CA2223435A1 - Use of benzimidazoles for the manufacture of a medicament for the treatment of leukemia - Google Patents
Use of benzimidazoles for the manufacture of a medicament for the treatment of leukemia Download PDFInfo
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- CA2223435A1 CA2223435A1 CA002223435A CA2223435A CA2223435A1 CA 2223435 A1 CA2223435 A1 CA 2223435A1 CA 002223435 A CA002223435 A CA 002223435A CA 2223435 A CA2223435 A CA 2223435A CA 2223435 A1 CA2223435 A1 CA 2223435A1
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- benzimidazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
A pharmaceutical composition for the treatment of leukemia in mammals is disclosed. The particular fungicide used is a benzimidazole derivative of formula (I), 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; and R is hydrogen or an alkyl group having from 1 to 8 carbon atoms, and R2 is 4-thiazolyl or NHCOOR1 wherein R1 is aliphatic hydrocarbon of less than 7 carbon atoms or the pharmaceutically acceptable inorganic or acid addition salts thereof.
Y is hydrogen, chlorine, nitro, methyl or ethyl; and R is hydrogen or an alkyl group having from 1 to 8 carbon atoms, and R2 is 4-thiazolyl or NHCOOR1 wherein R1 is aliphatic hydrocarbon of less than 7 carbon atoms or the pharmaceutically acceptable inorganic or acid addition salts thereof.
Description
W O 96/40122 PCT/U'~S.'~7445 USE OF BENZIMIDAZOLES FOR THE MANUFACTURE OF A MEDICAMENT FOR THE TREATMENT
TECHNICAL FIEID
This invention is a ph~rm~elltic~l composition that is useful for the trP~tm~nt of kpllk~mi~ particularly in human and warm blooded ~nim~lc. The composition contains a bel-7imi~l~7Qle derivative.
BACKGROUND OF 1~ rNVENTlON
0 Cancers, including lenk~mi~, are the leading cause of death in ~nim~lc and hnm~nc. The exact cause of lenkPmi~ is not known, but links between certain activities such as smoking or exposure to carcinogens and the incidence of certain types of leukPmi~ and tumors has been shown by a number of ~csea~;h~
Many types of chemothe.d~t;ulic agents have been shown to be effective against leukemia, but not all types of leukemia and tumor cells respond to theseagents. Unfortunately, many of these agents also destroy normal cells. The exactmechanism for the action of these chemotheldpeuLic agents are not always known.
Despite advances in the field of cancer and lçukt~mi~ trç~tm~ tc the leading therapies to date are radiation and chemoll.~.d~y and bone llla,low tr~n~l~ntc Chemc,ll.P.,~ ic approaches are said to fight cancers that are particularly aggressive. Such cytocidal or cytostatic agents work best on cancers with large growth factors, i.e., ones whose cells are rapidly dividing. To date, hormones, in particular estrogen, proge~len~lle and testosterone, and some antibiotics produced by a variety of microbes, alkylating agents, and anti-metabolites form the bulk of 2s therapies available to oncologists. Ideally cytotoxic agents that have specificity for lçnk~mi~, cancer and tumor cells while not affecting normal cells would be extremely desirable. Unfortunately, none have been found and instead agents which target çcpeci~lly rapidly dividing cells (both ~lice~ce~l and normal) have been used.
Clearly, the development of m~t~.ri~lc that would target leuk~mi~ cells due to some unique specificity for them would be a breakthrough. ~AltPrn~tively, materials that were cytotoxic to lPIlk~mi~ cells while exerting mild effects on normal cells would be desirable. Th~lc;rul~, it is an object of this invention to provide a pharrn~eutic~l composition that is effective in treating leuk~mi~ with mild or no effects on normal blood cells 2 PCTrUS96/0744 More specifically, it is an object of this invention to provide a composition comprising a pharm~re~tir~l carrier and a l~.-,;...i~1~7Qle derivative as defined herein along with a method for treating !e--kPmi~
SUMMARY OF 1~ INVENTION
s A ph~rm~re~ltic~l composition for tre~tmPnt of .. ~.. ~lc, and in particular, warm blooded animals and hllm~nc, which are affected by l~nklo.mi~ comprising a ph~rm~cel-ti~l carrier and an effective amount of a co.lll,uund s~lecte~ from the group consisting of:
Xn~2 wherein X is hydrogen, halogen, aLkyl of less than 7 carbon atoms or aL~oxy of less than 7 carbon atoms; n is a positive integer of less than 4; Y is hydrogen, chlorine, nitro, methyl or ethyl; and R is hydrogen, or an aLkyl group of from I to 8 carbon atoms and R2 is 4-thiazolyl, NHCOORl wherein Rl is aliphatic hydrocarbon of 5 less than 7 carbon atoms, and preferably an aLkyl group of less than 7 carbon atoms is cl~im~d Preferably the compositions are:
~2 wherein R is an aLkyl of 1 through 8 carbon atoms and R2 is sel~ted from the 20 group consisting of 4-thiazolyl, NHCOORl, wl~lein Rl is methyl, ethyl or is~ yl and the non-toxic, ph~rm~eutic~lly ~-cepf~hle acid addition salts with both organic and ~ ic acids. The most çlleÇ~,l.c;d col~uilds are 2-(4-thiazolyl)be~ 7Ole, methyl -(butylcarbamoyl)-2-bel~ J~llaLe and 2-methoxycarbonylamino-be.~,;...i~1~7Ole and those wherein Y is chloro.
These compositions can be used to inhibit the growth of l~ k~mi~ cells in hllm~nc or animals by ~lminictration of an effective amount either orally, rectally, topically or parenterally, or intravenously. These compositions do not cignifi~ntly affect healthy cells.
W O 96/40122 PCT/U~ v7445 DETAILl~n DESCRIPIION OF 1 H ~ INVENTION
A. Deffniti~!n~:
As used herein, the term "comprising" means various components can be conjointly employed in the ph~rm~- eutir~l composition of this invention.
s Accoldi~ly, the terms "concicting çccenti~lly of" and "concicting of" are embodied in the term comprising.
As used herein, a "ph~rm~-el-ti~lly acceptable" component is one that is suitable for use with hllm~nc and/or ~nim~lc without undue adverse side effects (such as toxicity, irritation, and allergic response) commen~ te with a reasonable o benefit/risk ratio.
As used herein, the term "safe and effective amount" refers to the quantity of a cu~ enl which is sl~fflcient to yield a desired Ih~ ic response willlou~
undue adverse side effects (such as toxicity, irritation, or allergic response) comme~ . with a reasonable benefit/risk ratio when used in the manner of this invention. Thespecific "safeandeffectiveamount" will, obviously, varywithsuch factors as the particular condition being treated, the physical condition of thepatient, the type of m~mm~l being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific form~ tions employed and the structure of the colll~unds or its derivatives.
As used herein, a "ph~rm~ellti~l addition salts" is salt of the anti-le Ikt~mi~
compound with an organic or inorganic acid. These ~ler~ d acid addition salts are chlorides, bromides, sulfates, nitrates, pho~hates, sulfonates, f,llllales, tartrates, m~ t~os, m~l~tçs, citrates, bel~o~lçs, salicylates, ascorbates, and the like.
As used herein, a "pharm~-~ellti~l carrier" is a pharm~celltif~lly acceptable 2s solvent, suspending agent or vehicle for delivering the anti-le~-kemi~ agent to the animal or human. The carrier may be liquid or solid and is sel~t~ with the planned 1ll~l of ~flmini.ctr~ti~)n in mind.
As used herein, "cancer" or "lel~k~mi~" refers to all types of cancers or neoplasm or m~lign~nt disease which attack normal healthy blood cells or bone 30 marrow which produces blood cells which are found in ~ lc.
As used herein, the "anti-lel~kemi~ compounds" are the bçn7imitl~7oles~ and their salts. The exact ben7imi~i~7oles are described in detail below. The ~l~rell~d m~teri~lc are the products sold under the names "thiabendazole~)", "benomyl(~)"
and "carbton-1~7im(~)" by BASF and Hoechst, DuPont and MSD-AgVet.
WO 96/40122 PCT/U~ 7445 B. l~IE ANTI-L~;uK~;~IA COMPOUNDS
The anti-lPukemi~ compounds are bc.~ ole derivatives which are known for their antifungal activities. They are systemic f Ingi~ les used to prevent and er~ tP. fungi. The coll~puullds have the following structure:
s y~2 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; and R is hy~gell or an aLkyl group having from 1 to 8 carbons, and R2 is 4-thiazolyl, NHCOORl whelcill Rl is aliphatic hydrocarbon of o less than 7 carbon atoms, and preferably and aLkyl group of less than 7 carbon atoms. Preferably the compositions are:
~2 wherein R is an aLkyl of 1 through 8 carbon atoms and R2 is sel~-~teA from the S group con.~i~ting of 4-thiazolyl, NHCOORl, wh~chl Rl is methyl, ethyl or isopropyl and the non-toxic, ph~rrn~eutif~lly ~c~cept~hle acid addition salts with both organic and illol~ ic acids.
The most l~lcrt;lled compounds are 2-(4-thiazolyl)~..~;...i-i~701e, methyl -(butylcarbamoyl)-2-ben~imi~1~7c 1P~rbamate and 2-methu~ycal~llyl~l~i~o-20 b~ 701e and the compounds wherein Y is chloro and X is hydrogen.
These cc,lll~uunds are prepared according to the method described in U.S.
TECHNICAL FIEID
This invention is a ph~rm~elltic~l composition that is useful for the trP~tm~nt of kpllk~mi~ particularly in human and warm blooded ~nim~lc. The composition contains a bel-7imi~l~7Qle derivative.
BACKGROUND OF 1~ rNVENTlON
0 Cancers, including lenk~mi~, are the leading cause of death in ~nim~lc and hnm~nc. The exact cause of lenkPmi~ is not known, but links between certain activities such as smoking or exposure to carcinogens and the incidence of certain types of leukPmi~ and tumors has been shown by a number of ~csea~;h~
Many types of chemothe.d~t;ulic agents have been shown to be effective against leukemia, but not all types of leukemia and tumor cells respond to theseagents. Unfortunately, many of these agents also destroy normal cells. The exactmechanism for the action of these chemotheldpeuLic agents are not always known.
Despite advances in the field of cancer and lçukt~mi~ trç~tm~ tc the leading therapies to date are radiation and chemoll.~.d~y and bone llla,low tr~n~l~ntc Chemc,ll.P.,~ ic approaches are said to fight cancers that are particularly aggressive. Such cytocidal or cytostatic agents work best on cancers with large growth factors, i.e., ones whose cells are rapidly dividing. To date, hormones, in particular estrogen, proge~len~lle and testosterone, and some antibiotics produced by a variety of microbes, alkylating agents, and anti-metabolites form the bulk of 2s therapies available to oncologists. Ideally cytotoxic agents that have specificity for lçnk~mi~, cancer and tumor cells while not affecting normal cells would be extremely desirable. Unfortunately, none have been found and instead agents which target çcpeci~lly rapidly dividing cells (both ~lice~ce~l and normal) have been used.
Clearly, the development of m~t~.ri~lc that would target leuk~mi~ cells due to some unique specificity for them would be a breakthrough. ~AltPrn~tively, materials that were cytotoxic to lPIlk~mi~ cells while exerting mild effects on normal cells would be desirable. Th~lc;rul~, it is an object of this invention to provide a pharrn~eutic~l composition that is effective in treating leuk~mi~ with mild or no effects on normal blood cells 2 PCTrUS96/0744 More specifically, it is an object of this invention to provide a composition comprising a pharm~re~tir~l carrier and a l~.-,;...i~1~7Qle derivative as defined herein along with a method for treating !e--kPmi~
SUMMARY OF 1~ INVENTION
s A ph~rm~re~ltic~l composition for tre~tmPnt of .. ~.. ~lc, and in particular, warm blooded animals and hllm~nc, which are affected by l~nklo.mi~ comprising a ph~rm~cel-ti~l carrier and an effective amount of a co.lll,uund s~lecte~ from the group consisting of:
Xn~2 wherein X is hydrogen, halogen, aLkyl of less than 7 carbon atoms or aL~oxy of less than 7 carbon atoms; n is a positive integer of less than 4; Y is hydrogen, chlorine, nitro, methyl or ethyl; and R is hydrogen, or an aLkyl group of from I to 8 carbon atoms and R2 is 4-thiazolyl, NHCOORl wherein Rl is aliphatic hydrocarbon of 5 less than 7 carbon atoms, and preferably an aLkyl group of less than 7 carbon atoms is cl~im~d Preferably the compositions are:
~2 wherein R is an aLkyl of 1 through 8 carbon atoms and R2 is sel~ted from the 20 group consisting of 4-thiazolyl, NHCOORl, wl~lein Rl is methyl, ethyl or is~ yl and the non-toxic, ph~rm~eutic~lly ~-cepf~hle acid addition salts with both organic and ~ ic acids. The most çlleÇ~,l.c;d col~uilds are 2-(4-thiazolyl)be~ 7Ole, methyl -(butylcarbamoyl)-2-bel~ J~llaLe and 2-methoxycarbonylamino-be.~,;...i~1~7Ole and those wherein Y is chloro.
These compositions can be used to inhibit the growth of l~ k~mi~ cells in hllm~nc or animals by ~lminictration of an effective amount either orally, rectally, topically or parenterally, or intravenously. These compositions do not cignifi~ntly affect healthy cells.
W O 96/40122 PCT/U~ v7445 DETAILl~n DESCRIPIION OF 1 H ~ INVENTION
A. Deffniti~!n~:
As used herein, the term "comprising" means various components can be conjointly employed in the ph~rm~- eutir~l composition of this invention.
s Accoldi~ly, the terms "concicting çccenti~lly of" and "concicting of" are embodied in the term comprising.
As used herein, a "ph~rm~-el-ti~lly acceptable" component is one that is suitable for use with hllm~nc and/or ~nim~lc without undue adverse side effects (such as toxicity, irritation, and allergic response) commen~ te with a reasonable o benefit/risk ratio.
As used herein, the term "safe and effective amount" refers to the quantity of a cu~ enl which is sl~fflcient to yield a desired Ih~ ic response willlou~
undue adverse side effects (such as toxicity, irritation, or allergic response) comme~ . with a reasonable benefit/risk ratio when used in the manner of this invention. Thespecific "safeandeffectiveamount" will, obviously, varywithsuch factors as the particular condition being treated, the physical condition of thepatient, the type of m~mm~l being treated, the duration of the treatment, the nature of concurrent therapy (if any), and the specific form~ tions employed and the structure of the colll~unds or its derivatives.
As used herein, a "ph~rm~ellti~l addition salts" is salt of the anti-le Ikt~mi~
compound with an organic or inorganic acid. These ~ler~ d acid addition salts are chlorides, bromides, sulfates, nitrates, pho~hates, sulfonates, f,llllales, tartrates, m~ t~os, m~l~tçs, citrates, bel~o~lçs, salicylates, ascorbates, and the like.
As used herein, a "pharm~-~ellti~l carrier" is a pharm~celltif~lly acceptable 2s solvent, suspending agent or vehicle for delivering the anti-le~-kemi~ agent to the animal or human. The carrier may be liquid or solid and is sel~t~ with the planned 1ll~l of ~flmini.ctr~ti~)n in mind.
As used herein, "cancer" or "lel~k~mi~" refers to all types of cancers or neoplasm or m~lign~nt disease which attack normal healthy blood cells or bone 30 marrow which produces blood cells which are found in ~ lc.
As used herein, the "anti-lel~kemi~ compounds" are the bçn7imitl~7oles~ and their salts. The exact ben7imi~i~7oles are described in detail below. The ~l~rell~d m~teri~lc are the products sold under the names "thiabendazole~)", "benomyl(~)"
and "carbton-1~7im(~)" by BASF and Hoechst, DuPont and MSD-AgVet.
WO 96/40122 PCT/U~ 7445 B. l~IE ANTI-L~;uK~;~IA COMPOUNDS
The anti-lPukemi~ compounds are bc.~ ole derivatives which are known for their antifungal activities. They are systemic f Ingi~ les used to prevent and er~ tP. fungi. The coll~puullds have the following structure:
s y~2 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; and R is hy~gell or an aLkyl group having from 1 to 8 carbons, and R2 is 4-thiazolyl, NHCOORl whelcill Rl is aliphatic hydrocarbon of o less than 7 carbon atoms, and preferably and aLkyl group of less than 7 carbon atoms. Preferably the compositions are:
~2 wherein R is an aLkyl of 1 through 8 carbon atoms and R2 is sel~-~teA from the S group con.~i~ting of 4-thiazolyl, NHCOORl, wh~chl Rl is methyl, ethyl or isopropyl and the non-toxic, ph~rrn~eutif~lly ~c~cept~hle acid addition salts with both organic and illol~ ic acids.
The most l~lcrt;lled compounds are 2-(4-thiazolyl)~..~;...i-i~701e, methyl -(butylcarbamoyl)-2-ben~imi~1~7c 1P~rbamate and 2-methu~ycal~llyl~l~i~o-20 b~ 701e and the compounds wherein Y is chloro and X is hydrogen.
These cc,lll~uunds are prepared according to the method described in U.S.
3,738,995 issued to Adams et al, June 12, 1973. The thiazolyl derivatives are prepared according to the method described in Brown et al., J. Am. Chem. Soc..
~ 1764 (1961) and Grenda et al., J. Org. Chem., 30, 259 (1965).
2s C. DOSAGE
Any suitable dosage may be given in the method of the invention. The type of colll~oulld and the carrier and the amount will vary widely depending on the species of the warm blooded animal or human, body weight, and the type of leukPmi~ being treated. Generally a dosage of between about 2 milligrams (mg) per 30 kilogram (kg) of body weight and about 400 mg per kg of body weight is suitable.
Preferably from lS mg to about 150 mg/kg of body weight is used. Generally, the WO 96/40122 PCT/U',~1~7445 dosage in man is lower than for small warm blooded .. ,.. ~ls such as mice. Adosage unit may comprise a single compound or IlPi~lul~s thereof with other c compounds or other cancer inhibiting compounds. The dosage unit can also comprise ~ ent~ extenders, carriers and the l~ke. The unit may be in solid or gel s form such as pills, tablets, capsules and the like or in liquid form suitable for oral, rectal, topical, intravenous injection or pa~ l A~lministrAtinn or injection into or around the bone lUa.llUW.
D. DOSAGE DELIVERY FORMS
The anti-lP~kPmiA compounds are typically mixed with a ph~rmA~ellti~lly 0 acceptable carrier. This carrier can be a solid or liquid and the type is gene~lly chosen based on the type of Allminictration being used. The active agent can be coA~imini~t~red in the form of a tablet or capsule, as an agglomP-rAtPci powder or in a liquid forrn. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily form~llAtPA and can be made easy to swallow or chew; ûther solid forms include grAmllP~s~ and bulk powders. Tablets may contain suitable binders, lubricants, tlihlP,nts, ~ ~~".~ E agents, coloringagents, flavoring agents, flow-in-l--cin~ agents, and meltinE agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmAceutically acceptable fats and oils, alcohols or other organic solvents, including esters, çm~ ions, syrups or elixirs, s--cpPnsinns, solutions and/or s--spen~ic ns lc;Co~ from non-effervescent grAnlli~S and effervescent ,p~ ns r~c~ ~JA from effervescent grAnlllPs Such liquid dosage forms may contain, for eY~mplP, suitable solvents, preservatives, emulsifying agents, suspending agents, ~lihlPnt~, sweeteners, thickeners, and m~lting agents. Oral dosage forms optionally contain flavorants and coloring agents. P~c;llttildl andintravenous forms would also include minerals and other mAtPriAl~ to make them co~ il.le with the type of injection or delivery system chosen.
Specific examples of ph~rmAceuticAl acceptable carriers and excipients that may be used to form~llAte oral dosage forms of the present invention are described in US. Pat. No. 3,903,297 to Robert, issued Sept. 2, 1975. Techniques and compositions for making dosage forms useful in the present invention are described 7 in the following references: 7 Modern PharmAcP-ltics, Ch~pt~prs 9 and 10 (13anker &
Rhodes, Editors, 1979); Liebc;l~ et al., PharmAcel-tirAl Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).
O 96/40122 PCT~US96/07445 E. METHOD OF TREATMENT
The method of tr~tmçnt can be any suitable method which is effective in the tre~tme-nt of the particular l~nk.omi~ type being treated. Tre~fment may be oral, rectal, topical, parenteral or intravenous ~1mini~tr~tinn or by injection into the bone marrow. The method of applying an effective amount also varies depçn-iing on the~ lk.omi~ being treated. It is believed that pal~ el~l tre~tm~nt by intravenous,subcutaneous, or int~mnsclll~r application of the b~ 7ole colllpounds, formulated with an appl..~l~L~ carrier, ~ lition~l cancer inhihitin~ compound orcompounds or diluent to f~ilit~te application will be the pl~;rt;ll~;d method of~lminictering the compounds to warm blooded ~nim~
The following example is illllst~tive and is not meant to be limiting to the invention.
Mice are randomly sel~tçd and divided into groups for Llc~ -l Five groups are infected with l~llkPmi~ The ~ e~ed ~nim~lc are dosed for five days, off two days and then dosed for another five days and then three days off, then dosed for five days and off for two days. This dosing on and off in an irregualrpattern was not an ideal regimi~n, but the results do show a positive benefit for the Carbçn-1~7imTM. One group of mice was treated with CytoxanTM, 2-[bis(2-chloroethyl)-amino-l-oxo-2-aza-5-oxophosphoridin, a control was dosed with canola oil and three groups were treated with various levels of Carblon-1~7imTM,methyl -(butylcarbamoyl)-2-b~n7imi-1~7ole-c~l,dlllale. A control with no tre~tmPnt was also used. The Call~ i...TM was dosed at three levels 4000 mg/kg, 2500 mg/kg and 1000 mg/kg. The CytoxanTM was dosed at 125 mg/kg. After 8 days, the no tr~tm~nt group had lost 1 mouse, by day 10, 8 mice were dead and at day 11 all ten mice were dead. The mice in the CytoxanTM group survived more than 21days. The higher dose Carbton-1~7imTM group had one mouse die on day 14, two died on days 15,16 and 17 and one each died on days 20, 21, and 22. The mean number of days for this group is 17.3. The int~rm~ te dosage group had 2 mice die on day 14, 4 on day 15, 1 on day 16, 2 on day 19 and 1 on day 21. The mean number of days for this group is 16.50. The lowest dosage group had 2 mice die on day 12, 13, 14, and 15; and 1 died on each of days 16 and 17. The mean number of days for this group is 14.1.
~ 1764 (1961) and Grenda et al., J. Org. Chem., 30, 259 (1965).
2s C. DOSAGE
Any suitable dosage may be given in the method of the invention. The type of colll~oulld and the carrier and the amount will vary widely depending on the species of the warm blooded animal or human, body weight, and the type of leukPmi~ being treated. Generally a dosage of between about 2 milligrams (mg) per 30 kilogram (kg) of body weight and about 400 mg per kg of body weight is suitable.
Preferably from lS mg to about 150 mg/kg of body weight is used. Generally, the WO 96/40122 PCT/U',~1~7445 dosage in man is lower than for small warm blooded .. ,.. ~ls such as mice. Adosage unit may comprise a single compound or IlPi~lul~s thereof with other c compounds or other cancer inhibiting compounds. The dosage unit can also comprise ~ ent~ extenders, carriers and the l~ke. The unit may be in solid or gel s form such as pills, tablets, capsules and the like or in liquid form suitable for oral, rectal, topical, intravenous injection or pa~ l A~lministrAtinn or injection into or around the bone lUa.llUW.
D. DOSAGE DELIVERY FORMS
The anti-lP~kPmiA compounds are typically mixed with a ph~rmA~ellti~lly 0 acceptable carrier. This carrier can be a solid or liquid and the type is gene~lly chosen based on the type of Allminictration being used. The active agent can be coA~imini~t~red in the form of a tablet or capsule, as an agglomP-rAtPci powder or in a liquid forrn. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily form~llAtPA and can be made easy to swallow or chew; ûther solid forms include grAmllP~s~ and bulk powders. Tablets may contain suitable binders, lubricants, tlihlP,nts, ~ ~~".~ E agents, coloringagents, flavoring agents, flow-in-l--cin~ agents, and meltinE agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmAceutically acceptable fats and oils, alcohols or other organic solvents, including esters, çm~ ions, syrups or elixirs, s--cpPnsinns, solutions and/or s--spen~ic ns lc;Co~ from non-effervescent grAnlli~S and effervescent ,p~ ns r~c~ ~JA from effervescent grAnlllPs Such liquid dosage forms may contain, for eY~mplP, suitable solvents, preservatives, emulsifying agents, suspending agents, ~lihlPnt~, sweeteners, thickeners, and m~lting agents. Oral dosage forms optionally contain flavorants and coloring agents. P~c;llttildl andintravenous forms would also include minerals and other mAtPriAl~ to make them co~ il.le with the type of injection or delivery system chosen.
Specific examples of ph~rmAceuticAl acceptable carriers and excipients that may be used to form~llAte oral dosage forms of the present invention are described in US. Pat. No. 3,903,297 to Robert, issued Sept. 2, 1975. Techniques and compositions for making dosage forms useful in the present invention are described 7 in the following references: 7 Modern PharmAcP-ltics, Ch~pt~prs 9 and 10 (13anker &
Rhodes, Editors, 1979); Liebc;l~ et al., PharmAcel-tirAl Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).
O 96/40122 PCT~US96/07445 E. METHOD OF TREATMENT
The method of tr~tmçnt can be any suitable method which is effective in the tre~tme-nt of the particular l~nk.omi~ type being treated. Tre~fment may be oral, rectal, topical, parenteral or intravenous ~1mini~tr~tinn or by injection into the bone marrow. The method of applying an effective amount also varies depçn-iing on the~ lk.omi~ being treated. It is believed that pal~ el~l tre~tm~nt by intravenous,subcutaneous, or int~mnsclll~r application of the b~ 7ole colllpounds, formulated with an appl..~l~L~ carrier, ~ lition~l cancer inhihitin~ compound orcompounds or diluent to f~ilit~te application will be the pl~;rt;ll~;d method of~lminictering the compounds to warm blooded ~nim~
The following example is illllst~tive and is not meant to be limiting to the invention.
Mice are randomly sel~tçd and divided into groups for Llc~ -l Five groups are infected with l~llkPmi~ The ~ e~ed ~nim~lc are dosed for five days, off two days and then dosed for another five days and then three days off, then dosed for five days and off for two days. This dosing on and off in an irregualrpattern was not an ideal regimi~n, but the results do show a positive benefit for the Carbçn-1~7imTM. One group of mice was treated with CytoxanTM, 2-[bis(2-chloroethyl)-amino-l-oxo-2-aza-5-oxophosphoridin, a control was dosed with canola oil and three groups were treated with various levels of Carblon-1~7imTM,methyl -(butylcarbamoyl)-2-b~n7imi-1~7ole-c~l,dlllale. A control with no tre~tmPnt was also used. The Call~ i...TM was dosed at three levels 4000 mg/kg, 2500 mg/kg and 1000 mg/kg. The CytoxanTM was dosed at 125 mg/kg. After 8 days, the no tr~tm~nt group had lost 1 mouse, by day 10, 8 mice were dead and at day 11 all ten mice were dead. The mice in the CytoxanTM group survived more than 21days. The higher dose Carbton-1~7imTM group had one mouse die on day 14, two died on days 15,16 and 17 and one each died on days 20, 21, and 22. The mean number of days for this group is 17.3. The int~rm~ te dosage group had 2 mice die on day 14, 4 on day 15, 1 on day 16, 2 on day 19 and 1 on day 21. The mean number of days for this group is 16.50. The lowest dosage group had 2 mice die on day 12, 13, 14, and 15; and 1 died on each of days 16 and 17. The mean number of days for this group is 14.1.
Claims (10)
1. A pharmaceutical composition for treating treating comprising a safe and effective amount of:
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; and R is hydrogen or an alkyl group having from 1 to 8 carbon atoms, and R2 is 4-thiazolyl or NHCOOR1 wherein R1 is aliphatic hydrocarbon of less than 7 carbon atoms or the pharmaceutically acceptable inorganic or acid addition salts 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; and R is hydrogen or an alkyl group having from 1 to 8 carbon atoms, and R2 is 4-thiazolyl or NHCOOR1 wherein R1 is aliphatic hydrocarbon of less than 7 carbon atoms or the pharmaceutically acceptable inorganic or acid addition salts thereof.
2. A pharmaceutical composition according to Claim 1 comprising a pharmaceutically acceptable carrier and a safe and effective amount of a benzimidazole selected from the group consisting of:
wherein R is hydrogen or an alkyl having from 1 to 8 carbon atoms and R2 is selected from the group consisting of 4-thiazolyl, NHCOOR1, wherein R1 is methyl, ethyl or isopropyl and the pharmaceutically acceptable organic or inorganic acidaddition salts thereof.
wherein R is hydrogen or an alkyl having from 1 to 8 carbon atoms and R2 is selected from the group consisting of 4-thiazolyl, NHCOOR1, wherein R1 is methyl, ethyl or isopropyl and the pharmaceutically acceptable organic or inorganic acidaddition salts thereof.
3. A pharmaceutical composition according to Claim 2 wherein said benzimidazole is selected from the group consisting of 2-(4-thiazolyl)benzimidazole, methyl -(butylcarbamoyl)-2-benzimidazolecarbamate and 2-methoxycarbonylamino-benzimidazole.
4. A pharmaceutical composition according to Claim 1, 2 or 3 wherein said pharmaceutical acceptable acid addition salts are selected from the group consisting of chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates and mixtures thereof.
5. A method of treating leukemia in warm blooded mammals comprising administering from 2 mg/kg body weight to 400 mg/kg of a pharmaceutical composition comprising a benzimidazole according to Claim 1, 2, 3 or 4.
6. A method according to Claim 5 wherein said benzimidazole is administered orally or enterically, intravenously, peritoneally, or by injection into the bone marrow.
7. A method according to Claim 5 or 6 wherein said benzimidazole is administered in a liquid form and wherein said liquid dosage from is selected from the group consisting of aqueous solutions, alcohol solutions, emulsions, suspensions, and suspensions reconstituted from non-effervescent and effervescent preparations and suspensions in pharmaceutically acceptable fats or oils.
8. A unit dosage composition for treating leukemia infections in animals or humans comprising a benzimidazole according to Claims 1, 2, 3 or 4.
9. A unit dosage composition according to Claim 8 wherein said benzimidazole is administered in a solid form, wherein said solid form includes a carrier selected from the group consisting of lactose, sucrose, gelatin and agar.
10. A unit dosage composition according to Claim 9 wherein said benzimidazole is administered in a liquid form wherein said liquid dosage from is selected from the group consisting of aqueous solutions, emulsions, suspension solutions, and suspensions reconstituted from non-effervescent and effervescent preparations.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US47381795A | 1995-06-07 | 1995-06-07 | |
| US08/473,817 | 1995-06-07 |
Publications (1)
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|---|---|
| CA2223435A1 true CA2223435A1 (en) | 1996-12-19 |
Family
ID=23881113
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002223435A Abandoned CA2223435A1 (en) | 1995-06-07 | 1996-05-22 | Use of benzimidazoles for the manufacture of a medicament for the treatment of leukemia |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0831816A1 (en) |
| JP (1) | JPH11506732A (en) |
| KR (1) | KR19990022617A (en) |
| CN (1) | CN1186433A (en) |
| AR (1) | AR003137A1 (en) |
| AU (1) | AU717382B2 (en) |
| BR (1) | BR9608730A (en) |
| CA (1) | CA2223435A1 (en) |
| CZ (1) | CZ391197A3 (en) |
| HU (1) | HUP9802634A3 (en) |
| IL (1) | IL118424A0 (en) |
| NO (1) | NO975660L (en) |
| PL (1) | PL324026A1 (en) |
| SK (1) | SK168697A3 (en) |
| TR (1) | TR199701536T1 (en) |
| WO (1) | WO1996040122A1 (en) |
| ZA (1) | ZA964373B (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6262093B1 (en) | 1995-04-12 | 2001-07-17 | The Proctor & Gamble Company | Methods of treating cancer with benzimidazoles |
| US6479526B1 (en) | 1995-04-12 | 2002-11-12 | The Procter & Gamble Company | Pharmaceutical composition for inhibiting the growth of viruses and cancers |
| US6177460B1 (en) | 1995-04-12 | 2001-01-23 | The Procter & Gamble Company | Method of treatment for cancer or viral infections |
| US5770616A (en) | 1995-06-07 | 1998-06-23 | The Procter & Gamble Company | Pharmaceutical composition for inhibiting the growth of cancers |
| US6265427B1 (en) | 1995-06-07 | 2001-07-24 | The Proctor & Gamble Company | Pharmaceutical composition for the method of treating leukemia |
| US6686391B2 (en) | 1995-08-04 | 2004-02-03 | University Of Arizona Foundation | N-chlorophenylcarbamate and N-chlorophenylthiocarbamate compositions |
| US5900429A (en) | 1997-01-28 | 1999-05-04 | The Procter & Gamble Company | Method for inhibiting the growth of cancers |
| US6506783B1 (en) | 1997-05-16 | 2003-01-14 | The Procter & Gamble Company | Cancer treatments and pharmaceutical compositions therefor |
| US6245789B1 (en) | 1998-05-19 | 2001-06-12 | The Procter & Gamble Company | HIV and viral treatment |
| US6423734B1 (en) | 1999-08-13 | 2002-07-23 | The Procter & Gamble Company | Method of preventing cancer |
| US6380232B1 (en) | 2000-09-26 | 2002-04-30 | The Procter & Gamble Company | Benzimidazole urea derivatives, and pharmaceutical compositions and unit dosages thereof |
| US6462062B1 (en) | 2000-09-26 | 2002-10-08 | The Procter & Gamble Company | Compounds and methods for use thereof in the treatment of cancer or viral infections |
| US6608096B1 (en) | 2000-09-26 | 2003-08-19 | University Of Arizona Foundation | Compounds and methods for use thereof in the treatment of cancer or viral infections |
| US6407105B1 (en) | 2000-09-26 | 2002-06-18 | The Procter & Gamble Company | Compounds and methods for use thereof in the treatment of cancer or viral infections |
| EP2251010A1 (en) | 2009-05-08 | 2010-11-17 | Sygnis Bioscience GmbH & Co. KG | Use of thiabendazole and derivatives thereof for the therapy of neurological conditions |
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|---|---|---|---|---|
| NL134354C (en) * | 1963-05-23 | |||
| FR2155888A1 (en) * | 1971-10-13 | 1973-05-25 | Agot Aime | Solid anthelmintic composn - for more economical treatment of ruminants |
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1996
- 1996-05-22 CZ CZ973911A patent/CZ391197A3/en unknown
- 1996-05-22 BR BR9608730A patent/BR9608730A/en not_active Application Discontinuation
- 1996-05-22 CN CN96194465A patent/CN1186433A/en active Pending
- 1996-05-22 EP EP96914749A patent/EP0831816A1/en not_active Withdrawn
- 1996-05-22 PL PL96324026A patent/PL324026A1/en unknown
- 1996-05-22 JP JP9500667A patent/JPH11506732A/en active Pending
- 1996-05-22 WO PCT/US1996/007445 patent/WO1996040122A1/en not_active Application Discontinuation
- 1996-05-22 HU HU9802634A patent/HUP9802634A3/en unknown
- 1996-05-22 KR KR1019970709098A patent/KR19990022617A/en not_active Application Discontinuation
- 1996-05-22 SK SK1686-97A patent/SK168697A3/en unknown
- 1996-05-22 AU AU58020/96A patent/AU717382B2/en not_active Ceased
- 1996-05-22 CA CA002223435A patent/CA2223435A1/en not_active Abandoned
- 1996-05-22 TR TR97/01536T patent/TR199701536T1/en unknown
- 1996-05-27 IL IL11842496A patent/IL118424A0/en unknown
- 1996-05-29 ZA ZA964373A patent/ZA964373B/en unknown
- 1996-06-07 AR ARP960103043A patent/AR003137A1/en not_active Application Discontinuation
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1997
- 1997-12-05 NO NO975660A patent/NO975660L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| NO975660D0 (en) | 1997-12-05 |
| JPH11506732A (en) | 1999-06-15 |
| AR003137A1 (en) | 1998-07-08 |
| AU5802096A (en) | 1996-12-30 |
| PL324026A1 (en) | 1998-05-11 |
| IL118424A0 (en) | 1996-09-12 |
| EP0831816A1 (en) | 1998-04-01 |
| WO1996040122A1 (en) | 1996-12-19 |
| TR199701536T1 (en) | 1998-02-21 |
| NO975660L (en) | 1998-02-09 |
| AU717382B2 (en) | 2000-03-23 |
| KR19990022617A (en) | 1999-03-25 |
| SK168697A3 (en) | 1998-12-02 |
| CZ391197A3 (en) | 1998-05-13 |
| HUP9802634A2 (en) | 1999-03-29 |
| ZA964373B (en) | 1996-09-02 |
| HUP9802634A3 (en) | 1999-05-28 |
| CN1186433A (en) | 1998-07-01 |
| BR9608730A (en) | 1999-06-29 |
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| FZDE | Discontinued |