WO2018188641A1 - 一种mor激动剂与kor激动剂的药物组合物及其用途 - Google Patents
一种mor激动剂与kor激动剂的药物组合物及其用途 Download PDFInfo
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- WO2018188641A1 WO2018188641A1 PCT/CN2018/082912 CN2018082912W WO2018188641A1 WO 2018188641 A1 WO2018188641 A1 WO 2018188641A1 CN 2018082912 W CN2018082912 W CN 2018082912W WO 2018188641 A1 WO2018188641 A1 WO 2018188641A1
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- 0 C*(C=N1)N=Cc2c1[o]cc2 Chemical compound C*(C=N1)N=Cc2c1[o]cc2 0.000 description 6
- ZXQYWDYMZQURAP-VZMZSXMMSA-N CC(C)C[C@H](C(NC(CCCCN)C(N(CC1)CCC1NC(NC)=O)=O)=O)NC([C@@H](Cc1ccccc1)NC([C@@H](Cc1ccccc1)N)=O)=O Chemical compound CC(C)C[C@H](C(NC(CCCCN)C(N(CC1)CCC1NC(NC)=O)=O)=O)NC([C@@H](Cc1ccccc1)NC([C@@H](Cc1ccccc1)N)=O)=O ZXQYWDYMZQURAP-VZMZSXMMSA-N 0.000 description 1
- ZXQYWDYMZQURAP-SEVDZJIVSA-N CC(C)C[C@H](C(N[C@H](CCCCN)C(N(CC1)CCC1NC(NC)=O)=O)=O)NC([C@@H](Cc1ccccc1)NC([C@@H](Cc1ccccc1)N)=O)=O Chemical compound CC(C)C[C@H](C(N[C@H](CCCCN)C(N(CC1)CCC1NC(NC)=O)=O)=O)NC([C@@H](Cc1ccccc1)NC([C@@H](Cc1ccccc1)N)=O)=O ZXQYWDYMZQURAP-SEVDZJIVSA-N 0.000 description 1
- IHXVKBXMBRRUHZ-LPYGTTGFSA-N CC(C)C[C@H](C(N[C@H](CCCCN)C(N(CC1)CCC1NC(Nc1ccccc1)=O)=O)=O)NC([C@@H](Cc1ccccc1)NC([C@@H](Cc1ccccc1)N)=O)=O Chemical compound CC(C)C[C@H](C(N[C@H](CCCCN)C(N(CC1)CCC1NC(Nc1ccccc1)=O)=O)=O)NC([C@@H](Cc1ccccc1)NC([C@@H](Cc1ccccc1)N)=O)=O IHXVKBXMBRRUHZ-LPYGTTGFSA-N 0.000 description 1
- JVDXQOSBEXXPNW-UHFFFAOYSA-N CC1=CN=C(C=CC=C2)C2=CC1 Chemical compound CC1=CN=C(C=CC=C2)C2=CC1 JVDXQOSBEXXPNW-UHFFFAOYSA-N 0.000 description 1
- MVHWRBZXLYFOMW-UHFFFAOYSA-N CC1=Cc2ccccc2NC1 Chemical compound CC1=Cc2ccccc2NC1 MVHWRBZXLYFOMW-UHFFFAOYSA-N 0.000 description 1
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- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- 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
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A61K31/445—Non condensed piperidines, e.g. piperocaine
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Definitions
- the present invention is in the field of medicine and relates to the use of a MOR agonist in combination with a KOR agonist for the preparation of a medicament for alleviating 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 MOR agonists, including morphine, tramadol, fentanyl, oxycodone, etc., but long-term use. These drugs 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 Patent Application No. PCT/CN2016/101064 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].
- CN107098871A discloses a novel KOR agonist whose structure is 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 use of MOR agonists in combination with KOR agonists is a potential method for pain relief and/or treatment.
- the present invention provides the use of a novel MOR agonist in combination with a KOR 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 MOR agonist in combination with a KOR agonist for the preparation of a medicament for alleviating and/or treating pain.
- the MOR 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:
- 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 are the same or different and are 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 the compounds of formula (I-A):
- R a and R b are each independently selected from 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 3 , -C(O)R 3 , -C(O)OR 3 , -S(O) m R 3 and -NR 4 R 5 , wherein the alkyl group, haloalkyl group, cycloalkyl group, hetero
- the cyclo, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocycle. Substituted by one or more substitu
- R a and R b together form a cycloalkyl or heterocyclic group, wherein said cycloalkyl or heterocyclic group is optionally selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy Substituted with one or more substituents of alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
- R 1 - R 5 , p, m and q are as defined in the compound of the formula (I).
- the MOR agonist is selected from the group consisting of the compounds of formula (I-B):
- R 1 , R 2 and p are as defined in the compound represented by the formula (I).
- the MOR agonist is selected from the group consisting of
- the KOR agonist is selected from the group consisting of a compound of the formula (II) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof.
- 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 3 , -C (O) R 3 , -C(O)OR 3 , -S(O) m R 3 and -NR 4 R 5 , 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, 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 heterocyclic group, an aryl group, a heteroaryl group, -OR 3 , -C(O)R 3 and -C(O)OR.
- alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are 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, 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 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;
- R 6 is a hydrogen atom or W
- R 7 is selected from a hydrogen atom, an alkyl group, C(O)R 8 , C(O)OR 8 , C(O)NR 9 R 10 or W, wherein the alkyl group is optionally selected from alkoxy groups, Substituted by one or more substituents of a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, a carboxylic acid group, and a carboxylate group;
- R 8 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkoxy group, an amino group, a cycloalkyl group, and a heterocyclic group, wherein the heterocyclic group is optionally selected from the group consisting of an alkyl group, an alkoxy group, a hydroxyalkyl group, and a cycloalkyl group. Substituting one or more substituents of a heterocyclic group, a carboxylic acid group, and a carboxylate group;
- R 9 and R 10 are each independently selected from a hydrogen atom, an alkyl group or a halogenated alkyl group; wherein the alkyl group is optionally selected from the group consisting of a carboxylic acid group, an alkoxy group, an amino group, a cyano group, a nitro group, a hydroxyl group, and a hydroxyalkane group. Substituted by one or more substituents of a group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
- R 9 and R 10 together with a nitrogen atom to which they are attached form a heterocyclic group, wherein said heterocyclic group contains 1-2 heteroatoms which are the same or different selected from N, O and S, and
- the heterocyclic group is optionally selected from the group consisting of alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, carboxylic acid, carboxylate, aryl And substituted with one or more substituents in the heteroaryl;
- W is an amino protecting group
- n 0, 1, or 2.
- the KOR agonist is selected from the group consisting of a compound of the formula (II-A) or a tautomer thereof, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
- R 1 and R 2 are as defined in the compound represented by the formula (II).
- the KOR agonist is selected from the group consisting of a compound of the formula (II-B) or a tautomer, a mesogen, a racemate, an enantiomer thereof. , diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,
- R 6 - R 7 and R 2 are as defined in the compound represented by the formula (II).
- the KOR agonist is selected from the group consisting of
- the KOR agonist is selected from the group consisting of difelikefalin, dinalbuphine, eluxadoline, nalmefene, nalfurafine, levorphanol, asimadolin, TH-030418, XE-440, CR-665, trimebutine, koji Mebutin-3-thiocarbamoyl-benzenesulfonate, WOL-071007, isoquinolinone 2.1, NKTR-195, 11C-FEKAP, SYK-524, nalbuphine, NRT-12, NRT-11, BU -08028, MCP-201, SA-14867, SA-14867, buprenorphine, NRT-10, GR-44821, MGM-9, KT-95, RDC-5768, GR-89696, U-50488, spiradoline, Xen-6205 , LPK-26, cocaine, EN-32
- the MOR agonist and the KOR agonist have a synergistic pharmacological effect of alleviating and/or treating pain; preferably, the compound 19 or a pharmaceutically acceptable salt thereof and the compound 35 or pharmaceutically acceptable thereof
- the salt has a synergistic pharmacological effect of relieving and/or treating pain
- the compound 19 or a pharmaceutically acceptable salt thereof and nalfurafine have a synergistic pharmacological effect of relieving and/or treating pain.
- a method of alleviating and/or treating pain comprising administering to a patient a MOR agonist and a KOR 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 the group consisting of pain with a VAS pain score of 4-10 points.
- the pain with a VAS pain score of 4-10 points is selected from the group consisting of traumatic pain, labor pain, and tumor. Pain, inflammatory pain.
- the pain with a VAS pain score of 4-10 is not suitable and/or insensitive to non-opioid analgesics, weak opioid analgesics.
- the present invention provides the above MOR agonist in combination with the above KOR agonist as a medicament for alleviating and/or treating pain.
- the weight ratio of the MOR agonist to the KOR agonist ranges from 0.001 to 100, preferably from 1/1000, 1/750, 1/500, 1/250, 1/100, 1 /90, 1/80, 1/75, 1/70, 1/60, 1/50, 1/40, 1/30, 7/30, 1/20, 7/20, 3/20, 9/20 , 1/25, 2/25, 3/25, 4/25, 6/25, 7/25, 8/25, 9/25, 18/25, 1/15, 2/15, 4/15, 1 /18,5/18,7/18,1/14,3/14,5/14,9/14,1/12,5/12,7/12,1/10,3/10,7/10 , 9/10, 1/9, 2/9, 4/9, 1/8, 3/8, 5/8, 1/7, 2/7, 3/7, 4/7, 5/7, 6 /7, 1/6, 5/6, 1/5, 2/5, 3/5, 4/5, 1/4, 3/4, 1/3,
- the MOR agonist is administered in an amount of 0.001-50 mg, preferably from 0.001 mg, 0.002 mg, 0.003 mg, 0.004 mg, 0.005 mg, 0.01 mg, 0.02 mg, 0.03 mg, 0.05 Mg, 0.1 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, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg; the KOR agonist is administered at a dose of 0.001 to 250 mg, preferably from 0.005 mg, 0.01 mg, 0.05 mg, 0.1 mg, 0.15
- the MOR agonist is selected from the group consisting of Compound 19 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 selected from the group consisting of Compound 35 or a pharmaceutically acceptable salt thereof, nalfurafine, administered at a dose of 0.001 to 100 mg, preferably from 0.005 mg, 0.01 mg, 0.05 mg, 0.1 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.
- the MOR 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,
- Gg/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, 80 ⁇ g/kg, 90 ⁇ g/kg, 100 ⁇ g/kg, 200 ⁇ g/kg, 250 ⁇ g/kg, 300 ⁇ g/k g, 400 ⁇ g/kg, 500 ⁇ g/kg.
- the MOR agonist is selected from the group consisting of Compound 19 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 KOR agonist is selected from the group consisting of Compound 35 or a pharmaceutically acceptable salt thereof, nalfurafine, at a dose of 0.01-150 ⁇ g/kg, preferably from 0.01 ⁇ g/kg, 0.05 ⁇ g/kg, 0.1 ⁇ g.
- ⁇ 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, 50 ⁇ g/kg , 75 ⁇ g / kg, 100 ⁇ 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 first dose of the MOR agonist is 1-50 times the maintenance dose, the KOR activation The first dose of the agent is 0.05-50 times the maintenance dose.
- 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 frequency of administration of the MOR agonist is once a day, twice a day, three times a day, once a week.
- the frequency of administration of KOR agonists 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 MOR agonist and a KOR 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 MOR agonist or a KOR 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 MOR agonist and KOR agonist pharmaceutical compositions of the invention may be administered alone or in combination with one or more therapeutic agents.
- 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 MOR agonist and a KOR agonist, or a MOR agonist and a KOR agonist with 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 MOR agonist and a KOR agonist, or a MOR agonist and a KOR 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 means -NH 2.
- 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.
- VAS pain score table refers to the standard of commonly used pain evaluation in clinical practice. It has an important guiding role for pain medication. The score ranges from 0 to 10; among them, 0 is painless, and 3 points or less has mild pain and can endure. 6 points of patients with pain and affect sleep, still can bear, 7-10 points patients have gradually strong pain, pain, unbearable, affecting appetite, affecting sleep.
- 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 MOR agonist of the present invention in combination with a KOR agonist (compound 19 and compound 35) on the threshold of mechanical stimulation of the rat in a wound pain test.
- Compound 19 was determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
- the NMR shift ( ⁇ ) is given in units of 10-6 (ppm).
- the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus.
- the solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethyl. Silane (TMS).
- 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, Companies such as Dare 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), and the system of the developing solvent used in the reaction was a dichloromethane and methanol system.
- TLC thin layer chromatography
- 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 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.
- Wistar male rats were purchased from Shanghai Slack Laboratory Animal Co., Ltd., purchased at 100-120g/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.
- Compound 19 was prepared using 10% absolute ethanol + 10% polyoxyethylene hydrogenated castor oil + 80% double distilled water; Compound 35 was prepared using physiological saline.
- the model group and the drug-administered group were subjected to incision surgery.
- Compound 19 was administered intravenously with the corresponding dose of Compound 19 and a blank solvent for formulating Compound 35; Compound 35 was administered alone with the corresponding dose of Compound 35 and a blank solvent for formulating Compound 19; A dose of Compound 35 was administered intravenously and a corresponding dose of Compound 19 was administered intravenously 30 minutes later. After 30 minutes of injection in each group, the mechanical pain threshold was measured by an electronic tactile measuring instrument to evaluate the analgesic effect of the drug on the pain of the surgical incision and the intensity of its action.
- the experimental results showed (Fig. 1) that the threshold of the normal control group was 37.68 g, and the threshold of the model group was 11.08 g. Compared with the normal group, the threshold of the model group was significantly decreased (P ⁇ 0.01). After 30 min, compared with the model group, the compound 19-0.1 mg/kg group significantly increased the tender threshold of the rats (P ⁇ 0.01), reaching 36.99 g, an increase of 233.8%; after 1 h of administration, compared with the model group, the compound The 35-0.3 mg/kg group significantly increased the tenderness threshold of the rats (P ⁇ 0.01), reaching 22.42 g, with an increase of 102.3%.
- compound 19 0.03mg/kg combined with compound 35 0.1mg/kg and 0.3mg/kg could significantly increase the tenderness threshold of rats (P ⁇ 0.01), reaching 36.16g and 39.5g, respectively.
- the amplitudes were 226.3% and 256.5%, respectively, showing that a lower dose of Compound 19 in combination with Compound 35 had a synergistic effect, and the dose of Compound 19 was significantly reduced on the premise of achieving the same analgesic effect;
- the combination of 0.1mg/kg and 0.3mg/kg of compound 35 could significantly increase the tenderness threshold of rats (P ⁇ 0.01), reaching 46.77g and 53.44g, respectively, with an increase of 322.1% and 382.3%, respectively.
- compound 19 0.03 mg/kg was combined with compound 35 0.1 mg/kg and 0.3 mg/kg analgesic efficacy (P>0.05), compound 19 0.1 mg/kg, respectively.
- the combination of compound 35 0.1 mg/kg and compound 35 0.3 mg/kg was more effective (P ⁇ 0.05); compared with compound 35 0.3 mg/kg, the four combination regimens had stronger analgesic effects ( P ⁇ 0.05).
- the compound 19-0.1 mg/kg group Compared with the compound 19-0.1 mg/kg group, the compound 19-0.3 mg/kg group, the compound 19-0.03 mg/kg+ compound 35-0.1 mg/kg group, the compound 19-0.03 mg/kg+ compound 35-0.3 mg/ In the kg group, the compound 19-0.1 mg/kg + compound 35-0.1 mg/kg group, the compound 19-0.1 mg/kg + compound 35-0.3 mg/kg group all met or exceeded the premise of the analgesic effect of the compound 19 alone. Under the observation, it was observed that the adverse reactions of the experimental animals were reduced.
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Abstract
Description
Claims (14)
- 一种μ阿片受体(MOR)激动剂与κ阿片受体(KOR)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MOR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: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。
- 如权利要求1-3任一项所述的用途,其特征在于,所述KOR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:其中:G为C=O或O=S=O;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 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、杂芳基和NR 6R 7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、杂环基、芳基、杂芳基、-OR 3、-C(O)R 3和-C(O)OR 3,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 3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 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;R 6为氢原子或W;R 7选自氢原子、烷基、C(O)R 8、C(O)OR 8、C(O)NR 9R 10或W,其中所述的烷基任选被选自烷氧基、羟烷基、环烷基、杂环基、羧酸基和羧酸酯基中的一个或多个取代基所取代;R 8选自氢原子、烷基、烷氧基、氨基、环烷基和杂环基,其中所述的杂环基任选被选自烷基、烷氧基、羟烷基、环烷基、杂环基、羧酸基和羧酸酯基中的一个或多个取代基所取代;R 9和R 10各自独立地选自氢原子、烷基或卤代烷基;其中所述的烷基任选被选自羧酸基、烷氧基、氨基、氰基、硝基、羟基、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,R 9和R 10与相连接的氮原子一起形成杂环基,其中所述的杂环基内含有1-2个相同或不同选自N、O和S的杂原子,并且所述的杂环基任选被选自烷基、烷氧基、卤素、氨基、氰基、硝基、羟基、羟烷基、环烷基、杂环基、羧酸基、羧酸酯基、芳基和杂芳基中的一个或多个取代基所取代;W为氨基保护基;且m为0、1或2。
- 如权利要求1-3任一项所述的用途,其特征在于,所述KOR激动剂选自difelikefalin、dinalbuphine、eluxadoline、nalmefene、nalfurafine、levorphanol、阿西马多林、TH-030418、XE-440、CR-665、trimebutine、曲美布汀-3-硫代氨基甲酰基-苯磺酸盐、WOL-071007、异喹啉酮2.1、NKTR-195、11C-FEKAP、SYK-524、nalbuphine、NRT-12、NRT-11、BU-08028、MCP-201、SA-14867、SA-14867、buprenorphine、NRT-10、GR-44821、MGM-9、KT-95、RDC-5768、GR-89696、U-50488、spiradoline、Xen-6205、LPK-26、可卡因、EN-3231、ADL-10-0101、DuP-747、fedotozine、ADL-10-0116、apadoline、ICI-204448、CJ-15161、FE-200041、ICI-199441、TAN-684、enadoline、ADL-1-0386、R-84760、E-2078、GR-103545、GR-91272、GR-86014、SEP-130551、SB-215519、SB-215520、niravoline、GR-102908、RP-61127、GR-107537、GR-129083、GR-38414、BRL-52656、GR-94839、GR-45809、EMD-60400、BRL-53001、BRL-53114、ZT-52537、N-CBM-TAMO,优选自difelikefalin、levorphanol、asimadoline、nalfurafine,更优选自nalfurafine。
- 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。
- 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,优选自白血病、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。
- 如权利要求10所述的用途,其特征在于,所述的疼痛选自VAS疼痛评分为4-10分的疼痛,优选自创伤性疼痛、分娩疼痛、肿瘤引起的疼痛、炎性疼痛。
- 如权利要求11所述的用途,其特征在于,所述的VAS疼痛评分为4-10 分的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。
- 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、局部麻醉药、抗抑郁药、钙离子拮抗剂、抗惊厥药物、肾上腺β受体阻断剂、麻醉剂、麻醉诱导剂。
- 一种药物组合物,含有权利要求1-8任一项所述的MOR激动剂与KOR激动剂,以及一种或多种可药用的赋型剂、稀释剂或载体。
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KR1020197032604A KR20190133047A (ko) | 2017-04-14 | 2018-04-13 | Mor 작용제 및 kor 작용제를 함유하는 약학적 조성물, 및 그의 용도 |
MX2019011904A MX2019011904A (es) | 2017-04-14 | 2018-04-13 | Composicion farmaceutica que contiene agonista de mor y agonista de kor, y sus usos. |
EP18783681.2A EP3610874A4 (en) | 2017-04-14 | 2018-04-13 | PHARMACEUTICAL COMPOSITION CONTAINING A MOR AGONIST AND A KOR AGONIST, AND ITS USES |
AU2018251118A AU2018251118A1 (en) | 2017-04-14 | 2018-04-13 | Pharmaceutical composition containing MOR agonist and KOR agonist, and uses thereof |
JP2019553307A JP2020516591A (ja) | 2017-04-14 | 2018-04-13 | Morアゴニストおよびkorアゴニストを含有する医薬組成物、およびその用途 |
CN201880004339.5A CN109982699A (zh) | 2017-04-14 | 2018-04-13 | 一种mor激动剂与kor激动剂的药物组合物及其用途 |
BR112019020691-4A BR112019020691A2 (pt) | 2017-04-14 | 2018-04-13 | Composição farmacêutica contendo agonista do mor e agonista do kor, e usos da mesma |
US16/499,931 US20200054594A1 (en) | 2017-04-14 | 2018-04-13 | Pharmaceutical composition containing mor agonist and kor agonist, and uses thereof |
CA3058272A CA3058272A1 (en) | 2017-04-14 | 2018-04-13 | Pharmaceutical composition containing mor agonist and kor agonist, and uses thereof |
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Cited By (11)
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CN113412263A (zh) * | 2020-01-17 | 2021-09-17 | 上海海雁医药科技有限公司 | 氮杂双环取代的氧杂螺环衍生物、其制法与医药上的用途 |
CN114615976A (zh) * | 2019-08-07 | 2022-06-10 | 人福医药美国公司 | κ阿片受体肽酰胺激动剂 |
RU2800295C1 (ru) * | 2020-01-17 | 2023-07-19 | Шанхай Хайян Фармасьютикал Текнолоджи Ко., Лтд. | Оптически чистое оксаспиро-замещенное производное пирролопиразола, способ его получения и его фармацевтическое применение |
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CA3180729A1 (en) | 2020-06-25 | 2021-12-30 | Subo Liao | Peptides for treatment of medical disorders |
EP4302779A1 (en) * | 2021-03-04 | 2024-01-10 | Socium Inc. | Cancer therapeutic agent |
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WO2019205983A1 (zh) * | 2018-04-28 | 2019-10-31 | 四川科伦博泰生物医药股份有限公司 | 氧杂螺环类化合物及其制备方法和用途 |
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CN111662284A (zh) * | 2019-03-06 | 2020-09-15 | 上海海雁医药科技有限公司 | 双杂环取代的氧杂螺环衍生物、其制法与医药上的用途 |
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Also Published As
Publication number | Publication date |
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EP3610874A1 (en) | 2020-02-19 |
TW201836606A (zh) | 2018-10-16 |
EP3610874A4 (en) | 2021-01-06 |
MX2019011904A (es) | 2019-11-25 |
BR112019020691A2 (pt) | 2020-05-12 |
CN109982699A (zh) | 2019-07-05 |
CA3058272A1 (en) | 2018-10-18 |
JP2020516591A (ja) | 2020-06-11 |
US20200054594A1 (en) | 2020-02-20 |
KR20190133047A (ko) | 2019-11-29 |
AU2018251118A8 (en) | 2019-10-31 |
AU2018251118A1 (en) | 2019-10-17 |
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