EP1017685A1 - Nouveaux derives de 2-(3h)-oxazolone - Google Patents

Nouveaux derives de 2-(3h)-oxazolone

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Publication number
EP1017685A1
EP1017685A1 EP98950000A EP98950000A EP1017685A1 EP 1017685 A1 EP1017685 A1 EP 1017685A1 EP 98950000 A EP98950000 A EP 98950000A EP 98950000 A EP98950000 A EP 98950000A EP 1017685 A1 EP1017685 A1 EP 1017685A1
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EP
European Patent Office
Prior art keywords
group
formula
compound
compound according
carbamate
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Withdrawn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
EP98950000A
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German (de)
English (en)
Inventor
Carles Puig Duran
Joan Feixas Gras
Juan M. Jimenez Mayorga
Ma Isabel Crespo Crespo
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Almirall SA
Original Assignee
Almirall Prodesfarma SA
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Publication of EP1017685A1 publication Critical patent/EP1017685A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/36—One oxygen atom
    • C07D263/38—One oxygen atom attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to new therapeutically useful 2- (3H) -oxazolone derivatives, to processes for their preparation and to pharmaceutical compositions containing them.
  • non steroidal anti-inflammatory drugs The mechanism of action of non steroidal anti-inflammatory drugs is believed to be the inhibition of the enzyme cyclooxygenase (COX) and consequently, the conversion of arachidonic acid into prostaglandins.
  • COX cyclooxygenase
  • COX-2 cyclooxygenase-2
  • the 2- (3H) -oxazolone derivative is a 4-aminosulphonylphenyl-2- (3H) oxazolone derivative having an aryl moiety at the oxazolone 3-position the substitution pattern of the aryl moiety is effectual in determining both the activity and selectivity of the compound.
  • R 1 is an alkyl or amino group
  • R 2 is a naphthyl, unsubstituted phenyl or phenyl group, substituted by from 1 to 3 halogen atoms (preferably chlorine, bromine or fluorine) or alkyl, alkoxy or trifiuoromethyl groups, and
  • R 3 is hydrogen or an alkyl group.
  • alkyl groups and moieties such as in the alkoxy groups, mentioned in relation to the groups R 1 to R 3 are usually "lower" alkyl, that is containing up to 6 and particularly up to 4 carbon atoms, the hydrocarbon chain being branched or straight.
  • a preferred alkyl group or moiety is methyl.
  • R 2 is a substituted phenyl group
  • substituents may be in any position on the phenyl group.
  • a single substituent may be on position 2, 3 or 4, (the 5 and 6 positions being equivalent to the 2 and 3 positions) ; and 2 or more substituents may be on any combination of positions 2, 3, 4, 5 and 6.
  • Preferred compounds of formula (I) are those in which R 1 is NH 2 or a methyl group; R 2 is a phenyl group substituted by from 1 to 3 substituents which may be the same or different and are selected from chlorine, fluorine and bromine atoms and methyl, ethyl, isopropyl, n-propyl, t-butyl, methoxy and trifiuoromethyl groups; and R 3 is hydrogen or methyl.
  • the phenyl group is preferably substituted by at least 2 alkyl groups which may be the same or different, 1 alkyl group and 1 alkoxy group, 1 alkyl group and 1 halogen atom, 1 alkoxy group and 1 halogen atom, 2 halogen atoms which may be the same as or different or 1 trifiuoromethyl group and 1 halogen atom.
  • R 2 represents a disubstituted phenyl group the substituents are preferably located at the 2 and 4, 2 and 5 or 3 and 4 positions.
  • R 2 is a phenyl group substituted by a methyl group, ethyl group, methoxy group or trifiuoromethyl group at the 3 or 4 position and which is optionally further substituted at any of the remaining positions by one or more chlorine or fluorine atoms.
  • Preferred compounds within this group are those wherein R 1 is NH 2 and R 3 is hydrogen or a methyl group, most preferably hydrogen.
  • R 2 is a difluoro phenyl group preferably a 2,5-difluoro diphenyl group or a 2,4-difluoro phenyl group.
  • R 2 is a phenyl group substituted by one or two halogen atoms, preferably fluorine or chlorine, and R 3 is a methyl group.
  • Particularly preferred compounds of formula (I) are the compounds of formula:
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is as defined below:
  • Another preferred group of compounds of the invention are compounds according to formula (I) in which R 1 is NH 2 ; R 2 is a 1-naphthyl or 2-naphthyl group; and R 3 is hydrogen or methyl.
  • the present invention also provides processes for preparing a compound of formula (I) which depends on the definition of R 1 .
  • the present invention provides a process for the preparation of a compound of formula (I) wherein R 1 is an alkyl group, viz. a 2- (3H) -oxazolone derivative of formula (II) :
  • R la is an alkyl group
  • R 2 and R 3 are as defined above which comprises reacting a carbamate of formula (V) :
  • R la , R 2 and R 3 are as defined above with anhydrous acetic acid.
  • the carbamate of formula (V) may be obtained, for example, by reacting a phenacyl alcohol of formula (III) :
  • R 2 is as defined above.
  • the reaction between the phenacyl alcohol of formula (III) and the isocyanate of formula (IV) may be carried out by heating a mixture of these two starting materials, optionally in the presence of an organic solvent such as toluene or xylene, at a temperature of from 80°C and 200°C.
  • the carbamate of formula (V) may also be prepared by reacting a thio derivative of general formula (VI) :
  • R la , R 2 and R 3 are as defined above, with an oxidizing agent, preferably magnesium monoperoxyphtalate or 3- chloroperoxybenzoic acid.
  • an oxidizing agent preferably magnesium monoperoxyphtalate or 3- chloroperoxybenzoic acid.
  • the reaction is preferably carried out in an organic solvent such as a mixture of methylene chloride with methanol or ethanol, at a temperature of from 10°C to 40°C.
  • the carbamate of formula (V) may be isolated after each process by known methods.
  • the carbamate may be heated to a temperature of from 80°C to 120°C with an excess of anhydrous acetic acid to give the compound of formula (II) .
  • the present invention also provides a process for the preparation of a compound of formula (I) wherein R 1 is an alkyl group, viz. a 2- (3H) -oxazolone derivative of formula (II), by reacting a mercapto derivative of formula (VII):
  • R la , R 2 and R 3 are as defined above, with an oxidizing agent, preferably with magnesium monoperoxyphtalate or 3- chloroperoxybenzoic acid.
  • the reaction between the mercapto derivative of formula (VII) and the oxidizing agent is preferably carried out, as previously disclosed for the compound of formula (VI), in an organic solvent such as a mixture of methylene chloride with methanol or ethanol, at a temperature of from 10°C to 40°C.
  • the present invention additionally provides a process for the preparation of a compound of formula (I) wherein R 1 is an amino group, viz. the 2- (3H) -oxazolone derivative of formula (VIII) :
  • R 2 and R 3 are as defined above with ammonia.
  • This reaction is preferably carried out at a temperature of from 10°C to 40°C.
  • the chlorosulphonyl derivative of formula (IX) may, for example, be prepared by reacting a compound of formula (X) :
  • R 2 and R 3 are as defined above with chlorosulphonic acid, preferably at a temperature of from 80°C to 120°C.
  • the present invention further provides a process for the preparation of a compound of formula (I) wherein R 1 is an amino group viz, the 2- (3H) -oxazolone derivative of formula (VIII) by debenzylation of the corresponding compound of formula (XI) :
  • R 2 and R 3 are as defined above.
  • the debenzylation is preferably carried out with an excess of trifluoroacetic, sulphuric or methanesulphonic acid at a temperature of from 0°C to 120°C.
  • intermediate compounds of formulae (VII) and (X) may be prepared by the same process disclosed for the preparation of compounds of formula (II), with the appropriate starting materials .
  • mice Male Wistar rats weighing 175-200 g with free access to food and water were used. On day 0, the animals received an intraplantar injection of a suspension of Mycobacterium tuberculosis in paraffin oil (0.5 mg/rat) on the left hind paw. A group of 8 nonarthritic control rats were injected with paraffin oil alone. On days 11 and 14 after induction of arthritis, the volume of the hind paw of each rat was measured using a water plehysmograph. Animals whose paw volumes increased during that time were selected. Rats were distributed into groups of 8 having equal mean paw volumes and an approximately equal standard deviation.
  • Test compounds were administered p.o. once daily for 7 days (days 14-20) .
  • Nonarthritic and arthritic control rats received vehicle alone for 7 days.
  • the hind paw volumes were measured 20h after the last dose (on day 21) .
  • the body weight was determined every second day.
  • results are expressed as the percentage of inhibition of inflammation (paw volume) for each treatment group, considering both the arthritic and nonarthritic vehicle controls.
  • the ANOVA test was used for statistical studies .
  • Animals Male Wistar rats (Interfauna, U.K., Ltd.) weighing about 150-175 g were used. Animals were maintained on a 12:12 hour light-dark cycle (lights on at 7:00 am) at room temperature (22 ⁇ 1°C) . Food and water were allowed ad libi tum.
  • Procedure The compounds were administered by the oral route once a day for 4 consecutive days. The body weight of each rat was assessed every day before drug administration. The animals were anesthesized 24h after the last dosing and 1 ml of blood was extracted by cardiac puncture using heparin (10 U/ml) as anticoagulant. The percentage of hematocrit was measured. The intestines were removed, opened longitudinally and gently washed. The macroscopic severity of the intestinal eorsions was assessed using a parametric scale, evaluating the number of the perforated and non-perforated intestinal ulcers by means of a lesion index ranging from 0 to 3 (0:no ulcers, 1:>10 ulcers, 2:10-25 ulcers to 3:>25 ulcers). No gastric ulcers are observed using this protocol.
  • the compounds of formula (I) are selective and potent COX-2 inhibitors.
  • the compounds of the invention are more effective in inhibiting COX-2 activity than they are inhibiting COX-1 activity, whereas the reference compound indomethacin is a equipotent as COX-2 and COX-1 inhibitor .
  • the preferred compounds of formula (I) have a ratio of (COX-1 IC 50 ) ⁇ M/ (COX-2 IC 50 ) ⁇ M of at least 3, preferably at least 4.5 and most preferably at least 10.
  • the preferred compounds of formula (I) are potent COX-2 inhibitors having a COX-2 IC 50 value of less than 5 ⁇ M preferably less than 3 ⁇ M and most preferably less than 2 ⁇ M.
  • the compounds of formula (I) Due to their low COX-1 activity, the compounds of formula (I) present an important anti-inflammatory activity (see Table 2) and the benefit of significantly less harmful side effects than the non-steroidal anti-inflammatory drugs commonly used (e.g. gastrointestinal toxicity (see Table 3), renal side-effects, reduced effect on bleeding times and asthma induction in aspirin-sensitive subjects) .
  • the present invention provides a compound of formula (I) for use in a method of treatment of the human or animal body by therapy, in particular for the treatment of pain, fever or inflammation, to inhibit prostanoid-induced smooth muscle contraction or for the prevention of colorectal cancer.
  • the present invention also provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment of pain, fever or inflammation, to inhibit prostanoid-induced smooth muscle contraction or for the prevention of colorectal cancer.
  • the compounds of formula (I) are useful for relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhoea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, bursitis, tendinitis, injuries, following surgical and dental procedures and arthritis including rheumatoid arthritis, osteoarthritis, gouty arthritis, spondyloarthopathies, systemic lupus erythematosus and juvenile arthritis. They may also be used in the treatment of skin inflammation disorders such as psoriasis, eczema, burning and dermatitis. In addition, such compounds
  • the compounds of formula (I) will also inhibit prostanoid- induced smooth muscle contraction and therefore may be used in the treatment of dysmenorrhoea, premature labour, asthma and bronchitis .
  • the compounds of formula (I) can be used as alternative to conventional non-steroidal anti-inflammatory drugs, particularly where such non-steroidal anti-inflammatory drugs may be contra-indicated such as the treatment of patients with gastrointestinal disorders including peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, Crohn's disease, inflammatory bowel syndrome and irritable bowl syndrome, gastrointestinal bleeding and coagulation disorders, kidney disease (e.g. impaired renal function), those prior to surgery or taking anticoagulants, and those susceptible to non- steroidal anti-inflammatory drugs induced asthma.
  • non-steroidal anti-inflammatory drugs may be contra-indicated such as the treatment of patients with gastrointestinal disorders including peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, Crohn's disease, inflammatory bowel syndrome and irritable bowl syndrome, gastrointestinal bleeding and coagulation disorders, kidney disease (e.g. impaired renal function), those prior to surgery or taking anticoagulants, and those susceptible to non- steroidal
  • the compounds can further be used to treat inflammation in diseases such as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anaemia, Hodgkin' s disease, scleroderma, type I diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, hypersensitivity, conjunctivitis, gingivitis and myocardial ischaemia.
  • diseases such as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anaemia, Hodgkin' s disease, scleroderma, type I diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, hypersensitivity, conjunctivitis, gingivitis and myocardial ischaemia.
  • Compounds of the present invention are inhibitors of cyclo
  • the present invention furthermore provides a pharmaceutical composition which comprises, as active ingredient, at least one 2- (3H) -oxazolone derivative of formula (I) and a pharmaceutically acceptable carrier or diluent.
  • a pharmaceutically acceptable carrier or diluent Preferably the compositions are in a form suitable for oral, topical, inhalation, rectal, transdermal, nasal or parenteral administration.
  • the pharmaceutically-acceptable carriers or diluents which are admixed with the active compound or compounds to form the compositions of this invention are well known per se and the actual excipients used depend inter alia on the intended method of administration of the compositions.
  • Compositions of this invention are preferably adapted for administration per os .
  • compositions for oral administration may take the form of tablets, capsules, lozenges or effervescent granules or liquid preparations such as elixirs, syrups or suspensions, all containing one or more compounds of the invention.
  • Such preparations may be made by methods well known in the art, for instance by mixing the 2- (3H) -oxazolone derivative of formula (I) with the pharmaceutically acceptable carrier or diluent.
  • the diluents which may be used in the preparation of the compositions include those liquid and solid diluents which are compatible with the active ingredient, together with colouring or flavouring agents if desired.
  • Tablets or capsules may conveniently contain between 10 and 500 mg and preferably from 15 to 100 mg of active ingredient.
  • the compounds may also be incorporated into pellets coated with appropriate natural or synthetic polymers known in the art to produce sustained release characteristics or incorporated with polymers into tablet form to produce the same characteristics.
  • the liquid compositions adapted for oral use may be in the form of solutions, suspensions or aerosols.
  • the solutions may be aqueous-alcoholic solutions of a 2- (3H) -oxazolone in association with, for example, sucrose or sorbitol to form a syrup.
  • the suspensions may comprise an insoluble or microencapsulated form of an active compound of the invention in association with water and other acceptable solvents together with a suspending agent or flavouring agent.
  • compositions for inahalation administration may be in the form of solutions, suspensions or micronized powder, contained in an appropriate inhaler.
  • Compositions for parenteral injection may be prepared in the form of microemulsions or microsuspensions in water or an appropriate parenteral injection fluid.
  • the doses of the 2- (3H) -oxazolone derivatives depend on the desired effect and duration of the treatment; adult doses are generally between 15 mg and 500 mg per day. In general the physician will decide the posology taking into account the age and weight of the patient being treated.
  • the 2- (3H) -oxazolone derivatives of formula (I) may be used in a method of treatment of any of the above conditions which comprises administering to a subject in need of such treatment an effective amount of the derivative of formula (I) .
  • Example 1 was repeated except that 3-fluoro-4- methoxyphenyl isocyanate (2.9g, 17.6 mmol) was used in place of the 4-ethylphenyl isocyanate. 3- (3-fluoro-4-methoxyphenyl) -4- (4-methylsulfonylphenyl) -2- (3H) -oxazolone (0.8g) was obtained and purified by column chromatography with silica gel, .p. 151°C (compound 2 in Table 4) .
  • EXAMPLE 3 a) A solution of 4- (N,N-dibenzylaminosulfonyl) phenacyl- N- (3-methylphenyl) carbamate (20 g; 37.8 mmoles) in anhydrous acetic acid (100 ml) was boiled under reflux for 6 hours. The solvent was removed under reduced pressure and the obtained solid was treated with diethyl ether. 3- (3-methylphenyl) -4- [4- N,N dibenzylaminosulfonyl) phenyl] -2- (3H) -oxazolone crystallized (16 g) , m.p.l60-162°C.
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl)phenacyl-N- (2-methylphenyl) carbamate (4.0g, 7.6 mmol) was used in place of the 4-(N,N- dibenzylaminosulfonyl)phenacyl-N- (3-methylphenyl) carbamate.3- (2-methylphenyl) -4- (4-aminosulfonylphenyl) -2- (3H) -oxazolone (0.8g) was obtained and purified by column chromatography with silica gel, m.p. 99-101 (d) °C (compound 4 in Table 4).
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl)phenacyl-N- (4-methylphenyl) carbamate (3.3g, 6.3 mmol) was used in place of the 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-methylphenyl) carbamate.3- (4-methylphenyl) -4- (4-aminosulfonylphenyl) -2- (3H) -oxazolone (l.Og) was obtained and purified by column chromatography with silica gel, m.p. 225°C (compound 5 in Table 4) .
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl)phenacyl-N-phenyl carbamate (7.2g, 13.9 mmol) was used in place of the 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-methylphenyl) carbamate.3- phenyl-4- (4-aminosulfonylphenyl) -2- (3H) -oxazolone (2.8g) was obtained and purified by column chromatography with silica gel, m.p. 208°C (compound 6 in Table 4) .
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (4-ethylphenyl) carbamate (2.6g, 4.8 mmol) was used in place of the 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-methylphenyl) carbamate.3- (4-ethylphenyl) -4- (4-aminosulfonylphenyl) -2- (3H) -oxazolone (250mg) was obtained and purified by column chromatography with silica gel, m.p. 199°C (compound 7 in Table 4) .
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (2-chlorophenyl) carbamate
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (4-bromophenyl) carbamate (12.4g, 20.9 mmol) was used in place of the 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-methylphenyl) carbamate.
  • 3- (4-bromophenyl) -4- (4-aminosulfonylphenyl ) -2- (3H) -oxazolone (3.8g) was obtained and purified by recrystallisation from ethyl acetate m.p. 226°C (compound 9 in Table 4) .
  • Example 3 was repeated except that 4-(N,N- dibenzyla inosulfonyl) phenacyl-N- (4-trifluoromethylphenyl) carbamate (4.9g, 8.4 mmol) was used in place of the 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-methylphenyl) carbamate.
  • 3- (4-trifluoromethylphenyl) -4- (4-aminosulfonylphenyl) -2- (3H) - oxazolone (1.7g) was obtained and purified by column chromatography with silica gel and n-hexane/ethyl acetate (2:1) as eluent m.p. 196°C (compound 10 in Table 4) .
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (4-methoxyphenyl) carbamate
  • Example 3 was repeated except that 4- (N, N- dibenzyl amino sulfonyl ) phenacyl-N- ( 2 - f luoro- 4 -methy lphenyl ) carbamate ( 8 . 7g, 15 . 9 mmol ) was used in place of the 4- (N, N- dibenzylaminosul fonyl ) phenacyl-N- ( 3-me thylphenyl ) carbamate .
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-fluoro-4-methylphenyl) carbamate (2.9g, 5.3 mmol) was used in place of the 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-methylphenyl) carbamate.3- (3-fluoro-4-methylphenyl) -4- (4-aminosulfonylphenyl) -2- (3H) - oxazolone (480mg) was obtained and purified by column chromatography with silica gel, m.p. 166°C (compound 13 in Table 4) .
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-chloro-4-methylphenyl) carbamate (5.6g 10.0 mmol) was used in place of the 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-methylphenyl) carbamate.3- (3-chloro-4-methylphenyl) -4- (4-aminosulfonylphenyl) -2- (3H) - oxazolone (2.2g) was obtained and purified by column chromatography with silica gel, m.p. 92-95°C (compound 14 in Table 4) .
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl)phenacyl-N- (3, 4-difluorophenyl) carbamate (3.6g, 6.5 mmol) was used in place of the 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-methylphenyl) carbamate.3- (3, 4-difluorophenyl) -4- (4-ar ⁇ inosulfonylphenyl) -2- (3H) -oxazolone (4.2g) was obtained and purified by column chromatography with silica gel, m.p. 168°C (compound 15 in Table 4) .
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (2, 5-difluorophenyl) carbamate (4.5g, 8.2 mmol) was used in place of the 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-methylphenyl) carbamate.3-
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-fluoro-4-methoxyphenyl) carbamate (10.8g, 19.2 mmol) was used in place of the 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-methylphenyl) carbamate.3- (3-fluoro-4-methoxyphenyl ) -4- ( 4-aminosulfonylphenyl) -2- (3H) - oxazolone (3.6g) was obtained and purified by column chromatography with silica gel, m.p. 184°C (compound 17 in Table 4) .
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-chloro-4-methoxyphenyl) carbamate (8.8g, 15.2 mmoles) was used in place of the 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-methylphenyl) carbamate.3- (3-chloro-4-methoxyphenyl) -4- (4-aminosulfonylphenyl) -2- (3H) - oxazolone (3.1g) was obtained and purified by column chromatography with silica gel and n-hexane/ethyl acetate (1:1) as eluent m.p. 194°C (compound 18 in Table 4) .
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (2-naphthyl) carbamate (8.2g,
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl) 2-methylphenacyl-N-phenyl carbamate (3.4g, 6.5 mmol) was used in place of the 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-methylphenyl) carbamate.3- phenyl-4- ( 4-aminosulfonylphenyl) -5-methyl-2- (3H) -oxazolone (170mg) was obtained and purified by column chromatography with silica gel and n-hexane/ethyl acetate (1:1) as eluent m.p. 101°C (compound 20 in Table 4) .
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl) -2-methylphenacyl-N- (2-fluorophenyl) carbamate (1.5g, 2.7 mmol) was used in place of the 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-methylphenyl) carbamate.3- (2-fluorophenyl) -4- (4-aminosulfonylphenyl) -5-methyl-2- (3H) - oxazolone (480mg) was obtained and purified by column chromatography with silica gel and n-hexane/ethyl acetate (2:5) as eluent m.p. 110-113°C (compound 21 in Table 4) .
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl) -2-methylphenacyl-N- (4-fluorophenyl) carbamate (3.1g, 5.6 mmol) was used in place of the 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-methylphenyl) carbamate.3- ( 4-fluorophenyl ) -4- ( 4-aminosulfonylphenyl ) -5-methyl-2- ( 3H) - oxazolone (200mg) was obtained and purified by column chromatography with silica gel, m.p. 100-105°C (compound 22 in Table 4) .
  • Example 3 was repeated except that 4- (N, N- dibenzyl aminosul fonyl ) 2-methylphenacyl-N- ( 4 -chlorophenyl ) carbamate ( 2 . 5g, 4 . 4 mmol ) was used in place of the 4- (N, N- dibenzylaminosulfonyl ) phenacyl-N- ( 3-methylphenyl ) carbamate .
  • 3- (4-chlorophenyl) -4- ( 4-aminosulfonylphenyl) -5-methyl-2- (3H) - oxazolone (360mg) was obtained and purified by column chromatography with silica gel, m.p. 223°C (compound 23 in Table 4) .
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl) 2-methylphenacyl-N- ( 4 - trifluoromethylphenyl) carbamate (3.6g, 6.0 mmol) was used in place of the 4- (N,N-dibenzylaminosulfonyl)phenacyl-N- (3- methylphenyl) carbamate.
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl) 2-methylphenacyl-N- (3-methylphenyl) carbamate (6.4g, 11.8 mmol) was used in place of the 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-methylphenyl) carbamate.3- (3-methylphenyl) -4- (4-aminosulfonylphenyl) -5-methyl-2- (3H) - oxazolone (850mg) was obtained and purified by column chromatography with silica gel, m.p. 165°C (compound 25 in Table 4) .
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl) 2-methylphenacyl-N- (4-methylphenyl) carbamate (1.2g, 2.2 mmol) was used in place of the 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-methylphenyl) carbamate.3- (4-methylphenyl) -4- (4-aminosulfonylphenyl) -5-methyl-2- (3H) - oxazolone (370mg) was obtained and purified by column chromatography with silica gel, m.p. 103-104°C (compound 26 in Table 4) .
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl) 2-methylphenacyl-N- ( 4-methoxyphenyl) carbamate (3.0g, 5.4 mmol) was used in place of the 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-methylphenyl) carbamate.3- (4-methoxyphenyl) -4- (4-aminosulfonylphenyl) -5-methyl-2- (3H) - oxazolone (580mg) was obtained and purified by column chromatography with silica gel, m.p. 210°C (compound 27 in Table 4) .
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulfonyl) -2-methylphenacyl-N- (3, 4-dichlorophenyl) carbamate (4.7g, 7.9 mmol) was used in place of the 4-(N,N- dibenzylaminosulfonyl) phenacyl-N- (3-methylphenyl) carbamate.3- (3, 4-dichlorophenyl) -4- (4-aminosulfonylphenyl) -5-methyl-2- (3H) - oxazolone (l.Og) was obtained and purified by column chromatography with silica gel, m.p. 132-136°C (compound 28 in Table 4) .
  • Example 3 was repeated except that 4-(N,N- dibenzylaminosulf onyl) -2-methylphenacyl-N- (3-fluoro-4- methylphenyl) carbamate (5.6g, 10.0 mmol) was used in place of the 4- (N, N-dibenzylaminosulf onyl) phenacyl-N- (3-methylphenyl) carbamate .
  • the above ingredients were sieved through a 60-mesh sieve, and were loaded into a suitable mixer and filled into 100,000 gelatine capsules.

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  • Pain & Pain Management (AREA)
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Abstract

Cette invention a trait à un composé de 2-(3H)-oxazolone correspondant à la formule (I) dans laquelle R1 représente un alkyle ou un groupe amino, R2 représente un naphtyle, un phényle ou un groupe phényle non substitué, substitué par de 1 à 3 atomes halogènes ou par un alkyle, un alcoxy ou par des groupes trifluorométhyle et dans laquelle R3 représente un hydrogène ou un groupe alkyle.
EP98950000A 1997-09-12 1998-09-08 Nouveaux derives de 2-(3h)-oxazolone Withdrawn EP1017685A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ES9701928 1997-09-12
ES009701928A ES2131015B1 (es) 1997-09-12 1997-09-12 Nuevos derivados de 2-(3h)-oxazolona, procedimientos para su preparacion y su empleo en composiciones farmaceuticas.
PCT/EP1998/005694 WO1999014205A1 (fr) 1997-09-12 1998-09-08 Nouveaux derives de 2-(3h)-oxazolone

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EP1017685A1 true EP1017685A1 (fr) 2000-07-12

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AR (1) AR017097A1 (fr)
AU (1) AU9623698A (fr)
CO (1) CO5011110A1 (fr)
ES (1) ES2131015B1 (fr)
PE (1) PE116999A1 (fr)
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US6833373B1 (en) 1998-12-23 2004-12-21 G.D. Searle & Co. Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
ES2166710B1 (es) * 2000-04-25 2004-10-16 J. URIACH & CIA, S.A. Nuevos compuestos heterociclicos con actividad antiinflamatoria.
US20030105144A1 (en) 2001-04-17 2003-06-05 Ping Gao Stabilized oral pharmaceutical composition
US6673818B2 (en) 2001-04-20 2004-01-06 Pharmacia Corporation Fluoro-substituted benzenesulfonyl compounds for the treatment of inflammation
ES2213485B1 (es) 2003-02-13 2005-12-16 Almirall Prodesfarma, S.A. Derivados de la 2-fenilpiran-4-ona.
WO2022195579A1 (fr) 2021-03-15 2022-09-22 Saul Yedgar Dipalmitoyl-phosphatidyl-éthanol-amine conjuguée à l'acide hyaluronique en combinaison avec des médicaments anti-inflammatoires non stéroïdiens (ains) pour traiter ou soulager des maladies inflammatoires

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US5380738A (en) * 1993-05-21 1995-01-10 Monsanto Company 2-substituted oxazoles further substituted by 4-fluorophenyl and 4-methylsulfonylphenyl as antiinflammatory agents
AU5860396A (en) * 1995-05-19 1996-11-29 G.D. Searle & Co. Substituted oxazoles for the treatment of inflammation
ES2125161B1 (es) * 1996-03-21 1999-11-16 Grupo Farmaceutico Almirall S Nuevos derivados de 2-(3h)-oxazolona.
FR2753449B1 (fr) * 1996-09-13 1998-12-04 Union Pharma Scient Appl Nouveaux derives 3,4-diaryloxazolone, leurs procedes de preparation, et leurs utilisations en therapeutique

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Title
See references of WO9914205A1 *

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WO1999014205A1 (fr) 1999-03-25
AR017097A1 (es) 2001-08-22
PE116999A1 (es) 1999-12-13
ZA988303B (en) 1999-03-11
ES2131015A1 (es) 1999-07-01
JP2001516750A (ja) 2001-10-02
CO5011110A1 (es) 2001-02-28
ES2131015B1 (es) 2000-03-01
UY25179A1 (es) 2000-12-29
AU9623698A (en) 1999-04-05

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