CA2161789A1 - 2-substituted-3,4-diarylthiophene derivatives as inhibitors of cyclooxygenase - Google Patents
2-substituted-3,4-diarylthiophene derivatives as inhibitors of cyclooxygenaseInfo
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- CA2161789A1 CA2161789A1 CA002161789A CA2161789A CA2161789A1 CA 2161789 A1 CA2161789 A1 CA 2161789A1 CA 002161789 A CA002161789 A CA 002161789A CA 2161789 A CA2161789 A CA 2161789A CA 2161789 A1 CA2161789 A1 CA 2161789A1
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- hydrogen
- thiadiazol
- oxadiazol
- halo
- Prior art date
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Classifications
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/18—Radicals substituted by singly bound hetero atoms other than halogen by sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/28—Halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/42—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms with nitro or nitroso radicals directly attached to ring carbon atoms
- C07D333/44—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms with nitro or nitroso radicals directly attached to ring carbon atoms attached in position 5
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Disclosed are compounds of formula (I) use-ful in the treatment of cyclooxygenase mediated dis-eases such as pain, fever and inflammation of a va-riety of conditions including rheumatic fever, symp-toms associated with influenza or other viral infec-tions, common cold, low back and neck pnin, dys-menorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, injuries and Alzheimer's disease. R3 is selected from the group consisting of (1) -S(O)2CH3,(2)-S(O)(NH)CH3,(3) -S(O)NH2, and (4) -S(O)2NH2.
Description
21~1789 TITLE OF THE INVENTION
2-SUBSTITUTED-3,4-DL~RYLTHIOPHENE DERIVATIVES AS
IN~BITORS OF CYCLOOXYGENASE
This invention relates to compounds and ph~rm~ceutical compositions for the treatment of cyclooxygenase mediated diseases and methods of treatment thereof.
Non-steroidal, antiinfl~mm~tory drugs exert most of their antiinfl~mm~tory, 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. Up until recently, only one form of cyclooxygenase had been characterized, this corresponding to cyclooxygenase-1 or the 15 constitutive enzyme, as originally identified in bovine seminal vesicles.
Recently the gene for an inducible form of cyclooxygenase (cyclooxygenase-2) has been cloned, sequenced and characterized from chicken, murine and human sources. This enzyme is distinct from the cyclooxygenase-1 which has now also been cloned, sequenced and 20 characterized from sheep, murine and hllm~n sources. The second form of cyclooxygenase, cyclooxygenase-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. As prostaglandins have physiological and pathological roles, we have concluded that the constitutive enzyme, 25 cyclooxygenase-1, is responsible, in large part, for endogenous basal release of prost~gl~nclinc and hence is important in their physiological functions such as the m~intenance of gastrointestinal integrity and renal blood flow. In contrast, we have concluded that the inducible form, cyclooxygenase-2, is mainly responsible for the pathological effects of 30 pros~gl~n~lin~ where rapid induction of the enzyme would occur in response to such agents as infl~mm~tory agents, hormones, growth factors, and cytokines. Thus, a selective inhibitor of cyclooxygenase-2 will have similar antiinfl~mm~tory, antipyretic and analgesic properties to a conventional non-steroidal ~ntiinfl~mm~tory drug (NSAID), and in 21~178~
addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a ~limini~hed ability to induce some of the mech~ni~m-based side effects. In particular, 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.
SUMMARY OF THE INVENTION
The invention encompasses compounds of Formula I
S~ R4 which are useful in the treatment of cyclooxygenase mediated diseases, 20 in particular cyclooxygenase-2 mediated diseases.
The invention also encomp~ses ph~ eutical compositions for inhibiting cyclooxygenase and for treating cyclooxygenase mediated diseases as disclosed herein comprising a ph~ ceutically acceptable carrier and a non-toxic therapeutically 25 effective amount of compound of Formula I as described herein.
The invention also encompasses me~ods of inhibiting cyclooxygenase and treating cyclooxygenase mediated diseases comprising:
~lmini~tration to a patient in need of such tre~tmtont of a non-toxic 30 therapeutically effective amount of a compound of Formula I as disclosed herein.
DETAILED DESCRIPTION OF THE ~VENTION
The invention encompasses compounds of Formula I
~ WO 94/26731 2 1 ~ 1 7 ~ !~ PCT/CA94/00264 S~ R4 and pharmaceutically acceptable salts thereof wherein:
o R1 is selected from the group consisting of (a) hydrogen, (b) halo, including fluoro, chloro, bromo and iodo, (c) CN, (d) N02, (e) CF3, and (f) Cl 6aLkYl;
R2 is selected from the group consisting of (a) C3 6alkyl, (b) mono or di substituted phenyl wherein the substitutents are selected from the group consisting of (1) hydrogen, (2) halo as defined above, (3) C1 6alkoxy, (4) C1 6alkylthio, (S) CN, (6) CF3, (7) C1 6aLkyl, and (8) N3, (c) mono or di substituted heteroaryl wherein heteroaryl is (1) a monocyclic aromatic ring of ~ atoms, cont~ining one hetero atom which is S, O or N and optionally 1, 2, or 3 additional hetero atoms which are N, or (2) a monocyclic aromatic ring of 6 atoms, con~ining 1, 2, 3, or 4 hetero atoms which are N, and WO 94/26731 PCTICA94/00264 ~
wherein the sub~ uLel-ts on the heteroaryl are selected from the group consisting of (1 ) hydrogen, (2) halo as defined above, (3) C1 6aLkoxy, (4) Cl 6alkylthio, (5) CN, (6) CF3, (7) C1 6a1~cyl, o (8) N3, R3 is selected from the group consisting of (1 ) -S(0)2CH3, (2) -S(O)(NH)CH3, (3) -S(O)NH2, and 4) -S(0)2N~2;
R4 is selected from the group consisting of (1) hydrogen, (2) halo as defined above, (3) carboxy, and (4) CF3.
For purposes of this specification aLkyl is defined to include linear, branched, and cyclic structures, with Cl 6alkyl including including methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Sirnilarly, Cl 6aLkoxY is inten-led to include alkoxy groups of from 1 to 6 carbon atoms of a straight, branched, or cyclic configuration. Examples of lower aLkoxy groups include methoxy, O ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the 3 like. Likewise, C1 6alkylthio is intended to include alkylthio groups of from 1 to 6 carbon atoms of a straight, branched or cyclic configuration. Examples of lower alkylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc. By way of illustration, the propylthio group signifies -SCH2CH2CH3.
~WO 94/26731 2 1 6 ~ 7 8 9 PCT/CA94/00264 In one genus the invention encompasses compounds of Formula I
~R3 S~ R4 and pharmaceutically acceptable salts thereof wherein:
R4 is hydrogen, and R2 is selected from the group consisting of (a) C3 6alkyl, (b) mono or di substituted phenyl, and (c) mono or di substituted heteroaryl wherein heteroaryl is selected from the group consisting of (1) furanyl, (2) diazinyl, triazinyl, tetrazinyl, (3) imidazolyl, (4) isoxazolyl, (S) isothiazolyl, (6) oxadiazolyl, (7) oxazolyl, (8) pyrazolyl, (9) pyrrolyl, (10) th~ 7olyl~
(11 ) thiazolyl, (12) thienyl, 3 (13) triazolyl, (14) pyridyl, and (15) tetrazolyl.
Exemplifying the invention are the compounds of Table 1 including:
3 -(4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)thiophene, V~O 94/26731 , ~ PCT/CA94/00264 ~
2-Nitro-3 -(4-fluorophenyl)-4-((4 -methylsulfonyl)phenyl)thiophene, 2-Bromo-3 -(4-fluorophenyl)-4-((4-methylsulfonyl)phenyl)thiophene, and 3 -(4-Fluorophenyl)-4-(4-sulfamoylphenyl)thiophene.
In a second embo-lim~nt, the invention encompasses ph~rm~ceutical compositions for inhibiting cyclooxygenase and for treating cyclooxygenase mediated diseases as disclosed herein comprising a ph~ ceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of Formula I as described above.
Within this embodiment the invention encompasses ph~ eutical compositions for inhibiting cyclooxygenase-2 and for treating cyclooxygenase-2 mediated diseases as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of Formula I as described above.
In a third emborliment, the invention encompasses a method of inhibiting cyclooxygenase and treating cyclooxygenase mediated diseases as disclosed herein comprising:
~dmini~tration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of Formula I as disclosed herein.
Within this embodiment the invention encompasses a method of inhibiting cyclooxygenase-2 and treating cyclooxygenase-2 mediated diseases as disclosed herein comprising:
~lmini~tration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of Formula I as disclosed herein.
The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a ph~ ceutically acceptable salt, thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from ph~ ceutically acceptable non-toxic bases including .
~WO 94/26731 2 16 17 ~ ~ PCT/CA94/00264 inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, coRer, ferric, ferrous, lithium, m~gnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, 5 m~ nesium, potassium, and sodium salts. Salts derived from ph~ ceutically 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 algi~ le, betaine, caffeine, choline, N,N-diberl~ylethylenerli~mine, diethyl~mine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethano!~mine, ethylene(li~mine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropyl~mine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, 15 theobromine, triethyl~mine, trimethylamine, tripropyl~mine, trometh~mine, and the like.
It will be understood that in the discussion of methods of treatment which follows, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
As disclosed elsewhere in this specification in further detail, these diseases include pain, fever and infl~mm~tion 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, toothache, sprains and strains, myositis, 25 neuralgia, synovitis, ar~ritis, including rheumatoid ~llllilis degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, injuries.
Compounds of Formula I are useful for the relief of pain, fever and infl~mm~tion 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, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, WO 94/26731 f~ ~ - PCT/CA94/00264 injuries, following surgical and dental procedures. In addition, such compounds may inhibit cellular neoplastic transformations and metastic tumor gro~vth and hence can be used in the treatment of cancer.
Compounds of Formula I will also inhibit prostanoid-induced smooth 5 muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labor and asthma and Alzheimers disease.
By virtue of their high cyclooxygenase-2 (COX-2) activity and/or their specificity for cyclooxygenase-2 over cyclooxygenase-1 (COX-1), compounds of Formula I will prove useful as alternatives to conventional non-steroidal anti-infl~mm~tory drugs (NSAID'S) particularly where such non-steroidal anti-infl~mm~tory drugs may be contra-indicated such as in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of 15 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 .
Similarly, compounds of Formula I, will be useful as a partial or complete substitute for conventional NSAID'S in preparations wherein they are presently co-~(lmini~tered with other agents or ingredients. Thus in further aspects, the invention encompasses pharmaceutical compositions for treating cyclooxygenase-2 mediated diseases as defined above comprising a non-toxic therapeutically 25 effective amount of compound of Formula I as defined above and one or more ingredients such as another pain reliever including acetaminophen or phenacetin; a potentiator including caffeine; an H2-antagonist, all~minllm or m~gnesium hydroxide, simethicone, a decongestant including phenylephrine, phenylpropanol~mine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an ~ntitllssive including codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; a sedating or non-~ WO 94/26731 21817 8 ~ PCT/CA94/00264 sedating ~ntihi,st~mine. In addition the invention encompasses a methodof treating cyclooxygenase mediated diseases comprising ~dmini~tration to a patient in need of such treatment a non-toxic therapeutically effective amount of compound of Formula I, optionally 5 co-administered with one or more of such ingredients as listed immediately above.
Compounds of the present invention are inhibitors of cyclooxygenase-2 and are thereby useful in the treatment of cyclooxygenase-2 mediated diseases as enumerated above. This activit~
is illustrated by their ability to selectively inhibit cyclooxygenase-2 over cyclooxygenase-l. Accordingly, in one assay, the ability of the compounds of this invention to treat cyclooxygenase mediated diseases can be demonstrated by measuring the amount of prostaglandin E2 (PGE2) synthesized in the presence of arachidonic acid, 5 cyclooxygenase-l or cyclooxygenase-2 and a compound of Formula I.
The ICS0 values represent the concentration of inhibitor required to return PGE2 synthesis to 50% of that obtained as compared to the uninhibited control. Illustrating this aspect, we have found that Compounds 1 through 25 are more than 100 times more effective in inhibiting COX-2 than they are at inhibiting COX-1. In addition they all have a COX-2 IC50 of 1 nM to 1 ,uM. By way of comparison, Ibuprofen has an ICS0 for COX-2 of 1 ~lM, and Indomethacin has an ICS0 for COX-2 of approximately 100 nM.
For the treatment of any of these cyclooxygenase mediated 25 diseases compounds of Formula I may be ~-lmini.ctered orally, topically, parenterally, by inh~l~tion spray or rectally in dosage unit formulations cont~ining conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal 3 injection or infusion techniques. In addition to the treatment of warm-blooded ~nim~l~ such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the compounds of the invention are effective in the tre~tment of hllm~n.~.
2161~8~
As indicated above, phàImaceutical compositions for treating cyclooxygenase-2 mediated diseases as defined may optionally include one or more ingredients as listed above.
The ph~rm~celltical compositions cont~ining the active 5 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 ph~rm~ceutical 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 ph~rTn~ceutically elegant and palatable preparations. Tablets contain the active ingredient in ~-lmixt~lre with non-toxic pharmaceutically acceptable excipients which are suitable for the m~nuf~rture of tablets.
These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; gran~ ting and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example m~gnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay ~ integration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl 5 monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108;
4,166,452; and 4,265,874 to form osmotic ~erapeutic tablets for control release.
Forrn~ tions for oral use may also be presented as hard 30 gelatin capsules wherein the active ingredient is mixed with an ~nert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
~ ~=
~WO 94126731 21 G 1 7 8 ~ PCT/CA94100264 Aqueous suspensions contain the active materials in admixture with excipients suitable for the m~nllf~cture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-5 cellulose, sodium ~l~in~te, 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 polyethylene sorbitan monooleate. 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 or saccharin.
Oily suspensions may be form~ ted by suspending the 20 active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a 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, suspen~1ing agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
21~1~89 WO 94/26731 PCT/CA94/00264 ~
The pharmaceutical compositions of the invention may also be in the form of 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 ~ese. Suitable emulsifying 5 agents may be naturally-occurring gums, for example gum acacia or gum tr~c~nth, 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 contlenc~tion products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be form~ te-l 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 ph~rm~ceutical 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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending merlillm. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of forrnula (I) may also be ~lministered in 30 the form of suppositories for rectal ~tlmini.ctration of the drug. These compositions can be prepared by mixing ~e 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. Such materials are cocoa butter and polyethylene glycols.
~ WO 94/26731 2 1 6 1 7 8 !~ PCT/CA94/00264 For topical use, creams, ointments, jellies, solutions or suspensions, etc., cont~ining the compounds of Formula (I) are employed. (For purposes of this application, topical application shall include mouth washes and gargles.) Dosage levels of the order of from about 0.01 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 gms per patient per day. For example, infl~mm~tion may be effectively treated by the a~lministration 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 gms 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 minictration. For example, a form~ tion intended for the oral ~lminictration of hllm~nc may contain from 0.5 mg to 5 gm 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.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of ~lminictration, route of ~lminictration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
The compounds of the present invention are conviently prepared using the procedures described below.
Method A
The compounds of the present invention can be prepared by the general method described by J. Nakayama et al., Tetrahedron Lett., 2 ~
WO 94/26731 PCT/CA94/00264 ~
~ - 14-26 (16), 1983-1984 (1985). Accordingly, intermediate III, obtained from the base catalyzed coupIing of an a-mercaptoacetophenone and an a-haloacetophenone, is treated with tit~nium tetrachloride and zinc at low temperature in an inert solvent such as tetrahydrofuan to give an 5 intermediate 3,4-dihydroxythiolane IV. This compound can then be dehydrated by heating it in a solvent such as toluene in the presence of an acid such as p-toluenesulfonic acid to yield II. This compound can be oxidized with a reagent such as the magnesium salt of mono-peroxyphtalic acid (MMPP) or m-chloroperoxybenzoic acid (mCPBA) to yield I.
METHOD A
~SMe 2 base HS~R4 + X~R
O O
O O ,~SMe MeS ~ ~ R2 TiCI4/Zn S/~J~R4 IV
2s H+ S~ SMe ~SRO42Me heat R2 [ R2 R1 Rl ll 1 a (R3 = SO2Me) ~WO 94/26731 21 G 17 ~ 9 PCT/CA94/00264 Method B
If I contains a substituent R1 which can be introduced by an aromatic electrophilic substitution, this can be carried out either on I or II. Accordingly, I can be treated with a halogenating agent such as 5 bromine in a solvent such as glacial acetic acid to give the desired 2-bromothiophene (R1 = Br). When it is desired to have a nitrogen substituent at this position, for example R1 = N02, a cold mixhlre of I
in a solvent such as acetic anhydride is treated with nitric acid to introduce the nitro group at the desired position.
METHOD B
la (R~ = H) R ~SO2Me R1 Rl 2161~89 WO 94/26731 PCT/CA94/00264 ~
Method C
When R3 is a sulfonarnide group such as R3 = S02NH2, this substituent can be introduced by treating V with a base such as n-BuLi at low temperature and quenching ~e anion with sulfur dioxide to 5 give a lithium arylsulfinate intermediate. This intermediate can then be converted to an arylsulfonyl chloride which will react with NH3 to provide Id. This general procedure has been described by T. Hameda and O. Yonemitsu, Synthesis, 852 (1986).
METHOD C
1S ~R4 2)S2 ~SO2NH2 R2 3) SO2CI2 R2 R1 4) NH3 R1 V Id (R3=So2NH2) Table I illustrates compounds of Formula I, which are representative of the present invention. Representative biological data and the assays utilized to generate the data is provided immediately thereafter.
~WO 94/26731 ~ 1 G 17 ~ 9 PCT/CA94/00264 - TABLE I
~R3 S/~--R4 ~, Compound R1 R2 R3 R4 H 4-fluorophenyl -S(0)2CH3 H
2 N2 -S(0)2CH3 H
3 Br " -S(0)2CH3 H
4 H " -S(0)2NH2 H
F " -s(o)2cH3 H
6 Cl " -S(0)2CH3 H
2 0 7 I .. -S(0)2CH3 H
8 CH3 cyclohexyl -s(o)2cH3 H
9 CF3 4-fluorophenyl -S(0)2CH3 H
CN ~ -S(0)2CH3 H
11 H " -S(O)(NH)CH3 H
IN~BITORS OF CYCLOOXYGENASE
This invention relates to compounds and ph~rm~ceutical compositions for the treatment of cyclooxygenase mediated diseases and methods of treatment thereof.
Non-steroidal, antiinfl~mm~tory drugs exert most of their antiinfl~mm~tory, 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. Up until recently, only one form of cyclooxygenase had been characterized, this corresponding to cyclooxygenase-1 or the 15 constitutive enzyme, as originally identified in bovine seminal vesicles.
Recently the gene for an inducible form of cyclooxygenase (cyclooxygenase-2) has been cloned, sequenced and characterized from chicken, murine and human sources. This enzyme is distinct from the cyclooxygenase-1 which has now also been cloned, sequenced and 20 characterized from sheep, murine and hllm~n sources. The second form of cyclooxygenase, cyclooxygenase-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. As prostaglandins have physiological and pathological roles, we have concluded that the constitutive enzyme, 25 cyclooxygenase-1, is responsible, in large part, for endogenous basal release of prost~gl~nclinc and hence is important in their physiological functions such as the m~intenance of gastrointestinal integrity and renal blood flow. In contrast, we have concluded that the inducible form, cyclooxygenase-2, is mainly responsible for the pathological effects of 30 pros~gl~n~lin~ where rapid induction of the enzyme would occur in response to such agents as infl~mm~tory agents, hormones, growth factors, and cytokines. Thus, a selective inhibitor of cyclooxygenase-2 will have similar antiinfl~mm~tory, antipyretic and analgesic properties to a conventional non-steroidal ~ntiinfl~mm~tory drug (NSAID), and in 21~178~
addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a ~limini~hed ability to induce some of the mech~ni~m-based side effects. In particular, 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.
SUMMARY OF THE INVENTION
The invention encompasses compounds of Formula I
S~ R4 which are useful in the treatment of cyclooxygenase mediated diseases, 20 in particular cyclooxygenase-2 mediated diseases.
The invention also encomp~ses ph~ eutical compositions for inhibiting cyclooxygenase and for treating cyclooxygenase mediated diseases as disclosed herein comprising a ph~ ceutically acceptable carrier and a non-toxic therapeutically 25 effective amount of compound of Formula I as described herein.
The invention also encompasses me~ods of inhibiting cyclooxygenase and treating cyclooxygenase mediated diseases comprising:
~lmini~tration to a patient in need of such tre~tmtont of a non-toxic 30 therapeutically effective amount of a compound of Formula I as disclosed herein.
DETAILED DESCRIPTION OF THE ~VENTION
The invention encompasses compounds of Formula I
~ WO 94/26731 2 1 ~ 1 7 ~ !~ PCT/CA94/00264 S~ R4 and pharmaceutically acceptable salts thereof wherein:
o R1 is selected from the group consisting of (a) hydrogen, (b) halo, including fluoro, chloro, bromo and iodo, (c) CN, (d) N02, (e) CF3, and (f) Cl 6aLkYl;
R2 is selected from the group consisting of (a) C3 6alkyl, (b) mono or di substituted phenyl wherein the substitutents are selected from the group consisting of (1) hydrogen, (2) halo as defined above, (3) C1 6alkoxy, (4) C1 6alkylthio, (S) CN, (6) CF3, (7) C1 6aLkyl, and (8) N3, (c) mono or di substituted heteroaryl wherein heteroaryl is (1) a monocyclic aromatic ring of ~ atoms, cont~ining one hetero atom which is S, O or N and optionally 1, 2, or 3 additional hetero atoms which are N, or (2) a monocyclic aromatic ring of 6 atoms, con~ining 1, 2, 3, or 4 hetero atoms which are N, and WO 94/26731 PCTICA94/00264 ~
wherein the sub~ uLel-ts on the heteroaryl are selected from the group consisting of (1 ) hydrogen, (2) halo as defined above, (3) C1 6aLkoxy, (4) Cl 6alkylthio, (5) CN, (6) CF3, (7) C1 6a1~cyl, o (8) N3, R3 is selected from the group consisting of (1 ) -S(0)2CH3, (2) -S(O)(NH)CH3, (3) -S(O)NH2, and 4) -S(0)2N~2;
R4 is selected from the group consisting of (1) hydrogen, (2) halo as defined above, (3) carboxy, and (4) CF3.
For purposes of this specification aLkyl is defined to include linear, branched, and cyclic structures, with Cl 6alkyl including including methyl, ethyl, propyl, 2-propyl, s- and t-butyl, butyl, pentyl, hexyl, 1,1-dimethylethyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Sirnilarly, Cl 6aLkoxY is inten-led to include alkoxy groups of from 1 to 6 carbon atoms of a straight, branched, or cyclic configuration. Examples of lower aLkoxy groups include methoxy, O ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the 3 like. Likewise, C1 6alkylthio is intended to include alkylthio groups of from 1 to 6 carbon atoms of a straight, branched or cyclic configuration. Examples of lower alkylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc. By way of illustration, the propylthio group signifies -SCH2CH2CH3.
~WO 94/26731 2 1 6 ~ 7 8 9 PCT/CA94/00264 In one genus the invention encompasses compounds of Formula I
~R3 S~ R4 and pharmaceutically acceptable salts thereof wherein:
R4 is hydrogen, and R2 is selected from the group consisting of (a) C3 6alkyl, (b) mono or di substituted phenyl, and (c) mono or di substituted heteroaryl wherein heteroaryl is selected from the group consisting of (1) furanyl, (2) diazinyl, triazinyl, tetrazinyl, (3) imidazolyl, (4) isoxazolyl, (S) isothiazolyl, (6) oxadiazolyl, (7) oxazolyl, (8) pyrazolyl, (9) pyrrolyl, (10) th~ 7olyl~
(11 ) thiazolyl, (12) thienyl, 3 (13) triazolyl, (14) pyridyl, and (15) tetrazolyl.
Exemplifying the invention are the compounds of Table 1 including:
3 -(4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)thiophene, V~O 94/26731 , ~ PCT/CA94/00264 ~
2-Nitro-3 -(4-fluorophenyl)-4-((4 -methylsulfonyl)phenyl)thiophene, 2-Bromo-3 -(4-fluorophenyl)-4-((4-methylsulfonyl)phenyl)thiophene, and 3 -(4-Fluorophenyl)-4-(4-sulfamoylphenyl)thiophene.
In a second embo-lim~nt, the invention encompasses ph~rm~ceutical compositions for inhibiting cyclooxygenase and for treating cyclooxygenase mediated diseases as disclosed herein comprising a ph~ ceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of Formula I as described above.
Within this embodiment the invention encompasses ph~ eutical compositions for inhibiting cyclooxygenase-2 and for treating cyclooxygenase-2 mediated diseases as disclosed herein comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound of Formula I as described above.
In a third emborliment, the invention encompasses a method of inhibiting cyclooxygenase and treating cyclooxygenase mediated diseases as disclosed herein comprising:
~dmini~tration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of Formula I as disclosed herein.
Within this embodiment the invention encompasses a method of inhibiting cyclooxygenase-2 and treating cyclooxygenase-2 mediated diseases as disclosed herein comprising:
~lmini~tration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of Formula I as disclosed herein.
The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a ph~ ceutically acceptable salt, thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from ph~ ceutically acceptable non-toxic bases including .
~WO 94/26731 2 16 17 ~ ~ PCT/CA94/00264 inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, coRer, ferric, ferrous, lithium, m~gnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, 5 m~ nesium, potassium, and sodium salts. Salts derived from ph~ ceutically 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 algi~ le, betaine, caffeine, choline, N,N-diberl~ylethylenerli~mine, diethyl~mine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethano!~mine, ethylene(li~mine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropyl~mine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, 15 theobromine, triethyl~mine, trimethylamine, tripropyl~mine, trometh~mine, and the like.
It will be understood that in the discussion of methods of treatment which follows, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
As disclosed elsewhere in this specification in further detail, these diseases include pain, fever and infl~mm~tion 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, toothache, sprains and strains, myositis, 25 neuralgia, synovitis, ar~ritis, including rheumatoid ~llllilis degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, injuries.
Compounds of Formula I are useful for the relief of pain, fever and infl~mm~tion 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, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, WO 94/26731 f~ ~ - PCT/CA94/00264 injuries, following surgical and dental procedures. In addition, such compounds may inhibit cellular neoplastic transformations and metastic tumor gro~vth and hence can be used in the treatment of cancer.
Compounds of Formula I will also inhibit prostanoid-induced smooth 5 muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labor and asthma and Alzheimers disease.
By virtue of their high cyclooxygenase-2 (COX-2) activity and/or their specificity for cyclooxygenase-2 over cyclooxygenase-1 (COX-1), compounds of Formula I will prove useful as alternatives to conventional non-steroidal anti-infl~mm~tory drugs (NSAID'S) particularly where such non-steroidal anti-infl~mm~tory drugs may be contra-indicated such as in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a recurrent history of 15 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 .
Similarly, compounds of Formula I, will be useful as a partial or complete substitute for conventional NSAID'S in preparations wherein they are presently co-~(lmini~tered with other agents or ingredients. Thus in further aspects, the invention encompasses pharmaceutical compositions for treating cyclooxygenase-2 mediated diseases as defined above comprising a non-toxic therapeutically 25 effective amount of compound of Formula I as defined above and one or more ingredients such as another pain reliever including acetaminophen or phenacetin; a potentiator including caffeine; an H2-antagonist, all~minllm or m~gnesium hydroxide, simethicone, a decongestant including phenylephrine, phenylpropanol~mine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an ~ntitllssive including codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; a sedating or non-~ WO 94/26731 21817 8 ~ PCT/CA94/00264 sedating ~ntihi,st~mine. In addition the invention encompasses a methodof treating cyclooxygenase mediated diseases comprising ~dmini~tration to a patient in need of such treatment a non-toxic therapeutically effective amount of compound of Formula I, optionally 5 co-administered with one or more of such ingredients as listed immediately above.
Compounds of the present invention are inhibitors of cyclooxygenase-2 and are thereby useful in the treatment of cyclooxygenase-2 mediated diseases as enumerated above. This activit~
is illustrated by their ability to selectively inhibit cyclooxygenase-2 over cyclooxygenase-l. Accordingly, in one assay, the ability of the compounds of this invention to treat cyclooxygenase mediated diseases can be demonstrated by measuring the amount of prostaglandin E2 (PGE2) synthesized in the presence of arachidonic acid, 5 cyclooxygenase-l or cyclooxygenase-2 and a compound of Formula I.
The ICS0 values represent the concentration of inhibitor required to return PGE2 synthesis to 50% of that obtained as compared to the uninhibited control. Illustrating this aspect, we have found that Compounds 1 through 25 are more than 100 times more effective in inhibiting COX-2 than they are at inhibiting COX-1. In addition they all have a COX-2 IC50 of 1 nM to 1 ,uM. By way of comparison, Ibuprofen has an ICS0 for COX-2 of 1 ~lM, and Indomethacin has an ICS0 for COX-2 of approximately 100 nM.
For the treatment of any of these cyclooxygenase mediated 25 diseases compounds of Formula I may be ~-lmini.ctered orally, topically, parenterally, by inh~l~tion spray or rectally in dosage unit formulations cont~ining conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal 3 injection or infusion techniques. In addition to the treatment of warm-blooded ~nim~l~ such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the compounds of the invention are effective in the tre~tment of hllm~n.~.
2161~8~
As indicated above, phàImaceutical compositions for treating cyclooxygenase-2 mediated diseases as defined may optionally include one or more ingredients as listed above.
The ph~rm~celltical compositions cont~ining the active 5 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 ph~rm~ceutical 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 ph~rTn~ceutically elegant and palatable preparations. Tablets contain the active ingredient in ~-lmixt~lre with non-toxic pharmaceutically acceptable excipients which are suitable for the m~nuf~rture of tablets.
These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; gran~ ting and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example m~gnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay ~ integration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl 5 monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108;
4,166,452; and 4,265,874 to form osmotic ~erapeutic tablets for control release.
Forrn~ tions for oral use may also be presented as hard 30 gelatin capsules wherein the active ingredient is mixed with an ~nert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
~ ~=
~WO 94126731 21 G 1 7 8 ~ PCT/CA94100264 Aqueous suspensions contain the active materials in admixture with excipients suitable for the m~nllf~cture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-5 cellulose, sodium ~l~in~te, 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 polyethylene sorbitan monooleate. 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 or saccharin.
Oily suspensions may be form~ ted by suspending the 20 active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a 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, suspen~1ing agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
21~1~89 WO 94/26731 PCT/CA94/00264 ~
The pharmaceutical compositions of the invention may also be in the form of 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 ~ese. Suitable emulsifying 5 agents may be naturally-occurring gums, for example gum acacia or gum tr~c~nth, 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 contlenc~tion products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be form~ te-l 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 ph~rm~ceutical 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. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending merlillm. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of forrnula (I) may also be ~lministered in 30 the form of suppositories for rectal ~tlmini.ctration of the drug. These compositions can be prepared by mixing ~e 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. Such materials are cocoa butter and polyethylene glycols.
~ WO 94/26731 2 1 6 1 7 8 !~ PCT/CA94/00264 For topical use, creams, ointments, jellies, solutions or suspensions, etc., cont~ining the compounds of Formula (I) are employed. (For purposes of this application, topical application shall include mouth washes and gargles.) Dosage levels of the order of from about 0.01 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 gms per patient per day. For example, infl~mm~tion may be effectively treated by the a~lministration 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 gms 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 minictration. For example, a form~ tion intended for the oral ~lminictration of hllm~nc may contain from 0.5 mg to 5 gm 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.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of ~lminictration, route of ~lminictration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
The compounds of the present invention are conviently prepared using the procedures described below.
Method A
The compounds of the present invention can be prepared by the general method described by J. Nakayama et al., Tetrahedron Lett., 2 ~
WO 94/26731 PCT/CA94/00264 ~
~ - 14-26 (16), 1983-1984 (1985). Accordingly, intermediate III, obtained from the base catalyzed coupIing of an a-mercaptoacetophenone and an a-haloacetophenone, is treated with tit~nium tetrachloride and zinc at low temperature in an inert solvent such as tetrahydrofuan to give an 5 intermediate 3,4-dihydroxythiolane IV. This compound can then be dehydrated by heating it in a solvent such as toluene in the presence of an acid such as p-toluenesulfonic acid to yield II. This compound can be oxidized with a reagent such as the magnesium salt of mono-peroxyphtalic acid (MMPP) or m-chloroperoxybenzoic acid (mCPBA) to yield I.
METHOD A
~SMe 2 base HS~R4 + X~R
O O
O O ,~SMe MeS ~ ~ R2 TiCI4/Zn S/~J~R4 IV
2s H+ S~ SMe ~SRO42Me heat R2 [ R2 R1 Rl ll 1 a (R3 = SO2Me) ~WO 94/26731 21 G 17 ~ 9 PCT/CA94/00264 Method B
If I contains a substituent R1 which can be introduced by an aromatic electrophilic substitution, this can be carried out either on I or II. Accordingly, I can be treated with a halogenating agent such as 5 bromine in a solvent such as glacial acetic acid to give the desired 2-bromothiophene (R1 = Br). When it is desired to have a nitrogen substituent at this position, for example R1 = N02, a cold mixhlre of I
in a solvent such as acetic anhydride is treated with nitric acid to introduce the nitro group at the desired position.
METHOD B
la (R~ = H) R ~SO2Me R1 Rl 2161~89 WO 94/26731 PCT/CA94/00264 ~
Method C
When R3 is a sulfonarnide group such as R3 = S02NH2, this substituent can be introduced by treating V with a base such as n-BuLi at low temperature and quenching ~e anion with sulfur dioxide to 5 give a lithium arylsulfinate intermediate. This intermediate can then be converted to an arylsulfonyl chloride which will react with NH3 to provide Id. This general procedure has been described by T. Hameda and O. Yonemitsu, Synthesis, 852 (1986).
METHOD C
1S ~R4 2)S2 ~SO2NH2 R2 3) SO2CI2 R2 R1 4) NH3 R1 V Id (R3=So2NH2) Table I illustrates compounds of Formula I, which are representative of the present invention. Representative biological data and the assays utilized to generate the data is provided immediately thereafter.
~WO 94/26731 ~ 1 G 17 ~ 9 PCT/CA94/00264 - TABLE I
~R3 S/~--R4 ~, Compound R1 R2 R3 R4 H 4-fluorophenyl -S(0)2CH3 H
2 N2 -S(0)2CH3 H
3 Br " -S(0)2CH3 H
4 H " -S(0)2NH2 H
F " -s(o)2cH3 H
6 Cl " -S(0)2CH3 H
2 0 7 I .. -S(0)2CH3 H
8 CH3 cyclohexyl -s(o)2cH3 H
9 CF3 4-fluorophenyl -S(0)2CH3 H
CN ~ -S(0)2CH3 H
11 H " -S(O)(NH)CH3 H
12 H 2-pyridyl -S(0)2CH3 H
13 H 2-thienyl -S(0)2CH3 H
- 3 14 H -n-pentyl -S(0)2CH3 H
15 H 4-cyanophenyl -s(o)2cH3 H
16 H 4-fluorophenyl -S(0)2CH3 Br 17 H 4-fluorophenyl -S(0)2CH3 C02H
WO 94/26731 PCT/CA94/00264 ~
Whole Cell Cvclooxygenase Assays Human osteosarcoma 143.98.2 cells were cultured in DULBECCOS MOD~D EAGLES MEDIUM (SIGMA) cont~inin~;
3.7 g/l NaHCO3 (SIGMA), 100 ,ug/l ge~t~",icin (GIBCO), 25 mM
HEPES, pH 7.4 (SIGMA), 100 IU/ml penicillin (FLOW LABS), 100 ,ug/ml streptomycin (FLOW LABS), 2 mM gl~ ";lle (FLOW LABS) and 10% fetal bovine serum (GIBCO). Cells were rn~int~ined at 37C, 6% C02 in 150 cm2 tissue culture flasks (CORNING). For routine subculturing, media was removed from confluent cultures of cells, which were then incubated with 0.25% trypsin/0.1% EDTA (JR~I
BIOSCIENCES) and incubated at room temperature for approxirnately 5 minutes. The trypsin solution was then aspirated, and cells resuspended in fresh medium and dispensed at a ratio of 1:10 or 1:20 into new flasks.
U-937 cells (ATCC CRL 1593) were cultured in 89%
RPMI-1640 (SIGMA), 10% fetal bovine serum (GIBCO), cont~ining 50 IU/ml penicillin (FLOW LABS), 50 ~g/ml streptomycin (FLOW
LABS) and 2 g/l NaHCO3 (SIGMA). Cells were m~in~ined at a density of 0.1-2.0 x 1o6lml in 1 liter spinner flasks (CORNING) at 37C, 6%
CO2. For routine subculturing, cells were diluted in fresh medium and transferred to fresh flasks.
Assay Protocol For cyclooxygenase assays, osteosarcoma 143.98.2 cells 2s were cultured in 1 ml of media in 24-well multidishes (NUNCLON) until confluent. The number of cells per assay was determined from replicate plates prior to assays, using standard procedures. Lmmediately prior to cyclooxygenase assays, media was aspirated from cells, and the cells washed once with 2 ml of Hanks b~l~n~ed salts solution (~SS;
SIGMA) prewarmed to 37C. 1 ml of prewarmed HBSS was then added per well.
Irnmediatley prior to cyclooxygenase assays, the appropriate number of U-937 cells were removed from spinner cultures and centrifuged at 300 x g for 10 minlltes. The supern~t~nt was ~WO 94/26731 21617 ~ 9 PCT/CA94/00264 decanted and cells washed in 50 ml of HBSS prewarmed to 37C. Cells were again pelleted at 300 x g for 10 ~ s and resuspended in prewarmed HBSS to a final cell density of approximately 1.5 x 106 cells/ml. 1 ml aliquots of cell suspension were transferred to 1.5 ml 5 microcentrifuge tubes or 24-well multidishes (NUNCLON).
Following washing and resuspension of osteosarcoma 143 and U-937 cells in 1 ml of HBSS, 1 ,ul of test compounds or DMSO
vehicle were added, and samples gently mixed. All assays were performed in triplicate. Samples were then incubated for 15 minlltes at 37C, prior to the addition of 10 ~l of peroxide-free arachidonic acid (CAYMAN) diluted to 1 mM in HBSS. Control samples contained ethanol vehicle instead of arachidonic acid. Samples were again gently mixed and incubated for a further 10 minlltes at 37C. For osteosarcoma cells, reactions were then stopped by the addition of 100 5 ~11 of lN HCl, with mixing, or by the rapid removal of media directly from cell monolayers. For U-937 cells, reactions in multiwell dishes or microcentrifuge tubes were stopped by the addition of 100 ~l of lN
HCl, with mixing. Samples assayed in 24-multidishes were then transferred to microcentrifuge tubes. If necessary, samples were stored 20 at 4C prior to analysis of PGE2 levels.
Ouantitation of PGE~ Concentrations Osteosarcoma 143.98.2 and U-937 samples were neutralized by the addition of 100 ,ul of lN NaOH. Samples were then 25 mixed by vortexing, and PGE2 levels measured using a PGE2 radio-immllnoassay (NEW ENGLAND NUCLEAR-DUPONT) according to the manufacturers instructions. This procedure was automated using a BIOMEK 1000 (BECKMAN). Levels of PGE2 were calculated from the standard curve determined using BECKMAN IMMUNO~l l 30 EL~/RLA analysis software.
2161~89 WO 94/26731 PCT/CA94/0026~ ~
- 20 -~ ~
.~
Results Compound Drug Concen- % Of Inhibition tration nM Whole Cells Mic-osomes (osteosar- (U937) (osteosar- (U937) coma) coma) EXAMPLES
The invention will now be illustrated by the following non-limiting examples. Unless stated otherwise: (i) all operations were carried out at room or ambient temperature, that is, at a temperature in the range 18-25C; (ii) evaporation of solvent was carried out using a 25 rotary evaporator under reduced pressure (600-4000 pascals: 4.5-30 me. Hg) with a bath temperature of up to 60C; (iii) the course of reactions was followed by ~in layer chromatography (TLC) and reaction times are given for illustration only; (iv) melting points are uncorrected and `d' indicates decomposition; the melting points given 30 are those obtained for the materials prepared as described;
polymorphism may result in isolation of materials with different melting points in soee preparations; (v) the structure and purity of all final products were assured by at least one of the following techniques:
TLC, mass spectrometry, nuclear m~gnetic resonance (NMR) spectrometry or microanalytical data; (vi) yields are given for ~ WO 94/26731 21 6 17 8 9 PCT/CA94/00264 - illustration only; (vii) 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 5 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 me~nin~;~; the following abbreviations have also been used v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (liter(s)), mL (milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq (equivalent(s)).
Further, unless otherwise stated the following abbreviations have the indicated m~nin~:
DMF = N,N-dimethylformamide DMSO = dimethyl sulfoxide Et3N = triethyl~mine MMMP = m~p;nesium monoperoxyphth~l~te Ph = phenyl r.t. = room temperature 2 THF = tetrahydrofuran TLC = thin layer chromatography Alkyl group abbreviations Me = methyl Et = ethyl n-Pr = normal propyl i-Pr = isopropyl n-Bu = normal butyl i-Bu = isobutyl s-Bu = secondary butyl t-Bu = tertiary butyl Optical Isomers - Diastereomers - Geometric Isomers Wa~9~;t2~731 ~ PCT/CA94/00264 ~
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, 5 enantiomerically pure forms and ph~ ceutically acceptable salts thereof.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
EXAMPLE 1 (Compound 1) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenvl)thiophene 5 Step 1: 4'-(Methylthio)-2-chloroacetophenone To a -5C solution of thioanisole (26.4 g) and chloroacetyl chloride (27 g) in dichloromethane (600 mL) was added AIC13 (33.2 g) portion-wise. The mixture was allowed to warm up to 25C and was stirred for 16 h. It was poured over ice water and stirred for 1.~ h.
20 The mi~ul~e was extracted with CH2C12 (2 x 600 mL) and the combined extracts were washed with brine and dried with MgSO4. The solvent was removed in vacuo and the residue swished in 1:25 ethyl acetate:hexanes. The solid was filtered and dried to yield 18 g of the title compound.
25 lH NMR (CD3COCD3): ~ 2.55 (3H, s), 4.95 (2H, s), 7.35-8.0 (4H, m).
Step 2: 4'-(Methylthio)-2-(acetylthio)acetophenone To a 0C suspension of 4'-(methyl~io)-2-chloro-30 acetophenone (18 g) from Step 1 in THF (20 mL) and DMF (180 mL)was added potassium thioacetate (11.6 g). The mixture was warmed to 25C and stirred 1.5 h. It was poured over ice/dilute NaHCO3. The mixture was extracted with ethyl acetate:ether (2 x 200 mL) and the combined extracts were washed with H20, brine and dried with MgSO4. After removal of the solvents in vacuo, the residue was ¦~wo 94/26731 2 ~ G 17 8 9 PCT/CA94/00264 - swished in 1:25 ethyl acetate-hex~nes and the solid was filtered and dried to yield 18 g of the title compound.
lH NMR (CD3COCD3): ~ 2.35 (3H, s), 2.55 (3H, s), 4.45 (2H, s), 7.35-7.95 (4H, m)-Step 3: 4'-(Methylthio)phenacyl-4-fluorophenacyl sulfide To a -5C solution of 4'-(methylthio)-2-(acetylthio)-acetophenone (18 g) from Step 2 in THF (50 mL) and DMF (100 mL) was added hydrazine (2.6 mL). After 0.5 h Cs2C03 (26 g) and 4-fluorophenacylchloride (21.6 g) were added and the mixtllre was poured over ice/dilute HCl. It was extracted with ethyl acetate (2 x 200 mL) and the combined extracts were washed with H20, brine and dried with MgS04. After removal of the solvents the residue was purified by chromatography to yield the title compound (12.76 g).
5 lH NMR (CD3COCD3): ~ 2.55 (3H, s), 4.05 (2H, s), 4.1 (2H, s), 7.2-8.2 (8H, m).
Step 4: 3-(4-Fluorophenyl)-4-((4-methylthio)phenyl)thiophene To a -35C solution of 4'-(methylthio)phenacyl-4-20 fluorophenacyl sulfide (8.8 g) from Step 3 in THF (225 mL) was added TiCl4 (23.71 g) dropwise and the mix~lre was stirred for 0.5 h. Zinc powder (16.4 g) was added portionwise with vigourous stirring and the dark green suspension was stirred for 1 h at -35C. The mixture was transferred via a c~m-l~ to ice cold 1 M tartaric acid (1000 mL) and the 2s mixture was stirred for 1 h. It was extracted with ethyl acetate (3 x 200 mL) and the combined extracts were washed with brine and dried with MgS04. After removal of the solvents the residue was dissolved in toluene (50 mL) cont~inin~ p-TsOH (50 mg) and the mixture was refluxed for 3 h. The solvent was removed and the residue purified by 30 chromatography to afford the title compound.
lH NMR (CD3COCD3): ~ 2.45 (3H, s), 7.0-7.5 (lOH, m).
21 ~1789 Step 5: 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)thiophene To a 0C suspension of 3-(4-fluorophenyl)-4-((4-methylthio)phenyl)thiophene (3 g) fr~om Step 4 in MeOH and CH2cl2 (50 mL) was added portionwise MMPP (6.8 g) and the mixtl-re was allowed to react for 3 h while warming to 25C. It was diluted with CH2C12 (50 mL) and filtered through celite. The filtrate was concentrated to dryness and purified by chromatography to yield the title compound (3.16 g).
lH NMR (CD3COCD3): ~ 3.05 (3H, s), 6.95-7.9 (lOH, m).
EXAMPLE 2 (Compound 2) 2-Nitro-3 -(4-fluorophenyl)-4-((4-methylsulfonyl)phenyl)thiophene To a 0C suspension of 3-(4-fluorophenyl)-4-((4-methylsulfonyl)phenyl) thiophene (1.32 g) from Example 1 in nitromethane (10 mL) and acetic anhydride (10 mL) was added 70%
aqueous HN03 (320 ,uL). The cold bath was removed and the mixture was stirred 2 h at 25C. It was then poured over ice H20 and extracted with ethyl acetate (3 x 25 mL). The combined extracts were washed with brine, dried with MgS04 and the solvents were removed in vacuo.
The residue was purified by chromatography to afford the title compound (858 mg).
Analysis calculated for Cl7Hl2FNo4s2:
C, 54.10; H, 3.21; N, 3.71.
2s Found: C, 53.77; H, 3.39; N, 3.62.
EXAMPLE 3 (Compound 3) 2-Bromo-3-(4-fluorophenyl)-4-(f4-methylsulfonyl)phenyl)thiophene To a 0C solution of 3-(4-fluorophenyl)-4-((4-methyl-sulfonyl)phenyl)thiophene (332 mg) from Example 1 in CH2Cl2 (2 mL) and acetic acid (2 mL) was added a 1 M solution of Br2 in CCl4 (1.1 mL) and the mixtllre was reacted for 2 h at 0C. The mi~ re was then concentrated to dryness and the residue purified by chromatography to afford the title compound (203 mg).
- Analysis calculated for cl7Hl2BrFs2o2:
C, 49.65; H, 2.94.
Found: C, 49.83; H, 2.89.
EXAMPLE 4 (Compound 4) 3 -(4-Fluorophenyl)-4-(4-sulfamoylphenyl)thiophene Step 1: 3-(4-Fluorophenyl)-4-(4-bromophenyl)thiophene Following the procedures of Example 1, Steps 2-7, but replacing 4'-(methyl~io)-2-chloroacetophenone by 4-bromophenyl bromide in Step 2, there was obtained the title compound.
1H NMR (CD3COCD3): o 7.0-7.3 (4H, m), 7.4-7.6 (6H, m) 5 Step 2: 3-(4-Fluorophenyl)-4-(4-sulfamoylphenyl)thiophene To a -78C solution of 3-(4-fluorophenyl)-4-(4-bromophenyl)thiophene (999 mg) in tetrahydrofuran (10 mL) was added 2.27 M n-BuLi (1.45 mL) and the mixtllre was stirred for 0.5 h at -78C. It was then transferred dropwise into a -78C solution of 20 sulfur dioxide (10 mL) and tetrahydrofuran (10 r~T ) and the mi~ture was allowed to warm slowly to 25C. The solvents were removed in vacuo and the solid obtained was suspended in hexanes (15 mL) and the suspension was cooled to 0C. A 1 M dichloromethane solution of sulfuryl chloride (3 mL) was then added dropwise and the mixh-re was 2S stirred for 0.5 h at 25C. It was cooled again at 0C and filtered. The solid obtained was taken into tetrahydrofuran and the mixture was cooled to 0C before NH3 was bubbled in for a few minlltes. Removal of the solvents followed by purification on silica gel yielded the title compound (350 mg).
1H NMR (CD3COCD3): ~ 6.5-6.6 (2H, broad), 7.0-7.4 (6 H, m), 7.55 (l H, d), 7.65 (lH, d), 7.75-7.8 (2H, d).
- 3 14 H -n-pentyl -S(0)2CH3 H
15 H 4-cyanophenyl -s(o)2cH3 H
16 H 4-fluorophenyl -S(0)2CH3 Br 17 H 4-fluorophenyl -S(0)2CH3 C02H
WO 94/26731 PCT/CA94/00264 ~
Whole Cell Cvclooxygenase Assays Human osteosarcoma 143.98.2 cells were cultured in DULBECCOS MOD~D EAGLES MEDIUM (SIGMA) cont~inin~;
3.7 g/l NaHCO3 (SIGMA), 100 ,ug/l ge~t~",icin (GIBCO), 25 mM
HEPES, pH 7.4 (SIGMA), 100 IU/ml penicillin (FLOW LABS), 100 ,ug/ml streptomycin (FLOW LABS), 2 mM gl~ ";lle (FLOW LABS) and 10% fetal bovine serum (GIBCO). Cells were rn~int~ined at 37C, 6% C02 in 150 cm2 tissue culture flasks (CORNING). For routine subculturing, media was removed from confluent cultures of cells, which were then incubated with 0.25% trypsin/0.1% EDTA (JR~I
BIOSCIENCES) and incubated at room temperature for approxirnately 5 minutes. The trypsin solution was then aspirated, and cells resuspended in fresh medium and dispensed at a ratio of 1:10 or 1:20 into new flasks.
U-937 cells (ATCC CRL 1593) were cultured in 89%
RPMI-1640 (SIGMA), 10% fetal bovine serum (GIBCO), cont~ining 50 IU/ml penicillin (FLOW LABS), 50 ~g/ml streptomycin (FLOW
LABS) and 2 g/l NaHCO3 (SIGMA). Cells were m~in~ined at a density of 0.1-2.0 x 1o6lml in 1 liter spinner flasks (CORNING) at 37C, 6%
CO2. For routine subculturing, cells were diluted in fresh medium and transferred to fresh flasks.
Assay Protocol For cyclooxygenase assays, osteosarcoma 143.98.2 cells 2s were cultured in 1 ml of media in 24-well multidishes (NUNCLON) until confluent. The number of cells per assay was determined from replicate plates prior to assays, using standard procedures. Lmmediately prior to cyclooxygenase assays, media was aspirated from cells, and the cells washed once with 2 ml of Hanks b~l~n~ed salts solution (~SS;
SIGMA) prewarmed to 37C. 1 ml of prewarmed HBSS was then added per well.
Irnmediatley prior to cyclooxygenase assays, the appropriate number of U-937 cells were removed from spinner cultures and centrifuged at 300 x g for 10 minlltes. The supern~t~nt was ~WO 94/26731 21617 ~ 9 PCT/CA94/00264 decanted and cells washed in 50 ml of HBSS prewarmed to 37C. Cells were again pelleted at 300 x g for 10 ~ s and resuspended in prewarmed HBSS to a final cell density of approximately 1.5 x 106 cells/ml. 1 ml aliquots of cell suspension were transferred to 1.5 ml 5 microcentrifuge tubes or 24-well multidishes (NUNCLON).
Following washing and resuspension of osteosarcoma 143 and U-937 cells in 1 ml of HBSS, 1 ,ul of test compounds or DMSO
vehicle were added, and samples gently mixed. All assays were performed in triplicate. Samples were then incubated for 15 minlltes at 37C, prior to the addition of 10 ~l of peroxide-free arachidonic acid (CAYMAN) diluted to 1 mM in HBSS. Control samples contained ethanol vehicle instead of arachidonic acid. Samples were again gently mixed and incubated for a further 10 minlltes at 37C. For osteosarcoma cells, reactions were then stopped by the addition of 100 5 ~11 of lN HCl, with mixing, or by the rapid removal of media directly from cell monolayers. For U-937 cells, reactions in multiwell dishes or microcentrifuge tubes were stopped by the addition of 100 ~l of lN
HCl, with mixing. Samples assayed in 24-multidishes were then transferred to microcentrifuge tubes. If necessary, samples were stored 20 at 4C prior to analysis of PGE2 levels.
Ouantitation of PGE~ Concentrations Osteosarcoma 143.98.2 and U-937 samples were neutralized by the addition of 100 ,ul of lN NaOH. Samples were then 25 mixed by vortexing, and PGE2 levels measured using a PGE2 radio-immllnoassay (NEW ENGLAND NUCLEAR-DUPONT) according to the manufacturers instructions. This procedure was automated using a BIOMEK 1000 (BECKMAN). Levels of PGE2 were calculated from the standard curve determined using BECKMAN IMMUNO~l l 30 EL~/RLA analysis software.
2161~89 WO 94/26731 PCT/CA94/0026~ ~
- 20 -~ ~
.~
Results Compound Drug Concen- % Of Inhibition tration nM Whole Cells Mic-osomes (osteosar- (U937) (osteosar- (U937) coma) coma) EXAMPLES
The invention will now be illustrated by the following non-limiting examples. Unless stated otherwise: (i) all operations were carried out at room or ambient temperature, that is, at a temperature in the range 18-25C; (ii) evaporation of solvent was carried out using a 25 rotary evaporator under reduced pressure (600-4000 pascals: 4.5-30 me. Hg) with a bath temperature of up to 60C; (iii) the course of reactions was followed by ~in layer chromatography (TLC) and reaction times are given for illustration only; (iv) melting points are uncorrected and `d' indicates decomposition; the melting points given 30 are those obtained for the materials prepared as described;
polymorphism may result in isolation of materials with different melting points in soee preparations; (v) the structure and purity of all final products were assured by at least one of the following techniques:
TLC, mass spectrometry, nuclear m~gnetic resonance (NMR) spectrometry or microanalytical data; (vi) yields are given for ~ WO 94/26731 21 6 17 8 9 PCT/CA94/00264 - illustration only; (vii) 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 5 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 me~nin~;~; the following abbreviations have also been used v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (liter(s)), mL (milliliters), g (gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq (equivalent(s)).
Further, unless otherwise stated the following abbreviations have the indicated m~nin~:
DMF = N,N-dimethylformamide DMSO = dimethyl sulfoxide Et3N = triethyl~mine MMMP = m~p;nesium monoperoxyphth~l~te Ph = phenyl r.t. = room temperature 2 THF = tetrahydrofuran TLC = thin layer chromatography Alkyl group abbreviations Me = methyl Et = ethyl n-Pr = normal propyl i-Pr = isopropyl n-Bu = normal butyl i-Bu = isobutyl s-Bu = secondary butyl t-Bu = tertiary butyl Optical Isomers - Diastereomers - Geometric Isomers Wa~9~;t2~731 ~ PCT/CA94/00264 ~
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, 5 enantiomerically pure forms and ph~ ceutically acceptable salts thereof.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
EXAMPLE 1 (Compound 1) 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenvl)thiophene 5 Step 1: 4'-(Methylthio)-2-chloroacetophenone To a -5C solution of thioanisole (26.4 g) and chloroacetyl chloride (27 g) in dichloromethane (600 mL) was added AIC13 (33.2 g) portion-wise. The mixture was allowed to warm up to 25C and was stirred for 16 h. It was poured over ice water and stirred for 1.~ h.
20 The mi~ul~e was extracted with CH2C12 (2 x 600 mL) and the combined extracts were washed with brine and dried with MgSO4. The solvent was removed in vacuo and the residue swished in 1:25 ethyl acetate:hexanes. The solid was filtered and dried to yield 18 g of the title compound.
25 lH NMR (CD3COCD3): ~ 2.55 (3H, s), 4.95 (2H, s), 7.35-8.0 (4H, m).
Step 2: 4'-(Methylthio)-2-(acetylthio)acetophenone To a 0C suspension of 4'-(methyl~io)-2-chloro-30 acetophenone (18 g) from Step 1 in THF (20 mL) and DMF (180 mL)was added potassium thioacetate (11.6 g). The mixture was warmed to 25C and stirred 1.5 h. It was poured over ice/dilute NaHCO3. The mixture was extracted with ethyl acetate:ether (2 x 200 mL) and the combined extracts were washed with H20, brine and dried with MgSO4. After removal of the solvents in vacuo, the residue was ¦~wo 94/26731 2 ~ G 17 8 9 PCT/CA94/00264 - swished in 1:25 ethyl acetate-hex~nes and the solid was filtered and dried to yield 18 g of the title compound.
lH NMR (CD3COCD3): ~ 2.35 (3H, s), 2.55 (3H, s), 4.45 (2H, s), 7.35-7.95 (4H, m)-Step 3: 4'-(Methylthio)phenacyl-4-fluorophenacyl sulfide To a -5C solution of 4'-(methylthio)-2-(acetylthio)-acetophenone (18 g) from Step 2 in THF (50 mL) and DMF (100 mL) was added hydrazine (2.6 mL). After 0.5 h Cs2C03 (26 g) and 4-fluorophenacylchloride (21.6 g) were added and the mixtllre was poured over ice/dilute HCl. It was extracted with ethyl acetate (2 x 200 mL) and the combined extracts were washed with H20, brine and dried with MgS04. After removal of the solvents the residue was purified by chromatography to yield the title compound (12.76 g).
5 lH NMR (CD3COCD3): ~ 2.55 (3H, s), 4.05 (2H, s), 4.1 (2H, s), 7.2-8.2 (8H, m).
Step 4: 3-(4-Fluorophenyl)-4-((4-methylthio)phenyl)thiophene To a -35C solution of 4'-(methylthio)phenacyl-4-20 fluorophenacyl sulfide (8.8 g) from Step 3 in THF (225 mL) was added TiCl4 (23.71 g) dropwise and the mix~lre was stirred for 0.5 h. Zinc powder (16.4 g) was added portionwise with vigourous stirring and the dark green suspension was stirred for 1 h at -35C. The mixture was transferred via a c~m-l~ to ice cold 1 M tartaric acid (1000 mL) and the 2s mixture was stirred for 1 h. It was extracted with ethyl acetate (3 x 200 mL) and the combined extracts were washed with brine and dried with MgS04. After removal of the solvents the residue was dissolved in toluene (50 mL) cont~inin~ p-TsOH (50 mg) and the mixture was refluxed for 3 h. The solvent was removed and the residue purified by 30 chromatography to afford the title compound.
lH NMR (CD3COCD3): ~ 2.45 (3H, s), 7.0-7.5 (lOH, m).
21 ~1789 Step 5: 3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)thiophene To a 0C suspension of 3-(4-fluorophenyl)-4-((4-methylthio)phenyl)thiophene (3 g) fr~om Step 4 in MeOH and CH2cl2 (50 mL) was added portionwise MMPP (6.8 g) and the mixtl-re was allowed to react for 3 h while warming to 25C. It was diluted with CH2C12 (50 mL) and filtered through celite. The filtrate was concentrated to dryness and purified by chromatography to yield the title compound (3.16 g).
lH NMR (CD3COCD3): ~ 3.05 (3H, s), 6.95-7.9 (lOH, m).
EXAMPLE 2 (Compound 2) 2-Nitro-3 -(4-fluorophenyl)-4-((4-methylsulfonyl)phenyl)thiophene To a 0C suspension of 3-(4-fluorophenyl)-4-((4-methylsulfonyl)phenyl) thiophene (1.32 g) from Example 1 in nitromethane (10 mL) and acetic anhydride (10 mL) was added 70%
aqueous HN03 (320 ,uL). The cold bath was removed and the mixture was stirred 2 h at 25C. It was then poured over ice H20 and extracted with ethyl acetate (3 x 25 mL). The combined extracts were washed with brine, dried with MgS04 and the solvents were removed in vacuo.
The residue was purified by chromatography to afford the title compound (858 mg).
Analysis calculated for Cl7Hl2FNo4s2:
C, 54.10; H, 3.21; N, 3.71.
2s Found: C, 53.77; H, 3.39; N, 3.62.
EXAMPLE 3 (Compound 3) 2-Bromo-3-(4-fluorophenyl)-4-(f4-methylsulfonyl)phenyl)thiophene To a 0C solution of 3-(4-fluorophenyl)-4-((4-methyl-sulfonyl)phenyl)thiophene (332 mg) from Example 1 in CH2Cl2 (2 mL) and acetic acid (2 mL) was added a 1 M solution of Br2 in CCl4 (1.1 mL) and the mixtllre was reacted for 2 h at 0C. The mi~ re was then concentrated to dryness and the residue purified by chromatography to afford the title compound (203 mg).
- Analysis calculated for cl7Hl2BrFs2o2:
C, 49.65; H, 2.94.
Found: C, 49.83; H, 2.89.
EXAMPLE 4 (Compound 4) 3 -(4-Fluorophenyl)-4-(4-sulfamoylphenyl)thiophene Step 1: 3-(4-Fluorophenyl)-4-(4-bromophenyl)thiophene Following the procedures of Example 1, Steps 2-7, but replacing 4'-(methyl~io)-2-chloroacetophenone by 4-bromophenyl bromide in Step 2, there was obtained the title compound.
1H NMR (CD3COCD3): o 7.0-7.3 (4H, m), 7.4-7.6 (6H, m) 5 Step 2: 3-(4-Fluorophenyl)-4-(4-sulfamoylphenyl)thiophene To a -78C solution of 3-(4-fluorophenyl)-4-(4-bromophenyl)thiophene (999 mg) in tetrahydrofuran (10 mL) was added 2.27 M n-BuLi (1.45 mL) and the mixtllre was stirred for 0.5 h at -78C. It was then transferred dropwise into a -78C solution of 20 sulfur dioxide (10 mL) and tetrahydrofuran (10 r~T ) and the mi~ture was allowed to warm slowly to 25C. The solvents were removed in vacuo and the solid obtained was suspended in hexanes (15 mL) and the suspension was cooled to 0C. A 1 M dichloromethane solution of sulfuryl chloride (3 mL) was then added dropwise and the mixh-re was 2S stirred for 0.5 h at 25C. It was cooled again at 0C and filtered. The solid obtained was taken into tetrahydrofuran and the mixture was cooled to 0C before NH3 was bubbled in for a few minlltes. Removal of the solvents followed by purification on silica gel yielded the title compound (350 mg).
1H NMR (CD3COCD3): ~ 6.5-6.6 (2H, broad), 7.0-7.4 (6 H, m), 7.55 (l H, d), 7.65 (lH, d), 7.75-7.8 (2H, d).
Claims (23)
1. A compound of Formula I
I
or a pharmaceutically acceptable salt thereof wherein:
R1 is selected from the group consisting of (a) hydrogen, (b) halo, including fluoro, chloro, bromo and iodo, (c) CN, (d) NO2, (e) CF3, and (f) C1-6alkyl;
R2 is selected from the group consisting of (a) C3-6alkyl, (b) mono or di substituted phenyl wherein the substitutents are selected from the group consisting of (1) hydrogen, (2) halo as defined above, (3) C1-6alkoxy, (4) C1-6alkylthio, (5) CN, (6) CF3, (7) C1-6alkyl, (8) N3, (c) mono or di substituted heteroaryl wherein heteroaryl is (1) a monocyclic aromatic ring of 5 atoms, containing one hetero atom which is S, O or N and optionally 1, 2, or 3 additional hetero atoms which are N, or (2) a monocyclic aromatic ring of 6 atoms, containing 1, 2, 3, or 4 hetero atoms which are N, and wherein the substitutents on the heteroaryl are selected from the group consisting of (1) hydrogen, (2) halo as defined above, (3) C1-6alkoxy, (4) C1-6alkylthio, (5) CN, (6) CF3, (7) C1-6alkyl, (8) N3;
R3 is selected from the group consisting of (1) -S(O)2CH3, (2) -S(O)(NH)CH3, (3) -S(O)NH2, and (4) -S(O)2NH2;
R4 is selected from the group consisting of (1) hydrogen, (2) halo as defined above, (3) carboxy, and (4) CF3.
I
or a pharmaceutically acceptable salt thereof wherein:
R1 is selected from the group consisting of (a) hydrogen, (b) halo, including fluoro, chloro, bromo and iodo, (c) CN, (d) NO2, (e) CF3, and (f) C1-6alkyl;
R2 is selected from the group consisting of (a) C3-6alkyl, (b) mono or di substituted phenyl wherein the substitutents are selected from the group consisting of (1) hydrogen, (2) halo as defined above, (3) C1-6alkoxy, (4) C1-6alkylthio, (5) CN, (6) CF3, (7) C1-6alkyl, (8) N3, (c) mono or di substituted heteroaryl wherein heteroaryl is (1) a monocyclic aromatic ring of 5 atoms, containing one hetero atom which is S, O or N and optionally 1, 2, or 3 additional hetero atoms which are N, or (2) a monocyclic aromatic ring of 6 atoms, containing 1, 2, 3, or 4 hetero atoms which are N, and wherein the substitutents on the heteroaryl are selected from the group consisting of (1) hydrogen, (2) halo as defined above, (3) C1-6alkoxy, (4) C1-6alkylthio, (5) CN, (6) CF3, (7) C1-6alkyl, (8) N3;
R3 is selected from the group consisting of (1) -S(O)2CH3, (2) -S(O)(NH)CH3, (3) -S(O)NH2, and (4) -S(O)2NH2;
R4 is selected from the group consisting of (1) hydrogen, (2) halo as defined above, (3) carboxy, and (4) CF3.
2. A compound according to Claim 1 wherein R2 is selected from the group consisting of (a) C3-6alkyl, (b) mono or di substituted phenyl, and (c) mono or di substituted heteroaryl wherein heteroaryl is selected from the group consisting of (1) furanyl, (2) diazinyl, triazinyl, tetrazinyl, (3) imidazolyl, (4) isoxazolyl, (5) isothiazolyl, (6) oxadiazolyl, (7) oxazolyl, (8) pyrazolyl, (9) pyrrolyl, (10) thiadiazolyl, (11) thiazolyl, (12) thienyl, (13) triazolyl, (14) pyridyl, and (15) tetrazolyl, and wherein the substitutents on the phenyl or heteroaryl are selected from the group consisting of (1) hydrogen, (2) halo, (3) C1-6alkoxy, (4) C1-6alkylthio, (5) CN, (6) CF3, (7) C1-6alkyl, and (8) N3.
3. A compound according to Claim 2 wherein R2 is selected from the group consisting of (a) cyclohexyl, and (b) mono or di substituted phenyl, and wherein the substitutents are selected from the group consisting of (1) hydrogen, (2) halo, (3) C1-6alkoxy, (4) C1-6alkylthio, (5) CN, (6) CF3, (7) C1-6alkyl, (8) N3;
R4 is selected from the group consisting of (1) hydrogen, (2) halo as defined above, and (3) carboxy.
R4 is selected from the group consisting of (1) hydrogen, (2) halo as defined above, and (3) carboxy.
4. A compound according to Claim 3 wherein Rl is selected from the group consisting of (a) hydrogen, (b) halo selected from the group consisting of fluoro, chloro and bromo, (c) CN, (d) C1-3alkyl;
R2 is selected from the group consisting of (a) cyclohexyl, and (b) mono or di substituted phenyl wherein the substitutents are selected from the group consisting of (1) hydrogen, (2) halo, selected from the group consisting of fluoro, chloro and bromo, (3) C1-3alkoxy, (4) C1-3alkylthio, (5) CN, and (6) C1-3alkyl;
R4 is hydrogen.
R2 is selected from the group consisting of (a) cyclohexyl, and (b) mono or di substituted phenyl wherein the substitutents are selected from the group consisting of (1) hydrogen, (2) halo, selected from the group consisting of fluoro, chloro and bromo, (3) C1-3alkoxy, (4) C1-3alkylthio, (5) CN, and (6) C1-3alkyl;
R4 is hydrogen.
5. A compound according to Claim 4 wherein R3 is selected from the group consisting of (1) -S(O)2CH3, (2) -S(O)(NH)CH3, and (3) -S(O)NH2, and (4) -S(O)2NH2.
6. A compound according to Claim 5 wherein R1 is selected from the group consisting of (a) hydrogen, (b) halo selected from the group consisting of fluoro, chloro and bromo, (c) CN, and (d) C1-3alkyl;
R2 is selected from the group consisting of (a) cyclohexyl, and (b) mono substituted phenyl wherein the substitutents are selected from the group consisting of (1) hydrogen, (2) halo, selected from the group consisting of fluoro, chloro and bromo, (3) C1-3alkoxy, (4) C1-3alkylthio, (5) CN, and (6) C1-3alkyl.
R2 is selected from the group consisting of (a) cyclohexyl, and (b) mono substituted phenyl wherein the substitutents are selected from the group consisting of (1) hydrogen, (2) halo, selected from the group consisting of fluoro, chloro and bromo, (3) C1-3alkoxy, (4) C1-3alkylthio, (5) CN, and (6) C1-3alkyl.
7. A compound according to Claim 2 wherein R2 is a mono or di substituted heteroaryl wherein heteroaryl is selected from the group consisting of (1) furanyl, (2) diazinyl, triazinyl, tetrazinyl, (3) imidazolyl, (4) isoxazolyl, (5) isothiazolyl, (6) oxadiazolyl, (7) oxazolyl, (8) pyrazolyl, (9) pyrrolyl, (10) thiadiazolyl, (11) thiazolyl, (12) thienyl, (13) triazolyl, (14) pyridyl, and (15) tetrazolyl, and wherein the substitutents are selected from the group consisting of (1) hydrogen, (2) halo, (3) C1-6alkoxy, (4) C1-6alkylthio, (5) CN, (6) CF3, (7) C1-6alkyl, (8) N3, R4 is selected from the group consisting of (1) hydrogen, (2) halo as defined above, (3) carboxy.
8. A compound according to Claim 7 wherein R2 is a mono or di substituted heteroaryl wherein heteroaryl is selected from the group consisting of (1) 2-furanyl, (2) 3-furanyl, (3) 2-thienyl, (4) 3-thienyl, (5) 3-isoxazolyl, (6) 4-isoxazolyl, (7) 5-isoxazolyl, (8) 3-isothiazolyl, (9) 4-isothiazolyl, (10) 5-isothiazolyl, (11) 2-oxazolyl, (12) 4-oxazolyl, (13) 5-oxazolyl, (14) 2-thiazolyl, (15) 4-thiazolyl, (16) 5-thiazolyl, (17) 1,2,3-thiadiazol-4-yl, (18) 1,2,3-thiadiazol-5-yl, (19) 1,2,4-thiadiazol-3-yl, (20) 1,2,4-thiadiazol-5-yl, (21) 1,3,4-thiadiazol-2-yl, (22) 1,2,5-thiadiazol-3-yl, (23) 1,2,3-oxadiazol-4-yl, (24) 1,2,3-oxadiazol-5-yl, (25) 1,2,4-oxadiazol-3-yl, (26) 1,2,4-oxadiazol-5-yl, (27) 1,3,4-oxadiazol-2-yl, (28) 1,2,5-oxadiazol-3-yl, (29) pyrazol-4-yl, (30) pyrazol-5-yl, (31) 1,2,3-triadiazol-4-yl, (32) 1,2,3-triadiazol-5-yl, (33) 1,2,4-triadiazol-3-yl, (34) 1,2,4-triadiazol-5-yl, (35) 1,2-diazinyl, (36) 1,3-diazinyl, (37) 1,4-diazinyl, (38) 1,2,3,4-tetrazin-5-yl, (39) 1,2,4,5-tetrazin-4-yl, (40) 1,3,4,5-tetrazin-2-yl,and (41) 1,2,3,5-tetrazin-4-yl.
9. A compound according to Claim 8 wherein the heteroaryl is selected from the group consisting of (1) 3-isoxazolyl, (2) 4-isoxazolyl, (3) 5-isoxazolyl, (4) 3-isothiazolyl, (5) 4-isothiazolyl, (6) 5-isothiazolyl, (7) 2-oxazolyl, (8) 4-oxazolyl, (9) 5-oxazolyl, (10) 2-thiazolyl, (11) 4-thiazolyl, (12) 5-thiazolyl, (13) 1,2,3-thiadiazol-4-yl, (14) 1,2,3-thiadiazol-5-yl, (15) 1,2,4-thiadiazol-3-yl, (16) 1,2,4-thiadiazol-5-yl, (17) 1,3,4-thiadiazol-2-yl, (18) 1,2,5-thiadiazol-3-yl, (19) 1,2,3-oxadiazol-4-yl, (20) 1,2,3-oxadiazol-5-yl, (21) 1,2,4-oxadiazol-3-yl, (22) 1,2,4-oxadiazol-5-yl, (23) 1,3,4-oxadiazol-2-yl, (24) 1,2,5-oxadiazol-3-yl, (25) 1,2-diazinyl, (26) 1,3-diazinyl, and (27) 1,4-diazinyl.
10. A compound according to Claim 9 wherein the hetreoaryl is selected from the group consisting of (1) 2-oxazolyl, (2) 4-oxazolyl, (3) 5-oxazolyl, (4) 3-thiazolyl, (5) 4-thiazolyl, (6) 5-thiazolyl, (7) 1,3,4-thiadiazol-2-yl, (8) 1,2,5-thiadiazol-3-yl, (9) 1,3,4-oxadiazol-2-yl, (10) 1,2,5-oxadiazol-3-yl, (11) 1,2-diazinyl, (12) 1,3-diazinyl, and (13) 1,4-diazinyl, and wherein the substitutents are selected from the group consisting of (1) hydrogen, (2) halo, selected from the group consisting of fluoro, chloro and bromo, (3) C1-3alkoxy, (4) C1-3alkylthio, (5) CN, and (6) C1-3alkyl.
11. A compound according to Claim 10 wherein the hetreoaryl is selected from the group consisting of (1) 2-oxazolyl, (2) 4-oxazolyl, (3) 5-oxazolyl, (4) 2-thiazolyl, (5) 4-thiazolyl, (6) 5-thiazolyl, (7) 1,3,4-thiadiazol-2-yl, (8) 1,2,5-thiadiazol-3-yl, (9) 1,3,4-oxadiazol-2-yl, (10) 1,2,5-oxadiazol-3-yl, (11) 1,2-diazinyl, (12) 1,3-diazinyl, and (13) 1,4-diazinyl.
12. A compound according to Claim 11 wherein R1 is selected from the group consisting of (a) hydrogen, (b) halo selected from the group consisting of fluoro, chloro and bromo, (c) CN, and (d) C1-3alkyl;
R4 is hydrogen.
R4 is hydrogen.
13. A compound according to Claim 11 wherein R3 is selected from the group consisting of (1) -S(O)2CH3, and (2) -S(O)2NH2;
R4 is hydrogen.
R4 is hydrogen.
14. A compound according to Claim 13 wherein R1 is selected from the group consisting of (a) hydrogen, (b) halo selected from the group consisting of fluoro, chloro and bromo, (c) CN, and (d) C1-3alkyl;
R2 is selected from the group consisting of (1) 2-oxazolyl, (2) 4-oxazolyl, (3) 5-oxazolyl, (4) 2-thiazolyl, (5) 4-thiazolyl, (6) 5-thiazolyl, (7) 1,3,4-thiadiazol-2-yl, (8) 1,2,5-thiadiazol-3-yl, (9) 1,3,4-oxadiazol-2-yl, (10) 1,2,5-oxadiazol-3-yl, (11) 1,2-diazinyl, (12) 1,3-diazinyl, and (13) 1,4-diazinyl, wherein the substitutents are selected from the group consisting of (1) hydrogen, (2) halo, selected from the group consisting of fluoro, chloro and bromo, (3) C1-3alkoxy, (4) C1-3alkylthio, (5) CN, and (6) C1-3alkyl;
R4 is hydrogen.
R2 is selected from the group consisting of (1) 2-oxazolyl, (2) 4-oxazolyl, (3) 5-oxazolyl, (4) 2-thiazolyl, (5) 4-thiazolyl, (6) 5-thiazolyl, (7) 1,3,4-thiadiazol-2-yl, (8) 1,2,5-thiadiazol-3-yl, (9) 1,3,4-oxadiazol-2-yl, (10) 1,2,5-oxadiazol-3-yl, (11) 1,2-diazinyl, (12) 1,3-diazinyl, and (13) 1,4-diazinyl, wherein the substitutents are selected from the group consisting of (1) hydrogen, (2) halo, selected from the group consisting of fluoro, chloro and bromo, (3) C1-3alkoxy, (4) C1-3alkylthio, (5) CN, and (6) C1-3alkyl;
R4 is hydrogen.
15. A compound of Formula I wherein
16. A pharmaceutical composition for inhibiting cyclooxygenase comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound or salt according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15.
17. A pharmaceutical composition for inhibiting cycloxygenase-2 comprising a pharmaceutically acceptable carrier and a non-toxic therapeutically effective amount of compound or salt according to Claim 1, 2, 3, 4, 5, 6, 7, 8? 9, 10, 11, 12, 13, 14 or 15.
18. A method of inhibiting cyclooxygenase comprising:
administration to a patient in need of such inhibition of a non-toxic therapeutically effective amount of a compound according to Claim 1.
administration to a patient in need of such inhibition of a non-toxic therapeutically effective amount of a compound according to Claim 1.
19. A method of inhibiting cyclooxygenase-2 comprising:
administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound according to Claim 1.
administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound according to Claim 1.
20. A pharmaceutical composition for the treatment of cyclooxygenase-2 mediated disease comprising a non-toxic therapeutically effective amount of compound according to Claim 1 and at least one or more ingredients selected from a pain reliever including acetaminophen or phenacetin; a potentiator including caffine;
an H2-antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant including phenylephrine, phenylpropanolamine, pseudopheorine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desocyephedrine, an antitussive including codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine.
an H2-antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant including phenylephrine, phenylpropanolamine, pseudopheorine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desocyephedrine, an antitussive including codeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; a diuretic; and a sedating or non-sedating antihistamine.
21. A cyclooxygenase inhibitor pharmaceutical composition comprising an acceptable cyclooxygenase inhibiting amount of a compound of formula (I), as defined in Claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
22. Use of a compound of foImula a) as defined in Claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cyclooxygenase mediated diseases.
23. A compound of formula (I), as defined in Claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, or a pharmaceutically acceptable salt thereof for use in inhibiting cyclooxygenase.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US6135493A | 1993-05-13 | 1993-05-13 | |
| US061,354 | 1993-05-13 | ||
| PCT/CA1994/000264 WO1994026731A1 (en) | 1993-05-13 | 1994-05-11 | 2-substituted-3,4-diarylthiophene derivatives as inhibitors of cyclooxygenase |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2161789A1 true CA2161789A1 (en) | 1994-11-24 |
Family
ID=22035257
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002161789A Abandoned CA2161789A1 (en) | 1993-05-13 | 1994-05-11 | 2-substituted-3,4-diarylthiophene derivatives as inhibitors of cyclooxygenase |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU6718494A (en) |
| CA (1) | CA2161789A1 (en) |
| WO (1) | WO1994026731A1 (en) |
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| GB9420616D0 (en) * | 1994-10-12 | 1994-11-30 | Merck Sharp & Dohme | Method, compositions and use |
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| GB2294879A (en) * | 1994-10-19 | 1996-05-15 | Merck & Co Inc | Cylcooxygenase-2 Inhibitors |
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| CA2223154A1 (en) | 1995-06-02 | 1996-12-05 | G.D. Searle & Co. | Heterocyclo substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors |
| US5643933A (en) * | 1995-06-02 | 1997-07-01 | G. D. Searle & Co. | Substituted sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors |
| US6515014B2 (en) | 1995-06-02 | 2003-02-04 | G. D. Searle & Co. | Thiophene substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors |
| US6512121B2 (en) | 1998-09-14 | 2003-01-28 | G.D. Searle & Co. | Heterocyclo substituted hydroxamic acid derivatives as cyclooxygenase-2 and 5-lipoxygenase inhibitors |
| US5700816A (en) * | 1995-06-12 | 1997-12-23 | Isakson; Peter C. | Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitor and a leukotriene A4 hydrolase inhibitor |
| ATE301457T1 (en) * | 1995-06-12 | 2005-08-15 | Searle & Co | AGENT CONTAINING A CYCLOOXYGENASE-2 INHIBITOR AND A 5-LIPOXYGENASE INHIBITOR |
| US6342510B1 (en) | 1995-06-12 | 2002-01-29 | G. D. Searle & Co. | Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitors and a leukotriene B4 receptor antagonist |
| AU716582B2 (en) * | 1995-10-17 | 2000-03-02 | G.D. Searle & Co. | Method of detecting cyclooxygenase-2 |
| DE69715382T2 (en) | 1996-02-13 | 2003-04-30 | Searle & Co | DRUG COMBINATIONS WITH IMMUNOSUPPRESSIVE EFFECTS WHICH CONTAIN CYCLOOXYGENASE-2 INHIBITORS AND LEUKOTRIES LTA4 HYDRASE INHIBITORS |
| DK0888127T3 (en) | 1996-02-13 | 2002-04-08 | Searle & Co | Combinations with immunosuppressive effects containing cyclooxygenase-2 inhibitors and 5-lipooxygenase inhibitors |
| DE69733338T2 (en) | 1996-02-13 | 2006-03-16 | G.D. Searle & Co., Chicago | PREPARATIONS, CONTAINING A CYCLOOXYGENASE-2 INHIBITOR AND A LEUKOTRIEN B4 RECEPTOR ANTAGONIST |
| ES2311571T3 (en) | 1996-04-12 | 2009-02-16 | G.D. Searle Llc | BENCENOSULFONAMIDE DERIVATIVES SUBSTITUTED AS COX-2 INHIBITORS PROFARMS. |
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| BR9813164A (en) * | 1997-10-31 | 2000-08-22 | Searle & Co | Method of using cyclooxygenase-2 inhibitors to maintain the fetal arterial duct during treatment and prevent premature labor pains |
| US6025353A (en) * | 1997-11-19 | 2000-02-15 | G.D. Searle & Co. | Method of using cyclooxygenase-2 inhibitors as anti-angiogenic agents |
| US6833373B1 (en) | 1998-12-23 | 2004-12-21 | G.D. Searle & Co. | Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia |
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| AU2014306759B2 (en) | 2013-08-12 | 2018-04-26 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded immediate release abuse deterrent pill |
| WO2015095391A1 (en) | 2013-12-17 | 2015-06-25 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
| US9492444B2 (en) | 2013-12-17 | 2016-11-15 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
| EP3169315B1 (en) | 2014-07-17 | 2020-06-24 | Pharmaceutical Manufacturing Research Services, Inc. | Immediate release abuse deterrent liquid fill dosage form |
| US20160106737A1 (en) | 2014-10-20 | 2016-04-21 | Pharmaceutical Manufacturing Research Services, Inc. | Extended Release Abuse Deterrent Liquid Fill Dosage Form |
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| CA1242725A (en) * | 1982-03-03 | 1988-10-04 | E. I. Du Pont De Nemours And Company | Antiinflammatory and/or analgesic 2,3-diaryl-5-halo thiophenes |
| EP0365089A3 (en) * | 1988-10-18 | 1991-06-05 | Merck & Co. Inc. | 2-aryl-5(3-methoxy-5-(hydroxypropylsulfonyl)-4-propoxyphenyl) tetrahydrothiophen and analogs |
| WO1994015932A1 (en) * | 1993-01-15 | 1994-07-21 | G.D. Searle & Co. | Novel 3,4-diaryl thiophenes and analogs thereof having use as antiinflammatory agents |
-
1994
- 1994-05-11 AU AU67184/94A patent/AU6718494A/en not_active Abandoned
- 1994-05-11 CA CA002161789A patent/CA2161789A1/en not_active Abandoned
- 1994-05-11 WO PCT/CA1994/000264 patent/WO1994026731A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO1994026731A1 (en) | 1994-11-24 |
| AU6718494A (en) | 1994-12-12 |
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