WO2020259612A1 - Antidepressant steroid compound - Google Patents

Abstract

Disclosed in the present invention are a compound represented by general formula I, a pharmaceutically acceptable salt, solvate, or stereoisomeride containing mixtures at different ratios thereof, and a pharmaceutical composition containing the compound. R₁, R₂, R₃, R_4a, R_4b, R_4c, R_4d, R_6a, R_6b, R_6c, R_6d, R_6e, R_7a, R_7b, R_8a, R_8b, R_9a, R_9b, R_10a, R_10b, X₁, X₂, X₃, X₄, etc. have the meanings given in the description. The present invention also relates to a preparation method for the compound, and use of the compound and the pharmaceutically acceptable salt, solvate, or stereoisomeride containing mixtures at different ratios thereof, particularly use in the preparation of drugs for preventing, treating, curing, or relieving depression.

Description

一种抗抑郁甾体化合物An antidepressant steroid compound 技术领域Technical field

本发明一种化合物及其药学上可接受的盐、溶剂化物、各种比例混合物在内的立体异构体以及含有所述化合物的药物组合物。本发明还涉及该类化合物其药学上可接受的盐、溶剂化物、各种比例混合物在内的立体异构体的用途，特别是在制备用于防护、处理、治疗或减轻抑郁症的药物中的用途。A compound of the present invention, pharmaceutically acceptable salts, solvates, stereoisomers including mixtures in various ratios, and pharmaceutical compositions containing the compound. The present invention also relates to the use of such compounds as pharmaceutically acceptable salts, solvates, and stereoisomers in various ratios of mixtures, especially in the preparation of drugs for protection, treatment, treatment or alleviation of depression the use of.

背景技术Background technique

抑郁症是危害人类健康的常见病和多发病。在我国，情感性精神病的发病率为0.76％。抑郁症的发病率很高，但现在对它的发病原因仍不十分清楚。临床上当前应用较为常用的抗抑郁药物有：三环和四环类抗抑郁药、单胺氧化酶抑制剂、选择性5-HT重吸收抑制剂(SSRI)、非典型抗抑郁药和锂盐等。Depression is a common and frequently-occurring disease that endangers human health. In my country, the incidence of affective psychosis is 0.76%. The incidence of depression is very high, but the cause of it is still not very clear. The most commonly used antidepressants in clinical applications include tricyclic and tetracyclic antidepressants, monoamine oxidase inhibitors, selective 5-HT reuptake inhibitors (SSRI), atypical antidepressants and lithium salts.

针对抑郁症的治疗，本领域还需进行深入研究和开发。For the treatment of depression, in-depth research and development are needed in this field.

发明内容Summary of the invention

本发明的目的在于提供一种菝葜皂苷元衍生物及其药学上可接受的盐。The purpose of the present invention is to provide a smilogenin derivative and a pharmaceutically acceptable salt thereof.

本发明的第一方面，提供一种式I所示的化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体、立体异构体或它们的混合物，The first aspect of the present invention provides a compound represented by formula I, or a pharmaceutically acceptable salt, solvate, optically pure isomer, stereoisomer, or mixture thereof,

所述式I所示的化合物由以下片段A和片段B连接而成，The compound represented by formula I is formed by connecting the following fragment A and fragment B,

X ₁、X ₂、X ₃、X ₄各自独立地选自N、C、CR _5a，R _5a选自氢、氰基、卤素、羟基、烷氧基、氨基、取代的氨基， X ₁ , X ₂ , X ₃ , and X ₄ are each independently selected from N, C, CR _5a , and R _{5a is} selected from hydrogen, cyano, halogen, hydroxy, alkoxy, amino, and substituted amino,

R ₁独立地选自氢、烷基、取代的烷基、烷氧基、芳氧基、烷酰氧基、芳酰氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺(其中所述的两个氨基取代基选自烷基、芳基或芳基烷基)，烷酰基、取代的烷酰基、烷氧基羰基、芳基烷氧基羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基甲酰基、取代的氨基甲酰基、酰基氨基、取代的酰基氨基， R _{1 is} independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkylamino, arylamino, arylalkylamino, Disubstituted amine (wherein the two amino substituents are selected from alkyl, aryl or arylalkyl), alkanoyl, substituted alkanoyl, alkoxycarbonyl, arylalkoxycarbonyl, alkyl Sulfonyl, arylsulfonyl, arylalkylsulfonyl, carbamoyl, substituted carbamoyl, acylamino, substituted acylamino,

R ₂选自氢、烷基、取代的烷基、烷氧基、芳氧基、烷酰氧基、芳酰氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺(其中所述的两个氨基取代基选自烷基、芳基或芳基烷基)，烷酰基、取代的烷酰基、烷氧基羰基、芳基烷氧基羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基甲酰基、取代的氨基甲酰基、酰基氨基、取代的酰基氨基； R _{2 is} selected from hydrogen, alkyl, substituted alkyl, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted The amine (wherein the two amino substituents are selected from alkyl, aryl or arylalkyl), alkanoyl, substituted alkanoyl, alkoxycarbonyl, arylalkoxycarbonyl, alkylsulfonyl , Arylsulfonyl, arylalkylsulfonyl, carbamoyl, substituted carbamoyl, acylamino, substituted acylamino;

R ₃选自氢、烷基、杂芳基、取代的杂芳基、卤素、羟基、烷氧基、氨基、取代的氨基、氰基， R _{3 is} selected from hydrogen, alkyl, heteroaryl, substituted heteroaryl, halogen, hydroxy, alkoxy, amino, substituted amino, cyano,

R _4a、R _4b、R _4c、R _4d各自独立地选自氢、烷基、取代的烷基、烯基、取代的烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环基、取代的杂环基、卤素、羟基、烷氧基、氨基、取代的氨基、氰基、羧基、烷氧羰基、氨基酰基、取代的氨基酰基、硝基、-S-烷基， R _4a , R _4b , R _4c , R _4d are each independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, Heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclic, halogen, hydroxy, alkoxy, amino, substituted amino, cyano, carboxy, alkoxycarbonyl, aminoacyl, substituted aminoacyl , Nitro, -S-alkyl,

R _6a、R _6b、R _6c、R _6d、R _6e、R _6f、R _7a、R _7b、R _8a、R _8b、R _9a、R _9b、R _10a、R _10b各自独立地选自无、氢、卤素、烷基、羟基、糖基，或者R _6a、R _6b两两之间和/或R _7a、R _7b两两之间和/或R _8a、R _8b两两之间和/或R _9a、R _9b两两之间和/或R _10a、R _10b两两之间合并成羰基， R _6a , R _6b , R _6c , R _6d , R _6e , R _6f , R _7a , R _7b , R _8a , R _8b , R _9a , R _9b , R _10a , R _10b are each independently selected from none, hydrogen, Halogen, alkyl, hydroxyl, sugar group, or between R _6a and R _6b and/or between R _7a and R _7b and/or between R _8a and R _8b and/or R _9a , R _9b and/or R _10a and R _10b are combined to form a carbonyl group,

表示单键或者双键，

Means single bond or double bond,

各*独立地表示消旋、S或R构型。Each * independently represents the racemic, S or R configuration.

在另一优选例中，所述化合物具有以下结构：In another preferred embodiment, the compound has the following structure:

式中，X ₁、X ₂、X ₃、X ₄、R _4a、R _4b、R _4c、R _4d、*的定义如前所述。 In the formula, X ₁ , X ₂ , X ₃ , X ₄ , R _4a , R _4b , R _4c , R _4d , and * are as defined above.

在另一优选例中，所述化合物具有以下结构：In another preferred embodiment, the compound has the following structure:

式中，X ₁、X ₂、X ₃、X ₄、R _4a、R _4b、R _4c、R _4d的定义如前所述。 In the formula, X ₁ , X ₂ , X ₃ , X ₄ , R _4a , R _4b , R _4c , and R _4d are as defined above.

在另一优选例中，所述片段A为：In another preferred example, the segment A is:

在另一优选例中，所述片段B选自下组：In another preferred embodiment, the segment B is selected from the following group:

R _4e选自氢、甲基、三氟甲基、甲氧基、氟、氯、溴、碘、羟基、氨基、烷基酰基氨基、氰基、羧基、烷氧羰基、氨基酰基、取代的氨基酰基、硝基、-S-烷基。 R _{4e is} selected from hydrogen, methyl, trifluoromethyl, methoxy, fluorine, chlorine, bromine, iodine, hydroxy, amino, alkylacylamino, cyano, carboxyl, alkoxycarbonyl, aminoacyl, substituted amino Acyl, nitro, -S-alkyl.

在另一优选例中，所述片段A选自下组：In another preferred embodiment, the fragment A is selected from the following group:

片段B选自下组：Fragment B is selected from the following group:

R _4e选自氢、甲基、三氟甲基、甲氧基、卤素、羟基、氨基、烷基酰基氨基、氰基、羧基、烷氧羰基、氨基酰基、取代的氨基酰基、硝基、-S-烷基。 R _{4e is} selected from hydrogen, methyl, trifluoromethyl, methoxy, halogen, hydroxy, amino, alkylacylamino, cyano, carboxy, alkoxycarbonyl, aminoacyl, substituted aminoacyl, nitro,- S-alkyl.

在另一优选例中，所述化合物为：In another preferred embodiment, the compound is:

本发明的另一方面提供一种药物混合物，包含选自下组的两种或三种以上的化合物：所述的式I的化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体、立体异构体。Another aspect of the present invention provides a pharmaceutical mixture comprising two or more compounds selected from the group consisting of: the compound of formula I, or a pharmaceutically acceptable salt, solvate, or optical purity thereof Constructs, stereoisomers.

本发明的另一方面提供了一种药物组合物，包含一种或多种所述的式I的化合物或其药学上可接受的盐、溶剂化物或其异构体，以及药学上可接受的载体、稀释剂、赋形剂、辅剂、媒介物或它们的组合。这些组合物亦可在食品或保健品中有所应用。Another aspect of the present invention provides a pharmaceutical composition comprising one or more of the compound of formula I or a pharmaceutically acceptable salt, solvate or isomer thereof, and a pharmaceutically acceptable Carriers, diluents, excipients, adjuvants, vehicles, or combinations thereof. These compositions can also be used in food or health products.

所述的药物组合物可以包含一种或多种所述的式I的化合物，也可以更进一步地包含附加治疗剂，这些附加治疗剂选自：抗抑郁药或它们的组合。The pharmaceutical composition may include one or more of the compounds of formula I, and may further include additional therapeutic agents selected from: antidepressants or their combinations.

本发明的另一方面提供了用所述的式I化合物来制备用于防护、处理、治疗或减轻患者疾病、病症或病状的药物的用途，其包含给需要的哺乳动物施用有效量的本发明的 化合物或其立体异构体、几何异构体、互变异构体、溶剂合物和“可接受的盐”。所述的疾病、病症或病状为抑郁症。Another aspect of the present invention provides the use of the compound of formula I to prepare a medicament for the protection, treatment, treatment or alleviation of a patient’s disease, disorder or condition, which comprises administering an effective amount of the present invention to a mammal in need The compound or its stereoisomers, geometric isomers, tautomers, solvates and "acceptable salts". The disease, disorder or condition is depression.

本发明的另一方面提供了用包含所述的式I化合物的药物组合物来制备用于防护、处理、治疗或减轻患者疾病、病症或病状的药物的用途。这些药物组合物包含一种或多种所述的式I的化合物或其药学上可接受的盐、溶剂化物或其异构体，以及药学上可接受的载体、稀释剂、赋形剂、辅剂、媒介物或它们的组合。所述的疾病、病症或病状的为抑郁症。Another aspect of the present invention provides the use of a pharmaceutical composition comprising the compound of formula I to prepare a medicament for protection, treatment, treatment or alleviation of a patient's disease, disorder or condition. These pharmaceutical compositions contain one or more of the compounds of formula I or their pharmaceutically acceptable salts, solvates or isomers thereof, and pharmaceutically acceptable carriers, diluents, excipients, and auxiliary agents. Agents, vehicles, or combinations thereof. The disease, disorder or condition is depression.

具体实施方式Detailed ways

定义definition

下面是本说明书中所用术语的定义。除非另外指出，本文所提供的基团或术语的初始定义适用于本书明说中单独地或作为其他基团的一部分的基团或者术语。The following are definitions of terms used in this specification. Unless otherwise indicated, the initial definitions of the groups or terms provided herein apply to the groups or terms described in this manual alone or as part of other groups.

术语“取代的”是指本发明说明书中提到的任一取代基，包括但不限于，卤素、硝基、氰基、羧基、氧代基、烷基、取代的烷基、环烷基、取代的环烷基、链烯基、取代的链烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环、取代的杂环、羟基、烷氧基、芳氧基、烷酰氧基、芳酰氧基、氨基、烷酰基氨基、芳酰基氨基、芳基烷基酰基氨基、杂芳基烷基酰基氨基、氨基烷基酰基氨基、烷基氨基烷基酰基氨基、二烷基氨基烷基酰基氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺(其中所述的两个氨基取代基选自烷基、芳基或芳基烷基)、烷酰基、取代的烷酰基、芳酰基、杂芳酰基、羧基、烷氧基羰基、芳氧基羰基、烷氨基羰基、芳氨基羰基、芳基烷氧基羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基甲酰基、取代的氨基甲酰基、取代的烷基氨基甲酰基、酰胺、取代的酰胺、磺酰胺基、取代的磺酰胺基。The term "substituted" refers to any substituent mentioned in the specification of the present invention, including but not limited to halogen, nitro, cyano, carboxy, oxo, alkyl, substituted alkyl, cycloalkyl, Substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, Hydroxy, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkanoylamino, aroylamino, arylalkylacylamino, heteroarylalkylacylamino, aminoalkylacylamino , Alkylamino alkyl acyl amino, dialkyl amino alkyl acyl amino, alkyl amino, aryl amino, aryl alkyl amino, di-substituted amine (wherein the two amino substituents are selected from alkyl , Aryl or arylalkyl), alkanoyl, substituted alkanoyl, aroyl, heteroaroyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, arylalkoxy Carbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, carbamoyl, substituted carbamoyl, substituted alkylcarbamoyl, amide, substituted amide, sulfonamide, substituted sulfonyl Amide group.

术语“卤素”或“卤”是指氟、氯、溴、碘。The term "halogen" or "halo" refers to fluorine, chlorine, bromine, and iodine.

术语“烷基”是指直链或者支链未取代的具有1-20个碳原子、优选1-7或1-6或1-4个碳原子的烃基团。“烷基”的实例包括但是不要局限于甲基、乙基、1-丙基、2-丙基、1-丁基、2-丁基等等。The term "alkyl" refers to a straight or branched unsubstituted hydrocarbon group having 1-20 carbon atoms, preferably 1-7 or 1-6 or 1-4 carbon atoms. Examples of "alkyl" include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, and the like.

术语“取代的烷基”是指由1-4个取代基取代的烷基，所述的取代基诸如：卤素、硝基、氰基、羧基、氧代基、烷基、取代的烷基、环烷基、取代的环烷基、链烯基、取代的链烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环、取代的杂环、羟基、烷氧基、芳氧基、烷酰氧基、芳酰氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺(其中所述的两个氨基取代基选自烷基、芳基或芳基烷基)、烷酰基、取代的烷酰基、烷氧基羰基、芳基烷氧基羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基甲酰基、取代的氨基甲酰基、酰胺、取代的酰胺、磺酰胺基、取代的磺酰胺基。The term "substituted alkyl" refers to an alkyl group substituted with 1 to 4 substituents, such as halogen, nitro, cyano, carboxy, oxo, alkyl, substituted alkyl, Cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted The heterocyclic ring, hydroxyl, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine (the two One amino substituent is selected from alkyl, aryl or arylalkyl), alkanoyl, substituted alkanoyl, alkoxycarbonyl, arylalkoxycarbonyl, alkylsulfonyl, arylsulfonyl, aryl Alkylsulfonyl, carbamoyl, substituted carbamoyl, amide, substituted amide, sulfonamide, substituted sulfonamide.

术语“链烯基”是指具有2-20个碳原子、优选2-15个碳原子、最优选2-8个碳原子，且具有1-4个双键的直链或支链烃基团。The term "alkenyl" refers to a straight or branched hydrocarbon group having 2-20 carbon atoms, preferably 2-15 carbon atoms, most preferably 2-8 carbon atoms, and having 1-4 double bonds.

术语“取代的链烯基”是指由1-2个取代基取代的链烯基，所述取代基例如：卤素、硝基、 氰基、芳基、取代的芳基、杂芳基、取代的杂芳基、The term "substituted alkenyl" refers to an alkenyl group substituted with 1-2 substituents such as halogen, nitro, cyano, aryl, substituted aryl, heteroaryl, substituted Of heteroaryl,

烷氧基、芳氧基、烷酰氧基、芳酰氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺(其中所述的两个氨基取代基选自烷基、芳基或芳基烷基)。Alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine (wherein the two amino substituents are selected from Alkyl, aryl or arylalkyl).

术语“炔基”是指具有2-20个碳原子、优选2-15个碳原子、最优选2-8个碳原子，且具有1-4个三键的直链或支链烃基团。The term "alkynyl" refers to a straight or branched hydrocarbon group having 2-20 carbon atoms, preferably 2-15 carbon atoms, most preferably 2-8 carbon atoms, and having 1-4 triple bonds.

术语“取代的炔基”是指由以下取代基取代的炔基，所述取代基例如：卤素、硝基、氰基、芳基、取代的芳基、杂芳基、取代的杂芳基、羟基、烷氧基、芳氧基、烷酰氧基、芳酰氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺(其中所述的两个氨基取代基选自烷基、芳基或芳基烷基)。The term "substituted alkynyl" refers to an alkynyl group substituted with a substituent such as halogen, nitro, cyano, aryl, substituted aryl, heteroaryl, substituted heteroaryl, Hydroxy, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amine (wherein the two amino substituents (Selected from alkyl, aryl or arylalkyl).

术语“芳基”是指在环部分中具有6-12个碳原子的单环或双环芳烃基团。芳基包括二环基团，该二环将基团中包括稠合至饱和的或部分不饱和的芳族环，或者芳族碳环或杂环的环。通常芳基基团包括但是不局限于以下的基团：苯、萘、蒽、联苯基、1,2-二氢萘、1,2,3,4-四氢萘基等等。The term "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6-12 carbon atoms in the ring portion. The aryl group includes a bicyclic group that includes an aromatic ring fused to a saturated or partially unsaturated group, or an aromatic carbocyclic or heterocyclic ring. Generally aryl groups include, but are not limited to, the following groups: benzene, naphthalene, anthracene, biphenyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like.

术语“取代的芳基”是指由1-4个取代基取代的芳基，所述取代基例如：卤素、卤素、硝基、氰基、脲基、羧基、三氟甲氧基、三氟甲基、烷基、取代的烷基、环烷基、取代的环烷基、链烯基、取代的链烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环、取代的杂环、羟基、烷氧基、芳氧基、烷酰氧基、芳酰氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺(其中所述的两个氨基取代基选自烷基、芳基或芳基烷基)，烷酰基、取代的烷酰基、烷氧基羰基、芳基烷氧基羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基甲酰基、取代的氨基甲酰基、酰胺、取代的酰胺、磺酰胺基、取代的磺酰胺基。The term "substituted aryl" refers to an aryl group substituted with 1-4 substituents, such as halogen, halogen, nitro, cyano, ureido, carboxy, trifluoromethoxy, trifluoro Methyl, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl , Substituted heteroaryl, heterocycle, substituted heterocycle, hydroxyl, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkylamino, arylamino, arylalkylamino , Disubstituted amines (wherein the two amino substituents are selected from alkyl, aryl or arylalkyl), alkanoyl, substituted alkanoyl, alkoxycarbonyl, arylalkoxycarbonyl, alkane Sulfonyl, arylsulfonyl, arylalkylsulfonyl, carbamoyl, substituted carbamoyl, amide, substituted amide, sulfonamide, substituted sulfonamide.

术语“环烷基”是指非芳族的、饱和的或部分不饱和的环烃基团，所述环烷基可以任意地被一个或多个本申请所述的取代基取代，其具有3-30个碳原子成为单环的环，或者7-12The term "cycloalkyl" refers to a non-aromatic, saturated or partially unsaturated cyclic hydrocarbon group. The cycloalkyl group can be optionally substituted with one or more substituents described in the application, which has a 3- 30 carbon atoms become a monocyclic ring, or 7-12

个碳原子成为二环的环。单环环烷基的实例包括但是不局限于环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、1-环己-1-烯基、环庚基、环辛基。示例性的成桥二环环烷基包括但是不局限于二环[2.2.1]庚烷、二环[2.2.2]辛烷、二环[3.2.2]壬烷。A carbon atom becomes a bicyclic ring. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3 -Alkenyl, cyclohexyl, 1-cyclohex-1-enyl, cycloheptyl, cyclooctyl. Exemplary bridged bicyclic cycloalkyl groups include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane.

术语“杂环”、“杂环的”和“杂环基”是指任选取代的、完全饱和的或不饱和的、芳族或非芳族环基团，例如它可以是4-7元单环、7-11元双环或10-15元三环体系，其在至少一个含碳原子的环中具有至少一个杂原子。含杂原子的杂环基的每个环可以具有1、2或3个选自氮原子、氧原子和硫原子的杂原子。所述“杂环基”可以任意地被一个或多个本申请所述的取代基取代，“杂环基”的实例包括但是不局限于吡咯烷基、四氢呋喃基、四氢吡喃基、吗啉代、硫吗啉代、哌嗪基、高哌嗪基、环氧丙烷基、咪唑烷基、3-氮杂二环[3.1.0]己烷基、3-氮杂二环[4.1.0]庚烷基、氮杂二环[2.2.2]己烷基、N-吡啶基脲、嘧啶酮基和1,1-二氧代-硫吗啉基。The terms "heterocyclic", "heterocyclic" and "heterocyclyl" refer to an optionally substituted, fully saturated or unsaturated, aromatic or non-aromatic ring group, for example it can be 4-7 membered Monocyclic, 7-11 membered bicyclic or 10-15 membered tricyclic ring system, which has at least one heteroatom in at least one ring containing carbon atoms. Each ring of the heteroatom-containing heterocyclic group may have 1, 2, or 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms. The "heterocyclic group" may be optionally substituted with one or more substituents described in this application. Examples of "heterocyclic group" include but are not limited to pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and Pholino, thiomorpholino, piperazinyl, homopiperazinyl, propylene oxide, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1. 0]Heptyl, azabicyclo[2.2.2]hexyl, N-pyridylurea, pyrimidinone and 1,1-dioxo-thiomorpholinyl.

术语“杂芳基”是指5-、6-、7-、8、9或10-元环的一价芳香基团，并且包括5-20个原子的稠合***，含有一个或多个选自氮、氧、磷和硫的杂原子，可以任意地被一个或多个本申 请所述的取代基取代。“杂芳基”的实例包括但是不局限于吡啶基、咪唑基、咪唑并吡啶基、嘧啶基、吡唑基、***基、吡嗪基、四唑基、呋喃基、噻吩基、噻唑基、喹啉基、吲哚基等等。The term "heteroaryl" refers to a 5-, 6-, 7-, 8, 9 or 10-membered ring monovalent aromatic group, and includes a fused system of 5-20 atoms, containing one or more options The heteroatoms from nitrogen, oxygen, phosphorus and sulfur can be optionally substituted by one or more substituents described in this application. Examples of "heteroaryl" include, but are not limited to, pyridyl, imidazolyl, imidazopyridyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, thiazolyl , Quinolinyl, indolyl and so on.

术语“氧代基”代表二价基＝O。The term "oxo" represents the divalent group =O.

术语“氨基甲酰基”是指-OC(＝O)NH ₂基团。 The term "carbamoyl" refers to the -OC(=O)NH ₂ group.

术语“酰胺”是指-C(＝O)NH ₂基团。 The term "amide" refers to the -C(=O)NH ₂ group.

术语“磺酰胺基”是指-SO ₂NH ₂基团。 The term "sulfonamido" refers to the -SO ₂ NH ₂ group.

术语“取代的氨基甲酰基”、“取代的酰胺”、“取代的磺酰胺基”是指酰胺、磺酰胺或氨基甲酸酯分别至少有一个氢被选自烷基、取代的烷基、链烯基、取代的链烯基、环烷基、取代的环烷基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环基、取代的杂环基的基团所取代。The terms "substituted carbamoyl", "substituted amide", and "substituted sulfonamide group" mean that the amide, sulfonamide or carbamate each has at least one hydrogen selected from alkyl, substituted alkyl, chain Alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclic group replace.

短语“可接受的盐”，是指本发明化合物的药学上可接受有机或无机盐。示例性的盐包括但是不局限于硫酸盐、枸橼酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、酸式硫酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸式枸橼酸盐、琥珀酸盐、马来酸盐、延胡索酸盐、葡萄糖酸盐、甲酸盐、甲磺酸盐和巴莫酸盐。“可接受的盐”可涉及包括另一分子例如马来酸盐或其他平衡离子。平衡离子在母体化合物中稳定电荷。“可接受的盐”可以有多于一个的荷电原子，多个荷电原子可具有多个平衡离子。The phrase "acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of the compound of the present invention. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, acid sulfate, isonicotinate, lactate , Salicylate, acid citrate, succinate, maleate, fumarate, gluconate, formate, methanesulfonate and palmoate. "Acceptable salt" may involve the inclusion of another molecule such as maleate or other counterions. The counterion stabilizes the charge in the parent compound. An "acceptable salt" can have more than one charged atom, and multiple charged atoms can have multiple counter ions.

如果本发明化合物是碱，需要的“可接受的盐”可通过适宜的方法制备，例如，用以下的无机酸处理该游离碱：盐酸、氢溴酸、硫酸、硝酸、磷酸；或者用如下的有机酸：乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、水杨酸、吡喃糖苷基酸如葡萄糖醛酸或半乳糖醛酸、α-羟基酸如枸橼酸或酒石酸、氨基酸如谷氨酸、芳香族酸如苯甲酸或肉桂酸、磺酸如甲磺酸或对甲苯磺酸。If the compound of the present invention is a base, the required "acceptable salt" can be prepared by a suitable method, for example, treating the free base with the following mineral acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; or using the following Organic acids: acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, salicylic acid, pyranoside acid such as glucuronic acid or galacturonic acid, α-hydroxy acid such as Citrate or tartaric acid, amino acids such as glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, sulfonic acids such as methanesulfonic acid or p-toluenesulfonic acid.

如果本发明化合物是酸，需要的“可接受的盐”可通过适宜的方法制备，例如，用如下的无机碱或者有机碱处理该游离酸：胺、碱金属氢氧化物或碱土金属氢氧化物等。适宜的盐的示例性的示例包括但是不限于由氨基酸得到的有机盐，伯、仲、叔胺盐，以及环状胺例如哌啶、吗啉和哌嗪的盐，以及由钠、钙、钾、镁、锰、铁、铜、锌、铝和锂得到的无机盐。If the compound of the present invention is an acid, the required "acceptable salt" can be prepared by a suitable method, for example, treating the free acid with the following inorganic or organic bases: amine, alkali metal hydroxide or alkaline earth metal hydroxide Wait. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids, primary, secondary, and tertiary amine salts, and salts of cyclic amines such as piperidine, morpholine and piperazine, and salts derived from sodium, calcium, and potassium. , Magnesium, manganese, iron, copper, zinc, aluminum and lithium.

溶剂合物是指一个或多个溶剂分子与本发明化合物的结合物或络合物。形成溶剂合物的溶剂的示例包括但是不局限于水、异丙醇、乙醇、甲醇、二甲亚砜、乙酸乙酯、乙酸和乙醇胺。本发明化合物可以以非溶剂化形式存在，也可以与药学上可接受的溶剂如水、乙醇等以溶剂化形式存在，所以本发明将包括溶剂化和非溶剂化的形式。Solvate refers to a combination or complex of one or more solvent molecules with the compound of the present invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine. The compound of the present invention may exist in an unsolvated form, or in a solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc., so the present invention will include both solvated and unsolvated forms.

本发明的化合物可以含有不对称中心或手性中心，并且因此存在不同的立体异构体形式。本发明化合物的所有立体异构体形式，包括但不局限于，非对映体、对映体和位阻异构体，以及它们的混合物例如外消旋混合物，将形成本发明的一部分。在本文中，当任何特定手性原子的立体化学未确定时，所有立体异构体均被考虑。此外，本发明涉及所有的几何和位置异构体。本发明化合物可以以不同的互变异构体形式存在，并且所有这些形式均包括在 本发明范围内。本发明化合物的所有立体异构体预期包括混合物形式或纯的或基本上纯的形式。可以通过物理方法例如分步结晶、非对映体衍生物的分离或结晶、或者通过手性柱层析分离来拆分。The compounds of the present invention may contain asymmetric centers or chiral centers, and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and hindered isomers, and their mixtures such as racemic mixtures, will form part of the present invention. In this article, when the stereochemistry of any particular chiral atom is not determined, all stereoisomers are considered. In addition, the present invention relates to all geometric and positional isomers. The compounds of the present invention may exist in different tautomeric forms, and all these forms are included in the scope of the present invention. All stereoisomers of the compounds of the present invention are expected to include mixture forms or pure or substantially pure forms. It can be resolved by physical methods such as fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography.

本发明的化合物可以单独使用，或者与其他治疗剂联合使用。联合治疗可以提供协同作用，即当活性成分一起使用时达到的效果，大于分别使用所述化合物所产生效果的加和。The compounds of the present invention can be used alone or in combination with other therapeutic agents. Combination therapy can provide synergy, that is, the effect achieved when the active ingredients are used together is greater than the sum of the effects produced by using the compounds separately.

所述联合治疗可以以同时或连续的方案施用。当连续施用时，所述组合可以以两种或多种用法来施用。化合物可以再单一的药物组合中一起施用，或分开施用，且当分开施用时，可以同时地或以任意次序先后地进行。所述的附加治疗剂包含但是不局限于吗氯贝胺、托洛沙酮、氟西汀、帕罗西汀、西酞普兰、舍曲林、文拉法辛、曲米帕明、曲唑酮、丙咪嗪、地昔帕明、氯米帕明、阿米替林、去甲替林、多塞平、马普替林、洛沙平、阿莫沙平、米氮，或它们的组合。The combination therapy can be administered on a simultaneous or continuous regimen. When administered continuously, the combination can be administered in two or more usages. The compounds may be administered together in a single drug combination, or administered separately, and when administered separately, they may be administered simultaneously or sequentially in any order. The additional therapeutic agents include, but are not limited to, moclobemide, troxanone, fluoxetine, paroxetine, citalopram, sertraline, venlafaxine, trimipramine, trazodone, Imipramine, desipramine, clomipramine, amitriptyline, nortriptyline, doxepin, maprotiline, loxapine, amoxapine, mirtaza, or combinations thereof.

本发明化合物可以通过适宜所治疗病况的任何途径施用。适宜的途径包括但是不局限于口腔、胃肠外(包括皮下、肌内、静脉内、动脉内、皮内)、***、腹膜内、肺内和鼻内。应当理解，优选的途径可以因例如病人的病况变化。当所述化合物经口施用时，可以将其与药学上可接受的载体或赋形剂配制成丸剂、胶囊剂、片剂等。当所述化合物配制成胃肠外时，其可以与药学上可接受的胃肠外载体配制。The compounds of the present invention can be administered by any route suitable for the condition being treated. Suitable routes include, but are not limited to, oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal), vaginal, intraperitoneal, intrapulmonary, and intranasal. It should be understood that the preferred route may vary due to, for example, the condition of the patient. When the compound is administered orally, it can be formulated into pills, capsules, tablets and the like with pharmaceutically acceptable carriers or excipients. When the compound is formulated parenterally, it can be formulated with a pharmaceutically acceptable parenteral carrier.

本发明可以以任意方便的制剂形式施用化合物，本发明所称的“制剂”是指含有本发明通式I化合物的有利于给药(drug delivery)的剂型，如：但不仅限于，水溶液注射剂、粉针剂、丸剂、散剂、片剂、贴剂、栓剂、乳剂、霜剂、凝胶剂、颗粒剂、胶囊剂、气雾剂、喷雾剂、粉雾剂、缓释剂和控释剂等。这些药用辅料既可以是各种制剂中常规使用的，如：但不仅限于，等渗剂、缓冲液、矫味剂、赋形剂、填充剂、粘合剂、崩解剂和润滑剂等；也可以是为了与所述物质相适应而选择使用的，如：乳化剂、增溶剂、抑菌剂、止痛剂和抗氧剂等，这类辅料能有效提高组合物所含化合物的稳定性和溶解性或改变化合物的释放速率和吸收速率等，从而改善本发明化合物在生物体内的代谢，进而增强给药效果。此外，还可以为实现特定的给药目的或方式，如：缓释给药、控释给药和脉冲给药等，而使用的辅料，如：但不仅限于，明胶、白蛋白、壳聚糖、聚醚和聚酯类高分子材料，如：但不仅限于，聚乙二醇、聚氨酯、聚碳酸酯及其共聚物等。所称的“有利于给药”的主要表现有：但不仅限于提高治疗效果、提高生物利用度、降低毒副作用和提高患者顺应性等。The present invention can administer the compound in any convenient formulation form. The “preparation” referred to in the present invention refers to a dosage form that contains the compound of general formula I of the present invention that is convenient for drug delivery, such as, but not limited to, aqueous injection, Powder injections, pills, powders, tablets, patches, suppositories, emulsions, creams, gels, granules, capsules, aerosols, sprays, powder mists, sustained release agents and controlled release agents, etc. These pharmaceutical excipients can be conventionally used in various preparations, such as: but not limited to, isotonic agents, buffers, correctives, excipients, fillers, binders, disintegrants, lubricants, etc. ; It can also be selected to adapt to the substance, such as: emulsifiers, solubilizers, bacteriostatic agents, analgesics and antioxidants, etc., such auxiliary materials can effectively improve the stability of the compounds contained in the composition And the solubility or change the release rate and absorption rate of the compound, etc., thereby improving the metabolism of the compound of the present invention in the body, thereby enhancing the administration effect. In addition, it can also be used to achieve specific purposes or methods of drug delivery, such as: sustained-release drug delivery, controlled-release drug delivery and pulsed drug delivery, etc., and the use of auxiliary materials, such as: but not limited to, gelatin, albumin, chitosan , Polyether and polyester polymer materials, such as: but not limited to, polyethylene glycol, polyurethane, polycarbonate and their copolymers. The main manifestations of the so-called "facilitating administration" include: but are not limited to improving the therapeutic effect, increasing bioavailability, reducing toxic side effects and improving patient compliance.

在以下实施例中，仅以阐明本发明方法的方式给出本发明的部分实施例。然而，这些实施例不以任何方式限制本发明的范围，在本发明的构思前提下对本发明制备方法的简单改进都属于本发明要求保护的范围。也就是，结合所列举的实施方案来描述本发明时，应当理解为其无意将本发明限制为那些实施方案。相反，本发明意欲包括所有的变化、改良和等价形式。本领域技术人员会认识到与本申请所述的那些类似或等同的许多方法和物质，它们可以用于实现本发明。In the following examples, only some examples of the present invention are given by way of illustrating the method of the present invention. However, these examples do not limit the scope of the present invention in any way, and simple improvements to the preparation method of the present invention under the concept of the present invention belong to the scope of the present invention. That is, when the present invention is described in conjunction with the enumerated embodiments, it should be understood that it is not intended to limit the present invention to those embodiments. On the contrary, the present invention is intended to include all changes, modifications, and equivalent forms. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described in this application can be used to implement the present invention.

在下文描述的实施例中，除非另外说明，所有温度均以摄氏度给出。除非另外说明，试剂从商业供应商购置或者定制，例如国药、韶远、安耐吉、TCI、Sigma等等。In the examples described below, unless otherwise specified, all temperatures are given in degrees Celsius. Unless otherwise specified, reagents are purchased or customized from commercial suppliers, such as Sinopharm, Shaoyuan, Anaiji, TCI, Sigma, etc.

实施例1化合物1～化合物12的合成Example 1 Synthesis of compound 1 to compound 12

第1步：称取2g菝葜皂苷元，加入乙酸酐10ml，以及吡啶0.4ml和氯化铵260mg，在150℃下回流搅拌7-8h。待反应液冷却至室温，加入乙酸4ml，二氯乙烷4ml以及水0.5ml。配置氧化液：三氧化铬1.5g，水1.8ml以及乙酸0.6ml，配成溶液，在冰浴中冷却备用。在冰浴条件下，将氧化液缓慢滴加到反应瓶中，然后缓慢升至室温，搅拌反应1h。向反应液中加入氯化钠1g，水15ml以及甲醇0.2ml，室温搅拌1h。向反应液加入水，二氯乙烷萃取3次(3x100ml)，分出有机层，浓缩。向二氯乙烷浓缩液加入乙酸50ml，在150℃下回流搅拌3-4h。冷却至室温，减压旋除乙酸，加入二氯甲烷稀释浓缩物，饱和碳酸氢钠洗涤、饱和食盐水洗涤、无水硫酸钠干燥，得到粗产物。粗产物经硅胶柱层析分离纯化，洗脱剂二氯甲烷：甲醇＝15:1，产物为白色固体1g，产率58％。Step 1: Weigh 2g of Smilaxogenin, add 10ml of acetic anhydride, 0.4ml of pyridine and 260mg of ammonium chloride, reflux and stir at 150°C for 7-8h. After the reaction solution was cooled to room temperature, 4ml of acetic acid, 4ml of dichloroethane and 0.5ml of water were added. Prepare oxidation solution: 1.5g chromium trioxide, 1.8ml water and 0.6ml acetic acid, make a solution, and cool in an ice bath for later use. Under ice bath conditions, slowly add the oxidizing solution dropwise to the reaction flask, and then slowly rise to room temperature, and stir the reaction for 1 hour. Add 1 g of sodium chloride, 15 ml of water and 0.2 ml of methanol to the reaction solution, and stir at room temperature for 1 hour. Water was added to the reaction solution, and dichloroethane was extracted three times (3x100ml), the organic layer was separated and concentrated. Add 50ml of acetic acid to the dichloroethane concentrate, reflux and stir at 150°C for 3-4 hours. Cool to room temperature, spin off acetic acid under reduced pressure, add dichloromethane to dilute the concentrate, wash with saturated sodium bicarbonate, saturated brine, and dry with anhydrous sodium sulfate to obtain a crude product. The crude product was separated and purified by silica gel column chromatography, eluent dichloromethane: methanol = 15:1, the product was 1 g of white solid, and the yield was 58%.

第2步：底物1.1g(3.1mmol)，七水合三氯化铈1.7g(4.6mmol)溶于200ml甲醇。冰浴下，加入硼氢化钠230mg(6.1mmol)。反应2小时，反应完全，加水淬灭反应。减压除去甲醇，乙酸乙酯萃取，得到粗产物无色油状液体1.0g。不经处理，将粗产物1.0g，TBSCl 0.9g(6mmol)，咪唑408mg(6mmol)，溶于10ml DMF。室温反应6小时，反应完全。水淬灭，乙酸乙酯萃取，用硅胶柱以石油醚：乙酸乙酯＝70:1洗脱剂分离，得到产物无色油状液体1.4g，两步总产率96.0％。Step 2: 1.1 g (3.1 mmol) of substrate and 1.7 g (4.6 mmol) of cerium trichloride heptahydrate were dissolved in 200 ml of methanol. Under ice bath, 230 mg (6.1 mmol) of sodium borohydride was added. After reacting for 2 hours, the reaction was complete, and water was added to quench the reaction. The methanol was removed under reduced pressure and extracted with ethyl acetate to obtain 1.0 g of the crude product as a colorless oily liquid. Without treatment, the crude product 1.0g, TBSCl 0.9g (6mmol), imidazole 408mg (6mmol), dissolved in 10ml DMF. The reaction was completed at room temperature for 6 hours. It was quenched with water, extracted with ethyl acetate, and separated with a silica gel column with petroleum ether: ethyl acetate=70:1 eluent to obtain 1.4 g of the product as a colorless oily liquid. The total yield of the two steps was 96.0%.

第3步：底物1.4g(2.9mmol)，氢氧化钠350mg(8.8mmol)溶于20ml甲醇，再加入5ml水。70℃回流6小时，反应完全，减压除去甲醇，二氯甲烷萃取。用硅胶柱以石油醚：乙酸 乙酯＝15:1洗脱剂分离，得到产物白色固体0.9g，产率70.3％。Step 3: 1.4g (2.9mmol) of the substrate, 350mg (8.8mmol) of sodium hydroxide were dissolved in 20ml of methanol, and then 5ml of water was added. Reflux at 70°C for 6 hours, the reaction was complete, methanol was removed under reduced pressure, and extracted with dichloromethane. Separate with a silica gel column with petroleum ether: ethyl acetate = 15:1 eluent to obtain 0.9 g of white solid product with a yield of 70.3%.

第4步：将底物300mg(0.69mmol)，三苯基膦365g(1.39mmol),邻苯二甲酰亚胺205mg(1.39mmol)溶于10ml二氯甲烷中。在冰浴氮气保护下，逐滴加入0.28ml偶氮二甲酸二异丙酯(1.39mmol)。室温下反应过夜，反应完全。将反应液减压旋干，用硅胶柱以石油醚：乙酸乙酯＝100:1洗脱剂分离，得到产物白色固体200mg，产率51.3％。Step 4: Dissolve 300 mg (0.69 mmol) of the substrate, 365 g (1.39 mmol) of triphenylphosphine, and 205 mg (1.39 mmol) of phthalimide in 10 ml of dichloromethane. Under the protection of nitrogen in an ice bath, 0.28 ml of diisopropyl azodicarboxylate (1.39 mmol) was added dropwise. The reaction was completed overnight at room temperature. The reaction solution was spin-dried under reduced pressure and separated with a silica gel column with petroleum ether:ethyl acetate=100:1 eluent to obtain 200 mg of white solid product with a yield of 51.3%.

第5步：将所得到的产物200mg(0.36mmol)悬浮于5ml无水乙醇中，加入80％水合肼0.11ml(1.8mmol),80℃回流3小时。反应完全，将反应液减压旋干，再用20ml二氯甲烷溶解，过滤除去絮状不溶物。滤液浓缩，用硅胶柱以二氯甲烷：甲醇＝15:1洗脱剂分离，得到产物白色固体90mg，产率58.8％。Step 5: Suspend 200 mg (0.36 mmol) of the obtained product in 5 ml of absolute ethanol, add 0.11 ml (1.8 mmol) of 80% hydrazine hydrate, and reflux at 80°C for 3 hours. After the reaction was complete, the reaction solution was spin-dried under reduced pressure, and then dissolved with 20 ml of dichloromethane, and the flocculent insoluble matter was removed by filtration. The filtrate was concentrated and separated with a silica gel column with dichloromethane: methanol = 15:1 eluent to obtain 90 mg of white solid product with a yield of 58.8%.

第6步：底物(1.0eq)，溶于吡啶(0.1M)中，加入乙酸酐(5.0eq)。室温搅拌3h，减压除去溶剂，残余物用DCM溶解，1M HCl洗，饱和碳酸氢钠洗，饱和氯化钠洗。用硅胶柱以二氯甲烷：甲醇＝200:1洗脱剂分离，得到产物白色固体，产率70％。Step 6: Substrate (1.0eq), dissolved in pyridine (0.1M), add acetic anhydride (5.0eq). Stir at room temperature for 3 hours, remove the solvent under reduced pressure, and dissolve the residue with DCM, wash with 1M HCl, wash with saturated sodium bicarbonate, and wash with saturated sodium chloride. Separate with a silica gel column with dichloromethane:methanol=200:1 eluent to obtain a white solid product with a yield of 70%.

第7步：底物(1.0eq)80mg(0.14mmol)，四丁基氟化铵(3.0eq)，溶于四氢呋喃(0.03M)，70℃回流6小时。反应完全，水淬灭，二氯甲烷萃取，得到粗产物白色固体64mg。不经处理，将DMP氧化剂(1.5eq)，碳酸氢钠(5.0eq)溶于二氯甲烷(0.1M)中，室温搅拌0.5小时，再加入上一步粗产物的二氯甲烷溶液。室温搅拌2小时，反应完全，加饱和碳酸氢钠：饱和硫代硫酸钠＝1:1的水溶液淬灭，二氯甲烷萃取。用硅胶柱以二氯甲烷：甲醇＝100:1洗脱剂分离，得到产物白色固体，两步总产率65％。Step 7: Substrate (1.0eq) 80mg (0.14mmol), tetrabutylammonium fluoride (3.0eq), dissolved in tetrahydrofuran (0.03M), refluxed at 70°C for 6 hours. The reaction was complete, quenched with water, and extracted with dichloromethane to obtain 64 mg of the crude product as a white solid. Without treatment, DMP oxidant (1.5eq) and sodium bicarbonate (5.0eq) were dissolved in dichloromethane (0.1M), stirred at room temperature for 0.5 hours, and then the dichloromethane solution of the crude product in the previous step was added. Stir at room temperature for 2 hours, the reaction is complete, add saturated sodium bicarbonate: saturated sodium thiosulfate=1:1 aqueous solution for quenching, and extract with dichloromethane. A silica gel column was used for separation with dichloromethane:methanol=100:1 eluent to obtain the product as a white solid. The total yield of the two steps was 65%.

第8步：将底物(1.0eq)，氮杂环(2.0eq)，碳酸铯(2.0eq)溶于DMF(0.05M)，氮气保护，室温反应过夜。反应完全，加水淬灭，乙酸乙酯萃取。用硅胶柱以二氯甲烷：甲醇＝50:1洗脱剂分离，得到化合物1-12。Step 8: Dissolve the substrate (1.0eq), nitrogen heterocycle (2.0eq), and cesium carbonate (2.0eq) in DMF (0.05M), under nitrogen protection, and react at room temperature overnight. The reaction was complete, quenched with water, and extracted with ethyl acetate. Separate with a silica gel column with dichloromethane:methanol=50:1 eluent to obtain compound 1-12.

实施例2化合物13～化合物16的合成Example 2 Synthesis of compound 13-16

化合物13-16的合成路线参考化合物1-12的合成路线，用薯蓣皂苷元替换菝葜皂苷元可以顺利制备化合物13-16。The synthetic route of compound 13-16 refers to the synthetic route of compound 1-12. Substituting diosgenin for smilagein can successfully prepare compound 13-16.

实施例3悬尾试验(TST)考察本发明化合物的抗抑郁活性Example 3 Tail suspension test (TST) to investigate the antidepressant activity of the compounds of the present invention

实验选用雄性ICR小鼠，体重(20±2)g，购自中科院动物中心，自由摄食饮水，室温 (23±2)℃。所有小鼠随机分组分为空白对照组和试验组，每组10只，5只/笼，于饲养环境中适应3天后开始实验。具体给药方法为灌胃给药，空白对照组一组给予等体积的生理盐水。For the experiment, male ICR mice weighing (20±2) g, purchased from the Animal Center of the Chinese Academy of Sciences, were free to eat and drink at room temperature (23±2)°C. All mice were randomly divided into a blank control group and a test group, each with 10 mice, 5 mice/cage, and the experiment started after 3 days of acclimatization in the breeding environment. The specific administration method was intragastric administration, and the blank control group was given an equal volume of normal saline.

具体操作：连续给药6天，末次给药后1小时进行测试。用胶带将小鼠尾在距尾尖2厘米处粘在横杠上，四周以板隔离动物视线，横杠距地面约25厘米，使小鼠距地面约10厘米，计时6min，记录后4分钟内累计不动时间，各组小鼠平行操作。Specific operation: continuous administration for 6 days, test 1 hour after the last administration. Use tape to stick the tail of the mouse on the horizontal bar at a distance of 2 cm from the tip of the tail. Use a board to isolate the animal’s sight. The horizontal bar is about 25 cm from the ground, and the mouse is about 10 cm from the ground. Time for 6 minutes and 4 minutes after recording. The accumulated immobility time was accumulated in each group of mice in parallel.

实验数据处理：实验结果以均值±标准误差(x±SD)表示。采用t检验进行统计分析，判断是否具有显著性意义(P＜0.05说明统计学有显著性差异)。Experimental data processing: experimental results are expressed as mean±standard error (x±SD). Use t test for statistical analysis to determine whether it is significant (P<0.05 indicates statistically significant difference).

表1菝葜皂苷元与薯蓣皂苷元对ICR小鼠悬尾实验中不动时间的影响Table 1 Effects of Smilaxogenin and Diosgenin on Immobility Time in ICR Mouse Tail Suspended Experiment

P<0.01**,P<0.05*vs空白组P<0.01**, P<0.05*vs blank group

实验结果表明，与空白组比较，自然界存在的化合物菝葜皂苷元与薯蓣皂苷元，30mg/kg给药剂量下，在小鼠悬尾模型上，不能显著降低小鼠悬尾不动时间，统计学上无显著性差异。The experimental results show that compared with the blank group, the natural compounds Smilagenin and Diosgenin, at a dose of 30 mg/kg, in the mouse tail suspension model, can not significantly reduce the immobility time of the mouse tail. Statistics There is no significant difference in academics.

表2化合物1与化合物3对ICR小鼠悬尾实验中不动时间的影响Table 2 The effect of compound 1 and compound 3 on immobility time in ICR mouse tail suspension experiment

P<0.01**,P<0.05*vs空白组P<0.01**, P<0.05*vs blank group

实验结果表明，与空白组比较，10mg/kg给药剂量下，在小鼠悬尾模型上，由天然产物菝葜皂苷元为原料制备的3位乙酰氨基取代以及16位含N杂芳基取代的甾体衍生物化合物1、化合物3均可显著减少小鼠悬尾实验不动时间(P＜0.05)，统计学有显著性差异。化合物1与化合物3具有显著的抗抑郁活性(P＜0.05)。The experimental results showed that, compared with the blank group, at a dose of 10 mg/kg, on a mouse tail suspension model, the 3-acetamido substitution and the 16-position N-containing heteroaryl substitution were prepared from the natural product Smilax sapogenin as the raw material The steroid derivatives of compound 1 and compound 3 can significantly reduce the immobility time of mouse tail suspension experiment (P<0.05), and there is a statistically significant difference. Compound 1 and Compound 3 have significant antidepressant activity (P<0.05).

实施例4强迫游泳试验(FST)考察本发明化合物的抗抑郁活性Example 4 Forced Swimming Test (FST) to investigate the antidepressant activity of the compounds of the present invention

实验选用雄性ICR小鼠，体重(20±2)g，购自中科院动物中心，自由摄食饮水，室温 (23±2)℃。所有小鼠随机分组分为空白对照组和试验组，每组10只，5只/笼，于饲养环境中适应3天后开始实验。具体给药方法为灌胃给药，空白对照组一组给予等体积的生理盐水。For the experiment, male ICR mice weighing (20±2) g, purchased from the Animal Center of the Chinese Academy of Sciences, were free to eat and drink at room temperature (23±2)°C. All mice were randomly divided into a blank control group and a test group, each with 10 mice, 5 mice/cage, and the experiment started after 3 days of acclimatization in the breeding environment. The specific administration method was intragastric administration, and the blank control group was given an equal volume of normal saline.

具体操作：连续给药6天，末次给药后1小时进行测试。将小鼠单独放入高20厘米、直径14厘米的圆柱型玻璃缸中，缸内水深10厘米，水温23℃-25℃。从小鼠入水后计时6分钟，记录后4分钟内的累计不动时间(判定不动标准：小鼠在水中停止挣扎，或呈漂浮状态，仅有细小的肢体运动以保持头部浮在水面)。各组小鼠平行操作。Specific operation: continuous administration for 6 days, test 1 hour after the last administration. The mice were individually placed in a cylindrical glass cylinder with a height of 20 cm and a diameter of 14 cm, with a water depth of 10 cm and a water temperature of 23°C-25°C. Count 6 minutes after the mouse enters the water, and record the cumulative immobility time within 4 minutes (criteria for determination of immobility: the mouse stops struggling in the water, or floats, and only small limbs move to keep the head floating on the water) . Each group of mice was operated in parallel.

实验数据处理：实验结果以均值±标准误差(x±SD)表示。采用t检验进行统计分析，判断是否具有显著性意义(P＜0.05说明统计学有显著性差异)。Experimental data processing: experimental results are expressed as mean±standard error (x±SD). Use t test for statistical analysis to determine whether it is significant (P<0.05 indicates statistically significant difference).

表3化合物1与化合物3对ICR小鼠强迫游泳不动时间的影响Table 3 The effect of compound 1 and compound 3 on forced swimming immobility time in ICR mice

“*”表示P＜0.05；“**”表示P＜0.01"*" means P＜0.05; "**" means P＜0.01

实验结果表明，与空白组比较，40mg/kg给药剂量下，在小鼠强迫游泳模型上，天然产物菝葜皂苷元不能显著降低小鼠强迫游泳不动时间，统计学无显著性差异。由天然产物菝葜皂苷元为原料制备的3位乙酰氨基取代以及16位含N杂芳基取代的甾体衍生物化合物1、化合物3均可显著减少小鼠强迫游泳实验不动时间。化合物1与化合物3具有显著的抗抑郁活性(P＜0.05)。The experimental results showed that compared with the blank group, at a dose of 40 mg/kg, the natural product Smilax sapogenin could not significantly reduce the time of forced swimming immobility in mice at a dose of 40 mg/kg, and there was no statistically significant difference. Compound 1 and Compound 3, which were prepared from natural product Smilaxogenin as raw materials, were substituted with 3-acetylamino group and substituted with 16-position containing N-heteroaryl group, which can significantly reduce the immobility time of mice in forced swimming experiments. Compound 1 and Compound 3 have significant antidepressant activity (P<0.05).

本发明部分化合物与部分天然产物的抗抑郁比较试验结果表明，自然界中存在的菝葜皂苷元在两种动物模型上都没有抗抑郁效果。在与上述天然产物比较的同批动物药效筛选中，本发明化合物，由天然产物菝葜皂苷元为原料制备的3位乙酰氨基取代以及16位含N杂芳基取代的甾体衍生物，在两种动物模型上都显示了显著的抗抑郁活性。在悬尾模型中，本发明中化合物1与化合物3都显示出显著的抗抑郁活性(P＜0.05)，而且，化合物1与化合物3的给药剂量明显低于天然产物菝葜皂苷元。在强迫游泳模型中，本发明中的化合物1与化合物3都显示出显著的抗抑郁活性(P＜0.05)。The antidepressant comparison test results of some compounds of the present invention and some natural products show that the smilagenin existing in nature has no antidepressant effect on the two animal models. In the same batch of animal drug efficacy screening compared with the above-mentioned natural products, the compound of the present invention is a steroid derivative with 3-acetylamino substitution and 16-position N-heteroaryl substitution prepared from natural product Smilaxone as a raw material. Both animal models showed significant antidepressant activity. In the tail suspension model, both Compound 1 and Compound 3 of the present invention showed significant antidepressant activity (P<0.05), and the dosage of Compound 1 and Compound 3 was significantly lower than the natural product Smilaxogenin. In the forced swimming model, both compound 1 and compound 3 of the present invention showed significant antidepressant activity (P<0.05).

自然界的天然产物中，部分甾体类分子骨架具有一定的抗抑郁等活性，但活性较弱。为提高甾体类分子的药效强度，目前文献报道的神经甾体衍生物设计策略，往往在孕烯醇酮、 别孕烷醇酮等甾体骨架上，保留C-3位羟基，在C-21位引入极性基团，比如羟基、杂环等。而本发明则是对天然产物菝葜皂苷元进行结构修饰。菝葜皂苷元的结构特点之一在于A/B环为顺式稠合，这是与常见内源性神经甾体骨架A/B环反式稠合不同的结构类型。本发明的改造策略是在菝葜皂苷元的甾体骨架上，在C-3位引入3α-乙酰氨基，以及在C-16位引入含N杂芳基。Among the natural products in nature, some steroidal molecular skeletons have certain antidepressant activities, but their activities are weak. In order to improve the potency of steroid molecules, the current design strategies for neurosteroid derivatives reported in the literature often retain the C-3 hydroxyl group on the steroid skeleton such as pregnenolone and allopregnanolone. The -21 position introduces a polar group, such as a hydroxyl group, a heterocyclic ring, etc. In the present invention, the natural product Smilaxogenin is structurally modified. One of the structural characteristics of Smilaxogenin is that the A/B ring is cis-fused, which is a different structural type from the trans-fused A/B ring of the common endogenous neurosteroid skeleton. The transformation strategy of the present invention is to introduce 3α-acetylamino groups at the C-3 position and N-containing heteroaryl groups at the C-16 position on the steroidal skeleton of smilagenin.

与现有文献报道策略的区别在于：一是本发明采用的甾体骨架源于菝葜皂苷元，A/B环为顺式稠合，区别于文献常见报道的孕烯醇酮、别孕烷醇酮等；二是本发明在C-3位引入乙酰氨基，区别于文献常见的3位羟基；三是本发明在C-16引入含N杂芳基，区别于文献常见的C-21位结构修饰。The difference from the existing literature report strategy is: First, the steroidal skeleton used in the present invention is derived from Smilax sapogenin, and the A/B ring is cis-fused, which is different from pregnenolone and allopregnane commonly reported in the literature. Alcohol, ketone, etc.; Second, the present invention introduces acetamido at C-3 position, which is different from the 3-position hydroxyl group commonly seen in literature; Third, the present invention introduces N-containing heteroaryl group at C-16, which is different from the common literature C-21 position Structural modification.

药理筛选结果表明相对于先导化合物菝葜皂苷元，按本发明结构修饰策略合成制备的衍生物抗抑郁药效显著提高。The pharmacological screening results showed that compared with the lead compound Smilaxogenin, the antidepressant effect of the derivative synthesized and prepared according to the structure modification strategy of the present invention was significantly improved.

Claims (10)

1. 一种式I所示的化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体、立体异构体或它们的混合物，A compound represented by formula I, or a pharmaceutically acceptable salt, solvate, optically pure isomer, stereoisomer or mixture thereof,

   

   

   所述式I所示的化合物由以下片段A和片段B连接而成，The compound represented by formula I is formed by connecting the following fragment A and fragment B,

   

   

   X ₁、X ₂、X ₃、X ₄各自独立地选自N、C、CR _5a，R _5a选自氢、氰基、卤素、羟基、烷氧基、氨基、取代的氨基， X ₁ , X ₂ , X ₃ , and X ₄ are each independently selected from N, C, CR _5a , and R _{5a is} selected from hydrogen, cyano, halogen, hydroxy, alkoxy, amino, and substituted amino,

   R ₁独立地选自氢、烷基、取代的烷基、烷氧基、芳氧基、烷酰氧基、芳酰氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺(其中所述的两个氨基取代基选自烷基、芳基或芳基烷基)，烷酰基、取代的烷酰基、烷氧基羰基、芳基烷氧基羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基甲酰基、取代的氨基甲酰基、酰基氨基、取代的酰基氨基， R _{1 is} independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkylamino, arylamino, arylalkylamino, Disubstituted amine (wherein the two amino substituents are selected from alkyl, aryl or arylalkyl), alkanoyl, substituted alkanoyl, alkoxycarbonyl, arylalkoxycarbonyl, alkyl Sulfonyl, arylsulfonyl, arylalkylsulfonyl, carbamoyl, substituted carbamoyl, acylamino, substituted acylamino,

   R ₂选自氢、烷基、取代的烷基、烷氧基、芳氧基、烷酰氧基、芳酰氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺(其中所述的两个氨基取代基选自烷基、芳基或 芳基烷基)，烷酰基、取代的烷酰基、烷氧基羰基、芳基烷氧基羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、氨基甲酰基、取代的氨基甲酰基、酰基氨基、取代的酰基氨基； R _{2 is} selected from hydrogen, alkyl, substituted alkyl, alkoxy, aryloxy, alkanoyloxy, aroyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted The amine (wherein the two amino substituents are selected from alkyl, aryl or arylalkyl), alkanoyl, substituted alkanoyl, alkoxycarbonyl, arylalkoxycarbonyl, alkylsulfonyl , Arylsulfonyl, arylalkylsulfonyl, carbamoyl, substituted carbamoyl, acylamino, substituted acylamino;

   R ₃选自氢、烷基、杂芳基、取代的杂芳基、卤素、羟基、烷氧基、氨基、取代的氨基、氰基， R _{3 is} selected from hydrogen, alkyl, heteroaryl, substituted heteroaryl, halogen, hydroxy, alkoxy, amino, substituted amino, cyano,

   R _4a、R _4b、R _4c、R _4d各自独立地选自氢、烷基、取代的烷基、烯基、取代的烯基、炔基、取代的炔基、芳基、取代的芳基、杂芳基、取代的杂芳基、杂环基、取代的杂环基、卤素、羟基、烷氧基、氨基、取代的氨基、氰基、羧基、烷氧羰基、氨基酰基、取代的氨基酰基、硝基、-S-烷基， R _4a , R _4b , R _4c , R _4d are each independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, Heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclic, halogen, hydroxy, alkoxy, amino, substituted amino, cyano, carboxy, alkoxycarbonyl, aminoacyl, substituted aminoacyl , Nitro, -S-alkyl,

   R _6a、R _6b、R _6c、R _6d、R _6e、R _6f、R _7a、R _7b、R _8a、R _8b、R _9a、R _9b、R _10a、R _10b各自独立地选自无、氢、卤素、烷基、羟基、糖基，或者R _6a、R _6b两两之间和/或R _7a、R _7b两两之间和/或R _8a、R _8b两两之间和/或R _9a、R _9b两两之间和/或R _10a、R _10b两两之间合并成羰基， R _6a , R _6b , R _6c , R _6d , R _6e , R _6f , R _7a , R _7b , R _8a , R _8b , R _9a , R _9b , R _10a , R _10b are each independently selected from none, hydrogen, Halogen, alkyl, hydroxyl, sugar group, or between R _6a and R _6b and/or between R _7a and R _7b and/or between R _8a and R _8b and/or R _9a , R _9b and/or R _10a and R _10b are combined to form a carbonyl group,

   

   表示单键或者双键，

   

   Means single bond or double bond,

   各*独立地表示消旋、S或R构型。Each * independently represents the racemic, S or R configuration.
2. 根据权利要求1所述的化合物，其特征在于，所述化合物具有以下结构：The compound of claim 1, wherein the compound has the following structure:

   

   

   式中，X ₁、X ₂、X ₃、X ₄、R _4a、R _4b、R _4c、R _4d、*的定义如权利要求1所述。 In the formula, X ₁ , X ₂ , X ₃ , X ₄ , R _4a , R _4b , R _4c , R _4d , * are defined as described in claim 1.
3. 根据权利要求1所述的化合物，其特征在于，所述化合物具有以下结构：The compound of claim 1, wherein the compound has the following structure:

   

   

   式中，X ₁、X ₂、X ₃、X ₄、R _4a、R _4b、R _4c、R _4d的定义如权利要求1所述。 In the formula, X ₁ , X ₂ , X ₃ , X ₄ , R _4a , R _4b , R _4c , and R _4d are as defined in claim 1.
4. 根据权利要求1所述的化合物，其特征在于，所述片段A为：The compound of claim 1, wherein the fragment A is:

   

   
5. 根据权利要求1所述的化合物，其特征在于，所述片段B选自下组：The compound of claim 1, wherein the fragment B is selected from the following group:

   

   

   R _4e选自氢、甲基、三氟甲基、甲氧基、氟、氯、溴、碘、羟基、氨基、烷基酰基氨基、氰基、羧基、烷氧羰基、氨基酰基、取代的氨基酰基、硝基、-S-烷基。 R _{4e is} selected from hydrogen, methyl, trifluoromethyl, methoxy, fluorine, chlorine, bromine, iodine, hydroxy, amino, alkylacylamino, cyano, carboxyl, alkoxycarbonyl, aminoacyl, substituted amino Acyl, nitro, -S-alkyl.
6. 根据权利要求1所述的化合物，其特征在于，所述片段A选自下组：The compound of claim 1, wherein the fragment A is selected from the following group:

   

   

   片段B选自下组：Fragment B is selected from the following group:

   

   

   R _4e选自氢、甲基、三氟甲基、甲氧基、卤素、羟基、氨基、烷基酰基氨基、氰基、羧基、烷氧羰基、氨基酰基、取代的氨基酰基、硝基、-S-烷基。 R _{4e is} selected from hydrogen, methyl, trifluoromethyl, methoxy, halogen, hydroxy, amino, alkylacylamino, cyano, carboxy, alkoxycarbonyl, aminoacyl, substituted aminoacyl, nitro,- S-alkyl.
7. 根据权利要求1所述的化合物，其特征在于，所述化合物为：The compound of claim 1, wherein the compound is:

   

   

   

   
8. 一种药物混合物，其特征在于，所述药物混合物包含选自下组的两种或三种以上的化合物：权利要求1-7任一项所述的化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体、立体异构体。A drug mixture, characterized in that the drug mixture comprises two or more compounds selected from the following group: the compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, Solvates, optically pure isomers, stereoisomers.
9. 一种药物组合物，其特征在于，所述药物组合物包含权利要求1-7任一项所述的化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体或立体异构体，或权利要求8所述的药物混合物；以及药学上可接受的载体。A pharmaceutical composition, characterized in that it comprises the compound according to any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, optically pure isomer or stereoisomer thereof Body, or the drug mixture of claim 8; and a pharmaceutically acceptable carrier.
10. 如权利要求1-7任一项所述的化合物，或其药学上可接受的盐、溶剂化物、光学纯异构体或立体异构体、权利要求8所述的药物混合物物或权利要求9所述的药物组合物的用途，其特征在于，用于制备防护、处理、治疗或减轻患者疾病、病症或病状的药物的用途，所述的疾病、病症或病状为抑郁症。The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, optically pure isomer or stereoisomer thereof, the drug mixture of claim 8 or claim 9 The use of the pharmaceutical composition is characterized in that it is used to prepare a medicine for protecting, treating, treating or alleviating a patient's disease, disease or condition, and the disease, disease or condition is depression.