WO2017107907A1 - Dérivé d'acide γ-aminé à cycle condensé, et son procédé de préparation et son utilisation médicale - Google Patents

Dérivé d'acide γ-aminé à cycle condensé, et son procédé de préparation et son utilisation médicale Download PDF

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WO2017107907A1
WO2017107907A1 PCT/CN2016/111218 CN2016111218W WO2017107907A1 WO 2017107907 A1 WO2017107907 A1 WO 2017107907A1 CN 2016111218 W CN2016111218 W CN 2016111218W WO 2017107907 A1 WO2017107907 A1 WO 2017107907A1
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group
bicyclo
hept
compound
aminomethyl
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PCT/CN2016/111218
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English (en)
Chinese (zh)
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李瑶
范江
李升�
徐波
陈清平
朱凤飞
肖志阳
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四川海思科制药有限公司
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Priority to CN201680042369.6A priority Critical patent/CN107848953B/zh
Publication of WO2017107907A1 publication Critical patent/WO2017107907A1/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D305/06—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring atoms
    • 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 ring ⁇ -amino acid derivative represented by the formula (I), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a drug thereof Compositions and uses in the field of analgesia.
  • 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 , 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 ring ⁇ -amino acid derivative having novel structure and good medicinal effect, or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or former Medicine, its pharmaceutical composition and its 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 3′ , R 4′ or R 5 are present or absent;
  • R 1 , R 5 , R 8 and R 8 ' are each independently selected from H, F, Cl, Br, I or C 1-6 alkyl, preferably H or C 1-6 alkyl, more preferably H, said The alkyl group is optionally further substituted with 0 to 2 selected from the group consisting of F, Cl, Br, I, hydroxy, C 1-6 alkyl, 3 to 6 membered carbocyclic group or 3 to 6 membered heterocyclic group, preferably further Substituted by 0 to 2 selected from F, Cl, Br, hydroxy, C 1-4 alkyl or a 3 to 6 membered carbocyclic group;
  • the a side, the b side, the c side or the d side are each independently selected from a double bond or a single bond, and the a side, the b side, the c side, and the d side are the most One more is selected from double bonds, and the other is selected from single bonds;
  • any group of R 2 , R 2 ' , R 3 , R 3 ' , R 4 or R 4 ' is selected from - (CR).
  • the remaining groups are each independently selected from the group consisting of H, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 sulfanyl, 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, alkoxy group, thioalkyl group, alkenyl group, alkynyl group,
  • the carbocyclic group or the heterocyclic group is optionally further substituted with 0 to 6 selected from F, Cl, Br, I, hydroxy, C 1-6 alkyl or a 3 to 6 membered carbocyclic group, said heterocyclic group Containing 1 to 2 heteroatoms selected from N, O or S;
  • n is selected from 0 to 6;
  • R 9 and R 9 ' are each independently selected from H, F, Cl, Br, I or C 1-6 alkyl, and the alkyl group is optionally further from 0 to 6 selected from F, Cl, Br, I. Substituted by a hydroxyl group, a C 1-6 alkyl group, a 3 to 5 membered carbocyclic group or a 3 to 5 membered heterocyclic group;
  • R 10 is selected from a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group, and the carbocyclic group or heterocyclic group is further optionally 0 to 6 selected from the group consisting of F, Cl, Br, I, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 thioalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 6 membered carbocyclic group or 3 to 6 membered hetero Substituted by a cyclic group, the heterocyclic group contains 1 to 2 hetero atoms selected from N, O or S, and when n is 0, the carbocyclic group is an unsaturated carbocyclic group;
  • R 2 , R 2 ' , R 3 , R 3 ' , R 4 or R 4 ' are each independently selected from H, F, Cl, Br, I, hydroxy, cyano, C 2-6 alkenyl or C 2-6 alkynyl, said alkenyl or alkynyl optionally further from 0 to 6 selected from the group consisting of F, Cl, Br, I, hydroxy Substituted with a C 1-6 alkyl group, a 3 to 6 membered carbocyclic group or a 3 to 6 membered heterocyclic group containing 1 to 2 hetero atoms selected from N, O or S, and R 2 , R 2 ' , R 3 , R 3 ' , R 4 or R 4 'is not H at the same time;
  • R 2 and R 2′ , R 3 and R 3′ , R 4 and R 4′ may form a double bond together with a carbon atom to which they are bonded, and the double bond may optionally be further 0 to 2 Substituted from F, Cl, Br, I, C 2-6 alkyl, -(CR 11 R 11' ) m R 12 or a 3 to 6 membered carbocyclic group;
  • n is selected from 0 to 5;
  • R 11 and R 11 ' are each independently selected from H, F, Cl, Br, I or C 1-6 alkyl, and the alkyl group is optionally further from 0 to 6 selected from the group consisting of F, Cl, Br, I Substituted by a hydroxyl group, a C 1-6 alkyl group, a 3 to 5 membered carbocyclic group or a 3 to 5 membered heterocyclic group;
  • R 12 is selected from a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group, and the carbocyclic or heterocyclic group is optionally further selected from 0 to 6 selected from the group consisting of F, Cl, Br, I, and a hydroxyl group.
  • C 1-6 alkyl, C 1-6 alkoxy, C 1-6 thioalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 6 membered carbocyclic group or 3 to 6 membered hetero Substituted by a cyclic group, the heterocyclic group containing 1 to 2 hetero atoms selected from N, O or S;
  • 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 (II), or all stereoisomers, solvates thereof, Metabolites, pharmaceutically acceptable salts, eutectic or prodrugs:
  • the a side, the b side, the c side or the d side are each independently selected from a double bond or a single bond, and among the a side, the b side, the c side, and the d side, at most one is selected from a double bond, and the other is selected from a single bond. ;
  • R 2 ' , R 3' or R 4' is the presence or absence
  • any group of R 2 , R 2 ' , R 3 , R 3 ' , R 4 or R 4 ' is selected from - (CR).
  • the remaining groups are each independently selected from the group consisting of H, F, Cl, Br, I, 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 H, F, Cl, C 1-6 alkyl, C 2-6 alkenyl a C 2-6 alkynyl group or a 3 to 6 membered carbocyclic group, more preferably H, F, C 1-4 alkyl or a 3 to 6 membered carbocyclic group, said alkyl group, alkoxy group, sulfanyl group Or an alkenyl, alkynyl, carbocyclyl or heterocyclic group optionally further substituted by 0 to 6 selected from F, Cl, Br, I, hydroxy, C 1-6 alkyl or a 3 to 6 membered carbocycl
  • n is selected from 0 to 6, preferably 0 to 4, more preferably 0 to 3, further preferably 1 or 2;
  • R 9 and R 9 ' are each independently selected from H, F, Cl, Br, I or C 1-6 alkyl, preferably H, F, Cl or C 1-4 alkyl, said alkyl optionally further Substituted by 0 to 6 selected from F, Cl, Br, I, hydroxy, C 1-6 alkyl, 3 to 5 membered carbocyclic group or 3 to 5 membered heterocyclic group, preferably further 0 to 4 F , Cl, Br, hydroxy, C 1-4 alkyl or a 3 to 5 membered carbocyclic group, more preferably further substituted with 0 to 4 F, Cl, Br or C 1-4 alkyl;
  • R 10 is selected from a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group, and the carbocyclic group or heterocyclic group is further optionally 0 to 6 selected from the group consisting of F, Cl, Br, I, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 thioalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 6 membered carbocyclic group or 3 to 6 membered hetero Substituted by a cyclic group, the heterocyclic group contains 1 to 2 hetero atoms selected from N, O or S, and when n is 0, the carbocyclic group is an unsaturated carbocyclic group;
  • R 2 , R 2 ' , R 3 , R 3 ' , R 4 or R 4 ' are each independently selected from H, F, Cl, Br, I, hydroxy, cyano, C 2-6 alkenyl or C 2-6 alkynyl, preferably H, F, Cl, Br, hydroxy, C 2-4 alkenyl or C 2-4 alkynyl, more preferably H, F, Cl, C 2-4 alkenyl or C 2-4 alkynyl, said alkenyl or alkynyl optionally further from 0 to 6 selected from the group consisting of F, Cl, Br, I, hydroxy, C 1 Substituted by a -6 alkyl group or a 3 to 6 membered carbocyclic group, R 2 , R 2 ' , R 3 , R 3 ' , R 4 or R 4 'is not H at the same time;
  • R 2 and R 2′ , R 3 and R 3′ , R 4 and R 4′ may form a double bond together with a carbon atom to which they are bonded, and the double bond may optionally be further 0 to 2 Substituted from F, Cl, Br, I, C 2-6 alkyl, -(CR 11 R 11' ) m R 12 or a 3 to 5 membered carbocyclic group;
  • n is selected from 0 to 5, preferably 0 to 4, more preferably 0 to 3, further preferably 0, 1 or 2;
  • R 11 and R 11 ' are each independently selected from H, F, Cl, Br, I or C 1-6 alkyl, preferably H, F, Cl or C 1-4 alkyl, said alkyl optionally further Substituted by 0 to 6 heterocyclic groups selected from the group consisting of F, Cl, Br, I, hydroxy, C 1-6 alkyl, 3 to 5 membered carbocyclic or 3 to 5 membered heterocyclic;
  • R 12 is selected from a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group, and the carbocyclic or heterocyclic group is optionally further selected from 0 to 6 selected from the group consisting of F, Cl, Br, I, and a hydroxyl group.
  • the heterocyclic group contains 1 to 2 hetero atoms selected from N, O or S.
  • Preferred embodiments of the invention include a compound of the formula (IIa), (IIb), (IIc) or (IId), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts thereof, Eutectic or prodrug:
  • R 2 , R 2 ' , R 3 , R 3 ' , R 4 or R 4 ' is selected from -(CR 9 R 9' ) n R 10 , and the remaining groups are each independently selected from H, F, Cl, Br, I, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 thioalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 6 membered carbocyclic group Or a 3 to 6 membered heterocyclic group, preferably H, F, Cl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl or a 3 to 6 membered carbocyclic group, more preferably H, F a C 1-4 alkyl group or a 3 to 6 membered carbocyclic group, the alkyl group, alkoxy group, thioalkyl group, alkenyl group, alkynyl group, carbocyclic group or heterocyclic group optionally further
  • n is selected from 0 to 6, preferably 0 to 4, more preferably 0 to 3, further preferably 1 or 2;
  • R 9 and R 9 ' are each independently selected from H, F, Cl, Br, I or C 1-6 alkyl, preferably H, F, Cl or C 1-4 alkyl, said alkyl optionally further Substituted by 0 to 6 selected from F, Cl, Br, I, hydroxy, C 1-6 alkyl, 3 to 5 membered carbocyclic group or 3 to 5 membered heterocyclic group, preferably further 0 to 4 F , C, Br, C 1-4 alkyl or a 3 to 5 membered carbocyclic group, more preferably further substituted with 0 to 4 F, Cl, Br or C 1-4 alkyl;
  • R 10 is selected from a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group, and the carbocyclic group or heterocyclic group is further optionally 0 to 6 selected from the group consisting of F, Cl, Br, I, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 thioalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 6 membered carbocyclic group or 3 to 6 membered hetero Substituted by a cyclic group, the heterocyclic group contains 1 to 2 hetero atoms selected from N, O or S, and when n is 0, the carbocyclic group is an unsaturated carbocyclic group.
  • Preferred embodiments of the invention include a compound of the formula (IIa), (IIb), (IIc) or (IId), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts thereof, Eutectic or prodrug:
  • R 2 , R 2 ' , R 3 , R 3 ' , R 4 or R 4 ' is selected from -(CR 9 R 9' ) n R 10 , and the remaining groups are each independently selected from H, F, Cl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CHFCH 3 , CHFCH 2 F, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl , tert-butyl, hydroxymethyl, hydroxyethyl, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
  • n is selected from 0, 1 or 2, preferably 1 or 2;
  • R 9 and R 9 ' are each independently selected from the group consisting of H, F, Cl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CHFCH 3 , CHFCH 2 F, methyl, ethyl, n-propyl, Isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, hydroxymethyl or hydroxyethyl;
  • R 10 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, furyl, thienyl, pyrrolyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyrrolyl, Oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxolyl, 1,4-dioxane , 1,5-dioxane, oxacyclopentyl, azacyclopentyl, oxetanyl, azacyclohexyl, or When substituted, optionally further from 0 to 4 selected from the group consisting of F, Cl, Br, hydroxy, methyl, ethyl, propyl, isopropyl, n-butyl, iso
  • Preferred embodiments of the invention include a compound of the formula (IIe), or all stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs thereof:
  • R 2 , R 2 ' , R 3 , R 3 ' , R 4 or R 4 ' are each independently selected from H, F, Cl, Br, I, hydroxy, cyano, C 2-6 alkenyl or C 2 - 6 alkynyl, preferably H, F, Cl, Br, hydroxy, C 2-4 alkenyl or C 2-4 alkynyl, more preferably H, F, Cl, C 2-4 alkenyl or C 2-4 alkynyl Said alkenyl or alkynyl group is optionally further substituted by 0 to 6 selected from F, Cl, Br, I, hydroxy, C 1-6 alkyl or a 3 to 6 membered carbocyclic group, and R 2 , R 2 ' , R 3 , R 3' , R 4 or R 4' are not H at the same time;
  • R 2 and R 2′ , R 3 and R 3′ , R 4 and R 4′ may form a double bond together with a carbon atom to which they are bonded, and the double bond may optionally be further 0 to 2 Substituted from F, Cl, Br, I, C 2-6 alkyl, -(CR 11 R 11 ' ) m R 12 or a 3 to 5 membered carbocyclic group;
  • n is selected from 0 to 5, preferably 0 to 4, more preferably 0 to 3, further preferably 0, 1 or 2;
  • R 11 and R 11 ' are each independently selected from H, F, Cl, Br, I or C 1-6 alkyl, preferably H, F, Cl or C 1-4 alkyl, said alkyl optionally further Substituted by 0 to 6 heterocyclic groups selected from the group consisting of F, Cl, Br, I, hydroxy, C 1-6 alkyl, 3 to 5 membered carbocyclic or 3 to 5 membered heterocyclic;
  • R 12 is selected from a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group, and the carbocyclic or heterocyclic group is optionally further selected from 0 to 6 selected from the group consisting of F, Cl, Br, I, and a hydroxyl group.
  • C 1-6 alkyl, C 1-6 alkoxy, C 1-6 thioalkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3 to 6 membered carbocyclic group or 3 to 6 membered hetero Substituted by a cyclic group, the heterocyclic group contains 1 to 2 hetero atoms selected from N, O or S.
  • a preferred embodiment of the invention a compound of the formula (IIe), or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof:
  • R 2 and R 2′ , R 3 and R 3′ , R 4 and R 4′ may form a double bond together with a carbon atom to which they are bonded, and the double bond may optionally be further 0 to 2 Substituted from F, Cl, Br, C 2-6 alkyl or -(CR 11 R 11' ) m R 12 ;
  • n is selected from 0, 1 or 2;
  • R 11 and R 11 ' are each independently selected from the group consisting of H, F, Cl, CH 2 F, CHF 2 , CF 3 , CH 2 CH 2 F, CHFCH 3 , CHFCH 2 F, methyl, ethyl, n-propyl, Isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, hydroxymethyl or hydroxyethyl;
  • R 12 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, furyl, thienyl, pyrrolyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyrrolyl, Oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxolyl, 1,4-dioxane , 1,5-dioxane, oxacyclopentyl, azacyclopentyl, oxetanyl, azacyclohexyl, or When substituted, optionally further from 0 to 4 selected from the group consisting of F, Cl, Br, hydroxy, methyl, ethyl, propyl, isopropyl, n-butyl, iso
  • the present invention relates to a compound of the formula (III), or all stereoisomers, solvates, prodrug metabolites, pharmaceutically acceptable salts or co-crystals thereof:
  • R a , R b , R c are each independently selected from H, F, Cl, Br, I, C 2-6 alkenyl or C 2-6 alkynyl, preferably, R a , R b , R c are each independently Is selected from H, F, Cl, Br, C 2-4 alkenyl or C 2-4 alkynyl, and R a , R b , R c up to 2 are selected from H;
  • R a ' , R b ' and R c ' are each independently selected from H, C 1-6 alkyl.
  • a preferred embodiment of the invention a compound of the formula (III), or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof:
  • R a , R b , R c are each independently selected from the group consisting of H, F, Cl, Br, I, vinyl, propenyl, allyl, butenyl, 2-enbutyl, 3-enbutyl, pentane Alkenyl, hexenyl, ethynyl, propynyl, preferably, R a , R b , R c are each independently selected from H, F, Cl, Br, vinyl, propenyl, allyl, ethynyl Or propynyl, and at most 2 of R a , R b , R c are selected from H;
  • R a′ , R b′ , R c′ are each independently selected from the group consisting of H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl Base, n-hexyl.
  • the invention relates to a compound selected from, but not limited to:
  • the present invention relates to a pharmaceutically acceptable salt of the compound of the formula (I), which is p-toluenesulfonate.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the general formula (I), (II), (IIa), (IIb), (IIc), (IId) or (IIe) A compound or all of its stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs, and one or more pharmaceutically acceptable carriers and/or excipients.
  • the present invention relates to a compound of the formula (I), (II), (IIa), (IIb), (IIc), (IId) or (IIe), or all stereoisomers thereof, Solvates, metabolites, pharmaceutically acceptable salts, eutectic or prodrugs, in the preparation Use in the treatment and/or prevention of pain medications, 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 neuralgia or non-neuralgia, acute Or use in chronic tension headache, postoperative 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 compound of the invention, or a stereoisomer, solvate, metabolite, prodrug thereof, pharmaceutically An acceptable salt or eutectic, or a pharmaceutical composition of the invention.
  • the pain is selected from the group consisting of: 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, epilepsy, generalized anxiety disorder or restless leg syndrome.
  • 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 6 selected from the group consisting of F, Cl, Br, I, hydroxy, decyl, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxy Alkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy Substituted by a substituent of a carboxy group or a carboxylate group.
  • 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 is nail acyl, phenyl, methoxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, 9-fluorenylmethyloxycarbonyl, adamantyloxycarbonyl, benzyloxycarbonyl, benzyl Alkylcarbonyl, benzyl, benzyl, trityl, phthaloyl.
  • Carboxy protecting group means methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl , trichloroethyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, p-methoxybenzyl, p-tert-butylbenzyl, acetoxymethyl, propionyloxymethyl, butyl Acyloxymethyl, isobutyryloxymethyl, pentoxymethyl, pivaloyloxymethyl, acetoxyethyl, acetoxypropyl, acetoxybutyl, propionyloxy Ethyl, propionyloxypropyl, butyryloxyethyl, isobutyryloxyethyl, pivaloyloxy
  • “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.
  • “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
  • 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 half inhibitory concentration of inhibitors measured: The concentration required to inhibit the binding of gabapentin to calcium channel by testing the test compound 50%.
  • Figure 1 is a graph showing the pain response of an animal of the compound of Example 6;
  • Figure 2 is a graph showing the pain response of an animal of the compound of Example 12;
  • Figure 3 is a graph showing the pain response of an animal of the compound of isomer 1 of Example 32.
  • 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 synthesis of the chiral configuration is involved, and if not specified, the chiral configuration is determined by comparison with the positive compound meribillin (CN101878193 Example 21);
  • 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;
  • Step 6 ( ⁇ )-2-((1R,5S)-3-(cyclopropylmethyl)bicyclo[3.2.0]hept-3-ene-6-ylidene)-tert-butyl ester (1G)
  • reaction mixture was poured into ice-water mixture (300 mL), solid ammonium chloride was added to sat., ethyl acetate (300 mL ⁇ 3)
  • organic phase was washed with a saturated sodium chloride solution (300 mL ⁇ 1), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure.
  • Step 7 ( ⁇ )-2-((1R,5S,6S)-3-(cyclopropylmethyl)-6-(nitromethyl)bicyclo[3.2.0]hept-3-ene-6 -yl)tert-butyl acetate (intermediate 1)
  • peak 1 2-((1R,5S,6S)-3-(cyclopropylmethyl)-6-(nitromethyl)bicyclo[3.2.0]hept-3-ene-6-yl) Tert-butyl acetate (Intermediate 2) (colorless oily liquid, 1.15 g, yield: 61%, Chiral-HPLC: 100%); peak 2 is 2-((1S,5R,6R)-3- (ring Propylmethyl)-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid tert-butyl ester (Intermediate 3) (colorless oily liquid, 1.24 g, yield : 65%, Chiral-HPLC: 99.4%).
  • Step 6 ( ⁇ )-2-((1R,5S)-3-(cyclobutylmethyl)bicyclo[3.2.0]hept-3-ene-6-ylidene acetate tert-butyl ester (4G)
  • Step 7 2-((1R,5S,6S)-3-(cyclobutylmethyl)-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid tert-butyl Ester (intermediate 4)
  • peak 1 is 2-((1R,5S,6S)-3-(cyclobutylmethyl)-6-(nitromethyl)bicyclo[3.2.0]hept-3-ene-6-yl)acetic acid Butyl ester (intermediate 5) (colorless oily liquid, 0.8 g, yield: 53%, Chiral-HPLC: 98.04%); peak 2 is 2-((1S,5R,6R)-3-(cyclobutylmethyl) - 6-(Nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid tert-butyl ester (Intermediate 6) (colorless oily liquid, 0.75 g, yield: 50%, Chiral-HPLC: 99.26%).
  • Sodium hydride (12.9 g, 323 mmol) was added to dry THF (460 mL). After stirring at ° C for 10 minutes, the system was cooled to -5 ° C, n-butyllithium (101 mL, 2.5 M n-hexane solution, 253 mmol) was added dropwise, and the mixture was stirred at 0 ° C for 10 minutes, and bromomethylcyclopentane was added dropwise.
  • Step 6 ( ⁇ )-2-((1R,5S)-3-(cyclopentylmethyl)bicyclo[3.2.0]hept-3-ene-6-ylidene acetate tert-butyl ester (7G)
  • Step 7 2-((1R,5S,6S)-3-(cyclopentylmethyl)-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid Tert-butyl ester (intermediate 7)
  • peak 1 (retention time: 2.76 minutes, 2.26 g), peak 2 (retention time: 3.59 minutes, 2.06 g).
  • peak 1 is 2-((1R,5S,6S)-3-(cyclopentylmethyl)-6-(nitromethyl)bicyclo[3.2.0]hept-3-ene-6-yl) Tert-butyl acetate (colorless oily liquid, intermediate 8);
  • peak 2 is 2-((1S,5R,6R)-3-(cyclopentylmethyl)-6-(nitromethyl)bicyclo[3.2 .0] tert-butyl hept-3-en-6-yl)acetate (colorless oily liquid, intermediate 9).
  • the sodium hydride (16.77 g, 420 mmol) was added to dry tetrahydrofuran (600 mL), and the mixture was cooled to 0 ° C under nitrogen atmosphere, and ethyl acetoacetate (1A) (39 g, 300 mmol) was added dropwise with stirring. After stirring at 0 ° C for 10 minutes, it was cooled to -5 ° C, n-butyllithium (131 mL, 2.5 M-hexane solution, 329 mmol) was added dropwise. After the addition, the mixture was stirred at 0 ° C for 10 minutes, and bromomethylcyclohexane was added dropwise.
  • Step 6 ( ⁇ )-2-((1R,5S)-3-(cyclohexylmethyl)bicyclo[3.2.0]hept-3-ene-6-ylidene acetate tert-butyl ester (10G)
  • Step 7 ( ⁇ )-2-((1R,5S,6S)-3-(cyclohexylmethyl)-6-(nitromethyl)bicyclo[3.2.0]hept-3-ene-6- Tert-butyl acetate (intermediate 10)
  • peak 1 retention time: 3.46 minutes, 1.52 g
  • peak 2 retention time: 3.84 minutes, 1.33 g
  • peak 1 was 2-((1R, 5S, 6S) --3-(cyclohexylmethyl)-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid tert-butyl ester (intermediate 11)
  • peak 2 is 2- ((1S,5R,6R)-3-(cyclohexylmethyl)-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid tert-butyl ester (intermediate 12 ).
  • Peak 1 1 H NMR (400 MHz, CDCl 3 ): ⁇ 5.25 (s, 1H), 4.86-4.73 (m, 2H), 3.21 (s, 1H), 2.87-2.81 (m, 1H), 2.48-2.43 (m, 3H), 2.33 - 2.27 (m, 1H), 2.04-2.00 (m, 3H), 1.69-1.67 (m, 5H), 1.48-1.45 (m, 11H), 1.27-1.33 (m, 3H) , 0.95-0.87 (m, 2H).
  • Peak 2 1 H NMR (400MHz, CDCl 3 ): ⁇ 5.25 (s, 1H), 4.86-4.73 (m, 2H), 3.21 (s, 1H), 2.87-2.81 (m, 1H), 2.48-2.43 (m, 3H), 2.33 - 2.27 (m, 1H), 2.04-2.00 (m, 3H), 1.69-1.67 (m, 5H), 1.48 - 1.45 (m, 11H), 1.27 - 1.33 (m, 3H) , 0.95-0.87 (m, 2H).
  • Ethyl butyl 3-oxopentanoate (13D) (10.5 g, 44.9 mmol) was stirred at 0 ° C for 10 min, cooled to -5 ° C, and n-butyllithium (22 mL, 2.5 M) N-hexane solution, 53.8mmoL), stirred at 0 ° C for 10 minutes, added 3-bromopropene (5.1mL, 58.3mmoL), naturally warmed to room temperature, reacted at room temperature for 3 hours, cooled to -10 ° C, Concentrated hydrochloric acid was added dropwise to a pH of about 3, water (300 mL) was added, and extracted with ethyl acetate (300 mL ⁇ 3).
  • Step 5 4-((3,3-Difluorocyclobutyl)methyl)-3-hydroxyhept-6-enoic acid ethyl ester (13F)
  • Step 7 ( ⁇ )-(1R,5S)-3-((3,3-bisfluorocyclobutyl)methyl)bicyclo[3.2.0]hept-3-ene-6-one (13H)
  • Step 8 ( ⁇ )-2-((1R,5S)-3-((3,3-bisfluorocyclobutyl)methyl)bicyclo[3.2.0]hept-3-ene-6-subunit ) tert-butyl acetate (13I)
  • Step 9 ( ⁇ )-2-((1R,5S,6S)-3-((3,3-bisfluorocyclobutyl)methyl)-6-(nitromethyl)bicyclo[3.2.0 Tert-butyl hept-3-en-6-yl)acetate (intermediate 13)
  • peak 1 retention time: 1.91 minutes, 1.02 g
  • peak 2 retention time: 2.67 minutes, 1.00 g
  • peak 1 was 2-((1R, 5S, 6S) --3-((3,3-Difluorocyclobutyl)methyl)-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl)acetic acid tert-butyl ester (middle) Body 14
  • peak 2 is 2-((1S,5R,6R)-3-((3,3-bisfluorocyclobutyl)methyl)-6-(nitromethyl)bicyclo[3.2.0] tert-Butyl hept-3-en-6-yl)acetate (Intermediate 15).
  • Triethylaluminum (222 mL, 1 M solution in n-hexane, 222 mmol) was added to the reaction flask, cooled to -10 ° C under argon atmosphere, and dichloromethane (69.4 g, 259.11 mmol) of dichloromethane (150 mL) was slowly added dropwise. The solution was reacted at 0 ° C for 30 minutes, and a solution of 4-bromobutene (24A) (10 g, 74.07 mmol) dissolved in dichloromethane (50 mL) was added dropwise.
  • reaction solution was added dropwise to a 2M aqueous solution of hydrochloric acid (500 mL), and extracted with methyl tert-butyl ether (75 mL ⁇ 2), and the organic phase was combined, dried, filtered, and evaporated at atmospheric temperature (90 ° C - 150 ° C) , until no fraction is dropped), the heating is turned off after 1 hour.
  • the oil was purified by silica gel column chromatography (yield: petroleum ether) toield (2-ethylethylethyl) hexane (24B) (8 g, yield: 55.10%).
  • the third step 4-(2-cyclopropylethyl)-3-hydroxyhept-6-enoic acid (24D)
  • Dichloromethane (100 mL ⁇ 2) was added to the reaction mixture, and the layers were separated, and the mixture was adjusted to pH with concentrated hydrochloric acid, and extracted with ethyl acetate (100 mL ⁇ 2) and layered. The dichloromethane layer was back extracted with 2M sodium hydroxide solution (200 mL), and the aqueous phase was concentrated hydrochloric acid. The mixture was acidified and extracted with ethyl acetate (100 mL ⁇ 2). Acid (24D) (1.6 g) was used directly in the next step.
  • Step 5 ( ⁇ )-2-((1R,5S)-3-(2-cyclopropylethyl)bicyclo[3.2.0]heptane-3-ene-6-ylidene acetate tert-butyl ester (24F)
  • Step 6 ( ⁇ )-2-((1R,5S,6S)-3-(2-cyclopropylethyl)-6-(nitromethyl)bicyclo[3.2.0]heptane-3- Tert-butylene-6-yl)acetate (24G)
  • Step 7 ( ⁇ )-2-((1R,5S,6S)-6-(aminomethyl)-3-(2-cyclopropylethyl)bicyclo[3.2.0]heptane-3-ene -6-base)
  • B Tert-butyl acid ester (24H)
  • Isomer 2 of (24H), isomer 2 of (24H) is selected from or
  • Step 8 ( ⁇ )-2-((1R,5S,6S)-6-(aminomethyl)-3-(2-cyclopropylethyl)bicyclo[3.2.0]heptane-3-ene -6-yl)acetic acid (compound 24)
  • the oxetanone (25A) (36 g, 0.5 mol) was dissolved in dichloromethane (500 mL), cooled to 0 ° C, and ethyl 2-(triphenylphosphene)acetate (191.6 g, 0.55 After stirring for 1 hour at room temperature, the reaction mixture was concentrated under reduced pressure. Petroleum ether (1500 mL) was added to the residue, stirred for 30 min, filtered, and the filter cake was washed with petroleum ether (150 mL ⁇ 2).
  • Ethyl 2-(oxetane-3-methylene)acetate (25B) (62 g, 0.437 mol) was dissolved in anhydrous ethanol (300 mL) and palladium charcoal (20 g, 5% (w%) After the addition, the mixture was hydrogenated three times and hydrogenated at room temperature for 4 hours, filtered, and the filter cake was washed with anhydrous ethanol (25 mL ⁇ 2), and the filtrate was concentrated under reduced pressure to give a colorless oily liquid 2-(oxetane) -3-yl)ethyl acetate (25C) (56 g, yield: 89%).
  • reaction solution was cooled to room temperature, poured into ice-water mixture (200 g), and extracted with diethyl ether (100 mL ⁇ 4) The organic phase was washed with anhydrous sodium sulfate, filtered, and evaporated to dryness to give the product (2-( oxetane-3-yl)acetic acid allyl ester (25E) 19 g, yield: 83%).
  • Lithium diisopropylamide (67 mL, 0.134 mol) was dissolved in tetrahydrofuran (100 mL), cooled to -78 ° C, and 2-(oxetane-3-yl)acetic acid allyl ester (25E) was added dropwise. (19 g, 0.122 mol) in tetrahydrofuran (100 mL), stirred at -78 ° C for 30 minutes, trimethylchlorosilane (14.55 g, 0.134 mol) was added dropwise, and naturally stirred at room temperature for 1 hour and then refluxed at 80 ° C.
  • reaction solution was cooled to room temperature, 5% (w%) sodium hydroxide solution (200 mL) was added, stirred for 1 hour, extracted with diethyl ether (100 mL ⁇ 4), and the aqueous phase was adjusted to pH 2 with 2M hydrochloric acid. 3, extraction with ethyl acetate (100 mL ⁇ 3), EtOAc (EtOAc) -enoic acid (25F) (11.5 g, yield: 60%).
  • Lithium aluminum hydride (2.17 g, 0.057 mol) and diethyl ether (80 mL) were added to the reaction flask, the temperature was lowered to -78 ° C, and N-methoxy-N-methyl-2-(oxetane-3) was added dropwise.
  • Step 8 4-(oxetan-3-yl)heptane-2,6-dienoic acid ethyl ester (25I)
  • Triethyl phosphonoacetate (2.64 g, 11.78 mmol) was dissolved in tetrahydrofuran (12 mL), cooled to 0 ° C, 3M solution of potassium tert-butoxide (3.53 mL, 10.7 mmol) in tetrahydrofuran was added dropwise, stirring at 0 ° C After 30 minutes, a solution of 2-(oxetan-3-yl)pent-4-enal (25H) (1.5 g, 10.7 mmol) in tetrahydrofuran (3 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours.
  • reaction solution was poured into a saturated aqueous solution of ammonium chloride (50 mL), and extracted with diethyl ether (50 mL ⁇ 3). The organic phase was combined and washed with saturated sodium chloride solution (100 mL ⁇ 3). The sodium was dried, filtered, and the filtrate was evaporated, evaporated, mjjjjjjjjjjjj -yl)heptane-2,6-dienoic acid ethyl ester (25I) (2 g, yield: 88.9%).
  • Ethyl 4-(oxetan-3-yl)heptane-2,6-dienoate (25I) (5.7 g, 27.1 mmol) was dissolved in ethanol (30 mL).
  • a solution of sodium (2.1 g, 54.2 mmol) in water (10 mL) was added at room temperature for 5 hours, concentrated under reduced pressure to remove ethanol, extracted with diethyl ether (20 mL ⁇ 3), and the organic phase was discarded.
  • the pH was adjusted to 2-3 with EtOAc (EtOAc) (EtOAc) Gheptyl-2,6-dienoic acid (25J) (4.6 g, yield: 93.8%).
  • Step 10 ( ⁇ )-(1R,5S)-3-(oxetan-3-yl)bicyclo[3.2.0]hept-3-ene-6-one (25K)
  • Step 12 ( ⁇ )-2-((1R,5S,6S)-6-(nitromethyl)-3-(oxetan-3-yl)bicyclo[3.2.0]heptane- Tert-butyl 3-yl 6-yl)acetate (25M)
  • Step 13 ( ⁇ )-2-((1S,5R,6R)-6-(aminomethyl)-3-(oxetan-3-yl)bicyclo[3.2.0]hept-3 -tert-butyl-6-yl acetate (25N)
  • Isomer 2 of (Compound 25), Isomer 2 of (Compound 25) is selected from or
  • reaction solution was cooled to room temperature, and a saturated aqueous solution of sodium hydrogencarbonate (500 mL) was added, and concentrated to remove most of toluene, and water (500 mL) was added, and extracted with ethyl acetate (1000 mL ⁇ 3).
  • the third step ( ⁇ )-(1R, 2S, 5R)-2-bromospiro[bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolan]-3-one ( 32D)
  • Step 4 ( ⁇ )-(1R,5R)-spiro[bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolan-3-one (32E)
  • Step 5 ( ⁇ )-(1R,5R)-3-methyl snail [bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolane] (32F)
  • Triphenylphosphine bromide (25.49 g, 71.35 mmol) and tetrahydrofuran (150 mL) were added to the reaction flask, and the mixture was cooled to 0 ° C, and potassium t-butoxide (8 g, 71.35 mmol) was slowly added portionwise with stirring, and the mixture was warmed to room temperature.
  • Step 6 ( ⁇ )-(1R,3R,5R)-spiro[bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolan-3-ylmethanol (32G)
  • Step 7 ( ⁇ )-(1R,3R,5R)-spiro[bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolane-3-carbaldehyde (32H)
  • Step 8 ( ⁇ )-(1R,3R,5R)-spiro[bicyclo[3.2.0]heptane-6,2'-[1,3]dioxolan-3-ylethene (32I)
  • Step 9 ( ⁇ )-(1R,3R,5R)-3-vinylbicyclo[3.2.0]heptane-6-one (32J)
  • Step 10 ( ⁇ )-2-((1R,3R,5R)-3-vinylbicyclo[3.2.0]heptane-6-ylene)acetic acid tert-butyl ester (32K)
  • Step 12 ( ⁇ )-2-((1R,3R,5R,6S)-6-(aminomethyl)-3-vinylbicyclo[3.2.0]heptane-6-yl)acetic acid tert-butyl Ester (32M)
  • Step 13 ( ⁇ )-2-((1R,3R,5R,6S)-6-(aminomethyl)-3-vinylbicyclo[3.2.0]heptane-6-yl)acetic acid (compound) 32)
  • EtOAc EtOAc Isomer 1 (0.4) of 2-((1R,3R,5R,6S)-6-(aminomethyl)-3-vinylbicyclo[3.2.0]heptan-6-yl)acetic acid (Compound 32) g, yield: 63%).
  • Isomer 2 of (Compound 32), Isomer 2 of (Compound 32) is selected from or

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Abstract

La présente invention concerne un dérivé d'acide γ-aminé à cycle condensé et son utilisation médicale, et concerne en particulier le dérivé d'acide γ-aminé à cycle condensé tel que représenté dans la formule (I), ou un stéréoisomère, un solvate, un métabolite, un promédicament, un sel pharmaceutiquement acceptable ou un cocristal de ce dernier, une composition pharmaceutique le comprenant et une utilisation du composé ou de la composition de la présente invention dans le domaine de l'analgésie, les définitions des divers groupes substituants dans la formule (I) étant identiques à celles indiquées dans la description.
PCT/CN2016/111218 2015-12-25 2016-12-21 Dérivé d'acide γ-aminé à cycle condensé, et son procédé de préparation et son utilisation médicale WO2017107907A1 (fr)

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US10654794B2 (en) 2016-09-14 2020-05-19 Sichuan Haiso Pharmaceutical Co., Ltd. Fused tricyclic Γ-amino acid derivative, preparation method therefor, and medical use thereof
WO2020210508A1 (fr) 2019-04-09 2020-10-15 Nurix Therapeutics, Inc. Composés de pipéridine substitués en position 3 pour l'inhibition de cbl-b, et utilisation d'un inhibiteur de cbl-b en combinaison avec un vaccin contre le cancer et/ou un virus oncolytique
WO2021021761A1 (fr) 2019-07-30 2021-02-04 Nurix Therapeutics, Inc. Composés d'urée, d'amide et d'hétéroaryle substitué pour l'inhibition de cbl-b
CN114264751A (zh) * 2021-12-28 2022-04-01 江苏威凯尔医药科技有限公司 一种高效液相色谱法分离米洛巴林中间体及其对映异构体的方法
EP4183771A4 (fr) * 2020-07-20 2024-04-24 Sichuan Haisco Pharmaceutical Co Ltd Formulation pharmaceutique à libération prolongée de dérivé d'acide gamma-aminé tricyclique fusionné et procédé de préparation associé

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CN101878193A (zh) * 2007-09-28 2010-11-03 第一三共株式会社 双环γ-氨基酸衍生物
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10654794B2 (en) 2016-09-14 2020-05-19 Sichuan Haiso Pharmaceutical Co., Ltd. Fused tricyclic Γ-amino acid derivative, preparation method therefor, and medical use thereof
WO2020210508A1 (fr) 2019-04-09 2020-10-15 Nurix Therapeutics, Inc. Composés de pipéridine substitués en position 3 pour l'inhibition de cbl-b, et utilisation d'un inhibiteur de cbl-b en combinaison avec un vaccin contre le cancer et/ou un virus oncolytique
WO2021021761A1 (fr) 2019-07-30 2021-02-04 Nurix Therapeutics, Inc. Composés d'urée, d'amide et d'hétéroaryle substitué pour l'inhibition de cbl-b
EP4183771A4 (fr) * 2020-07-20 2024-04-24 Sichuan Haisco Pharmaceutical Co Ltd Formulation pharmaceutique à libération prolongée de dérivé d'acide gamma-aminé tricyclique fusionné et procédé de préparation associé
CN114264751A (zh) * 2021-12-28 2022-04-01 江苏威凯尔医药科技有限公司 一种高效液相色谱法分离米洛巴林中间体及其对映异构体的方法
CN114264751B (zh) * 2021-12-28 2024-02-27 江苏威凯尔医药科技有限公司 一种高效液相色谱法分离米洛巴林中间体及其对映异构体的方法

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