CN114685519B - Pyranocarbazole alkaloid derivatives and application thereof in treating Alzheimer's disease - Google Patents

Pyranocarbazole alkaloid derivatives and application thereof in treating Alzheimer's disease Download PDF

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CN114685519B
CN114685519B CN202011605797.XA CN202011605797A CN114685519B CN 114685519 B CN114685519 B CN 114685519B CN 202011605797 A CN202011605797 A CN 202011605797A CN 114685519 B CN114685519 B CN 114685519B
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dmso
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piperidin
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CN114685519A (en
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张东明
张丹
臧应达
鲍秀琦
李创军
马洁
盛莉
刘珂
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Institute of Materia Medica of CAMS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Abstract

The invention relates to the fields of natural medicines and medicinal chemistry, and discloses pyranocarbazole alkaloid derivatives and application thereof in treating Alzheimer's disease. Specifically, the invention discloses a pyran [3,2-a ] containing a benzylpiperazine segment as shown in a general formula I, II]Carbazole alkaloids. The compounds are prepared by artificial synthesis, pharmaceutical compositions containing the compounds and the pharmaceutical application of the compounds in preparing medicines for treating Alzheimer disease.

Description

Pyranocarbazole alkaloid derivatives and application thereof in treating Alzheimer's disease
Technical Field
The invention relates to the fields of natural medicines and medicinal chemistry, in particular to pyran [3,2-a ] carbazole alkaloids containing a benzylpiperazine fragment. The invention discloses a preparation method of the compound, a pharmaceutical composition and application thereof in the aspect of treating Alzheimer disease.
Background
Neurodegenerative diseases, characterized by massive loss of specific neurons, are a complex disease that develops progressively and is disabling. It can be classified into acute and chronic neurodegenerative diseases. The former mainly comprises stroke and brain injury; the latter mainly includes Amyotrophic Lateral Sclerosis (ALS), huntington's Disease (HD), parkinson's Disease (PD), alzheimer's Disease (AD), and the like. Although the lesions and etiology of such diseases vary, neurodegenerative diseases are common to them.
Pyranocarbazoles alkaloids and donepezil all possess a broad range of neuroprotective activity. Claulonsine F (Clau F) is pyranocarbazole alkaloid separated from clausena lansium stem. Clau F has remarkable inhibition effect on sodium nitroprusside-induced apoptosis of rat pheochromocytoma PC12 cells. Clau F inhibits hydroxyl radicalsIs of (2) 50 The value was reduced by about 400 times compared to edaravone. CZ-7 is a structurally optimized analog of Clau F with better neuroprotective activity and is currently in preclinical development. Donepezil is an acetylcholinesterase (AchE) inhibitor approved by the U.S. food and drug administration (Food and Drug Administration, FDA) for sale. It can improve cognitive function in patients with Alzheimer's disease by increasing acetylcholine levels in the central nervous system.
Based on this, the pyranocarbazole mother nucleus of Clau F or CZ-7 and the benzylpiperazine pharmacophore of donepezil are spliced into one molecule, and a derivative which has both free radical scavenging activity and cholinesterase inhibiting activity is expected to be obtained for treating Alzheimer's disease.
Disclosure of Invention
The invention solves the technical problems of providing a compound with general formulas I and II, a preparation method, a pharmaceutical composition and application thereof, and pharmacological experiments show that the compound has obvious improvement effect on in-vitro nerve cell oxygen glucose deprivation injury, has different degrees of inhibition effect on acetylcholinesterase and can also remove hydroxyl free radicals. Therefore, the compounds of the general formulas I and II can be used for preparing medicines for preventing and/or treating Alzheimer's disease.
In order to solve the technical problems of the invention, the invention provides the following technical scheme:
the first aspect of the technical scheme of the invention relates to a pyranocarbazole alkaloid derivative shown in a general formula I or pharmaceutically acceptable salt thereof:
R 1 、R 2 independently of each other, can be independently selected from H, CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH 2 CH 2 CH 3 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、t-Bu、OCH 3 、OCH 2 CH 3 、OCH 2 CH 2 CH 3 、CF 3 、OCF 3 ；
R 3 Selected from H, CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH 2 CH 2 CH 3 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 ；
The compounds of the present invention represented by the general formula I can be prepared by the following method:
wherein the reaction condition (a) is reactant malonic acid, the solvent is pyridine, the catalyst is piperidine, and the reaction is carried out at 40 ℃.
In a second aspect, the present invention provides a pyranocarbazole alkaloid derivative according to formula II:
R 1 、R 2 independently of each other, can be selected from H, CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH 2 CH 2 CH 3 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、t-Bu、OCH 3 、OCH 2 CH 3 、OCH 2 CH 2 CH 3 、CF 3 、OCF 3 ；
R 3 Selected from H, CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH 2 CH 2 CH 3 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 ；
R 4 、R 5 、R 6 Independently of each other, can be selected from H, CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH 2 CH 2 CH 3 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、t-Bu、OCH 3 、OCH 2 CH 3 、OCH 2 CH 2 CH 3 、CF 3 、OCF 3 Halogen (F, cl, br, I);
n＝0-2
the compound represented by the general formula I I of the present invention can be prepared by the following method:
synthetic methods for intermediates 1 and 2 reference (ACS chem. Neurosci.2017,8, 2496-2511)
Wherein, the condition b) is reactant 2-substituted, 3-substituted or 4-substituted benzyl bromide, sodium hydride, tetrahydrofuran as solvent, room temperature; the condition c) is trifluoroacetic acid as a reactant, methylene dichloride as a solvent and the reaction is carried out at 0 ℃.
Wherein, the condition d) is condensing agent 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 1-hydroxybenzotriazole (HOBt), the solvent is tetrahydrofuran, and the reaction is carried out at room temperature.
In the first and second aspects of the present invention, preferred compounds are:
in a third aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention as an active ingredient. The compound comprises the compound shown in the first aspect or the second aspect or pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition is prepared according to methods well known in the art. Any dosage form suitable for human or animal use may be made by combining the compounds of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the present invention are typically present in the pharmaceutical compositions thereof in an amount of 0.1 to 95% by weight.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by the enteral or parenteral route, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral, ocular, pulmonary and respiratory routes, skin, vaginal, rectal and the like.
The dosage form may be a liquid, solid or semi-solid dosage form. The liquid preparation can be solution (including true solution and colloid solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including injection solution, powder injection and transfusion), eye drop, nasal drop, lotion, liniment, etc.; the solid dosage forms can be tablets (including common tablets, enteric coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules and enteric coated capsules), granules, powder, micropills, dripping pills, suppositories, films, patches, aerosol (powder) and sprays; the semisolid dosage form may be an ointment, gel, paste, or the like.
The compound of the invention can be prepared into common preparations, sustained release preparations, controlled release preparations, targeted preparations and various microparticle administration systems.
For the purpose of tableting the compounds of the present invention, various excipients well known in the art may be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannose, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent can be water, ethanol, isopropanol, etc.; the binder may be starch slurry, dextrin, syrup, mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrating agent can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bi-and multi-layered tablets.
In order to make the administration unit into a capsule, the compound of the present invention as an active ingredient may be mixed with a diluent, a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. The active ingredient of the compound can be prepared into particles or pellets by mixing with a diluent, an adhesive and a disintegrating agent, and then placed into hard capsules or soft capsules. Various diluents, binders, wetting agents, disintegrants and glidants used in the preparation of the tablets of the compounds of the invention may also be used in the preparation of the capsules of the compounds of the invention.
For the preparation of the compound of the present invention into injection, water, ethanol, isopropanol, propylene glycol or their mixture may be used as solvent, and appropriate amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator commonly used in the art may be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc. The pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol, glucose, etc. can be added as propping agent for preparing lyophilized powder for injection.
In addition, colorants, preservatives, fragrances, flavoring agents, or other additives may also be added to the pharmaceutical formulation, if desired.
For the purpose of administration, the drug or the pharmaceutical composition of the present invention can be administered by any known administration method to enhance the therapeutic effect.
The dosage of the pharmaceutical composition of the present invention may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, etc. Generally, suitable dosages of the compounds of the present invention are in the range of 0.001 to 150mg/kg body weight, preferably 0.1 to 100mg/kg body weight, more preferably 1 to 60mg/kg body weight, and most preferably 2 to 30mg/kg body weight per day. The above-mentioned dosages may be administered in one dosage unit or in several dosage units, depending on the clinical experience of the physician and the dosage regimen involved in the application of other therapeutic means.
The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention has a synergistic effect with other therapeutic agents, its dosage should be adjusted according to the actual circumstances.
According to a fourth aspect of the present invention there is provided the use of a compound according to the first or second aspect or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prophylaxis and/or treatment of Alzheimer's disease.
Some of the compounds of the present invention represented by general formula I, II were subjected to neuroprotection-related pharmacological experiments. The oxygen glucose deprivation injury neuron model and the acetylcholinesterase inhibition model are all related pharmacological models of neuroprotection advocated by a plurality of domestic and foreign scholars in recent years. Meanwhile, the two models have low requirements on conditions, the technology is easy to master, the reliability is high, and the repeatability is good. Thus, both models were used in this study to evaluate the neuroprotective activity of the compounds. Electron spin resonance spectroscopy (ESR) is a means for detecting free radicals and is very sensitive. Thus, this study used this method to test compounds for their ability to scavenge hydroxyl radicals.
Pharmacological experiments show that the compounds shown in the general formulas I and II have good protection effect on oxygen glucose deprivation injured neurons, and have stronger cholinesterase activity inhibition and hydroxyl radical removal capabilities. Therefore, the preparation method can be used for preparing the medicine for preventing and/or treating the Alzheimer disease.
Beneficial technical effects
The existing anti-Alzheimer disease drugs can only aim at a single target point. Such as donepezil, has only an inhibitory effect on acetylcholinesterase. However, the pathogenesis of Alzheimer's disease is complex, and single-target drugs can only improve the symptoms of cognitive decline and hypomnesis of patients, and cannot completely cure the disease. The compound disclosed by the invention not only has better inhibitory activity on acetylcholinesterase, but also has the effect of antagonizing oxidative stress. Can make up for the deficiency of single-target medicines and can better treat Alzheimer's disease.
Drawings
FIG. 1 free radical scavenging intensity
Detailed Description
Example 1 preparation of (E) -3- (8-methoxy-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylic acid (1)
Claulonsine F (10 g,1 equiv) and malonic acid (10.16 g,3 equiv) were dissolved in 100ml of anhydrous pyridine, then 200. Mu.l piperidine was added and reacted overnight at 40 ℃. The reaction was cooled to room temperature, 600ml of water was added thereto, and the pH was adjusted to 7-8 with 4.8N sodium hydroxide solution at 0℃until no significant particulate matter was present. Extracting with dichloromethane (3×300 ml), leaving a water layer, decolorizing with active carbon, suction filtering, carefully acidifying the pale yellow filtrate with 1.5N hydrochloric acid, freeze-settling the separated yellowish green solid for 1h, suction filtering, washing with cold water, and drying to obtain crude product. Ethanol was recrystallized to give 6.52g of pale yellow product with a yield of 57.4%.
1 H NMR(400MHz,DMSO-d 6 )δ12.11(s,1H),11.30(s,1H),8.41(s,1H),7.95(d,J＝16.0Hz,1H),7.70(d,J＝2.5Hz,1H),7.33(d,J＝8.7Hz,1H),6.96(dd,J＝8.7,2.5Hz,1H),6.90(d,J＝9.8Hz,1H),6.58(d,J＝16.0Hz,1H),5.86(d,J＝9.9Hz,1H),3.83(s,3H),1.48(s,6H).
13 C NMR(100MHz,DMSO-d 6 )δ168.4,153.6,149.7,139.7,138.7,135.0,129.3,123.6,119.9,117.6,117.3,115.5,114.3,114.0,111.5,104.3,103.2,76.7,55.5,27.4.HRESIMS m/z＝350.13959[M+H] + (calcd for C 21 H 20 O 4 N,350.13868).
EXAMPLE 2 preparation of (E) -3- (8-tert-butyl-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylic acid (2)
8-tert-butyl-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazole-5-carbaldehyde (10 g,1 equiv) and malonic acid (9.37 g,3 equiv) by the method of example 1, 7.24g of a pale yellow product was obtained in 63.7% yield.
1 H NMR(400MHz,DMSO-d 6 )δ12.09(s,1H),11.35(s,1H),8.47(s,1H),8.13(d,J＝1.9Hz,1H),7.96(d,J＝16.0Hz,1H),7.40(dd,J＝8.5,1.9Hz,1H),7.34(d,J＝8.5Hz,1H),6.92(d,J＝9.8Hz,1H),6.62(d,J＝16.0Hz,1H),5.87(d,J＝9.8Hz,1H),1.48(s,6H),1.39(s,9H).
13 C NMR(100MHz,DMSO-d 6 )δ168.4,149.5,142.0,139.7,138.5,129.3,122.9,122.8,119.6,117.7,117.4,116.3,115.5,114.4,110.3,104.2,76.6,34.4,31.8,27.4.HRESIMS m/z＝376.19064[M+H] + (calcd for C 24 H 26 O 3 N,376.19072).
Example 3 (E) -N- (1-Benzylpiperidin-4-yl) -3- (8-methoxy-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (3)
Compound 1 (100 mg,1 equiv), 1-benzylpiperidin-4-amine (109 mg,2 equiv) was dissolved in tetrahydrofuran, then EDCI (102 mg,2 equiv), HOBt (72 mg,2 equiv) was added. Stir at room temperature overnight. The reaction was stopped, 50ml of water was added, then extracted twice with ethyl acetate (50 ml. Times.2), the organic layers were combined, then the organic layers were washed twice with water (100 ml. Times.2), saturated brine was washed once, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin-drying to obtain a crude product. Silica gel column chromatography purification gave 111mg of white powder, yield 79.9%.
1 H NMR(600MHz,DMSO-d 6 )δ11.26(s,1H),8.13(s,1H),7.94(d,J＝7.4Hz,1H),7.73(d,J＝15.8Hz,1H),7.58(d,J＝2.5Hz,1H),7.33(d,J＝8.6Hz,1H),7.33–7.27(m,4H),7.27–7.21(m,1H),6.96(dd,J＝8.6,2.5Hz,1H),6.90(d,J＝9.8Hz,1H),6.70(d,J＝15.8Hz,1H),5.85(d,J＝9.8Hz,1H),3.83(s,3H),3.73–3.65(m,1H),3.35(s,2H),2.81–2.74(m,2H),2.11–2.01(m,2H),1.83–1.72(m,2H),1.48(s,6H),1.47–1.41(m,2H).
13 C NMR(150MHz,DMSO-d 6 )δ165.1,162.3,153.5,149.5,138.6,137.9,134.8,134.7,129.3,128.7,128.2,126.8,123.4,119.8,119.2,117.1,115.4,113.8,111.5,104.4,102.8,76.5,62.2,55.5,52.0,46.7,31.8,27.4.
HRESIMS m/z＝522.27576[M+H] + (calcd for C 33 H 36 O 3 N 3 ,522.27512).
Example 4 (E) -N- (1- (2-fluorobenzyl) piperidin-4-yl) -3- (8-methoxy-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (4)
Compound 1 (100 mg,1 equiv), 1- (2-fluorobenzyl) piperidin-4-amine (119 mg,2 equiv), EDCI, HOBt amounts and synthetic method are described in example 3. 106mg of product was obtained in a yield of 68.8%.
1H NMR(600MHz,DMSO-d6)δ8.13(s,1H),7.94(d,J＝7.2Hz,1H),7.74(d,J＝15.7Hz,1H),7.58(d,J＝2.5Hz,1H),7.42–7.38(m,1H),7.33(d,J＝8.7Hz,1H),7.32–7.28(m,1H),7.20–7.13(m,2H),6.96(dd,J＝8.7,2.5Hz,1H),6.90(d,J＝9.7Hz,1H),6.70(d,J＝15.8Hz,1H),5.84(d,J＝9.8Hz,1H),3.83(s,3H),3.68(d,J＝7.2Hz,1H),3.52(s,2H),2.79(d,J＝11.2Hz,2H),2.10(t,J＝11.2Hz,2H),1.79(dd,J＝12.8,4.0Hz,2H),1.48(s,6H),1.46–1.42(m,2H).
13C NMR(150MHz,DMSO-d6)δ165.1,160.8(d,J＝244.4Hz),153.5,149.5,137.9,134.8,134.7,131.5(d,J＝4.9Hz),129.3,129.0(d,J＝8.2Hz),124.9(d,J＝14.6Hz),124.2(d,J＝3.3Hz),123.4,119.8,119.2,117.4,117.2,115.4,115.1(d,J＝21.9Hz),113.8,111.5,104.4,102.8,76.5,59.8,55.5,51.8,45.9,31.7,27.4.
HRESIMS m/z＝540.26569[M+H]+(calcd for C33H35O3N3F,540.26570).
Example 5 (E) -N- (1- (2-chlorobenzyl) piperidin-4-yl) -3- (8-methoxy-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (5)
Compound 1 (100 mg,1 equiv), 1- (2-chlorobenzyl) piperidin-4-amine (128 mg,2 equiv), EDCI, HOBt amounts and synthetic method are described in example 3. 95mg of product was obtained in 59.7% yield.
1 H NMR(600MHz,DMSO-d 6 )δ11.25(s,1H),8.13(s,1H),7.95(d,J＝7.7Hz,1H),7.74(d,J＝15.8Hz,1H),7.58(d,J＝2.5Hz,1H),7.48(d,J＝7.7Hz,1H),7.42(d,J＝7.7Hz,1H),7.36–7.25(m,3H),6.96(dd,J＝8.7,2.5Hz,1H),6.90(d,J＝9.8Hz,1H),6.72(d,J＝15.8Hz,1H),5.85(d,J＝9.8Hz,1H),3.83(s,3H),3.78–3.67(m,1H),3.56(s,2H),2.85–2.76(m,2H),2.22–2.11(m,2H),1.84–1.76(m,2H),1.54–1.43(m,8H).
13 C NMR(150MHz,DMSO-d 6 )δ165.1,153.5,149.5,137.9,136.0,134.8,134.7,133.3,130.7,129.3,129.2,128.5,127.0,123.4,119.8,119.2,117.4,117.1,115.4,113.8,111.5,104.4,102.8,76.5,58.7,55.5,52.1,45.9,31.8,27.4.
HRESIMS m/z＝556.23633[M+H] + (calcd for C 33 H 35 O 3 N 3 Cl,556.23615).
Example 6 (E) -N- (1- (2-methylbenzyl) piperidin-4-yl) -3- (8-methoxy-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (6)
Compound 1 (100 mg,1 equiv), 1- (2-methylbenzyl) piperidin-4-amine (117 mg,2 equiv), EDCI, HOBt amounts and methods of synthesis are described in example 3. 102mg of product was obtained in 66.7% yield.
1 H NMR(600MHz,DMSO-d 6 )δ8.12(s,1H),7.93(d,J＝7.7Hz,1H),7.72(d,J＝15.8Hz,1H),7.57(d,J＝2.5Hz,1H),7.33(d,J＝8.7Hz,1H),7.24–7.20(m,1H),7.17–7.11(m,3H),6.96(dd,J＝8.7,2.5Hz,1H),6.90(d,J＝9.8Hz,1H),6.70(d,J＝15.8Hz,1H),5.85(d,J＝9.8Hz,1H),3.83(s,3H),3.75–3.64(m,1H),3.42(s,2H),2.81–2.73(m,2H),2.32(s,3H),2.09(s,2H),1.82–1.74(m,2H),1.48(s,6H),1.46–1.41(m,2H).
13 C NMR(150MHz,DMSO-d 6 )δ165.1,153.5,149.5,137.9,137.0,136.7,134.8,134.7,130.1,129.5,129.3,126.9,125.4,123.4,119.8,119.3,117.4,117.1,115.4,113.8,111.5,104.4,102.8,76.5,59.8,55.5,52.1,46.0,31.8,27.4,18.8.
Example 7 (E) -N- ((1-Benzylpiperidin-4-yl) methyl) -3- (8-methoxy-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (7)
Compound 1 (100 mg,1 equiv), (1-benzylpiperidin-4-yl) methylamine (117 mg,2 equiv), EDCI, HOBt amounts and methods of synthesis are described in example 3. 85mg of product is obtained in 55.6% yield.
1 H NMR(600MHz,DMSO-d 6 )δ11.31(s,1H),8.24(s,1H),8.14(s,1H),7.75(d,J＝15.8Hz,1H),7.58(d,J＝2.5Hz,1H),7.38–7.22(m,6H),6.96(dd,J＝8.6,2.5Hz,1H),6.91(d,J＝9.8Hz,1H),6.75(d,J＝15.8Hz,1H),5.84(d,J＝9.8Hz,1H),3.83(s,3H),3.58(s,2H),3.13–3.07(m,2H),2.93–2.84(m,2H),2.14–2.05(m,2H),1.72–1.62(m,2H),1.51–1.44(m,7H),1.30–1.20(m,2H).
13 C NMR(150MHz,DMSO-d 6 )δ165.9,153.5,149.5,138.0,137.0,134.9,134.7,129.2,128.2,127.3,123.4,123.4,119.5,119.2,117.4,117.2,115.3,113.8,111.5,104.4,102.8,76.5,61.7,55.5,52.5,44.0,35.5,29.1,27.4.
HRESIMS m/z＝536.29095[M+H] + (calcd for C 34 H 38 O 3 N 3 ,536.29077).
Example 8 (E) -N- ((1- (2-fluorobenzyl) piperidin-4-yl) methyl) -3- (8-methoxy-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (8)
Compound 1 (100 mg,1 equiv), (1- (2-fluorobenzyl) piperidin-4-yl) methylamine (127 mg,2 equiv), EDCI, HOBt amounts and methods of synthesis are described in example 4. 102mg of product was obtained in 64.6% yield.
1 H NMR(600MHz,DMSO-d 6 )δ11.25(s,1H),8.13(s,1H),8.01(d,J＝6.1Hz,1H),7.73(d,J＝15.8Hz,1H),7.58(d,J＝2.5Hz,1H),7.42–7.36(m,1H),7.33(d,J＝8.6Hz,1H),7.33–7.26(m,1H),7.19–7.11(m,2H),6.95(dd,J＝8.6,2.5Hz,1H),6.90(d,J＝9.8Hz,1H),6.73(d,J＝15.8Hz,1H),5.85(d,J＝9.8Hz,1H),3.83(s,3H),3.48(s,2H),3.12–3.04(m,2H),2.84–2.75(m,2H),2.00–1.89(m,2H),1.67–1.59(m,2H),1.50–1.45(m,7H),1.24–1.13(m,2H).
13 C NMR(150MHz,DMSO-d 6 )δ165.9,160.8(d,J＝244.1Hz),153.5,149.5,137.9,134.8,134.6,131.4(d,J＝4.6Hz),129.3,128.9(d,J＝8.3Hz),125.0(d,J＝14.6Hz),124.1(d,J＝3.2Hz),123.4,119.6,119.2,117.4,117.1,115.3,115.1(d,J＝22.1Hz),113.8,111.5,104.4,102.8,76.5,59.8,55.5,52.8,44.3,35.8,29.7,27.4.
HRESIMS m/z＝554.28119[M+H] + (calcd for C 34 H 37 O 3 N 3 F,554.28135).
Example 9 (E) -N- ((1- (2-chlorobenzyl) piperidin-4-yl) methyl) -3- (8-methoxy-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (9)
Compound 1 (100 mg,1 equiv), (1- (2-chlorobenzyl) piperidin-4-yl) methylamine (136 mg,2 equiv), EDCI, HOBt amounts and methods of synthesis are described in example 4. 92mg of product was obtained in 56.4% yield.
1 H NMR(600MHz,DMSO-d 6 )δ8.13(s,1H),8.03(d,J＝6.0Hz,1H),7.73(d,J＝15.8Hz,1H),7.58(d,J＝2.5Hz,1H),7.52–7.23(m,5H),6.95(dd,J＝8.7,2.5Hz,1H),6.90(d,J＝9.8Hz,1H),6.73(d,J＝15.8Hz,1H),5.85(d,J＝9.8Hz,1H),3.83(s,3H),3.53(s,2H),3.13–3.05(m,2H),2.87–2.78(m,2H),2.05–1.96(m,2H),1.69–1.62(m,2H),1.51–1.43(m,7H),1.26–1.15(m,2H).
13 C NMR(150MHz,DMSO-d 6 )δ165.8,153.5,149.5,137.9,136.0,134.8,134.6,133.2,130.7,129.3,129.2,128.5,127.0,123.4,119.6,119.2,117.4,117.1,115.3,113.8,111.5,104.4,102.8,76.5,58.9,55.5,53.1,44.1,35.8,29.8,27.4.
HRESIMS m/z＝570.25189[M+H] + (calcd for C 34 H 37 O 3 N 3 Cl,570.25180).
Example 10 (E) -10-N- ((1- (2-methylbenzyl) piperidin-4-yl) methyl) -3- (8-methoxy-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (10)
Compound 1 (100 mg,1 equiv), (1- (2-methylbenzyl) piperidin-4-yl) methylamine (125 mg,2 equiv), EDCI, HOBt amounts and methods of synthesis are described in example 4. 115mg of product was obtained in 73.1% yield.
1 H NMR(600MHz,DMSO-d 6 )δ8.14(s,1H),8.02(t,J＝5.8Hz,1H),7.75(d,J＝
15.8Hz,1H),7.58(d,J＝2.4Hz,1H),7.34(d,J＝8.6Hz,1H),7.22–7.18(m,1H),7.16–7.07(m,3H),6.96(dd,J＝8.6,2.4Hz,1H),6.90(d,J＝9.8Hz,1H),6.74(d,J＝15.8Hz,1H),5.85(d,J＝9.8Hz,1H),3.83(s,3H),3.37(s,2H),3.12–3.06(m,2H),2.82–2.71(m,2H),2.29(s,3H),1.97–1.88(m,2H),1.68–1.60(m,2H),1.52–1.42(m,7H),1.22–1.10(m,2H).
13 C NMR(150MHz,DMSO-d 6 )δ165.9,153.5,149.5,137.9,136.9,136.7,134.8,134.6,130.0,129.4,129.3,126.7,125.3,123.4,119.6,119.2,117.4,117.1,115.3,113.8,111.5,104.4,102.8,76.5,60.5,55.5,53.2,44.3,36.0,29.9,27.4,18.8.
HRESIMS m/z＝550.30609[M+H] + (calcd for C 35 H 40 O 3 N 3 ,550.30642).
Example 11 (E) -N- ((1-Benzylpiperidin-4-yl) ethyl) -3- (8-methoxy-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide
Compound 1 (100 mg,1 equiv), (1-benzylpiperidin-4-yl) ethylamine (125 mg,2 equiv), EDCI, HOBt amounts and synthetic method are described in example 4. 106mg of product was obtained in 67.5% yield.
1 H NMR(600MHz,DMSO-d 6 )δ8.14(s,1H),7.98(t,J＝5.6Hz,1H),7.73(d,J＝15.8Hz,1H),7.59(d,J＝2.5Hz,1H),7.38–7.18(m,6H),6.96(dd,J＝8.7,2.5Hz,1H),6.90(d,J＝9.8Hz,1H),6.69(d,J＝15.8Hz,1H),5.85(d,J＝9.8Hz,1H),3.83(s,3H),3.44(s,2H),3.25–3.16(m,2H),2.86–2.73(m,2H),1.98–1.84(m,2H),1.71–1.58(m,2H),1.48(s,6H),1.44–1.37(m,2H),1.36–1.25(m,1H),1.22–1.09(m,2H).
13 C NMR(150MHz,DMSO-d 6 )δ165.7,153.5,149.5,138.1,137.9,134.8,134.6,129.3,128.8,128.1,126.8,123.4,119.7,119.2,117.4,117.1,115.3,113.8,111.5,104.4,102.8,76.5,62.4,55.5,53.2,36.3,36.0,32.8,31.8,27.4.
HRESIMS m/z＝550.30670[M+H] + (calcd for C 35 H 40 O 3 N 3 ,550.30642).
Example 12 (E) -N- ((1- (2-fluorobenzyl) piperidin-4-yl) ethyl) -3- (8-methoxy-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide
Compound 1 (100 mg,1 equiv), (1- (2-fluorobenzyl) piperidin-4-yl) ethanamine (135 mg,2 equiv), EDCI, HOBt amounts and synthetic method are described in example 4. 113mg of product was obtained in 69.6% yield.
1 H NMR(400MHz,DMSO-d 6 )δ11.26(s,1H),8.13(s,1H),7.96(t,J＝5.6Hz,1H),7.72(d,J＝15.8Hz,1H),7.58(d,J＝2.5Hz,1H),7.41–7.36(m,1H),7.33(d,J＝8.7Hz,1H),7.31–7.26(m,1H),7.19–7.11(m,2H),6.95(dd,J＝8.7,2.5Hz,1H),6.90(d,J＝9.9Hz,1H),6.68(d,J＝15.8Hz,1H),5.85(d,J＝9.9Hz,1H),3.83(s,3H),3.48(s,2H),3.24–3.15(m,2H),2.84–2.72(m,2H),1.98–1.88(m,2H),1.70–1.59(m,2H),1.48(s,6H),1.44–1.35(m,2H),1.25–1.21(m,1H),1.20–1.08(m,2H).
13 C NMR(100MHz,DMSO-d 6 )δ165.7,160.8(d,J＝244.2Hz),153.5,149.4,138.0,134.9,134.5,131.5(d,J＝4.5Hz),129.3,128.9(d,J＝8.1Hz),124.9(d,J＝14.7Hz),124.1(d,J＝3.5Hz),123.4,119.7,119.2,117.4,117.2,115.3,115.1(d,J＝22.0Hz),113.8,111.5,104.4,102.8,76.5,55.5,54.9,53.1,36.2,36.0,32.7,31.8,27.4.
HRESIMS m/z＝568.29767[M+H] + (calcd for C 35 H 39 O 3 N 3 F,568.29809).
Example 13 (E) -N- ((1- (2-chlorobenzyl) piperidin-4-yl) ethyl) -3- (8-methoxy-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide
Compound 1 (100 mg,1 equiv), (1- (2-chlorobenzyl) piperidin-4-yl) ethanamine (144 mg,2 equiv), EDCI, HOBt amounts and synthetic method are described in example 4. 89mg of the product was obtained in 53.3% yield.
1 H NMR(400MHz,DMSO-d 6 )δ11.24(s,1H),8.13(s,1H),7.97(t,J＝5.6Hz,1H),7.72(d,J＝15.8Hz,1H),7.59(d,J＝2.5Hz,1H),7.51–7.38(m,2H),7.36–7.23(m,3H),6.95(dd,J＝8.7,2.5Hz,1H),6.90(d,J＝9.8Hz,1H),6.69(d,J＝15.8Hz,1H),5.85(d,J＝9.8Hz,1H),3.83(s,3H),3.53(s,2H),3.27–3.17(m,2H),2.91–2.74(m,2H),2.07–1.93(m,2H),1.72–1.62(m,2H),1.48(s,6H),1.45–1.37(m,2H),1.38–1.26(m,1H),1.23–1.11(m,2H).
13 C NMR(100MHz,DMSO-d 6 )δ165.7,153.5,149.4,138.0,136.1,134.9,134.5,133.2,130.7,129.3,129.2,128.5,127.0,123.4,119.7,119.2,117.4,117.2,115.3,113.8,111.5,104.4,102.8,76.5,59.0,55.5,53.4,36.2,36.0,32.7,31.9,27.4.
HRESIMS m/z＝584.26843[M+H] + (calcd for C 35 H 39 O 3 N 3 Cl,584.26745).
Example 14 (E) -N- ((1- (2-methylbenzyl) piperidin-4-yl) ethyl) -3- (8-methoxy-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide
Compound 1 (100 mg,1 equiv), (1- (2-methylbenzyl) piperidin-4-yl) ethanamine (133 mg,2 equiv), EDCI, HOBt amounts and synthetic method are described in example 4. 105mg of product was obtained in 65.1% yield.
1 H NMR(600MHz,DMSO-d 6 )δ8.14(s,1H),7.98(t,J＝5.7Hz,1H),7.74(d,J＝15.8Hz,1H),7.59(d,J＝2.5Hz,1H),7.34(d,J＝8.6Hz,1H),7.22–7.07(m,4H),6.96(dd,J＝8.6,2.5Hz,1H),6.90(d,J＝9.8Hz,1H),6.70(d,J＝15.8Hz,1H),5.85(d,J＝9.8Hz,1H),3.83(s,3H),3.37(s,2H),3.26–3.18(m,2H),2.80–2.71(m,2H),2.29(s,3H),1.95–1.85(m,2H),1.68–1.60(m,2H),1.48(s,6H),1.42–1.37(m,2H),1.35–1.27(m,1H),1.20–1.06(m,2H).
13 C NMR(150MHz,DMSO-d 6 )δ165.7,153.5,149.5,137.9,136.9,136.7,134.8,134.6,130.0,129.4,129.3,126.7,125.3,123.4,119.7,119.2,117.4,117.1,115.3,113.8,111.5,104.4,102.8,76.5,60.5,55.5,53.5,36.3,36.0,33.0,32.0,27.4,18.8.
HRESIMS m/z＝564.32147[M+H] + (calcd for C 36 H 42 O 3 N 3 ,564.32207).
Example 15 (E) -N- (1-Benzylpiperidin-4-yl) -3- (8-methoxy-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (15)
Compound 2 (100 mg,1 equiv), 1-benzylpiperidin-4-amine (101 mg,2 equiv), EDCI, HOBt amounts and synthetic procedure were as described in example 4. 102mg of product was obtained in 69.9% yield.
1 H NMR(400MHz,DMSO-d 6 )δ11.31(s,1H),8.16(s,1H),8.01(s,1H),7.93(d,J＝7.7Hz,1H),7.74(d,J＝15.7Hz,1H),7.44–7.22(m,7H),6.92(d,J＝9.8Hz,1H),6.72(d,J＝15.8Hz,1H),5.86(d,J＝9.8Hz,1H),3.76–3.61(m,1H),3.48(s,2H),2.84–2.74(m,2H),2.17–2.01(m,2H),1.83–1.75(m,2H),1.48(s,6H),1.46–1.43(m,2H),1.38(s,9H).
13 C NMR(100MHz,DMSO-d 6 )δ165.0,149.3,141.8,138.4,138.4,137.8,134.5,129.4,128.8,128.2,126.9,122.8,122.6,119.7,118.7,117.4,117.4,115.6,115.4,110.3,104.4,76.5,62.1,51.9,45.9,34.4,31.8,31.7,27.4.
HRESIMS m/z＝584.32721[M+H] + (calcd for C 36 H 42 O 2 N 3 ,548.32715).
EXAMPLE 16 (E) -N- (1- (2-fluorobenzyl) piperidin-4-yl) -3- (8-tert-butyl-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (16)
Compound 2 (100 mg,1 equiv), 1- (2-fluorobenzyl) piperidin-4-amine (111 mg,2 equiv), EDCI, HOBt amounts and synthetic method are described in example 3. 95mg of product was obtained in 62.9% yield.
1 H NMR(400MHz,DMSO-d 6 )δ11.34(s,1H),8.16(s,1H),8.00(s,2H),7.75(d,J＝15.7Hz,1H),7.54–7.30(m,4H),7.28–7.13(m,2H),6.93(d,J＝9.8Hz,1H),6.72(d,J＝15.7Hz,1H),5.85(d,J＝9.8Hz,1H),3.88–3.51(m,3H),3.07–2.77(m,2H),2.50(s,2H),1.93–1.78(m,2H),1.62–1.50(m,2H),1.48(s,6H),1.38(s,9H).
13 C NMR(100MHz,DMSO-d 6 )δ165.1,160.9(d,J＝245.8Hz).,149.3,141.8,138.4,137.8,134.6,132.0,129.4,128.7,124.5,124.4,122.8,122.6,119.6,118.6,117.5,117.4,115.6,115.3,115.2,110.4,104.4,76.5,59.7,51.5,45.0,34.4,31.8,31.7,27.4.HRESIMS m/z＝566.31696[M+H] + (calcd for C 36 H 41 O 2 N 3 F,566.31773).
EXAMPLE 17 (E) -N- (1- (2-chlorobenzyl) piperidin-4-yl) -3- (8-methoxy-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (17)
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Compound 2 (100 mg,1 equiv), 1- (2-chlorobenzyl) piperidin-4-amine (119 mg,2 equiv), EDCI, HOBt amounts and synthetic method are described in example 3. 102mg of product was obtained in 65.8% yield.
1 H NMR(400MHz,DMSO-d 6 )δ11.34(s,1H),8.17(s,1H),8.01(d,J＝1.8Hz,1H),7.94(d,J＝7.7Hz,1H),7.76(d,J＝15.8Hz,1H),7.48(dd,J＝7.5,1.9Hz,1H),7.43–7.25(m,5H),6.93(d,J＝9.8Hz,1H),6.74(d,J＝15.8Hz,1H),5.85(d,J＝9.8Hz,1H),3.79–3.66(m,1H),3.55(s,2H),2.82–2.78(m,2H),2.21–2.10(m,2H),1.85–1.75(m,2H),1.55–1.43(m,8H),1.38(s,9H).
13 C NMR(100MHz,DMSO-d 6 )δ165.1,149.3,141.8,138.4,137.8,136.0,134.5,133.2,130.7,129.3,129.2,128.5,127.0,122.8,122.6,119.7,118.7,117.5,117.4,115.6,115.4,110.3,104.4,76.5,58.7,52.0,45.8,34.4,31.8,31.8,27.4.
HRESIMS m/z＝582.28790[M+H] + (calcd for C 36 H 41 O 2 N 3 Cl,582.28818).
Example 18 (E) -N- (1- (2-methylbenzyl) piperidin-4-yl) -3- (8-tert-butyl-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (18)
Compound 2 (100 mg,1 equiv), 1- (2-methylbenzyl) piperidin-4-amine (117 mg,2 equiv), EDCI, HOBt amounts and methods of synthesis are described in example 3. 91mg of product was obtained in 60.7% yield.
1 H NMR(400MHz,DMSO-d 6 )δ11.37(s,1H),8.16(s,1H),8.00(d,J＝1.8Hz,1H),7.92(d,J＝7.8Hz,1H),7.74(d,J＝15.8Hz,1H),7.40(dd,J＝8.4,1.8Hz,1H),7.35(d,J＝8.4Hz,1H),7.23–7.20(m,1H),7.16–7.11(m,3H),6.93(d,J＝9.8Hz,1H),6.72(d,J＝15.8Hz,1H),5.85(d,J＝9.8Hz,1H),3.77–3.64(m,1H),3.41(s,2H),2.78–2.74(m,2H),2.32(s,3H),2.13–2.02(m,2H),1.85–1.73(m,2H),1.48(s,6H),1.47–1.41(m,2H),1.38(s,9H).
13 C NMR(100MHz,DMSO-d 6 )δ165.0,149.3,141.7,138.4,137.8,137.0,136.7,134.5,130.0,129.5,129.3,126.8,125.4,122.8,122.6,119.8,118.7,117.5,117.4,115.6,115.4,110.4,104.4,76.5,60.3,52.1,46.0,34.4,31.9,31.8,27.4,18.8.
HRESIMS m/z＝562.34235[M+H] + (calcd for C 37 H 44 O 2 N 3 ,562.34280).
Example 19 (E) -N- ((1-Benzylpiperidin-4-yl) methyl) -3- (8-tert-butyl-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (19)
Compound 2 (100 mg,1 equiv), (1-benzylpiperidin-4-yl) methylamine (109 mg,2 equiv), EDCI, HOBt amounts and synthetic method are described in example 3. 96mg of product was obtained in 64% yield.
1 H NMR(400MHz,DMSO-d 6 )δ11.30(s,1H),8.16(s,1H),8.01(d,J＝1.8Hz,1H),7.98(d,J＝5.9Hz,1H),7.74(d,J＝15.8Hz,1H),7.40(dd,J＝8.6,1.8Hz,1H),7.35(d,J＝8.6Hz,1H),7.33–7.26(m,4H),7.26–7.21(m,1H),6.91(d,J＝9.8Hz,1H),6.75(d,J＝15.8Hz,1H),5.86(d,J＝9.8Hz,1H),3.45(s,2H),3.12–3.06(m,2H),2.86–2.77(m,2H),1.91(s,2H),1.69–1.59(m,2H),1.48(s,6H),1.40–1.36(m,10H),1.28–1.12(m,2H).
13 C NMR(100MHz,DMSO-d 6 )δ165.9,149.3,141.8,138.7,138.4,137.8,134.4,129.4,128.8,128.1,126.9,122.8,122.6,119.6,118.6,117.4,117.4,115.7,115.4,110.3,104.4,76.5,62.4,53.0,44.3,35.9,34.4,31.8,29.7,27.4.
HRESIMS m/z＝562.34210[M+H] + (calcd for C 37 H 44 O 2 N 3 ,562.34280).
Example 20 (E) -N- ((1- (2-fluorobenzyl) piperidin-4-yl) methyl) -3- (8-tert-butyl-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (20)
Compound 2 (100 mg,1 equiv), (1- (2-fluorobenzyl) piperidin-4-yl) methylamine (118 mg,2 equiv), EDCI, HOBt amounts and methods of synthesis are described in example 4. 113mg of product was obtained in 73.4% yield.
1 H NMR(400MHz,DMSO-d 6 )δ11.32(s,1H),8.16(s,1H),8.05–7.94(m,2H),7.74(d,J＝15.7Hz,1H),7.45–7.09(m,6H),6.92(d,J＝9.8Hz,1H),6.75(d,J＝15.7Hz,1H),5.85(d,J＝9.8Hz,1H),3.49(s,2H),3.12–3.03(m,2H),2.81(d,J＝11.3Hz,2H),1.94(t,J＝11.3Hz,2H),1.69–1.58(m,2H),1.48(s,6H),1.40–1.35(m,10H),1.26–1.11(m,2H).
13 C NMR(100MHz,DMSO-d 6 )δ165.9,160.7(d,J＝244.1Hz),149.3,141.8,138.4,137.8,134.4,131.4(d,J＝4.7Hz),129.4,128.9(d,J＝8.2Hz),125.0(d,J＝14.5Hz),124.1(d,J＝3.4Hz),122.8,122.6,119.6,118.6,117.5,117.3,115.6,115.4,115.1(d,J＝22.0Hz).,110.3,104.4,76.5,54.9,52.9,44.2,35.8,34.4,31.8,29.7,27.4.
HRESIMS m/z＝580.33258[M+H] + (calcd for C 37 H 43 O 2 N 3 F,580.233338).
Example 21 (E) -N- ((1- (2-chlorobenzyl) piperidin-4-yl) methyl) -3- (8-tert-butyl-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (21)
Compound 2 (100 mg,1 equiv), (1- (2-chlorobenzyl) piperidin-4-yl) methylamine (127 mg,2 equiv), EDCI, HOBt amounts and methods of synthesis are described in example 4. 89mg of product was obtained in 56% yield.
1 H NMR(400MHz,DMSO-d 6 )δ11.31(s,1H),8.16(s,1H),8.05–7.95(m,2H),7.74(d,J＝15.7Hz,1H),7.51–7.23(m,6H),6.92(d,J＝9.8Hz,1H),6.75(d,J＝15.7Hz,1H),5.86(d,J＝9.8Hz,1H),3.52(s,2H),3.13–3.04(m,2H),2.83(d,J＝11.3Hz,2H),2.01(t,J＝11.3Hz,2H),1.71–1.62(m,2H),1.48(s,6H),1.40–1.35(m,10H),1.26–1.15(m,2H).
13 C NMR(101MHz,DMSO)δ165.9,149.3,141.8,138.4,137.8,136.1,134.4,133.2,130.6,129.4,129.2,128.4,127.0,122.8,122.6,119.6,118.6,117.4,117.4,115.7,115.4,110.3,104.4,76.5,58.9,53.1,44.3,35.9,34.4,31.8,29.8,27.4.
HRESIMS m/z＝596.30298[M+H] + (calcd for C 37 H 43 O 2 N 3 Cl,596.30383).
Example 22 (E) -N- ((1- (2-methylbenzyl) piperidin-4-yl) methyl) -3- (8-methoxy-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (22)
Compound 2 (100 mg,1 equiv), (1- (2-methylbenzyl) piperidin-4-yl) methylamine (116 mg,2 equiv), EDCI, HOBt amounts and methods of synthesis are described in example 4. 114mg of the product was obtained in 74.5% yield.
1 H NMR(400MHz,DMSO-d 6 )δ11.33(s,1H),8.16(s,1H),8.05–7.96(m,2H),7.74(d,J＝15.8Hz,1H),7.46–7.32(m,2H),7.27–7.07(m,4H),6.92(d,J＝9.8Hz,1H),6.75(d,J＝15.8Hz,1H),5.85(d,J＝9.8Hz,1H),3.38(s,2H),3.13–3.05(m,2H),2.79(d,J＝11.4Hz,2H),2.30(s,3H),1.93(t,J＝11.4Hz,2H),1.70–1.59(m,2H),1.48(s,6H),1.48–1.41(m,1H),1.38(s,9H),1.25–1.06(m,2H).
13 C NMR(151MHz,DMSO)δ165.9,153.5,149.5,137.9,136.9,136.7,134.8,134.6,130.0,129.4,129.3,126.7,125.3,123.4,119.6,119.2,117.4,117.1,115.3,113.8,111.5,104.4,102.8,76.5,60.5,55.5,53.2,44.3,36.0,29.9,27.4,18.8.
HRESIMS m/z＝576.35785[M+H] + (calcd for C 38 H 46 O 2 N 3 ,576.35785).
Example 23 (E) -N- ((1- (3-chlorobenzyl) piperidin-4-yl) methyl) -3- (8-tert-butyl-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (23)
Compound 2 (100 mg,1 equiv), (1- (3-chlorobenzyl) piperidin-4-yl) methylamine (127 mg,2 equiv), EDCI, HOBt amounts and methods of synthesis are described in example 4. 95mg of product was obtained in 59.7% yield.
1 H NMR(400MHz,DMSO-d 6 )δ11.30(s,1H),8.16(s,1H),8.07–7.93(m,2H),7.74(d,J＝15.7Hz,1H),7.40(dd,J＝8.5,1.9Hz,1H),7.37–7.32(m,3H),7.32–7.26(m,2H),6.91(d,J＝9.8Hz,1H),6.75(d,J＝15.7Hz,1H),5.86(d,J＝9.8Hz,1H),3.46(s,2H),3.14–3.05(m,2H),2.83–2.74(m,2H),1.97–1.85(m,2H),1.69–1.61(m,2H),1.48(s,6H),1.38(s,10H),1.25–1.16(m,2H).
13 C NMR(100MHz,DMSO-d 6 )δ165.9,149.3,141.8,138.4,137.8,136.1,134.4,132.9,130.0,129.4,128.2,127.3,126.8,122.8,122.6,119.6,118.6,117.4,117.4,115.7,115.4,110.3,104.4,76.5,61.5,53.0,44.3,35.9,34.4,31.8,29.8,27.4.
HRESIMS m/z＝596.30365[M+H] + (calcd for C 37 H 43 O 2 N 3 Cl,596.30383).
Example 24 (E) -N- ((1- (4-chlorobenzyl) piperidin-4-yl) methyl) -3- (8-tert-butyl-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (24)
Compound 2 (100 mg,1 equiv), (1- (4-chlorobenzyl) piperidin-4-yl) methylamine (127 mg,2 equiv), EDCI, HOBt amounts and methods of synthesis are described in example 4. 102mg of product was obtained in 64.2% yield.
1 H NMR(400MHz,DMSO-d 6 )δ11.30(s,1H),8.16(s,1H),8.01(d,J＝1.8Hz,1H),7.98(d,J＝5.9Hz,1H),7.74(d,J＝15.8Hz,1H),7.40(dd,J＝8.5,1.9Hz,1H),7.40–7.32(m,3H),7.31(d,J＝8.5Hz,2H),6.92(d,J＝9.8Hz,1H),6.75(d,J＝15.8Hz,1H),5.86(d,J＝9.8Hz,1H),3.42(s,2H),3.13–3.04(m,2H),2.82–2.72(m,2H),1.96–1.84(m,2H),1.68–1.58(m,2H),1.48(s,6H),1.38(s,9H),1.26–1.11(m,3H).
13 C NMR(100MHz,DMSO-d 6 )δ165.9,149.3,141.8,138.4,137.8,134.4,131.2,130.4,129.4,128.1,122.8,122.6,119.6,118.6,117.4,117.4,115.7,115.4,110.3,104.4,76.5,61.5,52.9,48.6,44.3,35.9,34.4,31.8,29.8,27.4.
HRESIMS m/z＝596.30365[M+H] + (calcd for C 37 H 43 O 2 N 3 Cl,596.30383).
Example 25 (E) -N- ((1-Benzylpiperidin-4-yl) ethyl) -3- (8-tert-butyl-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (25)
Compound 2 (100 mg,1 equiv), (1-benzylpiperidin-4-yl) ethylamine (116 mg,2 equiv), EDCI, HOBt amounts and synthetic method are described in example 4. 106mg of product was obtained in 69.3% yield.
1 H NMR(400MHz,DMSO-d 6 )δ11.34(s,1H),8.17(s,1H),8.01(d,J＝1.8Hz,1H),7.97(t,J＝5.6Hz,1H),7.74(d,J＝15.8Hz,1H),7.40(dd,J＝8.5,1.9Hz,1H),7.37–7.31(m,5H),7.30–7.26(m,1H),6.93(d,J＝9.8Hz,1H),6.71(d,J＝15.8Hz,1H),5.85(d,J＝9.8Hz,1H),3.60(s,2H),3.27–3.14(m,2H),2.89(s,2H),2.26–1.98(m,2H),1.75–1.64(m,2H),1.48(s,6H),1.45–1.40(m,2H),1.38(s,9H),1.29–1.13(m,3H).
13 C NMR(100MHz,DMSO-d 6 )δ165.7,149.3,143.9,141.7,138.4,137.8,137.7,134.4,129.3,128.9,128.2,122.8,122.6,119.6,118.7,117.5,117.3,115.7,115.3,110.3,104.4,76.5,59.8,52.8,36.1,35.9,34.4,32.3,31.8,31.2,27.4.
HRESIMS m/z＝576.35858[M+H] + (calcd for C 38 H 46 O 2 N 3 ,576.35845).
EXAMPLE 26 (E) -N- ((1- (2-fluorobenzyl) piperidin-4-yl) ethyl) -3- (8-tert-butyl-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (26)
Compound 2 (100 mg,1 equiv), (1- (2-fluorobenzyl) piperidin-4-yl) ethylamine (126 mg,2 equiv), EDCI, HOBt amounts and synthetic method are described in example 4. 93mg of product was obtained in 58.9% yield.
1 H NMR(400MHz,DMSO-d 6 )δ11.35(s,1H),8.17(s,1H),8.01(s,1H),7.96(t,J＝5.7Hz,1H),7.73(d,J＝15.8Hz,1H),7.40(dd,J＝8.4,1.8Hz,1H),7.38–7.26(m,3H),7.19–7.11(m,2H),6.93(d,J＝9.8Hz,1H),6.71(d,J＝15.8Hz,1H),5.85(d,J＝9.8Hz,1H),3.49(s,2H),3.27–3.15(m,2H),2.83–2.76(m,2H),2.02–1.88(m,2H),1.71–1.59(m,2H),1.48(s,6H),1.45–1.39(m,2H),1.38(s,10H),1.21–1.08(m,2H).
13 C NMR(100MHz,DMSO-d 6 )δ165.7,160.8(d,J＝244.5Hz),149.3,141.8,138.4,137.8,134.3,131.5(d,J＝5.0Hz),129.3,128.9(d,J＝8.3Hz),124.9(d,J＝14.6Hz),124.1(d,J＝3.2Hz),122.8,122.6,119.6,118.7,117.5,117.4,115.7,115.3,115.1(d,J＝22.0Hz),110.3,104.4,76.5,54.9,53.1,36.2,36.0,35.0,34.4,32.7,31.8,27.4.HRESIMS m/z＝594.34808[M+H] + (calcd for C 38 H 45 O 2 N 3 F,594.34903).
Example 27 (E) -N- ((1- (2-chlorobenzyl) piperidin-4-yl) ethyl) -3- (8-tert-butyl-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (27)
Compound 2 (100 mg,1 equiv), (1- (2-chlorobenzyl) piperidin-4-yl) ethanamine (134 mg,2 equiv), EDCI, HOBt amounts and synthetic method are described in example 4. 109mg of product was obtained in 67.3% yield.
1 H NMR(400MHz,DMSO-d 6 )δ11.31(s,1H),8.17(s,1H),8.02(d,J＝1.8Hz,1H),7.96(t,J＝5.6Hz,1H),7.75(d,J＝15.8Hz,1H),7.49–7.23(m,6H),6.92(d,J＝9.8Hz,1H),6.72(d,J＝15.8Hz,1H),5.85(d,J＝9.8Hz,1H),3.51(s,2H),3.26–3.17(m,2H),2.86–2.71(m,2H),2.08–1.92(m,2H),1.72–1.58(m,2H),1.48(s,6H),1.45–1.40(m,2H),1.38(s,10H),1.27–1.05(m,2H).
13 C NMR(100MHz,DMSO-d 6 )δ165.7,149.3,141.8,138.4,137.8,136.1,134.4,133.2,130.7,129.3,129.2,128.4,126.9,122.8,122.6,119.6,118.7,117.5,117.4,115.7,115.4,110.3,104.4,76.4,59.0,53.4,36.9,36.2,34.9,34.4,32.7,31.8,27.4.
HRESIMS m/z＝610.31873[M+H] + (calcd for C 38 H 45 O 2 N 3 Cl,610.31948).
EXAMPLE 28 (E) -N- ((1- (2-methylbenzyl) piperidin-4-yl) ethyl) -3- (8-sh tert-butyl-3, 3-dimethyl-3, 11-dihydropyran [3,2-a ] carbazol-5-yl) acrylamide (28)
Compound 2 (100 mg,1 equiv), (1- (2-methylbenzyl) piperidin-4-yl) ethanamine (124 mg,2 equiv), EDCI, HOBt amounts and synthetic method are described in example 4. 95mg of product was obtained in 60.5% yield.
1 H NMR(400MHz,DMSO-d 6 )δ11.34(s,1H),8.17(s,1H),8.02(d,J＝1.8Hz,1H),7.96(t,J＝5.6Hz,1H),7.75(d,J＝15.7Hz,1H),7.40(dd,J＝8.6,1.8Hz,1H),7.35(d,J＝8.6Hz,1H),7.22–7.16(m,1H),7.14–7.08(m,3H),6.93(d,J＝9.8Hz,1H),6.72(d,J＝15.7Hz,1H),5.85(d,J＝9.8Hz,1H),3.36(s,2H),3.26–3.17(m,2H),2.81–2.71(m,2H),2.29(s,3H),1.96–1.86(m,2H),1.69–1.60(m,2H),1.48(s,6H),1.45–1.39(m,2H),1.39–1.37(m,10H),1.19–1.05(m,2H).
13 C NMR(100MHz,DMSO-d 6 )δ165.7,149.3,141.8,138.4,137.8,136.9,136.8,134.4,130.0,129.4,129.3,126.7,125.3,122.8,122.6,119.6,118.7,117.5,117.4,115.7,115.4,110.3,104.4,76.5,60.6,53.5,36.3,36.1,34.4,32.9,32.0,31.8,27.4,18.8.HRESIMS m/z＝590.37402[M+H] + (calcd for C 39 H 48 O 2 N 3 ,590.37410).
Pharmacological experiments
Experimental example 1 protective Activity of Compounds against oxygen glucose deprivation damaged primary neurons
The method comprises the following steps: taking Wistar rat mammary rat cortical neuron within 12 hours of birth, and regulating cell concentration to 2×10 with growth medium 5 Per mL, to 96-well plates pre-coated (18-24 h) with 0.1mg/mL polylysine. The positive tool Dizocilpine (10. Mu. Mol/L), PHPB (10. Mu. Mol/L), and the screening compound (10. Mu. Mol/L) were incubated with primary neurons for 1 hour, respectively. Discarding normal culture medium, adding low sugarThe culture medium is put into a three-gas incubator for 3.5 hours. (three gas culture device: carbon dioxide partial pressure 5%, oxygen 1%, nitrogen 94%), discarding low sugar medium, replacing normal medium, placing into normal incubator, reoxygenation for 20h, and detecting cell survival rate by CCK-8 method at 450 nm.
The screening results of primary neuronal protection against oxygen glucose deprivation injury by compounds 2, 17, 18, 20, 21, 22, 25, 26, 27, 29, positive control drug Potassium Hydroxypentylbenzoate (PHPB), dezocilpine (diazocilpine) are shown in table 1. As shown in table 1, compounds 2, 17, 18, 20, 21, 22, 25, 26, 27, 29 all increased neuronal survival to varying degrees at 10 μm concentrations for neuronal damage caused by oxygen glucose deprivation. Among them, compounds 2, 18, 20, 21, 22, 29 were significantly different from the model group ratios.
Protective Activity of the compounds of Table 1 against oxygen-glucose deprived damaged primary neurons
Experimental example 2 inhibitory Activity of Compounds against acetylcholinesterase
The method comprises the following steps: AChE activity detection kit (A024-1-1) was used for acetylcholinesterase (AChE) activity detection, and was purchased from Nanjing build company. AChE belongs to serine hydrolases and is widely found in various animal tissues and serum. AChE can catalyze the hydrolysis of acetylcholine, playing an important role in the mediation of nerve conduction. AChE catalyzes the hydrolysis of acetylcholine to choline, which reacts with dithio-p-nitrobenzoic acid (DTNB) to 5-mercapto-nitrobenzoic acid (TNB); TNB has an absorption peak at 412nm, and AChE activity is calculated by measuring the rate of increase in absorbance at 412 nm.
The specific detection scheme is as follows: AChE (AChE, E.C.3.1.1.7, from electric eel) standards, purchased from Sigma-Aldrich, were prepared as standard solutions (0.22U/mL prepared in 50mM Tris-HCl, pH=8.0, 0.1% w/v, BSA). 50. Mu.L of the above standard solution was mixed with 10. Mu.L of test compounds of different concentrations (0, 20. Mu.M, 40. Mu.M, 60. Mu.M, 80. Mu.M, 100. Mu.M) and sampled for detection. Sample pair AChEInhibition activity can be assessed by the Ellman's method. Enzyme IC 50 Values were analyzed by nonlinear regression of response concentration (log) curves using the Graph-Pad Prism program package (Graph Pad Software; san Diego, calif.). Each test sample was tested three times and the results are expressed as mean ± SEM.
The inhibition of AchE by compound 9 to 15, 19 to 26, 28 and the positive control drug donepezil is shown in table 2. As shown in table 2, these compounds all inhibited AchE to varying degrees. Among them, the inhibition effect of the compounds 2, 19-25 is more remarkable.
Inhibitory Activity of the compounds of Table 2 against acetylcholinesterase
Experimental example 3 test of the scavenging ability of Compounds for hydroxyl radicals
Hydroxyl radicals are widely present in the body and are involved in a variety of pathological injury processes. Edaravone is a very good hydroxyl radical scavenger. The present experiment compares the hydroxyl radical scavenging ability of compound 2 with edaravone by electron spin resonance spectroscopy (ESR).
The method comprises the following steps: into two centrifuge tubes, 10. Mu.L of a 0.2M solution of 5, 5-dimethyl-1-pyrroline-N-oxide (DMPO), 40. Mu.L of a 0.1M solution of ferrous ion, 5. Mu.L of a 0.3% hydrogen peroxide solution and 5. Mu.L of a 0.1% glacial acetic acid buffer were added, respectively, and mixed uniformly. And then respectively adding 1mg of edaravone and 1mg of compound 2 into the two centrifuge tubes, vibrating uniformly and sucking into a sample tube. ESR signal was measured at room temperature. Test parameters: the power is 4.0mW, the central magnetic field intensity is 335.4mT, the scanning width is 10mT, the scanning time is 2min, the modulation amplitude is 0.2mT, and the response time is 0.3s.
The results show that the compound 2 can remove hydroxyl free radicals and has strong removal capacity of Yu Yida-ravone (figure 1).

Claims (5)

1. Pyranocarbazole alkaloid compounds represented by general formula I or pharmaceutically acceptable salts thereof:
R 1 、R 2 independently of each other, each independently selected from H, CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH 2 CH 2 CH 3 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、t-Bu、OCH 3 、OCH 2 CH 3 、OCH 2 CH 2 CH 3 、CF 3 、OCF 3 ；
R 3 Selected from H, CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH 2 CH 2 CH 3 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 。
2. A pyranocarbazole alkaloid compound represented by the general formula II:
R 1 、R 2 independently of each other, each independently selected from H, CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH 2 CH 2 CH 3 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、t-Bu、OCH 3 、OCH 2 CH 3 、OCH 2 CH 2 CH 3 、CF 3 、OCF 3 ；
R 3 Selected from H, CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH 2 CH 2 CH 3 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 ；
R 4 、R 5 、R 6 Independently of each other, each independently selected from H, CH 3 、CH 2 CH 3 、CH 2 CH 2 CH 3 、CH(CH 3 ) 2 、CH 2 CH 2 CH 2 CH 3 、CH 2 CH(CH 3 ) 2 、CH(CH 3 )CH 2 CH 3 、t-Bu、OCH 3 、OCH 2 CH 3 、OCH 2 CH 2 CH 3 、CF 3 、OCF 3 Halogen;
n＝0、1、2。
3. a pyranocarbazole alkaloid compound according to any of claims 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
4. a pharmaceutical composition comprising, as an active ingredient, a compound as set forth in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
5. Use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention and/or treatment of alzheimer's disease.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103172643A (en) * 2011-12-26 2013-06-26 中国医学科学院药物研究所 Carbazole alkaloids of clausena lansium and preparation method thereof and medical composition and use thereof
CN108239095A (en) * 2016-12-26 2018-07-03 中国医学科学院药物研究所 A kind of pyrans and carbazole alkaloid and preparation method thereof and its pharmaceutical composition and purposes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103172643A (en) * 2011-12-26 2013-06-26 中国医学科学院药物研究所 Carbazole alkaloids of clausena lansium and preparation method thereof and medical composition and use thereof
CN108239095A (en) * 2016-12-26 2018-07-03 中国医学科学院药物研究所 A kind of pyrans and carbazole alkaloid and preparation method thereof and its pharmaceutical composition and purposes

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