RU2776842C2 - Use of a kor agonist in combination with a mor agonist to obtain a drug for the treatment of pain - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention relates to the use of a combination of the effective amount of the κ-opioid receptor (KOR) agonist, which is compound 5, and the μ-opioid receptor (MOR) agonist, which is compound 20, to obtain a drug for the relief and/or treatment of traumatic pain, where the mass ratio of the KOR agonist and the MOR agonist is 1-50, the dose of administration of the KOR agonist is 0.005-0.5 mg, and the dose of administration of the MOR agonist is 0.001-0.01 mg.

EFFECT: synergistic effect on the relief and/or treatment of traumatic pain.

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Description

FIELD OF THE INVENTION

The present invention relates to the field of medicine and relates to the use of a combination of a KOR agonist and a MOR agonist for the preparation of a medicament for the relief and/or treatment of pain.

PRIOR ART

Pain refers to the functional or essential feelings of a person. The classification of pain is difficult. According to etiology, pain is mainly classified as traumatic pain, pathological pain, pain caused by metabolic diseases, neuropathic pain, pain caused by malformation of tissues and organs, psychological pain, and pain caused by combined factors. Depending on the duration, pain is mainly classified into transient pain, acute pain and chronic pain. Depending on the degree, pain is classified into mild pain, moderate pain, severe pain and very severe pain. Depending on the anatomy, pain is mainly classified into headache, maxillofacial pain, cervical and occipital pain, neck and shoulder pain, upper limb pain, chest pain, abdominal pain, and lumbosacral pain. . Depending on the location and cause, pain is classified into peripheral pain, central pain, and psychological pain. The causes of pain are complex and the symptoms vary. The degree of pain tolerance and response to treatment varies greatly between patients. Currently, clinically used drugs for the treatment of pain mainly include anti-inflammatory analgesics, narcotic analgesics, local anesthetics, antiepileptic drugs, antidepressants and the like. Although there are many drugs aimed at pain relief, there are still problems such as constipation, respiratory depression, lethargy and drowsiness, nausea and vomiting, acute poisoning, physical dependence and resistance of microorganisms to the drug, psychological dependence and the like.

Opioids are widely used analgesics in clinical practice and especially play an important role in the treatment of patients with very severe pain and advanced cancer. Opioids exert analgesic effects primarily by acting on the opioid receptor. The opioid receptor is a member of the G-protein coupled receptor superfamily and is involved in various physiological actions such as analgesia, gastrointestinal motility suppression, respiratory depression, myocardial protection, immune response, and the like. In general, the opioid receptor can be divided into four subtypes: μ opioid receptor (MOR), δ opioid receptor (DOR), κ opioid receptor (KOR), and opioid-like receptor 1 (ORL-1). Research shows that the MOR receptor has the strongest ability to bind to morphine-1. Therefore, opioid analgesics used in clinical practice are mainly MOR agonists such as morphine, tramadol, fentanyl, oxycodone and the like. However, long-term use of these drugs can cause serious side effects such as pain resistance, dependence, addiction, and the like. The MOR agonist currently in a phase III clinical trial includes TRV-130, which is developed by Trevena Inc. WO2017063509 discloses a novel MOR agonist whose structure is as follows:

WO2012129495 discloses a MOR agonist with a similar structure.

Studying the structure and function of various opioid receptor subtypes breaks the previous understanding that a highly selective ligand that targets a single opioid receptor will have high potency and low toxicity side effects. More research is now showing that a highly selective agonist may increase side effects rather than decrease them. Research shows that there are varying degrees of structural or functional interactions between different opioid receptor subtypes that together are involved in physiological actions such as pain relief and the like. A study by Fujita-Hamabe et al. (Journal of Pharmacy and Pharmacology, 2010, 62(8): 995-1002) demonstrates that KOR can inhibit MOR desensitization, accelerate MOR intracellular circulation to increase the surface receptor, and reduce protein kinase C activity, thereby inhibiting pain resistance and dependence from MOR agonists. A study by Cunha TM et al. ([J]. Molecular pain, 2012, 8(1): 10) showed that peripheral MOR activation can inhibit inflammatory pain and prostatin E2-induced progressive pain sensitization. It has been reported that KOR activation can also inhibit inflammatory pain hypersensitivity, and this mechanism may involve activation of the PI3Kγ/AKT signaling pathway via the nNOS/NO signaling pathway. Rong LIU et al. ([J]. China Pharmaceuticals, 2016, 25(22): 41-44) report the analgesic and sedative effects of the KOR agonist nalbuphine and the MOR agonist sufentanil after total hip arthroplasty in the elderly, demonstrating that the combined administration has a better analgesic effect than administration alone, and greatly reduces adverse reactions such as nausea, vomiting, pruritus and the like.

Patent application PCT/CN2017/087328 discloses a novel KOR agonist. It has an extremely low distribution in brain tissue, little effect on the central nervous system, and negligible effect on serum sodium. Practically does not cause dependence, and has higher safety. Its structure is presented as follows:

WO2008060552 discloses a similarly structured KOR agonist and its use for pain relief in combination with other opioid receptor agonists, NSAIDs and antidepressants. WO2016073443 discloses the use of a similar KOR agonist for the treatment of surgical and sclerotic pain. WO2008057608 discloses the use of a combination of a similar KOR agonist and a MOR agonist for the treatment of pain, as well as dose reduction of the MOR agonist and adverse reactions. WO2015065867 discloses the use of a similar KOR agonist administered after administration of an MOR agonist to reduce emesis induced by the MOR agonist. Thus, the combined administration of a KOR agonist and a MOR agonist is a potential way to alleviate and/or treat pain. The present invention provides the use of a combination of a novel structure of a KOR agonist and a MOR agonist for the preparation of a medicament for the alleviation and/or treatment of pain.

BRIEF DESCRIPTION OF THE INVENTION

The technical problem to be solved by the present invention is to provide the use of a combination of a KOR agonist and a MOR agonist to provide a drug for the relief and/or treatment of pain.

A KOR agonist is a compound of formula (I) having the following structure:

or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

where:

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 hydrogen, alkyl, alkoxy, haloalkyl, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁷ , -C(O)R ⁷ , -C(O )OR ⁷ , -S(O) _m R ⁷ and -NR ⁸ R ⁹ , wherein each alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, halogen , amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,

R ² is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -OR ⁷ , -C(O)R ⁷ and -C(O)OR ⁷ where each alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl is optionally substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,

R ³ is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -OR ⁷ , -C(O)R ⁷ and -C(O)OR ⁷ where each alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl is optionally substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,

R ⁴ is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, alkoxy, hydroxyalkyl, amino, alkoxycarbonyl, heterocyclyl, aryl, heteroaryl, -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 each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of alkyl , halogen, hydroxy, amino, alkoxycarbonyl, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,

R ⁵ and R ⁶ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxyalkyl, hydroxy, amino, alkoxycarbonyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, 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 each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more substituents selected from the group , consisting of alkyl, halogen, hydroxy, amino, alkoxycarbonyl, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,

R ⁷ is selected from the group consisting of hydrogen, alkyl, amino, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of alkyl , halogen, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,

R ⁸ and R ⁹ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxyalkyl, hydroxy, amino, alkoxycarbonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, amino, alkoxycarbonyl, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, and

m is 0, 1, or 2.

Preferably the KOR agonist is a compound of formula (I-A):

or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

where:

G, R ² and R ³ are as defined for the compound of formula (I).

More preferably, the KOR agonist is a compound of formula (I-B):

or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

where:

G and R ² are as defined for the compound of formula (I).

Even more preferably, the KOR agonist is a compound of formula (I-C):

or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

where:

R ² is as defined for the compound of formula (I).

Even more preferably, the KOR agonist, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

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and preferably

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In the above preferred embodiments, the MOR agonist is a compound of formula (II):

or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

where:

ring A is selected from the group consisting of cycloalkyl and heterocyclyl,

R is selected from the group consisting of aryl and heteroaryl, where each aryl and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl , aryl, heteroaryl, -OR ³ , -C(O)R ³ , -C(O)OR ³ , -S(O) _m R ³ and -NR ⁴ R ⁵ ,

each R ¹ is the same or different, and each is independently selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ³ , -C( O)R ³ , -C(O)OR ³ , -S(O) _m R ³ and -NR ⁴ R ⁵ , wherein each alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more substituents selected from a group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,

each R ² is the same or different, and each is independently selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, halogen, amino, nitro, hydroxy, cyano, oxo, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ³ , -C(O)R ³ , -C(O)OR ³ , -S(O) _m R ³ and -NR ⁴ R ⁵ where each alkyl, alkoxy, alkenyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optional substituted with one or more substituents selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,

or two R ² are taken together to form cycloalkyl or heterocyclyl, where cycloalkyl or heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl , heterocyclyl, aryl and heteroaryl,

R ³ is selected from the group consisting of hydrogen, alkyl, deuterated alkyl, amino, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents selected from the group , consisting of alkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,

R ⁴ and R ⁵ are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxyalkyl, hydroxy, amino, alkoxycarbonyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, hydroxy, amino, alkoxycarbonyl, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,

p and q are each independently 0, 1, 2, 3, or 4, and

m is 0, 1, or 2.

Preferably the MOR agonist is a compound of formula (II-B):

or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

where:

R ¹ , R ² and p are as defined for the compound of formula (II).

More preferably, the MOR agonist, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

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and preferably

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In another preferred embodiment of the present invention, the MOR agonist is selected from the group consisting of dihydromorphone hydrochloride, morphine, oxycodone, buprenorphine, sufentanil, fentanyl, trifentanyl, remifentanil, tapentadol, NKTR-181, eluxadoline, benzohydrocodone, loperamide, oliceridine, samidorphan, cebranopadol, tapentadol, methadone, tramadol, TV-46763, hydrocodone, dexketoprofen, oxymorphone, MH-200, levorphanol, sedatin, desmethyl tramadol, IBCh-07, HS-731, Cyt-1010, trimebutine 3-thiocarbamoylbenzenesulfonate, thienorphine, trimebutine, TRV- 734, TRK-130, hydromorphone, hydromorphone prodrugs, 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, Endomorphine, NKTR-196, NKTR-174, NKTR-192, NESS-117-OPB, SYK-524, HS-731, HS-198, Dmt-analog Tic, Endorphin Derivative 1, 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-3 231, NRP-290, NS-7051, CDS-PM-101, frakefamide, BCH-2687, SS-620, VANH-36, 443C81, OHM-329, tetrapeptide dermorphin analog, sameridine, OHM-3507, SEP-130551, BW-2378W92, sulfazocine, Z-4349, RP-63494, BCH-150, CP-840 and CP-0719.

In the above embodiments, the combination of a KOR agonist and a MOR agonist has a synergistic effect in alleviating and/or treating pain. Preferably, the combination of Compound 5 or a pharmaceutically acceptable salt thereof and Compound 20 or a pharmaceutically acceptable salt thereof has a synergistic effect in alleviating and/or treating pain.

The present invention provides a method for alleviating and/or treating pain, comprising administering to a patient the above salt of a KOR agonist and a MOR agonist.

In accordance with the practice of the present invention, pain is selected from the group consisting of acute pain and chronic pain, and chronic pain is selected from the group consisting of headache, maxillofacial pain, cervical and occipital pain, neck and shoulder pain, pain in the upper limb, pain in the thoracic region, abdominal pain in, pain in the lumbosacral region, pain in the genital tract, pain in the urinary tract and dysmenorrhea.

In accordance with the application of the present invention, 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 malformation of tissues and organs, labor pain and pain caused by malignant proliferative diseases. .

In accordance with the application of the present invention, traumatic pain is selected from the group consisting of pain caused by surgery (for example, postoperative pain caused by appendectomy, open colorectal surgery, hernia repair, prostatectomy, colonectomy, gastrectomy, splenectomy, colectomy, colostomy, pelvic laparoscopy , tubal ligation, hysterectomy, vasectomy, or cholecystectomy), post-treatment pain (eg, pain following a colonoscopy, cystoscopy, hysteroscopy, or biopsy of the cervix or endometrium), fracture pain, burn pain, pain from abdominal trauma, pain from spinal trauma, pain in trauma of the thoracic region and post-traumatic headache.

In accordance with the use of the present invention, inflammatory pain is selected from the group consisting of inflammatory headache, inflammatory tissue pain (for example, in rheumatoid arthritis, rheumatoid arthritis, osteoarthritis), inflammatory pain in organs and glands (for example, in gastroesophageal reflux disease, pancreatitis, acute pyelonephritis, ulcerative colitis, cholecystitis, cirrhosis, liver cyst, hepatitis, duodenal or gastric ulcer, esophagitis, gastritis, gastroenteritis, colitis, diverticulitis, intestinal obstruction, ovarian cyst, pelvic inflammatory disease, perforated ulcer, peritonitis, prostatitis , interstitial cystitis) and inflammatory vascular pain.

In accordance with the practice of the present invention, ischemic pain is selected from the group consisting of ischemic headache, ischemic limb pain, ischemic pain in tissues, organs and glands.

In accordance with the application of the present invention, the pain caused by metabolic diseases is selected from the group consisting of pain caused by gout and pain caused by diabetes.

In accordance with the use of the present invention, neuropathic pain is selected from the group consisting of phantom limb pain, stump pain, neuralgia burning sensation, postherpetic neuralgia, pain associated with the sympathetic nervous system, pain caused by burning legs syndrome, peripheral neuralgia with folate deficiency. acid, peripheral neuralgia with vitamin B12 deficiency, multiple neuralgia with vitamin B1 deficiency, and leprosy neuralgia.

According to the present invention, pain caused by malignant proliferative diseases is pain caused by tumors, including, but not limited to, pain caused by leukemia, lymphoma, myeloma, breast cancer, lung cancer, esophageal cancer, stomach cancer, colorectal cancer, cancer liver, pancreatic cancer, head and neck cancer, kidney cancer, bladder cancer, prostate cancer, ovarian cancer, endometrial cancer, cervical cancer, osteosarcoma, soft tissue sarcoma, melanoma, brain tumor.

In accordance with the application of the present invention, pain is moderate to very severe pain. Preferably, moderate to very severe pain is selected from the group consisting of traumatic pain, labor pain, pain caused by tumors, and inflammatory pain.

In accordance with the use of the present invention, for moderate to very severe pain, no non-opioid analgesics or weak opioid analgesics are used and/or moderate to severe pain is not responsive to non-opioid analgesics or weak opioid analgesics.

The present invention provides a combination of the above KOR agonist and the above MOR agonist for use as a drug for alleviating and/or treating pain.

In accordance with the application of the present invention, the mass ratio of KOR agonist to MOR agonist is from 0.01 to 1000 or 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, 3/2, 2/1, 1/1, 1/2, 1/3, 1/5, 1/10, 1/20, 1/25, 1/30 and 1/50, and preferably 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 or 250/1.

According to the application of the present invention, the administration dose of the KOR agonist is 0.001 to 250 mg, and preferably 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, or 250 mg, and the administration dose of the MOR agonist is 0.001 to 50 mg and preferably 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, 0.025 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.075 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0 .3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.9 mg, 1 mg, 1.2 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 m g, 2.2 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 or 50 mg.

According to the use of the present invention, more preferably the KOR agonist is Compound 5 or a pharmaceutically acceptable salt thereof, wherein the administration dose is 0.001 to 20 mg and preferably 0.005 mg, 0.01 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, 18 mg or 20 mg.

According to the use of the present invention, more preferably, the MOR agonist is compound 20 or a pharmaceutically acceptable salt thereof, wherein the administration dose is 0.001 to 20 mg and preferably 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, 0.025 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.075 mg , 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.75 mg, 0.8 mg , 0.9 mg, 1 mg, 1.2 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.2 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 or 20 mg.

In accordance with the application of the present invention, the administration dose of the KOR agonist is from 0.01 to 500 μg/kg and preferably 0.01 μg/kg, 0.05 μg/kg, 0.1 μg/kg, 0.2 μg/kg , 0.25 mcg/kg, 0.3 mcg/kg, 0.4 mcg/kg, 0.5 mcg/kg, 0.6 mcg/kg, 0.7 mcg/kg, 0.8 mcg/kg, 0.9 mcg/kg, 1 mcg/kg, 2 mcg/kg, 2.5 mcg/kg, 3 mcg/kg, 4 mcg/kg, 5 mcg/kg, 8 mcg/kg, 10 mcg/kg, 15 mcg/kg, 20 mcg/kg, 24 mcg/kg, 25 mcg/kg, 30 mcg/kg, 40 mcg/kg, 50 mcg/kg, 60 mcg/kg, 70 mcg/kg, 75 mcg/kg, 80 mcg/kg, 90 mcg/kg, 100 mcg/kg, 200 mcg/kg, 250 mcg/kg 300 mcg/kg, 400 mcg/kg or 500 mcg/kg, and the dose of administration of the MOR agonist is from 0.001 to 500 mcg/ kg and preferably 0.003 µg/kg, 0.005 µg/kg, 0.01 µg/kg, 0.05 µg/kg, 0.1 µg/kg, 0.2 µg/kg, 0.25 µg/kg, 0, 3 mcg/kg, 0.4 mcg/kg, 0.5 mcg/kg, 0.6 mcg/kg, 0.7 mcg/kg, 0.8 mcg/kg, 0.9 mcg/kg, 1 mcg/kg kg, 2 mcg/kg, 2.5 mcg/kg, 3 mcg/kg, 4 mcg/kg, 5 mcg/kg, 8 mcg/kg, 10 mcg/kg, 15 mcg/kg, 20 mcg/kg, 24 mcg/kg, 25 mcg/kg, 30 mcg/kg, 40 mcg/kg, 50 mcg/kg, 60 mcg/kg, 70 mcg /kg, 75 µg/kg, 80 µg/kg, 90 µg/kg, 100 µg/kg, 200 µg/kg, 250 µg/kg, 300 µg/kg, 400 µg/kg or 500 µg/kg.

According to the use of the present invention, the KOR agonist is Compound 5 or a pharmaceutically acceptable salt thereof, wherein the administration dose is 0.01 to 150 μg/kg and preferably 0.01 μg/kg, 0.05 μg/kg, 0.1 μg /kg, 0.2 µg/kg, 0.25 µg/kg, 0.3 µg/kg, 0.4 µg/kg, 0.5 µg/kg, 0.6 µg/kg, 0.7 µg/ kg, 0.8 µg/kg, 0.9 µg/kg, 1 µg/kg, 2 µg/kg, 2.5 µg/kg, 3 µg/kg, 4 µg/kg, 5 µg/kg, 8 µg /kg, 10 µg/kg, 15 µg/kg, 20 µg/kg, 24 µg/kg, 25 µg/kg, 40 µg/kg, 50 µg/kg, 75 µg/kg or 100 µg/kg.

According to the use of the present invention, the MOR agonist is Compound 20 or a pharmaceutically acceptable salt thereof, wherein the administration dose is 0.001 to 150 μg/kg and preferably 0.003 μg/kg, 0.005 μg/kg, 0.01 μg/kg, 0 .05 mcg/kg, 0.1 mcg/kg, 0.2 mcg/kg, 0.25 mcg/kg, 0.3 mcg/kg, 0.4 mcg/kg, 0.5 mcg/kg, 0, 6 mcg/kg, 0.7 mcg/kg, 0.8 mcg/kg, 0.9 mcg/kg, 1 mcg/kg, 2 mcg/kg, 2.5 mcg/kg, 3 mcg/kg, 4 mcg /kg, 5 µg/kg, 8 µg/kg, 10 µg/kg, 15 µg/kg, 20 µg/kg, 24 µg/kg, 25 µg/kg, 30 µg/kg, 40 µg/kg, 50 µg /kg, 60 µg/kg, 70 µg/kg, 75 µg/kg, 80 µg/kg, 90 µg/kg or 100 µg/kg.

The mode of administration of the combination of the present invention is selected from the group consisting of: simultaneous administration, joint administration after separate preparation, and sequential administration after separate preparation.

The present invention also relates to the use of a combination of a MOR agonist and a KOR agonist for the preparation of a medicament for alleviating and/or treating pain, wherein the initial administration dose of the KOR agonist is 0.05 to 50 times the maintenance dose and the initial administration dose of the MOR agonist is 1 to 50 times the maintenance dose.

The present invention also relates to the use of a combination of a KOR agonist and a MOR agonist for the preparation of a medicament for the relief 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, once every two weeks, once every three weeks, once a month, and the frequency of administration of the MOR agonist is once a day, twice a day, three times a day, once a week, once every two weeks, one once every three weeks, once a month.

In the above embodiments, the combination also optionally contains a third component selected from the group consisting of an opioid, a glucocorticoid, a non-steroidal anti-inflammatory drug, a local anesthetic, an antidepressant, a calcium channel antagonist, an anticonvulsant, an adrenal beta receptor blocker, an anesthetic, and an analgesic stimulant. .

The present invention also relates to a pharmaceutical composition of a KOR agonist and a MOR agonist, optionally containing one or more pharmaceutically acceptable carriers, excipients and/or diluents. The pharmaceutical composition may be in the form of any of the pharmaceutically acceptable dosage forms. For example, a pharmaceutical composition containing a KOR agonist and a MOR agonist as active ingredients can be prepared as a tablet, capsule, pill, granule, solution, suspension, syrup, injection (including injection solution, sterile injection powder, and concentrated injection solution). ), suppository, inhaler or spray.

The pharmaceutical composition of the KOR agonist and MOR agonist of the present invention may be administered alone or in combination with one or more therapeutic agents.

When using a KOR agonist and a MOR agonist for the preparation of the pain relief and/or treatment medicament of the present invention, the KOR agonist and the MOR agonist may be administered orally or parenterally (including, but not limited to, subcutaneous injection, intravenous injection, and intraperitoneal injection).

The components to be combined (eg, KOR agonist and MOR agonist, KOR agonist and MOR agonist, and optional third component) may be administered simultaneously or sequentially separately. Moreover, the components to be combined can also be administered together in the same composition or separately in different compositions.

In the present invention, the term "combined administration" or "co-administration" is an administration method including various situations in which two or more drugs are administered sequentially or simultaneously. The term "simultaneously" in this document means that the KOR agonist and the MOR agonist or the KOR agonist and the MOR agonist and the optional third component are administered during one administration cycle, e.g., two or more drugs are administered over the course of one day, three days, one week , two weeks or one month. The term "sequential or consecutive" administration includes situations in which the KOR agonist and the MOR agonist or the KOR agonist and the MOR agonist and the optional third component are administered in different administration cycles, respectively. All of these routes of administration are included in the combined administration of the present invention.

The term "effective amount" in accordance with the present invention refers to an amount sufficient to improve or prevent a symptom or sign of a medical condition. The term "effective amount" also refers to an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or animal subject may vary, depending on factors such as the condition being treated, the general health of the patient, the route and dose of administration, and the severity of side effects. An effective amount may be the maximum dose or schedule of administration that avoids significant side effects or toxic effects.

DEFINITIONS

In the description and claims of the present application, unless otherwise indicated, the scientific and technical terms used herein have the meanings generally understood by a person skilled in the art. However, for a better understanding of the present invention, some related terms are defined and explained. In addition, when the definitions and explanations of terms provided in this application do not correspond to the meanings commonly understood by a person skilled in the art, the definitions and explanations of terms provided in this application shall prevail.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy, where alkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.

The term "hydroxy" refers to the -OH group.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "amino" refers to the group -NH ₂ .

The term "cyano" refers to the -CN group.

The term "nitro" refers to the -NO ₂ group.

The term "carboxy" refers to the group -C(O)OH.

The term "alkoxycarbonyl" refers to the group -C(O)O(alkyl) or -C(O)O(cycloalkyl), where alkyl and cycloalkyl are as defined above.

All of "X is selected from the group consisting of A, B or C", "X is selected from the group consisting of A, B and C", "X is A, B or C", "X is A, B and C" and the like have the same meaning, i.e. X can be any one or more of A, B, and C.

"Optional" or "optional" means that the event or circumstance described below may occur, but does not necessarily occur, and such description includes the situation where the event or circumstance occurs or does not occur. For example, the phrase "heterocyclyl optionally substituted with alkyl" means that an alkyl group may be present, but not necessarily present, and such description includes the situation where the heterocyclyl is substituted with alkyl and the situation where the heterocyclyl is not substituted with alkyl.

"Substituted" refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently substituted with the appropriate number of substituents. It goes without saying that substituents exist only in their possible chemical position. One skilled in the art, without undue effort, is able to determine by experiment or theory whether substitution is possible or not. For example, an amino or hydroxy combination having free hydrogen and carbon atoms having unsaturated bonds (such as olefins) can be unstable.

"Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention or their physiologically/pharmaceutically acceptable salts or prodrugs with other chemical components and other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate the administration of a compound to the body, thereby facilitating the absorption of the active ingredient in a manner that exhibits biological activity.

A "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is safe and effective in mammals and has the desired biological activity.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably alkyl having 1 to 12 carbon atoms and more preferably alkyl having 1 to 6 carbon atoms. carbon. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-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, 5-methylhexyl, 2.3 -dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl , 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl , 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and their various branched isomers. More preferably, the alkyl group is a lower alkyl having 1 to 6 carbon atoms, and 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 and the like. The alkyl group may be substituted or unsubstituted. Once substituted, the substituent(s) group(s) may be substituted(s) at any available point of attachment. The substituent(s) group(s) preferably represents(s) one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heteroalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy and alkoxycarbonyl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent group having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms, and most preferably 5 to 6 carbon atoms. . Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like. Polycyclic cycloalkyl includes cycloalkyl having a spiro ring, a fused ring, or an internally bridged ring.

The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group with individual rings connected via one common carbon atom (called a spiro atom), where the rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron systems. Spirocycloalkyl is preferably 6-14 membered spirocycloalkyl and more preferably 7-10 membered spirocycloalkyl. According to the number of common spiro atoms between the rings, spirocycloalkyl can be divided into monospirocycloalkyl, dispirocycloalkyl or polyspirocycloalkyl, and spirocycloalkyl is preferably monospirocycloalkyl or dispirocycloalkyl and more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/ 6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

.

.

The term "fused cycloalkyl" refers to a 5-20 membered whole carbon polycyclic group where each ring in the system shares an adjacent pair of carbon atoms with another ring, where one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. The fused cycloalkyl is preferably a 6-14 membered fused cycloalkyl and more preferably a 7-10 membered fused cycloalkyl. Depending on the number of rings, the fused cycloalkyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, and the fused cycloalkyl is preferably bicyclic or tricyclic fused cycloalkyl and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused cycloalkyl. Non-limiting examples of fused cycloalkyl include:

.

.

The term "internally bridged cycloalkyl" refers to a 5-20 membered whole carbon polycyclic group where every two rings in the system share two unbonded carbon atoms, where the rings may have one or more double bonds, but none of the rings is fully conjugated. π-electron system. The internally bridged cycloalkyl is preferably a 6-14 membered internally bridged cycloalkyl and more preferably a 7-10 membered internally bridged cycloalkyl. Depending on the number of rings, internally bridged cycloalkyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic internally bridged cycloalkyl and internally bridged cycloalkyl preferably is internally bridged bicyclic, tricyclic or tetracyclic cycloalkyl and more preferably internally bicyclic or tricyclic cycloalkyl bridge. Non-limiting examples of internally bridged cycloalkyls include:

The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocyclyl ring, where the ring associated with the parent structure is cycloalkyl. Non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl and the like, and preferably benzocyclopentyl, tetrahydronaphthyl. Cycloalkyl may be optionally substituted or unsubstituted. When substituted, the substituent(s) group(s) preferably is(are) one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano , cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heteroalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy and alkoxycarbonyl.

The term "heterocyclyl" refers to a 3-20 membered saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group, where one or more ring atoms are heteroatoms selected from the group consisting of N, O and S(O) _m (where m is is an integer from 0 to 2), but excluding -OO-, -OS- or -SS- in the ring, with the remaining ring atoms being carbon atoms. Preferably a heterocyclyl has 3 to 12 ring atoms where 1 to 4 atoms are heteroatoms, more preferably a heterocyclyl has 3 to 8 ring atoms where 1 to 3 ring atoms are heteroatoms and most preferably a heterocyclyl has 5 to 6 ring atoms, where 1 to 2 or 1 to 3 atoms are heteroatoms. Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like, and preferably tetrahydropyranyl, piperidinyl, pyrrolidinyl. Polycyclic heterocyclyl includes a heterocyclyl having a spiro ring, a fused ring, or an internally bridged ring.

The term "spiroheterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl group with individual rings connected via a single common atom (called a spiro atom), where one or more of the ring atoms are heteroatoms selected from the group consisting of N, O, and S( O) _m (where m is an integer from 0 to 2), with the remaining ring atoms being carbon atoms, where the rings may contain one or more double bonds, but none of the rings has a fully conjugated system of π electrons. Spiroheterocyclyl is preferably 6-14 membered spiroheterocyclyl and more preferably 7-10 membered spiroheterocyclyl. According to the number of common spiroatoms between the rings, spiroheterocyclyl can be divided into monospiroheterocyclyl, dispyroheterocyclyl or polyspiroheterocyclyl, and spiroheterocyclyl is preferably monospiroheterocyclyl or dispyroheterocyclyl and more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered /6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyls include:

.

.

The term "fused heterocyclyl" refers to a 5-20 membered polycyclic heterocyclyl group where each ring in the system shares an adjacent pair of atoms with another ring, where one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system, and where one or more ring atoms are heteroatoms selected from the group consisting of N, O and S(O) _m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon atoms. The fused heterocyclyl is preferably a 6-14 membered fused heterocyclyl and more preferably a 7-10 membered fused heterocyclyl. Depending on the number of rings, fused heterocyclyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl and fused heterocyclyl is preferably bicyclic or tricyclic fused heterocyclyl and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclyl include:

и

.

and

.

The term "internally bridged heterocyclyl" refers to a 5-14 membered polycyclic heterocyclyl group where every two rings in the system share two unbonded atoms, where the rings may have one or more double bonds, but none of the rings has a fully conjugated π -electron system and where one or more ring atoms are heteroatoms selected from the group consisting of N, O and S(O) _m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon atoms . The internally bridged heterocyclyl is preferably a 6-14-membered internally bridged heterocyclyl, and more preferably a 7-10-membered internally bridged heterocyclyl. According to the number of rings, internally bridged heterocyclyl can be divided into bicyclic, tricyclic, tetracyclic or polycyclic internally bridged heterocyclyl, and internally bridged heterocyclyl is preferably bicyclic, tricyclic or tetracyclic internally bridged heterocyclyl and more preferably bicyclic or tricyclic heterocyclyl with internal bridge. Non-limiting examples of internally bridged heterocyclyls include:

.

.

The heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, where the ring linked to the parent structure is heterocyclyl. Non-limiting examples of it include:

и тому подобное.

etc.

The heterocyclyl may be optionally substituted or unsubstituted. When substituted, the substituent(s) group(s) preferably is(are) one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano , cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heteroalkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxy and alkoxycarbonyl.

The term "aryl" refers to a 6-14 membered full carbon monocyclic ring or polycyclic fused ring (i.e. each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) having a conjugated π electron system, preferably 6- 10 membered aryl and more preferably 5-6 membered aryl, such as phenyl and naphthyl. An aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, where the ring linked to the parent structure is an aryl ring. Non-limiting examples of these include:

и

.

and

.

Aryl may be substituted or unsubstituted. When substituted, the substituent(s) group(s) preferably is(are) one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano , cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heteroalkoxy, cycloalkylthio, heterocyclylthio, carboxy and alkoxycarbonyl.

The term "heteroaryl" refers to a 5-14 membered heteroaromatic system having 1 to 4 heteroatoms selected from the group consisting of O, S, and N. Heteroaryl is preferably a 5-10 membered heteroaryl having 1 to 3 heteroatoms , more preferably 5- or 6-membered heteroaryl having 1 to 2 heteroatoms, preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl and the like, preferably imidazolyl, pyrazolyl, pyrimidinyl, thiazolyl, and more preferably pyrazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring associated with the parent structure is a heteroaryl ring. Non-limiting examples of these include:

и

.

and

.

Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituent(s) group(s) preferably is(are) one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano , cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heteroalkoxy, cycloalkylthio, heterocyclylthio, carboxy and alkoxycarbonyl.

The term "alkoxy" refers to the group -O-(alkyl) or -O-(unsubstituted cycloalkyl), where alkyl is as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted. When substituted, the substituent(s) group(s) preferably is(are) one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano , cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heteroalkoxy, cycloalkylthio, heterocyclylthio, carboxy and alkoxycarbonyl.

The term "amino protecting group" refers to a group suitable for protecting (preventing exposure to) an amino group from a chemical reaction and is easily removed after the completion of the chemical reaction in other parts of the molecule. Typical representatives of these groups include unsubstituted or substituted acyl, unsubstituted or substituted allyl, aryl, arylalkoxymethyl, arylalkyl, or heterocyclyl formed together with a nitrogen atom and a salt. Non-limiting examples of the amino protecting group include tert-butoxycarbonyl (Boc), benzyloxycarbonyl, isobutoxycarbonyl, fluorenylmethoxycarbonyl (Fmoc), benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, phthaloyl (Pht), succinimidyl, maleimido, benzyl, allyloxycarbonyl, p-methoxybenzyl, and the like. similar. These groups may be optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy, hydroxy, nitro, acylamino, benzyl substituted with acyl and the like, o-methylbenzyl, trityl and diphenylmethyl. The amino protecting group is preferably t-butoxycarbonyl and fluorenylmethoxycarbonyl (Fmoc).

The term "synergistic action" includes additive action, potentiating action and sensitizing action. The "synergistic effect" of the present invention includes, but is not limited to, reduced resistance when a KOR agonist or MOR agonist is used as monotherapy, dose reduction when a KOR agonist or MOR agonist is used as monotherapy, reduced side effects when a KOR agonist or a MOR agonist is used in a monotherapy regimen, an improvement in the action of alleviating and/or treating pain when a dose of a KOR agonist and/or the same dose of an MOR agonist is used in a monotherapy regimen.

The term "acute pain" refers to pain caused by a harmful stimulus resulting from damage and/or disease to the skin, deep body structures or organs, or transient pain caused by abnormal muscle or organ function that does not cause actual tissue damage.

The term "chronic pain" refers to pain that continues beyond the normal course of an acute illness or a reasonable time for injury to heal, pain associated with a chronic pathological process that causes persistent pain, or pain that recurs after a certain interval (several days, weeks, months and years). In addition, chronic pain also includes pain that is still present after a cure has been achieved or after a normal course of treatment.

The term "inflammatory pain" refers to pain caused by nerve stimulation in local acute inflammation or chronic inflammation.

The term "ischemic pain" refers to pain caused by poor blood supply to the extremities or organs.

The term "neuropathic pain" refers to pain caused by a primary or secondary injury, or dysfunction or temporary disturbance of the peripheral or central nervous system.

The term "pain caused by malignant proliferative diseases" refers to pain caused by tumors and cancer resulting from malignant proliferation of somatic cells, pain caused by lesions resulting from malignant proliferation of a virus in human organs, glands, blood system and skin, and pain caused by damage resulting from the malignant reproduction of bacteria in the organs, glands, blood system and skin of a person.

The term "tissue" refers to a population of cells that are identical or similar in morphology and identical in function, including, but not limited to, epithelial tissue, connective tissue, muscle tissue, and nervous tissue, such as cartilage tissue, bone tissue, skeletal muscle , myocardium and smooth muscle.

The term "moderate to very severe pain" refers to very severe pain that can only be relieved by pain medication, pain that affects disease management and/or vital signs, and persistent pain that affects recovery.

The term "initial dose" refers to the dose administered for the first time to eliminate clinical symptoms, when continuous administration is required.

The term "maintenance dose" refers to the dose administered to consolidate and maintain efficacy after clinical symptoms are controlled or alleviated.

The term "administration in accordance with the need for pain" refers to the introduction with the aim of alleviating and/or treating pain in accordance with the degree of subjective perception of pain in mammals.

The meaning of the term "surgery" is not limited to the generally accepted definition of surgery, which includes the content disclosed in the Catalog of the Classification of Surgery (2011 edition) of the Ministry of Health. Surgery according to the present invention broadly includes surgical procedures in which at least one incision is made in the skin and mucosa, and non-traditional medical procedures (eg, interventional procedures involving diagnosis and treatment).

The term "pain induced by surgery" refers to pain response following trauma or stimulation during surgery on body tissue, including preoperative, intraoperative, and postoperative pain during the perioperative period, including, but not limited to, pain following surgical procedures (e.g., postoperative pain caused by appendectomy, open colorectal surgery, hernia repair, prostatectomy, colonectomy, gastrectomy, splenectomy, colectomy, colostomy, pelvic laparoscopy, tubal ligation, hysterectomy, vasectomy, or cholecystectomy), pain after treatment (eg, pain after colonoscopy, cystoscopy, hysteroscopy or biopsy of the cervix or endometrium).

The term "pain caused by tumors" refers to pain directly caused by tumors, pain caused by treatment of tumors, pain indirectly caused by tumors.

BRIEF DESCRIPTION OF THE DRAWINGS

In FIG. 1 shows the effect of the combination of a KOR agonist and a MOR agonist (Compound 5 and Compound 20) of the present invention on mechanical withdrawal threshold in rats in the incision pain test.

DETAILED DESCRIPTION OF THE INVENTION

Illustrative experimental solutions for the use of the composition of the present invention for the relief and/or treatment of pain are provided below in order to demonstrate the beneficial activity and beneficial technical effects of the composition of the present invention. However, it should be understood that the following experimental solutions are merely examples of the present invention and are not intended to limit the scope of the present invention. A person skilled in the art, based on the provisions of the description, can make suitable modifications or changes in the technical solutions of the present invention, without departing from the essence and scope of the present invention.

Example 1 Preparation of Compound 5

Compound 5 was identified by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts (δ) are given in 10 ^-6 ( ^ppm ). NMR was performed on a Bruker AVANCE-400 instrument. Deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), and deuterated methanol (CD ₃ OD) served as the determination solvents, and tetramethylsilane (TMS) served as the internal standard.

MS was determined using a FINNIGAN LCQAd mass spectrometer (ESI) (manufacturer: Thermo, type: Finnigan LCQ advantage MAX).

A Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate was used as a silica gel thin layer chromatography (TLC) plate. The size of the silica gel plate used in TLC was 0.15 to 0.2 mm, and the size of the silica gel plate used in product purification was 0.4 mm to 0.5 mm.

Yantai Huanghai silica gel with a size of 200 to 300 mesh was generally used as the support for column chromatography.

Prep Star SD-1 (Varian Instruments Inc.) or SFC-multigram (Berger Instruments Inc.) was used for chiral preparative column chromatography.

Known starting materials of the present invention can be obtained by methods known in the art or can be obtained from ABCR GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, Accela ChemBio Inc. or Dari Chemical Company, etc.

Unless otherwise indicated, a solution refers to an aqueous solution.

Unless otherwise indicated, the reaction temperature is room temperature from 20 to 30°C.

The reaction progress of the examples was monitored by thin layer chromatography (TLC), and the developing solvent system used in the reactions included: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether and ethyl acetate system, D: acetone. The volume ratio of solvents was adjusted according to the polarity of the compounds. The eluent system in column chromatography and the system of developing solvents in thin layer chromatography for purification of compounds included: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: dichloromethane and acetone system. The volume ratio of solvents was adjusted according to the polarity of the compounds, and a small amount of an alkaline reagent such as triethylamine or an acidic reagent such as acetic acid may also be added to adjust.

The chromatograph used to carry out the HPLC in the examples was Gilson-281, the chromatographic column was Shim-pack PREP-ODS purchased from Shimadzu, the mobile phase used was a trifluoroacetic acid buffer system, i. water (containing 0.05% trifluoroacetate)-acetonitrile.

Each of the compounds in the form of trifluoroacetate salt in the examples can be obtained in the free state by the following general method: its trifluoroacetate salt was dissolved in a suitable solvent (such as methanol, ethanol, tetrahydrofuran, acetone, etc.) and a weak base (such as bicarbonate) was added sodium, sodium carbonate, potassium carbonate, etc.) to bring the pH to neutral, the solution was concentrated under reduced pressure, and the residue was purified to obtain a free state.

4-amino-1-((2R,5R,8R,14R)-2-(4-aminobutyl)-8-benzyl-5-isobutyl-4,7,10-trioxo-14-phenyl-3,6,9 ,12-tetraazapentadecan-1-oil)piperidine-4-carboxylic acid

Stage 1

4-benzyl 1-tert-butyl-4-(((benzyloxy)carbonyl)amino)piperidine-1,4-dicarboxylate 1b

4-(((Benzyloxy)carbonyl)amino)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid 1a (1.2 g, 0.0032 mol, prepared by a known method disclosed in "Bioorganic Medicinal Chemistry Letters", 2007, 7(9), 2448-2451"), benzyl bromide (0.65 g, 0.0038 mol) and cesium carbonate (2.1 g, 0.0064 mol) were dissolved in 20 ml of N,N-dimethylformamide and stirred for 12 hours at room temperature The reaction solution was poured into water and extracted with ethyl acetate (30 ml x 3) The organic phases were combined, dried over anhydrous sodium sulfate and filtered The filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography using eluent system B to give the title compound 1b (800 mg, colorless viscous, yield: 53%).

Stage 2

Benzyl 4-(((benzyloxy)carbonyl)amino)piperidine-4-carboxylate hydrochloride 1c

1b (800 mg, 1.71 mmol) was dissolved in 2 ml of dichloromethane and 2 ml of a solution of 4M hydrochloric acid in 1,4-dioxane was added. After stirring for 4 hours at room temperature, the reaction solution was concentrated under reduced pressure to give the crude title compound 1c (800 mg, light yellow viscous) which was used directly in the next step without purification.

Stage 3

(R)-Benzyl 1-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-((tert-butoxycarbonyl)amino)hexanoyl)-4-(((benzyloxy)carbonyl )amino)piperidine-4-carboxylate 1e

Crude compound 1c (800 mg, 1.97 mmol) and (R)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-6-((tert-butoxycarbonyl)amino)hexanoic acid 1d (926 mg, 1.97 mmol, obtained by a known method disclosed in "ChemMedChem, 2015, 10(7), 1232-1239") was dissolved in 20 ml of N,N-dimethylformamide. 2-(7-Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.12 g, 3.0 mmol) and N,N-diisopropylethylamine (0.7 ml, 3.94 mmol) were added. After stirring for 12 hours at room temperature, the reaction solution was poured into a 2N citric acid solution and extracted with ethyl acetate (30 ml×3). The organic phases were combined, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude title compound 1e (1.6 g, yellow viscous) which was used directly in the next step without purification.

Stage 4

(R)-Benzyl 1-(2-amino-6-((tert-butoxycarbonyl)amino)hexanoyl)-4-(((benzyloxy)carbonyl)amino)piperidine-4-carboxylate 1f

The crude compound 1e (1.6 g, 0.002 mol) was dissolved in 10 ml of dichloromethane and then 10 ml of piperidine was added. After stirring for 2 hours at room temperature, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography using eluent system A to give the title compound 1f (900 mg, light yellow solid, yield: 77%).

Stage 5

(R)-Benzyl 2-((R)-2-(2-chloroacetamido)-3-phenylpropionamido)-4-methylpentanoate 1i

(R)-Benzyl 2-((R)-2-amino-3-phenylpropanamido)-4-methylpentanoate 1 g (500 mg, 1.36 mmol, obtained by the method disclosed in patent application "US20110212882A1") and triethylamine ( 275 mg, 2.72 mmol) was dissolved in 10 ml of dichloromethane and then chloroacetyl chloride (230 mg, 2 mmol) was added dropwise. After stirring for 12 hours at room temperature, the reaction solution was poured into water and washed with a saturated ammonium chloride solution. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude title product 1i (500 mg, yellow viscous) which was used directly in the next step without purification.

Stage 6

(R)-Benzyl 4-methyl-2-((R)-3-phenyl-2-(2-(((R)-2-phenylpropyl)amino)acetamido)propanamido)pentanoate 5b

1i (500 mg, 1.12 mmol) and (R)-2-phenylpropan-1-amine 5a (228 mg, 1.68 mmol) obtained by a known method disclosed in "Angewandte Chemie, International Edition, 2003, 42( 39), 4793-4795") was dissolved in 10 ml of N,N-dimethylformamide and then potassium iodide (372 mg, 2.24 mmol) and potassium carbonate (309 mg, 2.24 mmol) were added. The reaction solution was heated to 60°C and stirred for 12 hours. The reaction solution was cooled to room temperature, water was added and extracted with dichloromethane (30 ml×3). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude title compound 5b (600 mg, brown viscous) which was used directly in the next step without purification.

Stage 7

(9R,12R)-Benzyl 9-benzyl-12-isobutyl-2,2-dimethyl-4,7,10-trioxo-5-((R)-2-phenylpropyl)-3-oxa-5,8,11 -triazatridecan-13-oat 5c

The crude compound 5b (600 mg, 1.1 mmol) was dissolved in 20 ml dichloromethane and then di-tert-butyl dicarbonate (361 mg, 1.66 mmol) and triethylamine (222 mg, 2.2 mmol) were added. After stirring for 12 hours at room temperature, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography using elution system A to give the title compound 5c (580 mg, light yellow viscous, yield: 82%).

Stage 8

(9R,12R)-9-benzyl-12-isobutyl-2,2-dimethyl-4,7,10-trioxo-5-((R)-2-phenylpropyl)-3-oxa-5,8,11- triazatridecan-13-oic acid 5d

5c (580 mg, 0.9 mmol) was dissolved in 10 ml of methanol and then palladium charcoal (60 mg, catalytic amount) was added. After completion of the addition, the reaction system was purged with hydrogen three times and stirred for 12 hours at room temperature. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to give crude title compound 5d (500 mg, light yellow viscous substance), which was used directly in the next step without purification.

Stage 9

Benzyl 1-((9R,12R,15R)-9-benzyl-15-(4-((tert-butoxycarbonyl)amino)butyl)-12-isobutyl-2,2-dimethyl-4,7,10,13- tetraoxo-5-((R)-2-phenylpropyl)-3-oxa-5,8,11,14-tetraazahexadecane-16-oil)-4-(((benzyloxy)carbonyl)amino)piperidine-4-carboxylate 5e

Crude compound 5d (365 mg, 0.66 mmol), 1f (393 mg, 0.66 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (376 mg, 0.66 mmol) 99 mmol) and N,N-diisopropylethylamine (0.16 ml, 0.99 mmol) was dissolved in 10 ml of N,N-dimethylformamide. After stirring for 2 hours at room temperature, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography using eluent system A to give the title compound 5e (170 mg, light yellow solid, yield: 23%).

Stage 10

4-amino-1-((9R,12R,15R)-9-benzyl-15-(4-((tert-butoxycarbonyl)amino)butyl)-12-isobutyl-2,2-dimethyl-4,7,10 ,13-tetraoxo-5-((R)-2-phenylpropyl)-3-oxa-5,8,11,14-tetraazahexadecane-16-oil)piperidine-4-carboxylic acid 5f

5e (80 mg, 0.0706 mmol) was dissolved in 10 ml of methanol, then palladium charcoal (10 mg, catalytic amount) was added. After completion of the addition, the reaction system was purged with hydrogen three times and stirred for 12 hours at room temperature. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the crude title compound 5f (60 mg, white solid), which was used directly in the next step without purification.

Stage 11

Trifluoroacetate 4-amino-1-((2R,5R,8R,14R)-2-(4-aminobutyl)-8-benzyl-5-isobutyl-4,7,10-trioxo-14-phenyl-3,6, 9,12-Tetraazapentadecan-1-oil)piperidine-4-carboxylic acid 5g

The crude product 5f (60 mg, 0.066 mmol) was dissolved in 2 ml of dichloromethane and then 1 ml of a solution of 4M hydrochloric acid in 1,4-dioxane was added. After stirring for 2 hours at room temperature, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by high performance liquid chromatography to give the title compound 5g (30 mg, white solid).

MS m/z (ESI): 708.6 [M+1].

Stage 12

4-amino-1-((2R,5R,8R,14R)-2-(4-aminobutyl)-8-benzyl-5-isobutyl-4,7,10-trioxo-14-phenyl-3,6,9 ,12-tetraazapentadecan-1-oil)piperidine-4-carboxylic acid 5

5g (30 mg, 0.028 mmol) was dissolved in 5 ml of a mixed solvent of methanol/water (v:v = 10:1), and then solid sodium bicarbonate (10 mg) was added to adjust the pH to 7. The reaction solution was stirred for 30 minutes and then concentrated under reduced pressure. To the resulting residue was added 10 ml of dichloromethane, stirred for 30 minutes and filtered. The filter cake was washed with 10 ml of dichloromethane and the filtrate was concentrated under reduced pressure to give the title compound 5 (17 mg, white solid).

MS m/z (ESI): 708.6 [M+1].

¹ H NMR (400 MHz, CD ₃ OD): δ 7.33-7.19 (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).

Example 2 Preparation of Compound 20

The device, equipment and materials needed to obtain compound 20 are shown in example 1.

(1S,4S)-4-ethoxy-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)-1,2,3 ,4-tetrahydronaphthalene-1-amine

Stage 1

(S)-Tert-butyl (1,2,3,4-tetrahydronaphthalen-1-yl)carbamate 11a

(S)-1,2,3,4-tetrahydronaphthalene-1-amine 10a (3 g, 20.41 mmol) prepared according to the known method disclosed in "Angewandte Chemie-International Edition, 45(28), 4641 -4644, 2006") was dissolved in 100 ml dichloromethane, then triethylamine (5.7 ml, 40.82 mmol) and di-tert-butyl dicarbonate (4.9 g, 22.45 mmol) were added. After stirring for 12 hours, the reaction solution was washed successively with water (100 ml) and saturated sodium bicarbonate solution (100 ml). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the crude title product 11a (5.6 g) as a light yellow oil, which was used directly in the next step without purification.

MS m/z (ESI): 248.3 [M+1]

Stage 2

(S)-Tert-butyl (4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate 11b

The crude (S)-tert-butyl (1,2,3,4-tetrahydronaphthalen-1-yl)carbamate 11a (5.6 g, 20.41 mmol) was dissolved in 90 ml of a mixed solution of acetone and water (v/v = 2:1), then magnesium sulfate (5.5 g, 45.66 mmol) was added and potassium permanganate (7.22 g, 45.66 mmol) was added slowly with stirring. The reaction system was stirred for 12 hours. The reaction solution was then concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using n-hexane/ethyl acetate to give the title product 11b (3.1 g, 52% yield) as an off-white solid.

MS m/z (ESI): 262.3 [M+1].

Stage 3

tert-Butyl ((1S,4S)-4-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate 14a

(S)-Tert-butyl (4-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate 11b (100 mg, 0.883 mmol) was dissolved in 5 ml of toluene. The reaction solution was cooled to 0°C, (R)-2-methyl-CBS-oxazaborolidin (0.1 ml, 0.076 mmol) was added and stirred for 5 minutes. Borane methyl sulfide (0.88 ml, 0.76 mmol) was then added and the reaction mixture was stirred for 2 hours. The reaction was quenched by adding 50 ml of saturated sodium chloride solution and was extracted with ethyl acetate (30 ml×3). The organic phases were combined, washed with saturated sodium chloride solution (30 ml×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by dichloromethane/methanol thin layer chromatography to give the title product 14a (60 mg, 60% yield) as a white solid.

MS m/z (ESI): 208.3 [M-55].

Stage 2

Tert-butyl ((1S,4S)-4-ethoxy-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate 19a

Crude tert-butyl ((1S)-4-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate 14a (850 mg, 3.23 mmol), silver oxide (76 mg, 0.33 mmol) and iodoethane (1.3 ml, 16.15 mmol) were dissolved in 30 ml of dichloromethane, and the reaction solution was stirred for 48 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 19a (800 mg) as a yellow oil, which was used directly in the next step without purification.

MS m/z (ESI): 236.1 [M-55]

Stage 3

(1S,4S)-4-ethoxy-1,2,3,4-tetrahydronaphthalene-1-amine 19b

The crude compound 19a (698 mg, 2.4 mmol) was dissolved in 4 ml of dichloromethane, then 8 ml of a solution of 4M hydrochloric acid in 1,4-dioxane was added. After stirring for 2 hours, the reaction solution was concentrated under reduced pressure, triturated with ethyl acetate (30 ml) and filtered. The filter cake was dissolved in 20 ml of a mixed solution of dichloromethane and methanol (v:v = 5:1). A saturated sodium bicarbonate solution was added to adjust the pH of the reaction solution to a value of 7 to 8. The reaction solution was concentrated under reduced pressure, washed with a mixed solution of dichloromethane and methanol (v:v = 5:1) (30 ml×2) and filtered. The filtrate was concentrated under reduced pressure to give the crude title product 19b (310 mg) as a yellow liquid, which was used directly in the next step without purification.

MS m/z (ESI): 191.1 [M+1]

Stage 4

(1S,4S)-4-ethoxy-N-(2-((R)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethyl)-1,2,3 ,4-tetrahydronaphthalene-1-amine 20

(R)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)acetaldehyde 5a (500 mg, 1.85 mmol) obtained according to the method disclosed in the application patent "WO2012129495") and the crude compound 19b (310 mg, 1.85 mmol) was dissolved in 30 ml of dichloromethane and the mixture was stirred for 40 minutes, then sodium triacetoxyborohydrib (980 mg, 4.63 mmol) was added. After stirring for 2 hours, the reaction solution was washed successively with saturated sodium bicarbonate solution (30 ml×3) and saturated sodium chloride solution (30 ml×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by dichloromethane/methanol flash chromatography to give the title product 20 (280 mg, 35% yield) as a yellow viscous solid.

MS m/z (ESI): 435.3 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.74 (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).

Example 3 Therapeutic effect of the combination of KOR agonist and MOR agonist of the present invention on incision pain in rats

Compounds tested

Compound 5 (obtained in accordance with the method described in Example 1) and compound 20 (obtained in accordance with the method described in Example 2). The dose of the compound was calculated from the original data.

Test animals

Experimental male Wistar rats were purchased from Shanghai Slac Laboratory Animal Co., Ltd. Rats weighed between 140 and 160 g at purchase and were housed at 5 rats per cage, under conditions of 12/12 hour light/dark cycle adjustment, constant temperature 23 ± 1°C, humidity 50 to 60%, and free access to food and water. After purchase, the animals were subjected to adaptive feeding for more than 3 days before the start of the experiment.

Experiment device

Electronic Von Frey: UGO BASILE, type 38450.

Test compound solution composition

Both compound 5 and compound 20 were prepared using saline.

Tested method

Rats were randomly divided into the following groups based on body weight: control group (n=10), model group (n=10) and drug group (n=50). The drug-administered group was divided into the following groups: compound group 20-0.03mg/kg (n=10), compound group 5-0.3mg/kg (n=10), compound group 5-0, 1 mg/kg + compound 20-0.03 mg/kg (n = 10), group compound 5-0.3 mg/kg + compound 20-0.03 mg/kg (n = 10) and group compound 5- 1 mg/kg + compound 20-0.03 mg/kg (n = 10). The model group and the drug-administered group were subjected to incision surgery. During the operation, rats were anesthetized with isoflurane. An incision (1 cm long) through the skin and fascia was made with a #10 surgical blade in the middle of the left hind paw. The skin was closed with a sterile 3-0 silk surgical suture. The damaged area was disinfected with an antibiotic ointment and iodophor. Animals were returned to their original location for recovery overnight. After 24 hours, the drug was administered through the tail vein, and the control group and the model group were administered saline twice with an interval of 15 minutes. Compound 20 alone group was intravenously injected with an appropriate dose of compound 20 and pure solvent to obtain compound 5. Compound 5 alone was administered with an appropriate dose of compound 5 and pure solvent intravenously to obtain compound 20. an appropriate dose of Compound 5 was administered intravenously, followed by an appropriate dose of Compound 20 intravenously 15 minutes later. Mechanical pain threshold in each group was measured with an Electronic Von Frey device 30 minutes after injection to evaluate the analgesic effect of the drug on surgical incision pain and its intensity.

Data presentation and statistical processing

Experimental data were expressed as mean ± standard deviation (standard deviation). Statistical comparisons were made using the t-test in Excel software. The data between the model group and the control group were analyzed and compared to determine if there were significant statistical differences. #P less than 0.05 indicates that there is a significant difference between the model group and the control group, and ##P less than 0.01 indicates that there is a highly significant difference between the model group and the control group. ΔP less than 0.05 indicates that there is a significant difference between the drug-administered group and the model group, and ΔΔP less than 0.01 indicates that there is a highly significant difference between the drug-administered group and the model group. *P less than 0.05 indicates that there is a significant difference between the combination drug group and the single drug group, and **P less than 0.01 indicates that there is a highly significant difference between the group which was administered a combination of drugs and group, which was administered a single drug.

Experiment results

The results are shown in figure 1.

Experimental findings

The results of the experiment (Figure 1, mpk is the abbreviation of mg/kg) showed that the sensitivity threshold of the control group of rats was 14.48 g, and the sensitivity threshold of the model group was 8.91 g. Compared with the control group, the sensitivity threshold of the model group was significantly reduced (P less than 0.05). After administration of the drug, compared with the model group, the threshold of sensitivity in the compound 20-0.03 mg/kg group (compound 20, dose 0.03 mg/kg) increased significantly (P less than 0.01) to 14.46 g, with an increase of 62.3%, the threshold of sensitivity in the compound group 5-0.3 mg/kg was significantly increased (P less than 0.01) to 17.92 g, with an increase of 101.1%.

Compared to the model group, all combinations of compound 20-0.03 mg/kg and compound 5-0.1 mg/kg, compound 5-0.3 mg/kg, or compound 5-1 mg/kg can significantly increase (P less than 0.01) sensitivity threshold in rats up to 17.96 g, 22.29 g or 33.46 g, with an increase of 101.6%, 150.1% or 275.5%, respectively, indicating a dose-dependence the effect of a KOR agonist. The combined effects with three doses were better than the effect of compound 20-0.03 mg/kg alone. The combination of compound 20-0.03 mg/kg and compound 5-0.3 mg/kg or compound 5-1 mg/kg had a statistically significant difference (P less than 0.01).

Compared to compound 5-0.3 mg/kg alone, the combination of compound 20-0.03 mg/kg + compound 5-0.1 mg/kg had an equivalent increase in threshold. The combined effects of compound 20-0.03 mg/kg and compound 5-0.3 mg/kg or compound 5-1 mg/kg were better than compound 5-0.3 mg/kg alone. The combination of compound 20-0.03 mg/kg and compound 5-1 mg/kg had a statistically significant difference (P less than 0.01).

Thus, administration to the rat of compound 20-0.03mg/kg alone or compound 5-0.3mg/kg alone had a good effect of reducing incision pain (P less than 0.01). In addition, the results of testing the combined administration group showed that compound 20 and compound 5 had a synergistic effect, and the combined effect of compound 20 and compound 5 was more effective than the effect of the compound administered separately at the same dose.

Claims (8)

1. The use of a combination of an effective amount of a κ-opioid receptor (KOR) agonist and a μ-opioid receptor (MOR) agonist to produce a medicament for alleviating and/or treating traumatic pain, characterized in that the KOR agonist is

, and the MOR agonist is

, where the weight ratio of the KOR agonist to the MOR agonist is 1-50, the administration dose of the KOR agonist is 0.005-0.5 mg, and the administration dose of the MOR agonist is 0.001-0.01 mg. 2. Use according to claim 1, characterized in that the traumatic pain is selected from the group consisting of surgical pain, fracture pain, burn pain, abdominal trauma pain, spinal trauma pain, thoracic trauma pain, and post-traumatic pain. headache. 3. The use according to claim 2, characterized in that non-opioid analgesics or weak opioid analgesics are not used for traumatic pain and / or traumatic pain is not sensitive to non-opioid analgesics or weak opioid analgesics. 4. Use according to claim 1, characterized in that the combination also contains a third component selected from the group consisting of an opioid, a glucocorticoid, a non-steroidal anti-inflammatory drug, an anesthetic, a local anesthetic, an antidepressant, a calcium channel antagonist, an anticonvulsant, a blocker adrenal beta receptors and an analgesic stimulant.

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