EP1718618A1 - Pyrazoline derivatives useful for the treatment of cancer - Google Patents
Pyrazoline derivatives useful for the treatment of cancerInfo
- Publication number
- EP1718618A1 EP1718618A1 EP05707483A EP05707483A EP1718618A1 EP 1718618 A1 EP1718618 A1 EP 1718618A1 EP 05707483 A EP05707483 A EP 05707483A EP 05707483 A EP05707483 A EP 05707483A EP 1718618 A1 EP1718618 A1 EP 1718618A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- cancer
- formula
- compound
- treatment
- compound according
- 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- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to new substituted pyrazoline compounds, pharmaceutical compositions containing such compounds and the use of these compounds for the treatment of cancer, in particular for the treatment of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer, especially for the treatment of colon cancer and/or bowel cancer and/or prostata cancer.
- WO 00/76503 discloses 1-(4-aminosulfonylaryl)-3-substituted 5-aryl-4,5-dihydro- pyrazoles as inhibitors of cyclooxygenase-2, for the treatment of inflammation and inflammation-related disorders as well as inhibitors of cellular neoplastic transformations and metastatic tumor growth.
- substituted pyrazoline compounds of formula I and of the formula I' show improved antitumoral activity in the treatment of cancer, especially of colon and/or prostata cancer, although these compounds do not inhibit cyclooxygenase-1 and/or cyclooxygenase-2.
- one aspect of the present invention is to provide compounds formula I and of the formula I'
- R 1 and R 2 is a methyl group
- R 3 and R 4 are a C- ⁇ - 6 alkyl group, of which at least one is substituted with at least one halogen atom,
- R 3 and R 4 are C-
- R 3 and R 4 is a methyl group, of which at least one is substituted with at least one halogen atom, and their diastereomers and/or enantiomers or mixtures thereof including their racemates and pharmaceutically acceptable salts thereof.
- R 3 and R 4 is a methyl group, of which at least one is substituted with at least one fluorine and/or chlorine atom, and their diastereomers and/or enantiomers or mixtures thereof including their racemates and pharmaceutically acceptable salts thereof.
- R 3 and R 4 is a methyl group and is substituted with at least one fluorine and/or chlorine atom, and their diastereomers and/or enantiomers or mixtures thereof including their racemates and pharmaceutically acceptable salts thereof.
- R 3 and R 4 is a CF 3 group, and their diastereomers and/or enantiomers or mixtures thereof including their racemates and pharmaceutically acceptable salts thereof.
- the inventive compound of the formula I can be prepared via a general route according to the following reaction scheme:
- R 1 and R 2 have the meaning given above.
- the inventive compound of the formula I is obtained by reaction of a compound of the formula II
- the reaction is preferably carried out in an organic solvent like an alcohol, methanol or ethanol, or an ether, dioxane or tetrahydrofurane.
- the reaction preferably takes place in acidic medium.
- Preferred is the addition of an organic acid like acetic acid or an inorganic acid like hydrochloric acid.
- the reaction can also take place in basic medium.
- Preferred is the addition of a base like piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide, or sodium ethoxide.
- the reaction temperature can range from ambient temperature to the refluxing temperature of the organic solvent and the reaction time can last from hours up to days.
- the compounds of the formula I' according to the invention can be prepared via a general route according to the following scheme:
- R 3 and R 4 have the meaning given above.
- a inventive compound of the general formula I' can be obtained by reacting a compound of the general formula II'
- the reaction can be carried out in an organic solvent like an alcohol, e.g. methanol or ethanol, or an ether, e.g. dioxane or tetrahydrofurane.
- the reaction can take place in acidic medium.
- Preferred is the addition of an organic acid like acetic acid or an inorganic acid like hydrochloric acid.
- the reaction can also take place in basic medium. Preferred is therefore the addition of a base like piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide.
- the reaction temperature can range from ambient temperature up to the refluxing temperature of the organic solvent and the reaction time can last from hours up to days.
- the compound of the formula II an intermediate for the synthetic pathway to obtain the inventive compound of the formula I, can be prepared via a well known route by reacting a substituted benzaldehyde according to formula IV IV
- R 1 and R 2 have the above mentioned meanings, with either N-phenyl-1- chloro-trifluoroacetimide in presence of a dialkylphosphonate like diethylmethylphosphonate and a strong base, preferably an organic base like LDA or by a Wittig reaction with mono-, di- or trifluoracetylmethylentriphenylphosphoran and a base like sodium carbonate or potassium carbonate.
- the reaction can be carried out in a solvent like dichloromethane, chloroforme, or an ether like tetrahydrofurane, .ethyl ether, dimethoxyethane or dioxane.
- the reaction temperatures can range from -70°C to the refluxing temperature of the organic solvent.
- the reaction time can range from minutes up to several hours.
- the compound of the formula II can also be prepared via an aldol condensation of an aldehyde of the general formula IV, in which R 1 and R 2 have the above mentioned meanings, and 1 ,1 ,1-trifluoracetone.
- the reaction can be carried out in presence of an inorganic base, e.g. a hydroxide of an alkali metal such as lithium, sodium or potassium hydroxide, or an organic base such as piperidine in an organic solvent like tetrahydrofurane, dimethoxyethane, dimethylsulfoxide, dimethylformamide, methanol, ethanol, optionally in presence of water.
- the temperature of the condensation reaction can range from -20°C to room temperature and the reaction time can range from hours up to days.
- the compound of the formula II' can be prepared via a general route by reacting a substituted benzaldehyde according to formula IV IV
- R 3 and R 4 have the above mentioned meanings, with either N-phenyl-1- chlor-trifluoracetimide in presence of a dialkylphosphonate like diethylmethylphosphonate and a strong base, preferably an organic base like LDA or by a Wittig reaction with mono-, di- or trifluoracetylmethylentriphenylphosphoran and a base like sodium carbonate or potassium carbonate.
- the reaction can be carried out in an organic solvent like dichloromethane, chloroforme, or an ether like tetrahydrofurane, ethyl ether, dimethoxyethane or dioxane.
- the reaction temperatures can range from -70°C to the refluxing temperature of the organic solvent.
- the reaction time can range from minutes up to several hours.
- the compound of the formula II can also be prepared via an aldol condensation of an aldehyde of the general formula IV, in which R 3 and R 4 have the above mentioned meanings, and 1 ,1 ,1-trifluoracetone.
- the reaction can be carried out in presence of an inorganic base, e.g. a hydroxide of an alkali metal such as lithium, sodium or potassium hydroxide, or an organic base such as piperidine in a solvent like tetrahydrofurane, dimethoxyethane, dimethylsulfoxide, dimethylformamide, methanol, ethanol, optionally in presence of water.
- the temperature of the condensation reaction can range from -20°C and room temperature and the reaction time ranges from hours up to days.
- inventive compounds of formula I and I' can be isolated in form of their bases or in form of any of their pharmaceutically acceptable salts.
- the present invention also relates to the use of at least one substituted pyrazoline compound of the general formula I and/or formula I' for the manufacture of a medicament for the treatment of cancer, in particular for the treatment of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer, prostata cancer, colon cancer and/or bowel cancer, especially for the treatment of colon cancer, prostata cancer and/or bowel cancer.
- the present invention also relates to a pharmaceutical composition
- a pharmaceutical composition comprising at least one compound of the general formula I and/or formula I' for administering to humans or animals, preferably humans including infants, children and adults.
- the inventive composition can be produced by standard procedures known to those skilled in the art.
- the composition of the medicament may vary depending on the route of administration by the addition of well known auxiliaries.
- inventive pharmaceutical compositions of the present invention may for example be administered parentally in combination with conventional injectable liquid carriers, such as water or suitable alcohols.
- conventional pharmaceutical excipients for injection such as stabilizing agents, solubilizing agents, and buffers, may be included in such injectable compositions.
- These pharmaceutical compositions may preferably be injected intramuscularly, intraperitoneally, or intravenously.
- inventive pharmaceutical preparations may also be formulated as orally administrable preparations containing one or more physiologically compatible carriers or excipients, in solid or liquid form. These preparations may contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents.
- the preparations may take any convenient form, such as tablets, pellets, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, or dry powdered forms suitable for reconstitution with water or other suitable liquid medium before use, for immediate or retarded release.
- the inventive compositions may be also formulated multi particular.
- the liquids for oral administration may also contain certain additives such as sweeteners, flavoring, preservatives, and emulsifying agents.
- Non-aqueous liquid compositions for oral administration may also be formulated, containing edible oils. Such liquid compositions may be conveniently encapsulated in e.g., gelatin capsules in a unit dosage amount.
- compositions respectively preparations of the present invention may also be administered topically or via a suppository.
- the daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, sex, weight or degree of illness and so forth.
- the daily dosage for humans may preferably be in the range froml to 2000, preferably 1 to 1500, more preferably 1 to 1000 milligrams of active substance to be administered during one or several intakes per day.
- inventive compounds were evaluated measuring cell metabolic capacity (viability), using the XTT kit and following the recommendations of the manufacturer (Roche Diagnostics).
- the assays were carried out a minimum of five times, with controls containing unexposed cells, cells with vehicle, or media plus compound. Cells were seeded into 96-well plates in 100 ⁇ l of media and incubated for 24 h. Afterwards, the inventive compounds were added at different combination of concentrations (from 1 ⁇ M to 80 ⁇ M) for 4 h (short time XTT) or 60h (long time XTT). At the end of the incubation period, 50 ⁇ l of a mixture containing XTT and electron coupling reagent to each well were added.
- the inhibitory concentration 50 (IC 5 o) was determined from the dose-response curves of compound concentration versus percentage of cell viability with the Hill sigmoidal equation (three parameters), using Sigmaplot 5.0 software.
- the compounds of Examples 1 and 2 do not display any inhibiting activity of enzymes COX-1 and COX-2.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES200400362A ES2238923B1 (es) | 2004-02-16 | 2004-02-16 | Nuevos derivados pirazolinicos sustituidos. |
US10/804,695 US20050182119A1 (en) | 2004-02-16 | 2004-03-19 | Substituted pyrazoline derivatives |
PCT/EP2005/001656 WO2005077910A1 (en) | 2004-02-16 | 2005-02-16 | Pyrazoline derivatives useful for the treatment of cancer |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1718618A1 true EP1718618A1 (en) | 2006-11-08 |
Family
ID=34863166
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP05707483A Withdrawn EP1718618A1 (en) | 2004-02-16 | 2005-02-16 | Pyrazoline derivatives useful for the treatment of cancer |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP1718618A1 (no) |
JP (1) | JP2007522180A (no) |
KR (1) | KR20070044799A (no) |
AU (1) | AU2005212833A1 (no) |
BR (1) | BRPI0507718A (no) |
CA (1) | CA2556478A1 (no) |
NO (1) | NO20064185L (no) |
RU (1) | RU2006133150A (no) |
WO (1) | WO2005077910A1 (no) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008308473A (ja) * | 2007-06-18 | 2008-12-25 | Japan Health Science Foundation | 癌治療剤 |
CN101735150B (zh) * | 2009-12-16 | 2011-12-28 | 南京大学 | 一类含有吡唑环的硫脲类衍生物及其制法和用途 |
CN101759695B (zh) * | 2009-12-30 | 2011-09-14 | 南京大学 | 一类含有吡唑环的噻唑类衍生物及其制法和用途 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE361748T1 (de) * | 1999-06-16 | 2007-06-15 | Univ Temple | 1-(4-sulfamylphenyl)-3-trifluormethyl-5-aryl-2- pyrazoline als cyclooxygenase-2 inhibitoren |
ES2174757B1 (es) * | 2001-04-06 | 2003-11-01 | Esteve Labor Dr | Empleo de derivados de firazolinas en la elaboracion de un medicamentopara la prevencion y/o el tratamiento de enfermedades proliferativas celulares. |
-
2005
- 2005-02-16 JP JP2006552580A patent/JP2007522180A/ja active Pending
- 2005-02-16 KR KR1020067018161A patent/KR20070044799A/ko not_active Application Discontinuation
- 2005-02-16 BR BRPI0507718-4A patent/BRPI0507718A/pt not_active IP Right Cessation
- 2005-02-16 AU AU2005212833A patent/AU2005212833A1/en not_active Abandoned
- 2005-02-16 RU RU2006133150/04A patent/RU2006133150A/ru unknown
- 2005-02-16 WO PCT/EP2005/001656 patent/WO2005077910A1/en active Application Filing
- 2005-02-16 EP EP05707483A patent/EP1718618A1/en not_active Withdrawn
- 2005-02-16 CA CA002556478A patent/CA2556478A1/en not_active Abandoned
-
2006
- 2006-09-15 NO NO20064185A patent/NO20064185L/no not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO2005077910A1 * |
Also Published As
Publication number | Publication date |
---|---|
KR20070044799A (ko) | 2007-04-30 |
NO20064185L (no) | 2006-11-13 |
CA2556478A1 (en) | 2005-08-25 |
BRPI0507718A (pt) | 2007-07-03 |
AU2005212833A1 (en) | 2005-08-25 |
JP2007522180A (ja) | 2007-08-09 |
RU2006133150A (ru) | 2008-04-10 |
WO2005077910A1 (en) | 2005-08-25 |
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Legal Events
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