WO2000076983A1 - 1-(4-arylesulfonyle)-3-substitue-5-aryle-2-pyrazolines comme inhibiteurs de la cyclo-oxygenase-2 - Google Patents

1-(4-arylesulfonyle)-3-substitue-5-aryle-2-pyrazolines comme inhibiteurs de la cyclo-oxygenase-2 Download PDF

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WO2000076983A1
WO2000076983A1 PCT/US2000/016727 US0016727W WO0076983A1 WO 2000076983 A1 WO2000076983 A1 WO 2000076983A1 US 0016727 W US0016727 W US 0016727W WO 0076983 A1 WO0076983 A1 WO 0076983A1
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pharmaceutically acceptable
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E. Premkumar Reddy
M. V. Ramana Reddy
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Temple University - Of The Commonwealth System Of Higher Education
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the invention relates generally to anti-inflammatory drugs, and more particularly to novel compounds which inhibit the activity of cyclooxygenase-2.
  • prostaglandins mediate both beneficial and -undesirable biological reactions.
  • the production of prostaglandins induces pain, swelling, heat and redness which are characteristic features of inflammation.
  • the chronic inflammation associated with prostaglandin production leads to the breakdown of the injured tissue and angiogenesis.
  • pathologic chronic inflammation normal tissues can be destroyed and the new blood vessel formation can support growth of abnormal tissue.
  • Prostaglandins are also important for normal physiological processes in different organs. In the stomach, prostaglandins protect mucosa from acid. They also regulate blood flow and salt-water balance in the kidney. Prostaglandins are also important in platelets aggregation and participate in memory and other cognitive functions.
  • Prostaglandins are produced from cell membrane phospholipids by a cascade of enzymes. The enzymatic activities involve release of arachidonic acid from the cell membrane by phospholipase A 2 , followed by the conversion of arachidonic acid to a common prostaglandin precursor, PGH 2 , by cyclooxygenase (also called prostaglandin H synthase). PGH 2 is finally converted to various types of prostaglandins (PGE T , PGE 2 , PGI 2 or prostacyclin, PGF 2 ⁇ and thromboxane) by cell- specific synthases.
  • PGE T PGE T , PGE 2 , PGI 2 or prostacyclin, PGF 2 ⁇ and thromboxane
  • Aspirin and other nonsteroidal anti-inflammatory drugs block the formation of prostaglandins by inhibiting cyclooxygenase activity. They have analgesic, antipyretic and anti- inflammatory activities.
  • chronic treatment with the available NSAIDs often leads to disruption of beneficial prostaglandin-mediated processes.
  • the side effects associated with constant usage of NSAIDs include gastrointestinal (Gl) irritation and formation of life-threatening Gl ulcers.
  • Gl gastrointestinal
  • a dramatic advance in the field of inflammation research came with discovery of multiple enzymes for each step of the prostaglandin synthase cascade. The research suggested that in some situations, such as inflammation, cyclooxygenase was inducible.
  • COX-1 The cyclooxygenase known at the time, cyclooxygenase- 1 (COX-1), was clearly non-inducible or modulated by glucocorticoids.
  • COX-1 is the constitutive cyclooxygenase isoform and is mainly responsible for the synthesis of cytoprotective prostaglandins in the Gl tract and the synthesis of thromboxane which triggers platelet aggregation in blood platelets.
  • COX-2 is inducible and short lived except in the case of certain tumors where it is constitutively activated.
  • COX-2 expression is stimulated in response to endotoxins, cytokines, hormones, growth factors and mitogens.
  • endotoxins, cytokines, hormones, growth factors and mitogens These observations suggest that COX-1 and COX-2 serve different physiological and pathophysiological functions. Indeed, it has been suggested that COX-1 is responsible for endogenous basal release of prostaglandins and hence is important to the physiological functions of prostaglandins such as Gl integrity and renal blood flow. On the other hand, it has been suggested that COX-2 is mainly responsible for the pathological effects of prostaglandins, where induction of the enzyme occurs in response to inflammatory agents, hormones, growth factors and cytokines. See, U.S. Pat. 5,604,253, incorporated herein by reference, for a discussion of the advantages of selective COX-2 inhibition. Principally, a selective COX-2 inhibitor is expected to possess similar anti- inflammatory, antipyretic and analgesic properties to a conventional NSAID but with reduced potential for gastrointestinal toxicity, and
  • the differential tissue distribution of COX-1 and COX-2 provides an approach to develop selective inhibitors for COX-2 with reduced effect on COX-1 , thereby preventing gastric side effects.
  • 5,604,253 discloses N- benzylindol-3-yl propanoic acid derivatives as cyclooxygenase inhibitors. What is needed are additional COX-2 inhibitors, particularly compounds which selectively inhibit the cyclooxygenase activity of COX-2 over COX-1. Summary of the Invention
  • X is selected from the group consisting of C C 6 trihalomethyl, preferably trifluoromethyl; C C 6 alkyl, and an optionally substituted or di- substituted phenyl group of formula II:
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, halogen, preferably chlorine, fluorine and bromine; hydroxyl; nitro; C C 6 alkyl, preferably C r C 3 alkyl; C r C 6 alkoxy, preferably C C 3 alkoxy; carboxy; C r C 6 trihaloalkyl, preferably trihalomethyl, most preferably trifluoromethyl; and cyano; Z is selected from the group consisting of substituted and unsubstituted aryl; and Q is selected from the group consisting of substituted and unsubstituted phenyl.
  • the carbon chains in the alkyl and alkoxy groups which may occur in X, Z and Q may be straight or branched.
  • aryl alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
  • aryl is intended to include not only aromatic systems containing only carbon ring atoms but also systems containing one or more non-carbon atoms as ring atoms. Such systems may be known as “heteroaryl” systems. The term “aryl” is thus deemed to include “heteroaryl”.
  • Preferred aryl groups Z include phenyl and heteroaryl.
  • the aryl groups may be substituted or unsubstituted.
  • substituted is meant any level of substitution, although mon- di- and tri-substitution are preferred.
  • the substituents are independently selected.
  • the substituents are preferably selected from the group consisting of halogen, particularly chlorine, fluorine and bromine; hydroxyl; nitro; C C 6 alkyl, preferably C C 3 alkyl, most preferably methyl; C C 6 alkoxy, preferably C C 3 alkoxy, most preferably methoxy; carboxy; C C 6 trihaloalkyl, preferably trihalomethyl, most preferably trifluoromethyl; and cyano.
  • mono-, di- and tri- substitution are preferred, full substitution, particularly on phenyl, is possible.
  • Z is phenyl, and is mono-, di-, tri-, tetra- or penta-substituted with halogen.
  • Q is phenyl mono-, di-, tri-, tetra- or penta- substituted with halogen.
  • the halogen atoms may be the same or different.
  • Z is an aryl group other than phenyl or substituted phenyl, particularly substituted or unsubstituted heteroaryl.
  • heteroaryl radicals include, for example, pyridyl, particularly 2-, 3- and 4-pyridyl; thienyl, particularly 2- and 3-thienyl; furyl, particularly 2- and 3-furyl; indolyl, particularly 3-, 4-, 5-, 6-, 7- and 8-indolyl; benzothienyl, particularly 3-, 4-, 5-, 6-, 7- and 8-benzothienyl; benzofuryl, particularly 3-, 4-, 5-, 6-, 7- and 8 benzofuryl; imidazolyl, particularly 2- and 5-imidazolyl; pyrazolyl, particularly 3- and 5-pyrazolyl; 2-thiazolyl; 2- benzothazolyl; quinolinyl, particularly 2-, 3- and 4-quinolinyl; and 4-(2- benzyloxazolyl).
  • Representative preferred substituted heteroaryl groups include 6-methyl-2-pyridyl, 5-halo-2-thienyl, 5-methyl-2-thienyl, 5-halo-2- furyl, 5-halo-3-furyl, 2,5-dimethyl-3-thienyl and 2,5-dimethyl-3-furyl.
  • Z is an optionally 2- or 4-substituted (or 2,4-di-substituted) phenyl group of the formula III:
  • R., and R 2 are independently selected from the group consisting of hydrogen; halogen, particularly fluorine, bromine and chlorine; hydroxyl; nitro; C,-C 6 alkyl; C,-C 6 alkoxy; and carboxy.
  • Q is selected from the group consisting of phenyl and 4-alkyl phenyl, wherein the alkyl is O, to C 6 alkyl, most preferably C C 3 alkyl.
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, fluorine, bromine, chlorine, C C 3 alkyl, 0 ⁇ 3 alkoxy, hydroxy and nitro.
  • R 3 is hydrogen and R 4 is other than hydrogen
  • the preferred ring attachment position of R 4 is the 2- or 4- position, most preferably the 4-position.
  • the preferred positions of substitution are the 2- and 4-positions, or the 3- and 4-positions.
  • the invention is also directed to isolated optical isomers of compounds according to formula I.
  • isolated means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula.
  • the isolated isomer is at least about 80% pure, more preferably at least 90% pure, even more preferably at least 98% pure, most preferably at least about 99% pure, by weight.
  • the invention is also directed to novel intermediates of the formula IV
  • a method for preparing a compound of formula IV comprises
  • X is C,-C 6 alkyl, or a radical of the formula
  • Z is selected from the group consisting of substituted and unsubstituted aryl
  • reaction temperature is maintained in the range of from about 15°C to about 30°C, but higher temperatures are possible depending on the boiling points of the reactants.
  • An alternative method is provided for preparing the aforesaid intermediates of formula IV wherein X is trihalomethyl, preferably trifluoro-, tribromo-, or trichloromethyl. The method comprises:
  • Z is selected from the group consisting substituted and unsubstituted aryl
  • Methods are also provided for preparing compounds according to formula I, by reacting the formula IV intermediate with other compounds. Accordingly, a method for producing a compound of the formula I, wherein the groups Z, X and Q are defined above. The method comprises reacting a compound of the formula IV
  • the invention is also directed to a pharmaceutical composition of one or more compounds of formula I in combination with a pharmaceutically effective carrier.
  • a method for treating a cyclooxygenase-mediated disease comprising administering an effective amount of a compound according to formula I to an animal in need of such treatment.
  • the expression "animal” is inclusive of human beings.
  • Fig.1 shows the inhibition of colorectal cancer cell colony growth in the presence of compounds of the invention, as to compared celecoxib.
  • the compounds of formula I are potent inhibitors of COX-2.
  • COX-2 activity was demonstrated by a cell-free assay in which human recombinant COX-2 was incubated with test compound and [ 14 C]- arachidonic acid.
  • the resulting radiolabeled prostanoid compounds i.e., the products of COX-2 reaction with arachidonic acid, were quantified.
  • the compounds of the invention are prepared via a trans- 1 ,1 ,1-trifluoromethyl-4-aryl-buten-2-one of formula I:
  • Z-CH where Z is defined as above, is added dropwise for 10 minutes.
  • the resulting mixture is warmed to room temperature over 2 hours and then stirred overnight.
  • 20 ml of dilute hydrochloric acid is added and stirred at room temperature for 4 hours.
  • the solution is extracted thrice with diethyl ether (20 ml each time) and washed successively with 5% sodium bicarbonate and brine until the pH of the solution is 6.
  • the ethereal layer is separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield crude trans -1 ,1 ,1 -trifluoromethyl -4-aryl-3- buten-2-one.
  • the product is purified either by column chromatography or by recrystallization.
  • the appropriate 1 ,1 ,1-trihaloacetone can be substituted for 1 ,1 ,1-trifluoroacetone in Procedure 1 to provide other trans-1 ,1 ,1-trihalo-4- aryl-3-buten-2-one intermediate.
  • other N-phenyltrihaloacetimidoyl chlorides can be substituted for N-phenyltrifluoroacetimidoyl chloride in Procedure 1A to produce other trans-1 , 1 ,1-trihalo-4-aryl-3-buten-2-one intermediates.
  • Procedure 4 Synthesis of 1 -arylsulfonyl-3- (alkyl or optionally substituted aryl)-5-aryl-2- pyrazoline
  • a trans- 1 -(alkyl or optionally substituted aryl)-3-aryl-2-propen-1-one 5 mmol
  • an aryl sulfonyl hydrazide of formula V and concentrated hydrochloric acid (0.5 ml).
  • the mixture is refluxed with stirring overnight on a hot plate with a stirrer.
  • the solution is cooled and poured onto crushed ice and solid material is separated by filtration.
  • the compounds of the invention preferably are characterized by a selectivity ratio for COX-2 inhibition over COX-1 inhibition of at least about 50, more preferably at least about 100.
  • COX inhibition may be determined in vitro by enzyme assays well-known to those skilled in the art, such as the enzyme assay method described later herein.
  • the compounds of the present invention may take the form o pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases.
  • compound of formula I or a “compound of the invention”
  • pharmaceutically acceptable salts are also included.
  • the nature of the salt is not critical, provided that it is pharmaceutically- acceptable.
  • Suitable pharmaceutically acceptable acid addition salts of compounds of formula I may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
  • organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, example of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicyclic, salicyclic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2- hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, algenic, beta-hydroxybutyric, sali
  • Suitable pharmaceutically acceptable base addition salts of compounds of formula I include metallic salts made from calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared by conventional means from the corresponding compound of formula I by reacting, for example, the appropriate acid or base with the compound of formula I.
  • the compounds of the present invention may be administered in the form of a pharmaceutical composition, in combination with a pharmaceutically acceptable carrier.
  • the active ingredient in such formulations may comprise from 0.1 to 99.99 weight percent.
  • pharmaceutically acceptable carrier is meant any carrier, diluent or excipient which is compatible with the other ingredients of the formulation and to deleterious to the recipient.
  • the compounds of the invention may be administered to individuals
  • cyclooxygenase- mediated disorder any disorder characterized by undesirable prostaglandin production resulting from cyclooxygenase activity, particularly COX-2 activity
  • the compounds of the invention are believed useful in treating inflamation and inflamation-related disorders, by administering to a subject having or susceptible to such inflamation or inflamation-related disorder and effective amount of a compound according to formula I. Inflamation is associated with a variety of disease conditions. For a list of such disease conditions treatable by cyclooxygenase inhibitors, and COX-2 inhibitors in particular, see U.S. Patents 5,604,253 and 5,908,852, the entire disclosures of which are incorporated herein by reference.
  • Such conditions include, for example, arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis.
  • Such conditions further include rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, gout and ankylosing spondylitis, bursitis, and following surgical and dental procedures.
  • the compounds of the invention are believed useful as analgesics for treating or alleviating all forms of pain.
  • the compounds are believed useful in the treatment of other disorders including asthma, bronchitis, tendinitis, bursitis; skin related conditions such as psoriasis, eczema, burns and dermatitis; gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis and for the prevention of colorectal cancer; the treatment of inflamation in such diseases as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, type I diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, conjunctivitis, swelling occurring after injury, myocardial ischemia, and the like.
  • the compounds of the invention are believed useful as antipyretics for the treatment of fever.
  • compounds of formula I may inhibit cellular neoplastic transformations and metastatic tumor growth and hence can be used in the treatment of cancer.
  • the present invention provides a method for treating or preventing a neoplasia that produces a prostaglandin in a subject in need of such treatment or prevention, the method comprises treating the subject with a therapeutically effective amount of a compound of formula I.
  • neoplasia includes neoplasia that produce prostaglandins or express a cyclooxygenase, including both benign and cancerous tumors, growths and polyps. Neoplasias believed treatable with cyclooxygenase inhibitors are discussed in U. S. Pat. 5,972,986, the entire disclosure of which is incorporated herein by reference.
  • the compounds may be used to inhibit the growth or an established neoplasm, i.e., to induce regression, or to prevent or delay the onset of the neoplasm.
  • neoplasias that produce prostaglandins include brain cancer, bone cancer, epithelial cell-derived neoplasia (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer, mouth cancer, esophageal cancer, small bowel cancer and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as squamous cell and basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that effect epithelial cells throughout the body.
  • epithelial cell-derived neoplasia epithelial carcinoma
  • basal cell carcinoma such as basal cell carcinoma, adenocarcinoma
  • gastrointestinal cancer such as lip cancer, mouth cancer, esophageal cancer, small bowel cancer and stomach cancer
  • colon cancer liver cancer, bladder cancer, pancreas cancer
  • ovary cancer such as squamous
  • the compounds of the invention may also be useful in the treatment of angiogenesis-mediated disorders.
  • a method fortreating, inhibiting or delaying the onset of an angiogenesis-mediated disorder in a subject comprising administering to a subject in need of such treatment an effective amount of a compound according to formula I.
  • Angiogenesis- mediated disorders which may be treatable with cyclooxygenase inhibitors are discussed in U. S. Pat. 6,025,353, the entire disclosure of which is incorporated herein by reference. According to U. S. Pat.
  • such disorders include, for example, metastasis, corneal graft rejection, ocular neovascularization, retinal neovascularization, diabetic retinopathy, retrolental fibroplasia, neovascular glaucoma, gastric ulcer, infantile hemaginomas, angiofibroma of the nasopharynx, avascular necrosis of bone, and endometriosis.
  • the compounds may be administered by any route, including oral and parenteral administration.
  • Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intraperitoneal, intranasal, rectal, topical, transdermal or subcutaneous administration.
  • the active agent may also be administered by inhalation.
  • the active agent is preferably administered with a pharmaceutically acceptable carrier selected on the basis of the selected route of administration and standard pharmaceutical practice.
  • the active agent may be formulated into dosage forms according to standard practices in the field of pharmaceutical preparations. See Alphonso Gennaro, ed., Remington's Pharmaceutical Sciences, 18th Ed., (1990) Mack Publishing Co., Easton, PA. Suitable dosage forms may comprise, for example, tablets, capsules, solutions, parenteral solutions, troches, suppositories, or suspensions.
  • the active agent may be mixed with a suitable carrier or diluent such as water, an oil, saline solution, aqueous dextrose (glucose) and related sugar solutions, or a glycol such as propylene glycol or polyethylene glycol.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active agent.
  • Stabilizing agents, antioxidizing agents and preservatives may also be added.
  • Suitable antioxidizing agents include sulfite, ascorbic acid, citric acid and its salts, and sodium EDTA.
  • Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben, and chlorbutanol.
  • the active agent may be combined with one or more solid inactive ingredients for the preparation of tablets, capsules, or other suitable oral dosage forms.
  • the active agent may be combined with carboxymethylcellulose calcium, magnesium stearate, mannitol and starch, and then formed into tablets by conventional tableting methods.
  • the specific dose of compound according to the invention to obtain therapeutic benefit will, of course, be determined by the particular circumstances of the individual patient including, the size, weight, age and sex of the patient, the nature and stage of the disease, the aggressiveness of the disease, and the route of administration. For example, a daily dosage of from about 0.01 to about 150 mg/kg/day may be utilized. Higher or lower doses are also contemplated.
  • the compounds of the present invention are optically active due to the presence of a chiral carbon atom at position 5 of the pyrazoline nucleus:
  • Isolated optical isomers may be purified from racemic mixtures by well- known chiral separation techniques. According to one such method, a racemic mixture of a compound having the structure of formula I, or chiral intermediate thereof, is separated into 99% wt.% pure optical isomers by HPLC using a suitable chiral column, such as DAICEL CHIRALPAK AD (Daicel Chemical Industries, Ltd., Tokyo, Japan).
  • a suitable chiral column such as DAICEL CHIRALPAK AD (Daicel Chemical Industries, Ltd., Tokyo, Japan).
  • This column contains a packing of amylose tris(3,5-dimethylphenyl) carbamate coated on a 10 ⁇ m silica-gel substrate.
  • the column has a size of 250 x4.6 mm (L x l.D.).
  • the column is operated according to the manufacturer's instructions.
  • a flow rate should be maintained that will result in column pressures of less than 430 psi (30 kg/cm2).
  • a typical flow rate is 1.0 ml/min.
  • the operating temperature range is 0°C - 40 °C.
  • the maximum operating pressure is 1200 psi.
  • One suitable mobile phase system is hexane/2-propanol (100/0 to 0/100 v/v).
  • a typical hexane/2-propanol mobile phase is hexane/2- propanol (90/10 v/v).
  • Another suitable mobile phase system is hexane/ethanol (100/0 to 85/15 v/v), (40/60 to 0/100 v/v).
  • Suitable mobile phase modifiers include N,N-diethylamine for a basic sample, and trifluoroacetic acid for an acidic sample.
  • Trans-1 , 1 ,1-trifluoro-4-phenyl-3-buten-2-one was prepared according to Procedure 1 from 1 ,1 ,1-trifluoroacetone and benzaldehyde.
  • Example 1 and Example 2 compounds were tested for inhibitory activity against COX-1 and COX-2, demonstrating the selective action of the compounds for inhibiting COX-2.
  • Cyclooxygenase activity of ovine COX-1 (Oxford Biomedical
  • [1 - 14 C] arachidonic acid 50 ⁇ M, 51 mCi/mmol (DuPont NEN) was added and incubated at 37°C for 2 minutes. The reaction was terminated by extraction with 1 ml of ethyl acetate. The ethyl acetate layer was transferred into a fresh tube and evaporated to dryness in a Speedvac vacuum dryer. The contents of the tubes were reconstituted in 20 ml of ethyl acetate and spotted on a TLC plate (J.T. Baker, Phillipsburg, NJ) and developed in a mobile phase containing chloroform/methanol (95:5) at4°C.
  • TLC plate J.T. Baker, Phillipsburg, NJ
  • Radiolabeled prostanoid compounds (the products of COX enzymatic reaction with radiolabeled arachidonic acid substrate) were quantitated with a radioactivity scanner (Fuji, Phosphorimager). The percentage of total products observed at different inhibitor concentrations was divided by the percentage of the products observed for protein samples pre incubated for the same time with DMSO. The results are shown in Table 3. The Example 1 and 2 compounds are more than one hundred times more active in inhibiting COX-2 compared to COX-1. Table 3: Inhibition of Cyclooxygenase Activity
  • DLD- 1 cells are human colorectal carcinoma cells that overexpress COX-2.
  • DLD-1 cells grow in soft agar and form tumors in nude mice.
  • the soft agar assay was performed as follows. A layer of bottom agar (8% noble agar) was placed onto 60 mm 2 tissue culture dishes. The tumor cells were trypsinized from normal growth flasks while in exponential growth. The cells were counted by using a hemacytometer and 1.0 x 10 5 cells were placed into the top agar mixture containing growth medium, 4% noble agar and various concentrations of drugs.
  • the concentration range was normally between 10 ⁇ M to 75 ⁇ M.
  • the cells were not refed during the assay system; therefore, the cells were treated with one dose of the agents.
  • the plates were stained 20 days later with a 0.05% (w/v) nitroblue tetrazolium solution (which stains only viable cells) for 48 hours. The results are shown in Fig. 1 , the y-axis being the percent of cell colonies remaining in comparison to untreated control cells.
  • the compounds of the invention are significantly more active than celecoxib. All references cited herein are incorporated herein by reference.

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Abstract

L'invention concerne des composés de la formule (I) dans laquelle, X est sélectionné dans le groupe comprenant trihalométhyle, C1-C6 alkyle, et un groupe de formule (II): dans laquelle : R3 et R4 sont sélectionnés indépendamment l'un de l'autre dans le groupe comprenant hydrogène, halogène; hydroxyle; nitro; C1-C6 alkyle; C1-C6 alcoxy; carboxy; C1-C6 trihaloalkyle; et cyano; Z est sélectionné dans le groupe composé d'aryle substitué et non-substitué, et Q est sélectionné dans le groupe composé de phényle substitué et non-substitué, ou d'un sel pharmaceutiquement acceptable de ceux-ci. Les composés sont des inhibiteurs de l'activité de la cyclo-oxygénase-2. Ils servent à traiter les inflammations et les troubles induits par la cyclo-oxygénase.
PCT/US2000/016727 1999-06-16 2000-06-16 1-(4-arylesulfonyle)-3-substitue-5-aryle-2-pyrazolines comme inhibiteurs de la cyclo-oxygenase-2 WO2000076983A1 (fr)

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EP1492487A2 (fr) * 2002-03-08 2005-01-05 Merck & Co., Inc. Inhibiteurs de kinesine mitotique
WO2008045663A2 (fr) * 2006-10-06 2008-04-17 Kalypsys, Inc. Inhibiteurs hétérocycliques de pde4 aryl-substitués

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1492487A2 (fr) * 2002-03-08 2005-01-05 Merck & Co., Inc. Inhibiteurs de kinesine mitotique
EP1492487B1 (fr) * 2002-03-08 2009-11-11 Merck & Co., Inc. Inhibiteurs de kinesine mitotique
US7745639B2 (en) 2002-03-08 2010-06-29 Merck & Co., Inc. Mitotic kinesin inhibitors
WO2008045663A2 (fr) * 2006-10-06 2008-04-17 Kalypsys, Inc. Inhibiteurs hétérocycliques de pde4 aryl-substitués
WO2008045663A3 (fr) * 2006-10-06 2009-02-12 Kalypsys Inc Inhibiteurs hétérocycliques de pde4 aryl-substitués

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