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Beta-substituted beta-amino acids and analogs as chemotherapeutic agents and uses thereof

A compound and hydrocarbon-based technology, applied in the direction of chemical instruments and methods, active ingredients of heterocyclic compounds, medical preparations containing active ingredients, etc., can solve the problem of not giving the composition, etc., and achieve the effect of high intake selectivity

Active Publication Date: 2018-05-11
QUADRIGA BIOSCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While the general concept of using LAT1 / 2Fhc-selective compounds to deliver therapeutics to tumors is understood, the prior art gives no guidance on how to prepare compositions utilizing LAT1 / 4F2hc-selective compounds

Method used

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  • Beta-substituted beta-amino acids and analogs as chemotherapeutic agents and uses thereof
  • Beta-substituted beta-amino acids and analogs as chemotherapeutic agents and uses thereof
  • Beta-substituted beta-amino acids and analogs as chemotherapeutic agents and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1457] 3-Amino-3-[5-[bis(2-chloroethyl)amino]-2-methyl-phenyl]propanoic acid (1)

[1458]

[1459] Step A: (2-Methyl-5-nitro-phenyl)methanol (1a)

[1460] Following the general procedure described in Description 1, borane dimethyl sulfide complex (2.0M BH 3 ·SMe 2 (2-Methyl-5-nitro-phenyl)methanol (1a) was prepared from commercially available 2-methyl-5-nitrobenzoic acid (50.0 g, 276 mmol) (166 mL, 332 mmol) to give 44.0 g (˜quantitative yield) of the target compound (1a) as a pale yellow solid of sufficient purity to be used directly in the next step without further isolation and purification. R f : ~0.50 (EtOAc / Hxn=1:1, v / v). 1 H NMR (300MHz, CDCl 3 ): δ8.30(d, J=2.4Hz, 1H), 8.05(dd, J=8.4, 2.4Hz, 1H), 7.31(d, J=8.1Hz, 1H), 4.78(d, J=5.1Hz , 2H), 2.41 (s, 3H), 1.87 (br.t, J=5.1Hz, 1H) ppm. The compounds are also commercially available.

[1461] Step B: 2-Methyl-5-nitro-benzaldehyde (1b)

[1462] Following the general procedure described in 2 (Variant A), dimethyl...

Embodiment 2

[1478] 3-Amino-3-[4-[bis(2-chloroethyl)amino]-2-methyl-phenyl]propanoic acid (2)

[1479]

[1480] Step A: (2-Methyl-4-nitro-phenyl)methanol (2a)

[1481] Following the general procedure described in Description 1, borane dimethyl sulfide complex (2.0M BH 3 ·SMe 2 THF) (27.6 mL, 55.2 mmol), (2-methyl-4-nitro-phenyl)methanol (2a ), affording 4.62 g (˜quantitative yield) of the target compound (1a) as a pale yellow solid of sufficient purity to be used directly in the next step without further isolation and purification. R f : ~0.50 (EtOAc / Hxn=1:1, v / v). 1 H NMR (300MHz, CDCl 3):δ8.07(dd,J=8.4,2.1Hz,1H),8.02(d,J=2.1Hz,1H),7.62(d,J=8.1Hz,1H),4.79(s,2H),2.38 (s, 3H), 1.87 (br.s, 1H) ppm. Spectral data are consistent with those presented in the literature. The compounds are also commercially available.

[1482] Step B: 2-Methyl-4-nitro-benzaldehyde (2b)

[1483] Following the general procedure described in 2 (Variant B), in manganese dioxide (MnO 2 2-Methyl-4-nitro-be...

Embodiment 3

[1497] 3-Amino-4-[5-[bis(2-chloroethyl)amino]-2-methyl-phenyl]butanoic acid (3)

[1498]

[1499] Step A: 2-(Bromomethyl)-1-methyl-4-nitro-benzene (3a)

[1500] According to the general procedure described in 10, by using phosphorus tribromide (PBr 3 ) (1.0M PBr in DCM 3 ) solution (65.8 mL) bromination of (2-methyl-5-nitro-phenyl)methanol (1a) (11.0 g, 65.8 mmol) dissolved in dichloromethane (DCM) (110 mL) (as in Example 1) to prepare 2-(bromomethyl)-1-methyl-4-nitro-benzene (3a). Aqueous workup afforded 11.3 g (75% yield) of a pale yellow solid (3a) of sufficient purity to be used directly in the next step without further isolation and purification. R f : ~0.56 (EtOAc / Hxn=1:5, v / v). 1 H NMR (300MHz, CDCl 3 ): δ8.19(d, J=2.4Hz, 1H), 8.07(dd, J=8.4, 2.7Hz, 1H), 7.36(d, J=8.7Hz, 1H), 4.53(s, 2H), 2.52 (s,2H)ppm. Spectral data are consistent with those presented in the literature. The compounds are also commercially available.

[1501] Step B: Diethyl 2-acetylamino-...

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Abstract

Beta-Substituted Beta-amino acids, Beta-substituted Beta-amino acid derivatives, and Beta-substituted Beta-amino acid analogs and (bio)isosteres and their use as chemotherapeutic agents are disclosed.The Beta-substituted Beta-amino acid derivatives and Beta -substituted Beta-amino acid analogs and (bio)isosteres are selective LAT1 / 4F2hc substrates and exhibit rapid uptake and retention in tumorsexpressing the LAT1 / 4F2hc transporter. Methods of synthesizing the Beta-substituted Beta-amino acid derivatives and Beta-substituted Beta-amino acid analogs and methods of using the compounds for treating cancer are also disclosed. The Beta-substituted Beta-amino acid derivatives and Beta-substituted Beta-amino acid analogs exhibit selective uptake in tumor cells expressing the LAT1 / 4F2hc transporter and accumulate in cancerous cells when administered to a subject in vivo. The Beta-substituted Beta-amino acid derivatives and Beta-substituted Beta-amino acid analogs and (bio)isosteres exhibit cytotoxicity toward several tumor types.

Description

[0001] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 62 / 200,541, filed August 3, 2015, which is hereby incorporated by reference in its entirety. technical field [0002] Disclosed herein are β-substituted β-amino acids, β-substituted β-amino acid derivatives and β-substituted β-amino acid analogs and their use as therapeutic agents. The β-substituted β-amino acid derivatives and β-substituted β-amino acid analogs are selective substrates of LAT1 / 4F2hc and exhibit rapid uptake and retention in tissues such as tumors expressing the LAT1 / 4F2hc transporter . Pharmaceutical compositions comprising β-substituted β-amino acid derivatives and β-substituted β-amino acid analogs and uses thereof are also disclosed. Background technique [0003] The ability to selectively target chemotherapy has enormous value in clinical practice. Malignant tumors are the leading cause of death in developed countries, where one in three people will ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/34C07C215/68C07C229/22C07C229/42C07C229/60C07C233/54C07C237/04C07C237/30C07C239/20C07C271/14C07C271/22C07C271/46C07C309/66C07D303/46C07F9/48A61K31/197A61K31/27A61K31/336A61K31/662A61P35/00
CPCA61K31/137A61K31/196A61K31/197A61K31/245A61K31/255A61K31/27A61K31/336A61K31/365A61K31/42A61K31/519A61K31/662A61P13/08A61P15/14A61P25/00A61P35/00A61P35/02C07B2200/07C07C215/68C07C229/22C07C229/34C07C229/42C07C229/60C07C233/54C07C237/04C07C237/30C07C239/20C07C271/14C07C271/22C07C271/46C07C291/04C07C309/69C07D303/36C07F9/4808A61K45/06C07D303/32
Inventor 伯恩德·简德雷特沃尔夫-尼古拉斯·菲舍尔凯瑞·J·科勒戈登·林戈尔德
Owner QUADRIGA BIOSCI
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