A terpene lactone derivative and its medical use

Abstract

The present application relates to a terpene lactone derivative and its application in the preparation of tranquilizers, in particular to a terpene lactone derivative as shown in general formula (I), or its stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal, wherein the definitions of the substituents in general formula (I) are the same as those in the specification

Description

[0001] This application is a divisional application of the application with the application number 202210342140.1, the application date of March 30, 2022, and the invention name of "a terpenoid derivative and its application in medicine". TECHNICAL FIELD

[0002] The present application relates to a terpenoid derivative, or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and its application in the preparation of a sedative drug. BACKGROUND

[0003] Sedative drugs have a wide inhibitory effect on the central nervous system, which helps to relieve depression and anxiety, and are used to treat mental tension without affecting normal brain activity. Commonly used sedative drugs include phenobarbital (barbiturates), clorazepate (benzodiazepines), diazepam (benzodiazepines), and chlorpromazine (phenothiazines), etc. However, these drugs generally have obvious side effects, such as causing hypotension, respiratory depression, etc., and long-term use can also cause addiction and drug resistance problems.

[0004] Therefore, it is urgent to develop a safer sedative drug.

[0005] Research has found that terpenoid has the effects of neuron protection, nerve function repair and reconstruction, and the development of terpenoid derivatives for the preparation of sedative drugs has broad clinical application value and prospect. SUMMARY

[0006] In order to meet the clinical needs, the present application provides the application of a terpenoid derivative or its stereoisomer, hydrate, metabolite, solvate, pharmaceutically acceptable salt or co-crystal in the preparation of a sedative or a drug for preventing and / or treating diseases or disorders related to non-sedative states.

[0007] Specifically, the present application provides a compound represented by general formula (I), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof:

[0008]

[0009] wherein:

[0010] R is selected from C 1-6 alkyl.

[0011] The compound described in the present application, or its stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from:

[0012] or

[0013] In particular, the present application provides a compound of general formula (II), or a stereoisomer, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof:

[0014]

[0015] wherein:

[0016] R is selected from C 1-6 alkyl, C 1-6 alkoxy, alkynyl or -Si(R1)3; wherein R1 is selected from C 1-3 alkyl.

[0017] The present application provides a compound, or a stereoisomer, solvate, metabolite, prodrug, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from:

[0018] or

[0019] The present application also provides a pharmaceutical composition comprising:

[0020] (1) a compound of the present application or a stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or prodrug thereof;

[0021] (2) optionally one or more other active ingredients; and

[0022] (3) a pharmaceutically acceptable carrier and / or excipient.

[0023] The present application also provides the use of a compound or a pharmaceutical composition as described above for the manufacture of a medicament for sedation or for the prevention and / or treatment of a disease or disorder associated with a non-sedated state.

[0024] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0025] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present application include their isotopic cases, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present application are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super-heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include32 S, 33 S, 34 S and 36 S, isotopes of nitrogen include 14 N and 15 N, isotopes of fluorine include 17 F and 19 F, isotopes of chlorine include 35 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br.

[0026] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof means a salt of a compound of the present application that retains the biological effectiveness and properties of the free acids or free bases and is obtained by reaction of a free acid with a non-toxic inorganic or organic base or of a free base with a non-toxic inorganic or organic acid.

[0027] "Pharmaceutical composition" means a mixture of one or more compounds of the present application, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, such as pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0028] "Carrier" refers to a material that does not itself induce the production of antibodies to it, and which does not have significant biological activity and does not substantially diminish the biological activity and properties of the administered compound.

[0029] "Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, binders, and disintegrating agents.

[0030] "Prodrug" refers to a compound that can be converted into a biologically, pharmaceutically or pharmacologically active compound of the present application by metabolic means (e.g., by hydrolytic cleavage) in vivo. Prodrugs of the present application are prepared by modifying the amino or carboxyl groups of the compounds of the present application in such a way that the modifications are cleaved in vivo to give the parent compound. When a prodrug of the present application is administered to a mammalian subject, the prodrug is cleaved to form the free amino or carboxyl groups.

[0031] "Cocrystal" refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a cocrystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein the pure state of the API and the CCF are both solid at room temperature, and there is a fixed stoichiometric ratio between the components. Cocrystals are a kind of multi-component crystals, including binary cocrystals formed between two neutral solids, and multi-component cocrystals formed between a neutral solid and a salt or a solvate.

[0032] "stereoisomers" refer to isomers that differ only in the arrangement of atoms in space, and include enantiomers and diastereomers.

[0033] "optional" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance can or can not occur, and this description includes instances in which the event or circumstance occurs and instances in which it does not. For example, "heterocyclyl optionally substituted with alkyl" means that the alkyl group can or can not be present, and this description includes instances in which the heterocyclyl is substituted with alkyl, and instances in which the heterocyclyl is not substituted with alkyl. DETAILED DESCRIPTION

[0034] The present application is described in detail in the specification herein, which should be considered as exemplary of the application, and not as limiting the application to the specific embodiments described. It is understood that modifications and variations of the application are possible, and that such modifications and variations are considered to be within the scope of the application as set forth in the claims. The beneficial effects of the application are illustrated in the following examples.

[0035] Example 1

[0036] (3aS,6aS)-5-(tert-butyl)-4-formyl-2-oxo-2,3,6,6a-tetrahydro-3aH-cyclopenta[b]furan-3a-carboxylate

[0037] (3aS,6aS)-5-(tert-butyl)-4-formyl-2-oxo-2,3,6,6a-tetrahydro-3aH-cyclopenta[b]furan-3a-carboxylate

[0038]

[0039] In a 500 mL round bottom flask, under nitrogen atmosphere, was added 1a (3.0 g, 9.2 mmol), silver oxide (8.95 g, 38.6 mmol), iodomethane (12.5 g, 88.3 mmol) and 100 mL of 1,2-dichloroethane. The reaction was heated to reflux under nitrogen atmosphere for 1 h. After the heating was stopped, the reaction was cooled, the insoluble solid in the reaction was filtered, and washed with dichloromethane. The organic solvent in the filtrate was removed under reduced pressure, and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:2, Rf = 0.4) to obtain the target product (3aS,6aS)-5-(tert-butyl)-4-formyl-2-oxo-2,3,6,6a-tetrahydro-3aH-cyclopenta[b]furan-3a-carboxylic acid methyl ester Compound 1, yellow solid (1.56 g, yield 50%).

[0040] 1 H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 5.00-4.95 (m, 1H), 3.60 (s, 3H), 3.36 (d, J = 18.4 Hz, 1H), 3.21 (dd, J = 20.0, 6.3 Hz, 1H), 3.00 (dd, J = 19.9, 1.2 Hz, 1H), 2.60 (d, J = 18.4 Hz, 1H), 1.31 (s, 9H).

[0041] LC-MS m / z (ESI) = 267.10 [M+1].

[0042] Example 2

[0043] (3aS,6aS)-5-(tert-butyl)-4-formyl-2-oxo-2-3,6,6a-tetrahydro-3aH-cyclopenta[b]furan-3a-carboxylic acid ethyl ester Compound 2

[0044] Ethyl (3aS,6aS)-5-(tert-butyl)-4-formyl-2-oxo-2,3,6,6a-tetrahydro-3aH-cyclopenta[b]furan-3a-carboxylate

[0045]

[0046] In a 100 mL round bottom flask, under nitrogen protection, was added 1a (1.0 g, 3.06 mmol), silver oxide (3.0 g, 12.8 mmol), iodoethane (4.6 g, 29.4 mmol) and 50 mL of 1,2-dichloroethane. The reaction was heated to reflux under nitrogen protection for 1 hour. After the heating was stopped, the reaction was cooled, the insoluble solid in the reaction was filtered, and washed 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 = 1:6, Rf = 0.1) to obtain the target product (3aS,6aS)-5-(tert-butyl)-4-formyl-2-oxo-2-3,6,6a-tetrahydro-3aH- cyclopenta[b]furan-3a-carboxylic acid ethyl ester compound 2, yellow solid (382 mg, yield 35%).

[0047] 1 H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 4.95 (dd, J = 6.2, 1.2 Hz, 1H), 4.04 (qd, J = 7.1, 2.6 Hz, 2H), 3.35 (d, J = 17.9 Hz, 2H), 3.20 (dd, J = 20.0, 6.2 Hz, 1H), 3.04 - 2.95 (m, 1H), 2.58 (d, J = 18.4 Hz, 1H), 1.31 (s, 9H), 1.11 (t, J = 7.1 Hz, 3H).

[0048] LC-MS m / z (ESI) = 281.10 [M+1].

[0049] Example 3

[0050] (1S,4R,7R,9R,11S)-9-tert-Butyl-9-hydroxy-7-(methoxymethoxy)-3,5,12-trioxatetracyclo[6.6.0.01,11.04,]tetradecane-2,6,13-trione compound 3

[0051] (1S,4R,7R,9R,11S)-9-Tert-butyl-9-hydroxy-7-(methoxymethoxy)-3,5,12-trioxatetracyclo[6.6.0.01,11.04,]tetradecane-2,6,13-trione

[0052]

[0053] In a 25 mL round bottom flask, compound 1a (326 mg, 1 mmol), dimethoxymethane (858 mg, 11.3 mmol) and 5 mL dichloromethane were added. Subsequently, phosphorous pentoxide (71 mg, 0.5 mmol) was added in several portions. The reaction was stirred at room temperature for 5 hours, TLC and LC-MS showed 50% conversion. The insoluble solid in the reaction was filtered and washed with dichloromethane. The organic solvent in the filtrate was removed under reduced pressure, and the residue was purified by column chromatography (ethyl acetate: petroleum ether = 1:3, Rf = 0.3) to obtain the target product (1S,4R,7R,9R,11S)-9-tert-butyl-9-hydroxy-7-(methoxymethoxy)-3,5,12-trioxatetracyclo[6.6.0.01,11.04,]tetradecane-2,6,13-trione compound 3, yellow solid (80 mg, yield 21%).

[0054] 1 H NMR (600 MHz, DMSO-d6) δ 6.36 (s, 1H), 5.56 (s, 1H), 5.46 (s, 1H), 5.07 (d, J = 6.3 Hz, 1H), 4.95 (t, J = 6.8 Hz, 1H), 4.80 (d, J = 6.3 Hz, 1H), 3.29 (s, 3H), 3.00 (d, J = 18.2 Hz, 1H), 2.71 (d, J = 18.1 Hz, 1H), 2.63 (dd, J = 13.5, 7.2 Hz, 1H), 2.04 (dd, J = 13.5, 6.6 Hz, 1H), 1.06 (s, 9H).

[0055] LC-MS m / z (ESI) = 371.1 [M+1].

[0056] Example 4

[0057] (7R,9R,11S)-9-tert-butyl-9-hydroxy-7-(prop-2-yn-1-yloxy)-3,5,12-trioxatetracyclo[6.6.0.01,11.04,]tetradecane-2,6,13-trione compound 4

[0058] (7R,9R,11S)-9-Tert-butyl-9-hydroxy-7-(prop-2-yn-1-yloxy)-3,5,12-trioxatetracyclo[6.6.0.01,11.04,]tetradecane-2,6,13-trione

[0059]

[0060] To a solution of 1a (978 mg, 3.0 mmol) in 10 ml of dimethyl sulfoxide, potassium tert-butoxide (1346.0 mg, 12.0 mmol) was added under ice bath, and 3-bromopropynyl 4b (1428.0 mg, 12.0 mmol) was added, followed by increasing the temperature to 25°C, and then the reaction was allowed to proceed for 16 hours. After the reaction, the reaction solution was added to 30 ml of water, washed with saturated brine 30 ml, and the organic phase was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (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[6.6.0.01,11.04,]tetradecane-2,6,13-trione compound 4 (brown solid, 120.0 mg, yield 11.0%).

[0061] 1 H NMR (400 MHz, DMSO-d6) δ 6.37 (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).

[0062] LC-MS m / z (ESI) = 365.10 [M+1].

[0063] Example 5

[0064] (7R,9R,11S)-9-tert-butyl-9-hydroxy-7-[(trimethylsilyl)oxy]-3,5,12-trioxatetracyclo[6.6.0.01,11.04,]tetradecane-2,6,13-trione compound 5

[0065] (7R,9R,11S)-9-Tert-butyl-9-hydroxy-7-[(trimethylsilyl)oxy]-3,5,12-trioxatetracyclo[6.6.0.01,11.04,]tetradecane-2,6,13-trione

[0066]

[0067]

[0068] To a solution of 1a (163.1 mg, 0.5 mmol) in 5 ml of dichloromethane, triethylamine (101.2 mg, 1.0 mmol) was added under ice bath, followed by 5 ml of dichloromethane solution of trimethylsilyl chloride 5b (81.5 mg, 0.75 mmol) and 4-dimethylaminopyridine (61.2 mg, 0.5 mmol), and then the reaction was allowed to react at room temperature 25 °C. After 4 hours of reaction, the reaction solution was added to 30 ml of water, washed with saturated brine 30 ml, and the organic phase was dried over anhydrous sodium sulfate and rotary evaporated. Purification by silica gel column chromatography (dichloromethane: acetone = 200:1) gave the target product (7R,9R,11S)-9-tert-butyl-9-hydroxy-7-[(trimethylsilyl)oxy]-3,5,12-trioxatetracyclo[6.6.0.0 1 , 11 .0 4 ,]tetradecane-2,6,13-trione compound 5 (white solid, 166.0 mg, yield 83.4%).

[0069] 1 H NMR (400 MHz, DMSO-d6) δ 6.29 (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, 6.6 Hz, 1H), 1.04 (s, 9H), 0.18 (s, 9H).

[0070] LC-MS m / z (ESI) = 399.10 [M+1].

[0071] Example 6

[0072] (7R,9R,11S)-9-tert-butyl-9-hydroxy-7-[(trimethylsilyl)oxy]-3,5,12-trioxatetracyclo[6.6.0.0 1 , 11 .0 4 ,]tetradecane-2,6,13-trione compound 5

[0073] (7R,9R,11S)-9-Tert-butyl-9-hydroxy-7-[(triethylsilyl)oxy]-3,5,12-trioxatetracyclo[6.6.0.0 1 , 11 .0 4 ,]tetradecane-2,6,13-trione

[0074]

[0075] To a solution of 1a (326.3 mg, 1.0 mmol) in 5 ml of dichloromethane, triethylamine (202.4 mg, 2.0 mmol) was added under ice bath, followed by the addition of a solution of triethylsilyl chloride 6b (301.4 mg, 2.0 mmol) in 5 ml of dichloromethane and 4-dimethylaminopyridine (244.3 mg, 2.0 mmol), followed by the reaction at room temperature 25 °C, and the reaction was carried out for 4 hours. After the reaction, the reaction solution was added to 30 ml of water, washed with saturated brine 30 ml, and the organic phase was dried over anhydrous sodium sulfate and rotary evaporated. Purification was performed by silica gel column chromatography (dichloromethane: acetone = 50:1) to obtain the target product (7R, 9R, 11S)-9-tert-butyl-9-hydroxy-7-[(triethylsilyl)oxy]-3,5,12-trioxatetradecane-2,6,13-trione 6 (white solid, 349.0 mg, yield 79.3%). 1 , 11 .0 4 ,]tetradecane-2,6,13-trione compound 6 (white solid, 349.0 mg, yield 79.3%).

[0076] 1 H NMR (400 MHz, DMSO-d6) δ 6.28 (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, 6.9 Hz, 1H), 1.05 (s, 9H), 0.92 (t, 9H), 0.79-0.64 (m, 6H).

[0077] LC-MS m / z (ESI) = 441.20 [M+1].

[0078] Biological test

[0079] Sedative effect of terpene lactone derivatives on mice

[0080] Experimental animals 20 ICR mice were randomly divided into 5 groups, 4 in each group (purchased from Chengdu Dashuo Experimental Animal Co., Ltd., body weight 22-26 g). The experimental compounds were dissolved with DMSO+HS-15+NS (1:1:8, v / v / v) solvent formula. The experimental group was administered with 50 mg / kg or 100 mg / kg of the compound by gavage, and the administration volume was 10 ml / kg; the blank control group was administered with 10 ml / kg of the blank solvent by gavage. The occurrence and disappearance times of sedative behavior of each animal within 4 hours after administration were observed. The experimental data of each group were represented by the average value. The experimental results are shown in the following table:

[0081]

[0082] Results and Conclusion: Compared with the blank control group, the mice in the experimental group all showed sedative behavior after administration, especially the mice administered with 50mg / kg of compound 1 showed sedative behavior within 30 minutes, and the duration was more than 160 minutes; the mice administered with 100mg / kg of compound 5 showed sedative behavior in nearly 30 minutes, and the duration was more than 190 minutes; and the blank control group did not show any sedative behavior within the observation time, indicating that the terpene lactone derivative has the potential to prepare sedative drugs.

[0083] The specific embodiments are described in detail in the specification of the present application, and those skilled in the art should recognize that the above-mentioned embodiments are exemplary and cannot be understood as limiting the present application, and for those skilled in the art, through several improvements and modifications of the present application, the technical solutions obtained by the improvements and modifications also fall within the protection scope of the claims of the present application without departing from the principles of the present application.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, said compound having the following structure: or 2. A pharmaceutical composition comprising: (1) The compound of claim 1 or a pharmaceutically acceptable salt; (2) One or more other active ingredients may be selected; as well as (3) Pharmaceutically acceptable carriers and / or excipients.

3. The use of the compound of claim 1 or the pharmaceutical composition of claim 2 in the preparation of a medicament for sedation or prevention and / or treatment of diseases or conditions associated with a non-sedated state.

Images