CN111704647B - A class of triterpenoid derivatives and their use as programmed cell necrosis inhibitors - Google Patents

A class of triterpenoid derivatives and their use as programmed cell necrosis inhibitors Download PDF

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CN111704647B
CN111704647B CN202010542966.3A CN202010542966A CN111704647B CN 111704647 B CN111704647 B CN 111704647B CN 202010542966 A CN202010542966 A CN 202010542966A CN 111704647 B CN111704647 B CN 111704647B
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庄春林
王志斌
张万年
马皓
黄嘉璇
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Abstract

The invention discloses a triterpenoid derivative, or a prodrug of an isomer, a salt or a solvate thereof, which has a general structure shown in a formula I:
Figure DDA0002539571130000011
the details of each substituent in the formula are shown in the specification. The triterpenoid derivative or the prodrug of the isomer, the salt or the solvate thereof can be used as a programmed cell necrosis inhibitor to effectively inhibit programmed cell necrosis; can be used for preparing medicines for preventing and treating ischemic diseases related to programmed cell necrosis.

Description

Triterpenoid derivatives and application thereof as programmed cell necrosis inhibitor
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to triterpenoid derivatives and application thereof as a programmed cell necrosis inhibitor.
Background
Triterpenoids are natural products that are similar to steroids in biological activity after cyclization of squalene. Triterpenoids, such as oleanolic acid and ursolic acid, are used in drug therapy in many asian countries and have weak anti-tumor and anti-inflammatory properties. A large number of oleanolic acid and ursolic acid derivatives have now been synthesized and tested for use as potential chemotherapeutic agents. 2-cyano-3, 12-dioxooleanane-1, 9(11) -diene-28-carboxylic acid (CDDO) (R.Borella, L.Forti, L.Gibellini et al, Synthesis and Anticancer Activity of CDDO and CDDO-Me, Two Derivatives of Natural Triteroils [ J ] Molecules,24(22): 4097-. The chemical structure is as follows:
Figure BDA0002539571110000011
programmed cell necrosis, as a currently studied and widespread cell death pathway, plays an important role in multiple physiological processes such as organ development, homeostasis of the immune system, and pathogenesis of diseases; induced by tumor necrosis factor receptor and Toll-like receptor family, receptor-interacting protein kinases RIPK1(receptor interacting protein kinase 1) and RIPK3 mediate and recruit phosphorylated mixed lineage kinase domain-like protein (MLKL), so that a RIPK1-RIPK3-MLKL compound is formed, and finally the phenomenon of integrity loss of cell membranes, organelle swelling, mitochondrial dysfunction and the like is shown. Studies have shown that programmed cell necrosis is closely associated with human central nervous system diseases, such as stroke (Degterev A, Huang Z, Boyce M, et al. chemical inhibitor of non-porous cell de with thermal potential for abnormal damage in J. natural chemical biology,2005,1(2): 112. quadrature. 119.), amyotrophic lateral sclerosis (Ito Yasushi, office Dimit, Najafov Ayaz et al. RIPK1 media access degradation by simulation infection and neural degeneration in ALS. [ J. Science,2016,353:603-8.) and Alzheimer' S disease (cancer Annona. calcium carbide, branched carbide, peptide 1247. biological, N.J.. 20. organism J. biological damage, N.S. 19. biological damage, N.S. 2016. biological damage, N.S. J. Ischemic stroke is a central nervous system disease that can lead to death and disability, and is caused by ischemia, hypoxia, and ischemic necrosis of brain tissue or brain softening due to blood supply disorder of brain. After cerebral ischemia, the expression of RIPK3 and MLKL is increased and is mainly distributed in neurons and astrocytes, and the RIPK3 and the MLKL positive cells show the characteristic of a necrotic ultrastructure. Ischemia reperfusion (I/R) is another manifestation of injury after cerebral ischemia, and its pathogenesis is also considered to be related to programmed cell necrosis. One study indicated that TRAF2 is a novel modulator of ischemic brain injury, knockout TRAF2 aggravates microglial Cell Death and neuronal Cell Death, and that Nec-1 pretreatment prior to MCAO inhibited TRAF2 knockout aggravated Cell Death (j.li, j.zhang, y.zhang, z.wang, y.song, s.wei, m.he, s.you, j.jia, j.cheng, TRAF2 protects against heart branched-induced damage co-surgery, Cell Death Dis 10(5 (2019)) 328), suggesting that ischemic brain injury may be associated with programmed Cell target necrosis.
Recently, the research finds that the oleanane derivative can be used as a novel programmed cell necrosis inhibitor, and further researches the application of the compound in the preparation of medicines for programmed cell necrosis and medicines for cerebral ischemia/reperfusion injury.
Disclosure of Invention
The first purpose of the invention is to provide a class of triterpenoid derivatives containing amide or ester side chains.
The invention also aims to provide a preparation method of the triterpenoid derivative.
Still another object of the present invention is to provide a use of said triterpenoid derivative as an inhibitor of programmed cell necrosis.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
in a first aspect of the present invention, there is provided a class of triterpene derivatives, or their isomers, salts or solvates prodrugs, having a general structure shown in formula I:
Figure BDA0002539571110000021
R1is one of the following groups: amino (-NH)2) Halogen (F, Cl, Br, I), -NHR3、-NHCOOR4、-OR5、-NR6R7；
R3Is one of the following groups: C3-C20 alkyl, phenyl, benzyl, naphthyl, C1-C20 alkyl in which at least one hydrogen of the alkyl is substituted by halogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2,3, 4-tetrahydronaphthyl, and- (CH)2)nNHCOOCR8R9R10(ii) a n is an integer of 1 to 4, R8、R9、R10Hydrogen, methyl, ethyl and n-propyl at the same time or at different times;
R4is one of the following groups: C1-C20 alkyl, phenyl and naphthyl;
R5is one of the following groups: C2-C20 alkyl, phenyl, benzotriazolyl, pyridotriazolyl;
R6、R7a group in which at least one hydrogen atom in the ring of C3 to C8, or the above-mentioned ring of C3 to C8 is substituted with pyridine; does not comprise
Figure BDA0002539571110000031
More preferably, in the triterpene derivatives,
R1is one of the following groups: amino (-NH)2) Halogen (F, Cl, Br, I), -NHR3、-NHCOOR4、-OR5、
Figure BDA0002539571110000032
R3Is one of the following groups: n-propyl, n-pentyl, phenyl, benzyl, naphthyl, -CH2Br、-CH2CH2Br, cyclopropylalkyl, cyclobutylalkyl, cyclopentylalkyl, cyclohexylalkyl, 1,2,3, 4-tetrahydronaphthyl, -CH2NHCOOC(CH3)3、-CH2CH2NHCOOC(CH3)3、-CH2CH2CH2NHCOOC(CH3)3；
R4Is one of the following groups: methyl, ethyl, n-propyl, n-pentyl, phenyl, naphthyl;
R5is one of the following groups: ethyl, n-propyl, n-pentyl, phenyl, benzotriazolyl (C)
Figure BDA0002539571110000033
) Pyridotriazolyl (a) to (b)
Figure BDA0002539571110000034
)。
Most preferably, the triterpene derivative is selected from one of the following structures:
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -N-benzyl-11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, -dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-cetylhydropyridine-4 a (2H) -carboxamide; (Compound I-4)
Ethyl tert-butyl (2- (((4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-octadecatetraenoic acid-4 a-carboxamido) carbamate; (Compound I-5)
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -N- (2-bromoethyl) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxamide; (Compound I-6)
4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-N-cyclohexyl-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxamide; (Compound I-7)
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-N- ((R) -1,2,3, 4-tetrahydronaphthalen-1-yl) -1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydronaphthalene 4a (2H) -carboxamide; (Compound I-8)
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-N- ((S) -1,2,3, 4-tetrahydronaphthalen-1-yl) -1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydronaphthalene 4a (2H) -carboxamide; (Compound I-9)
(4aR,6aS,6bR,8aS,12 bR,14bS) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-8 a- (4- (pyridin-2-yl) -1H-imidazole-1-carbonyl) -3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14 b-octadecanedihydropyridine-2-carbonitrile; (Compound I-11)
(4aR,6aS,6bR,8aS,12 bR,14bS) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-8 a- (4- (pyridin-3-yl) -1H-imidazole-1-carbonyl) -3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14 b-octadecanedihydropyridine-2-carbonitrile; (Compound I-12)
1H-benzo [ d ] [1,2,3] triazol-1-yl (4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyrido 4a (2H) -carboxylate; (Compound I-13)
3H- [1,2,3] triazolo [4,5-b ] pyridin-3-yl (4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxylate (Compound I-14).
The compounds of the present invention can be prepared in the form of pharmaceutically acceptable salts according to conventional methods.
The medicinal salt is organic acid or inorganic acid salt.
The inorganic acid refers to hydrochloric acid, sulfuric acid, phosphoric acid, diphosphoric acid, hydrobromic acid, nitric acid and the like.
The organic acid is acetic acid, malic acid, maleic acid, citric acid, fumaric acid, tartaric acid, succinic acid, lactic acid, p-toluenesulfonic acid, salicylic acid or oxalic acid.
In a second aspect of the present invention, there is provided a preparation method of the triterpenoid derivative, comprising the following steps:
Figure BDA0002539571110000041
dissolving 2-cyano-3, 12-dioxooleanane-1, 9(11) -diene-28-carboxylic acid compound CDDO in dichloromethane, adding a catalytic amount of dimethylformamide, slowly dropwise adding excessive oxalyl chloride in ice bath, continuing to react, slowly returning to room temperature for reaction, concentrating and evaporating the reaction solution to dryness, and directly using the obtained crude product for the next reaction; dissolving the crude product in dry dichloromethane, sequentially adding excessive amine catalyst and excessive amine compound under ice bath, slowly heating to room temperature after reaction for continuous reaction, washing the reaction solution with water and salt after complete reaction, adding anhydrous sodium sulfate for drying, and purifying by a column to obtain the triterpenoid derivative shown in the general formula I;
or dissolving 2-cyano-3, 12-dioxooleanane-1, 9(11) -diene-28-carboxylic acid compound CDDO in dichloromethane, adding a catalytic amount of dimethylformamide, slowly dropwise adding excessive oxalyl chloride in ice bath, continuing to react after the addition is finished, slowly returning to room temperature for reaction, then adding excessive alcohol substances into the reaction liquid, continuing to react, and purifying by a column to obtain the triterpenoid derivative shown in the general formula I;
or dissolving 2-cyano-3, 12-dioxooleanane-1, 9(11) -diene-28-carboxylic acid compound CDDO in chloroform, adding excessive triethylamine, stirring at room temperature for reaction, adding excessive phosphate substances, stirring for reaction, and purifying by a column to obtain the triterpenoid derivative shown in the general formula I.
The amine catalyst is triethylamine.
The amine compound is benzylamine, tert-butyl (2-aminoethyl) carbamate, aminocyclohexane, (R) -1,2,3, 4-tetrahydronaphthalene-1-amine, (S) -1,2,3, 4-tetrahydronaphthalene-1-amine, 2- (1H-imidazol-4-yl) pyridine, and 2- (1H-imidazol-4-yl) pyridine.
The alcohol substance is one of ethanol and n-propanol.
The phosphate substances are 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) and O-benzotriazole-tetramethyluronium Hexafluorophosphate (HBTU).
In a third aspect of the invention, the use of the triterpenoid derivative as an inhibitor of programmed cell necrosis is provided.
The triterpene derivative, or a prodrug of an isomer, a salt or a solvate thereof has a general structure shown in formula I or II:
Figure BDA0002539571110000051
R1is one of the following groups: hydroxy, amino (-NH)2) Halogen (F, Cl, Br, I), -NHR3、-NHCOOR4、-OR5、-NR6R7；
R3Is one of the following groups: C1-C20 alkyl, phenyl, benzyl, naphthyl, C1-C20 alkyl in which at least one hydrogen of the alkyl is substituted by halogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2,3, 4-tetrahydronaphthyl, and- (CH)2)nNHCOOCR8R9R10(ii) a n is an integer of 1 to 4, R8、R9、R10Hydrogen, methyl, ethyl and n-propyl at the same time or at different times;
R4is one of the following groups: C1-C20 alkyl, phenyl and naphthyl;
R5is one of the following groups: C1-C20 alkyl, phenyl, benzotriazolyl, pyridotriazolyl;
R6、R7a group in which at least one hydrogen atom in the ring of C3 to C8, or the above-mentioned ring of C3 to C8 is substituted with pyridine;
R2is one of the following groups: hydroxy, C1-C20 alkylAnd a C1-C20 alkyl group in which at least one hydrogen atom in the alkyl group is substituted by fluorine.
More preferably, in the triterpene derivatives,
R1is one of the following groups: hydroxy, amino (-NH)2) Halogen (F, Cl, Br, I), -NHR3、-NHCOOR4、-OR5、
Figure BDA0002539571110000061
R3Is one of the following groups: methyl, ethyl, n-propyl, n-pentyl, phenyl, benzyl, naphthyl, -CH2Br、-CH2CH2Br, cyclopropylalkyl, cyclobutylalkyl, cyclopentylalkyl, cyclohexylalkyl, 1,2,3, 4-tetrahydronaphthyl, -CH2NHCOOC(CH3)3、-CH2CH2NHCOOC(CH3)3、-CH2CH2CH2NHCOOC(CH3)3；
R4Is one of the following groups: methyl, ethyl, n-propyl, n-pentyl, phenyl, naphthyl;
R5is one of the following groups: methyl, ethyl, n-propyl, n-pentyl, phenyl, benzotriazolyl(s) (iii)
Figure BDA0002539571110000062
) Pyridotriazolyl (a) to (b)
Figure BDA0002539571110000063
)；
R2Is one of the following groups: hydroxy, methyl, ethyl, n-propyl, n-pentyl, -CF3、-CF2CH3。
Most preferably, the triterpene derivative is selected from one of the following structures:
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxylic acid; (Compound CDDO)
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-N, 2,2,6a,6b,9,9,12 a-octamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexahydropyridine-4 a (2H) -carboxamide; (Compound I-1)
Methyl (4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxylate; (Compound I-2)
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-N-ethyl-2, 2,6a,6b,9,9,12 a-heptylmethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxamide; (Compound I-3)
N- (((4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridin-4 a (2H) -yl) -2, 2-difluoropropionamide (Compound II-1)
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -N-benzyl-11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, -dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-cetylhydropyridine-4 a (2H) -carboxamide; (Compound I-4)
Ethyl tert-butyl (2- (((4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-octadecatetraenoic acid-4 a-carboxamido) carbamate; (Compound I-5)
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -N- (2-bromoethyl) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxamide; (Compound I-6)
4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-N-cyclohexyl-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxamide; (Compound I-7)
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-N- ((R) -1,2,3, 4-tetrahydronaphthalen-1-yl) -1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydronaphthalene 4a (2H) -carboxamide; (Compound I-8)
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-N- ((S) -1,2,3, 4-tetrahydronaphthalen-1-yl) -1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydronaphthalene 4a (2H) -carboxamide; (Compound I-9)
(4aR,6aS,6bR,8aS,12 bR,14bS) -8a- (1H-imidazole-1-carbonyl) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-3, 4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14 b-octadecahydropyridine-2-carbonitrile; (Compound I-10)
(4aR,6aS,6bR,8aS,12 bR,14bS) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-8 a- (4- (pyridin-2-yl) -1H-imidazole-1-carbonyl) -3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14 b-octadecanedihydropyridine-2-carbonitrile; (Compound I-11)
(4aR,6aS,6bR,8aS,12 bR,14bS) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-8 a- (4- (pyridin-3-yl) -1H-imidazole-1-carbonyl) -3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14 b-octadecanedihydropyridine-2-carbonitrile; (Compound I-12)
1H-benzo [ d ] [1,2,3] triazol-1-yl (4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyrido 4a (2H) -carboxylate; (Compound I-13)
3H- [1,2,3] triazolo [4,5-b ] pyridin-3-yl (4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxylate (Compound I-14).
Further, the fourth aspect of the present invention provides an application of the triterpene derivative, or the isomer, the salt or the solvate thereof in the preparation of drugs for resisting programmed cell necrosis.
The triterpene derivative, or a prodrug of an isomer, a salt or a solvate thereof has a general structure shown in formula I or II:
Figure BDA0002539571110000081
R1is one of the following groups: hydroxy, amino (-NH)2) Halogen (F, Cl, Br, I), -NHR3、-NHCOOR4、-OR5、-NR6R7；
R3Is one of the following groups: C1-C20 alkyl, phenyl, benzyl, naphthyl, C1-C20 alkyl in which at least one hydrogen of the alkyl is substituted by halogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2,3, 4-tetrahydronaphthyl, and- (CH)2)nNHCOOCR8R9R10(ii) a n is an integer of 1 to 4, R8、R9、R10Hydrogen, methyl, ethyl and n-propyl at the same time or at different times;
R4is one of the following groups: C1-C20 alkyl, phenyl and naphthyl;
R5is one of the following groups: C1-C20 alkyl, phenyl, benzotriazolyl, pyridotriazolyl;
R6、R7a group in which at least one hydrogen atom in the ring of C3 to C8, or the above-mentioned ring of C3 to C8 is substituted with pyridine;
R2is one of the following groups: hydroxyl, C1-C20 alkyl, and C1-C20 alkyl in which at least one hydrogen of the alkyl is substituted by fluorine.
More preferably, in the triterpene derivatives,
R1is one of the following groups: hydroxy, amino (-NH)2) Halogen (F, Cl, Br, I), -NHR3、-NHCOOR4、-OR5、
Figure BDA0002539571110000091
R3Is one of the following groups: methyl, ethyl, n-propyl, n-pentyl, phenyl, benzyl, naphthyl, -CH2Br、-CH2CH2Br, cyclopropylalkyl, cyclobutylalkyl, cyclopentylalkyl, cyclohexylalkyl, 1,2,3, 4-tetrahydronaphthyl, -CH2NHCOOC(CH3)3、-CH2CH2NHCOOC(CH3)3、-CH2CH2CH2NHCOOC(CH3)3；
R4Is one of the following groups: methyl, ethyl, n-propyl, n-pentyl, phenyl, naphthyl;
R5is one of the following groups: methyl, ethyl, n-propyl, n-pentyl, phenyl, benzotriazolyl(s) (iii)
Figure BDA0002539571110000092
) Pyridotriazolyl (a) to (b)
Figure BDA0002539571110000093
)；
R2Is one of the following groups: hydroxy, methyl, ethyl, n-propyl, n-pentyl, -CF3、-CF2CH3。
Most preferably, the triterpene derivative is selected from one of the following structures:
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxylic acid; (Compound CDDO)
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-N, 2,2,6a,6b,9,9,12 a-octamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexahydropyridine-4 a (2H) -carboxamide; (Compound I-1)
Methyl (4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxylate; (Compound I-2)
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-N-ethyl-2, 2,6a,6b,9,9,12 a-heptylmethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxamide; (Compound I-3)
N- (((4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridin-4 a (2H) -yl) -2, 2-difluoropropionamide (Compound II-1)
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -N-benzyl-11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, -dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-cetylhydropyridine-4 a (2H) -carboxamide; (Compound I-4)
Ethyl tert-butyl (2- (((4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-octadecatetraenoic acid-4 a-carboxamido) carbamate; (Compound I-5)
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -N- (2-bromoethyl) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxamide; (Compound I-6)
4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-N-cyclohexyl-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxamide; (Compound I-7)
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-N- ((R) -1,2,3, 4-tetrahydronaphthalen-1-yl) -1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydronaphthalene 4a (2H) -carboxamide; (Compound I-8)
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-N- ((S) -1,2,3, 4-tetrahydronaphthalen-1-yl) -1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydronaphthalene 4a (2H) -carboxamide; (Compound I-9)
(4aR,6aS,6bR,8aS,12 bR,14bS) -8a- (1H-imidazole-1-carbonyl) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-3, 4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14 b-octadecahydropyridine-2-carbonitrile; (Compound I-10)
(4aR,6aS,6bR,8aS,12 bR,14bS) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-8 a- (4- (pyridin-2-yl) -1H-imidazole-1-carbonyl) -3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14 b-octadecanedihydropyridine-2-carbonitrile; (Compound I-11)
(4aR,6aS,6bR,8aS,12 bR,14bS) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-8 a- (4- (pyridin-3-yl) -1H-imidazole-1-carbonyl) -3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14 b-octadecanedihydropyridine-2-carbonitrile; (Compound I-12)
1H-benzo [ d ] [1,2,3] triazol-1-yl (4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyrido 4a (2H) -carboxylate; (Compound I-13)
3H- [1,2,3] triazolo [4,5-b ] pyridin-3-yl (4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxylate (Compound I-14).
Further, the fifth aspect of the present invention provides a use of the triterpene derivative, or the isomer, the salt or the solvate thereof, as a prodrug in preparing a medicament for treating cerebral ischemia/reperfusion injury.
The triterpene derivative, or a prodrug of an isomer, a salt or a solvate thereof has a general structure shown in formula I or II:
Figure BDA0002539571110000111
R1is one of the following groups: hydroxy, amino (-NH)2) Halogen (F, Cl, Br, I), -NHR3、-NHCOOR4、-OR5、-NR6R7；
R3Is one of the following groups: C1-C20 alkyl, phenyl, benzyl, naphthyl, C1-C20 alkyl in which at least one hydrogen of the alkyl is substituted by halogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2,3, 4-tetrahydronaphthyl, and- (CH)2)nNHCOOCR8R9R10(ii) a n is an integer of 1 to 4, R8、R9、R10Hydrogen, methyl, ethyl and n-propyl at the same time or at different times;
R4is one of the following groups: c1-C20 alkyl, phenyl, naphthyl;
R5is one of the following groups: C1-C20 alkyl, phenyl, benzotriazolyl, pyridotriazolyl;
R6、R7a group in which at least one hydrogen atom in the ring of C3 to C8, or the above-mentioned ring of C3 to C8 is substituted with pyridine;
R2is one of the following groups: hydroxyl, C1-C20 alkyl, and C1-C20 alkyl in which at least one hydrogen of the alkyl is substituted by fluorine.
More preferably, in the triterpene derivatives,
R1is one of the following groups: hydroxy, amino (-NH)2) Halogen (F, Cl, Br, I), -NHR3、-NHCOOR4、-OR5、
Figure BDA0002539571110000112
R3Is one of the following groups: methyl, ethyl, n-propyl, n-pentyl, phenyl, benzyl, naphthyl, -CH2Br、-CH2CH2Br, cyclopropylalkyl, cyclobutylalkyl, cyclopentylalkyl, cyclohexylalkyl, 1,2,3, 4-tetrahydronaphthyl, -CH2NHCOOC(CH3)3、-CH2CH2NHCOOC(CH3)3、-CH2CH2CH2NHCOOC(CH3)3；
R4Is one of the following groups: methyl, ethyl, n-propyl, n-pentyl, phenyl, naphthyl;
R5is one of the following groups: methyl, ethyl, n-propyl, n-pentyl, phenyl, benzotriazolyl(s) (iii)
Figure BDA0002539571110000121
) Pyridotriazolyl (a) to (b)
Figure BDA0002539571110000122
)；
R2Is as followsOne of the groups: hydroxy, methyl, ethyl, n-propyl, n-pentyl, -CF3、-CF2CH3。
Most preferably, the triterpene derivative is selected from one of the following structures:
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxylic acid; (Compound CDDO)
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-N, 2,2,6a,6b,9,9,12 a-octamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexahydropyridine-4 a (2H) -carboxamide; (Compound I-1)
Methyl (4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxylate; (Compound I-2)
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-N-ethyl-2, 2,6a,6b,9,9,12 a-heptylmethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxamide; (Compound I-3)
N- (((4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridin-4 a (2H) -yl) -2, 2-difluoropropionamide (Compound II-1)
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -N-benzyl-11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, -dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-cetylhydropyridine-4 a (2H) -carboxamide; (Compound I-4)
Ethyl tert-butyl (2- (((4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-octadecatetraenoic acid-4 a-carboxamido) carbamate; (Compound I-5)
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -N- (2-bromoethyl) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxamide; (Compound I-6)
4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-N-cyclohexyl-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxamide; (Compound I-7)
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-N- ((R) -1,2,3, 4-tetrahydronaphthalen-1-yl) -1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydronaphthalene 4a (2H) -carboxamide; (Compound I-8)
(4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-N- ((S) -1,2,3, 4-tetrahydronaphthalen-1-yl) -1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydronaphthalene 4a (2H) -carboxamide; (Compound I-9)
(4aR,6aS,6bR,8aS,12 bR,14bS) -8a- (1H-imidazole-1-carbonyl) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-3, 4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14 b-octadecahydropyridine-2-carbonitrile; (Compound I-10)
(4aR,6aS,6bR,8aS,12 bR,14bS) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-8 a- (4- (pyridin-2-yl) -1H-imidazole-1-carbonyl) -3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14 b-octadecanedihydropyridine-2-carbonitrile; (Compound I-11)
(4aR,6aS,6bR,8aS,12 bR,14bS) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-8 a- (4- (pyridin-3-yl) -1H-imidazole-1-carbonyl) -3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14 b-octadecanedihydropyridine-2-carbonitrile; (Compound I-12)
1H-benzo [ d ] [1,2,3] triazol-1-yl (4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyrido 4a (2H) -carboxylate; (Compound I-13)
3H- [1,2,3] triazolo [4,5-b ] pyridin-3-yl (4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxylate (Compound I-14).
In the definitions of the formulae I or II given above, the terms used in the collection are generally defined as follows:
the term alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon group containing 1 to 20 carbon atoms, for example: methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and the like.
The term C1-C20 alkyl wherein at least one hydrogen on the alkyl group is replaced by a halogen, such as-CH2Br、-CH2CH2Br。
The term C3-C8 ring is imidazolyl, piperidinyl, etc.
The term C3-C8 group wherein at least one hydrogen of the ring is replaced by a pyridine such as
Figure BDA0002539571110000131
The term C1-C20 alkyl wherein at least one hydrogen on the alkyl group is replaced by fluorine, such as-CF3、-CF2CH3And the like.
Due to the adoption of the technical scheme, the invention has the following advantages and beneficial effects:
the triterpenoid derivative or the prodrug of the isomer, the salt or the solvate thereof can be used as a programmed cell necrosis inhibitor to effectively inhibit programmed cell necrosis; can be used for preparing medicines for preventing and treating ischemic diseases related to programmed cell necrosis.
Drawings
FIG. 1 is a graph showing the effect of the compound prepared in example 13 on the overall survival rate and body temperature of mice injected with TNF- α, wherein A is a statistical graph of the overall survival rate of mice and B is a record graph of the body temperature of mice.
Fig. 2 is a statistical schematic diagram of MCAO rat cerebral infarction indexes, wherein a is a schematic diagram of nerve function evaluation, and B is a schematic diagram of rat cerebral infarction proportion statistics.
FIG. 3 is a graph of representative TTC staining of MCAO rat cerebral mesencephalon infarction.
FIG. 4 is a graph of HE staining of hippocampus and cortex in MCAO rat brain: ischemic cerebral cortex cortices (magnification:. times.200), ischemic hippocampal CA3 (magnification:. times.100) and ischemic hippocampal CA1 (magnification:. times.200).
Detailed Description
In order to more clearly illustrate the invention, the invention is further described below in connection with preferred embodiments. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and is not to be taken as limiting the scope of the invention.
Example 1
Preparation of 4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-N, 2,2,6a,6b,9,9,12 a-octamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxamide:
Figure BDA0002539571110000141
30mg of 2-cyano-3, 12-dioxooleanane-1, 9(11) -diene-28-carboxylic acid (Bardoxolone, CDDO, available from eagle's grain reagent net (www.integle.com), manufactured by Biddy pharmaceutical science and technology Co., Ltd., specification 1g) was dissolved in 5mL of dichloromethane, a catalytic amount of dimethylformamide was added, 16. mu.L of oxalyl chloride was slowly dropped in ice bath, the reaction was continued for 10 minutes after the addition was completed, and the reaction was slowly returned to room temperature for 1 hour. The reaction solution was concentrated and evaporated to dryness, and the crude product was used directly in the next reaction.
Dissolving the crude product in 5mL of dry dichloromethane, sequentially adding 16 mu L of triethylamine and 20 mu L of methylamine under ice bath, reacting for 10 minutes, slowly raising the temperature to room temperature, continuing to react for 4 hours, washing and salt-washing the reaction solution, adding anhydrous sodium sulfate for drying, and purifying by a column to obtain 25mg of white solid, namely the triterpenoid derivative compound I-1 with the yield of 77%.
Example 2
Preparation of methyl (4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxylate
Figure BDA0002539571110000151
30mg CDDO is dissolved in 5mL dichloromethane, a catalytic amount of dimethylformamide is added, 16 μ L oxalyl chloride is slowly dropped in ice bath, the reaction is continued for 10 minutes after the addition is finished, and the reaction is slowly returned to room temperature for 1 hour. Excess methanol was added to the reaction solution, and the reaction was continued for 1 hour. Purifying with column to obtain 29mg white solid, i.e. triterpenoid derivative compound I-2, with a yield of 96%.
Example 3
Preparation of (4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-N-ethyl-2, 2,6a,6b,9,9,12 a-heptylmethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxamide
Figure BDA0002539571110000152
40mg CDDO dissolved in 10mL dichloromethane, adding a catalytic amount of two methyl formamide, ice bath slowly dropwise add 25 u L oxalyl chloride, after the addition, continue the reaction for 10 minutes, slowly return to room temperature reaction for 1 hours. The reaction solution was concentrated and evaporated to dryness, and the crude product was used directly in the next reaction. Dissolving the crude product in 10mL of dry dichloromethane, sequentially adding 25 mu L of triethylamine and 40 mu L of ethylamine under ice bath, reacting for 10 minutes, slowly raising the temperature to room temperature, continuing to react for 4 hours, washing and salt-washing the reaction solution, adding anhydrous sodium sulfate for drying, and purifying by a column to obtain 30mg of white solid, namely the triterpenoid derivative compound I-3 with the yield of 71%.
Example 4
Preparation of N- (((4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridin-4 a (2H) -yl) -2, 2-difluoropropionamide
Figure BDA0002539571110000161
Compounds were purchased directly from the MCE small molecule inhibitor library (https:// www.medchemexpress.cn /), synonymously named: RTA-408; catalog number: HY-12212, HPLC purity: 99.4 percent.
Example 5
Preparation of (4aS,6aR,6bS,8aR,12aS,14aR,14bS) -N-benzyl-11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, -dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxamide
Figure BDA0002539571110000162
30mg CDDO is dissolved in 5mL dichloromethane, a catalytic amount of dimethylformamide is added, 16 μ L oxalyl chloride is slowly dropped in ice bath, the reaction is continued for 10 minutes after the addition is finished, and the reaction is slowly returned to room temperature for 1 hour. The reaction solution was concentrated and evaporated to dryness, and the crude product was used directly in the next reaction. Dissolving the crude product in 10mL of dry dichloromethane, sequentially adding 16 mu L of triethylamine and 20 mu L of benzylamine under ice bath, reacting for 10 minutes, slowly raising the temperature to room temperature, continuing to react for 4 hours, washing the reaction solution with water and salt, and adding anhydrous sodium sulfate for drying. After column purification (petroleum ether/ethyl acetate 5:1), 25mg of white solid, namely the triterpenoid derivative compound I-4, is obtained with a yield of 74%.1H NMR(600MHz,CDCl3)δ:0.90(s,3H,CH3),0.99(s,3H,CH3),1.00(s,3H,CH3),1.15(s,3H,CH3),1.16(s,3H,CH3),1.24(s,3H,CH3),1.29-1.36(m,2H,CH2),1.46(s,3H,CH3),1.49-1.75(m,10H,5CH2),1.83-1.88(dt,1H,J1＝4.9Hz,J2＝13.5Hz,8-CHa),1.96-2.01(dt,1H,J1＝3.5Hz,J2＝13.5Hz,8-CHb),2.91-2.93(dt,1H,J1＝4.2Hz,J2＝13.5Hz,14b-CH),3.00-3.01(1H,d,J＝4.2Hz,14a-CH),4.43-4.51(m,2H,NCH2),5.96(s,1H,13-CH),6.18-6.20(t,1H,J＝5.6Hz,NH),7.26-7.30(m,5H,Ar-H),8.04(s,1H,12-CH).13C NMR(75MHz,CDCl3)δ:18.24,21.56,21.73,23.13,24.70,26.62,27.00,27.74,30.63,31.66,32.01,33.26,34.11,34.61,36.11,42.11,42.53,43.69,45.01,45.85,46.50,47.70,49.49,114.40,114.58,123.95,127.45,127.98,128.69,138.85,165.79,168.71,176.92,196.56,198.95.MS(ESI):581.402(M+H)+,603.343(M+Na)+,619.317(M+K)+.
Example 6
Preparation of ethyl tert-butyl (2- (((4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1, 2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-octapicene-4 a-carboxamido) carbamate
Figure BDA0002539571110000171
60mg CDDO is dissolved in 15mL dichloromethane, a catalytic amount of dimethylformamide is added, 35 μ L oxalyl chloride is slowly dropped in ice bath, the reaction is continued for 10 minutes after the addition is finished, and the reaction is slowly returned to room temperature for 1 hour. The reaction solution was concentrated and evaporated to dryness, and the crude product was used directly in the next reaction. Dissolving the crude product in 15mL of dry dichloromethane, sequentially adding 30 mu L of triethylamine and 40 mu L of (2-aminoethyl) carbamic acid tert-butyl ester under ice bath, reacting for 10 minutes, slowly heating to room temperature, continuing to react for 4 hours, washing the reaction liquid with water, washing with salt, adding anhydrous sodium sulfate, drying, and purifying by a column (petroleum ether/ethyl acetate 5:1) to obtain 58mg of white solid, namely the triterpenoid derivative compound I-5 with the yield of 92%.1H NMR(600MHz,CDCl3)δ:0.92(s,3H,CH3),1.02(s,3H,CH3),1.04(s,3H,CH3),1.19(s,3H,CH3),1.28(s,3H,CH3),1.35(s,3H,CH3),1.26-1.30(m,4H,2CH2),1.47(s,9H,3CH3),1.50(s,3H,CH3),1.53-1.81(m,8H,4CH2),1.83-1.86(dt,1H,J1＝4.5Hz,J2＝13.5Hz,8-CHa),2.01-2.05(dt,1H,J1＝3.9Hz,J2＝13.5Hz,8-CHb),2.97-2.99(dt,1H,J1＝3.0Hz,J2＝14.2Hz,14b-CH),3.11-3.11(1H,d,J＝3.0Hz,14a-CH),3.28-3.36(m,2H,CH2),3.41-3.42(m,2H,NCH2),5.99(s,1H,13-CH),6.85(s,1H,NH),8.08(s,1H,12-CH).13C NMR(75MHz,CDCl3)δ:14.21,18.24,21.56,21.72,23.02,23.10,24.80,26.60,26.98,27.84,28.39,30.62,31.66,33.30,34.00,34.64,35.99,42.14,42.54,45.01,45.86,46.41,47.74,49.41,60.40,114.39,114.57,124.05,157.22,165.80,171.17,178.10,196.58,199.01.MS(ESI):656.428(M+Na)+,672.394(M+K)+.
Example 7
Preparation of (4aS,6aR,6bS,8aR,12aS,14aR,14bS) -N- (2-bromoethyl) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxamide
Figure BDA0002539571110000181
50mg of CDDO is dissolved in 15ml of dichloromethane, a catalytic amount of dimethylformamide is added, 35. mu.l of oxalyl chloride is slowly added dropwise in ice bath, the reaction is continued for 10 minutes after the addition is finished, and the reaction is slowly returned to room temperature for 1 hour. The reaction solution was concentrated and evaporated to dryness, and the crude product was used directly in the next reaction. Dissolving the crude product in 15ml of dry dichloromethane, sequentially adding 30 ml of triethylamine and 40 ml of (2-aminoethyl) carbamic acid tert-butyl ester under ice bath, reacting for 10 minutes, slowly heating to room temperature, continuing to react for 4 hours, washing the reaction liquid with water, washing the reaction liquid with salt, adding anhydrous sodium sulfate for drying, and purifying by a column (petroleum ether/ethyl acetate 4: 1-3: 1) to obtain 45.5 mg of white solid, namely the triterpenoid derivative compound I-6 with the yield of 80%.1H NMR(600MHz,CDCl3)δ:0.90(s,3H,CH3),1.01(s,3H,CH3),1.01(s,3H,CH3),1.16(s,3H,CH3),1.25(s,3H,CH3),1.34(s,3H,CH3),1.47(s,3H,CH3),1.51-1.58(m,4H,2CH2),2.99-3.02(dt,1H,J1＝4.5Hz,J2＝14.2Hz,14b-CH),3.18-3.19(1H,d,J＝4.5Hz,14a-CH),3.83-3.86(dt,2H,J1＝3.4Hz,J2＝9.3Hz,CH2),4.18-4.23(dd,2H,J1＝9.3Hz,J2＝9.3Hz,CH2),5.96(s,1H,13-CH),8.04(s,1H,12-CH).13C NMR(75MHz,CDCl3)δ:19.19,22.99,23.12,23.77,24.62,26.62,27.00,27.49,28.94,30.39,31.65,32.02,33.06,33.29,34.40,35.69,38.76,40.94,42.12,42.52,45.02,45.84,47.77,49.26,114.39,114.59,124.09,165.78,167.77,173.13,196.60,199.17.
Example 8
Preparation of 4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-N-cyclohexyl-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxamide
Figure BDA0002539571110000182
50mg of CDDO is dissolved in 15ml of dichloromethane, a catalytic amount of dimethylformamide is added, 35 microliters of oxalyl chloride is slowly dropped in ice bath, the reaction is continued for 10 minutes after the addition is finished, and the reaction is slowly returned to room temperature for 1 hour. The reaction solution was concentrated and evaporated to dryness, and the crude product was used directly in the next reaction. Dissolving the crude product in 15ml of dry dichloromethane, sequentially adding 30 microliters of triethylamine and 30 microliters of aminocyclohexane under ice bath, reacting for 10 minutes, slowly raising the temperature to room temperature, continuing to react for 4 hours, washing and salting the reaction liquid, adding anhydrous sodium sulfate for drying, and purifying by a column (petroleum ether/ethyl acetate 5:1) to obtain 43 mg of white solid, namely the triterpenoid derivative compound I-7 with the yield of 74%.1H NMR(600MHz,CDCl3)δ:0.90(s,3H,CH3),0.99(s,3H,CH3),1.01(s,3H,CH3),1.05-1.08(m,1H,CH),1.09-1.16(m,2H,CH2),1.18(s,3H,CH3),1.25(s,3H,CH3),1.31(s,3H,CH3),1.36-1.38(m,1H,CH),1.44-1.47(dt,1H,J1＝3.3Hz,J2＝14.2Hz,CH),1.48(s,3H,CH3),1.51-1.54(dt,1H,J1＝3.3Hz,J2＝13.5Hz,CH),1.57-1.72(m,8H,4CH2),1.76-1.81(m,5H,2CH2,CH),1.84-1.91(m,2H,2CH),1.93-1.99(dt,1H,J1＝3.9Hz,J2＝13.5Hz,8-CHb),2.85-2.87(dt,1H,J1＝4.4Hz,J2＝13.5Hz,14b-CH),3.06-3.07(d,1H,J＝4.4Hz,14a-CH),3.80-3.82(m,1H,CH),5.57-5.58(d,1H,J＝8.0Hz,NH),5.97(s,1H,13-CH),8.04(s,1H,12-CH).13C NMR(75MHz,CDCl3)δ:18.24,21.56,21.74,23.00,23.14,24.91,24.95,25.53,26.62,27.00,27.76,30.64,31.67,31.95,33.21,33.29,33.32,34.17,34.62,36.12,42.13,42.54,45.02,45.96,46.28,47.73,48.03,49.48,114.38,114.60,123.99,165.72,168.65,175.95,196.56,199.03.MS(ESI):573.467(M+H)+,595.398(M+Na)+.
Example 9
Preparation of (4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-N- ((R) -1,2,3, 4-tetrahydronaphthalen-1-yl) -1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydronaphthalene 4a (2H) -carboxamide
Figure BDA0002539571110000191
60mg CDDO is dissolved in 15mL dichloromethane, a catalytic amount of dimethylformamide is added, 35 μ L oxalyl chloride is slowly dropped in ice bath, the reaction is continued for 10 minutes after the addition is finished, and the reaction is slowly returned to room temperature for 1 hour. The reaction solution was concentrated and evaporated to dryness, and the crude product was used directly in the next reaction. Dissolving the crude product in 15mL of dry dichloromethane, sequentially adding 30 mu L of triethylamine and 50 mu L of (R) -1,2,3, 4-tetrahydronaphthalene-1-amine under ice bath, reacting for 10 minutes, slowly heating to room temperature, continuing to react for 4 hours, washing the reaction liquid with water and salt, adding anhydrous sodium sulfate for drying, and purifying by a column (petroleum ether/ethyl acetate 5:1) to obtain 52mg of white solid, namely the triterpenoid derivative compound I-8 with the yield of 84%.1H NMR(600MHz,CDCl3)δ:0.90(s,3H,CH3),0.96(s,3H,CH3),1.02(s,3H,CH3),1.18(s,3H,CH3),1.26(s,3H,CH3),1.29-1.36(m,2H,CH2),1.40(s,3H,CH3),1.50(s,3H,CH3),1.53-1.57(m,3H,CH2,CH),1.60(m,5H,2CH2,CH),1.67-1.69(m,1H,CH),1.73-1.76(m,2H,CH2),1.79-1.80(m,4H,2CH2),1.83-1.90(m,2H,CH2),1.93-2.03(m,2H,8-CH2),2.73-2.85(m,3H,CH2,14b-CH),3.07-3.08(d,1H,J＝4.5Hz,14a-CH),5.20-5.23(m,1H,CH),5.94-5.96(d,1H,J＝8.2Hz,NH),5.97(s,1H,13-CH),7.12-7.21(m,4H,Ar-H),8.03(s,1H,12-CH).13C NMR(75MHz,CDCl3)δ:18.28,20.10,21.57,21.80,22.90,23.13,24.99,26.66,27.03,27.82,29.27,30.42,30.64,31.72,32.14,33.25,34.18,34.60,36.19,42.16,42.56,45.03,46.00,46.57,47.34,47.74,49.62,114.36,124.04,126.37,127.36,128.35,129.43,136.77,137.75,165.62,168.81,176.15,196.52,198.84.MS(ESI):621.416(M+H)+,643.386(M+Na)+,659.359(M+K)+.
Example 10
Preparation of (4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-N- ((S) -1,2,3, 4-tetrahydronaphthalen-1-yl) -1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydronaphthalene 4a (2H) -carboxamide
Figure BDA0002539571110000201
50mg CDDO is dissolved in 15mL dichloromethane, a catalytic amount of dimethylformamide is added, 35 μ L oxalyl chloride is slowly added dropwise in ice bath, the reaction is continued for 10 minutes after the addition is finished, and the reaction is slowly returned to room temperature for 1 hour. The reaction solution was concentrated and evaporated to dryness, and the crude product was used directly in the next reaction. Dissolving the crude product in 15mL of dry dichloromethane, sequentially adding 30 mu L of triethylamine and 45 mu L of (S) -1,2,3, 4-tetrahydronaphthalene-1-amine under ice bath, reacting for 10 minutes, slowly heating to room temperature, continuing to react for 4 hours, washing the reaction liquid with water and salt, adding anhydrous sodium sulfate for drying, and performing column purification (petroleum ether/ethyl acetate 5:1) to obtain 45mg of white solid, namely the triterpenoid derivative compound I-9 with the yield of 73%.1H NMR(600MHz,CDCl3)δ:0.86(s,3H,CH3),1.01(s,3H,CH3),1.02(s,3H,CH3),1.17(s,3H,CH3),1.18-1.20(dt,1H,J1＝3.5Hz,J2＝13.3Hz,CH),1.25(s,3H,CH3),1.32-1.33(dt,1H,J1＝4.0Hz,J2＝14.0Hz,CH),1.39(s,3H,CH3),1.48-1.50(m,5H,CH2,CH3),1.55-1.57(dt,1H,J1＝2.8Hz,J2＝13.5Hz,CH),1.60-1.62(dt,1H,J1＝2.8Hz,J2＝13.3Hz,CH),1.67-1.74(m,3H,CH,CH2),1.76-1.84(m,7H,CH,3CH2),1.89-1.95(dt,1H,J1＝4.6Hz,J2＝13.3Hz,8-CHa),2.04-2.07(dt,1H,J1＝4.0Hz,J2＝13.5Hz,8-CHb),2.07-2.08(m,1H,CH),2.75-2.80(dt,1H,J1＝6.2Hz,J2＝16.8Hz,2’-CHa),2.81-2.86(dt,1H,J1＝6.2Hz,J2＝17.1Hz,2’-CHb),3.01-3.03(dt,1H,J1＝4.5Hz,J2＝13.0Hz,14b-CH),3.16-3.17(d,1H,J＝4.5Hz,14a-CH),5.20-5.23(m,1H,CH),5.91-5.92(d,1H,J＝8.2Hz,NH),5.96(s,1H,13-CH),7.10-7.18(m,4H,Ar-H),8.04(s,1H,12-CH).13C NMR(75MHz,CDCl3)δ:18.24,20.17,21.55,21.64,23.11,23.37,24.88,26.67,27.00,27.80,29.29,30.41,30.65,31.72,33.28,34.21,34.69,35.97,42.17,42.52,45.01,46.38,47.38,47.74,49.41,114.37,114.57 124.13,126.33,127.33,128.44,129.31,136.72,137.67,165.78,168.15,176.13,196.56,198.81.MS(ESI):621.393(M+H)+.
Example 11
Preparation of (4aR,6aS,6bR,8aS,12aS,12bR,14bS) -8a- (1H-imidazole-1-carbonyl) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-3, 4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14 b-octadecane-hydroxypyridine-2-carbonitrile
Figure BDA0002539571110000211
50mg CDDO is dissolved in 15mL dichloromethane, a catalytic amount of dimethylformamide is added, 35 μ L oxalyl chloride is slowly added dropwise in ice bath, the reaction is continued for 10 minutes after the addition is finished, and the reaction is slowly returned to room temperature for 1 hour. The reaction solution was concentrated and evaporated to dryness, and the crude product was used directly in the next reaction. Dissolving the crude product in 15mL of dry dichloromethane, sequentially adding 30 mu L of triethylamine and 21mg of imidazole under ice bath, reacting for 10 minutes, slowly raising the temperature to room temperature, continuing to react for 4 hours, washing and salting the reaction solution, adding anhydrous sodium sulfate for drying, and purifying by a column to obtain 40mg of white solid, namely the triterpenoid derivative compound I-10 with the yield of 63%.
Example 12
Preparation of (4aR,6aS,6bR,8aS,12aS,12bR,14bS) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-8 a- (4- (pyridin-2-yl) -1H-imidazole-1-carbonyl) -3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14 b-octadecane-dihydropyridine-2-carbonitrile
Figure BDA0002539571110000221
50mg CDDO is dissolved in 15mL dichloromethane, a catalytic amount of dimethylformamide is added, 35 μ L oxalyl chloride is slowly added dropwise in ice bath, the reaction is continued for 10 minutes after the addition is finished, and the reaction is slowly returned to room temperature for 1 hour. The reaction solution was concentrated and evaporated to dryness, and the crude product was used directly in the next reaction. Dissolving the crude product in 15mL of dry dichloromethane, sequentially adding 30 mu L of triethylamine and 44mg of 2- (1H-imidazol-4-yl) pyridine under ice bath, reacting for 10 minutes, slowly heating to room temperature, continuing to react for 4 hours, washing the reaction liquid with water and salt, adding anhydrous sodium sulfate for drying, and purifying by a column to obtain 40mg of white solid, namely the triterpenoid derivative compound I-11 with the yield of 63%.1H NMR(400MHz,DMSO-d6)δ:0.93(s,3H,CH3),0.95(s,3H,CH3),0.99(s,3H,CH3),1.04(s,3H,CH3),1.15(s,3H,CH3),1.21(s,3H,CH3),1.42(s,3H,CH3),1.22-1.42(m,3H,CH,CH2),2.08-2.30(m,3H,CH,8-CH2),2.99-3.02(d,1H,J＝4.2Hz,14a-CH),3.12-3.13(m,1H,14b-CH),6.26(s,1H,13-CH),7.31-7.34(dd,1H,J1＝6.4Hz,J2＝4.0Hz,Ar-H),7.88-7.90(m,1H,Ar-H),7.95-7.97(d,1H,J＝8.0Hz,Ar-H),8.26(s,1H,12-CH),8.58-8.59(d,1H,J＝4.0Hz,Ar-H),8.68(s,1H,Ar-H),8.74(s,1H,Ar-H).MS(ESI):619.54(M+H)+HPLC purity:>98%, Rt 6.538 min, UV 210nm, 80% methanol, flow rate 0.5mL/min.
Example 13
Preparation of (4aR,6aS,6bR,8aS,12aS,12bR,14bS) -4,4,6a,6b,11,11,14 b-heptamethyl-3, 13-dioxo-8 a- (4- (pyridin-3-yl) -1H-imidazole-1-carbonyl) -3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14 b-octadecane-dihydropyridine-2-carbonitrile
Figure BDA0002539571110000222
50mg CDDO is dissolved in 15mL dichloromethane, a catalytic amount of dimethylformamide is added, 35 μ L oxalyl chloride is slowly added dropwise in ice bath, the reaction is continued for 10 minutes after the addition is finished, and the reaction is slowly returned to room temperature for 1 hour. The reaction solution was concentrated and evaporated to dryness, and the crude product was used directly in the next reaction. Dissolving the crude product in 15mL of dry dichloromethane, sequentially adding 30 mu L of triethylamine and 44mg of 2- (1H-imidazol-4-yl) pyridine under ice bath, reacting for 10 minutes, slowly heating to room temperature, continuing to react for 4 hours, washing the reaction liquid with water and salt, adding anhydrous sodium sulfate for drying, and purifying by a column to obtain 45mg of white solid, namely the triterpenoid derivative compound I-12 with the yield of 71%.1H NMR(400MHz,DMSO-d6)δ:0.95(s,6H,2CH3),1.00(s,3H,CH3),1.08(s,3H,CH3),1.16(s,3H,CH3),1.20(s,3H,CH3),1.43(s,3H,CH3),2.20-2.30(m,3H,CH,8-CH2),2.90-3.05(d,1H,J＝4.2Hz,14a-CH),3.16-3.17(m,1H,14b-CH),6.26(s,1H,13-CH),7.43-7.46(dd,1H,J1＝4.0Hz,J2＝7.9Hz,Ar-H),8.28-8.30(m,1H,Ar-H),8.49-8.50(d,1H,J＝4.1Hz,Ar-H),8.59(s,1H,12-CH),8.68(s,1H,Ar-H),8.72(s,1H,Ar-H),9.16(s,1H,Ar-H).MS(ESI):619.54(M+H)+HPLC purity:>98%, Rt 12.983 min, UV 210nm, 70% methanol, flow rate 0.5mL/min.
Example 14
Preparation of 1H-benzo [ d ] [1,2,3] triazol-1-yl (4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyrido 4a (2H) -carboxylate
Figure BDA0002539571110000231
50mg of CDDO was dissolved in 15mL of chloroform, and 40. mu.L of triethylamine was added to stir the reaction at room temperature for 10 minutes. 77mg of HATU were then added and stirred for 4 hours. The reaction was extracted with ethyl acetate and saturated brineWashed with water and dried over anhydrous sodium sulfate. The combined organic phases were evaporated to dryness to give a crude product, which was purified by silica gel column chromatography using PE/EtOAc (5: 1-3: 1) as eluent to give 56mg of white solid product i.e. triterpenoid derivative compound I-13, yield: 90.4 percent.1H NMR(600MHz,CDCl3)δ:0.99(s,3H,CH3),1.09(s,6H,2CH3),1.19(s,3H,CH3),1.27(s,3H,CH3),1.33-1.37(m,1H,CH),1.42-1.48(m,5H,CH2,CH3),1.51(s,3H,CH3),1.63-1.65(m,2H,CH2),1.72-1.74(m,2H,CH2),1.78-1.84(m,3H,CH,CH2),1.99-2.06(m,3H,CH,CH2),2.18-2.23(dt,1H,J1＝3.2Hz,J2＝14.7Hz,8-CHa),2.25-2.31(dt,1H,J1＝4.4Hz,J2＝13.7Hz,8-CHb),3.18-3.19(d,1H,J＝4.7Hz,14a-CH),3.20-3.24(dt,1H,J1＝4.7Hz,J2＝13.5Hz,14b-CH),6.00(s,1H,13-CH),7.36-7.37(d,1H,J＝8.5Hz,4’-PhH),7.43-7.45(dd,1H,J1＝7.7Hz,J2＝8.5Hz,5’-PhH),7.54-7.57(dd,1H,J1＝7.7Hz,J2＝8.5Hz,6’-PhH),8.04(s,1H,12-CH),8.07-8.08(d,1H,J＝8.5Hz,7’-PhH).13C NMR(75MHz,CDCl3)δ:18.23,21.58,21.63,22.81,23.03,24.82,26.62,26.96,28.28,30.61,31.71,31.92,32.89,33.10,34.24,35.35,42.22,42.62,45.06,46.04,47.83,49.52,107.89,114.36,114.66,120.67,123.89,124.87,128.69,128.80,143.62,165.47,168.80,174.04,196.48,197.88.MS(ESI):609.366(M+H)+.
Example 15
Preparation of 3H- [1,2,3] triazolo [4,5-b ] pyridin-3-yl (4aS,6aR,6bS,8aR,12aS,14aR,14bS) -11-cyano-2, 2,6a,6b,9,9,12 a-heptamethyl-10, 14-dioxo-1,3,4,5,6,6a,6b,7,8,8a,9,10,12a,14,14a,14 b-hexadecahydropyridine-4 a (2H) -carboxylate
Figure BDA0002539571110000241
50mg of CDDO was dissolved in 15mL of chloroform, and 40. mu.L of triethylamine was added to stir the reaction at room temperature for 10 minutes. Then add76mg HBTU was added and stirred for 4 hours. The reaction mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The combined organic phases were evaporated to dryness to give a crude product, which was purified by silica gel column chromatography using PE/EtOAc (5: 1-3: 1) as eluent to give 56.9mg of white solid product i.e. triterpenoid derivative compound I-14, yield: 92 percent.1H NMR(600MHz,CDCl3)δ:0.97(s,3H,CH3),1.08(s,3H,CH3),1.10(s,3H,CH3),1.19(s,3H,CH3),1.28(s,3H,CH3),1.33-1.37(m,1H,CH),1.42-1.49(m,3H,CH,CH2),1.51(s,3H,CH3),1.64-1.67(m,1H,CH),1.69-1.72(m,1H,CH),1.75-1.85(m,4H,2CH2),2.01-2.07(m,2H,CH2),2.12-2.23(m,2H,2CH),2.33-2.38(dt,1H,J1＝4.3Hz,J2＝13.5Hz,8-CHb),3.23-3.25(m,2H,14a-CH,14b-CH),6.01(s,1H,13-CH),7.43-7.45(dd,1H,J1＝4.2Hz,J2＝8.4Hz,5’-PhH),8.06(s,1H,12-CH),8.41-8.43(dd,1H,J1＝1.4Hz,J2＝8.4Hz,4’-PhH),8.66-8.67(dd,1H,J1＝1.2Hz,J2＝4.4Hz,6’-PhH).13C NMR(75MHz,CDCl3)δ:18.26,21.58,21.66,22.86,23.01,24.86,26.68,27.00,28.22,30.60,31.74,31.97,32.68,33.10,34.18,35.43,42.30,42.60,45.04,46.08,47.69,47.76,49.60,114.38,114.63,120.86,123.93,135.07,140.72,151.61,165.65,168.91,173.65,195.55,198.09.MS(ESI):610.361(M+H)+,632.333(M+Na)+.
Example 16
Anti-cell necrosis Activity assay
The triterpenoid derivatives prepared in the embodiments 1-15 of the invention are subjected to an anti-cell necrosis activity test, and the method mainly adopted is a CellTiter Glo kit detection method.
The tested cells were selected from L-929 (mouse fibroblast) and HT-29 (human colon cancer cell). The culture medium is DMEM + 10% FBS + 1% double antibody, and the cell culture conditions are 36.5 +/-0.5 ℃ and 5% carbon dioxide.
The triterpene derivatives prepared in the embodiments 1 to 15 of the present invention are dissolved in DMSO (merck) to prepare a 50mM solution, and then the solution is diluted with DMSO to a concentration to be measured, generally three times diluted. Apoptosis can be induced by pre-treating test cells with z-VAD-fmk (20 mu M) and Smac simulant (10 mu M) or cycloheximide (5 mu g/mL) for 30 minutes, then with TNF-alpha (20ng/mL) for 12 or 10 minutes, and the cells can be detected within 16-24 h. TNF-alpha (20ng/mL) and Smac mimetics (10nM) induced apoptosis and cells were tested after 24 h. The triterpene derivatives prepared in the embodiments 1-15 of the invention are prepared into 1mM mother liquor, then diluted 100 times to 10 μ M as initial concentration, and then diluted according to 3 times gradient, namely 10 μ M, 3.3 μ M, 1.1 μ M, 0.37 μ M, 0.12 μ M and 0.04 μ M. Diluted compounds were added to one of the above combinations and cells were incubated for 16 hours or 24 hours and examined for cell viability using the CellTiter-Glo cell viability kit.
The test results are shown in table 1, wherein the samples refer to the triterpenoid derivatives prepared in the corresponding examples.
TABLE 1 anti-necrotizing Activity of triterpene derivatives
Figure BDA0002539571110000251
The experimental results show that the triterpenoid derivatives prepared in the embodiments 1-15 of the invention have good anti-cell necrosis activity, and are all in micromolar level. Examples 12 and 13 have excellent anti-necrosis activity, reaching nanomolar levels. The activity of the compound of example 12 was increased 5-fold in HT-29 cell line and more than 16-fold in L-929 cell line relative to CDDO; the compound of example 13 was increased 4-fold in the HT-29 cell line and at least 11-fold in the L-929 cell line. Therefore, the triterpenoid derivatives and salts thereof prepared in the embodiments 1-15 of the invention can be used as a programmed cell necrosis inhibitor and can be used for preparing a medicament for programmed cell necrosis.
Example 17
Protective activity of Systemic Inflammatory Response Syndrome (SIRS) of mice, anti-SIRS experiments are carried out on the triterpenoid derivative prepared by the invention.
For TNF-. alpha.induced SIRS, female C57BL/6 mice (6-8 weeks old) were purchased from the Changzhou Kavin center (Jiangsu province, China) and cultured in a pathogen-free environment (temperature: 21-26 ℃ C., humidity: 40-70%).
The triterpene derivative prepared in example 13 was suspended in 0.5% sodium carboxymethylcellulose solution, and 3% tween-80 was added and ground to prepare an emulsion. Overnight fasted mice were randomly divided into control and treatment groups (n-12 per group). In the drug treatment group, different concentrations (10mg/Kg and 20mg/Kg) of the triterpene derivative prepared in example 13 were administered to the mice by gavage 2 hours before the TNF-. alpha.injection. Murine TNF-. alpha.was diluted in endotoxin-free PBS and injected intravenously in 200. mu.L volumes (administration concentrations of 250. mu.g/kg or 400. mu.g/kg). Mice were injected intraperitoneally with 200 μ g Z-VAD-fmk 15 minutes before TNF- α administration, with 75 μ g Z-VAD-fmk 1 hour after TNF-a administration, and body temperature was monitored with an electronic thermometer.
FIG. 1 is a graph showing the effect of the compound prepared in example 13 on the overall survival rate and body temperature of mice injected with TNF- α, wherein A is a statistical graph of the overall survival rate of mice and B is a record graph of the body temperature of mice. As can be seen from fig. a, the mice of the group (Vehicle) to which the compound prepared in example 13 was not administered all died within 20 hours, the mice of the group (10mg/Kg) to which the compound prepared in example 13 was administered still survived 6 mice for 60 hours, and the mice of the group (20mg/Kg) to which the compound prepared in example 13 was administered all survived. As can be seen from FIG. B, the body temperature of the mice in the control group (Vehicle) decreased rapidly, the lowest body temperature recorded within 20 hours was below 26 ℃, and the body temperature of the mice in the administered group returned rapidly to normal levels after a time-lapse drop, indicating that the compound prepared in example 13 reversed the dysfunction of the mice caused by TNF-a induced cellular necrosis. The above experiment shows that the compound prepared in example 13 has a good anti-TNF-a induced cell necrosis effect.
Example 18
Establishment of MCAO rat model:
the triterpene derivatives prepared in the embodiments 1 to 15 of the invention are subjected to MCAO rat model test.
Healthy adult Sprague-Dawley rats weighing 180-. Rats were anesthetized with 10% chloral hydrate (300mg/kg, intraperitoneal), and monofilament nylon suture was inserted into the Internal Carotid Artery (ICA) and then advanced to occlude the left Middle Cerebral Artery (MCA). After 2 hours of occlusion, the wire was carefully removed to achieve 24 hours of reperfusion. Sham operated mice received the same surgery except for arterial occlusion.
All rats were randomized into the following six groups using a random number table: sham operated (sham), I/R (live), I/R + RTA-402 (the compound prepared in example 4, here designated RTA-402) (100mg/kg), I/R + CDDO-3-P-Im (the compound prepared in example 13, I-12, here designated CDDO-3-P-Im) (100mg/kg) and I/R + nimodipine (1 mg/kg). Nimodipine is a first-line treatment for stroke, a drug acting on L-type voltage-gated calcium channels, which causes vasodilation of vascular smooth muscle cells (Daou, b.j.et., Clinical and experimental therapies of cardiovascular subarachnoid nature, cns Neurosci Ther,2019,25(10), 1096-. Therefore, Nimodipine (Nimodipine) was used as a positive control.
Neurological deficit scoring: neurological deficits were assessed 24 hours after reperfusion using the Zea-Longa scoring system. Reference is made to literature procedures (Bederson, J.B.et. al., Rat middle nuclear association: evaluation of the model and level of neurological evolution. Stroke 1986,17(3), 472-. The scoring system is as follows: 0-no signs of impaired neurological function, normal activity; 1-the contralateral anterior paw cannot be fully extended; 2, turning towards the opposite side when walking; 3, dumping to the opposite side; it does not disappear spontaneously and is unconscious.
Infarct volume assessment: after 24 hours of reperfusion, six animals per group were subjected to cervical dislocation, decapitated after sacrifice, and the brains were removed and immediately measured for infarct volume. Animal brains were cut into 2 mm thick coronal sections of 5-6 slices, immersed in 4% paraformaldehyde at 4 ℃ for 4h and exposed to staining under TTC. The unstained area was defined as infarct and measured using microscopic Image analysis software (Image-Pro Plus), and the proportion of cerebral infarction was calculated (infarct proportion ═ infarct area/whole brain area × 100%).
HE staining: after 24 hours of reperfusion, rats were anesthetized with 10% chloral hydrate, perfused with physiological saline and 4% paraformaldehyde, and sacrificed before decapitation. The brains were removed and embedded in paraffin, frozen rapidly and cut into 5 μm coronal sections. Subsequently, brain sections were deparaffinized and hydrated for HE staining.
The test results are shown in fig. 2 to 4. Fig. 2 is a statistical schematic diagram of MCAO rat cerebral infarction indexes, wherein a is a schematic diagram of nerve function evaluation, and B is a schematic diagram of rat cerebral infarction proportion statistics. FIG. 3 is a graph of representative TTC staining of MCAO rat cerebral mesencephalon infarction. FIG. 4 is a graph of HE staining of hippocampus and cortex in MCAO rat brain: ischemic cerebral cortex cortices (magnification:. times.200), ischemic hippocampal CA3 (magnification:. times.100) and ischemic hippocampal CA1 (magnification:. times.200). In FIGS. 2 and 3, the compound prepared in example 4 (100mg/kg) and the compound prepared in example 13 (100mg/kg) had the effect of preventing I/R injury in MCAO rats.
After 24 hours of reperfusion, the neurological score was first examined to determine neurological deficit. The neurological deficit scores were significantly reduced in the two groups of example 4 and example 13 compared to the I/R group (A in FIG. 2). Infarct volume in the ischemic brain region was measured by 2,3, 5-triphenyltetrazolium chloride (TTC) staining, and pretreatment of the compound prepared in example 4 or the compound prepared in example 13 reduced the infarct volume (fig. 2B and fig. 3). Treatment with the compound prepared in example 4 reduced infarct volume from 36.8 ± 3.2% to 13.7 ± 2.9% at a dose of 100mg/kg, which is much higher than the effect of the reference drug nimodipine (26.8 ± 1.7%). The compound prepared in example 13 can reduce infarct size to 22.8 ± 3.7% compared to nimodipine.
The protective effect of the compound prepared in example 4 and the compound prepared in example 13 was further confirmed by HE staining sections from ischemic hippocampus and cortex 24 hours after reperfusion. The cells of group I/R were reduced and arranged irregularly, and schizophrenia was observed. In contrast, the compound prepared in example 4 and the compound pretreatment prepared in example 13 reversed the pathological changes to some extent, indicating that the triterpene derivatives prepared by the present invention can protect the brain from I/R injury. Ischemic cerebral cortex cortices (magnification: × 200), ischemic hippocampal CA3 (magnification: × 100) and ischemic hippocampal CA1 (magnification: × 200), with n ═ 6 per group. (p <0.05, p <0.01, p <0.001, compared to I/R groups.)
The experimental results show that the triterpenoid derivatives prepared in the embodiments 1-15 have the effect of preventing I/R injury of rats.
Although the present invention has been described with reference to a preferred embodiment, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (2)

1. A class of triterpenoid derivatives or salts, characterized in that the triterpenoid derivative is selected from one of the following structures:
Figure FDA0003216724370000011
2. use of a triterpenoid derivative or salt in the preparation of an inhibitor of programmed cell necrosis, wherein the triterpenoid derivative is selected from one of the following structures:
Figure FDA0003216724370000012
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