Naphthalenyloxypropenyl derivatives having inhibitory activity against histone deacetylase and pharmaceutical composition comprising the same

• US 8,053,435 B2
• Filed: 11/01/2007
• Issued: 11/08/2011
• Est. Priority Date: 11/03/2006
• Status: Active Grant

• Current Assignee: CrystalGenomics, Inc., Korea Research Institute of Chemical Technology
• Original Assignee: CrystalGenomics, Inc., Korea Research Institute of Chemical Technology
• Inventors: Kim, Jae Hak, Jeong, Won Jang, Lee, Cheol Hae, Jung, Hee Jung, Ro, Seong Gu, Lee, Cheol Soon, Shin, Dongkyu, Cho, Joong Myung, Hyun, Young Lan
• Primary Examiner(s): Chu; Yong
• Assistant Examiner(s): BARKER, MICHAEL P
• Application Number:
  US12/513,021
• Publication Number:
  US 20100069630A1
• Time in Patent Office: 1,468 Days
• Field of Search: None
• US Class Current: 514/237.8
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 259/06 having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 259/10 having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2601/16 the ring being unsaturated
• CPC Class Codes: C07D 207/27 with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 207/335 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 211/10 with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 295/13 to an acyclic saturated chain
• CPC Class Codes: C07D 307/14 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/52 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 333/20 by nitrogen atoms nitro, nitroso radicals C07D333/12

Abstract

The present invention discloses novel naphthalenyloxypropenyl derivatives useful for inhibiting the enzyme activity of histone deacetylase, leading effective suppression of cancer cell proliferation.

Claims

1. A naphthalenyloxypropenyl derivative of formula (1) or its pharmaceutically acceptable salt:

2. The compound of claim 1, which is selected from the group consisting of:

(E)-4-(3-(1-methylpiperidin-4-ylamino)-2-((naphthalen-1-yloxy)methyl)-3-oxoprop-1-enyl)-N-hydroxybenzamide;

(E)-4-(3-(3-(1H-imidazol-1-yl)propylamino)-2-((naphthalen-1-yloxy)-methyl)-3-oxopropenyl)-N-hydroxybenzamide;

(E)-4-(3-(4-methoxyphenethylamino)-2-((naphthalen-1-yloxy)-methyl)-3-oxoprop-1-enyl)-N-hydroxybenzamide;

(E)-4-(3-(3-dimethylamino)-2,2-dimethylpropylamino)-2-((naphthalen-1-yloxy)methyl)-3-oxoprop-1-enyl)-N-hydroxybenzamide;

(E)-4-(3-(2-diisopropylamino)ethylamino)-2-((naphthalen-1-yloxy)-methyl)-3-oxoprop-1-enyl)-N-hydroxybenzamide;

(E)-4-(3-(1-methoxypropan-2-ylamino)-2-((naphthalen-1-yloxy)-methyl)-3-oxoprop-1-enyl)-N-hydroxybenzamide;

(E)-4-(3-(4-methoxybenzylamino)-2-((naphthalen-1-yloxy)methyl)-3-oxo-prop-1-enyl)-N-hydroxybenzamide;

(E)-4-(3-(4-fluorophenethylamino)-2-((naphthalen-1-yloxy)methyl)-3-oxo-prop-1-enyl)-N-hydroxybenzamide;

(E)-4-(3-(tetrahydrofuran-2-yl)methylamino)-2-((naphthalen-1-yloxy)-methyl)-3-oxoprop-1-enyl)-N-hydroxybenzamide;

(E)-4-(3-(2-cyclohexenylethylamino)-2-((naphthalen-1-yloxy)methyl)-3-oxoprop-1-enyl)-N-hydroxybenzamide;

(E)-4-(3-(3-(2-oxopyrrolidin-1-yl)propylamino)-2-((naphthalen-1-yloxy)-methyl)-3-oxoprop-1-enyl)-N-hydroxybenzamide;

(E)-4-(3-(furan-2-ylmethylamino)-2-((naphthalen-1-yloxy)methyl)-3-oxo-prop-1-enyl)-N-hydroxybenzamide;

(E)-4-(3-(4-(dimethylamino)benzylamino)-2-((naphthalen-1-yloxy)-methyl)-3-oxoprop-1-enyl)-N-hydroxybenzamide;

(E)-4-(3-(2-methoxyethylamino)-2-((naphthalen-1-yloxy)methyl)-3-oxo-prop-1-enyl)-N-hydroxybenzamide;

(E)-4-(3-(cyclohexylamino)-2-((naphthalen-1-yloxy)methyl)-3-oxoprop-1-enyl)-N-hydroxybenzamide;

(E)-4-(3-(thiophen-2-ylmethylamino)-2-((naphthalen-1-yloxy)methyl)-3-oxoprop-1-enyl)-N-hydroxybenzamide;

(E)-4-(3-(1-ethylpiperidin-4-ylamino)-2-((naphthalen-1-yloxy)methyl)-3-oxoprop-1-enyl)-N-hydroxybenzamide;

(E)-4-(3-(3-morpholinopropylamino)-2-((naphthalen-1-yloxy)methyl)-3-oxoprop-1-enyl)-N-hydroxybenzamide;

(E)-(3-(3-(2-methylpiperidin-1-yl)propylamino)-2-((naphthalen-1-yloxy)-methyl)-3-oxoprop-1-enyl)-N-hydroxybenzamide;

(E)-(3-(3-pyrrolidin-1-yl)propylamino)-2-((naphthalen-1-yloxy)methyl)-3-oxoprop-1-enyl)-N-hydroxybenzamide;

(E)-4-(3-(3-ethoxypropylamino)-2-((naphthalen-1-yloxy)methyl)-3-oxo-prop-1-enyl)-N-hydroxybenzamide;

(E)-4-(3-(2-(1-methylpyrrolidin-2-yl)ethylamino)-2-((naphthalen-1-yloxy)-methyl)-3-oxoprop-1-enyl)-N-hydroxybenzamide; and

(E)-4-(3-(1-isopropylpiperidin-4-ylamino)-2-((naphthalen-1-yloxy)methyl)-3-oxoprop-1-enyl)-N-hydroxybenzamide.

9. An anti-cancer composition comprising a naphthalenyloxypropenyl derivative of claim 1.

3. A naphthalenyloxypropenyl derivative of formula (2) or its pharmaceutically acceptable salt:

4. The compound of claim 3, which is selected from the group consisting of:

(E)-N1-(3-(1H-imidazol-1-yl)propyl)-N8-hydroxy-2-((naphthalen-1-yloxy)-methyl)octenediamide;

(E)-N8-hydroxy-N1-(4-hydroxyphenethyl)-2-((naphthalen-1-yloxy)methyl)-2-octenediamide;

(E)-N1-(3-(dimethylamino)-2,2-dimethylpropyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)octenediamide;

(E)-N1-(2-(diisopropylamino)ethyl)-N8-hydroxy-2-((naphthalen-1-yloxy)-methyl)octenediamide;

(E)-N8-hydroxy-N1-(1-methoxypropan-2-yl)-2-((naphthalen-1-yloxy)-methyl)-2-octenediamide;

(E)-N8-hydroxy-N1-(4-methoxybenzyl)-2-((naphthalen-1-yloxy)methyl)-2-octenediamide;

(E)-N1-(4-fluorophenethyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide;

(E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-(tetrahydrofuran-2-yl)-methyl)-2-octenediamide;

(E)-N1-(2-cyclohexenylethyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide;

(E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-(3-(2-oxopyrrolidin-1-yl)propyl)-2-octenediamide;

(E)-N1-(furan-2-ylmethyl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide

(E)-N1-(4-(dimethylamino)benzyl)-N8-hydroxy-2-((naphthalen-1-yloxy)-methyl)-2-octenediamide;

(E)-N8-hydroxy-N1-(2-methoxyethyl)-2-((naphthalen-1-yloxy)methyl)-2-octenediamide;

(E)-N1-cyclohexyl-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide;

(E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-(thiophen-2-ylmethyl)-2-octenediamide;

(E)-N8-hydroxy-N1-(4-methoxyphenethyl)-2-((naphthalen-1-yloxy)-methyl)-2-octenediamide;

(E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-(4-(trifluoromethoxy)-benzyl)-2-octenediamide;

(E)-N1-(1-cyclohexylmethyl)pyrrolidin-3-yl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide;

(E)-N1-(1-cyclopentylpiperidin-4-yl)-N8-hydroxy-2-((naphthalen-1-yloxy)-methyl)-2-octenediamide;

(E)-N1-(1-benzylpyrrolidin-3-yl)-N8-hydroxy-2-((naphthalen-1-yloxy)-methyl)-2-octene diamide;

(E)-N8-hydroxy-N1-(1-isopropylpyrrolidin-3-yl)-2-((naphthalen-1-yloxy)-methyl)-2-octenediamide;

(E)-N1-(1-(cyclohexanecarbonyl)pyrrolidin-3-yl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide;

t-butyl

(E)-3-(8-(hydroxyamino)-2-((naphthalen-1-yloxy)methyl)-8-oxo-2-octeneamido)pyrrolidine-1-carboxylate;

(E)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-N1-(pyrrolidin-3-yl)-2-octenediamide;

(E)-N1-(1-cyclohexylpyrrolidin-3-yl)-N8-hydroxy-2-((naphthalen-2-yloxy)-methyl)-2-octenediamide;

(E)-N1-(1-cyclopropylpyrrolidin-3-yl)-N8-hydroxy-2-((naphthalen-1-yloxy)methyl)-2-octenediamide;

(E)-N1-(1-cyclopropylpiperidin-4-yl)-N8-hydroxy-2-((naphthalen-1-yloxy)-methyl)-2-octenediamide;

(E)-N1-(1-ethylpiperidin-4-yl)-N8-hydroxy-2-((naphthalen-1-yloxy)-methyl)-2-octenediamide;

(E)-N1-(1-ethylpyrrolidin-3-yl)-N8-hydroxy-2-((naphthalen-1-yloxy)-methyl)-2-octenediamide; and

(E)-N8-hydroxy-N1-(1-isopropylpiperidin-4-yl)-2-((naphthalen-1-yloxy)-methyl)-2-octenediamide.

10. An anti-cancer composition comprising a naphthalenyloxypropenyl derivative of claim 3.

13. The compound of claim 3, wherein R′

₁ is a C_1-3alkyl substituted with diC1-3alkylamino group.

5. A naphthalenyloxypropenyl derivative of formula (3) or its pharmaceutically acceptable salt:

6. The compound of claim 5, which is selected from the group consisting of:

(Z)—

N-hydroxy-8-(2-morpholinoethylamino)-7-((naphthalen-1-yloxy)-methyl)oct-6-en-amide;

(Z)—

N-hydroxy-8-(1-methoxypropan-2-ylamino)-7-((naphthalen-1-yloxy)-methyl)oct-6-enamide;

(Z)—

N-hydroxy-8-(naphthalen-1-yloxy)-7-((3-(2-oxopyrrolidin-1-yl)propyl-amino)methyl)oct-6-enamide;

(Z)-8-(3-(1H-imidazol-1-yl)propylamino)-N-hydroxy-7-((naphthalen-1-yloxy)methyl)oct-6-enamide;

(Z)—

N-hydroxy-8-(3-(2-methylpiperidin-1-yl)propylamino)-7-((naphthalen-1-yloxy)methyl)oct-6-enamide;

(Z)-8-(3-(dimethylamino)propylamino)-N-hydroxy-7-((naphthalen-1-yloxy)methyl)oct-6-enamide;

(Z)-8-(3-(dimethylamino)-2,2-dimethylpropylamino)-N-hydroxy-7-((naphthalen-1-yloxy)methyl)oct-6-enamide;

(Z)—

N-hydroxy-8-(naphthalen-1-yloxy)-7-((2-(pyrrolidin-1-yl)ethylamino)-methyl)oct-6-enamide;

(Z)-8-(4-fluorophenethylamino)-N-hydroxy-7-((naphthalen-1-yloxy)-methyl)oct-6-enamide;

(Z)—

N-hydroxy-8-(2-methoxyethylamino)-7-((naphthalen-1-yloxy)methyl)-oct-6-enamide

(Z)—

N-hydroxy-8-(1-isopropylpiperidin-4-ylamino)-7-((naphthalen-1-yloxy)methyl)oct-6-enamide;

(Z)-8-(3-(diethylamino)propylamino)-N-hydroxy-7-((naphthalen-1-yloxy)-methyl)oct-6-enamide;

(Z)-8-(2-diisopropylamino)ethylamino))-N-hydroxy-7-((naphthalen-1-yloxy)methyl)oct-6-enamide; and

(Z)—

N-hydroxy-8-(naphthalen-1-yloxy)-7-(thiophen-2-ylmethylamino)-methyl)oct-6-enamide.

11. An anti-cancer composition comprising a naphthalenyloxypropenyl derivative of claim 5.

7. A naphthalenyloxypropenyl derivative of formula (4) or its pharmaceutically acceptable salt:

8. The compound of claim 7, which is selected from the group consisting of:

(Z)-4-(3-(1-ethylpiperidin-4-ylamino)-2-((naphthalen-1-yloxy)methyl)-prop-1-enyl)-N-hydroxybenzamide;

(Z)-4-(3-(1-ethylpyrrolidin-3-ylamino)-2-((naphthalen-1-yloxy)methyl)-prop-1-enyl)-N-hydroxybenzamide;

(Z)—

N-hydroxy-4-(3-(naphthalen-1-yloxy)-2-((4-(trifluoromethoxy)-benzylamino)methyl)prop-1-enyl)benzamide;

t-butyl

(Z)-3-(3-(4-(hydroxycarbamoyl)phenyl-2-((naphthalen-1-yloxy)-methyl)allylamino)pyrrolidine-1-carboxylate;

(Z)—

N-hydroxy-4-(3-(naphthalen-1-yloxy)-2-((pyrrolidin-3-ylamino)-methyl)prop-1-enyl)benzamide;

(Z)-4-(3-(1-(cyclohexylcarbonyl)pyrrolidin-3-ylamino)-2-((naphthalen-1-yloxy)methyl)prop-1-enyl)-N-hydroxybenzamide;

(Z)-4-(3-(1-cyclopentylpiperidin-4-ylamino)-2-((naphthalen-1-yloxy)-methyl)prop-1-enyl)-N-hydroxybenzamide;

(Z)-4-(3-(1-(cyclohexylmethyl)pyrrolidin-3-ylamino)-2-((naphthalen-1-yloxy)methyl)prop-1-enyl)-N-hydroxybenzamide;

(Z)-4-(3-(1-benzylpyrrolidin-3-yl-amino)-2-((naphthalen-1-yloxy)methyl)-prop-1-enyl)-N-hydroxybenzamide

(Z)-4-(3-(1-cyclopropylpiperidin-4-ylamino)-2-((naphthalen-1-yloxy)-methyl)prop-1-enyl)-N-hydroxybenzamide;

(Z)-4-(3-(1-cyclopropylpyrrolidin-3-ylamino)-2-((naphthalen-1-yloxy)-methyl)prop-1-enyl)-N-hydroxybenzamide;

(Z)-4-(3-(1-cyclohexylpyrrolidin-3-ylamino)-2-((naphthalen-1-yloxy)-methyl)prop-1-enyl)-N-hydroxybenzamide;

(Z)—

N-hydroxy-4-(3-(1-methoxypropan-2-ylamino)-2-((naphthalen-1-yloxy)methyl)prop-1-enyl)benzamide;

(Z)—

N-hydroxy-4-(3-(2-(1-methylpyrrolidin-2-yl)ethylamino)-2-((naphthalene-1-yloxy)methyl)prop-1-enyl)benzamide;

(Z)—

N-hydroxy-4-(3-(2-(1-isopropylpiperidin-4-ylamino)-2-((naphthalen-1-yloxy)methyl)prop-1-enyl)benzamide;

(Z)-4-(3-(3-(1H-imidazol-1-yl)propylamino)-2-((naphthalen-1-yloxy)-methyl)prop-1-enyl)-N-hydroxybenzamide;

(Z)—

N-hydroxy-4-(3-(4-hydroxyphenethylamino)-2-((naphthalen-1-yloxy)-methyl)prop-1-enyl)benzamide;

(Z)-4-(3-(3-(dimethylamino)-2,2-dimethylpropylamino)-2-((naphthalen-1-yloxy)methyl)prop-1-enyl)-N-hydroxybenzamide;

(Z)-4-(3-(2-(diisopropylamino)ethylamino)-2-((naphthalen-1-yloxy)-methyl)prop-1-enyl)-N-hydroxybenzamide;

(Z)—

N-hydroxy-4-(3-(2-methoxyethylamino)-2-((naphthalen-1-yloxy)-methyl)prop-1-enyl)benzamide;

(Z)-4-(3-(cyclohexylamino)-2-((naphthalen-1-yloxy)methyl)prop-1-enyl)-N-hydroxybenzamide;

(Z)—

N-hydroxy-4-(3-(naphthalen-1-yloxy)-2-((thiophen-2-ylmethylamino)-methyl)prop-1-enyl)benzamide;

(Z)—

N-hydroxy-4-(3-(4-methoxyphenethylamino)-2-((naphthalen-1-lyoxy)-methyl)prop-1-enyl)benzamide; and

(Z)-4-(3-(4-(dimethylamino)benzylamino))-2-((naphthalen-1-yloxy)-methyl)prop-1-enyl)-N-hydroxybenzamide.

12. An anti-cancer composition comprising a naphthalenyloxypropenyl derivative of claim 7.