Combination therapy using signal transduction inhibitors with paclitaxel and other taxane analogs

• US 5,565,478 A
• Filed: 03/14/1994
• Issued: 10/15/1996
• Est. Priority Date: 03/14/1994
• Status: Expired due to Term

• Current Assignee: United States Department Of Health And Human Services
• Original Assignee: United States Department Of Health And Human Services
• Inventors: Liotta, Lance A., Reed, Eddie, Kohn, Elise C.
• Primary Examiner(s): Cintins, Marianne M.
• Assistant Examiner(s): Spivack, Phyllis G.
• Application Number:
  US08/212,612
• Time in Patent Office: 946 Days
• Field of Search: 514/359, 514/396, 514/449, 514/399, 514/255, 514/383, 514/8
• US Class Current: 514/359
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/415 1,2-Diazoles

Abstract

The present invention provides compositions and methods for the treatment of cancer in a subject wherein compounds of formula I defined herein in combination with paclitaxel or other modified taxane analogs provide enhanced anticancer effects over the effects achieved with the individual compounds.

Claims

1. A pharmaceutical composition comprising, an effective amount of a first compound having formula I:

space="preserve" listing-type="equation">Y--(CH.sub.2).sub.p --Ar.sup.11 --X--Ar.sup.12 (I)

wherein;

is an integer of from 0 to 4;

Ar¹¹ and Ar¹² are each aromatic moieties independently selected from the group consisting of phenyl, naphthyl, halo-substituted phenyl, halo-substituted naphthyl;

X is a linking moiety selected from the group consisting of O, S, SO₂, CO, CHCN, straight chain alkyl, alkoxy, and alkoxyalkyl; and

Y is a nitrogen-containing heterocyclic moiety of formula II;

##STR5## wherein;

A is a member selected from the group consisting of N and CH;

R¹ is a member selected from the group consisting of hydrogen, --CONH₂, --CONHR³, --CO2H, --CO₂ R³, and --SO₂ NH₂, R² is a member selected from the group consisting of hydrogen, --NHCOC₆ H₅, --NH₂, --NHR³, --NC(R³)₂, --NHCOR³, and --NHCHO; and

R³ is lower alkyl of from 1 to 6 carbon atoms, and an effective amount of a second compound selected from the group consisting of paclitaxel, motere, and modified taxane analogs in a pharmaceutically acceptable carrier.

2. A composition in accordance with claim 1 wherein said first compound is 5-amino-1-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)- 1,2,3-triazo-4-carboxamide.

3. A composition in accordance with claim 1 wherein said first compound is 5,amino-1-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)-1,2,3-triazole-4-carboxamide and said second compound is paclitaxel.

4. A composition in accordance with claim 1 further comprising an antimycotic imidazole selected from the group consisting of ketoconazole, fluconazole, itraconazole, econazole and miconazole.

5. A method for treating cancer in a subject, said cancer being selected from the group consisting of breast cancer, lung cancer, melanoma, and ovarian cancer, said method comprising:

(i) administering to said subject an effective amount of a compound of formula I;

space="preserve" listing-type="equation">Y--(CH.sub.2).sub.p --Ar.sup.11 --X--Ar.sup.12 (I)

wherein;

p is an integer of from 0 to 4;

Ar¹¹ and Ar¹² are each aromatic moieties independently selected from the group consisting of phenyl, naphthyl, halo-substituted phenyl, halo-substituted naphthyl;

X is a linking moiety selected from the group consisting of O, S, SO₂, CO, CHCN, straight chain alkyl, alkoxy, and alkoxyalkyl; and

Y is a nitrogen-containing heterocyclic moiety of formula II;

##STR6## wherein;

A is a member selected from the group consisting of N and CH;

R¹ is a member selected from the group consisting of hydrogen,

--CONH₂, --CONHR³, --CO₂ H, --CO₂ R³, and --SO₂ NH₂, R² is a member selected from the group consisting of hydrogen, --NHCOC₆ H₅, --NH₂, --NHR³, --N(R³)₂, --NHCOR³, and --NHCHO; and

R³ is lower alkyl of from 1 to 6 carbon atoms,

and

(ii) administering to said subject an effective amount of a second compound selected from the group consisting of paclitaxel, taxotere and modified taxane analogs.

6. A method in accordance with claim 5 wherein step (i) is carded out prior to step (ii).

7. A method in accordance with claim 5 wherein step (ii) is carried out prior to step (i).

8. A method in accordance with claim 5 wherein said effective amount of said compound of step (i) is from the range of from about 50 mg/m² to about 500 mg/m² of body surface area of said subject.

9. A method in accordance with claim 5 wherein said effective amount of said compound of step (i) is from the range of from about 50 mg/m² to about 500 mg/m² of body surface area of said subject and said effective amount of said compound of step (ii) is selected from the range of from about 75 mg/m² to about 300 mg/m² of body surface area of said subject.

10. A method in accordance with claim 5 wherein said subject is human.

11. A method in accordance with claim 5 wherein said subject is human, said compound of step (i) is 5-amino-1-(4-(4-chlorobenzoyl)-3,5-dichlorobenzyl)- 1,2,3-triazole-4-carboxamide and said compound of step (ii) is paclitaxel.

12. A method in accordance with claim 5 wherein said first compound is administered orally.

13. A method in accordance with claim 5 wherein said second compound is administered by intravenous injection.

14. A method in accordance with claim 5 wherein said compounds of steps (i) and (ii) are administered in combination with a compound selected from the group consisting of G-CSF, an antimycotic imidazole, and a mixture thereof.