Combinations of drugs (e.g., a benzimidazole and pentamidine) for the treatment of neoplastic disorders

• US 20020165261A1
• Filed: 01/24/2001
• Published: 11/07/2002
• Est. Priority Date: 01/24/2001
• Status: Active Grant

• Current Assignee: Zalicus Inc. (EPIRUS Biopharmaceuticals, Inc.)
• Original Assignee: CombinatoRx, Inc. (EPIRUS Biopharmaceuticals, Inc.)
• Inventors: Foley, Michael A., Keith, Curtis, Stockwell, Brent R., Borisy, Alexis
• Granted Patent: US 6,693,125 B2
• Time in Patent Office: Days
• US Class Current: 514/394
• 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 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The invention features a method for treating a patient having a cancer or other neoplasm, by administering to the patient (i) a benzimidazole or a metabolite or analog thereof; and (ii) pentamidine or a metabolite or analog thereof simultaneously or within 14 days of each other in amounts sufficient to inhibit the growth of the neoplasm.

Claims

1. A method for treating a patient having a neoplasm or a person at risk for developing a neoplasm, said method comprising administering to said patient the drugs (i) pentamidine, and (ii) albendazole, mebendazole, or oxibendazole, wherein the drugs (i) and (ii) are administered simultaneously or within 14 days of each other, in amounts sufficient to inhibit the growth of a neoplasm in said person.

2. The method of claim 1, wherein drugs (i) and (ii) are administered within ten days of each other.

3. The method of claim 2, wherein drugs (i) and (ii) are administered within five days of each other.

4. The method of claim 3, wherein drugs (i) and (ii) are administered within twenty-four hours of each other.

5. The method of claim 1, wherein said neoplasm is cancer.

6. The method of claim 5, wherein said cancer is lung cancer.

7. The method of claim 6, wherein said lung cancer is selected from the group consisting of squamous cell carcinoma, adeno carcinoma, and large cell carcinoma.

8. The method of claim 5, wherein said cancer is selected from the group consisting of brain cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, kidney cancer, leukemia, liver cancer, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, sarcoma, skin cancer, testicular cancer, and uterine cancer.

9. The method of claim 1, wherein drugs (i) and (ii) are administered to said patient by intravenous, intramuscular, inhalation, rectal, or oral administration.

22. The pharmaceutical pack of claim 21, wherein drugs (i) and (ii) are formulated separately and in individual desage amounts.

10. A method for treating a patient having a neoplasm or a person at risk for developing a neoplasm, said method comprising administering to said patient:

a) a first compound selected from albendazole, albendazole sulfonate, albendazole sulfone, albendazole sulfoxide, astemizole, benomyl, 2-benzimidazolylurea, benzthiazuron, cambendazole, cyclobendazole, domperidone, droperidol, fenbendazole, flubendazole, frentizole, 5-hydroxymebendazole, lobendazole, luxabendazole, mebendazole, methabenzthiazuron, mercazole, midefradil, nocodozole, omeprazole, oxfendazole, oxibendazole, parbendazole, pimozide, tioxidazole (or a salt of any of the above), NSC_181928, and TN-16; and

b) a second compound selected from pentamidine, propamidine, butamidine, heptamidine, nonamidine, stilbamidine, hydroxystilbamidine, diminazene, benzamidine, phenamidine, dibrompropamidine, 1,3-bis(4-amidino-2-methoxyphenoxy)propane, netropsin, distamycin, phenamidine, amicarbalide, bleomycin, actinomycin, and daunorubicin;

wherein said first and second compounds are administered simultaneously or within 14 days of each other, and wherein said first and second compounds are administered in amounts sufficient to inhibit the growth of a neoplasm in said patient.

11. A method for treating a patient having a neoplasm or a person at risk for developing a neoplasm, said method comprising administering to said patient:

a) a first compound having the formula (I);

 

wherein R₁ is selected from the group consisting of;

—

H 

 

(A-4);

 

R₂ is selected from the group consisting of;

 

and each of R₃ and R4 is selected from the group consisting of;

 

and

b) a second compound having the formula (II);

 

wherein each of Y and Z is, independently, O or N;

each of R₅ and R₆ is, independently, H, OH, Cl, Br, OCH₃, OCF₃, NO₂, or NH₂;

n is an integer between 2 and 6, inclusive; and

each of R₇ and R₈ is, independently, at the meta or para position and is selected from the group consisting of;

 

wherein said first and second compounds are administered simultaneously or within 14 days of each other in amounts sufficient to inhibit the growth of a neoplasm in said person.

14. The method of claim 13, wherein drug (ii) is present in said composition in an amount of 10 to 2500 milligrams and drug (i) is present in said composition in an amount of 1 to 1000 milligrams.

15. The method of claim 13, wherein drug (ii) is present in said composition in an amount of 50 to 1000 milligrams and drug (i) is present in said composition in an amount of 10 to 250 milligrams.

16. The method of claim 13, wherein said composition is administered to said patient by intravenous, intramuscular, inhalation, rectal, or oral administration.

18. The composition of claim 17, wherein the amount of drug (ii) in said composition is 10 to 2500 milligrams and the amount of drug (i) in said composition is 1 to 1000 milligrams.

19. The method of claim 17, wherein drug (ii) is present in said composition in an amount of 50 to 1000 milligrams and drug (i) is present in said composition in an amount of 10 to 250 milligrams.

20. The composition of claim 17, wherein said composition is formulated for intravenous, intramuscular, rectal, inhalation, or oral administration.

12. A method for treating a patient having a neoplasm or a person at risk for developing a neoplasm, said method comprising administering to said patient:

a) a first compound having the formula (III);

 

wherein;

A is selected from the group consisting of O, S, and NR₁₂;

R₉ is selected from the group consisting of;

each of R₁₀ and R₁₁ is independently selected from the group consisting of —

H, -halo, —

NO₂, —

OH, —

SH, —

O-C_1-10 alkyl, —

O—

(C_1-10)_0-1-aryl, —

O—

(C_1-10 alkyl)_0-1-heteroaryl, —

O—

(C_1-10 alkyl)_0-1-heterocyclyl, -C_1-10 alkoxycarbonyl, —

S(O)_0-2-C_1-10 alkyl, —

S(O)_0-2-(C_1-10 alkyl)_0-1-aryl, —

S(O)_0-2-(C_1-10 alkyl)_0-1-heteroaryl, -S(O)_0-2-(C_1-10 alkyl)_0-1-heterocyclyl, and -C_1-10 alkyl or -C_2-10 alkenyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of -aryl, -heteroaryl, -heterocyclyl, —

O-C_1-10 alkyl, —

O—

(C_1-10 alkyl)_0-1-aryl, —

O—

(C_1-10 alkyl)_0-1-heteroaryl, —

O—

(C_1-10 alkyl)_0-1-heterocyclyl, -C_1-10 alkoxycarbonyl, —

S(O)_0-2-C_1-10 alkyl, —

S(O)_0-2-(C_1-10 alkyl)_0-1-aryl, —

S(O)_0-2-(C_1-10alkyl)_0-1-heteroaryl, —

S(O)_0-1-(C_1-10 alkyl)_0-1-heterocyclyl, —

N(R₁₃)₂, —

OR₁₃, -oxo, -cyano, -halogen, —

NO₂, —

OH, and —

SH;

R₁₂ is selected from the group consisting of —

H and -C_1-10 alkyl or -C_2-10 alkenyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of -aryl, -heteroaryl, -heterocyclyl, —

OC_1-10 alkyl, —

O-(C_1-10)0-1-aryl, —

O—

(C_1-10 alkyl)_0-1-heteroaryl, —

O—

(C_1-10 alkyl)_0-1-heterocyclyl, -C_1-10 alkoxycarbonyl, —

S(O)_0-2-C_1-10 alkyl, —

S(O)_0-2-(C_1-10 alkyl)0-1-aryl, —

S(O)_0-2-(C_1-10 alkyl)_0-1-heteroaryl, —

S(O)_0-2-(C_1-10 alkyl)_0-1-heterocyclyl, —

N(R₁₃)2, —

OR₁₃, -oxo, -cyano, -halo, —

NO₂, —

OH, and —

SH;

each R₁₃ is selected from the group consisting of H and C_1-10 alkyl or C_2-10 alkenyl that is unsubstituted or substituted by one or more substituents selected from the group consisting of -aryl, -heteroaryl, -heterocyclyl, —

O-C_1-10 alkyl, —

O—

(C_1-10)_0-1-aryl, —

O—

(C_1-10 alkyl)_0-1-heteroaryl, —

O—

(C_1-10 alkyl)_0-1-heterocyclyl, -C_1-10 alkoxycarbonyl, -oxo, -cyano, -halo, —

NO₂, —

OH, and —

SH; and

b) a second compound having the formula (II);

 

wherein each of Y and Z is, independently, O or N;

each of R₅ and R₆ is, independently, —

H, —

OH, -halogen, —

O-C_1-10 alkyl, —

OCF₃, —

NO₂, or NH₂;

n is an integer between 2 and 6, inclusive; and

each of R₇ and R₈ is, independently, at the meta or para position and is selected from the group consisting of;

 

wherein the first and second compounds are administered simultaneously or within 14 days of each other in amounts sufficient to inhibit the growth of a neoplasm in said person.

13. A method for treating a patient having a neoplasm or a person at risk for developing a neoplasm, said method comprising administering to said patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the drugs (i) pentamidine and (ii) albendazole, mebendazole, or oxibendazole, at dosages that together inhibit the growth of a neoplasm in said person.

17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the drugs (i) albendazole, mebendazole, or oxibendazole;

and (ii) pentamidine;

wherein drugs (i) and (ii) are each present in amounts that, when administered together to a patient having a neoplasm, inhibit the growth of said neoplasm.

21. A pharmaceutical pack comprising the drugs (i) albendazole, mebendazole, or oxibendazole;

and (ii) pentamidine.

23. The pharmaceutical pack of claim 21, wherein drugs (i) and (ii) are formulated together and in individual dosage amounts.

24. A method for identifying combinations of compounds useful for treating a patient having a neoplasm, said method comprising the steps of:

(a) contacting cancer cells in vitro with (i) pentamidine or a benzimidazole and (ii) a candidate compound; and

(b) determining whether the combination of said pentamidine or benzimidazole and said candidate compound reduces growth of said cancer cells relative to cancer cells contacted with said benzimidazole or pentamidine but not contacted with said candidate compound, or cancer cells contacted with said candidate compound but not with said benzimidazole or pentamidine, wherein a reduction of said growth identifies said combination as a combination that is useful for treating a patient having a neoplasm.