CN113831381A - A steroid compound used to treat depression - Google Patents

Abstract

The present invention discloses a new compound represented by general formula 1, pharmaceutically acceptable salts, solvates and stereoisomers thereof including mixtures in various ratios and pharmaceutical compositions containing the compounds, R ₁ , R ₂ , R ₃ , R _4a , R _4b , R ₅ , R _6a , R _6b , R _6c , R _6d , R _6e , R _7a , R _7b , R _8a , R _8b , R _9a , R _9b , R _10a , R _10b , A ring and the like have the meanings given in the specification. The present invention also relates to the preparation method of such compounds, and also relates to the use of the stereoisomers of such compounds including their pharmaceutically acceptable salts, solvates, mixtures in various ratios, especially in the preparation of protective, Use in a medicament for the treatment, treatment or alleviation of depression.

Description

Steroid compound for treating depression

Technical Field

The invention relates to a novel compound, a pharmaceutically acceptable salt, a solvate, a stereoisomer containing a mixture in various proportions and a pharmaceutical composition containing the compound. The invention also relates to application of stereoisomers including pharmaceutically acceptable salts, solvates and mixtures in various proportions of the compounds, in particular to application in preparing medicaments for preventing, treating or relieving depression.

Background

Depression is a common and frequently occurring disease that endangers human health. In China, the incidence of affective disorder is 0.76%. The incidence of depression is high, but the cause of its onset is still not well understood at present. The antidepressant drugs which are currently used clinically and are more commonly used are: tricyclic and tetracyclic antidepressants, monoamine oxidase inhibitors, selective 5-HT reuptake inhibitors (SSRI), atypical antidepressants, lithium salts, and the like.

Disclosure of Invention

The invention aims to provide a sarsasapogenin and diosgenin derivative and a pharmaceutically acceptable salt thereof.

In a first aspect of the present invention, there is provided a compound represented by formula 1, or a pharmaceutically acceptable salt, solvate, optically pure isomer, stereoisomer or mixture thereof,

R₁selected from hydrogen, alkyl, substituted alkyl, NR_1aR_1b、NR_1bCOR_1a、NR_1bCONR_1aR_1cWherein R is_1a、R_1b、R_1cEach independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, R_1a、R_1bTogether with the atoms to which they are attached form a mono-or bicyclic or tricyclic, saturated or unsaturated, aromatic or non-aromatic heterocyclic ring having 1 to 4 atoms of N, O and/or S, which may be unsubstituted or mono-, di-, tri-or tetrasubstituted by: hydrogen, alkyl, substituted alkyl, halogen, cyano,

R₂selected from hydrogen, alkyl, substituted alkyl, halogen,

R₃selected from hydrogen, alkyl, halogen, substituted alkyl,

R_4a、R_4beach independently selected from hydrogen, alkyl, OR_4c、OCOR_4c、NR_4cR_4d、NR_4eCOR_4c、NR_4eCONR_4cR_4dOr R is_4a、R_4bCombined with the carbon to which it is attached to form a carbonyl group, R_4c、R_4d、R_4eEach independently selected from hydrogen, alkyl, substituted alkyl (e.g. -alkylene N (alkyl)₂) Alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or R_4c、R_4dTogether with the atoms to which they are attached form a saturated or unsaturated, aromatic or non-aromatic heterocyclic ring which may be unsubstituted or further mono-, di-or trisubstituted by: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycleA group, a substituted heterocyclic group, halogen, hydroxyl, alkoxy, amino, substituted amino, cyano, carboxyl, alkoxycarbonyl, aminoacyl, substituted aminoacyl, nitro,

R₅selected from the group consisting of hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, alkanoyloxy,

R_6a、R_6b、R_6c、R_6d、R_6e、R_6f、R_7a、R_7b、R_8a、R_8b、R_9a、R_9b、R_10a、R_10beach independently selected from none, hydrogen, halogen, hydroxy, or R_6a、R_6bBetween and/or R_7a、R_7bBetween and/or R_8a、R_8bBetween and/or R_9a、R_9bBetween and/or R_10a、R_10bThe two are combined into a carbonyl group,

ring A is a monocyclic or bicyclic or tricyclic, saturated or unsaturated, aromatic or nonaromatic heterocyclic ring having 1 to 4N, 0 to 4O and/or 0 to 4S atoms which may be unsubstituted or mono-, di-, tri-or tetrasubstituted by: halogen, nitro, cyano, N₃、B、OR₁₁、SR₁₁、NHR₁₁、N(R₁₁)₂、COR₁₁、SO₂NHR₁₁、SO₂N(R₁₁)₂、SONHR₁₁、SON(R₁₁)₂、COOR₁₁、CONHR₁₁、CON(R₁₁)₂、-OCOR₁₁、OCONHR₁₁、OCON(R₁₁)₂、NR₁₁COB、NBCOR₁₁、NR₁₁CONHB、NBCONHR₁₁、NR₁₁CON(B)₂、NBCON(R₁₁)₂、NR₁₁SO₂B or NBSO₂R₁₁Each substituent is independent of the other, R₁₁Is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic group, substituted heterocyclic group, B is a compound having 1-1Branched or unbranched alkyl of 0 carbon atoms, in which 0-4 CH₂The radicals being replaced by O or S atoms and/or-CH ═ CH-radicals, and/or 0 to 7H atoms being replaced by halogen, hydroxyl, amino,

represents a single bond or a double bond,

each independently represents a racemic, S or R configuration.

In another preferred embodiment, the compound of formula 1 has a structure represented by formula 2 or formula 3, or a pharmaceutically acceptable salt, solvate, optically pure isomer, stereoisomer or mixture thereof,

R₁₂selected from the group consisting of hydrogen, methyl, substituted methyl,

R₁₃selected from OR_14a、OCOR_14a、NR_14aR_14b、NR₁₅COR_14a、NR₁₅CONR_14aR_14b，R_14a、R_14b、R₁₅Each independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or R_14a、R_14bTogether with the atoms to which they are attached form a 4-to 7-membered saturated or unsaturated, aromatic or non-aromatic heterocyclic ring having 1 to 4N, 0 to 4O and/or 0 to 4S atoms, which may be unsubstituted or further mono-, di-or trisubstituted by: hydrogen, alkyl, substituted alkyl, halogen, hydroxy, alkoxy, cyano, carboxy,

X₁selected from N, CR_16a，R_16aSelected from the group consisting of hydrogen, alkyl, substituted alkyl, cyano, halogen, hydroxy, alkoxy, ammoniaA group, a substituted amino group, an aminocarbonyl group,

X₂selected from N, CR_16b，R_16bSelected from the group consisting of hydrogen, alkyl, substituted alkyl, cyano, halogen, hydroxy, alkoxy, amino, substituted amino, aminocarbonyl,

X₃selected from N, CR_16c，R_16cSelected from the group consisting of hydrogen, alkyl, substituted alkyl, cyano, halogen, hydroxy, alkoxy, amino, substituted amino, aminocarbonyl,

X₄selected from N, CR_16d，R_16dSelected from the group consisting of hydrogen, alkyl, substituted alkyl, cyano, halogen, hydroxy, alkoxy, amino, substituted amino, aminocarbonyl,

each independently represents a racemic, S or R configuration.

In another preferred embodiment, the substituted alkyl is-alkylene N (alkyl)₂E.g. -CH₂N (C1-C4 alkyl) (C1-C4 alkyl), -CH₂CH₂N (C1-C4 alkyl) (C1-C4 alkyl), -CH₂CH₂CH₂N (C1-C4 alkyl) (C1-C4 alkyl), etc. In another preferred embodiment, the compound of formula 2 has a structure represented by formula 4 or formula 5, or a pharmaceutically acceptable salt, solvate, optically pure isomer, stereoisomer or mixture thereof, and the compound of formula 3 has a structure represented by formula 6 or formula 7, or a pharmaceutically acceptable salt, solvate, optically pure isomer, stereoisomer or mixture thereof,

R_13aselected from OR_17a、OCOR_17a、NR_17aR_17b、NHCOR_17a、NHCONR_17aR_17b，R_17a、R_17bEach independently selected from hydrogen and alkylSubstituted alkyl, or R_17a、R_17bTogether with the atoms to which they are attached form a 4-to 7-membered saturated or unsaturated, aromatic or non-aromatic heterocyclic ring having 1 to 4N, 0 to 4O and/or 0 to 4S atoms, which may be unsubstituted or further mono-, di-or trisubstituted by: hydrogen, alkyl, substituted alkyl, halogen, hydroxy, alkoxy,

X₅selected from N, CR₁₈，R₁₈Selected from hydrogen, alkyl, substituted alkyl, cyano, halogen.

In another preferred embodiment, the compound is characterized in that:

definition of

The following are definitions of terms used in this specification. Unless otherwise indicated, the initial definitions of groups or terms provided herein apply to groups or terms in the present specification, individually or as part of other groups.

The term "substituted" refers to any of the substituents mentioned in the present specification, including, but not limited to, halogen, nitro, cyano, carboxy, oxo, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, hydroxyl, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkanoylamino, aroylamino, arylalkylacylamino, heteroarylalkylacylamino, aminoalkylacylamino, alkylaminoalkylacylamino, dialkylaminoalkylacylamino, alkylamino, arylamino, arylalkylamino, disubstituted amine (wherein the two amino substituents are selected from alkyl, aryl or arylalkyl), alkanoyl, oxo, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, hydroxy, alkoxy, aryloxy, aroyloxy, amino, acylamino, dialkylaminoalkyl, disubstituted amine (wherein the two amino substituents are selected from alkyl, aryl or arylalkyl), alkanoyl, amino, substituted amino, or substituted amino, or substituted amino, or substituted amino, or substituted amino, or substituted amino, or substituted, Substituted alkanoyl, aroyl, heteroaroyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, arylalkoxycarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, carbamoyl, substituted alkylcarbamoyl, amide, substituted amide, sulfonamide, substituted sulfonamide.

The term "halogen" or "halo" refers to fluorine, chlorine, bromine, iodine.

The term "alkyl" refers to a straight or branched chain unsubstituted hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms. Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, and the like. "alkylene" is obtained by removing two hydrogen atoms from a single carbon atom or from two carbon atoms of the alkane structure in question.

The term "substituted alkyl" refers to an alkyl group substituted with 1 to 4 substituents such as: halogen, nitro, cyano, carboxyl, oxo, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, hydroxyl, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine (wherein the two amino substituents are selected from alkyl, aryl or arylalkyl), alkanoyl, substituted alkanoyl, alkoxycarbonyl, arylalkoxycarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, carbamoyl, substituted carbamoyl, amide, substituted amide, sulfonamide, substituted sulfonamide.

The term "alkenyl" refers to a straight or branched hydrocarbon group having 2 to 20 carbon atoms, preferably 2 to 15 carbon atoms, most preferably 2 to 8 carbon atoms, and having 1 to 4 double bonds.

The term "substituted alkenyl" refers to alkenyl substituted with 1-2 substituents such as: halogen, nitro, cyano, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine (wherein the two amino substituents are selected from alkyl, aryl or arylalkyl).

The term "alkynyl" refers to a straight or branched hydrocarbon group having 2-20 carbon atoms, preferably 2-15 carbon atoms, most preferably 2-8 carbon atoms, and having 1-4 triple bonds.

The term "substituted alkynyl" refers to alkynyl groups substituted with substituents such as: halogen, nitro, cyano, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hydroxy, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine (wherein the two amino substituents are selected from alkyl, aryl or arylalkyl).

The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 12 carbon atoms in the ring portion. Aryl includes bicyclic groups, which bicyclic groups include rings fused to a saturated or partially unsaturated aromatic ring, or an aromatic carbocyclic or heterocyclic ring. Typical aryl groups include, but are not limited to, the following: benzene, naphthalene, anthracene, biphenyl, 1, 2-dihydronaphthalene, 1,2,3, 4-tetrahydronaphthyl, and the like.

The term "substituted aryl" refers to aryl substituted with 1 to 4 substituents, such as: halogen, nitro, cyano, ureido, carboxyl, trifluoromethoxy, trifluoromethyl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, hydroxyl, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine (wherein the two amino substituents are selected from alkyl, aryl or arylalkyl), alkanoyl, substituted alkanoyl, alkoxycarbonyl, arylalkoxycarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, carbamoyl, substituted carbamoyl, amide, substituted amide, sulfonamide, substituted sulfonamide.

The term "cycloalkyl" refers to a non-aromatic, saturated or partially unsaturated cyclic hydrocarbon group, which cycloalkyl group may be optionally substituted with one or more substituents described herein, having from 3 to 30 carbon atoms in a monocyclic ring, or from 7 to 12 carbon atoms in a bicyclic ring. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, cycloheptyl, cyclooctyl. Exemplary bridged bicyclic cycloalkyl groups include, but are not limited to, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane.

The terms "heterocycle", "heterocyclic" and "heterocyclyl" refer to an optionally substituted, fully saturated or unsaturated, aromatic or non-aromatic cyclic group, which may be, for example, a 4-7 membered monocyclic, 7-11 membered bicyclic, or 10-15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom containing ring. Each ring of the heteroatom-containing heterocyclic group may have 1,2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms. The "heterocyclic group" may be optionally substituted with one or more substituents described herein, and examples of the "heterocyclic group" include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholino, thiomorpholino, piperazinyl, homopiperazinyl, glycidylalkyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, azabicyclo [2.2.2] hexanyl, N-pyridylurea, pyrimidinonyl and 1, 1-dioxo-thiomorpholinyl.

The term "heteroaryl" refers to a monovalent aromatic group of a 5-, 6-, 7-, 8, 9, or 10-membered ring, and includes fused systems of 5-20 atoms containing one or more heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, which may be optionally substituted with one or more substituents described herein. Examples of "heteroaryl" include, but are not limited to, pyridyl, imidazolyl, imidazopyridyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, thiazolyl, quinolinyl, indolyl, and the like.

The term "oxo" represents a divalent radical ═ O.

The term "carbamoyl" refers to-OC (═ O) NH₂A group.

The term "amide" refers to-C (═ O) NH₂A group.

The term "sulfonamide" refers to-SO₂NH₂A group.

The terms "substituted carbamoyl", "substituted amide", "substituted sulfonamide" mean that the amide, sulfonamide or carbamate, respectively, has at least one hydrogen substituted with a group selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl.

The phrase "acceptable salt" refers to pharmaceutically acceptable organic or inorganic salts of the compounds of the present invention. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, acid sulfate, isonicotinate, lactate, salicylate, acid citrate, succinate, maleate, fumarate, gluconate, formate, methanesulfonate, and pamoate. An "acceptable salt" may be referred to as including another molecule such as a maleate salt or other counterion. The counterion stabilizes the charge in the parent compound. An "acceptable salt" may have more than one charged atom, and multiple charged atoms may have multiple counterions.

If the compound of the invention is a base, the desired "acceptable salt" may be prepared by a suitable method, for example, by treating the free base with the following mineral acid: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or with the following organic acids: acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, salicylic acid, pyranosidyl acids such as glucuronic acid or galacturonic acid, alpha-hydroxy acids such as citric acid or tartaric acid, amino acids such as glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, sulfonic acids such as methanesulfonic acid or p-toluenesulfonic acid.

If the compound of the invention is an acid, the desired "acceptable salt" may be prepared by a suitable method, for example, by treating the free acid with an inorganic or organic base as follows: amines, alkali metal hydroxides or alkaline earth metal hydroxides, and the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids, salts of primary, secondary and tertiary amines, and salts of cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

Solvates refers to conjugates or complexes of one or more solvent molecules with the compounds of the present invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine. The compounds of the present invention may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and thus the present invention is intended to include both solvated and unsolvated forms.

The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and hindered isomers, as well as mixtures thereof, e.g., racemic mixtures, will form part of the present invention. Herein, when the stereochemistry of any particular chiral atom is not determined, all stereoisomers are contemplated. Furthermore, the present invention relates to all geometric and positional isomers. The compounds of the present invention may exist in different tautomeric forms and all such forms are included within the scope of the present invention. All stereoisomers of the compounds of the present invention are intended to include mixtures or pure or substantially pure forms. The resolution can be carried out by physical methods such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography.

In another aspect of the present invention, there is provided a pharmaceutical mixture comprising two or more compounds of the compound of formula 1, or pharmaceutically acceptable salts, solvates, optically pure isomers, stereoisomers thereof.

Another aspect of the present invention provides a pharmaceutical composition comprising one or more of the compounds of formula 1 or pharmaceutically acceptable salts, solvates or isomers thereof, and a pharmaceutically acceptable carrier, diluent, excipient, adjuvant, vehicle or combination thereof. The compositions may also find use in food or health care products.

The pharmaceutical composition may comprise one or more compounds of formula 1, and may further comprise an additional therapeutic agent selected from the group consisting of: an antidepressant or a combination thereof.

Another aspect of the present invention provides the use of a compound of formula 1 as described for the preparation of a medicament for the prevention, treatment or alleviation of a disease, disorder or condition in a patient, which comprises administering to a mammal in need thereof an effective amount of a compound of the present invention, or stereoisomers, geometric isomers, tautomers, solvates and "acceptable salts" thereof. The disease, disorder or condition is depression.

Another aspect of the present invention provides the use of said compound of formula 1 for modulating GABA in a mammal in need thereof_AThe receptor is expressed.

Another aspect of the present invention provides the use of said compound of formula 1 for modulating NMDA receptor expression in a mammal in need thereof.

Another aspect of the invention provides the use of a pharmaceutical mixture or pharmaceutical composition comprising a compound of formula 1 as described for the manufacture of a medicament for the prevention, treatment or alleviation of a disease, disorder or condition in a patient. These pharmaceutical compositions comprise one or more of the compounds of formula 1, or a pharmaceutically acceptable salt, solvate, or isomer thereof, and a pharmaceutically acceptable carrier, diluent, excipient, adjuvant, vehicle, or combination thereof. The disease, disorder or condition is depression.

Another aspect of the present invention provides the use of a pharmaceutical mixture or pharmaceutical composition for modulating GABA in a mammal in need thereof_AThe receptor is expressed.

Another aspect of the invention provides the use of a pharmaceutical mixture or pharmaceutical composition for modulating NMDA receptor expression in a mammal in need thereof.

The compounds of the present invention may be used alone or in combination with other therapeutic agents. Combination therapy can provide a synergistic effect, i.e., the effect achieved when the active ingredients are used together is greater than the sum of the effects produced by the separate use of the compounds. The combination therapy may be administered in a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. The compounds may be administered together in a single pharmaceutical combination or separately and, when administered separately, may be administered simultaneously or sequentially in any order. The additional therapeutic agents include, but are not limited to, moclobemide, toloxatone, fluoxetine, paroxetine, citalopram, sertraline, venlafaxine, trimipramine, trazodone, imipramine, desipramine, clomipramine, amitriptyline, nortriptyline, doxepin, maprotiline, loxapine, amoxapine, mitrazine, or combinations thereof.

The compounds of the present invention may be administered by any route appropriate to the condition being treated. Suitable routes include, but are not limited to, oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal), vaginal, intraperitoneal, intrapulmonary and intranasal. It will be appreciated that the preferred route may vary, for example, depending on the condition of the patient. When the compound is administered orally, it may be formulated with a pharmaceutically acceptable carrier or excipient into pills, capsules, tablets, and the like. When the compound is formulated parenterally, it may be formulated with a pharmaceutically acceptable parenteral carrier.

The compounds of the invention may be administered in any convenient formulation, by "formulation" herein is meant a dosage form useful for administration (drug delivery) containing a compound of formula I of the invention, such as: but not limited to, aqueous solution injection, powder injection, pill, powder, tablet, patch, suppository, emulsion, cream, gel, granule, capsule, aerosol, spray, powder spray, sustained release agent, controlled release agent, etc. These pharmaceutical excipients may be those conventionally used in various formulations, such as: but are not limited to, isotonic agents, buffers, flavoring agents, excipients, fillers, binders, disintegrating agents, lubricants, and the like; it may also be selected for use in accordance with the substance, such as: the auxiliary materials can effectively improve the stability and solubility of the compounds contained in the composition or change the release rate, absorption rate and the like of the compounds, thereby improving the metabolism of the compounds in organisms and further enhancing the administration effect. In addition, specific administration purposes or modes may be achieved, such as: sustained release administration, controlled release administration, pulse administration, and the like, and used auxiliary materials such as: but are not limited to, gelatin, albumin, chitosan, polyether and polyester-based polymeric materials, such as: but are not limited to, polyethylene glycol, polyurethane, polycarbonate, copolymers thereof, and the like. The main indications of so-called "facilitated administration" are: but not only improving the treatment effect, improving the bioavailability, reducing the toxic and side effects, improving the compliance of patients and the like.

Detailed Description

In the following examples, only some of the examples of the present invention are given by way of illustration of the process of the present invention. However, these examples do not limit the scope of the present invention in any way, and simple modifications of the preparation process of the present invention based on the idea of the present invention are within the scope of the present invention as claimed. That is, while the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which can be used in the practice of the present invention.

In the examples described below, all temperatures are given in degrees celsius unless otherwise indicated. Unless otherwise indicated, reagents were purchased or custom-made from commercial suppliers, such as national medicine, Shaoyuan, Annaige, TCI, Sigma, and the like.

EXAMPLE 1 Synthesis of Compound S1 and Compound S2

Step 1: weighing 2g sarsasapogenin, adding 10ml acetic anhydride, 0.4ml pyridine and 260mg ammonium chloride, and refluxing and stirring at 150 deg.C for 7-8 h. After the reaction mixture was cooled to room temperature, 4ml of acetic acid, 4ml of dichloroethane and 0.5ml of water were added. Preparing an oxidizing solution: chromium trioxide (1.5 g), water (1.8 ml) and acetic acid (0.6 ml) were dissolved in water and cooled in an ice bath. Under the ice-bath condition, the oxidizing solution is slowly dripped into the reaction bottle, then the temperature is slowly raised to the room temperature, and the reaction is stirred for 1 hour. To the reaction mixture were added 1g of sodium chloride, 15ml of water and 0.2ml of methanol, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and dichloroethane was extracted 3 times (3X100ml), and the organic layer was separated and concentrated. 50ml of acetic acid was added to the dichloroethane concentrate, and the mixture was stirred under reflux at 150 ℃ for 3 to 4 hours. Cooling to room temperature, removing acetic acid under reduced pressure, adding dichloromethane to dilute the concentrate, washing with saturated sodium bicarbonate, washing with saturated brine, and drying with anhydrous sodium sulfate to obtain a crude product. The crude product was separated and purified by silica gel column chromatography eluting with dichloromethane: methanol 15:1, product 1g as white solid, 58% yield.

Step 2: substrate 1.1g (3.1mmol), cerous trichloride heptahydrate 1.7g (4.6mmol) were dissolved in 200ml of methanol. Under ice-bath, 230mg (6.1mmol) of sodium borohydride was added. The reaction was completed after 2 hours, and water was added to quench the reaction. Methanol was removed under reduced pressure, and extraction was performed with ethyl acetate to obtain 1.0g of a crude colorless oily liquid. Without work-up, 1.0g of crude product, 0.9g (6mmol) of TBSCl, 408mg (6mmol) of imidazole are dissolved in 10ml of DMF. The reaction was completed after 6 hours at room temperature. Water quenching, ethyl acetate extraction, silica gel column with petroleum ether: the product was isolated with 70:1 eluent as ethyl acetate to give 1.4g of a colorless oily liquid, 96.0% overall yield over two steps.

And 3, step 3: substrate 1.4g (2.9mmol), sodium hydroxide 350mg (8.8mmol) are dissolved in 20ml of methanol and 5ml of water are added. Refluxing at 70 deg.C for 6 hr to complete the reaction, removing methanol under reduced pressure, and extracting with dichloromethane. Silica gel column with petroleum ether: the product was isolated with 15:1 eluent as ethyl acetate to give 0.9g of white solid in 70.3% yield.

And 4, step 4: 300mg (0.69mmol) of substrate, 365g (1.39mmol) of triphenylphosphine and 205mg (1.39mmol) of phthalimide are dissolved in 10ml of dichloromethane. 0.28ml diisopropyl azodicarboxylate (1.39mmol) was added dropwise under nitrogen protection in an ice bath. The reaction was completed overnight at room temperature. The reaction solution was spin-dried under reduced pressure, and the mixture was purified by silica gel column with petroleum ether: separation with 100:1 eluent gave the product as a white solid 200mg, 51.3% yield.

And 5, step 5: 200mg (0.36mmol) of the obtained product was suspended in 5ml of anhydrous ethanol, 0.11ml (1.8mmol) of 80% hydrazine hydrate was added, and the mixture was refluxed at 80 ℃ for 3 hours. After completion of the reaction, the reaction mixture was spin-dried under reduced pressure, dissolved in 20ml of methylene chloride, and filtered to remove flocculent insoluble matter. The filtrate was concentrated, purified by silica gel column with dichloromethane: methanol 15:1 eluent separation gave the product as a white solid 90mg, 58.8% yield.

And 6, step 6: substrate (1.0eq), dissolved in pyridine (0.1M), was added acetic anhydride (5.0 eq). Stir at rt for 3h, remove solvent under reduced pressure, dissolve the residue with DCM, wash with 1M HCl, saturated sodium bicarbonate, and saturated sodium chloride. Silica gel column with dichloromethane: the product was obtained as a white solid with 70% yield by eluting with methanol at 200: 1.

And 7, step 7: the substrate (1.0eq) was 80mg (0.14mmol), tetrabutylammonium fluoride (3.0eq), dissolved in tetrahydrofuran (0.03M) and refluxed at 70 ℃ for 6 hours. The reaction was complete, quenched with water and extracted with dichloromethane to give the crude product as a white solid, 64 mg. Without further treatment, DMP oxidant (1.5eq), sodium bicarbonate (5.0eq) were dissolved in dichloromethane (0.1M), stirred at room temperature for 0.5 h, and a solution of the crude product from the previous step in dichloromethane was added. After stirring at room temperature for 2 hours, the reaction was completed, and saturated sodium bicarbonate: saturated sodium thiosulfate in 1:1 aqueous solution was quenched and extracted with dichloromethane. Silica gel column with dichloromethane: the product was obtained as a white solid with an eluent separation of methanol 100:1, overall yield of two steps 65%.

And 8, step 8: the substrate (1.0eq), nitrogen heterocycle (2.0eq), cesium carbonate (2.0eq) were dissolved in DMF (0.05M) and reacted at room temperature overnight under nitrogen. The reaction was completed, quenched with water and extracted with ethyl acetate. Silica gel column with dichloromethane: methanol-50: 1 eluent separation gave compound S1 and compound S2.

EXAMPLE 2 Synthesis of Compound 1

Compound S1(120mg, 0.28mmol) was dissolved in 5ml of methanol, and sodium borohydride (21mg, 0.56mmol) was added in portions under ice-bath, followed by reaction at room temperature for 2 h. TLC monitored the reaction was complete, quenched with water, rotary evaporated to remove methanol, the aqueous phase was extracted 3 times with ethyl acetate (3X10ml), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was separated and purified by silica gel column chromatography eluting with dichloromethane: methanol 100:1, the product was 100mg of white solid, 83% yield of compound 1.

¹H NMR(400MHz,CDCl₃)δ7.51(s,1H),7.41(s,1H),6.23(s,1H),5.52(d,J＝10.2Hz,1H),4.40(t,J＝9.1Hz,1H),3.93(dq,J＝12.3,6.1Hz,1H),3.85–3.71(m,1H)，2.22(t,J＝8.4Hz,1H),1.97(s,3H),0.94(s,3H),0.92(d,J＝6.2Hz,3H),0.88(s,3H).

¹³C NMR(101MHz,CDCl₃)δ169.57,139.16,128.54,105.31,68.97,64.01,63.46,54.14,49.40,44.13,42.35,40.67,40.09,35.89,35.34,35.17,34.58,33.78,27.98,26.88,26.25,23.73,23.55,22.91,20.60,13.77.

HRMS(ESI+):calcd for C₂₆H₄₂N₃O₂[M+H]⁺,428.3272；found:428.3274.

EXAMPLE 3 Synthesis of Compound 9

Compound S2(120mg, 0.28mmol) was dissolved in 5ml of methanol, and sodium borohydride (21mg, 0.56mmol) was added in portions under ice-bath, followed by reaction at room temperature for 2 h. TLC monitored the reaction was complete, quenched with water, rotary evaporated to remove methanol, the aqueous phase was extracted 3 times with ethyl acetate (3X10ml), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was separated and purified by silica gel column chromatography eluting with dichloromethane: methanol 100:1, the product was 100mg of white solid, compound 9 yield 75%.

¹H NMR(400MHz,CDCl₃)δ8.27(s,1H),7.99(s,1H),5.40(d,J＝8.1Hz,1H),4.54(t,J＝8.9Hz,1H),4.05–3.88(m,1H),3.85-3.66(m,1H),1.97(s,3H),0.95(d,J＝7.4Hz,3H),0.94(s,3H),0.89(s,3H).

¹³C NMR(101MHz,DMSO)δ167.90,151.49,143.35,66.84,63.19,60.05,53.45,48.13,43.75,41.83,40.08,35.64,34.97,34.52,34.13,32.84,27.27,26.54,26.03,23.26,22.83,20.07,13.16.

HRMS(ESI+):calcd for C₂₅H₄₁N₄O₂[M+H]⁺,429.3224；found:429.3230.

EXAMPLE 4 Synthesis of Compounds 10-14

Weighing 700mg of compound S2, adding 40ml of anhydrous methanol for dissolving, adding NHR_17aR_17b(2eq) and acetic acid (0.2eq) were stirred at room temperature for 1h, sodium cyanoborohydride (1.5eq) was added and stirring continued for 24h, and the plates were spottedThe reaction was followed to completion. And (3) removing the solvent by spinning out under reduced pressure, adding DCM and water into the residue, separating an organic layer, extracting a water layer by using DCM, combining the organic layers, washing by using NaOH aqueous solution, washing by using saturated sodium chloride, drying by using anhydrous sodium sulfate, spinning out the organic solvent under reduced pressure, and separating the crude product by silica gel column chromatography to obtain the target compound.

EXAMPLE 5 Synthesis of Compound 15

700mg of compound S2 was weighed, 40ml of absolute methanol was added to dissolve it, ammonium acetate (8eq) was added and stirred at room temperature for 1h, sodium cyanoborohydride (1.5eq) was added and stirring was continued for 24h, and the reaction was followed by spotting. And (3) removing the solvent by spinning out under reduced pressure, adding DCM and water into the residue, separating an organic layer, extracting a water layer by using DCM, combining the organic layers, washing by using NaOH aqueous solution, washing by using saturated sodium chloride, drying by using anhydrous sodium sulfate, spinning out the organic solvent under reduced pressure, and separating the crude product by silica gel column chromatography to obtain the target compound.

EXAMPLE 6 Synthesis of Compounds 16-18

Weighing triphosgene (1mmol) and dissolving in 60ml DCM, dissolving compound 15(1mmol) in 30ml DCM, slowly dropping into the reaction system, dissolving triethylamine (2.2mmol) in 30ml DCM, slowly dropping into the reaction system, removing solvent under reduced pressure, dissolving the residue in DCM60ml, and dissolving amine compound NHR_17aR_17b(2mmol) in 30ml DCM was slowly added dropwise to the reaction system overnight. Washed with 1M hydrochloric acid, saturated sodium bicarbonate, saturated sodium chloride and dried over anhydrous sodium sulfate. Separating by silica gel column chromatography to obtain the target compound.

EXAMPLE 7 Synthesis of Compounds 16-18

Example 7 Tail Suspension Test (TST) examination of antidepressant Activity of Compounds of the invention

Male ICR mice, weighing 20 + -2 g, were selected for the experiment, purchased from the center of the Chinese academy of sciences, and were allowed to ingest water ad libitum at room temperature (23 + -2). degree.C. All mice were randomly divided into blank control and experimental groups of 10 mice each, 5 mice per cage, and the experiment was started after 3 days of acclimation in the breeding environment. The specific administration method is intragastric administration, and a group of blank control groups is administered with physiological saline with the same volume.

The method comprises the following specific operations: the dosing was continued for 6 days and the test was performed 1 hour after the last dose. Adhering the tail of the mouse to a horizontal bar at a position 2 cm away from the tail tip by using an adhesive tape, isolating the sight lines of the animal by plates at the periphery, keeping the horizontal bar at a position 25 cm away from the ground, keeping the distance between the mouse and the ground at about 10 cm, timing for 6min, recording the cumulative motionless time within 4 min, and operating all groups of mice in parallel.

And (3) processing experimental data: the results are expressed as mean ± standard error (x ± SD). And (4) carrying out statistical analysis by adopting a t test to judge whether the significance is significant (P is less than 0.05, which indicates that the statistics have significant difference).

TABLE 1 influence of Sarsasapogenin and diosgenin on immobility time in ICR mouse tail suspension experiment

P <0.01 and P <0.05 vs blank group

The experimental result shows that compared with the blank group, the sarsasapogenin and the diosgenin existing in the nature can not obviously reduce the mouse tail suspension immobility time on a mouse tail suspension model under the administration dosage of 30mg/kg, and has no statistically significant difference.

Example 8 Forced Swim Test (FST) examination of antidepressant Activity of Compounds of the invention

Male ICR mice, weighing 20 + -2 g, were selected for the experiment, purchased from the center of the Chinese academy of sciences, and were allowed to ingest water ad libitum at room temperature (23 + -2). degree.C. All mice were randomly divided into blank control and experimental groups of 10 mice each, 5 mice per cage, and the experiment was started after 3 days of acclimation in the breeding environment. The specific administration method is intragastric administration, and a group of blank control groups is administered with physiological saline with the same volume.

The method comprises the following specific operations: the dosing was continued for 6 days and the test was performed 1 hour after the last dose. The mice are independently placed into a cylindrical glass jar with the height of 20 cm and the diameter of 14 cm, the depth of water in the jar is 10 cm, and the water temperature is 23-25 ℃. The time was measured 6 minutes after the mouse was submerged and the cumulative immobility time was recorded for 4 minutes later (criterion of immobility: the mouse stopped struggling in water, or in a floating state with only small limb movements to keep the head floating on the water). Groups of mice were operated in parallel.

And (3) processing experimental data: the results are expressed as mean ± standard error (x ± SD). And (4) carrying out statistical analysis by adopting a t test to judge whether the significance is significant (P is less than 0.05, which indicates that the statistics have significant difference).

EXAMPLE 9 bioavailability study of Compounds of the invention

The specific experimental steps are as follows: healthy male SD rats weighing about 270g were fasted for 10h before administration and had free access to water. The compound of the invention (CMC-Na solvent suspension) is perfused, the dosage is 100mg/kg rat body weight, the time point of orbital blood collection is 30min after administration, 1h,2h,4h,6h,8h,10h,24h and 48h (n is 5). C-49 (10% ethanol/15% tween 80/75% normal saline solution) was injected into tail vein at a dose of 1mg/kg rat body weight, and the time points for orbital bleeding were 5min,10min,30min,1h,2h,4h, and 8h (n ═ 4). The plasma was placed in a heparin-coated centrifuge tube and centrifuged for 10min (8000r) before taking the supernatant. Storing in a refrigerator at-80 deg.C. After acetonitrile precipitation treatment, HPLC-QQQ is used for detection. Pharmacokinetic parameters PK parameters were calculated for each mouse by a non-compartmental model of WinNonlin (Pharsight 6.2, NC, USA). All parameters are expressed as Mean ± s.d. Bioavailability (F) ═ AUC oral/Dose oral)/(AUC tail vein/Dose tail vein)

In nature, the steroid molecular skeleton has a certain depression resistance tendency, the depression resistance activity is poor, and the bioavailability is low. The neurosteroid derivative design strategy reported in the literature at present is to introduce polar groups such as hydroxyl, heterocycle and the like into the C-21 position on the basis of reserving the 3-position hydroxyl, so as to improve the solubility of the neurosteroid derivative, improve the pharmacological activity such as anti-epilepsy and the like, improve the bioavailability and the like. The invention modifies the structure of the natural product smilagenin, and 3 alpha-acetamido substitution and 16-position N-containing heteroaryl substitution steroid derivatives are obtained on the steroid skeleton of the smilagenin, and the differences from the C-21 position introduced heterocyclic ring reported in the literature and the 3-position introduced acetamido. Pharmacological screening results also show that the antidepressant activity and bioavailability are remarkably improved compared with the lead compound smilagenin.

EXAMPLE 10 NMDA receptor Activity Studies of Compounds of the invention

And (3) separating and culturing Xenopus laevis oocytes: collecting mature female Xenopus laevis, anesthetizing with 0.17% tricaine solution, and surgically collecting ovum, ND-96 solution (NaCl 96.0mmol/L, KCl 2.0mmol/L, CaCl)₂ 1.8mmol/L，MgCl₂1.0mmol/L, HEPES 5.0mmol/L), and transferred to a digestion solution containing collagenase I-A (0.25mg/mL) for digestion. Removing the filter membrane after the cells are basically dispersed, and using OR-2 solution (NaCl 82.5mmol/L, KCl 2.5mmol/L, MgCl)₂1.0mmol/L, HEPES 5.0mmol/L) 2 times, and placed in a petri dish containing a solution of gentamicin (0.1mg/mL) in ND-96, in a biochemical incubator at 18 ℃.

Microinjection of xenopus oocytes: cells after overnight culture were removed, oocytes in V-VI stage were selected under microscope for microinjection, mineral oil was poured, 1. mu.L of mixed mRNA mixture was aspirated, and about 50nL was injected per cell. The injected oocyte is placed in ND-96 solution containing gentamicin (0.1mg/mL), and detection is started after 48 hours of culture at 18 ℃, and the solution needs to be changed in the culture process.

Whole cell patch clamp recordings of xenopus oocytes: oocytes 48h after microinjection were placed in a recording bath and perfused with extracellular fluid (NaCl 116.0mmol/L, KCl 2.0mmol/L, BaCl) at 2mL/min₂0.3mmol/L, HEPES 5.0 mmol/L). The glass electrode is drawn into a tip with the diameter of 1-2 mu M by using a micro-motor drawing instrument, the resistance is 0.5-5M omega, 3mmol/L KCl is filled as electrode inner liquid, a double-electrode voltage clamp mode is adopted, the clamping voltage is set to-60 mV, the whole-cell current is recorded, and the experimental temperature is controlled at 25 ℃.

The compounds of the present invention can be used to modulate NMDA receptor expression in a mammal in need thereof.

EXAMPLE 11 Compounds of the invention GABA_AExamination of receptor Activity

LTK cells stably transfected alpha to GABA receptors by the Lipofecatamine method₁β₂γ₂Subunit, CHO cells only transiently transfected with alpha₄β₃A delta subunit. Cells were passaged at approximately 50-80% confluence and then seeded into 35mm sterile petri dishes containing 2ml of antibiotic or antifungal drug free medium.

All test electrolytes contained: NaCl 137mM, KCl 4mM, CaCl₂ 1.8mM,MgCl₂1mM, HEPES 10mM, D-Glucose 10mM, pH (NaOH) 7.4. Intracellular (pipette) solutions contain: KCl 130mM, MgCl₂1mM, Mg-ATP 5mM, HEPES 10mM, EGTA 5mM, pH 7.2. During the experiment, the cells and solution were kept at room temperature (20 ℃ to 25 ℃). For manual patch clamp recordings, the cell culture dish was placed on the dish holder of the microscope and the whole cell was recorded with continuous lavage (1ml/min) with electrolyte.

The compounds of the present invention can be used to modulate GABA in a mammal in need thereof_AThe receptor is expressed.

Claims (10)

1. A compound represented by formula 1, or a pharmaceutically acceptable salt, solvate, optically pure isomer, stereoisomer or mixture thereof,

R₁selected from hydrogen, alkyl, substituted alkyl, NR_1aR_1b、NR_1bCOR_1a、NR_1bCONR_1aR_1cWherein R is_1a、R_1b、R_1cEach independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted ringAlkyl, heterocyclic, substituted heterocyclic, R_1a、R_1bTogether with the atoms to which they are attached form a mono-or bicyclic or tricyclic, saturated or unsaturated, aromatic or non-aromatic heterocyclic ring having 1 to 4 atoms of N, O and/or S, which may be unsubstituted or mono-, di-, tri-or tetrasubstituted by: hydrogen, alkyl, substituted alkyl, halogen, cyano,

R₂selected from hydrogen, alkyl, substituted alkyl, halogen,

R₃selected from hydrogen, alkyl, halogen, substituted alkyl,

R_4a、R_4beach independently selected from hydrogen, alkyl, OR_4c、OCOR_4c、NR_4cR_4d、NR_4eCOR_4c、NR_4eCONR_4cR_4dOr R is_4a、R_4bTogether with the atom to which they are attached form a carbonyl group, R_4c、R_4d、R_4eEach independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or R_4c、R_4dTogether with the atoms to which they are attached, form a saturated or unsaturated, aromatic or non-aromatic heterocyclic ring which is unsubstituted or further mono-, di-or trisubstituted by: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, halogen, hydroxy, alkoxy, amino, substituted amino, cyano, carboxy, alkoxycarbonyl, aminoacyl, substituted aminoacyl, nitro,

R₅selected from the group consisting of hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, alkanoyloxy,

R_6a、R_6b、R_6c、R_6d、R_6e、R_7a、R_7b、R_8a、R_8b、R_9a、R_9b、R_10a、R_10beach independently selected from none, hydrogen, halogen, hydroxy, or R_6a、R_6bBetween and/or R_7a、R_7bBetween and/or R_8a、R_8bBetween and/or R_9a、R_9bBetween and/or R_10a、R_10bThe two are combined into a carbonyl group,

ring A is a monocyclic or bicyclic or tricyclic, saturated or unsaturated, aromatic or nonaromatic heterocyclic ring having 1 to 4N, 0 to 4O and/or 0 to 4S atoms which is unsubstituted or mono-, di-, tri-or tetrasubstituted by: halogen, nitro, cyano, N₃、B、OR₁₁、SR₁₁、NHR₁₁、N(R₁₁)₂、COR₁₁、SO₂NHR₁₁、SO₂N(R₁₁)₂、SONHR₁₁、SON(R₁₁)₂、COOR₁₁、CONHR₁₁、CON(R₁₁)₂、-OCOR₁₁、OCONHR₁₁、OCON(R₁₁)₂、NR₁₁COB、NBCOR₁₁、NR₁₁CONHB、NBCONHR₁₁、NR₁₁CON(B)₂、NBCON(R₁₁)₂、NR₁₁SO₂B or NBSO₂R₁₁Each substituent is independent of the other, R₁₁Is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, B is a branched or unbranched alkyl group having 1-10 carbon atoms, wherein 0-4 CH₂The radicals being replaced by O or S atoms and/or-CH ═ CH-radicals, and/or 0 to 7H atoms being replaced by halogen, hydroxyl, amino,

represents a single bond or a double bond,

each independently represents a racemic, S or R configuration.

2. The compound of claim 1, wherein the compound of formula 1 has a structure represented by formula 2 or formula 3, or a pharmaceutically acceptable salt, solvate, optically pure isomer, stereoisomer, or mixture thereof,

R₁₂selected from the group consisting of hydrogen, methyl, substituted methyl,

R₁₃selected from OR_14a、OCOR_14a、NR_14aR_14b、NR₁₅COR_14a、NR₁₅CONR_14aR_14bWherein R is_14a、R_14b、R₁₅Each independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or R_14a、R_14bTogether with the atoms to which they are attached form a 4-to 7-membered saturated or unsaturated, aromatic or non-aromatic heterocyclic ring having 1 to 4N, 0 to 4O and/or 0 to 4S atoms, which may be unsubstituted or further mono-, di-or trisubstituted by: hydrogen, alkyl, substituted alkyl, halogen, hydroxy, alkoxy, cyano, carboxy,

X₁selected from N, CR_16a，R_16aSelected from the group consisting of hydrogen, alkyl, substituted alkyl, cyano, halogen, hydroxy, alkoxy, amino, substituted amino, aminocarbonyl,

X₂selected from N, CR_16b，R_16bSelected from the group consisting of hydrogen, alkyl, substituted alkyl, cyano, halogen, hydroxy, alkoxy, amino, substituted amino, aminocarbonyl,

X₃selected from N, CR_16c，R_16cSelected from the group consisting of hydrogen, alkyl, substituted alkyl, cyano, halogen, hydroxy, alkoxy, amino, substituted amino, aminocarbonyl,

X₄selected from N, CR_16d，R_16dSelected from the group consisting of hydrogen, alkyl, substituted alkyl, cyano, halogen, hydroxy, alkoxy, amino, substituted amino, aminocarbonyl,

each independently represents a racemic, S or R configuration.

3. The compound of claim 2, wherein the compound of formula 2 has a structure represented by formula 4 or formula 5, or a pharmaceutically acceptable salt, solvate, optically pure isomer, stereoisomer, or mixture thereof,

R_13aselected from OR_17a、OCOR_17a、NR_17aR_17b、NHCOR_17a、NHCONR_17aR_17b，R_17a、R_17bEach independently selected from hydrogen, alkyl, substituted alkyl, or R_17a、R_17bTogether with the atoms to which they are attached form a 4-to 7-membered saturated or unsaturated, aromatic or non-aromatic heterocyclic ring having 1 to 4N, 0 to 4O and/or 0 to 4S atoms, which may be unsubstituted or further mono-, di-or trisubstituted by: hydrogen, alkyl, substituted alkyl, halogen, hydroxy, alkoxy, X₅Selected from N, CR₁₈，R₁₈Selected from hydrogen, alkyl, substituted alkyl, cyano, halogen.

4. The compound of claim 2, wherein the compound of formula 3 has a structure represented by formula 6 or formula 7, or a pharmaceutically acceptable salt, solvate, optically pure isomer, stereoisomer, or mixture thereof,

R_13aselected from OR_17a、OCOR_17a、NR_17aR_17b、NHCOR_17a、NHCONR_17aR_17b，R_17a、R_17bEach independently selected from hydrogen, alkyl, substituted alkyl, or R_17a、R_17bTogether with the atoms to which they are attached form a 4-to 7-membered saturated or unsaturated, aromatic or non-aromatic heterocyclic ring having 1 to 4N, 0 to 4O and/or 0 to 4S atoms, which may be unsubstituted or further mono-, di-or trisubstituted by: hydrogen, alkyl, substituted alkyl, halogen, hydroxy, alkoxy, X₅Selected from N, CR₁₈，R₁₈Selected from hydrogen, alkyl, substituted alkyl, cyano, halogen.

5. The compound of any one of claims 1-4, wherein the compound is:

6. a pharmaceutical mixture comprising two or more compounds selected from the group consisting of: the compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, optically pure isomer, stereoisomer thereof.

7. A pharmaceutical composition comprising a compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, optically pure isomer or stereoisomer thereof, or a pharmaceutical mixture of claim 6; and a pharmaceutically acceptable carrier.

8. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, optically pure isomer or stereoisomer thereof, a pharmaceutical mixture according to claim 6, or a pharmaceutical composition according to claim 7, for the manufacture of a medicament for the prevention, treatment or alleviation of a disease, disorder or condition of a patient which is depression.

9. Use of a compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, optically pure isomer or stereoisomer thereof, a pharmaceutical mixture of claim 6, or a pharmaceutical composition of claim 7, for modulating GABA in a mammal in need thereof_AThe receptor is expressed.

10. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, optically pure isomer or stereoisomer thereof, a pharmaceutical mixture according to claim 6, or a pharmaceutical composition according to claim 7, for modulating NMDA receptor expression in a mammal in need thereof.