Salt of morphinan ring compound as well as preparation method and application thereof
The morphine ring compound salt prepared by reacting with acid in solvents has solved the problem of limited effects of existing analgesic drugs, achieved an improvement of the analgesic effect of more than 60%, significantly improved the pain threshold, and provided a new Highly effective pain-analgesic drugs.
Patent Information
- Application Number
- CN202310805992.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2023-07-03
- Publication Date
- 2025-01-03
AI Technical Summary
Existing analgesic drugs have limited effectiveness in moderate to severe pain treatment, especially in postoperative conditions, cancer and biliary colic, where a new compound with excellent analgesic effects is needed.
A salt of a morphine ring compound is provided, prepared by reacting with D-tartrate or hydrochloride in the presence of a specific solvent and additive to form an excellent analgesic drug. The method includes reacting with an acid in a solvent, using activated carbon, palladium carbon or ruthenium carbon as additives, and controlling the reaction conditions such as temperature and time to obtain a high purity cationic salt.
The analgesic effect of this compound is significantly better than that of existing drugs, and is about 60% higher than that of Butorphinol tartaric acid. It showed a 10-fold increase in pain threshold in mouse hot plate experiments, proving its excellent analgesic effect.
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Figure CN119241436A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to a salt of a morphinan ring compound, a preparation method and application thereof, and belongs to the field of organic chemistry. Background Art
[0002] Butorphanol, with the chemical name of L-(-)-17-cyclobutylmethyl-3,14-dihydroxymorphinan, is a central analgesic with minimal side effects developed by Bristol-Myers Squibb Co. It is clinically used to treat moderate to severe pain such as postoperative pain, cancer, and biliary colic. Butorphanol is a mixed opioid agonist-antagonist (OAA), and its tartrate salt is used clinically. Summary of the invention
[0003] The technical problem to be solved by the present invention is to provide a new compound with excellent analgesic effect. To this end, the present invention provides a salt of a morphinan ring compound, a preparation method and use thereof, wherein the salt of the morphinan ring compound has excellent analgesic effect.
[0004] The present invention provides a salt of a cation represented by formula A;
[0005]
[0006] Among them, the salt of the cation represented by formula A is electrically neutral, and the salt of the cation represented by formula A is D-tartrate or hydrochloride. Those skilled in the art can determine the structural formula of the salt of the cation represented by formula A based on common sense and the type of the salt of the cation represented by formula A.
[0007] In one embodiment, the salt of the cation represented by formula A is
[0008]
[0009] The present invention provides a method for preparing a salt of a cation represented by formula A, comprising the following steps: in a solvent, in the presence of an additive, reacting compound 1 with an acid to obtain a salt of a cation represented by formula A,
[0010]
[0011] Wherein, the solvent is one or more of water, alcohol solvent, ketone solvent, lipid solvent and aromatic hydrocarbon solvent;
[0012] The acid is D-tartrate or hydrochloride;
[0013] The additive is one or more of activated carbon, palladium carbon, rhodium carbon and ruthenium carbon.
[0014] In one embodiment, the acid is D-tartaric acid, and the salt of the cation represented by formula A is
[0015] In one embodiment, the acid is hydrochloric acid, and the salt of the cation represented by formula A is
[0016] In one embodiment, in the above preparation method, the solvent is one or more of water, methanol, ethanol, isopropanol, n-butanol, acetone, ethyl acetate and toluene.
[0017] In one embodiment, in the above preparation method, the additive is one or more of activated carbon, palladium carbon and ruthenium carbon.
[0018] In one embodiment, in the above preparation method, the mass ratio of the additive to compound 1 is 0.1-10; preferably 0.5-1; further preferably 0.5, 0.6, 0.7, 0.8, 0.9 or 1.
[0019] In one embodiment, in the above preparation method, the molar ratio of the compound 1 to M is 0.1:1-10:1; preferably 0.5:1 to 2:1; and more preferably 30:33.
[0020] In one embodiment, in the above preparation method, the reaction temperature is 30-200°C or the boiling point of the solvent; preferably 56-172°C; further preferably 56°C, 64°C, 75°C, 78°C, 82°C, 100°C, 110°C, 117°C or 172°C.
[0021] In one embodiment, in the above preparation method, the volume mass ratio of the solvent to compound 1 is 3-20 mL / g; preferably 9-12 mL / g; further preferably 9 mL / g, 10 mL / g, 11 mL / g or 12 mL / g.
[0022] In one embodiment, the reaction time of the above preparation method is the time until the initial reactants no longer react; preferably 24-120 hours; more preferably 36-102 hours; further preferably 36 hours, 44 hours, 70 hours, 77 hours, 85 hours, 94 hours or 102 hours.
[0023] The present invention also provides a pharmaceutical composition, which comprises a salt of a cation represented by formula A described in any one of the above items and a pharmaceutically acceptable excipient.
[0024] The present invention also provides the use of the salt of the cation represented by formula A described in any one of the above items in the preparation of analgesic drugs.
[0025] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.
[0026] The reagents and raw materials used in the present invention are commercially available.
[0027] The positive improvement effect of the present invention is that the salt of the cation represented by formula A of the present application has excellent analgesic effect, and its analgesic effect is improved by about 60% compared with butorphanol tartrate. DETAILED DESCRIPTION
[0028] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are selected according to conventional methods and conditions, or according to the product specifications. The reagents used in the following examples are all commercially available, and some reagent information is as follows:
[0029]
[0030] In the following examples, the HPLC chromatographic conditions are as follows:
[0031]
[0032]
[0033] The HPLC conditions in the following examples are as follows:
[0034]
[0035] The elemental analysis results in the following examples were obtained using Thermo FLASH 2000 under standard analysis conditions.
[0036] Example 1
[0037] At room temperature, 0.5 g of compound 1 was added to 5 mL of ethanol, 0.5 g of activated carbon and 1 mL of hydrochloric acid, and the mixture was refluxed at 78 ° C for 70 hours, filtered while hot, and the filtrate was concentrated under reduced pressure to obtain 400 mg of an orange solid, wherein the cation represented by formula A had an HPLC content of 4.32% and a retention time of 22.7 min. After high-efficiency preparative liquid phase preparation, 13 mg of the hydrochloride of the cation represented by formula A was obtained with a purity of >99.40%. 1H NMR(400MHz,D2O)δppm 0.88(q,J=13.43Hz,1H),1.25-1.38(m,2H),1.40-1.44(m,1H),1.44-1.70 (m,2H),1.47-1.65(m,2H),1.71-1.81(m,1H),1.89-1.97(m,1H),2.08(br d,J=14.09Hz,1H),2.59-2.70(m,1H),2.73(s,1H),2.94-3.02(m,1H),3.14(br dd,J=18.59,4.89Hz,1H)3.61(br dd,J=12.91,9.78Hz,1H),3.77-3.90(m,2H),6.57(dd,J=8.41,2.15Hz,1H),6.71(s,1H),6.88(d,J=8.61Hz,1H),8.29(br s,1H). 13 C NMR(100MHz,D2O)δ176.79,171.80,155.09,141.15,131.27,120.92,114.80,111.70,68.72,65 .66,63.91,43.34,37.19,32.60,30.69,29.40,24.94,24.69,20.01,17.37.HRMS(HESI)m / z:[M] + 326.2114.
[0038] Elemental analysis test results:
[0039] Molecular formula: C 21 H 28 NO2Cl
[0040]
[0041] Cl element detection results:
[0042]
[0043] Example 2
[0044] 0.5 g of compound 1 was added to 5 mL of ethanol at room temperature, and 0.5 g of activated carbon and 0.25 g of D-tartaric acid were added. The mixture was refluxed at 78°C for 70 hours, filtered while hot, and the filtrate was concentrated under reduced pressure to obtain 400 mg of an orange solid. The content of the cation represented by formula A was 3.71% by HPLC. After high-efficiency preparative liquid phase preparation, 10 mg of tartrate containing the cation represented by formula A was obtained, with a purity of >99.20%. 1HNMR(400MHz,D2O)δppm 0.88(q,J=13.43Hz,1H),1.25-1.38(m,2H),1.40-1.44(m,1H),1.44-1.70 (m,2H),1.47-1.65(m,2H),1.71-1.81(m,1H),1.89-1.97(m,1H),2.08(br d,J=14.09Hz,1H),2.59-2.70(m,1H),2.73(s,1H),2.94-3.02(m,1H),3.14(br dd,J=18.59,4.89Hz,1H)3.61(br dd,J=12.91,9.78Hz,1H),3.77-3.90(m,2H),6.57(dd,J=8.41,2.15Hz,1H),6.71(s,1H),6.88(d,J=8.61Hz,1H),8.29(br s,1H). 13 C NMR(100MHz,D2O)δ176.79,171.80,155.09,141.15,131.27,120.92,114.80,111.70,68.72,65 .66,63.91,43.34,37.19,32.60,30.69,29.40,24.94,24.69,20.01,17.37.HRMS(HESI)m / z:[M] + 326.2114.
[0045] Elemental analysis test results:
[0046] Molecular formula: C 21 H 28 NO2·1 / 2C4H6O6
[0047]
[0048] Example 3
[0049] 1 g of compound 1 was added to 10 mL of methanol at room temperature, and 0.5 g of activated carbon and 0.5 g of D-tartaric acid were added. The mixture was refluxed at 64°C for 85 hours, filtered while hot, and the filtrate was concentrated under reduced pressure to obtain 720 mg of an orange solid. The content of the cation represented by formula A was 10.91% as measured by HPLC. After high-efficiency preparative liquid phase preparation, 60 mg of a tartrate containing the cation represented by formula A was obtained. 1 H NMR, 13 The C NMR, mass spectrum data and elemental analysis test results are the same as those in Example 2.
[0050] Example 4
[0051] 1 g of compound 1 was added to 9 mL of purified water at room temperature, and 0.8 g of activated carbon and 0.5 g of D-tartaric acid were added. The mixture was refluxed at 100°C for 85 hours, filtered while hot, and the filtrate was concentrated under reduced pressure to obtain 900 mg of an orange solid. The content of the cation represented by formula A was 4.21% as measured by HPLC. After high-efficiency preparative liquid phase preparation, 24 mg of a tartrate containing the cation represented by formula A was obtained. 1 HNMR, 13 The C NMR, mass spectrum data and elemental analysis test results are the same as those in Example 2.
[0052] Example 5
[0053] At room temperature, 1 g of compound 1 was added to 10 mL of purified water, 0.7 g of palladium carbon, and 0.5 g of D-tartaric acid, and the mixture was refluxed at 100°C for 36 hours, filtered while hot, and the filtrate was concentrated under reduced pressure to obtain 630 mg of an orange solid, wherein the content of the cation represented by formula A was 8.35% as measured by HPLC. After high-efficiency preparative liquid phase preparation, 48 mg of a tartrate containing the cation represented by formula A was obtained. 1 H NMR, 13 The C NMR, mass spectrum data and elemental analysis test results are the same as those in Example 2.
[0054] Example 6
[0055] 1 g of compound 1 was added to 9 mL of isopropanol at room temperature, and 0.6 g of palladium carbon and 0.5 g of D-tartaric acid were added. The mixture was refluxed at 82°C for 44 hours, filtered while hot, and the filtrate was concentrated under reduced pressure to obtain 608 mg of an orange solid. The content of the cation represented by formula A was 5.15% as measured by HPLC. After high-efficiency preparative liquid phase preparation, 24 mg of a tartrate containing the cation represented by formula A was obtained. 1 H NMR, 13 The C NMR, mass spectrum data and elemental analysis test results are the same as those in Example 2.
[0056] Example 7
[0057] 1 g of compound 1 was added to 10 mL of n-butanol at room temperature, and 0.9 g of palladium carbon and 0.5 g of D-tartaric acid were added. The mixture was refluxed at 117°C for 94 hours, filtered while hot, and the filtrate was concentrated under reduced pressure to obtain 715 mg of an orange solid. The content of the cation represented by formula A was 7.12% as measured by HPLC. After high-efficiency preparative liquid phase preparation, 37 mg of tartrate containing the cation represented by formula A was obtained. 1 HNMR, 13 The C NMR, mass spectrum data and elemental analysis test results are the same as those in Example 2.
[0058] Example 8
[0059] 1 g of compound 1 was added to 9 mL of ethyl acetate at room temperature, and 0.7 g of ruthenium carbon and 0.5 g of D-tartaric acid were added. The mixture was refluxed at 75°C for 44 hours, filtered while hot, and the filtrate was concentrated under reduced pressure to obtain 645 mg of an orange solid. The content of the cation represented by formula A was 6.45% as measured by HPLC. After high-efficiency preparative liquid phase preparation, 28 mg of a tartrate containing the cation represented by formula A was obtained. 1 HNMR, 13 The C NMR, mass spectrum data and elemental analysis test results are the same as those in Example 2.
[0060] Example 9
[0061] 1 g of compound 1 was added to 12 mL of toluene at room temperature, and 0.5 g of ruthenium carbon and 0.5 g of D-tartaric acid were added. The mixture was refluxed at 110°C for 102 hours, filtered while hot, and the filtrate was concentrated under reduced pressure to obtain 715 mg of an orange solid. The content of the cation represented by formula A was 4.38% as measured by HPLC. After high-efficiency preparative liquid phase preparation, 18 mg of a tartrate containing the cation represented by formula A was obtained. 1 H NMR, 13 The C NMR, mass spectrum data and elemental analysis test results are the same as those in Example 2.
[0062] Example 10
[0063] 1 g of compound 1 was added to 12 mL of acetone at room temperature, and 0.8 g of ruthenium carbon and 0.5 g of D-tartaric acid were added. The mixture was refluxed at 56°C for 77 hours, filtered while hot, and the filtrate was concentrated under reduced pressure to obtain 532 mg of an orange solid. The content of the cation represented by formula A was 7.42% as measured by HPLC. After high-efficiency preparative liquid phase preparation, 29 mg of tartrate containing the cation represented by formula A was obtained. 1 H NMR, 13 The CNMR, mass spectrum data and elemental analysis test results are the same as those in Example 2.
[0064] Embodiment 11
[0065] 1 g of compound 1 was added to 11 mL of isopropanol at room temperature, and 0.6 g of activated carbon and 0.5 g of D-tartaric acid were added. The mixture was refluxed at 172°C for 44 hours, filtered while hot, and the filtrate was concentrated under reduced pressure to obtain 715 mg of an orange solid. The content of the cation represented by formula A was 5.15% as measured by HPLC. After high-efficiency preparative liquid phase preparation, 21 mg of a tartrate containing the cation represented by formula A was obtained. 1 HNMR, 13 The C NMR, mass spectrum data and elemental analysis test results are the same as those in Example 2.
[0066] Effect Example: Hot Plate Test for Determination of Analgesia Threshold of the Salt of the Cation Represented by Formula A
[0067] Pre-selected animals:
[0068] Place the mice on a hot plate (temperature 55±0.5℃), and use the mice licking their hind feet as an observation indicator to measure the pain threshold (time, s) of the mice. Repeat twice, with an interval of 20 minutes each time. Pre-select the mice that have a pain response within 30 seconds.
[0069] Grouping and dosing:
[0070] Twenty mice were pre-selected and randomly divided into four groups: a butorphanol tartrate group of 6 mice, a tartrate containing a cation represented by formula A obtained in Example 2, and a Group 6, the hydrochloride of the cation represented by formula A obtained in Example 1 above The mice were injected intraperitoneally (IP) with 0.5 mg / kg, 1.0 mg / kg and 1.5 mg / kg, respectively. The mice were injected intraperitoneally (IP) with 2 mice at each dose. The mice were injected IP with 1 mL of saline with 2 mice in the normal saline group.
[0071] Determining pain threshold:
[0072] The pain threshold of mice was measured 30 and 60 minutes after administration, and the average time of mice licking their hind paws on the hot plate was calculated. If the mice showed no pain reaction within 60 seconds, they were immediately removed and the time was calculated as 60 seconds.
[0073] Measurement results:
[0074] 1. 30 minutes after administration
[0075]
[0076] Control group (normal saline group): 2.3s, 3.1s, average 2.7s
[0077] 2. 60 minutes after administration
[0078]
[0079]
[0080] Control group (normal saline group): 2.3s, 3.1s, average 2.7s
[0081] 3. Calculation of analgesic effect:
[0082] The time values of the tartrate group containing the cation represented by formula A, the hydrochloride group containing the cation represented by formula A, the control group (normal saline group), and the butorphanol tartrate group were compared to evaluate the effect of the salt of the cation represented by formula A.
[0083] Percentage increase in pain threshold:
[0084] (1) Compared with the control group (normal saline group):
[0085]
[0086] Calculation method: Percentage of pain threshold increase = [(pain threshold after drug administration - pain threshold of control group) / pain threshold of control group] × 100%.
[0087] (2) Compared with the butorphanol tartrate group:
[0088]
[0089]
[0090] Calculation method: percentage of pain threshold increase = [(pain threshold after administration of the salt of the cation represented by formula A - pain threshold of butorphanol tartrate) / pain threshold of butorphanol tartrate] × 100%.
[0091] in conclusion:
[0092] The salt of the cation represented by formula A showed obvious analgesic effect in the mouse hot plate test: compared with the control group (normal saline group), the pain threshold of the tartrate group and the hydrochloride group containing the cation represented by formula A was increased by about 10 times; compared with butorphanol tartrate, the pain threshold of the tartrate group and the hydrochloride group containing the cation represented by formula A was increased by about 60%.
Claims
1. A salt of a cation represented by formula A; in, The salt of the cation represented by formula A is electrically neutral, and the salt of the cation represented by formula A is D-tartrate or hydrochloride.
2. The cationic salt of formula A as claimed in claim 1, which is 3. A method for preparing a salt of a cation represented by formula A as claimed in claim 1, comprising the following steps: reacting compound 1 with an acid in a solvent in the presence of an additive to obtain a salt of a cation represented by formula A, in, The solvent is one or more of water, alcohol solvents, ketone solvents, lipid solvents and aromatic hydrocarbon solvents; The acid is D-tartrate or hydrochloride; The additive is one or more of activated carbon, palladium carbon, rhodium carbon and ruthenium carbon.
4. The method for preparing the salt of the cation represented by formula A as claimed in claim 3, characterized in that: The preparation method meets one or more of the following conditions: The solvent is one or more of water, methanol, ethanol, isopropanol, n-butanol, acetone, ethyl acetate and toluene; The additive is one or more of activated carbon, palladium carbon and ruthenium carbon; The mass ratio of the additive to compound 1 is 0.1-10; The molar ratio of the compound 1 to M is 0.1:1-10:1; The reaction temperature of the preparation method is 30-200°C or the boiling point of the solvent; The volume mass ratio of the solvent to compound 1 is 3-20 mL / g; The reaction time of the preparation method is the time until the initial reactants no longer react.
5. The method for preparing the salt of the cation represented by formula A as claimed in claim 4, characterized in that: The preparation method meets one or more of the following conditions: The mass ratio of the additive to compound 1 is 0.5-1; The molar ratio of the compound 1 to M is 0.5:1 to 2:1; The reaction temperature of the preparation method is 56-172°C; The volume mass ratio of the solvent to compound 1 is 9-12 mL / g; The reaction time of the preparation method is 24-120 hours.
6. The method for preparing the salt of the cation represented by formula A as claimed in claim 5, characterized in that: The preparation method meets one or more of the following conditions: The mass ratio of the additive to compound 1 is 0.5, 0.6, 0.7, 0.8, 0.9 or 1; The molar ratio of compound 1 to M is 30:33; The reaction temperature of the preparation method is 56°C, 64°C, 75°C, 78°C, 82°C, 100°C, 110°C, 117°C or 172°C; The volume mass ratio of the solvent to compound 1 is 9 mL / g, 10 mL / g, 11 mL / g or 12 mL / g; The reaction time of the preparation method is 36-102 hours.
7. The method for preparing the salt of the cation represented by formula A as claimed in claim 5, characterized in that: The reaction time of the preparation method is 36 hours, 44 hours, 70 hours, 77 hours, 85 hours, 94 hours or 102 hours.
8. A method for preparing a salt of a cation represented by formula A according to any one of claims 3 to 7, characterized in that: The acid is D-tartaric acid, and the salt of the cation represented by formula A is Or, the acid is hydrochloric acid, and the salt of the cation represented by formula A is 9. A pharmaceutical composition comprising a salt of a cation represented by formula A as claimed in claim 1 or 2 and a pharmaceutically acceptable excipient.
10. Use of a salt of a cation represented by formula A as claimed in claim 1 or 2 in the preparation of analgesic drugs.