WO2020135454A1 - Classe de composés stéroïdes et leur utilisation - Google Patents

Classe de composés stéroïdes et leur utilisation Download PDF

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WO2020135454A1
WO2020135454A1 PCT/CN2019/128092 CN2019128092W WO2020135454A1 WO 2020135454 A1 WO2020135454 A1 WO 2020135454A1 CN 2019128092 W CN2019128092 W CN 2019128092W WO 2020135454 A1 WO2020135454 A1 WO 2020135454A1
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alkyl
compound
alkenyl
alkynyl
aryl
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PCT/CN2019/128092
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Chinese (zh)
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吴振
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张家口华健致远生物科技有限公司
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Priority to CN201980085667.7A priority Critical patent/CN113272315B/zh
Publication of WO2020135454A1 publication Critical patent/WO2020135454A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton

Definitions

  • the present invention relates to novel compounds of formula (I) and (II) or pharmaceutically acceptable salts, tautomers or hydrolysable precursors in vivo, their compositions and methods of their use, and these novel compounds and Its use in medicine.
  • GABA Gamma-aminobutyric acid
  • GABA receptors can be divided into three pharmacological subtypes-GABA A , GABA B and GABA C.
  • GABA A receptor is the most important one of the three types of receptors. Its dysfunction is closely related to neurological and mental disorders such as depression, insomnia, epilepsy, anxiety, and schizophrenia.
  • the GABA A receptor is a pentagonal heterogeneous polypeptide oligomer composed of 5 different subunits, and a GABA-gated Cl - channel with a diameter of 0.5 nm is formed in the central part.
  • the presence of six ⁇ , three ⁇ , three ⁇ , one ⁇ , one ⁇ , one ⁇ , one ⁇ , and three ⁇ subunits in GABA A receptor and their distribution in different regions and cells in the brain produces The composition of multiple GABA A receptor subtypes with different subunits and different pharmacological properties.
  • the natural GABA A receptor in the mammalian brain is mainly composed of ⁇ , ⁇ and ⁇ subunits, and 2 ⁇ 1 , 2 ⁇ 2 and 1 ⁇ 2 subunits are the most common combined forms.
  • the binding sites of the GABA A receptor include GABA sites, benzodiazepine sites, barbiturate sites, steroid sites, tetrodotoxin sites and metal ion sites.
  • the GABA A receptor When the GABA A receptor binds to GABA, the GABA A receptor opens the chloride ion channel, increases the permeability of the cell membrane to chloride ions, and chloride ion influx, so that the neurons become hyperpolarized and the neuron excitability decreases accordingly.
  • GABA A receptor modulators have a variety of pharmacological activities, including anti-anxiety, sedation, anti-convulsant, anti-depression, and treatment of epilepsy.
  • Depression also known as depressive disorder, is the main type of mood disorder.
  • the main clinical feature is a significant and persistent mood depression.
  • traditional drugs have a slow onset of action, and it takes a relatively long time to gradually eliminate the symptoms; they cannot cover all the symptoms or characteristics of depression, and the effect is not prominent, such as postpartum depression, there are currently no drugs on the market; and, some drugs will Adverse reactions occur, and many patients even experience sexual dysfunction, which affects the quality of life in the future.
  • the present invention provides a compound of formula (I), its stereoisomer, tautomer or pharmaceutically acceptable salt,
  • R 1 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or -C 3-6 carbocyclyl, wherein alkyl, alkenyl, alkynyl or carbon Cyclic groups can be optionally substituted; including fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, deuterium atoms;
  • Ring A is a nitrogen-containing heteroaromatic heterocyclic ring which may be optionally substituted.
  • R 1 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or -C 3-6 carbocyclyl, wherein alkyl, alkenyl, alkynyl or carbon
  • the cyclic group may be substituted with a substituent selected from halogen, -C 1-6 alkoxy, -C 1-6 alkyl; including fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, deuterium atoms;
  • X is a nitrogen atom or a carbon atom
  • R 5 and R 6 are independently selected from hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, heteroalkyl, aryl , Aralkyl, heteroaryl or heterocyclic group, wherein, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, aralkyl, heteroaryl or heterocyclic group may be optionally substituted ;
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring which may be substituted with at least one R 7 ;
  • Each R 7 is independently selected from -H, halogen, -C 1-6 alkyl or oxo;
  • n is selected from 0, 1 or 2;
  • n is selected from 1, 2 or 3.
  • R 1 is selected from -C 1-6 alkyl, -CF 3, -CHF 2, -CH 2 F, -CH 2 OCH 3 or -CH 2 OCH 2 CH 3 .
  • R 5 and R 6 are independently selected from hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, heteroalkyl, aryl , Aralkyl, heteroaryl or 3 to 8 membered heterocyclic group, wherein, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, aralkyl, heteroaryl or heterocyclic group May be substituted by a substituent selected from -C 1-6 alkyl, halogen, -OH, oxo, -C 1-6 alkoxy;
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a saturated or unsaturated heterocyclic ring which may be substituted with at least one R 7 ;
  • Each R 7 is independently selected from -H, halogen, -C 1-6 alkyl or oxo;
  • n is selected from 0, 1 or 2;
  • n is selected from 1, 2 or 3.
  • the present invention provides a compound of formula (III), its stereoisomer, tautomer or pharmaceutically acceptable salt,
  • R 1 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or -C 3-6 carbocyclyl, wherein alkyl, alkenyl, alkynyl or carbon
  • the cyclic group can be optionally substituted, including fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, deuterium atoms;
  • Ring B is a nitrogen-containing heterocyclic ring which may be optionally substituted.
  • the present invention provides a method for preparing the compound of formula (I), its stereoisomer, tautomer or pharmaceutically acceptable salt, which includes the following steps:
  • Step 1 In a suitable solvent and at a suitable temperature, compound SM and paraformaldehyde are coupled to form compound M1;
  • Step 2 In the presence of a suitable solvent and a suitable base, at a suitable temperature, compound M1 is reacted with compound M2 to obtain a compound of formula (I).
  • the present invention provides a compound of formula (IV), its stereoisomer, tautomer or pharmaceutically acceptable salt,
  • R 1 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl or -C 3-6 carbocyclyl, wherein alkyl, alkenyl, alkynyl or carbon Cyclic groups can be optionally substituted; including fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, deuterium atoms;
  • R a , R b are selected from hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-8 cycloalkyl, heteroalkyl, aryl, aryl Alkyl, heteroaryl or 3- to 8-membered heterocyclic group, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, aralkyl, heteroaryl or heterocyclic group may be It is substituted with a substituent selected from -C 1-6 alkyl, halogen, -OH, oxo, and -C 1-6 alkoxy.
  • the present invention includes the following compounds, their stereoisomers, tautomers or pharmaceutically acceptable salts,
  • the present invention provides a pharmaceutical composition and its use in the preparation of a medicament for preventing and/or treating diseases related to GABA function.
  • the present invention provides a method for treating and/or preventing diseases related to GABA function, which comprises administering to a patient a therapeutically effective amount of a compound of the present invention and a pharmaceutical composition comprising the compound of the present invention, wherein the disease related to GABA function For various nervous system diseases.
  • the present invention provides a method for treating and/or preventing various neurological diseases, which comprises administering to a patient a therapeutically effective amount of a compound of the present invention and a pharmaceutical composition comprising the compound of the present invention, wherein the neurological disease is selected from depression , Sleep disorders, schizophrenia, autism, personality disorders, emotional disorders, anxiety, epilepsy.
  • halogen refers herein to -F, -Cl, -Br and -I.
  • fluorine refers herein to -F.
  • chlorine refers herein to -Cl.
  • bromine refers herein to -Br.
  • cyano refers herein to -CN.
  • amino herein refers to -NH 2.
  • hydroxyl refers herein to -OH.
  • nitro refers to -NO 2.
  • aryl refers to a 6 to 10 membered all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) groups, a polycyclic (ie, with There are rings of adjacent pairs of carbon atoms.
  • the aryl group can be covalently linked to the defined chemical structure on any carbon atom that results in a stable structure.
  • aryl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, acyl, amide Group, ester group, amine group, sulfonyl group, sulfinyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, alkenyl group, alkynyl group and cycloalkoxy group.
  • substituents fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, acyl, amide Group, ester group, amine group, sulfonyl group, sulfinyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, alkenyl group, alkyny
  • heteroaryl refers to an aromatic group composed of 5 to 10 atoms and containing at least one heteroatom selected from N, O, or S.
  • the term may have a single ring (non-limiting examples include furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, oxazole, thiazole, etc.) or multiple condensed rings (non-limiting examples include benzothiophene, benzofuran , Indole, isoindole, etc.), where the fused ring may or may not be an aromatic group containing a heteroatom, assuming that the point of attachment is through an atom of an aromatic heteroaryl group.
  • heteroaryl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, amino, alkyl, alkoxy, acyl, acyloxy Group, amido group, ester group, amine group, sulfonyl group, sulfinyl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, alkenyl group, alkynyl group and cycloalkoxy group.
  • cycloalkyl refers herein to cyclic alkyl groups having 3 to 10 carbon atoms and having monocyclic or polycyclic rings (including fused rings, bridged rings, and spiro ring systems).
  • Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • cycloalkyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, oxo, alkoxy , Acyl, acyloxy, amido, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, aryl or heteroaryl .
  • heterocyclic group refers to a substituted or unsubstituted saturated or unsaturated aromatic ring containing at least 1 to 5 heteroatoms selected from N, O or S, non-aromatic ring, aromatic ring, non-aromatic ring may be
  • the 3 to 10 membered monocyclic ring, the 4 to 20 membered spiro ring, the bicyclic or bridged ring, and the N, S optionally substituted in the heterocyclic ring can be oxidized to various oxidation states.
  • a 3 to 12-membered heterocyclic ring is preferred.
  • Non-limiting examples include oxepanyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, oxetanyl, aziridine, azetidine Group, azacyclopentyl, azacyclohexyl, azacyclopropenyl, 1,3-dioxacyclopentyl, 1,4-dioxacyclopentyl, 1,3-dioxacyclopentyl, 1 ,3-Dioxocyclohexyl, 1,3-dithiocyclohexyl, azepanyl, morpholinyl, piperazinyl, pyridyl, furyl, thienyl, pyrrolyl, pyranyl, N- Alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl,
  • heterocycloalkyl refers herein to a non-aromatic cycloalkyl group containing at least one heteroatom selected from O, N, and S, and optionally containing one or more double or triple bonds.
  • the heterocycloalkyl group as a whole may have 3 to 10 ring atoms.
  • the heterocycloalkyl group can be covalently linked to the defined chemical structure on any heteroatom or carbon atom that results in a stable structure.
  • Non-limiting examples of heterocycloalkyl include: pyrrolinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyranyl, and the like.
  • heterocycloalkyl group can be oxidized (eg morpholine N-oxide, thiomorpholine S-oxide, thiomorpholine S, S-dioxide).
  • Heterocycloalkyl can also contain one or more oxo groups, such as phthalimido, piperidone, oxazolidinyl, 2,4(1H,3H)-dioxo-pyrimidinyl , Pyridine-2(1H)-keto, etc.
  • heterocycloalkyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, oxygen Substituted, acyl, acyloxy, amido, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, aryl or heteroaryl base.
  • alkenyl refers herein to an alkenyl group having 2 to 8 carbon atoms and having at least one site of alkenyl unsaturation.
  • alkenyl groups include vinyl, propenyl, allyl, isopropenyl, butenyl, isobutenyl and the like.
  • alkenyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, oxo, Acyl, acyloxy, amido, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, alkynyloxy, cycloalkoxy, aryl or Heteroaryl.
  • substituents fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, oxo, Acyl, acyloxy, amido, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl,
  • alkyl refers herein to a saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, and the term includes straight-chain and branched-chain hydrocarbon groups.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, and the like.
  • alkyl groups described herein may be optionally substituted with one or more of the following substituents: fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxy, carboxy, amino, alkyl, alkoxy, acyl, acyl Oxygen, oxo, amido, ester, amine, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl, cycloalkoxy, heterocycloalkyloxy, Aryloxy, heteroaryloxy, aryl or heteroaryl.
  • the above-mentioned alkyl group also includes an alkyl group substituted with one or more deuterium atoms.
  • heteroalkyl refers herein to an alkyl group that includes at least one heteroatom.
  • alkoxy refers herein to an alkyl group attached to the rest of the molecule through an oxygen atom (-O-alkyl), where the alkyl group is as defined herein.
  • alkoxy groups include methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, n- Pentoxy etc.
  • ⁇ refers herein to -NR 8 -C(O)-alkyl, -NR 8 -C(O)-cycloalkyl, -NR 8 -C(O)-cycloalkenyl, -NR 8 -C(O)-aryl, -NR 8 -C(O)-heteroaryl and -NR 8 -C(O)-heterocycloalkyl, where R 8 is hydrogen, cycloalkyl, cycloalkenyl , Aryl, heteroaryl, heterocycloalkyl and alkyl. Wherein said hydrogen, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyl and alkyl groups are as defined herein.
  • acyl refers herein to HC(O)-, R 9 R 10 NC(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, cycloalkenyl-C( O)-, heterocycloalkyl-C(O)-, aryl-C(O)- and heteroaryl-C(O)-, wherein R 9 and R 10 are independently selected from hydrogen, hydroxyl , Alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl or cycloalkyl.
  • sulfonyl refers herein to R 11 R 12 NS(O) 2 -, cycloalkyl-S(O) 2 -, cycloalkenyl-S(O) 2 -, aryl-S(O) 2 -, heteroaryl-S(O) 2 -, heterocycloalkyl-S(O) 2 -and alkyl-S(O) 2 -, wherein R 11 and R 12 are each independently selected from hydrogen , Hydroxy, alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl or cycloalkyl.
  • sulfinyl refers herein to R 13 R 14 NS(O)-, cycloalkyl-S(O)-, cycloalkenyl-S(O)-, aryl-S(O)-, Heteroaryl-S(O)-, heterocycloalkyl-S(O)- or alkyl-S(O)-, wherein R 13 and R 14 are independently selected from hydrogen, hydroxyl, alkyl, Heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl or cycloalkyl.
  • acyloxy refers herein to -OC(O)-alkyl, -OC(O)-cycloalkyl, -OC(O)-cycloalkenyl, -OC(O)-aryl,- OC(O)-heteroaryl and -OC(O)-heterocycloalkyl, wherein the alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycloalkyl groups are as described herein Defined in.
  • ester group refers herein to alkyl-OC(O)-, cycloalkyl-OC(O)-, cycloalkenyl-OC(O)-, heterocycloalkyl-OC(O)-, Aryl-OC(O)- and heteroaryl-OC(O)-, wherein the alkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl groups are as described herein As defined.
  • substituents refers herein to any group that is mono- or poly-substituted by the specified substituent to the extent that such mono- or poly-substitution (including multiple substitutions in the same part) is chemically allowed, each substituent may It is located at any available position on the group and can be connected by any available atom on the substituent.
  • Any available position refers to any position on the group of a molecule that is chemically available by methods known in the art or methods taught herein, and does not produce an excessively unstable molecule. When there are two or more substituents on any group, each substituent is defined independently of any other substituent, and therefore may be the same or different.
  • the substituents of the compounds of the present invention are disclosed in the form of groups or ranges. This specifically means that the present invention includes each member of such groups and ranges or a sub-combination of each individual in the member.
  • the term “C 1-6 alkyl” specifically means that methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl are individually disclosed.
  • the term "compounds of the invention” refers herein to compounds of formula (I) and formula (II) and all pure and mixed stereoisomers, geometric isomers, tautomers Body, solvates, prodrugs and isotopically labeled compounds and any pharmaceutically acceptable salts.
  • the solvate of the compound of the present invention refers to a compound or salt thereof combined with stoichiometric and non-stoichiometric solvents, such as hydrate, ethanolate, methanolate, acetoneate, and the like.
  • the compound may also exist in one or more crystalline states, i.e. as a eutectic, polymorph, or it may exist as an amorphous solid. All such forms are covered by the claims.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients constituting the formulation and/or the mammal being treated with it.
  • stereoisomer refers herein to compounds having one or more stereocenters with different chiralities, including the corresponding isomers and diastereomers.
  • tautomer means herein that structural isomers with different energies can cross the low energy barrier and thus convert to each other.
  • Valence tautomers include some bond-forming electronic recombination for interconversion.
  • prodrug herein refers to any derivative of the compound of the present invention capable of directly or indirectly providing the compound of the present invention, its active metabolite or residue when administered to a subject. Particularly preferred are those derivatives or prodrugs that increase the bioavailability of the compounds of the invention, improve metabolic stability and tissue targeting.
  • the compounds of the present invention can be used in the form of salts, such as "pharmaceutically acceptable salts" derived from inorganic or organic acids. These include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, ethanesulfonate, hydrogen sulfate Salt, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentane propionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerol phosphate, semi Sulfate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, mesylate, Ethylsulfonate, hydrochloride, 2-naphthalenesulf
  • the basic nitrogen-containing groups can be quaternized with the following reagents to form quaternary ammonium salts: such as lower alkyl halides, including methyl, ethyl, propyl and butyl chloride, bromide and iodine Compounds; such as dialkyl sulfates, including dimethyl, diethyl, dibutyl, and dipentyl sulfates; such as long-chain halides, including decyl, lauryl, myristyl, and stearyl Chloride, bromide and iodide; such as aralkyl halides, such as benzyl and phenethyl bromide.
  • lower alkyl halides including methyl, ethyl, propyl and butyl chloride, bromide and iodine Compounds
  • dialkyl sulfates including dimethyl, diethyl, dibutyl, and dipentyl s
  • the present invention also includes isotopically-labeled compounds of the present invention, that is, the same structure as disclosed above, but one or more atoms in the structure are replaced by atoms having the same number of protons but different numbers of neutrons.
  • isotopes incorporating the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, and iodine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F, 36 Cl and 131 I etc.
  • the compounds of the present invention are all within the scope of the present invention.
  • Certain isotopically-labeled compounds of the present invention such as those labeled with 3 H or 14 C, can be used in pharmaceutical tissue distribution tests. Therefore, these 3 H or 14 C isotopes are particularly preferred because of their ease of preparation and detection.
  • the compound of formula (I) of the present invention can be prepared according to the following scheme 1.
  • a suitable solvent such as THF, DMF, acetonitrile, dioxane, NMP, DMSO and DMA, etc.
  • the compound SM is in an acid such as trifluoroacetic acid, phosphoric acid, methanesulfonic acid, etc., and a base such as diisopropylamine, di
  • a suitable solvent such as THF, DMF, acetonitrile, dioxane, NMP, DMSO and DMA, etc.
  • the compound SM is in an acid such as trifluoroacetic acid, phosphoric acid, methanesulfonic acid, etc.
  • a base such as diisopropylamine, di
  • ethylamine, dimethylamine, piperidine, tetrahydropyrrole, etc. it reacts with paraformaldehyde at a suitable temperature to generate intermediate M1.
  • R 1 and M2 in a suitable solvent, such as THF, acetonitrile, ethanol, methanol, dioxane, DMF, etc., in a base, such as K 2 CO 3 , Na 2 CO 3 , NaH, CsCO 3 , DBU, tert-butyl
  • a suitable solvent such as THF, acetonitrile, ethanol, methanol, dioxane, DMF, etc.
  • a base such as K 2 CO 3 , Na 2 CO 3 , NaH, CsCO 3 , DBU, tert-butyl
  • the compounds provided by the present invention can be prepared by standard synthetic methods well known in the art. This specification provides general methods for preparing the compounds of the present invention.
  • the starting materials are usually commercially available, for example by Alfa It can be purchased from other companies or prepared by methods well known to those skilled in the art.
  • the structures of the compounds of the following examples are characterized by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • reaction starting materials, intermediates and example compounds can be separated and purified by conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography (such as column chromatography, TLC separation and purification, etc.).
  • reaction conditions reaction temperature, reaction solvent, molar ratio of reactants or/and reaction duration
  • reaction temperature reaction temperature, reaction solvent, molar ratio of reactants or/and reaction duration
  • the progress of the reaction can be monitored by TLC, and an appropriate time can be selected to terminate the reaction and perform post-treatment accordingly.
  • the purification conditions of the compound may also change.
  • the appropriate column chromatography eluent is selected according to the R f value of TLC, or the corresponding compound is separated and purified by preparing TLC.
  • Toluene (300ml) and methylaluminum bis(2,6-di-tert-butyl-4-anisole) (66g) were added to the 2L reaction flask in turn, the temperature was lowered to 0°C, and 2.0M trimethylaluminum/toluene was added The solution (76 ml) was stirred at 20°C for 1 hour after the addition, and then the temperature was lowered to -80°C. Slowly add SA-B (16g) in 200ml toluene solution, and continue stirring for 1 hour after the addition.
  • compound 4 can also be prepared according to the following scheme:
  • Toluene (260g), ethyltriphenylphosphonium bromide (96g), potassium tert-butoxide (29g) were added to a 2L reaction flask in this order, and the temperature was raised to 60°C and stirred for 2 hours.
  • a toluene solution (100 g) of SAD-C (30 g) was added, and the temperature was raised to 90°C to react for 2 hours.
  • the reaction solution was cooled to room temperature, 390 g of saturated ammonium chloride solution was added to quench the reaction and stirred for 15 to 30 minutes. After standing, the layers were separated, and the aqueous layer was extracted once with 100 g of ethyl acetate.
  • N,N-dimethylacetamide (28g) and diisopropylamine (6g) in sequence, lower the temperature to below 10°C, and add N,N dimethylacetamide solution of trifluoroacetic acid (10g) (28g), after the addition is completed, the temperature is stopped and stirred for 30 minutes.
  • a solution of SAD-F (15g) in N,N-dimethylacetamide (80g) was added, followed by paraformaldehyde (6g). After the addition, the temperature was raised to 90°C and reacted for 20 hours.
  • reaction solution was cooled to room temperature, 200 g of ethyl acetate and 400 g of water were added, stirred for 10 minutes, and allowed to stand for liquid separation.
  • the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, washed twice with saturated sodium chloride, and anhydrous sulfuric acid Sodium was dried, filtered, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography to obtain 10g of light yellow solid.
  • the voltage clamp recording mode was used to clamp the cell membrane potential to -60mV. After stabilization, the first round of stimulation of GABA was given instantaneously; then the second round of stimulation with GABA and the compound was given under the same voltage mode.
  • the current value induced by 5 ⁇ M GABA acting on the cell is measured, and then the current value induced by 5 ⁇ M GABA and 10 ⁇ M test compound acting on the cell is measured, thereby calculating the combined effect of 5 ⁇ M GABA and 10 ⁇ M.
  • A 0 ⁇ E max ⁇ 200
  • B 200 ⁇ E max ⁇ 500
  • C E max >500.
  • SAGE-547 is an allosteric modulator of GABAA receptors and has shown significant therapeutic effects in a phase 3 clinical trial for the treatment of postpartum depression.
  • compound 4 (20 mg/kg) was administered by gavage, and no animal deaths were observed until 24 hours.
  • SAGE-217 is a steroid drug undergoing clinical trials.
  • 96 SD rats were randomly divided into 6 groups, 16 in each group, half male and female.
  • the 6 groups were given vehicle, compound 1 (2 mg/kg), compound 2 (2 mg/kg), compound 4 (1.5 mg/kg), compound 11 (2 mg/kg), paroxetine (20 mg/kg). Except for the paroxetine group, which was administered 3 times at 23.5h, 5h, and 1h before the test, the other groups were administered once a day for 3 consecutive days.
  • the compounds of the examples of the present invention showed a significant effect of reducing immobility time in the forced swimming test of rats.

Abstract

La présente invention concerne des composés de formules (I), (II), (III) et (IV), un stéréoisomère, un tautomère ou un sel pharmaceutiquement acceptable de ceux-ci. L'invention concerne un procédé de préparation de tels composés et l'utilisation des composés dans le traitement de maladies, telles que diverses maladies du système nerveux.
PCT/CN2019/128092 2018-12-26 2019-12-24 Classe de composés stéroïdes et leur utilisation WO2020135454A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021188778A3 (fr) * 2020-03-18 2021-10-28 Sage Therapeutics, Inc. Stéroïdes neuroactifs et leurs procédés d'utilisation
US11718642B2 (en) 2018-01-12 2023-08-08 Sage Therapeutics, Inc. Compositions and methods for treating CNS disorders

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018013615A1 (fr) * 2016-07-11 2018-01-18 Sage Therapeutics, Inc. Stéroïdes neuroactifs substitués en c7, c12 et c16 et méthodes d'utilisation associées
WO2018195186A1 (fr) * 2017-04-18 2018-10-25 Marinus Pharmaceuticals, Inc Formulations de neurostéroïde injectables à libération prolongée
CN109503694A (zh) * 2018-11-21 2019-03-22 苏州闻天医药科技有限公司 一种新型gabaa受体调节剂及其用途
WO2019094724A1 (fr) * 2017-11-10 2019-05-16 Marinus Pharmaceuticals, Inc. Ganaxolone destinée à être utilisée dans le traitement de troubles épileptiques génétiques
WO2019154257A1 (fr) * 2018-02-11 2019-08-15 江苏豪森药业集团有限公司 Régulateur de dérivé de stéroïde, son procédé de préparation et son utilisation
WO2019154247A1 (fr) * 2018-02-11 2019-08-15 江苏豪森药业集团有限公司 Régulateur de dérivé de stéroïde, son procédé de préparation et son utilisation

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018013615A1 (fr) * 2016-07-11 2018-01-18 Sage Therapeutics, Inc. Stéroïdes neuroactifs substitués en c7, c12 et c16 et méthodes d'utilisation associées
WO2018195186A1 (fr) * 2017-04-18 2018-10-25 Marinus Pharmaceuticals, Inc Formulations de neurostéroïde injectables à libération prolongée
WO2019094724A1 (fr) * 2017-11-10 2019-05-16 Marinus Pharmaceuticals, Inc. Ganaxolone destinée à être utilisée dans le traitement de troubles épileptiques génétiques
WO2019154257A1 (fr) * 2018-02-11 2019-08-15 江苏豪森药业集团有限公司 Régulateur de dérivé de stéroïde, son procédé de préparation et son utilisation
WO2019154247A1 (fr) * 2018-02-11 2019-08-15 江苏豪森药业集团有限公司 Régulateur de dérivé de stéroïde, son procédé de préparation et son utilisation
CN109503694A (zh) * 2018-11-21 2019-03-22 苏州闻天医药科技有限公司 一种新型gabaa受体调节剂及其用途

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11718642B2 (en) 2018-01-12 2023-08-08 Sage Therapeutics, Inc. Compositions and methods for treating CNS disorders
WO2021188778A3 (fr) * 2020-03-18 2021-10-28 Sage Therapeutics, Inc. Stéroïdes neuroactifs et leurs procédés d'utilisation

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