WO2006063466A1 - 2-(phenyl or heterocyclic)-1h-phenantrho[9,10-d]imidazoles as mpges-1 inhibitors - Google Patents
2-(phenyl or heterocyclic)-1h-phenantrho[9,10-d]imidazoles as mpges-1 inhibitors Download PDFInfo
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- WO2006063466A1 WO2006063466A1 PCT/CA2005/001921 CA2005001921W WO2006063466A1 WO 2006063466 A1 WO2006063466 A1 WO 2006063466A1 CA 2005001921 W CA2005001921 W CA 2005001921W WO 2006063466 A1 WO2006063466 A1 WO 2006063466A1
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- 0 *c1c(*)c2c3N[C@](C(C(C#N)=II)=NCl)Nc3c(c(*)c(*)c(*)c3*)c3c2c(*)c1* Chemical compound *c1c(*)c2c3N[C@](C(C(C#N)=II)=NCl)Nc3c(c(*)c(*)c(*)c3*)c3c2c(*)c1* 0.000 description 8
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Definitions
- NSAIDs and COX-2 inhibitors block the activity of cyclooxygenases and their ability to convert arachidonic acid (AA) into prostaglandin (PG) H2.
- PGH2 can be subsequently metabolized by terminal prostaglandin synthases to the corresponding biologically active PGs, namely, PGI2, thromboxane (Tx) A2, PGD2, PGF2 ⁇ , and PGE2.
- a combination of pharmacological, genetic, and neutralizing antibody approaches demonstrates the importance of PGE2 in inflammation.
- disruption of PGE2-dependent signalling in animal models of inflammation can be as effective as treatment with NSAIDs or COX-2 inhibitors.
- microsomal prostaglandin E synthase- 1 (mPGES-1) is an inducible PGES after exposure to pro-inflammatory stimuli.
- mPGES-1 is induced in the periphery and in the CNS by inflammation and represents therefore a novel target for acute and chronic inflammatory disorders.
- the rationale for the development of specific mPGES-1 inhibitors revolves around the hypothesis that the therapeutic utility of NSAIDs and Cox-2 inhibitors would be largely due to inhibition of pro-inflammatory PGE2 while the side effect profile would be largely due to inhibition of other prostaglandins.
- the present invention is directed to novel compounds that are selective inhibitors of the microsomal prostaglandin E synthase- 1 enzyme and would therefore be useful for the treatment of pain and inflammation in a variety of diseases or conditions, such as osteoarthritis, rheumatoid arthritis and acute or chronic pain. Furthermore, by selectively inhibiting the pro-inflammatory PGE2, it is believed the compounds of the invention would have a reduced potential for side effects associated with the inhibition of other prostaglandins by conventional non-steoidal anti-inflammatory drugs, such as gastrointestinal and renal toxicity.
- microsomal prostaglandin E synthase- 1 mPGES-1
- mPGES-1 microsomal prostaglandin E synthase- 1
- Methods of treating diseases or conditions mediated by the mPGES-1 enzyme and pharmaceutical compositions are also encompassed.
- the invention encompasses a genus of compounds represented by Formula I
- J is selected from the group consisting of -C( ⁇ 2)- and -N-
- K is selected from the group consisting of -C(X ⁇ )- and -N-
- L is selected from the group consisting of -C( ⁇ 4)- and -N-
- Ci_6alkyl, C2-6alkenyl or C2-6alkynyl wherein one or more of the hydrogen atoms attached to said Ci_6alkyl, C2-6alkenyl or C2-6alkynyl may be replaced with a flouro atom, and said Ci_6alkyl, C2-6alkenyl or C2-6alkynyl may be optionally substituted with a hydroxy group; (10) Ci_4alkoxy; (11) NR9R10-C(O)-C i_4alkyl-O; (12) Ci_4alkyl-S(O)k-; (13) -NO2; (14) C3_6cycloalkyl, (15) C3_6cycloalkoxy; (16)
- Rl 5 R2, R3, R4 ; R5, R6 5 R7 and R ⁇ are independently selected from the group consisting of: (1) H; (2) F; (3) Cl; (4) Br; (5) I; (6) -CN; (7) Ci_6alkyl or C2-6alkenyl, wherein one or more of the hydrogen atoms attached to said Cl_6alkyl or C2-6alkenyl may be replaced with a fluoro atom, and wherein said Ci- ⁇ alkyl or C2-6alkenyl may be optionally substituted with one to three substituents independently selected from the group consisting of: -OH, methoxy, Rl l-O-C(O)-, cyclopropyl, pyridyl and phenyl; (8) C3- 6cycloalkyl; (9) R.12-O-; (10) Rl3-S(O)k- 5 (11) Rl4-S(O)k-N(Rl5)-; (12) Rl6-C(O
- each R9, RlO 5 Rl5 ⁇ R24 & n ⁇ R32 is independently selected from the group consisting of: (1) H; and (2) Ci_ 4 alkyl;
- each k is independently 0, 1 or 2.
- the invention encompasses a sub-genus of compounds represented by
- the invention encompasses a class of compounds of Formula A wherein:
- X 2 , ⁇ 3, ⁇ 4 and ⁇ 5 are independently selected from the group consisting of: (1) H; (2) -CN; (3) F; (4) Cl; (5) Br; and (6) I. Also within this sub-genus, the invention encompasses a class of compounds of Formula A wherein X2, ⁇ 3 and ⁇ 4 are H, and X ⁇ is other than H. Within this class, the invention encompasses a sub-class of compounds of Formula A wherein ⁇ 5 is -CN.
- the invention encompasses a class of compounds of Formula A wherein at least one of Rl or R.8 is other than H.
- the invention encompasses a class of compounds of Formula A wherein at least one of R2 or R? is other than H.
- the invention encompasses a class of compounds of Fo ⁇ nula A wherein at least one of R4 or R ⁇ is other than H.
- the invention encompasses a class of compounds of Formula A wherein: at least one of R3 or Bfi is other than H; and Rl, R2, R4, R5, R7 and R8 are H.
- the invention encompasses a sub-class of compounds of Formula A wherein R3 and R6 are both other than H.
- the invention encompasses compounds of Formula A wherein: one of R3 or R6 is independently selected from the group consisting of: F, Cl, Br and I; and the other of R ⁇ or R6 is Z-C ⁇ C.
- the invention encompasses a sub-class of compounds of Formula A wherein: R3 and R ⁇ are independently selected from the group consisting of: hydrogen, fluoro, chloro, bromo, iodo, cyano, methyl, ethyl, vinyl, cyclopropyl, -C ⁇ 2/-Pr, -CO2CH3, -SO2CF3, 3-pyridyl, acetyl,
- the invention encompasses a class of compounds of Formula B wherein: one of R ⁇ or R6 is independently selected from the group consisting of: F, Cl, Br and I; and the other of R3 or R6 is Z-C ⁇ C.
- the invention encompasses a sub-genus of compounds of Formula I in accordance with Formula C
- Yl is selected from the group consisting of: (1) Ci_6alkyl; (2) PO4-Ci_4alkyl-; (3) Ci_4alkyl-C(O)-O- CH2-, wherein the Ci-4alkyl portion is optionally substituted with R ⁇ 3-0-C(0)-; and (4) Ci_4alkyl-O- C(O)-; and
- R33 is selected from the group consisting of: (1) H; (2) Ci_4alkyl, (3) C3_6cycloalkyl; (4) phenyl; (5) benzyl; and (6) pyridyl; said Ci_4alkyl, C3_6cycloalkyl, phenyl, benzyl and pyridyl may each be optionally substituted with 1 to 3 substituents independently selected from the group consisting of: OH,
- the invention also encompasses a pha ⁇ naceutical composition comprising a compound of Formula I in combination with a pharmaceutically acceptable carrier.
- the invention also encompasses a method for treating a microsomal prostaglandin E synthase- 1 mediated disease or condition in a human patient in need of such treatment comprising administering to said patient a compound according to Claim 1 in an amount effective to treat the microsomal prostaglandin E synthase- 1 mediated disease or condition.
- the disease or condition is selected from the group consisting of: acute or chronic pain, osteoarthritis, rheumatoid arthritis, bursitis, ankylosing sponylitis and primary dysmenorrhea.
- the invention includes, as appropriate, pharmaceutically acceptable salts of any of the aforementioned compounds.
- the heading "R ⁇ /R.6” means that the substituent indicated in that column is substituted at the position represented by either R3 or R6.
- the heading "R6/R3” means the indicated substituent is substituted at the position R3 or R6 not substituted in the previous column.
- halogen or halo includes F, Cl, Br, and I.
- alkyl means linear or branched structures and combinations thereof, having the indicated number of carbon atoms.
- Cl-6alkyl includes methyl, ethyl, propyl, 2- propyl, s- and t-butyl, butyl, pentyl, hexyl and 1,1-dimethylethyl.
- alkenyl means linear or branched structures and combinations thereof, of the indicated number of carbon atoms, having at least one carbon-to-carbon double bond, wherein hydrogen may be replaced by an additional carbon-to-carbon double bond.
- C2-6alkenyl for example, includes ethenyl, propenyl, 1-methylethenyl, butenyl and the like.
- alkynyl means linear or branched structures and combinations thereof, of the indicated number of carbon atoms, having at least one carbon-to-carbon triple bond.
- C3_6alkynyl for example, includes , propenyl, 1-methylethenyl, butenyl and the like.
- alkoxy means alkoxy groups of a straight, branched or cyclic configuration having the indicated number of carbon atoms.
- Ci_6alkoxy for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.
- cycloalkyl means mono-, bi- or tri-cyclic structures, optionally combined with linear or branched structures, having the indicated number of carbon atoms.
- cycloalkyl groups include cyclopropyl, cyclopentyl, cycloheptyl, adamantyl, cyclododecylmethyl, 2-ethyl-l- bicyclo[4.4.0]decyl, cyclobutylmethyl cyclopropylmethyl and the like.
- Compounds described herein may contain an asymmetric center and may thus exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centers, they may additionally exist as diastereomers.
- the present invention includes all such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers.
- the above Formula I is shown without a definitive stereochemistry at certain positions.
- O includes all stereoisomers of Formula I and pharmaceutically acceptable salts thereof.
- Diastereoisomeric pairs of enantiomers may be separated by, for example, fractional crystallization from a suitable solvent, and the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid or base as a resolving agent or on a chiral HPLC column. Further, any enantiomer or diastereomer of a .5 compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
- tautomers Some of the compounds described herein may exist with different points of attachment ,0 of hydrogen, referred to as tautomers.
- the compound of Formula I exists in the following tautomeric forms:
- the present invention includes within its scope prodrugs of the compounds of this invention.
- prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound.
- the term “administering” shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
- Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985. Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.
- Exemplifying prodrugs of the invention are compounds of Formula C.
- treating a microsomal prostaglandin E synthase- 1 mediated disease or condition means treating or preventing any disease or condition that is advantageously treated or prevented by inhibiting the microsomal prostaglandin E synthase- 1 (mPGES-1) en2yme.
- the te ⁇ n includes the 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, dysmenorrhea, headache, migraine (acute and prophylactic treatment), toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, acute, subacute and chronic musculoskeletal pain syndromes such as bursitis, burns, injuries, and pain following surgical and dental procedures as well as the preemptive treatment of surgical pain.
- the term includes the inhibition cellular neoplastic transformations and metastic tumor growth and hence the treatment of cancer.
- the term also includes the treatment of endometriosis and Parkinson's disease as well as the treatment of mPGES-1 mediated proliferative disorders such as may occur in diabetic retinopathy and tumor angiogenesis.
- treating encompasses not only treating a patient to relieve the patient of the signs and symptoms of the disease or condition but also prophylactically treating an asymptomatic patient to prevent the onset or progression of the disease or condition.
- amounts that are effective to treat is intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
- the te ⁇ n also encompasses the amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician.
- Suitable dosage levels of the compound of Formula I used in the present invention are described below.
- the compound may be administered on a regimen of once or twice per day.
- compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt, thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
- pharmaceutically acceptable salts include salts prepared from bases that result in non-toxic pharmaceutically acceptable salts, including inorganic bases and organic bases. 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
- salts may be prepared from acids that result in pharmaceutically acceptable salts, including inorganic and organic acids.
- acids include acetic, adipic, aspartic, 1,5-naphthalenedisulfonic, benzenesulfonic, benzoic, camphorsulfonic, citric, 1,2-ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, fumaric, glucoheptonic, gluconic, glutamic, hydriodic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, 2-naphthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, pivalic, propionic, salicylic, stearic, succinic, sulfuric, tartaric, p-toluenesulfonic acid
- the compounds of Formula I are useful for the 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, dysmenorrhea, headache, migraine (acute and prophylactice treatment), toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, acute, subacute and chronic musculoskeletal pain syndromes such as bursitis, burns, injuries, and pain following surgical and dental procedures as well as the preemptive treatment of surgical pain.
- Such a compound may inhibit cellular neoplastic transformations and metastic tumor growth and hence can be used in the treatment of cancer.
- Compounds of Formula I may also be useful for the treatment or prevention of endometriosis and Parkinson's disease. 2 U u ;> / u u * " « * *•
- Compounds of Fo ⁇ nula I will 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 and asthma.
- the compounds of 5 Formula I will prove useful as an alternative to conventional non-steroidal antiinflammatory drugs
- NSAID'S particularly where such non-steroidal antiinflammatory drugs may be contra-indicated such as in patients with peptic ulcers, gastritis, regioal enteritis, ulcerative colitis, diverticulitis or with a recurrent history of gastrointestinal lesions; GI bleeding, coagulation disorders including anemia such as hypoprotlirombinemia, haemophilia or other bleeding problems (including those relating to reduced or [0 impaired platelet function); kidney disease (e.g. impaired renal function); those prior to surgery or taking anticoagulants; and those susceptible to NSAID induced asthma.
- anemia such as hypoprotlirombinemia, haemophilia or other bleeding problems (including those relating to reduced or [0 impaired platelet function); kidney disease (e.g. impaired renal function); those prior to surgery or taking anticoagulants; and those susceptible to NSAID induced asthma.
- compositions for treating L 5 mPGES-1 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 acetaminophen or phenacetin; opioid analgesics, such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphine, propoxyphene, buprenorphine, butorphanol, dezocine, nalbuphine and pentazocine; a potentiator including caffeine; an 20 H2-antagonist; aluminum or magnesium hydroxide; simethicone; a decongestant including phenylephrine, phenylpropan
- the invention also encompasses co-administration with a 5-HT agonist such as rizatriptan, sumatriptan, zolmitriptan and naratriptan.
- a 5-HT agonist such as rizatriptan, sumatriptan, zolmitriptan and naratriptan.
- the invention encompasses a method of treating mPGES-1 mediated diseases comprising: administration to a patient in need of such treatment a nontoxic therapeutically effect amount of the compound of Formula I, optionally co-administered with one or more of such ingredients as listed immediately above.
- pharmaceutical compositions for treating mPGES-1 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 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 carboxymethyl-cellulose, methylcellulose, hydroxypropylmethy-cellulose, sodium alginate, polyvinylpyrrolidone, 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 heptadecaethylene-oxycetanol, 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 polyethylene sorbitan monooleate.
- dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecit
- 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.
- preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
- coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
- coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
- coloring agents such as sucrose, saccharin or aspartame
- sweetening agents such as sucrose, saccharin or aspartame.
- sweetening agents such as sucrose, saccharin or aspartame.
- Liquid formulations include the use of self-emulsyfying drug delivery systems and NanoCrystal® technology. Cyclodextrin
- 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., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
- 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 polyoxyethylene 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.
- 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 5 glycols.
- topical use creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
- compositions of the invention may also utilize absorption enhancers such 10 as tween 80, tween 20, Vitamin E TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate) and Gelucire®.
- absorption enhancers such as tween 80, tween 20, Vitamin E TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate) and Gelucire®.
- 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 15 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, preferably 2.5 mg to 1 g per patient per day.
- a formulation intended for the oral administration of humans may contain 10 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.
- Dosage amounts of 4 mg, 8 mg, 18 mg, 20 mg, 36 mg, 40 mg, 80 mg, 160 mg, 320 mg and 640 mg may also be employed.
- the £5 following table exemplifies formulations that may be employed for the present invention.
- the compounds of Formula I of the present invention can be prepared according to the synthetic routes outlined in Schemes 1 and 4 below and by following the methods described therein.
- the imidazole of Formula I may be prepared in a multi-step sequence from the requisite phenanthrenequinone i.
- the phenanthrene imidazole iii is obtained by treating the phenanthrenequinone i and an appropriately substituted aldehyde ii with a reagent such as NH4OAC or NH4HCO3 in a solvent such as acetic acid.
- Subsequent functional group interconversion can be done at any of the Rl to IIS positions.
- Ia could be converted to Ib by placing Ia in the presence of a monosubstituted alkynyl, a stannane, a boronic acid, a borane or a boronate under conditions that promote cross coupling reaction, such as heating in the presence of a catalyst, such as Pd(PPh3)4 and
- Phenanthrenequinone i can be prepared according to the sequences outlined in Scheme 2 and 3.
- Deprotonation of the phosphonium salt iv (Scheme 2) in the presence of a base, such as sodium »0 hydride or sodium methoxide, in a solvent such as DMF followed by the addition of the aldehyde v produces the stylbene vi as a mixture of E and Z isomers.
- Intramolecular cyclisation of this mixture upon exposition to UV light in the presence of an oxidizing agent, such as iodine, and an acid scavenger, such as propylene oxide, in a suitable solvent such as cyclohexanne produces the phenanthrene vii.
- This phenanthrene viia can be directly oxidized with an oxidizing agent, such as C1O3, in a suitable solvent, such as acetic acid, to provide the phenanthrenequinone i, or optionally, phenanthrene viia could be further elaborated to phenanthrene viib by the appropriate interconversion of any of the functional group Rl to R.8, such as transmetallation with an organometallic reagent, such as butyl lithium, in a suitable solvent such as THF, followed by the addition of an electrophile, such as iodine or carbon dioxide.
- an oxidizing agent such as C1O3
- a suitable solvent such as acetic acid
- phenylacetic acid viii can be condensed with the aldehyde ix in the presence of a base, such as potassium carbonate, and in the presence of acetic anhydride to afford the nitro stylbene x.
- a base such as potassium carbonate
- acetic anhydride to afford the nitro stylbene x.
- This nitro aryl x is then reduced with an appropriate reducing agent, such as iron or iron sulfate, in the presence of ammonium hydroxide in a suitable solvent, such as acetic acid, to produce the amine xi.
- an appropriate reducing agent such as iron or iron sulfate
- aqueous hydroxide such as sodium hydroxide
- acid such as sulfuric acid and sulfamic acid
- a catalyst such as copper or a ferrocene
- This phenanthrene can be oxidized and simultaneously decarboxylated using an appropriate oxidizing agent, such as chromium trioxide in suitable solvent, such as acetic acid, to afford the phenanthrenequinone i.
- a nucleophilic reagent such as an organolithium, organocerium or Grignard reagent in an organic solvent, such as ether, THF or methylene chloride (Grinard reagent)
- an organic solvent such as ether, THF or methylene chloride (Grinard reagent)
- Grinard reagent a nucleophilic reagent
- an organic solvent such as ether, THF or methylene chloride
- Id could be converted to Ie by placing Id in the presence of a monosubstituted alkynyl, a stannane, a boronic acid, a borane or a boronate under conditions that promote cross coupling reaction, such as heating in the presence of a catalyst such as Pd(PPIy )4 and CuI, and in the presence of a base, such as sodium carbonate or diisopropylamine, in a suitable solvent, such as THF, DMF or DME.
- a catalyst such as Pd(PPIy )4 and CuI
- a base such as sodium carbonate or diisopropylamine
- the imidazole secondary amine can be substituted as described in Scheme 5 by treating an appropriately fimctionalized phenanthrene imidazole I with a reagent such as an acylating agent or an alkylating agent such as methyl iodide in the presence of a base such as sodium hydride in a suitable solvent such as DMF.
- a reagent such as an acylating agent or an alkylating agent such as methyl iodide
- Step 1 6,9-dibromo-2-(2-chloro-6-fluorophenyl)-lH-phenanthro[9,10-rf]imidazole To a solution of 30 g (82 mmol) of 3 ,6-dibromophenanthrene-9, 10-dione (Bhatt,
- Step 3 2-[9-chloro-6-(3-hydroxy-3-methylbutyl-l-yn-l-yl)-lH-phenanthro[9,10- ⁇ TIimidazol-2-yl]-3- fluorobenzonitrile
- Step 1 l-(3-phenanthryl)ethanone oxime
- This imidazole was prepared by following the procedure describe in Example 14, Step 1, but substituting 3-chlorophenanthrene-9,10-dione for 3,6-dibromophenanthrene-9,10-dione and substituting 2,6-dibromobenzaldehyde for 2-fluoro-6-chlorobenzaldehyde to afford 27 g of 6 ⁇ chloro-2- (2,6-dibromophenyl)-lH-phenanthro[9,10-t/]imidazole as an off-white solid.
- Step 1 1 -bromo-4-[2-(4-chlorophenyl)vinyl]benzene
- a 2 L vessel equipped with a pyrex inner water-cooled jacket was charged wjth 5.16 g (17 mmol) of l-bromo-4-[2-(4-chlorophenyl)vinyl]benzene from Step 1, 2 L of cyclohexane, 25 niL of 0 THF, 25 niL of propylene oxide and 6.7 g (26 mmol) of iodine.
- the stirring solution was degassed by bubbling nitrogen and was exposed to UV light for 24 hrs by inserting a 450 W medium pressure mercury lamp in the inner.
- the reaction was quenched with 10% Na2S2 ⁇ 3 and aqueous layer was extracted with ethyl acetate. Combined organic layers were washed with brine, dried over Na2SO4 and volatiles were removed under reduced pressure. The residue was swished in a minimal amount of ethyl
- Step 4 9-bromo-6-chloro-2-(2,6-dibromophenyl)-lH-phenanthro[9,10-(5(]imidazole
- Step 5 2-(9-bromo-6-chloro- lH-phenanthro [9, 10-d] imidazol-2-yl)isophthalonitrile
- Stepl (2£)-2-(4-bromophenyl)-3-(4-chloro-2-nitrophenyl)acrylic acid
- Step 2 (2 J E)-3-(2-amino-4-chlorophenyl)-2-(4-bromophenyl)acrylic acid
- This quinone can be obtained by following the procedure describe in Example 36, Step 1 to 3, or by the using the following procedure: to a 0 0 C solution of 118 mL of concentrated sulphuric acid in 1.0 L of water was added drop wise a solution prepared as follows: 65 g of (22 ⁇ )-3-(2-arnino-4- chlorophenyl)-2-(4-bromophenyl)acrylic acid from Step 2 in 1 L of water followed by the addition of 11 g of NaOH, stirring for 10 minutes at 0 0 C, addition of NaNO2 (15 g) and stirring of the resulting
- Step 4 9-bromo-6-chloro-2-(2,6-dibromophenyl)-lH-phenanthro[9,10-(/]imidazole
- Step 1 2-(2,6-dibromophenyl)-lH-phenanthro[9,10- ⁇ T
- This imidazole was obtained following the procedure described in Example 36, Step 4, but substituting the phenanthrene-9,10-dione for the 3-bromo-6-chlorophenanthrene-9,10-dione to afford the 2-(2,6-dibromophenyl)-lH-phenanthro[9, 10-cT] imidazole
- Step 2 2-(lH-phenantliro[9,10-(flimidazol-2-yl)isophthalonitrile
- This compound was obtained by using the procedure described in Example 36, Step 5, but substituting the 2-(2,6-dibromophenyl)-lH-phenanthro[9,10- ⁇ f]imidazole for the 9-bromo-6-chloro-2- (2,6-dibromophenyl)-lH-phenanthro[9,10- ⁇ f]imidazole to afford the desired 2-(lH-phenanthro[9,10- ⁇ i]imidazol-2-yl)isophthalonitrile.
- Step 3 2-[ 1 -(chloromethyl)- lH-phenanthro[9, 10- ⁇ T]imidazol-2-yl]isophthalonitrile
- Step 4 2-( 1 - ⁇ [dihydroxy(dioxido)phosphino]methyl ⁇ - lH-phenanthro [9, 10-d] imidazol-2- yl)isophthalonitrile
- Step 2 6,9-dibromo-2-(2,6-dibromophenyl)- 1 - ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ - lH-phenanthro[9, 10-
- reaction was quenched by pouring it into water and ethyl acetate. It was then filtered through Celite, the aqueous phase extracted with ethyl acetate, the organic layer washed once with brine, dried over Na2SO4, filtered and concentrated.
- Step 4 2-[6-bromo-2-(2,6-dibromophenyl)-lH-phenanthro[9,10-c(]imidazol-9-yl]propan-2-ol
- Step 5 2-[6-bromo-9-(l -hydroxy- 1-methylethyl)- lH-phenanthro[9,10- ⁇ imidazol-2-yl]isophthalonitrile Copper cyanide (420 mg, 4.7 mmol) was added to a room temperature solution of 2-[6- bromo-2-(2,6-dibromophenyl)-lH-phenanthro[9,10-(f]imidazol-9-yl]propan-2-ol from Step 4 (1.25 g, 2.1 mmol) in DMF (100 mL) and the mixture heated at 80 0 C for 18 h, after which it was poured into a mixture of N ⁇ 4O ⁇ and ethyl acetate and stirred for 1 h.
- Step 1 2-[6-(cyclopropylethynyl)-9-(l -hydroxy- 1-methylethyl)- lH-phenanthro[9,10-c(]imidazol-2- yl]isophthalonitrile
- the resulting mixture was heated at 60-65 0 C for 3.5 h, cooled to room temperature and then poured into a mixture of N ⁇ 4O ⁇ and ethyl acetate and stirred for 1 h.
- the aqueous phase was extracted with ethyl acetate, the organic layer washed once with water, once with brine, dried over Na2SO4, filtered and concentrated.
- Step 1 2-[9-chloro-6-(3-hydroxy-3-methylbutyl)-lH-phenanthro[9,10- ⁇ i]imidazol-2-yl)isophthalonitrile
- Step l 2-[6-chloro-9-(3-methylbut-3-en-l-yn-l-yl)-lH-phenanthro[9,10--/]imidazol-2-yl]isophthalonitrile
- Step 2 ( ⁇ )-2-[9-chloro-6-(3,4-dihydroxy-3-methylbut-l-yn-l-yl)-lH-phenanthro[9,10-tf]imidazol-2- yl] isophthalonitrile
- prostaglandin E synthase activity Compounds are tested as inhibitors of prostaglandin E synthase activity in microsomal prostaglandin e synthases, whole cell and in vivo assays. These assays measure prostaglandin E2 (PGE2) synthesis using either Enzymatic Immunoassay (EIA) or mass spectrometry.
- EIA Enzymatic Immunoassay
- Cells used for microsomal preparation are CHO-Kl cells transiently transfected with plasmids encoding the human mPGES-1 cDNA.
- Cells used for cell-based experiments are human A549 (which express human mPGES-1). Guinea pigs are used to test the activity of selected compounds in vivo. In all these assays, 100% activity is defined as the PGE2 production in vehicle-treated samples.
- IC50 and ED50 represent the concentration or dose of inhibitor required to inhibit PGE2 synthesis by 50% as compared to the uninhibited control.
- Prostaglandin E synthase microsomal fractions are prepared from CHO-Kl cells transiently transfected with plasmid encoding the human mPGES-1 cDNA. Microsomes are then prepared and the PGES assay begins with the incubation of 5 ⁇ g/ml microsomal PGES-I with compound or DMSO (final 1%) for 20-30 minutes at room temperature. The enzyme reactions are performed in 20OmM KPi pH 7.0, 2mM EDTA and 2.5mM GSH-reduced form. The enzymatic reaction is then initiated by the addition of l ⁇ M final PGH2 substrate prepared in isopropanol (3.5% final in assay well) and incubated at room temperature for 30 seconds.
- the reaction is terminated by the addition of SnCl2 in IN HCl (lmg/ml final).
- Measurement of PGE2 production in the enzyme reaction aliquots is done by EIA using a standard commercially available kit (Cat #: 901-001 from Assay Designs). Data from this assay for representative compounds is shown in the table below.
- Whole cells provide an intact cellular environment for the study of cellular permeability and biochemical specificity of anti-inflammatory compounds such as prostaglandin E synthase inhibitors.
- human A549 cells are stimulated with lOng/ml recombinant human IL- l ⁇ for 24 hours.
- the production of PGE2 and PGF2 ⁇ are measured by EIA at the end of the incubation as readouts for selectivity and effectiveness against mPGES-1 -dependent PGE2 production.
- Human A549 cells specifically express human microsomal prostaglandin E synthase-1 and induce its expression following treatment with IL-l ⁇ for 24 hours.
- 2.5xl ⁇ 4 cells seeded in lOOul/well (96-well plate) and incubated overnight under standard conditions.
- 100 ul of cell culture media containing lOng/ml IL-l ⁇ is then added to the cells followed by the addition of either 2% FBS containing RPMI or 50% FBS containing RPMI.
- 2 ⁇ l of drugs or vehicle (DMSO) are then added and samples are mixed immediately. Cells are incubated for 24 hours and following the incubation 175 ⁇ l of medium is harvested and assayed for PGE2 and PGF2 ⁇ contents by EIA.
- Freshly isolated venous blood from human volunteers is collected in heparinized tubes. These subjects have no apparent inflammatory conditions and have not taken any NSAIDs for at least 7 days prior to blood collection. 250 ⁇ l of blood is pre-incubated with 1 ul vehicle (DMSO) or 1 ul of test compound.
- Bacterial LPS at lOO ⁇ g/ml E. CoIi serotype 0111:B4 diluted in 0.1% w/v bovine serum albumin in phosphate buffered saline
- Unstimulated control blood at time zero (no LPS) is used as blank.
- the blood is centrifuged at 3000rpm for 10 min at 4°C.
- the plasma is assayed for PGE2 and TxB2 using an EIA kit as indicated above.
- the whole animal provides an integrated physiological system to confirm the antiinflammatory activity of test compounds characterized in vitro.
- animals are dosed with compounds either prior or after the inflammatory stimulus, LPS.
- LPS is injected into the hind paw of guinea pigs and hyperalgesia measurements are recorded 4.5 and/or 6 hrs after the injection.
- the time it takes for the animal to remove its paw is recorded.
- the infrared light immediately shuts off when the animal withdraws its paw from the area.
- the light will also shut off automatically when the time reaches 20 seconds.
- Test compounds are orally dosed at 5ml/kg using an 18-gauge feeding needle.
- LPS serotype 0111 :B4, 10 ⁇ g
- 0.9% saline is injected into the plantar region of the left hind paw at a volume of 100 ⁇ l using a 26 gauge needle 1 hour following compound administration. Rectal temperature and thermal paw withdrawal latency are taken 4.5 hours after LPS administration.
- the animals are euthanized following the measurements using CO2 and lumbar spinal cord, hind paw and blood samples collected.
- Thermal paw withdrawal of each animal is determined before and 3 hours following sub- plantar injection of LPS. Animals which have received LPS and do not show a decrease in withdrawal latency at the 3 hour time point will be removed from study and euthanized. Test compounds are dosed p.o. at 5ml/kg immediately following the thermal paw withdrawal measurement. Thermal withdrawal latency is taken 1.5 and 3hours following compound administration (4.5 and 6 hours post-LPS administration). After the final reading, the animals are euthanized using CO2 and lumbar spinal cord and blood samples collected for prostaglandin determination by mass spectrometry and drug level, respectively.
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Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
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JP2007545802A JP5086809B2 (en) | 2004-12-17 | 2005-12-15 | 2- (Phenyl or heterocyclic) -1H-phenanthro [9,10-d] imidazole as mPGES-1 inhibitor |
AU2005316091A AU2005316091B2 (en) | 2004-12-17 | 2005-12-15 | 2-(phenyl or heterocyclic)-1H-phenantrho[9,10-D]imidazoles as mPGES-1 inhibitors |
CA2591724A CA2591724C (en) | 2004-12-17 | 2005-12-15 | 2-(phenyl or heterocyclic)-1h-phenantrho[9,10-d]imidazoles as mpges-1 inhibitors |
CN2005800433134A CN101119973B (en) | 2004-12-17 | 2005-12-15 | 2-(phenyl or heterocyclic)-1h-phenantrho[9,10-d]imidazoles as mpges-1 inhibitors |
EP05823957A EP1828143B1 (en) | 2004-12-17 | 2005-12-15 | 2-(phenyl or heterocyclic)-1h-phenantrho[9,10-d]imidazoles as mpges-1 inhibitors |
ES05823957T ES2410905T3 (en) | 2004-12-17 | 2005-12-15 | 2- (Phenyl or heterocycle) -1H-phenanthro [9,10-d] imidazoles as inhibitors of MPGES-1 |
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US73933805P | 2005-11-23 | 2005-11-23 | |
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Cited By (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007059610A1 (en) * | 2005-11-23 | 2007-05-31 | Merck Frosst Canada Ltd. | 2-(phenyl or heterocyclic)-1h-phenantrho[9,10-d]imidazoles as mpges-1 inhibitors |
WO2007095753A1 (en) * | 2006-02-24 | 2007-08-30 | Merck Frosst Canada Ltd. | 2-(phenyl or heterocyclic) - 1h-phenanthro [9,10-d] imidazoles |
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Also Published As
Publication number | Publication date |
---|---|
ES2410905T3 (en) | 2013-07-03 |
JP5086809B2 (en) | 2012-11-28 |
JP2008524121A (en) | 2008-07-10 |
EP1828143A1 (en) | 2007-09-05 |
EP1828143A4 (en) | 2009-08-26 |
AU2005316091B2 (en) | 2011-12-01 |
AU2005316091A1 (en) | 2006-06-22 |
CA2591724A1 (en) | 2006-06-22 |
CN101119973B (en) | 2011-08-03 |
CN101119973A (en) | 2008-02-06 |
CA2591724C (en) | 2014-08-05 |
EP1828143B1 (en) | 2013-03-20 |
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