Carbazole sulfonamide derivative prodrug or medicinal salts thereof and preparation method and applications thereof

A technology of carbazole sulfonamide and medicinal salt, which is applied in the field of biopharmaceuticals and can solve problems such as complex chemical structure, neurotoxicity, and difficult chemical total synthesis

Active Publication Date: 2019-11-19
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, paclitaxel and vinblastine microtubule inhibitors occupy an important position in the treatment of tumor vascular blockade, but there are also the following disadvantages: macromolecular compounds derived from natural products have complex chemical structures, and it is difficult to carry out chemical total synthesis
Most paclitaxel and vinblastine antineoplastic drugs are the substrates of P-gp expressed by the multidrug resistance gene (MDR), which is prone to drug resistance of tumor chemotherapy, which is why these drugs are clinically used in tumor chemotherapy. main problem
These drugs commonly suffer from neurotoxicity, poor solubility, and low bioavailability

Method used

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  • Carbazole sulfonamide derivative prodrug or medicinal salts thereof and preparation method and applications thereof
  • Carbazole sulfonamide derivative prodrug or medicinal salts thereof and preparation method and applications thereof
  • Carbazole sulfonamide derivative prodrug or medicinal salts thereof and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] (S)-N-(2,6-dimethoxypyridin-3-yl)-2-(2-amino-3-(4-hydroxy)phenyl-propionylamino)-N-methyl-6 -Synthesis of carbazole sulfonamide hydrochloride (11a)

[0081] Step (1), synthesis of reaction intermediate product 10: under ice-bath conditions (eg -20°C to -10°C), N-Boc-AA (amino acid protected by N-terminal tert-butoxycarbonyl group) was dissolved in DMF, and 1 -Hydroxybenzotriazole (HOBt), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), stir and mix (generally 0.5h to 1h), add The reactant 9a is kept stirring for a period of time (for example, 0.5-2 hours, such as 1 hour) and then turned to room temperature until the reaction is complete (generally, the reaction can be completed in 4-10 hours). Add ethyl acetate to extract and wash with water at the same time, further wash the extracted product with saturated brine, then dry over anhydrous sodium sulfate, concentrate, and if necessary, further purify by column chromatography to obtain the product 10; ...

Embodiment 2

[0096] (S)-N-(2,6-dimethoxypyridin-3-yl)-2-(2-amino-3-(4-hydroxy)phenyl-propionylamino)-N-methyl-6 -Synthesis of carbazolesulfonamide trifluoroacetate (11b)

[0097] The synthetic process is referring to embodiment 1, and specific conditions are as follows:

[0098] Step (1): Synthesis of (S)-N-(2,6-dimethoxypyridin-3-yl)-2-(2-tert-butoxyamido-3-(4-hydroxy)phenyl-propane Amino)-N-methyl-6-carbazolesulfonamide (10a)

[0099]

[0100] Reactant 9a (200mg, 0.485mmol), Boc-L-tyrosine (Boc-L-Try, 164mg, 0.582mmol), HOBt (78.6mg, 0.582mmol), EDCI (139mg, 0.73mmol), dissolved in 10 mL of DMF, reacted for 6 h, and column chromatography (PE:EA=1:1) gave 311 mg of the product (10a).

[0101] Yield: 95%.

[0102] 1 H NMR (500MHz, DMSO-d 6 )δppm 10.26(s,1H),9.32(s,1H),9.19(s,1H),8.41(s,1H),8.17(d,J=8.4Hz,1H),8.07(s,1H),7.72 (s,2H),7.45(d,J=8.3Hz,1H),7.39(d,J=8.1Hz,1H),7.15(d,J=7.7Hz,2H),7.09(d,J=7.8Hz ,1H),6.69(d,J=7.9Hz,2H),6.32(d,J=8.3Hz,1H),4.33(s,1H),3.89(s,3H),3.75(s,3H),3....

Embodiment 3

[0110] Synthesis of N-(2,6-dimethoxypyridin-3-yl)-2-(2-amino-acetylamino)-N-methyl-6-carbazolesulfonamide·hydrochloride (11c)

[0111] The synthetic process is referring to embodiment 1, and specific conditions are as follows:

[0112] Step (1): Synthesis of N-(2,6-dimethoxypyridin-3-yl)-2-(2-tert-butoxyamido-acetylamino)-N-methyl-6-carbazolesulfonamide (10c)

[0113]

[0114] Reactant 9a (200mg, 0.485mmol), Boc-glycine (11mg, 0.582mmol), HOBt (79mg, 0.582mmol), EDCI (139mg, 0.727mmol) were dissolved in 10mLDMF, reacted for 6h, column chromatography (PE:EA =1:3) yielded 260 mg of product (10c).

[0115] Yield: 96.7%.

[0116] 1 H NMR (500MHz, DMSO-d 6 )δppm: 10.17(s, 1H), 9.29(s, 1H), 8.38(s, 1H), 8.14(d, J=8.3Hz, 1H), 8.09(s, 1H), 7.69(s, 2H), 7.41(d,J=8.3Hz,1H),7.33(s,1H),7.08(s,1H),6.29(d,J=7.9Hz,1H),3.86(s,3H),3.77(d,J =25.1Hz, 3H), 3.73(s, 3H), 3.43(s, 3H), 1.41(s, 9H).

[0117] 13 C NMR (101MHz, DMSO-d 6)δppm: 172.26, 143.02–142.82, 139.82–139.62, 127.89, 11...

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Abstract

The invention provides carbazole sulfonamide derivative prodrug or medicinal salts thereof and a preparation method and applications thereof. The carbazole sulfonamide derivative prodrug or medicinalsalts thereof has a structure of a general formula (I) shown in the description. In the formula (I), R-CO-NH- is connected to a 2 or 3 position of a carbazole ring, and the selection of the R satisfies the rules that the R-CO-NH- is an amide structure formed by a combination of an amino acid molecule with -NH- or the R is -(CH2)n-NR1. As a micromolecular tubulin inhibitor, the carbazole sulfonamide derivative prodrug or the medicinal salts thereof provided by the invention has a good anti-microtubule effect and has the advantages of strong antitumor activity, small toxic and side effects, highwater solubility and the like.

Description

technical field [0001] The invention relates to a carbazole sulfonamide derivative prodrug or a pharmaceutically acceptable salt thereof and a preparation method and application thereof, belonging to the technical field of biopharmaceuticals. Background technique [0002] Tumors need a functional vascular network to provide oxygen, nutrients, and remove metabolites in a timely manner. Although tumors can obtain some blood vessels by integrating with host blood vessels, they must also build their own vascular system by forming a new vascular network in order to continue to grow and develop. Solid tumors do not grow more than 1mm without the vasculature to provide oxygen and nutrients 3 . In view of its important role in the development of tumors, tumor blood vessels have become an important target for anti-tumor therapy. [0003] Therapeutic regimens targeting tumor vasculature use drugs that target the tumor vascular supply, rather than the traditional cytotoxic drugs that...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D401/14A61P35/00A61K31/4439A61K31/5377A61K31/496A61K31/4545
CPCA61P35/00C07D401/12C07D401/14
Inventor 胡来兴王晨曦白利平赵曦刘永华王天琦
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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