WO2019000224A1 - Dérivé de bisindolylmaléimide, son procédé de préparation et son utilisation - Google Patents

Dérivé de bisindolylmaléimide, son procédé de préparation et son utilisation Download PDF

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WO2019000224A1
WO2019000224A1 PCT/CN2017/090349 CN2017090349W WO2019000224A1 WO 2019000224 A1 WO2019000224 A1 WO 2019000224A1 CN 2017090349 W CN2017090349 W CN 2017090349W WO 2019000224 A1 WO2019000224 A1 WO 2019000224A1
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group
compound
alkyl
formula
hydroxy
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PCT/CN2017/090349
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朱伟明
马红光
王立平
徐志红
张亚鹏
王乂
刘培培
郝杰杰
Original Assignee
中国海洋大学
贵州省中国科学院天然产物化学重点实验室
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Priority to PCT/CN2017/090349 priority Critical patent/WO2019000224A1/fr
Publication of WO2019000224A1 publication Critical patent/WO2019000224A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a biguanide maleimide derivative, a process for its preparation and use.
  • Tumors are common and frequently-occurring diseases that endanger human life and health in today's world. According to the World Health Organization, there are about 76 million cancer patients in the world, 6 million deaths due to cancer, accounting for 12% of the total deaths, and their incidence is increasing every year (Tang Jun; Fu Dazhao. Targeting small molecule innovation Drugs. Progress in Modern Biomedicine. 2010, 10(20): 3997). The annual incidence of cancer in China is about 1.6 million, and the number of patients currently suffering from it is 2 million. The number of deaths per year is 1.3 million, and it is on the rise. In recent years, although the treatment of tumors such as leukemia and malignant lymphoma has made some progress, the survival time of tumor patients has been significantly prolonged, but the treatment of the most deadly solid tumor has not achieved satisfactory results.
  • Zhu Weiming et al. disclosed a carbazole and biguanide maleimide alkaloid with protein kinase C (PKC) inhibitory activity and antitumor effect (Zhu Weiming, Xu Zhihong, Zhang Yapeng, Wang Wei, Liu Peipei. Preparation method and application of carbazole and biguanide maleimide.
  • PKC protein kinase C
  • Diabetes is divided into type 1 diabetes (insulin-dependent diabetes) and type 2 diabetes (non-insulin-dependent diabetes), and more than 90% of patients are type 2 diabetes.
  • Patients with type 2 diabetes do not need insulin therapy, can regulate blood sugar, and only use drug-assisted treatment when the diet is not effective.
  • the starch in the food is digested into oligosaccharides of glucose molecules by oral saliva and pancreatic amylase.
  • the function of ⁇ -glucosidase is to break the ⁇ -1,4-glycosidic bond of these oligosaccharides at the non-reducing end, releasing glucose.
  • Glucose is absorbed by the small intestine epithelium and then enters the blood circulation, becoming blood sugar.
  • Alpha-glucosidase inhibitors delay or slow the increase in postprandial blood glucose by reversibly or competitively inhibiting the activity of the small intestinal brush border alpha-glucosidase.
  • ⁇ -glucosidase inhibitors are a class of oral hypoglycemic drugs that delay the absorption of intestinal saccharides to achieve diabetes.
  • the clinically applied ⁇ -glucosidase inhibitors are mainly: acarbose, voglibose and miglitol. After taking these three drugs, they do not break down the sugars themselves. Directly reaching the large intestine, there will be adverse reactions such as abdominal discomfort, flatulence, and exhaust. Therefore, it is necessary to find a new ⁇ -glucosidase inhibitor drug.
  • Diabetic Kidney Disease is one of the most common severe microvascular complications of diabetes. The incidence is about 30%-40% of diabetic patients, and it has become the first in End Stage Renal Disease (ESRD). The reason is also the leading cause of diabetes.
  • ESRD End Stage Renal Disease
  • anti-DKD drugs the existing clinical treatments such as blood pressure control, blood sugar, blood lipids and anti-inflammatory can only delay the progression of DKD to renal failure, and cannot reverse or prevent the progression of the disease. At the same time, it faces problems such as ineffective efficacy and large side effects (Curr Diabetes Rev 2005; 1:281-286), so there is an urgent need to develop new and safe anti-DKD drugs for new targets.
  • the biguanide maleimide derivative has been widely concerned due to its structural diversity and good biological activity, and the inventors have devoted themselves to the biguanide. Drug development of quinone maleimide derivatives. Moreover, the present inventors have made efforts to develop an antitumor biguanide maleimide derivative which is more effective. In addition, the inventors have found that biguanide maleimide derivatives have important prospects in the treatment of drug-resistant tumors. On the other hand, the biguanide maleimide derivative has an ⁇ -glucosidase inhibitory activity and an antidiabetic effect.
  • the dotted line indicates that there is no chemical bond or a single bond
  • R 1 and R 2 are each independently selected from: -H; alkyl, optionally substituted by amino, cyano, hydroxy, carboxy, alkoxy, heteroheterocyclyl, aryl, heteroaryl, - COA substituted; alkenyl group, optionally substituted by amino group, cyano group, hydroxyl group, carboxyl group, alkoxy group, aliphatic heterocyclic group, aryl group, heteroaryl group, -COA; monosaccharide group, said monosaccharide The hydroxy group of the group is optionally substituted by an alkyl group; wherein A is selected from the group consisting of hydrogen, -NR 13 R 14 , aryl, arylamino, alkyl optionally substituted by hydroxy, halo, alkoxy optionally substituted by hydroxy, halo base;
  • R 1 and R 2 together form - (CH 2) m1 -O- ( CH 2) m2 -, wherein the H is optionally substituted with - (CH 2) 0 ⁇ 8 -NR 13 R substituent 14, m 1 and m 2 are each independently an integer of 1 to 6;
  • R 1 and R 2 together form the following groups:
  • Y 2 is selected from the group consisting of: alkyl; alkoxy; hydroxylamine; -NR 13 R 14 ; aryl, optionally substituted by amino, hydroxy, halogen, alkoxy, alkyl, haloalkyl; a heteroaryl group optionally substituted by an amino group, a hydroxyl group, a halogen, an alkoxy group, an alkyl group or a halogenated alkyl group; an aliphatic heterocyclic group optionally substituted with an amino group, a hydroxyl group, a halogen or an alkane An oxy group, an alkyl group, a halogenated alkyl group; an aliphatic heterocyclic group-substituted alkyl-substituted aliphatic heterocyclic group, which is optionally an amino group, a hydroxyl group, a halogen group, an alkoxy group, an alkyl group or an alkyl halide.
  • Y 3 is an aryl group optionally substituted by halogen or haloalkyl
  • a 1 is selected from -H, an alkyl group optionally substituted by a heteroaryl group;
  • R 13 and R 14 are each independently selected from -H; amino; monosaccharide group, the hydroxy hydrogen of said monosaccharide group optionally substituted by an alkyl group; alkyl group optionally selected from halogen, hydroxy group, Cyano, nitro, carboxy, azido, -NR 13 R 14 , -S(O) 0-2 R 34 substituted; aryl, which is optionally substituted by amino, hydroxy, halo, alkyl, The alkyl group is optionally substituted with a halogen, a hydroxyl group, a cyano group, a nitro group, a carboxyl group, an azide group, -NR 13 R 14 , -S(O) 0-2 R 34 ; an aliphatic heterocyclic group, The aliphatic heterocyclic group is optionally substituted by an amino group, a hydroxyl group, a halogen, an alkyl group, which is optionally selected from the group consisting of halogen
  • R 11 , R 12 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 are each independently selected from: -H; alkyl; aryl;
  • heteroheterocyclyl and heteroaryl each independently contain from 1 to 4 heteroatoms selected from the group consisting of N, O, and S.
  • the alkyl group and the alkyl group in the haloalkyl group, the alkoxy group or the alkoxy group are a C 1 - C 20 alkyl group, or a C 1 -C 18 alkyl group, or a C 1 -C 6 alkyl group, or a C 1 -C 4 alkyl group;
  • the alkenyl group being a C 2 -C 20 alkenyl group or a C 2 -C 18 alkenyl group Or a C 2 -C 6 alkenyl group, or a C 2 -C 4 alkenyl group;
  • the alkynyl group is a C 2 -C 20 alkynyl group, or a C 2 -C 18 alkynyl group, or a C 2 -C 6 alkynyl, or a C 2 -C 4 alkynyl group;
  • R 1 and R 2 are each independently selected from: -H; C 1 ⁇ C 6 alkyl group, a C 1 ⁇ C 6 alkyl group optionally substituted by amino, cyano, hydroxy, carboxy, C 1 ⁇ C 6 alkoxy a 5-, 6- or 6-membered alicyclic, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, -COA substituted; C 2 -C 6 alkenyl, optionally C 2 -C 6 alkenyl Substituted by amino group, cyano group, hydroxyl group, carboxyl group, C 1 -C 6 alkoxy group, 5- or 6-membered aliphatic heterocyclic group, C 6 -C 10 aryl group, 5- to 10-membered heteroaryl group, -COA; a hydroxyl group of the monosaccharide group optionally substituted by a C 1 -C 6 alkyl group; wherein A is selected from the group consisting of hydrogen, -NR
  • R 1 and R 2 together form the following groups:
  • R 8 is selected from the group consisting of: -H; hydroxy; C 1 -C 18 alkyl, said C 1 -C 18 alkyl optionally substituted by C 1 -C 6 alkoxy; C 2 -C 18 alkenyl; C 2 ⁇ C 18 alkynyl group; C 6 ⁇ C 10 aryl group, a C 6 ⁇ C 10 aryl group optionally substituted by amino, hydroxy, halo, C 1 ⁇ C 6 alkoxy group, C 1 ⁇ C 6 alkyl, C a 1- to C 6 haloalkyl group; a 5 or 6 membered alicyclic group optionally substituted with an amino group, a hydroxyl group, a halogen, a C 1 -C 6 alkoxy group, a C 1 -C 6 alkyl group, or a C 1 to C 6 haloalkyl substituted; 5 to 10 membered heteroaryl, the heteroaryl optionally being amino, hydroxy, halogen,
  • Y 2 is selected from the group consisting of: C 1 -C 18 alkyl; C 1 -C 18 alkoxy; hydroxylamine; -NR 13 R 14 ; C 6 -C 10 aryl, optionally C 6 -C 10 aryl Substituted by amino, hydroxy, halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; 5-10 membered heteroaryl, optionally substituted by amino a hydroxyl group, a halogen, a C 1 -C 6 alkoxy group, a C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group; a 5 or 6-membered aliphatic heterocyclic group, said aliphatic heterocyclic group optionally being Amino, hydroxy, halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloal
  • Y 3 is a C 6 -C 10 aryl group optionally substituted by halogen, halogenated C 1 -C 6 alkyl;
  • a 1 is selected from -H, C 1 -C 6 alkyl optionally substituted by 5 to 10 membered heteroaryl;
  • R 13 and R 14 are each independently selected from -H; amino; monosaccharide group, the hydroxy hydrogen of said monosaccharide group is optionally substituted by C 1 -C 6 alkyl; C 1 -C 6 alkyl, said C The 1 -C 6 alkyl group is optionally substituted with halogen, hydroxy, cyano, nitro, carboxy, azide, -NR 13 R 14 , -S(O) 0-2 R 34 ; C 6 - C 10 an aryl group, a C 6 ⁇ C 10 aryl group optionally substituted by amino, hydroxy, halo, C 1 ⁇ C 6 alkyl group, a C 1 ⁇ C 6 alkyl group optionally substituted selected from halogen, hydroxy, cyano , nitro, carboxyl, azido, -NR 13 R 14 , -S(O) 0-2 R 34 substituted; 5 or 6-membered alicyclic group, optionally substituted with amino group, hydroxy
  • R 11 , R 12 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 are each independently selected from: -H; C 1 -C 6 alkyl; C 6 -C 10 aryl;
  • heteroheterocyclyl and heteroaryl each independently contain from 1 to 4 heteroatoms selected from the group consisting of N, O, and S.
  • the compound of the above formula A, a pharmaceutically acceptable salt or prodrug thereof is a compound of the formula I, a compound of the formula II or a pharmaceutically acceptable salt or prodrug thereof,
  • the dotted line indicates that there is no chemical bond or a single bond
  • G 1 to G 8 are each independently selected from -H; halogen; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl;
  • R 3 is selected from -H; -NR 13 R 14 ; C 1 -C 6 alkyl, the C 1 -C 6 alkyl group optionally being hydroxy, cyano, carboxyl, monosaccharide, C 1 -C 6 alkane
  • Substituting -NR 13 R 14 the 5- or 6-membered alicyclic group, 5- to 10-membered heteroaryl group, C 6 -C 10 aryl group optionally being amino group, hydroxy group, halogen, C 1 -C 6 alkyl group, C 1 -C 6 haloalkyl substituted;
  • a 1 is selected from the group consisting of: -H; C 1 -C 6 alkyl, the C 1 -C 6 alkyl group is optionally substituted by a 5-10 membered heteroaryl group, and the 5-10 membered heteroaryl group is optionally Amino, hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl;
  • R 13 , R 14 are each independently selected from: -H; C 1 -C 6 alkyl;
  • R 1 and R 2 are each independently selected from: -H; C 1 -C 6 alkyl, the C 1 -C 6 alkyl optionally being cyano, hydroxy, carboxy, C 6 -C 10 aryl, 5 ⁇ 10-membered heteroaryl substituted, the C 6 -C 10 aryl, 5- to 10-membered heteroaryl optionally substituted by amino, hydroxy, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl ;
  • G 1 to G 8 are each independently selected from -H; halogen;
  • R 3 is selected from -H; C 1 -C 6 alkyl, and the C 1 -C 6 alkyl group is optionally a hydroxyl group, a cyano group, a carboxyl group, a monosaccharide group, a C 1 -C 6 alkoxy group, or a C 6 - C 10 aryl, 5- to 10-membered heteroaryl, 5- or 6-membered aliphatic heterocyclic group, -NH-CO-C 1 -C 6 alkylene (NH 2 )(A 1 ), -NR 13 R 14 substituted
  • the 5- or 6-membered alicyclic group, 5- to 10-membered heteroaryl group, and C 6 -C 10 aryl group are optionally amino, hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkane Base substitution
  • a 1 is selected from the group consisting of: -H; C 1 -C 6 alkyl, the C 1 -C 6 alkyl group is optionally substituted by a 5-10 membered heteroaryl group, and the 5-10 membered heteroaryl group is optionally Amino, hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl;
  • R 13 , R 14 are each independently selected from: -H; C 1 -C 6 alkyl;
  • R 4 and R 5 or R 6 and R 7 do not constitute 0, each is independently selected from -H or -OR 35 , and R 35 is -H or C 1 -C 6 alkyl;
  • R 9 and R 10 are independently -H or C 1 -C 6 alkyl;
  • Y 2 is selected from the group consisting of hydroxylamine groups; C 6 -C 10 aryl groups, and the C 6 -C 10 aryl group is optionally an amino group, a hydroxyl group, a halogen, a C 1 -C 6 alkoxy group, a C 1 -C 6 alkyl group, C 1 -C 6 haloalkyl substituted; 5-10 membered heteroaryl, the 5-10 membered heteroaryl optionally being amino, hydroxy, halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkane a C 1 -C 6 haloalkyl group; a 5 or 6 membered alicyclic group, optionally substituted by amino, hydroxy, halo, C 1 -C 6 alkoxy, C 1 ⁇ C 6 alkyl, C 1 -C 6 haloalkyl substituted; 5 or 6-membered alicyclic substituted C 1 -C 6 alkyl substituted 5 or
  • Y 3 is a C 6 -C 10 aryl group optionally substituted by halogen, halogenated C 1 -C 6 alkyl;
  • the dotted line indicates that there is no chemical bond or a single bond
  • G 1 to G 8 are as defined in the compound of formula I as claimed in claim 4;
  • R 3 is selected from -H; -NR 13 R 14 ; C 1 -C 6 alkyl, the C 1 -C 6 alkyl group optionally being hydroxy, cyano, carboxyl, monosaccharide, C 1 -C 6 alkane Oxyl, morpholinyl, piperidinyl, piperazinyl, pyridyl, phenyl or -NH-CO-C 1 -C 6 alkylene (NH 2 )(A 1 ), -NR 13 R 14 substituted,
  • the morpholinyl, piperidinyl, piperazinyl, pyridyl, phenyl is optionally substituted by amino, hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl;
  • a 1 is selected from the group consisting of: -H; a C 1 -C 6 alkyl group, and the C 1 -C 6 alkyl group is optionally substituted with an imidazolyl group, a fluorenyl group, optionally an amino group, a hydroxyl group, a halogen, a C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group;
  • R 13 and R 14 are each independently selected from: -H; a C 1 -C 6 alkyl group;
  • R 1 and R 2 are each independently selected from -H; C 1 -C 6 alkyl, and the C 1 -C 6 alkyl group is optionally substituted by cyano, hydroxy, carboxy, phenyl, naphthyl, pyridyl, The phenyl, naphthyl, pyridyl group is optionally substituted with an amino group, a hydroxyl group, a halogen, a C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group;
  • G 1 to G 8 are as defined in the compound of formula II as claimed in claim 4;
  • R 3 is selected from -H; C 1 -C 6 alkyl, and the C 1 -C 6 alkyl group is optionally substituted with amino, hydroxy, phenyl, morpholinyl, piperidinyl, piperazinyl, said benzene
  • the group, morpholinyl, piperidinyl, piperazinyl is optionally substituted by amino, hydroxy, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl;
  • R 4 and R 5 or R 6 and R 7 do not constitute 0, each independently selected from -H or -OH;
  • R 9 and R 10 are a methyl group
  • Y 2 is selected from the group consisting of: hydroxylamine; phenyl, which is optionally substituted by amino, hydroxy, halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl; Imidazolyl; piperazinyl, said piperazinyl optionally substituted by morpholinyl; alkylamino, said alkylamino substituted by at least one of oxygen, hydroxy, thiol, phenyl;
  • Y 3 is phenyl optionally substituted by halogen, C 1 -C 6 haloalkyl
  • the dotted line indicates that there is no chemical bond or a single bond
  • G 1 to G 8 are as defined in the compound of formula I as claimed in claim 4;
  • R 3 is selected from a C 1 -C 6 alkyl group, and the C 1 -C 6 alkyl group is morpholinyl, piperidinyl, piperazinyl, pyridyl, phenyl or -NH-CO-C 1 -C At least one of 6 alkylene (NH 2 )(A 1 ), the morpholinyl, piperidinyl, piperazinyl, pyridyl, phenyl optionally being amino, hydroxy, halogen, C 1 -C a 6 alkyl group, a C 1 -C 6 haloalkyl group; a C 2 -C 6 alkyl group, the C 2 -C 6 alkyl group being substituted by a hydroxy group; a C 3 -C 6 alkyl group, the C 3 -C 6 alkane Substituted by -NR 13 R 14 ;
  • a 1 is selected from the group consisting of: -H; a C 1 -C 6 alkyl group, and the C 1 -C 6 alkyl group is optionally substituted with an imidazolyl group, a fluorenyl group, optionally an amino group, a hydroxyl group, a halogen, a C 1 -C 6 alkyl group, a C 1 -C 6 haloalkyl group;
  • R 13 and R 14 are each independently selected from: -H; a C 1 -C 6 alkyl group;
  • R 1 and R 2 are each independently selected from a C 1 -C 6 alkyl group, and the C 1 -C 6 alkyl group is substituted with at least one of a phenyl group, a naphthyl group, and a pyridyl group;
  • the dotted line indicates that there is no chemical bond or a single bond
  • G 1 to G 8 are each independently selected from -H, halogen, allyl, isopentenyl;
  • R 3 is selected from -H; -Me; -(CH 2 ) 1 to 6 OH; -(CH 2 ) 0 to 6 NH 2 ; -(CH 2 ) 1 to 4 NMe 2 ; -(CH 2 ) 1 to 4 CN; -(CH 2 ) 1 to 4 CO 2 H; -(CH 2 ) 1 to 4 C 6 H 5 OH; -(CH 2 ) 1 to 4 C 6 H 5 OMe; -(CH 2 ) 1 to 4 C 6 H 5 NH 2 ; -(CH 2 ) 1 to 4 M; morpholine ethyl; piperidinyl ethyl; piperazinyl ethyl; methyl piperazinyl ethyl; pyridylethyl; halophenylethyl; (CH 2 ) 1 to 6 -NH-CO-CH(NH 2 )(A 1 ); wherein A 1 , R 13 and R 14 are
  • the R 3 is selected from the group consisting of morpholine ethyl; piperidinyl ethyl; piperazinyl ethyl; methyl piperazinyl ethyl; pyridylethyl; aminobenzyl; aminophenethyl; hydroxybenzyl; Benzene ethyl; -(CH 2 ) 1 ⁇ 6 -NH-CO-CH(NH 2 )(A 1 ); -(CH 2 ) 2 to 4 OH; -(CH 2 ) 3 to 6 NH 2 ;- (CH 2 ) 1 to 4 NMe 2 ; wherein A 1 is selected from -H; imidazole methyl;
  • said R 3 is selected from the group consisting of 2-(4-morpholinyl)ethyl; 2-(piperidin-1-yl)ethyl; 2-(piperazin-1-yl)ethyl; 2-(4 -methylpiperazin-1-yl)ethyl; 2-(pyridin-2-yl)ethyl; p-aminobenzyl; p-aminophenethyl; p-hydroxybenzyl; 2-(2-chloro- 6-fluorophenyl)ethyl; -(CH 2 ) 1 to 6 -NH-CO-CH(NH 2 )(A 1 ); -(CH 2 ) 2 to 4 OH; -(CH 2 ) 3 to 6 NH 2 ; -(CH 2 ) 1 to 4 NMe 2 ; wherein A 1 is selected from -H; (imidazol-4-yl)methyl; (indol-3-yl)methyl;
  • R 1 and R 2 are each independently selected from -H; -Et; -(CH 2 ) 1 to 4 CN; -(CH 2 ) 1 to 4 CO 2 H; -(CH 2 ) 1 to 4 OH; Naphthylethyl; pyridylethyl;
  • each of R 1 and R 2 is independently selected from phenethyl; naphthylethyl; pyridylethyl;
  • G 1 to G 8 are each independently selected from -H; halogen;
  • R 3 is -H
  • R 4 and R 5 or R 6 and R 7 do not constitute 0, each is independently selected from -H or -OR 35 , and R 35 is -H or C 1 -C 6 alkyl;
  • R 9 and R 10 are both methyl
  • Y 2 is selected from the group consisting of: hydroxylamine; phenyl, which is optionally substituted by halogen, C 1 -C 6 haloalkyl; imidazolyl; oxoindenylamino; oxyphenylethylamino; (morpholine) Ethyl)piperazinyl; (halophenyl)methylamino; (halophenyl)ethylamino; (halomethylphenyl)ethylamino; phenylmethylamino; (methoxyphenyl)methylamino ; hydroxypropylamino; 4-(N,N-bis(2-chloroethyl)amino)phenylpropyl;
  • Y 2 is selected from the group consisting of: hydroxylamine; phenyl; halophenyl; trifluoromethyl substituted phenyl; 2-oxophenyl-2-(1H-indol-3-yl)-1-ethylamino ; imidazol-1-yl; 2-oxophenyl-2-phenyl-1-ethylamino; 4-(2(morpholin-1-yl)ethyl)piperazin-1-yl; (2,6- Difluorophenyl)methylamino; (3-chloro-4-fluorophenyl)methylamino; 2-(2-chloro-6-fluorophenyl)-1-ethylamino; 2-(4-trifluoromethyl Phenyl)-1-ethylamino; phenylmethylamino; (4-methoxyphenyl)methylamino; (S)-2-hydroxy-1-propylamino; 4-(N,N,N
  • Y 3 is phenyl optionally substituted by halogen, C 1 -C 6 haloalkyl
  • Y 3 is selected from halophenyl; trifluoromethyl substituted phenyl;
  • R 8 is selected from -H; C 1 -C 18 alkyl; C 1 -C 6 alkoxy-substituted C 1 -C 18 alkyl; or R 8 is methyl.
  • a compound of the above formula A a pharmaceutically acceptable salt or prodrug thereof, selected from the group consisting of the following compounds, pharmaceutically acceptable salts or prodrugs thereof:
  • the pharmaceutically acceptable salt comprises a salt of an organic or inorganic acid; alternatively, the pharmaceutically acceptable salt is selected a salt formed from the compound of the formula A with the following acid compound: hydrochloric acid; sulfuric acid; phosphoric acid; formic acid; acetic acid; propionic acid; lactic acid; citric acid; tartaric acid; succinic acid; fumaric acid; maleic acid; ; camphorsulfonic acid;
  • the pharmaceutically acceptable prodrug comprises a phosphate prodrug or carbamate prodrug of the compound of formula A.
  • G 1 to G 8 , R 1 and R 2 are as defined above, and the preparation steps of the compound of the formula I-1 include:
  • Process (2) a compound of the formula a2, a compound of the formula a6 and a compound of the formula a7 are reacted by Grignard and reacted with ethyl iodide to prepare a compound of the formula a8, and then the compound of the formula a8 is obtained by hydrolysis under basic conditions and then acidification.
  • the compound of the formula I-1 is obtained by reacting a compound of the formula a3;
  • G 1 to G 8 , R 1 , R 2 and R 3 are as defined above, but R 3 is not H, and the preparation step of the compound of the formula I-2 includes: a compound of formula I-2;
  • G 1 to G 8 , R 1 , R 2 and R 3 are as defined above, and the preparation steps of the compound of the formula I-3 include:
  • a compound of the formula I-1 is obtained by a cyclization reaction or an oxidative cyclization reaction of dichlorodiacyanyl p-benzoquinone (DDQ), and a compound of the formula I-3 is obtained from a compound of the formula a5, wherein In the compound of formula I-3, R 3 is H;
  • a compound of the formula 1-2 is obtained by a photo-cyclization reaction or an oxidative cyclization reaction of dichlorodicyan-p-benzoquinone (DDQ), wherein the compound of the formula I-3 is not R 3 H;
  • DDQ dichlorodicyan-p-benzoquinone
  • R 1 and R 2 are a reactive group, the protecting group is optionally protected;
  • R 9 and R 10 are -H or an alkyl group; and G 1 to G 8 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as described above.
  • the preparation step of the compound of the formula II-1 includes: a compound of the group II-1-A, a compound of the group II-1-B, a compound of the group II-1-C, a compound of the group II-1-D or a compound of the group II-1-E. Preparation steps,
  • the preparation step of the II-1-A compound comprises: preparing the compound of the formula b1 by an acylation reaction with an arylformyl reagent or an arylsulfonyl reagent, in the arylformyl reagent or the arylsulfonyl reagent
  • the substituent on the aryl group is the same as the substituent on the Y 2 aryl group; in the compound of the formula b1, G 1 to G 8 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 as described in the class II-1-A compound;
  • a haloalkyl group an alkylamino group substituted with at least one of an oxygen group, a hydroxyl group, a heteroaryl group, and an aryl group, optionally substituted with an amino group, a hydroxyl group, a halogen group, an alkoxy group, Alkyl, haloalkyl substituted; wherein R 13 , R 14 are as described above; the preparation of the II-1-C compound comprises: reacting a compound of formula b2 with methyl iodide to form a compound of formula b3, a compound of formula b3 and compound R The reaction is prepared; wherein the compound R is selected from the group consisting of an aliphatic heterocyclic group-substituted alkyl-substituted aliphatic heterocyclic ring, and the heterocyclic heterocyclic group and the heterocyclic heterocyclic ring are optionally an amino group, a hydroxyl group, a halogen, an alkoxy group.
  • an alkyl group, a halogenated alkyl group an alkylamine substituted with at least one of an oxygen group, a hydroxyl group, a heteroaryl group, and an aryl group, the heteroaryl group and the aryl group being optionally an amino group , a hydroxyl group, a halogen, an alkoxy group, an alkyl group, a halogenated alkyl group;
  • the compound of the formula c5 is further reacted to obtain the compound of the formula c6, and the compound of the formula c7 is obtained by the reaction, and the compound of the formula c8 is obtained by the reaction, and the compound of the formula c9 is obtained by the reaction, and the compound of the formula II-2 is obtained by the reaction. ;
  • R 3 is a reactive group, it is optionally protected with a protecting group
  • the Perkin condensation reaction is carried out in the presence of oxalyl chloride, triethylamine (Et 3 N), dichloromethane;
  • the aminolysis reaction is carried out in the presence of hexamethyldisilazide (HMDS), N,N-dimethylformamide and methanol;
  • HMDS hexamethyldisilazide
  • N,N-dimethylformamide N,N-dimethylformamide
  • methanol hexamethyldisilazide
  • the photo-cyclization reaction uses acetone as a solvent, using iodine as a catalyst, and performing under high-pressure mercury lamp illumination;
  • DDQ dichlorodicyanoquinone
  • the compound of the formula a6 is obtained by reacting dibromomaleimide with methyl iodide;
  • the compound of the formula a8 is hydrolyzed in an alkaline solution such as KOH or NaOH, and acidified with hydrochloric acid or the like to obtain a compound of the formula a3;
  • the protecting group is selected from (Boc) 2 O;
  • the acylation reaction, a halogenation reaction, an oxidation reaction are carried out in an optional order; alternatively, the oxidation reaction is carried out using the following reagents: O 2 , DMSO, t-BuOK, and optionally NaOH;
  • the preparation of the II-1-B compound is carried out by the following method: Method 1: Dissolving cruciferine in dichloromethane, then adding triethylamine, and reacting with 1,1'-thiocarbonyldiimidazole Or method 2: dissolving cruciferine in tetrahydrofuran, then adding diisopropylethylamine and triphosgene to react, dissolving the crude product in tetrahydrofuran, adding diisopropylethylamine, imidazole and p-dimethylamino Made from pyridine;
  • the preparation step of the 1-C compound comprises: forming a salt of the compound of the formula b2 with iodomethane in an acetonitrile solvent, then dissolving in dichloromethane, adding triethylamine and compound R to carry out a reaction to replace the imidazole salt;
  • the preparation method of the compound comprises the following steps: preparing a reaction of Fradcarbazole C with hydroxylamine hydrochloride;
  • the preparation step of the 1-E compound comprises: reacting staurosporine with chlorambucil;
  • the preparation steps of the compound include: 1 using glucose as a raw material, undergoing peracetylation, 1-position bromination, 1,2-position olefination reaction, deacetylation, 6-position hydroxyl group TIPS protection, 3,4-position Constructing oxazolone, methylation, reduction of sodium hydroxymercury hydride to introduce hydroxyl group at 1-position to obtain sugar donor; 2 using 2,3-dibromomaleimide as raw material, protected by BOM, and The ⁇ ⁇ reagent reacts to introduce one molecule of hydrazine, and then protects the hydrazine nitrogen hydrogen with Boc, and then reacts with the ⁇ ⁇ reagent to obtain a mother nucleus; 3 the sugar donor described in step 1 and step 2 The mother nucleus, using the Mitsunobu reaction
  • the compound of the formula II-2 is prepared by using a D-glucose or an L-glucose to carry out a glycosidic bond and an isomer of a different configuration of the oxazolidine.
  • Compounds 82 to 101 can be prepared from halogen-substituted anthracene and dibromomaleimide by the following chemical synthesis methods:
  • G 5 to G 8 are each independently -H, -F, -Cl or -Br;
  • X is -H, -Me or -CH 2 OH, and
  • R 1 and R 2 are each independently -H, -Et or -CH 2 OH.
  • G 5 to G 8 are both -H;
  • R 1 is phenylethyl or 2-(naphthalen-1-yl)ethyl.
  • Compounds 130-157 can be prepared from staurosporine and halogen-containing benzoyl reagents and benzenesulfonyl reagents by the following chemical synthesis methods:
  • R 1 is -H, -F, -Cl, -Br, -I or -CF 3 ;
  • Compounds 167-184 may be prepared from staurosporine and thiocarbonyldiimidazole or triphosgene, imidazole, methyl iodide, and amine compounds; or from staurosporine and chlorambucil by the following chemical synthesis methods:
  • R 5 represents 2-oxophenyl-2-(1H-indol-3-yl)-1-ethylamino, imidazole-1- , hydroxylamine, 2-oxophenyl-2-phenyl-1-ethylamino, 4-(2-(4-morpholinyl)ethyl)piperazin-1-yl, (2,6-difluoro Phenyl)methylamino, (3-chloro-4-fluorophenyl)methylamino, 2-(2-chloro-6-fluorophenyl)-1-ethylamino, 2-(3-trifluoromethylphenyl )-1-ethylamino, phenylmethylamino, (4-methoxyphenyl)methylamino, (S)-2-hydroxy-1-propylamino, 4-(N,N-bis(2-chloro) Ethyl)a
  • the compound of the formula A-VIII is 185-196, wherein the compound 185-187 can be obtained by the following chemical synthesis method from D-glucose and dibromomaleimide.
  • 188-190 can be obtained from the compound 26b. It is prepared in the same manner; 191 to 195 can be obtained by the same method as L-glucose instead of D-glucose.
  • an antitumor pharmaceutical composition comprising at least one of the above compound of formula A, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient; alternatively, The anti-tumor drug is an anti-drug resistant drug; optionally, the anti-tumor drug is an anti-leukemia drug, an anti-breast cancer drug, an anti-lung cancer drug or an anti-hepatocarcin drug; alternatively, the anti-tumor drug is an anti-tumor drug The leukemia drug or the anti-mutation lung cancer drug; optionally, the anti-tumor drug is an acute acute promyelocytic drug, an anti-chronic myeloid leukemia drug, an anti-T lymphocytic leukemia drug, an anti-FLT3-ITD mutation, and an acute person Double phenotype (B, mononuclear) myeloid leukemia drug, anti-adriamycin-resistant leukemia drug, anti-breas
  • the anti-tumor drug is acute promyelocytic leukemia HL-60 inhibitor, chronic myeloid leukemia K562 inhibitor, T lymphocytic leukemia Jurkat inhibitor, FLT3-ITD mutant human acute double phenotype (B, Mononuclear) myeloid leukemia MV-4-11 inhibition Agent, doxorubicin-resistant leukemia K562/A02 inhibitor, breast invasive ductal carcinoma MCF-7 inhibitor, lung adenocarcinoma A549 inhibitor, gefitinib or erlotinib acquired EGFR-T790M/L858R lung Adenocarcinoma resistant mutant H1975 inhibitor or hepatoma cell HepG2 inhibitor.
  • the compound of the formula A, its pharmaceutically acceptable salt or prodrug or antitumor pharmaceutical composition can be administered by oral administration and injection, and is also suitable for other administration methods such as transdermal administration and the like.
  • the above antitumor pharmaceutical composition may be in the form of a preparation such as a tablet, a capsule, a powder, a granule, a lozenge, a suppository, an oral solution or a sterile parenteral suspension.
  • Injection forms such as injections, lyophilized powders and the like of various capacities are also included.
  • the above dosage forms of the drug can be prepared according to a conventional method in the pharmaceutical field.
  • the excipients used include excipients conventional in the art, such as diluents, fillers, binders, wetting agents, absorption enhancers, surfactants, adsorption carriers, lubricants and the like.
  • the compound of formula A, a pharmaceutically acceptable salt or prodrug thereof can also be used as a low molecular biological probe for inhibiting cell proliferation, for use in life science research, as a probe, a compound of formula A, a pharmaceutically acceptable salt thereof Or the prodrug may be dissolved in methanol, water or aqueous methanol, or may be dissolved in an aqueous solution of dimethyl sulfoxide.
  • a compound of the above formula A, a pharmaceutically acceptable salt or prodrug thereof for the preparation of an antitumor drug, optionally, the antitumor drug is an anti-drug resistant drug;
  • the anti-tumor drug is an anti-leukemia drug, an anti-breast cancer drug, an anti-lung cancer drug or an anti-liver cancer drug; optionally, the anti-tumor drug is an anti-mutagenic leukemia drug or an anti-mutation lung cancer drug;
  • the anti-tumor drug is an acute double-phenotypic (B, mononuclear) myeloid leukemia drug against acute promyelocytic leukemia drugs, anti-chronic myeloid leukemia drugs, anti-T lymphocytic leukemia drugs, anti-FLT3-ITD mutations , anti-adriamycin-resistant leukemia drugs, anti-mammary invasive ductal carcinoma drugs, anti-lung adenocarcinoma drugs
  • a method of preventing or treating a tumor comprising administering to a patient a prophylactically or therapeutically effective amount of a compound of the above formula A, a pharmaceutically acceptable salt or prodrug thereof, optionally, said tumor Is a drug-resistant tumor; optionally, the tumor is leukemia, breast cancer, lung cancer or liver cancer; optionally, the tumor is a mutant leukemia or a mutant lung cancer; alternatively, the tumor is acute promyelocytic Cell leukemia, chronic myelogenous leukemia, T lymphocytic leukemia, FLT3-ITD mutant human acute double phenotype (B, mononuclear) myeloid leukemia, adriamycin-resistant leukemia, breast invasive ductal carcinoma, lung adenocarcinoma , K-ras mutant lung adenocarcinoma, gefitinib or erlotinib acquired EGFR-T790M/L858R mutant lung
  • an alpha-glucosidase inhibiting composition comprising at least one of the compound of formula A above, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient.
  • an anti-diabetic pharmaceutical composition comprising at least one of the compound of formula A above, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable adjuvant.
  • the anti-diabetic agent is a drug that is resistant to alpha-glucosidase mediated diabetes.
  • a pharmaceutical composition for anti-diabetic complications comprising at least one of a compound of formula A above, a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient.
  • the diabetic complication is diabetic nephropathy.
  • the compound of the formula A, a pharmaceutically acceptable salt or prodrug thereof, the ⁇ -glucosidase inhibiting composition, or the antidiabetic pharmaceutical composition can be administered by oral administration and injection, and is also suitable for other administration methods, such as Skin administration, etc.
  • the above antidiabetic pharmaceutical composition may be in the form of a preparation such as a tablet, a capsule, a powder, a granule, a lozenge, a suppository, an oral solution or a sterile parenteral suspension. Injection forms such as injections, lyophilized powders and the like of various capacities are also included.
  • the above dosage forms of the drug can be prepared according to a conventional method in the pharmaceutical field.
  • excipients used include excipients conventional in the art, such as diluents, fillers, binders, wetting agents, absorption enhancers, surfactants, adsorption carriers, lubricants and the like.
  • a compound of the above formula A a pharmaceutically acceptable salt or prodrug thereof, for the preparation of an anti-diabetic agent, optionally, the anti-diabetic agent is mediated by an anti- ⁇ -glucosidase Diabetes medication.
  • a compound of the above formula A for the manufacture of a medicament for the prevention of diabetes complications, optionally wherein the diabetes is alpha-glucosidase mediated diabetes.
  • the diabetic complication is diabetic nephropathy.
  • a method of preventing or treating diabetes comprising administering to a patient a prophylactically or therapeutically effective amount of a compound of formula A above, a pharmaceutically acceptable salt or prodrug thereof.
  • the diabetes is alpha-glucosidase mediated diabetes.
  • a method of preventing or treating a diabetic complication comprising administering to a patient a prophylactically or therapeutically effective amount of a compound of the above formula A, a pharmaceutically acceptable salt or prodrug thereof, optionally, the complication For diabetic nephropathy.
  • Human leukemia cell inhibitory activity strong human acute promyelocytic leukemia HL-60 inhibitory activity; strong human chronic myeloid leukemia K562 inhibitory activity; strong human T lymphocyte leukemia Jurkat inhibitory activity;
  • Human mutant leukemia cell inhibitory activity strong FLT3-ITD mutant human acute double phenotype (B, mononuclear) myeloid leukemia MV-4-11 inhibitory activity, can be used for precise treatment of such leukemia patients;
  • Human drug-resistant leukemia cell inhibitory activity strong doxorubicin-resistant leukemia K562/A02 inhibitory activity, can be used for precise treatment of such drug-resistant leukemia patients;
  • Human breast cancer cell inhibitory activity strong human breast invasive ductal carcinoma MCF-7 inhibitory activity
  • Human lung cancer inhibitory activity strong human lung adenocarcinoma A549 inhibitory activity
  • Inhibitory activity of human-resistant lung adenocarcinoma cells the inhibitory activity of gefitinib or erlotinib-acquired EGFR-T790M/L858R lung adenocarcinoma resistant mutant H1975, which can be used for the accuracy of such lung cancer patients treatment;
  • Human hepatoma cell inhibitory activity strong human hepatoma cell HepG2 inhibitory activity
  • It has an ⁇ -glucosidase inhibitory activity and has anti-diabetic and anti-diabetic complications such as diabetic nephropathy.
  • Figure 1 H&E staining photomicrograph of renal cortical tissue sections showing the therapeutic effect of Compound 49 on diabetic nephropathy rats: x 400.
  • A is the normal group
  • B is the db/db model group
  • C is the model group + losartan group (positive drug)
  • D is the model group + compound 49 (0.5 mg/kg/day) group
  • E is the model group + compound Group 49 (1.0 mg/kg/day)
  • F was the model group + compound 49 (2.0 mg/kg/day) group.
  • the aqueous layer was acidified to weak acid with 6N hydrochloric acid and extracted with ethyl acetate (100 mL ⁇ 3 times), and the ethyl acetate layer was combined, dried over anhydrous Na 2 SO 4 , vacuum The mixture was evaporated to dryness, and then purified by EtOAc EtOAc.
  • the compound 3b (452 mg, 2.46 mmol), oxalyl chloride (469 mg, 3.69 mmol), the compound 8a (595 mg, 2.46 mmol), and triethylamine (497 mg, 4.92 mmol) were prepared as a raw material.
  • indole acetic acid 1.69 g, yield 83%.
  • NaH 1.69 g, yield 83%.
  • bromopenteronitrile 2mL, 16mmol
  • the sample 13d was dissolved in 1 mL of CH 2 Cl 2 , 4 mL of anhydrous methanol was added, NaOMe/MeOH was added dropwise with stirring at 0 ° C, to pH 9-10, and the reaction was allowed to rise to room temperature for 30 min, and no residual material was detected by TLC. The reaction was stopped by adding a saturated NH 4 Cl solution at 0 °C. The mixture was extracted with ethyl acetate and evaporated to dryness.
  • the compound 3c 24 mg, 56.7 ⁇ mol
  • ethylenediamine were used as a raw material
  • the column chromatography on silica gel and dichloromethane:methanol 10:1 (v/v) eluted to obtain a dark red solid N.
  • glycine 1.0 g, 13 mmol
  • acetonitrile dissolved Boc anhydride (2.84 g, 13 mmol) was added dropwise at -5 ° C, and the mixture was allowed to warm to room temperature and stirred.
  • white needle-like crystals (20a) (0.66 g) were obtained from L-alanine (1.3 g, 15 mmol).
  • the compound 20a (30 mg, 0.16 mmol), the compound 14 (50 mg, 0.11 mmol), DMAP (4 mg, 0.03 mmol) and DCC (35 mg, 0.17 mmol) were used as raw materials to obtain an orange-red solid (20b) 45 mg, yield 65%.
  • the compound (20) (23.4 mg) was obtained from the compound 20b (30 mg, 0.049 mmol).
  • the compound (21b) was obtained from the compound 21a (80.9 mg, 0.16 mmol), the compound 14 (50 mg, 0.11 mmol), DMAP (4.2 mg, 0.03 mmol) and DCC (35 mg, 0.17 mmol). 35 mg, yield 45%.
  • ESI-MS m/z 775.5 [M+H] + .
  • the compound (21) (20.2 mg) was obtained from the compound 21b (30 mg, 0.039 mmol), and the yield was 90%.
  • white needle-like crystals (22a) (1.3 g) were obtained from tryptophan (1.0 g, 5 mmol), yield 63.3%.
  • the compound (22b) 80 mg was obtained from the compound 22a (72 mg, 0.17 mmol), the compound 13 (50 mg, 0.11 mmol), DMAP (4.2 mg, 0.03 mmol) and DCC (35 mg, 0.17 mmol). The yield was 89%.
  • the compound 24a (356 mg, 1.72 mmol), oxalyl chloride (328 mg, 2.58 mmol), the compound 1a (349 mg, 1.72 mmol) and Et 3 N (347 mg, 3.44 mmol) were used as raw materials to obtain a red solid ( 24b) 299 mg, yield 39%.
  • the compound 24c (100 mg, 0.225 mmol) was dissolved in DMSO (0.85 mL), and 1 M t-BuOK/THF solution (8.4 mL, 8.4 mmol) was added dropwise with stirring, and the addition was completed, and O was added to the reaction solution. 2 about 30min, saturated ammonium chloride solution was added to terminate the reaction, extracted with ethyl acetate (100mL ⁇ 3 times), the organic layer was combined and dried over anhydrous Na 2 SO 4, evaporated to dryness in vacuo.
  • the compound was suspended in 20 mL of 10% aqueous KOH solution for 24 days (50 mg, 0.14 mmol), refluxed at 110 ° C for 40 min, cooled to room temperature, acidified with 2N hydrochloric acid, extracted with ethyl acetate, and combined with organic layer.
  • the compound 24d (55mg, 0.154mmol), N,N-dimethylethylenediamine (84.4 ⁇ L, 0.772mmol) and catalytic amount Et 3 N were dissolved in 30mL of toluene, dissolved in toluene, and condensed water at 110 ° C under nitrogen protection. After refluxing for 17 h, the solvent was evaporated to dryness.
  • the compound hydrochloride N-(N,N-dimethylaminoethyl)-2-(1-ethyl-3-indole) was obtained from the compound 24 (50 mg, 0.117 mmol). ⁇ )-3-(3-indole) maleimide hydrochloride (25) (48 mg, yield 90%).
  • the compound 24a (1100 mg, 3.86 mmol), (COCl) 2 (500 ⁇ L, 5.79 mmol), the compound 1c (783 mg, 3.86 mmol) and Et 3 N (1070 ⁇ L, 7.72 mmol) were prepared as a starting material.
  • the methanol was recrystallized to give 652 mg of red powder (26b), yield: 32.2%.
  • the compound hydrochloride (N,N-N-dimethylaminoethyl)-2-(1-ethyl-3-indole) was obtained from the compound 26 (100 mg, 0.198 mmol). ⁇ )-3-(6-Bromo-3-indole) maleimide hydrochloride (27) (91 mg, yield 85%).
  • the compound hydrochloride (N-(2-aminoethyl)-2-(1-ethyl-3-indole)-3- was obtained from the compound 28 (200 mg, 0.42 mmol). (6-Bromo-3-indole) Maleimide hydrochloride (29) 172 mg, yield 80%.
  • compound 35 (59 mg, 0.128 mmol) and NaHCO 3 (53.7 mg, 0.64 mmol) were used as raw materials to obtain a dark red solid N-(4-hydroxybenzyl)-2-(1-B Methyl-3-indole-3-(1-hydroxymethyl-3-indole) maleimide (36) 50 mg, yield 80%.
  • the compound (39 mg, 0.435 mmol) was used as a starting material to prepare the hydrochloride salt: N-(2-(2-pyridyl)ethyl)-2-(1-ethyl-3-indole ⁇ )-3-(3-indole) maleimide hydrochloride (40) 173 mg, yield 80%.
  • 6-fluoroindole (675 mg, 5 mmol), NaH (300 mg, 7.5 mmol, 60% by mass, dispersed in paraffin) and benzyl bromide (1283 mg, 7.5 mmol) were used as raw materials.
  • the crystalline powder (43a) was 1.01 g, and the yield was 90%.
  • 6-chloroindole 303 mg, 2 mmol
  • NaH 120 mg, 3 mmol, 60% by mass, dispersed in paraffin
  • benzyl bromide 513 mg, 3 mmol
  • Chromatography, petroleum ether: ethyl acetate 60:1 (v/v) eluted to yield white powdery solid (46a) 483mg, yield 100%.
  • the compound 4-bromoindole 700 mg, 3.59 mmol
  • NaH 129 mg, 5.38 mmol, 60% by mass, dispersed in paraffin
  • benzyl bromide 0.64 mL, 5.38 mmol
  • the compound 5-bromoindole 700 mg, 3.59 mmol
  • NaH 129 mg, 5.38 mmol, 60% by mass, dispersed in paraffin
  • benzyl bromide 0.64 mL, 5.38 mmol
  • the compound 52a (1100 mg, 3.86 mmol), (COCl) 2 (500 ⁇ L, 5.79 mmol), the compound 1a (783 mg, 3.86 mmol) and Et 3 N (1.07 mL, 7.72 mmol) were prepared.
  • the pure methanol was recrystallized to give a red powder (52b) 652 mg, yield 32.2%.
  • the compound 7-bromoindole 700 mg, 3.59 mmol
  • NaH 129 mg, 5.38 mmol, 60% by mass, dispersed in paraffin
  • benzyl bromide 0.64 mL, 5.38 mmol
  • compound 62 43 mg, 0.1088 mmol
  • a formaldehyde solution 3 mL, mass fraction: 37%)
  • NaHCO 3 46 mg, 0.544 mmol
  • a deep red solid N-hydroxymethyl group- 2-(1-Ethyl-3-indole)-3-(1-hydroxymethyl-6-isopentenyl-3-indole) maleimide 63) 17 mg, yield 34%.
  • compound 1 (40 mg, 0.1 mmol) was dissolved in 1.0 L of acetone, and a catalytic amount of I 2 was added thereto. The mixture was stirred under a 250 W mercury lamp for 24 hours, and most of the solvent was evaporated in vacuo, and then poured into 100 mL of Na 2 .
  • the compound 73a (470 mg, 1.33 mmol) was suspended in 100 mL of 10% KOH aqueous solution, and the mixture was refluxed at 110 ° C for 1.5 h, dissolved in a pale yellow clear solution, cooled to room temperature, acidified with 2N hydrochloric acid, ethyl acetate (100 mL ⁇ 3 times), organic The layer was evaporated to dryness to give 465 mg of crude 12-ethyl-12,13-dihydrofuran[3,4-c]indole[2,3-a]oxazol-5,7-dione (73b). Very poor, but the reaction is complete, the product is single, so directly into the next step without separation.
  • the compound 73b 49 mg, 0.14 mmol
  • 4-hydroxybenzylamine 51 mg, 0.42 mmol
  • a catalytic amount of Et 3 N were used as raw materials to obtain a yellow solid 6-(4-hydroxybenzyl).
  • -12-ethyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione (76) 15 mg, The rate is 23%.
  • the compound 73b 35 mg, 0.098 mmol
  • 4-(2-aminoethyl)morpholine 104 ⁇ L, 0.79 mmol
  • a catalytic amount of Et 3 N were used as raw materials to obtain a yellow solid 6-( 2-(4-morpholine)ethyl)-12-ethyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7 ( 6H)-dione (77) 33 mg, yield 72%.
  • the compound 73b (100 mg, 0.282 mmol), N,N-dimethylethylenediamine (247.7 ⁇ L, 2.256 mmol) and a catalytic amount of Et 3 N were used as raw materials to obtain a yellow solid 6-( 2-(N,N-dimethylaminoethyl))-12-ethyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5 , 7(6H)-dione (78) 95.7 mg, yield 80%.
  • the compound 73b (80 mg, 0.226 mmol), 2-(2-aminoethyl)pyridine (135.3 ⁇ L, 1.13 mmol) and a catalytic amount of Et 3 N were used as raw materials to obtain a yellow solid 6-( 2-(2-pyridyl)ethyl)-12-ethyl-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7(6H )-Dione (79) 25 mg, yield 64%. 72.5 mg, yield 70%.
  • the compound 62 (41 mg, 0.09 mmol) was used as a starting material to obtain a yellow solid 2-isopentenyl-12-ethyl-12,13-dihydro-5H-indole [2,3- a] Pyrrole [3,4-c]carbazole-5,7(6H)-dione (80) 38 mg, yield 90%.
  • compound 80 (30 mg, 0.071 mmol) and formaldehyde solution (3 mL, mass fraction: 37%) were used as raw materials to obtain a yellow solid 2-isopentenyl-6-hydroxymethyl-12-ethyl -12,13-Dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione (81) 13 mg, yield 25%.
  • compound 82 (257 mg, 0.63 mmol) was dissolved in 10 mL of DMF, and NaH (28 mg, 0.69 mmol, mass fraction 60%, dispersed in paraffin) was added under stirring at -5 ° C. After 30 min of low temperature reaction, slowly drip. EtI (108 mg, 0.69 mmol) was added and the reaction was carried out at low temperature for 30 min.
  • compound 83 (100 mg, 0.23 mmol) was suspended in 10 mL of ethanol, 10 mL of 5 M KOH solution was added, refluxed at 78 ° C for 8 h, cooled to room temperature, acidified with 6N hydrochloric acid, extracted with ethyl acetate, The organic layer was dried over anhydrous sodium sulfate and evaporated.
  • the compound 84a 53 mg, 0.125 mmol
  • HMDS 2.6 mL, 12.5 mmol
  • MeOH 0.6 mL, 6.25 mmol
  • compound 86 506 mg, 1.02 mmol
  • NaH 81 mg, 2.04 mmol, 60% by mass, dispersed in paraffin
  • ethyl iodide 90 ⁇ L, 1.2 mmol
  • compound 90 506 mg, 1.2 mmol
  • NaH 80 mg, 2.04 mmol, 60% by mass, dispersed in paraffin
  • EtI 90 ⁇ L, 1.2 mmol
  • petroleum ether: ethyl acetate 3:1 (v / v) eluted to obtain an orange-red solid N-methyl-2-(1-ethyl-5-bromo-3-indole)-3-(5- Bromo-3-indole maleimide (91) 200 mg, yield 36%.
  • 6-bromoindole 850 mg, 5.58 mmol
  • Mg 134 mg, 5,58 mmol
  • compound 82 300 mg, 1.12 mmol
  • an orange-red solid N-methyl- 2,3-bis(6-bromo-3-indolyl)maleimide 94) 180 mg, yield 30%.
  • the magnesium chips (360 mg, 15 mmol) were suspended in THF (5 mL) in a 50 mL two-necked flask. Ethyl bromide (1.12 mL, 15 mmol) was slowly added dropwise, stirred at room temperature for 20 min, then warmed to 45 ° C, stirred for 20 min, and dissolved in THF (5 mL) The hydrazine (1.75 g, 15 mmol) was stirred for 30 min. After cooling to room temperature, compound 82a (2 g, 7.5 mmol) dissolved in THF (10 mL) was evaporated.
  • Phenylethanol (2 g, 16.3 mmol) was dissolved in dichloromethane (50 mL) in a 250 mL two-necked flask at 0 ° C, triethylamine (3.38 mL, 24.5 mmol) was added, and dichloromethane (20 mL) was added dropwise to dissolve toluene.
  • Sulfonyl chloride (4.67 g, 24.5 mmol) was added dropwise to room temperature and allowed to react overnight.
  • a yellow solid 6-(3-aminopropyl)-12-(1-naphthylethyl) was synthesized from compound 121 (25 mg, 0.04 mmol) )-12,13-dihydro-5H-indole[2,3-a]pyrrole[3,4-c]indazole-5,7(6H)-dione hydrochloride (122) 20 mg, yield 90%.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un dérivé de bisindolylmaléimide, son procédé de préparation et son utilisation. Le dérivé de bisindolylmaléimide a un bon effet thérapeutique sur les tumeurs, en particulier sur certaines tumeurs résistantes aux médicaments, ce qui permet d'obtenir un traitement précis de ces tumeurs résistantes aux médicaments. Selon un autre mode de réalisation de la présente invention, le dérivé de bisindolylmaléimide a un bon effet inhibiteur d'alpha-glucosidase et peut être utilisé dans la prévention ou le traitement du diabète.
PCT/CN2017/090349 2017-06-27 2017-06-27 Dérivé de bisindolylmaléimide, son procédé de préparation et son utilisation WO2019000224A1 (fr)

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CN114015708A (zh) * 2021-11-16 2022-02-08 中南大学 一种深海细菌来源的α-葡萄糖苷酶QsGH13及其编码基因与应用
CN114015708B (zh) * 2021-11-16 2023-07-21 中南大学 一种深海细菌来源的α-葡萄糖苷酶QsGH13及其编码基因与应用

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