CN115141169B - Terpene lactone derivative and application thereof in medicine - Google Patents

Terpene lactone derivative and application thereof in medicine Download PDF

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CN115141169B
CN115141169B CN202210342140.1A CN202210342140A CN115141169B CN 115141169 B CN115141169 B CN 115141169B CN 202210342140 A CN202210342140 A CN 202210342140A CN 115141169 B CN115141169 B CN 115141169B
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CN115141169A (en
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高涵
袁永海
魏用刚
孙毅
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Chengdu Baiyu Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
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    • C07—ORGANIC CHEMISTRY
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    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
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Abstract

The invention relates to a terpene lactone derivative and application thereof in preparing sedative drugs, in particular to a terpene lactone derivative shown in a general formula (I), or stereoisomers, solvates, metabolites, prodrugs, pharmaceutically acceptable salts or eutectic crystals thereof, wherein the definition of each substituent group in the general formula (I) is the same as that of the specification

Description

Terpene lactone derivative and application thereof in medicine
Technical Field
The invention relates to a terpene lactone derivative, or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, and application thereof in preparing sedative drugs.
Background
Sedative drugs have broad inhibitory effects on the central nervous system, help relieve depression and anxiety, and are used to treat mental stress without affecting normal brain activity. Typical sedatives include phenobarbital (barbiturates), clodiazepines (benzodiazepines), diazepams (benzodiazepines), and chlorpromazine (phenothiazines), however, these drugs generally have significant side effects such as hypotension, respiratory depression, etc., and also cause addiction and drug resistance problems after long-term administration.
Thus, there is a need to develop a safer sedative.
The research shows that terpene lactone has the functions of neuron protection, nerve function repair and reconstruction, and the development of terpene lactone derivatives has wide clinical application value and prospect in preparing sedative drugs.
Disclosure of Invention
In order to meet clinical needs, the invention provides the use of terpene lactone derivatives or stereoisomers, hydrates, metabolites, solvates, pharmaceutically acceptable salts or co-crystals thereof for the manufacture of a medicament for sedation or for the prevention and/or treatment of a disease or condition associated with a non-sedated state.
Specifically, the invention provides a compound shown in a general formula (I), or a stereoisomer, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof:
wherein:
r is selected from C 1-6 An alkyl group.
A compound of the invention, or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from the group consisting of:
or->
Specifically, the present invention provides a compound represented by the general formula (II), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof:
wherein:
r is selected from C 1-6 Alkyl, C 1-6 Alkoxy, alkynyl or-Si (R) 1 ) 3 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 1 Selected from C 1-3 An alkyl group.
A compound of the invention, or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from the group consisting of:
or->
The present invention also provides a pharmaceutical composition comprising:
(1) The compounds of the invention or stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or prodrugs thereof;
(2) Optionally one or more other active ingredients; and
(3) Pharmaceutically acceptable carriers and/or excipients.
The invention also provides the use of a compound or pharmaceutical composition as hereinbefore described in the manufacture of a medicament for sedation or the prevention and/or treatment of a disease or condition associated with a non-sedated state.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The carbon, hydrogen, oxygen, sulfur, nitrogen or F, cl, br, I referred to in the groups and compounds of the invention each include their isotopic condition, and the carbon, hydrogen, oxygen, sulfur or nitrogen referred to in the groups and compounds of the invention are optionally further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C、 13 C and C 14 Isotopes of C, hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), isotopes of oxygen include 16 O、 17 O and 18 isotopes of O, sulfur include 32 S、 33 S、 34 S and 36 isotopes of S, nitrogen include 14 N and 15 isotopes of N, fluorine include 17 F and F 19 Isotopes of F, chlorine include 35 Cl and Cl 37 Isotopes of Cl, bromine include 79 Br and 81 Br。
by "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base obtained by reaction with a non-toxic inorganic or organic base.
"pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.
By "carrier" is meant a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance that is added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.
"prodrug" means a compound of the invention which is converted into a biologically active form by in vivo metabolism. Prodrugs of the invention are prepared by modifying amino or carboxyl groups in the compounds of the invention, which modifications may be removed by conventional procedures or in vivo to give the parent compound. When the prodrugs of the invention are administered to a mammalian subject, the prodrugs are cleaved to form the free amino or carboxyl groups.
"co-crystals" refers to crystals of Active Pharmaceutical Ingredient (API) and co-crystal former (CCF) that are bound by hydrogen bonds or other non-covalent bonds, wherein the pure states of the API and CCF are both solid at room temperature and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.
"stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group, and cases where the heterocyclic group is not substituted with an alkyl group.
Detailed Description
While the specification describes in detail specific embodiments of the present invention, those skilled in the art will recognize that the following embodiments are illustrative and not to be construed as limiting the invention, and that many modifications and variations may be made thereto without departing from the spirit of the invention, which is intended to fall within the scope of the appended claims. The advantageous effects of the present invention are specifically illustrated by examples below.
Example 1
(3 aS,6 aS) -5- (tert-butyl) -4-formyl-2-oxo-2, 3,6 a-tetrahydro-3 aH-cyclopenta-me thyl [ b ] furan-3 a-carboxylic acid methyl ester compound 1
Methyl(3aS,6aS)-5-(tert-butyl)-4-formyl-2-oxo-2,3,6,6a-tetrahydro-3a H-cyclopenta[b]furan-3a-carboxylate
In a 500mL round bottom flask, 1a (3.0 g,9.2 mmol), silver oxide (8.95 g,38.6 mmol), methyl iodide (12.5 g,88.3 mmol) and 100mL 1, 2-dichloroethane were added under nitrogen. The reaction solution was heated under reflux for 1 hour under nitrogen protection. After the heating was stopped, the reaction mixture was cooled, and insoluble solids in the reaction mixture were filtered and washed with methylene chloride. The organic solvent in the filtrate was removed by reduced pressure, and the residue was purified by column chromatography (ethyl acetate: petroleum ether=1:2, rf=0.4) to give the objective product (3 as,6 as) -5- (tert-butyl) -4-formyl-2-oxo-2, 3,6 a-tetrahydro-3 aH-cyclopenta-methyl [ b ] furan-3 a-carboxylic acid methyl ester compound 1, yellow solid (1.56 g, yield 50%).
1 HNMR(400 MHz,DMSO-d 6 )δ10.16(s,1H),5.00-4.95(m,1H),3.60(s,3H),3.36(d,J＝18.4Hz,1H),3.21(dd,J＝20.0,6.3Hz,1H),3.00(dd,J＝19.9,1.2Hz,1H),2.60(d,J＝18.4Hz,1H),1.31(s,9H).
LC-MS m/z(ESI)＝267.10[M+1].
Example 2
(3 aS,6 aS) -5- (tert-butyl) -4-formyl-2-oxo-2-3, 6 a-tetrahydro-3 aH-cyclopenta-ethyl [ b ] furan-3 a-carboxylic acid ethyl ester compound 2
Ethyl(3aS,6aS)-5-(tert-butyl)-4-formyl-2-oxo-2,3,6,6a-tetrahydro-3a H-cyclopenta[b]furan-3a-carboxylate
In a 100mL round bottom flask, 1a (1.0 g,3.06 mmol), silver oxide (3.0 g,12.8 mmol), ethyl iodide (4.6 g,29.4 mmol) and 50mL 1, 2-dichloroethane were added under nitrogen. The reaction solution was heated under reflux for 1 hour under nitrogen protection. After the heating was stopped, the reaction mixture was cooled, and insoluble solids in the reaction mixture were filtered and washed with methylene chloride. The organic solvent in the filtrate was removed by reduced pressure, and the residue was purified by column chromatography (ethyl acetate: petroleum ether=1:6, rf=0.1) to give the objective (3 as,6 as) -5- (tert-butyl) -4-formyl-2-oxo-2-3, 6 a-tetrahydro-3 aH-cyclopenta-ethyl [ b ] furan-3 a-carboxylate compound 2 as a yellow solid (382 mg, yield 35%).
1 H NMR(400MHz,DMSO-d6)δ10.17(s,1H),4.95(dd,J＝6.2,1.2Hz,1H),4.04(qd,J＝7.1,2.6Hz,2H),3.35(d,J＝17.9Hz,2H),3.20(dd,J＝20.0,6.2Hz,1H),3.04-2.95(m,1H),2.58(d,J＝18.4Hz,1H),1.31(s,9H),1.11(t,J＝7.1Hz,3H).
LC-MS m/z(ESI)＝281.10[M+1].
Example 3
(1S, 4R,7R,9R, 11S) -9-tert-butyl-9-hydroxy-7- (methoxymethoxy) -3,5,12-trioxatetracyclo [6.6.0.01,11.0 4 , 8 ]Tetradecane-2, 6, 13-trione compound 3
(1S,4R,7R,9R,11S)-9-Tert-butyl-9-hydroxy-7-(methoxymethoxy)-3,5,12-trioxatetra cyclo[6.6.0.01,11.0 4 , 8 ]tetradecane-2,6,13-trione
In a 25mL round bottom flask, compound 1a (326 mg,1 mmol), dimethoxymethane (858 mg,11.3 mmol) and 5mL dichloromethane were added. Phosphorus pentoxide (71 mg,0.5 mmol) was then added in portions. Stirring at room temperature for 5 hours, TLC and LC-MS detection of 50% conversion, filtering insoluble solids in the reaction solution and washing with dichloromethane. The organic solvent in the filtrate was removed by reduced pressure, and the residue was purified by column chromatography (ethyl acetate: petroleum ether=1:3, rf=0.3) to give the objective product (1 s,4r,7r,9r,11 s) -9-tert-butyl-9-hydroxy-7- (methoxymethoxy) -3,5,12-trioxatetracyclo [ 6.6.0.0) 1 , 11 .0 4 , 8 ]Tetradecane-2, 6, 13-trione compound 3, yellow solid (80 mg, yield 21%).
1 H NMR(600 MHz,DMSO-d6)δ6.36(s,1H),5.56(s,1H),5.46(s,1H),5.07(d,J＝6.3Hz,1H),4.95(t,J＝6.8Hz,1H),4.80(d,J＝6.3Hz,1H),3.29(s,3H),3.00(d,J＝18.2Hz,1H),2.71(d,J＝18.1Hz,1H),2.63(dd,J＝13.5,7.2Hz,1H),2.04(dd,J＝13.5,6.6Hz,1H),1.06(s,9H).
LC-MS m/z(ESI)＝371.1[M+1].
Example 4
(7R, 9R, 11S) -9-tert-butyl-9-hydroxy-7- (prop-2-yn-1-yloxy) -3,5,12-trioxatetracyclo [6.6.0.0 1 , 11 .0 4 , 8 ]Tetradecane-2, 6, 13-trione compound 4
(7R,9R,11S)-9-Tert-butyl-9-hydroxy-7-(prop-2-yn-1-yloxy)-3,5,12-trioxatetracyclo[6.6.0.0 1 , 11 .0 4 , 8 ]tetradecane-2,6,13-trione
1a (978 mg,3.0 mmol) was dissolved in 10ml dimethyl sulfoxide solution, potassium tert-butoxide (1346.0 mg,12.0 mmol) was added under ice bath, 3-bromopropyne 4b (1428.0 mg,12.0 mmol) was added, followed byAfter reaction at 25 ℃ for 16 hours at room temperature, the reaction solution is added into 30ml of water to wash, saturated saline is washed with 30ml, the organic phase is dried by anhydrous sodium sulfate, dried by spin, and purified by silica gel column chromatography (dichloromethane: acetone=100:1) to obtain the target product (7R, 9R, 11S) -9-tert-butyl-9-hydroxy-7- (prop-2-yn-1-yloxy) -3,5,12-trioxatetracyclo [ 6.6.0.0) 1 , 11 .0 4 , 8 ]Tetradecane-2, 6, 13-trione compound 4 (brown solid, 120.0mg, 11.0% yield).
1 H NMR(400 MHz,DMSO-d 6 )δ6.37(s,1H),5.55(s,1H),5.35(s,1H),4.92(t,1H),4.65(dd,1H),4.54(dd,1H),3.59(t,1H),3.00(d,1H),2.70(d,1H),2.59(dd,1H),2.07-1.98(m,1H),1.05(s,9H).
LC-MS m/z(ESI)＝365.10[M+1].
Example 5
(7R, 9R, 11S) -9-tert-butyl-9-hydroxy-7- [ (trimethylsilyl) oxy]3,5,12-trioxatetracyclo [6.6.0.0 ] 1 , 11 .0 4 , 8 ]Tetradecane-2, 6, 13-trione compound 5
(7R,9R,11S)-9-Tert-butyl-9-hydroxy-7-[(trimethylsilyl)oxy]-3,5,12-trioxatetracyclo[6.6.0.01,11.0 4 , 8 ]tetradecane-2,6,13-trione
1a (163.1 mg,0.5 mmol) was dissolved in 5ml of methylene chloride solution, triethylamine (101.2 mg,1.0 mmol) was added under ice bath, then 5ml of methylene chloride solution of trimethylchlorosilane 5b (81.5 mg,0.75 mmol) and 4-dimethylaminopyridine (61.2 mg,0.5 mmol) were added, then the reaction was carried out at room temperature of 25℃to react for 4 hours, after the reaction solution was added to 30ml of water for washing, saturated brine was washed with 30ml, and the organic phase was dried over anhydrous sodium sulfate, and the dried and spun dry, and purified by silica gel column chromatography (methylene chloride: acetone=200:1) to give the objective product (7R, 9R, 11S) -9-tert-butyl-9-hydroxy-7- [ (trimethylsilyl) oxy group]3,5,12-trioxatetracyclo [6.6.0.01,11.0 ] 4 , 8 ]Tetradecane-2, 6, 13-trione Compound 5 (white solid, 166.0mg, yield)83.4％)。
1 H NMR(400MHz,DMSO-d 6 )δ6.29(s,1H),5.49(s,1H),5.33(s,1H),4.93(t,1H),2.99(d,1H),2.67-2.55(m,2H),1.98(dd,6.6Hz,1H),1.04(s,9H),0.18(s,9H).
LC-MS m/z(ESI)＝399.10[M+1].
Example 6
(7R, 9R, 11S) -9-tert-butyl-9-hydroxy-7- [ (triethylsilyl) oxy]3,5,12-trioxatetracyclo [6.6.0.0 ] 1 , 11 .0 4 , 8 ]Tetradecane-2, 6, 13-trione compound 6
(7R,9R,11S)-9-Tert-butyl-9-hydroxy-7-[(triethylsilyl)oxy]-3,5,12-trioxatetracyclo[6.6.0.0 1 , 11 .0 4 , 8 ]tetradecane-2,6,13-trione
1a (326.3 mg,1.0 mmol) was dissolved in 5ml of methylene chloride solution, triethylamine (202.4 mg,2.0 mmol) was added under ice bath, 5ml of methylene chloride solution of triethylchlorosilane 6b (301.4 mg,2.0 mmol) and 4-dimethylaminopyridine (244.3 mg,2.0 mmol) were then added, the reaction was allowed to react at room temperature of 25℃to give a reaction solution, after 4 hours of reaction, the reaction solution was washed with 30ml of water, 30ml of saturated brine was washed, and the organic phase was dried over anhydrous sodium sulfate, and the resultant was purified by silica gel column chromatography (methylene chloride: acetone=50:1) to give the objective product (7R, 9R, 11S) -9-tert-butyl-9-hydroxy-7- [ (triethylsilyl) oxy group]3,5,12-trioxatetracyclo [6.6.0.0 ] 1 , 11 .0 4 , 8 ]Tetradecane-2, 6, 13-trione compound 6 (white solid, 349.0mg, 79.3% yield).
1 H NMR(400MHz,DMSO-d 6 )δ6.28(s,1H),5.51(s,1H),5.31(s,1H),4.93(t,1H),2.99(d,1H),2.76-2.58(m,2H),2.01(dd,6.9Hz,1H),1.05(s,9H),0.92(t,9H),0.79-0.64(m,6H).
LC-MS m/z(ESI)＝441.20[M+1].
Biological assay
Sedative effect of terpene lactone derivatives on mice
The experimental animals 20 ICR mice were randomly divided into 5 groups of 4 animals (purchased from Chengdu experimental animals Inc., weight 22-26 g). The test compounds were dissolved in a DMSO+HS-15+NS (1:1:8, v/v/v) solvent formulation, respectively. The experimental group is administrated by stomach irrigation, 50mg/kg or 100mg/kg of the compound is administrated by 10ml/kg of the administration volume; the blank control group was administered with 10ml/kg of blank solvent by intragastric administration. The time to appearance and disappearance of sedation within 4 hours of each animal was observed after dosing. Each set of experimental data is represented as an average. The experimental results are shown in the following table:
results and conclusions: compared with the blank control group, the mice in the experimental group all show sedative behavior after administration, particularly 50mg/kg of compound 1 is given to the mice, the sedative behavior is shown in 30 minutes, the duration of time exceeds 160 minutes, 100mg/kg of compound 5 is given to the mice, and the sedative behavior is shown in 30 minutes or more, the duration of time exceeds 190 minutes; the blank group does not show any sedative behavior in the observation time, which shows that the terpene lactone derivative has the potential of preparing sedative drugs.
While the specification describes in detail specific embodiments of the present invention, those skilled in the art will recognize that the foregoing embodiments are illustrative and not to be construed as limiting the invention, and that many variations and modifications of the invention may be made without departing from the spirit of the invention, which is intended to fall within the scope of the appended claims.

Claims (4)

1. A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof:
wherein:
r is selected from C 1-6 An alkyl group.
2. A compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is selected from:
or->
3. A pharmaceutical composition, the pharmaceutical composition comprising:
(1) A compound according to claim 1 or 2, or a stereoisomer or pharmaceutically acceptable salt thereof;
(2) Optionally one or more other active ingredients; and
(3) Pharmaceutically acceptable carriers and/or excipients.
4. Use of a compound according to claim 1 or 2 or a pharmaceutical composition according to claim 3 in the manufacture of a medicament for sedation or the prevention and/or treatment of a disease or condition associated with a non-sedated state.
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CN110882243A (en) * 2018-09-10 2020-03-17 武汉联合药业有限责任公司 Sedative use of terpene lactones

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WO1999020291A2 (en) * 1997-10-23 1999-04-29 Pharmaprint, Inc. Pharmaceutical grade ginkgo biloba
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