Inadone and tetralone compounds for inhibiting cell proliferation

• US 6,162,810 A
• Filed: 09/04/1998
• Issued: 12/19/2000
• Est. Priority Date: 11/17/1997
• Status: Expired due to Fees

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Cottam, Howard B., Leoni, Lorenzo, Shih, Hsien C., Carson, Dennis A.
• Primary Examiner(s): McKane, Joseph K.
• Assistant Examiner(s): Solola, Taofiq A.
• Application Number:
  US09/148,576
• Time in Patent Office: 837 Days
• Field of Search: 514/277, 514/465, 514/506, 514/532, 514/569, 549/440, 549/366, 546/348, 546/339, 546/346, 560/21, 560/100, 562/488, 562/490
• US Class Current: 514/277
• CPC Class Codes: C07C 205/45 the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
• CPC Class Codes: C07C 225/22 having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 251/44 with the carbon atom of at least one of the oxyimino groups being part of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 2602/08 the other ring being five-membered, e.g. indane
• CPC Class Codes: C07C 2602/10 the other ring being six-membered, e.g. tetraline
• CPC Class Codes: C07C 45/74 combined with dehydration
• CPC Class Codes: C07C 49/747 containing six-membered aromatic rings
• 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: C07D 213/50 Ketonic radicals
• CPC Class Codes: C07D 213/89 with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 317/70 condensed with ring systems containing two or more relevant rings
• CPC Class Codes: C07F 9/3882 Arylalkanephosphonic acids C07F9/3839 takes precedence

Abstract

A new family of inadone and tetralone tubulin-binding compounds (TBs) is disclosed. Unlike classical TBs, which inhibit mitosis among affected dividing cells, the TBs of the invention possess two unique properties: (1) they induce apoptosis among stationary phase (non-dividing) malignant cells, yet do not impair the viability of normal nonproliferating cells; and, (2) they affect cells which have acquired MDR more powerfully than they affect cells without MDR. Thus, the TBs of the invention provide means to target malignant cells for chemotherapy, even after previous therapies have failed, without affecting normal cells and tissues in the host.

Claims

1. A compound having the structural formula:

##STR9## wherein, A is (CH₂)_n, and n is 1 or 2;

R₁ and R₂ are each independently OR, lower alkoxy, halo, NO, NO₂, NH₂, acyl, acyloxy, acylamino, diacyl, carboxyacyl, amino-oxalyl, or together form --O--(CH₂)_a --O--, where a is 1, 2, or 3; and

R₁ may also be alkyl;

but R₁ and R₂ cannot both be OH; and

, where X₁, X₂ or X₃ is lower alkoxy, R₁ and R₂ cannot both be methyloxy;

Y₁ and Y₂ are each independently H, OH, NH₂, carboxyl or together form ═

O or ═

NOH;

X₂ and X₃ are each independently halo, lower alkyl, lower alkoxy, NO₂, acyl, acyloxy, aryl, heteroaryl, acylphosphonate, or together form --O--(CH₂)_b --O--, where b is 1, 2, or 3; and

,

X₁ is H, OH, lower alkyl, lower alkoxy, NH₂, acyl, acyloxy, aryl, heteroaryl, acylphosphonate, or X₁ may form --O--(CH₂)_b --O-- together with either X₂ or X₃, where b is 1, 2, or 3.

2. The compound of claim 1, wherein n is 1.

3. The compound of claim 2, wherein Y₁ and Y₂ together form ═

O.

4. The compound of claim 2, wherein R₁ and R₂ are each CH₃ O.

5. The compound of claim 4, wherein X₂ is 3-OCH₃ and X₃ is 5-OCH₃.

6. The compound of claim 3, wherein X₂ is 3-CH₃ and X₃ is 5-CH₃.

7. The compound of claim 3, wherein X₂ and X₃ are halo.

8. The compound of claim 7, wherein X₂ and X₃ are iodo, and X₁ is OH.

9. The compound of claim 7, wherein X₂ and X₃ are chloro.

10. The compound of claim 9, wherein X₁ is pyridin-4-yl.

11. The compound of claim 3, wherein X₂ and X₃ are CH₃.

12. The compound of claim 11, wherein X₁ is 4-phosphonoacetyl.

13. The compound of claim 2, wherein X₂ and X₃ are NO₂.

14. The compound of claim 2, wherein Y₁ is H and Y₂ is OH, NH, or carboxyl.

15. The compound of claim 14, wherein X₁ and X₂ are CH₃.

16. The compound of claim 1, wherein X₁ and X₂ are CH₃, and Y1 and Y₂ together form ═

O.

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

26. A method for inhibiting the growth of malignant cells in a host, comprising administering the compound of claim 1 to the host in a manner which will bring the compound into contact with the malignant cells.

27. A method for inhibiting the growth of malignant, multiple drug resistant (MDR) cells in a host, comprising administering the compound of claim 1 to the host in a manner which will bring the compound into contact with the malignant, MDR cells.

28. A method for inhibiting the growth of stationary phase malignant, multiple drug resistant (MDR) cells in a host, comprising administering the compound of claim 1 to the host in a manner which will bring the compound into contact with the stationary phase malignant, MDR cells.

35. A method for inhibiting the growth of virus-infected cells in a host, comprising administering the compound of claim 1 to the host in a manner which will bring the compound into contact with the virus-infected cells.

36. A method for inhibiting the growth of virus-infected, multiple drug resistant (MDR) cells in a host, comprising administering the compound of claim 1 to the host in a manner which will bring the compound into contact with the virus-infected, MDR cells.

41. The compound of claim 1, wherein X₁ is acylphosphonate.

17. A compound having the structural formula:

##STR10## wherein, A is (CH₂)n, and n is 1 or 2;

R₁ and R₂ are each independently, OH, lower alkoxy, halo, NO, NO₂, NH₂, acyl, acyloxy, acylamino, diacyl, carboxyacyl, amino-oxalyl, or together form --O--(CH₂)_a --O--, where a is 1, 2, or 3;

; and

R₁ may also be alkyl except that R₁ and R₂ cannot both be OH or methyloxy;

R₃ is H, NO₂, NH₂, acyloxy, carboxyacyl, or O--C--O--Z, where Z is O-aryl or --CO-carboxyacyl;

R₄ is H, acyl, acyloxy or carboxyacyl;

Y₁ and Y₂ are each independently H, OH, NH₂, carboxyl or together form ═

O or ═

NOH;

X₂ and X₃ are each halo, lower alkyl, lower alkoxy, NO₂, NH₂, acyl, acyloxy, aryl, heteroaryl, acylphosphonate, or together form --O--(CH₂)_b --O--, where b is 1, 2, or 3; and

,

X₁ is H, OH, lower alkyl, lower alkoxy, NO₂, NH₂, acyl, acyloxy, aryl, heteroaryl, acylphosphonate, or X₁ may form --O--(CH₂)_b --O-- together with either X₂ or X₃, where b is 1, 2, or 3.

18. The compound of claim 17, wherein A is CH₂ ;

R₁ is methyl;

Y₁ and Y₂ together form ═

O or ═

NOH;

X₂ and X₃ are methyl or methyloxy; and

X₁ is H, OH, or NH₂.

19. The compound of claim 17, wherein R₁ is methyl;

R₃ is H;

Y₁ and Y₂ together form ═

O;

X₂ and X₃ are each methyl; and

X₁ is H.

20. The compound of claim 17, wherein R₁ is methyl;

R₃ is H;

Y₁ and Y₂ together form ═

O;

X₂ and X₃ are methyl; and

X₁ is OH.

21. The compound of claim 18, wherein R₃ is NH₂.

22. The compound of claim 21, wherein X₁ is NH₂.

24. A pharmaceutical composition comprising the compound of claim 17 and a pharmaceutically acceptable carrier.

25. A pharmaceutical composition comprising the compound of any of claims 18, 19, 20, 21 or 22, together with a pharmaceutically acceptable carrier.

29. A method for inhibiting the growth of malignant cells in a host, comprising administering the compound of claim 17 to the host in a manner which will bring the compound into contact with the malignant cells.

30. A method for inhibiting the growth of malignant, multiple drug resistant (MDR) cells in a host, comprising administering the compound of claim 17 to the host in a manner which will bring the compound into contact with the malignant, MDR cells.

31. A method for inhibiting the growth of stationary phase malignant, multiple drug resistant (MDR) cells in a host, comprising administering the compound of claim 17 to the host in a manner which will bring the compound into contact with the stationary phase malignant, MDR cells.

32. A method for inhibiting the growth of malignant cells in a host, comprising administering the compound of any of claims 18, 19, 20, 21 or 22 to the host in a manner which will bring the compound into contact with the malignant cells.

33. A method for inhibiting the growth of malignant, multiple drug resistant (MDR) cells in a host, comprising administering the compound of any of claims 18, 19, 20, 21 or 22 to the host in a manner which will bring the compound into contact with the malignant, MDR cells.

34. A method for inhibiting the growth of stationary phase malignant, multiple drug resistant (MDR) cells in a host, comprising administering the compound of any of claims 18, 19, 20, 21 or 22 to the host in a manner which will bring the compound into contact with the stationary phase malignant, MDR cells.

37. A method for inhibiting the growth of virus-infected cells in a host, comprising administering the compound of claim 17 to the host in a manner which will bring the compound into contact with the virus-infected cells.

38. A method for inhibiting the growth of virus-infected, multiple drug resistant (MDR) cells in a host, comprising administering the compound of claim 17 to the host in a manner which will bring the compound into contact with the virus-infected, MDR cells.

39. A method for inhibiting the growth of virus-infected cells in a host, comprising administering the compound of any of claims 18, 19, 20, 21 or 22 to the host in a manner which will bring the compound into contact with the virus-infected cells.

40. A method for inhibiting The growth of virus-infected, multiple drug resistant (MDR) cells in a host, comprising administering the compound of any of claims 18, 19, 20, 21 or 22 to the host in a manner which will bring the compound into contact with the virus-infected, MDR cells.

42. The compound of claim 17, wherein X₁ is acylphosphonate.