EP0831816A1 - 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

Info

Publication number
EP0831816A1
EP0831816A1 EP96914749A EP96914749A EP0831816A1 EP 0831816 A1 EP0831816 A1 EP 0831816A1 EP 96914749 A EP96914749 A EP 96914749A EP 96914749 A EP96914749 A EP 96914749A EP 0831816 A1 EP0831816 A1 EP 0831816A1
Authority
EP
European Patent Office
Prior art keywords
benzimidazole
group
carbon atoms
less
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96914749A
Other languages
German (de)
English (en)
French (fr)
Inventor
James Berger Camden
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Procter and Gamble Co
Original Assignee
Procter and Gamble Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Procter and Gamble Co filed Critical Procter and Gamble Co
Publication of EP0831816A1 publication Critical patent/EP0831816A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • 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

Definitions

  • This invention is a pharmaceutical composition that is useful for the treatment of leukemia, particularly in human and warm blooded animals.
  • the composition contains a benzimidazole derivative.
  • chemotherapeutic agents Many types have been shown to be effective against leukemia, but not all types of leukemia and tumor cells respond to these agents. Unfortunately, many of these agents also destroy normal cells. The exact mechanism for the action of these chemotherapeutic agents are not always known.
  • cytocidal or cytostatic agents work best on cancers with large growth factors, i.e., ones whose cells are rapidly dividing.
  • hormones in particular estrogen, progesterone and testosterone, and some antibiotics produced by a variety of microbes, alkylating agents, and anti-metabolites form the bulk of therapies available to oncologists.
  • cytotoxic agents that have specificity for leukemia, cancer and tumor cells while not affecting normal 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.
  • a pharmaceutical composition for treatment of mammals, and in particular, warm blooded animals and humans, which are affected by leukemia comprising a pharmaceutical carrier and an effective amount of a compound selected from the group consisting of:
  • 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 of from 1 to 8 carbon atoms and R2 is 4-thiazolyl, NHCOOR j wherein Rj is aliphatic hydrocarbon of less than 7 carbon atoms, and preferably an alkyl group of less than 7 carbon atoms is claimed.
  • the compositions are:
  • R is an alkyl of 1 through 8 carbon atoms and R2 is selected from the group consisting of 4-thiazolyl, NHCOORi , wherein Rj is methyl, ethyl or isopropyl and the non-toxic, pharmaceutically acceptable acid addition salts with both organic and inorganic acids.
  • the most preferred compounds are 2-(4- thiazolyl)benzimidazole, methyl -(butylcarbamoyl)-2-benzimidazolecarbamate and 2-methoxycarbonylamino-benzimidazole and those wherein Y is chloro.
  • compositions can be used to inhibit the growth of leukemia cells in humans or animals by administration of an effective amount either orally, rectally, topically or parenterally, or intravenously. These compositions do not significantly affect healthy cells.
  • the term “comprising” means various components can be conjointly employed in the pharmaceutical composition of this invention. Accordingly, the terms “consisting essentially of and “consisting of are embodied in the term comprising.
  • 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.
  • safe and effective amount 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, obviously, vary with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal 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.
  • a “pharmaceutical addition salts” is salt of the anti-leukemia compound with an organic or inorganic acid.
  • These preferred acid addition salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like.
  • a “pharmaceutical carrier” is a pharmaceutically acceptable solvent, suspending agent or vehicle for debvering the anti-leukemia agent to the animal or human.
  • the carrier may be liquid or solid and is selected with the planned manner of administration in mind.
  • cancer or “leukemia” refers to all types of cancers or neoplasm or malignant disease which attack normal healthy blood cells or bone marrow which produces blood cells which are found in mammals.
  • the "anti-leukemia compounds” are the benzimidazoles, and their salts.
  • the exact " benzimidazoles are described in detail below.
  • the preferred materials are the products sold under the names “thiabendazole®”, “benomyl®” and “carbendazim®” by BASF and Hoechst, DuPont and MSD-AgVet.
  • the anti-leukemia compounds are benzimidazole derivatives which are known for their antifungal activities. They are systemic fungicides used to prevent and eradicate fungi.
  • the compounds have the following structure:
  • 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 carbons, and R2 is 4-thiazolyl, NHCOORi wherein R is aliphatic hydrocarbon of less than 7 carbon atoms, and preferably and alkyl group of less than 7 carbon atoms.
  • the compositions are:
  • R is an alkyl of 1 through 8 carbon atoms and R2 is selected from the group consisting of 4-thiazolyl, NHCOORi , wherein R ⁇ is methyl, ethyl or isopropyl and the non-toxic, pharmaceutically acceptable acid addition salts with both organic and inorganic acids.
  • any suitable dosage may be given in the method of the invention.
  • the type of compound 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 leukemia being treated. Generally a dosage of between about 2 milligrams (mg) per kilogram (kg) of body weight and about 400 mg per kg of body weight is suitable.
  • a dosage unit may comprise a single compound or mixtures thereof with other compounds or other cancer inhibiting compounds.
  • the dosage unit can also comprise diluents, extenders, carriers and the like.
  • the unit may be in solid or gel form such as pills, tablets, capsules and the like or in liquid form suitable for oral, rectal, topical, intravenous injection or parenteral administration or injection into or around the bone marrow.
  • the anti-leukemia compounds are typically mixed with a pharmaceutically acceptable carrier.
  • This carrier can be a solid or liquid and the type is generally chosen based on the type of administration being used.
  • the active agent can be coadministered in the form of a tablet or capsule, as an agglomerated powder or in a liquid form.
  • suitable solid carriers include lactose, sucrose, gelatin and agar.
  • Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • liquid dosage forms examples include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
  • Oral dosage forms optionally contain flavorants and coloring agents.
  • Parenteral and intravenous forms would also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
  • the method of treatment can be any suitable method which is effective in the treatment of the particular leukemia type being treated.
  • Treatment may be oral, rectal, topical, parenteral or intravenous administration or by injection into the bone marrow.
  • the method of applying an effective amount also varies depending on the leukemia being treated. It is believed that parenteral treatment by intravenous, subcutaneous, or intramuscular application of the benzimidazole compounds, formulated with an appropriate carrier, additional cancer inhibiting compound or compounds or diluent to facilitate application will be the preferred method of administering the compounds to warm blooded animals.
  • mice are randomly selected and divided into groups for treatment. Five groups are infected with leukemia. The diseased animals 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 irregualr pattern was not an ideal mitien, but the results do show a positive benefit for the CarbendazimTM.
  • mice 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 CarbendazimTM, methyl -(butylcarbamoyl)-2-benzimidazole-carbamate. A control with no treatment was also used. The CarbendazimTM 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 treatment group had lost 1 mouse, by day 10, 8 mice were dead and at day 11 all ten mice were dead.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Hematology (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)
EP96914749A 1995-06-07 1996-05-22 Use of benzimidazoles for the manufacture of a medicament for the treatment of leukemia Withdrawn EP0831816A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US47381795A 1995-06-07 1995-06-07
US473817 1995-06-07
PCT/US1996/007445 WO1996040122A1 (en) 1995-06-07 1996-05-22 Use of benzimidazoles for the manufacture of a medicament for the treatment of leukemia

Publications (1)

Publication Number Publication Date
EP0831816A1 true EP0831816A1 (en) 1998-04-01

Family

ID=23881113

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96914749A Withdrawn EP0831816A1 (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 (zh)
JP (1) JPH11506732A (zh)
KR (1) KR19990022617A (zh)
CN (1) CN1186433A (zh)
AR (1) AR003137A1 (zh)
AU (1) AU717382B2 (zh)
BR (1) BR9608730A (zh)
CA (1) CA2223435A1 (zh)
CZ (1) CZ391197A3 (zh)
HU (1) HUP9802634A3 (zh)
IL (1) IL118424A0 (zh)
NO (1) NO975660L (zh)
PL (1) PL324026A1 (zh)
SK (1) SK168697A3 (zh)
TR (1) TR199701536T1 (zh)
WO (1) WO1996040122A1 (zh)
ZA (1) ZA964373B (zh)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6177460B1 (en) 1995-04-12 2001-01-23 The Procter & Gamble Company Method of treatment for cancer or viral infections
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
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
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
US6380232B1 (en) 2000-09-26 2002-04-30 The Procter & Gamble Company Benzimidazole urea derivatives, and pharmaceutical compositions and unit dosages thereof
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
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
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

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996032107A1 (en) * 1995-04-12 1996-10-17 The Procter & Gamble Company A pharmaceutical composition containing benzimidazole for inhibiting the growth of cancers

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL134354C (zh) * 1963-05-23
FR2155888A1 (en) * 1971-10-13 1973-05-25 Agot Aime Solid anthelmintic composn - for more economical treatment of ruminants

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996032107A1 (en) * 1995-04-12 1996-10-17 The Procter & Gamble Company A pharmaceutical composition containing benzimidazole for inhibiting the growth of cancers

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
LAPPRAS M, ET AL.: "ETUDE EXPERIMENTALE DES PROPTIETES ANTICANCEREUSES POTENTIELLES DU PARBENDAZOLE (SKF 29044)", BULLETIN DE LA SOCIETE DES SCIENCES VETERINAIRES ET DE MEDECINECOMPAREE DE LYON, DE LYON, LYON, vol. 77, 1 January 1975 (1975-01-01), pages 379 - 397, XP000915864, ISSN: 0301-1194 *
MARINOVICH M., GUIZZETTI M., GALLI C. L.: "MIXTURES OF BENOMYL, PIRIMIPHOS-METHYL, DIMETHOATE, DIAZINON AND AZINPHOS-METHYL AFFECT PROTEIN SYNTHESIS IN HL-60 CELLS DIFFERENTLY", TOXICOLOGY., LIMERICK, IR, vol. 94., no. 01/03., 1 January 1994 (1994-01-01), IR, pages 173 - 185., XP000579566, ISSN: 0300-483X, DOI: 10.1016/0300-483X(94)90036-1 *
See also references of WO9640122A1 *

Also Published As

Publication number Publication date
AR003137A1 (es) 1998-07-08
NO975660L (no) 1998-02-09
AU5802096A (en) 1996-12-30
JPH11506732A (ja) 1999-06-15
BR9608730A (pt) 1999-06-29
HUP9802634A2 (hu) 1999-03-29
IL118424A0 (en) 1996-09-12
CZ391197A3 (cs) 1998-05-13
TR199701536T1 (xx) 1998-02-21
HUP9802634A3 (en) 1999-05-28
KR19990022617A (ko) 1999-03-25
AU717382B2 (en) 2000-03-23
CN1186433A (zh) 1998-07-01
PL324026A1 (en) 1998-05-11
SK168697A3 (en) 1998-12-02
CA2223435A1 (en) 1996-12-19
WO1996040122A1 (en) 1996-12-19
NO975660D0 (no) 1997-12-05
ZA964373B (en) 1996-09-02

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