CN117700419A - Nitric oxide donor carbazole derivatives and their use in the treatment of neoplastic diseases - Google Patents

Nitric oxide donor carbazole derivatives and their use in the treatment of neoplastic diseases Download PDF

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CN117700419A
CN117700419A CN202211106807.4A CN202211106807A CN117700419A CN 117700419 A CN117700419 A CN 117700419A CN 202211106807 A CN202211106807 A CN 202211106807A CN 117700419 A CN117700419 A CN 117700419A
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branched
substituents
pharmaceutically acceptable
acetone
och
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张东明
陈晓光
臧应达
来芳芳
李创军
马洁
陈欣怡
黄蕾
吴海杰
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Institute of Materia Medica of CAMS
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Abstract

The invention belongs to the fields of natural medicines and medicinal chemistry, and discloses a nitric oxide donor type pyranocarbazole alkaloid derivative, a preparation method thereof, a medicinal composition and application thereof. Specifically, the invention discloses carbazole alkaloids shown in general formulas I and II. The alkaloid is prepared by artificial synthesis, a pharmaceutical composition containing the alkaloid and application of the alkaloid in preparing medicines for treating tumor diseases.

Description

Nitric oxide donor carbazole derivatives and their use in the treatment of neoplastic diseases
Technical Field
The invention relates to the fields of natural medicines and pharmaceutical chemistry, in particular to a nitric oxide donor type pyranocarbazole alkaloid derivative. The invention also discloses a preparation method of the derivative, a pharmaceutical composition and application of the derivative in anti-tumor aspect.
Background
Carbazole is a tricyclic structure consisting of two six-membered benzene rings fused on both sides of a five-membered nitrogen-containing ring, and is present in large amounts in leaves, fruits, roots and bark of rutaceae plants. Carbazole rings are widely used as effective frameworks for drug discovery, and derivatives thereof can trigger various cancer cell death pathways, such as Ellipticine, celiptium and alectrinib are carbazole anticancer drugs approved for chemotherapy, which proves the potential of carbazole derivatives as candidate anticancer drugs. The prior researches of the inventor show that the introduction of the nitrogenous fragment at the 3 position of the pyranocarbazole can improve the anti-tumor activity of the pyranocarbazole alkaloid, such as the IC of the compound 3 on various tumor cells 50 The values are in the range of 1.16-4.96. Mu.M (KeLiu, YIngda Zang, biorg. Med. Chem. Lett.,2021, 33:127739), exhibiting good anti-tumor cytotoxic activity.
Nitric oxide has a dual role in anti-tumour, depending mainly on the concentration, time and site of action of nitric oxide generation. Sustained low concentrations of nitric oxide promote tumor cell growth, while high concentrations of nitric oxide exert antitumor activity by generating cytotoxicity. Furazan nitroxides as nitric oxide donors can release high concentrations of nitric oxide in vivo (Kerwin j.f., heller m., med. Res. Rev.,1994,14 (1): 23). The conjugate of nitric oxide donor and medicine often has the function of acting in synergy with the original medicine, so that the conjugate is more interesting in new medicine research.
In order to obtain a compound with better antitumor activity than the compound 3, a structure modification study of pyranocarbazole alkaloids is carried out. The invention discloses a furazan oxynitride nitric oxide donor type pyranocarbazole alkaloid derivative with medicinal value and pharmaceutically acceptable salts thereof, and no report on the compound is yet seen.
Disclosure of Invention
The invention solves the technical problem of providing a compound with a general formula I and a general formula II and application thereof, and pharmacological experiments show that the compound has obvious apoptosis effect on various tumor cells. Therefore, the general formula I and the general formula II can be used for preventing and/or treating tumor diseases.
In order to solve the technical problems of the invention, the invention provides the following technical scheme:
according to a first aspect of the present invention there is provided a compound of formula I:
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 ；
X is selected from substituted amine groups, wherein the substituents may be selected from linear or branched C 1-6 Alkyl 0, C 3-6 Cycloalkyl or substituents together with the N atom forming five-, six-or seven-membered hetero atoms containing 1-3 hetero atomsSaturated heterocycles, which may have substituents on the heterocycle, where the substituents on the heterocycle may be selected from-OH, -F, -Cl, br, -COOH, straight or branched C 1-6 Alkyl, C 3-6 Cycloalkyl, straight or branched C 1-6 Alkoxy, substituted or unsubstituted phenyl, wherein the substituents on the phenyl groups may be selected from-OH, -F, -Cl, br, -COOH, straight or branched C 1-6 Alkyl, -CHF 2 、-CF 3 、-CN、-NO 2 、-OCF 3 、-ONO 2 、-NH 2 Or C being linear or branched 1-6 An alkoxy group.
The first aspect of the present invention also provides a compound having the structure of formula II or a pharmaceutically acceptable salt thereof,
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 ；
X is selected from substituted amine groups, wherein the substituents may be selected from linear or branched C 1-6 Alkyl, C 3-6 Cycloalkyl or substituent and N atom together form a five-, six-or seven-membered saturated heterocyclic ring containing 1-3 hetero atoms, wherein the heterocyclic ring can have substituents, and the substituents on the heterocyclic ring can be selected from-OH, -F and-FCl, br, -COOH, straight or branched C 1-6 Alkyl, C 3-6 Cycloalkyl, straight or branched C 1-6 Alkoxy, substituted or unsubstituted phenyl, wherein the substituents on the phenyl groups may be selected from-OH, -F, -Cl, br, -COOH, straight or branched C 1-6 Alkyl, -CHF 2 、-CF 3 、-CN、-NO 2 、-OCF 3 、-ONO 2 、-NH 2 Or C being linear or branched 1-6 An alkoxy group.
The compound is selected from the group consisting of:
according to a second aspect of the present technical scheme, there is provided a method for preparing the compound according to the first aspect.
The compounds of the general formula I according to the invention can be prepared by the following processes:
wherein, condition a: reactant HXOH (X is as defined in claim 1), 30% NaOH, tetrahydrofuran as solvent, and reacting at normal temperature; condition b: the catalyst is EDCI, HOBt and the solvent is dichloromethane. Processes for the preparation of intermediate 1 and intermediate 2 are described in J.Med.chem.2011,54,3251-3259 and in molecular 2021,26,1303
The compounds of the invention of formula II can be prepared by the following method:
wherein condition a is as above; condition c: the reagent XH (X is selected from substituted amino, as above), the reducing agent is sodium borohydride acetate, the catalyst is acetic acid, the solvent is anhydrous tetrahydrofuran, and the temperature is room temperature.
According to a third aspect of the present invention, there is provided a pharmaceutical composition comprising, as an active ingredient, a compound of FN-1 to 7, CY-1 to 3, CY-5, CY-7 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
The application of the compounds described by FN-1-7, CY-1-3, CY-5 and CY-7 or pharmaceutically acceptable salts thereof in preparing medicines for preventing and/or treating tumor diseases.
In a further aspect the invention relates to pharmaceutical compositions comprising the compounds of the invention as active ingredient. 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 aspect or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prophylaxis and/or treatment of a neoplastic disease.
The compound or the pharmaceutically acceptable salt thereof can be applied to the pharmaceutical field, for example, in vivo pharmacodynamics experiments for preparing an anti-breast cancer medicament show that the compound FN-1 has remarkable anti-breast cancer activity and about 50.91 percent of tumor inhibition rate when the oral dosage of the compound FN-1 is 150 mg/kg. Preliminary oral acute toxicity experiments show that the half-Lethal Dose (LD) of the compound FN-1 of the invention 50 ) Greater than 2g/kg. The above results indicate that FN-1 is a highly safe compound having an anti-breast cancer activity.
Description of the drawings:
FIG. 1 is a photograph of tumor tissue of an in vivo activity test of compound FN-1 on EMT6 cells of breast cancer in mice
Detailed Description
Chemical experiments
Examples 1-7 can be synthesized according to the following scheme:
example 1 preparation (FN-1)
J-1 (25 mg,1.5 eq) was dissolved in 2ml of tetrahydrofuran, CZA-1 (96 mg,1 eq) was added successively, EDCI (98 mg,2 eq), HOBt (69 mg,2 eq), stirred overnight, quenched with water dropwise, extracted with ethyl acetate-water, and the ethyl acetate layer scraped (petroleum ether: acetone=2:1 spread). 87mg of yellow powder was obtained in 53.0% yield. 1 H NMR(500MHz,Acetone-d 6 )δ8.25(s,1H),8.09(dt,J＝26.1,11.7Hz,5H),7.82(t,J＝7.7Hz,1H),7.73(t,J＝7.8Hz,3H),7.43(d,J＝8.5Hz,1H),7.36(d,J＝8.5Hz,1H),6.92(dd,J＝16.9,12.7Hz,2H),5.85(d,J＝9.8Hz,1H),3.85(t,J＝5.5Hz,2H),1.53(s,6H),1.42(s,9H),1.29(s,1H). 13 C NMR(101MHz,Acetone)δ167.5,160.2,151.1,143.3,139.5,139.1,139.0,137.2,136.6,130.7,130.4,129.6,124.1,123.8,120.2,119.7,118.9,118.2,116.9,116.6,111.6,111.2,105.7,77.5,71.2,38.7,35.2,32.3,27.9.
HRESIMS m/z＝643.22[M+H] +
Example 2 preparation (FN-2)
J-1 (100 mg,1.5 eq) was dissolved in 3ml of tetrahydrofuran, CZA-1 (63 mg,1 eq), EDCI (64 mg,2 eq), HOBt (45 mg,2 eq) were added sequentially, stirred overnight, quenched with water, extracted with ethyl acetate-water, and the ethyl acetate layer scraped (petroleum ether: acetone=2:1 spread). 69mg of yellow powder was obtained in 62.7% yield. 1 H NMR(500MHz,Acetone-d 6 )δ8.22(s,1H),8.12(t,J＝7.7Hz,2H),8.07(t,J＝2.2Hz,1H),8.04(dd,J＝15.7,5.1Hz,1H),7.83(dt,J＝15.3,8.2Hz,1H),7.73(q,J＝7.6Hz,2H),7.42(dd,J＝8.6,2.0Hz,1H),7.35(d,J＝8.5Hz,1H),6.92(d,J＝9.8Hz,1H),6.84(dd,J＝15.7,4.0Hz,1H),5.84(d,J＝9.8Hz,1H),4.61–4.46(m,2H),2.81(s,1H),1.95(s,1H),1.53–1.46(m,7H),1.41(s,9H),1.39(d,J＝6.5Hz,2H),1.28(s,1H),1.19(s,1H). 13 C NMR(101MHz,Acetone)δ167.6,160.3,151.1,143.3,139.1,137.0,136.6,136.6,130.7,130.7,130.4,129.6,129.5,123.8,119.8,118.2,116.6,116.6,111.2,111.2,105.7,77.5,74.3,35.2,32.3,27.9,27.8,17.5.
HRESIMS m/z＝657.23[M+H] +
Example 3 preparation (FN-3)
J-3 (140 mg,2 eq) was dissolved in 3ml of tetrahydrofuran, CZA-1 (77 mg,1 eq), EDCI (79 mg,2 eq), HOBt (56 mg,2 eq) were added sequentially, stirred overnight, quenched with water, extracted with ethyl acetate-water, and the ethyl acetate layer scraped (petroleum ether: acetone=2:1 spread). 93mg of yellow powder was obtained in 64.6% yield. 1 H NMR(500MHz,Acetone-d 6 )δ8.13–8.05(m,4H),7.89(t,J＝7.5Hz,1H),7.77(t,J＝7.8Hz,2H),7.46–7.37(m,2H),7.36(d,J＝8.2Hz,1H),6.94(d,J＝9.8Hz,1H),5.85(d,J＝9.8Hz,1H),4.39(d,J＝6.1Hz,2H),2.78(s,2H),2.09(s,2H),1.52(s,6H),1.41(s,9H). 13 C NMR(101MHz,Acetone)δ166.3,160.2,151.0,143.3,139.6,139.5,139.2,139.1,138.9,136.7,130.8,130.2,129.4,124.3,123.8,120.3,119.0,118.9,118.3,117.4,116.7,116.1,111.4,111.2,111.1,105.7,105.6,77.4,75.8,36.7,35.2,32.3,27.9.
HRESIMS m/z＝697.27[M+H] +
Example 4 preparation (FN-4)
J-4 (140 mg,2 eq) was dissolved in 3ml of tetrahydrofuran, CZA-1 (81 mg,1 eq), EDCI (83 mg,2 eq), HOBt (58 mg,2 eq) were added in sequence, stirred overnight, quenched with water, extracted with ethyl acetate-water, and the ethyl acetate layer scraped (petroleum ether: acetone=2:1 spread). 91mg of yellow powder was obtained in 61.9% yield. 1 H NMR(500MHz,Acetone-d 6 )δ8.40(s,1H),8.16–8.03(m,5H),7.71(t,J＝7.8Hz,2H),7.43(d,J＝8.7Hz,1H),7.36(d,J＝8.5Hz,1H),7.22(d,J＝15.5Hz,1H),6.94(d,J＝9.8Hz,1H),5.86(d,J＝9.8Hz,1H),4.60(dt,J＝10.0,5.3Hz,2H),3.96(s,1H),3.84(q,J＝8.2Hz,1H),2.80(d,J＝16.8Hz,4H),2.09(s,2H),1.54(d,J＝6.6Hz,7H),1.41(s,11H). 13 C NMR(101MHz,Acetone)δ166.5,160.4,151.3,143.4,138.8,136.6,130.7,130.2,129.4,123.8,121.0,118.3,117.8,117.1,116.8,111.2,111.2,105.7,77.5,72.0,56.3,48.1,35.2,32.3,28.0,25.0.HRESIMS m/z＝683.25[M+H] +
Example 5 preparation (FN-5)
J-5 (260 mg,2 eq) was dissolved in 5ml of tetrahydrofuran, CZA-1 (150 mg,1 eq), EDCI (154 mg,2 eq), HOBt (108 mg,2 eq) were added in sequence, stirred overnight, quenched with water, extracted with ethyl acetate-water, and the ethyl acetate layer scraped (petroleum ether: acetone=2:1 spread). A yellow powder 183mg was obtained in 67.0% yield. 1 H NMR(500MHz,Acetone-d 6 )δ8.40(s,1H),8.15–8.04(m,4H),7.90(t,J＝7.6Hz,1H),7.77(t,J＝7.8Hz,2H),7.43(dd,J＝8.5,1.9Hz,1H),7.36(dd,J＝12.0,3.5Hz,2H),6.94(d,J＝9.7Hz,1H),5.86(d,J＝9.8Hz,1H),5.28(dt,J＝7.0,3.5Hz,1H),2.79(s,2H),2.09(s,2H),1.54(s,6H),1.42(s,9H). 13 C NMR(101MHz,Acetone)δ166.5,159.2,151.0,143.3,139.7,139.5,139.2,139.1,139.0,136.7,130.8,130.3,129.5,124.3,123.8,120.3,119.0,118.9,118.3,117.4,116.7,115.7,111.6,105.7,105.6,78.5,77.5,44.2,35.2,32.3,27.9.
HRESIMS m/z＝683.25[M+H] +
Example 6 preparation (FN-6)
J-6 (110 mg,2 eq) was dissolved in 3ml of tetrahydrofuran, CZA-1 (69 mg,1 eq), EDCI (71 mg,2 eq), HOBt (50 mg,2 eq) were added in sequence, stirred overnight, quenched with water, extracted with ethyl acetate-water, and the ethyl acetate layer scraped (petroleum ether: acetone=2:1 spread). 83mg of yellow powder was obtained in a yield of 68.6%. 1 H NMR(500MHz,Acetone-d 6 )δ8.25(s,1H),8.18–8.12(m,2H),8.09(dt,J＝6.8,3.7Hz,2H),7.88–7.80(m,1H),7.76(q,J＝7.7Hz,2H),7.45(dd,J＝8.5,2.0Hz,1H),7.38(d,J＝8.6Hz,1H),6.95(d,J＝9.8Hz,1H),6.87(dd,J＝15.7,4.0Hz,1H),5.87(d,J＝9.8Hz,1H),1.59–1.48(m,8H),1.44(s,12H). 13 C NMR(101MHz,Acetone)δ166.8,160.3,151.1,143.3,139.6,139.5,139.1,139.1,136.6,130.7,130.7,130.7,130.7,130.4,130.4,129.6,129.6,129.5,129.5,123.8,123.8,119.8,118.2,32.3,27.9,27.8.
HRESIMS m/z＝657.24[M+H] +
Example 7 preparation (FN-7)
J-7 (133 mg,2 eq) was dissolved in 3ml of tetrahydrofuran, CZA-1 (71 mg,1 eq), EDCI (72 mg,2 eq), HOBt (51 mg,2 eq) were added successively, stirred overnight, quenched with water, extracted with ethyl acetate-water, and the ethyl acetate layer scraped (petroleum ether: acetone=2:1 spread). 85mg of yellow powder was obtained in 63.0% yield. 1 H NMR(500MHz,Acetone-d 6 )δ8.40(d,J＝3.8Hz,1H),8.14–8.10(m,2H),8.09(dd,J＝14.9,4.4Hz,2H),8.00–7.92(m,1H),7.90(s,1H),7.78(dt,J＝12.0,5.7Hz,2H),7.72(dd,J＝8.5,4.1Hz,1H),7.55(dt,J＝11.9,5.8Hz,1H),7.44(s,2H),7.39–7.28(m,2H),6.97–6.91(m,1H),5.89–5.82(m,1H),4.65(q,J＝4.6Hz,2H),3.74(s,5H),2.96(q,J＝4.9Hz,2H),1.57–1.47(m,6H),1.46(s,1H),1.42(t,J＝5.5Hz,10H),1.32–1.27(m,1H),1.20(d,J＝3.7Hz,1H). 13 C NMR(101MHz,Acetone)δ166.4,160.3,151.0,143.3,139.5,139.3,139.0,139.0,136.7,130.8,130.3,129.4,128.0,125.2,124.2,123.8,120.2,120.1,118.9,118.3,117.3,116.7,115.7,111.2,110.3,105.6,77.4,70.2,56.8,35.2,32.3,27.9.
HRESIMS m/z＝712.28[M+H] +
Examples 8-12 can be synthesized according to the following scheme:
example 8 preparation (CY-1)
J-1 (25 mg,2 eq) was dissolved in 2ml of tetrahydrofuran, CZB (15 mg,1 eq) and AcOH (5. Mu.L, 2 eq) were added in sequence, stirred at normal temperature for 1h, naBH (OAc) was added 3 (19 mg,2 eq) was stirred overnight, quenched with dropwise water, extracted with ethyl acetate-water, and the ethyl acetate layer was scraped (acetone: petroleum ether=2:1). 19mg of yellow powder was obtained in 71.9% yield. 1 H NMR(700MHz,Acetone-d 6 )δ8.10–8.01(m,5H),7.79–7.71(m,3H),7.64–7.61(m,2H),7.40(dd,J＝8.4,1.9Hz,1H),7.36(d,J＝8.6Hz,1H),6.95(d,J＝9.8Hz,1H),5.80(d,J＝9.8Hz,1H),4.68(t,J＝5.3Hz,2H),4.16(s,2H),3.68(dt,J＝16.2,5.6Hz,2H),3.47(t,J＝5.5Hz,1H),3.31–3.25(m,2H),1.50(s,5H),1.47(d,J＝7.6Hz,2H),1.40(d,J＝1.7Hz,2·H),1.39(s,2H),1.38(s,6H),1.38(s,2H),1.37(d,J＝2.1Hz,1H). 13 C NMR(176MHz,Acetone)δ206.4,206.3,160.2,150.3,142.8,139.2,136.9,136.0,134.0,130.8,130.6,130.5,130.1,129.5,124.2,123.2,122.1,118.5,116.4,111.0,105.6,71.5,60.8,60.5,48.9,46.9,35.2,32.3.
HRESIMS m/z＝603.23[M+H] +
Example 9 preparation (CY-2)
J-2 (100 mg,2 eq) was dissolved in 3ml of tetrahydrofuran, CZB (56 mg,1 eq) and AcOH (19. Mu.L, 2 eq) were added in sequence, stirred at normal temperature for 1h, naBH (OAc) was added 3 (70 mg,2 eq) was stirred overnight, quenched with dropwise water, extracted with ethyl acetate-water, and the ethyl acetate layer was scraped (acetone: petroleum ether=2:1). 75mg of yellow powder was obtained in 72.8% yield. 1 H NMR(500MHz,Acetone-d 6 )δ8.06(d,J＝7.7Hz,4H),8.03(d,J＝3.6Hz,3H),7.94(s,2H),7.64–7.56(m,3H),7.35(d,J＝6.5Hz,2H),6.94(dd,J＝9.8,2.5Hz,2H),5.80(dt,J＝9.9,3.3Hz,2H),4.09(s,1H),4.03(s,1H),1.57–1.45(m,14H),1.43(d,J＝24.9Hz,9H),1.39(d,J＝6.6Hz,11H),1.36(dd,J＝6.6,3.1Hz,13H),1.20(s,8H),1.16(t,J＝6.7Hz,3H),0.96(d,J＝6.7Hz,1H),0.91–0.81(m,5H). 13 C NMR(151MHz,Acetone)δ138.7,136.0,134.1,130.4,129.8,129.7,129.5,128.6,127.0,124.5,116.5,112.1,111.1,35.7,32.4,32.0,28.0,27.8,25.7,24.3,23.4,14.4.
HRESIMS m/z＝617.24[M+H] +
Example 10 preparation (CY-3)
J-3 (140 mg,2 eq) was dissolved in 3ml of tetrahydrofuran, CZB (69 mg,1 eq) and AcOH (24. Mu.L, 2 eq) were added in sequence, stirred at normal temperature for 1h, naBH (OAc) was added 3 (87 mg,2 eq) was stirred overnight, quenched with dropwise water, extracted with ethyl acetate-water, and the ethyl acetate layer was scraped (acetone: petroleum ether=2:1). 82mg of yellow powder was obtained in 60.3% yield. 1 H NMR(500MHz,Acetone-d 6 )δ8.12–8.05(m,4H),7.84(t,J＝7.5Hz,1H),7.74(t,J＝7.7Hz,2H),7.44–7.33(m,2H),6.95(d,J＝9.8Hz,1H),5.82(d,J＝9.8Hz,1H),4.36(d,J＝6.7Hz,2H),3.45(d,J＝6.3Hz,1H),1.98(s,3H),1.51(s,6H),1.40(s,11H). 13 C NMR(151MHz,Acetone)δ150.6,143.2,137.3,135.9,135.8,130.9,130.8,130.4,130.2,129.5,128.4,127.0,126.6,125.2,125.2,124.1,117.8,116.5,112.4,110.9,107.8,78.4,77.7,66.4,60.9,60.1,56.1,55.6,55.3,37.7,36.4,35.3,32.7,32.0,28.5,23.4,14.4.
HRESIMS m/z＝657.27[M+H] +
Example 11 preparation (CY-5)
J-5 (260 mg,2 eq) was dissolved in 5ml of tetrahydrofuran, CZB (133 mg,1 eq) and AcOH (46. Mu.L, 2 eq) were added in sequence, stirred at normal temperature for 1h, naBH (OAc) was added 3 (169 mg,2 eq) was stirred overnight, quenched with dropwise water, extracted with ethyl acetate-water, and the ethyl acetate layer was scraped (acetone: petroleum ether=2:1). 152mg of yellow powder was obtained in 59.1% yield. 1 H NMR(500MHz,Acetone-d 6 )δ8.06(d,J＝7.0Hz,3H),8.01(s,1H),7.85(t,J＝7.6Hz,1H),7.71(t,J＝7.8Hz,2H),7.43–7.32(m,2H),6.94(d,J＝9.8Hz,1H),5.80(d,J＝9.8Hz,1H),5.02(s,1H),3.80(s,1H),2.14(s,2H),1.96(s,2H),1.50(s,6H),1.42(s,9H),1.20(s,1H). 13 C NMR(101MHz,Acetone)δ159.3,150.6,142.8,139.3,139.3,139.2,136.6,130.7,130.0,129.4,124.3,124.3,123.2,118.7,118.2,118.1,116.4,111.5,111.0,110.9,105.5,105.5,76.9,56.4,50.2,35.2,32.4,27.9.
HRESIMS m/z＝643.26[M+H] +
Example 12 preparation (CY-7)
J-7 (110 mg,2 eq) was dissolved in 3ml of tetrahydrofuran, CZB (61 mg,1 eq) and AcOH (21. Mu.L, 2 eq) were added in sequence, stirred at normal temperature for 1h, naBH (OAc) was added 3 (78 mg,2 eq) was stirred overnight, quenched with dropwise water, extracted with ethyl acetate-water, and the ethyl acetate layer scraped (acetone: petroleum ether=2:1). 68mg of yellow powder was obtained in 60.2% yield. 1 H NMR(500MHz,Acetone-d 6 )δ8.08(s,3H),8.03(d,J＝7.5Hz,2H),7.71(t,J＝7.5Hz,1H),7.64(t,J＝7.7Hz,2H),7.41(d,J＝10.0Hz,1H),7.36(d,J＝8.6Hz,1H),6.94(d,J＝9.8Hz,1H),5.81(d,J＝9.8Hz,1H),4.57(t,J＝5.2Hz,2H),1.97(s,3H),1.50(s,7H),1.41(s,11H). 13 CNMR(101MHz,Acetone)δ160.2,150.8,143.0,139.3,139.2,136.6,130.7,130.1,129.3,124.2,123.4,118.4,116.6,111.0,105.5,77.3,70.2,56.6,56.1,53.0,35.2,32.4,27.9.
HRESIMS m/z＝672.29[M+H] +
Pharmacological experiments
EXAMPLE 1 cytotoxic Activity test
1. Experimental materials: tetramethyl azoazole salt (MTT, manufactured by Serva company, prepared temporarily from fresh 1640 culture solution), H460 (human lung cancer cells), heLa (cervical cancer cells), MDA-MB-231 (human breast cancer cells), and BIORAD 550 type enzyme-labeled instrument.
2. Experimental method
(1) Cell culture: the cells were incubated at 37℃with 5% CO using RRMI1640 medium containing 10% bovine fetal serum, 100U/mL penicillin and 100mg/L 2 Subculturing in a saturated humidity incubator, and selecting logarithmic growth cycle cells for experiment.
(2) MTT method: taking logarithmic growth phase cells, digesting, fully blowing into single cell suspension, counting, and diluting to 1×10 4 cell/mL, 100. Mu.L/well in 96-well plates. Each sample was set at 4-5 concentration levels, and then 100. Mu.L of medium for samples of different concentration levels was added to the experimental wells, each concentration level being parallel to 3 wells. An equal volume of solvent was added to the control group. 96-well plates were placed at 37℃in 5% CO 2 After 96 hours of incubation in a saturated humidity incubator, the broth was discarded, fresh formulated serum-free medium containing 0.20mg/mL MTT was added to each well, and after further incubation at 37℃for 4 hours, centrifugation was performed to remove the supernatant. 150. Mu.L of DMSO was added to each well to dissolve formazan precipitate, and the mixture was allowed to stir for 5 minutes with a small amount of shaking to allow complete dissolution. The optical density at 570nm was measured on a BIORAD 550 type microplate reader. The tumor cell growth inhibition was calculated according to the following formula, and the drug concentration was plotted against the tumor cell growth inhibition to obtain a measurement curve, and the half Inhibition Concentration (IC) of the drug was read from the curve 50 ) Values.
Tumor cell growth inhibition (%) = (1-experimental well assay/control well assay) ×100%
3. Experimental results: as shown in table 1.
TABLE 1 tumor cytotoxic Activity
Example 2 FN-1 in vivo anti-tumor efficacy against mouse breast cancer EMT6
1. Experimental materials: test compound FN-1; paclitaxel (positive drug); BALB/c mice, 18-20g in body weight, SPF grade, female, provided by the institute of medical laboratory animals, national academy of medical science.
2. The experimental method comprises the following steps:
(1) The method comprises the following steps: the passaged EMT6 tumor strain is homogenized by a homogenizer, washed twice with sterile physiological saline, counted, and the cell concentration is adjusted to 1.26X10 with physiological saline 7 Per ml, 0.2ml of the cell suspension was inoculated in the right armpit of the mice. Animals were randomly grouped the next day after inoculation, 6 animals per group were dosed after weighing, the test compound was dosed 1 time per day, body weights were weighed after 14 consecutive days of dosing, animals were sacrificed, tumor tissue was removed and weighed. And finally, calculating the tumor inhibition rate, and evaluating the anti-tumor action intensity according to the tumor inhibition rate.
(2) Grouping: blank control, positive drug control (Taxol, administered once every three days) 24mg/kg (peritoneal cavity); FN-1 100mg/kg (lavage), FN-1 150mg/kg (lavage).
(3) The calculation method comprises the following steps:
relative tumor proliferation rate T/C (%): T/C% = T/c×100%. (T: tumor weight of treatment group; C: tumor weight of negative control group).
Tumor proliferation inhibition rate TGI (%): tgi= (1-T/C) ×100. (T: tumor weight of treatment group; C: tumor weight of negative control group).
3. Experimental results:
tumor weights were weighed for animals treated 14 days after dosing, and the effect of compounds on EMT6 in mice is shown in FIG. 1 and Table 2.
TABLE 2 growth inhibition of EMT6 subcutaneous allograft tumors by Compounds FN-1
1.TTEST, * P<0.05, ** P<0.01
NA-inapplicable
Example 3 FN-1 preliminary oral acute toxicity test
1. Experimental materials: test compound FN-1; a mouse weighing meter; a gastric lavage needle (12 gauge); ICR mice were male and female halves, 18-20g in weight, purchased from Beijing Fukang Biotech Co., ltd.
2. The experimental method comprises the following steps: compound FN-1 was dissolved in CMC-Na to prepare suspensions at a dose of 1g/kg, 2g/kg. After 1 time of divided gastric administration, the mice were observed for weight change and survival within 14 days.
3. Experimental results: during the observation period, the body weight of the mice did not change significantly, and no significant toxic reaction was seen. The survival rate reaches 100 percent. The compound has low toxicity and LD 50 ＞2g/kg。

Claims (5)

1. A compound having the structure of formula I or a pharmaceutically acceptable salt thereof,
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 ；
X is selected from substituted amine groups, wherein the substituents may be selected from linear or branched C 1-6 Alkyl, C 3-6 Cycloalkyl or substituents together with the N atom form a five-, six-or seven-membered saturated heterocyclic ring containing 1 to 3 heteroatoms, which may have substituents on the heterocyclic ring, where the substituents on the heterocyclic ring may be selected from-OH, -F, -Cl, br, -COOH, straight-chain or branched C 1-6 Alkyl, C 3-6 Cycloalkyl, straight or branched C 1-6 Alkoxy, substituted or unsubstituted phenyl, wherein the substituents on the phenyl groups may be selected from-OH, -F, -Cl, br, -COOH, straight or branched C 1-6 Alkyl, -CHF 2 、-CF 3 、-CN、-NO 2 、-OCF 3 、-ONO 2 、-NH 2 Or C being linear or branched 1-6 An alkoxy group.
2. A compound having the structure of formula II or a pharmaceutically acceptable salt thereof,
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 ；
X is selected from the group consisting of substitutionAmino groups, wherein the substituents may be selected from linear or branched C 1-6 Alkyl, C 3-6 Cycloalkyl or substituents together with the N atom form a five-, six-or seven-membered saturated heterocyclic ring containing 1 to 3 heteroatoms, which may have substituents on the heterocyclic ring, where the substituents on the heterocyclic ring may be selected from-OH, -F, -Cl, br, -COOH, straight-chain or branched C 1-6 Alkyl, C 3-6 Cycloalkyl, straight or branched C 1-6 Alkoxy, substituted or unsubstituted phenyl, wherein the substituents on the phenyl groups may be selected from-OH, -F, -Cl, br, -COOH, straight or branched C 1-6 Alkyl, -CHF 2 、-CF 3 、-CN、-NO 2 、-OCF 3 、-ONO 2 、-NH 2 Or C being linear or branched 1-6 An alkoxy group.
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 according to 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 1-3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of a neoplastic disease.
CN202211106807.4A 2022-09-13 2022-09-13 Nitric oxide donor carbazole derivatives and their use in the treatment of neoplastic diseases Pending CN117700419A (en)

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