WO2021098872A1 - Allopregnenolone phosphonamide derivative, preparation method therefor and pharmaceutical use thereof - Google Patents

Abstract

The present invention relates to a compound represented by general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, and the pharmaceutical use thereof. The compound of general formula (I) has a structure as follows, and the definitions of the groups thereof are consistent with the definitions in the description.

Description

An allopregnenolone phosphonamide derivative, its preparation method and its medical use

This application claims the priority of the Chinese patent application 201911150746.X whose filing date is November 21, 2019. This application quotes the full text of the aforementioned Chinese patent application.

Technical field

The invention relates to an allopregnenolone phosphonamide derivative, an intermediate and a preparation method thereof, and use in the preparation of medicines.

Background technique

Allopregnenolone, a metabolite of naturally occurring neurosteroids and progesterone, is an allosteric GABA-A receptor modulator. In the currently published patents and literature, allopregnenolone is administered by injection and cannot be administered orally.

According to the principle of prodrugs, the present invention transforms the hydroxyl group of allopregnenolone into precursors to improve its solubility and stability, so as to improve the physical and chemical properties of the drug, and improve the absorption, distribution, metabolism and excretion process of the drug in the body. , Improve the oral bioavailability, increase the selectivity of the drug's action on the target site, reduce the toxic and side effects of the drug, and prolong the action time. After entering the body, these drugs can release allopregnenolone at a certain rate of hydrolysis according to the design requirements, thereby treating central nervous system-related diseases, including tremor, depression, postpartum depression, insomnia, mood disorders, and convulsions. Disorders, memory disorders, attention disorders, anxiety, bipolar disorder, schizophrenia, bipolar disorder, schizoaffective mental disorder, mood disorder, anxiety disorder, personality disorder, psychosis, obsessive-compulsive disorder, post-traumatic stress disorder, Autism spectrum disorder, depression, social anxiety disorder, obsessive-compulsive disorder, pain, sleep disorders, memory disorders, dementia, Alzheimer's disease, episodic disease, traumatic brain injury, stroke, addictive disorder, self Autism, Huntington’s disease, Parkinson’s disease, Rett syndrome, withdrawal syndrome or tinnitus; thereby helping to overcome the shortcomings of poor water solubility and stability of allopregnenolone.

Summary of the invention

In the present invention, the physicochemical properties of allopregnenolone are changed through the phosphoamide group, such as changing the original properties, stability, fat solubility, etc. of allopregnenolone, thereby changing the transmembrane absorption, distribution and metabolic behavior in the body. After the phosphoamide-modified drug enters the body, it is hydrolyzed to release allopregnenolone under the action of hydrolase in the body. By controlling the hydrolysis rate of the phosphonamide drug, the existence time of the drug in the body can be prolonged, and the specific effect of the drug on the target site can be improved through the distribution of hydrolytic enzymes and other characteristics.

The present invention relates to a compound represented by general formula (I), its stereoisomer, its tautomer or its pharmaceutically acceptable salt,

among them:

R ^{1 is} selected from C ₁ -C ₆ alkoxy or C ₃ -C ₈ cycloalkyloxy;

R ^{2 is} selected from a hydrogen atom or a C ₁ -C ₆ alkyl group;

R ³ and R ⁴ are each independently selected from a hydrogen atom or a C ₁ -C ₆ alkyl group, wherein the alkyl group is optionally further substituted with one or more halogens;

Alternatively, R ³ and R ⁴ together with the carbon atoms to which they are attached may form a 3- to 6-membered ring, the ring contains 0 to 6 heteroatoms selected from N, O or S, and the ring may optionally further Is substituted by one or more substituents selected from hydroxyl, halogen or amino; and

R ^{5 is} selected from C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or benzyl.

In a preferred embodiment of the present invention, a compound of general formula (I), its stereoisomers, its tautomers or pharmaceutically acceptable salts thereof are a compound of general formula (II) Compound, its stereoisomer, its tautomer or its pharmaceutically acceptable salt:

The definitions of R ¹ to R ⁵ are as described in the general formula (I).

In a preferred embodiment of the present invention, a compound represented by general formula (I) or (II), its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof, wherein R ^{1 is} selected from C _1- C ₆ alkoxy.

In a preferred embodiment of the present invention, a compound represented by general formula (I) or (II), its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof, wherein one of R ³ and R ⁴ is The hydrogen atom and the other is a C ₁ -C ₆ alkyl group.

In a preferred embodiment of the present invention, a compound represented by general formula (I) or (II), its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof, wherein R ^{5 is} selected from C _1- C ₆ alkyl.

In a preferred embodiment of the present invention, a compound represented by general formula (I) or (II), its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof, wherein:

R ^{1 is} selected from a C ₁ -C ₆ alkoxy group; R ^{2 is} selected from a hydrogen atom; one of R ³ and R ^{4 is} a hydrogen atom and the other is a C ₁ -C ₆ alkyl group; and R ^{5 is} selected from a C ₁ -C ₆ alkyl.

In a preferred embodiment of the present invention, a compound represented by general formula (I) or (II), its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof, wherein R ^{1 is} selected from methoxy , Ethoxy or isopropoxy.

In a preferred embodiment of the present invention, a compound represented by general formula (I) or (II), its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof, wherein R ^{2 is} selected from a hydrogen atom, Methyl or ethyl.

In a preferred embodiment of the present invention, a compound represented by the general formula (I) or (II), its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof, wherein R ^{2 is} selected from a hydrogen atom.

In a preferred embodiment of the present invention, a compound represented by the general formula (I) or (II), its stereoisomer, its tautomer, or a pharmaceutically acceptable salt thereof, wherein R ^{3 is} selected from a hydrogen atom; R ^{4 is} selected from methyl.

In a preferred embodiment of the present invention, a compound represented by general formula (I) or (II), its stereoisomers, its tautomers, or pharmaceutically acceptable salts thereof, wherein R ^{5 is} selected from ethyl or Isopropyl. Typical compounds of the present invention include, but are not limited to:

Or its stereoisomer or its pharmaceutically acceptable salt.

The present invention relates to a pharmaceutical composition containing a therapeutically effective dose of a compound represented by general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier And excipients.

The present invention relates to a compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its composition, used in the preparation of treatment and/or prevention of diseases related to the central nervous system Uses, wherein the central nervous system related diseases are selected from tremor, depression, insomnia, mood disorders, convulsive disorders, memory disorders, attention disorders, anxiety, bipolar disorder, schizophrenia, bipolar disorder, emotion Schizophrenic disorder, mood disorder, anxiety disorder, personality disorder, psychosis, obsessive-compulsive disorder, post-traumatic stress disorder, autism spectrum disorder, psychiatric depression, social anxiety disorder, obsessive-compulsive disorder, pain, sleep disorder, memory disorder , Dementia, Alzheimer’s disease, paroxysmal disease, traumatic brain injury, stroke, addictive disorder, autism, Huntington’s disease, Parkinson’s disease, Rett syndrome, withdrawal syndrome or tinnitus; among them, preferred It is tremor or depression; the depression described therein is preferably postpartum depression.

The present invention relates to a compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition, which is used in the preparation of a compound for improving the oral bioavailability of a drug and prolonging the parent drug The pharmacodynamic half-life of the drug, reducing the dosage and frequency of administration, or extending the half-life of the drug.

Detailed description of the invention

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur, Nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include ¹² C, ¹³ C and ¹⁴ C, and hydrogen isotopes include protium (H) and deuterium (D, also known as heavy hydrogen). ), tritium (T, also known as superheavy hydrogen), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, and nitrogen isotopes include ¹⁴ N and ¹⁵ N, the isotope of fluorine is ¹⁹ F, the isotope of chlorine includes ³⁵ Cl and ³⁷ Cl, and the isotope of bromine includes ⁷⁹ Br and ⁸¹ Br.

"Alkyl" when regarded as a group or a part of a group refers to a straight or branched aliphatic hydrocarbon group containing 1 to 20 carbon atoms. It is preferably 1 to 10 alkyl groups, more preferably 1 to 6 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait. Alkyl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups: alkyl, alkoxy, halogen, hydroxyl, nitro, cyano, cycloalkyl, ring Alkyloxy or amino.

"Cycloalkyl" refers to a saturated or partially saturated monocyclic, fused ring, bridged ring, and spirocyclic carbocyclic ring, but none of the rings has a fully conjugated π-electron aromatic ring system. It is preferably a 3 to 12 membered cycloalkyl group, more preferably a 3 to 8 membered cycloalkyl group, and most preferably a 3 to 6 membered cycloalkyl group. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc., preferably cyclopropyl and cyclohexenyl.

Cycloalkyl groups can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups: alkyl, alkoxy, halogen, hydroxy, nitro, cyano, cycloalkyl, cycloalkyloxy or amino.

"Alkoxy" refers to a (alkyl-O-) group. Among them, the alkyl group is defined in this article. C ₁ -C ₆ alkoxy groups are preferred. Examples thereof include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.

"Cycloalkyloxy" refers to a (cycloalkyl-O-) group. Among them, cycloalkyl see the relevant definitions herein. C ₃ -C ₈ cycloalkoxy is preferred. Examples thereof include, but are not limited to: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.

"Hydroxy" refers to -OH.

"Amino" refers to -NH ₂ .

"Halogen" refers to fluorine, chlorine, bromine and iodine.

"DMSO" means dimethyl sulfoxide.

"Et" means ethyl.

"Optional" or "optionally" means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur. For example: "Alkyl optionally substituted by F" means that an alkyl group may but need not be substituted by F, and the description includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.

"Pharmaceutical composition" means a mixture of one or more of the compounds described in the text or their physiologically/pharmaceutically acceptable salts and other components, wherein the other components include physiologically/pharmaceutically acceptable carriers and excipients.

"Carrier" refers to a carrier or diluent that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound.

"Excipient" refers to an inert substance that is added to a pharmaceutical composition to further depend on the administration of the compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, ingredients Granules, lubricants, binders, disintegrants, etc.

"Prodrug" refers converted by solvolysis or biologically active drug under physiological conditions. The prodrug of the present invention is prepared by modifying the functional groups in allopregnenolone, and the modification can be removed by conventional operations or in vivo to obtain allopregnenolone.

"Stereoisomers" refer to isomers arising from the different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.

"Effective dose" refers to the amount of a compound that causes a physiological or medical response in a tissue, system, or subject. This amount is sought and includes one or more of the compounds that are sufficient to prevent the disease or condition being treated when administered to the subject. The amount of the compound that occurs or alleviates the symptoms to a certain degree.

In the present invention, pharmaceutically acceptable salts and pharmaceutically acceptable salts have the same definition.

Detailed ways

The following examples are used to further describe the present invention, but these examples do not limit the scope of the present invention.

Example

The examples show the preparation of representative compounds represented by formula (I) and related structure identification data. It must be noted that the following examples are used to illustrate the present invention but not to limit the present invention.

The structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).

¹ H NMR is measured by Bruker instrument (400MHz), and chemical shift is expressed in ppm. Using tetramethylsilane internal standard (0.00ppm), the determination solvent is deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), the internal standard is tetra Methylsilane (TMS). ¹ H NMR expression method: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broadened, dd = doublet of doublet, dt = triplet The doublet of the peak. If the coupling constant is provided, its unit is Hz.

The mass spectrum is measured by an LC/MS instrument, and the ionization method can be ESI or APCI.

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm～0.2mm, and the size of the thin layer chromatography separation and purification product is 0.4mm. ~0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

HPLC measurement uses Agilent 1260DAD high pressure liquid chromatograph (Zorba x SB-C18 100x4.6mm).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm～0.20mm, and the size of thin layer chromatography separation and purification products is 0.4mm ~0.5mm.

In the following examples, unless otherwise specified, all temperatures are in degrees Celsius.

Unless otherwise specified, various starting materials and reagents are commercially available or synthesized according to known methods. Commercial raw materials and reagents are used directly without further purification. Unless otherwise specified, commercial manufacturers include but are not limited to Aldrich Chemical Company, ABCR GmbH & Co.KG, Acros Organics, Shaoyuan Chemical Technology (Shanghai) Co., Ltd., Sinopharm Group Pharmaceutical Co., Ltd., Bailingwei Technology Co., Ltd. and other companies.

The compound was purified by silica gel column chromatography and thin layer chromatography, wherein the eluent system was selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane: acetic acid Ethyl; D: petroleum ether: dichloromethane system; the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents can also be added to adjust, such as acetic acid or triethylamine.

Example 1

(S)-2-[[[((3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexahydro-1hydro-cyclopenta[ a]phenanthrene-3-yl]oxy]-ethoxycarbonyl-phosphono]amino]isopropyl propionate (compound 1)

(2S)-isopropyl 2-(((((3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-yl )oxy)(ethoxycarbonyl)phosphoryl)amino)propanoate(1)

Ethyl diethoxyphosphonocarboxylate 1a (210.0 g, 1.0 mol) was dissolved in 800 mL of acetonitrile, and bromotrimethylsilane (460.0 g, 3.0 mol) was added dropwise, and reacted at 65°C for 2 hours. After the reaction, concentrate under reduced pressure to obtain the crude ethoxycarbonylphosphonic acid trimethylsilyl ester, dissolve it in 650mL dichloromethane, add oxalyl chloride (510.0g, 4.0mol), N , N-Dimethylformamide (10 drops), warm to room temperature and react for 2 hours. After the reaction, it was concentrated under reduced pressure, and dichloromethane was added to concentrate to remove excess oxalyl chloride (100mLx3). The resulting liquid was distilled under reduced pressure to obtain ethyl dichlorophosphonoformate, yellow liquid (115.0g, 0.61mol, yield 61%) .

Ethyl dichlorophosphonocarboxylate (10.0g, 52.4mol) was dissolved in 100mL of dichloromethane, and allopregnenolone (10.0g, 31.3mmol) was added at -20°C. Synthesis of J.Med.Chem. 2009,52,6012-6023) and triethylamine (11.5g, 0.112mol) in dichloromethane (50mL) solution, incubate the reaction for 30 minutes, drop in L-alanine isopropyl ester hydrochloride (8.8g , 52.4mmol) in dichloromethane (50mL) solution, triethylamine (11.5g, 0.112mol), stirred at room temperature for 2 hours. Add water (500mL), wash with saturated brine (200mL), dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography as eluent system A) to obtain (S)-2-[[[[ (3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexadecylhydro-1hydro-cyclopentan(a)phenanthrene-3-yl)oxy ]-Ethoxycarbonyl-phosphono]amino]isopropyl propionate (Compound 1) (8.0 g, 14.1 mmol, yield 45%).

³¹ P NMR (162MHz, CDCl ₃ ): δ0.19, -0.15

LC-MS m/z=568[M+1].

Example 2

(S)-2-[[(S)-[[((3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexadecylhydro-1 hydrogen -Cyclopentan[a]phenanthrene-3-yl]oxy]-ethoxycarbonyl-phosphono]amino]isopropyl propionate (compound 2)

(S)-isopropyl 2-[[(S)-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren -3-yl]oxy]-(ethoxycarbonyl)phosphoryl]amino]propanoate(2)

Compound 1 (8.0 g, 14.1 mmol) was dissolved in 35 mL of n-heptane, placed at -20° C. for 7 days, and filtered to obtain compound 2 (2.0 g, 3.5 mmol, yield 25%).

¹ H NMR (400MHz, CDCl ₃ ): δ5.02-5.08 (m, 1H), 4.87-4.90 (m, 1H), 4.30 (t, J = 7.2Hz, 2H), 4.04-4.10 (m, 1H) ,3.63(t,J=10.4Hz,1H),2.53(t,J=8.8Hz,1H),2.12(s,3H),1.99–2.02(m,1H),1.88-1.92(m,1H), 1.15-1.72 (m, 31H), 0.90-1.05 (m, 1H), 0.78 (s, 3H), 0.60 (s, 3H).

³¹ P NMR (162MHz, CDCl ₃ ): δ-0.15

LC-MS m/z=568[M+1].

Example 3

(S)-2-[[[((3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexahydro-1hydro-cyclopenta[ a]Phenanthrene-3-yl]oxy]-ethoxycarbonyl-phosphono]amino]ethyl propionate (compound 3)

(2S)-ethyl 2-(((((3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexadecahydro-1H-cyclo-penta[a]phenanthren-3 -yl)oxy)(ethoxycarbonyl)phosphoryl)amino)propanoate(3)

Dissolve ethyl dichlorophosphonocarboxylate (10.0g, 52.4mol) in 100mL of dichloromethane, add allopregnenolone (10.0g, 31.3mmol) and triethylamine (10.6g, 0.105mol) at -20°C ) In dichloromethane (50mL), incubate the reaction for 30 minutes, drop L-alanine ethyl ester hydrochloride (8.04g, 52.4mmol) in dichloromethane (50mL) solution, triethylamine (10.6g , 0.105mol), stirred at room temperature for 2 hours. Add water (500mL), wash with saturated brine (200mL), dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is separated and purified by silica gel column chromatography as eluent system A) to obtain (S)-2-[[[[ (3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexadecylhydro-1hydro-cyclopentan(a)phenanthrene-3-yl)oxy ]-Ethoxycarbonyl-phosphono]amino] ethyl propionate (compound 3) (1.8 g, 3.3 mmol, yield 10%).

³¹ P NMR (162MHz, CDCl ₃ ): δ0.16, -0.21

LC-MS m/z=554[M+1].

Example 4

(S)-2-[[(S)-[[((3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexadecylhydro-1 hydrogen -Cyclopentan[a]phenanthrene-3-yl]oxy]-ethoxycarbonyl-phosphono]amino]ethyl propionate (Compound 4)

(S)-ethyl 2-[((S)-[[(3R,5S,8R,9S,10S,13S,14S,17S)-17-acetyl-10,13-dimethylhexadecahydro-1H-cyc-lopenta[a ]phenanthren-3-yl]oxy]-(ethoxycarbonyl)phosphoryl]amino]propanoate(4)

Compound 3 (1.8g, 3.3mmol) was dissolved in 10mL petroleum ether/ethyl acetate solution (5:1) under heating, placed at -20°C for 7 days, and filtered to obtain compound 4 (0.3g, 0.54mmol, yield 17 %).

¹ H NMR (400MHz, CDCl ₃ ): δ 4.90-4.92 (m, 1H), 4.32 (q, J = 7.2 Hz, 2H), 4.23 (t, J = 7.2 Hz, 2H), 4.13 (q, J ＝8.0Hz,1H),3.85(brs,1H),3.63(t,J＝10.8Hz,1H),2.55(t,J＝8.0Hz,1H),2.13(s,3H),2.01-2.04(m ,1H),1.90-1.95(m,1H),1.15-1.72(m,27H),0.95-0.99(m,1H),0.80(s,3H),0.62(s,3H).

³¹ P NMR (162MHz, CDCl ₃ ): δ-0.21

LC-MS m/z=554[M+1].

Biological evaluation

Test Example 1. In vivo pharmacokinetic study of SD rats

Experimental animals: 9 healthy adult SD rats, male, 180-250g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

Drug preparation: accurately weigh a certain amount of test compound, add DMSO and Solutol HS-15 to dissolve, then add physiological saline, vortex to mix evenly. The final dosing solvent ratio was DMSO: Solutol HS-15: physiological saline (10:10:80, v/v/v), and all test compounds were prepared fresh before use.

Administration and testing: SD rats were randomly divided into 3 groups, 3 in each group; fasting for no less than 8 hours before administration, free drinking, and 4 hours after administration before eating. The three groups of animals were given intravenous (IV) allopregnenolone (IV, dose of 5mg/kg) or intragastric (PO) given compound 2 (PO, dose of 25mg/kg) and 4 (PO , The dosage is 25mg/kg), about 0.1ml of venous blood is collected before and at different times after the administration, heparin is anticoagulated, the plasma is separated by centrifugation, and stored at -80°C. The LC-MS/MS method was used to determine the concentration of the original drug (prodrug) and hydrolyzed metabolite (technical drug) in the plasma, and the main pharmacokinetic parameters were calculated. The results are shown in Table 1:

Table 1 Pharmacokinetic test results of SD rats

Remarks: SD rats were intragastrically administered the compound of the present invention, and no prodrug form was detected in the plasma at any time, only allopregnenolone was detected and the pharmacokinetic parameters were calculated.

Conclusion: Compounds 2 and 4 are rapidly absorbed by rats after intragastric administration, mainly in the form of allopregnenolone. The absolute oral bioavailability of allopregnenolone is 33.1% and 19.9, respectively. %, indicating good oral absorption characteristics.

All documents mentioned in the present invention are cited as references in this application, as if each document was individually cited as a reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (10)

1. A compound represented by general formula (I), its stereoisomer, its tautomer or its pharmaceutically acceptable salt:

   

   among them:

   R ^{1 is} selected from C _1- C ₆ alkoxy or C _3- C ₈ cycloalkyloxy;

   R ^{2 is} selected from a hydrogen atom or a C _1- C ₆ alkyl group;

   R ³ and R ⁴ are each independently selected from a hydrogen atom or a C _1- C ₆ alkyl group, wherein the alkyl group is optionally further substituted with one or more halogens;

   Alternatively, R ³ and R ⁴ together with the carbon atoms to which they are attached may form a 3- to 6-membered ring, the ring contains 0 to 6 heteroatoms selected from N, O or S, and the ring may optionally further Is substituted by one or more substituents selected from hydroxyl, halogen or amino; and

   R ⁵ is selected from C _1- C ₆ alkyl, C _3- C ₈ cycloalkyl or benzyl.
2. The compound, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt according to claim 1, which is the compound represented by the general formula (II), its stereoisomer, its mutual Tautomer or its pharmaceutically acceptable salt:

   

   Wherein: R ¹ to R ⁵ are as defined in claim 1.
3. The compound, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt according to any one of claims 1 to 2, wherein R ^{1 is} selected from methoxy, ethoxy or isopropoxy base.
4. The compound, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt according to any one of claims 1 to 2, wherein R ^{2 is} selected from a hydrogen atom, a methyl group or an ethyl group.
5. The compound, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt according to any one of claims 1 to 2, wherein R ^{3 is} selected from a hydrogen atom; R ^{4 is} selected from a methyl group.
6. A compound according to any one of claims 1 or 2, a stereoisomer, a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from ethyl or isopropyl.
7. The compound, its stereoisomer, its tautomer, or its pharmaceutically acceptable salt according to any one of claims 1 to 2, wherein the compound is selected from:

   
8. A pharmaceutical composition containing an effective dose of the compound, its stereoisomer, its tautomer or its pharmaceutically acceptable salt according to any one of claims 1 to 7 , And pharmaceutically acceptable carriers, excipients or combinations thereof.
9. The compound according to any one of claims 1-7, its stereoisomer, its tautomer or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 8 is used in the preparation of therapeutic and / Or use in the prevention of central nervous system related diseases, wherein the central nervous system related diseases are selected from the group consisting of tremor, depression, insomnia, mood disorders, convulsive disorders, memory disorders, attention disorders, anxiety, and bipolar disorder Disorders, schizophrenia, bipolar disorder, schizoaffective mental disorder, mood disorder, anxiety disorder, personality disorder, psychosis, obsessive-compulsive disorder, post-traumatic stress disorder, autism spectrum disorder, depression, social anxiety disorder , Obsessive-Compulsive Disorder, Pain, Sleep Disorder, Memory Disorder, Dementia, Alzheimer's Disease, Paroxysmal Disease, Traumatic Brain Injury, Stroke, Addictive Disorder, Autism, Huntington's Disease, Parkinson's Disease, Rett Syndrome Symptoms, withdrawal syndrome or tinnitus; among them, tremor or depression is preferred; wherein the depression is preferably postpartum depression.
10. The compound according to any one of claims 1 to 7 or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 8, in preparation for Use in drugs that improve the oral bioavailability of the drug, extend the pharmacodynamic half-life of the parent drug, reduce the dosage and frequency of administration, or extend the half-life.