸、柠檬酸、乙烯磺酸、蚁酸、富马酸、糠酸、葡萄糖酸、葡萄糖醛酸、谷氨酸、乙醇酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、粘液酸、双羟萘酸、泛酸、硬脂酸、琥珀酸、磺胺酸、酒石酸、对甲苯磺酸、丙二酸、2-羟基丙酸、草酸、羟乙酸、葡萄糖醛酸、半乳糖醛酸、枸橼酸、赖氨酸、精氨酸、门冬氨酸、肉桂酸、对甲苯磺酸、甲磺酸、乙磺酸和三氟甲磺酸。
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物，其中，“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的氨基或者羧基来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。当本发明的前药被施予哺乳动物个体时，前药被割裂形成游离的氨基或者羧基。
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体，其中API和CCF的纯态在室温下均为固体，并且各组分间存在固定的化学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共晶，也包含中性固体与盐或溶剂化物形成的多元共晶。非限定性实例包括丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、色氨酸、蛋氨酸、甘氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬酰胺、谷氨酰胺、赖氨酸、精氨酸、组氨酸、天冬氨酸、门冬氨酸、谷氨酸、焦谷氨酸、硫酸、磷酸、硝酸、氢溴酸、盐酸、甲酸、乙酸、丙酸、苯磺 酸、苯甲酸、苯乙酸、水杨酸、褐藻酸、氨茴酸、樟脑酸、柠檬酸、乙烯磺酸、蚁酸、富马酸、糠酸、葡萄糖酸、葡萄糖醛酸、谷氨酸、乙醇酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、粘液酸、双羟萘酸、泛酸、硬脂酸、琥珀酸、磺胺酸、酒石酸、对甲苯磺酸、丙二酸、2-羟基丙酸、草酸、羟乙酸、葡萄糖醛酸、半乳糖醛酸、枸橼酸、肉桂酸、对甲苯磺酸、甲磺酸、乙磺酸或三氟甲磺酸、氨、异丙基胺、三甲基胺、二乙胺、三乙胺、三丙基胺、二乙醇胺、乙醇胺、二甲基乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己基胺、咖啡碱、普鲁卡因、胆碱、甜菜碱、苯明青霉素、乙二胺、葡萄糖胺、甲基葡糖胺、可可碱、三乙醇胺、氨丁三醇、嘌呤、哌嗪、哌啶和N-乙基哌啶。
“动物”是指包括哺乳动物，例如人、陪伴动物、动物园动物和家畜，优选人、马或者犬。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生，该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如，“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在，该描述包括其中杂环基被烷基取代的情况，及其中杂环基未被烷基取代的情况。
IC50(被测量的抑制剂的半抑制浓度)：通过测试受试化合物50％抑制gabapentin与钙离子通道结合所需的浓度。
具体实施方式
以下结合附图及实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)；
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM)；
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm；
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体；
本发明的己知起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司；
氮气氛是指反应瓶连接一个约1L容积的氮气气球；
氢气氛是指反应瓶连接一个约1L容积的氢气气球；
氢化反应通常抽真空，充入氢气，反复操作3次；
实施例中无特殊说明，反应在氮气氛下进行；
实施例中无特殊说明，溶液是指水溶液；
实施例中无特殊说明，反应的温度为室温，室温最适宜的反应温度，为20℃-30℃；
Et，乙基；
tBu：叔丁基；
Ms：甲磺酰基；
PhSO3H：苯磺酸。
中间体1：(1aR,1a1r,3as,5aS)-八氢-1H-环丁烷[cd]戊搭烯-1-酮
(1aR,1a1r,3as,5aS)-octahydro-1H-cyclobuta[cd]pentalen-1-one
Figure PCTCN2016110946-appb-000018
第一步：(1S,5R,7S)-7-(2-氯乙基)双环[3.2.0]庚-2-烯-6-酮(1B)
(1S,5R,7S)-7-(2-chloroethyl)bicyclo[3.2.0]hept-2-en-6-one
Figure PCTCN2016110946-appb-000019
向反应瓶中加入1,3-环戊二烯(1A)(6.6g，0.1mol)，环己烷(350mL)，充氮气保护，加入三乙胺(3.5g，35mmol)，加热回流下，滴加4-氯丁酰氯(4.9g，35.0mmol)的环己烷(25mL)溶液，加完回流反应4小时。冷却至室温后将反应液抽滤，用环己烷洗涤(20mL×3)，合并滤液，依次用饱和氯化铵(150mL×3)和水(150mL×3)洗涤，有机相用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝80:1)得到淡黄色油状液体(1S,5R,7S)-7-(2-氯乙基)双环[3.2.0]庚-2-烯-6-酮(1B)(1.4g，产率：26％)。
1H NMR(400MHz,CDCl3)δ5.95-5.85(m,1H),5.76(ddd,J＝6.0,4.1,2.1Hz,1H),3.90-3.79(m,1H),3.74-3.52(m,4H),2.71-2.58(m,1H),2.48-2.33(m,1H),2.04(dq,J＝14.3,6.3Hz,1H),1.91-1.77(m,1H)。
第二步：(1aR,1a1r,3as,5aS)-八氢-1H-环丁烷[cd]戊搭烯-1-酮(中间体1)
(1aR,1a1r,3as,5aS)-octahydro-1H-cyclobuta[cd]pentalen-1-one
Figure PCTCN2016110946-appb-000020
向反应瓶中加入(1S,5R,7S)-7-(2-氯乙基)双环[3.2.0]庚-2-烯-6-酮(1B)(0.5g，3mmol)，充氮气保护，加入甲苯(125mL)，加热至回流，缓慢滴加三正丁基氢化锡(1.7g，6mmol)和偶氮二异丁腈(0.1g，0.6mmol)的甲苯溶液(40mL)，加毕回流下搅拌2小时。将反应液冷却，用水(150mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝100:1)得到无色油状液体(1aR,1a1r,3as,5aS)-八氢-1H-环丁烷[cd]戊搭烯-1-酮(中间体1)(0.2g，产率：50％)。
1H NMR(400MHz,CDCl3)δ3.53-3.38(m,2H),3.17(q,J＝7.6Hz,1H),2.85(tt,J＝12.5,6.2Hz,1H),2.00(ddd,J＝13.0,7.9,2.3Hz,2H),1.93-1.70(m,4H),1.54(dt,J＝11.8,6.6Hz,2H)。
实施例1
2-((1r,1aR,1a1r,3as,5aS)-1-(氨甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(化合物1)
2-((1r,1aR,1a1r,3as,5aS)-1-(aminomethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic  acid
Figure PCTCN2016110946-appb-000021
第一步：(2-((1aR,1a1r,3as,5aS)-八氢-1H-环丁烷[cd]戊搭烯-1-亚基)乙酸乙酯(1C)
Ethyl 2-((1aR,1a1r,3as,5aS)-octahydro-1H-cyclobuta[cd]pentalen-1-ylidene)acetate
Figure PCTCN2016110946-appb-000022
向反应瓶中加入氢化钠(60％，60mg，2.4mmol)和四氢呋喃(6mL)，冰水浴降至0℃，滴加三乙基磷酰乙酸酯(0.54g，2.4mmol)的四氢呋喃(2mL)溶液，0℃反应1小时，滴加(1aR,1a1r,3as,5aS)-八氢-1H-环丁烷[cd]戊搭烯-1-酮(中间体1)(0.2g，1.5mmol)的四氢呋喃(2mL)溶液，升至室温反应2小时。向反应液中加入水(10mL)和乙酸乙酯(10mL)，搅拌分液，水相用乙酸乙酯(10mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝40:1)得到无色油状液体(2-((1aR,1a1r,3as,5aS)-八氢-1H-环丁烷[cd]戊搭烯-1-亚基)乙酸乙酯(1C)(0.18g，产率：60％)。
MS m/z(ESI):207.3(M+1)。
1H NMR(400MHz,CDCl3)δ5.56(t,J＝2.2Hz,1H),4.22-4.08(q,2H),3.59-3.46(m,1H),3.27-3.12(m,1H),2.99(q,J＝7.4Hz,1H),2.74-2.57(m,1H),1.87-1.48(m,8H),1.30-1.23(t,3H)。
第二步：2-((1r,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸乙酯(1D)
ethyl 2-((1r,1aR,1a1r,3as,5aS)-1-(nitromethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetate
Figure PCTCN2016110946-appb-000023
向反应瓶中加入(2-((1aR,1a1r,3as,5aS)-八氢-1H-环丁烷[cd]戊搭烯-1-亚基)乙酸乙酯(1C)(2.0g，10.0mmol)，硝基甲烷(30mL)和1,8-二氮杂双环[5.4.0]十一碳-7-烯(1.5g，10.0mmol)，升温至70℃反应8小时。向反应液中加入乙酸乙酯(30mL)和1M的盐酸水溶液(20mL)，分液，水相用乙酸乙酯萃取(30mL×2)，合并有机相，用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝40:1)，得到无色油状液体2-((1r,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸乙酯(1D)(1.6g，产率：60％)。
1H NMR(400MHz,CDCl3)δ4.83(s,2H),4.13(q,J＝7.1Hz,2H),2.97(q,J＝7.9Hz,1H),2.65-2.45(m,5H),1.82-1.65(m,4H),1.64-1.53(m,2H),1.52-1.39(m,2H),1.26(dd,J＝8.4,5.9Hz,3H)。
第三步：2-((1r,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(1E)
2-((1r,1aR,1a1r,3as,5aS)-1-(nitromethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid
Figure PCTCN2016110946-appb-000024
向反应瓶中加入2-((1r,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸乙酯(1D)(1.5g，5.6mmol)，甲醇(18mL)，滴加氢氧化钠(0.3g，5.6mmol)的水溶液(6mL)，60℃下反应5小时。冰浴下滴加1M的盐酸至pH约为2，用乙酸乙酯(60mL×3)萃取，合并有机相，用水(60mL×3)洗涤，无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离纯化(二氯甲烷/甲醇(v/v)＝50:1)得到淡黄色油状液体2-((1r,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(1E)(0.8g，产率：61％)。
MS m/z(ESI):262.1(M+23)。
1H NMR(400MHz,CDCl3)δ4.83(s,2H),2.98(q,J＝7.9Hz,1H),2.66-2.46(m,5H),1.86-1.67(m,4H),1.66-1.53(m,2H),1.53-1.40(m,2H)。
第四步：2-((1r,1aR,1a1r,3as,5aS)-1-(氨甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(化合物1)
2-((1r,1aR,1a1r,3as,5aS)-1-(aminomethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid
Figure PCTCN2016110946-appb-000025
向反应瓶中依次加入2-((1r,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(1E)(0.6g，2.5mmol)，甲醇(15mL)，钯/碳(10％(w％)，0.6g)，氢气换气三次，35℃下氢化反应3小时，将反应液抽滤，甲醇(20mL×3)洗涤，合并滤液，将滤液减压浓缩得到白色固体，将所得固体用二氯甲烷(50mL)打浆，抽滤，二氯甲烷(15mL×3)洗涤，干燥，得到白色固体2-((1r,1aR,1a1r,3as,5aS)-1-(氨甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(化合物1)(0.22g，产率：46％)。
MS m/z(ESI):210.2(M+1)。
1H NMR(400MHz,CD3OD)δ3.13(s,2H),3.05-2.93(m,2H),2.42(s,2H),2.37(dd,J＝10.2,5.4Hz,2H),1.83-1.65(m,6H),1.58(qd,J＝10.7,5.2Hz,2H)。
实施例2
2-((1s,1aR,1a1r,3as,5aS)-1-(氨基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(化合物2)
2-((1s,1aR,1a1r,3as,5aS)-1-(aminomethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid
Figure PCTCN2016110946-appb-000026
第一步：(1aR,1a1r,3as,5aS)-1-(硝基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-醇(2B)
(1aR,1a1r,3as,5aS)-1-(nitromethyl)octahydro-1H-cyclobuta[cd]pentalen-1-ol
Figure PCTCN2016110946-appb-000027
向反应瓶中依次加入(1aR,1a1r,3as,5aS)-八氢-1H-环丁烷[cd]戊搭烯-1-酮(中间体1)(9.7g，71.2mmol)，硝基甲烷(100mL)和1,8-二氮杂双环[5.4.0]十一碳-7-烯(23.9g，157.0mmol)，室温反应7小时。加入饱和氯化铵溶液(150mL)，用二氯甲烷(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝100:1-10:1)得到无色油状液体(1aR,1a1r,3as,5aS)-1-(硝基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-醇(2B)(5.8g，产率：41％)。
MS m/z(ESI):220.2(M+23)。
1H NMR(400MHz,CDCl3)δ4.54(s,2H),2.75-2.67(m,1H),2.64(ddd,J＝10.6,7.1,3.2Hz,1H),2.59-2.53(m,2H),1.97-1.88(m,2H),1.78-1.51(m,6H)。
第二步：(1aR,1a1r,3as,5aS)-1-(硝基亚甲基)八氢-1H-环丁烷[cd]戊搭烯(2C)
(1aR,1a1r,3as,5aS)-1-(nitromethylene)octahydro-1H-cyclobuta[cd]pentalene
Figure PCTCN2016110946-appb-000028
向反应瓶中加入(1aR,1a1r,3as,5aS)-1-(硝基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-醇(2B)(8.5g，43.0mmol)，三乙胺(13.0g，130.0mmol)和二氯甲烷(215mL)，冷却至0℃，滴加甲烷磺酰氯(15.0g，130.0mmol)，室温反应2小时。向反应液中加入水(50mL)，分液，用二氯甲烷(50mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝200:1)得到无色油状液体(1aR,1a1r,3as,5aS)-1-(硝基亚甲基)八氢-1H-环丁烷[cd]戊搭烯(2C)(4.0g，产率：52％)。
MS m/z(ESI):202.2(M+23)。
1H NMR(400MHz,CDCl3)δ6.85(t,J＝2.0Hz,1H),3.77-3.69(m,1H),3.32(td,J＝7.8,2.0Hz,1H),3.10(q,J＝7.3Hz,1H),2.75(dd,J＝11.1,6.3Hz,1H),2.10(dtd,J＝14.6,8.7,5.9Hz,1H),2.03-1.93(m,2H),1.91-1.75(m,2H),1.68-1.52(m,3H)。
第三步：2-((1s,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸乙酯(2D)
ethyl 2-((1s,1aR,1a1r,3as,5aS)-1-(nitromethyl)octahydro-1H-cyclobuta[cd]pentalen-1- yl)acetate
Figure PCTCN2016110946-appb-000029
向反应瓶中加入双(三甲硅基)氨基锂(1.0mol/L，6.7g，40.0mmol)，冷却至-78℃，滴加乙酸乙酯(3.5g，40.0mmol)的四氢呋喃(4mL)溶液，搅拌20分钟，滴加(1aR,1a1r,3as,5aS)-1-(硝基亚甲基)八氢-1H-环丁烷[cd]戊搭烯(2C)(4.0g，22.0mmol)的四氢呋喃(15mL)溶液，-78℃下反应2小时，加入水(50mL)，用乙酸乙酯(30mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝100:1)得到淡黄色油状液体2-((1s,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸乙酯(2D)(4.0g，产率：67％)。
MS m/z(ESI):290.1(M+23)。
1H NMR(400MHz,CDCl3)δ4.68(s,2H),4.15(q,J＝7.1Hz,2H),2.98(q,J＝7.8Hz,1H),2.77(s,2H),2.65-2.56(m,1H),2.48(td,J＝7.8,4.0Hz,2H),1.83-1.72(m,4H),1.72-1.61(m,2H),1.53-1.44(m,2H),1.26(dd,J＝8.9,5.4Hz,3H)。
第四步：2-((1s,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(2E)
2-((1s,1aR,1a1r,3as,5aS)-1-(nitromethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid
Figure PCTCN2016110946-appb-000030
向反应瓶中加入2-((1s,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸乙酯(2D)(4.0g，15.0mmol)，甲醇(24mL)，滴加氢氧化钠(0.9g，22.0mmol)的水溶液(8mL)，60℃下反应5小时。冰浴下滴加1M的盐酸至pH约为2，用乙酸乙酯(60mL×3)萃取，合并有机相，用水(60mL×3)洗涤，无水硫酸钠干燥，过滤，将滤液减压浓缩，残留物用硅胶柱色谱分离纯化(二氯甲烷/甲醇(v/v)＝50:1)得到淡黄色油状液体2-((1s,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(2E)(2.7g，产率：75％)。
MS m/z(ESI):262.1(M+23)。
1H NMR(400MHz,CDCl3)δ4.68(s,2H),3.00(q,J＝7.8Hz,1H),2.87(s,2H),2.61(dt,J＝15.6,6.0Hz,1H),2.49(dt,J＝11.6,5.8Hz,2H),1.84-1.72(m,4H),1.71-1.61(m,2H), 1.55-1.43(m,2H)。
第五步：2-((1s,1aR,1a1r,3as,5aS)-1-(氨基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(化合物2)
2-((1s,1aR,1a1r,3as,5aS)-1-(aminomethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid
Figure PCTCN2016110946-appb-000031
向反应瓶中依次加入2-((1s,1aR,1a1r,3as,5aS)-1-(硝基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(2E)(2.7g，11.3mmol)，甲醇(60mL)，钯/碳(10％(w％)，2.7g)，氢气换气三次，35℃下氢化反应3小时，将反应液抽滤，甲醇(20mL×3)洗涤，将合并后的滤液减压浓缩，所得的固体用二氯甲烷(60mL)打浆，抽滤，二氯甲烷(15mL×3)洗涤，干燥，得到白色固体2-((1s,1aR,1a1r,3as,5aS)-1-(氨基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(化合物2)(1.0g，产率：42％)。
MS m/z(ESI):210.2(M+1)。
1H NMR(400MHz,CD3OD)δ3.05(q,J＝7.9Hz,1H),2.97(s,2H),2.69(s,2H),2.60(dt,J＝11.4,5.4Hz,1H),2.44(td,J＝7.9,3.9Hz,2H),1.85-1.72(m,4H),1.69-1.59(m,2H),1.59-1.51(m,2H)。
实施例3
2-((1r,1aR,1a1r,3as,5aS)-1-(氨甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基乙酸苯磺酸盐(1:1)(化合物3)
2-((1r,1aR,1a1r,3as,5aS)-1-(aminomethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid benzenesulfonic acid(1:1)
Figure PCTCN2016110946-appb-000032
第一步：2-((1r,1aR,1a1r,3as,5aS)-1-(氨甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸苯 磺酸盐(1:1)(化合物3)
2-((1r,1aR,1a1r,3as,5aS)-1-(aminomethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid benzenesulfonic acid(1:1)
Figure PCTCN2016110946-appb-000033
向反应瓶中加入2-((1r,1aR,1a1r,3as,5aS)-1-(氨甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(化合物1)(0.32g，1.53mmol)，甲醇(50mL)，搅拌至完全溶解，滴加苯甲磺酸(0.24g，1.53mmol)的甲醇(5mL)溶液，35℃下反应1小时，将反应液浓缩至干，得到白色固体2-((1r,1aR,1a1r,3as,5aS)-1-(氨甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸苯磺酸盐(1:1)(化合物3)(0.55g，产率：99％)。
1H NMR(400MHz,CD3OD)δ7.91-7.79(m,2H),7.52-7.37(m,3H),3.33(s,2H),3.01(q,J＝7.9Hz,1H),2.62(ddd,J＝12.1,7.9,4.3Hz,1H),2.47(s,2H),2.39(td,J＝7.7,3.9Hz,2H),1.86-1.63(m,6H),1.61-1.47(m,2H)。
实施例4
2-((1r,1aR,1a1r,3as,5aS)-1-(氨基甲基)-3a-乙基八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(化合物4)
2-((1r,1aR,1a1r,3as,5aS)-1-(aminomethyl)-3a-ethyloctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid
Figure PCTCN2016110946-appb-000034
Figure PCTCN2016110946-appb-000035
第一步：(±)-(1S,5R,7S)-7-(2-溴乙基)双环[3.2.0]庚-2-烯-6-酮(4B)
(1S,5R,7S)-7-(2-bromoethyl)bicyclo[3.2.0]hept-2-en-6-one
Figure PCTCN2016110946-appb-000036
向反应瓶中加入1,3-环戊二烯(1A)(26.4g，0.4mol)和环己烷(1200mL)，充氮气保护，加入三乙胺(24.2g，0.24mol)，加热至回流，滴加4-溴丁酰氯(44.4g，0.24mol)的环己烷溶液(50mL，25mL/h)，加完回流反应4小时，将反应液抽滤，用环己烷(100mL×3)洗涤滤渣，合并滤液，依次用饱和氯化铵(500mL×3)洗涤，水(500mL×3)洗，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝80:1)得到淡黄色油状液体(±)-(1S,5R,7S)-7-(2-溴乙基)双环[3.2.0]庚-2-烯-6-酮(4B)(12g，产率：24％)。
1H NMR(400MHz,CDCl3)δ5.97-5.85(m,1H),5.80-5.70(m,1H),3.91-3.79(m,1H),3.67(dd,J＝9.7,5.5Hz,2H),3.47(t,J＝6.8Hz,2H),2.68(ddd,J＝18.3,15.2,3.9Hz,1H),2.47-2.31(m,1H),2.13(dq,J＝21.0,6.5Hz,1H),1.93(ddd,J＝21.5,12.2,7.1Hz,1H)。
第二步：(±)-(1S,5R,7S)-7-(2-溴乙基)螺[双环[3.2.0]庚-[2]烯-6,2'-[1,3]二恶茂烷](4C)
(±)-(1S,5R,7S)-7-(2-bromoethyl)spiro[bicyclo[3.2.0]hept[2]ene-6,2'-[1,3]dioxolane]
Figure PCTCN2016110946-appb-000037
向反应瓶中依次加入(±)-(1S,5R,7S)-7-(2-溴乙基)双环[3.2.0]庚-2-烯-6-酮(4B)(37g，0.173mol)，对甲苯磺酸一水合物(1.6g，8.6mmol)，乙二醇(42.9g，0.692mol)和甲苯(320mL)，加热回流分水5小时，冷却后将反应液倒入冰水中，加入碳酸氢钠固体调节pH至中性，用乙酸乙酯(400mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(乙酸乙酯/石油醚＝1:100)得到黄色油状液体(±)-(1S,5R,7S)-7-(2-溴乙基)螺[双环[3.2.0]庚-[2]烯-6,2'-[1,3]二恶茂烷](4C)(27.4g，产率：61％)。
1H NMR(400MHz,CDCl3)δ5.94-5.83(m,1H),5.67-5.56(m,1H),3.95-3.75(m,4H),3.36-3.25(m,2H),3.23-3.12(m,1H),3.02(ddd,J＝22.9,15.7,8.0Hz,2H),2.48-2.25(m,2H),1.99-1.78(m,2H)。
第三步：(±)-(1S,5R,7S)-7-(2-溴乙基)螺[双环[3.2.0]庚-6,2'-[1,3]二氧戊烷]-3-醇(4D-1)
(±)-(1S,5R,7S)-7-(2-bromoethyl)spiro[bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolan]-2-ol
(±)-(1S,5R,7S)-7-(2-溴乙基)螺[双环[3.2.0]庚-6,2'-[1,3]二氧戊烷]-3-醇(4D-2)
(1S,5R,7S)-7-(2-bromoethyl)spiro[bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolan]-3-ol
Figure PCTCN2016110946-appb-000038
向反应瓶中加入(±)-(1S,5R,7S)-7-(2-溴乙基)螺[双环[3.2.0]庚-[2]烯-6,2'-[1,3]二恶茂烷](4C)(27.4g，0.11mol)和四氢呋喃(330mL)，冰水浴下滴加硼烷二甲硫醚溶液(55mL，0.55mol)，加完0℃下反应2个小时，冰水浴下滴加纯化水(1.1mol)，3M的氢氧化钠溶液(360mL)和双氧水(含双氧水1.1mol)，加完升至室温反应3小时，用乙酸乙酯(500mL×3)萃取，合并有机相，用饱和碳酸氢钠溶液(500mL×2)和水(500mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到淡黄色油状液体(±)-(1S,5R,7S)-7-(2-溴乙基)螺[双环[3.2.0]庚-6,2'-[1,3]二氧戊烷]-3-醇(4D-1)和(±)-(1S,5R,7S)-7-(2-溴乙基)螺[双环[3.2.0]庚-6,2'-[1,3]二氧戊烷]-3-醇(4D-2)的混合物(30g)，直接用于下一步反应。
第四步：(±)-(1S,5R,7S)-7-(2-溴乙基)螺[双环[3.2.0]庚-6,2'-[1,3]二氧戊烷]-2-酮(4E-1)
(±)-(1S,5R,7S)-7-(2-bromoethyl)spiro[bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolan]-2-one
(±)-(1S,5R,7S)-7-(2-溴乙基)螺[双环[3.2.0]庚-6,2'-[1,3]二氧戊烷]-3-酮(4E-2)
(±)-(1S,5R,7S)-7-(2-bromoethyl)spiro[bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolan]-3-one
Figure PCTCN2016110946-appb-000039
向反应瓶中加入(±)-(1S,5R,7S)-7-(2-溴乙基)螺[双环[3.2.0]庚-6,2'-[1,3]二氧戊烷]-3-醇(4D-1)和(±)-(1S,5R,7S)-7-(2-溴乙基)螺[双环[3.2.0]庚-6,2'-[1,3]二氧戊烷]-3-醇(4D-2)的混合物(30g，0.11mol)和二氯甲烷(500mL)，冰水浴下分批加入戴斯马丁氧化剂(70g，0.17mol)，室温反应2小时，向反应液中加入二氯甲烷(300mL)和2M的硫代硫酸钠水溶液(500mL)，搅拌30分钟，分液，水相用二氯甲烷(300mL×2)萃取，合并有机相，依次用2M的氢氧化钠溶液(500mL×2)和水(500mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1)得到淡黄色油状液体(±)-(1S,5R,7S)-7-(2-溴乙基)螺[双环[3.2.0]庚-6,2'-[1,3]二氧戊烷]-2-酮(4E-1)(15g，产率：50.4％)和淡黄色油状液体(±)-(1S,5R,7S)-7-(2-溴乙基)螺[双环[3.2.0]庚-6,2'-[1,3]二氧戊烷]-3-酮(4E-2)(3.7g，产率：12.4％)。
4E-1：1H NMR(400MHz,CDCl3)δ4.02-3.81(m,4H),3.40(dd,J＝10.3,3.8Hz,2H),3.15(td,J＝10.3,4.9Hz,2H),2.61(ddd,J＝20.6,14.0,8.1Hz,2H),2.27(ddt,J＝18.9,9.6,1.8Hz,1H),2.12-2.00(m,1H),1.99-1.70(m,3H)。
4E-2：1H NMR(400MHz,CDCl3)δ3.97-3.77(m,4H),3.30(dd,J＝10.5,3.6Hz,2H),3.17(t,J＝8.4Hz,1H),3.03(ddd,J＝15.6,7.7,3.2Hz,1H),2.83(qd,J＝8.8,6.2Hz,1H),2.34-2.24(m,3H),2.17(ddd,J＝18.7,8.6,1.5Hz,1H),2.01(dt,J＝14.2,7.1Hz,1H),1.91(dt,J＝14.5,7.3Hz,1H)。
第五步：(±)-2-((1S,5R,7S)-7-(2-溴乙基)螺[双环[3.2.0]庚烷-6,2'-[1,3]二氧戊环]-2-亚基)乙酸乙酯(4F)
(±)-ethyl-2-((1S,5R,7S)-7-(2-bromoethyl)spiro[bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolan]-2-ylidene)acetate
Figure PCTCN2016110946-appb-000040
将氢化钠(1.08g，16mmol)加入反应瓶中，加入四氢呋喃(30mL)，降温至0℃，滴加三乙基膦酰乙酸酯(5.4g，24mmol)的四氢呋喃溶液(10mL)，滴完，保温反应1小时，得到淡黄色溶液备用；在另一反应瓶中加入(±)-(1S,5R,7S)-7-(2-溴乙基)螺[双环[3.2.0]庚烷-6,2'-[1,3]二氧戊环]-2-酮(4E-1)(3.0g，11mmol)及四氢呋喃(20mL)，降温至0℃，滴加上述制备好的淡黄色溶液，滴完升温至10-15℃反应1小时。向反应液中加入水(100mL)和乙酸乙酯各(100mL)，搅拌分液，水相用乙酸乙酯(50mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝50:1-20:1)得到淡黄色液体(±)-2-((1S,5R,7S)-7-(2-溴乙基)螺[双环[3.2.0]庚烷-6,2'-[1,3]二氧戊环]-2-亚基)乙酸乙酯(4F)(1.5g，产率：40％)。
第六步：2-((1aR,1a1r,3as,5aS)-八氢螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊环]-3a-基)乙酸乙酯(4G)
Ethyl-2-((1aR,1a1r,3as,5aS)-octahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolan]-3a-yl)acetate
Figure PCTCN2016110946-appb-000041
反应瓶中加入(±)-2-((1S,5R,7S)-7-(2-溴乙基)螺[双环[3.2.0]庚烷-6,2'-[1,3]二氧戊环]-2-亚基)乙酸乙酯(4F)(0.5g，1.4mmol)，甲苯(50mL)，加热至90℃，滴加三丁基锡氢(0.84g，2.9mmol)及偶氮二异丁腈(0.048g，0.29mmol)预先溶于甲苯(25mL)的混合溶液(12.5mL/h)，滴完于90℃反应3小时。将反应液冷却至室温，加入饱和氟化钾水溶液(50mL)，搅拌后过滤，滤饼用乙酸乙酯(20mL×2)洗涤，将滤液分液，水相用乙酸乙酯(20mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝50:1-20:1)得到无色油状液体2-((1aR,1a1r,3as,5aS)-八氢螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊环]-3a-基)乙酸乙酯(4G)(0.1g，产率：30％)。
MS m/z(ESI):289.3(M+23)。
1H NMR(400MHz,CDCl3)δ4.13(d,2H),3.85(d,4H),3.16(q,1H),2.81-2.70(m,1H),2.62-1.51(m,2H),2.37(s,2H),1.87-1.62(m,2H),1.51–1.44(m,3H),1.24(t,4H),0.82(t,1H)。
第七步：2-((1aR,1a1r,3as,5aS)-八氢螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊环]-3a-基)乙醇(4H)
2-((1aR,1a1r,3as,5aS)-octahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolan]-3a-yl)ethanol
Figure PCTCN2016110946-appb-000042
反应瓶中加入四氢铝锂(0.014g，0.38mmol)和四氢呋喃(2mL)，冰浴冷却，滴加2-((1aR,1a1r,3as,5aS)-八氢螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊环]-3a-基)乙酸乙酯(4G)(0.1g，0.38mmol)的四氢呋喃溶液(1mL)，冰浴下反应1小时，向反应液中滴加水(1mL)，过滤，滤饼用乙酸乙酯(5mL×2)洗涤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝5:1-3:1)得到无色油状物2-((1aR,1a1r,3as,5aS)-八氢螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊环]-3a-基)乙醇(4H)(0.05g，产率：60％)。
MS m/z(ESI):225.2(M+1)。
1H NMR(400MHz,CDCl3)δ3.91-3.82(m,4H),3.74(t,2H),2.83-2.67(m,1H),2.58-2.49(m,2H),1.76-1.26(m,9H),1.10(dd,1H)。
第八步：2-((1aR,1a1r,3as,5aS)-八氢螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊环]-3a-基)乙基甲磺酸酯(4I)
2-((1aR,1a1r,3as,5aS)-octahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolan]-3a-yl)ethylmethanesulfonate
Figure PCTCN2016110946-appb-000043
向反应瓶中依次加入2-((1aR,1a1r,3as,5aS)-八氢螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊环]-3a-基)乙醇(4H)(1.80g，8.02mmol)，二氯甲烷(20mL)和三乙胺(1.62g，16.0mmol)，冰浴冷却，滴加甲烷磺酰氯(1.38g，12.0mmol)，室温反应2小时，向反应液中加入二氯甲烷(10mL)和水(10mL)，搅拌分液，水层用二氯甲烷(10mL×2)萃取，合并有机相，用1M的盐酸(10mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1-3:1)得到无色油状物2-((1aR,1a1r,3as,5aS)-八氢螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊环]-3a-基)乙基甲磺酸酯(4I)(2.2g，产率：91％)。
1H NMR(400MHz,CDCl3)δ4.32(t,2H),3.91-3.81(m,4H),3.00(s,3H),2.81-2.69(m,1H),2.65-2.44(m,2H),1.94-1.20(m,9H),1.11(dd,1H)。
第九步：(1aR,1a1r,3as,5aS)-3a-乙基八氢螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊环](4J)(1aR,1a1r,3as,5aS)-3a-ethyloctahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolane]
Figure PCTCN2016110946-appb-000044
向反应瓶中加入2-((1aR,1a1r,3as,5aS)-八氢螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊环]-3a-基)乙基甲磺酸酯(4I)(2.2g，7.3mmol)和四氢呋喃(35mL)，降温至0℃，加入四氢铝锂(0.83g，22mmol)，加完升至室温反应3小时，冰浴冷却反应液，滴加水(1mL)，过滤，滤饼用乙酸乙酯(10mL×2)洗涤，将滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝200:1-100:1)得到无色油状物(1aR,1a1r,3as,5aS)-3a-乙基八氢螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊环](4J)(1.3g，产率：86％)。
1H NMR(400MHz,CDCl3)δ3.91-3.82(m,4H),2.80-2.65(m,1H),2.57-2.50(m,2H),1.64-1.26(m,9H),1.02(dd,1H),0.88(t,3H)。
第十步：(1aR,1a1r,3as,5aS)-3a-乙基八氢-1氢-环丁烷[cd]戊搭烯-1-酮(4K)
(1aR,1a1r,3as,5aS)-3a-ethyloctahydro-1H-cyclobuta[cd]pentalen-1-one
Figure PCTCN2016110946-appb-000045
向反应瓶中加入(1aR,1a1r,3as,5aS)-3a-乙基八氢螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊环](4J)(1.3g，6.24mmol)，四氢呋喃(15mL)，水(5mL)和三氟醋酸(15mL)，升温至50℃反应3小时，过滤，滤液减压浓缩，加入乙酸乙酯(50mL)和水(50mL)，搅拌分液，水相用乙酸乙酯(20mL×2)萃取，合并有机相，用饱和碳酸氢钠溶液(20mL)洗涤，有机相无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝100:1-50:1)得到无色油状物(1aR,1a1r,3as,5aS)-3a-乙基八氢-1氢-环丁烷[cd]戊搭烯-1-酮(4K)(1.0g，产率：97.6％)。
MS m/z(ESI):187.2(M+23)。
1H NMR(400MHz,CDCl3)δ3.44-3.38(d,1H),3.28-3.07(m,1H),2.77(dd,1H),1.87-1.70(m,2H),1.62(ddd,1H),1.55-1.37(m,5H),1.31-1.23(m,2H),0.90(t,3H)。
第十一步：2-((1aR,1a1r,3as,5aS)-3a-乙基八氢-1氢-环丁烷[cd]戊搭烯-1-亚基)乙酸叔丁酯(4L)
tert-butyl-2-((1aR,1a1r,3as,5aS)-3a-ethyloctahydro-1H-cyclobuta[cd]pentalen-1-ylidene)a cetate
Figure PCTCN2016110946-appb-000046
将氢化钠(0.37g，9.1mmol，60％)和四氢呋喃(20mL)加入反应瓶中，降温至0℃，滴加二乙基膦酰基乙酸叔丁酯(2.3g，9.1mmol)的四氢呋喃溶液(5mL)，0℃反应1小时，滴加(1aR,1a1r,3as,5aS)-3a-乙基八氢-1氢-环丁烷[cd]戊搭烯-1-酮(4K)(1.0g，6.1mmol)的四氢呋喃溶液(5mL)，滴完升至室温反应1小时。向反应液中加入乙酸乙酯(20mL)和水(20mL)，搅拌分液，水相用乙酸乙酯(10mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝200:1-100:1)，得到无色油状物2-((1aR,1a1r,3as,5aS)-3a-乙基八氢-1氢-环丁烷[cd]戊搭烯-1-亚基)乙酸叔丁酯(4L)(1.3g，产率：81％)。
第十二步：2-((1r,1aR,1a1r,3as,5aS)-3a-乙基-1-(硝基甲基)八氢-1氢-环丁烷[cd]戊搭烯-1-基)乙酸叔丁酯(4M)
tert-butyl 2-((1r,1aR,1a1r,3as,5aS)-3a-ethyl-1-(nitromethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetate
Figure PCTCN2016110946-appb-000047
向反应瓶中加入2-((1aR,1a1r,3as,5aS)-3a-乙基八氢-1氢-环丁烷[cd]戊搭烯-1-亚基)乙酸叔丁酯(4L)(1.3g，4.95mmol)，1,5-二氮杂二环[5.4.0]十一-5-烯(1.51g，9.91mmol)和硝基甲烷(20mL)，升温至90℃反应8小时。将反应液降温至室温，加入二氯甲烷(50mL)及水(50mL)，搅拌分液，水相用二氯甲烷(20mL×2)萃取，合并有机相，用水(20mL×3)洗涤，有机相无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝200:1)得到无色油状2-((1r,1aR,1a1r,3as,5aS)-3a-乙基-1-(硝基甲基)八氢-1氢-环丁烷[cd]戊搭烯-1-基)乙酸叔丁酯(4M)(0.8g，产率：50％)。
1H NMR(400MHz,CDCl3)δ4.82(s,2H),2.87(dt,1H),2.61-2.56(m,1H),2.51(q,2H),2.33(dt,1H),1.79-1.26(m,18H),1.08(dd,1H),0.88(t,3H)。
第十三步：2-((1r,1aR,1a1r,3as,5aS)-1-(氨基甲基)-3a-乙基八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸叔丁酯(4N)
tert-butyl 2-((1r,1aR,1a1r,3as,5aS)-1-(aminomethyl)-3a-ethyloctahydro-1H-cyclobuta [cd]pentalen-1-yl)acetate
Figure PCTCN2016110946-appb-000048
向反应瓶中依次加入2-((1r,1aR,1a1r,3as,5aS)-3a-乙基-1-(硝基甲基)八氢-1氢-环丁烷[cd]戊搭烯-1-基)乙酸叔丁酯(4M)(1.25g，3.87mmol)，铁粉(1.08g，19.3mmol)，氯化铵(1.03g，19.3mmol)，乙醇(10mL)和水(5mL)，升温至回流反应6小时。过滤，滤饼用乙醇(10mL×3)洗涤，滤液减压浓缩，加入乙酸乙酯(50mL)和水(50mL)，搅拌分液，水相用乙酸乙酯(20mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(二氯甲烷/甲醇(v/v)＝20:1-15:1)得到无色糖浆状2-((1r,1aR,1a1r,3as,5aS)-1-(氨基甲基)-3a-乙基八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸叔丁酯(4N)(1.1g，产率：97％)。
MS m/z(ESI):294.2(M+1)。
1H NMR(400MHz,CDCl3)δ3.29(d,2H),2.95-2.88(m,1H),2.67-2.40(m,3H),2.25(brs,1H),1.76-1.26(m,18H),1.06(dd,1H),0.87(t,3H)。
第十四步：2-((1r,1aR,1a1r,3as,5aS)-1-(氨基甲基)-3a-乙基八氢-1氢-环丁烷[cd]戊搭烯-1-基)乙酸(化合物4)
2-((1r,1aR,1a1r,3as,5aS)-1-(aminomethyl)-3a-ethyloctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid
Figure PCTCN2016110946-appb-000049
向反应瓶中加入2-((1r,1aR,1a1r,3as,5aS)-1-(氨基甲基)-3a-乙基八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸叔丁酯(4N)(1.1g，3.75mmol)，三氟醋酸(7mL)和二氯甲烷(7mL)，室温搅拌3小时，滤液减压浓缩，加入二氯甲烷(20mL)，用三乙胺调节体系pH为8-9，过滤，滤饼用二氯甲烷(10mL×3)洗涤，得到白色固体2-((1r,1aR,1a1r,3as,5aS)-1-(氨基甲基)-3a-乙基八氢-1氢-环丁烷[cd]戊搭烯-1-基)乙酸(化合物4)(0.7g，产率：79％)。
MS m/z(ESI):238.3(M+1)。
1H NMR(400MHz,MeOD)δ3.15(d,2H),2.89(dd,1H),2.59-2.46(m,3H),2.12-2.08(m,1H),1.77-1.31(m,9H),1.09(dd,1H),0.93(t,3H)。
实施例5
2-((1r,1aR,1a1r,3as,5aS)-1-(氨基甲基)-3a-乙基八氢-1氢-环丁烷[cd]戊搭烯-1-基)乙酸苯磺酸盐(1:1)(化合物5)
2-((1r,1aR,1a1r,3as,5aS)-1-(aminomethyl)-3a-ethyloctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid benzenesulfonic acid(1:1)
Figure PCTCN2016110946-appb-000050
第一步：2-((1r,1aR,1a1r,3as,5aS)-1-(氨基甲基)-3a-乙基八氢-1氢-环丁烷[cd]戊搭烯-1-基)乙酸苯磺酸盐(1:1)(化合物5)
2-((1r,1aR,1a1r,3as,5aS)-1-(aminomethyl)-3a-ethyloctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid benzenesulfonic acid(1:1)
Figure PCTCN2016110946-appb-000051
向反应瓶中加入2-((1r,1aR,1a1r,3as,5aS)-1-(氨基甲基)-3a-乙基八氢-1氢-环丁烷[cd]戊搭烯-1-基)乙酸(化合物4)(0.4g，1.7mmol)，苯磺酸一水合物(0.45g，2.55mmol)和甲醇(8mL)，室温搅拌30分钟，过滤，滤液减压浓缩，加入乙酸乙酯(10mL)打浆，过滤，滤饼用乙酸乙酯(5mL)洗涤，得到白色固体2-((1r,1aR,1a1r,3as,5aS)-1-(氨基甲基)-3a-乙基八氢-1氢-环丁烷[cd]戊搭烯-1-基)乙酸苯磺酸盐(1:1)(化合物5)(0.56g，产率：84％)。
MS m/z(ESI):238.3(M+1)。
1H NMR(400MHz,MeOD)δ7.85(dd,2H),7.44(dd,3H),3.30(d,2H),2.91(dd,1H),2.68-2.41(m,3H),2.27-2.06(m,1H),1.85-1.37(d,9H),1.11(dd,1H),0.93(t,3H)。
实施例6
(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨甲基)-3-亚甲基八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(化合物6)
(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(aminomethyl)-3-methyleneoctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid
Figure PCTCN2016110946-appb-000052
第一步：(±)-(1aR,1a1R,3aR,5aS)-六氢螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊烷]-3(1a1H)-酮(6B)
(±)-(1aR,1a1R,3aR,5aS)-hexahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolan]-3(1a1H)-one
Figure PCTCN2016110946-appb-000053
向反应瓶中加入叔丁醇钾(0.58g，5.2mmol)和甲苯(40mL)，充氮气保护，降温至-15℃，滴加(±)-(1S,5R,7S)-7-(2-溴乙基)螺[双环[3.2.0]庚-6,2'-[1,3]二氧戊烷]-3-酮(4E-2)(1.1g，4mmol)的甲苯(5mL)溶液，加完-15℃下搅拌1小时，升温至0℃搅拌1小时，冰水浴下滴加饱和氯化铵溶液至pH为约为7，用乙酸乙酯(80mL×3)萃取，合并有机相，用水(80mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝8:1)得到淡黄色油状液体(±)-(1aR,1a1R,3aR,5aS)-六氢螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊烷]-3(1a1H)-酮(6B)(0.5g，产率：61％)。
1H NMR(400MHz,CDCl3)δ3.99-3.77(m,4H),3.30(t,J＝7.1Hz,1H),3.17(t,J＝8.4Hz,1H),3.09-2.96(m,1H),2.83(qd,J＝8.8,6.3Hz,1H),2.34-2.24(m,3H),2.24-2.12(m,1H), 2.02(dd,J＝14.3,7.2Hz,1H),1.90(dd,J＝14.6,7.4Hz,1H)。
第二步：(±)-(1aR,1a1R,3aR,5aS)-3-亚甲基八氢螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊烷](6C)
(±)-(1aR,1a1R,3aR,5aS)-3-methyleneoctahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolane]
Figure PCTCN2016110946-appb-000054
向反应瓶中加入三苯基甲基溴化膦(10.7g，30mmol)和四氢呋喃(60mL)，氮气保护，降温至0℃，分批加入叔丁醇钾(3.4g，30mmol)，室温搅拌30分钟，冰水浴下滴加(±)-(1aR,1a1R,3aR,5aS)-六氢螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊烷]-3(1a1H)-酮(6B)(1.94g，10mmol)的四氢呋喃(10mL)溶液，加完升温至室温反应2小时，冰水浴下滴加饱和氯化铵溶液至pH约为7，用乙酸乙酯(100mL×3)萃取，合并有机相，用水(150mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1)得到淡黄色油状液体(±)-(1aR,1a1R,3aR,5aS)-3-亚甲基八氢螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊烷](6C)(1.4g，产率：74％)。
第三步：(±)-(1aR,1a1R,3aR,5aS)-3-亚甲基八氢-1H-环丁烷[cd]戊搭烯-1-酮(6D)
(±)-(1aR,1a1R,3aR,5aS)-3-methyleneoctahydro-1H-cyclobuta[cd]pentalen-1-one
Figure PCTCN2016110946-appb-000055
向反应瓶中加入(±)-(1aR,1a1R,3aR,5aS)-3-亚甲基八氢螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊烷](6C)(0.77g，4mmol)，加入四氢呋喃(6mL)和水(2mL)，冰浴下滴加三氟醋酸(2mL)，50℃反应3小时，冰浴下滴加饱和碳酸氢钠溶液至pH约为7，用乙酸乙酯(60mL×3)萃取，合并有机相，用水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝100:1)得到白色固体(±)-(1aR,1a1R,3aR,5aS)-3-亚甲基八氢-1H-环丁烷[cd]戊搭烯-1-酮(6D)(0.54g，产率：90％)。
1H NMR(400MHz,CDCl3)δ4.94(d,J＝18.3Hz,2H),3.54-3.37(m,2H),3.15-3.02(m,1H),2.70(dd,J＝8.6,5.7Hz,1H),2.22-2.07(m,1H),1.94-1.83(m,1H),1.62-1.46(m,2H), 1.46-1.30(m,2H)。
第四步：(±)-2-((1aR,1a1R,3aR,5aS)-3-亚甲基八氢-1H-环丁烷[cd]戊搭烯-1-亚基)乙酸叔丁酯(6E)
(±)-tert-butyl 2-((1aR,1a1R,3aR,5aS)-3-methyleneoctahydro-1H-cyclobuta[cd]pentalen-1-ylidene)acetate
Figure PCTCN2016110946-appb-000056
向反应瓶中加入氢化钠(60％，0.13g，5.4mmol)和四氢呋喃(10mL)，降温至0℃，滴加二乙基磷酰乙酸叔丁酯(1.2g，5.4mmol)的四氢呋喃(3mL)溶液，滴完0℃下反应20分钟，滴加(±)-(1aR,1a1R,3aR,5aS)-3-亚甲基八氢-1H-环丁烷[cd]戊搭烯-1-酮(6D)(0.54g，3.6mmol)的四氢呋喃(2mL)溶液，升温至室温反应2小时，向反应液中加入水(50mL)和乙酸乙酯(50mL)，搅拌，分液，水相用乙酸乙酯(40mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝100:1)得到淡黄色油状液体(±)-2-((1aR,1a1R,3aR,5aS)-3-亚甲基八氢-1H-环丁烷[cd]戊搭烯-1-亚基)乙酸叔丁酯(6E)(0.65g，产率：81％)。
1H NMR(400MHz,CDCl3)δ5.49(dd,J＝22.2,20.7Hz,1H),4.78(dd,J＝14.8,13.6Hz,2H),3.83-3.62(m,1H),3.32-3.17(m,1H),3.09-2.98(m,1H),2.63(dd,J＝8.3,6.0Hz,1H),2.15-1.89(m,2H),1.76(ddd,J＝9.8,5.6,2.2Hz,1H),1.64-1.55(m,1H),1.53-1.41(m,11H)。
第五步：(±)-2-((1R,1aR,1a1R,3aR,5aS)-3-亚甲基-1-(硝基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸叔丁酯(6F)
(±)-tert-butyl 2-((1R,1aR,1a1R,3aR,5aS)-3-methylene-1-(nitromethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetate
Figure PCTCN2016110946-appb-000057
向反应瓶中加入(±)-2-((1aR,1a1R,3aR,5aS)-3-亚甲基八氢-1H-环丁烷[cd]戊搭烯-1-亚基)乙酸叔丁酯(6E)(3.2g，14.7mmol)，硝基甲烷(50mL)和1,8-二氮杂双环[5.4.0]十一碳-7-烯(3.3g，22mmol)，升温至70℃反应6小时。向反应液中加入乙酸乙酯(60mL)和1M 的盐酸溶液(60mL)，搅拌，分液，水相用乙酸乙酯(100mL×2)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝100:1)，得到无色油状液体(±)-2-((1R,1aR,1a1R,3aR,5aS)-3-亚甲基-1-(硝基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸叔丁酯(6F)(3.5g，产率：85％)。
1H NMR(400MHz,CDCl3)δ4.91-4.70(m,4H),3.15-3.05(m,1H),2.75-2.60(m,3H),2.58(d,J＝1.5Hz,2H),2.15(dt,J＝13.7,9.0Hz,1H),1.94(dddd,J＝15.4,9.0,6.3,1.5Hz,1H),1.81-1.52(m,4H),1.46(s,9H)。
第六步：(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨甲基)-3-亚甲基八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸叔丁酯(6G)
(±)-tert-butyl 2-((1R,1aR,1a1R,3aR,5aS)-1-(aminomethyl)-3-methyleneoctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetate
Figure PCTCN2016110946-appb-000058
向反应瓶中加入(±)-2-((1R,1aR,1a1R,3aR,5aS)-3-亚甲基-1-(硝基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸叔丁酯(6F)(4g，13mmol)，乙醇(32mL)和水(16mL)，加入还原铁粉(4.3g，78mmol)和氯化铵(4.1g，78mmol)，回流反应6小时。将反应液冷却后抽滤，用乙酸乙酯(50L×3)洗涤滤渣，收集滤液，减压浓缩，水相用乙酸乙酯(10L×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(二氯甲烷/甲醇(v/v)＝40:1-10:1)，得到白色固体(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨甲基)-3-亚甲基八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸叔丁酯(6G)(3.0g，产率：83％)。
第七步：(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨甲基)-3-亚甲基八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(化合物6)
(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(aminomethyl)-3-methyleneoctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid
Figure PCTCN2016110946-appb-000059
向反应瓶中加入(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨甲基)-3-亚甲基八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸叔丁酯(6G)(0.28g，1mmol)，甲醇(3mL)和水(3mL)，加入氢氧化 钠(0.72g，18mmol)，回流反应10小时，减压浓缩以除去甲醇，用2M的盐酸调节pH为7-8，有白色固体析出，抽滤，滤饼用水(20mL×3)和二氯甲烷(30mL×3)洗涤，烘干，得到白色固体(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨甲基)-3-亚甲基八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(化合物6)(0.15g，产率：68％)。
MS m/z(ESI):222.3(M+1)。
1H NMR(400MHz,D2O)δ4.82(d,J＝1.7Hz,1H),4.74(d,J＝1.6Hz,1H),3.31-3.19(m,2H),3.13-3.04(m,1H),2.65(t,J＝6.9Hz,1H),2.53(dt,J＝24.1,16.9Hz,3H),2.35(d,J＝2.6Hz,1H),2.16-2.01(m,1H),1.91-1.79(m,1H),1.72(dt,J＝13.7,9.5Hz,1H),1.60(d,J＝13.9Hz,1H),1.57-1.37(m,2H)。
实施例7
(±)-2-((1R,1aR,1a1R,3aS,5aS)-1-(氨甲基)-3-甲基八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(化合物7)
(±)-2-((1R,1aR,1a1R,3aS,5aS)-1-(aminomethyl)-3-methyloctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid
Figure PCTCN2016110946-appb-000060
第一步：(±)-(1R,1aR,1a1R,3aR,5aS)-3-亚甲基八氢螺[环丁烷[cd]戊搭烯-1,3'-吡咯烷]-5'-酮(7B)
(±)-(1R,1aR,1a1R,3aR,5aS)-3-methyleneoctahydrospiro[cyclobuta[cd]pentalene-1,3'-pyrrolidin]-5'-one
Figure PCTCN2016110946-appb-000061
向反应瓶中加入(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨甲基)-3-亚甲基八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸叔丁酯(6G)(1.12g，4mmol)，甲醇(15mL)和水(15mL)，加入氢氧 化钠(0.72g，18mmol)，回流反应1小时，冷却后减压浓缩以除去甲醇，用二氯甲烷(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，减压浓缩，得到灰白色固体(±)-(1R,1aR,1a1R,3aR,5aS)-3-亚甲基八氢螺[环丁烷[cd]戊搭烯-1,3'-吡咯烷]-5'-酮(7B)(0.5g，产率：61％)，直接用于下一步反应。
第二步：(±)-(1R,1aR,1a1R,3aR,5aS)-3-甲基八氢螺[环丁烷[cd]戊搭烯-1,3'-吡咯烷]-5'-酮(7C)
(±)-(1R,1aR,1a1R,3aS,5aS)-3-methyloctahydrospiro[cyclobuta[cd]pentalene-1,3'-pyrrolidin]-5'-one
Figure PCTCN2016110946-appb-000062
向反应瓶中加入(±)-(1R,1aR,1a1R,3aR,5aS)-3-亚甲基八氢螺[环丁烷[cd]戊搭烯-1,3'-吡咯烷]-5'-酮(7B)(0.5g，2.46mmol)，甲醇(10mL)，和钯/碳(10％(w％)，0.5g)，体系用氢气置换三次，35℃下氢化3小时，将反应液抽滤，用甲醇(20mL×3)洗涤滤渣，合并滤液，将滤液减压浓缩，残留物用硅胶柱色谱分离纯化(二氯甲烷/甲醇(v/v)＝40:1-10:1)，得到白色固体(±)-(1R,1aR,1a1R,3aR,5aS)-3-甲基八氢螺[环丁烷[cd]戊搭烯-1,3'-吡咯烷]-5'-酮(7C)(0.2g，产率：40％)。
1H NMR(400MHz,CDCl3)δ3.56-3.37(m,2H),2.65-2.35(m,2H),2.22(dt,J＝6.2,3.9Hz,2H),2.08-1.90(m,2H),1.88-1.75(m,2H),1.75-1.63(m,1H),1.51-1.22(m,3H),1.11(d,J＝7.2Hz,3H),0.70(d,J＝7.0Hz,1H)。
第三步：(±)-2-((1R,1aR,1a1R,3aS,5aS)-1-(氨甲基)-3-甲基八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(化合物7)
(±)-2-((1R,1aR,1a1R,3aS,5aS)-1-(aminomethyl)-3-methyloctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid
Figure PCTCN2016110946-appb-000063
向反应瓶中加入(±)-(1R,1aR,1a1R,3aR,5aS)-3-甲基八氢螺[环丁烷[cd]戊搭烯-1,3'-吡咯烷]-5'-酮(7C)(0.2g，0.97mmol)，甲醇(3mL)和水(3mL)，加入氢氧化钠(0.72g，18mmol)，回流反应6小时，减压浓缩以除去甲醇，加入水(10mL)，用二氯甲烷(30mL×3)萃取，水相用2M的盐酸调节pH为7-8后用磺酸树脂柱色谱分离提纯(水(50mL)-氨水 (10％(v％)，100mL))，得到白色固体(±)-2-((1R,1aR,1a1R,3aS,5aS)-1-(氨甲基)-3-甲基八氢-1H-环丁烷[cd]戊搭烯-1-yl)乙酸(化合物7)(0.06g，产率：30％)。
MS m/z(ESI):224.3(M+1)。
1H NMR(400MHz,D2O)δ3.22(q,J＝13.1Hz,2H),2.64-2.31(m,5H),2.01(dd,J＝23.1,13.6Hz,3H),1.89-1.73(m,2H),1.72-1.62(m,1H),1.56-1.43(m,2H),1.33(dd,J＝14.2,10.8Hz,1H),1.05(d,J＝7.1Hz,3H),0.65(d,J＝7.0Hz,1H)。
实施例8
(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨基甲基)-3,3-二氟八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(化合物8)
(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(aminomethyl)-3,3-difluorooctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid
Figure PCTCN2016110946-appb-000064
第一步：(±)-(1aR,1a1R,3aR,5aS)-3,3-二氟八氢螺螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊环](8B)
(±)-(1aR,1a1R,3aR,5aS)-3,3-difluorooctahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolane]
Figure PCTCN2016110946-appb-000065
向反应瓶中加入(±)-(1aR,1a1R,3aR,5aS)-六氢螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊 烷]-3(1a1H)-酮(6B)(6.0g，31mmol)和干燥的二氯甲烷(130mL)，充氮气保护，冷却至0℃，滴加二乙胺基三氟化硫(50g，310mmol)，加热至回流反应10小时，将冷至室温的反应液滴加至冰冷的饱和碳酸氢钠溶液(800mL)中，用二氯甲烷(150mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝50:1)得到黄色油状液体(±)-(1aR,1a1R,3aR,5aS)-3,3-二氟八氢螺螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊环](8B)(5.2g，收率：78％)。
MS m/z(ESI):239.2(M+23)。
1H NMR(400MHz,CDCl3)δ3.94-3.83(m,4H),2.85-2.78(m,1H),2.77-2.70(m,1H),2.63-2.52(m,1H),2.33-2.23(m,1H),2.21-2.09(m,1H),2.08-1.97(m,1H),1.85-1.72(m,1H),1.71-1.56(m,2H),1.55-1.44(m,1H)。
19F NMR(376MHz,CDCl3)δ(-97.33)-(-97.93)(1F),(-118.13)-(-118.73)(1F)。
第二步：(±)-(1aR,1a1R,3aR,5aS)-3,3-二氟八氢-1H-环丁烷[cd]戊搭烯-1-酮(8C)
(±)-(1aR,1a1R,3aR,5aS)-3,3-difluorooctahydro-1H-cyclobuta[cd]pentalen-1-one
Figure PCTCN2016110946-appb-000066
向反应瓶中加入(±)-(1aR,1a1R,3aR,5aS)-3,3-二氟八氢螺螺[环丁烷[cd]戊搭烯-1,2'-[1,3]二氧戊环](8B)(3.0g，14mmol)，水(16mL)和四氢呋喃(28mL)，冷却至0℃，滴加三氟乙酸(15mL)，加热至90℃反应12小时，加入饱和碳酸氢钠溶液调节pH至中性，用二氯甲烷(25mL×3)萃取，合并有机层，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝100:1)得到黄色固体(±)-(1aR,1a1R,3aR,5aS)-3,3-二氟八氢-1H-环丁烷[cd]戊搭烯-1-酮(8C)(1.7g，收率：71％)。
1H NMR(400MHz,CDCl3)δ3.49(ddt,J＝11.5,9.8,5.9Hz,2H),2.98-2.85(m,1H),2.47(tdd,J＝8.2,6.0,1.9Hz,1H),2.39-2.17(m,2H),1.82-1.48(m,4H)。
19F NMR(376MHz,CDCl3)δ(-96.18)-(-96.79)(1F),(-116.52)-(-117.13)(1F)。
第三步：(±)-2-((1aR,1a1R,3aR,5aS)-3,3-二氟八氢-1H-环丁烷[cd]戊搭烯-1-亚基)乙酸叔丁酯(8D)
(±)-tert-butyl 2-((1aR,1a1R,3aR,5aS)-3,3-difluorooctahydro-1H-cyclobuta[cd]pentalen-1-ylidene)acetate
Figure PCTCN2016110946-appb-000067
向反应瓶中加入氢化钠(0.6g，13mmol)和四氢呋喃(10mL)，冷却至0℃，滴加二乙基膦酰基乙酸叔丁酯(2.9g，12mmol)溶于四氢呋喃(10mL)的溶液，0℃下搅拌30分钟，滴加(±)-(1aR,1a1R,3aR,5aS)-3,3-二氟八氢-1H-环丁烷[cd]戊搭烯-1-酮(8C)(1.8g，10mmol)的四氢呋喃(10mL)溶液，升至室温搅拌1.5小时，加入饱和氯化铵溶液(30mL)，用乙酸乙酯(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝200:1)，得到无色油状液体(±)-2-((1aR,1a1R,3aR,5aS)-3,3-二氟八氢-1H-环丁烷[cd]戊搭烯-1-亚基)乙酸叔丁酯(8D)(2.0g，收率：71％)。
MS m/z(ESI):293.2(M+23)。
1H NMR(400MHz,CDCl3)δ5.53(dd,J＝13.1,11.5Hz,1H),3.81-3.65(m,1H),3.35-3.18(m,1H),2.95-2.76(m,1H),2.41-2.16(m,3H),1.95-1.72(m,2H),1.73-1.61(m,1H),1.51-1.37(m,11H)。
第四步：(±)-2-((1R,1aR,1a1R,3aR,5aS)-3,3-二氟-1-(硝基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸叔丁酯(8E)
(±)-tert-butyl 2-((1R,1aR,1a1R,3aR,5aS)-3,3-difluoro-1-(nitromethyl)octahydro-1H-cyclobuta[cd]pentalen-1-yl)acetate
Figure PCTCN2016110946-appb-000068
向反应瓶中加入(±)-2-((1aR,1a1R,3aR,5aS)-3,3-二氟八氢-1H-环丁烷[cd]戊搭烯-1-亚基)乙酸叔丁酯(8D)(2.0g，7.4mmol)，硝基甲烷(65mL)和1,8-二氮杂二环十一碳-7-烯(5.6g，37mmol)，80℃反应7小时，冷却至室温，用2M的盐酸调节溶液pH至中性，加入水(30mL)，用乙酸乙酯(30mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝400:1)，得到无色油状液体(±)-2-((1R,1aR,1a1R,3aR,5aS)-3,3-二氟-1-(硝基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸叔丁酯(8E)(1.4g，收率：57％)。
MS m/z(ESI):354.3(M+23)。
1H NMR(400MHz,CDCl3)δ4.80(q,J＝12.0Hz,2H),2.87(ddd,J＝11.6,8.4,3.9Hz,1H),2.77-2.61(m,2H),2.54(q,J＝17.6Hz,2H),2.44-2.17(m,3H),1.90-1.68(m,2H),1.62-1.53(m,1H),1.53-1.40(m,10H)。
19F NMR(376MHz,CDCl3)δ(-100.02)-(-100.63)(1F),(-121.03)-(-121.64)(1F)。
第五步：(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨基甲基)-3,3-二氟八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸叔丁酯(8F)
(±)-tert-butyl 2-((1R,1aR,1a1R,3aR,5aS)-1-(aminomethyl)-3,3-difluorooctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetate
Figure PCTCN2016110946-appb-000069
向反应瓶中依次加入(±)-2-((1R,1aR,1a1R,3aR,5aS)-3,3-二氟-1-(硝基甲基)八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸叔丁酯(8E)(1.4g，4.2mmol)，铁粉(2.4g，32mmol)，氯化铵(0.9g，17mmol)，乙醇(32mL)和水(16mL)，加热至90℃反应6小时，过滤，将滤液减压浓缩，残留物中加入饱和氯化钠溶液(50mL)，用二氯甲烷(50mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(二氯甲烷/甲醇(v/v)＝50:1-10:1)，得到白色固体(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨基甲基)-3,3-二氟八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸叔丁酯(8F)(1.2g，产率：94％)。
MS m/z(ESI):302.3(M+1)。
1H NMR(400MHz,CDCl3)δ3.35(d,J＝20.4Hz,2H),2.87(tt,J＝34.0,17.0Hz,1H),2.63(ddd,J＝33.8,19.2,10.4Hz,4H),2.43-2.15(m,3H),1.90-1.65(m,2H),1.65-1.34(m,11H)。
19F NMR(376MHz,CDCl3)δ(-99.71)-(-100.31)(1F),(-120.87)-(-121.48)(1F)。
第六步：(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨基甲基)-3,3-二氟八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(化合物8)
(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(aminomethyl)-3,3-difluorooctahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid
Figure PCTCN2016110946-appb-000070
向反应瓶中加入(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨基甲基)-3,3-二氟八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸叔丁酯(8F)(1.2g，4.0mmol)，二氯甲烷(30mL)，滴加三氟乙酸(15mL)，室温反应3小时，减压浓缩，残留物中加入二氯甲烷(20mL)，加入三乙胺至溶液pH约为7，有固体析出，过滤。用二氯甲烷(20mL×3)洗涤滤饼，得到白色固体(±)-2-((1R,1aR,1a1R,3aR,5aS)-1-(氨基甲基)-3,3-二氟八氢-1H-环丁烷[cd]戊搭烯-1-基)乙酸(化合物8)(0.75g，产率：77％)。
MS m/z(ESI):246.3(M+1)。
1H NMR(400MHz,MeOD)δ3.24-3.11(m,2H),2.92-2.80(m,1H),2.64-2.48(m,3H),2.47-2.10(m,4H),1.99-1.71(m,3H),1.66-1.55(m,1H)。
19F NMR(376MHz,MeOD)δ(-100.62)-(-101.23)(1F),(-122.11)-(-122.72)(1F)。
实施例9
(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(氨基甲基)-4-乙基-1a,1a1,2,3,3a,5a-六氢-1H-环丁[cd]戊搭烯-1-基)乙酸
(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(aminomethyl)-4-ethyl-1a,1a1,2,3,3a,5a-hexahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid
Figure PCTCN2016110946-appb-000071
Figure PCTCN2016110946-appb-000072
第一步：(±)-2-((1aR,1a1R,3aR,5aS)-六氢螺环[环丁[cd]戊搭烯-1,2'-[1,3]二氧杂环戊烷]-3(1a1H)-亚基)乙酸乙酯(9B)
(±)-ethyl-2-((1aR,1a1R,3aR,5aS)-hexahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolan]-3(1a1H)-ylidene)acetate
Figure PCTCN2016110946-appb-000073
将氢化钠(2.1g，52.5mmol)加入干燥的四氢呋喃(128mL)中，充氮气保护，冷却至0℃，滴加三乙氧基磷酰基乙酸酯(10.8g，48.2mmol)，0℃下搅拌30分钟，滴加(±)-(1aR,1a1R,3aR,5aS)-六氢螺环[环丁[cd]戊搭烯-1,2'-[1,3]二氧杂环戊烷]-3(1a1H)-酮(6B)(6.22g，32.0mmol)，自然升至室温搅拌1.5小时，冷却至-5℃，滴加饱和氯化铵溶液(150mL)，用乙酸乙酯(150mL×3)萃取，有机相用饱和氯化钠溶液(300mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯＝10:1)，得到无色液体(±)-2-((1aR,1a1R,3aR,5aS)-六氢螺环[环丁[cd]戊搭烯-1,2'-[1,3]二氧杂环戊烷]-3(1a1H)-亚基)乙酸乙酯(9B)(6.1g，产率：72％)。
第二步：(±)-2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-六氢螺环[环丁[cd]环戊二烯-1,2'-[1,3]二氧杂环戊烷]-4-基)乙酸乙酯(9C)
(±)-ethyl 2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-hexahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolan]-4-yl)acetate
Figure PCTCN2016110946-appb-000074
将(±)-2-((1aR,1a1R,3aR,5aS)-六氢螺环[环丁[cd]戊搭烯-1,2'-[1,3]二氧杂环戊烷]-3(1a1H)-亚基)乙酸乙酯(9B)(6.14g，23.2mmol)溶于硝基甲烷(80mL)，加入1,8-二氮杂二环[5.4.0]十一碳-7-烯(5.3g，35mmol)，升温至70℃搅拌5小时，体系冷却至室温后冰水浴下滴加浓盐酸至pH约为6，加入水(200mL)，用乙酸乙酯(200mL×3)萃取，合并 有机相，用饱和氯化钠溶液(400mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝15:1)，得无色液体(±)--2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-六氢螺环[环丁[cd]环戊二烯-1,2'-[1,3]二氧杂环戊烷]-4-基)乙酸乙酯(9C)(4.5g，产率：73％)。
MS M/Z(ESI):265.1(M+1)；287.1(M+23)。
1H NMR(400MHz,CDCl3)δ5.41(s,1H),4.18-4.12(m,2H),3.99-3.69(m,4H),3.47-3.07(m,1H),3.03-2.69(m,3H),1.88-1.48(m,6H),1.41-1.13(m,3H)。
第三步：(±)-2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-六氢螺环[环丁[cd]戊搭烯-1,2'-[1,3]二氧杂环戊烷]-4-基)乙烷-1-醇(9D)
(±)-2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-hexahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolan]-4-yl)ethan-1-ol
Figure PCTCN2016110946-appb-000075
将(±)-2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-六氢螺环[环丁[cd]环戊二烯-1,2'-[1,3]二氧杂环戊烷]-4-基)乙酸乙酯(9C)(4.5g，17mmol)溶于四氢呋喃(50mL)中，降温至0℃，分批加入四氢铝锂(1g，26.35mmol)，加毕于0℃下搅拌1小时，依次滴加水(1mL)，氢氧化钠溶液(15％(w％)，2mL)，水(2mL)，抽滤，用乙酸乙酯(5mL×3)洗涤滤渣，将滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝2:1)，得到无色液体(±)-2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-六氢螺环[环丁[cd]戊搭烯-1,2'-[1,3]二氧杂环戊烷]-4-基)乙烷-1-醇(9D)(2.8g，产率：74％)。
MS M/Z(ESI):223.1(M+1)；245.2(M+23)。
1H NMR(400MHz,CDCl3)δ5.32(s,1H),4.02-3.88(m,2H),3.88-3.70(m,4H),3.44-3.31(m,1H),3.19(t,J＝6.5Hz,1H),3.00-2.86(m,1H),2.84-2.71(m,1H),2.46-2.33(m,1H),2.30-2.18(m,1H),1.86-1.54(m,4H)。
第四步：(±)-2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-六氢螺环[环丁[cd]戊搭烯-1,2'-[1,3]二氧杂环戊烷]-4-基)乙基甲磺酸酯(9E)
(±)-2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-hexahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolan]-4-yl)ethyl methanesulfonate
Figure PCTCN2016110946-appb-000076
将(±)-2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-六氢螺环[环丁[cd]戊搭烯-1,2'-[1,3]二氧杂环戊烷]-4-基)乙烷-1-醇(9D)(2.8g，13mmol)溶于二氯甲烷(50mL)中，加入三乙胺(3.6mL)，冷却至0℃，滴加甲基磺酰氯(1.73g，15.1mmol)，搅拌1小时，用浓盐酸调节pH约为6，加入水(50mL)，用二氯甲烷(50mL×3)萃取，有机相用水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝2:1)，得无色油状产物(±)-2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-六氢螺环[环丁[cd]戊搭烯-1,2'-[1,3]二氧杂环戊烷]-4-基)乙基甲磺酸酯(9E)(3.6g，产率：95％)。
1H NMR(400MHz,CDCl3)δ5.29(s,1H),4.37-4.28(m,2H),3.96-3.85(m,2H),3.85-3.70(m,2H),3.41-3.26(m,1H),3.16(t,J＝6.3Hz,1H),2.99(s,3H),2.93-2.83(m,1H),2.82-2.67(m,1H),2.62-2.47(m,1H),2.43-2.29(m,1H),1.83-1.68(m,2H),1.67-1.50(m,2H)。
第五步：(±)-(1aS,1a1R,3aR,5aS)-4-ethyl-1a,1a1,2,3,3a,5a-六氢螺环[环丁[cd]戊搭烯-1,2'-[1,3]二氧杂环戊烷](9F)
(±)-(1aS,1a1R,3aR,5aS)-4-ethyl-1a,1a1,2,3,3a,5a-hexahydrospiro[cyclobuta[cd]pentalene-1,2'-[1,3]dioxolane]
Figure PCTCN2016110946-appb-000077
反应瓶中加入(±)-2-((1aS,1a1R,3aR,5aS)-1a,1a1,2,3,3a,5a-六氢螺环[环丁[cd]戊搭烯-1,2'-[1,3]二氧杂环戊烷]-4-基)乙基甲磺酸酯(9E)(3.6g，12mmol)和四氢呋喃(60mL)，冷却至0℃，分批加入四氢铝锂(1.4g，37mmol)，室温下搅拌2小时，冷却至0℃，依次滴加水(1.4mL)，氢氧化钠溶液(15％(w％)，2.8mL)和水(2.8mL)，抽滤，用乙酸乙酯(10mL×3)洗涤滤渣，将滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1)，得无色油状(±)-(1aS,1a1R,3aR,5aS)-4-ethyl-1a,1a1,2,3,3a,5a-六氢螺环[环丁[cd]戊搭烯-1,2'-[1,3]二氧杂环戊烷](9F)(2g，产率：81％)。
1H NMR(400MHz,CDCl3)δ5.18(s,1H),4.05-3.69(m,4H),3.50-3.25(m,1H),3.15(t,J＝6.6Hz,1H),2.97-2.81(m,1H),2.81-2.63(m,1H),2.26-2.01(m,1H),2.01-1.84(m,1H),1.84-1.47(m,4H),1.07(t,J＝7.4Hz,3H)。
第六步：(±)-(1aS,1a1R,3aR,5aS)-4-乙基-1a,1a1,2,3,3a,5a-六氢-1H-环丁[cd]戊搭烯-1-酮(9G)
(±)-(1aS,1a1R,3aR,5aS)-4-ethyl-1a,1a1,2,3,3a,5a-hexahydro-1H-cyclobuta[cd]pentalen-1-one
Figure PCTCN2016110946-appb-000078
将(±)-(1aS,1a1R,3aR,5aS)-4-ethyl-1a,1a1,2,3,3a,5a-六氢螺环[环丁[cd]戊搭烯-1,2'-[1,3]二氧杂环戊烷](9F)(1.1g，5.3mmol)溶于乙酸溶液(30％(w％)，30mL)中，升温至70℃搅拌2小时，冷却至室温，加入水(30mL)，用二氯甲烷(60mL×3)萃取，有机相用饱和氯化钠溶液(200mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝60:1)，得到无色油状(±)-(1aS,1a1R,3aR,5aS)-4-乙基-1a,1a1,2,3,3a,5a-六氢-1H-环丁[cd]戊搭烯-1-酮(9G)(0.72g，产率：83％)。
1H NMR(400MHz,CDCl3)δ5.09(s,1H),4.11-3.92(m,1H),3.57-3.36(m,2H),3.22-3.06(m,1H),2.13-1.84(m,4H),1.84-1.66(m,1H),1.63-1.45(m,1H),1.08(t,J＝7.4Hz,3H)。
第七步：(±)-2-((1aS,1a1R,3aR,5aS)-4-乙基-1a,1a1,2,3,3a,5a-六氢-1H-环丁[cd]戊搭烯-1-亚基)乙酸叔丁酯(9H)
(±)-tert-butyl 2-((1aS,1a1R,3aR,5aS)-4-ethyl-1a,1a1,2,3,3a,5a-hexahydro-1H-cyclobuta[cd]pentalen-1-ylidene)acetate
Figure PCTCN2016110946-appb-000079
将氢化钠(0.22g，5.5mmol)加入到干燥的四氢呋喃(15mL)中，冷却至0℃，滴加二甲氧基磷酰基乙酸叔丁酯(1.17g，5.22mmol)，搅拌30分钟，加入(±)-(1aS,1a1R,3aR,5aS)-4-乙基-1a,1a1,2,3,3a,5a-六氢-1H-环丁[cd]戊搭烯-1-酮(9G)(0.72g，4.4mmol)，加毕自然升温，于室温下搅拌1小时，冷却至0℃，滴加饱和氯化铵溶液(50mL)，用乙酸乙酯(50mL×3)萃取，合并有机相，有机相用水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1)，得到无色油状(±)-2-((1aS,1a1R,3aR,5aS)-4-乙基-1a,1a1,2,3,3a,5a-六氢-1H-环 丁[cd]戊搭烯-1-亚基)乙酸叔丁酯(9H)(1g，产率：87％)。
第八步：(±)-2-((1R,1aS,1a1R,3aR,5aS)-4-乙基-1-(硝基甲基)-1a,1a1,2,3,3a,5a-六氢-1H-环丁[cd]戊搭烯-1-基)乙酸叔丁酯(9I)
(±)-tert-butyl 2-((1R,1aS,1a1R,3aR,5aS)-4-ethyl-1-(nitromethyl)-1a,1a1,2,3,3a,5a-hexahydro-1H-cyclobuta[cd]pentalen-1-yl)acetate
Figure PCTCN2016110946-appb-000080
将(±)-2-((1aS,1a1R,3aR,5aS)-4-乙基-1a,1a1,2,3,3a,5a-六氢-1H-环丁[cd]戊搭烯-1-亚基)乙酸叔丁酯(9H)(1g，3.84mmol)溶于硝基甲烷(15mL)中，加入1,8-二氮杂二环十一碳-7-烯(0.78g，5.1mmol)，加热至70℃搅拌7小时，冷却至0℃，用浓盐酸调pH约为6，加入水(60mL)，用乙酸乙酯(60mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(石油醚/乙酸乙酯(v/v)＝10:1)，得到无色油状液体(±)-2-((1R,1aS,1a1R,3aR,5aS)-4-乙基-1-(硝基甲基)-1a,1a1,2,3,3a,5a-六氢-1H-环丁[cd]戊搭烯-1-基)乙酸叔丁酯(9I)(0.8g，产率：60％)。
MS M/Z(ESI):344.2(M+23)。
1H NMR(400MHz,CDCl3)δ5.17(s,1H),4.86(d,J＝11.6Hz,1H),4.77(d,J＝11.6Hz,1H),3.25-2.97(m,3H),2.59-2.45(m,1H),2.43(s,2H),2.21-2.04(m,1H),2.04-1.88(m,1H),1.88-1.79(m,1H),1.79-1.65(m,1H),1.65-1.47(m,1H),1.43(d,J＝13.2Hz,9H),1.41-1.27(m,1H),1.08(t,J＝7.4Hz,3H)。
第九步：(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(氨基甲基)-4-乙基-1a,1a1,2,3,3a,5a-六氢-1H-环丁[cd]戊搭烯-1-基)乙酸叔丁酯(9J)
(±)-tert-butyl 2-((1R,1aS,1a1R,3aR,5aS)-1-(aminomethyl)-4-ethyl-1a,1a1,2,3,3a,5a-hexahydro-1H-cyclobuta[cd]pentalen-1-yl)acetate
Figure PCTCN2016110946-appb-000081
将(±)-2-((1R,1aS,1a1R,3aR,5aS)-4-乙基-1-(硝基甲基)-1a,1a1,2,3,3a,5a-六氢-1H-环丁[cd]戊搭烯-1-基)乙酸叔丁酯(9I)(0.8g，2mmol)溶于乙醇(10mL)中，加入水(5mL)，还 原铁粉(0.56g，10mmol)和氯化铵(0.22g，4.1mmol)，升温至100℃，搅拌3小时，冷却至室温，加入水(50mL)，用乙酸乙酯(60mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用硅胶柱色谱分离纯化(二氯甲烷/甲醇(v/v)＝10:1)，得无色油状(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(氨基甲基)-4-乙基-1a,1a1,2,3,3a,5a-六氢-1H-环丁[cd]戊搭烯-1-基)乙酸叔丁酯(9J)(0.8g，产率：100％)。
1H NMR(400MHz,CDCl3)δ5.19(s,1H),3.41(d,J＝13.1Hz,1H),3.30(d,J＝13.1Hz,1H),3.26-3.13(m,1H),3.11-2.94(m,2H),2.66-2.32(m,3H),2.20-2.01(m,1H),2.01-1.86(m,1H),1.85-1.65(m,2H),1.63-1.48(m,1H),1.44(s,9H),1.31-1.21(m,1H),1.07(t,J＝7.4Hz,3H)。
第十步：(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(氨基甲基)-4-乙基-1a,1a1,2,3,3a,5a-六氢-1H-环丁[cd]戊搭烯-1-基)乙酸(化合物9)
(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(aminomethyl)-4-ethyl-1a,1a1,2,3,3a,5a-hexahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid
Figure PCTCN2016110946-appb-000082
反应瓶中加入(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(氨基甲基)-4-乙基-1a,1a1,2,3,3a,5a-六氢-1H-环丁[cd]戊搭烯-1-基)乙酸叔丁酯(9J)(0.8g，3mmol)和二氯甲烷(14mL)，冰水浴冷却，滴加三氟乙酸(7mL)，于室温下搅拌4小时，减压浓缩，残留物中加入二氯甲烷(100mL)，逐滴加入三乙胺调节pH值7-8，抽滤，滤饼用二氯甲烷(5mL×3)洗涤，得到白色固体(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(氨基甲基)-4-乙基-1a,1a1,2,3,3a,5a-六氢-1H-环丁[cd]戊搭烯-1-基)乙酸(化合物9)(0.42g，产率：70％)。
MS M/Z(ESI):236.2(M+1)。
1H NMR(400MHz,CD3OD)δ5.27(s,1H),3.24-2.99(m,4H),2.86-2.72(m,1H),2.65-2.52(m,1H),2.49-2.29(m,2H),2.23-2.06(m,1H),2.06-1.90(m,1H),1.90-1.81(m,1H),1.80-1.67(m,1H),1.65-1.43(m,2H),1.09(t,J＝7.4Hz,3H)。
实施例10
(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(氨基甲基)-4-乙基-1a,1a1,2,3,3a,5a-六氢-1H-环丁[cd]戊搭烯-1-基)乙酸苯磺酸盐(1:1)(化合物10)
(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(aminomethyl)-4-ethyl-1a,1a1,2,3,3a,5a-hexahydro-1H-c yclobuta[cd]pentalen-1-yl)acetic acid benzenesulfonic acid(1:1)
Figure PCTCN2016110946-appb-000083
第一步：(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(氨基甲基)-4-乙基-1a,1a1,2,3,3a,5a-六氢-1H-环丁[cd]戊搭烯-1-基)乙酸苯磺酸盐(1:1)(化合物10)
(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(aminomethyl)-4-ethyl-1a,1a1,2,3,3a,5a-hexahydro-1H-cyclobuta[cd]pentalen-1-yl)acetic acid benzenesulfonic acid(1:1)
Figure PCTCN2016110946-appb-000084
反应瓶中加入(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(氨基甲基)-4-乙基-1a,1a1,2,3,3a,5a-六氢-1H-环丁[cd]戊搭烯-1-基)乙酸(化合物9)(0.34g，1.4mmol)和甲醇(10mL)，加入苯磺酸·1.5水合物(0.41g，2.1mmol)，搅拌30分钟，减压浓缩，残留物中加入乙酸乙酯(10mL×3)打浆，抽滤，得到白色固体(±)-2-((1R,1aS,1a1R,3aR,5aS)-1-(氨基甲基)-4-乙基-1a,1a1,2,3,3a,5a-六氢-1H-环丁[cd]戊搭烯-1-基)乙酸苯磺酸盐(化合物10)(1:1)(0.33g，产率：58％)。
1H NMR(400MHz,CD3OD)δ7.96-7.72(m,2H),7.51-7.32(m,3H),5.24(s,1H),3.43-3.22(m,2H),3.23-3.05(m,2H),2.96-2.82(m,1H),2.58-2.36(m,3H),2.25-2.09(m,1H),2.08-1.93(m,1H),1.93-1.83(m,1H),1.81-1.67(m,1H),1.66-1.48(m,1H),1.46-1.31(m,1H),1.10(t,J＝7.4Hz,3H)。
生物测试例
化合物对钙离子通道蛋白Cavα2δ的竞争结合能力测试
取大鼠大脑皮质组织于10倍体积(w/v)冰冷的0.32M蔗糖/5mMTris-乙酸(pH 7.4)，匀浆后，蔗糖密度梯度离心法制备突触质膜，保存于Tris-乙酸(pH 7.4)缓冲液，临用前 重悬于10mM HEPES(pH 7.4)缓冲液。测试化合物溶于1％DMSO，并稀释成梯度浓度(1nM-1000nM)，与20nM[3H]加巴喷丁一起加入突触质膜悬液(约0.05-0.1mg总蛋白质)，25℃孵育30分钟。反应结束后反应体系经真空滤过至Whatman GFB滤膜，滤膜以5mL 100mM冰冷的氯化钠溶液洗3次，液闪基数测定滤膜的放射性。非特异结合以100M加巴喷丁封闭。计算化合物对放射标记加巴喷丁与突触质膜的结合的抑制率，并计算化合物的IC50。实验结果：见表1。
表1受试化合物的IC50值
实施例 IC50(nM)
1 7.72
3 5.53
9 8.05
结论：本发明化合物具有较好的对钙离子通道蛋白Cavα2δ的竞争结合能力。
药代动力学评价
雄性SD大鼠(购自维通利华实验动物有限公司)180-240g，禁食给水过夜，3只大鼠口服灌胃10mg/kg，3只大鼠静脉注射5mg/kg。口服给药组，受试化合物以0.5％甲基纤维素(MC)溶液配制成1.0mg/mL的混悬液，在给药前和在给药后30分钟以及1、2、4、6、8、12和24小时采血各200μL；静脉给药组，化合物以生理盐水配制成1.0mg/mL的溶液，在给药前和在给药后5、15和30分钟以及1、2、4、8、12和24小时采血，采集的样品均肝素抗凝。血样5500转/分钟离心10分钟，收集血浆，于-20℃保存。取各时间点大鼠血浆10μL，加入含内标的乙腈溶液500μL混合后，涡旋混合10分钟，3700转/分钟离心18分钟，取上清液50μL与100μL水混合，涡旋混合10分钟，取混和液5μL进行LC-MS/MS分析，测定原形药物的血药浓度。主要药代动力学参数用WinNonlin 6.3软件非房室模型分析。试验结果见表2。
表2大鼠药代动力学实验数据
Figure PCTCN2016110946-appb-000085
Figure PCTCN2016110946-appb-000086
结论：本发明化合物表现出良好的药代动力学性质。

Claims (14)

  1. 一种通式(I)所示的化合物，或者其立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或共晶：
    Figure PCTCN2016110946-appb-100001
    其中：
    R1、R2、R2’、R3、R4、R4’或R5各自独立地选自H、F、Cl、Br、I、羟基、氰基、C1-6烷基、C1-6烷氧基、C1-6硫烷基、C2-6烯基、C2-6炔基、3至6元碳环基或者3至6元杂环基，所述的烷基、烷氧基、硫烷基、烯基、炔基、碳环基或者杂环基任选进一步被0至6个选自F、Cl、Br、I、羟基、C1-6烷基或者3至6元碳环基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子；
    作为选择，R1与R2、R2与R2’、R2与R3、R3与R4、R4与R4’、R4与R5任意一组相结合与其相连的原子一起形成双键，所述的双键任选进一步被0至2个选自F、Cl、Br、I、C1-6烷基、3至6元碳环基或者被1至3个卤素取代的C1-6烷基所取代；所述的卤素选自F、Cl或者Br；
    作为选择，R2与R2’、R4与R4’任意一组与其相连的碳原子一起形成3至6元碳环，所述的碳环任选进一步被0至6个选自F、Cl、Br、I、C1-6烷基、C1-6烷氧基或者C1-6硫烷基所取代；
    R6选自H、C1-6烷基或氨基保护基；
    R7选自H、C1-6烷基或羧基保护基。
  2. 根据权利要求1所述的的化合物，或者其立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或共晶，其中该化合物选自通式(Ia)或者(Ib)所示的化合物：
    Figure PCTCN2016110946-appb-100002
    或者
    Figure PCTCN2016110946-appb-100003
  3. 根据权利要求1至2中任一项所述的化合物，或者其立体异构体、溶剂化物、代 谢产物、前药、药学上可接受的盐或共晶，其中：
    R1、R2、R2’各自独立地选自H，或者R1与R2、R2与R2’任意一组相结合与其相连的原子一起形成双键，所述的双键任选进一步被0至2个选自F、Cl、C1-6烷基或者3至6元碳环基所取代；
    R3、R4、R4’或R5各自独立地选自H、F、Cl、羟基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、3至6元碳环基或者3至6元杂环基，所述的烷基、烷氧基、烯基、炔基、碳环基或者杂环基任选进一步被0至6个选自F、Cl、Br、羟基、C1-6烷基或者3至6元碳环基所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子；
    作为选择，R4与R4’、R4与R5任意一组相结合与其相连的原子一起形成双键，所述的双键任选进一步被0至2个选自F、Cl、C1-6烷基或者3至6元碳环基所取代；
    作为选择，R4与R4’可与其相连的碳原子一起形成3至6元碳环，所述的碳环任选进一步被0至6个选自F、Cl、Br、I、C1-6烷基、C1-6烷氧基或者C1-6硫烷基所取代；
    R6选自H或者C1-6烷基；
    R7选自H或者C1-6烷基。
  4. 根据权利要求3中所述的化合物，或者其立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或共晶，其中：
    R1、R2、R2’各自独立地选自H；
    R3、R4、R4’或R5各自独立地选自H、F、Cl、羟基或者C1-4烷基；
    作为选择，R4与R4’、R4与R5任意一组相结合与其相连的原子一起形成双键，所述的双键任选进一步被0至2个选自F、Cl、C1-4烷基或者3至6元碳环基所取代；
    作为选择，R4与R4’可与其相连的碳原子一起形成3至6元碳环，所述的碳环任选进一步被0至6个选自F、Cl、Br、I、C1-4烷基或者C1-4烷氧基所取代；
    R6选自H或者C1-4烷基；
    R7选自H或者C1-4烷基。
  5. 根据权利要求4所述的化合物，或者其立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或共晶，其中所述化合物选自以下结构之一：
    Figure PCTCN2016110946-appb-100004
    Figure PCTCN2016110946-appb-100005
  6. 一种制备通式(I)、(Ia)或(Ib)所示的化合物或其立体异构体的中间体，该中间体选自如下通式(II)所示的化合物或其立体异构体：
    Figure PCTCN2016110946-appb-100006
    其中：
    Ra或Rb各自独立地选自羟基或者C1-4烷基，所述的烷基任选进一步被0至2个选自硝基或者-COORx所取代；
    作为选择，Ra与Rb相结合与其相连的原子一起形成双键、C＝O或者Ra、Rb与其相连的碳原子一起形成3至6元杂环基，所述的双键任选进一步被0至2个选自F、C1-4烷基、硝基或者-COORx所取代，所述的杂环基含有1至2个选自N、O或者S的杂原子， 且任选被0至2个＝O所取代；
    Rc、Rd、Rd’或Re各自独立地选自H、F、Cl、羟基或者C1-4烷基，所述的烷基任选进一步被0至2个选自F、羟基、-OMs、或者-COORx所取代；
    作为选择，Rd与Rd’、Rd与Re任意一组相结合与其相连的原子一起形成双键或者C＝O，所述的双键任选进一步被0至2个选自F、C1-4烷基或者-COORx所取代；
    作为选择，Rd与Rd’可与其相连的碳原子一起形成3至6元碳环，所述的碳环任选进一步被0至6个选自F、Cl、Br、I、C1-4烷基或者C1-4烷氧基所取代；
    Rx选自H或者C1-4烷基。
  7. 根据权利要求6所述的化合物或者其立体异构体，其中所述化合物选自以下结构之一：
    Figure PCTCN2016110946-appb-100007
    Figure PCTCN2016110946-appb-100008
  8. 根据权利要求1、2、4或5中任一项所述的化合物，或者其立体异构体、溶剂化物、代谢产物、前药、药学上可接受的盐或共晶，其中所述的盐为对甲苯磺酸盐。
  9. 一种药物组合物，所述药物组合物包含权利要求1～5任一项所述的化合物或其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药，和一种或者多种药学上可接受的载体和/或赋形剂。
  10. 根据权利要求9的药物组合物或者权利要求1～5任一项所述的化合物或其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药在制备治疗和/或预防疼痛的药物中的用途。
  11. 根据权利要求10的所述的治疗和/或预防疼痛中的用途，所述的疼痛包括：疱疹后神经痛、三叉神经痛、偏头痛、与骨关节炎或关节风湿病相关的疼痛、下背疼痛、坐骨神经痛、牙痛、由烧伤引起的疼痛、由糖尿病性神经病引起的疼痛、由化疗诱导的神经病变引起的疼痛、与HIV相关的神经痛、与AIDS相关的神经痛、与癌症相关的神经痛或非神经痛、急性或慢性紧张性头痛、手术后疼痛、纤维肌痛。
  12. 一种治疗和/或预防疼痛的方法，所述方法包括给予哺乳动物治疗有效量的权利要求9的药物组合物或者权利要求1～5任一项所述的化合物或其立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或者前药。
  13. 根据权利要求12的所述的方法，所述的疼痛包括：疱疹后神经痛、三叉神经痛、偏头痛、与骨关节炎或关节风湿病相关的疼痛、下背疼痛、坐骨神经痛、牙痛、由烧伤引起的疼痛、由糖尿病性神经病引起的疼痛、由化疗诱导的神经病变引起的疼痛、与HIV相关的神经痛、与AIDS相关的神经痛、与癌症相关的神经痛或非神经痛、急性或慢性紧张性头痛、手术后疼痛、纤维肌痛。
  14. 根据权利要求13的所述的方法，所述的哺乳动物为人。
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