Modified chalcone compounds as antimitotic agents

• US 7,714,025 B2
• Filed: 05/03/2007
• Issued: 05/11/2010
• Est. Priority Date: 05/10/2006
• Status: Expired due to Fees

• Current Assignee: Arizona Biomedical Research Commission
• Original Assignee: Arizona Biomedical Research Commission
• Inventors: Rose, Seth D., Hartman, Rosemarie F.
• Primary Examiner(s): Andres; Janet L.
• Assistant Examiner(s): COVINGTON, RAYMOND K
• Application Number:
  US11/744,027
• Publication Number:
  US 20070265317A1
• Time in Patent Office: 1,104 Days
• Field of Search: 568/336, 568/327, 548/376.1, 514/629, 514/630, 514/676
• US Class Current: 514/629
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07C 327/32 having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 69/653 Acrylic acid esters; Methacrylic acid esters; Haloacrylic acid esters; Halomethacrylic acid esters
• CPC Class Codes: C07D 209/12 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 213/50 Ketonic radicals
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 307/46 Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
• CPC Class Codes: C07D 311/28 with aromatic rings attached in position 2 only

Abstract

Antimitotic agents comprising a modified chalcone or modified chalcone derivative are disclosed. The modified chalcone or modified chalcone derivative compounds are of the general formula CHAL-LIN—COV, wherein CHAL is a chalcone or chalcone derivative portion, LIN is an optional linker portion, and COV is a covalent bonding portion (e.g., an α,β-unsaturated thiol ester group). The modified chalcone or modified chalcone derivative compounds provide an improved method of interference with tubulin polymerization, for example by covalent (and essentially irreversible) bonding between tubulin and the covalent bonding portion, potentially resulting in a decrease in tumor size and/or disappearance of the cancer, to the benefit of cancer patients.

Claims

1. A compound represented by the formula

2. The compound of claim 1, or a pharmaceutically acceptable salt or ester thereof, wherein

R³ and R⁴ are hydrogen or

R³, R⁴, and the optional substituents of R¹ and R² are independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkynyl, (heterocycloalkyl)alkyl, (heterocycloalkyl)alkenyl, (heterocycloalkyl)alkynyl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, hydroxy, alkoxy, alkenoxy, alkynoxy, cycloalkoxy, heterocycloalkoxy, aryloxy, heteroaryloxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxy(cycloalkyl), hydroxy(heterocycloalkyl), hydroxy(aryl), hydroxy(heteroaryl), alkoxyalkyl, alkoxyalkenyl, alkoxyalkynyl, alkoxy(cycloalkyl), alkoxy(heterocycloalkyl), alkoxy(aryl), alkoxy(heteroaryl), alkenoxyalkyl, alkenoxyalkenyl, alkenoxyalkynyl, alkenoxy(cycloalkyl), alkenoxy(heterocycloalkyl), alkenoxy(aryl), alkenoxy(heteroaryl), alkynoxyalkyl, alkynoxyalkenyl, alkynoxyalkynyl, alkynoxy(cycloalkyl), alkynoxy(heterocycloalkyl), alkynoxy(aryl), alkynoxy(heteroaryl), cycloalkoxyalkyl, cycloalkoxyalkenyl, cycloalkoxyalkynyl, cycloalkoxy(cycloalkyl), cycloalkoxy(heterocycloalkyl), cycloalkoxy(aryl), cycloalkoxy(heteroaryl), heterocycloalkoxyalkyl, heterocycloalkoxyalkenyl, heterocycloalkoxyalkynyl, heterocycloalkoxy(cycloalkyl), heterocycloalkoxy(heterocycloalkyl), heterocycloalkoxy(aryl), heterocycloalkoxy(heteroaryl), aryloxyalkyl, aryloxyalkenyl, aryloxyalkynyl, aryloxy(cycloalkyl), aryloxy(heterocycloalkyl), aryloxy(aryl), aryloxy(heteroaryl), heteroaryloxyalkyl, heteroaryloxyalkenyl, heteroaryloxyalkynyl, heteroaryloxy(cycloalkyl), heteroaryloxy(heterocycloalkyl), heteroaryloxy(aryl), heteroaryloxy(heteroaryl), carbonyl, hydroxycarbonyl, hydroxycarbonylalkyl, hydroxycarbonylalkenyl, hydroxycarbonylalkynyl, hydroxycarbonyl(cycloalkyl), hydroxycarbonyl(heterocycloalkyl), hydroxycarbonyl(aryl), hydroxycarbonyl(heteroaryl), alkanoyl, alkenoyl, alkynoyl, cycloalkanoyl, heterocycloalkanoyl, aroyl, heteroaroyl, hydroxyalkanoyl, hydroxyalkenoyl, hydroxyalkynoyl, hydroxycycloalkanoyl, hydroxyheterocycloalkanoyl, hydroxyaroyl, hydroxyheteroaroyl, carbonyloxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, cycloalkanoyloxy, heterocycloalkanoyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, cycloalkoxycarbonyl, heterocycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, thiol, alkylthiol, alkenylthiol, alkynylthiol, thiolalkyl, thiolalkenyl, thiolalkynyl, amino, alkylamino, alkenylamino, alkynylamino, (cycloalkyl)amino, (heterocycloalkyl)amino, arylamino, (heteroaryl)amino, hydroxyamino, alkoxyamino, alkenoxyamino, alkynoxyamino, cycloalkoxyamino, heterocycloalkoxyamino, aryloxyamino, heteroaryloxyamino, aminocarbonyl, aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl, aminocarbonyl(cycloalkyl), aminocarbonyl(heterocycloalkyl), aminocarbonyl(aryl), aminocarbonyl(heteroaryl), halo, haloalkyl, haloalkenyl, haloalkynyl, halo(cycloalkyl), halo(heterocycloalkyl), halo(aryl), halo(heteroaryl), amido, alkylamido, alkenylamido, alkynylamido, (cycloalkyl)amido, (heterocycloalkyl)amido, arylamido,(heteroaryl)amido, hydroxyamido, alkoxyamido, alkenoxyamido, alkynoxyamido, cycloalkoxyamido, heterocycloalkoxyamido, aryloxyamido, and heteroaryloxyamido.

3. The compound of claim 2, or a pharmaceutically acceptable salt or ester thereof, wherein

R³ and R⁴ are hydrogen or

R³, R⁴, and the optional substituents of R¹ and R² are independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, aralkyl, heteroaralkyl, hydroxy, alkoxy, cycloalkoxy, aryloxy, hydroxycarbonyl, hydroxycarbonylalkyl, alkanoyl, alkanoyloxy, alkoxycarbonyl, thiol, alkylthiol, amino, halo, haloalkyl, amido, alkylamido, (cycloalkyl)amido, (heterocycloalkyl)amido, arylamido, and (heteroaryl)amido.

4. The compound of claim 3, or a pharmaceutically acceptable salt or ester thereof, wherein

R³ and R⁴ are hydrogen or R³, R⁴, and the optional substituents of R¹ and R² are independently alkyl, hydroxy, or alkoxy.

5. The compound of claim 1, or a pharmaceutically acceptable salt or ester thereof, wherein

R¹ and R² are independently selected from the group consisting of phenyl, naphthyl, pyridyl, furyl, thienyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, and isoindolyl.

6. The compound of claim 1, or a pharmaceutically acceptable salt or ester thereof, wherein

R⁵ is selected from the group consisting of -oxycarbonylalkyl-, -oxycarbonylalkenyl-, -oxycarbonylalkynyl-, -(secondary)aminocarbonylalkyl-, -(secondary)aminocarbonylalkenyl-, -(secondary)aminocarbonylalkynyl-, -(thiol)carbonylalkyl-, -(thiol)carbonylalkenyl-, -(thiol)carbonylalkynyl-, -oxy(thiocarbonyl)alkyl-, -oxy(thiocarbonyl)alkenyl-, -oxy(thiocarbonyl)alkynyl-, -(secondary)amino(thiocarbonyl)alkyl-, -(secondary)amino(thiocarbonyl)alkenyl-, -(secondary)amino(thiocarbonyl)alkynyl-, -(thiol)(thiocarbonyl)alkyl-, -(thiol)(thiocarbonyl)alkenyl-, -(thiol)(thiocarbonyl)alkynyl-, -oxyiminoalkyl-, -oxyiminoalkenyl-, -oxyiminoalkynyl-, -(secondary)aminoiminoalkyl-, -(secondary)aminoiminoalkenyl-, -(secondary)aminoiminoalkynyl-, -(thiol)iminoalkyl-, -(thiol)iminoalkenyl-, and -(thiol)iminoalkynyl-,

wherein alkyl, alkenyl, and alkynyl, independently have from 0 to about 20 carbon atoms, wherein

(i) one or more carbon atoms having one or more bound hydrogen atoms are optionally independently substituted with alkyl having 1-3 carbon atoms, alkenyl having 1-3 carbon atoms, alkynyl having 1-3 carbon atoms, hydroxy, or alkyoxy having 1-3 alkyl carbon atoms;

(ii) one or more carbon atoms having two or more bound hydrogen atoms are optionally independently substituted with ═

O, ═

S, or ═

NH; and

(iii) one or more methylene carbon atoms (—

CH₂—

) are optionally independently replaced by —

O—

, —

NH—

, or —

S—

.

7. The compound of claim 1, or a pharmaceutically acceptable salt or ester thereof, wherein

in R⁵, alkyl, alkenyl, alkynyl, and the alkyl, alkenyl, and alkynyl portions of alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylthiol, alkenylthiol, and alkynylthiol independently have from 0 to about 20 carbon atoms, wherein

(a) one or more carbon atoms having one or more bound hydrogen atoms are optionally substituted with methyl or ethyl radicals;

(b) one or more carbon atoms having two or more bound hydrogen atoms are optionally substituted with ═

O; and

(c) either (I) the carbon atom of the alkyl, alkenyl, or alkynyl portion of alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino, alkynylamino, alkylthiol, alkenylthiol, and alkynylthiol that is (i) adjacent to either R² or Y in Formula (1a′

), (ii) adjacent to either R¹ or Y in Formula (1b′

), (iii) adjacent to either Y or the carbon atom sharing a double bond with the carbon atom bonded to R⁴ in Formula (1c′

), or (iv) adjacent to either Y or the carbon atom bonded to R² in Formula (1d′

) or (II) the carbon atom of alkyl, alkenyl, or alkynyl, that is (i) adjacent to either R² or Y in Formula (1a′

), (ii) adjacent to either R¹ or Y in Formula (1b′

), (iii) adjacent to either Y or the carbon atom sharing a double bond with the carbon atom bonded to R⁴ in Formula (1c′

), or (iv) adjacent to either Y or the carbon atom bonded to R² in Formula (1d′

) or (c) both carbon atoms (I) and (II) are replaced by a divalent radical independently selected from —

O—

, —

NH—

, and —

S—

.

8. The compound of claim 1, or a pharmaceutically acceptable salt or ester thereof, wherein

Y is —

S—

, and Y′ and

Y″

are both ═

O.

9. The compound of claim 1, or a pharmaceutically acceptable salt or ester thereof, wherein

R¹ and R² are independently aryl pyridyl, furyl, thienyl, quinolinyl, isoquinolinyl, tetrahydroquinlinyl, tetrahydroisoquinolinyl, indolyl, or isoindolyl, optionally independently substituted at one or more substitutable ring positions with a radical selected from the group consisting of alkyl, hydroxy, and alkoxy;

R³, R⁴, R⁶, and R⁷ are hydrogen; and

R⁵ is -oxycarbonylmethyl-, -methoxycarbonylmethyl-, having methyl or methoxy carbon atoms optionally independently substituted with methyl; and

R⁸ is methyl.

10. The compound of claim 9, or a pharmaceutically acceptable salt or ester thereof, wherein

R¹ is aryl, optionally independently substituted at one or more substitutable ring positions with hydroxy or alkoxy;

and

R² is pyridyl, furyl, thienyl, quinolinyl, isoquinolinyl, tetrahydroquinlinyl, tetrahydroisoquinolinyl, indolyl, or isoindolyl, optionally independently substituted at one or more substitutable ring positions with hydroxy or alkoxy.

11. The compound of claim 10, or a pharmaceutically acceptable salt or ester thereof, wherein

R¹ is phenyl, optionally independently substituted at one or more substitutable ring positions with hydroxy or alkoxy;

and

R² is pyridyl, furyl, thienyl, quinolinyl, isoquinolinyl, tetrahydroquinlinyl, tetrahydroisoquinolinyl, indolyl, or isoindolyl.

12. The compound of claim 11 or a pharmaceutically acceptable salt or ester thereof, wherein

R¹ is phenyl, methoxyphenyl, dimethoxyphenyl, or trimethoxyphenyl, and

R² is furyl, pyridyl, or indolyl.

13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

14. A method of inhibiting the growth of a cancer cell in a patient, the method comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition of claim 13.

15. The method of claim 14, wherein the cancer cell is selected from the group consisting of breast, colon and colorectal, leukemia, pancreatic, central nervous system, non-small-cell lung, ovarian, prostate, melanoma, renal, fibrosarcoma, and urinary bladder cancer cells.

16. The method of claim 15, wherein the cancer cell is selected from the group consisting of breast, colon and colorectal, leukemia, pancreatic, central nervous system, non-small-cell lung, ovarian, and prostate cancer cells.

17. The method of claim 14, wherein the patient is a human.

18. A method of inhibiting the growth of a cancer cell in vitro, the method comprising contacting the cancer cell with a compound of claim 1.

19. The method of claim 18, wherein 50% growth inhibition of said cancer cells is achieved with a concentration of said compound (GI₅₀) of less than about 50 micromolar.

20. A method for the treatment of cancer in a patient, the method comprising administering to said patient a therapeutically effective amount of a pharmaceutical composition of claim 13.