Agents for potentiating the effects of antitumor agents and combating multiple drug resistance

• US 5,364,843 A
• Filed: 06/10/1992
• Issued: 11/15/1994
• Est. Priority Date: 06/19/1989
• Status: Expired due to Fees

• Current Assignee: Burroughs Wellcome and Co.
• Original Assignee: Burroughs Wellcome and Co.
• Inventors: King, Ann C.
• Primary Examiner(s): Nutter, Nathan M.
• Application Number:
  US07/895,925
• Time in Patent Office: 888 Days
• Field of Search: 514/15, 514/33, 514/35, 514/37, 514/43, 514/283, 514/352, 514/353, 514/357, 514/449, 514/656, 514/683
• US Class Current: 514/19.3
• 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 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: C07D 213/55 Acids; Esters
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 295/073 with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/096 with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/155 with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 313/12 [b,e]-condensed

Abstract

Potentiating agents which enhance the efficacy of antineoplastic agents are disclosed. The potentiating agents disclosed are piperazinyl benzyl compounds such as 1-[α-(4-Chlorophenyl)-3-methoxybenzyl]-4-allylpiperazine dihydrochloride.

Claims

1. A method of increasing the sensitivity of a tumor to an antineoplastic agent, which tumor is harbored in a subject and which tumor is resistant to said antineoplastic agent, comprising concurrently administering to said subject an antineoplastic agent and a potentiating agent, said potentiating agent selected from the class consisting of ##STR2## wherein:

R₁ is halogen;

R₂ is selected from the class consisting of hydrogen, halogen, C_1-4 alkoxy, --OCH₂ C₆ H₅, and --CH═

CHCO₂ R, wherein R is C_1-4 alkyl; and

R₃ is selected from the class consisting of C_1-4 alkyl, --CH₂ CH═

CH₂, and--CH₂ C₆ H₄ CH_3;

and the pharmaceutically acceptable salts thereof,

said potentiating agent being administered in an amount effective to increase the sensitivity of said tumor to said antineoplastic agent.

2. A method according to claim 1, wherein said antineoplastic agent is administered to said subject parenterally and said potentiating agent is administered to said subject parenterally.

3. A method according to claim 1, wherein said antineoplastic agent is selected from the class consisting of vinca alkaloids, epipodophyllotoxins, anthracycline antibiotics, actinomycin D, plicamycin, puromycin, gramicidin D, taxol, colchicine, cytochalasin B, emetine, maytansine, and amsacrine.

4. A method according to claim 1, wherein said tumor is an adenocarcinoma.

5. A method according to claim 1, wherein said compound is 1-(3-Bromo-4'"'"'-chlorobenzhydryl)-4-methylpiperazine dihydrochloride.

6. A method according to claim 1, wherein said compound is (E)-Ethyl 3-(4-chloro-α

-(4-methyl-l-piperazinyl)-benzyl)cinnamate dihydrochloride.

7. A method according to claim 1, wherein said compound is 1-(3-Benzyloxy-4'"'"'-chlorobenzhydryl)-4-methylpiperazine dihydrochloride.

8. A method according to claim 1, wherein said compound is 1-(3-Benzyloxy-4'"'"'-chlorobenzhydryl)-4-(3-methylbenzyl)piperazine dihydrochloride.

9. A method according to claim 1, wherein said compound is 1-(2-Bromo-4'"'"'-chlorobenzhydryl)-4-methylpiperazine dihydrochloride.

10. A method according to claim 1, wherein said compound is 1-(α

-(4-Bromophenyl)-3-methoxybenzyl)-4-methylpiperazine dihydrochloride.

11. A method according to claim 1, wherein said compound is 1-[α

-(4-Chlorophenyl)-3-methoxybenzyl]-4-allylpiperazine dihydrochloride.