WO2001017996A1 - Thiadiazoles-1,2,3, et leur utilisation comme inhibiteurs de cox-2 - Google Patents

Thiadiazoles-1,2,3, et leur utilisation comme inhibiteurs de cox-2 Download PDF

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Publication number
WO2001017996A1
WO2001017996A1 PCT/CA2000/001040 CA0001040W WO0117996A1 WO 2001017996 A1 WO2001017996 A1 WO 2001017996A1 CA 0001040 W CA0001040 W CA 0001040W WO 0117996 A1 WO0117996 A1 WO 0117996A1
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group
hydrogen
cox
4alkyl
phenyl
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PCT/CA2000/001040
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English (en)
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Cheuk K. Lau
Chun Sing Li
Michel Therien
Jacques Y. Gauthier
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Merck Frosst Canada & Co.
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Priority to AU69764/00A priority Critical patent/AU6976400A/en
Publication of WO2001017996A1 publication Critical patent/WO2001017996A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • This invention relates to methods of treating cyclooxygenase mediated diseases and certain pharmaceutical compositions therefore.
  • Non-steroidal, anti-inflammatory drugs exert most of their anti- inflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase.
  • cyclooxygenase also known as cyclooxygenase.
  • COX-1 cyclooxygenase- 1
  • COX-2 More recently the gene for a second inducible form of cyclooxygenase, cyclooxygenase-2 (COX-2) has been cloned, sequenced and characterized initially from chicken, murine and human sources.
  • COX-1 This enzyme is distinct from the COX-1 which has been cloned, sequenced and characterized from various sources including the sheep, the mouse and man.
  • the second form of cyclooxygenase, COX-2 is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors.
  • prostaglandins have both physiological and pathological roles, we have concluded that the constitutive enzyme, COX-1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow.
  • COX-2 the inducible form
  • a selective inhibitor of COX-2 will have similar anti-inflammatory, antipyretic and analgesic properties to a conventional non-steroidal anti-inflammatory drug, and in addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a diminished ability to induce some of the mechanism-based side effects.
  • such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and possibly a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
  • COX-2 inhibitors A brief description of the potential utilities of COX-2 inhibitors is given in an article by John Vane, Nature, Vol. 367, pp. 215-216, 1994 and in an article in Drug News and Perspectives, Vol. 7, pp. 501-512, 1994.
  • Rl is selected from the group consisting of: (a) S(O) 2 CH 3 ,
  • R2 and R3 are each independently selected from the group consisting of:
  • R4 is selected from the group consisting of H, C ⁇ _6alkyl, phenyl and benzyl, and R- ⁇ R° and R' are each independently selected from the group consisting of:
  • compositions and methods of treatment are also included.
  • the invention encompasses compounds represented by formula I:
  • Rl is selected from the group consisting of: (a) S(O) 2 CH 3 ,
  • R2 and R3 are each independently selected from the group consisting of: (a) hydrogen,
  • R4 is selected from the group consisting of H, C ⁇ _6alkyl, phenyl and benzyl, and R ⁇ , R° and R 7 are each independently selected from the group consisting of:
  • formula I includes, compounds of formulas la and lb.
  • Rl is selected from the group consisting of:
  • R2 and R3 are each independently selected from the group consisting of: (a) hydrogen,
  • R4 is selected from the group consisting of hydrogen, Ci_4alkyl, phenyl and benzyl.
  • R4 is selected from the group consisting of hydrogen, Ci_4alkyl, phenyl and benzyl.
  • R ⁇ , R6 and R 7 are each independently selected from the group consisting of: (a) hydrogen, and
  • Another aspect of the invention that is of particular interests relates to compounds of formula I wherein at least one of the nitrogen atoms present is in the form of the N-oxide Withm this subset, all other vanables are as ongmally descnbed with respect to formula I
  • Rl is selected from the group consisting of:
  • R2 and R3 are each independently selected from the group consisting of
  • R4 is selected from the group consisting of hydrogen, C ⁇ _4alkyl, phenyl and benzyl, and
  • R5, R6 and R 7 are each independently selected from the group consisting of: (a) hydrogen, and (b) Ci-4alkyl.
  • Rl is selected from the group consisting of:
  • R4 is selected from the group consisting of hydrogen, Ci- 3 alkyl, phenyl and benzyl; R5 and R" are each independently selected from the group consisting of: (a) hydrogen, and
  • R is selected from the group consisting of: (a) S(O) 2 CH 3 , (b) S(O) 2 NHR 4 ,
  • R2 and R3 are each independently selected from the group consisting of: (a) hydrogen, (b) halo,
  • R4 is selected from the group consisting of hydrogen, Ci-4alkyl, phenyl and benzyl; R5 and R ⁇ are each independently selected from the group consisting of: (a) hydrogen, and (b) Ci- 3 alkyl.
  • Rl is selected from the group consisting of:
  • R4 is selected from the group consisting of hydrogen, C ⁇ _ 3 alkyl, phenyl and benzyl; R5 and R ⁇ are each independently selected from the group consisting of:
  • Rl is selected from the group consisting of:
  • R2 and R3 are each independently selected from the group consisting of: (a) hydrogen, (b) halo,
  • Alkyl is defined to include linear, branched and cyclic structures, of the indicated number of carbon atoms, including, but not restricted to, methyl, ethyl, propyl, 2-propyl, n-, i-, s- and t-butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Alkoxy is intended to include alkoxy groups of the indicated number of carbon atoms of a straight, branched, or cyclic configuration. Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like.
  • Alkylthio is intended to include alkylthio groups of the indicated numer of carbon atoms of a straight, branched or cyclic configuration. Examples of lower alkylthio groups include methylthio, n-propylthio, isopropylthio, cyclohexylthio, etc. By way of illustration, the propylthio group signifies - SCH 2 CH 2 CH 3 .
  • Halo includes F, Cl, Br and I.
  • Fluoroalkyl includes alkyl groups of the indicated number of carbon atoms of a straight, branched or cyclic configuration, in which one or more hydrogens are replaced by fluorine. Up to the maximum number of hydrogens are replaced, such as in perfluoroalkyl. Examples are -CHF 2 , CH 2 F, -CF 3 , -CH 2 CF 3 , c-pr-F5, c-Hex- F ⁇ i, and the like.
  • Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
  • the present invention is meant to comprehend such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof.
  • the invention encompasses a pharmaceutical composition comprising a compound of formula I in combination with a pharmaceutically acceptable carrier.
  • compositions for inhibiting COX-2 and for treating or preventing COX-2 mediated diseases comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of Formula I as described above.
  • the invention encompasses a method of inhibiting cyclooxygenase, or treating or preventing a cyclooxygenase mediated disease or condition, comprising administering to a patient in need thereof, an effective amount of a compound of formula I.
  • the disease or condition is mediated by cyclooxygenase-2.
  • compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as
  • references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
  • the compounds of formula I are useful for the relief of pain, fever and inflammation due to a variety of conditions, e.g., 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, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, injuries, following surgical and dental procedures.
  • such a compound may inhibit cellular neoplastic transformations and metastatic tumor growth and hence can be used in the treatment of cancer, as well as for preventing or treating the conversion of non- cancerous polyps, such as adenomas to cancerous lesions, e.g., carcinoadenomas.
  • Compound I may also be of use in the treatment and/or prevention of cyclooxygenase-mediated proliferative disorders such as may occur in diabetic retinopathy and tumour angiogenesis.
  • the compounds of formula I also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labor, asthma and eosinophil related disorders. It will also be of use in the treatment of Alzheimer's disease, and for the prevention of bone loss (treatment of osteoporosis).
  • the compounds are useful as an alternative to conventional NSAIDs particularly where such non-steroidal antiinflammatory drugs may be contraindicated, such as in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal lesions; GI bleeding, coagulation disorders including anemia such as hypoprothrombinemia, haemophilia or other bleeding problems; kidney disease; those prior to surgery or taking anticoagulants.
  • the compounds are useful as a partial or complete substitute for conventional NSAIDs in preparations wherein they are presently co-administered with other agents or ingredients.
  • the invention encompasses pharmaceutical compositions for treating COX-2 mediated diseases as defined above comprising a non-toxic therapeutically effective amount of the compound of Formula I as defined above and one or more ingredients such as another pain reliever including acetominophen or phenacetin; a potentiator including caffeine; an H 2 -antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant including phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an antiitussive including codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan;
  • the invention encompasses a method of treating cyclooxygenase mediated diseases comprising: administration to a patient in need of such treatment a non-toxic therapeutically effect amount of the compound of Formula I, optionally co-administered with one or more of such ingredients as listed immediately above.
  • a method of treating cyclooxygenase mediated diseases comprising: administration to a patient in need of such treatment a non-toxic therapeutically effect amount of the compound of Formula I, optionally co-administered with one or more of such ingredients as listed immediately above.
  • Compound I may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • the compound of the invention is effective in the treatment of humans.
  • compositions for treating COX-2 mediated diseases as defined may optionally include one or more ingredients as listed above.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Patent 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water or miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or miscible solvents such as propylene glycol, PEGs and ethanol
  • an oil medium for example, peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethycellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, poly
  • the aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example, liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example, soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example, sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example, polyoxy-ethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally- acceptable diluent or solvent, for example, as a solution in 1,3-butane diol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Compound I may also be administered in the form of a suppository for rectal administration.
  • compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.
  • Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day.
  • inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
  • the compounds of the present invention can be prepared according to the following methods.
  • Compound I can be prepared from an appropriately substituted 2- ethanone. Following the method of Hurd and Mori, the ketones II were treated with an acyl hydrazine in refluxing toluene to form acylhydrazones HI. Treatment of these acylhyrazones with thionyl chloride gives the corresponding thiadiazoles. See Hurd, C. D. and Mori, R.I. J. Am Chem. Soc. 1955, 77, 5359. The thiadiazoles are oxidized to the corresponding N-oxides using H 2 O 2 /TFA (1:1) at 45°C.
  • osteosarcoma cells are cultured in 1 mL of media in 24-well multidishes (Nunclon) until confluent (1-2 x 10 ⁇ cells/well).
  • U-937 cells are grown in spinner flasks and resuspended to a final density of 1.5 x 10" cells/mL in 24-well multidishes (Nunclon).
  • 1 ⁇ L of a DMSO solution of test compound or DMSO vehicle is added, and samples gently mixed. All assays are performed in triplicate.
  • U937 cell are pelleted by centrifuhation at 500 x g for 5 min and washed once with phosphate-buffered saline and repelleted.
  • Cells are resuspended in homogenization buffer consisting of 0.1 M Tris-HCl, pH 7.4., 10 mM EDTA, 2 ⁇ g/ml leupeptin, 2 ⁇ g/ml soybean trypsin inhibitor, 2 ⁇ g/ml aprotinin and 1 mM phenyl methyl sulfinyl fluoride.
  • the cell suspension is sonicated 4 times for 10 sec and is centrifuged at 10,000 x g for 10 min at 4 °C.
  • the suspension is centrifuged at 100,000 x g for 1 hr at 4°C.
  • the 100,000 x g microsomal pellet is resuspended in 0.1 M Tris- HCl, pH 7.4, 10 mM EDTA to approximately 7 mg protein/ml and stored at -80°C.
  • Microsomal preparations are thawed immediately prior to use, subjected to a brief sonication, and then diluted to a protein concentration of 125
  • the enzyme activity is measured using a chromogenic assay based on the oxidation of N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) during the reduction of PGG 2 to PGH 2 by COX-2.
  • TMPD N,N,N',N'-tetramethyl-p-phenylenediamine
  • the assay mixture (180 ⁇ l) contains 100 mM sodium phosphate, pH 6.5, 2mM genapol X-100, l ⁇ M hematin, 1 mg/ml gelatin, 80-100 units of purified enzyme (one unit of enzyme is defined as the amount of enzyme required to produce an O.D. change of 0.001/min at 610 nm) and 4 ⁇ l of the test compound in DMSO.
  • the enzyme is pre-incubated at room temperature (22 °C) for 15 min prior to initiation of the enzymatic reaction by the addition of 20 ⁇ l of a sonicated solution of 1 mM arachidonic acid (AA) and 1 mM TMPD in assay buffer (without enzyme or hematin).
  • the enzyme activity is measured by estimation of the initial velocity of TMPD oxidation over the first 36 sec of the reaction. A non-specific rate of oxidation is observed in the absence of enzyme (0.007-0.010 O.D./min) and is subtracted before the calculation of the percent inhibition.
  • IC50 values are derived from 4-paramater least squares non-linear regression analysis of the log-dose vs percent inhibition plot.
  • the animals were then injected subplantarly with 50 ⁇ l of 1% carrageenan solution in saline (FMC Corp, Maine) into the paw using an insulin syringe with a 25-gauge needle (i.e., 500 ⁇ g carrageenan per paw). Three hr later, the paw volume (V 3 ) was measured and the increases in paw volume (V 3 -Vo) were calculated. The animals were sacrificed by CO 2 asphyxiation and the absence or presence of stomach lesions scored. Data were compared with the vehicle-control values and percent inhibition calculated. ED ⁇ Q values were used for comparison. All treatment groups were coded to eliminate observer bias.
  • NSAIDs are their ability to produce gastric lesions in man. This action is believed to be caused by inhibition of COX-1 in the gastrointestinal tract. Rats are particularly sensitive to the actions of NSAIDS. In fact, rat models have been used commonly in the past to evaluate the gastrointestinal side effects of current conventional NSAIDs. In the present assay, NSAID-induced gastrointestinal damage is observed by measuring fecal 51Q- excretion after systemic injection of 51 Cr-labeled red blood cells. Fecal 51Q- excretion is a well-established and sensitive technique to detect gastrointestinal integrity in animals and man.
  • mice Male Sprague Dawley rats (150 - 200 g) are administered orally a test compound, either once (acute dosing) or b.i.d. for 5 days (chronic dosing). Immediately after the administration of the last dose, the rats are injected via a tail vein with 0.5 mL of 51Cr-labeled red blood cells from a donor rat. The animals are placed individually in metabolism cages with food and water ad lib. Feces are collected for a 48 h period and ⁇ lCr fecal excretion is calculated as a percent of total injected dose.
  • 51Cr-labeled red blood cells are prepared using the following procedures. Ten mL of blood is collected in heparinized tubes via the vena cava from a donor rat. Plasma is removed by centrifugation and replenished with equal volume of HBSS. The red blood cells are incubated with 400 ⁇ Ci of sodium bichromate for 30 min at 37°C. At the end of the incubation, the red blood cells are washed twice with 20 mL HBSS to remove free sodium bichromate. The red blood cells are finally reconstituted in 10 mL HBSS and 0.5 mL of the solution (about 20 DCi) is injected per rat.
  • Protein-losing gastropathy (manifested as appearance of cirulating cells and plasma proteins in the GI tract) is a significant and dose-limiting adverse response to standard NSAIDs. This can be quantitatively assessed by intravenous administration of 51CrCl 3 solution. This isotopic ion can avidly bind to cell and serum globins and cell endoplasmic reticulum. Measurement of radioactivity appearing in feces collected for 24 h after administration of the isotope thus provides a sensitive and quantitative index of protein-losing gastropathy.
  • Groups of male squirrel monkeys (0.8 to 1.4 kg) are treated by gavage with either 1% methocel or 5% Tween 80 in H 2 O vehicles, (3 mlVkg b.i.d.) or test compounds at doses from 1 - 100 mg/kg b.i.d. for 5 days.
  • Intravenous 51Cr (5 ⁇ Ci/kg in 1 ml/kg PBS) is administered 1 h after the last drug/vehicle dose, and feces collected for 24 h in a metabolism cage and assessed for excreted 51Q- by gamma- counting.
  • Venous blood is sampled 1 h and 8 h after the last drug dose, and plasma concentrations of drug measured by RP-HPLC.
  • Human whole blood provides a protein and cell-rich milieu appropriate for the study of biochemical efficacy of anti-inflammatory compounds such as selective COX-2 inhibitors.
  • This assay can be used to evaluate the inhibitory effect of selective COX-2 inhibitors on PGE production.
  • platelets in whole blood contain a large amount of the COX-1 enzyme. Immediately following blood clotting, platelets are activated through a thrombin-mediated mechanism.
  • TxB thromboxane B
  • COX-1 thromboxane B
  • LPS 100 ⁇ g/ml final concentration, Sigma Chem, #L-2630 from E. coli; diluted in 0.1% BSA-Phosphate buffered saline
  • Fresh blood was collected into vacutainers containing no anticoagulants. Aliquots of 500 ⁇ L were immediately transferred to siliconized microcentrifuge tubes preloaded with 2 ⁇ L of either DMSO or a test compound at final concentrations varying from 10 nM to 30 ⁇ M. The tubes were vortexed and incubated at 37°C for 1 hour to allow blood to clot. At the end of incubation, serum was obtained by centrifugation (12,000 x g for 5 min). A 100 ⁇ L aliquot of serum was mixed with 400 ⁇ L of methanol for protein precipitation. The supernatant was obtained and was assayed for TxB 2 using a enzyme immunoassay kit (Cayman, #519031) according to the manufacturer's instruction.
  • a enzyme immunoassay kit (Cayman, #519031) according to the manufacturer's instruction.
  • REPRESENTATIVE BIOLOGICAL DATA Compounds of the present invention are inhibitors of COX-2 and are thereby useful in the treatment of COX-2 mediated diseases as enumerated above.
  • the activities of the compounds against cyclooxygenase may be seen in the representative results shown below.
  • inhibition is determined by measuring the amount of prostaglandin E 2 (PGE 2 ) synthesized in the presence of arachidonic acid, COX-1 or COX-2 and a putative inhibitor.
  • the IC50 values represent the concentration of putative inhibitor required to return PGE 2 synthesis to
  • Table 1 The results for inhibition of PGE production in whole blood and edema inhibition in rat paw may be seen in Table 1.
  • Table 2 For comparison purposes, the Table also contains data for the conventional NSAID indomethacin.
  • AIBN 2.2-azobisisobutyronitrile
  • HWB human whole blood
  • KHMDS potassium hexamethyldisilazane
  • LPS lipopolysaccharide
  • NBS N-bromosuccinimide
  • NCS N-chlorosuccinimide
  • NIS N-iodosuccinimide
  • NSAID non-steroidal anti-inflammatory drug
  • PCC pyridinium chlorochromate
  • Ph phenyl
  • NMR data when given, NMR data is in the form of delta ( ⁇ ) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300 MHz or 400 MHz using the indicated solvent; conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc.: in addition "Ar” signifies an aromatic signal; (viii) chemical symbols have their usual meanings; the following abbreviations have also been used v (volume), w (weight), b.p. (boiling point), m.p.
  • Step 4 Ethyl- l-((4-(methylsulfonyl)phenyl)methyl)-l-((6-Methyl-3- pyridyl)methylidene)hydrazinocarboxylate
  • Step 5 4-(6-Methyl-3-pyridyl)-5-(4-(methylsulfonyl)phenyl-l-2-3-thiadiazole
  • step 4 To the product of step 4 (750 mg, 2.0 mmol) at 0°C was added SOCl 2 (5 mL). The mixture was refluxed for 0.5 h. Excess SOCl was removed under vaccum. The residue was dissolved in EtOAc and washed with IN NaOH. The EtOAc extract was washed with brine, dried and concentrated. The residue was chromatographed on silica gel to give 380 mg of the title compound. 1H NMR (Acetone-d ⁇ ) ⁇ 8.66 (d, IH), 8.05 (d, 2H), 7.87 (dd, IH), 7.77 (d, 2H), 7.31 (d, IH), 3.20 (s, 3H), 2.53 (s, 3H).
  • Rl is selected from the group consisting of: (a) S(O) 2 CH 3 ,
  • R4 is selected from the group consisting of H, Ci- ⁇ alkyl, phenyl and benzyl
  • R5, R and R 7 are each independently selected from the group consisting of:
  • Rl is selected from the group consisting of: (a) S(O) 2 CH 3 ,
  • R2 and R are each independently selected from the group consisting of:
  • R4 is selected from the group consisting of hydrogen, C ⁇ _4alkyl, phenyl and benzyl.
  • R R° and R7 are each independently selected from the group consisting of: (a) hydrogen, and
  • a compound in accordance with claim 1 wherein at least one of the nitrogen atoms present is in the form of the N-oxide.
  • Rl is selected from the group consisting of:
  • R2 and R3 are each independently selected from the group consisting of:

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Abstract

L'invention concerne des composés de formule (I) ainsi qu'une méthode de traitement de maladies induites par la COX-2, consistant à administrer à un patient une quantité non toxique thérapeutiquement efficace d'un composé de formule (I). L'invention concerne également certaines compositions pharmaceutiques destinées au traitement de maladies induites par la COX-2, et qui contiennent des composés de formule (I).
PCT/CA2000/001040 1999-09-08 2000-09-07 Thiadiazoles-1,2,3, et leur utilisation comme inhibiteurs de cox-2 WO2001017996A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001083475A1 (fr) * 2000-04-25 2001-11-08 J. Uriach & Cia S.A. Nouveaux composes heterocycliques a activite anti-inflammatoire

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994026731A1 (fr) * 1993-05-13 1994-11-24 Merck Frosst Canada Inc. Inhibiteurs de la cyclogenase
WO1995000501A2 (fr) * 1993-06-24 1995-01-05 Merck Frosst Canada Inc. Heterocycles phenyle utilises comme inhibiteurs de la cyclo-oxygenase-2
US5677318A (en) * 1996-07-11 1997-10-14 Merck Frosst Canada, Inc. Diphenyl-1,2-3-thiadiazoles as anti-inflammatory agents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994026731A1 (fr) * 1993-05-13 1994-11-24 Merck Frosst Canada Inc. Inhibiteurs de la cyclogenase
WO1995000501A2 (fr) * 1993-06-24 1995-01-05 Merck Frosst Canada Inc. Heterocycles phenyle utilises comme inhibiteurs de la cyclo-oxygenase-2
US5677318A (en) * 1996-07-11 1997-10-14 Merck Frosst Canada, Inc. Diphenyl-1,2-3-thiadiazoles as anti-inflammatory agents

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BLACK W C ET AL: "2,3-Diarylcyclopentenones as orally active, highly selective cyclooxygenase-2 inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 42, no. 7, 8 April 1999 (1999-04-08), pages 1274 - 1281, XP002154882 *
GAUTHIER J Y ET AL: "Synthesis and biological evaluation of 2,3-diarylthiophenes as selective cox-2 inhibitors. Part II: replacing the heterocycle", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 6, no. 1, 9 January 1996 (1996-01-09), pages 87 - 92, XP004135129, ISSN: 0960-894X *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001083475A1 (fr) * 2000-04-25 2001-11-08 J. Uriach & Cia S.A. Nouveaux composes heterocycliques a activite anti-inflammatoire

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