US 10,590,101 B2Granted

Benzo-N-hydroxy amide compounds having antitumor activity

AssigneeItalfarmaco S.p.A.

InventorsAndrea Stevenazzi, Giovanni Sandrone, Daniela Modena, Samuele Pietro Pozzi, Barbara Vergani, Maria Lattanzio, Paolo Mascagni, Christian Steinkühler, Gianluca Fossati

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Abstract

The present invention relates to new benzo-N-hydroxy amide compounds of formula (I) and pharmaceutically acceptable salts, isomers and prodrugs thereof, which show a significant inhibitory activity on the proliferation of tumor cells and specifically of cancer stem cells.

Claims10

Dependent claims

A compound of the formula (I)

or pharmaceutically acceptable salts, isomers, or prodrugs thereof,
wherein:
n is 0, 1 or 2;
A is a mono or di-carbocyclic residue, optionally partially or totally unsaturated, comprising carbon atoms and optionally one or more heteroatoms selected from N, S or O;
or
A is H;
R1 and R2 are independently selected from the group consisting of —H, —OH, —OMe, —CN, —NH2, —NO2, —Cl, —COOH, -halogen, —CF3, —N(Ra)2, linear or branched C1-C4 alkyl, aryl, arylalkyl, arylcarbonyl, alkoxy, aryloxy residue, sulphonylamino and —CH2N(CH2CH3)2;
provided that when A is H, R1 and R2 are absent:
Ra is a linear or branched C1-C3 alkyl residue;
X is C, CH, or N;
R3 and R4 are independently selected from the group consisting of —H, —OMe, —OPh, —NO2, —NMe2, —NH2, -halogen, —CF3, —N(Ra)2, linear or branched C1-C4 alkyl, aryl, arylalkyl, arylcarbonyl, alkoxy, aryloxy residue and sulphonylamino, or R3 and R4 together form a heteropentacyclic moiety comprising —(—OCH2O—).

8 more elements

A compound selected from the group consisting of:

(2S)-2-[[(E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-3-(4-methoxyphenyl)propanamide (1D);
(2S)-N-[4-(hydroxycarbamoyl)phenyl]-3-(4-methoxyphenyl)-2-[[(E)-3-phenylprop-2-enoyl]amino]propanamide (2D);
(2S)-2-[[(E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-3-phenyl-propanamide (4D);
(2S)-N-[4-(hydroxycarbamoyl)phenyl]-3-phenyl-2-[[(E)-3-phenylprop-2-enoyl]amino]propanamide (5D);
(2S)-2-[[(E)-3-(2,5-dimethoxyphenyl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-3-(4-hydroxyphenyl)propanamide (7D);
(E)-3-(2,5-dimethoxyphenyl)-N-[(1R)-2-[4-(hydroxycarbamoyl)anilino]-1-indan-2-yl-2-oxo-ethyl]prop-2-enamide (8D);
(2S)-2-[[(E)-3-(2,5-dimethoxyphenyl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-4-phenyl-butanamide (9D);
(2S)-2-[[(E)-3-(2,5-dimethoxyphenyl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-3-phenyl-propanamide (10D);
(2S)-2-[[(E)-3-(2,5-dimethoxyphenyl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-3-(2-naphthyl)propanamide (11D);
(E)-3-(2,5-dimethoxyphenyl)-N-[2-[4-(hydroxycarbamoyl)anilino]-2-oxo-ethyl]prop-2-enamide (12D);
(2S)-2-[[(E)-3-(2,5-dimethoxyphenyl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]propanamide (13D);
(2S)-2-[[(E)-3-(2,5-dimethoxyphenyl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-3-(3-quinolyl)propanamide (14D);
(2S)-2-[[(E)-3-(2,5-dimethoxyphenyl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-3-(3-pyridyl)propanamide (15D);
(2S)-2-[[(E)-3-(2,5-dimethoxyphenyl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-3-(4-nitrophenyl)propanamide (16D);
(2S)-2-[[(E)-3-(4-aminophenyl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-3-phenyl-propanamide (17D);
(2S)-3-(4-aminophenyl)-2-[[(E)-3-(2,5-dimethoxyphenyl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]propanamide (18D);
(2S)-3-(4-cyanophenyl)-2-[[(E)-3-(2,5-dimethoxyphenyl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]propanamide (19D);
(2S)-N-[4-(hydroxycarbamoyl)phenyl]-2-[[(E)-3-(4-nitrophenyl)prop-2-enoyl]amino]-3-phenyl-propanamide (20D);
(2S)-2-[[(E)-3-(2,5-dimethoxyphenyl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-3-(1H-imidazol-5-yl)propanamide (21D);
(2S)-2-[[(E)-3-(3,4-dimethoxyphenyl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-3-(3-pyridyl)propanamide (22D);
(2S)-2-[[(E)-3-(3,5-dimethoxyphenyl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-3-(3-pyridyl)propanamide (23D);
(2S)-2-[[(E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-3-(3-pyridyl)propanamide (24D);
(2S)-2-[[(E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]amino]-3-(benzothiophen-3-yl)-N-[4-(hydroxycarbamoyl)phenyl]propanamide (25D);
(2S)-2-[[(E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-3-thiazol-4-yl-propanamide (26D);
(2S)-2-[[(E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-4-phenyl-butanamide (27D);
(2S)-2-[[(E)-3-(3,4-dimethoxyphenyl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-3-phenyl-propanamide (28D);
(2S)-2-[[(E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]amino]-3-(4-cyanophenyl)-N-[4-(hydroxycarbamoyl)phenyl]propanamide (29D);
(2S)-2-[[(E)-3-(3,4-dimethoxyphenyl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-3-(1H-indol-3-yl)propanamide (30D);
(2S)-2-[[(E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-3-(1H-indol-3-yl)propanamide (31D);
(2S)-2-[[(E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-3-(4-nitrophenyl)propanamide (32D);
(2S)-2-[[(E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]amino]-3-(4-chlorophenyl)-N-[4-(hydroxycarbamoyl)phenyl]propanamide (33D);
(2S)-3-(4-aminophenyl)-2-[[(E)-3-(3,4-dimethoxyphenyl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]propanamide (34D);
(2S)-3-(4-aminophenyl)-2-[[(E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]propanamide (35D);
4-[(2S)-2-[[(E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]amino]-3-[4-(hydroxycarbamoyl)anilino]-3-oxo-propyl]benzoic acid (36D);
(2S)-2-[[(E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]amino]-3-(3,4-dichlorophenyl)-N-[4-(hydroxycarbamoyl)phenyl]propanamide (37D);
(2S)-N-[4-(hydroxycarbamoyl)phenyl]-3-(4-methoxyphenyl)-2-[[(E)-3-phenylprop-2-enoyl]amino]propanamide (38D);
(2S)-2-[[(E)-3-(4-dimethylaminophenyl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-3-phenyl-propanamide (39D);
(2S)-2-[[(E)-3-(4-dimethylaminophenyl)prop-2-enoyl]amino]-N-[4-(hydroxycarbamoyl)phenyl]-3-(4-methoxyphenyl)propanamide;
2,2,2-trifluoroacetic acid (40D);
(E)-N-[2-[[4-(hydroxycarbamoyl)phenyl]methylamino]-2-oxo-ethyl]-3-phenyl-prop-2-enamide (41D);
(E)-3-(1,3-benzodioxol-5-yl)-N-[2-[[4-(hydroxycarbamoyl)phenyl]methylamino]-2-oxo-ethyl]prop-2-enamide (43D);
(2 S)-3-[4-(diethylaminomethyl)phenyl]-N-[4-(hydroxycarbamoyl)phenyl]-2-[[(E)-3-phenylprop-2-enoyl]amino]propanamide;
2,2,2-trifluoroacetic acid (45D);
(2S)-2-[[(E)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl]amino]-3-[4-(diethylaminomethyl)phenyl]-N-[4-(hydroxycarbamoyl)phenyl]propanamide;
2,2,2-trifluoroacetic acid (46D);
(2S)-N-[4-(hydroxycarbamoyl)phenyl]-3-(2-naphthyl)-2-[[(E)-3-(6-phenoxy-3-pyridyl)prop-2-enoyl]amino]propanamide (47D).

43 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/315,576Filed 14 Jul 2017
Priority: IT 102016007460618 Jul 2016
Published: US 2019/0300496 A13 Oct 2019
Granted: 17 Mar 2020
Term ends: Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 317/60
With only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring: radicals…
A61P 35/00
Antineoplastic agents
A61P 35/04
Antineoplastic agents: specific for metastasis
C07C 259/10
Without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids: having carbon atoms of hydroxamic groups bound to…

Family

US 2019/0300496 A1Pre-grant publication · published 3 Oct 2019
US 10,590,101 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Facts

Application

16/315,576Filed 14 Jul 2017

Priority

IT 102016007460618 Jul 2016

Published

US 2019/0300496 A13 Oct 2019

Granted

17 Mar 2020

Term ends

Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 317/60
With only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring: radicals…
A61P 35/00
Antineoplastic agents
A61P 35/04
Antineoplastic agents: specific for metastasis
C07C 259/10
Without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids: having carbon atoms of hydroxamic groups bound to…