WO2019109937A1 - Kor激动剂与mor激动剂联合在制备治疗疼痛的药物中的用途 - Google Patents

Kor激动剂与mor激动剂联合在制备治疗疼痛的药物中的用途 Download PDF

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WO2019109937A1
WO2019109937A1 PCT/CN2018/119313 CN2018119313W WO2019109937A1 WO 2019109937 A1 WO2019109937 A1 WO 2019109937A1 CN 2018119313 W CN2018119313 W CN 2018119313W WO 2019109937 A1 WO2019109937 A1 WO 2019109937A1
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group
pain
cycloalkyl
aryl
alkyl
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PCT/CN2018/119313
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English (en)
French (fr)
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黄晓星
曹国庆
杨昌永
张连山
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江苏恒瑞医药股份有限公司
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Priority to BR112020010429-9A priority Critical patent/BR112020010429A2/pt
Priority to CN201880059072.XA priority patent/CN111065390B/zh
Priority to JP2020529356A priority patent/JP2021505547A/ja
Priority to RU2020115687A priority patent/RU2776842C2/ru
Priority to AU2018380173A priority patent/AU2018380173A1/en
Priority to US16/767,523 priority patent/US11471503B2/en
Priority to CA3083028A priority patent/CA3083028A1/en
Priority to MX2020005660A priority patent/MX2020005660A/es
Priority to KR1020207018160A priority patent/KR20200096787A/ko
Priority to EP18885338.6A priority patent/EP3714882A4/en
Publication of WO2019109937A1 publication Critical patent/WO2019109937A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the invention belongs to the field of medicine and relates to the use of a KOR agonist in combination with a MOR agonist for the preparation of a medicament for relieving and/or treating pain.
  • Pain refers to a person's functional or substantial feelings.
  • the classification of pain is more complicated. According to the etiology classification, it is mainly divided into traumatic pain, pathological pain, pain caused by metabolic diseases, neuropathic pain, pain caused by tissue and organ malformation, psychological pain, and pain caused by compound factors. According to the course of disease, it can be divided into transient pain, acute pain and chronic pain. According to the degree of pain, it can be divided into slight pain, mild pain, very pain, and severe pain. According to the anatomy, it can be divided into headache and maxillofacial pain. Pillow pain, neck and shoulder pain, upper limb pain, chest pain, abdominal pain, low back pain; according to the location of the pain and causes, can be divided into peripheral pain, central pain, psychological pain.
  • the causes of painful diseases are complex, and the symptoms are different.
  • the degree of patient tolerance to pain and the response to treatment vary widely.
  • the commonly used drugs for the treatment of pain mainly include anti-inflammatory analgesics and narcotic analgesics.
  • drugs for analgesia there are still constipation, respiratory depression, sedation and lethargy, nausea and vomiting, acute poisoning, physical dependence and drug resistance, Problems such as spiritual dependence.
  • Opioids are commonly used analgesics in clinical practice, especially in the treatment of patients with severe pain and advanced cancer, mainly through the action of opioid receptors to produce analgesic effects.
  • Opioid receptors are members of the G-protein coupled receptor superfamily and participate in various physiological activities such as analgesia, inhibition of gastrointestinal motility, respiratory depression, myocardial protection, and immune response.
  • Opioid receptors are generally considered to be classified into four subtypes: ⁇ opioid receptor (MOR), ⁇ opioid receptor (DOR), kappa opioid receptor (KOR), and opioid receptor-1 (ORL-1).
  • MOR receptors have the strongest binding ability to morphin 1 , so the opioid analgesics used in clinical practice are mainly MOR agonists, including morphine, tramadol, fentanyl, oxycodone, etc., but long-term The use of this class of drugs can cause severe side effects such as analgesic tolerance, dependence and addiction.
  • Phase III clinical MOR agonists are TRV-130 being developed by Trevena Inc.
  • WO2017063509 discloses a novel MOR agonist whose structure is as follows:
  • WO2012129495 discloses a structurally similar MOR agonist.
  • KOR kinase C activity thereby inhibiting the analgesic tolerance and dependence of MOR agonists; CunhaTM et al. found that ([J]. Molecular pain, 2012, 8(1): 10) peripheral activation of KOR can inhibit inflammatory pain And activation of peripheral MOR can inhibit prostaglandin E2-induced progressive hyperalgesia. It has been reported that activation of KOR can also inhibit inflammatory hyperalgesia, and its mechanism may activate PI3K ⁇ /AKT signaling pathway through nNOS/NO signaling pathway; Liu Rong et al reported KOR agonist nalbuphine and MOR agonist sufentanil for postoperative analgesic sedation after total hip arthroplasty ([J]. China Pharmaceuticals, 2016, 25(22): 41-44), showing joint The analgesic effect of administration was better than that of single administration, and adverse reactions such as nausea and vomiting and itching of the skin were also significantly reduced.
  • Patent application PCT/CN2017/087328 provides a novel KOR agonist that is extremely low in brain tissue, has little effect on the central nervous system, has little effect on serum sodium, is not easily addicted, and is more safe, its structure As follows:
  • WO2008060552 discloses a structurally similar KOR agonist, and its use in combination with other opioid receptor agonists, NSAIDs, antidepressants for analgesia;
  • WO2016073443 discloses a similar KOR agonist for the treatment of surgical pain Use of hard tissue pain;
  • WO2008057608 discloses the use of a similar KOR agonist in combination with a MOR agonist to treat pain and reduce the dose of MOR agonist to reduce adverse reactions;
  • WO2015065867 discloses a similar KOR agonist in MOR Use after agonist administration to reduce the vomiting effect of MOR agonists.
  • the combination of a KOR agonist with a MOR agonist is a potential method for pain relief and/or treatment.
  • the present invention provides the use of a novel KOR agonist in combination with a MOR agonist for the manufacture of a medicament for the relief and/or treatment of pain.
  • the technical problem to be solved by the present invention is to provide a use of a KOR agonist in combination with a MOR agonist for the preparation of a medicament for alleviating and/or treating pain.
  • the KOR agonist is selected from the group consisting of a compound of the formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof a form, or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (I) has the following structure:
  • G is selected from the group consisting of O, -NR 4 and -CR 5 R 6 ;
  • R 1 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 7 , -C (O) R 7 , -C(O)OR 7 , -S(O) m R 7 and -NR 8 R 9 , wherein the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and The heteroaryl group is optionally selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and hetero
  • R 2 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclic group, a heterocyclic alkyl group, an aryl group, an arylalkyl group, a heteroaryl group, a hetero Arylalkyl, -OR 7 , -C(O)R 7 and -C(O)OR 7 wherein alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetero
  • the cycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl groups are optionally selected from the group consisting of alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkyl Substituted by
  • R 3 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a cycloalkyl group, a cycloalkylalkyl group, a heterocyclic group, a heterocyclic alkyl group, an aryl group, an arylalkyl group, a heteroaryl group, a hetero Arylalkyl, -OR 7 , -C(O)R 7 and -C(O)OR 7 wherein alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetero
  • the cycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl groups are optionally selected from the group consisting of alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkyl Substituted by
  • R 4 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a cycloalkyl group, an alkoxy group, a hydroxyalkyl group, an amino group, a carboxylate group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 7 , -C ( O) R 7 , -C(O)OR 7 , -S(O) m R 7 , -NR 8 R 9 and -NHC(O)NR 8 R 9 wherein the alkyl group, cycloalkyl group, hetero
  • the cyclo, aryl and heteroaryl groups are optionally selected from the group consisting of alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, Substituting one or more substituents in the aryl and heteroaryl groups
  • R 5 and R 6 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyalkyl group, a hydroxyl group, an amino group, a carboxylate group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 7 , —C(O)R 7 , —C(O)OR 7 , —S(O) m R 7 , —NR 8 R 9 and —NHC(O)NR 8 R 9 , wherein said alkyl group,
  • the cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally selected from the group consisting of alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl Substituting one or more substituents in a heterocyclic group, an aryl group, and a heteroary
  • R 7 is selected from the group consisting of a hydrogen atom, an alkyl group, an amino group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group,
  • the aryl and heteroaryl are optionally selected from the group consisting of alkyl, halo, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents;
  • R 8 and R 9 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyalkyl group, a hydroxyl group, an amino group, a carboxylate group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.
  • alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally selected from the group consisting of alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkane Substituted by one or more substituents of a group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • n 0, 1, or 2.
  • the KOR agonist is selected from the group consisting of the compounds of the formula (I-A):
  • R 2 and R 3 are as defined in the compound represented by the formula (I).
  • the KOR agonist is selected from the group consisting of the compounds of the formula (I-B):
  • G and R 2 are as defined in the compound represented by the formula (I).
  • the KOR agonist is selected from the group consisting of the compounds of the formula (I-C):
  • R 2 is as defined in the compound represented by the formula (I).
  • the KOR agonist or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • the MOR agonist is selected from the group consisting of a compound represented by the formula (II) or a tautomer, a mesogen, a racemate, an enantiomer, and a diastereomer. Isomers or mixtures thereof, or a pharmaceutically acceptable salt thereof:
  • Ring A is selected from the group consisting of a cycloalkyl group and a heterocyclic group
  • R is selected from the group consisting of aryl and heteroaryl, wherein the aryl and heteroaryl are optionally selected from the group consisting of alkyl, haloalkyl, halo, amino, nitro, cyano, alkoxy, haloalkoxy, hydroxy Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 3 , -C(O)R 3 , -C(O)OR 3 , -S(O)mR 3 and -NR 4 R Substituting one or more substituents in 5 ;
  • R 1 is the same or different and is each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.
  • alkyl group, haloalkyl group, cycloalkyl group, Heterocyclyl, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, hetero Substituting one or more substituents of a cyclic group, an aryl group, and a heteroaryl group;
  • R 2 is the same or different and is each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a halogen group, an amino group, a nitro group, a hydroxyl group, a cyano group, an oxo group, an alkenyl group, a cycloalkyl group, a heterocyclic ring.
  • alkyl group, Alkoxy, alkenyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from the group consisting of a halogen atom, an alkyl group, a halogenated alkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, Substituted with one or more substituents of alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • the two R 2 together form a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is optionally selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkane Substituted by one or more substituents of an oxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 3 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an amino group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group And a heterocyclic group, an aryl group and a heteroaryl group are optionally selected from the group consisting of alkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and Substituting one or more substituents in the heteroaryl;
  • R 4 and R 5 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyalkyl group, a hydroxyl group, an amino group, a carboxylate group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group.
  • alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally selected from the group consisting of alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkane Substituted by one or more substituents of a group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • p, q are each independently 0, 1, 2, 3 or 4;
  • n 0, 1, or 2.
  • the MOR agonist is selected from the group consisting of a compound of the formula (II-B) or a tautomer thereof, a mesogen, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 1 , R 2 and p are as defined in the compound represented by the formula (II).
  • the MOR agonist or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
  • the MOR agonist is selected from the group consisting of hydromorphone hydrochloride, morphine, oxycodone, buprenorphine, sufentanil, fentanyl, and fentanyl, and rifampicin.
  • the KOR agonist and the MOR agonist have synergistic pharmacological effects for relieving and/or treating pain; preferably, the compound 5 or a pharmaceutically acceptable salt thereof and the compound 20 or pharmaceutically acceptable thereof
  • the salt has a synergistic pharmacological effect of relieving and/or treating pain.
  • a method of alleviating and/or treating pain comprising administering to a patient a KOR agonist salt and a MOR agonist as described above.
  • the pain is selected from the group consisting of acute pain and chronic pain
  • the chronic pain is selected from the group consisting of headache, maxillofacial pain, occipital pain, neck and shoulder pain, upper limb pain, chest pain, abdominal pain, Low back pain, genital pain, urinary tract pain, dysmenorrhea.
  • the pain is selected from the group consisting of traumatic pain, inflammatory pain, ischemic pain, pain caused by metabolic diseases, neuropathic pain, pain caused by tissue and organ malformation, labor pain, malignancy Pain caused by proliferative diseases.
  • the traumatic pain is selected from surgery-induced pain (eg, appendectomy, open colorectal surgery, hernia repair, prostatectomy, colonectomy, gastrectomy, splenectomy, Colectomy, colostomy, pelvicoscopy, tubal ligation, hysterectomy, post-operative pain due to vasectomy or cholecystectomy), pain after medical treatment (eg colonoscopy, cystoscopy, Hysteroscopy or pain after cervical or endometrial biopsy), fracture pain, burn pain, abdominal traumatic pain, spinal traumatic pain, chest traumatic pain, post-traumatic headache.
  • surgery-induced pain eg, appendectomy, open colorectal surgery, hernia repair, prostatectomy, colonectomy, gastrectomy, splenectomy, Colectomy, colostomy, pelvicoscopy, tubal ligation, hysterectomy, post-operative pain due to vasectomy or cholecystectomy
  • pain after medical treatment eg colonos
  • the inflammatory pain is selected from the group consisting of inflammatory headache, tissue inflammatory pain (such as rheumatoid arthritis, rheumatoid arthritis, osteoarthritis), organ and glandular inflammatory pain (eg , gastroesophageal reflux disease, pancreatitis, acute pyelonephritis, ulcerative colitis, cholecystitis, cirrhosis, hepatic cyst, hepatitis, duodenal ulcer or gastric ulcer, esophagitis, gastritis, gastroenteritis, colon Inflammation, diverticulitis, intestinal obstruction, ovarian cysts, pelvic inflammatory disease, ulcer perforation, peritonitis, prostatitis, interstitial cystitis, vasculitic pain.
  • tissue inflammatory pain such as rheumatoid arthritis, rheumatoid arthritis, osteoarthritis
  • organ and glandular inflammatory pain eg , gastroesophageal reflux
  • the ischemic pain is selected from the group consisting of ischemic headache, limb ischemic pain, tissue ischemic pain, organ and gland ischemic pain.
  • the pain caused by the metabolic disease is selected from the group consisting of pain caused by gout and pain caused by diabetes.
  • the neuropathic pain is selected from the group consisting of phantom limb pain, stump pain, burning neuralgia, postherpetic neuralgia, sympathetic-related pain, and pain caused by burning foot syndrome. , folic acid deficiency peripheral neuralgia, vitamin B12 deficiency peripheral neuralgia, vitamin B1 deficiency polyneuropathy, leprosy neuralgia.
  • the pain caused by the malignant proliferative disease is selected from the group consisting of tumor-induced pain, including but not limited to leukemia, lymphoma, myeloma, breast cancer, lung cancer, esophageal cancer, gastric cancer, colon cancer, liver cancer, Pain caused by pancreatic cancer, head and neck cancer, kidney cancer, bladder cancer, prostate cancer, ovarian cancer, endometrial cancer, cervical cancer, osteosarcoma, soft tissue sarcoma, melanoma, and brain tumor.
  • tumor-induced pain including but not limited to leukemia, lymphoma, myeloma, breast cancer, lung cancer, esophageal cancer, gastric cancer, colon cancer, liver cancer, Pain caused by pancreatic cancer, head and neck cancer, kidney cancer, bladder cancer, prostate cancer, ovarian cancer, endometrial cancer, cervical cancer, osteosarcoma, soft tissue sarcoma, melanoma, and brain tumor.
  • the pain is selected from moderate to severe pain.
  • the moderate to severe pain is selected from the group consisting of traumatic pain, labor pain, tumor-induced pain, and inflammatory pain.
  • the moderate to severe pain is not suitable and/or insensitive to non-opioid analgesic drugs, weak opioid analgesics.
  • the present invention provides the above KOR agonist in combination with the above MOR agonist as a medicament for alleviating and/or treating pain.
  • the weight ratio of the KOR agonist to the MOR agonist ranges from 0.01 to 1000, selected from the group consisting of 1000/1, 750/1, 500/1, 400/1, 250/1, 200 /1, 100/1, 100/3, 90/1, 80/1, 75/1, 70/1, 60/1, 50/1, 40/1, 30/1, 30/7, 20/1 , 20/7, 20/3, 20/9, 25/1, 25/2, 25/3, 25/4, 25/6, 25/7, 25/8, 25/9, 25/18, 15 /1, 15/2, 15/4, 18/1, 18/5, 18/7, 14/1, 14/3, 14/5, 14/9, 12/1, 12/5, 12/7 , 10/1, 10/3, 10/7, 10/9, 9/1, 9/2, 9/4, 8/1, 8/3, 8/5, 7/1, 7/2, 7 /3, 7/4, 7/5, 7/6, 6/1, 6/5, 5/1, 5/2, 5/3, 5/4, 4/1, 4/3, 3/1 , 3
  • the KOR agonist is administered in a dose of 0.001 to 250 mg, preferably from 0.001 mg, 0.002 mg, 0.003 mg, 0.004 mg, 0.005 mg, 0.006 mg, 0.007 mg, 0.008 mg, 0.009.
  • Mg 0.01 mg, 0.02 mg, 0.03 mg, 0.05 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.75 mg, 0.8 mg, 0.9 mg, 1 mg, 1.25 mg, 1.5 Mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5 mg, 3.75 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 7 mg, 7.5 mg, 8 mg, 9 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 18 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg; the MOR agonist is administered at a dose of 0.001-50 mg, preferably from 0.001 mg, 0.002 mg, 0.003 mg, 0.004 mg, 0.005 mg, 0.006 mg, 0.007 mg, 0.008 mg, 0.009 mg, 0.01 mg, 0.
  • the KOR agonist is selected from the compound 5 or a pharmaceutically acceptable salt thereof, and is administered at a dose of 0.001 to 20 mg, preferably from 0.005 mg, 0.01 mg, 0.03 mg, 0.05 mg.
  • the MOR agonist is selected from the group consisting of Compound 20 or a pharmaceutically acceptable salt thereof, and is administered at a dose of 0.001 to 20 mg, preferably from 0.001 mg, 0.002 mg, 0.003 mg, 0.004 mg.
  • the KOR agonist is administered at a dose of 0.01-500 ⁇ g/kg, preferably from 0.01 ⁇ g/kg, 0.05 ⁇ g/kg, 0.1 ⁇ g/kg, 0.2 ⁇ g/kg, 0.25 ⁇ g/ Kg, 0.3 ⁇ g/kg, 0.4 ⁇ g/kg, 0.5 ⁇ g/kg, 0.6 ⁇ g/kg, 0.7 ⁇ g/kg, 0.8 ⁇ g/kg, 0.9 ⁇ g/kg, 1 ⁇ g/kg, 2 ⁇ g/kg, 2.5 ⁇ g/kg, 3 ⁇ g/kg, 4 ⁇ g/kg, 5 ⁇ g/kg, 8 ⁇ g/kg, 10 ⁇ g/kg, 15 ⁇ g/kg, 20 ⁇ g/kg, 24 ⁇ g/kg, 25 ⁇ g/kg, 30 ⁇ g/kg, 40 ⁇ g/kg, 50 ⁇ g/kg, 60 ⁇ g/ Kg, 70 ⁇ g/kg, 75 ⁇ g/kg,
  • the KOR agonist is selected from the group consisting of Compound 5 or a pharmaceutically acceptable salt thereof, at a dose of 0.01-150 ⁇ g/kg, preferably from 0.01 ⁇ g/kg, 0.05 ⁇ g/kg, 0.1 ⁇ g/kg.
  • the MOR agonist is selected from the group consisting of Compound 20 or a pharmaceutically acceptable salt thereof, and is administered at a dose of 0.001 to 150 ⁇ g/kg, preferably from 0.003 ⁇ g/kg, 0.005 ⁇ g/kg, 0.01 ⁇ g/kg.
  • the combined modes of administration of the present invention are selected from the group consisting of simultaneous administration, independent formulation and co-administration or independent formulation and sequential administration.
  • the invention further relates to the use of a MOR agonist in combination with a KOR agonist for the preparation of amelioration and/or treatment of pain, wherein the KOR agonist is administered for a first time at a dose of 0.05-50 times the maintenance dose, said MOR agonist
  • the first dose of the agent is 1-50 times the maintenance dose.
  • the invention further relates to the use of a KOR agonist in combination with a MOR agonist for the preparation of amelioration and/or treatment of pain, wherein the frequency of administration of the KOR agonist is once a day, twice a day, three times a day, once a week. Second, once every three weeks, once a month, the frequency of MOR agonist administration is once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, once a month.
  • the combination further comprises optionally comprising a third component selected from the third component selected from the group consisting of an opioid, a glucocorticoid, a non-steroidal anti-inflammatory drug, and a topical component.
  • a third component selected from the third component selected from the group consisting of an opioid, a glucocorticoid, a non-steroidal anti-inflammatory drug, and a topical component.
  • the invention further relates to a pharmaceutical composition of a KOR agonist and a MOR agonist, comprising optionally one or more pharmaceutically acceptable carriers, excipients and/or diluents.
  • the pharmaceutical composition can be formulated into any of the pharmaceutically acceptable dosage forms.
  • a pharmaceutical preparation containing the active ingredient as a KOR agonist or a MOR agonist can be formulated into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, injections, etc.) Bacterial powder and concentrated solution for injection), suppository, inhalant or spray.
  • the KOR agonist and MOR agonist pharmaceutical compositions of the invention may be administered alone or in combination with one or more therapeutic agents.
  • KOR agonist and MOR agonist for the preparation of a medicament for the preparation and/or treatment of pain
  • the KOR agonist and the MOR agonist may be administered orally, parenterally (including but not limited to It is administered in the form of subcutaneous injection, intravenous injection, or intraperitoneal injection.
  • the components to be combined may be administered simultaneously or sequentially.
  • the ingredients to be combined may also be administered in combination in the form of the same formulation or in separate separate formulations.
  • the term "combination or combination” is a mode of administration comprising two or more drugs sequentially or simultaneously, and the term “simultaneously” means the same administration.
  • Periodically administering a KOR agonist with a MOR agonist, or a KOR agonist with a MOR agonist and any other third component drug for example, within two days, within three days, within a week, within two weeks, within one month, two or two The above drugs.
  • the so-called “sequential or sequential" administration includes the administration of a KOR agonist and a MOR agonist, or a KOR agonist and a MOR agonist, and any other third component drug, respectively, in different administration cycles.
  • an "effective amount” as used herein includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition.
  • An effective amount also means an amount sufficient to allow or facilitate the diagnosis.
  • An effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition to be treated, the overall health of the patient, the route and dosage of the method of administration, and the severity of the side effects.
  • An effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
  • hydroxy refers to an -OH group.
  • halogen means fluoro, chloro, bromo or iodo.
  • amino refers to -NH2.
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • carboxylic acid group refers to -C(O)OH.
  • carboxylate group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
  • X is selected from A, B, or C
  • X is selected from A, B, and C
  • X is A, B, or C
  • X is A, B, and C
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • the alkyl group of the atom is a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl,
  • lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • an alkane Base alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, hetero
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom, most preferably from 5 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
  • spirocycloalkyl refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have complete Conjugate ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, more preferably a bicyclic ring or a tricyclic ring.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene A benzocycloheptyl group or the like; preferably a phenylcyclopentyl group or a tetrahydronaphthyl group.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O).
  • a hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like are preferably tetrahydropyranyl, piperidinyl or pyrrolidinyl.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O). ) m (where m is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
  • Non-limiting examples of spiroheterocyclyl groups include:
  • fused heterocyclyl refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining rings
  • the atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused heterocyclic groups include:
  • bridge heterocyclyl refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total A ⁇ -electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bridge heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (i.e., a ring sharing a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, more preferably 5 to 6 yuan, such as phenyl and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 10 members, and has 1 to 3 hetero atoms; more preferably 5 or 6 members, and 1 to 2 hetero atoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridyl
  • the oxazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like are preferably an imidazolyl group, a pyrazolyl or pyrimidinyl group, or a thiazolyl group; more preferably a pyrazolyl group.
  • the heteroaryl ring may be fused to an aryl
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • amino protecting group refers to a group suitable for protecting (preventing) an amino group from chemical reaction, but which is easily removed after the end of the chemical reaction required elsewhere in the molecule.
  • Typical representatives of these groups are unsubstituted or substituted acyl groups, unsubstituted or substituted allyl groups, aryl groups, aralkyloxymethyl groups, aralkyl groups or together with a nitrogen atom to form heterocyclic groups and salts.
  • Non-limiting examples include tert-butoxycarbonyl (Boc), benzyloxycarbonyl, isobutoxycarbonyl, fluorenylmethoxycarbonyl (Fmoc), benzoyl, substituted benzoyl, butyryl, acetyl, tri Fluoroacetyl, ortho-dimethylimido (Pht), succinimidyl, maleimido, benzyl, allyloxycarbonyl and p-methoxybenzyl.
  • Boc tert-butoxycarbonyl
  • benzyloxycarbonyl isobutoxycarbonyl
  • fluorenylmethoxycarbonyl Fmoc
  • benzoyl substituted benzoyl
  • butyryl acetyl
  • tri Fluoroacetyl ortho-dimethylimido
  • succinimidyl maleimido
  • benzyl allyloxycarbonyl and p-methoxybenzyl.
  • These groups may be optionally substituted with a benzyl group, an o-methylbenzyl group, a trityl group and a diphenylmethyl group substituted with a halogen, an alkyl group, an alkoxy group, a hydroxyl group, a nitro group, an acylamino group, an acyl group or the like. Substituted by one or more substituents.
  • the amino protecting group is preferably t-butoxycarbonyl and fluorenylmethoxycarbonyl (Fmoc).
  • the term "synergistic effect” includes additive effect, potentiating effect, and potentiating effect, and “synergistic effect” of the present invention includes, but is not limited to, reducing resistance when KOR agonist or MOR agonist is used alone. Symptoms, reduce the dose of KOR agonists, MOR agonists alone, reduce the adverse effects of KOR agonists, MOR agonists when used alone, enhance the use of the same dose of KOR agonists and / or the same dose of MOR agonists alone The effect of relieving and/or treating pain.
  • acute pain refers to pain caused by harmful irritation caused by damage to skin, deep body structures or organs and/or diseases, or short-term pain caused by abnormal function of muscles or organs that do not cause actual tissue damage.
  • chronic pain refers to a reasonable period of time beyond the usual course of the acute disease or the healing of the injury, or to a chronic pathological process that causes persistent pain, or pain that recurs at intervals of days, weeks, months, years; Chronic pain also includes the presence of pain if it should have been cured or after the usual course of treatment.
  • inflammatory pain refers to local acute inflammation or chronic inflammation that stimulates nerve-induced pain.
  • ischemic pain refers to pain caused by poor blood supply to the limb or organ.
  • neuroopathic pain refers to pain caused by primary or secondary damage or dysfunction or transient disturbance of the surrounding or central nervous system.
  • pain caused by malignant proliferative diseases refers to tumors caused by malignant proliferation of somatic cells, pain caused by cancer, pain caused by diseases caused by malignant proliferation of human organs, glands, blood system and skin, bacteria in human organs and glands The blood system and the malignant proliferation of the skin cause pain caused by the lesion.
  • tissue refers to a population of cells that are identical in morphology or similar and functionally identical, including but not limited to epithelial tissue, connective tissue, muscle tissue, neural tissue, such as cartilage tissue, bone tissue, skeletal muscle, cardiac muscle, smooth muscle.
  • Moderate to severe pain refers to severe pain that requires painkillers to relieve, painful treatments that affect disease treatment and/or vital signs, and effects that affect rehabilitation.
  • first dose refers to the dose administered for the first time in the course of eliminating clinical symptoms and requiring continuous administration.
  • maintenance dose refers to the amount used to consolidate and maintain a therapeutic effect after the clinical symptoms are controlled or alleviated.
  • administered according to the need for pain refers to the administration of a mammalian self to the extent of pain perception for the purpose of relieving and/or treating pain.
  • the meaning of the term "surgery” is not limited to the definition of a conventional surgery, which includes the contents of the classification according to the classification of the Department of Health of the Ministry of Health (2011 edition).
  • the surgery described in the present invention encompasses at least one of the skin and the mucosa.
  • Surgical incision, non-traditionally defined medical procedures eg, interventional procedures involving diagnosis and treatment).
  • surgical-induced pain refers to a pain response after injury or stimulation of the tissue of the body, including preoperative, intraoperative, and postoperative pain during perioperative procedures, including but not limited to post-surgical pain ( For example, appendectomy, open colorectal surgery, hernia repair, prostatectomy, colonectomy, gastrectomy, splenectomy, colectomy, colostomy, pelvic laparotomy, tubal ligation, hysterectomy Postoperative pain caused by surgery, vasectomy or cholecystectomy), pain after medical treatment (eg colonoscopy, cystoscopy, hysteroscopy or pain after cervical or endometrial biopsy).
  • post-surgical pain For example, appendectomy, open colorectal surgery, hernia repair, prostatectomy, colonectomy, gastrectomy, splenectomy, colectomy, colostomy, pelvic laparotomy, tubal ligation, hysterectomy
  • tumor-induced pain refers to pain directly caused by a tumor, pain caused by tumor treatment, and pain caused by a tumor indirectly.
  • Figure 1 is a graph showing the effect of a KOR agonist of the present invention in combination with a MOR agonist (Compound 5 and Compound 20) on the threshold of mechanical stimulation of the rat in a wound pain test.
  • Compound 5 was determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • the NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), internal standard was four.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methyl silane
  • the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • 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 ⁇ 0.2mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Companies such as chemicals.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature and is 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • Purification compounds using column chromatography eluent systems and thin layer chromatography developer systems include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: dichloromethane and acetone
  • A dichloromethane and methanol systems
  • B n-hexane and ethyl acetate systems
  • C dichloromethane and acetone
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid may be added for adjustment.
  • the high-pressure liquid chromatography used in the high performance liquid chromatography in the examples was (Gilson-281), the column was Shim-pack PREP-ODS of Shimadzu, and the mobile phase used was a trifluoroacetic acid buffer system, namely water ( Containing 0.05% trifluoroacetate)-acetonitrile.
  • each of the compounds in the form of a trifluoroacetate salt in the examples can be obtained in a free state by the following general method: the trifluoroacetate salt is dissolved in a suitable solvent (e.g., methanol, ethanol, tetrahydrofuran, acetone, etc.), and a weak base is added. (such as sodium bicarbonate, sodium carbonate, potassium carbonate, etc.) adjust the pH to neutrality, concentrate under reduced pressure, and purify the residue to give a free state.
  • a suitable solvent e.g., methanol, ethanol, tetrahydrofuran, acetone, etc.
  • a weak base such as sodium bicarbonate, sodium carbonate, potassium carbonate, etc.
  • the crude product 5f (60 mg, 0.066 mmol) was dissolved in dichloromethane (2 mL), and 1 mL of 4M hydrogen chloride in 1,4-dioxane solution was added, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced vacuo.
  • Example 1 The apparatus, equipment and materials required for the preparation of the compound 20 are shown in Example 1.
  • the reaction mixture was washed with EtOAcqqqqqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH
  • the crude compound 19a (698 mg, 2.4 mmol) was dissolved in 4 mL of dichloromethane, and 8 mL of 4M hydrogen chloride in 1,4-dioxane solution was added, and the reaction was stirred for 2 hours.
  • Example 3 Effect of the KOR agonist of the present invention in combination with a MOR agonist on the treatment of incisional pain in rats
  • Wistar male rats were purchased from Shanghai Slack Laboratory Animal Co., Ltd., purchased at 140-160g/head, 5/cage, 12/12 hour light/dark cycle adjustment, temperature 23 ⁇ 1°C constant temperature, humidity 50 to 60%, free to eat into the water. After the animals were purchased, the experiment was started after adaptive feeding for more than 3 days.
  • Electronic tactile measuring instrument (electronic Von Frey): UGO BASILE, model 38450.
  • Both Compound 5 and Compound 20 were prepared using physiological saline.
  • the model group and the drug-administered group were subjected to incision surgery. After anesthesia with isoflurane during surgery, a 1 cm long incision was made in the middle of the left hind paw with a surgical blade No.
  • Experimental data is expressed as mean (Mean) ⁇ standard deviation (S.D.). Statistical comparisons were performed using the excel software t test. Comparing the model group with the blank control group data, whether there is significant statistical significance, #P ⁇ 0.05 indicates that the model group has significant difference compared with the blank control group, ##P ⁇ 0.01 indicates that the model group has a comparison with the blank control group. Highly significant differences. ⁇ P ⁇ 0.05 indicates that there is a significant difference between the test group and the model group, and ⁇ P ⁇ 0.01 indicates that the test group has a highly significant difference compared with the model group. *P ⁇ 0.05 indicates that there was a significant difference between the drug combination group and the single use group, and **P ⁇ 0.01 indicates that the drug combination group had a highly significant difference compared with the single use group.
  • the threshold of the normal control group was 14.48 g
  • the threshold of the model group was 8.91 g.
  • the threshold of the model group decreased significantly ( P ⁇ 0.05);
  • the compound 20-0.03 mg/kg group significantly increased the tenderness threshold of the rats (P ⁇ 0.01), reaching 14.46 g, with an increase of 62.3%; compound 5-0.3
  • the mg/kg group significantly increased the tender threshold of the rats (P ⁇ 0.01), reaching 17.92 g, with an increase of 101.1%.
  • the compound 20-0.03mg/kg combined with the compound 5-0.1mg/kg, the compound 5-0.3mg/kg, and the compound 5-1mg/kg can significantly increase the tenderness threshold of the rats.
  • the ratios of 17.96g, 22.29g and 33.46 were increased by 101.6%, 150.1% and 275.5% (P ⁇ 0.01), respectively, reflecting the dose-effect relationship of KOR agonists.
  • the efficacy of the three doses was better than that of the single compound 20-0.03 mg/kg, which was statistically different from the compound 5-0.3 mg/kg and the compound 5-1 mg/kg (P ⁇ 0.01).
  • Compound 20-0.03 mg/kg+ compound 5-0.1 mg/kg is equivalent to the increase of pain threshold compared with 5-0.3 mg/kg of compound alone; compound 20-0.03 mg/kg combined with compound 5-0.3 mg/kg The compound 5-1 mg/kg was superior to the single compound 5-0.3 mg/kg, and the combined compound 5-1 mg/kg was statistically different (p ⁇ 0.01).
  • the compounds 20-0.03 mg / kg and the compound 5-0.3 mg / kg were given to rats with good inhibition of incisional pain (P ⁇ 0.01); in addition, the test results of the combined drug group showed Compound 20 has a synergistic effect with Compound 5, and its combined efficacy is superior to the same dose alone.

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Abstract

KOR激动剂与MOR激动剂联合在制备治疗疼痛的药物中的用途。所述KOR激动剂选自如通式（I）所示化合物，所述MOR激动剂选自如通式（II）所示化合物，其中通式（I）、（II）的各取代基与说明书中的定义相同。

Description

KOR激动剂与MOR激动剂联合在制备治疗疼痛的药物中的用途 技术领域
本发明属于医药领域，涉及一种KOR激动剂与MOR激动剂联合在制备缓解和/或治疗疼痛的药物中的用途。
背景技术
疼痛指一种人的官能性或实质性的感受。疼痛的分类较为复杂，按照病因分类主要分为外伤性疼痛，病理性疼痛，代谢性疾病引起的疼痛，神经源性疼痛，组织、器官畸形引起的疼痛，心理性疼痛，复合因素引起的疼痛；按照病程分类主要可分为短暂性疼痛，急性疼痛，慢性疼痛；按照疼痛程度分类可分为微痛，轻痛，甚痛，剧痛；按照解剖部位主要可分为头痛，颌面部痛，项枕部疼痛，颈肩痛，上肢痛，胸部痛，腹痛，腰腿痛；按照疼痛发生部位和引起原因等可分为末梢性疼痛，中枢性疼痛，心理性疼痛。疼痛性疾病的病因复杂，表现的症状各异，患者对疼痛耐受的程度和治疗的反应个体差异很大，目前临床常用治疗疼痛的药物主要有抗炎镇痛药，麻醉性镇痛药，局部麻醉药，抗癫痫药，抗抑郁药物等，虽然用于镇痛的药物较多，但是依然存在着便秘、呼吸抑制、镇静和嗜睡、呕心和呕吐、急性中毒、身体依赖和耐药性、精神依赖等问题。
阿片类药物是临床常用的镇痛药物，尤其是重度疼痛和晚期癌症患者的治疗中占据重要位置，主要通过作用于阿片类受体产生镇痛作用。阿片类受体是G蛋白偶联受体超家族的一员，参与镇痛、抑制肠胃蠕动、呼吸抑制、心肌保护、免疫反应等多种生理活动。一般认为阿片受体可以分为4种亚型：μ阿片受体(MOR)，δ阿片受体(DOR)，κ阿片受体(KOR)和阿片样受体-1(ORL-1)。研究发现，MOR受体与吗啡肽1的结合能力最强，因此临床上使用的阿片类镇痛剂主要为MOR激动剂，有吗啡、曲马多、芬太尼、羟考酮等，但是长期使用该类药物会造成镇痛耐受，依赖和成瘾等严重副作用，目前正在进行III期临床的MOR激动剂有Trevena Inc公司正在开发的TRV-130。WO2017063509公开了一种新的MOR激动剂，其结构如下所示：
Figure PCTCN2018119313-appb-000001
WO2012129495公开了一种结构类似的MOR激动剂。
基于对阿片类受体各亚型结构与功能认识的研究，打破了以前一般认为针对单一阿片受体的高选择性配体会有高活性低毒副作用，现在更多研究发现高选择性激动剂反而会增强副作用。研究认为不同亚型的阿片受体之间存在不同程度的结构或功能上的相互作用，共同参与镇痛等生理活动。Fujita-Hamabe等人的研究证实(Journal of Pharmacy and Pharmacology，2010，62(8)：995-1002)KOR可以抑制MOR的脱敏，加速MOR细胞内循环使表面受体增加，同时还能够降低蛋白激酶C的活性，从而抑制MOR激动剂的镇痛耐受和依赖作用；Cunha TM等人的研究发现([J].Molecular pain，2012，8(1)：10)外周激活KOR可以抑制炎症痛，而且激活外周MOR能够抑制前列腺素E2诱导的进行性痛觉过敏，现有报道激活KOR也能够抑制炎症痛觉过敏，其机制可能通过nNOS/NO信号通路激活PI3Kγ/AKT信号通路；刘荣等报道了KOR激动剂纳布啡与MOR激动剂舒芬太尼用于老年全髋关节置换术后镇痛镇静效果([J].中国药业，2016，25(22)：41-44)，显示联合给药镇痛效果优于单独给药，恶心呕吐、皮肤瘙痒等不良反应也显著降低。
专利申请PCT/CN2017/087328提供一种新的KOR激动剂，在脑组织中分布极低，对中枢神经系统影响较小、对血清钠几乎不影响，不易成瘾，安全性更高，其结构如下所示：
Figure PCTCN2018119313-appb-000002
WO2008060552公开了一种结构类似的KOR激动剂，以及与其他阿片受体激动剂、NSAIDs、抗抑郁药联用用于镇痛的用途；WO2016073443公开了一种类似的KOR 激动剂用于治疗手术疼痛、硬组织疼痛的用途；WO2008057608公开了类似的KOR激动剂与MOR激动剂联用治疗疼痛，并减少MOR激动剂剂量、达到减少不良反应的用途；WO2015065867公开了一种类似的KOR激动剂在MOR激动剂给药后使用，用于减轻MOR激动剂致呕吐作用的用途。综上所述，KOR激动剂与MOR激动剂联用是颇具潜力的用于疼痛的缓解和/或治疗的方法。本发明提供了一种结构新颖的KOR激动剂与MOR激动剂联合在制备缓解和/或治疗疼痛的药物中的用途。
发明内容
本发明要解决的技术问题是提供一种KOR激动剂与MOR激动剂联合在制备缓解和/或治疗疼痛的药物中的用途。
所述KOR激动剂选自如通式(I)所示化合物、或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中通式(I)所示的化合物结构如下：
Figure PCTCN2018119313-appb-000003
其中：
G选自O、-NR 4和-CR 5R 6；
R 1选自氢原子、烷基、烷氧基、卤代烷基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 7、-C(O)R 7、-C(O)OR 7、-S(O) mR 7和-NR 8R 9，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 2选自氢原子、烷基、烷氧基、卤代烷基、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、-OR 7、-C(O)R 7和-C(O)OR 7，其中所述的烷基、卤代烷基、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基和杂芳基烷基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 3选自氢原子、烷基、烷氧基、卤代烷基、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、-OR 7、-C(O)R 7和-C(O)OR 7，其中所述的烷基、卤代烷基、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基和杂芳基烷基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 4选自氢原子、烷基、卤代烷基、环烷基、烷氧基、羟烷基、氨基、羧酸酯基、杂环基、芳基、杂芳基、-OR 7、-C(O)R 7、-C(O)OR 7、-S(O) mR 7、-NR 8R 9和-NHC(O)NR 8R 9，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、羧酸酯基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 5和R 6各自独立地选自氢原子、烷基、烷氧基、羟烷基、羟基、氨基、羧酸酯基、环烷基、杂环基、芳基、杂芳基、-OR 7、-C(O)R 7、-C(O)OR 7、-S(O) mR 7、-NR 8R 9和-NHC(O)NR 8R 9，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、羧酸酯基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 7选自氢原子、烷基、氨基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 8和R 9各自独立地选自氢原子、烷基、烷氧基、羟烷基、羟基、氨基、羧酸酯基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、羧酸酯基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
m为0、1或2。
优选的，所述的KOR激动剂选自如通式(I-A)所示的化合物：
Figure PCTCN2018119313-appb-000004
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，
其中：
G、R 2、R 3如通式(I)所示的化合物中所定义。
进一步优选的，所述KOR激动剂选自如通式(I-B)所示的化合物：
Figure PCTCN2018119313-appb-000005
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，
其中：
G和R 2如通式(I)所示的化合物中所定义。
进一步优选的，所述KOR激动剂选自如通式(I-C)所示的化合物：
Figure PCTCN2018119313-appb-000006
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
其中：
R 2如通式(I)所示的化合物中所定义。
进一步优选的，所述的KOR激动剂或其可药用盐选自：
Figure PCTCN2018119313-appb-000007
Figure PCTCN2018119313-appb-000008
Figure PCTCN2018119313-appb-000009
优选
Figure PCTCN2018119313-appb-000010
上述优选的方案中，所述的MOR激动剂选自如通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐：
Figure PCTCN2018119313-appb-000011
其中：
环A选自环烷基和杂环基；
R选自芳基和杂芳基，其中所述的芳基和杂芳基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 3、-C(O)R 3、-C(O)OR 3、-S(O)mR 3和-NR 4R 5中的一个或多个取代基所取代；
R 1相同或不同，且各自独立地选自氢原子、烷基、烷氧基、卤代烷基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 3、-C(O)R 3、-C(O)OR 3、-S(O)mR 3和-NR 4R 5，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 2相同或不同，且各自独立地选自氢原子、烷基、烷氧基、卤代烷基、卤素、 氨基、硝基、羟基、氰基、氧代基、烯基、环烷基、杂环基、芳基、杂芳基、-OR 3、-C(O)R 3、-C(O)OR 3、-S(O)mR 3和-NR 4R 5，其中所述的烷基、烷氧基、烯基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
或者两个R 2一起形成环烷基或杂环基，其中所述的环烷基或杂环基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 3选自氢原子、烷基、氘代烷基、氨基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
R 4和R 5各自独立地选自氢原子、烷基、烷氧基、羟烷基、羟基、氨基、羧酸酯基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、羧酸酯基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
p、q各自独立地为0、1、2、3或4；且
m为0、1或2。
优选的，所述的MOR激动剂选自如通式(II-B)所示化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
Figure PCTCN2018119313-appb-000012
其中：
R 1、R 2和p如通式(II)所示的化合物中所定义。
进一步优选的，所述的MOR激动剂或其可药用盐选自：
Figure PCTCN2018119313-appb-000013
Figure PCTCN2018119313-appb-000014
Figure PCTCN2018119313-appb-000015
优选
Figure PCTCN2018119313-appb-000016
在本发明另一个优选的方案中，所述的MOR激动剂选自盐酸二氢吗啡酮、吗啡、羟考酮、丁丙诺啡、舒芬太尼、芬太尼、曲芬太尼、瑞芬太尼、他喷他多、NKTR-181、艾沙度林、苯并氢可酮、洛哌丁胺、oliceridine、samidorphan、cebranopadol、他喷他多、美沙酮、曲马朵、TV-46763、氢可酮、dexketoprofen、羟吗啡酮、MH-200、左啡诺、Sedatin、去甲基曲马多、IBCh-07、HS-731、Cyt-1010、曲美布汀3-硫代 氨基甲酰基-苯磺酸盐、thienorphine、trimebutine、TRV-734、TRK-130、氢吗啡酮、氢吗啡酮前药、EU-178、OREX-1038、AIKO-152、TH-030418、CC-408、XE-440、CYX-6、Org-41793、DPI-125、KN-203、JVA-3025、suboxone、AT-121、VRP-26、内吗啡肽、NKTR-196、NKTR-174、NKTR-192、NESS-117-OPB、SYK-524、HS-731、HS-198、Dmt-Tic类似物、内啡肽1衍生物、MMP-2200、SEO-16、TLI-0326、BU-08028、BU-08073、TLI-1186、KIN-3031、Neo-1509、GRT-6006、MCP-201、NE-2、MGM-9、EN-3231、NRP-290、NS-7051、CDS-PM-101、frakefamide、BCH-2687、SS-620、VANH-36、443C81、OHM-329、皮啡肽四肽类似物、sameridine、OHM-3507、SEP-130551、BW-2378W92、sulfazocine、Z-4349、RP-63494、BCH-150、CP-840、CP-0719。
上述方案中，所述的KOR激动剂与MOR激动剂具有缓解和/或治疗疼痛的协同药效作用；优选的，所述的化合物5或其可药用的盐与化合物20或其可药用的盐具有缓解和/或治疗疼痛的协同药效作用。
在本发明中，提供了一种缓解和/或治疗疼痛的办法，包括向患者施用上述KOR激动剂盐和MOR激动剂。
本发明所述的用途，所述的疼痛选自急性疼痛、慢性疼痛，所述的慢性疼痛选自头痛、颌面部痛、项枕部疼痛、颈肩痛、上肢痛、胸部痛、腹痛、腰腿痛、生殖道疼痛、泌尿道疼痛、痛经。
本发明所述的用途，所述的疼痛选自创伤性疼痛，炎性疼痛，缺血性疼痛，代谢性疾病引起的疼痛，神经源性疼痛，组织、器官畸形引起的疼痛，分娩疼痛，恶性增殖疾病引起的疼痛。
本发明所述的用途，所述的创伤性疼痛选自手术引起的疼痛(例如阑尾切除术、开放式结肠直肠手术、疝气修复、前列腺切除术、结肠摘除术、胃切除术、脾切除术、结肠切除术、结肠造口术、骨盆腹镜检查书、输卵管结扎、子宫切除术、输精管切除术或胆囊切除术导致的手术后疼痛)、医疗处理后疼痛(例如结肠镜检查、膀胱镜检查、宫腔镜检查或者宫颈或子宫内膜活组织检查之后的疼痛)、骨折疼痛、烧伤性疼痛、腹部外伤性疼痛、脊柱外伤性疼痛、胸部外伤性疼痛、外伤后头痛。
本发明所述的用途，所述的炎性疼痛选自炎性头痛、组织炎性疼痛(例如类风湿性关节炎、风湿性关节炎、骨关节炎)、器官及腺体炎性疼痛(例如，胃食管 反流性疾病、胰腺炎、急性肾盂肾炎、溃疡性结肠炎、胆囊炎、肝硬化、肝囊肿、肝炎、十二指肠溃疡或胃溃疡、食道炎、胃炎、胃肠炎、结肠炎、憩室炎、肠梗阻、卵巢囊肿、盆腔炎症疾病、溃疡穿孔、腹膜炎、前列腺炎、问质性膀胱炎)、血管炎性疼痛。
本发明所述的用途，所述的缺血性疼痛选自缺血性头痛、肢体缺血性疼痛、组织缺血性疼痛、器官及腺体缺血性疼痛。
本发明所述的用途，所述的代谢性疾病引起的疼痛选自痛风引起的疼痛、糖尿病引起的疼痛。
本发明所述的用途，所述的神经源性疼痛选自幻肢痛、残端痛、灼性神经痛、带状疱疹后遗神经痛、交感神经相关性疼痛、灼热足综合征引发的疼痛、叶酸缺乏性周围神经痛、维生素B12缺乏性周围神经痛、维生素B1缺乏性多发性神经、麻风病性神经痛。
本发明所述的用途，所述的恶性增殖疾病引起的疼痛选自肿瘤引起的疼痛，包括但不限于白血病、淋巴瘤、骨髓瘤、乳腺癌、肺癌、食管癌、胃癌、大肠癌、肝癌、胰腺癌、头颈部癌、肾癌、膀胱癌、前列腺癌、卵巢癌、子宫内膜癌、子宫颈癌、骨肉瘤、软组织肉瘤、黑色素瘤、脑瘤引起的疼痛。
本发明所述的用途，所述的疼痛选自中至重度疼痛，优选的，所述的中至重度疼痛选自创伤性疼痛、分娩疼痛、肿瘤引起的疼痛、炎性疼痛。
本发明所述的用途，所述的中至重度疼痛对非阿片类镇痛药物、弱阿片类镇痛药物不适用和/或不敏感。
本发明提供上述KOR激动剂联合上述MOR激动剂作为缓解和/或治疗疼痛的药物。
本发明所述的用途，其中，所述的KOR激动剂与MOR激动剂重量比例范围为0.01-1000，选自1000/1、750/1、500/1、400/1、250/1、200/1、100/1、100/3、90/1、80/1、75/1、70/1、60/1、50/1、40/1、30/1、30/7、20/1、20/7、20/3、20/9、25/1、25/2、25/3、25/4、25/6、25/7、25/8、25/9、25/18、15/1、15/2、15/4、18/1、18/5、18/7、14/1、14/3、14/5、14/9、12/1、12/5、12/7、10/1、10/3、10/7、10/9、9/1、9/2、9/4、8/1、8/3、8/5、7/1、7/2、7/3、7/4、7/5、7/6、6/1、6/5、5/1、5/2、5/3、5/4、4/1、4/3、3/1、3/2、2/1、1/1、1/2、1/3、1/5、1/10、1/20、1/25、1/30、1/50，优选自1/1、5/3、2/1、15/7、5/2、3/1、10/3、15/4、4/1、9/2、5/1、6/1、25/4、 20/3、15/2、8/1、9/1、10/1、12/1、25/2、15/1、20/1、25/1、30/1、40/1、50/1、60/1、70/1、75/1、80/1、90/1、100/3、100/1、200/1、250/1。
本发明所述的用途，其中，所述的KOR激动剂给药剂量为0.001-250mg，优选自0.001mg、0.002mg、0.003mg、0.004mg、0.005mg、0.006mg、0.007mg、0.008mg、0.009mg、0.01mg、0.02mg、0.03mg、0.05mg、0.15mg、0.2mg、0.25mg、0.3mg、0.4mg、0.5mg、0.6mg、0.75mg、0.8mg、0.9mg、1mg、1.25mg、1.5mg、1.75mg、2mg、2.25mg、2.5mg、2.75mg、3mg、3.25mg、3.5mg、3.75mg、4mg、4.5mg、5mg、6mg、7mg、7.5mg、8mg、9mg、10mg、12.5mg、15mg、17.5mg、18mg、20mg、25mg、30mg、40mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、250mg；所述的MOR激动剂给药剂量为0.001-50mg，优选自0.001mg、0.002mg、0.003mg、0.004mg、0.005mg、0.006mg、0.007mg、0.008mg、0.009mg、0.01mg、0.02mg、0.025mg、0.03mg、0.04mg、0.05mg、0.06mg、0.07mg、0.075mg、0.15mg、0.2mg、0.25mg、0.3mg、0.4mg、0.5mg、0.6mg、0.7mg、0.75mg、0.8mg、0.9mg、1mg、1.2mg、1.25mg、1.5mg、1.75mg、2mg、2.2mg、2.25mg、2.5mg、2.75mg、3mg、3.25mg、3.5mg、3.75mg、4mg、4.5mg、5mg、6mg、7mg、7.5mg、8mg、9mg、10mg、12.5mg、15mg、17.5mg、20mg、25mg、30mg、40mg、50mg。
本发明所述的用途，其中，进一步优选的，所述KOR激动剂选自化合物5或其可药用盐，给药剂量为0.001-20mg，优选自0.005mg、0.01mg、0.03mg、0.05mg、0.1mg、0.15mg、0.2mg、0.25mg、0.3mg、0.4mg、0.5mg、0.6mg、0.75mg、0.8mg、0.9mg、1mg、1.25mg、1.5mg、1.75mg、2mg、2.25mg、2.5mg、2.75mg、3mg、3.25mg、3.5mg、3.75mg、4mg、4.5mg、5mg、6mg、7mg、7.5mg、8mg、9mg、10mg、12.5mg、15mg、17.5mg、18mg、20mg。
本发明所述的用途，其中，进一步优选的，所述MOR激动剂选自化合物20或其可药用盐，给药剂量为0.001-20mg，优选自0.001mg、0.002mg、0.003mg、0.004mg、0.005mg、0.006mg、0.007mg、0.008mg、0.009mg、0.01mg、0.02mg、0.025mg、0.03mg、0.04mg、0.05mg、0.06mg、0.07mg、0.075mg、0.15mg、0.2mg、0.25mg、0.3mg、0.4mg、0.5mg、0.6mg、0.7mg、0.75mg、0.8mg、0.9mg、1mg、1.2mg、1.25mg、1.5mg、1.75mg、2mg、2.2mg、2.25mg、2.5mg、2.75mg、3mg、3.25mg、3.5mg、3.75mg、4mg、4.5mg、5mg、6mg、7mg、7.5mg、8mg、9mg、10mg、12.5mg、15mg、17.5mg、20mg。
本发明所述的用途，其中，所述的KOR激动剂给药剂量为0.01-500μg/kg，优选自0.01μg/kg、0.05μg/kg、0.1μg/kg、0.2μg/kg、0.25μg/kg、0.3μg/kg、0.4μg/kg、0.5μg/kg、0.6μg/kg、0.7μg/kg、0.8μg/kg、0.9μg/kg、1μg/kg、2μg/kg、2.5μg/kg、3μg/kg、4μg/kg、5μg/kg、8μg/kg、10μg/kg、15μg/kg、20μg/kg、24μg/kg、25μg/kg、30μg/kg、40μg/kg、50μg/kg、60μg/kg、70μg/kg、75μg/kg、80μg/kg、90μg/kg、100μg/kg、200μg/kg、250μg/kg、300μg/kg、400μg/kg、500μg/kg；所述的MOR激动剂给药剂量为0.001-500μg/kg，优选自0.003μg/kg、0.005μg/kg、0.01μg/kg、0.05μg/kg、0.1μg/kg、0.2μg/kg、0.25μg/kg、0.3μg/kg、0.4μg/kg、0.5μg/kg、0.6μg/kg、0.7μg/kg、0.8μg/kg、0.9μg/kg、1μg/kg、2μg/kg、2.5μg/kg、3μg/kg、4μg/kg、5μg/kg、8μg/kg、10μg/kg、15μg/kg、20μg/kg、24μg/kg、25μg/kg、30μg/kg、40μg/kg、50μg/kg、60μg/kg、70μg/kg、75μg/kg、80μg/kg、90μg/kg、100μg/kg、200μg/kg、250μg/kg 300μg/kg、400μg/kg、500μg/kg。
本发明所述的用途，所述的KOR激动剂选自化合物5或其可药用盐，给药剂量为0.01-150μg/kg，优选自0.01μg/kg、0.05μg/kg、0.1μg/kg、0.2μg/kg、0.25μg/kg、0.3μg/kg、0.4μg/kg、0.5μg/kg、0.6μg/kg、0.7μg/kg、0.8μg/kg、0.9μg/kg、1μg/kg、2μg/kg、2.5μg/kg、3μg/kg、4μg/kg、5μg/kg、8μg/kg、10μg/kg、15μg/kg、20μg/kg、24μg/kg、25μg/kg、40μg/kg、50μg/kg、75μg/kg、100μg/kg。
本发明所述的用途，所述的MOR激动剂选自化合物20或其可药用盐，给药剂量为0.001-150μg/kg，优选自0.003μg/kg、0.005μg/kg、0.01μg/kg、0.05μg/kg、0.1μg/kg、0.2μg/kg、0.25μg/kg、0.3μg/kg、0.4μg/kg、0.5μg/kg、0.6μg/kg、0.7μg/kg、0.8μg/kg、0.9μg/kg、1μg/kg、2μg/kg、2.5μg/kg、3μg/kg、4μg/kg、5μg/kg、8μg/kg、10μg/kg、15μg/kg、20μg/kg、24μg/kg、25μg/kg、30μg/kg、40μg/kg、50μg/kg、60μg/kg、70μg/kg、75μg/kg、80μg/kg、90μg/kg、100μg/kg。
本发明所述联合的给药方式选自：同时给药、独立地配制并共给药或独立地配制并相继给药。
本发明进一步涉及一种MOR激动剂与KOR激动剂联合在制备缓解和/或治疗疼痛中的用途，其中，所述KOR激动剂首次给药剂量为维持剂量的0.05-50倍，所述MOR激动剂首次给药剂量为维持剂量的1-50倍。
本发明进一步涉及一种KOR激动剂与MOR激动剂联合在制备缓解和/或治疗疼痛中的用途，其中KOR激动剂的给药频次为一日一次、一日二次、一日三次、 一周一次、二周一次、三周一次、一月一次，MOR激动剂的给药频次为一日一次、一日二次、一日三次、一周一次、二周一次、三周一次、一月一次。
在上述方案中，所述联合还包含任选包含第三组分，所述第三组分选自所述第三组分选自阿片类药物、糖皮质激素、非甾体抗炎药、局部麻醉药、抗抑郁药、钙离子通道拮抗剂、抗惊厥药物、肾上腺β受体阻断剂、麻醉药以及麻醉诱导剂。
本发明还涉及一种KOR激动剂与MOR激动剂的药物组合物，包含任选的一种或多种药用载体、赋形剂和/或稀释剂。所述药物组合物可以制成药学上可接受的任一剂型。例如，包含活性成分为KOR激动剂、MOR激动剂的药物制剂，可以配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。
本发明所述的KOR激动剂与MOR激动剂药物组合物，可以单独给药，或者与一种或多种治疗剂联合使用。
本发明所述的KOR激动剂与MOR激动剂在制备制备缓解和/或治疗疼痛的药物中的用途，所述KOR激动剂和MOR激动剂可通过口服、胃肠外给药(包括但不限于皮下注射、静脉注射、腹腔注射)形式给药。
待组合的各成分(例如，KOR激动剂与MOR激动剂，KOR激动剂与MOR激动剂与其他任意第三组分药物)可同时给药或依次顺序地分开用药。此外，待组合的各成分还可以以同一制剂形式或以分开的不同制剂的形式联合给药。
本发明中，所谓“联合或联用”是一种给药方式，其包括两种或两种以上药物先后，或同时给药的各种情况，此处所谓“同时”是指在同一给药周期给予KOR激动剂与MOR激动剂，或KOR激动剂与MOR激动剂与其他任意第三组分药物，例如一天内、三天内、一周内、二周内、一个月内给予两种或两种以上药物。所谓“先后或相继”给药，则包括在不同给药周期内分别给予KOR激动剂与MOR激动剂，或KOR激动剂与MOR激动剂与其他任意第三组分药物的情况。这些给药方式，均属于本发明所述的联合给药。
本发明所述的“有效量”包含足以改善或预防医字病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
发明详述
在本申请的说明书和权利要求书中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。然而，为了更好地理解本发明，下面提供了部分相关术语的定义和解释。另外，当本申请所提供的术语的定义和解释与本领域技术人员所通常理解的含义不一致时，以本申请所提供的术语的定义和解释为准。
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“羧酸基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基、环烷基如上所定义。
“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中任意一种或几种。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链 基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2，3-二甲基戊基、2，4-二甲基戊基、2，2-二甲基戊基、3，3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2，3-二甲基己基、2，4-二甲基己基、2，5-二甲基己基、2，2-二甲基己基、3，3-二甲基己基、4，4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2，2-二乙基戊基、正癸基、3，3-二乙基己基、2，2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子，最优选包含5至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
Figure PCTCN2018119313-appb-000017
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2018119313-appb-000018
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2018119313-appb-000019
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等；优选苯基并环戊基、四氢萘基。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；最优选包含3至8个环原子，其中1～3个是杂原子；最优选包含5至6个环原子，其中1～2或1～3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等，优选四氢吡喃基、哌啶基、吡咯烷基。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂 环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2018119313-appb-000020
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2018119313-appb-000021
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2018119313-appb-000022
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2018119313-appb-000023
等。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，更优选5至6元，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2018119313-appb-000024
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为咪唑基、吡唑基或嘧啶基、噻唑基；更优选吡唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2018119313-appb-000025
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基如上所定义。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“氨基保护基”指适用于保护(阻止)氨基发生化学反应的基团，但它在分子其他部位需要进行的化学反应结束后容易被脱除。这些基团的典型代表有未取代的或取代的酰基、未取代的或取代的烯丙基、芳基、芳烷氧基甲基、芳烷基或与氮原子一起形成杂环基以及盐。非限制性实施例包含叔丁氧羰基(Boc)、苄氧基羰基、异丁氧基羰基、芴甲氧羰基(Fmoc)、苯甲酰基、取代的苯甲酰基、丁酰基、乙酰基、三氟乙酰基、邻本二甲酰亚胺基(Pht)、琥珀酰亚氨基、马来酰亚氨基、苄基、烯丙氧羰基和对甲氧基苄基等。这些基团可任选地被选自卤素、烷基、烷氧基、羟基、硝基、酰基氨基、酰基等取代的苄基、邻甲基苄基、三苯甲基和二苯甲基的一个或多个取代基所取代。所述氨基保护基优选为叔丁氧羰基和芴甲氧羰基(Fmoc)。
术语“协同药效作用”包含药效相加作用、药效增强作用、药效增敏作用，本发明的“协同药效作用”包括但不限于减少单独使用KOR激动剂、MOR激动剂时耐受现象，减少单独使用KOR激动剂、MOR激动剂时的剂量，减少KOR激动剂、MOR激动剂单独使用时的不良反应，增强单独使用相同剂量的KOR激动剂和/或相同剂量的MOR激动剂的缓解和/或治疗疼痛的效果。
术语“急性疼痛”指由皮肤、深部身体结构或器官的损伤和/或疾病产生的有害刺激引起的疼痛，或由不产生实际组织损伤的肌肉或器官的异常功能引起的短时间疼痛。
术语“慢性疼痛”指持续超出急性疾病通常的病程或损伤治愈的合理时间，或 与引起持续疼痛的慢性病理过程有关，或疼痛以一定间隔复发数天、数周、数月、数年；此外慢性疼痛还包括如果在应该已经达到治愈后或超过通常的治疗过程后仍存在疼痛。
术语“炎性疼痛”指局部急性炎症或是慢性炎症刺激神经所致的疼痛。
术语“缺血性疼痛”指肢体或脏器血供不佳产生的疼痛。
术语“神经源性疼痛”指周围或中枢神经系统原发性或继发性损害或功能障碍或短暂紊乱引起的疼痛。
术语“恶性增殖疾病引起的疼痛”指体细胞恶性增殖导致的肿瘤、癌症引起的疼痛，病毒在人体器官、腺体、血液系统、皮肤恶性增殖导致病变引起的疼痛，细菌在人体器官、腺体、血液系统、皮肤恶性增殖导致病变引起的疼痛。
术语“组织”指一些形态相同或类似、机能相同的细胞群，包括但不限于上皮组织、结缔组织、肌肉组织、神经组织，例如软骨组织、骨组织、骨骼肌、心肌、平滑肌。
术语“中至重度疼痛”指需用止痛药物才能缓解的剧烈疼痛、影响疾病治疗和/或生命体征、影响康复的持续性疼痛。
术语“首次剂量”指消除临床症状且需进行连续用药时，第一次所给予的剂量。
术语“维持剂量”指在临床症状得到控制或缓解后，为巩固和维持疗效的用量。
术语“按疼痛需求给药”指按哺乳动物自我对疼痛感知程度的大小，以缓解和/或治疗疼痛的目的进行给药。
术语“手术”所指含义并不局限于传统手术定义，所述手术包含按照卫生部手术分级分类目录(2011年版)收载内容，本发明所述的手术广泛的包含至少在皮肤和粘膜具有一个切口的外科手术，非传统定义的内科手术操作(例如涉及诊断及治疗的介入操作)。
术语“手术引起的疼痛”指机体的组织受到手术伤害损伤或刺激后的一种疼痛反应，涵盖围手术期间的术前、术中、术后引起的疼痛，包含但不限于外科手术后疼痛(例如阑尾切除术、开放式结肠直肠手术、疝气修复、前列腺切除术、结肠摘除术、胃切除术、脾切除术、结肠切除术、结肠造口术、骨盆腹镜检查术、输卵管结扎、子宫切除术、输精管切除术或胆囊切除术导致的手术后疼痛)、医疗处理后疼痛(例如结肠镜检查、膀胱镜检查、宫腔镜检查或者宫颈或子宫内膜活组织检查之后的疼痛)。
术语“肿瘤引起的疼痛”指肿瘤直接引起的疼痛，肿瘤治疗引起的疼痛，肿瘤间接引起的疼痛。
附图说明
图1为本发明的KOR激动剂与MOR激动剂(化合物5与化合物20)联用在切口疼痛试验中对大鼠机械刺激缩抓阈值的影响。
具体实施方式
以下提供本发明的组合物在缓解和/或治疗疼痛用途中的示例性试验方案，以显示本发明组合物的有利活性或有益技术效果。但是应当理解，下述试验方案仅仅是对本发明内容的示例，而不是对本发明范围的限制。本领域技术人员在本说明书的教导下，能够对本发明的技术方案进行适当的修改或改变，而不背离本发明的精神和范围。
实施例1、化合物5的制备
化合物5是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商：Thermo，型号：Finnigan LCQ advantage MAX)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
手性制备柱层析使用Prep Star SD-1(Varian Instruments Inc.)或SFC-multigram(Berger Instruments Inc.)
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：石油醚和乙酸乙酯体系，D：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：二氯甲烷和丙酮体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例中的高效液相色谱法所用的高压液相色谱仪为(Gilson-281)，色谱柱为Shimadzu的Shim-pack PREP-ODS，所使用的流动相为三氟醋酸缓冲体系，即水(含0.05％三氟醋酸盐)-乙腈。
实施例中的各个以三氟醋酸盐形式存在的化合物可以采用以下通用方法得到游离态：将其三氟醋酸盐用合适的溶剂(如甲醇，乙醇，四氢呋喃，丙酮等)溶解，加入弱碱(如碳酸氢钠，碳酸钠，碳酸钾等)调节pH值至中性，减压浓缩，纯化残余物得到游离态。
Figure PCTCN2018119313-appb-000026
4-氨基-1-((2R，5R，8R，14R)-2-(4-氨基丁基)-8-苄基-5-异丁基-4，7，10-三氧代-14-苯基-3，6，9，12-四氮杂十五-1-酰基)哌啶-4-羧酸
Figure PCTCN2018119313-appb-000027
第一步
4-苄基1-叔丁基4-(((苄氧基)羰基)氨基)哌啶-1，4-二羧酸1b
将4-(((苄氧基)羰基)氨基)-1-(叔丁氧羰基)哌啶-4-羧酸1a(1.2g，0.0032mol，采用公知的方法“Bioorganic Medicinal Chemistry Letters，2007，7(9)，2448-2451”制备而得)，苄溴(0.65g，0.0038mol)，碳酸铯(2.1g，0.0064mol)溶于20mL N，N-二甲基甲酰胺中，室温搅拌反应12小时。将反应液倒入水中，用乙酸乙酯萃取(30mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩后用薄层色谱法以展开剂体系B纯化所得残余物，得到标题产物1b(800mg，无色粘稠状物)，产率：53％。
第二步
4-(((苄氧基)羰基)氨基)哌啶-4-羧酸苄酯盐酸盐1c
将1b(800mg，1.71mmol)溶于2mL二氯甲烷中，加入2mL 4M氯化氢的1，4-二氧六环溶液，室温搅拌反应4小时。反应液减压浓缩，得到粗品标题产物1c(800mg，浅黄色粘稠状物)，产品不经纯化直接进行下一步反应。
第三步
(R)-1-(2-((((9H-芴-9-基)甲氧基)羰基)氨基)-6-((叔丁氧羰基)氨基)己酰基)-4-(((苄氧基)羰基)氨基)哌啶-4-羧酸苄酯1e
将粗品1c(800mg，1.97mmol)和(R)-2-((((9H-芴-9-基)甲氧基)羰基)氨基)-6-((叔丁氧羰基)氨基)己酸1d(926mg，1.97mmol，采用公知的方法“ChemMedChem，2015，10(7)，1232-1239”制备而得)溶于20mL N，N-二甲基甲酰胺中，加入2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(1.12g，3.0mmol)和N，N-二异丙基乙胺(0.7mL，3.94mmol)，室温搅拌反应12小时。反应液倒入2N柠檬酸溶液中，用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和碳酸氢钠溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物1e(1.6g，黄色粘稠状物)，产品不经纯化直接进行下一步反应。
第四步
(R)-1-(2-氨基-6-((叔丁氧羰基)氨基)己酰基)-4-(((苄氧基)羰基)氨基)哌啶-4-羧酸苄酯1f
将粗品1e(1.6g，0.002mol)溶于10mL二氯甲烷中，加入10mL哌啶，室温搅拌反应2小时。反应液减压浓缩后用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物1f(900mg，浅黄色固体)，产率：77％。
第五步
(R)-2-((R)-2-(2-氯乙酰胺基)-3-苯基丙酰胺基)-4-甲基戊酸苄酯1i
将(R)-2-((R)-2-(2-氨基-3-苯基丙酰胺基)-4-甲基戊酸苄酯1g(500mg，1.36mmol，采用专利申请“US20110212882A1”公开的方法制备而得)和三乙胺(275mg，2.72mmol)溶于10mL二氯甲烷中，滴加入氯乙酰氯(230mg，2mmol)，室温搅拌反应12小时。反应液倒入水中，用饱和氯化铵溶液洗涤，有机相用无水硫酸钠干燥， 过滤，滤液减压浓缩，得到粗品标题产物1i(500mg，黄色粘稠状物)，产品不经纯化直接进行下一步反应。
第六步
(R)-4-甲基-2-((R)-3-苯基-2-(2-(((R)-2-苯基丙基)氨基)乙酰胺基)丙酰胺基)戊酸苄酯5b
将1i(500mg，1.12mmol)和(R)-2-苯基丙-1-胺5a(228mg，1.68mmol，采用公知的方法“Angewandte Chemie，International Edition，2003，42(39)，4793-4795”制备而得)溶于10mL N，N-二甲基甲酰胺中，加入碘化钾(372mg，2.24mmol)和碳酸钾(309mg，2.24mmol)，升温至60℃搅拌反应12小时。反应液冷却至室温，加入水，用二氯甲烷萃取(30mL×3)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物5b(600mg，棕黄色粘稠状物)，产品不经纯化直接进行下一步反应。
第七步
(9R，12R)-9-苄基-12-异丁基-2，2-二甲基-4，7，10-三氧代-5-((R)-2-苯基丙基)-3-氧杂-5，8，11-三氮杂十三-13-酸苄酯5c
将粗品5b(600mg，1.1mmol)溶于20mL二氯甲烷中，加入二碳酸二叔丁酯(361mg，1.66mmol)和三乙胺(222mg，2.2mmol)，室温搅拌反应12小时。反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物5c(580mg，浅黄色粘稠状物)，产率：82％。
第八步
(9R，12R)-9-苄基-12-异丁基-2，2-二甲基-4，7，10-三氧代-5-((R)-2-苯基丙基)-3-氧杂-5，8，11-三氮杂十三-13-甲酸5d
将5c(580mg，0.9mmol)溶于10mL甲醇中，加入钯碳(60mg，催化量)，加毕，氢气置换三次，室温搅拌反应12小时。反应液用硅藻土过滤，滤液减压浓缩，得到粗品标题产物5d(500mg，浅黄色粘稠状物)，产品不经纯化直接进行下一步反应。
第九步
1-((9R，12R，15R)-9-苄基-15-(4-((叔丁氧羰基)氨基)丁基)-12-异丁基-2，2-二甲基-4，7，10，13-四氧代-5-((R)-2-苯基丙基)-3-氧杂-5，8，11，14-四氮杂十六-16-酰基)-4-(((苄氧基)羰基)氨基)哌啶-4-羧酸苄酯5e
将粗品5d(365mg，0.66mmol)，1f(393mg，0.66mmol)，2-(7-偶氮苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(376mg，0.99mmol)和N，N-二异丙基乙胺(0.16mL，0.99mmol)溶于10mL N，N-二甲基甲酰胺中，室温搅拌反应2小时。反应液减压浓缩，用薄层色谱法以展开剂体系A纯化所得残余物，得到标题产物5e(170mg，浅黄色固体)，产率：23％。
第十步
4-氨基-1-((9R，12R，15R)-9-苄基-15-(4-((叔丁氧羰基)氨基)丁基)-12-异丁基-2，2-二甲基-4，7，10，13-四氧代-5-((R)-2-苯基丙基)-3-氧杂-5，8，11，14-四氮杂十六-16-酰基)哌啶-4-羧酸5f
将5e(80mg，0.0706mmol)溶于10mL甲醇中，加入钯碳(10mg，催化量)，加毕，氢气置换三次，室温搅拌反应12小时。反应液用硅藻土过滤，滤液减压浓缩，得到粗品标题产物5f(60mg，白色固体)，产品不经纯化直接进行下一步反应。
第十一步
4-氨基-1-((2R，5R，8R，14R)-2-(4-氨基丁基)-8-苄基-5-异丁基-4，7，10-三氧代-14-苯基-3，6，9，12-四氮杂十五-1-酰基)哌啶-4-羧酸三氟醋酸盐5g
将粗品5f(60mg，0.066mmol)溶于2mL二氯甲烷中，加入1mL 4M氯化氢的1，4-二氧六环溶液，室温搅拌反应2小时。反应液减压浓缩后用高效液相色谱法纯化所得残余物，得到标题产物5g(30mg，白色固体)。
MS m/z(ESI)：708.6[M+1]
第十二步
4-氨基-1-((2R，5R，8R，14R)-2-(4-氨基丁基)-8-苄基-5-异丁基-4，7，10-三氧代-14-苯基-3，6，9，12-四氮杂十五-1-酰基)哌啶-4-羧酸5
将5g(30mg，0.028mmol)用5mL甲醇/水混合溶剂(V∶V＝10∶1)溶解，加入碳酸氢钠固体(10mg)搅拌30分钟，调节pH值至7左右，减压浓缩，所得残余物中加入10mL二氯甲烷，搅拌30分钟，过滤，滤饼用10mL二氯甲烷淋洗，滤液减压浓缩，得到标题产物5(17mg，白色固体)。
MS m/z(ESI)：708.6[M+1]
1H NMR(400MHz，CD 3OD)：δ7.33-7.19(m，10H)，4.90-4.84(m，2H)，4.64-4.61(m，2H)，4.42-4.39(m，1H)，3.86-3.74(m，5H)，3.20-3.12(m，4H)，2.94-2.84(m，4H)，2.61-2.54(m，2H)，2.20-2.15(m，3H)，1.79-1.70(m，2H)，1.68-1.60(m，8H)，1.45-1.40(m，3H)，1.30-1.20(m，5H)，0.99-0.76(m，6H).
实施例2、化合物20的制备
化合物20在制备过程中所需仪器、设备、物料如实施例1所示。
Figure PCTCN2018119313-appb-000028
(1S，4S)-4-乙氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1，2，3，4-四氢萘-1-胺
Figure PCTCN2018119313-appb-000029
第一步
(S)-1，2，3，4-四氢萘-1-氨基甲酸叔丁酯11a
将(S)-1，2，3，4-四氢-1-萘胺10a(3g，20.41mmol，采用“Angewandte Chemie-International Edition，45(28)，4641-4644，2006”公开的方法制备而得)溶解于100mL二氯甲烷中，加入三乙胺(5.7mL，40.82mmol)，加入二叔丁基二碳酸酯(4.9g，22.45mmol)，搅拌反应12小时。反应液依次用水(100mL)，饱和碳酸氢钠溶液洗涤(100mL)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到粗品标题产物11a(5.6g，淡黄色油状物)，产物不经纯化直接进行下步反应。
MS m/z(ESI)：248.3[M+1]
第二步
(S)-4-羰基-1，2，3，4-四氢萘-1-氨基甲酸叔丁酯11b
将粗品(S)-1，2，3，4-四氢萘-1-氨基甲酸叔丁酯11a(5.6g，20.41mmol)溶解于90mL丙酮和水(V/V＝2∶1)混合溶剂中，加入硫酸镁(5.5g，45.66mmol)，搅拌下缓慢加入高锰酸钾(7.22g，45.66mmol)，搅拌反应12小时。反应液减压浓缩，用硅胶柱色谱法以正己烷和乙酸乙酯体系纯化所得残余物，得到标题产物11b(3.1g，类白色固体)，产率：52％。
MS m/z(ESI)：262.3[M+1]
第三步
(1S，4S)-4-羟基-1，2，3，4-四氢萘-1-氨基甲酸叔丁酯14a
将(S)-4-羰基-1，2，3，4-四氢萘-1-氨基甲酸叔丁酯11b(100mg，0.883mmol)溶解于5mL甲苯中，降温至0℃，加入(R)-2-甲基-CBS-恶唑硼烷(0.1ml，0.076mmol)，搅拌5分钟，加入硼烷甲基硫醚(0.88ml，0.76mmol)，搅拌反应2小时。加入50ml饱和氯化钠溶液淬灭反应，用乙酸乙酯萃取(30mL×3)，合并有机相，有机相用饱 和氯化钠溶液洗涤(30mL×3)，无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法以二氯甲烷和甲醇体系纯化所得残余物，得到标题产物14a(60mg，白色固体)，产率60％。
MS m/z(ESI)：208.3[M-55]
第二步
(1S，4S)-4-乙氧基-1，2，3，4-四氢萘-1-氨基甲酸叔丁酯19a
将粗品(1S)-4-羟基-1，2，3，4-四氢萘-1-氨基甲酸叔丁酯14a(850mg，3.23mmol)，氧化银(76mg，0.33mmol)和碘乙烷(1.3mL，16.15mmol)溶解于30mL二氯甲烷中，搅拌反应48小时。过滤，滤液减压浓缩，得到粗品标题产物19a(800mg，黄色油状物)，产物不经纯化直接进行下步反应。
MS m/z(ESI)：236.1[M-55]
第三步
(1S，4S)-4-乙氧基-1，2，3，4-四氢萘-1-胺19b
将粗品化合物19a(698mg，2.4mmol)溶解于4mL二氯甲烷中，加入8mL4M氯化氢的1，4-二氧六环溶液，搅拌反应2小时。反应液减压浓缩，乙酸乙酯打浆(30mL)，过滤，滤饼溶于20mL二氯甲烷和甲醇(V∶V＝5∶1)的混合溶剂中，用饱和碳酸氢钠溶液调节反应液pH为7～8，反应液减压浓缩，用二氯甲烷和甲醇(V∶V＝5∶1)的混合溶剂洗涤(30mL×2)，过滤，滤液减压浓缩，得到粗品标题产物19b(310mg，黄色液体)，产物不经纯化直接进行下步反应。
MS m/z(ESI)：191.1[M+1]
第四步
(1S，4S)-4-乙氧基-N-(2-((R)-9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙基)-1，2，3，4-四氢萘-1-胺20
将(R)-2-(9-(吡啶-2-基)-6-氧杂螺[4.5]癸烷-9-基)乙醛5a(500mg，1.85mmol，采用专利申请“WO2012129495”公开的方法制备而得)，粗品化合物19b(310mg，1.85mmol)溶解于30mL二氯乙烷中，搅拌反应40分钟，加入三乙酰氧基硼氢化钠(980mg，4.63mmol)，搅拌反应2小时。依次用饱和碳酸氢钠溶液(30mL×3)，用饱和氯化钠溶液洗涤(30mL×3)，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，用薄层色谱法以二氯甲烷和甲醇体系纯化所得残余物，得到标题产物20(280mg，黄色粘稠固体)，产率：35％。
MS m/z(ESI)：435.3[M+1]
1H NMR(400MHz，CDCl 3)δ9.74(d，1H)，9.58(d，1H)，8.94(d，1H)，8.37(d，1H)，7.94(d，1H)，7.67(d，1H)，7.52(d，1H)，7.47(t，1H)，4.46-4.49(m，1H)，4.30-4.33(m，1H)，3.84-3.87(m，1H)，3.66-3.70(m，2H)，3.53-3.56(m，2H)，2.82-2.85(d，2H)，2.67(s，2H)，2.39-2.41(m，4H)，2.30-2.33(m，4H)，1.85(s，2H)，1.48-1.52(m，6H)，1.27(m，3H).
实施例3、本发明KOR激动剂与MOR激动剂联用对大鼠切口疼痛治疗的效 果
供试品
化合物5(按照实施例1所述方法制备)、化合物20(按照实施例2所述方法制备)，药物剂量均按碱基计算。
试验动物
实验用Wistar雄性大鼠，购自上海斯莱克实验动物有限公司，购入时140-160g/只，5只/笼饲养，12/12小时光/暗周期调节，温度23±1℃恒温，湿度50～60％，自由进食进水。动物购进后，进行适应性饲养3天以上后开始实验。
试验仪器
电子触觉测量仪(电子Von Frey)：UGO BASILE，型号38450。
供试品溶液配制
化合物5、化合物20均采用生理盐水配制。
实验方法
大鼠按照体重随机分组，分为空白对照组(n＝10)，模型组(n＝10)及给药组(n＝50)。其中，给药组分为化合物20-0.03mg/kg(n＝10)，化合物5-0.3mg/kg组(n＝10)，化合物5-0.1mg/kg+化合物20-0.03mg/kg组(n＝10)，化合物5-0.3mg/kg+化合物20-0.03mg/kg组(n＝10)，化合物5-1mg/kg+化合物20-0.03mg/kg组(n＝10)。其中模型组和给药组进行切口手术。手术时用异氟烷麻醉后，用10号手术刀片在左后爪足底中部切开1cm长的切口，通过皮肤和筋膜，用3-0无菌丝手术缝合线缝合皮肤。受伤部位用抗生素软膏和碘伏消毒，动物放回原处过夜恢复。24h后尾静脉注射药物，空白对照组和模型组生理盐水注射15min后再次注射生理盐水。单独给予化合物20组静脉注射相应剂量的化合物20和用于配制化合物5的空白溶剂；单独给予化合物5组静脉注射相应剂量的化合物5和用于配制化合物20的空白溶剂；联用组先给予相应剂量的化合物5进行静脉注射，15min后再给予相应剂量的化合物20进行静脉注射。各组注射30min后采用电子触觉测量仪测定机械疼痛阈值，评价药物对手术切口疼痛的镇痛作用及其作用强度。
数据表达和统计学处理
实验数据表示为平均数(Mean)±标准差(S.D.)。采用excel软件t检验进行统计比较。将模型组与空白对照组数据进行分析比较，是否存在显著数理统计意义，#P＜0.05表示模型组与空白对照组比较具有显著性差异，##P＜0.01表示模型 组与空白对照组比较具有高度显著性差异。ΔP＜0.05表示受试药组与模型组比较具有显著性差异，ΔΔP＜0.01表示受试药组与模型组比较具有高度显著性差异。*P＜0.05表示药物联用组与单用组比较具有显著性差异，**P＜0.01表示药物联用组与单用组比较具有高度显著性差异。
实验结果：
见附图1
实验结论：
实验结果显示(附图1，mpk为mg/kg缩写)，正常对照组大鼠触痛阈值为14.48g，模型组触痛阈值为8.91g，与正常组比较，模型组触痛阈值明显下降(P＜0.05)；给药后与模型组比较，化合物20-0.03mg/kg组能明显增加大鼠的触痛阈值(P＜0.01)，达到14.46g，增加幅度为62.3％；化合物5-0.3mg/kg组能明显增加大鼠的触痛阈值(P＜0.01)，达到17.92g，增加幅度为101.1％。
与模型组比较，化合物20-0.03mg/kg分别与化合物5-0.1mg/kg、化合物5-0.3mg/kg、化合物5-1mg/kg联用均能明显增加大鼠的触痛阈值，分别达到17.96g、22.29g和33.46，增加幅度分别为101.6％、150.1％和275.5％(P＜0.01)，体现出KOR激动剂的量效关系。三个剂量联用药效均优于单用化合物20-0.03mg/kg，其中与化合物5-0.3mg/kg、化合物5-1mg/kg联用具有统计学差异(P＜0.01)。
与单用化合物5-0.3mg/kg相比，化合物20-0.03mg/kg+化合物5-0.1mg/kg与其痛阈增加幅度相当；化合物20-0.03mg/kg联用化合物5-0.3mg/kg、化合物5-1mg/kg药效均优于单用化合物5-0.3mg/kg，其中联用化合物5-1mg/kg具有统计学差异(p＜0.01)。
综上所述，化合物20-0.03mg/kg和化合物5-0.3mg/kg单独给予大鼠均具有较好的抑制切口疼痛作用(P＜0.01)；此外，联合给药组的试验结果表现出化合物20与化合物5具有协同作用，其联用药效均优于相同剂量的单独使用。

Claims (14)

  1. 一种κ阿片受体(KOR)激动剂与μ阿片受体(MOR)激动剂联合在制备缓解和/或治疗疼痛的药物中的用途，其特征在于，所述KOR激动剂选自如通式(I)所示化合物，或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐，
    Figure PCTCN2018119313-appb-100001
    其中：
    G选自O、-NR 4和-CR 5R 6；
    R 1选自氢原子、烷基、烷氧基、卤代烷基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 7、-C(O)R 7、-C(O)OR 7、-S(O) mR 7和-NR 8R 9，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 2选自氢原子、烷基、烷氧基、卤代烷基、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、-OR 7、-C(O)R 7和-C(O)OR 7，其中所述的烷基、卤代烷基、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基和杂芳基烷基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 3选自氢原子、烷基、烷氧基、卤代烷基、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、-OR 7、-C(O)R 7和-C(O)OR 7，其中所述的烷基、卤代烷基、环烷基、环烷基烷基、杂环基、杂环基烷基、芳基、芳基烷基、杂芳基和杂芳基烷基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 4选自氢原子、烷基、卤代烷基、环烷基、烷氧基、羟烷基、氨基、羧酸酯基、杂环基、芳基、杂芳基、-OR 7、-C(O)R 7、-C(O)OR 7、-S(O) mR 7、-NR 8R 9和-NHC(O)NR 8R 9，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、羧酸酯基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 5和R 6各自独立地选自氢原子、烷基、烷氧基、羟烷基、羟基、氨基、羧酸酯基、环烷基、杂环基、芳基、杂芳基、-OR 7、-C(O)R 7、-C(O)OR 7、-S(O) mR 7、-NR 8R 9和-NHC(O)NR 8R 9，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、羧酸酯基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 7选自氢原子、烷基、氨基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 8和R 9各自独立地选自氢原子、烷基、烷氧基、羟烷基、羟基、氨基、羧酸酯基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、羧酸酯基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    m为0、1或2。
  2. 如权利要求1所述的用途，其特征在于，所述的KOR激动剂选自通式(I-B)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
    Figure PCTCN2018119313-appb-100002
    其中：
    G和R 2如权利要求1中所定义。
  3. 如权利要求1-2任一项所述的用途，其特征在于，所述的KOR激动剂选自通式(I-C)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
    Figure PCTCN2018119313-appb-100003
    其中：
    R 2如权利要求1中所定义。
  4. 如权利要求1-3任一项所述的用途，其特征在于，所述的KOR激动剂或其可药用盐选自：
    Figure PCTCN2018119313-appb-100004
    Figure PCTCN2018119313-appb-100005
    优选
    Figure PCTCN2018119313-appb-100006
  5. 如权利要求1-4任一项所述的用途，其特征在于，所述MOR激动剂选自如通式(II)所示化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用的盐：
    Figure PCTCN2018119313-appb-100007
    其中：
    环A选自环烷基和杂环基；
    R选自芳基和杂芳基，其中所述的芳基和杂芳基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 3、-C(O)R 3、-C(O)OR 3、-S(O)mR 3和-NR 4R 5中的一个或多个取代基所取代；
    R 1相同或不同，且各自独立地选自氢原子、烷基、烷氧基、卤代烷基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 3、-C(O)R 3、-C(O)OR 3、-S(O)mR 3和-NR 4R 5，其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 2相同或不同，且各自独立地选自氢原子、烷基、烷氧基、卤代烷基、卤素、氨基、硝基、羟基、氰基、氧代基、烯基、环烷基、杂环基、芳基、杂芳基、-OR 3、-C(O)R 3、-C(O)OR 3、-S(O)mR 3和-NR 4R 5，其中所述的烷基、烷氧基、烯基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    或者两个R 2一起形成环烷基或杂环基，其中所述的环烷基或杂环基任选被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 3选自氢原子、烷基、氘代烷基、氨基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    R 4和R 5各自独立地选自氢原子、烷基、烷氧基、羟烷基、羟基、氨基、羧酸酯基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选被选自烷基、卤素、羟基、氨基、羧酸酯基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；
    p、q各自独立地为0、1、2、3或4；且
    m为0、1或2。
  6. 如权利要求5所述的用途，其特征在于，所述的MOR激动剂选自如通式(II-B)所示化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式，或其可药用盐，
    Figure PCTCN2018119313-appb-100008
    其中：
    R 1、R 2和p如权利要求5中所定义。
  7. 如权利要求5-6任一项所述的用途，其特征在于，所述的MOR激动剂或其可药用盐选自：
    Figure PCTCN2018119313-appb-100009
    Figure PCTCN2018119313-appb-100010
    Figure PCTCN2018119313-appb-100011
    优选
    Figure PCTCN2018119313-appb-100012
  8. 如权利要求1-4任一项所述的用途，其特征在于，所述MOR激动剂选自盐酸二氢吗啡酮、吗啡、羟考酮、丁丙诺啡、舒芬太尼、芬太尼、曲芬太尼、瑞芬太尼、他喷他多、NKTR-181、艾沙度林、苯并氢可酮、洛哌丁胺、oliceridine、samidorphan、cebranopadol、他喷他多、美沙酮、曲马朵、TV-46763、氢可酮、dexketoprofen、羟吗啡酮、MH-200、左啡诺、Sedatin、去甲基曲马多、IBCh-07、HS-731、Cyt-1010、曲美布汀3-硫代氨基甲酰基-苯磺酸盐、thienorphine、trimebutine、TRV-734、TRK-130、氢吗啡酮、氢吗啡酮前药、EU-178、OREX-1038、AIKO-152、TH-030418、CC-408、XE-440、CYX-6、Org-41793、DPI-125、KN-203、JVA-3025、suboxone、AT-121、VRP-26、内吗啡肽、NKTR-196、NKTR-174、NKTR-192、NESS-117-OPB、SYK-524、HS-731、HS-198、Dmt-Tic类似物、内啡肽1衍生物、MMP-2200、SEO-16、TLI-0326、BU-08028、BU-08073、TLI-1186、KIN-3031、Neo-1509、GRT-6006、MCP-201、NE-2、MGM-9、EN-3231、NRP-290、NS-7051、CDS-PM-101、frakefamide、BCH-2687、SS-620、VANH-36、443C81、OHM-329、皮啡肽四肽类似物、sameridine、OHM-3507、SEP-130551、BW-2378W92、sulfazocine、Z-4349、RP-63494、BCH-150、CP-840、CP-0719。
  9. 如权利要求1的用途，其特征在于，所述的疼痛选自急性疼痛、慢性疼痛，所述的慢性疼痛选自头痛、颌面部痛、项枕部疼痛、颈肩痛、上肢痛、胸部痛、腹痛、腰腿痛、生殖道疼痛、泌尿道疼痛、痛经。
  10. 如权利要求1所述的用途，其特征在于，所述疼痛选自创伤性疼痛、炎性疼痛、缺血性疼痛、代谢性疾病引起的疼痛、神经源性疼痛、组织及器官畸形引起的疼痛、分娩疼痛、恶性增殖疾病引起的疼痛，所述的创伤性疼痛选自手术引起的疼痛、骨折疼痛、烧伤性疼痛、腹部外伤性疼痛、脊柱外伤性疼痛、胸部外伤性疼痛、外伤后头痛；所述的炎性疼痛选自炎性头痛、组织炎性疼痛、器官及腺体炎性疼痛、血管炎性疼痛；所述的缺血性疼痛选自缺血性头痛、肢体缺血性疼痛、组织缺血性疼痛、器官及腺体缺血性疼痛；所述的代谢性疾病引起的疼痛选自痛风引起的疼痛、糖尿病引起的疼痛；所述的神经源性疼痛选自幻肢痛、残端痛、灼性神经痛、带状疱疹后遗神经痛、交感神经相关性疼痛、灼热足综合征引发的疼痛、叶酸缺乏性周围神经痛、维生素B12缺乏性周围神经痛、维生素B1缺乏性多发性神经、麻风病性神经痛；所述的恶性增殖疾病引起的疼痛选自肿瘤引起的疼痛，优选为白血病、淋巴瘤、骨髓瘤、乳腺癌、肺癌、食管癌、胃癌、大肠癌、肝癌、胰腺癌、头颈部癌、肾癌、膀胱癌、前列腺癌、卵巢癌、子宫内膜癌、子宫颈癌、骨肉瘤、软组织肉瘤、黑色素瘤、脑瘤引起的疼痛。
  11. 如权利要求10所述的用途，其特征在于，所述的疼痛选自中至重度疼痛，优选自创伤性疼痛、分娩疼痛、肿瘤引起的疼痛、炎性疼痛。
  12. 如权利要求11所述的用途，其特征在于，所述的中至重度疼痛对非阿片类镇痛药物、弱阿片类镇痛药物不适用和/或不敏感。
  13. 如有权利要求1所述的用途，其特征在于，所述联合还包含第三组分，所述第三组分选自阿片类药物、糖皮质激素、非甾体抗炎药、麻醉药、局部麻醉药、抗抑郁药、钙离子通道拮抗剂、抗惊厥药物、肾上腺β受体阻断剂、麻醉诱导剂。
  14. 一种药物组合物，含有权利要求1-8任一项所述的MOR激动剂或其可药用盐与KOR激动剂或其可药用盐，以及一种或多种可药用的赋型剂、稀释剂或载 体。
PCT/CN2018/119313 2017-12-06 2018-12-05 Kor激动剂与mor激动剂联合在制备治疗疼痛的药物中的用途 WO2019109937A1 (zh)

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BR112020010429-9A BR112020010429A2 (pt) 2017-12-06 2018-12-05 uso de agonista de kor em combinação com agonista de mor na preparação de fármaco para tratamento da dor
CN201880059072.XA CN111065390B (zh) 2017-12-06 2018-12-05 Kor激动剂与mor激动剂联合在制备治疗疼痛的药物中的用途
JP2020529356A JP2021505547A (ja) 2017-12-06 2018-12-05 疼痛を治療するための薬物の製造におけるｍｏｒアゴニストと組み合わせたｋｏｒアゴニストの使用
RU2020115687A RU2776842C2 (ru) 2017-12-06 2018-12-05 Применение агониста kor в комбинации с агонистом mor для получения лекарственного средства для лечения боли
AU2018380173A AU2018380173A1 (en) 2017-12-06 2018-12-05 Use of KOR agonist in combination with MOR agonist in preparing drug for treating pain
US16/767,523 US11471503B2 (en) 2017-12-06 2018-12-05 Use of KOR agonist in combination with MOR agonist in preparing drug for treating pain
CA3083028A CA3083028A1 (en) 2017-12-06 2018-12-05 Use of kor agonist in combination with mor agonist in preparing drug for treating pain
MX2020005660A MX2020005660A (es) 2017-12-06 2018-12-05 Uso de un agonista de kor en combinacion con un agonista de mor para preparar medicamentos para tratar el dolor.
KR1020207018160A KR20200096787A (ko) 2017-12-06 2018-12-05 통증을 치료하는 약물의 제조에 있어서의 kor 작용제 및 mor 작용제의 조합의 용도
EP18885338.6A EP3714882A4 (en) 2017-12-06 2018-12-05 USE OF A KOR AGONIST IN COMBINATION WITH A MOR AGONIST IN THE PREPARATION OF A MEDICINAL PRODUCT FOR THE TREATMENT OF PAIN

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