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Methods for synthesizing heterocycles and therapeutic use of the heterocycles for cancers

a technology of heterocycles and heterocyclic compounds, applied in the field of tetrahydroquinoline derivative synthesis, can solve the problems of no procedure available to synthesize 2-substituted tetrahydroquinoline derivatives, and achieve the effects of shortening the synthetic steps, high cost, and being environmentally friendly and practical

Inactive Publication Date: 2007-11-29
LI CHAO JUN +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This method provides a practical, environmentally friendly, and versatile route to tetrahydroquinoline derivatives, accessible in various structural forms, suitable for pharmaceutical and agrochemical synthesis, with reduced costs and enhanced safety.

Problems solved by technology

Unfortunately, none have been found and instead agents that target especially rapidly dividing cells (both tumor and normal) have been generally used.
No procedure was available to synthesize 2-substituted tetrahydroquinoline derivatives via a simple and direct coupling between an aniline derivative and a cyclic enol ether or a cyclic hemiacetal (or its equivalent).

Method used

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  • Methods for synthesizing heterocycles and therapeutic use of the heterocycles for cancers
  • Methods for synthesizing heterocycles and therapeutic use of the heterocycles for cancers
  • Methods for synthesizing heterocycles and therapeutic use of the heterocycles for cancers

Examples

Experimental program
Comparison scheme
Effect test

example 1

synthesis of 2,3,3a,4,5,9b-hexahydro-4-(3-hydroxypropyl)-8-phenylamino-furano[3,2-c]quinoline (Formula 3-2)

[0084] The mixture of 4-(N-phenylamino)-aniline (2 mmol), 2,3-dihrdrofuran (4 mmol) and indium chloride (0.2-0.4 mmol) in water was stirred at room temperature for 10 h. TLC showed the completion of the reaction. The reaction mixture was extracted with diethyl ether (3×20 ml) and drived over MgSO4. Removal of solvent and flash column chromatography on silica gel gave the 1,2,3,4-tetrahydroquinoline derivative 3-1 in 65% yield (cis / trans=86:14). IR (film): 3326, 2932, 1595, 1504, 1047 cm−1. 1HNMR and —13CNMR (DMSO-d6 / TMS): cis-isomer, 7.53 (s, 1H, NH), 7.08 (m, 2H, Ar—H), 6.85 (s, 1H, Ar—H), 6.76 (m, 3H, Ar—H), 6.58 (m, 2H, Ar—H), 5.09 (s, 1H, NH), 4.92 (d, 9b-H, J=8.0 Hz), 4.50 (t, 1H, OH, J=4.8 Hz), 3.60 (m, 2H), 3.30 (m, 2H), 3.23 (m, 1H), 2.48 (m, 1H), 1.35-1.85 (m, 6H). 146.77, 141.62, 133.52, 129.66, 123.36, 122.18, 121.69, 118.01, 115.69, 114.66, 75.75, 66.39, 61.52, 52....

example 2

Synthesis of 3,4,4a,5,6,10b-hexahydro-5-(4-hydroxybutyl)-9-phenylamino-2H-pyrano[3,2-c]quinoline (compound 3-1)

Procedure 1:

[0086] Via general procedure 1, the titled compound was prepared from 4-(N-phenylamino)-aniline (2 mmol), 3,4-dihydropyran (4 mmol) and indium chloride (0.2-0.4 mmol) in water at room temperature for 10 h. Yield: 87%. Trans / cis=53:47. IR (film): 3379, 2936, 1599, 1501, 1065 cm−1. 1HNMR and 13CNMR (DMSO-d6 / TMS): cis-isomer, 7.51 (s, 1H, Ar—H), 7.06 (m, 2H, Ar—H), 6.94 (d, 1H, Ar—H, J=2.0 Hz), 6.75 (m, 2H, Ar—H), 6.57 (m, 1H, Ar—H), 6.49 (d, 1H, Ar—H, J=3.2 Hz), 5.12 (s, 1H, NH), 4.90 (d, 10b-H, J=5.6 Hz), 4.43 (t, 1H, OH, J=4.8 Hz), 3.20-3.60 (m, 5H), 1.84 (m, 1H), 1.30-1.70 (m, 10H). 147.09, 141.62, 132.78, 129.64, 123.29, 121.88, 120.43, 117.78, 115.18, 114.43, 72.37, 61.43, 60.56, 54.20, 35.27, 33.45, 31.94, 25.76, 22.42, 18.26. trans-isomer, 7.43 (s, 1H, Ar—H), 7.06 (m, 2H, Ar—H), 6.81 (d, 1H, Ar—H, J=2.4 Hz), 6.75 (m, 2H, Ar—H), 6.57 (m, 1H, Ar—H), 6.51 (...

example 3

Synthesis of 2,3,3a,4,5,9b-hexahydro-4-(3-hydroxypropyl)-8-dimethylamino-furano[3,2-c]quinoline (compound 3-3)

[0088] Via the general procedure 1, compound 3-3 was prepared from 4-(N,N-dimethylamino)-aniline (2 mmol), 3,4-dihydropyran (4 mmol) and indium chloride (0.2-0.4 mmol) in water at room temperature for 5 h. Yield: 46%. Trans / cis=31:69. IR (film): 3329, 2935, 1511, 1451, 1064 cm−1. 1HNMR and 13CNMR (DMSO-d6 / TMS): cis-isomer, 6.59 (s, 1H, Ar—H), 6.51 (m, 2H, Ar—H), 4.90 (d, 9b-H, J=8.0 Hz), 4.76 (s, 1H, NH), 4.49 (t, 1H, OH, J=5.2 Hz), 3.58 (m, 2H), 3.30 (m, 1H), 3.14 (m, 1H), 2.67 (s, 6H, N—CH3), 2.50 (m, 1H), 1.95 (m, 1H), 1.30-1.85 (m, 5H). 144.21, 138.76, 123.35, 115.98, 115.79, 115.40, 76.15, 66.37, 61.54, 52.95, 42.62, 42.34, 31.05, 29.46, 24.26. trans-isomer, 6.60 (s, 1H, Ar—H), 6.51 (m, 2H, Ar—H), 5.08 (s, 1H, NH), 4.49 (t, 1H, OH, J=5.2 Hz), 4.33 (d, 9b-H, J=6.0 Hz), 3.74 (m, 1H), 3.58 (m, 2H), 3.30 (m, 2H), 2.68 (s, 6H, N—CH3), 2.05 (m, 1H), 1.30-1.85 (m, 5H). 143.65...

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Abstract

The present invention provides methods for synthesizing novel tetrahydroquinoline derivatives that are useful for cancer chemotherapy and anti-viral applications. The present invention provides compounds useful for cancer chemotherapy and methods for the preparation of these compounds. The present invention also includes cancer chemotherapy methods.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is based on and claims priority of our U.S. provisional application Ser. No. 60 / 324,392, filed 24 Sep. 2001, incorporated herein by reference in full.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [0002] This invention was made with partial government support under grant numbers CHE-9733256 from the National Science Foundation. The U.S. government has certain rights in this invention.REFERENCE TO A “MICROFICHE APPENDIX”[0003] Not applicable BACKGROUND OF THE INVENTION [0004] 1. Field of the Invention [0005] The invention relates to the synthesis of tetrahydroquinoline derivatives and their use in the treatment of various carcinomas. [0006] 2. General Background of the Invention [0007] U.S. Pat. No. 6,077,862, incorporated herein by reference, provides an excellent background for the cancer chemotherapeutic use of the this invention. [0008] Chemotherapeutic approaches are most effective to fight cancers ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/695A61P31/12C07D491/044A61K31/4743A61K31/4745A61K47/48C07D491/04
CPCC07D491/04A61K47/48169A61K47/56A61P31/12
Inventor LI, CHAO-JUNZHANG, JIANHENG
Owner LI CHAO JUN