Steroid compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention provides a steroid compound as well as a preparation method, a pharmaceutical composition and application thereof, and belongs to the technical field of medicines. The invention provides a steroid compound, a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a prodrug, a solvate or an isotope compound thereof. The steroid compound has a structure as shown in a formula I in the specification. The compound provided by the invention has a strong positive regulation effect on a GABAA receptor, and has potential application in treatment of central nervous system related diseases. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to steroid compounds, preparation methods, pharmaceutical compositions and applications thereof. Background Art

[0002] Brenolone is a synthetic allopregnanolone analog that can enhance the expression of recombinant GABA A The current mediated by GABA in mammalian cells with receptors. However, due to its low oral bioavailability, brexanolone is administered by continuous intravenous infusion for more than 60 hours. During the two and a half days of brexanolone infusion, medical staff must be on site to continuously monitor the patient, which is particularly inconvenient.

[0003] Therefore, developing more types of new compounds in order to achieve better therapeutic effects and convenience in the treatment of central nervous system-related diseases such as postpartum depression is a technical problem that urgently needs to be solved. Summary of the invention

[0004] The object of the present invention is to provide a steroid compound and a preparation method, a pharmaceutical composition and application thereof. The steroid compound provided by the present invention has an effect on GABA A The receptor has a strong positive regulatory effect and has potential application in the treatment of central nervous system-related diseases.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0006] The present invention provides a steroid compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate or isotope compound thereof, wherein the steroid compound has a structure shown in Formula I:

[0007]

[0008] In formula I, R1, R2, R3 and R4 are independently selected from any of the following groups:

[0009] -H, -CN, -NO2, -COOH, halogen group, formaldehyde oxime group, formaldehyde oxime ether group;

[0010] C1-C6 alkane or halogen substituents thereof, C1-C6 alkane or halogen substituents containing heteroatoms, C3-C7 cycloalkane or halogen substituents thereof, C3-C7 cycloalkane or halogen substituents containing heteroatoms or halogen substituents thereof, wherein the heteroatoms in the C1-C6 alkane or C3-C7 cycloalkane containing heteroatoms are independently selected from one or more of nitrogen, oxygen and sulfur;

[0011] C2-C6 alkene group or its halogen substitution, C2-C6 alkynyl group or its halogen substitution;

[0012] A five-membered aromatic hydrocarbon group or a five-membered heteroaromatic hydrocarbon group, wherein the heteroatom in the five-membered heteroaromatic hydrocarbon group is selected from one or more of nitrogen, oxygen and sulfur;

[0013] Six-membered aromatic hydrocarbon group, six-membered nitrogen heterocyclic aromatic hydrocarbon group, the number of nitrogen in the six-membered nitrogen heterocyclic aromatic hydrocarbon group is ≥1;

[0014] Sulfoxide groups connected to C1-C6 chain alkane groups, sulfoxide groups connected to C3-C6 cycloalkane groups, sulfoxide groups connected to five-membered aromatic hydrocarbon groups, and sulfoxide groups connected to six-membered aromatic hydrocarbon groups;

[0015] Sulfone groups connected to C1-C6 chain alkane groups, sulfone groups connected to C3-C6 cycloalkane groups, sulfone groups connected to five-membered aromatic hydrocarbon groups, and sulfone groups connected to six-membered aromatic hydrocarbon groups;

[0016] Hydroxyl, hydroxyl connected to a five-membered aromatic hydrocarbon group, hydroxyl connected to a five-membered heteroaromatic hydrocarbon group, hydroxyl connected to a six-membered aromatic hydrocarbon group, hydroxyl connected to a six-membered nitrogen heteroaromatic hydrocarbon group, hydroxyl connected to a C3-C7 cycloalkane group, hydroxyl connected to a heteroatom-containing C3-C7 cycloalkane group;

[0017] Amino group, amino group connected to a five-membered aromatic hydrocarbon group, amino group connected to a five-membered heteroaromatic hydrocarbon group, amino group connected to a six-membered aromatic hydrocarbon group, amino group connected to a six-membered nitrogen heteroaromatic hydrocarbon group, amino group connected to a C3-C7 cycloalkane group, amino group connected to a heteroatom-containing C3-C7 cycloalkane group;

[0018] thiol, thiol connected to a five-membered aromatic hydrocarbon group, thiol connected to a five-membered heteroaromatic hydrocarbon group, thiol connected to a six-membered aromatic hydrocarbon group, thiol connected to a six-membered nitrogen heteroaromatic hydrocarbon group, thiol connected to a C3-C7 cycloalkane group, thiol connected to a heteroatom-containing C3-C7 cycloalkane group;

[0019] Sulfonamide, sulfonamide connected to a C1-C6 chain alkane group, sulfonamide connected to a C3-C6 cycloalkane group, sulfonamide connected to a five-membered ring aromatic group, sulfonamide connected to a six-membered ring aromatic group;

[0020] An amide group, an amide group connected to a C0-C6 chain alkane group, an amide group connected to a C3-C6 cycloalkane group, an amide group connected to a five-membered ring aromatic group, and an amide group connected to a six-membered ring aromatic group;

[0021] Alkanoyl or a halogen substituent thereof, alkenoyl or a halogen substituent thereof, alkynoyl or a halogen substituent thereof, alkoxycarbonyl or a halogen substituent thereof, alkenyloxycarbonyl or a halogen substituent thereof, alkynyloxycarbonyl or a halogen substituent thereof, aryloxycarbonyl or a halogen substituent thereof, heteroaryloxycarbonyl or a halogen substituent thereof, alkylaminocarbonyl or a halogen substituent thereof, enaminocarbonyl or a halogen substituent thereof, alkynylaminocarbonyl or a halogen substituent thereof, arylaminocarbonyl or a halogen substituent thereof, heteroarylaminocarbonyl or a halogen substituent thereof.

[0022] Preferably, the halogen substituent is a substituent comprising one or more of -F, -Cl, -Br and -I.

[0023] Preferably, the halogen group is selected from -F, -Cl, -Br or -I;

[0024] The C1-C6 alkane group is a methyl group, an ethyl group or a propyl group; the halogen substituent of the C1-C6 alkane group is a fluorine-substituted methyl group, a fluorine-substituted ethyl group or a fluorine-substituted propyl group, and the number of -F in the fluorine-substituted methyl group, the fluorine-substituted ethyl group and the fluorine-substituted propyl group is independently 1, 2 or 3; the heteroatom in the heteroatom-containing C1-C6 alkane group is oxygen, and the number of oxygen in the heteroatom-containing C1-C6 alkane group is 1 or 2;

[0025] The C2-C6 olefin group is vinyl, propenyl or butenyl; the halogen substituent of the C2-C6 olefin group is fluorine-substituted vinyl, fluorine-substituted propenyl or fluorine-substituted butenyl, and the number of -F in the fluorine-substituted vinyl, fluorine-substituted propenyl or fluorine-substituted butenyl is independently 1, 2 or 3;

[0026] The C2-C6 alkynyl group is ethynyl, propynyl or butynyl; the halogen substituent of the C2-C6 alkynyl group is fluorine-substituted ethynyl, fluorine-substituted propynyl or fluorine-substituted butynyl, and the number of -F in the fluorine-substituted ethynyl, fluorine-substituted propynyl or fluorine-substituted butynyl is independently 1, 2 or 3;

[0027] The sulfoxide group connected to a C1-C6 alkane group is a sulfoxide group connected to a methyl group, a sulfoxide group connected to an ethyl group, or a sulfoxide group connected to a propyl group;

[0028] The five-membered heterocyclic aromatic hydrocarbon group is a substituted five-membered heterocyclic aromatic hydrocarbon group or an unsubstituted five-membered heterocyclic aromatic hydrocarbon group, the number of substituents in the substituted five-membered heterocyclic aromatic hydrocarbon group is 1 to 4, and the substituents in the substituted five-membered heterocyclic aromatic hydrocarbon group are selected from halogen groups, alkane groups, alkene groups or alkyne groups; the number of heteroatoms in the five-membered heterocyclic aromatic hydrocarbon group is 1 to 4;

[0029] The heteroaromatic hydrocarbon in the heteroaromatic amine carbonyl group is a substituted five-membered heteroaromatic hydrocarbon, an unsubstituted five-membered heteroaromatic hydrocarbon group, a substituted six-membered heteroaromatic hydrocarbon or an unsubstituted six-membered heteroaromatic hydrocarbon group, the number of substituents in the substituted five-membered heteroaromatic hydrocarbon and the substituted six-membered heteroaromatic hydrocarbon is independently 1 to 4, and the substituents in the substituted five-membered heteroaromatic hydrocarbon and the substituted six-membered heteroaromatic hydrocarbon are independently selected from halogen groups, alkane groups, alkene groups or alkynyl groups; the number of heteroatoms in the heteroaromatic hydrocarbon in the heteroaromatic amine carbonyl group is 1 to 4.

[0030] Preferably, R1, R2, R3 and R4 are independently selected from -H, -F, -Cl, -Br, -I, -CN, -CH3, -CF3, -CH2OCH3, -NO2, -SO2CH3, -CH=CF2, -COOH, -CHF2, -CH2F, ethynyl, -OCH3, -CH=NOH, -CH=NOCH3, -CONH2,

[0031] Preferably, R1, R2, R3 and R4 are not -H; or, only one of R1, R2, R3 and R4 is -H; or, only two of R1, R2, R3 and R4 are -H; or, only three of R1, R2, R3 and R4 are -H; or, all of R1, R2, R3 and R4 are -H.

[0032] Preferably, the steroid compound is any one of the following compounds:

[0033]

[0034]

[0035] The present invention provides a method for preparing the steroid compound described in the above technical solution, comprising the following steps:

[0036] Compound BA, a pyrrolyl-containing compound, a base reagent and an organic solvent are mixed to carry out a substitution reaction to obtain a steroid compound having a structure shown in Formula I;

[0037] The compound BA has a structure shown in formula II, and the pyrrolyl-containing compound has a structure shown in formula III:

[0038]

[0039] The R1, R2, R3 and R4 are as defined in Formula I.

[0040] The present invention provides a pharmaceutical composition, the active ingredients of which include one or more of the steroid compound described in the above technical solution, its pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate and isotope compound.

[0041] The present invention provides the use of the steroid compound described in the above technical scheme, its pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate or isotope compound or the pharmaceutical composition described in the above technical scheme in the preparation of drugs for treating mood disorders, mental diseases, neurodegenerative diseases or neuropathic pain.

[0042] Preferably, the mood disorder includes generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, social anxiety disorder, premenstrual dysphoric disorder, major depression or postpartum depression; the psychiatric disease includes epilepsy, convulsions or insomnia; the neurodegenerative disease includes Alzheimer's disease, Parkinson's disease, multiple sclerosis or Niemann-Pick type C disease; the neuropathic pain includes menstrual migraine, postmenopausal migraine, diabetic peripheral neuropathy, chemotherapy pain or sciatica.

[0043] Beneficial effects: The steroidal compounds provided by the present invention can act on multiple GABA on the synaptic surface at the same time through allosteric regulation. A Ion channel receptors promote the flow of chloride ions into cells along the electrochemical gradient of the GABA receptor complex (GRC). The increase in the intracellular chloride ion level leads to hyperpolarization of the transmembrane potential, making neurons less sensitive to excitatory input, that is, brain excitability is reduced. Therefore, the steroid compounds provided by the present invention have a strong effect on GABA A The receptor has a strong positive regulatory effect and has potential application in the treatment of central nervous system-related diseases.

[0044] In addition, the steroid compound provided by the present invention has a high oral bioavailability and can be used to prepare an oral drug for treating central nervous system-related diseases, which is expected to solve the problem that the existing drug brexanolone requires long-term intravenous drip to cause inconvenience to patients. DETAILED DESCRIPTION

[0045] The present invention provides a steroid compound, a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate or isotope compound thereof, wherein the steroid compound has a structure shown in Formula I:

[0046]

[0047] In formula I, R1, R2, R3 and R4 are independently selected from any of the following groups:

[0048] -H, -CN, -NO2, -COOH, halogen group, formaldehyde oxime group, formaldehyde oxime ether group;

[0049] C1-C6 alkane or halogen substituents thereof, C1-C6 alkane or halogen substituents containing heteroatoms, C3-C7 cycloalkane or halogen substituents thereof, C3-C7 cycloalkane or halogen substituents containing heteroatoms or halogen substituents thereof, wherein the heteroatoms in the C1-C6 alkane or C3-C7 cycloalkane containing heteroatoms are independently selected from one or more of nitrogen, oxygen and sulfur;

[0050] C2-C6 alkene group or its halogen substitution, C2-C6 alkynyl group or its halogen substitution;

[0051] A five-membered aromatic hydrocarbon group or a five-membered heteroaromatic hydrocarbon group, wherein the heteroatom in the five-membered heteroaromatic hydrocarbon group is selected from one or more of nitrogen, oxygen and sulfur;

[0052] Six-membered aromatic hydrocarbon group, six-membered nitrogen heterocyclic aromatic hydrocarbon group, the number of nitrogen in the six-membered nitrogen heterocyclic aromatic hydrocarbon group is ≥1;

[0053] Sulfoxide groups connected to C1-C6 chain alkane groups, sulfoxide groups connected to C3-C6 cycloalkane groups, sulfoxide groups connected to five-membered aromatic hydrocarbon groups, and sulfoxide groups connected to six-membered aromatic hydrocarbon groups;

[0054] Sulfone groups connected to C1-C6 chain alkane groups, sulfone groups connected to C3-C6 cycloalkane groups, sulfone groups connected to five-membered aromatic hydrocarbon groups, and sulfone groups connected to six-membered aromatic hydrocarbon groups;

[0055] Hydroxyl, hydroxyl connected to a five-membered aromatic hydrocarbon group, hydroxyl connected to a five-membered heteroaromatic hydrocarbon group, hydroxyl connected to a six-membered aromatic hydrocarbon group, hydroxyl connected to a six-membered nitrogen heteroaromatic hydrocarbon group, hydroxyl connected to a C3-C7 cycloalkane group, hydroxyl connected to a heteroatom-containing C3-C7 cycloalkane group;

[0056] Amino group, amino group connected to a five-membered aromatic hydrocarbon group, amino group connected to a five-membered heteroaromatic hydrocarbon group, amino group connected to a six-membered aromatic hydrocarbon group, amino group connected to a six-membered nitrogen heteroaromatic hydrocarbon group, amino group connected to a C3-C7 cycloalkane group, amino group connected to a heteroatom-containing C3-C7 cycloalkane group;

[0057] thiol, thiol connected to a five-membered aromatic hydrocarbon group, thiol connected to a five-membered heteroaromatic hydrocarbon group, thiol connected to a six-membered aromatic hydrocarbon group, thiol connected to a six-membered nitrogen heteroaromatic hydrocarbon group, thiol connected to a C3-C7 cycloalkane group, thiol connected to a heteroatom-containing C3-C7 cycloalkane group;

[0058] Sulfonamide, sulfonamide connected to a C1-C6 chain alkane group, sulfonamide connected to a C3-C6 cycloalkane group, sulfonamide connected to a five-membered ring aromatic group, sulfonamide connected to a six-membered ring aromatic group;

[0059] An amide group, an amide group connected to a C0-C6 chain alkane group, an amide group connected to a C3-C6 cycloalkane group, an amide group connected to a five-membered ring aromatic group, and an amide group connected to a six-membered ring aromatic group;

[0060] Alkanoyl or a halogen substituent thereof, alkenoyl or a halogen substituent thereof, alkynoyl or a halogen substituent thereof, alkoxycarbonyl or a halogen substituent thereof, alkenyloxycarbonyl or a halogen substituent thereof, alkynyloxycarbonyl or a halogen substituent thereof, aryloxycarbonyl or a halogen substituent thereof, heteroaryloxycarbonyl or a halogen substituent thereof, alkylaminocarbonyl or a halogen substituent thereof, enaminocarbonyl or a halogen substituent thereof, alkynylaminocarbonyl or a halogen substituent thereof, arylaminocarbonyl or a halogen substituent thereof, heteroarylaminocarbonyl or a halogen substituent thereof.

[0061] As an embodiment of the present invention, the halogen substituent may be a substituent containing one or more of -F, -Cl, -Br and -I.

[0062] As an embodiment of the present invention, the halogen group may be selected from -F, -Cl, -Br or -I.

[0063] As an embodiment of the present invention, the C1-C6 alkane group may be a methyl group, an ethyl group or a propyl group.

[0064] As an embodiment of the present invention, the halogen substituent of the C1-C6 alkane group may be a fluorine-substituted methyl group, a fluorine-substituted ethyl group or a fluorine-substituted propyl group, and the number of -F in the fluorine-substituted methyl group, the fluorine-substituted ethyl group and the fluorine-substituted propyl group may be 1, 2 or 3 independently.

[0065] As an embodiment of the present invention, the heteroatom in the C1-C6 chain alkane group containing heteroatoms may be oxygen, and the number of oxygen in the C1-C6 chain alkane group containing heteroatoms may be 1 or 2.

[0066] As an embodiment of the present invention, the C2~C6 olefin group may be vinyl, propenyl or butenyl; the halogen substituent of the C2~C6 olefin group may be fluorine-substituted vinyl, fluorine-substituted propenyl or fluorine-substituted butenyl, and the number of -F in the fluorine-substituted vinyl, fluorine-substituted propenyl or fluorine-substituted butenyl may be independently 1, 2 or 3.

[0067] As an embodiment of the present invention, the C2-C6 alkynyl group may be an ethynyl group, a propynyl group or a butynyl group.

[0068] As an embodiment of the present invention, the halogen substituent of the C2-C6 alkynyl group may be a fluorine-substituted ethynyl, a fluorine-substituted propynyl or a fluorine-substituted butynyl, and the number of -F in the fluorine-substituted ethynyl, the fluorine-substituted propynyl or the fluorine-substituted butynyl may be independently 1, 2 or 3.

[0069] As an embodiment of the present invention, the sulfoxide group connected to a C1-C6 alkane group may be a sulfoxide group connected to a methyl group, a sulfoxide group connected to an ethyl group, or a sulfoxide group connected to a propyl group.

[0070] As an embodiment of the present invention, the five-membered heterocyclic aromatic hydrocarbon group may be a substituted five-membered heterocyclic aromatic hydrocarbon group or an unsubstituted five-membered heterocyclic aromatic hydrocarbon group; the number of substituents in the substituted five-membered heterocyclic aromatic hydrocarbon group may be 1 to 4, specifically 1, 2, 3 or 4; the substituents in the substituted five-membered heterocyclic aromatic hydrocarbon group may be selected from a halogen group, an alkane group, an alkene group or an alkynyl group, for example, a C1 to C6 chain alkane group, specifically a methyl group; the number of heteroatoms in the five-membered heterocyclic aromatic hydrocarbon group may be 1 to 4, specifically 1, 2, 3 or 4; the heteroatoms in the five-membered heterocyclic aromatic hydrocarbon group may be selected from one or more of nitrogen, oxygen and sulfur, specifically nitrogen.

[0071] As an embodiment of the present invention, the heterocyclic aromatic hydrocarbon in the heteroaromatic amine carbonyl group may be a substituted five-membered heterocyclic aromatic hydrocarbon, an unsubstituted five-membered heterocyclic aromatic hydrocarbon group, a substituted six-membered heterocyclic aromatic hydrocarbon or an unsubstituted six-membered heterocyclic aromatic hydrocarbon group; the number of substituents in the substituted five-membered heterocyclic aromatic hydrocarbon and the substituted six-membered heterocyclic aromatic hydrocarbon may be independently 1 to 4, specifically 1, 2, 3 or 4; the substituents in the substituted five-membered heterocyclic aromatic hydrocarbon and the substituted six-membered heterocyclic aromatic hydrocarbon are independently selected from halogen groups, alkane groups, alkene groups or alkyne groups, for example, they may be C1 to C6 chain alkane groups, specifically methyl groups; the number of heteroatoms in the heterocyclic aromatic hydrocarbon in the heteroaromatic amine carbonyl group may be 1 to 4, specifically 1, 2, 3 or 4; the heteroatoms in the heterocyclic aromatic hydrocarbon in the heteroaromatic amine carbonyl group may be selected from one or more of nitrogen, oxygen and sulfur, specifically nitrogen.

[0072] As an embodiment of the present invention, the R1, R2, R3 and R4 can be independently selected from -H, -F, -Cl, -Br, -I, -CN, -CH3, -CF3, -CH2OCH3, -NO2, -SO2CH3, -CH=CF2, -COOH, -CHF2, -CH2F, ethynyl, -OCH3, -CH=NOH, -CH=NOCH3, -CONH2,

[0073] As an embodiment of the present invention, R1, R2, R3 and R4 may not be -H.

[0074] As an embodiment of the present invention, one and only one of R1, R2, R3 and R4 may be -H, for example, only R1 may be -H, or only R2 may be -H, or only R3 may be -H, or only R4 may be -H.

[0075] As an embodiment of the present invention, one and only two of R1, R2, R3 and R4 may be -H, for example, only R1 and R2 may be -H, or only R1 and R3 may be -H, or only R1 and R4 may be -H, or only R2 and R3 may be -H, or only R2 and R4 may be -H, or only R3 and R4 may be -H.

[0076] As an embodiment of the present invention, only three of R1, R2, R3 and R4 may be -H, for example, only R1, R2 and R3 may be -H, or only R1, R2 and R4 may be -H, or only R1, R3 and R4 may be -H, or only R2, R3 and R4 may be -H.

[0077] As an embodiment of the present invention, R1, R2, R3 and R4 may all be -H.

[0078] The structures and numbers of the compounds involved in the examples of the present invention are shown in Table 1.

[0079] Table 1 Compound structures and numbers

[0080]

[0081]

[0082]

[0083] In the present invention, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with other ingredients comprising the formulation and / or mammals to be treated therewith.

[0084] In the present invention, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reaction, etc., and is commensurate with a reasonable benefit / risk ratio within the scope of reliable medical judgment. "Pharmaceutically acceptable salts" are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 119. The pharmaceutically acceptable salts of the steroid compound having the structure shown in Formula I of the present invention include salts derived from suitable inorganic acids and organic acids and bases. As an embodiment of the present invention, "pharmaceutically acceptable salts" can be salts formed by amino groups and inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or perchloric acid, or salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or salts formed using methods well known in the art, such as ion exchange methods. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, or valerate salts. As one embodiment of the present invention, a "pharmaceutically acceptable salt" may be a pharmaceutically acceptable salt derived from a suitable base, such as an alkali metal salt, an alkaline earth metal salt, an ammonium salt or a quaternary ammonium salt; representative alkali metal salts or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts or magnesium salts; if appropriate, further "pharmaceutically acceptable salts" include non-toxic ammonium salts, quaternary ammonium salts or amine cation salts formed using counter ions, such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate or aryl sulfonate.

[0085] In the present invention, the term "stereoisomer" refers to a compound with the same chemical composition and connectivity, but whose atoms have different orientations in space, which cannot be interchanged by single bond rotation. "Stereoisomer" includes "diastereomers" and "enantiomers". "Diastereomers" refer to stereoisomers with two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral characteristics and reactivity. Diastereomeric mixtures can be separated under high-resolution analytical procedures (such as crystallization, electrophoresis and chromatography). "Enantiomers" refer to two stereoisomers that are non-overlapping mirror images of each other.

[0086] In the present invention, the term "tautomer" refers to the coexistence of two (or more) compounds that differ only in the position and electron distribution of one (or more) mobile atoms, such as keto-enol tautomers.

[0087] In the present invention, the term "solvate" refers to an association or complex of one or more solvent molecules and the steroid compound of the present invention having the structure shown in Formula I. As an embodiment of the present invention, the solvent forming the solvate includes but is not limited to water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and ethanolamine; when the solvent forming the solvate is water, the solvate is a hydrate, that is, an association or complex of water and the steroid compound of the present invention having the structure shown in Formula I.

[0088] In the present invention, the term "isotopic compound" refers to a compound labeled with an isotope, and these forms of compounds may also be referred to as "isotopic labels" or "isotope-enriched analogs". As one embodiment of the present invention, the "isotopic compound" has a structure as shown in Formula I, except that one or more atoms are replaced by atoms with a selected atomic mass or mass number. Isotopes that can be incorporated into the steroid compound having the structure as shown in Formula I of the present invention may include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, for example, including but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I and 125I. Such compounds can be synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced with deuterium.

[0089] The present invention provides a pharmaceutical composition, the active ingredients of which include one or more of the steroid compound described in the above technical solution, its pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate and isotope compound.

[0090] As an embodiment of the present invention, the pharmaceutical composition can be administered alone or in combination with other therapeutic agents; such pharmaceutical compositions are prepared in a manner well known in the art (e.g., Reminton's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & C.T. Rhodes, Eds.).

[0091] As an embodiment of the present invention, the pharmaceutical composition includes a pharmaceutically acceptable carrier, and the pharmaceutically acceptable carrier can be solid or liquid. Among them, the solid pharmaceutically acceptable carrier (referred to as a solid carrier) can be used as one or more substances in an excipient, a diluent, a sweetener, a solubilizer, a lubricant, an adhesive, a tablet disintegrant, a stabilizer, a preservative, and an encapsulating material. The liquid pharmaceutically acceptable carrier (referred to as a liquid carrier) can be a solvent or a liquid dispersion medium. As one embodiment of the present invention, suitable solid carriers include, but are not limited to, one or more of cellulose, glucose, lactose, mannitol, magnesium stearate, magnesium carbonate, sodium carbonate, sodium saccharin, sucrose, dextrin, talc, starch, pectin, gelatin, tragacanth gum, gum arabic, sodium alginate, parabens, methylcellulose, sodium carboxymethyl cellulose, low melting point wax and cocoa butter; suitable liquid carriers include, but are not limited to, water, ethanol, polyols (e.g., one or more of glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils (e.g., one or more of peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycerides, agar, pyrogen-free water, isotonic saline and Ringer's solution.

[0092] The pharmaceutical composition of the present invention can be in any form suitable for the intended method of administration. For example, when used for oral use, it can be prepared into tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs, solutions, sprays. The pharmaceutical composition for oral use can be prepared according to any method known in the art for making pharmaceutical compositions. The pharmaceutical composition of the present invention can also be prepared into preparations suitable for intrapulmonary or intranasal administration, such as preparations for aerosol or dry powder administration, nasal drops or nasal sprays. The pharmaceutical composition of the present invention can also be prepared into suppositories suitable for rectal administration. The pharmaceutical composition of the present invention can also be prepared into transdermal preparations for topical administration or eye drops suitable for ocular administration.

[0093] The pharmaceutical composition of the present invention can be administered parenterally, intramuscularly, subcutaneously, orally, topically in single doses or multiple doses.

[0094] The effective dose of the compounds of the invention depends at least on the nature of the condition being treated, toxicity, delivery method and pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected that about 0.0001 to 100 mg per kilogram of body weight per day; usually about 0.01 to 10 mg per kilogram of body weight per day; more typically, about 0.01 to 5 mg per kilogram of body weight per day; most typically about 0.05 to 0.5 mg per kilogram of body weight per day. For example, a candidate daily dose for an adult of about 70 kg body weight will be in the range of 1 to 1000 mg, preferably in the range of 5 to 500 mg, and can be administered in a single dose or multiple doses.

[0095] The present invention provides the use of the steroid compound described in the above technical scheme, its pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate or isotope compound or the pharmaceutical composition described in the above technical scheme in the preparation of drugs for treating mood disorders, mental diseases, neurodegenerative diseases or neuropathic pain.

[0096] As an embodiment of the present invention, the emotional disorder may include generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, social anxiety disorder, premenstrual dysphoric disorder, major depression or postpartum depression; the mental illness may include epilepsy, convulsions or insomnia; the neurodegenerative disease may include Alzheimer's disease, Parkinson's disease, multiple sclerosis or Niemann-Pick type C disease; the neuropathic pain may include menstrual migraine, postmenopausal migraine, diabetic peripheral neuropathy, chemotherapy pain or sciatica.

[0097] The present invention provides a method for preparing the steroid compound described in the above technical solution, comprising the following steps:

[0098] Compound BA, a pyrrolyl-containing compound, a base reagent and an organic solvent are mixed to carry out a substitution reaction to obtain a steroid compound having a structure shown in Formula I;

[0099] The compound BA has a structure shown in formula II, and the pyrrolyl-containing compound has a structure shown in formula III:

[0100]

[0101] The R1, R2, R3 and R4 are as defined in Formula I.

[0102] In the present invention, unless otherwise specified, the raw materials used are commercially available products well known to those skilled in the art or are prepared by methods well known to those skilled in the art.

[0103] First, the preparation method of the compound BA (chemical name: (3R, 5S, 8R, 9S, 10S, 13S, 14S, 17S)-3-hydroxy-10, 13-dimethylestragen-21-bromide) of the present invention is described below. As an embodiment of the present invention, the preparation method of the compound BA may include the following steps:

[0104] Pregnenolone (denoted as compound A1), a hydrogenation catalyst and an organic solvent are mixed, and a hydrogenation reaction is performed in a hydrogen atmosphere to obtain compound A2;

[0105] The compound A2, chloroacetic acid, triphenylphosphine, diisopropyl azodicarboxylate and an organic solvent are mixed to carry out an esterification reaction to obtain a compound A3;

[0106] The compound A3, an alkali reagent and methanol are mixed to carry out a hydrolysis reaction to obtain a compound A4;

[0107] The compound A4, concentrated hydrobromic acid aqueous solution, pyridinium tribromide salt and an organic solvent are mixed to carry out a substitution reaction to obtain the compound BA.

[0108] The present invention mixes compound A1, a hydrogenation catalyst and an organic solvent, and performs a hydrogenation reaction in a hydrogen atmosphere to obtain compound A2. As an embodiment of the present invention, the hydrogenation catalyst can be palladium carbon (the palladium content in the palladium carbon can be 10wt%); the organic solvent can be methanol and dichloromethane, and the volume ratio of methanol and dichloromethane can be 1:0.5-1.5, specifically 1:1; the present invention does not specifically limit the amount of the hydrogenation catalyst and the organic solvent, as long as the reaction is carried out smoothly. In an embodiment of the present invention, an organic solvent is added to a high-pressure reactor, compound A1 is added under stirring, and after sufficient stirring, a hydrogenation catalyst is added, the high-pressure reactor is closed, and after checking the air tightness, the air in the high-pressure reactor is replaced by nitrogen 3 times, and then the nitrogen in the high-pressure reactor is replaced by hydrogen 3 times, and a hydrogenation reaction is carried out. In an embodiment of the present invention, the temperature of the hydrogenation reaction can be 30-40°C, specifically 35°C; the time can be 8-15h, specifically 11h; the hydrogen pressure can be 0.3-0.4MPa.

[0109] As an embodiment of the present invention, after the hydrogenation reaction, the temperature can be specifically lowered to 25°C and the high-pressure reactor can be slowly depressurized, the obtained product system can be filtered, the filter cake can be rinsed with dichloromethane, the filtrate can be concentrated under reduced pressure, 2-butanone can be added to the obtained concentrate, heated to 80°C and refluxed for 30 minutes, and then the temperature is lowered (20°C / h) to 0°C and stirred for crystallization for 3 hours, the obtained material can be transferred to a centrifuge for centrifugation, the obtained solid material can be rinsed with cold 2-butanone, and then dried in a vacuum drying oven to obtain compound A2.

[0110] After obtaining compound A2, the present invention mixes the compound A2, chloroacetic acid, triphenylphosphine, diisopropyl azodicarboxylate and an organic solvent to carry out an esterification reaction to obtain compound A3. As an embodiment of the present invention, the organic solvent may be 1,4-dioxane. The present invention does not specifically limit the amount of the organic solvent, as long as the reaction can proceed smoothly. In the embodiment of the present invention, specifically in a protective atmosphere, the organic solvent, compound A2, chloroacetic acid and triphenylphosphine are mixed, and then the temperature is lowered to below 15°C, and diisopropyl azodicarboxylate is added dropwise, and the temperature is controlled below 15°C during the addition; after the addition is completed, the temperature is raised to carry out the esterification reaction. As an embodiment of the present invention, the temperature of the esterification reaction may be 30 to 40°C, specifically 35°C; the time may be 2.5 to 3.5h, specifically 3h.

[0111] As an embodiment of the present invention, after the esterification reaction, the obtained product system can be cooled to 25°C and purified water is added dropwise. After the addition is completed, the temperature is cooled to 20°C and stirred for 3 hours, and then transferred to a centrifuge for centrifugation. The obtained solid material is rinsed with an aqueous solution of 1,4-dioxane (the volume ratio of 1,4-dioxane to water is 1:1), and a crude product is obtained after drying. The crude product and n-heptane are added to a reaction bottle, heated to 85°C to dissolve, cooled to 5°C, stirred and crystallized for 3 hours, and the obtained material is transferred to a centrifuge for centrifugation. The solid material is rinsed with cold n-heptane and dried to obtain compound A3.

[0112] After obtaining compound A3, the present invention mixes the compound A3, an alkali reagent and methanol to perform a hydrolysis reaction to obtain compound A4. As an embodiment of the present invention, the alkali reagent can be potassium carbonate; the present invention has no special restrictions on the amount of the alkali reagent and methanol, as long as the reaction can proceed smoothly. As an embodiment of the present invention, the temperature of the hydrolysis reaction can be 30 to 40°C, specifically 35°C; the time can be 1.5 to 2.5h, specifically 2h.

[0113] As an embodiment of the present invention, after the hydrolysis reaction, the obtained product system can be cooled to 25°C and purified water is added dropwise. After the addition is completed, the temperature is cooled to 5°C and stirred for 3 hours, and then transferred to a centrifuge for centrifugation. The obtained solid material is rinsed with methanol aqueous solution (the volume ratio of methanol to water is 2:1), and the crude product 1 is obtained after drying; methanol and crude product 1 are added to a reaction bottle, heated to 50°C to dissolve, and then cooled to 30°C and purified water is added dropwise, stirred for 30 minutes, cooled to 10°C and stirred for crystallization for 3 hours, and the obtained material is transferred to a centrifuge for centrifugation. The solid material is rinsed with methanol aqueous solution, and the crude product 2 is obtained after drying; n-heptane and crude product 2 are added to the reaction bottle, heated to 85°C and stirred for 30 minutes, and then cooled to 45°C and stirred for crystallization for 3 hours. The obtained material is transferred to a centrifuge for centrifugation, and the solid material is rinsed with n-heptane. Compound A4 is obtained after drying.

[0114] After obtaining compound A4, the present invention mixes the compound A4, concentrated hydrobromic acid aqueous solution, tribromopyridinium salt and organic solvent to carry out substitution reaction to obtain the compound BA. As an embodiment of the present invention, the concentration of hydrobromic acid in the concentrated hydrobromic acid aqueous solution can be 48wt%; the organic solvent can be methanol. The present invention does not specifically limit the amount of the organic solvent, as long as the reaction proceeds smoothly. In the embodiment of the present invention, specifically, compound A4, concentrated hydrobromic acid aqueous solution and part of the organic solvent are mixed, the temperature is maintained at 0°C, and then the pre-prepared tribromopyridinium salt solution (prepared from tribromopyridinium salt and the remaining organic solvent) is added to carry out substitution reaction. As an embodiment of the present invention, the temperature of the substitution reaction can be 10-20°C, specifically 15°C; the time can be 2.5-3.5h, specifically 3h.

[0115] As an embodiment of the present invention, after the substitution reaction, a sodium bicarbonate aqueous solution with a concentration of 8.7 wt% can be added to the obtained product system to quench the reaction, and then purified water is added, stirred at 25° C. for 1 h, filtered, and the filter cake is rinsed with purified water and dried to obtain compound BA.

[0116] The method for preparing a steroid compound having a structure shown in Formula I by using the compound BA of the present invention is described in detail below. The reaction formula is shown below:

[0117]

[0118] The present invention mixes compound BA, a pyrrolyl-containing compound, an alkaline reagent and an organic solvent to carry out a substitution reaction to obtain a steroid compound having a structure shown in Formula I. As an embodiment of the present invention, the alkaline reagent may be potassium carbonate, and the organic solvent may be N,N-dimethylformamide. The present invention does not specifically limit the amount of the alkaline reagent and the organic solvent, as long as the reaction can proceed smoothly. In an embodiment of the present invention, specifically, compound BA is dissolved in an organic solvent, and then a pyrrolyl-containing compound and an alkaline reagent are added to carry out a substitution reaction. As an embodiment of the present invention, the temperature of the substitution reaction may be 20 to 30°C, specifically room temperature (25°C); the time may be 10 to 15h, specifically 12h.

[0119] As an embodiment of the present invention, after the substitution reaction, water can be added to the obtained product system, extracted with ethyl acetate, the organic phase is collected, dried over anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure, the obtained crude product is purified by silica gel column chromatography, the solvent in the obtained purified solution is removed, and water and acetonitrile are added for freeze drying to obtain a steroid compound having a structure shown in Formula I. In the embodiment of the present invention, the eluent used for the silica gel column chromatography purification can be ethyl acetate (EA) and petroleum ether (PE), and the volume ratio of ethyl acetate to petroleum ether can be 1:1-2.

[0120] It should be noted that the pyrrole-containing compound of the present invention can be prepared according to actual needs using commercially available products well known to those skilled in the art or using methods well known to those skilled in the art. For example, when preparing compound 15 in Example 5, the pyrrole-containing compound used is specifically compound 15-INT1; when preparing compound 22 in Example 8, the pyrrole-containing compound used is specifically compound 22-INT1; when preparing compound 28 in Example 9, the pyrrole-containing compound used is specifically compound 28-INT1; the structural formulas and preparation methods of the three are detailed in the corresponding embodiments. Other pyrrole-containing compounds not involved can be prepared by referring to similar methods, which will not be repeated here.

[0121] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0122] Preparation Example 1 Synthesis of Compound BA

[0123]

[0124] (1) Synthesis of Compound A2:

[0125] Methanol and dichloromethane (methanol and dichloromethane volume ratio of 1:1) were added to the autoclave, stirring was started, pregnenolone (compound A1) was added and stirred thoroughly, palladium carbon (10%) was added, the autoclave was closed, and after checking the air tightness, the air in the autoclave was replaced with nitrogen 3 times, and then the nitrogen in the autoclave was replaced with hydrogen 3 times, the pressure was maintained at 0.3 MPa, and the temperature was raised to 35°C for reaction for 11 hours; after the reaction was completed, the temperature was lowered to 25°C and the autoclave was depressurized, the obtained product system was filtered, the filter cake was rinsed with dichloromethane, the filtrate was concentrated under reduced pressure, 2-butanone was added to the obtained concentrate, heated to 80°C and refluxed for 30 minutes, and then the temperature was lowered (20°C / h) to 0°C and stirred for crystallization for 3 hours, the obtained material was transferred to a centrifuge for centrifugation, the obtained solid material was rinsed with cold 2-butanone, and then dried in a vacuum drying oven to obtain compound A2.

[0126] (2) Synthesis of Compound A3:

[0127] Under nitrogen protection, 1,4-dioxane, compound A2, chloroacetic acid and triphenylphosphine (PPh3) were added to the reaction kettle in sequence, and then the temperature was lowered to below 15°C, and diisopropyl azodicarboxylate (DIAD) was added dropwise. The temperature was controlled below 15°C during the addition, and the temperature was raised to 35°C for reaction for 3h after the addition was completed. After the reaction was completed, the temperature was lowered to 25°C and purified water was added dropwise. After the addition was completed, the temperature was lowered to 20°C and stirred for 3h, and then the mixture was transferred to a centrifuge for centrifugation. The solid material was rinsed with a 1,4-dioxane aqueous solution (the volume ratio of 1,4-dioxane to water was 1:1), and a crude product was obtained after drying. The crude product and n-heptane were added to a reaction bottle, heated to 85°C to dissolve, and then cooled to 5°C and stirred for crystallization for 3h. The obtained material was transferred to a centrifuge for centrifugation. The solid material was rinsed with cold n-heptane and dried to obtain compound A3.

[0128] (3) Synthesis of Compound A4:

[0129] Methanol, potassium carbonate and compound A3 were added to a reaction kettle in sequence, and the temperature was raised to 35°C for reaction for 2 hours. After the reaction was completed, the temperature was lowered to 25°C and purified water was added dropwise. After the addition was completed, the temperature was lowered to 5°C and stirred for 3 hours, and then the mixture was transferred to a centrifuge for centrifugation. The solid material was rinsed with a methanol aqueous solution (the volume ratio of methanol to water was 2:1), and the crude product 1 was obtained after drying. Methanol and crude product 1 were added to a reaction bottle, heated to 50°C to dissolve, and then the temperature was lowered to 30°C and purified water was added dropwise, stirred for 30 minutes, and then the temperature was lowered to 10°C and stirred for crystallization for 3 hours. The obtained material was transferred to a centrifuge for centrifugation, and the solid material was rinsed with a methanol aqueous solution, and the crude product 2 was obtained after drying. n-heptane and crude product 2 were added to the reaction bottle, heated to 85°C and stirred for 30 minutes, and then the temperature was lowered to 45°C and stirred for crystallization for 3 hours. The obtained material was transferred to a centrifuge for centrifugation, and the solid material was rinsed with n-heptane, and compound A4 was obtained after drying.

[0130] (4) Synthesis of compound BA:

[0131] Add methanol, compound A4 and concentrated hydrobromic acid aqueous solution (concentration of 48wt%) to the reactor, place the three-necked flask in an ice-water bath, maintain the temperature at 0°C, add the prepared methanol solution of tribromopyridinium salt to the three-necked flask, and react at 15°C for 3h after the addition; after the reaction is completed, add 8.7wt% sodium bicarbonate aqueous solution to quench the reaction, then add purified water, stir at 25°C for 1h, filter, rinse the filter cake with purified water and dry under vacuum to obtain compound BA.

[0132] Example 1 Synthesis of Compound 1

[0133]

[0134] Compound BA was dissolved in N,N-dimethylformamide (DMF), and 2-cyanopyrrole and potassium carbonate were added after stirring to dissolve, and the reaction was carried out at room temperature for 12 hours. TLC (the reagent used was EA:PE=1:1 by volume ratio) detected that the reaction was complete (no compound BA remained); water was added to the obtained product system, and the mixture was extracted with ethyl acetate three times. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (the eluent used was EA:PE=1:1 by volume ratio). After removing the solvent from the obtained purified solution, water and acetonitrile were added for freeze-drying to obtain compound 1 as a white solid.

[0135] LCMS: MS Calcd.:408.28; MS Found:407.25[MH] - .

[0136] 1H NMR (400MHz, DMSO-d6) δ7.13-7.04(m,1H),6.94(dd,J=4.0,1.6Hz,1H),6.19(dd,J=4.0,2.6H z,1H),5.16(d,J=18.7Hz,1H),4.94(d,J=18.7Hz,1H),4.16(d,J=3.0Hz,1H),3.81(q,J=2.9Hz ,1H),2.70(t,J=8.8Hz,1H),2.15-1.94(m,2H),1.73-1.61(m,3H),1.60-1.43(m,4H),1.43-1 .28(m,4H),1.27-1.08(m,6H),0.93(ddt,J=17.3,11.6,7.0Hz,1H),0.74(s,4H),0.60(s,3H).

[0137] Example 2 Synthesis of Compound 4

[0138]

[0139] The method of Example 1 was used as described above, except that 2-cyanopyrrole was replaced by 3-cyanopyrrole. The final compound 4 was an off-white solid.

[0140] LCMS: MS Calcd.:408.28; MS Found:407.30[MH] - .

[0141] 1 H NMR (400MHz, DMSO-d6) δ7.46(d,J=2.1Hz,1H),6.80(t,J=2.5Hz,1H),6.43(t,J=2.3Hz,1H),5. 01(d,J=18.3Hz,1H),4.86(d,J=18.4Hz,1H),4.17(d,J=3.0Hz,1H),3.88-3.76(m,1H),2.65(t ,J=8.6Hz,1H),2.05(t,J=10.8Hz,2H),1.72-1.60(m,3H),1.57-1.47(m,3H),1.36(dq,J=14.6 ,11.2,9.4Hz,5H),1.27-1.09(m,8H),0.91(dd,J=17.8,11.8Hz,1H),0.74(s,4H),0.56(s,3H).

[0142] Example 3 Synthesis of Compound 6

[0143]

[0144] The method of Example 1 was used as described above, except that 2-cyanopyrrole was replaced by 3-trifluoromethylpyrrole. The final compound 6 was a white solid.

[0145] LCMS: MS Calcd.:451.27; MS Found:452.30[M+H] + .

[0146] 1 H NMR(400MHz, DMSO-d6)δ7.25-7.16(m,1H),6.78(d,J=2.6Hz,1H),6.28(t,J= 2.4Hz,1H),4.98(d,J=18.4Hz,1H),4.84(d,J=18.4Hz,1H),4.16(d,J=2.9Hz, 1H),3.81(q,J=2.9Hz,1H),2.64(d,J=8.8Hz,1H),2.13-1.99(m,2H),1.72-1 .47(m,7H),1.43-1.08(m,12H),0.99-0.86(m,1H),0.74(s,4H),0.57(s,3H).

[0147] Example 4 Synthesis of Compound 7

[0148]

[0149] The method of Example 1 was used as described above, except that 2-cyanopyrrole was replaced by 3-nitropyrrole, and the reagent used for silica gel column chromatography purification was EA:PE=1:2. The final compound 7 was obtained as a yellow solid.

[0150] LCMS: MS Calcd.:428.27; MS Found:427.25[MH] - .

[0151] 1H NMR(400MHz,DMSO-d6)δ7.85(t,J=2.0Hz,1H),6.79(dd,J=3.2,2.3Hz,1H),6.64(d d,J=3.2,1.8Hz,1H),5.05(d,J=18.2Hz,1H),4.91(d,J=18.3Hz,1H),4.16(d,J=3. 0Hz,1H),3.81(s,1H),2.66(s,1H),2.09(s,2H),1.63(d,J=15.5Hz,7H),1.34(d,J =12.3Hz,5H),1.26-1.07(m,6H),0.93(t,J=9.3Hz,1H),0.74(s,4H),0.58(s,3H).

[0152] Example 5 Synthesis of Compound 15

[0153]

[0154] Add acetic anhydride and 2-cyanopyrrole to a reaction flask, cool to -20°C, and under this condition, add dropwise acetic anhydride solution of concentrated nitric acid (obtained by mixing concentrated nitric acid and acetic anhydride). After the addition is complete, keep warm and react for 3 hours. Add ethyl acetate and water to the obtained product system, extract and separate the liquids, and then wash the organic phase with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in turn. Collect the organic phase, dry it over anhydrous sodium sulfate, filter it, and concentrate the filtrate under reduced pressure. Purify the obtained crude product by silica gel column chromatography (the eluent used is EA:PE=1:10 by volume), remove the solvent in the obtained eluent to obtain compound 15-INT1 as a yellow solid.

[0155] The procedure of Example 1 was then followed, except that 2-cyanopyrrole was replaced by compound 15-INT1, and the reagent used for silica gel column chromatography purification was EA:PE=1:2. Finally, compound 15 was obtained as a yellow solid.

[0156] LCMS: MS Calcd.:453.26; MS Found:452.25[MH] - .

[0157] 1H NMR (400MHz, DMSO-d6) δ8.24(d,J=1.9Hz,1H),7.76(d,J=1.9Hz,1H),5.31(d,J=18. 6Hz,1H),5.12(d,J=18.6Hz,1H),4.17(d,J=2.9Hz,1H),3.81(s,1H),2.74(t,J=8.8 Hz,1H),2.07(dd,J=13.4,9.8Hz,2H),1.82-1.46(m,8H),1.34(q,J=14.1,13.4Hz,4 H), 1.19 (dt, J = 35.9, 12.6Hz, 6H), 0.94 (d, J = 8.5Hz, 1H), 0.74 (s, 4H), 0.61 (s, 3H).

[0158] Example 6 Synthesis of Compound 16

[0159]

[0160] The method of Example 1 was used as described above, except that 2-cyanopyrrole was replaced by 3,4-difluoropyrrole, and the reagent used for silica gel column chromatography purification was EA:PE=1:2. Finally, the obtained compound 16 was a white solid.

[0161] LCMS: MS Calcd.:419.26; MS Found:420.30[M+H] + .

[0162] 1 H NMR (400MHz, DMSO-d6) δ6.58(d,J=1.4Hz,2H),4.74(d,J=18.3Hz,1H),4.59(d,J=18.4Hz,1H),4.16(d,J=3.0Hz,1H),3.81(q,J=2.9Hz,1H),2.59(t ,J=8.8Hz,1H),2.09-1.93(m,2H),1.70-1.47(m,7H),1.41-1.27(m,5H),1 .27-1.08(m,7H),0.92(dd,J=10.0,7.1Hz,1H),0.73(s,4H),0.55(s,3H).

[0163] Example 7 Synthesis of Compound 18

[0164]

[0165] The method of Example 1 was used as described above, except that 2-cyanopyrrole was replaced by 2-fluoro-4-nitropyrrole. The final compound 18 was a yellow solid.

[0166] LCMS: MS Calcd.:446.26; MS Found:445.25[MH] - .

[0167] 1 H NMR (400MHz, DMSO-d6) δ7.66(t,J=2.6Hz,1H),6.36(dd,J=4.1,2.4Hz,1H),5.09(d,J=18.5Hz,1H),4.92(d,J=18.6Hz,1H),4.16(d,J=3.0Hz,1H) ,3.81(s,1H),2.70(d,J=9.0Hz,1H),2.12-1.95(m,2H),1.76-1.46(m,8 H), 1.41-1.08 (m, 11H), 0.94 (d, J = 7.6Hz, 1H), 0.74 (s, 3H), 0.56 (s, 3H).

[0168] Example 8 Synthesis of Compound 22

[0169]

[0170] Add 2-cyanopyrrole and acetonitrile to a reaction bottle, stir to dissolve, and place the reaction bottle in an ice-water bath; dissolve chlorosulfonyl isocyanate (CSI) in acetonitrile, and then add the obtained CSI solution to the reaction bottle, and then place the reaction bottle at room temperature to react for 3 hours; then place the reaction bottle in an ice-water bath, add DMF thereto, and then react the reaction bottle at 50°C for 30 minutes, and TLC detects that the reaction is complete; pour the obtained product system into ice water, extract 3 times with dichloromethane, collect the organic phase, wash with 5wt% sodium bicarbonate aqueous solution, and then dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the obtained crude product by silica gel column chromatography, remove the solvent in the obtained eluent, and obtain compound 22-INT1.

[0171] The reaction was then carried out in accordance with the method of Example 1, except that 2-cyanopyrrole was replaced by compound 22-INT1. The final compound 22 was a white solid.

[0172] LCMS: MS Calcd.:433.27; MS Found:432.25[MH] - .

[0173] 1H NMR (400MHz, DMSO-d6) δ7.88(d,J=1.7Hz,1H),7.56(d,J=1.7Hz,1H),5.28(d,J=18.7Hz,1H),5.08(d,J=18.7Hz,1H),4.16(s,1H),3.81(s,1H), 2.72(d,J=9.0Hz,1H),2.12-1.94(m,2H),1.73-1.46(m,8H),1.44-1.28 (m,4H),1.30-1.08(m,7H),1.02-0.84(m,1H),0.74(s,4H),0.60(s,3H).

[0174] Example 9 Synthesis of Compound 28

[0175]

[0176] Add 2-cyanopyrrole and acetonitrile to a reaction bottle, stir to dissolve, and place the reaction bottle in an ice-water bath; dissolve chlorosulfonyl isocyanate (CSI) in acetonitrile, and then add the obtained CSI solution to the reaction bottle, and then place the reaction bottle at room temperature to react for 3 hours; then place the reaction bottle in an ice-water bath, add DMF thereto, and then react the reaction bottle at 50°C for 30 minutes, and TLC detects that the reaction is complete; pour the obtained product system into ice water, extract 3 times with dichloromethane, collect the organic phase, wash with 5wt% sodium bicarbonate aqueous solution, and then dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the obtained crude product by silica gel column chromatography, remove the solvent in the obtained eluent to obtain compound 28-INT1.

[0177] The reaction was then carried out in accordance with the method of Example 1, except that 2-cyanopyrrole was replaced by compound 28-INT1 and the reagent used for detecting the completion of the reaction based on TLC was EA:PE=1:3. The final compound 28 was a white solid.

[0178] LCMS: MS Calcd.:433.27; MS Found:432.20[MH] - .

[0179] 1H NMR (400MHz, DMSO-d6) δ7.19(s,2H),5.33(d,J=19.1Hz,1H),5.14(d,J=19.2Hz,1H),4.16(d,J=3.0Hz,1H),3.81(s,1H),2.88(t,J=8.8Hz,1H),2.0 6(t,J=12.3Hz,2H),1.80-1.47(m,8H),1.34(d,J=12.0Hz,4H),1.21(s,3H ), 1.13 (d, J = 8.2Hz, 2H), 0.93 (t, J = 8.8Hz, 1H), 0.74 (s, 4H), 0.61 (s, 3H).

[0180] Although the present invention only uses Compound 1, Compound 4, Compound 6, Compound 7, Compound 15, Compound 16, Compound 18, Compound 22 and Compound 28 as examples to illustrate the synthesis route, those skilled in the art can understand that other compounds within the general formula defined in the present invention can also be prepared by referring to the above synthesis route.

[0181] Test Example 1 Electrophysiology Test

[0182] Shuranolone (SAGE-217) is a novel synthetic, clinical-stage neuroactive GABA steroid A Receptor positive allosteric modulators, with good oral pharmacokinetic properties, can support oral daily doses. The present invention uses the same test method to test the activity of the compounds of the present invention with SAGE-217 as a comparison.

[0183] Test method: Using a CHO cell line transiently expressing GABA (α4β3δ) receptors, the effects of compounds on GABA (α4β3δ) receptors were studied, and the half-maximal effect concentration (EC 50 ) value.

[0184] The experiment used a manual patch clamp system HEKAEPC 10 signal amplifier and a digital conversion system for whole-cell current recording of the chloride ion current of the GABA channel. The experiments were all carried out under normal room temperature conditions.

[0185] After the whole cell seal was formed, the cell membrane voltage was clamped at -70 mV. The peak current was recorded in the gap-free mode after GABA 5 nM, a mixture of the compound of the present invention and GABA 5 nM from low to high concentrations, and GABA 10 μM were sequentially injected onto the cell surface.

[0186] Administration of the test substance: GABA 5nM and each concentration of the compound of the present invention were mixed and administered 1-2 times, followed by washing with extracellular fluid for 1 min before testing the next concentration. The test data were collected by HEKA EPC 10 signal amplifier and stored in PatchMaster (HEKA) software.

[0187] Current recording: When administering, place the coverslip with cells in a recording bath under an inverted microscope, and flow the blank control external solution and the working solution of the compound of the present invention through the recording bath from low concentration to high concentration by gravity perfusion to act on the cells. During the recording, a peristaltic pump is used for liquid exchange. At least two cells are used for each concentration and the test is repeated twice independently.

[0188] The peak current of GABA (α4β3δ) receptor after the mixed solution of each concentration of the compound of the present invention and GABAECx was acted on GABA ECX+Compound ) and the peak current of GABAECx-induced receptors GABAECX ) was normalized to calculate the PAM effect (% Normalized to GABA ECX) of the compounds of the present invention, that is, (Peak current GABA ECX+Compound ) / (Peak current GABAECX ), with (Peak current GABA ECX+Compound ) / (Peak current GABAECX )≈X% was used as the quality control standard. Meanwhile, the mean, standard deviation and standard error were calculated for each concentration-effect ratio, and the data were expressed as mean±SE.

[0189] Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -X)×HillSlope)).

[0190] The EC of the compounds of the present invention was calculated by the above equation: 50 The dose-dependent effect was fitted nonlinearly, where EC 50 is the half-maximal effect concentration. EC 50 The calculation and curve fitting were completed using GraphPad Prism software.

[0191] The test results are shown in Table 2. 50 (nM) Range: A represents EC 50 <300nM, B means 300≤EC 50<500nM, C means 500≤EC 50 <1000nM, D means EC 50 ≥1000nM.

[0192] As shown in Table 2, the EC values ​​of Compound 1, Compound 4, Compound 7, Compound 11, Compound 12, Compound 13, Compound 14, Compound 15, Compound 18, Compound 22 and Compound 28 of the present invention on GABA (α4β3δ) activity 50 All of them were less than 300 nM, indicating that the compounds of the present invention have an effect on GABA A The receptor has a high positive regulation efficiency.

[0193] Table 2 Electrophysiological test results

[0194]

[0195] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A steroid compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate or isotope compound thereof, wherein the steroid compound has a structure as shown in Formula I: In formula I, R1, R2, R3 and R4 are independently selected from any of the following groups: -H, -CN, -NO2, -COOH, halogen group, formaldehyde oxime group, formaldehyde oxime ether group; C1-C6 alkane or halogen substituents thereof, C1-C6 alkane or halogen substituents containing heteroatoms, C3-C7 cycloalkane or halogen substituents thereof, C3-C7 cycloalkane or halogen substituents containing heteroatoms or halogen substituents thereof, wherein the heteroatoms in the C1-C6 alkane or C3-C7 cycloalkane containing heteroatoms are independently selected from one or more of nitrogen, oxygen and sulfur; C2-C6 alkene group or its halogen substitution, C2-C6 alkynyl group or its halogen substitution; A five-membered aromatic hydrocarbon group or a five-membered heteroaromatic hydrocarbon group, wherein the heteroatom in the five-membered heteroaromatic hydrocarbon group is selected from one or more of nitrogen, oxygen and sulfur; Six-membered aromatic hydrocarbon group, six-membered nitrogen heterocyclic aromatic hydrocarbon group, the number of nitrogen in the six-membered nitrogen heterocyclic aromatic hydrocarbon group is ≥1; Sulfoxide groups connected to C1-C6 chain alkane groups, sulfoxide groups connected to C3-C6 cycloalkane groups, sulfoxide groups connected to five-membered aromatic hydrocarbon groups, and sulfoxide groups connected to six-membered aromatic hydrocarbon groups; Sulfone groups connected to C1-C6 chain alkane groups, sulfone groups connected to C3-C6 cycloalkane groups, sulfone groups connected to five-membered aromatic hydrocarbon groups, and sulfone groups connected to six-membered aromatic hydrocarbon groups; Hydroxyl, hydroxyl connected to a five-membered aromatic hydrocarbon group, hydroxyl connected to a five-membered heteroaromatic hydrocarbon group, hydroxyl connected to a six-membered aromatic hydrocarbon group, hydroxyl connected to a six-membered nitrogen heteroaromatic hydrocarbon group, hydroxyl connected to a C3-C7 cycloalkane group, hydroxyl connected to a heteroatom-containing C3-C7 cycloalkane group; Amino group, amino group connected to a five-membered aromatic hydrocarbon group, amino group connected to a five-membered heteroaromatic hydrocarbon group, amino group connected to a six-membered aromatic hydrocarbon group, amino group connected to a six-membered nitrogen heteroaromatic hydrocarbon group, amino group connected to a C3-C7 cycloalkane group, amino group connected to a heteroatom-containing C3-C7 cycloalkane group; thiol, thiol connected to a five-membered aromatic hydrocarbon group, thiol connected to a five-membered heteroaromatic hydrocarbon group, thiol connected to a six-membered aromatic hydrocarbon group, thiol connected to a six-membered nitrogen heteroaromatic hydrocarbon group, thiol connected to a C3-C7 cycloalkane group, thiol connected to a heteroatom-containing C3-C7 cycloalkane group; Sulfonamide, sulfonamide connected to a C1-C6 chain alkane group, sulfonamide connected to a C3-C6 cycloalkane group, sulfonamide connected to a five-membered ring aromatic group, sulfonamide connected to a six-membered ring aromatic group; An amide group, an amide group connected to a C0-C6 chain alkane group, an amide group connected to a C3-C6 cycloalkane group, an amide group connected to a five-membered ring aromatic group, and an amide group connected to a six-membered ring aromatic group; Alkanoyl or a halogen substituent thereof, alkenoyl or a halogen substituent thereof, alkynoyl or a halogen substituent thereof, alkoxycarbonyl or a halogen substituent thereof, alkenyloxycarbonyl or a halogen substituent thereof, alkynyloxycarbonyl or a halogen substituent thereof, aryloxycarbonyl or a halogen substituent thereof, heteroaryloxycarbonyl or a halogen substituent thereof, alkylaminocarbonyl or a halogen substituent thereof, enaminocarbonyl or a halogen substituent thereof, alkynylaminocarbonyl or a halogen substituent thereof, arylaminocarbonyl or a halogen substituent thereof, heteroarylaminocarbonyl or a halogen substituent thereof.

2. The steroid compound, its pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate or isotope compound according to claim 1, characterized in that: The halogen substituent is one or more of -F, -Cl, -Br and -I.

3. The steroid compound, its pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate or isotope compound according to claim 2, characterized in that: The halogen group is selected from -F, -Cl, -Br or -I; The C1-C6 alkane group is a methyl group, an ethyl group or a propyl group; the halogen substituent of the C1-C6 alkane group is a fluorine-substituted methyl group, a fluorine-substituted ethyl group or a fluorine-substituted propyl group, and the number of -F in the fluorine-substituted methyl group, the fluorine-substituted ethyl group and the fluorine-substituted propyl group is independently 1, 2 or 3; the heteroatom in the heteroatom-containing C1-C6 alkane group is oxygen, and the number of oxygen in the heteroatom-containing C1-C6 alkane group is 1 or 2; The C2-C6 olefin group is vinyl, propenyl or butenyl; the halogen substituent of the C2-C6 olefin group is fluorine-substituted vinyl, fluorine-substituted propenyl or fluorine-substituted butenyl, and the number of -F in the fluorine-substituted vinyl, fluorine-substituted propenyl or fluorine-substituted butenyl is independently 1, 2 or 3; The C2-C6 alkynyl group is ethynyl, propynyl or butynyl; the halogen substituent of the C2-C6 alkynyl group is fluorine-substituted ethynyl, fluorine-substituted propynyl or fluorine-substituted butynyl, and the number of -F in the fluorine-substituted ethynyl, fluorine-substituted propynyl or fluorine-substituted butynyl is independently 1, 2 or 3; The sulfoxide group connected to a C1-C6 alkane group is a sulfoxide group connected to a methyl group, a sulfoxide group connected to an ethyl group, or a sulfoxide group connected to a propyl group; The five-membered heterocyclic aromatic hydrocarbon group is a substituted five-membered heterocyclic aromatic hydrocarbon group or an unsubstituted five-membered heterocyclic aromatic hydrocarbon group, the number of substituents in the substituted five-membered heterocyclic aromatic hydrocarbon group is 1 to 4, and the substituents in the substituted five-membered heterocyclic aromatic hydrocarbon group are selected from halogen groups, alkane groups, alkene groups or alkyne groups; the number of heteroatoms in the five-membered heterocyclic aromatic hydrocarbon group is 1 to 4; The heteroaromatic hydrocarbon in the heteroaromatic amine carbonyl group is a substituted five-membered heteroaromatic hydrocarbon, an unsubstituted five-membered heteroaromatic hydrocarbon group, a substituted six-membered heteroaromatic hydrocarbon or an unsubstituted six-membered heteroaromatic hydrocarbon group, the number of substituents in the substituted five-membered heteroaromatic hydrocarbon and the substituted six-membered heteroaromatic hydrocarbon is independently 1 to 4, and the substituents in the substituted five-membered heteroaromatic hydrocarbon and the substituted six-membered heteroaromatic hydrocarbon are independently selected from halogen groups, alkane groups, alkene groups or alkynyl groups; the number of heteroatoms in the heteroaromatic hydrocarbon in the heteroaromatic amine carbonyl group is 1 to 4.

4. The steroid compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate or isotope compound thereof according to any one of claims 1 to 3, characterized in that: The R1, R2, R3 and R4 are independently selected from -H, -F, -Cl, -Br, -I, -CN, -CH3, -CF3, -CH2OCH3, -NO2, -SO2CH3, -CH=CF2, -COOH, -CHF2, -CH2F, ethynyl, -OCH3, -CH=NOH, -CH=NOCH3, -CONH2, 5. The steroid compound, its pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate or isotope compound according to claim 4, characterized in that: Said R1, R2, R3 and R4 are not -H; Alternatively, one and only one of R1, R2, R3 and R4 is -H; Alternatively, only two of the R1, R2, R3 and R4 are -H; Alternatively, only three of R1, R2, R3 and R4 are -H; Alternatively, R1, R2, R3 and R4 are all -H.

6. The steroid compound, its pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate or isotope compound according to claim 5, characterized in that: The steroid compound is any one of the following compounds:

7. The method for preparing the steroid compound according to any one of claims 1 to 6, comprising the following steps: Compound BA, a pyrrolyl-containing compound, a base reagent and an organic solvent are mixed to carry out a substitution reaction to obtain a steroid compound having a structure shown in Formula I; The compound BA has a structure shown in formula II, and the pyrrolyl-containing compound has a structure shown in formula III: The R1, R2, R3 and R4 are as defined in Formula I.

8. A pharmaceutical composition, the active ingredient of which comprises one or more of the steroid compound according to any one of claims 1 to 6, and its pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, solvates and isotopic compounds.

9. Use of the steroid compound according to any one of claims 1 to 6, its pharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, solvate or isotope compound, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating mood disorders, mental illnesses, neurodegenerative diseases or neuropathic pain.

10. The use according to claim 9, characterized in that: The emotional disorders include generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, social anxiety disorder, premenstrual dysphoric disorder, major depression or postpartum depression; the psychiatric diseases include epilepsy, convulsions or insomnia; the neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, multiple sclerosis or Niemann-Pick type C disease; the neuropathic pain includes menstrual migraine, postmenopausal migraine, diabetic peripheral neuropathy, chemotherapy pain or sciatica.

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