Neurosteroid derivatives and their uses

Abstract

The present invention provides a neurosteroid derivative having the structure shown in formula (I) and uses thereof. The neurosteroid derivative having the structure shown in formula (I) provided by the present invention has significantly higher bioavailability than the prior art and can be administered via a non-intravenous route for the treatment and / or prevention of GABA-A receptor-mediated diseases. [C14] TIFF2026501665000029.tif46149

Description

[Technical Field]

[0001] The present invention relates to the field of medicinal chemistry, and in particular to neurosteroid derivatives and their medical uses. [Background technology]

[0002] GABA (γ-aminobutyric acid) is the major neurotransmitter in the central nervous system. It exerts physiological effects by increasing the flow of ions across neuronal membranes via the downstream ion channel GABA-A receptor. The active site of the GABA-A receptor can bind GABA and many drugs, including muscimol, gaboxadol, and bicuculline. There are many isomeric modulators that can indirectly modulate GABA-A receptor activity, including benzodiazepines, barbiturates, and inhaled anesthetics.

[0003] Neurosteroids are steroid hormone derivatives that do not have hormonal effects, but can affect neuronal excitability by modulating ionotropic receptors and bind to GABA-A receptors. Dehydroepiandrosterone, progesterone, and their metabolites can regulate the expression of GABA-A receptor subunits through genetic mechanisms, thereby affecting neurotransmitters. Neurosteroids have fewer subunit restrictions and a broader range of applications than benzodiazepines. Neurosteroid drugs targeting GABA-A receptors currently in development and / or under development include allopregnanolone, ganaxolone, antasidone, and alphadolone.

[0004] Allopregnanolone, also known as 5α-pregnan-3α-ol-20-one, is an endogenous inhibitory pregnane neurosteroid. The effects of allopregnanolone are similar to those of other positive allosteric modulators of GABA action at GABA-A receptors, such as benzodiazepines. Endogenously produced allopregnanolone plays an important neurophysiological role by fine-tuning GABA-A receptors and modulating the effects of multiple positive allosteric modulators and agonists at GABA-A receptors.

[0005] Ganaxolone, also known as 3α-hydroxy-3-methyl-5α-pregnan-20-one, is a synthetic neurosteroid analogue that acts as a positive allosteric modulator of GABA-A receptors. Ganaxolone shows promise for the treatment of temporal lobe seizures and catamenial epilepsy. Ganaxolone is also being investigated for the treatment of post-traumatic stress disorder, fragile X syndrome, neuropathic headache, neonatal seizures, and postpartum depression. Ganaxolone is approved by the U.S. FDA for the treatment of protocadherin 19 gene (PCDH19)-mediated female epilepsy and is well tolerated in adults and children.

[0006] GABA-A receptor positive allosteric modulators, such as allopregnanolone and ganaxolone, have drawbacks, such as low water solubility and poor metabolic stability, resulting in insufficient drug bioavailability in the human body and limiting their clinical application. Currently, structural modifications of GABA-A receptor positive allosteric modulators, such as allopregnanolone and ganaxolone, primarily focus on improving water solubility to promote drug absorption and improve bioavailability and pharmacokinetic properties. For example, Patent Document 1 discloses water-soluble allopregnanolone derivatives and their uses. The water-soluble allopregnanolone derivatives have good physical and chemical stability and water solubility, and are rapidly degraded in plasma to release the active drug (allopregnanolone), thereby rapidly exerting their pharmacological effects. In some cases, the structure of GABA-A receptor positive allosteric modulators has been modified to reduce their metabolic rate, enabling oral administration. For example, Patent Document 2 discloses a novel GABA-A receptor modulator that reduces the metabolic rate of the compound by introducing an aromatic or heteroaromatic group next to the 20-carbonyl group of allopregnanolone, thereby maintaining good biological activity and enabling oral administration. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] CN108148106A [Patent Document 2] CN109503694A Summary of the Invention [Problem to be solved by the invention]

[0008] Currently, there is an urgent clinical need for GABA-A receptor modulators with excellent bioavailability, particularly metabolic stability in vivo. The objective of the present invention is to discover drugs with excellent bioavailability in vivo, particularly metabolic stability in vivo, by modifying the structures of existing neurosteroid drugs. [Means for solving the problem]

[0009] In one aspect, the present invention provides a compound of formula (I): [ka] or stereoisomers, tautomers, isotopically enriched analogs, solvates, and pharmaceutically acceptable salts thereof, wherein R1 and R2 are as defined herein.

[0010] In one aspect, the present invention provides methods for preparing compounds of formula (I) or stereoisomers, tautomers, isotopically enriched analogs, solvates and pharmaceutically acceptable salts thereof.

[0011] In another aspect, the present invention provides a pharmaceutical composition for treating and / or preventing a central nervous system disorder, comprising a compound having the structure shown in Formula (I) or a stereoisomer, tautomer, isotopically enriched analogue, solvate, pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0012] In another aspect, the present invention also provides the use of a compound having the structure shown in Formula (I) or a stereoisomer, tautomer, isotopically enriched analogue, solvate, or pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and / or prevention of a central nervous system disorder.

[0013] In yet another aspect, the present invention also provides a method for treating and / or preventing a central nervous system disorder, comprising administering to an individual in need thereof a therapeutically effective amount of a compound having the structure shown in Formula (I) or a stereoisomer, tautomer, isotopically enriched analog, solvate, or pharmaceutically acceptable salt thereof. [Effects of the Invention]

[0014] As a beneficial effect, compared to the prior art, the compounds of the present invention or their stereoisomers, tautomers, isotopically enriched analogues, solvates and pharmaceutically acceptable salts exhibit significantly superior pharmacokinetic properties, particularly in vivo metabolic stability, and can be administered non-intravenously for the treatment of various central nervous system disorders. [Brief explanation of the drawings]

[0015] The drawings are used for further understanding of the present invention and constitute a part of the specification, and are used to explain the present invention together with the embodiments of the present invention, but are not intended to limit the present invention.

[0016] [Figure 1] The modulatory effect of Compound 1 of the present invention on GABA-A (α4β3δ) receptors was demonstrated. DETAILED DESCRIPTION OF THE INVENTION

[0017] definition As used herein, the following words and phrases generally have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0018] As used herein, the term "alkyl group" refers to a monovalent branched or unbranched saturated hydrocarbon chain having 1 to 12 carbon atoms (more typically 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 6 carbon atoms). The term includes methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 1-butyl (n-butyl), 2-methyl-1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (tert-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-propyl, 2-methyl-2 ... butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl, 1-nonyl, 1-decyl, and the like.

[0019] As used herein, the term "alkenyl group" refers to a monovalent linear or branched unsaturated hydrocarbon group having a designated number of carbon atoms (e.g., 2 to 12 carbon atoms, 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 to 6 carbon atoms, etc.) and having one, two, or three carbon-carbon double bonds. In some embodiments, examples of alkenyl groups include, but are not limited to, vinyl groups (i.e., -CH=CH), propen-1-yl (i.e., -CH=CHCH), propen-3-yl (or allyl groups, i.e., -CHCH=CH), propen-2-yl (i.e., -C(CH)=CH), butadienyl groups (including 1,2-butadienyl and 1,3-butadienyl groups), and the like.

[0020] As used herein, the term "alkynyl group" refers to a monovalent, linear or branched, unsaturated hydrocarbon group having a designated number of carbon atoms (e.g., 2 to 12 carbon atoms, 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 to 6 carbon atoms, etc.) and having one, two, or three carbon-carbon triple bonds. In some embodiments, examples of alkynyl groups include, but are not limited to, ethynyl groups (i.e., -C≡CH), propargyl groups (i.e., -CHC≡CH), propynyl groups (i.e., -C≡CCH), and the like.

[0021] As used herein, the term "cycloalkyl group" refers to a monovalent saturated carbocyclic group having a single ring or multiple fused or bridged rings, of 3 to 12 carbon atoms (more typically 3 to 10 carbon atoms, 3 to 8 carbon atoms, or 3 to 6 carbon atoms). In some embodiments, cycloalkyl groups include monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, or polycyclic structures such as adamantyl and bicyclo[2.2.1]heptanyl, or cycloalkyl groups fused to aryl groups such as indan, where the point of attachment is through the cycloalkyl group.

[0022] As used herein, the term "aryl" refers to an aromatic carbocyclic group of 6 to 14 carbon atoms (more typically 6 to 10 carbon atoms, or 6 carbon atoms) having a single ring (e.g., phenyl) or multiple rings (e.g., biphenyl) or multiple condensed (fused) rings (e.g., naphthyl, fluorenyl, anthracenyl). Examples of the term include groups such as phenyl, fluorenyl, naphthyl, anthracenyl, 1,2,3,4-tetrahydronaphthalene (where the point of attachment is through the aryl group), and the like.

[0023] As used herein, the term "heteroaryl group" refers to an aromatic ring group containing a single ring or multiple condensed (fused) rings (e.g., containing two or three rings) containing 5 to 14 ring atoms in the ring, which, in addition to carbon atoms, also contain at least one heteroatom selected from oxygen, nitrogen, and / or sulfur. When the ring is aromatic, the sulfur and nitrogen atoms may also be present in oxidized form. A multiple condensed (fused) ring heteroaryl group is a single ring heteroaryl group, as defined above, fused to one or more rings selected from heteroaryl groups (e.g., to form naphthyridinyl, e.g., 1,8-naphthyridinyl), heterocycles (e.g., to form 1,2,3,4-tetrahydronaphthyridinyl, e.g., 1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (e.g., to form 5,6,7,8-tetrahydroquinolinyl), and aryl groups (e.g., to form an indazolyl group) to form a multiple condensed ring system. Such multiple fused ring systems may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic portions of the fused rings. Where valency requirements permit, the rings of a multiple fused ring system can be connected to each other through fused, spiro, and bridged bonds. It is understood that the individual rings of a multiple fused ring system can be connected to each other in any order. It is also understood that the point of attachment of a multiple fused ring system can be at any position on the multiple fused ring system, including the heteroaryl, heterocyclic, aryl, or carbocyclic portions of the multiple fused ring system. It is also understood that the point of attachment of a heteroaryl group can be at any suitable atom of the heteroaryl group, including carbon atoms and heteroatoms (e.g., nitrogen).Exemplary heteroaryl groups include pyridinyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, Examples include, but are not limited to, 5,6,7,8-tetrahydroisoquinolinyl group, benzofuranyl group, benzimidazolyl group, thiaindenyl group, pyrrolo[2,3-b]pyridinyl group, quinazolinyl-4(3H)-one, triazolyl group, 4,5,6,7-tetrahydro-1H-indazolyl group, and 3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopentane[1,2-c]pyrazolyl group.

[0024] As used herein, the term "heterocyclic group" refers to a monoradical saturated or partially unsaturated group having 3 to 8 members, a single ring, or multiple condensed (fused) or bridged rings, with 3 to 14 ring atoms in the ring, which, in addition to carbon atoms, also includes at least one heteroatom selected from oxygen, nitrogen, and / or sulfur. Illustrative examples of heterocyclic groups include tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl, 4,5,6,7-tetrahydro-1H-benzo[d]imidazolyl, benzo[d]imidazolyl, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridinyl, aziridine, azetidinyl, tetrahydropyrrolyl, azepanyl, azocanyl, oxirane, oxetanyl, tetrahydrofuran ... Examples of such an alkyl group include, but are not limited to, a tetrahydropyranyl group, an oxepanyl group, an oxocanyl group, a thiirane group, a thietanyl group, a tetrahydrothiophenyl group, a tetrahydrothiopyranyl group, a thiepanyl group, a thiocanyl group, a tetrahydroimidazolyl group, a tetrahydropyrazolyl group, a tetrahydrooxazolyl group, a tetrahydroisoxazolyl group, a tetrahydrothiazolyl group, a tetrahydroisothiazolyl group, a dioxanyl group, a thioxanyl group, and a dithianyl group.

[0025] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0026] As used herein, the term "alkoxy" refers to an "alkyl-O-" group, where alkyl is as defined herein. Examples of this term include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

[0027] As used herein, the term "therapeutically effective amount" means an amount sufficient to produce a therapeutic effect, as defined below, when administered to a mammal in need of such treatment. The therapeutically effective amount varies depending on the subject and condition being treated, the subject's weight and age, the severity of the condition, the method of administration, etc., and can be readily determined by one skilled in the art.

[0028] As used herein, the term "stereoisomer" refers to compounds that have identical chemical composition and connectivity but differ in the orientation of their atoms in space and are not interchangeable by rotation of a single bond. "Stereoisomer" includes "non-enantiomers" and "enantiomers." "Non-enantiomers" refer to stereoisomers with two or more chiral centers and whose molecules are not mirror images of one another. Non-enantiomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Non-enantiomeric mixtures can be separated by high-resolution analytical procedures (e.g., crystallization, electrophoresis, chromatography). "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of each other.

[0029] As used herein, 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.

[0030] As used herein, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and / or toxicologically compatible with the other components of the formulation and / or the mammal being treated therewith.

[0031] Any formula or structure depicted herein, including Formula I or any formula disclosed herein, is intended to represent unlabeled and isotopically labeled forms of the compound. These forms of the compound may also be referred to as "isotopically labeled" or "isotopically enriched analogs." Isotopically labeled compounds have the structure depicted herein except that one or more atoms are replaced with an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 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 125 Examples of such compounds include, but are not limited to, I. Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogens have been replaced with deuterium.

[0032] The term "solvate" as used herein refers to the association or complex of one or more solvent molecules and the compound of the present invention.The examples of solvents that form solvates include but are not limited to water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, ethanolamine.The term "hydrate" refers to the complex where the solvent molecule is water.

[0033] compound In one embodiment, the present invention provides a compound having the structure shown in formula (I): [ka] or stereoisomers, tautomers, isotopically enriched analogs, solvates and pharmaceutically acceptable salts thereof, R1 is hydrogen or C1-C 12 alkyl groups, R2 is selected from R—(C═O)—, R—(C═S)—, R—(S═O)—, R—(SO2)—, R—CH(OH)—, RO—, RS—, NO2, where R is hydrogen, C1-C 12 Alkyl groups, C2-C 12 Alkenyl groups, C2-C 12 Alkynyl groups, C3-C 12 Cycloalkyl groups, C6-C 14 and R3', wherein the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group, and heterocyclic group are selected from halogen, cyano group, nitro group, hydroxyl group, C1-C 12 Alkoxy groups, C1-C 12 Alkoxycarbonyl group, C1-C 12 Alkoxycarbonyloxy group, C1-C 12 Alkyl acyloxy group, carboxyl group, sulfhydryl group, C1-C 12 alkylthio group, optionally substituted with NR4R4', where R3, R3', R4, and R4' are each independently hydrogen, C1-C 12 Alkyl groups, C2-C 12 Alkenyl groups, C2-C 12 Alkynyl groups, C3-C 12 Cycloalkyl groups, C6-C 14 It is selected from an aryl group, a heteroaryl group, a heterocyclic group, or R3 and R3', R4 and R4' together with the nitrogen atom to which they are attached form a heterocyclic group.

[0034] In one embodiment, the present invention provides a compound having the structure shown in formula (I) below, or a stereoisomer, tautomer, isotopically enriched analog, solvate, or pharmaceutically acceptable salt thereof, wherein R1 is hydrogen or a C1-C 12Preferably, R1 is selected from hydrogen or a C1-C6 alkyl group, more preferably, R1 is selected from hydrogen or a methyl group, and most preferably, R1 is selected from hydrogen.

[0035] In one embodiment, the present invention provides a compound having the structure shown in Formula (I) below, or a stereoisomer, tautomer, isotopically enriched analog, solvate, or pharmaceutically acceptable salt thereof, wherein R2 is selected from R—(C═O)—, R—(C═S)—, R—(S═O)—, R—CH(OH)—, RO—, RS—, and NO2, where R is hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C6 cycloalkyl group, a C6 ... 10 and R3, R3', R4, and R4' are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C6 alkyl acyl, C6-C6 alkylthio, and NR3R3', wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups are optionally substituted with halogen, cyano, nitro, hydroxyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkoxycarbonyloxy, C1-C6 alkylacyloxy, carboxyl, sulfhydryl, C1-C6 alkylthio, and NR4R4', and R3, R3', R4, and R4' are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C6 alkyl acyl, C6-C6 alkyl thio, and NR4R4'. 10 It is selected from an aryl group, a heteroaryl group, a heterocyclic group, or R3 and R3', R4 and R4' together with the nitrogen atom to which they are attached form a heterocyclic group.

[0036] In a preferred embodiment, the present invention provides a compound having the structure shown in the following formula (I), or a stereoisomer, tautomer, isotopically enriched analog, solvate, or pharmaceutically acceptable salt thereof, wherein R2 is selected from R—(C═O)—, R—(C═S)—, R—(S═O)—, R—(SO2)—, R—CH(OH)—, RO—, RS—, and NO2, wherein R is selected from hydrogen, a C1-C4 alkyl group, a C2-C4 alkenyl group, a C2-C4 alkynyl group, a C3-C6 cycloalkyl group, a phenyl group, a heteroaryl group, a heterocyclic group, and NRR3′, wherein the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, and heteroaryl group are each independently selected from the group consisting of phenyl, ... The heterocyclic group and the heterocyclic group are optionally substituted with halogen, cyano, nitro, hydroxyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkoxycarbonyloxy, C1-C4 alkylacyloxy, carboxyl, sulfhydryl, C1-C4 alkylthio, or NRR, where R, R, R, and R are each independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, phenyl, heteroaryl, and heterocyclic groups, or R and R, and R and R together with the nitrogen atom to which they are attached form a heterocyclic group.

[0037] In a preferred embodiment, the present invention provides a compound having the structure shown in the following formula (I), or a stereoisomer, tautomer, isotopically enriched analog, solvate, or pharmaceutically acceptable salt thereof, wherein R1 is selected from hydrogen or a C1-C6 alkyl group, and R2 is selected from R—(C═O)—, R—(C═S)—, R—(S═O)—, R—(SO2)—, R—CH(OH)—, RO—, RS—, or NO2, where R is hydrogen, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C6 cycloalkyl group, a C6-C6 alkyl group, or a C6-C6 alkyl group. 10and R3, R3', R4, and R4' are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C6 alkyl acyl, C6-C6 alkylthio, and NR3R3', wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclic groups are optionally substituted with halogen, cyano, nitro, hydroxyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkoxycarbonyloxy, C1-C6 alkylacyloxy, carboxyl, sulfhydryl, C1-C6 alkylthio, and NR4R4', and R3, R3', R4, and R4' are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C6 alkyl acyl, C6-C6 alkyl thio, and NR4R4'. 10 It is selected from an aryl group, a heteroaryl group, a heterocyclic group, or R3 and R3', R4 and R4' together with the nitrogen atom to which they are attached form a heterocyclic group.

[0038] In one preferred embodiment, the present invention provides a compound having the structure shown in Formula (II): [ka] where R1 and R2 are as defined herein.

[0039] In one preferred embodiment, the present invention provides a compound having the structure shown in Formula (III): [ka] where R1 and R2 are as defined herein.

[0040] In one preferred embodiment, the present invention provides a compound having the structure shown in formula (IV): [ka] where R1 and R2 are as defined herein.

[0041] In one preferred embodiment, the present invention provides compounds having the structure shown in the formula: or stereoisomers, tautomers, isotopically enriched analogs, solvates, and pharmaceutically acceptable salts thereof. [ka]

[0042] Pharmaceutical Compositions and Administration The compounds provided by the present invention, or pharmaceutically acceptable salts, stereoisomers, tautomers, prodrugs, and solvates thereof, are typically administered in the form of pharmaceutical compositions. Accordingly, the present invention provides pharmaceutical compositions comprising the compounds provided by the present invention as an active ingredient and one or more pharmaceutically acceptable carriers. The pharmaceutical compositions can be administered alone or in combination with other therapeutic agents. Such compositions can be prepared by methods 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 & CT Rhodes, Eds.)).

[0043] Pharmaceutically acceptable carriers can be solid or liquid.Here, solid carriers can be one or more substances used as excipients, diluents, sweeteners, solubilizers, lubricants, binders, tablet disintegrating agents, stabilizers, preservatives, or encapsulating materials.Liquid carriers can be solvents or liquid dispersion media.Suitable solid carriers include, but are not limited to, cellulose, glucose, lactose, mannitol, magnesium stearate, magnesium carbonate, sodium carbonate, sodium saccharin, sucrose, dextrin, talc, starch, pectin, gelatin, tragacanth, gum arabic, sodium alginate, parabens, methylcellulose, sodium carboxymethylcellulose, low-melting wax, cocoa butter, etc. Suitable liquid carriers include, but are not limited to, water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycerides, agar, pyrogen-free water, isotonic saline, Ringer's solution, and mixtures thereof.

[0044] Pharmaceutical compositions according to the present invention may be in any form suitable for the intended method of administration. For example, for oral use, they may be formulated into tablets, lozenges, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs, solutions, sprays, and the like. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions. Pharmaceutical compositions of the present invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. Pharmaceutical compositions of the present invention may also be formulated into formulations for aerosol or dry powder administration, or formulations suitable for pulmonary or intranasal administration, such as nasal drops or nasal sprays. Pharmaceutical compositions of the present invention may also be formulated into suppositories suitable for rectal administration. Pharmaceutical compositions of the present invention may also be formulated into transdermal formulations for topical administration or eye drops suitable for intraocular administration.

[0045] The pharmaceutical compositions of the present invention can be administered by intraarterial injection, intravenous injection, intraperitoneal injection, parenteral injection, intramuscular injection, subcutaneous injection, sublingual injection, oral administration, or topical administration in single or multiple doses.

[0046] The effective dosage of the compounds of the present invention will depend at least on the nature of the condition being treated, toxicity, method of administration, and pharmaceutical formulation, and will be determined by the clinician using routine dose escalation studies. A dosage of about 0.0001 to about 100 mg / kg of body weight per day is expected. Typically, the dosage is about 0.01 to about 10 mg / kg of body weight per day, more typically about 0.01 to about 5 mg / kg of body weight per day, and most typically about 0.05 to about 0.5 mg / kg of body weight per day. For example, the daily dosage of a candidate for an adult weighing about 70 kg will be in the range of 1 mg to 1000 mg, preferably 5 mg to 500 mg, and may be administered as a single dose or in multiple doses.

[0047] Indications The compounds of the present invention, or their stereoisomers, tautomers, isotopically enriched analogs, and solvates, can be used for the prevention and / or treatment of GABA-A receptor-mediated diseases. In particular, the compounds of the present invention, or their stereoisomers, tautomers, isotopically enriched analogs, and solvates, can be used for the prevention and / or treatment of central nervous system diseases. In particular, the compounds of the present invention, or stereoisomers, tautomers, isotopically enriched analogs, and solvates thereof, can be used for the treatment and / or prevention of diseases including, but not limited to, postpartum depression, depression, major depressive disorder, bipolar disorder, mood disorders, anxiety disorders, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder (SAD), social anxiety disorder, memory loss, stress intolerance, Niemann-Pick disease type C or related neurological or physical symptoms, epilepsy, essential tremor, epileptiform disorders, NMDA hypofunction, migraine, status epilepticus, sleep disorders, fragile X syndrome, 5α-reductase inhibitor-induced depression, PCDH19 female pediatric epilepsy, sexual dysfunction, cognitive impairment, Parkinson's disease, or Alzheimer's disease.

[0048] Combination drugs The compounds of the present invention can be used as monotherapy to treat and / or prevent GABA-A receptor-mediated disorders, or central nervous system disorders, or disorders selected from postpartum depression, depression, major depressive disorder, bipolar disorder, mood disorders, anxiety disorders, posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder (SAD), social anxiety disorder, memory loss, stress intolerance, Niemann-Pick disease type C or related neurological or physical symptoms, epilepsy, essential tremor, epileptiform disorders, NMDA hypofunction, migraine, status epilepticus, sleep disorders, fragile X syndrome, 5α-reductase inhibitor-induced depression, PCDH19 female pediatric epilepsy, sexual dysfunction, Parkinson's disease, or Alzheimer's disease, etc. The compounds of the present invention can also be used in combination with one or more additional therapeutic agents to treat the disorders described herein. The one or more additional therapeutic agents include, but are not limited to, neuroactive steroids such as pregnanolone, allopregnanolone, alphadolone, ganaxolone, alphaxalone, benzodiazepines, barbiturates.

[0049] Treatment methods and uses In one embodiment, the present invention provides a method for treating and / or preventing a GABA-A receptor mediated disease, said method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the present invention or a stereoisomer, tautomer, isotopically enriched analogue, solvate or pharmaceutical composition comprising same. In another embodiment, the present invention provides a method for treating and / or preventing a central nervous system disease, said method comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the present invention or a stereoisomer, tautomer, isotopically enriched analogue, solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In another embodiment, the present invention provides a method for treating and / or preventing diseases, including postpartum depression, depression, major depressive disorder, bipolar disorder, mood disorders, anxiety disorders, posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder (SAD), social anxiety disorder, memory loss, stress intolerance, Niemann-Pick disease type C or related neurological or physical symptoms, epilepsy, essential tremor, epileptiform disorder, NMDA hypofunction, migraine, status epilepticus, sleep disorders, fragile X syndrome, 5α-reductase inhibitor-induced depression, PCDH19 female childhood epilepsy, sexual dysfunction, cognitive impairment, Parkinson's disease, or Alzheimer's disease, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the present invention, or a stereoisomer, tautomer, isotopically enriched analogue, solvate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0050] The present invention provides the use of a compound of the present invention, or a stereoisomer, tautomer, isotopically enriched analogue, or solvate thereof, as an active therapeutic substance in the manufacture of a medicament for treating and / or preventing a GABA-A receptor-mediated disease. More specifically, the present invention provides the use of a compound of the present invention, or a stereoisomer, tautomer, isotopically enriched analogue, or solvate thereof, as an active therapeutic substance in the manufacture of a medicament for treating and / or preventing a central nervous system disease. More specifically, the present invention provides the use of a compound of the present invention, or a stereoisomer, tautomer, isotopically enriched analogue, or solvate thereof, as an active therapeutic substance in the manufacture of a medicament for treating and / or preventing the following diseases: These conditions include, but are not limited to, postpartum depression, depression, major depressive disorder, bipolar disorder, mood disorders, anxiety disorders, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder (SAD), social anxiety disorder, memory loss, stress intolerance, Niemann-Pick disease type C or related neurological or physical conditions, epilepsy, essential tremor, epileptiform disorders, NMDA hypofunction, migraine, status epilepticus, sleep disorders, fragile X syndrome, 5α-reductase inhibitor-induced depression, PCDH19 female pediatric epilepsy, sexual dysfunction, cognitive impairment, Parkinson's disease, or Alzheimer's disease.

[0051] General synthesis method The compounds of the present invention can be prepared using the methods disclosed herein and modified routes thereof, as well as methods known in the art. Exemplary embodiments of the compounds according to the present invention can be synthesized using the following general reaction process. It will be apparent from the description herein that by substituting reactants with other materials having similar structures, different products will be obtained accordingly. The reactants are typically obtained from commercial sources or synthesized using published methods.

[0052] Reaction Process [ka] The compound represented by formula (Ia) is reacted with an acid anhydride compound (acetic anhydride, trifluoroacetic anhydride, etc.) and nitric acid in a suitable solvent to obtain the compound represented by formula (I).

[0053] The following examples are offered to illustrate the preparation of compounds of the present invention and are not intended to limit the invention in any manner.

[0054] Example Example 1 Synthesis of Compound 1 [ka] A 250 ml three-neck flask was charged with 5.00 g of allopregnanolone and 105.0 ml of dichloromethane, stirred until dissolved, cooled to below -10°C, and 45.0 ml of acetic anhydride was added dropwise. At below -10°C, 10 ml of nitric acid was slowly added dropwise. Upon completion of the addition, the reaction was continued at below -10°C until completion. The reaction solution was added to 300 ml of water and stirred. The organic phase was washed twice with 200 ml of water. The organic phase was distilled under reduced pressure, and the residue was separated by column chromatography to obtain an off-white solid (4.86 g, 85% yield). 1H NMR (400 MHz,chloroform-d) δ 2.53 (t, J = 9.0 Hz, 1H), 2.39 (td, J = 14.5, 13.6, 6.5 Hz, 1H), 2.34 - 2.26 (m, 2H), 2.25 - 2.15 (m, 1H), 2.12 (s, 4H), 2.04 (dtt, J = 12.7, 6.2, 3.2 Hz, 3H), 1.76 - 1.61 (m, 5H), 1.61 - 1.49 (m, 1H), 1.48 - 1.40 (m, 3H), 1.40 - 1.32 (m, 3H), 1.26 (ddd, J = 23.2, 9.9, 4.4 Hz, 2H), 1.17 (ddd, J = 16.4, 9.5, 4.2 Hz, 2H), 1.01 (s, 3H), 0.94 (ddd, J = 24.6, 12.1, 5.5 Hz, 2H), 0.83 - 0.75 (m, 1H), 0.64 (s, 3H). MS: m / z [M+H]+ 364.15

[0055] Bioactivity Test I. Measurement of GABA-A receptor positive modulatory activity Experimental Method: In the experiment, we investigated the effects of compounds on GABA-A (α4β3δ) receptors using a HEK293 cell line transiently expressing GABA-A (α4β3δ) receptors, and measured the half-maximal effective concentration (EC 50 ) values ​​were tested. Experiments used a manual patch clamp system HEKA EPC 10 signal amplifier and a digital conversion system for whole-cell current recording of chloride ion currents of GABA-A channels. All experiments were performed at normal room temperature.

[0056] After whole-cell sealing, the cell membrane voltage was fixed at -70 mV. In gap-free mode, a mixture of GABA and 3 μM of the compound of the present invention was sprayed onto the cell surface in increasing concentrations, from low to high, and the peak current was recorded. Test substance administration method: A mixture of 3 μM of GABA and the compound of the present invention at each concentration was administered once or twice, followed by 1 minute of washing with extracellular solution. The next concentration was then detected. A microelectrode puller was used to pull a glass capillary into the recording electrode. An electrode filled with intracellular solution was attached to the electrode head, and the microelectrode manipulator was used under an inverted microscope to immerse the electrode in the extracellular solution, and the electrode resistance (Rpip) was recorded. The electrode was then brought into contact with the cell surface, and a high-resistance seal (GΩ) was formed by negative pressure suction. At this time, high-speed capacitance compensation was performed, and negative pressure was continuously applied to disrupt the cell membrane, forming the whole-cell recording mode. Next, slow-speed capacitance compensation was performed, and experimental parameters such as membrane capacitance (Cm) and series resistance (Rs) were recorded. No leakage compensation was applied.

[0057] The cover glass containing the cells was placed in a recording chamber under an inverted microscope, and a blank control external solution and a working solution of the compound of the present invention were perfused into the recording chamber by gravity in order of concentration from low to high. The liquid was exchanged using a peristaltic pump during recording. Each concentration was measured twice using at least two cells.

[0058] The GABA-A (α4β3δ) receptor current after the action of a 3 μM mixture of GABA at each concentration and the compound of the present invention was normalized by the current of a 3 μM mixture of saturated GABA and the compound of the present invention as a control.

number

[0059] The EC of the compounds of the present invention 50 values ​​were calculated and the dose-dependent effect was subjected to nonlinear fitting, where EC 50 was the half-maximal effective concentration. 50 Calculations and curve fitting were completed using GraphPad Prism software.

[0060] The above experiment was repeated using allopregnanolone instead of the compound of the present invention without changing the experimental scheme and experimental parameters, and the EC value of allopregnanolone was calculated using the above formula. 50 values ​​were calculated and the dose-dependent effect was nonlinearly fitted, where EC 50 was the half-maximal effective concentration. 50 Calculations and curve fitting were completed using GraphPad Prism software.

[0061] Test Results: The half-maximal effective concentration (EC) of Compound 1 of the present invention on GABA-A receptors 50 The half-maximal effective concentration (EC) of allopregnanolone on the GABA-A receptor was 10.514 nM. 50 The α-amyloid β ...

[0062] II. In vitro metabolic stability experiments Experimental Background Cytochrome P450 oxidases (CYP450), also known as hepatic microsomal mixed-function oxidases, are primarily present in the endoplasmic reticulum and the inner wall of mitochondria and are involved in the metabolism of various endogenous and exogenous substances, including drugs, carcinogens, steroid hormones, and fatty acids. CYP450 oxidoreductases (PORs), the sole electron donors for all hepatic microsomal enzymes, transfer electrons to CYP450 enzymes via reduced nicotinamide adenine dinucleotide phosphate (NADPH), which then undergo oxidation-reduction reactions with substrates to exert metabolic activity.

[0063] Liver microsomes contain most of the phase I enzymes, the most important of which is the microsomal mixed-function oxidase system, primarily composed of CYP450. When conducting studies using liver microsomes, the addition of the corresponding cofactor NADPH allows the reconstitution of the in vitro metabolic system, thereby enabling phase I metabolic stability studies to be performed by in vitro incubation.

[0064] Experimental Purpose The in vitro metabolic stability of Compound 1 and allopregnanolone is studied using a commercially available male SD rat liver Phase I metabolic stability kit (containing liver microsomes and the reagents used in the study).

[0065] Experimental Reagents Phase I metabolic stability kit (purchased from Beijing Kai Zhiheyuan Biotechnology Co., Ltd.), product composition is as follows: [Table 1] Solution A contains 26.1 mM NADP+, 66 mM 6-glucose phosphate, and 66 mM magnesium chloride. Solution B contains 40 U / mL 6-glucose phosphate dehydrogenase and 5 mM sodium citrate. Test substance: Compound 1 solution: Dissolve in acetonitrile to prepare a 40 μg / ml solution Allopregnanolone solution: Dissolve in acetonitrile to prepare a 40 μg / ml solution Experimental Method The positive substrate testosterone solution (10 mM) was diluted with acetonitrile to a 200 μM solution for later use. Stop solution and internal standard: Testosterone-D3 was dissolved in acetonitrile to prepare a 5 ng / ml solution for later use.

[0066] 1. Test group (1) Each component of the kit was thawed in an ice bath and kept on ice until use. (2) Preparation of incubation system (200 μL system as an example): [Table 2] (3) 160 μL of preincubation solution B was added to a centrifuge tube containing 40 μL of preincubation solution A, and the tube was mixed uniformly by spraying three times. The tube was then immediately placed in a 37°C water bath for incubation and timing. (4) At the set incubation time points of 0, 5, 10, 15, 30, 45, and 60 minutes, the incubation solution was quantitatively removed, and 200 μL of stop solution (5 ng / mL testosterone-D3 acetonitrile solution pre-cooled to 4°C) was added to stop the reaction (stop solution volume: incubation system volume = 1:1). Experimental samples were run in triplicate for each time point. 2. Positive control group To verify the validity of the experiment, a positive control group was set up throughout the experiment to evaluate whether the incubation system was functioning properly. The test object was replaced with the positive substrate testosterone (200 μM acetonitrile solution) from the Phase I metabolic stability kit. The other components of the incubation system and the experimental method were the same as those of the test group. 3. Data Processing The ratio of the chromatographic peak area of ​​the test substance to the peak area of ​​the testosterone-D3 internal standard was used as the calculation data. The peak area ratio of the test substance at time zero was set to 100%, and the peak area ratio at each time point was compared with the peak area ratio at time zero to determine the remaining percentage. The natural logarithm of the remaining percentage of the substrate at each time point was then linearly regressed against the incubation time to obtain the slope k. The in vitro metabolic half-life (T1 / 2) and intrinsic clearance rate (CLint) were then calculated using the following formula:

number

[0067] III. Pharmacokinetic analysis of mouse tail vein administration experimental drugs Allopregnanolone: ​​0.5 mg / ml aqueous solution (solubilized with 30% cyclodextrin) Compound 1: 0.5 mg / ml aqueous solution (solubilized with 30% cyclodextrin) experimental animals Female ICR mice weighing 20-22 g were purchased from Beijing Huafukang Biotechnology Co., Ltd. Experimental Method 1. Mouse tail vein administration and treatment: Sixty female ICR mice were divided into two groups, Group A and Group B, with 30 mice in each group (five mice per blood collection point). Allopregnanolone and Compound 1 were injected via the tail vein at a dose of 5 mg / kg each. Eyeballs were enucleated and blood samples were collected at 5 minutes, 30 minutes, 1 hour, 5 hours, 8 hours, and 12 hours after administration. The blood was anticoagulated with heparin, centrifuged to separate plasma, and stored at -80°C for analysis. Animals were sacrificed at 5 minutes, 1 hour, and 8 hours, and brain tissue was collected and stored at -80°C for analysis.

[0068] 2. Biological Sample Processing (1) Plasma sample 100 μl of plasma sample, 10 μl of internal standard solution (100 ng / ml testosterone D-3 solution), and 310 μl of acetonitrile were accurately measured, mixed uniformly by vortexing, centrifuged (14,000 rpm, 4°C), and the supernatant was collected. (2) Brain tissue samples Approximately 100 mg of brain tissue sample was collected and accurately weighed, and 100 μl of water and 400 μl of acetonitrile were added to homogenize it. 100 μl of brain tissue homogenate, 10 μl of internal standard solution (100 ng / ml testosterone D-3 solution), and 310 μl of acetonitrile were accurately weighed, mixed uniformly with a vortex, and centrifuged (14,000 rpm, 4°C) to obtain the supernatant.

[0069] 3. Measurement of Biological Samples (1) Preparation of standard solution series (1) Plasma matrix standard solution Appropriate amounts of allopregnanolone and compound 1 were taken and quantitatively diluted with acetonitrile to prepare mixed standard solutions containing 5000 ng, 2000 ng, 1000 ng, 500 ng, 200 ng, 100 ng, 50 ng, and 20 ng of allopregnanolone and compound 1 per ml. 100 μl of blank plasma sample, 10 μl of mixed standard solution, 10 μl of internal standard solution (100 ng / ml testosterone D-3 solution), and 300 μl of acetonitrile were accurately measured, mixed uniformly with a vortex, and centrifuged (14,000 rpm, 4°C) to obtain the supernatant. (2) Brain tissue matrix standard solution Appropriate amounts of allopregnanolone and compound 1 were quantitatively diluted with acetonitrile to prepare mixed standard solutions containing 5000 ng, 2000 ng, 1000 ng, 500 ng, 200 ng, 100 ng, and 50 ng of allopregnanolone and compound 1 per ml. Approximately 100 mg of blank brain tissue sample was collected and accurately weighed. 100 μl of water and 400 μl of acetonitrile were added and homogenized in a homogenizer. 100 μl of brain tissue homogenate, 10 μl of mixed standard solution, 10 μl of internal standard solution (100 ng / ml testosterone D-3 solution), and 300 μl of acetonitrile were accurately weighed and mixed uniformly in a vortex mix. The mixture was centrifuged (14,000 rpm, 4°C) and the supernatant was collected.

[0070] (2) Analysis method The UPLC-MS / MS method was used, and testosterone D-3 was used as an internal standard substance, and analysis and measurement were performed using the standard curve method. The UPLC parameters were as follows: [Table 5] MS parameters [Table 6] Note: * denotes quantitative ions.

[0071] 4. Experimental Results [Table 7] When administered via the tail vein, both compound 1 and allopregnanolone rapidly crossed the blood-brain barrier and entered the brain, exerting their therapeutic effects. However, the brain clearance rate of compound 1 was much slower than that of allopregnanolone. The brain tissue concentrations of compound 1 (ng / g) at 5 min, 1 h, and 8 h after administration were 1138.9, 652.0, and 31.0, respectively, while the brain tissue concentrations of allopregnanolone (ng / g) at 5 min, 1 h, and 8 h after administration were 1073.2, 47.3, and 14.4, respectively, indicating that the metabolism of compound 1 in brain tissue is more stable.

[0072] IV. Pharmacokinetic analysis of tail vein and oral administration in female rats experimental drugs Tail vein injection: Allopregnanolone: ​​0.5 mg / ml aqueous solution (solubilized with 30% cyclodextrin, A 静脈 (abbreviated as Compound 1: 0.5 mg / ml aqueous solution (solubilized with 30% cyclodextrin, B 静脈 (abbreviated as Oral intragastric administration: Allopregnanolone: ​​1.5 mg / ml oil solution (using sesame oil as the solvent, A 経口 (abbreviated as Compound 1: 1.5 mg / ml oil solution (using sesame oil as the solvent, B 経口 (abbreviated as experimental animals Female SD rats weighing 200-220 g were purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0073] Experimental Method 1. Administration and treatment into rat tail vein: Sixty female SD rats were divided into two groups (A 静脈 and B 静脈The rats were divided into 3 groups, with 30 rats in each group (5 rats at each blood collection point). Drugs were administered at 3 mg / kg (approximately 1.2 ml of drug solution) into the A and B veins via tail vein injection. Blood was collected from the orbital plexus at 5 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours after administration. The blood was anticoagulated with heparin and centrifuged. Plasma was separated and stored at -80°C until testing. After the 8-hour blood collection, the animals were sacrificed, and brain and liver tissues were collected and stored at -80°C for testing. 2. Oral intragastric administration and treatment in rats: Sixty female SD rats were divided into two groups (A 経口 and B 経口 ) with 30 rats in each group (5 rats at each blood sampling point). 経口 and B 経口 Each drug was administered orally and intragastricly at 12 mg / kg (approximately 1.6 ml of drug solution). Blood was collected from the orbital venous plexus at 5 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, and 8 hours after administration. The blood was anticoagulated with heparin and centrifuged. Plasma was separated and stored at -80°C until analysis. After the 8-hour blood collection, the animals were sacrificed, and brain and liver tissues were collected and stored at -80°C for analysis. 3. Sample Processing (1) Plasma sample 100 μl of plasma sample, 10 μl of internal standard solution (100 ng / ml testosterone D-3 solution), and 310 μl of acetonitrile were accurately measured, mixed uniformly using a vortex, and centrifuged (14,000 rpm, 4°C) to collect the supernatant, which was then detected using UPLC-MS / MS (the analytical method was the same as in the mouse pharmacokinetic analysis experiment). (2) Brain and liver tissue samples Approximately 100 mg of brain or liver tissue samples were collected and accurately weighed, and 100 μl of water and 400 μl of acetonitrile were added and homogenized. 100 μl of brain or liver tissue homogenate, 10 μl of internal standard solution (100 ng / ml testosterone D-3 solution), and 310 μl of acetonitrile were accurately weighed and mixed uniformly by vortexing. After centrifugation (14,000 rpm, 4°C), the supernatant was collected and subjected to UPLC-MS / MS detection (analysis method was the same as in the mouse pharmacokinetic analysis experiment). 4. Experimental Results Pharmacokinetic parameters after tail vein administration in rats [Table 8] Pharmacokinetic parameters after oral administration in rats [Table 9]

[0074] Allopregnanolone and compound 1 were administered to rats via the tail vein. Eight hours after administration, allopregnanolone was not detected in the brain tissue or plasma of rats in both groups. However, the concentration of compound 1 in the brain tissue of rats in the compound 1 administration group was still high (209.1 ng / g), with a brain / plasma ratio of 6.68. The results indicated that the clearance rate of compound 1 in the brain was much slower than that of allopregnanolone, and its metabolism in brain tissue was very stable.

[0075] After oral intragastric administration of allopregnanolone and Compound 1 to rats, allopregnanolone was not detected in the plasma or brain tissue of animals in the allopregnanolone group at any time point, indicating that allopregnanolone cannot be administered orally. After oral administration of Compound 1, plasma drug concentrations continued to increase, and even at 8 hours, C max Compound 1 was readily absorbed into the blood, had a low clearance rate, and was not detected as T maxThe oral bioavailability of Compound 1 was >8 hours, with an oral bioavailability of >65%. After oral administration, Compound 1 readily crossed the blood-brain barrier, and even 8 hours after administration, the concentration in brain tissue remained very high (1636.8 ng / g) with a brain / plasma ratio of 2.95, indicating that Compound 1 continuously crossed the blood-brain barrier to exert its therapeutic effects after oral administration and that its metabolism in the blood was very stable.

[0076] We also measured the drug content in liver tissue after tail vein and oral administration of allopregnanolone and Compound 1. The results showed that allopregnanolone was not detected in the liver 8 hours after either administration method. Even after oral administration of Compound 1, the plasma content of Compound 1 was still very high (3703.4 ng / g) 8 hours after administration (allopregnanolone was also detected in liver tissue (694.2 ng / g)). After intravenous administration of Compound 1, a small amount of Compound 1 (192.8 ng / g) was detected in the liver 8 hours after administration, but allopregnanolone was not detected. The results indicated that Compound 1 is highly stable in liver metabolism.

[0077] V. Pharmacokinetic analysis of oral administration in male rats experimental drugs Oral intragastric administration: Allopregnanolone: ​​1.5 mg / ml oil solution (using sesame oil as the solvent, A 経口 (abbreviated as Compound 1: 1.5 mg / ml oil solution (using sesame oil as the solvent, B 経口 (abbreviated as experimental animals Male SD rats weighing 230-250 g were purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0078] Experimental Method 1. Oral intragastric administration and treatment in rats: A total of 168 male SD rats were divided into two groups (A 経口 and B 経口) with 84 rats in each group (7 rats at each blood collection point). 経口 and B 経口 Each was administered orally by intragastric infusion at 12 mg / kg. Blood was collected from the orbital venous plexus 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 18 hours, and 24 hours after administration. The blood was anticoagulated with heparin and centrifuged, after which the plasma was separated and stored at -80°C until testing. 2. Sample Processing 100 μl of plasma sample, 10 μl of internal standard solution (100 ng / ml testosterone D-3 solution), and 310 μl of acetonitrile were accurately measured, mixed uniformly using a vortex, and centrifuged (14,000 rpm, 4°C) to collect the supernatant, which was then detected using UPLC-MS / MS (the analytical method was the same as in the mouse pharmacokinetic analysis experiment). 3. Experimental Results Pharmacokinetic parameters after administration (oral intragastric infusion) in rats [Table 10] [Table 11] [Table 12]

[0079] After oral intragastric administration of allopregnanolone and Compound 1 to male rats, allopregnanolone was not detected in the plasma of animals in the allopregnanolone group at any time point. This indicates that allopregnanolone is essentially not absorbed into the blood after oral administration. However, after oral administration of Compound 1, the drug concentration in plasma continued to increase, reaching C (C ) at approximately 10 hours. max This indicates that compound 1 is easily absorbed into the blood and has a low clearance rate, and T max The kinetics was approximately 10 hours, with a half-life of 4.5 hours.

[0080] All references mentioned in this specification are incorporated herein by reference. It should be understood that the technical solutions of the present invention can be changed and modified without departing from the spirit and scope of the present invention.

Claims

1. A compound having the structure shown in formula (I): 【Chemistry 9】 or stereoisomers, tautomers, isotopically enriched analogues, solvates and pharmaceutically acceptable salts thereof, wherein: R １ is hydrogen or C １ ~C １２ alkyl groups, R ２ are R-(C=O)-, R-(C=S)-, R-(S=O)-, R-(SO ２ )-, R-CH(OH)-, R-O-, R-S-, NO ２ wherein R is hydrogen, C １ ~C １２ Alkyl group, C ２ ~C １２ Alkenyl group, C ２ ~C １２ Alkynyl group, C ３ ~C １２ Cycloalkyl group, C ６ ~C １４ Aryl group, heteroaryl group, heterocyclic group, NR ３ R ３ ', wherein the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group, and heterocyclic group are selected from halogen, cyano group, nitro group, hydroxyl group, C １ ~C １２ Alkoxy group, C １ ~C １２ Alkoxycarbonyl group, C １ ~C １２ Alkoxycarbonyloxy group, C １ ~C １２ Alkyl acyloxy group, carboxyl group, sulfhydryl group, C １ ~C １２ Alkylthio group, NR ４ R ４ Optionally substituted with ', R ３ , R ３ ', R ４ , R ４ ' are each independently hydrogen, C １ ~C １２ Alkyl group, C ２ ~C １２ Alkenyl group, C ２ ~C １２ Alkynyl group, C ３ ~C １２ Cycloalkyl group, C ６ ~C １４ selected from an aryl group, a heteroaryl group, a heterocyclic group, or R ３ and R ３ ', R ４ and R ４ ' together with the nitrogen atom to which they are attached form a heterocyclic group or stereoisomers, tautomers, isotopically enriched analogues, solvates and pharmaceutically acceptable salts thereof.

2. R １ is hydrogen or C １ ~C ６ alkyl groups, R ２ are R-(C=O)-, R-(C=S)-, R-(S=O)-, R-(SO ２ )-, R-CH(OH)-, R-O-, R-S-, NO ２ wherein R is hydrogen, C １ ~C １２ Alkyl group, C ２ ~C １２ Alkenyl group, C ２ ~C １２ Alkynyl group, C ３ ~C １２ Cycloalkyl group, C ６ ~C １４ Aryl group, heteroaryl group, heterocyclic group, NR ３ R ３ ', wherein the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group, and heterocyclic group are selected from halogen, cyano group, nitro group, hydroxyl group, C １ ~C １２ Alkoxy group, C １ ~C １２ Alkoxycarbonyl group, C １ ~C １２ Alkoxycarbonyloxy group, C １ ~C １２ Alkyl acyloxy group, carboxyl group, sulfhydryl group, C １ ~C １２ Alkylthio group, NR ４ R ４ Optionally substituted with ', R ３ , R ３ ', R ４ , R ４ ' are each independently hydrogen, C １ ~C １２ Alkyl group, C ２ ~C １２ Alkenyl group, C ２ ~C １２ Alkynyl group, C ３ ~C １２ Cycloalkyl group, C ６ ~C １４ selected from an aryl group, a heteroaryl group, a heterocyclic group, or R ３ and R ３ ', R ４ and R ４ 10. The compound of claim 1, wherein: ' are taken together with the nitrogen atom to which they are attached to form a heterocyclic group; or stereoisomers, tautomers, isotopically enriched analogs, solvates, and pharmaceutically acceptable salts thereof.

3. R １ is hydrogen or C １ ~C ６ alkyl groups, R ２ are R-(C=O)-, R-(C=S)-, R-(S=O)-, R-(SO ２ )-, R-CH(OH)-, R-O-, R-S-, NO ２ wherein R is hydrogen, C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C ３ ~C ６ Cycloalkyl group, C ６ ~C １０ Aryl group, heteroaryl group, heterocyclic group, NR ３ R ３ ', wherein the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group, and heterocyclic group are selected from halogen, cyano group, nitro group, hydroxyl group, C １ ~C ６ Alkoxy group, C １ ~C ６ Alkoxycarbonyl group, C １ ~C ６ Alkoxycarbonyloxy group, C １ ~C ６ Alkyl acyloxy group, carboxyl group, sulfhydryl group, C １ ~C ６ Alkylthio group, NR ４ R ４ Optionally substituted with ', R ３ , R ３ ', R ４ , R ４ ' are each independently hydrogen, C １ ~C ６ Alkyl group, C ２ ~C ６ Alkenyl group, C ２ ~C ６ Alkynyl group, C ３ ~C ６ Cycloalkyl group, C ６ ~C １０ selected from an aryl group, a heteroaryl group, a heterocyclic group, or R ３ and R ３ ', R ４ and R ４ 10. The compound of claim 1, wherein: ' are taken together with the nitrogen atom to which they are attached to form a heterocyclic group; or stereoisomers, tautomers, isotopically enriched analogs, solvates, and pharmaceutically acceptable salts thereof.

4. The compound is a compound of formula (II), 【Chemistry 10】 Here, R １ , R ２ or a stereoisomer, tautomer, isotopically enriched analogue, solvate or pharmaceutically acceptable salt thereof, wherein:

5. The compound is a compound of formula (III): 【Chemistry 11】 Here, R １ , R ２ or a stereoisomer, tautomer, isotopically enriched analogue, solvate or pharmaceutically acceptable salt thereof, wherein:

6. The compound is a compound of formula (IV), 【Chemistry 12】 Here, R １ , R ２ or a stereoisomer, tautomer, isotopically enriched analogue, solvate or pharmaceutically acceptable salt thereof, wherein:

7. The compound 【Chemistry 13】 or a stereoisomer, tautomer, isotopically enriched analogue, solvate or pharmaceutically acceptable salt thereof.

8. 10. A pharmaceutical composition comprising a compound of any one of claims 1 to 7 or a stereoisomer, tautomer, isotopically enriched analogue, solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. 10. Use of a compound according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment and / or prevention of GABA-A receptor mediated diseases.

10. 10. The use of claim 9, wherein the GABA-A receptor mediated disorder comprises postpartum depression, depression, major depressive disorder, bipolar disorder, mood disorder, anxiety disorder, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), premenstrual syndrome, generalized anxiety disorder, seasonal affective disorder (SAD), social anxiety disorder, memory loss, stress intolerance, Niemann-Pick disease type C or related neurological or physical conditions, epilepsy, essential tremor, epileptiform disorders, NMDA hypofunction, migraine, status epilepticus, sleep disorders, fragile X syndrome, 5α-reductase inhibitor-induced depression, PCDH19 female childhood epilepsy, sexual dysfunction, cognitive impairment, Parkinson's disease, or Alzheimer's disease.

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