Triterpenoid derivatives and application thereof as programmed cell necrosis inhibitor

文档序号：1094426 发布日期：2020-09-25 浏览：12次中文

阅读说明：本技术 一类三萜类衍生物及其作为程序性细胞坏死抑制剂的用途 (Triterpenoid derivatives and application thereof as programmed cell necrosis inhibitor ) 是由庄春林王志斌 *** 马皓黄嘉璇于 2020-06-15 设计创作，主要内容包括：本发明公开了一类三萜类衍生物,或其异构体、盐或溶剂合物的前体药物,具有式I所示的通式结构：<Image he="490" wi="619" file="DDA0002539571130000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>式中各取代基详见说明书。本发明的三萜类衍生物或其异构体、盐或溶剂合物的前体药物可以作为程序性细胞坏死抑制剂,有效抑制细胞发生程序性坏死；可以用于制备程序性细胞坏死相关缺血性疾病的防治药物。(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: 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.)

1. A triterpene derivative, or a prodrug of an isomer, a salt or a solvate thereof, characterized by having a general structure shown in formula I:

R₁is one of the following groups: amino, halogen, -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

2. The triterpene derivative according to claim 1, or a prodrug of an isomer, a salt or a solvate thereof, wherein R in the triterpene derivative₁Is one of the following groups: amino, halogen, -NHR₃、-NHCOOR₄、-OR₅、

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, pyridotriazolyl.

3. A triterpene derivative according to claim 2, or a prodrug of an isomer, salt or solvate thereof, wherein 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;

tert-butyl (ethyl 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-4 a-carboxamido) carbamate;

(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;

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;

(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;

(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;

(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;

(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;

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;

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.

4. A process for the preparation of a prodrug of a triterpenoid derivative, or an isomer, salt or solvate thereof, as claimed in any one of claims 1 to 3, comprising the steps of:

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.

5. A process for the preparation of a prodrug of a triterpenoid derivative, or its isomer, salt or solvate according to claim 4, wherein 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;

the alcohol substance is one of ethanol and n-propanol;

the phosphate substances are 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea hexafluorophosphate and O-benzotriazole-tetramethylurea hexafluorophosphate.

6. Use of a triterpenoid derivative, or a prodrug of an isomer, salt or solvate thereof, as an inhibitor of programmed cell necrosis, wherein the triterpenoid derivative, or a prodrug of an isomer, salt or solvate thereof, has the general structure shown in formula I or II:

R₁is one of the following groups: hydroxy, amino, halogen, -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 alkyl, at least one hydrogen on the alkyl groupFluorine substituted C1-C20 alkyl.

7. Use of a triterpenoid derivative, or a prodrug of its isomer, salt or solvate according to claim 6, as an inhibitor of programmed cell necrosis,

R₁is one of the following groups: hydroxy, amino, halogen, -NHR₃、-NHCOOR₄、-OR₅、

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, pyridotriazolyl;

R₂is one of the following groups: hydroxy, methyl, ethyl, n-propyl, n-pentyl, -CF₃、-CF₂CH₃。

8. Use of a triterpenoid derivative, or a prodrug of its isomer, salt or solvate according to claim 7, as an inhibitor of programmed cell necrosis, 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;

(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;

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;

(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;

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;

(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;

(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;

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;

(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;

9. Use of a triterpene derivative, or a prodrug of an isomer, salt or solvate thereof, in the manufacture of a medicament for resisting programmed cell necrosis, wherein the triterpene derivative, or the prodrug of the isomer, salt or solvate thereof, has a general structure shown in formula I or II:

R₁is one of the following groups: hydroxy, amino, halogen, -NHR₃、-NHCOOR₄、-OR₅、-NR₆R₇；

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.

10. Use of a triterpene derivative, or a prodrug of an isomer, salt or solvate thereof, in the manufacture of a medicament for the treatment of cerebral ischemia/reperfusion injury, wherein the triterpene derivative, or the prodrug of the isomer, salt or solvate thereof, has the general structure shown in formula I or II:

R₁is one of the following groups: hydroxy, amino, halogen, -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 in the alkyl is substituted by halogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylAlkyl, 1,2,3, 4-tetrahydronaphthyl, - (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.

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, TwoDerivatives of Natural Triteroils [ J ] Molecules,24(22): 4097-. The chemical structure is as follows:

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 related to 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 ischemic in J. nature chemical biology 2005,1(2): 112. 119.), amyotrophic lateral sclerosis (Ito Yasushi, environmental index, Najav Ayaz et al, RIPK1 intermediates a promoter activity and neural antigens in ALS. [ J. Science 2016,353:603-8.) and Alzheimer disease (cancer Annona, brachia, Pivotanaceae J. 2016. Nature J.: 20. organism 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 currently 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 in secondary 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:

R₁is one of the following groups: amino (-NH)₂) Halogen (F, Cl, Br, I), -NHR₃、-NHCOOR₄、-OR₅、-NR₆R₇；

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

More preferably, in the triterpene derivatives,

R₁is one of the following groups: amino (-NH)₂) Halogen (F, Cl, Br, I), -NHR₃、-NHCOOR₄、-OR₅、

R₃Is one of the following groups: n-propyl, n-pentyl, phenyl, benzyl, naphthyl, -CH₂Br、-CH₂CH₂Br, cyclopropane group,Cyclobutyl, cyclopentyl, cyclohexyl, 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)) Pyridotriazolyl (a) to (b)

)。

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)

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:

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:

R₁is one of the following groups: hydroxy, amino (-NH)₂) Halogen (F, Cl, Br, I), -NHR₃、-NHCOOR₄、-OR₅、-NR₆R₇；

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、

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)) Pyridotriazolyl (a) to (b))；

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)

(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)

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:

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 group is substituted by halogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1,2,3, 4-tetrahydronaphthyl, - (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、

R₄Is one of the following groups: methyl, ethyl, n-propyl, n-pentyl, phenyl, naphthyl;

R₅is the following groupOne of (1): methyl, ethyl, n-propyl, n-pentyl, phenyl, benzotriazolyl(s) (iii)) Pyridotriazolyl (a) to (b)

)；

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) -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)

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:

R₁is one of the following groups: hydroxy, amino (-NH)₂) Halogen (F, Cl, Br, I), -NHR₃、-NHCOOR₄、-OR₅、-NR₆R₇；

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、

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)

) Pyridotriazolyl (a) to (b)

)；

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) -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)

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

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.

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Triterpenoid derivatives and application thereof as programmed cell necrosis inhibitor

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