Stilbene derivatives as anticancer agents

• US 5,430,062 A
• Filed: 06/23/1993
• Issued: 07/04/1995
• Est. Priority Date: 05/21/1992
• Status: Expired due to Term

• Current Assignee: Research Corporation Technologies
• Original Assignee: Research Corporation Technologies
• Inventors: Cushman, Mark S., Hamel, Ernest
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US08/081,755
• Time in Patent Office: 741 Days
• Field of Search: 556/445, 556/446, 564/221, 564/353, 564/354, 564/389, 564/443, 568/39, 568/62, 568/331, 568/465, 568/466, 514/630, 514/646, 514/651, 514/685, 514/713, 514/716, 514/720
• US Class Current: 514/646
• CPC Class Codes: C07C 205/35 having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 217/18 the six-membered aromatic ring or condensed ring system containing that ring being further substituted
• CPC Class Codes: C07C 217/58 with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
• CPC Class Codes: C07C 217/80 having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
• CPC Class Codes: C07C 217/84 the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
• CPC Class Codes: C07C 219/10 having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to an acyclic carbon atom of a carbon skeleton containing rings
• CPC Class Codes: C07C 233/25 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 235/34 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 235/56 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 251/16 containing six-membered aromatic rings
• CPC Class Codes: C07C 255/37 the carbon skeleton being further substituted by etherified hydroxy groups
• CPC Class Codes: C07C 2602/08 the other ring being five-membered, e.g. indane
• CPC Class Codes: C07C 323/18 having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
• CPC Class Codes: C07C 323/36 the sulfur atom of the sulfide group being further bound to an acyclic carbon atom
• CPC Class Codes: C07C 43/2055 containing more than one ether bond
• CPC Class Codes: C07C 43/215 having unsaturation outside the six-membered aromatic rings
• CPC Class Codes: C07C 43/225 containing halogen
• CPC Class Codes: C07C 43/23 containing hydroxy or O-metal groups
• CPC Class Codes: C07C 45/46 Friedel-Crafts reactions
• CPC Class Codes: C07C 45/71 being hydroxy groups
• CPC Class Codes: C07C 47/575 : containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 49/755 : a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
• CPC Class Codes: C07C 49/84 : containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 59/64 : containing six-membered aromatic rings
• CPC Class Codes: C07C 65/21 : containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 69/017 : Esters of hydroxy compounds having the esterified hydroxy group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 69/708 : Ethers
• CPC Class Codes: C07D 213/30 : Oxygen atoms
• CPC Class Codes: C07D 217/20 : with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
• CPC Class Codes: C07D 455/00 : Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
• CPC Class Codes: C07F 7/1804 : Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896

Abstract

The present invention relates to stilbene derivatives which possess utility as anti-cancer agents. The compounds can be used to treat cancers which are susceptible to treatment therewith, and can be utilized in a method of treating such cancers. Pharmaceutical compositions containing the compounds are disclosed. Three preferred compounds among those disclosed are (Z)-1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene, (Z)-1-(4-methylphenyl)-2-(3,4,5-trimethoxyphenyl)ethene, and 4-methyl-3'"'"',4'"'"',5'"'"'-trimethoxybenzylaniline hydrochloride.

Claims

1. A compound of the formula:

##STR27## and pharmaceutically acceptable salts thereof wherein X is a cis ethylene radical of the formula;

space="preserve" listing-type="equation">--(Y.sub.1)C═

C(Z.sub.1);

Y₁ and Z₁ are both hydrogen;

R₁, R₅, R₆ and R₈ are independently H, halo, amino, lower alkylamino, diloweralkylamino, mercapto, lower alkylthio, amino lower alkyl, lower alkanoyl, nitro, CF₃, amino lower alkoxy, lower alkylamino lower alkoxy, diloweralkylamino lower alkoxy,

R₂, R₃ and R₄ are lower alkoxy;

R₇ is lower alkoxy, amino, lower alkylamino, alkyl of 1-3 carbon atoms, diloweralkylamino, mercapto, lower alkylthio, amino lower alkyl, lower alkanoyl, nitro, CF₃, amino lower alkoxy, lower alkylamino lower alkoxy, and diloweralkylamino lower alkoxy.

2. The compound according to claim 1 wherein lower alkoxy is methoxy.

3. The compound according to claim 1 wherein R₅ is hydrogen or halo.

4. The compound according to claim 1 wherein R₁, R₆ and R₈ are hydrogen.

5. The compound according to claim 1 wherein R₁, R₆, R₈ are hydrogen and R₅ is hydrogen or halo.

6. The compound according to claim 1 wherein R₇ is lower alkoxy, lower alkyl, thio lower alkyl, mercapto, diloweralkylamino, amino or monoloweralkylamino.

7. The compound according to claim 1 wherein R₅ is halo or hydrogen, R₇ is lower alkoxy, lower alkyl, thio lower alkyl, mercapto, diloweralkylamino, amino, or monoloweralkylamino.

8. The compound according to claim 1 wherein R₇ is methoxy, ethoxy, propoxy, nitro, dimethylamino, methyl, isopropyl or t-butyl.

9. The compound according to claim 1 wherein R₅ is Cl or hydrogen and R₇ is methoxy, ethoxy, propoxy, nitro, dimethylamino, methyl, isopropyl or t-butyl.

10. The compound according to claim 1 having the formula:

##STR28## or pharmaceutically acceptable salts thereof wherein R₂, R₃ and R₄ are alkoxy containing 1-3 carbon atoms;

X is a cis ethylene radical of the formula;

space="preserve" listing-type="equation">--(Y.sub.1)C═

C(Z.sub.1);

Y₁ and Z₁ are both hydrogen;

R₁, R₆ and R₈ are hydrogen;

R₇ is alkoxy containing 1-3 carbon atoms;

amino, alkylamino containing 1-3 carbon atoms, dialkylamino containing 1-3 carbon atoms;

alkylthio containing 1-3 carbon atoms or mercapto and

R₅ is hydrogen or halo.

11. The compound according to claim 10 wherein R₅ is hydrogen and R₇ is alkoxy, amino, alkylamino, or dialkylamino.

12. The compound according to claim 10 wherein R₇ is methoxy, amino, methylamino or dimethylamino.

13. The compound according to claim 11 wherein R₇ is methoxy, amino, methylamino, or dimethylamino.

14. The compound according to claim 1 wherein the compound is (Z)-1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene.

15. The compound according to claim 1 wherein the compound is (Z)-1-(4-methoxy-2-chlorophenyl)-2-(3,4,5-trimethoxyphenyl)ethene, (Z)-1-(4-N,N-dimethylaminophenyl)-2-(3,4,5-trimethoxyphenyl)ethene, (Z)-1-(4-propoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene;

or (Z)-1-(4-thiomethylphenyl)-2-(3,4,5-trimethoxyphenyl)ethene.

16. The compound according to claim 1 wherein the compound is (Z)-1-(4-ethylphenyl)-2-(3,4,5-trimethoxyphenyl-ethene), (Z)-1-(4-methylphenyl)-2-(3,4,5-trimethoxyphenyl)ethene, or (Z)-1-(4-isopropylphenyl)-2-(3,4,5-trimethoxy-phenyl)ethene.

17. (E)-1-(4-N,N-dimethylamino)-2-(3,4,5-trimethoxyphenyl)ethene.

18. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the formula:

##STR29## and pharmaceutically acceptable salts thereof wherein X is a cis ethylene radical of the formula;

space="preserve" listing-type="equation">--(Y.sub.1)C═

C(Z.sub.1);

Y₁ and Z₁ are both hydrogen;

R₁, R₅, R₆ and R₈ are independently H, halo, amino, lower alkylamino, diloweralkylamino, mercapto, lower alkylthio, amino lower alkyl, lower alkanoyl, nitro, CF₃, amino lower alkoxy, lower alkylamino lower alkoxy, diloweralkylamino lower alkoxy,

R₂, R₃ and R₄ are lower alkoxy;

R₇ is lower alkoxy, amino, lower alkylamino, alkyl of 1-3 carbon atoms, diloweralkylamino, mercapto, lower alkylthio, amino lower alkyl, lower alkanoyl, nitro, CF₃, amino lower alkoxy, lower alkylamino lower alkoxy, and diloweralkylamino lower alkoxy; and

a pharmaceutical carrier therefor.

19. The pharmaceutical composition according to claim 18 wherein lower alkoxy is methoxy.

20. The pharmaceutical composition according to claim 18 wherein R₅ is hydrogen or halo.

21. The pharmaceutical composition according to claim 18 wherein R₁, R₆ and R₈ are hydrogen.

22. The pharmaceutical composition according to claim 18 wherein R₁, R₆, R₈ are hydrogen and R₅ is hydrogen or halo.

23. The pharmaceutical composition according to claim 18 wherein R₇ is lower alkoxy, lower alkyl, thio lower alkyl, mercapto, diloweralkylamino, amino or monoloweralkylamino.

24. The pharmaceutical composition according to claim 18 wherein R₅ is halo or hydrogen, R₇ is lower alkoxy, lower alkyl, thio lower alkyl, mercapto, diloweralkylamino, amino, or monoloweralkylamino.

25. The pharmaceutical composition according to claim 18 wherein R₇ is methoxy, ethoxy, propoxy, nitro, dimethylamino, methyl, isopropyl or t-butyl.

26. The pharmaceutical composition according to claim 18 wherein R₅ is Cl or hydrogen and R₇ is methoxy, ethoxy, propoxy, nitro, dimethylamino, methyl isopropyl or t-butyl.

27. The pharmaceutical composition according to claim 18 having the formula:

##STR30## or pharmaceutically acceptable salts thereof wherein R₂, R₃ and R₄ are alkoxy containing 1-3 carbon atoms;

X is a cis ethylene radical of the formula;

space="preserve" listing-type="equation">--(Y.sub.1)C═

C(Z.sub.1);

Y₁ and Z₁ are both hydrogen;

R₁, R₆ and R₈ are hydrogen;

R₇ is alkoxy containing 1-3 carbon atoms;

amino, alkylamino containing 1-3 carbon atoms, dialkylamino containing 1-3 carbon atoms;

alkylthio containing 1-3 carbon atoms or mercapto and

R₅ is hydrogen or halo; and

a pharmaceutical carrier therefor.

28. The pharmaceutical composition according to claim 27 wherein R₅ is hydrogen and R₇ is alkoxy, amino, alkylamino, or dialkylamino.

29. The pharmaceutical composition according to claim 27 wherein R₇ is methoxy, amino, methylamino or dimethylamino.

30. The pharmaceutical composition according to claim 27 wherein R₇ is methoxy, amino, methylamino, or dimethylamino.

31. The pharmaceutical composition according to claim 18 wherein the compound is (Z)-1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene.

32. The pharmaceutical composition according to claim 18 wherein the compound is (Z)-1-(4-methoxy-2-chlorophenyl)-2-(3,4,5-trimethoxyphenyl)ethene, (Z)-1-(4-N,N-dimethylaminophenyl)-2-(3,4,5-trimethoxyphenyl)ethene, (Z)-1-(4-propoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene;

or (Z)-1-(4-thiomethylphenyl)-2-(3,4,5-trimethoxyphenyl)ethene.

33. The pharmaceutical composition according to claim 18 wherein the compound is (Z)-1-(4-ethylphenyl)-2-(3,4,5-trimethoxyphenyl ethene), (Z)-1-(4-methylphenyl)-2-(3,4,5-trimethoxyphenyl)ethene or (Z)-1-(4-isopropylphenyl)-2-(3,4,5-trimethoxy-phenyl)ethene.

34. A pharmaceutical composition comprising a pharmaceutically effective amount of a (E)-1-(4-N,N-dimethylamino)-2-(3,4,5-trimethoxyphenyl)ethene and a pharmaceutical carrier therefor.