WO2020156522A1 - 地佐辛衍生物及其医药用途 - Google Patents

地佐辛衍生物及其医药用途 Download PDF

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WO2020156522A1
WO2020156522A1 PCT/CN2020/074131 CN2020074131W WO2020156522A1 WO 2020156522 A1 WO2020156522 A1 WO 2020156522A1 CN 2020074131 W CN2020074131 W CN 2020074131W WO 2020156522 A1 WO2020156522 A1 WO 2020156522A1
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compound
aliphatic hydrocarbon
group
hydrocarbon group
formula
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PCT/CN2020/074131
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English (en)
French (fr)
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邵黎明
胡涛
徐浩宇
陈令武
邹贻泉
蔡伟
杨希成
李浩冬
薛登启
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扬子江药业集团有限公司
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Priority to EP20749066.5A priority Critical patent/EP3919472A4/en
Priority to CA3128419A priority patent/CA3128419A1/en
Priority to KR1020217025120A priority patent/KR20210124256A/ko
Priority to US17/427,541 priority patent/US20220117913A1/en
Priority to AU2020214275A priority patent/AU2020214275A1/en
Priority to JP2021544654A priority patent/JP2022519086A/ja
Publication of WO2020156522A1 publication Critical patent/WO2020156522A1/zh

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    • C07C217/94—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
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    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
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    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
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    • C07—ORGANIC CHEMISTRY
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    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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Definitions

  • the present invention relates to the field of medical technology, in particular, to a new class of dazocine derivatives, pharmaceutical compositions containing the derivatives, preparation methods thereof, and medical uses thereof.
  • Dezocine is a mixed agonist-antagonist of opioid receptors similar in structure to pentazocine. It was developed by Wyeth-Ayerst Laboratories in the United States in the 1970s and was approved by the FDA in 1989. It is a commercial product The name Dalgan is marketed by Astrazeneca for the treatment of pain after surgery. Since its launch in China in 2009, it has been widely used in general anesthesia induction, postoperative analgesia and preemptive analgesia, and for the treatment of visceral pain and cancer pain.
  • the present invention provides a compound represented by formula I or a tautomer, optical isomer, nitrogen oxide, solvate, pharmaceutically acceptable salt or prodrug thereof:
  • R 1 and R 2 are each independently selected from H, deuterium, tritium, C 1 -C 12 aliphatic hydrocarbon group, C 6 -C 14 aryl group, C 6 -C 14 aryl group-C 1 -C 12 aliphatic hydrocarbon group, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl-C 1 -C 12 aliphatic hydrocarbon group, 5-14 membered heteroaryl, 5-14 membered heteroaryl-C 1 -C 12 aliphatic hydrocarbon group,
  • the C 6 -C 14 aryl group, C 3 -C 8 cycloalkyl group, and 5-14 membered heteroaryl group are optionally selected by more than one halogen, OH, C 1 -C 12 aliphatic hydrocarbon group, C 1 -C 12 aliphatic hydrocarbon group Oxy group, C 1 -C 12 aliphatic hydrocarbon group -S-substituted; or R 1 ,
  • R 3 is selected from H, deuterium, tritium, C 1 -C 12 aliphatic hydrocarbon group, C 6 -C 14 aryl group, C 6 -C 14 aryl group-C 1 -C 12 aliphatic hydrocarbon group, C 3 -C 8 cycloalkyl group , C 3 -C 8 cycloalkyl-C 1 -C 12 aliphatic hydrocarbon group, 5-14 membered heteroaryl group, 5-14 membered heteroaryl group-C 1 -C 12 aliphatic hydrocarbon group, the C 6 -C 14 aromatic Group, C 3 -C 8 cycloalkyl group, 5-14 membered heteroaryl group, optionally with more than one halogen, C 1 -C 12 aliphatic hydrocarbon group, C 1 -C 12 aliphatic hydrocarbon group, C 1 -C 12 aliphatic hydrocarbon group -S-Replace;
  • R 4 is selected from H, deuterium, tritium, OH, halogen, C 1 -C 12 aliphatic hydrocarbon group, C 1 -C 12 aliphatic hydrocarbon group oxy group, C 1 -C 12 aliphatic hydrocarbon group -S-;
  • At least one of R 1 , R 2 , and R 3 is not H;
  • A is selected from O or S; n is selected from 0,1,2.
  • R 1 and R 2 are each independently selected from H, deuterium, tritium, C 1 -C 12 aliphatic hydrocarbon group, C 6 -C 14 aryl-C 1 -C 6 aliphatic hydrocarbon group, C 3 -C 8 cycloalkyl group, C 3 -C 8 cycloalkyl group-C 1 -C 6 aliphatic hydrocarbon group, the C 6 -C 14 aryl group, C 3 -C 8 cycloalkyl group is optionally substituted by more than one halogen, OH, C 1 -C 6 aliphatic hydrocarbon group, C 1 -C 6 aliphatic hydrocarbon group oxy group, C 1 -C 6 aliphatic hydrocarbon group -S-substituted; or R 1 , R 2 and the connected N together form a 4-6 member containing N ring;
  • R 3 is selected from H, deuterium, tritium, C 1 -C 6 aliphatic hydrocarbon group, C 6 -C 14 aryl-C 1 -C 12 aliphatic hydrocarbon group, and the C 6 -C 14 aryl group is optionally substituted by more than one halogen, C 1 -C 6 aliphatic hydrocarbon group, C 1 -C 6 aliphatic hydrocarbon group oxy group, C 1 -C 6 aliphatic hydrocarbon group -S-substituted;
  • R 4 is selected from C 1 -C 6 aliphatic hydrocarbon group, C 1 -C 6 aliphatic hydrocarbon group oxy group, C 1 -C 6 aliphatic hydrocarbon group -S-;
  • At least one of R 1 , R 2 , and R 3 is not H;
  • A is selected from O or S; n is selected from 1,2.
  • R 1 and R 2 are each independently selected from H, deuterium, tritium, C 1 -C 12 alkyl, C 6 -C 14 aryl-C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkyl-C 1 -C 6 alkyl, the C 6 -C 14 aryl, C 3 -C 8 cycloalkyl is optionally substituted by more than one halogen, C 1- C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl-S-substituted; or R 1 , R 2 and the N connected to them together form a 5-membered ring containing N;
  • R 3 is selected from H, deuterium, tritium, C 1 -C 6 alkyl, C 6 -C 14 aryl-C 1 -C 12 alkyl, and the C 6 -C 14 aryl is optionally substituted by more than one halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl-S-substituted;
  • R 4 is selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl-S-;
  • At least one of R 1 , R 2 , and R 3 is not H;
  • A is selected from O; n is selected from 1.
  • R 1 is selected from hydrogen, deuterium, tritium, C 1 -C 6 alkyl
  • R 2 is selected from hydrogen, deuterium, tritium, C 1 -C 6 alkyl, C 6 -C 14 aryl-C 1 -C 6 alkyl;
  • R 3 is selected from H, deuterium, tritium, C 6 -C 14 aryl-C 1 -C 12 alkyl, the C 6 -C 14 aryl is optionally substituted by more than one halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl-S-substituted.
  • the C 1 -C 12 aliphatic hydrocarbon group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl , Neopentyl, n-hexyl, vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 1-ethylvinyl, 1-methyl-2-propenyl , 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 1-hexenyl, ethynyl, 1- Propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl and 1-hexynyl; the halogen is selected from F, Cl,
  • the pharmaceutically acceptable salt is selected from hydrochloride.
  • the structure of Formula I has the following structure of Formula II:
  • the compound of formula (I) is selected from the following compounds:
  • the compound of formula (I) is selected from the following compounds:
  • the compound of formula (I) is selected from the following compounds:
  • the compound of formula (I) is selected from the following compounds:
  • the compound of formula (I) is selected from the following compounds:
  • At least one of the ⁇ , ⁇ , and ⁇ opioid receptors has an IC 50 value of Grade A, more preferably at least two opioid receptors have an IC 50 value of Grade A, and the most Preferably, the IC 50 values of the three opioid receptors all reach A grade.
  • the present invention also provides a method for preparing the compound of formula I (including the compound of formula II), including the following schemes:
  • R 1 , R 2 , R 3 , R 4 , A, and n are as defined in formula I, but wherein R 1 and R 2 are not H; R b CHO corresponds to the introduction of R into the target compound of formula I 2- substituted aldehyde compounds.
  • R 3 , R 4 , A and n are as defined in formula I, m is 3-5; X is F, Cl, Br, I.
  • R 1 , R 2 , R 3 , R 4 , A, and n are as defined in formula I, but R 3 is not H; X is F, Cl, Br, or I.
  • T-4 completely removes the protective group to obtain the compound of formula I; or T-4 in the presence of reducing reagent B obtains the N-methylated product.
  • R 3 , R 4 , A, and n are as defined in formula I, but R3 is not H; X is F, Cl, Br, I; G is an amino protecting group.
  • G is an acyl protecting group (for example, t-Boc)
  • N-methylated products can be obtained in the presence of reducing reagent B.
  • Compound M-1, M-2 Compound R a CHO with an aldehyde or an aldehyde R b CHO during the reaction, addition of an alcohol and an organic acid reagent, the alcohol reagent may be selected from methanol, ethanol, propanol, ethylene glycol
  • the organic acid is selected from one or more of acetic acid, formic acid or propionic acid; the molar ratio of M-1 and M-2 to the aldehyde is 1:1-15, preferably It is 1:1-11, and those skilled in the art can understand that adjusting the molar ratio of M-1 and aldehyde can respectively obtain mono- and di-substituted products (for example, the molar ratio of M-1 and aldehyde is 1:9-11 When, a disubstituted product is obtained).
  • the reducing reagent A can be selected from sodium cyanoborohydride, sodium borohydride, sodium acetate borohydride One or more of them are preferably sodium cyanoborohydride.
  • the molar ratio of the compound M-1, the compound M-2 to the reducing agent is 1:1.5-8, and preferably 1:2-5.
  • the reduction reaction further includes a post-processing step: adjust the pH of the reaction mixture to 8-10 with an alkaline reagent, add an organic solvent (such as ethyl acetate) and separate the liquids, combine the organic phases, wash with saturated brine and dry , Separated by column chromatography to obtain the compound of formula I.
  • an organic solvent such as ethyl acetate
  • the reaction of compound M-3 and compound X (CH 2 ) m X is preferably carried out in the presence of organic solvent A and alkaline reagent A; the organic solvent A can be selected from one or more of acetonitrile, DMF and DMSO , Preferably acetonitrile.
  • the alkaline agent may be selected from hydroxides, carbonates or bicarbonates of alkali metals or alkaline earth metals, preferably sodium bicarbonate or potassium bicarbonate.
  • the molar ratio of the compound M-3, X(CH 2 ) m X and the alkaline reagent is 1:2-8:3-10, preferably 1:3-5:6-8.
  • the reaction further includes post-processing steps: filtering, evaporating the solvent and adding an organic solvent (such as ethyl acetate), using an alkaline reagent to adjust the pH of the reaction mixture to 8-10, adding organic solvent to dilute and separate, and combine The organic phase is washed with saturated brine and dried, and separated by column chromatography to obtain the compound of formula I.
  • an organic solvent such as ethyl acetate
  • the reaction further includes a post-processing step: distilling off HX, adding an organic solvent (such as ethyl acetate), adjusting the pH of the reaction mixture to 8-10 with an alkaline reagent, separating the liquids, combining the organic phases, and immersing them in saturated brine After washing and drying, the compound of formula I is obtained through column chromatography.
  • an organic solvent such as ethyl acetate
  • G can be selected from t-butoxycarbonyl, benzyloxycarbonyl, and p-toluenesulfonyl, and is preferably t-butoxycarbonyl.
  • the amino group protection reaction is carried out in the presence of organic solvent B and a catalyst.
  • the organic solvent B can be selected from one or more of dichloromethane, carbon tetrachloride, dichloroethane, ethyl acetate, DMF, and DMSO.
  • the catalyst can be selected from one or more of DIPEA, DBU, and triethylamine, preferably DIPEA.
  • the molar ratio of the compound M-5 to the amino protecting reagent is 1:1-2, preferably 1:1-1.5.
  • an organic solvent C and a basic reagent C are added, and the organic solvent C can be selected from acetone, dioxane, methanol, ethanol, propylene One or more of alcohol, tetrahydrofuran, DMF, and DMSO, preferably acetone.
  • the alkaline agent C may be selected from hydroxides, carbonates or bicarbonates of alkali metals or alkaline earth metals, preferably sodium carbonate, potassium carbonate, and cesium carbonate.
  • the molar ratio of T-3 to alkaline reagent is 0.8-2, preferably 1-1.5; the obtained T-4 intermediate is reacted in the presence of complete deprotection reagent or reducing reagent B, and the deprotection reagent used is selected from TFA, formic acid, acetic acid, hydrochloric acid, sulfuric acid, oxalic acid, preferably TFA, the reducing agent B used is selected from LiAlH 4 , DIBAL-H, red-Al, NaBH 4 , LiBH 4 , preferably LiAlH 4 .
  • an organic solvent D which is selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride, dichloroethane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, and dioxane One or more of them; the feed ratio of the T-4 intermediate to the deprotection reagent is 1 mmol: 2-8 ml, preferably 1 mmol: 3-5 ml.
  • the deprotection reagent reaction further includes a post-processing step: evaporate the solvent, add an organic solvent (such as ethyl acetate), use an alkaline reagent to adjust the pH of the reaction mixture to 8-10, separate the liquids, combine the organic phases, Wash with saturated brine and dry, and separate by column chromatography to obtain the compound of formula I.
  • an organic solvent such as ethyl acetate
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula I according to the present invention or its tautomers, optical isomers, nitrogen oxides, solvates, pharmaceutically acceptable salts or prodrugs.
  • the pharmaceutical composition of the present invention further comprises a therapeutically effective amount of the compound of formula I of the present invention or its tautomers, optical isomers, nitrogen oxides, solvates, pharmaceutically acceptable Accepted salt or prodrug and pharmaceutically acceptable carrier.
  • the carrier in the pharmaceutical composition is "acceptable", which is compatible with the active ingredient of the composition (and preferably capable of stabilizing the active ingredient) and is not harmful to the subject being treated.
  • One or more solubilizers can be used as pharmaceutical excipients for the delivery of active compounds.
  • the pharmaceutical composition of the present invention includes a second therapeutic agent, which includes a MOR antagonist, such as naloxone, naltrexone, tramadol, samidorphan.
  • a MOR antagonist such as naloxone, naltrexone, tramadol, samidorphan.
  • Such pharmaceutical compositions can be used to treat opioid receptor-related disorders, such as pain, via the opioid antagonist-mediated activation mechanism of MOR.
  • the pharmaceutical composition of the present invention administered orally can be any orally acceptable dosage form, including capsules, tablets, emulsions, aqueous suspensions, suppositories, sprays, inhalants, dispersions, and solutions.
  • aqueous suspension or emulsion is administered orally, the active ingredient may be suspended or dissolved in an oil phase combined with an emulsifier or suspending agent. If necessary, certain sweetening, flavoring or coloring agents can be added.
  • Oral solid dosage forms can be prepared by spray drying technology; hot melt extrusion strategy, micronization and nano-grinding technology. The spray or inhalation composition can be prepared according to techniques well known in the pharmaceutical formulation field.
  • this composition can be prepared as a saline solution using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and/or other solubilizers or dispersants known in the art.
  • the composition with the active compound may also be administered in the form of suppositories for rectal administration.
  • the compounds of the present invention or pharmaceutical compositions containing them can be administered orally, parenterally, by inhalation spray, topical, rectal, nasal, buccal, vaginal or via implantable reservoirs.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the compounds of the present invention and pharmaceutical compositions containing them have opioid receptor modulator activity and can be used to treat opioid receptor-related diseases. The conditions include pain, hyperalgesia, and cardiovascular and cerebrovascular diseases.
  • the present invention further provides the use of the compound or the pharmaceutical composition in the preparation of a medicament for the treatment of opioid receptor-related disorders, which may be pain, such as neuropathic pain or nociceptive pain.
  • opioid receptor-related disorders which may be pain, such as neuropathic pain or nociceptive pain.
  • the specific types of pain include, but are not limited to, acute pain, chronic pain, postoperative pain, pain due to neuralgia (for example, postherpetic neuralgia or trigeminal neuralgia), pain due to diabetic neuropathy, toothache, and Pain associated with arthritis or osteoarthritis and pain associated with cancer or its treatment.
  • the compound or pharmaceutical composition of the present invention is used to prepare analgesic drugs.
  • the present invention also provides that the compound of formula I, or its tautomers, optical isomers, nitrogen oxides, solvates, pharmaceutically acceptable salts or prodrugs or pharmaceutical compositions are used in the preparation and treatment of depression-related diseases and
  • the depressive symptoms can be acute stress disorder, depressed mood adjustment disorder, Asperger’s syndrome, attention deficit, bipolar disorder, borderline and personality disorders, circulatory disorders, depression such as Major depression (MDD) and treatment resistant disease (TRD), dysthymia, hyperactivity disorder, impulse control disorder, mixed mania, obsessive-compulsive personality disorder (OCD), paranoia, post-traumatic stress disorder, season Sexual affective disorder, self-harm separation, sleep disorder, emotional disorder caused by substance, etc.
  • MDD Major depression
  • TRD treatment resistant disease
  • dysthymia hyperactivity disorder
  • impulse control disorder mixed mania
  • paranoia post-traumatic stress disorder
  • season Sexual affective disorder self-harm separation
  • the compound or pharmaceutical composition of the present invention is used to prepare antidepressant drugs.
  • aliphatic hydrocarbon group includes saturated or unsaturated, linear or branched chain hydrocarbon groups.
  • the type of the aliphatic hydrocarbon group can be selected from alkyl, alkenyl, alkynyl, etc.
  • the number of carbon atoms of the aliphatic hydrocarbon group is preferably It is 1-12, and a further preferred range is 1-6, which can specifically include but are not limited to the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, N-pentyl, isopentyl, neopentyl, n-hexyl, vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 1-ethylvinyl, 1- Methyl-2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propeny
  • aryl (or aromatic ring) means that after removing a hydrogen atom from the aromatic nucleus carbon of an aromatic hydrocarbon molecule, a monovalent group remains, including C 6 -C 14 aryl, further including but not limited to phenyl, Naphthyl.
  • heteroaryl refers to a heteroaromatic heterocyclic ring having at least one ring heteroatom such as sulfur, oxygen, or nitrogen.
  • Heteroaryl groups include monocyclic ring systems and polycyclic ring systems (e.g., having 2, 3, or 4 fused rings).
  • heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indole Base, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4 -Thiadiazole, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, benzoxazolyl, azabenzoxazolyl, imidazothiazolyl, benzo[1 ,4]dioxolyl, benzo[1,3]dioxolyl, etc.
  • cycloalkyl should be understood to mean a saturated monocyclic, bicyclic hydrocarbon ring or bridged ring, usually having 3 to 20 carbon atoms, preferably "C 3-8 cycloalkyl".
  • C 3-8 cycloalkyl should be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring with 3, 4, 5, 6, 7, 8 carbon atoms.
  • the C 3-8 cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or a bicyclic hydrocarbon group such as decalin ring.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • substituted with more than one substituent includes, but is not limited to, substitution with one, two, three, or four substituents.
  • the compounds of the present invention include compounds or tautomers, optical isomers, nitrogen oxides, solvates, pharmaceutically acceptable salts or prodrugs thereof.
  • the pharmaceutically acceptable salts of the compounds of the present invention can be prepared by any suitable method provided in the literature, and can be selected from acid addition salts, including but not limited to hydrochloride, hydrofluoride, hydrobromide, Hydroiodide, sulfate, pyrosulfate, phosphate, nitrate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, toluenesulfonate, sulfamate , 2-Naphthalene sulfonate, formate, acetoacetic acid, pyruvic acid, lauric acid ester, cinnamate, benzoate, acetate, glyoxylate, trifluoroacetate, trimethyl Glycoacetate, propionate, butyrate, caproate, enanthate, undecanoate, stearate, ascorbate, camphorate, camphors
  • solvate refers to those forms of the compound of the present invention, which form a complex through coordination with solvent molecules in a solid or liquid state. Hydrates are a specific form of solvates in which the coordination is carried out with water. In the present invention, the preferred solvate is a hydrate.
  • prodrug represents the conversion of a compound into a compound represented by the aforementioned general formula or specific compound in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the maternal structure in the blood or tissue.
  • the prodrugs of the present invention may be esters. In the present invention, esters may be used as prodrugs including phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and Amino acid esters.
  • a compound in the present invention contains a hydroxyl/carboxyl group, that is, it can be acylated to obtain a compound in the form of a prodrug.
  • Other prodrug forms include phosphate esters, such as these phosphate ester compounds are obtained by phosphorylation of the hydroxyl group on the parent.
  • the compounds of the present invention may also contain one or more asymmetric centers.
  • Asymmetric carbon atoms can exist in (R) or (S) configuration. When there is only one asymmetric center, a racemic mixture is produced, and when multiple asymmetric centers are contained, a diastereomeric mixture is obtained. In some cases, there may also be asymmetry due to hindered rotation around a specific bond, for example, the central bond connects two substituted aromatic rings of a specific compound.
  • the substituents may also exist in cis or trans isomeric forms.
  • the compounds of the present invention also include all possible stereoisomers of each, which is a single stereoisomer or the stereoisomer (for example, R-isomer or S-isomer, or E-isomer or Z-isomer) in the form of any mixture in any ratio.
  • a single stereoisomer (e.g., single enantiomer or single diastereomer) of the compound of the present invention can be achieved by any suitable prior art method (e.g., chromatography, in particular, e.g., chiral chromatography) Separation.
  • the compounds may also exist in the form of tautomers.
  • the compound of the present invention includes all possible tautomers of the compound of formula (I), which is in the form of a single tautomer or any mixture of the tautomers in any ratio. All these isomers and their mixtures are included in the present invention.
  • the involved compounds also include isotopically-labeled compounds, which are the same as those shown in formula I, but in which one or more atoms are different from the usual atomic mass or mass number. Naturally occurring atomic mass or mass number atomic substitution.
  • isotopes that can be incorporated into the compounds of the present invention include isotopes of H, C, N, O, S, F, and Cl, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, respectively , 17 O, 32 P, 35 S, 18 F and 36 Cl.
  • the compound of the present invention containing the above-mentioned isotopes and/or other isotopes of other atoms, prodrugs thereof, or pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention.
  • Certain isotopically-labeled compounds of the present invention for example, compounds incorporating radioisotopes (such as 3 H and 14 C) can be used for drug and/or substrate tissue distribution determination. Tritium (ie 3 H) and carbon 14 (ie 14 C) isotopes are particularly preferred due to their ease of preparation and detectability.
  • the replacement of heavier isotopes can provide certain therapeutic advantages derived from higher metabolic stability (for example, increased in vivo half-life or reduced dosage requirements), and can therefore be used in It is preferred in some cases.
  • the compounds of the present invention as claimed in the claims can be specifically defined to be substituted with deuterium or tritium.
  • deuterium or tritium is not separately listed for hydrogen in the substituent does not mean that deuterium or tritium is excluded, but deuterium or tritium may also be included.
  • treatment refers to the application or administration of a compound to a subject for the purpose of curing, alleviating, alleviating, altering, remedying, ameliorating, or affecting a disease, disorder, or tendency.
  • Effective amount refers to the amount of a compound required to impart a desired effect to a subject. As recognized by those skilled in the art, the effective amount varies depending on the route of administration, the use of excipients, and the possibility of co-use with other therapeutic treatments (such as the use of other active agents).
  • the IC 50 values of the preferred compounds of the present invention for ⁇ , ⁇ and ⁇ opioid receptors are ⁇ 10 ⁇ M, respectively.
  • the more preferred compounds of the present invention have IC 50 values ⁇ 1 ⁇ M for ⁇ , ⁇ and ⁇ opioid receptors, respectively.
  • Even more preferred compounds of the invention are ⁇ 100nM 50 values for ⁇ , ⁇ and ⁇ opioid receptors IC.
  • the most preferred compounds of the present invention have IC 50 values ⁇ 10 nM for mu, kappa and delta opioid receptors, respectively.
  • a compound of the present invention to a value 50 ⁇ opioid receptor IC ⁇ 10 ⁇ M; compounds of the present invention, preferred values for the 50 ⁇ opioid receptor IC ⁇ 1 ⁇ M.
  • the IC 50 values of the more preferred compounds of the present invention for ⁇ opioid receptors are ⁇ 100 nM, respectively.
  • the most preferred compounds of the present invention have IC 50 values ⁇ 10 nM for ⁇ opioid receptors, respectively.
  • the IC 50 value of the preferred compound of the present invention for the kappa opioid receptor is ⁇ 10 ⁇ M. More preferred compounds of the present invention for IC ⁇ opioid receptor 50 values ⁇ 1 ⁇ M. Even more preferred compounds of the present invention, 50 values ⁇ 100nM for IC ⁇ opioid receptors. The most preferred compounds of the present invention, 50 values for ⁇ 10nM IC ⁇ opioid receptors.
  • the IC 50 value of the preferred compound of the present invention for the delta opioid receptor is ⁇ 10 ⁇ M.
  • the more preferred compounds of the present invention have an IC 50 value of ⁇ 1 ⁇ M for the delta opioid receptor.
  • the most preferred compound of the present invention has an IC 50 value ⁇ 10 nM for the delta opioid receptor.
  • the compounds of the present invention are selective for mu, kappa and delta opioid receptors.
  • some compounds are selective for mu opioid receptors, some compounds are selective for kappa opioid receptors; some compounds are selective for delta opioid receptors.
  • the compounds of the present invention have better selectivity for mu opioid receptors.
  • the preferred compounds 4, 8, 10, 11, 13-17, 28, 29, 35, 36 and 38 of the present invention are selective for mu opioid receptors. Among them, the selectivity of compounds 4, 8, 29, 36 and 38 is more preferred.
  • O-Methyl Dezocine (1-1, 0.732mmol) was dissolved in 5ml methanol, and HCHO solution (0.805mmol), NaBH 3 CN (1.464mmol) and acetic acid (0.2ml) were added in sequence, and reacted at room temperature overnight.
  • Examples 2-10 refer to the synthetic method of compound 1 to obtain target compounds 2-10
  • O-Methyl Dezocine (1-1, 0.732mmol) was dissolved in 5ml methanol, and HCHO solution (7.32mmol), NaBH 3 CN (1.464mmol) and acetic acid (0.2ml) were added in sequence. The reaction was carried out at room temperature overnight.
  • Example 14-17 refer to the synthetic method of compound 13 to obtain target compound 14-17
  • Example 19-34 refer to the synthetic method of compound 18 to obtain target compound 19-34
  • Example 36 compound 36 is obtained by referring to the synthetic method of compound 35
  • Example 38 compound 38 is obtained by referring to the synthetic method of compound 37
  • the IC50 of the compound was used as an indicator to evaluate the affinity of the compound to mu, kappa and delta opioid receptors.
  • the cell membrane is extracted from stable transfected cells constructed by Shanghai WuXi AppTec.
  • Tris base (Sigma,Cat:T6066-1KG), prepare 1M stock and adjust pH to 7.4.
  • test compound negative control (ie DMSO) and positive control (ie non-specific binding well compound) are prepared, transfer 1 ⁇ L to a 96-well plate;
  • the following table shows IC 50 values of the test compound for ⁇ , ⁇ and ⁇ opioid receptors.
  • Table 41 The IC 50 values of compounds against ⁇ , ⁇ and ⁇ opioid receptors
  • the in vitro activity test proves that the compounds of the present invention have IC 50 values ⁇ 10 ⁇ M for ⁇ , ⁇ and ⁇ opioid receptors respectively.
  • the more preferred compounds of the present invention have IC 50 values ⁇ 1 ⁇ M for ⁇ , ⁇ and ⁇ opioid receptors, respectively.
  • Even more preferred compounds of the invention are ⁇ 100nM 50 values for ⁇ , ⁇ and ⁇ opioid receptors IC.
  • the in vitro activity test also indicated that compounds 19-22, 25, 26, 28, 30-34, 39 and 40 are compounds of the present invention with higher activity, in particular, compounds 21, 22, 25, 26, 30, 33-34 And 40.
  • at least one of the IC 50 values of the ⁇ , ⁇ , and ⁇ opioid receptors reaches Grade A, more preferably the IC 50 values of at least two opioid receptors reach Grade A, and most preferably, three The IC 50 values of opioid receptors all reached A grade.
  • the most preferred compounds of the present invention have IC 50 values ⁇ 10 nM for ⁇ , ⁇ and ⁇ opioid receptors respectively; meanwhile, the compounds of the present invention are selective for ⁇ , ⁇ and ⁇ opioid receptors, and more preferably, the compounds of the present invention are ⁇ opioid receptors have better selectivity.
  • the preferred compounds 4, 8, 10, 11, 13-17, 28, 29, 35, 36 and 38 of the present invention are selective for mu opioid receptors. Among them, the selectivity of compounds 4, 8, 29, 36 and 38 is more preferred.
  • the analgesic intensity of the test compound was evaluated using the mouse thermal radiation pain model and the mouse hot plate pain model respectively.
  • the results in Table 42 show that compound 26 has the strongest analgesic effect in the four mouse models of pain, followed by compound 22, all stronger than dezocine.
  • Example 43 Pharmacokinetic experiment of intravenous administration in mice and rats
  • mice Male mice were injected intravenously with the compound of the present invention, and the concentration of the drug prototype in plasma and the concentration of the metabolite dezocine hydrochloride were measured after administration.

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Abstract

一种式I所示地佐辛衍生物或其互变异构体、光学异构体、氮氧化物、溶剂化物、药学上可接受的盐或前药，以及包含其的药物组合物，其制备方法，及其医药用途，所述式I结构如下：

Description

地佐辛衍生物及其医药用途
本申请要求2019年2月2日向中国国家知识产权局提交的，专利申请号为201910106523.7，发明名称为“地佐辛衍生物及其医药用途”的在先申请的优先权。所述申请的全文通过引用的方式结合于本申请中。
技术领域
本发明涉及医药技术领域，具体而言，涉及一类新的地佐辛衍生物，包含该衍生物的药物组合物，其制备方法，及其医药用途。
背景技术
地佐辛(dezocine)是一个结构类似喷他佐辛(pentazocine)的阿片受体混合激动－拮抗剂，于上世纪70年代由美国Wyeth-Ayerst实验室研发，1989年经FDA批准上市，以商品名Dalgan由Astrazeneca进行市场销售，用于治疗手术后疼痛。2009年在中国上市以来被广泛应用于全麻诱导、术后镇痛和超前镇痛，并用于治疗内脏疼痛和癌症疼痛。其化学名为：(-)-[5R-(5α,11α,13S*)]-13-氨基-5,6,7,8,9,10,11,12-八氢-5-甲基-5,11-甲撑苯并环癸烯-3-醇，结构式如下：
Figure PCTCN2020074131-appb-000001
发明内容
本发明提供了一种式I所示的化合物或其互变异构体、光学异构体、氮氧化物、溶剂化物、药学上可接受的盐或前药：
Figure PCTCN2020074131-appb-000002
Figure PCTCN2020074131-appb-000003
其中，R 1，R 2各自独立地选自H、氘、氚、C 1-C 12脂肪烃基、C 6-C 14芳基、C 6-C 14芳基-C 1-C 12脂肪烃基、C 3-C 8环烷基、C 3-C 8环烷基-C 1-C 12脂肪烃基、5-14元杂芳基、5-14元杂芳基-C 1-C 12脂肪烃基，所述C 6-C 14芳基、C 3-C 8环烷基、5-14元杂芳基任选被一个以上卤素、OH、C 1-C 12脂肪烃基、C 1-C 12脂肪烃基氧基、C 1-C 12脂肪烃基-S-取代；或R 1、R 2和与之相连的N一起形成含N的4-6元环，所述含N的4-6元环任选被一个以上卤素、OH、C 1-C 12脂肪烃基、C 1-C 12脂肪烃基氧基、C 1-C 12脂肪烃基-S-取代；
R 3选自H、氘、氚、C 1-C 12脂肪烃基、C 6-C 14芳基、C 6-C 14芳基-C 1-C 12脂肪烃基、C 3-C 8环烷基、C 3-C 8环烷基-C 1-C 12脂肪烃基、5-14元杂芳基、5-14元杂芳基-C 1-C 12脂肪烃基，所述C 6-C 14芳基、C 3-C 8环烷基、5-14元杂芳基任选被一个以上卤素、C 1-C 12脂肪烃基、C 1-C 12脂肪烃基氧基、C 1-C 12脂肪烃基-S-取代；
R 4选自H、氘、氚、OH、卤素、C 1-C 12脂肪烃基、C 1-C 12脂肪烃基氧基、C 1-C 12脂肪烃基-S-；
上述R 1、R 2、R 3中至少一个不为H；
A选自O或S；n选自0、1、2。
在一些实施方案中，R 1，R 2各自独立地选自H、氘、氚、C 1-C 12脂肪烃基、C 6-C 14芳基-C 1-C 6脂肪烃基、C 3-C 8环烷基、C 3-C 8环烷基-C 1-C 6脂肪烃基，所述C 6-C 14芳基、C 3-C 8环烷基任选被一个以上卤素、OH、C 1-C 6脂肪烃基、C 1-C 6脂肪烃基氧基、C 1-C 6脂肪烃基-S-取代；或R 1、R 2和与之相连的N一起形成含N的4-6元环；
R 3选自H、氘、氚、C 1-C 6脂肪烃基、C 6-C 14芳基-C 1-C 12脂肪烃基，所述C 6-C 14芳基任选被一个以上卤素、C 1-C 6脂肪烃基、C 1-C 6脂肪烃基氧基、C 1-C 6脂肪烃基-S-取代；
R 4选自C 1-C 6脂肪烃基、C 1-C 6脂肪烃基氧基、C 1-C 6脂肪烃基-S-；
上述R 1、R 2、R 3中至少一个不为H；
A选自O或S；n选自1、2。
在一些实施方案中，R 1，R 2各自独立地选自H、氘、氚、C 1-C 12烷基、C 6-C 14芳基-C 1-C 6烷基、C 3-C 8环烷基、C 3-C 8环烷基-C 1-C 6烷基，所述C 6-C 14芳基、C 3-C 8环烷基任选被一个以上卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷基-S-取代；或R 1、R 2和与之相连的N一起形成含N的5元环；
R 3选自H、氘、氚、C 1-C 6烷基、C 6-C 14芳基-C 1-C 12烷基，所述C 6-C 14芳基任选被一个以上卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷基-S-取代；
R 4选自C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷基-S-；
上述R 1、R 2、R 3中至少一个不为H；
A选自O；n选自1。
在一些实施方案中，
R 1选自氢、氘、氚、C 1-C 6烷基；
R 2选自氢、氘、氚、C 1-C 6烷基、C 6-C 14芳基-C 1-C 6烷基；
R 3选自H、氘、氚、C 6-C 14芳基-C 1-C 12烷基，所述C 6-C 14芳基任选被一个以上卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷基-S-取代。在一些实施方案中，所述C 1-C 12脂肪烃基选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、乙烯基、1-丙烯基、2-丙烯基、1-甲基乙烯基、1-丁烯基、1-乙基乙烯基、1-甲基-2-丙烯基、2-丁烯基、3-丁烯基、2-甲基-1-丙烯基、2-甲基-2-丙烯基、1-戊烯基、1-己烯基、乙炔基，1-丙炔基，2-丙炔基，1-丁炔基，1-甲基-2-丙炔基，3-丁炔基，1-戊炔基和1-己炔基；所述卤素选自F、Cl、Br、I；所述芳基选自苯基、萘基；所述C3-C8环烷基选自环丙基、环丁基、环戊基、环己基，所述含N的4-6元环选自氮杂环丙烷、吡咯烷、哌啶、哌嗪、吗啉、吡咯、咪唑、吡唑、噻唑、异噻唑、恶唑、异恶唑、吡啶、吡嗪、嘧啶、哒嗪。
在一些实施方案中，所述药学上可接受的盐选自盐酸盐。
在一些实施方案中，所述式I结构具有如下式II结构：
Figure PCTCN2020074131-appb-000004
优选的，式(I)化合物选自如下化合物：
Figure PCTCN2020074131-appb-000005
Figure PCTCN2020074131-appb-000006
更优选地，式(I)化合物选自如下化合物：
化合物1-11，13-36，38-40。
还更优选地，式(I)化合物选自如下化合物：
化合物3，4，8，18-34，36和38-40。
特别优选地，式(I)化合物选自如下化合物：
化合物19-22，25，26，28，30-34，39和40。
尤其是，式(I)化合物选自如下化合物：
化合物21，22，25，26，30，33-34和40。
其中，特别优选化合物和最优选化合物中，对于μ、κ和δ阿片类受体的IC 50值至少有一个达到A级，更优选至少两个阿片类受体的IC 50值达到A级，最优选地，三个阿片类受体的IC 50值均达到A级。
本发明还提供了一种式I化合物(包括式II化合物)的制备方法，包括如下方案：
方案1：
Figure PCTCN2020074131-appb-000007
(1)化合物M-1与醛R aCHO反应得到中间体T-1；
(2)中间体T-1经还原得到式I化合物；
方案1中，R 1、R 2、R 3、R 4、A、n如式I中所定义，但其中，R 1、R 2至少一个不为H；R aCHO为对应引入目标式I化合物中R 1、R 2取代基的醛类化合物(可发生N上单取代或二取代反应，其中，R 1，R 2均不为H时，对应二取代产物，R 1，R 2中的一个为H时，对应单取代产物)。
方案2：
Figure PCTCN2020074131-appb-000008
(1)化合物M-2与醛R bCHO反应得到中间体T-2；
(2)中间体T-2经还原得到式I化合物；
方案2中，R 1、R 2、R 3、R 4、A、n如式I中所定义，但其中，R 1、R 2不为H；R bCHO为对应引入目标式I化合物中R 2取代基的醛类化合物。
方案3：
Figure PCTCN2020074131-appb-000009
化合物M-3与化合物X(CH 2) mX反应得到式I-1化合物；
方案3中，R 3、R 4、A、n如式I中所定义，m为3-5；X为F、Cl、Br、I。
方案4
Figure PCTCN2020074131-appb-000010
化合物M-4与HX反应得到式I-2化合物；
方案4中，R 1、R 2、R 3、R 4、A、n如式I中所定义，但其中，R 3不为H；X为F、Cl、Br、I。
方案5
Figure PCTCN2020074131-appb-000011
(1)将化合物M-5与氨基保护试剂反应得到氨基保护的中间体T-3；
(2)T-3与R 3X反应得到中间体T-4；
(3)T-4完全脱除保护基得到式I化合物；或T-4在还原试剂B存在下得到N-甲基化产物。
方案5中，R 3、R 4、A、n如式I中所定义，但其中，R3不为H；X为F、Cl、Br、I；G为氨基保护基团。
进一步的，本领域技术人员可以理解，当G为酰基类保护基时(例如为t-Boc)，可以在还原试剂B存在下得到N-甲基化产物。
根据上述方案1-5，在一些实施方案中，
化合物M-1、化合物M-2与醛R aCHO或醛R bCHO反应过程中，加入醇类试剂和有机酸，所述醇类试剂可选自甲醇、乙醇、丙醇、乙二醇中的一种或几种，所述有机酸选自乙酸、甲酸或丙酸中的一种或几种；所述M-1、M-2分别与醛的摩尔比为1:1-15，优选为1:1-11，其中，本领域技术人员可以理解，调整M-1与醛的摩尔比可以分别得到单取代，二取代产物(例如M-1与醛的摩尔比为1:9-11时，得到二取代产物)。
随后由化合物M-1、化合物M-2得到的中间体T-1、中间体T-2进行的还原反应中，还原试剂A可选自氰基硼氢化钠，硼氢化钠、醋酸硼氢化钠中的一种或几种，优选为氰基硼氢化钠。所述化合物M-1、化合物M-2与还原试剂的摩尔比分别为1:1.5-8，优选为1:2-5。
所述还原反应进一步包括后处理步骤：使用碱性试剂调节反应混合液的pH值为8-10，加入有机溶剂(如乙酸乙酯)并分液，合并有机相，经饱和食盐水清洗并干燥，通过柱层析分离得到式I化合物。
化合物M-3与化合物X(CH 2) mX的反应，优选在有机溶剂A与碱性试剂A存在下进行；所述有机溶剂A可选自乙腈、DMF、DMSO中的一种或几种，优选为乙腈。所述碱性试剂可选自碱金属或碱土金属的氢氧化物、碳酸盐或碳酸氢盐，优选为碳酸氢钠或碳酸氢钾。所述化合物M-3、X(CH 2) mX与碱性试剂的摩尔比为1:2-8:3-10，优选为1:3-5:6-8。
所述反应进一步包括后处理步骤：过滤，蒸除溶剂并加入有机溶剂(如乙酸乙酯)，使用碱性试剂调节反应混合液的pH值为8-10，加入有机溶剂稀释并分液，合并有机相，经饱和食盐水清洗并干燥，通过柱层析分离得到式I化合物。
化合物M-4与HX反应过程中，每ml HX水溶液中加入0.02-0.08mmol的化合物M-4，优选为每ml HX水溶液中加入0.04-0.06mmol化合物M-4。
所述反应进一步包括后处理步骤：蒸除HX，加入有机溶剂(如乙酸乙酯)，使用碱性试 剂调节反应混合液的pH值为8-10，分液，合并有机相，经饱和食盐水清洗并干燥，通过柱层析分离得到式I化合物。
化合物M-5的氨基保护反应中，G可选自叔丁氧羰基、苄氧羰基、对甲苯磺酰基，优选为叔丁氧羰基。所述氨基保护反应在有机溶剂B、催化剂存在下进行，所述有机溶剂B可选自二氯甲烷、四氯化碳、二氯乙烷、乙酸乙酯、DMF、DMSO中的一种或几种，所述催化剂可选自DIPEA、DBU、三乙胺中的一种或几种，优选为DIPEA。所述化合物M-5与氨基保护试剂的摩尔比为1:1-2，优选为1:1-1.5。
所得到的氨基保护中间体T-3与R 3X进行的反应过程中，加入有机溶剂C和碱性试剂C，所述有机溶剂C可选自丙酮、二氧六环、甲醇、乙醇、丙醇、四氢呋喃、DMF、DMSO中的一种或几种，优选为丙酮。所述碱性试剂C可选自碱金属或碱土金属的氢氧化物、碳酸盐或碳酸氢盐，优选为碳酸钠、碳酸钾、碳酸铯。所述T-3与碱性试剂的摩尔比为0.8-2，优选为1-1.5；所得T-4中间体在完全脱保护试剂或还原试剂B存在下进行反应，采用的脱保护试剂选自TFA、甲酸，乙酸，盐酸，硫酸，草酸，优选为TFA，采用的还原试剂B选自LiAlH 4，DIBAL-H，red-Al,NaBH 4,LiBH 4，优选为LiAlH 4。
反应过程中，优选加入有机溶剂D，所述有机溶剂D选自二氯甲烷、三氯甲烷、四氯化碳、二氯乙烷、四氢呋喃、乙醚、甲基叔丁基醚、二氧六环中的一种或几种；所述T-4中间体与脱保护试剂的投料比为1mmol：2-8ml，优选为1mmol：3-5ml。
所述脱保护试剂反应进一步包括后处理步骤：蒸除溶剂，加入有机溶剂(如乙酸乙酯)，使用碱性试剂调节反应混合液的pH值为8-10，分液，合并有机相，经饱和食盐水清洗并干燥，通过柱层析分离得到式I化合物。
本发明进一步提供一种药物组合物，其包含本发明所述的式I化合物或其互变异构体、光学异构体、氮氧化物、溶剂化物、药学上可接受的盐或前药。
在一些实施方案中，本发明所述的药物组合物进一步包含治疗有效量的本发明所述式I化合物或其互变异构体、光学异构体、氮氧化物、溶剂化物、药学上可接受的盐或前药和药学上可接受的载体。
所述药物组合物中的载体为“可接受的”，其可与组合物的活性成分相容(并且优选地，能够稳定活性成分)并且对被治疗的受试者不是有害的。可以使用一种或多种增溶剂作为药物赋形剂用于递送活性化合物。
在一些实施方案中，本发明所述的药物组合物包含第二治疗剂，所述第二治疗剂包括 MOR拮抗剂，如纳洛酮、纳曲酮、曲马多、samidorphan。这样的药物组合物可以经由MOR的阿片拮抗剂-介导的活化机制，用于治疗阿片受体相关病症，如疼痛。
在一些实施方案中，口服施用的本发明药物组合物可以是任何口服可接受的剂型，包括胶囊、片剂、乳剂、水性混悬剂、栓剂、喷雾剂、吸入剂、分散体及溶液。
在片剂的情形下，常用的载体包括乳糖及玉米淀粉。通常还添加润滑剂，如硬脂酸镁。对于胶囊形式，可用的稀释剂包括乳糖及干玉米淀粉。当口服施用水性混悬剂或乳剂时，活性成分可以悬浮或溶解于组合有乳化剂或悬浮剂的油相中。如有需要，可以添加某些甜味剂、调味剂或着色剂。口服固体剂型可以通过喷雾干燥技术；热熔挤出策略、微粉化及纳米研磨技术制备。喷雾剂或吸入剂组合物可以根据药物制剂领域熟知的技术制备。例如，这种组合物可以制备成盐水溶液，使用苯甲醇或其它适合的防腐剂、吸收促进剂以增强生物利用度、氟碳化合物和/或本领域已知的其它增溶剂或分散剂。具有活性化合物的组合物还可以以栓剂的形式施用用于直肠施用。
在一些实施方案中，本发明的化合物或含有其的药物组合物可以口服、肠胃外、通过吸入喷雾、局部、经直肠、经鼻、经颊、经阴道或经由植入式贮存器施用。如本文中所用，术语“肠胃外”包括皮下、皮内、静脉内、肌内、关节内、动脉内、滑膜内、胸骨内、鞘内、病灶内及颅内注射或输注技术。本发明所述的化合物及包含其的药物组合物具有阿片受体调节剂活性，可用于治疗阿片受体相关病症。所述病症包括疼痛、痛觉过敏和心脑血管疾病等。
因此，本发明进一步提供所述化合物或药物组合物在制备治疗阿片受体相关病症的药物中的用途，所述病症可以为疼痛，如神经性疼痛或伤害性疼痛。所述疼痛的具体类型包括但不限于急性疼痛、慢性疼痛、手术后疼痛、由于神经痛导致的疼痛(例如，疱疹后神经痛或三叉神经痛)、由于糖尿病神经病变导致的疼痛、牙痛、与关节炎或骨关节炎相关的疼痛和与癌症或其治疗相关的疼痛。
进一步的，本发明所述化合物或药物组合物用于制备镇痛药物。
本发明还提供所述式I化合物，或其互变异构体、光学异构体、氮氧化物、溶剂化物、药学上可接受的盐或前药或药物组合物在制备治疗抑郁相关疾病和症状的药物中的用途，所述抑郁症状可为急性应激障碍，情绪低落的调节障碍，阿斯伯格综合征，注意力缺陷，双相障碍，边缘和人格障碍，循环障碍，抑郁症如重度抑郁症(MDD)和治疗抵抗性疾病(TRD)，心境恶劣障碍，多动障碍，冲动控制障碍，混合性躁狂，强迫性人格障碍(OCD)，偏执狂，创伤后应激障碍，季节性情感障碍，自我伤害分离，睡眠障碍，物质引起的情绪障碍等。
进一步的，本发明所述化合物或药物组合物用于制备抗抑郁药物。
术语解释
术语“脂肪烃基”包括饱和或不饱和，直链或具有支链的链状烃基，所述脂肪烃基的类型可选自烷基、烯基、炔基等，所述脂肪烃基的碳原子数优选为1-12，进一步的优选范围为1-6，具体可包括但不限于如下基团：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、乙烯基、1-丙烯基、2-丙烯基、1-甲基乙烯基、1-丁烯基、1-乙基乙烯基、1-甲基-2-丙烯基、2-丁烯基、3-丁烯基、2-甲基-1-丙烯基、2-甲基-2-丙烯基、1-戊烯基、1-己烯基、乙炔基，1-丙炔基，2-丙炔基，1-丁炔基，1-甲基-2-丙炔基，3-丁炔基，1-戊炔基和1-己炔基；其他基团中所含“脂肪烃基”部分同上述解释。
术语“芳基”(或称芳香环)是指芳烃分子的芳核碳上去掉一个氢原子后，剩下一价基团，包括C 6-C 14芳基，进一步包括但不限于苯基、萘基。
术语“杂芳基”指具有至少一个环杂原子(例如硫、氧或氮)的杂芳族杂环。杂芳基包括单环系统和多环系统(例如具有2、3或4个稠环)。杂芳基的实例包括但不限于吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、呋喃基、喹啉基、异喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、异噁唑基、吡唑基、三唑基、四唑基、吲唑基、1,2,4-噻二唑基、异噻唑基、苯并噻吩基、嘌呤基、咔唑基、苯并咪唑基、苯并噁唑基、氮杂苯并噁唑基、咪唑并噻唑基、苯并[1,4]二氧杂环己烯基、苯并[1,3]二氧杂环戊烯基等。所述杂芳基优选具有5至14个成环原子。
术语“环烷基”应理解为表示饱和的单环、双环烃环或桥环，通常具有3～20个碳原子，优选“C 3-8环烷基”。术语“C 3-8环烷基”应理解为表示饱和的单环或双环烃环，其具有3、4、5、6、7、8个碳原子。所述C 3-8环烷基可以是单环烃基，如环丙基、环丁基、环戊基、环己基、环庚基、环辛基，或者是双环烃基如十氢化萘环。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“被一个以上取代基取代”包括但不限于被一个、二个、三个或四个取代基取代。
本发明所述化合物包含化合物或其互变异构体、光学异构体、氮氧化物、溶剂化物、药学上可接受的盐或前药。
本发明中化合物的药学上可接受的盐，可以通过文献提供的任何合适的方法制备得到，可选自酸加成盐，包括但不限于盐酸盐、氢氟酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、焦硫酸盐、磷酸盐、硝酸盐、甲磺酸盐、乙磺酸盐、2-羟基乙磺酸盐、苯磺酸盐、甲苯磺酸盐、氨基磺酸盐、2-萘磺酸盐、甲酸盐、乙酰乙酸、丙酮酸、月硅酸酯、肉桂酸酯、苯甲酸盐、醋酸盐、 二羟乙酸盐、三氟乙酸盐、三甲基乙酸盐、丙酸盐、丁酸盐、己酸盐、庚酸盐、十一酸盐、硬脂酸盐、抗坏血酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、富马酸盐、苹果酸盐、马来酸盐、羟基马来酸盐、草酸盐、水杨酸盐、琥珀酸盐、葡萄糖酸盐、奎尼酸盐、双羟萘酸盐、甘醇酸盐、酒石酸盐、乳酸盐、2-(4-羟基苯甲酰基)苯甲酸盐、环戊烷丙酸盐、二葡糖酸盐、3-羟基-2-萘甲酸盐、烟酸盐、扑酸盐、果胶酯酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、衣康酸盐、三氟甲磺酸盐、十二烷基硫酸盐、对甲苯磺酸盐、萘二磺酸盐、丙二酸盐、己二酸盐、藻酸盐、扁桃酸盐、葡庚酸盐、甘油磷酸盐、磺基水杨酸盐、半硫酸或硫氰酸盐、天冬氨酸盐等；碱加成盐例如碱金属盐、碱土金属盐和铵盐等，具体包括但不限于：钠盐、锂盐、钾盐、铵盐(包括与NH 3和有机胺形成的盐)、铝盐、镁盐、钙盐、钡盐、铁盐、亚铁盐、锰盐、亚锰盐、锌盐、NH 4盐、甲胺盐、三甲胺盐、二乙胺盐、三乙胺盐、丙胺盐、三丙胺盐、异丙胺盐、叔丁胺盐、N,N'-二苄基乙二胺盐、二环己胺盐、1,6-己二胺盐、苄胺盐、乙醇胺盐、N,N-二甲基乙醇胺盐、N,N-二乙基乙醇胺盐、三乙醇胺盐、氨丁三醇盐、赖氨酸盐、精氨酸盐、组氨酸盐、葡糖胺盐、N-甲基葡糖胺盐、二甲基葡糖胺盐、乙基葡糖胺盐、葡甲胺盐、甜菜碱盐、咖啡因盐、氯普鲁卡因盐、普鲁卡因盐、利多卡因盐、吡啶盐、甲基吡啶盐、哌啶盐、吗啉盐、哌嗪盐、嘌呤盐、可可碱盐、胆碱盐等。
术语“溶剂化物”是本发明的化合物的那些形式，其以固体或液体的状态通过与溶剂分子的配位作用形成配合物。水合物是溶剂化物的特定形式，其中配位作用是与水进行。在本发明中，优选的溶剂化物是水合物。
术语“前药”或称为“药物前体”，代表化合物在体内转化为前述通式或具体化合物所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前药可以是酯，在本发明中酯可以作为前药的有苯酯类，脂肪族(C 1-24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基/羧基，即可以将其酰化得到前体药物形式的化合物。其他的前药形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。
根据不同取代基的位置和性质，本发明的化合物还可以包含一个或多个不对称中心。不对称碳原子可以(R)或(S)构型存在，仅有一个不对称中心时，产生外消旋混合物，含有多个不对称中心时，得到非对映异构体混合物。在某些情况下，由于围绕特定键的旋转受阻还可能存在不对称性，例如该中心键连接特定化合物的两个被取代的芳族环。并且，取代基还可以顺式或反式异构的形式存在。
本发明化合物还包括其各自所有可能的立体异构体，其是单一立体异构体或所述立体异 构体(例如R-异构体或S-异构体，或者E-异构体或Z-异构体)的任意比例的任意混合物的形式。可通过任意适合的现有技术方法(例如色谱法，特别是例如手性色谱法)实现本发明的化合物的单一立体异构体(例如单一对映异构体或单一非对映异构体)的分离。
另外，所述化合物还可以互变异构体的形式存在。本发明化合物包括式(I)化合物所有可能的互变异构体，其是单一互变异构体或所述互变异构体的任意比例的任意混合物的形式。所有这些异构体及它们的混合物都包括在本发明中。
在本发明中，所涉及的化合物亦包括经同位素标记的化合物，所述经同位素标记的化合物与式I中所示的那些相同，但是其中一或多个原子被原子质量或质量数不同于通常天然存在的原子质量或质量数的原子替代。可掺入本发明的化合物的同位素的实例包括H、C、N、O、S、F及Cl的同位素，分别诸如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 32P、 35S、 18F及 36Cl。含有上述同位素和/或其他原子的其他同位素的本发明的化合物、其前药、或者所述化合物或所述前药的药学上可接受的盐在本发明的范围内。本发明的某些经同位素标记的化合物，例如掺入放射性同位素(诸如 3H和 14C)的化合物可用于药物和/或底物组织分布测定。氚(即 3H)和碳14(即 14C)同位素因易于制备和可检测性而成为特别优选的。再者，以较重的同位素(诸如氘(即 2H))替代可提供源自更高的代谢稳定性的某些治疗优势(例如增加的体内半衰期或减少的剂量需求)，并因此可在某些情况下是优选的。如权利要求所请求保护的本发明化合物可特别地限定以氘或氚替代。此外，取代基中出现的氢未单独列明术语氘或氚并不表示排除氘或氚，而是同样也可以包含氘或氚。
术语“治疗”是指为了治愈、缓和、缓解、改变、补救、改善或影响疾病、病症或倾向的目的而将化合物应用或施用至受试者。“有效量”是指将所需效果赋予受试者所需要的化合物的量。如本领域技术人员所认识到的，有效量根据施用途径、赋形剂使用及与其它治疗性治疗(如使用其它活性剂)共同使用的可能性而改变。
本发明的有益效果：
(1)本发明优选的化合物对于μ、κ和δ阿片类受体的IC 50值分别≤10μM。本发明更优选的化合物对于μ、κ和δ阿片类受体的IC 50值分别≤1μM。本发明进一步更优选的化合物对于μ、κ和δ阿片类受体的IC 50值分别≤100nM。本发明最优选化合物对于μ、κ和δ阿片类受体的IC 50值分别≤10nM。
(2)本发明化合物对于μ阿片类受体的IC 50值≤10μM；本发明优选的化合物对于μ阿片类受体的IC 50值≤1μM。本发明更优选的化合物对于μ阿片类受体的IC 50值分别≤100nM。本发明最 优选化合物对于μ阿片类受体的IC 50值分别≤10nM。
(3)本发明优选的化合物对于κ阿片类受体的IC 50值≤10μM。本发明更优选的化合物对于κ阿片类受体的IC 50值≤1μM。本发明进一步更优选的化合物对于κ阿片类受体的IC 50值≤100nM。本发明最优选化合物对于κ阿片类受体的IC 50值≤10nM。
(4)本发明优选的化合物对于δ阿片类受体的IC 50值≤10μM。本发明更优选的化合物对于δ阿片类受体的IC 50值≤1μM。本发明进一步更优选的化合物对于δ阿片类受体的IC 50值≤100nM。本发明最优选化合物对于δ阿片类受体的IC 50值≤10nM。
(5)本发明化合物对于μ、κ和δ阿片类受体具有选择性。例如，有些化合物对于μ阿片类受体具有选择性，有些化合物对于κ阿片类受体具有选择性；有些化合物对于δ阿片类受体具有选择性。更优选地，本发明化合物对于μ阿片类受体具有更好的选择性。例如本发明优选化合物4、8、10、11、13-17、28、29、35、36和38对于μ阿片类受体均具有选择性。其中，更优选化合物4，8，29、36和38的选择性。
具体实施方式
下文将结合具体实施例对本发明的制备方法做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。下述实施例中所使用的实验方法如无特殊说明，均为常规方法；下述实施例中所用的试剂、材料等，如无特殊说明，均可从商业途径得到。
实施例1、化合物1的制备
Figure PCTCN2020074131-appb-000012
O-甲基地佐辛(1-1，0.732mmol)溶于5ml甲醇,依次加入HCHO溶液(0.805mmol)，NaBH 3CN(1.464mmol)和乙酸(0.2ml),室温反应过夜，TLC监测原料大量反应完毕后滴加氨水至PH＝9,30ml乙酸乙酯稀释，分液，水相乙酸乙酯洗(30ml),合并有机相，brine洗，无水硫酸钠干燥，柱层析(DCM/MeOH＝200:1),得到目标化合物1(淡黄色油状液体，120mg，60％)。
1H NMR(400MHz,CDCl 3)δ7.01(d,J＝8.4Hz,1H),6.77(d,J＝2.5Hz,1H),6.70(dd,J＝ 8.4,2.7Hz,1H),3.80(d,J＝0.6Hz,3H),3.05(dd,J＝16.5,7.0Hz,1H),2.69(dd,J＝10.7,5.6Hz,2H),2.60–2.32(m,4H),1.97(t,J＝13.3Hz,1H),1.77–1.34(m,11H),1.10–0.73(m,3H).Ms(m/z):274.2[M+H]。
实施例2-10、参照化合物1的合成方法得到目标化合物2～10
Figure PCTCN2020074131-appb-000013
Figure PCTCN2020074131-appb-000014
Figure PCTCN2020074131-appb-000015
实施例11、化合物11的合成
Figure PCTCN2020074131-appb-000016
O-甲基地佐辛(1-1，0.732mmol)溶于5ml甲醇,依次加入HCHO溶液(7.32mmol)，NaBH 3CN(1.464mmol)和乙酸(0.2ml)，室温反应过夜，TLC监测原料大量反应完毕后滴加氨水至PH＝9,30ml乙酸乙酯稀释，分液，水相乙酸乙酯洗(30ml),合并有机相，brine洗，无水硫酸钠干燥，柱层析(DCM/MeOH＝200:1),得到目标化合物11(淡黄色油状液体，155mg，74％)。
1H NMR(400MHz,CDCl 3)δ6.96(d,J＝8.3Hz,1H),6.74(d,J＝2.2Hz,1H),6.67(dd,J＝8.3,2.3Hz,1H),3.79(s,3H),3.08(dd,J＝16.1,6.4Hz,1H),2.68–2.42(m,9H),2.24(t,J＝13.6Hz,1H),1.95(t,J＝12.7Hz,1H),1.84–1.66(m,2H),1.66–1.35(m,6H),1.25(dd,J＝21.8,11.0Hz,1H),1.08(dd,J＝24.9,12.1Hz,1H),0.74(dd,J＝23.6,11.3Hz,1H).Ms(m/z):288.2[M+H]。
实施例12、化合物12的合成
Figure PCTCN2020074131-appb-000017
O-甲基地佐辛(1-1,0.732mmol)，1,4-diiodine(2.928mmol)，NaHCO 3(5.124mmol)溶于20ml乙腈,回流过夜，TLC监测原料反应完毕后过滤，旋去溶剂，20ml乙酸乙酯稀 释，滴加氨水至PH＝9,30ml乙酸乙酯稀释，分液，水相乙酸乙酯洗(30ml),合并有机相，brine洗，无水硫酸钠干燥，柱层析(PE-PE/EA＝100:1),得到目标化合物12(淡黄色油状液体，160mg，70％)。
1H NMR(400MHz,CDCl 3)δ6.95(d,J＝8.4Hz,1H),6.80(s,1H),6.67(d,J＝8.2Hz,1H),3.80(s,3H),3.21(s,1H),2.98(d,J＝16.8Hz,1H),2.72(d,J＝27.3Hz,3H),2.58–2.36(m,3H),2.27(t,J＝12.7Hz,1H),1.95(s,1H),1.78(d,J＝28.0Hz,4H),1.68–1.37(m,8H),1.26(s,1H),1.23–1.03(m,1H),0.89(s,1H).Ms(m/z):314.2[M+H]。
实施例13、化合物13的合成
Figure PCTCN2020074131-appb-000018
将化合物8(0.2mmol)溶于5ml甲醇,依次加入HCHO溶液(1mmol)，NaBH 3CN(0.4mmol)和乙酸(0.2ml),室温反应过夜，TLC监测原料大量反应完毕后滴加氨水至PH＝9,30ml乙酸乙酯稀释，分液，水相乙酸乙酯洗(30ml),合并有机相，brine洗，无水硫酸钠干燥，柱层析(DCM/MeOH＝200:1),得到目标化合物13(淡黄色油状液体，68mg，90％)。
1H NMR(400MHz,CDCl 3)δ7.18(t,J＝7.4Hz,2H),7.08(dd,J＝12.6,6.9Hz,3H),6.85(d,J＝8.3Hz,1H),6.63(s,1H),6.57(d,J＝8.3Hz,1H),3.66(s,3H),3.08(ddd,J＝22.9,17.1,7.2Hz,2H),2.84–2.67(m,4H),2.60(s,3H),2.53–2.39(m,2H),2.06–1.86(m,2H),1.83–1.71(m,1H),1.56(d,J＝15.8Hz,1H),1.51–1.41(m,2H),1.37(dd,J＝14.7,8.0Hz,1H),1.29(s,3H),1.06(q,J＝12.4Hz,1H),0.93(t,J＝12.8Hz,1H),0.65(q,J＝11.7Hz,1H).Ms(m/z):378.3[M+H]。
实施例14-17、参照化合物13的合成方法得到目标化合物14-17
Figure PCTCN2020074131-appb-000019
Figure PCTCN2020074131-appb-000020
实施例18、化合物18的合成
Figure PCTCN2020074131-appb-000021
将化合物1(0.09mmol)溶于40％HBr水溶液(2ml)中，升至回流反应8小时至原料完全转化，旋去大部分HBr，10ml乙酸乙酯稀释，冰浴下用氨水调至PH＝9，分液，水相EA洗(10ml)，合并有机相，brine洗，无水硫酸钠干燥，柱层析(DCM/MeOH＝20:1)，得目标化合物18(淡黄色油状液体20mg，85％)。
1H NMR(400MHz,CDCl 3)δ6.93(d,J＝8.0Hz,1H),6.75–6.61(m,2H),5.22(s,1H),3.04(dd,J＝16.7,6.7Hz,1H),2.88(s,1H),2.69(d,J＝22.1Hz,4H),2.52(s,1H),2.12–1.90(m,2H),1.74(s,3H),1.63–1.37(m,7H),1.15(d,J＝10.1Hz,1H),0.87(s,2H).Ms(m/z):260.2[M+H]。
实施例19-34、参照化合物18的合成方法得到目标化合物19-34
Figure PCTCN2020074131-appb-000022
Figure PCTCN2020074131-appb-000023
Figure PCTCN2020074131-appb-000024
Figure PCTCN2020074131-appb-000025
Figure PCTCN2020074131-appb-000026
Figure PCTCN2020074131-appb-000027
实施例35、化合物35的合成
Figure PCTCN2020074131-appb-000028
步骤1化合物35-2的合成
地佐辛(4.08mmol)溶于10ml二氯甲烷中，加入DIPEA(12.24mmol)，冰浴下逐滴滴入溶于5ml二氯甲烷的(Boc) 2O(4.50mmol)，升至室温反应过夜，50ml二氯甲烷稀释，2N HCl洗(20ml×2),brine洗(10ml)，无水硫酸钠干燥，柱层析(PE/EA＝100:1)，得化合物35-2(淡黄色油状液体,1.12g，收率80％)。
步骤2化合物35-3的合成
化合物35-2(1mmol)溶于10ml丙酮中，加入碳酸钾(1.2mmol)和卤代烷烃(1.1mmol)，回流过夜，降至室温，旋干，柱层析得化合物35-3(淡黄色油状液体，316mg，80％)。
1H NMR(400MHz,CDCl 3)δ6.99(d,J＝8.2Hz,1H),6.73(dd,J＝28.4,8.0Hz,2H),4.95(d,J＝9.9Hz,1H),4.04(ddt,J＝13.7,11.2,5.8Hz,3H),3.18(dd,J＝16.2,6.6Hz,1H),2.62(d,J＝16.3Hz,1H),2.31(s,1H),1.89–1.21(m,25H),0.95(d,J＝51.2Hz,3H).Ms(m/z):396.2[M+Na]
步骤3化合物35的合成
化合物35-3(0.28mmol)溶于5mlDCM，滴入TFA(1ml)，反应10分钟，旋去TFA，20mlEA稀释，滴加氨水至PH＝9，分液，水相EA洗(20ml×2)，合并有机相，brine洗，无水硫酸钠干燥，柱层析得目标化合物35(淡黄色油状液体，70mg，91％)。
1H NMR(400MHz,CDCl 3)δ6.99(d,J＝8.3Hz,1H),6.77(d,J＝2.1Hz,1H),6.74–6.61(m,1H),4.01(dt,J＝11.3,5.7Hz,2H),3.37–3.00(m,2H),2.66(d,J＝16.6Hz,1H),2.31(s,1H),2.11–1.90(m,1H),1.75(s,3H),1.67–1.31(m,9H),1.08(s,1H),0.91–0.67(m,2H).Ms(m/z):274.2[M+H]。
化合物36-3、参照化合物35-3的合成方法得到
Figure PCTCN2020074131-appb-000029
实施例36、化合物36参照化合物35的合成方法得到
Figure PCTCN2020074131-appb-000030
实施例37、化合物37的合成
Figure PCTCN2020074131-appb-000031
化合物35(0.28mmol)溶于5mlTHF，冰浴下滴入LiAlH 4的四氢呋喃溶液(1M，4eq),升至60℃反应过夜，降至冰浴，逐滴滴加水(10ml)，加入1N NaOH溶液(10ml)，30mlEA稀释，分液，水相EA洗(30ml)，合并，brine洗，无水硫酸钠干燥，柱层析得目标化合物37(淡黄色油状液体56mg，69％)。
1H NMR(400MHz,CDCl 3)δ6.86(d,J＝8.3Hz,1H),6.63(s,1H),6.55(d,J＝8.3Hz,1H),4.04–3.74(m,2H),2.91(dd,J＝16.5,6.9Hz,1H),2.64–2.48(m,2H),2.45–2.32(m,4H),1.82(t,J＝13.4Hz,1H),1.66–1.18(m,13H),1.02–0.54(m,3H).Ms(m/z):288.2[M+H]。
实施例38、化合物38参照化合物37的合成方法得到
Figure PCTCN2020074131-appb-000032
实施例39、化合物39的合成
Figure PCTCN2020074131-appb-000033
化合物38(0.3mmol)溶于5ml甲醇,依次加入苯甲醛(3mmol)，NaBH 3CN(1.5mmol)和乙酸(0.2ml),室温反应过夜，TLC监测原料大量反应完毕后滴加氨水至PH＝9,30ml乙酸乙酯稀释，分液，水相乙酸乙酯洗(30ml),合并有机相，brine洗，无水硫酸钠干燥，柱层析(PE/EA＝200:1),得到目标化合物39(淡黄色油状液体89mg，70％)。 1H NMR(400MHz,CDCl 3)δ7.35(dd,J＝37.1,31.4Hz,10H),6.98(s,1H),6.82(s,1H),6.75(s,1H),5.02(s,2H),4.08(d,J＝11.7Hz,1H),3.69(d,J＝12.5Hz,1H),3.01(d,J＝15.9Hz,1H),2.86(s,1H),2.67(d,J＝16.9Hz,1H),2.50(s,1H),2.00(s,1H),1.62(d,J＝43.5Hz,6H),1.38(d,J＝33.2Hz,5H),1.07(s,1H),0.86(d,J＝33.1Hz,2H).Ms(m/z):426.3[M+H]。
实施例40、化合物40的合成
Figure PCTCN2020074131-appb-000034
化合物39(0.15mmol)溶于5ml甲醇,依次加入HCHO溶液(1mmol)，NaBH 3CN(0.5mmol)和乙酸(0.2ml),室温反应过夜，TLC监测原料大量反应完毕后滴加氨水至PH＝9,30ml乙酸乙酯稀释，分液，水相乙酸乙酯洗(30ml),合并有机相，brine洗，无水硫酸钠干燥，柱层析(PE/EA＝200:1),得到目标化合物40(淡黄色油状液体，40mg，60％)。
1H NMR(400MHz,CDCl 3)δ7.57–7.26(m,10H),6.98(d,J＝8.2Hz,1H),6.86–6.62(m,2H),5.14–4.91(m,2H),4.27(s,1H),3.77(s,1H),3.09(d,J＝52.7Hz,2H),2.64(d,J＝17.1Hz,2H),2.47(s,2H),2.23(t,J＝13.7Hz,1H),2.07(d,J＝13.1Hz,1H),1.97(s,1H),1.73(s,1H),1.51(d,J＝14.9Hz,6H),1.26(s,1H),1.13(s,1H),1.05–0.72(m,2H).Ms(m/z):440.3[M+H]
实施例41、体外活性实验
1.实验目的
通过放射性同位素配体竞争性结合实验，以化合物的IC50为指标，来评价化合物对μ、κ和δ阿片类受体的亲和力。
2.实验材料
(1)试剂
细胞膜提取自上海药明康德构建的稳转细胞。
3H-diprenophrine(PerkinElmer,Cat:NET1121250UC,Lot:2143599)
3H-DAMGO(PerkinElmer,Cat:NET902250UC,Lot:2139100)
3H-DADLE(PerkinElmer,Cat:NET648250UC,Lot:2060549)
Tris base(Sigma,Cat:T6066-1KG),prepare 1M stock and adjust pH to 7.4.
0.5M EDTA(Invitrogen,Cat:15575-038)
1M MgCl2(Sigma,Cat:M1028-100ml)
PEI(Poly ethyleneimine)(Sigma,Cat:P3143)
Microscint 20cocktail(PerkinElmer,Cat:6013329)
Naltrindole(Sigma,Cat；N115)
(±)trans-U-50488(Sigma,Cat:D8040)
DAMGO(Sigma,Cat:E7384)
(2)实验缓冲液和洗板缓冲液
Figure PCTCN2020074131-appb-000035
(3)耗材及仪器
GF/C滤板,Perkin Elmer(Cat#6005174)
96-孔板,Agilent(Cat#5042-1385)
封板膜,Perkin Elmer(Cat#6005250)
MicroBeta2(PerkinElmer)
Cell harvest C961961,(Perkin Elmer)
3.方法步骤
1)细胞膜及放射性同位素配制
靶点 细胞膜蛋白浓度(ug/well) 放射性同位素 放射性同位素终浓度(nM)
DOR 6.7 [3H]-DADLE 0.5
MOR 20 [3H]DAMGO 0.5
KOR 6.7 [3H]Diprenorphine 0.3
2)化合物配制
Figure PCTCN2020074131-appb-000036
3)实验步骤
(1)待测试化合物、阴性对照(即DMSO)和阳性对照(即非特异性结合孔化合物)准备好之后，转移1μL至96孔板中；
(2)加入99μL配制好的阿片受体膜蛋白至含有1μL化合物的96孔板中；
(3)加入100μL 2x对应放射性同位素配体；
(4)置于摇床上300rpm室温孵育1小时；
(5)提前将GF/C板每孔用50μL 0.3％的PEI至少浸泡半小时以上；
(6)待孵育结束后，先用Harvest将GF/C板用洗板缓冲液冲洗1次。然后用Harvest将96孔板中的细胞膜收集到GF/C板上，再用洗板缓冲液洗涤GF/C板四次，每次250μL左 右；
(7)将GF/C板子置于50℃烘箱烘烤1小时；
(8)用封底膜将GF/C板底部封上，每孔加入50μL Microscint-20闪烁液，然后用透明封板膜封住板子；
(9)使用MicroBeta2读取放射性信号值CPM；
(10)用Prsim 5分析数据。计算百分百抑制率，计算公式为％Inh＝(1-Background subtracted Assay value/Background subtracted HC value)*100。
下表为待测化合物针对μ、κ和δ阿片类受体的IC 50值。
表41 化合物针对μ、κ和δ阿片类受体的IC 50值
供试样品 μIC 50 κIC 50 δIC 50
化合物1的盐酸盐 C D E
化合物2的盐酸盐 C D E
化合物3的盐酸盐 B C E
化合物4的盐酸盐 B D D
化合物5的盐酸盐 C D E
化合物6的盐酸盐 D D E
化合物7的盐酸盐 C C E
化合物8的盐酸盐 B E E
化合物9的盐酸盐 C C D
化合物10的盐酸盐 C D E
化合物11的盐酸盐 C E E
化合物12的盐酸盐 D E E
化合物13的盐酸盐 C E E
化合物14的盐酸盐 C D E
化合物15的盐酸盐 C D E
化合物16的盐酸盐 C E E
化合物17的盐酸盐 C E E
化合物18的盐酸盐 B C D
化合物19的盐酸盐 A B D
化合物20的盐酸盐 A B C
化合物21的盐酸盐 A B B
化合物22的盐酸盐 A B B
化合物23的盐酸盐 B C D
化合物24的盐酸盐 B C D
化合物25的盐酸盐 A C C
化合物26的盐酸盐 A A A
化合物27的盐酸盐 B B C
化合物28的盐酸盐 A C D
化合物29的盐酸盐 B D D
化合物30的盐酸盐 A B B
化合物31的盐酸盐 A C B
化合物32的盐酸盐 A B B
化合物33的盐酸盐 A C C
化合物34的盐酸盐 A A B
化合物35的盐酸盐 C E E
化合物36的盐酸盐 B D D
化合物37的盐酸盐 D D E
化合物38的盐酸盐 B D D
化合物39的盐酸盐 A C C
化合物40的盐酸盐 A A B
A：<10nM；10nM<B<100nM；100nM<C<1μM；1μM<D<10μM；E：>10μM
体外活性测试证明，本发明的化合物对于μ、κ和δ阿片类受体的IC 50值分别≤10μM。本发明更优选的化合物对于μ、κ和δ阿片类受体的IC 50值分别≤1μM。本发明进一步更优选的化合物对于μ、κ和δ阿片类受体的IC 50值分别≤100nM。
体外活性测试还标明，化合物19-22，25，26，28，30-34，39和40为活性较高的本发明化合物，尤其是，化合物21，22，25，26，30，33-34和40。其中，这些化合物中，对于μ、κ和δ阿片类受体的IC 50值至少有一个达到A级，更优选至少两个阿片类受体的IC 50值达到A级，最优选地，三个阿片类受体的IC 50值均达到A级。
本发明最优选化合物对于μ、κ和δ阿片类受体的IC 50值分别≤10nM；同时，本发明化合物对于μ、κ和δ阿片类受体具有选择性，更优选地，本发明化合物对于μ阿片类受体具有更好的选择性。例如本发明优选化合物4、8、10、11、13-17、28、29、35、36和38对于μ阿片类受体均具有选择性。其中，更优选化合物4，8，29、36和38的选择性。
实施例42.体内药效学研究
分别采用小鼠热辐射致痛模型、小鼠热板致痛模型评价受试化合物的镇痛强度。表42结果显示：化合物26在四个小鼠致痛模型中的镇痛作用均最强，化合物22次之，均强于地佐辛。
表42
Figure PCTCN2020074131-appb-000037
实施例43.小鼠、大鼠静脉给药药代实验
将雄性小鼠分别静脉注射给予本发明化合物，测定给药后的血浆中药物原型浓度及代谢物地佐辛盐酸盐浓度。
结果证明地佐辛盐酸盐在小鼠血浆中清除速度较快，T 1/2为0.903h，化合物21、22、25、26的盐酸盐在小鼠血浆中清除速度均比地佐辛盐酸盐慢，T 1/2分别为1.27h、1.24h、1.65h、1.35h。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种式I所示的化合物或其互变异构体、光学异构体、氮氧化物、溶剂化物、药学上可接受的盐或前药：
    Figure PCTCN2020074131-appb-100001
    其中，R 1，R 2各自独立地选自H、C 1-C 12脂肪烃基、C 6-C 14芳基、C 6-C 14芳基-C 1-C 12脂肪烃基、C 3-C 8环烷基、C 3-C 8环烷基-C 1-C 12脂肪烃基、5-14元杂芳基、5-14元杂芳基-C 1-C 12脂肪烃基，所述C 6-C 14芳基、C 3-C 8环烷基、5-14元杂芳基任选被一个以上卤素、OH、C 1-C 12脂肪烃基、C 1-C 12脂肪烃基氧基、C 1-C 12脂肪烃基-S-取代；或R 1、R 2和与之相连的N一起形成含N的4-6元环，所述含N的4-6元环任选被一个以上卤素、OH、C 1-C 12脂肪烃基、C 1-C 12脂肪烃基氧基、C 1-C 12脂肪烃基-S-取代；
    R 3选自H、C 1-C 12脂肪烃基、C 6-C 14芳基、C 6-C 14芳基-C 1-C 12脂肪烃基、C 3-C 8环烷基、C 3-C 8环烷基-C 1-C 12脂肪烃基、5-14元杂芳基、5-14元杂芳基-C 1-C 12脂肪烃基，所述C 6-C 14芳基、C 3-C 8环烷基、5-14元杂芳基任选被一个以上卤素、C 1-C 12脂肪烃基、C 1-C 12脂肪烃基氧基、C 1-C 12脂肪烃基-S-取代；
    R 4选自H、OH、卤素、C 1-C 12脂肪烃基、C 1-C 12脂肪烃基氧基、C 1-C 12脂肪烃基-S-；
    上述R 1、R 2、R 3中至少一个不为H；
    A选自O或S；n选自0、1、2。
  2. 根据权利要求所述式I所示的化合物或其互变异构体、光学异构体、氮氧化物、溶剂化物、药学上可接受的盐或前药，其特征在于，R 1，R 2各自独立地选自H、C 1-C 12脂肪烃基、C 6-C 14芳基-C 1-C 6脂肪烃基、C 3-C 8环烷基、C 3-C 8环烷基-C 1-C 6脂肪烃基，所述C 6-C 14芳基、C 3-C 8环烷基任选被一个以上卤素、OH、C 1-C 6脂肪烃基、C 1-C 6脂肪烃基氧基、C 1-C 6脂肪烃基-S-取代；或R 1、R 2和与之相连的N一起形成含N的4-6元环；R 3选自H、C 1-C 6脂肪烃基、C 6-C 14芳基-C 1-C 12脂肪烃基，所述C 6-C 14芳基任选被一个以上卤素、C 1-C 6脂肪烃基、C 1-C 6脂肪烃基氧基、C 1-C 6脂肪烃基-S-取代；R 4选自C 1-C 6脂肪烃基、C 1-C 6脂肪烃基氧基、C 1-C 6脂肪烃基-S-；上述R 1、R 2、R 3中至少一个不为H；A选自O或S；n选自1、2。
  3. 根据权利要求1或2所述式I所示的化合物或其互变异构体、光学异构体、氮氧化物、溶剂化物、药学上可接受的盐或前药，其特征在于，R 1，R 2各自独立地选自H、C 1-C 12烷基、C 6-C 14芳基-C 1-C 6烷基、C 3-C 8环烷基、C 3-C 8环烷基-C 1-C 6烷基，所述C 6-C 14芳基、C 3-C 8环烷基任选被一个以上卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷基-S-取代；或R 1、R 2和与之相连的N一起形成含N的5元环；R 3选自H、C 1-C 6烷基、C 6-C 14芳基-C 1-C 12烷基，所述C 6-C 14芳基任选被一个以上卤素、C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷基-S-取代；R 4选自C 1-C 6烷基、C 1-C 6烷氧基、C 1-C 6烷基-S-；上述R 1、R 2、R 3中至少一个不为H；A选自O；n选自1。
  4. 根据权利要求1-3任一项所述式I所示的化合物或其互变异构体、光学异构体、氮氧化物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述C 1-C 12脂肪烃基选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、乙烯基、1-丙烯基、2-丙烯基、1-甲基乙烯基、1-丁烯基、1-乙基乙烯基、1-甲基-2-丙烯基、2-丁烯基、3-丁烯基、2-甲基-1-丙烯基、2-甲基-2-丙烯基、1-戊烯基、1-己烯基、乙炔基，1-丙炔基，2-丙炔基，1-丁炔基，1-甲基-2-丙炔基，3-丁炔基，1-戊炔基和1-己炔基；所述卤素选自F、Cl、Br、I；所述芳基选自苯基、萘基；所述C 3-C 8环烷基选自环丙基、环丁基、环戊基、环己基，所述含N的4-6元环选自氮杂环丙烷、吡咯烷、哌啶、哌嗪、吗啉、吡咯、咪唑、吡唑、噻唑、异噻唑、恶唑、异恶唑、吡啶、吡嗪、嘧啶、哒嗪；所述药学上可接受的盐选自盐酸盐。
  5. 根据权利要求1-4任一项所述式I所示的化合物或其互变异构体、光学异构体、氮氧化物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述式I结构具有如下式II结构：
    Figure PCTCN2020074131-appb-100002
  6. 根据权利要求1-5任一项所述式I所示的化合物或其互变异构体、光学异构体、氮氧化物、溶剂化物、药学上可接受的盐或前药，其特征在于，所述式I为如下化合物结构：
    Figure PCTCN2020074131-appb-100003
    Figure PCTCN2020074131-appb-100004
  7. 根据权利要求1-6任一项所述式I所示的化合物或其互变异构体、光学异构体、氮氧化物、溶剂化物、药学上可接受的盐或前药的制备方法，其特征在于，选自如下合成方案：
    方案1：
    Figure PCTCN2020074131-appb-100005
    (1)化合物M-1与醛R aCHO反应得到中间体T-1；
    (2)中间体T-1经还原得到式I化合物；
    方案1中，R 1、R 2、R 3、R 4、A、n如式I中所定义，但其中，R 1、R 2至少一个不为H；R aCHO为对应引入目标式I化合物中R 1、R 2取代基的醛类化合物(可发生N上单取代或二取代反应，其中，R 1，R 2均不为H时，对应二取代产物，R 1，R 2中的一个为H时，对应单取代产物)。
    方案2：
    Figure PCTCN2020074131-appb-100006
    (1)化合物M-2与醛R bCHO反应得到中间体T-2；
    (2)中间体T-2经还原得到式I化合物；
    方案2中，R 1、R 2、R 3、R 4、A、n如式I中所定义，但其中，R 1、R 2不为H；R bCHO为对应引入目标式I化合物中R 2取代基的醛类化合物。
    方案3：
    Figure PCTCN2020074131-appb-100007
    化合物M-3与化合物X(CH 2) mX反应得到式I-1化合物；
    方案3中，R 3、R 4、A、n如式I中所定义，m为3-5；X为F、Cl、Br、I。
    方案4
    Figure PCTCN2020074131-appb-100008
    化合物M-4与HX反应得到式I-2化合物；
    方案4中，R 1、R 2、R 3、R 4、A、n如式I中所定义，但其中，R3不为H；X为F、Cl、Br、I。
    方案5
    Figure PCTCN2020074131-appb-100009
    (1)将化合物M-5与氨基保护试剂反应得到氨基保护的中间体T-3,；
    (2)T-3与R 3X反应得到中间体T-4；
    (3)T-4完全脱除保护基得到式I化合物；或T-4在还原试剂B存在下得到N-甲基化产物。
    方案5中，R 3、R 4、A、n如式I中所定义，但其中，R3不为H；X为F、Cl、Br、I；G为氨基保护基团。
  8. 一种药物组合物，其特征在于，所述药物组合物包含权利要求1-6任一项所述式I所示的化合物或其互变异构体、光学异构体、氮氧化物、溶剂化物、药学上可接受的盐或前药，优选的，所述药物组合物还可以包含第二治疗剂，所述第二治疗剂包括MOR拮抗剂，如纳洛酮、 纳曲酮、曲马多、samidorphan。
  9. 权利要求1-6任一项所述式I所示的化合物或其互变异构体、光学异构体、氮氧化物、溶剂化物、药学上可接受的盐或前药或权利要求8所述的一种药物组合物在制备治疗阿片受体相关病症的用途，所述病症包括疼痛、痛觉过敏和心脑血管疾病等，进一步的，所述病症可以为疼痛，如神经性疼痛或伤害性疼痛；所述疼痛的具体类型包括但不限于急性疼痛、慢性疼痛、手术后疼痛、由于神经痛导致的疼痛(例如，疱疹后神经痛或三叉神经痛)、由于糖尿病神经病变导致的疼痛、牙痛、与关节炎或骨关节炎相关的疼痛和与癌症或其治疗相关的疼痛。
  10. 权利要求1-6任一项所述式I所示的化合物或其互变异构体、光学异构体、氮氧化物、溶剂化物、药学上可接受的盐或前药或权利要求8所述的一种药物组合物在制备治疗抑郁相关疾病和症状的药物中的用途，所述抑郁相关疾病和症状可为急性应激障碍，情绪低落的调节障碍，阿斯伯格综合征，注意力缺陷，双相障碍，边缘和人格障碍，循环障碍，抑郁症如重度抑郁症(MDD)和治疗抵抗性疾病(TRD)，心境恶劣障碍，多动障碍，冲动控制障碍，混合性躁狂，强迫性人格障碍(OCD)，偏执狂，创伤后应激障碍，季节性情感障碍，自我伤害分离，睡眠障碍，物质引起的情绪障碍。
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