Cathepsin inhibitor and preparation method and application thereof
阅读说明：本技术 组织蛋白酶抑制剂及其制备方法和应用 (Cathepsin inhibitor and preparation method and application thereof ) 是由 袁雷 马恩龙 于 2018-08-10 设计创作，主要内容包括：本发明涉及药物化学领域,涉及组织蛋白酶抑制剂及其制备方法和应用,具体涉及一种新型的类肽类化合物或其药学上可接受的溶剂化物、药物组合物和药物制剂及其制备方法。还涉及所述化合物或其药学上可接受的溶剂化物、药物组合物和药物制剂在制备抗肿瘤药物中的应用。所述的化合物及其异构体如通式(I)所示,其中R<Sub>1</Sub>和R<Sub>2</Sub>如说明书和权利要求书所述。<Image he="343" wi="470" file="DDA0001760526290000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to the field of pharmaceutical chemistry, relates to a cathepsin inhibitor, a preparation method and application thereof, and particularly relates to a novel peptoid compound or a pharmaceutically acceptable solvate, a pharmaceutical composition, a pharmaceutical preparation and a preparation method thereof. And alsoRelates to the application of the compound or the pharmaceutically acceptable solvate, the pharmaceutical composition and the pharmaceutical preparation thereof in preparing antitumor drugs. The compound and the isomer thereof are shown as a general formula (I), wherein R 1 And R 2 As described in the specification and claims.)
1. A compound of the general formula (I) and isomers thereof:
wherein the content of the first and second substances,
R1is linear or branched C1-C10 alkyl, C5-C6 cycloalkyl, substituted or unsubstituted 5-10 membered aryl, 5-10 membered heterocyclic group, the substituent is halogen, hydroxyl, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, benzyloxy, indanyl, azo, C2-C4 carboxyl; the heterocyclyl or heterocyclylaryl group may optionally contain 1-3 heteroatoms of N, O or S;
R2is substituted or unsubstituted 5-10 membered aryl, 5-10 membered heterocyclic group, the substituent is halogen, hydroxyl, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, benzyloxy, indanyl, azo, C2-C4 carboxyl; the heterocyclic group or heterocyclic aryl group may optionally contain 1-3 heteroatoms of N, O or S.
2. A compound of the general formula (I) according to claim 1 and isomers thereof:
wherein the content of the first and second substances,
R1is linear or branched C1-C6 alkyl, C5-C6 cycloalkyl, substituted or unsubstituted 5-6 membered aryl, 5-6 membered heterocyclic aryl, 5-6 membered heteroThe substituent is halogen, hydroxyl, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, benzyloxy, indanyl, azo and C2-C4 carboxyl; the heterocyclic or heterocyclic aryl group may optionally contain 1-3 heteroatoms of N, O or S, R1Preferably a substituted or unsubstituted 5-6 membered aryl group, more preferably a substituted or unsubstituted phenyl group, said substituents being halogen, hydroxy, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, benzyloxy, indanyl, azo.
3. A compound of the general formula (I) according to claim 1 or 2 and isomers thereof:
wherein the content of the first and second substances,
R2is substituted or unsubstituted 5-6-membered aryl, 5-6-membered heterocyclic group, the substituent is halogen, hydroxyl, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, benzyloxy, indanyl, azo, C2-C4 carboxyl; the heterocyclyl or heterocyclylaryl group may optionally contain 1-3 heteroatoms of N, O or S; r2Preferably a substituted or unsubstituted 5-6 membered aryl group, more preferably a substituted or unsubstituted phenyl group, said substituents being halogen, hydroxy, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy.
4. A compound of general formula (I) according to any one of claims 1 to 3 and isomers thereof:
wherein R is1Is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, phenethyl, phenylpropyl, biphenyl, o-hydroxyphenyl, m-hydroxyphenyl, p-hydroxyphenyl, o-aminophenyl, m-aminophenyl, p-aminophenyl, o-carboxyphenyl, m-carboxyphenyl, p-carboxyphenyl, o-acetylphenyl, m-acetylphenyl, p-acetylphenyl, o-methylphenyl, m-methylphenyl, p-methylphenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, o-benzyloxyPhenyl, m-benzyloxyphenyl, p-benzyloxyphenyl, o-trifluoromethylphenyl, m-trifluoromethylphenyl, p-trifluoromethylphenyl, o-cyanophenyl, m-cyanophenyl, p-cyanophenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl, o-iodophenyl, m-iodophenyl, p-iodophenyl, o-nitrophenyl, m-nitrophenyl, p-nitrophenyl, o-diazophenyl, m-azophenyl, p-azophenyl, 2-chloro-4-fluorophenyl, 2-bromo-5-fluorophenyl, 3-chloro-2-fluorophenyl, 3-bromo-4-fluorophenyl, 4-bromo-3-fluorophenyl, 2, 3-dichlorophenyl, 2, 4-difluorophenyl, 2, 4-dibromophenyl, 3-fluoro-4-methoxyphenyl, 3-bromo-4-methoxyphenyl, 2,3, 4-trichlorophenyl, 2, 5-dichlorophenyl, 2, 4-difluorophenyl, 4-dibromophenyl, 3-bromo-4-difluorophenyl, 3-4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 3-trifluoromethylphenyl, 3-3, 3-trifluoromethylphenyl, 3-trifluoromethylphenyl, 3-3, 3-trifluoromethylphenyl, 3-3, 3-trifluoromethylphenyl, 3-3, 3-trifluoromethylphenyl, 3-trifluoromethylphenyl, 3-3, 3-trifluoromethylphenyl, 3-trifluoromethylphenyl, 3-3, 3-trifluoromethylphenyl, 3-trifluoromethylphenyl, 3-3, 3-trifluoromethylphenyl, 3-trifluoromethylphenyl, 3-trifluoromethylphenyl, 3-3, 3-3;
R2is phenyl, phenethyl, phenylpropyl, biphenyl, o-hydroxyphenyl, m-hydroxyphenyl, p-hydroxyphenyl, o-aminophenyl, m-aminophenyl, p-aminophenyl, o-carboxyphenyl, m-carboxyphenyl, p-carboxyphenyl, o-acetylphenyl, m-acetylphenylPhenyl, p-acetylphenyl, o-methylphenyl, m-methylphenyl, p-methylphenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, o-benzyloxyphenyl, m-benzyloxyphenyl, p-benzyloxyphenyl, o-trifluoromethylphenyl, m-trifluoromethylphenyl, p-trifluoromethylphenyl, o-cyanophenyl, m-cyanophenyl, p-cyanophenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl, o-iodophenyl, p-iodophenyl, o-nitrophenyl, m-nitrophenyl, p-nitrophenyl, o-azophenyl, m-azophenyl, p-azophenyl, 2-chloro-4-fluorophenyl, 2-bromo-5-fluorophenyl, 3-chloro-2-fluorophenyl, 3-bromo-4-fluorophenyl, 4-bromo-3-fluorophenyl, 2, 3-difluorophenyl, 2, 4-bromo-3-dichlorophenyl, 3-chloro-2-fluorophenyl, 3-bromo-4-fluorophenyl, 3-dichlorophenyl, 3-bromo-3-4-fluorophenyl, 3-dichlorophenyl, 3-bromo-4-3-trifluoromethylphenyl, 3-dichlorophenyl, 3-bromo-4-trifluoromethyl-3-bromo-3-4-chlorophenyl, 3-bromo-trifluoromethyl-5-fluorophenyl, 3-bromo-trifluoromethyl-3-chloro-5-bromo-fluorophenyl, 3-trifluoromethyl-bromo-3-trifluoromethyl-3-chloro-4-chloro-3-trifluoromethyl-chloro-5-phenyl, 3-bromo-trifluoromethyl-chloro-trifluoromethyl-chloro-phenyl, 3-4-trifluoromethyl-fluorophenyl, 3-bromo-trifluoromethyl-3-trifluoromethyl-phenyl, 3-chloro-trifluoromethyl-5-chloro-4-bromo-chloro-phenyl, 3-chloro-bromo-chloro-4-fluorophenyl, 3-bromo-4-trifluoromethyl-bromo-trifluoromethyl-chloro-phenyl, 3-4-chloro-bromo-fluorophenyl, 3-bromo-chloro-bromo-trifluoromethyl-4-chloro-bromo-chloro-4-chloro-bromo-chloro-3-bromo-chloro-4-chloro-phenyl, 3-trifluoromethyl-bromo-chloro-4-3-chloro-phenyl, 3-chloro-4-phenyl, 3-trifluoromethyl-bromo-phenyl, 3-trifluoromethyl-chloro-trifluoromethyl-4-phenyl, 3-4-chloro-trifluoromethyl-4-bromo-4-phenyl, 3-trifluoromethyl-phenyl, 3-5-bromo-trifluoromethyl-5-phenyl, 3-5-chloro-bromo-phenyl.
5. A compound as shown below, and isomers thereof, selected from the group consisting of:
(R) -N- (4-bromophenylsulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-bromophenylsulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-bromophenylsulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-bromophenylsulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-methoxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-methoxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-methoxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-methoxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-trifluoromethylbenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-trifluoromethylbenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-trifluoromethylbenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-trifluoromethylbenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-fluorobenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-fluorobenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-fluorophenylsulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-fluorobenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N-benzenesulfonylphenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N-benzenesulfonylphenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N-benzenesulfonylphenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N-benzenesulfonylphenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (3-bromophenylsulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (3-bromophenylsulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (3-bromophenylsulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (3-bromophenylsulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2-bromophenylsulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2-bromophenylsulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (2-bromophenylsulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (2-bromophenylsulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2, 4-difluorobenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2, 4-difluorobenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (2, 4-difluorobenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (2, 4-difluorobenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2, 6-difluorobenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2, 6-difluorobenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (2, 6-difluorobenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (2, 6-difluorobenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (5-bromo-2-methoxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (5-bromo-2-methoxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (5-bromo-2-methoxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (5-bromo-2-methoxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (5-chloro-2, 4-difluorobenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (5-chloro-2, 4-difluorobenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (5-chloro-2, 4-difluorobenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (5-chloro-2, 4-difluorobenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2, 5-Dimethoxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2, 5-Dimethoxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (2, 5-Dimethoxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (2, 5-Dimethoxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-Isopropoxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-Isopropoxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-Isopropoxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-Isopropoxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2-nitro-4-trifluoromethylbenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2-nitro-4-trifluoromethylbenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylalanine
(S) -N- (2-nitro-4-trifluoromethylbenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylalanine
(S) -N- (2-nitro-4-trifluoromethyl-benzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2, 4-Dimethoxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2, 4-Dimethoxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (2, 4-Dimethoxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (2, 4-Dimethoxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-nitro-3-trifluoromethylbenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-nitro-3-trifluoromethylbenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylalanine
(S) -N- (4-nitro-3-trifluoromethylbenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-nitro-3-trifluoromethylbenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-amino-3-trifluoromethylbenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-amino-3-trifluoromethylbenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-amino-3-trifluoromethylbenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-amino-3-trifluoromethylbenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-hydroxy-benzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-hydroxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-hydroxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-hydroxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester.
6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 and isomers thereof and one or more pharmaceutically acceptable carriers and/or diluents.
7. A process for the preparation of the compounds of general formula (I) and their isomers according to claim 1, characterized by the following reaction scheme:
8. use of a compound according to any one of claims 1 to 5 and isomers thereof or a pharmaceutical composition according to claim 6 for the preparation of a cathepsin inhibitor.
9. Use of a compound according to any one of claims 1 to 5 and isomers thereof or a pharmaceutical composition according to claim 6 for the preparation of an antitumor medicament.
10. Use according to claim 8, characterized in that: the cathepsin is cathepsin L or cathepsin S.
11. Use according to claim 8 or 9, characterized in that: the compounds act by inhibiting cathepsin enzymes to inhibit metastasis and invasion of tumor cells.
12. Use according to claim 8 or 9, characterized in that: the compounds exert their effect by completely inducing autophagy in tumor cells.
Technical Field
The invention relates to the field of pharmaceutical chemistry, relates to a cathepsin inhibitor, a preparation method and application thereof, and particularly relates to a novel peptoid compound or a pharmaceutically acceptable solvate, a pharmaceutical composition, a pharmaceutical preparation and a preparation method thereof. Also relates to application of the compound or the pharmaceutically acceptable solvate, the pharmaceutical composition and the pharmaceutical preparation thereof in preparing antitumor drugs.
Background
Malignant tumors are common and multiple diseases that severely threaten human health and life (Siegel r.l., Miller k.d., Jemal a.cancer statistics,2017.CA Cancer j.clin.,2017,67(1): 7-30). The medicine treatment plays an important role, and at present, the action mechanism of most of the clinically used cancer treatment medicines is to induce tumor cell apoptosis. However, the apoptosis sensitivity of tumor cells to these drugs varies greatly, and with the continued use of these drugs, the multidrug resistance of tumor cells has also greatly affected the effectiveness of chemotherapy. Meanwhile, there are well established data indicating that 90% of cancer-related deaths are caused by metastasis of primary tumor cells (Marx V. TrackingMetastasis and locking cancer. Nature,2013,494, 133-138). Therefore, the development of the antitumor drug which can inhibit the proliferation of tumor cells through a novel action mechanism and also has the function of inhibiting the metastasis of the tumor cells is a work with profound significance.
More and more researches in recent ten years prove that autophagy plays a key role in the processes of tumorigenesis and development. Regulation of autophagy has become a new strategy for killing tumor cells, and is the hotspot of research in the international oncology community (Morel, e., Mehrpour, m., Botti, j., Dupont, n., hami, a., Nascimbeni, a.c., codogo, p.autophagy: addressable process, annu.rev.pharmacol.toxicol, 2017,57, 375-398). The great corner classical has obtained the Nobel prize due to the achievement in the research field of the autophagy mechanism, and the research of autophagy is pushed to a new height. Therefore, the development of autophagy-modulating drugs is of great significance for the treatment of cancers for which drug resistance has developed.
On the other hand, cathepsin is also closely related to the occurrence and development of tumor cells. Since the 90 s of the 20 th century, the crystal structure of cathepsin was determined successively, including cathepsin B, C, H, L, K, S and the like. With the intensive research on cathepsin, it is found that in addition to playing an important role in turnover and turnover of intracellular proteins, cathepsin is also involved in many other physiological processes, such as cell proliferation, adhesion, apoptosis, lipid metabolism, immune response and the like. During cellular carcinogenesis, a large number of cathepsins are secreted into the cytoplasm to degrade the extracellular matrix and basement membrane, thereby promoting invasion and metastasis of tumor cells, and increasing the formation of new blood vessels to facilitate tumor growth.
Research shows that cathepsin B, K, L, S is often involved in important pathophysiological environment, and is the most closely related subtypes in various canceration and disease occurrence processes of human body. Cathepsin L participates in various physiological activities such as protein degradation, hormone precursor activation, antigen presentation, bone matrix degradation, development and maturation of the nervous system, and the like. In tumor tissues such as gastrointestinal stromal tumor, glioma, abdominal aortic aneurysm, endometrial cancer, ovarian cancer, bladder cancer, renal cancer, etc., cathepsin L expression is higher than that in normal tissues. Cathepsin S can keep proteolytic activity for a long time under the condition of neutral pH, and is closely related to the occurrence process of various diseases. For example, cathepsin S expression levels in lung cancer tissues and astrocytomas are significantly elevated. Ryshich et al found that cathepsin S may promote angiogenesis of hepatoma cells (aggregate N., Sloane B.F. cathepsin B: multiple roles in cancer. microorganisms Clin.appl.,2014,8(5-6): 427-437; Pranjol M.Z.I., Gutowski N., Hanneman M.P. promoter role of the proteases D and expression L in the promoter and expression of tumors, 5(4): 3260-3279; Tsai J.Y., Lee.J., Chang M.D., Wang H.C., Lin C.C.alpha.evaluation H.Effecting 3279; Tsai J.S.J.J., C.J.S. promoter H.J.S. Pat. No. 32, C.J.J., C.S. reaction H.J.S. 32, C.S.S. reaction H.J.S. 31. reaction J.31, C.S.S. Pat. No. 31. C.J.J.31. reaction J.32. reaction J., C.S.S. 5. reaction J.S. 3. reaction J.S. 1. C.S. Pat. J.J.S. 1. reaction J.32. reaction J.g. 1. reaction J.S. 1. reaction J.32. reaction No. 1. reaction H.g. 7. reaction J.g. 7. medium J.g. 1. C.S. C.g.g.S. C.g.S. 3. reaction J.S. C.g. C.g.g.g.g. C.S. C. 3. reaction J.g.g.S. C.g.g.S. reaction J.g. 3. medium J.g.g.g.g.g. C. C.g.g. C.g.g.g. C.g.g. C.g.g.g.g.g.g.g.g. C.g.g.g. C. C.g.g.g.g.J.g.g, strecker T.E., BarnesA.L., Sudhan D.R., Wittenborn T.R., Siemann D.W., Horsman M.R., Chaplin D.J., Tracwick M.L., Pinney K.G.Synthesis and biochemical evaluation of benzophenone thiosiloxane microorganisms and analytes as potential and selective inhibitors of cathepsin L.Bio.Med.chem.,2015,23, 6974-6992.).
Obviously, the cathepsin is closely related to the metastasis and invasion of the tumor and is a very potential target for blocking the metastasis and invasion of tumor cells. It follows that the development of cathepsin inhibitors is also of great interest for the treatment of tumours.
In summary, the study of developing a cathepsin inhibitor having dual actions of inducing autophagy and inhibiting tumor metastasis and invasion has an extraordinary significance for antitumor drug development.
Disclosure of Invention
The invention aims to provide a cathepsin inhibitor with double functions of inducing autophagy and inhibiting tumor metastasis and invasion. The inhibitor can be used for preparing medicine for treating and/or preventing tumor.
The specific technical scheme of the invention is as follows:
the invention provides a compound shown as a general formula (I) and an isomer thereof:
wherein the content of the first and second substances,
R1is linear or branched C1-C10 alkyl, C5-C6 cycloalkyl, substituted or unsubstituted 5-10 membered aryl, 5-10 membered heterocyclic group, the substituent is halogen, hydroxyl, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, benzyloxy, indanyl, azo, C2-C4 carboxyl; the heterocyclyl or heterocyclylaryl group may optionally contain 1-3 heteroatoms of N, O or S;
R2is substituted or unsubstituted 5-10 membered aryl, 5-10 membered heterocyclic group, the substituent is halogen, hydroxyl, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, benzyloxy, indanyl, azo, C2-C4 carboxyl; said heterocyclyl or heterocyclylaryl group may optionally contain 1-3N, O or SA heteroatom;
preferred compounds of the present invention have the general formula (I):
wherein the content of the first and second substances,
R1is linear or branched C1-C6 alkyl, C5-C6 cycloalkyl, substituted or unsubstituted 5-6 membered aryl, 5-6 membered heterocyclic group, the substituents are halogen, hydroxyl, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, benzyloxy, indanyl, azo, C2-C4 carboxyl; the heterocyclyl or heterocyclylaryl group may optionally contain 1-3 heteroatoms of N, O or S;
R2is substituted or unsubstituted 5-6-membered aryl, 5-6-membered heterocyclic group, the substituent is halogen, hydroxyl, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, benzyloxy, indanyl, azo, C2-C4 carboxyl; the heterocyclyl or heterocyclylaryl group may optionally contain 1-3 heteroatoms of N, O or S;
preferred compounds of the present invention have the general formula (I):
R1is substituted or unsubstituted 5-6-membered aryl, and the substituent is halogen, hydroxyl, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, benzyloxy, indanyl or azo;
R2is substituted or unsubstituted 5-6-membered aryl, and the substituent is halogen, hydroxyl, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, benzyloxy, indanyl or azo;
preferred compounds of the present invention have the general formula (I):
R1is substituted or unsubstituted phenyl, and the substituent is halogen, hydroxyl, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy;
R2is substituted or unsubstituted phenyl, and the substituent is halogen, hydroxyl, nitro, amino, C1-C6 alkyl, C1-C6 alkoxyHalogenated C1-C6 alkyl, halogenated C1-C6 alkoxy;
preferred compounds of the present invention have the general formula (I):
R1is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, phenethyl, phenylpropyl, biphenyl, o-hydroxyphenyl, m-hydroxyphenyl, p-hydroxyphenyl, o-aminophenyl, m-aminophenyl, p-aminophenyl, o-carboxyphenyl, m-carboxyphenyl, o-acetylphenyl, m-acetylphenyl, p-acetylphenyl, o-methylphenyl, m-methylphenyl, p-methylphenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, o-benzyloxyphenyl, m-benzyloxyphenyl, p-trifluoromethylphenyl, m-trifluoromethylphenyl, p-trifluoromethylphenyl, o-cyanophenyl, m-cyanophenyl, p-cyanophenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-chlorophenyl, m-chlorophenyl, p-chlorophenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl, o-iodophenyl, m-iodophenyl, o-nitrophenyl, m-nitrophenyl, o-chlorophenyl, m-chlorophenyl, 3-bromo-2-3-bromo-4-3-bromo-4, 3-bromo-4-bromo-3-bromo-4, 3-bromo-3-4, 3-bromo-4-bromo-3-bromo-4-bromo-3-4, 3-bromo-5-bromo-4-bromo-3-4-bromo-phenyl, 3-4-3-chloro-bromo-4-bromo-3-chloro-bromo-4-3-bromo-3-4, 5-bromo-chloro-4-bromo-4, 5-bromo-4-phenyl, 3-chloro-4-bromo-5-4-bromo-3-bromo-chloro-4-bromo-phenyl, o-bromo-phenyl, 3-bromo-4-bromo-3-bromo-3, p-bromo-4-bromo-4-phenyl, o-bromo-phenyl, p-bromo-phenyl, p-bromo-phenylThiazol-2-yl, pyrrol-3-yl, pyrazol-3-yl, furan-2-yl, furan-3-yl, quinolin-8-yl, isoquinolin-6-yl, morpholin-4-yl, N-CBZ-piperidin-4-yl, N-Boc-piperidin-4-yl; imidazol-1-yl, triazol-1-yl, uracil-3-yl, cytosin-1-yl, thymin-3-yl, adenin-7-yl, adenin-9-yl, guanine-7-yl, guanine-9-yl, indan-5-yl;
R2is o-aminophenyl, m-aminophenyl, p-aminophenyl, o-carboxyphenyl, m-carboxyphenyl, p-carboxyphenyl, o-acetylphenyl, m-acetylphenyl, p-acetylphenyl, o-methylphenyl, m-methylphenyl, p-methylphenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl, o-benzyloxyphenyl, m-benzyloxyphenyl, o-trifluoromethylphenyl, m-trifluoromethylphenyl, p-trifluoromethylphenyl, o-cyanophenyl, m-cyanophenyl, p-cyanophenyl, o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, o-chlorophenyl, p-nitrophenyl, 2-chloro-4-fluorophenyl, 2-bromo-5-fluorophenyl, 3-chloro-2-fluorophenyl, 3-difluoro-4-fluorophenyl, 3-bromo-4-fluorophenyl, 3-chloro-4-fluorophenyl, 3-bromo-4-dichlorophenyl, 3-bromo-3-4-bromo-3-trifluoromethyl-3-bromo-4-3-bromo-3-4-3-bromo-5-3-4-bromo-3-trifluoromethyl-3, 3-4-bromo-5-bromo-3-4-bromo-3-trifluoromethyl-5-bromo-3, 3-4-bromo-fluorophenyl, 3-4-fluorophenyl, 3-chloro-trifluoromethyl-4-fluorophenyl, 3-bromo-4-fluorophenyl, 3-bromo-4-trifluoromethyl-bromo-fluorophenyl, 3-4-fluorophenyl, p-nitrophenyl, p-fluorophenyl, p-Thiophen-2-yl, thiophen-3-yl, thiazol-2-yl, pyrrol-3-yl, pyrazol-3-yl, furan-2-yl, furan-3-yl, quinolin-8-yl, isoquinolin-6-yl, morpholin-4-yl, N-CBZ-piperidin-4-yl, N-Boc-piperidin-4-yl; imidazol-1-yl, triazol-1-yl, uracil-3-yl, cytosin-1-yl, thymin-3-yl, adenin-7-yl, adenin-9-yl, guanine-7-yl, guanine-9-yl,
all optical isomers are included, i.e.: (S, S) optical isomer, (R, R) optical isomer, and (S, R) optical isomer.
Particularly preferred compounds are those having the chemical names and structural formulae shown below:
(R) -N- (4-bromophenylsulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-bromophenylsulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-bromophenylsulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-bromophenylsulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-methoxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-methoxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-methoxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-methoxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-trifluoromethylbenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-trifluoromethylbenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-trifluoromethylbenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-trifluoromethylbenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-fluorobenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-fluorobenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-fluorophenylsulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-fluorobenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N-benzenesulfonylphenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N-benzenesulfonylphenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N-benzenesulfonylphenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N-benzenesulfonylphenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (3-bromophenylsulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (3-bromophenylsulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (3-bromophenylsulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (3-bromophenylsulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2-bromophenylsulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2-bromophenylsulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (2-bromophenylsulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (2-bromophenylsulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2, 4-difluorobenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2, 4-difluorobenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (2, 4-difluorobenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (2, 4-difluorobenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2, 6-difluorobenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2, 6-difluorobenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (2, 6-difluorobenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (2, 6-difluorobenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (5-bromo-2-methoxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (5-bromo-2-methoxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (5-bromo-2-methoxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (5-bromo-2-methoxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (5-chloro-2, 4-difluorobenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (5-chloro-2, 4-difluorobenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (5-chloro-2, 4-difluorobenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (5-chloro-2, 4-difluorobenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2, 5-Dimethoxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2, 5-Dimethoxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (2, 5-Dimethoxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (2, 5-Dimethoxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-Isopropoxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-Isopropoxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-Isopropoxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-Isopropoxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2-nitro-4-trifluoromethylbenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2-nitro-4-trifluoromethylbenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylalanine
(S) -N- (2-nitro-4-trifluoromethylbenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylalanine
(S) -N- (2-nitro-4-trifluoromethylbenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2, 4-Dimethoxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (2, 4-Dimethoxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (2, 4-Dimethoxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (2, 4-Dimethoxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-nitro-3-trifluoromethylbenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-nitro-3-trifluoromethylbenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylalanine
(S) -N- (4-nitro-3-trifluoromethylbenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-nitro-3-trifluoromethylbenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-amino-3-trifluoromethylbenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-amino-3-trifluoromethylbenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-amino-3-trifluoromethylbenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-amino-3-trifluoromethylbenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-hydroxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
(R) -N- (4-hydroxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-hydroxybenzenesulfonyl) -phenylalanine- (R) -2-benzamido-3-phenylpropyl ester
(S) -N- (4-hydroxybenzenesulfonyl) -phenylalanine- (S) -2-benzamido-3-phenylpropyl ester
The compounds of the invention all have the activity of inhibiting cathepsin (L or S subtype), and can completely induce autophagy of tumor cells and inhibit metastasis and invasion of the tumor cells so as to play the role of anti-tumor.
The invention further provides a preparation method of the partial compound, but not limited to the following preparation methods:
the method comprises the following steps of taking optically active N-Boc-phenylalanine as a raw material, and carrying out esterification reaction with optically active N- (substituted benzoyl) -phenylalaninol under the action of a condensation reagent under the condition of a proper solvent, wherein the condensation reagent comprises CDI, DCC, EDCI, HOBt and the like. The temperature is maintained at 1-100 deg.C, preferably 10-70 deg.C, and more preferably 20-40 deg.C. The reaction is carried out for a period of time, preferably 50 to 80 hours, more preferably 40 to 60 hours. To obtain optically active N-Boc-phenylalanine- (N-substituted benzamido) -3-phenylpropyl ester. The Boc protecting group is removed with a suitable reagent at a temperature of 1-100 deg.C, preferably 10-70 deg.C, more preferably 20-40 deg.C. The deprotection reagents include: trifluoroacetic acid, hydrochloric acid, hydrogen chloride/ethanol solution, hydrogen chloride/methanol solution, hydrogen chloride/tetrahydrofuran solution, hydrogen chloride/ethyl acetate solution, and the like. The reaction is carried out for a period of time, preferably 1 to 10 hours, more preferably 2 to 8 hours. Under the condition that the obtained deprotection product takes organic base as an acid-binding agent, the organic base is exemplified by: pyridine, triethylamine, diethylamine or piperidine, with substituted benzenesulfonyl chlorides at a temperature of 0-100 deg.C, preferably 10-70 deg.C, more preferably 20-40 deg.C. For a period of time, for example, 10 to 30 hours, to give the compound of formula I.
The invention also provides a pharmaceutical composition which takes the compound of the formula (I) or the isomer thereof as an active ingredient. The compound of the invention can be mixed with pharmaceutically acceptable diluents, adjuvants and/or carriers to prepare clinically required pharmaceutical compositions. When the pharmaceutical composition of the present invention is clinically used, it can be formulated into several dosage forms, such as: oral formulations (e.g., tablets, capsules, lozenges, solutions or suspensions); injectable formulations (e.g., injectable solutions or suspensions, or injectable dry powders, which are immediately ready for use by addition of water for injection prior to injection); topical formulations (e.g. ointments or solutions). The pharmaceutical composition carrier used in the present invention is a common carrier available in the pharmaceutical field, including: binders, lubricants, disintegrants, solubilizing agents, diluents, stabilizers, suspending agents, non-coloring agents, flavoring agents, etc. for oral preparations; preservatives, solubilizers, stabilizers and the like for injectable preparations; bases for topical formulations, diluents, lubricants, preservatives, and the like. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
The compounds of the invention have the following advantages over the closest prior art:
(1) a novel structural class of cathepsin inhibitors is provided.
(2) Such compounds also exhibit unique anti-tumor mechanisms. Is an antitumor effect exerted by completely inducing autophagy of tumor cells. The compounds all function to inhibit the metastasis and invasion of tumor cells by inhibiting cathepsins. And plays a role by completely inducing autophagy of tumor cells. The drug resistance is better, and the drug is worthy of clinical popularization and application.
(3) The compounds also show the effect of inhibiting tumor cell metastasis while inhibiting tumor proliferation.
The bifunctional molecule not only has a novel anti-tumor action mechanism, but also can inhibit tumor metastasis, and has incomparable advantages compared with other drugs.
(4) The compound of the invention has simple preparation process, high medicine purity, high yield, stable quality and easy large-scale production.
Drawings
FIG. 1 shows MDC assay for MDA-MB-231 tumor cell autophagy formation.
FIG. 2 shows MDA-MB-231 tumor cell metastasis inhibition and invasion experiments.
A. Performing scraper plate experiment; transwell chamber experiments.
Detailed Description
The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.