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Lox inhibitors

A compound, selected technology, applied in the field of pathological compounds

Pending Publication Date: 2021-09-07
THE INST OF CANCER RES ROYAL CANCER HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this compound is not believed to have been used clinically since 1978

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[1032] Example 1: 2-((2-((1R,5S)-6-(4-ethoxyphenyl)-9,9-dimethyl-3,6-diazabicyclo[3.2.2] Nonan-3-yl)ethyl)sulfonyl)ethan-1-amine (HCl salt)

[1033]

[1034] Using GP3, with (1R,5S)-6-(4-ethoxyphenyl)-9,9-dimethyl-3,6-diazabicyclo[3.2.2]nonane (600mg, 2.19mmol ), the intermediate N-benzyl-2-((2-((1R,5S)-6-(4-ethoxyphenyl)-9,9-dimethyl-3,6-diazo Heterobicyclo[3.2.2]nonan-3-yl)ethyl)sulfonyl)ethan-1-amine as a colorless oil (569.2 mg, 52% yield for two steps). 1 H NMR (500MHz, DMSO-d 6 )δ7.33-7.27(m,4H),7.24-7.20(m,1H),6.78-6.74(m,2H),6.51-6.47(m,2H),3.89(q,J=7.0Hz,2H) ,3.69(s,2H),3.44-3.36(m,1H),3.33-3.21(m,5H),3.16-3.12(m,1H),3.10-3.04(m,1H),3.02-2.93(m, 2H), 2.90(t, J=6.5Hz, 2H), 2.84-2.79(m, 2H), 2.33-2.26(m, 1H), 2.21(dd, J=11.5, 6.0Hz, 2H), 1.78(d ,J=12.8Hz,1H),1.29-1.20(m,4H),1.11(s,3H),0.76(s,3H);C 28 h 42 N 3 o 3 S(M+H + ) HRMS calculated value 500.2947; measured 500.5716.

[1035] Debenzylation, purification by carbamate protection, flash chromatography (...

Embodiment 5

[1039] Example 5: 4-(4-((1R,5S)-3-(2-((2-aminoethyl)sulfonyl)ethyl)-9,9-dimethyl-3,6-diazo Heterobicyclo[3.2.2]nonan-6-yl)phenyl)thiomorpholine 1,1-dioxide (HCl salt)

[1040]

[1041] Using GP4 steps 1-3 with 2-bromoethanol (1.80 mL, 25.4 mmol), the intermediate tert-butyl (2-((2-bromoethyl)sulfonyl)ethyl)carbamate was obtained as Yellow solid (1.15 g, 38% yield over three steps). 1H NMR (500MHz, CDCl3) δ5.16(br s, 1H), 3.72-3.64(m, 4H), 3.55(dd, J=8.4 and 6.9Hz, 2H), 3.32(dd, J=6.9 and 5.1Hz ,2H), 1.46(s,9H).

[1042] Using GP4 steps 4-5 with 4-(4-((1R,5S)-9,9-dimethyl-3,6-diazabicyclo[3.2.2]nonan-6-yl)phenyl ) thiomorpholine 1,1-dioxide (130mg, 0.36mmol), obtained 4-(4-((1R,5S)-3-(2-((2-aminoethyl)sulfonyl)ethyl base)-9,9-dimethyl-3,6-diazabicyclo[3.2.2]nonan-6-yl)phenyl)thiomorpholine-1,1-dioxide (HCl salt) (49.3 mg, 23% yield over two steps). 1H NMR (500MHz, DMSO-d6)δ; C23H39N4O 4 HRMS calculated value of S2 (M+H+) 499.2413; found 499.2418.

Embodiment 6

[1043] Example 6: 2-((3-((1R,5S)-6-(4-ethoxyphenyl)-9,9-dimethyl-3,6-diazabicyclo[3.2.2] Nonan-3-yl)propyl)sulfonyl)ethan-1-amine (HCl salt)

[1044]

[1045] Using GP4 steps 1-3 with 3-bromopropanol (2.71 mL, 30 mmol), the intermediate tert-butyl (2-((3-bromopropyl)sulfonyl)ethyl)carbamate was obtained as yellow Solid (2.65 g, 27% over three steps). 1H NMR (500MHz, CDCl 3 )δ5.17(br s,1H),3.67(q,J=6.0Hz,2H),3.56(t,J=6.2Hz,2H),3.25(t,J=6.0Hz,2H),3.23-3.19 (m,2H), 2.46-2.40(m,2H), 1.46(s,9H).

[1046] Using GP4 steps 4-5 with (1R,5S)-6-(4-ethoxyphenyl)-9,9-dimethyl-3,6-diazabicyclo[3.2.2]nonane ( 83.1 mg, 0.30 mmol), 2-((3-((1R,5S)-6-(4-ethoxyphenyl)-9,9-dimethyl-3,6-diazabicyclo [3.2.2] Nonan-3-yl)propyl)sulfonyl)ethane-1-amine (HCl salt) (90.1 mg, 98% yield in two steps). 1 H NMR (500MHz, DMSO-d 6 )δ8.49,8.39(2br s,2H),6.85-6.79(m,2H),6.76-6.71(m,1H),6.65-6.61(m,1H),3.91(2q,J=7.0Hz,2H ),3.80-2.98(m,15H),2.60-2.47(m,1H),2.38-2.04(m,2H),1.76(d,J=14.4Hz,1H),1.64,1.45(2...

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PUM

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Abstract

The disclosure relates to compounds of Formula I, or pharmaceutically acceptable salts thereof, Formula (I) as defined herein. Compounds according to Formula I are pharmacologically effective as lysyl oxidase (LOX) inhibitors and are believed to be useful in the treatment of, for instance, cancer.

Description

technical field [0001] The present invention relates to compounds useful as inhibitors of lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) family members (LOXL1, LOXL2, LOXL3, LOXL4), pharmaceutical compositions comprising these compounds, for use in Compounds for use in the treatment of conditions mediated by LOX and / or LOXL, such as cancer; LOX inhibitors for use in the treatment of cancers associated with EGFR. Background technique [0002] LOX (protein-6-lysine oxidase; EC 1.4.3.13) is an extracellular enzyme that catalyzes the oxidative deamination of primary lysine and hydroxylysine in proteins such as collagen and tropoelastin. Ammonia, yielding peptidyl-[α]-aminoadipic acid-[δ]-semialdehyde, an aldehyde that condenses spontaneously to form interchain and intrachain crosslinks (Lucero and Kagan 2006). LOX regulates the maturation of proteins in the extracellular matrix (ECM), thereby contributing to the tensile strength and function of the ECM, and thus plays an imp...

Claims

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Application Information

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IPC IPC(8): C07D241/04C07D403/04C07D487/04C07D487/08C07D487/10A61P35/00A61K31/439
CPCC07D487/08C07D487/04C07D403/04C07D241/04C07D487/10A61P35/00C07D239/48C07D295/088C07D295/108C07D471/08
Inventor 穆罕默德·阿尔贾拉丹·尼库莱斯库-杜瓦兹利昂·梁黛博拉·史密森迈克尔·布朗劳伦斯·克里斯多夫·戴维斯卡洛琳·斯普林格
Owner THE INST OF CANCER RES ROYAL CANCER HOSPITAL
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