Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-23
2003-04-22
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06552059
ABSTRACT:
TECHNICAL FIELD
This invention relates to a pharmaceutical composition for and a method of treating leukemia in mammals, wherein the composition comprises a benzimidazole derivative.
BACKGROUND OF THE INVENTION
Cancers, including leukemia, are the leading cause of death in animals and humans. The exact cause of many cancers is not known, but links between certain activities such as smoking or exposure to carcinogens and the incidence of certain types of carcinomas, lymphomas, e.g., leukemia and tumors, has been shown by a number of researchers.
Many types of chemotherapeutic agents have been shown to be effective against leukemia, but not all types of leukemia cells respond to these agents, and, unfortunately, many of these agents also destroy normal cells.
Despite advances in the field of leukemia treatments, the leading therapies to date are radiation, chemotherapy and bone marrow transplants. However, these therapies generally harm normal cells as well as leukemic cells. Ideally cytotoxic agents that have specificity for leukemia cells while only minimally affecting normal healthy cells would be extremely desirable. Unfortunately, none have been found and instead agents which target especially rapidly dividing cells (both diseased and normal) have been used.
SUMMARY OF THE INVENTION
The invention provides a method, and pharmaceutical composition therefor, of treating leukemia, inhibiting the growth or inhibiting the proliferation of leukemic cells while affecting little or no undesired side effects on normal cells, and extending the life span of a animal having leukemia. Accordingly, one aspect of the invention provides a method of treating leukemia in a animal comprising the step of administering to the animal a safe and effective amount of a compound of the Formula:
or a pharmaceutically acceptable salt or prodrug form thereof, wherein:
X is hydrogen, halogen, alkyl of less than 7 carbon atoms or alkoxy of less than 7 carbon atoms;
n is a positive integer of less than 4;
Y is hydrogen, chlorine, nitro, methyl or ethyl;
R is hydrogen or an alkyl group of from 1 to 8 carbon atoms; or alkylcarbamoyl wherein the alkyl group has from 3 to 6 carbon atoms;
R
2
is 4-thiazolyl or NHCOOR
1
; and
R
1
is an aliphatic hydrocarbon of less than 7 carbon atoms; and
a pharmaceutically acceptable carrier.
Preferably the compositions are:
wherein R is an alkyl of 1 through 8 carbon atoms and R
2
is selected from the group consisting of 4-thiazolyl, NHCOOR
1
, wherein R
1
is methyl, ethyl or isopropyl and the non-toxic, pharmaceutically acceptable acid addition salts with both organic and inorganic acids or prodrugs thereof.
R
1
is preferably an alkyl group of less than 7 carbon atoms. In other preferred embodiments, R is an alkyl of from 1 to 8 carbon atoms and R
1
is methyl, ethyl or isopropyl. The most preferred compounds include those wherein Y is chloro and X is hydrogen and also 2-(4-thiazolyl)benzimidazole (thiabendazole), methyl(butylcarbamoyl)-2-benzimidazolecarbamate (benomyl) and 2-(methoxycarbonylamino)benzimidzole(carbendazim).
The compound of the Formula I is used alone or in combination with a potentiator or other chemotherapeutic agent to treat leukemia.
Another aspect of the invention provides a method of inhibiting the proliferation of leukemic cells in vitro, in vivo or ex vivo comprising the step of treating said cells with an effective amount of the compound of the Formula I, as defined above. Optionally, one or more potentiators and chemotherapeutic agents are used in combination with the compound of the Formula I to inhibit the proliferation of leukemic cells.
Yet another aspect of the invention provides a method of inhibiting the growth of leukemic cells in vitro, in vivo or ex vivo comprising the step of treating said cells with an effective amount of the compound of the Formula I, as defined above. Optionally, one or more potentiators and chemotherapeutic agents are used in combination with the compound of the Formula I to inhibit the growth of leukemic cells.
Still another aspect of the invention provides a method of extending the life span of a animal having leukemia comprising the step of administering to the animal an effective amount of the compound of the Formula I, as defined above, whereby the life span of the animal is extended beyond the expected life span of a comparable animal having a comparable degree of leukemia development not being treated with a compound of the Formula I. Optionally, one or more potentiators and chemotherapeutic agents are used in combination with the compound of the Formula I to extend the life span of the animal.
A further aspect of the invention provides a pharmaceutical composition for the treatment of leukemia in a animal comprising a pharmaceutically acceptable carrier, an effective amount of a compound of the Formula I, as defined above, and a safe and effective amount of one or more potentiators and other chemotherapeutic agents.
The pharmaceutical composition of the invention includes all known stereoisomers, enantiomers, regioisomers, stereoisomers, and diastereomers of the compound of the Formula I as well as pharmaceutically acceptable salts and prodrugs thereof.
The compounds of the invention are administered orally, rectally, topically, intravenously, or parenterally.
DETAILED DESCRIPTION OF THE INVENTION
A. Definitions
As used herein, “Formula I” refers to a benzimidazole having the general formula:
or a pharmaceutically acceptable salt or prodrug form thereof, wherein:
X is hydrogen, halogen, alkyl of less than 7 carbon atoms or alkoxy of less than 7 carbon atoms;
n is a positive integer of less than 4;
Y is hydrogen, chlorine, nitro, methyl or ethyl;
R is hydrogen or an alkyl group of from 1 to 8 carbon atoms; or alkylcarbamoyl wherein the alkyl group has from 3 to 6 carbon atoms;
R
2
is 4-thiazolyl or NHCOOR
1
; and
R
1
is an aliphatic hydrocarbon of less than 7 carbon atoms
As used herein, a “pharmaceutically acceptable” component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio. It is expected, however, that some side effects may be observed during treatment with a compound of the Formula I.
As used herein, the term “animal” includes any warm blooded animal and the preferred animals are mammals.
As used herein, the term “safe and effective amount” or “therapeutically effective amounts” refers to the quantity of a component which is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention. The specific “safe and effective amount” will vary with such factors as the particular condition being treated, the physical condition of the patient, the type of animal being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific formulations employed and the structure of the compounds or its derivatives.
As used herein, the terms “pharmaceutical addition salt” and “pharmaceutically acceptable salt” refer to a salt of the anti-leukemia compound of the Formula I with an organic or inorganic acid. The preferred acid addition salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like.
“Prodrugs” are considered to be any covalently bonded carriers which release the active parent drug according to the formula of the benzimidazole derivatives described above in vivo when such prodrug is administered to an animal subject. Prodrugs of the benzimidazole compounds are prepared by modifying functional groups present in the Examples of prodrugs include, but are not limited to, acetate, formate, or benzoate derivatives of alcohol and amine functional groups in the benzimidazole derivatives; phosphate esters, dimethylglycine esters, aminoalkylbenzyl ester
Goldberg Jerome D.
Haynes and Boone LLP
University of Arizona Foundation
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