New uses for cyclic ketone compounds

Abstract

The present invention provides a new use of cyclic ketone compounds, which belongs to the pharmaceutical field. The present invention is the first to discover a new pharmaceutical use of the cyclic ketone compounds in the field of perioperative medicine, and the future application of the compounds is bright.

Description

[Technical Field]

[0001] The present invention belongs to the pharmaceutical field, and specifically relates to a new use of cyclic ketone compounds in the field of perioperative medicine. [Background technology]

[0002] General anesthetics, also known as general anesthetics, are drugs that suppress central nervous system function, causing reversible loss of consciousness, sensation, and reflexes, and skeletal muscle relaxation. They are primarily used for anesthesia in surgical procedures. Postoperative recovery time from anesthesia is a key clinical issue and is closely related to multiple factors. Prolonged postoperative recovery time from anesthesia increases the time required for intubation and the patient's exposure to the risks of general anesthesia, leading to increased cardiovascular and pulmonary complications and adverse outcomes for surgical patients. Furthermore, prolonged recovery time from anesthesia significantly reduces operating room utilization, increasing room vacancy rates and increasing costs for patients and medical staff. Furthermore, with the evolution of the concept of day surgery, rapid and quality recovery from anesthesia is essential for the widespread adoption and safety of day surgery.

[0003] With the increasing demand for safety and controllability in surgery, some anesthetic antagonists have emerged. For example, naloxone, an opioid antagonist, neostigmine, a broad-spectrum muscle relaxant antagonist, and sugammadex, a specific antagonist of the muscle relaxant rocuronium bromide, can quickly reverse the anesthetic effects of opioids or muscle relaxants, facilitating patient recovery and emergency anesthesia reversal. However, with regard to general anesthetics, there is still a lack of means or methods to resolve the delayed recovery caused by long-term injection or to reverse the effects of general anesthetics in emergencies.

[0004] Currently, the only drug in clinical use with clear antagonistic effects is flumazenil. Flumazenil is a specific antagonist of benzodiazepines and can reverse the anesthetic effects induced by benzodiazepines. However, studies have demonstrated that flumazenil does not significantly antagonize the anesthetic effects induced by propofol. Given that benzodiazepines are no longer routinely used in clinical anesthesia, there is an urgent need to develop a broader spectrum of general anesthetic antagonists, particularly those that cover common general anesthetic drugs such as propofol and etomidate. Summary of the Invention

[0005] An object of the present invention is to provide a new use of cyclic ketone compounds in the field of perioperative medicine.

[0006] The present invention provides the use of a compound of formula I, or a stereoisomer thereof, or a deuterated derivative thereof, or a tritiated derivative thereof, or a metabolite thereof, or a prodrug thereof, or a salt thereof, or a solvate thereof, in the manufacture of an anaesthetic and / or sedative reversal medicament. TIFF0007801365000001.tif64170

[0007] where n is 0 or 1, m is 0 or 1, and when m is 1, R 10 is not available, R0 is L0L1L2R x1 is selected from L0, L1, and L2 each independently represent none, substituted or unsubstituted NHCO, substituted or unsubstituted NHCS, substituted or unsubstituted CO, substituted or unsubstituted COO, substituted or unsubstituted OCO, substituted or unsubstituted OCOO, substituted or unsubstituted C(SO), substituted or unsubstituted O, substituted or unsubstituted S, substituted or unsubstituted SO, substituted or unsubstituted SO2, substituted or unsubstituted NH, substituted or unsubstituted CH=N, substituted or unsubstituted CONH, substituted or unsubstituted NH(CS)S(CH2), substituted or unsubstituted C 1~3Alkylene group, substituted or unsubstituted C 2~4 Alkenylene group, substituted or unsubstituted C 2~4 alkynylene groups, R x1 is hydrogen, deuterium, tritium, halogen, aldehyde group, CN, N3, NO2, OAc, substituted or unsubstituted OSiH3, substituted or unsubstituted OOSiH3, substituted or unsubstituted SO3H, substituted or unsubstituted SiH3, substituted or unsubstituted CS2H, substituted or unsubstituted CSNH2, substituted or unsubstituted NH2, substituted or unsubstituted COOH, substituted or unsubstituted SH, substituted or unsubstituted SeO2H, substituted or unsubstituted OH, substituted or unsubstituted N=NH, substituted or unsubstituted =O, substituted or unsubstituted CH=NH, substituted or unsubstituted C 1~5 Alkyl groups, substituted or unsubstituted C 1~5 Alkoxy groups, substituted or unsubstituted C 2~6 Alkenyl group, substituted or unsubstituted C 2~6 selected from alkynyl groups, substituted or unsubstituted saturated or unsaturated heterocyclic groups, substituted or unsubstituted saturated or unsaturated cycloalkyl groups, substituted or unsubstituted fused cycloalkyl groups, and substituted or unsubstituted fused heterocyclic groups; R1 and R2 are independently L3L4L5R x2 , =NL5R x2 , =C(L6R x3 )(L7R x4 or R1 and R2 are bonded to form a ring; L3, L4, L5, L6, and L7 each independently represent none, substituted or unsubstituted NHCO, substituted or unsubstituted NHCS, substituted or unsubstituted CO, substituted or unsubstituted COO, substituted or unsubstituted OCO, substituted or unsubstituted OCOO, substituted or unsubstituted C(SO), substituted or unsubstituted O, substituted or unsubstituted S, substituted or unsubstituted SO, substituted or unsubstituted SO2, substituted or unsubstituted NH, substituted or unsubstituted CH=N, substituted or unsubstituted CONH, substituted or unsubstituted NH(CS)S(CH2), substituted or unsubstituted C 1~3 alkylene groups, R x2 , R x3 , R x4are each independently hydrogen, deuterium, tritium, a halogen, an aldehyde group, CN, N3, NO2, OAc, substituted or unsubstituted OSiH3, substituted or unsubstituted OOSiH3, substituted or unsubstituted SO3H, substituted or unsubstituted SiH3, substituted or unsubstituted C5SH, substituted or unsubstituted NH2, substituted or unsubstituted COOH, substituted or unsubstituted SH, substituted or unsubstituted SeO2H, substituted or unsubstituted OH, substituted or unsubstituted N=NH, substituted or unsubstituted =O, substituted or unsubstituted CH=NH, substituted or unsubstituted C 1~5 Alkyl groups, substituted or unsubstituted C 1~5 Alkoxy groups, substituted or unsubstituted C 2~6 Alkenyl group, substituted or unsubstituted C 2~6 selected from alkynyl groups, substituted or unsubstituted saturated or unsaturated heterocyclic groups, substituted or unsubstituted saturated or unsaturated cycloalkyl groups, substituted or unsubstituted fused cycloalkyl groups, and substituted or unsubstituted fused heterocyclic groups; R3, R 10 are independently L8L9L 10 R x5 is selected from L8, L9, L 10 are each independently none, substituted or unsubstituted NHCO, substituted or unsubstituted NHCS, substituted or unsubstituted CO, substituted or unsubstituted COO, substituted or unsubstituted OCO, substituted or unsubstituted OCOO, substituted or unsubstituted C(SO), substituted or unsubstituted O, substituted or unsubstituted S, substituted or unsubstituted SO, substituted or unsubstituted SO2, substituted or unsubstituted NH, substituted or unsubstituted CH=N, substituted or unsubstituted CONH, substituted or unsubstituted NH(CS)S(CH2), substituted or unsubstituted C 1~3 alkylene groups, R x5is hydrogen, deuterium, tritium, halogen, aldehyde group, CN, N3, NO2, OAc, substituted or unsubstituted OSiH3, substituted or unsubstituted OOSiH3, substituted or unsubstituted SO3H, substituted or unsubstituted SiH3, substituted or unsubstituted CS2H, substituted or unsubstituted CSNH2, substituted or unsubstituted NH2, substituted or unsubstituted COOH, substituted or unsubstituted SH, substituted or unsubstituted SeO2H, substituted or unsubstituted OH, substituted or unsubstituted N=NH, substituted or unsubstituted =O, substituted or unsubstituted CH=NH, substituted or unsubstituted C 1~5 Alkyl groups, substituted or unsubstituted C 1~5 Alkoxy groups, substituted or unsubstituted C 2~6 Alkenyl group, substituted or unsubstituted C 2~6 selected from alkynyl groups, substituted or unsubstituted saturated or unsaturated heterocyclic groups, substituted or unsubstituted saturated or unsaturated cycloalkyl groups, substituted or unsubstituted fused cycloalkyl groups, and substituted or unsubstituted fused heterocyclic groups; R4, R5, R6, and R7 are each independently L 11 L 12 L 13 R x6 , =NL 13 R x6 , =C(L 14 R x7 )(L 15 R x8 ) and L 11 , L 12 , L 13 , L 14 , L 15 are each independently none, substituted or unsubstituted NHCO, substituted or unsubstituted NHCS, substituted or unsubstituted CO, substituted or unsubstituted COO, substituted or unsubstituted OCO, substituted or unsubstituted OCOO, substituted or unsubstituted C(SO), substituted or unsubstituted O, substituted or unsubstituted S, substituted or unsubstituted SO, substituted or unsubstituted SO2, substituted or unsubstituted NH, substituted or unsubstituted CH=N, substituted or unsubstituted CONH, substituted or unsubstituted NH(CS)S(CH2), substituted or unsubstituted C 1~3 alkylene groups, R x6 , R x7 , R x8are each independently hydrogen, deuterium, tritium, a halogen, an aldehyde group, CN, N3, NO2, OAc, substituted or unsubstituted OSiH3, substituted or unsubstituted OOSiH3, substituted or unsubstituted SO3H, substituted or unsubstituted SiH3, substituted or unsubstituted C5SH, substituted or unsubstituted NH2, substituted or unsubstituted COOH, substituted or unsubstituted SH, substituted or unsubstituted SeO2H, substituted or unsubstituted OH, substituted or unsubstituted N=NH, substituted or unsubstituted =O, substituted or unsubstituted CH=NH, substituted or unsubstituted C 1~5 Alkyl groups, substituted or unsubstituted C 1~5 Alkoxy groups, substituted or unsubstituted C 2~6 Alkenyl group, substituted or unsubstituted C 2~6 selected from alkynyl groups, substituted or unsubstituted saturated or unsaturated heterocyclic groups, substituted or unsubstituted saturated or unsaturated cycloalkyl groups, substituted or unsubstituted fused cycloalkyl groups, and substituted or unsubstituted fused heterocyclic groups; Or R 10 and R5 bond to form a ring, R8 and R9 are each independently L 16 L 17 L 18 R x9 is selected from L 16 , L 17 , L 18 are each independently none, substituted or unsubstituted NHCO, substituted or unsubstituted NHCS, substituted or unsubstituted CO, substituted or unsubstituted COO, substituted or unsubstituted OCO, substituted or unsubstituted OCOO, substituted or unsubstituted C(SO), substituted or unsubstituted O, substituted or unsubstituted S, substituted or unsubstituted SO, substituted or unsubstituted SO2, substituted or unsubstituted NH, substituted or unsubstituted CH=N, substituted or unsubstituted CONH, substituted or unsubstituted NH(CS)S(CH2), substituted or unsubstituted C 1~3 alkylene groups, R x9is hydrogen, deuterium, tritium, halogen, aldehyde group, CN, N3, NO2, OAc, substituted or unsubstituted OSiH3, substituted or unsubstituted OOSiH3, substituted or unsubstituted SO3H, substituted or unsubstituted SiH3, substituted or unsubstituted CS2H, substituted or unsubstituted CSNH2, substituted or unsubstituted NH2, substituted or unsubstituted COOH, substituted or unsubstituted SH, substituted or unsubstituted SeO2H, substituted or unsubstituted OH, substituted or unsubstituted N=NH, substituted or unsubstituted =O, substituted or unsubstituted CH=NH, substituted or unsubstituted C 1~5 Alkyl groups, substituted or unsubstituted C 1~5 Alkoxy groups, substituted or unsubstituted C 2~6 Alkenyl group, substituted or unsubstituted C 2~6 It is selected from an alkynyl group, a substituted or unsubstituted saturated or unsaturated heterocyclic group, a substituted or unsubstituted saturated or unsaturated cycloalkyl group, a substituted or unsubstituted fused cycloalkyl group, and a substituted or unsubstituted fused heterocyclic group.

[0008] Furthermore, the compound is of formula II. TIFF0007801365000002.tif64170

[0009] However, R0 is L0L1L2R x1 is selected from L0, L1, and L2 each independently represent none, substituted or unsubstituted NHCO, substituted or unsubstituted NHCS, substituted or unsubstituted CO, substituted or unsubstituted COO, substituted or unsubstituted OCO, substituted or unsubstituted OCOO, substituted or unsubstituted C(SO), substituted or unsubstituted O, substituted or unsubstituted S, substituted or unsubstituted SO, substituted or unsubstituted SO2, substituted or unsubstituted NH, substituted or unsubstituted CH=N, substituted or unsubstituted CONH, substituted or unsubstituted NH(CS)S(CH2), substituted or unsubstituted C 1~3 Alkylene group, substituted or unsubstituted C 2~4 Alkenylene group, substituted or unsubstituted C 2~4 alkynylene groups, R x1is hydrogen, deuterium, tritium, halogen, aldehyde group, CN, N3, NO2, OAc, substituted or unsubstituted OSiH3, substituted or unsubstituted OOSiH3, substituted or unsubstituted SO3H, substituted or unsubstituted SiH3, substituted or unsubstituted CS2H, substituted or unsubstituted CSNH2, substituted or unsubstituted NH2, substituted or unsubstituted COOH, substituted or unsubstituted SH, substituted or unsubstituted SeO2H, substituted or unsubstituted OH, substituted or unsubstituted N=NH, substituted or unsubstituted =O, substituted or unsubstituted CH=NH, substituted or unsubstituted C 1~5 Alkyl groups, substituted or unsubstituted C 1~5 Alkoxy groups, substituted or unsubstituted C 2~6 Alkenyl group, substituted or unsubstituted C 2~6 selected from alkynyl groups, substituted or unsubstituted saturated or unsaturated heterocyclic groups, substituted or unsubstituted saturated or unsaturated cycloalkyl groups, substituted or unsubstituted fused cycloalkyl groups, and substituted or unsubstituted fused heterocyclic groups; R1 and R2 are independently L3L4L5R x2 , =NL5R x2 , =C(L6R x3 )(L7R x4 or R1 and R2 are bonded to form a ring; L3, L4, L5, L6, and L7 each independently represent none, substituted or unsubstituted NHCO, substituted or unsubstituted NHCS, substituted or unsubstituted CO, substituted or unsubstituted COO, substituted or unsubstituted OCO, substituted or unsubstituted OCOO, substituted or unsubstituted C(SO), substituted or unsubstituted O, substituted or unsubstituted S, substituted or unsubstituted SO, substituted or unsubstituted SO2, substituted or unsubstituted NH, substituted or unsubstituted CH=N, substituted or unsubstituted CONH, substituted or unsubstituted NH(CS)S(CH2), substituted or unsubstituted C 1~3 alkylene groups, R x2 , R x3 , R x4are each independently hydrogen, deuterium, tritium, a halogen, an aldehyde group, CN, N3, NO2, OAc, substituted or unsubstituted OSiH3, substituted or unsubstituted OOSiH3, substituted or unsubstituted SO3H, substituted or unsubstituted SiH3, substituted or unsubstituted C5SH, substituted or unsubstituted NH2, substituted or unsubstituted COOH, substituted or unsubstituted SH, substituted or unsubstituted SeO2H, substituted or unsubstituted OH, substituted or unsubstituted N=NH, substituted or unsubstituted =O, substituted or unsubstituted CH=NH, substituted or unsubstituted C 1~5 Alkyl groups, substituted or unsubstituted C 1~5 Alkoxy groups, substituted or unsubstituted C 2~6 Alkenyl group, substituted or unsubstituted C 2~6 selected from alkynyl groups, substituted or unsubstituted saturated or unsaturated heterocyclic groups, substituted or unsubstituted saturated or unsaturated cycloalkyl groups, substituted or unsubstituted fused cycloalkyl groups, and substituted or unsubstituted fused heterocyclic groups; R3 is L8L9L 10 R x5 is selected from L8, L9, L 10 are each independently none, substituted or unsubstituted NHCO, substituted or unsubstituted NHCS, substituted or unsubstituted CO, substituted or unsubstituted COO, substituted or unsubstituted OCO, substituted or unsubstituted OCOO, substituted or unsubstituted C(SO), substituted or unsubstituted O, substituted or unsubstituted S, substituted or unsubstituted SO, substituted or unsubstituted SO2, substituted or unsubstituted NH, substituted or unsubstituted CH=N, substituted or unsubstituted CONH, substituted or unsubstituted NH(CS)S(CH2), substituted or unsubstituted C 1~3 alkylene groups, R x5is hydrogen, deuterium, tritium, halogen, aldehyde group, CN, N3, NO2, OAc, substituted or unsubstituted OSiH3, substituted or unsubstituted OOSiH3, substituted or unsubstituted SO3H, substituted or unsubstituted SiH3, substituted or unsubstituted CS2H, substituted or unsubstituted CSNH2, substituted or unsubstituted NH2, substituted or unsubstituted COOH, substituted or unsubstituted SH, substituted or unsubstituted SeO2H, substituted or unsubstituted OH, substituted or unsubstituted N=NH, substituted or unsubstituted =O, substituted or unsubstituted CH=NH, substituted or unsubstituted C 1~5 Alkyl groups, substituted or unsubstituted C 1~5 Alkoxy groups, substituted or unsubstituted C 2~6 Alkenyl group, substituted or unsubstituted C 2~6 selected from alkynyl groups, substituted or unsubstituted saturated or unsaturated heterocyclic groups, substituted or unsubstituted saturated or unsaturated cycloalkyl groups, substituted or unsubstituted fused cycloalkyl groups, and substituted or unsubstituted fused heterocyclic groups; R4, R5, R6, and R7 are each independently L 11 L 12 L 13 R x6 , =NL 13 R x6 , =C(L 14 R x7 )(L 15 R x8 ) and L 11 , L 12 , L 13 , L 14 , L 15 are each independently none, substituted or unsubstituted NHCO, substituted or unsubstituted NHCS, substituted or unsubstituted CO, substituted or unsubstituted COO, substituted or unsubstituted OCO, substituted or unsubstituted OCOO, substituted or unsubstituted C(SO), substituted or unsubstituted O, substituted or unsubstituted S, substituted or unsubstituted SO, substituted or unsubstituted SO2, substituted or unsubstituted NH, substituted or unsubstituted CH=N, substituted or unsubstituted CONH, substituted or unsubstituted NH(CS)S(CH2), substituted or unsubstituted C 1~3 alkylene groups, R x6 , R x7 , R x8are each independently hydrogen, deuterium, tritium, a halogen, an aldehyde group, CN, N3, NO2, OAc, substituted or unsubstituted OSiH3, substituted or unsubstituted OOSiH3, substituted or unsubstituted SO3H, substituted or unsubstituted SiH3, substituted or unsubstituted C5SH, substituted or unsubstituted NH2, substituted or unsubstituted COOH, substituted or unsubstituted SH, substituted or unsubstituted SeO2H, substituted or unsubstituted OH, substituted or unsubstituted N=NH, substituted or unsubstituted =O, substituted or unsubstituted CH=NH, substituted or unsubstituted C 1~5 Alkyl groups, substituted or unsubstituted C 1~5 Alkoxy groups, substituted or unsubstituted C 2~6 Alkenyl group, substituted or unsubstituted C 2~6 selected from alkynyl groups, substituted or unsubstituted saturated or unsaturated heterocyclic groups, substituted or unsubstituted saturated or unsaturated cycloalkyl groups, substituted or unsubstituted fused cycloalkyl groups, and substituted or unsubstituted fused heterocyclic groups; R8 and R9 are each independently L 16 L 17 L 18 R x9 is selected from L 16 , L 17 , L 18 are each independently none, substituted or unsubstituted NHCO, substituted or unsubstituted NHCS, substituted or unsubstituted CO, substituted or unsubstituted COO, substituted or unsubstituted OCO, substituted or unsubstituted OCOO, substituted or unsubstituted C(SO), substituted or unsubstituted O, substituted or unsubstituted S, substituted or unsubstituted SO, substituted or unsubstituted SO2, substituted or unsubstituted NH, substituted or unsubstituted CH=N, substituted or unsubstituted CONH, substituted or unsubstituted NH(CS)S(CH2), substituted or unsubstituted C 1~3 alkylene groups, R x9is hydrogen, deuterium, tritium, halogen, aldehyde group, CN, N3, NO2, OAc, substituted or unsubstituted OSiH3, substituted or unsubstituted OOSiH3, substituted or unsubstituted SO3H, substituted or unsubstituted SiH3, substituted or unsubstituted CS2H, substituted or unsubstituted CSNH2, substituted or unsubstituted NH2, substituted or unsubstituted COOH, substituted or unsubstituted SH, substituted or unsubstituted SeO2H, substituted or unsubstituted OH, substituted or unsubstituted N=NH, substituted or unsubstituted =O, substituted or unsubstituted CH=NH, substituted or unsubstituted C 1~5 Alkyl groups, substituted or unsubstituted C 1~5 Alkoxy groups, substituted or unsubstituted C 2~6 Alkenyl group, substituted or unsubstituted C 2~6 It is selected from an alkynyl group, a substituted or unsubstituted saturated or unsaturated heterocyclic group, a substituted or unsubstituted saturated or unsaturated cycloalkyl group, a substituted or unsubstituted fused cycloalkyl group, and a substituted or unsubstituted fused heterocyclic group.

[0010] Furthermore, the compound is of formula III. TIFF0007801365000003.tif64170

[0011] However, R0 is hydrogen, deuterium, tritium, C1 ~5 Alkyl group, 1 to 3 R a C replaced with 1~5 Alkyl group, C 1~5 Alkoxy group, 1 to 3 R a C replaced with 1~5 Alkoxy group, C 2~6 Alkenyl group, C 2~6 R is selected from an alkynyl group, a saturated or unsaturated heterocyclic group, a saturated or unsaturated cycloalkyl group, a fused cycloalkyl group, and a fused heterocyclic group; a are each independently selected from deuterium, tritium, a halogen, and a hydroxy group; R2 is hydrogen, deuterium, tritium, halogen, COOR e , S.R. e , OR e , C 1~5 Alkyl group, =NR h1 , C1~5 Alkoxy group, C 2~6 Alkenyl group, C 2~6 R is selected from an alkynyl group, a saturated or unsaturated heterocyclic group, a saturated or unsaturated cycloalkyl group, a fused cycloalkyl group, and a fused heterocyclic group; e are hydrogen, deuterium, tritium, C 1~5 alkyl groups, and R h1 is a hydroxy group, C 1~5 alkyl groups, R3 is hydrogen, deuterium, tritium, hydroxyl group, halogen, C 1~5 Alkyl group, L f COOR f , C 1~5 Alkoxy group, C 2~6 Alkenyl group, C 2~6 L is selected from an alkynyl group, a saturated or unsaturated heterocyclic group, a saturated or unsaturated cycloalkyl group, a fused cycloalkyl group, and a fused heterocyclic group; f is None or C 1~3 is an alkylene group, and R f are hydrogen, deuterium, tritium, C 1~5 alkyl groups, R5 is hydrogen, deuterium, tritium, halogen, hydroxyl group, OCOR b , C 1~5 Alkyl group, C 1~5 Alkoxy group, C 2~6 Alkenyl group, C 2~6 R is selected from an alkynyl group, a saturated or unsaturated heterocyclic group, a saturated or unsaturated cycloalkyl group, a fused cycloalkyl group, and a fused heterocyclic group; b is C 1~5 is an alkyl group, R6 and R7 are each independently hydrogen, deuterium, tritium, halogen, or C 1~5 Alkyl group, COOR g , C 1~5 Alkoxy group, C 2~6 Alkenyl group, C 2~6 R is selected from an alkynyl group, a saturated or unsaturated heterocyclic group, a saturated or unsaturated cycloalkyl group, a fused cycloalkyl group, and a fused heterocyclic group; g are hydrogen, deuterium, tritium, C1~5 alkyl groups, R8 and R9 are each independently hydrogen, deuterium, tritium, or C 1~5 Alkyl group, 1 to 3 R c C replaced with 1~6 Alkyl group, C 1~5 Alkoxy group, 1 to 3 R c C replaced with 1~5 Alkoxy group, C 2~6 Alkenyl group, C 2~6 R is selected from an alkynyl group, a saturated or unsaturated heterocyclic group, a saturated or unsaturated cycloalkyl group, a fused cycloalkyl group, and a fused heterocyclic group; c are each independently a halogen, COOR d , hydroxy group, C 1~5 R is selected from alkyl groups, deuterium, and tritium; d are hydrogen, deuterium, tritium, C 1~5 The alkyl group is selected from the group consisting of:

[0012] Furthermore, R0 can be hydrogen, deuterium, C 1~3 Alkyl group, 1 to 3 R a C replaced with 1~3 alkyl groups, and R a are each independently selected from deuterium, a halogen, and a hydroxy group; R2 is hydrogen, deuterium, halogen, COOR e , S.R. e , OR e , C 1~3 Alkyl group, =NR h1 Selected from R e are hydrogen, deuterium, and C 1~3 alkyl groups, and R h1 is a hydroxy group, C 1~3 alkyl groups, R3 is hydrogen, deuterium, hydroxyl group, halogen, C 1~3 Alkyl group, L f COOR f Selected from L f is None or C 1~3 is an alkylene group, and R f are hydrogen, deuterium, and C1~3 alkyl groups, R5 is hydrogen, deuterium, halogen, hydroxyl group, OCOR b Selected from R b is C 1~3 is an alkyl group, R6 and R7 are each independently hydrogen, deuterium, halogen, or C 1~3 Alkyl group, COOR g Selected from R g are hydrogen, deuterium, and C 1~3 alkyl groups, R8 and R9 are each independently hydrogen, deuterium, or C 1~3 Alkyl group, 1 to 3 R c C replaced with 1~3 alkyl groups, and R c are each independently a halogen, COOR d , hydroxy group, C 1~3 alkyl group, deuterium, R d are hydrogen, deuterium, and C 1~3 The alkyl group is selected from the group consisting of:

[0013] Additionally, the compound is shown in Formula IV. TIFF0007801365000004.tif64170

[0014] where R0 is a methyl group, 1 to 3 R a and each R a are each independently selected from deuterium, a halogen, and a hydroxy group; R2 is selected from hydrogen, halogen, COOH, SCH3, a methyl group, and =N-OH; R3 is hydrogen, hydroxyl group, halogen, C 1~3 Alkyl group, L f COOH, L f is methylene, R5 is hydrogen, halogen, hydroxyl group, OCOR b Selected from R b is a methyl group, R6 is selected from hydrogen, halogen, methyl group, and COOH; R8 and R9 are each independently a hydrogen atom, a methyl group, or 1 to 3 R c methyl groups substituted with R c are each independently selected from halogen, COOH, a hydroxy group, a methyl group, and deuterium.

[0015] Furthermore, the compound is TIFF0007801365000005.tif246170TIFF0007801365000006.tif248170TIFF00078013650 00007.tif74170TIFF0007801365000008.tif89170TIFF0007801365000009.tif247170TI FF0007801365000010.tif155170TIFF0007801365000011.tif137170TIFF0007801365000 012.tif233170TIFF0007801365000013.tif247170TIFF0007801365000014.tif217170TIF F0007801365000015.tif29170TIFF0007801365000016.tif250170TIFF000780136500001 7.tif79170TIFF0007801365000018.tif167170TIFF0007801365000019.tif191170TIFF0 Selected from 007801365000020.tif65170TIFF0007801365000021.tif99170TIFF0007801365000022.tif124170TIFF0007801365000023.tif155170TIFF0007801365000024.tif111170

[0016] Furthermore, the compound is TIFF0007801365000025.tif95170TIFF0007801365000026.tif137170TIFF0007801365000027.tif 74170TIFF0007801365000028.tif89170TIFF0007801365000029.tif204170TIFF0007801365000030 Selected from .tif103170TIFF0007801365000031.tif80170TIFF0007801365000032.tif190170TIFF0007801365000033.tif124170TIFF0007801365000034.tif155170TIFF0007801365000035.tif111170

[0017] Furthermore, the compound is TIFF0007801365000036.tif48170TIFF0007801365000037.tif64170TIFF0007801365000038.ti f36170TIFF0007801365000039.tif36170TIFF0007801365000040.tif59170TIFF00078013650000 Selected from 41.tif44170TIFF0007801365000042.tif53170TIFF0007801365000043.tif59170TIFF0007801365000044.tif77170TIFF0007801365000045.tif70170TIFF0007801365000046.tif45170

[0018] Furthermore, the anesthetic and / or sedative antagonist is an antagonist of an anesthetic drug and / or an antagonist of a sedative drug.

[0019] Additionally, the anesthetic and / or sedative antagonist is capable of reversing the anesthetic and / or sedative state induced or maintained by an anesthetic and / or sedative drug.

[0020] Additionally, the anesthetic and / or sedation antagonist may reduce the duration of anesthesia and / or sedation.

[0021] Additionally, the anesthetic drug is GABA A Includes receptor agonists.

[0022] Additionally, the anesthetic and / or sedative antagonist may be a GABA A It is a high-affinity receptor ligand and acts as a competitive antagonist of GABA A It is capable of antagonizing receptor agonists.

[0023] Further, the anesthetic drug is a general anesthetic drug.

[0024] Furthermore, the general anesthetic drugs include benzodiazepine drugs, substituted phenol drugs, imidazole drugs, GABA mimetic drugs, and phenylcyclohexylamine drugs.

[0025] Further, the benzodiazepine drug includes diazepam, midazolam, lorazepam, and remimazolam; The substituted phenolic drugs include propofol and ciprofol. The imidazole drug includes etomidate or a derivative thereof, The GABA mimetic drug includes gamma-aminobutyric acid, gamma-hydroxybutyric acid, The phenylcyclohexylamine drugs include ketamine and fluoroketamine.

[0026] Furthermore, the anesthetic and / or sedative antagonist is a formulation produced using the compound, or a stereoisomer thereof, or a deuterated derivative thereof, or a metabolite thereof, or a prodrug thereof, or a salt thereof, or a solvate thereof as an active ingredient, in addition to pharmaceutically acceptable auxiliary materials.

[0027] Furthermore, the preparation is a tablet, a capsule, an oral liquid, a granule, a pill, a powder, an injection liquid or a powder injection.

[0028] The definitions of terms used in the present invention are as follows: Unless otherwise specified, the initial definition provided for a group, radical, or term in the text applies to that group or term throughout the specification, and terms not specifically defined in the text represent the meaning that a person skilled in the art would have based on the disclosure and context.

[0029] The minimum and maximum carbon atom content in the hydrocarbon group is indicated by a prefix, e.g., the prefix C a~b The alkyl group represents an alkyl group containing any number of carbon atoms, from "a" to "b". For example, C 1~5 Alkyl group means a straight or branched chain alkyl group containing 1 to 5 carbon atoms.

[0030] As used herein, "substituted" means that one, two or more hydrogen atoms in a molecule have been replaced with other, different atoms or molecules, including one, two or more substitutions on isotopes or isomers in the molecule.

[0031] A "substituted or unsubstituted" group means that the group may be unsubstituted or may be further substituted with one or more substituents, which, unless otherwise specified, may be any substituent that stabilizes the structure of the final compound.

[0032] "Fused cycloalkyl group" means a polycyclic cycloalkyl group in which two rings share two adjacent carbon atoms.

[0033] A "fused heterocyclic group" means a polycyclic heterocyclic group in which two rings share two adjacent carbon atoms or heteroatoms.

[0034] "Halogen" is fluorine, chlorine, bromine or iodine.

[0035] "Deuterated derivative" means a compound in which one or more hydrogen atoms have been replaced with deuterium.

[0036] "Tritiated derivative" means a compound in which one or more hydrogen atoms have been replaced with tritium.

[0037] "Salts" refer to acidic and / or basic salts formed by a compound or its stereoisomer with inorganic and / or organic acids and / or bases, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts may be obtained directly during the final isolation and purification of the compound. They may also be obtained by mixing a compound or its stereoisomer with an appropriate amount of acid or base (e.g., equal equivalents). These salts can be obtained by forming a precipitate in a solution and collecting it by filtration, or by recovering it after evaporating the solvent, or by reacting it in an aqueous medium and then lyophilizing it.

[0038] The salts described in this invention may be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, butanedioate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate salts of the compound.

[0039] The present invention is the first to discover that the cyclic ketone compounds represented by Formula I have good antagonistic effects against general anesthesia and sedation. Experimental results show that the compounds of the present invention have good antagonistic effects against general anesthesia induced by several general anesthetic drugs (including propofol, etomidate, remimazolam, etc.), and significantly shorten the recovery time of the righting reflex after general anesthesia in mice, and significantly shorten the recovery time of normal walking in mice. Furthermore, the compounds of the present invention can also effectively antagonize general anesthesia maintained by continuous infusion of the general anesthetic drug propofol.

[0040] The present invention is an antagonist of anesthetic and / or sedative drugs, and in particular provides a new option as an antagonist of general anesthetic drugs, and is therefore promising.

[0041] Naturally, based on the above content of the present invention, various other forms of modifications, substitutions or alterations can be made in light of general technical knowledge and conventional means in this field, on the premise that they do not deviate from the above basic technical idea of ​​the present invention.

[0042] The above content of the present invention will be described in more detail below by way of specific embodiments in the form of examples. However, it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. Any technology realized based on the above content of the present invention belongs to the scope of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0043] All materials and equipment used in the present invention are conventional and purchased from commercial sources.

[0044] All compounds used in the following examples can be purchased commercially or synthesized by methods known in the art.

[0045] Example 1 Antagonistic effects of each compound against different general anesthetic drugs 1. Main reagents and drugs (1) Main reagents Propofol injection (lot number: 2010083, Xi'an Libang), etomidate injection (purity >98%), remimazolam (purity >98%), medium- and long-chain lipid emulsion injection. (2) Test drug Preparation method: Weigh out an appropriate amount of each test compound and add an appropriate amount of medium- and long-chain lipid emulsion injection solution using a pipette to prepare a 50 mmol / L test compound solution. The solution was filtered through a 0.22 μm micropore filter membrane and used immediately.

[0046] 2. Experimental Method Male ICR mice weighing 25 g ± 1 g were randomly divided into 8 groups with 8 mice per group and administered 22.11 mg / kg (1.5x ED) of propofol. 50 ), etomidate 4.48 mg / kg (2x ED 50), remimazolam 57.34 mg / kg (1.5 times ED 50 Anesthesia was induced by a single injection of each compound into the tail vein, with the injection time set to 15 seconds. After the loss of the righting reflex of the mouse was maintained for 30 seconds, 50 mg / kg of the test compound solution (solvent: medium- and long-chain lipid emulsion injection) or an equal volume of medium- and long-chain lipid emulsion injection was injected, and the total time of anesthesia of the mouse was observed and recorded. Here, the total time of anesthesia refers to the time from the loss of the righting reflex of the mouse to the recovery of the righting reflex of the mouse.

[0047] 3. Experimental Results The results are shown in Table 1. Table 1 Antagonistic effects of test drugs on the anesthetic effects of general anesthetic drugs

[0048] [Table 1] TIFF0007801365000048.tif250170TIFF0007801365000049.tif173170

[0049] Experiments have shown that none of the lipid emulsions have an anesthetic antagonizing effect against the general anesthetic drugs propofol, etomidate, and remimazolam, but the compounds listed in the table all have the antagonizing effect against general anesthetics, and have shown the efficacy of significantly shortening the total anesthesia time of mice.This indicates that the compounds provided by the present invention can antagonize the anesthetic effect of general anesthetic drugs, and can speed up the recovery speed.

[0050] Example 2 Antagonism of Compounds Against Continuous Infusion of General Anesthetic Drugs 1. Main reagents and drugs (1) Main reagents Propofol injection (lot number: 2010083, Xi'an Libang), medium- and long-chain lipid emulsion injection. (2) Test drug Preparation method: same as in Example 1.

[0051] 2. Experimental Method Twenty-four male SD rats weighing between 250 and 300 grams were randomly divided into four groups of six rats each and administered 22.11 mg / kg (1.5x EDTA) of benzodiazepine. 50 Anesthesia was induced continuously using 10 mg / kg propofol, and anesthesia was maintained for 30 minutes at a rate of 1 mg / (kg·min). After the drug was stopped, 10 mg / kg, 20 mg / kg, 50 mg / kg of the test compound solution (solvent: medium- and long-chain lipid emulsion injection) or an equal volume of medium- and long-chain lipid emulsion injection was immediately injected. The time to recovery from anesthesia after the drug was stopped was observed and recorded. Here, the time to recovery from anesthesia refers to the time from the cessation of propofol infusion to the recovery of the mouse's righting reflex.

[0052] 3. Experimental Results The results are shown in Table 2. Table 2. Antagonistic effects of test drugs on the maintenance of general anesthesia by continuous infusion of propofol

[0053] [Table 2]

[0054] The experimental results show that compound 85 provided by the present invention can effectively reverse the anesthesia maintenance effect of continuous infusion of propofol, and can dose-dependently shorten the anesthesia recovery time of rats.In addition, all of the compounds listed in the table can reverse the anesthesia maintenance effect of continuous infusion of propofol, and shorten the average recovery time of mice.

[0055] As described above, the present invention provides the use of a cyclic ketone compound represented by Formula I in the manufacture of an anesthetic and / or sedative antagonist. The present invention is the first to discover that this cyclic ketone compound has good antagonistic activity against general anesthesia and sedation. Experimental results show that the compound of the present invention has good antagonistic activity against general anesthesia induced by several general anesthetic drugs (including propofol, etomidate, remimazolam, etc.), significantly shortens the recovery time of the righting reflex after general anesthesia in mice, and significantly shortens the recovery time of normal walking in mice. Furthermore, the compound of the present invention can effectively antagonize general anesthesia maintained by continuous infusion of the general anesthetic drug propofol. The present invention is an antagonist of anesthetic and / or sedative drugs, and in particular provides a new option as an antagonist of general anesthetic drugs, and is therefore promising.

Claims

1. Use of a compound selected from the following, or a stereoisomer thereof, or a deuterated derivative thereof, or a tritiated derivative thereof, or a salt thereof, or a solvate thereof, in the manufacture of an anesthetic and / or sedative antagonist: 。

2. 2. The use according to claim 1, characterized in that the anesthesia and / or sedation antagonist is an antagonist of an anesthetic drug and / or an antagonist of a sedative drug.

3. 3. The use according to claim 2, characterized in that the anesthesia and / or sedation antagonist is capable of reversing the anesthesia and / or sedation state induced or maintained by an anesthesia and / or sedative drug.

4. 3. The use according to claim 2, characterized in that the anesthesia and / or sedation antagonist is capable of reducing the duration of anesthesia and / or sedation.

5. The anesthetic drug is GABA Ａ 3. The use according to claim 2, characterized in that it comprises a receptor agonist.

6. The anesthetic and / or sedative antagonist is GABA Ａ It is a high-affinity ligand for the receptor and acts as a competitive antagonist against GABA. Ａ The use according to claim 5, characterized in that it is capable of antagonizing a receptor agonist.

7. 3. The use according to claim 2, characterized in that the anesthetic drug is a general anesthetic drug.

8. The use according to claim 7, characterized in that the general anesthetic drug comprises a benzodiazepine drug, a substituted phenol drug, an imidazole drug, a GABA mimetic drug, or a phenylcyclohexylamine drug.

9. the benzodiazepine drug includes diazepam, midazolam, lorazepam, and remimazolam; the substituted phenolic drug includes propofol and ciprofol; the imidazole drug comprises etomidate or a derivative thereof; the GABA mimetic drug includes γ-aminobutyric acid, γ-hydroxybutyric acid; The use according to claim 8, characterized in that the phenylcyclohexylamine drug includes ketamine and fluoroketamine.

10. The use according to any one of claims 1 to 9, characterized in that the anesthetic and / or sedative reversal drug is a preparation produced using the compound, or a stereoisomer thereof, or a deuterated derivative thereof, or a salt thereof, or a solvate thereof as an active ingredient, in addition to pharmaceutically acceptable auxiliary materials.

11. The use according to claim 10, characterized in that the preparation is a tablet, a capsule, an oral liquid, a granule, a pill, a powder, an injection liquid or an injection powder.

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