Trichloroethanol derivative and use thereof

Abstract

The present invention belongs to the technical field of medicine, and specifically relates to a trichloroethanol derivative and the use thereof. The trichloroethanol derivative of the present invention exhibits low irritation, a high sleep-induction rate, and a prolonged sleep duration, and has a potential value for clinical use in multiple scenarios.

Description

A trichloroethanol derivative and its application Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a trichloroethanol derivative, its preparation method, and its application. Background Technology

[0002] The main pharmacological effects of sedative-hypnotic drugs are sedation and hypnosis. Currently, commonly used sedative-hypnotic agents in China include aldehydes, benzodiazepines, and barbiturates. Chloral hydrate is a hydrated form of trichloroacetaldehyde, belonging to the category of central sedative drugs. It can inhibit the ascending activating system of the brainstem reticular formation, and has no significant effect on sleep phases or the balance between REM and slow-wave sleep. Its effect is similar to physiological sleep, with no discomfort upon waking, no delayed effects, and no accumulation. It is a relatively safe hypnotic, sedative, and anticonvulsant drug, suitable for patients with difficulty falling asleep. However, its strong irritant effect, bitter taste, poor stability, and short duration of action limit its clinical application. Benzodiazepines enhance neurotransmission at inhibitory synapses, leading to increased positive allosteric regulation and consequently enhanced chloride ion flux, thus exhibiting hypnotic and sedative effects. Midazolam and oxazepam, among others, have rapid onset and short duration of action, classifying them as short-acting tranquilizers. However, their use is limited for insomnia patients requiring long-acting sedation due to early awakening or difficulty falling back asleep. Phenobarbital, a long-acting barbiturate, has central nervous system depressant effects varying with dosage, providing sedation, hypnosis, and anticonvulsant effects with a duration of action of 6-8 hours. It is suitable for refractory insomnia, but its clinical application is limited for patients requiring rapid, short-acting effects and experiencing difficulty falling asleep. Furthermore, repeated or continuous use of benzodiazepines and barbiturates in a short period can lead to tolerance and addiction, making them unsuitable for long-term use.

[0003] Based on this, developing a sedative, hypnotic, and anticonvulsant drug that is less irritating, more stable, provides rapid and relatively long-lasting sedation, and has a high safety profile, in order to expand its clinical application, would have a huge market potential. Summary of the Invention

[0004] To address at least one technical problem existing in the prior art, the present invention provides a novel trichloroethanol derivative to reduce irritation, improve efficacy, and prolong the duration of action.

[0005] On one hand, the present invention provides a compound of formula (I) or a stereoisomer thereof: R1 and R2 are independently selected from hydrogen, sucrose, glucose, fructose, glycerol, maltitol, sorbitol, mannitol, xylitol, erythritol, maltose, isomaltulose, or sucralose; or R1 and R2 are connected to form a five- or six-membered heterocycle.

[0006] Furthermore, R1 is selected from hydrogen; R2 is selected from sucrose, glucose, fructose, glycerol, maltitol, sorbitol, mannitol, xylitol, erythritol, maltose, isomaltulose, or sucralose; or R1 and R2 are connected to form a five- or six-membered heterocycle.

[0007] Furthermore, R1 is selected from hydrogen; R2 is selected from sucrose, glucose, fructose, glycerol, maltitol, sorbitol, mannitol, xylitol, erythritol, or sucralose; or R1 and R2 are connected to form a five- or six-membered heterocycle.

[0008] Furthermore, the above compounds are selected from:

[0009] Furthermore, at least one hydrogen atom in the structure of any of the above compounds or their stereoisomers may be substituted with deuterium.

[0010] In a second aspect, the present invention provides a pharmaceutical composition comprising any of the compounds described above or their stereoisomers, and a pharmaceutically acceptable carrier and / or excipients. Further, the above pharmaceutical composition can be used to prepare tablets, capsules, syrups, oral solutions, injections, small-volume injections, powder injections, or enemas; preferably syrups, oral solutions, or enemas.

[0011] Thirdly, the present invention provides the use of any of the above-described compounds or their stereoisomers in the preparation of sedative, hypnotic, anti-anxiety, or anticonvulsant drugs. Further, the present invention provides the use of any of the above-described compounds or their stereoisomers in the preparation of sedative and / or hypnotic drugs.

[0012] Fourthly, the present invention provides the use of any of the above-mentioned compounds or their stereoisomers in drug quality testing.

[0013] Beneficial effects: This invention provides a novel trichloroethanol derivative with low irritation, high sedation rate and relatively long sedation time, demonstrating better sedation effect and strong potential for clinical application. Detailed Implementation

[0014] The present invention will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Specific techniques or conditions not specified in the embodiments are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0015] Example 1: Preparation of Compound 1 and Compound 2 Sucrose (34.23 g, 1.00 eq.) and trichloroacetaldehyde (14.74 g, 1.00 eq.) were added to 300 ml of trifluoroacetic acid. The reaction mixture was heated to 40 °C and stirred overnight. The reaction solution was then cooled to 0–10 °C, and 500 ml of purified water was slowly added dropwise. The mixture was extracted and washed three times with dichloromethane at a controlled low temperature of 0–10 °C, using 800 ml each time. The aqueous extracts were collected. The aqueous phases were purified by reversed-phase preparative chromatography to yield 1.50 g of target compound 1 (97.5% purity) and 1.32 g of target compound 2 (96.8% purity).

[0016] Structure confirmation of compound 1: MS-ESI(+), m / z: 506.1 (M+NH4) + ), 1 H NMR: (400MHz, D2O) δ5.18(s,1H),5.10(d,1H),4.18–4.07(m,2H),4.02–3.96(m,2H),3.93–3.85(m,2H),3.82–3.60(m,5H),3.57–3.44(m,2H). 13 CNMR: (100MHz, D2O) δ105.12,101.03,100.78,93.11,80.58,77.07,76.16,74.65,74.40,72.02,70.37,65.61,63.22,61.74.

[0017] Structure confirmation of compound 2: MS-ESI(+), m / z: 506.1 (M+NH4) + ), 1 H NMR: (400MHz, D2O) δ5.18(s,1H),5.10(d,1H),,4.15–4.04(m,2H),4.00–3.90(m,2H),3.87–3.77(m,2H),3.76–3.59(m,6H),3.51–3.46(m,1H). 13 CNMR: (100MHz, D2O) δ104.53,101.03,100.76,93.36,81.98,77.13,75.66,74.73,74.63,73.04,71.03,67.00,63.22,62.43.

[0018] The chemical shifts of compound 1 (C-NMR) at 80.58 and 65.61 were compared with those of compound 2 (C-NMR) at 81.98 and 67.00 to further confirm the connection position between compound 1 and compound 2.

[0019] Example 2: Preparation of Compounds 3 and 4 Following the preparation method in Example 1, replacing sucrose with glucose yielded compound 3 (98.7% purity) and compound 4 (98.2% purity). The structure of compound 3 was confirmed by MS-ESI (+), m / z: 344.0 (M+NH4). + ), 1 ¹H NMR: (400MHz, D₂O) δ 5.12 (s, ¹H), 5.08 (d, ¹H), 3.66–3.63 (m, 2H), 3.47–3.43 (m, 2H), 3.30 (dd, ¹H), 3.13–3.09 (m, ¹H). HMBC two-dimensional NMR results showed an overlap between hydrogen at chemical shift 5.08 ppm and carbon at chemical shift 95.00 ppm, indicating that the linkage position of the compound is at a glycosidic bond, which is the target compound 3.

[0020] Structure confirmation of compound 4: MS-ESI(+), m / z: 344.0 (M+NH4) + ), 1 ¹H NMR: (400MHz, D₂O) δ 5.07 (s, ¹H), 4.93 (d, ¹H), 3.86–3.79 (m, ¹H), 3.72–3.68 (m, ¹H), 3.47–3.43 (m, 2H), 3.30 (dd, ¹H), 3.13–3.09 (m, ¹H). HMBC two-dimensional NMR results showed an overlap between hydrogen at chemical shift 3.47–3.43 ppm and carbon at chemical shift 96.80, indicating that the linkage position of the compound is at the primary alcohol hydroxyl group, which is the target compound 4.

[0021] Example 3: Preparation of Compounds 5 and 6 Following the preparation method in Example 1, replacing fructose with sucrose yielded compound 5 with a purity of 98.7% and compound 6 with a purity of 98.2%. The structure of compound 5 was confirmed by MS-ESI (+), m / z: 344.0 (M+NH4). + ), 1 H NMR: (400MHz, D2O) δ5.12(s,1H),3.89–3.80(m,5H),3.76(d,2H).

[0022] Structure confirmation of compound 6: MS-ESI(+), m / z: 344.0 (M+NH4) + ), 1 H NMR: (400MHz, D2O) δ5.12(s,1H),3.92(d,2H),3.87–3.73(m,5H).

[0023] Compounds 5 and 6 showed a difference in the chemical shift of the d peak CH2, further confirming the connection position between compounds 5 and 6.

[0024] Example 4: Preparation of Compounds 7 and 8 Following the preparation method in Example 1, replacing sucrose with maltitol yields two title compounds with purities of 99.0% and 98.7%, respectively.

[0025] Structure confirmation of compound 7: MS-ESI(+), m / z: 490.1 (M+NH4) + ), 1 H NMR: (400MHz, D2O) δ5.08(s,1H),5.00(d,1H),4.51–4.49(m,1H),4.08(s,1H) ,4.06–4.02(m,1H),3.92–3.85(m,3H),3.81–3.64(m,6H),3.62–3.49(m,2H).

[0026] Structure confirmation of compound 8: MS-ESI(+), m / z: 490.1 (M+NH4) + ), 1 H NMR: (400MHz, D2O) δ5.08(s,1H),4.93(d,1H),4.23–4.18(m,1H),4.00–3.96(m,2H),3.93–3.74(m,5H),3.74–3.59(m,4H),3.58–3.49(m,2H).

[0027] The multiplets of the proton NMR chemical shifts 4.51–4.49 of compound 7 were compared with those of the proton NMR chemical shifts 4.23–4.18 of compound 8 to further confirm the connection position between compounds 7 and 8.

[0028] Example 5: Preparation of Compound 9 and Compound 10 Following the preparation method in Example 1, replacing sucrose with sorbitol yielded two title compounds with purities of 97.6% and 98.1%, respectively.

[0029] Structure confirmation of compound 9: MS-ESI(+), m / z: 346.1 (M+NH4) + ), 1 H NMR: (400MHz, D2O) δ5.12(s,1H),3.89–3.76(m,6H),3.68–3.56(m,2H).

[0030] Structure confirmation of compound 10: MS-ESI(+), m / z: 328.1 (M+NH4) + ), 1 H NMR: (400MHz, D2O) δ5.08(s,1H),4.22–4.20(m,1H),4.05(d,1H),3.90–3.80(m,2H),3.77–3.69(m,2H),3.67–3.56(m,2H).

[0031] Example 6: Preparation of Compound 11 and Compound 12 Following the preparation method in Example 1, replacing sucrose with mannitol yielded two title compounds with purities of 97.9% and 98.7%, respectively.

[0032] Structure confirmation of compound 11: MS-ESI(+), m / z: 346.1 (M+NH4) + ), 1 H NMR: (400MHz, D2O) δ5.12(s,1H),3.89–3.84(m,2H),3.78(d,1H),3.74–3.63(m,4H),3.61–3.55(m,1H).

[0033] Structure confirmation of compound 12: MS-ESI(+), m / z: 328.1 (M+NH4) + ), 1 H NMR: (400MHz, D2O) δ5.08(s,1H),4.05–4.01(m,1H),4.00–3.98(m,1H),3.89–3.84(m,1H),3.80(d,1H),3.70–3.55(m,4H).

[0034] Example 7: Preparation of Compounds 13 and 14 Following the preparation method in Example 1, replacing sucrose with xylitol yields two title compounds with purities of 98.0% and 98.5%, respectively.

[0035] Structure confirmation of compound 13: MS-ESI(+), m / z: 316.1 (M+NH4) + ), 1 H NMR: (400MHz, D2O) δ5.12(s,1H),3.92–3.88(m,1H),3.88–3.83(m,1H),3.81–3.74(m,2H),3.74–3.54(m,3H).

[0036] Structure confirmation of compound 14: MS-ESI(+), m / z: 298.1 (M+NH4) + ), 1 H NMR: (400MHz, D2O) δ5.08(s,1H),4.12–4.08(m,1H),4.03–4.01(m,1H),3. 79–3.74(m,1H),3.88–3.82(m,2H),3.72–3.65(m,1H),3.60–3.55(m,1H).

[0037] Example 8: Preparation of Compounds 15 and 16 Following the preparation method in Example 1, replacing sucrose with erythritol yielded two title compounds with purities of 98.2% and 98.4%, respectively.

[0038] Structure confirmation of compound 15: MS-ESI(+), m / z: 286.1 (M+NH4) + ), 1 H NMR: (400MHz, D2O) δ5.12(s,1H),3.88(m,1H),3.81–3.69(m,3H),3.68–3.53(m,2H).

[0039] Structure confirmation of compound 16: MS-ESI(+), m / z: 268.1 (M+NH4) + ), 1 H NMR: (400MHz, D2O) δ5.08(s,1H),3.89–3.86(m,1H),4.05–3.78(m,3H),3.68–3.54(m,2H).

[0040] Example 9: Preparation of Compound 17 Compound 17 with a purity of 97.9% can be obtained by replacing sucrose with maltose according to the preparation method in Example 1.

[0041] Structure confirmation of compound 17: MS-ESI(+), m / z: 506.1 (M+NH4) + ), 1 H NMR: (400MHz, D2O) δ5.18(s,1H),5.07(d,1H),4.75(d,1H),3.90–3.73(m,7H) ,3.72–3.68(m,1H),3.67–3.65(m,1H),3.65–3.63(m,1H),3.54–3.48(m,2H).

[0042] Example 10: Preparation of Compounds 18 and 19 Following the preparation method in Example 1, replacing sucrose with isomaltulose yielded two title compounds with purities of 97.5% and 98.1%, respectively.

[0043] Structure confirmation of compound 18: MS-ESI(+), m / z: 506.1 (M+NH4) + ), 1 ¹H NMR: (400MHz, D₂O) δ 5.18 (s, 1H), 4.75 (d, 1H), 4.25–4.18 (m, 3H), 3.98–3.95 (m, 1H), 3.91–3.65 (m, 5H), 3.65–3.61 (m, 2H), 3.59–3.55 (m, 1H), 3.51–3.47 (m, 1H). The HMBC two-dimensional NMR results showed that hydrogen at chemical shifts 4.25–4.18 ppm and carbon at chemical shifts 206.67 and 93.15 ppm simultaneously exhibited cross-peaks, indicating that the compound is the target compound 18.

[0044] Structure confirmation of compound 19: MS-ESI(+), m / z: 506.1 (M+NH4) + ), 1 ¹H NMR: (400MHz, D₂O) δ 5.18 (s, 1H), 4.69 (d, 1H), 4.24–4.21 (m, 1H), 4.11–4.07 (m, 2H), 4.02–3.93 (m, 3H), 3.89–3.85 (m, 1H), 3.81–3.65 (m, 4H), 3.64–3.60 (m, 1H), 3.51–3.47 (m, 1H). The HMBC two-dimensional NMR results showed an overlap between hydrogen at chemical shifts of 4.02–3.93 ppm and carbon at chemical shift 92.69 ppm, indicating that the compound is the target compound 19.

[0045] Example 11: Preparation of Compound 20 Compound 20 was prepared by replacing sucrose with sucralose according to the preparation method in Example 1, with a purity of 97.2%. The structure of compound 20 was confirmed by MS-ESI (+), m / z: 560.1 (M+NH4). + ), 1 H NMR: (400MHz, D2O) δ5.12(s,1H),5.01(d,1H),4.39–4.32(m,2H),4.21–4.13(m,2H),4.09–4.03(m,2H),4.00–3.75(m,7H).

[0046] Example 12: Preparation of Compound 21 Compound 21 with a purity of 98.0% can be obtained by replacing sucrose with glycerol according to the preparation method in Example 1.

[0047] Structure confirmation of compound 21: MS-ESI(+), m / z: 238.1 (M+NH4) + ), 1 H NMR: (400MHz, D2O) δ5.08(s,1H),4.23–4.21(m,1H),4.06(dd,1H),3.95(dd,1H),3.74(d,2H).

[0048] Example 13: Preparation of Compounds 22 and 23 Step 1: Glycerol (30.00 g, 1.00 eq.) and trichloroacetic acid (53.25 g, 1.00 eq.) were added to 200 ml of dichloromethane. 1.5 eq of dicyclohexylcarbodiimide (DCC) and 0.2 eq of DMAP were added sequentially to the reaction solution. The reaction solution was heated to 30 °C and stirred overnight. The reaction solution was filtered, purified first by reversed-phase preparative chromatography, and then by chiral chromatography, yielding 1.1 g of compound 22-1 with a purity of 92.5% and 1.02 g of compound 23-1 with a purity of 94.8%.

[0049] Structure confirmation of compound 22-1: MS-ESI(+), m / z: 254.1 (M+NH4) + ), 1 H NMR (400MHz, DMSO-d6) δ4.42–4.33(m,2H),4.08(t,1H),3.75–3.55(m,3H),3.52(d,1H).

[0050] Structure confirmation of compound 23-1: MS-ESI(+), m / z: 254.1 (M+NH4) + ), 1 H NMR (400MHz, DMSO-d6) δ4.42–4.33(m,2H),4.08(t,1H),3.75–3.55(m,3H),3.52(d,1H).

[0051] Step 2: Under an argon atmosphere, compound 22-1 (1.00 g, 1.00 eq) was dissolved in tetrahydrofuran. The reaction mixture was cooled to -78°C, and a toluene solution of diisobutylaluminum hydride (DIBAL-H, 2.0 eq) was added dropwise over 15–20 minutes. The reaction mixture was stirred at -78°C for 2–3 hours, and the reaction was quenched by adding a saturated aqueous solution of potassium sodium tartrate. The mixture was extracted and washed three times with dichloromethane (50 ml each time), and the lower aqueous phase was collected. The mixture was first purified by reversed-phase preparative chromatography, and then by chiral chromatography to obtain compound 22, 210 mg, with a purity of 98.6%.

[0052] Following the preparation method in step two, compound 23 can be obtained by replacing compound 22-1 with compound 23-1, with a purity of 98.5%.

[0053] Structure confirmation of compound 22: MS-ESI(+), m / z: 256.1 (M+NH4) + ), 1 H NMR: (400MHz, D2O) δ5.14(s,1H),3.77–3.67(m,3H),3.54–3.48(m,1H),3.47–3.37(m,1H).

[0054] Structure confirmation of compound 23: MS-ESI(+), m / z: 256.1 (M+NH4) + ), 1 H NMR: (400MHz, D2O) δ5.14(s,1H),3.76–3.64(m,3H),3.58–3.49(m,2H).

[0055] The configurations of compounds 22 and 23 were confirmed by circular dichroism calculations.

[0056] Example 1: Study on the sedative effects of different compounds on mice. KM mice were randomly divided into groups of 10 each, half male and half female. Each group of mice received an intraperitoneal injection of either the corresponding drug or a positive control (chloral hydrate). The dosage of chloral hydrate was 0.36 mg / g. Other compounds were administered at equimolar doses, with an injection volume of 0.1 ml / 10 g per mouse. The blank control group received the same volume of physiological saline. Before injection, the weight of each mouse was recorded. After injection, the mice were placed on a heated blanket (temperature set to 37°C) to observe and record the sleep status of each group, including the number of mice falling asleep and the sleep duration. The sleep rate of each group was calculated. This experiment was repeated three times, with each group re-randomized, and a seven-day interval between experiments.

[0057] Judgment Criteria: Loss of righting reflex: This refers to the mouse not turning over within 1 minute while lying supine with limbs facing upwards, indicating the loss of the righting reflex. Recovery of righting reflex: This refers to the mouse being able to freely roll from supine to prone position. Sleep latency: This is the time taken from the start of drug injection until the righting reflex disappears. Sleep duration: This is the time taken from the disappearance of the righting reflex to its recovery; a loss of more than 1 minute is considered the criterion for sleep onset. Average sleep duration: This is the arithmetic mean of the sleep durations of all animals in the group that fall asleep. Sleep occurrence percentage (sleep onset rate) = (Number of animals falling asleep / Total number of animals) × 100%; Average sleep onset rate: The arithmetic mean of three sleep onset rates.

[0058] The experimental results are as follows: Note: Compared with the positive control group, *: P < 0.05; **: P < 0.01.

[0059] It is evident that compounds 1-16, 20, 22, and 23 of the present invention exhibit higher sleep onset rates and longer sleep durations compared to the positive control drugs, demonstrating significant differences. In particular, compounds 1-6 show significantly better sleep onset rates and longer sleep durations than the positive control drugs, and are expected to possess good clinical sedation and hypnotic potential.

[0060] The above embodiments are merely one of the preferred embodiments of the present invention and should not be used to limit the scope of protection of the present invention. Any modifications or refinements made to the main design concept and spirit of the present invention that are not of substantial significance, but solve the same technical problem as the present invention, should be included within the scope of protection of the present invention.

Claims

1. A compound of formula (I) or a stereoisomer thereof: in, R1 and R2 are independently selected from hydrogen, sucrose, glucose, fructose, glycerol, maltitol, sorbitol, mannitol, xylitol, erythritol, maltose, isomaltulose, or sucralose; or R1 and R2 are connected to form a five- or six-membered heterocycle.

2. The compound or its stereoisomer according to claim 1, characterized in that, R1 is selected from hydrogen; R2 is selected from sucrose, glucose, fructose, glycerol, maltitol, sorbitol, mannitol, xylitol, erythritol, maltose, isomaltulose, or sucralose; or R1 and R2 are connected to form a five- or six-membered heterocycle.

3. The compound or its stereoisomer according to claim 1, characterized in that, R1 is selected from hydrogen; R2 is selected from sucrose, glucose, fructose, glycerol, maltitol, sorbitol, mannitol, xylitol, erythritol, or sucralose; or R1 and R2 are connected to form a five- or six-membered heterocycle.

4. The compound or its stereoisomer as described in claim 1, characterized in that, The compound is selected from:

5. The compound or its stereoisomer according to any one of claims 1 to 4, characterized in that, At least one hydrogen atom in the compound may be replaced by deuterium.

6. A pharmaceutical composition comprising the compound of any one of claims 1-4 or a stereoisomer thereof, and a pharmaceutically acceptable carrier and / or excipient.

7. Use of the pharmaceutical composition of claim 6 in the preparation of tablets, capsules, syrups, oral solutions, injections, small injections, powder injections, or enemas.

8. Use of any compound or stereoisomer of claims 1 to 4 in the preparation of sedative, hypnotic, anxiolytic, or anticonvulsant drugs.

9. Use of any compound of claims 1 to 4 or its stereoisomers in the preparation of sedative and / or hypnotic drugs.

10. Use of any compound or stereoisomer thereof according to claims 1 to 4 in drug quality testing.

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