US20020198244A1 - Heterocyclic aromatic oxazole compounds and use thereof - Google Patents
Heterocyclic aromatic oxazole compounds and use thereof Download PDFInfo
- Publication number
- US20020198244A1 US20020198244A1 US09/906,764 US90676401A US2002198244A1 US 20020198244 A1 US20020198244 A1 US 20020198244A1 US 90676401 A US90676401 A US 90676401A US 2002198244 A1 US2002198244 A1 US 2002198244A1
- Authority
- US
- United States
- Prior art keywords
- compound
- optionally substituted
- fluorophenyl
- pharmaceutically acceptable
- cyclohexyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/007—Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Definitions
- the present invention relates to novel heterocyclic aromatic oxazole compounds. More particularly, the present invention relates to heterocyclic aromatic oxazole compounds having antipyretic activity, analgesic activity, anti-inflammatory activity, and in particular, selective inhibitory activity against cyclooxygenase-2 (COX-2), pharmaceutically acceptable salts thereof, intermediates for producing them and pharmaceuticals useful as anti-inflammatory agents causing less side-effects such as disorders in the digestive tract, which comprise these heterocyclic aromatic oxazole compounds.
- COX-2 cyclooxygenase-2
- Cyclooxygenase is a synthase which produces prostaglandin H 2 (PGH 2 ) from arachidonic acid via prostaglandin G 2 (PGG 2 ), and includes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2).
- COX-1 systemically and constantly exists in almost all cells and is physiologically concerned with the generation of prostaglandin (PG) necessary for the functions of, for example, stomach and kidney. Therefore, when COX-1 is inhibited, the biosynthesis of PG by vasodilative PGE 2 and PGI 2 , which protect gastric mucosa, is suppressed, and the protective action on the gastric mucosa becomes degraded, as a result of which ulcer is caused.
- the renal blood flow can be increased by promoting the production of vasodilative PGE 2 in the body, thereby to appropriately maintain glomerular filtration rate.
- the production of such vasodilative PG is suppressed due to the inhibition of COX-1, the renal blood flow becomes less, so that a side-effect such as the onset of ischemic acute renal insufficiency is sometimes caused.
- COX-2 exists in particular sites such as monocytes, synovial cells, granulosa cells and intravenous endothelial cells, and is topically expressed when inflammation is caused. It is therefore considered that PG generated by COX-2 is deeply concerned with inflammation and tissue disorders.
- NSAID non-steroidal anti-inflammatory drugs
- COX cyclooxygenase
- side-effects are considered to be caused by the fact that they, though certainly selectively inhibit COX, inhibit both COX-1 and COX-2.
- WO94/15932 discloses, as COX-2 inhibitors, 5-membered heterocyclic compounds substituted by bisaryl, such as thiophene, furan and pyrrole, which are specifically exemplified by 3-(4-methylsulfonylphenyl)-4-(4-fluorophenyl)thiophene.
- this publication merely shows a 5-membered heterocyclic compound such as thiophene having aryl or heteroaryl at the 3-position or 4-position.
- Japanese Patent Unexamined Publication No. 141261/1991 discloses pyrazole derivatives such as ethyl 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxylate; Japanese Patent Unexamined Publication No. 183767/1982 discloses thiazole derivatives such as 2-thylthio-5-phenyl-4-(3-pyridyl)thiazole; and Japanese Patent Unexamined Publication No. 58981/1985 discloses thiazole derivatives such as 2-ethyl-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole.
- These publications mention that they are useful as anti-inflammatory drugs, whereas they do not disclose if they have selective inhibitory action on COX-2 to reduce side-effects, or any suggestion of it.
- U.S. Pat. No. 4,632,930 discloses oxazole compounds such as 5-cyclohexyl-4-(4-methylsulfonylphenyl)- ⁇ , ⁇ -bis(trifluoromethyl)oxazole-2-methanol. Yet, the compounds disclosed therein are effective for hypertension and their usefulness as anti-inflammatory drugs or any suggestion to that effect are not included.
- Japanese Patent Application under PCT laid-open under Kohyo No. 500054/1984 discloses oxazole derivatives having heteroaryl or carbon ring aryl at the 4-position or 5-position of oxazole ring and having carboxy, ester or amidized carboxy via lower alkylene at the 2-position thereof, such as ethyl 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-propionate; and Japanese Patent Application under PCT laid-open under Kohyo No.
- imidazole derivatives having heteroaryl and/or carbon ring aryl at the 4-position or 5-position of imidazole ring and having formyl or acetalized formyl via lower alkylene at the 2-position thereof, such as 2-[4-phenyl-5-(3-pyridyl)-imidazol-2-yl]-acetaldehyde dimethyl acetal.
- These publications teach that these compounds are effective as dermal antiphlogistic or mucosal antiphlogistic for inflammatory dermal diseases, but do not teach or even suggest that they have selective inhibitory action on COX-2.
- Japanese Patent Unexamined Publication No. 70446/1993 discloses N-thiazolylsulfonamide derivatives such as N-[5-cyclohexyl-4-(4-methoxyphenyl)thiazol-2-yl]trifluoromethanesulfonamide; and Japanese Patent Unexamined Publication No. 83372/1990 discloses cyclohexylimidazole derivatives such as 4-cyclohexyl-5-phenyl-2-t-butyl-imidazole.
- WO94/27980 discloses oxazole compounds such as 2-phenyl-4-cyclohexyl-5-(4-methylsulfonylphenyl)oxazole as COX-2 inhibitors.
- the compounds described in this publication are mainly characterized by 4-fluorophenyl and 4 methylsulfonylphenyl at the 4-position and 5-position of oxazole ring, and do not suggest the compounds having specific substituents in combination, as in the present invention.
- phenyl substituent for 5-membered heterocyclic ring skeleton has been conventionally considered to be monosubstituted phenyl such as 4-methylsulfonylphenyl and 4-methoxyphenyl, and di-substituted phenyl has been barely tried (e.g., UK Patent No. 1206403).
- the present inventors have intensively studied with the aim of providing a novel compound having antipyretic activity, analgesic activity and anti-inflammatory activity, which is free of side-effects such as disorders in the digestive tract.
- a compound having a secondary substituent such as halogen atom, in particular, fluorine atom, introduced into phenyl such as 4-lower alkylsulfonylphenyl, 4-aminosulfonylphenyl or 4-lower alkylaminosulfonylphenyl, as a substituent for oxazole, has superior selective inhibitory action on COX-2, which resulted in the completion of the present invention.
- the present invention relates to heterocyclic aromatic oxazole compounds as shown in the following (1) to (21), pharmaceutically acceptable salts thereof, intermediate compounds for producing such compounds and pharmaceutical compositions comprising such heterocyclic aromatic oxazole compound.
- Z is an oxygen atom
- R and R 1 are a group of the formula
- R 3 is lower alkyl, amino or lower alkylamino
- R 4 , R 5 , R 6 and R 7 are the same or different and each is hydrogen atom, halogen atom, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy or amino, provided that at least one of R 4 , R 5 , R 6 and R 7 is not hydrogen atom, and the other is optionally substituted cycloalkyl, optionally substituted heterocyclic group or optionally substituted aryl; and
- R 2 is a lower alkyl or a halogenated lower alkyl, and pharmaceutically acceptable salts thereof.
- R 3 ′ is lower alkyl or amino
- at least one of R 4 ′, R 5 ′, R 6 ′ and R 7 ′ is halogen atom or lower alkyl and the rest is hydrogen atom or halogen atom, and pharmaceutically acceptable salts thereof.
- R 3 ′′ is methyl or amino
- R 5 ′′ is fluorine atom and R 6 ′′ is hydrogen atom or fluorine atom
- R 2 is methyl
- R 3 ′′, R 5 ′′ and R 6 ′′ are as defined in the above (3);
- R is optionally substituted cycloalkyl having 5 to 7 carbon atoms, optionally substituted thienyl, optionally substituted furyl, optionally substituted pyrrolyl, optionally substituted morpholino, optionally substituted piperazinyl, optionally substituted piperidyl, optionally substituted phenyl, optionally substituted naphthyl or optionally substituted biphenyl, and R 2 is methyl, and pharmaceutically acceptable salts thereof.
- Heterocyclic aromatic oxazole compounds of the above (1) which are selected from the group of:
- R 4 , R 5 , R 6 and R 7 are as defined in the above (1), and R′′ is optionally substituted cycloalkyl or optionally substituted aryl.
- R 1 ′′ and R′′ are respectively as defined in the above (9).
- R′′′ is optionally substituted cycloalkyl having 5 to 7 carbon atoms, optionally substituted phenyl or optionally substituted thienyl
- R 1 ′′′ is a group of the formula
- R 3 ′, R 4 ′, R 5 ′, R 6 ′ and R 7 ′ are as defined in the above (2).
- R, R 1 , R 2 and Z are as defined in the above (1).
- R 1 ′′ and R′′ are respectively as defined in the above (9), and Z and R 2 are as defined in the above (1).
- compositions comprising a pharmaceutically acceptable carrier, and a heterocyclic aromatic oxazole compound of the above (1) or a pharmaceutically acceptable salt thereof.
- Cyclooxygenase-2 inhibitors comprising a pharmaceutically acceptable carrier, and a heterocyclic aromatic oxazole compound of the above (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
- Anti-inflammatory agents comprising a pharmaceutically acceptable carrier, and a heterocyclic aromatic oxazole compound of the above (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
- lower alkyl means an optionally branched alkyl having 1 to 4 carbon atoms, which is exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, with preference given to methyl.
- Lower alkylamino is that wherein amino group is substituted by the above-mentioned lower alkyl, and is exemplified by methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino and tert-butylamino. Preferred are methylamino and dimethylamino.
- Halogen atom means chlorine atom, bromine atom, fluorine atom and the like, with preference given to chlorine atom and fluorine atom. Particularly preferred is fluorine atom.
- Lower alkoxy is an optionally branched alkoxy having 1 to 4 carbon atoms, which is exemplified by methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy, with preference given to methoxy.
- Cycloalkyl means a cycloalkyl having 3 to 8 carbon atoms, which is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, with preference given to cycloalkyl having 5 to 7 carbon atoms, such as cyclopentyl, cyclohexyl and cycloheptyl. Particularly preferred is cyclohexyl.
- Heterocyclic group is a 5- or 6-membered aromatic heterocyclic ring, saturated heterocyclic ring or condensed heterocyclic ring of these heterocyclic rings and benzene ring, all having, besides carbon atom, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom as atom(s) constituting the ring.
- Examples thereof include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, morpholino, piperazinyl, piperidyl, pyranyl, thiopyranyl, pyridyl, benzothienyl, benzofuranyl, indole, 4,5,6,7-tetrahydroindole, 4,5,6,7-tetrahydrobenzothienyl and 4,5,6,7-tetrahydrobenzofuranyl, with preference given to thienyl, furyl, pyrrolyl, morpholino, piperazinyl and piperidyl, and particular preference given to thienyl.
- Aryl is, for example, phenyl, naphthyl or biphenyl. Preferred is phenyl.
- Halogenated lower alkyl is that wherein lower alkyl is substituted by the above-mentioned halogen atom, and is exemplified by fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, fluoroethyl, chloroethyl, difluoroethyl, dichloroethyl, trifluoroethyl, trichloroethyl, tetrachloroethyl, pentafluoroethyl and fluoropropoyl, with preference given to fluoromethyl, chloromethyl, dichloromethyl, difluoromethyl, trichloromethyl and trifluoromethyl.
- Optidnally substituted means that the group may be substituted by 1 to 3 substituents wherein said substituents may be the same or different.
- the position of the substituents is optional and is not particularly limited. Specific examples include lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl; hydroxy; lower alkoxy such as methoxy, ethoxy, propoxy and butoxy; halogen atom such as fluorine, chlorine and bromine; nitro; cyano; acyl such as formyl, acetyl and propionyl; acyloxy such as formyloxy, acetyloxy and propionyloxy; mercapto; alkylthio such as methylthio, ethylthio, propylthio, butylthio and isobutylthio; amino; alkylamino such as methylamino, ethylamino, prop
- optionally substituted aryl means an aryl which may be substituted-by halogen atom, hydroxy, lower alkyl, lower alkoxy, lower alkylsulfonyl and aminosulfonyl, particularly phenyl, and is exemplified by phenyl, fluorophenyl, methylphenyl, methoxyphenyl, methylsulfonylphenyl and aminosulfonylphenyl, with preference given to phenyl and 4-fluorophenyl.
- Optionally substituted heterocyclic group means a heterocyclic group which may be substituted by halogen atom, hydroxy, lower alkyl, lower alkoxy, lower alkylsulfonyl and aminosulfonyl, and particularly means thienyl, furyl, 5-methylthienyl and 5-chlorothienyl.
- Optionally substituted cycloalkyl means a cycloalkyl which may be substituted by the same substituents as above, with preference given to cyclohexyl.
- R of the heterocyclic aromatic oxazole compounds of the present invention examples include cyclohexyl, 4-fluorophenyl and 5-chlorothienyl, with particular preference given to cyclohexyl.
- Preferred as R 1 is a group of the formula
- R 3 , R 4 , R 5 , R 6 and R 7 are as defined above, with particular preference given to a group wherein R 3 is amino or methyl, R 4 and R 7 are hydrogen atoms and at least one of R 5 and R 6 is fluorine atom.
- Specific examples include 4-aminosulfonyl-3-fluorophenyl, 3-fluoro-4-methylsulfonylphenyl, 4-aminosulfonyl-3,5-difluorophenyl and 3,5-difluoro-4-methylsulfonylphenyl, with particular preference given to 4-aminosulfonyl-3-fluorophenyl.
- R 2 is methyl.
- Pharmaceutically acceptable salt may be any as long as it forms a non-toxic salt with the oxazole derivative of the formula (I).
- Alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salt, organic base salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt and N,N′-dibenzylethylenediamine salt, and amino acid salts such as lysine salt and arginine salt are among the examples. It may be a hydrate as the case demands.
- the compound of the present invention has particularly superior selective inhibitory action on COX-2 and is expected to make a therapeutic drug useful for antipyresis, pain relief and anti-inflammation, which is free of side-effects such as digestive tract disorders.
- the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof is used as a pharmaceutical preparation, it is generally admixed with pharmacologically acceptable carriers, excipients, diluents, extenders, disintegrators, stabilizers, preservatives, buffers, emulsifying agents, aromatics, colorings, sweeteners, thickeners, flavorings, solubilizers and other additives known Per se, such as water, vegetable oil, alcohol such as ethanol and benzyl alcohol, polyethylene glycol, glycerol triacetate gelatin, carbohydrates such as lactose and starch, magnesium stearate, talc, lanolin and petrolatum, and formulated into, by a conventional method, tablets, pills, powders, granules, suppositories, injections, eye drops, liquids, capsules, troches, aerosols, elixirs, suspensions, emulsions, syrups and the like,
- the compounds of the present invention can be produced, for example, by the following methods. It is needless to say that the method for producing the compounds of the present invention is not limited to these methods.
- R 2 ′ is lower alkyl or halogenated lower alkyl wherein R 2 ′ may be the same with or different from R 2 , X and X′ are the same or different and each is halogen atom such as bromine atom and chlorine atom, X 1 is halogen atom or hydroxy, X 1 ′ is halogen atom or hydroxy or alkali metal derivative thereof, and R, R 1 , R 2 and Z are as defined above.
- Compound (IV) can be synthesized by reacting compound (II) with compound (III) in the presence of a metal such as zinc and magnesium in an inert solvent such as 1,2-dimethoxyethane, dioxane, ether, tetrahydrofuran, methylene chloride, benzene and toluene at room temperature.
- a catalyst such as palladium(O) complex and copper(I) complex may be added.
- Compound (V) can be synthesized by reacting compound (IV) in acetic acid solvent in the presence of lead tetraacetate, or by refluxing compound (IV) under heating in the presence of a complex such as manganese acetate, in lower alkanecarboxylic acid such as acetic acid and propionic acid corresponding to R 2 COOH wherein R 2 is as defined above and benzoic acid and a solvent such as benzene as necessary.
- Compound (I) can be synthesized by refluxing compound (V) under heating in the presence of ammonium salt (e.g., lower alkanecarboxylic acid ammonium such as ammonium acetate and ammonium formate), and inorganic ammonium such as ammonium carbonate in an acidic solvent such as lower alkanecarboxylic acid (e.g., formic acid, acetic acid and propionic acid).
- ammonium salt e.g., lower alkanecarboxylic acid ammonium such as ammonium acetate and ammonium formate
- inorganic ammonium such as ammonium carbonate
- an acidic solvent such as lower alkanecarboxylic acid
- R or R 1 is aromatic heterocycle, isomers may be produced wherein the 4-position R and the 5-position R 1 are reversed.
- Compound (I) can be also synthesized by the following route.
- Step 6 and Step 7 are advantageous when R 2 (e.g., methyl) is converted to other R 2 (e.g., R 2 ′ such as ethyl).
- R 2 e.g., methyl
- R 2 ′ such as ethyl
- compound (VI) can be synthesized by reacting compound (V) in the presence of a base such as potassium carbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide in an organic solvent such as methanol, ethanol and dioxane, water or a mixed solvent thereof from under cooling to under heating.
- a base such as potassium carbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide
- organic solvent such as methanol, ethanol and dioxane, water or a mixed solvent thereof from under cooling to under heating.
- Compound (VI) can be also synthesized by the following Step 5.
- Step 5 Wherein X 1 is halogen Atom or Hydroxy
- Compound (VI) can be synthesized by reacting compound (IV) in the presence of a halogenating agent such as bromine, chlorine and N-bromosuccinimide in an inert solvent such as acetic acid, 1,2-dimethoxyethane, dioxane, ether, tetrahydrofuran, methylene chloride, benzene and toluene to give compound (VI) wherein X 1 is halogen atom.
- a halogenating agent such as bromine, chlorine and N-bromosuccinimide
- an inert solvent such as acetic acid, 1,2-dimethoxyethane, dioxane, ether, tetrahydrofuran, methylene chloride, benzene and toluene
- Compound (VI) wherein X 1 is hydroxy can be synthesized by oxidizing compound (IV) with an oxidizing agent such as benzene iodoacetate, or by treating the halogenated compound (VI) obtained above with water in an inert solvent such as acetone, 1,2-dimethoxyethane, dioxane, ether, tetrahydrofuran, benzene and toluene.
- an oxidizing agent such as benzene iodoacetate
- Compound (V′) can be obtained by reacting compound (VI) and compound (VII′) by a known method. Specifically, compound (VI) wherein X 1 is hydroxy and compound (VII′) wherein X 1 ′ is halogen atom, or compound (VI) wherein X 1 is halogen atom and compound (VII′) wherein X 1 ′ is hydroxy are reacted in pyridine, or in the presence of a base such as triethylamine and sodium hydroxide, in an organic solvent such as methylene chloride, chloroform and ethanol, from under cooling to under heating.
- a base such as sodium acetate may be used instead of carboxylic acid compound (VII′). In this case, a base may or may not be added.
- Compound (I′) can be obtained by treating compound (V′) in the same manner as in Step 3.
- the compound when a compound wherein either R or R 1 is 4-aminosulfonyl-3-fluorophenyl is desired, the compound can be produced from a compound having 3-fluoro-4-methylsulfonylphenyl corresponding to the objective compound by a known method.
- R 4 , R 5 , R 6 and R 7 are as defined above, may be used as a starting material to give compound (IV′) according to Step 10, which compound is then converted to aminosulfonyl or methylsulfonyl according to the method of Step 15 to give compound (IV).
- such starting materials (II′) and (III′) may be used to give a non-sulfonylated oxazole compound (XIII) corresponding to the ultimate compound (I) or (I′) according to Step 1 to Step 7, and the obtained compound (XIII) may be subjected to sulfonylation in the same manner as in Step 15 to give the objective compound (I) or (I′).
- R 8 or R 9 is methoxysulfonylphenyl of the formula
- R 4 , R 5 , R 6 and R 7 are as defined above, and the other is optionally substituted cycloalkyl, optionally substituted heterocyclic group or optionally substituted aryl, and R, R 1 , X and X′ are as defined above.
- Compound (X) can be synthesized in the same manner as in Step 1, using compound (VIII) and compound (IX).
- compound (IV) can be synthesized by heating compound (X) in pyridine, or refluxing compound (X) under heating in the presence of sodium iodide, potassium iodide, lithium iodide and the like, in an organic solvent such as acetone and tetrahydrofuran, after which the obtained compound is reacted with thionyl chloride or oxalyl chloride under heating. Then, the resulting product is aminated or alkylaminated or alkylated by a known method.
- amination or alkylamination is carried out by reacting the resulting product in the presence of aqueous ammonia or alkylamine, or a base such as sodium acetate and ammonium salt such as alkylamine hydrochloride, in an organic solvent such as tetrahydrofuran, ether, toluene, benzene, methylene chloride and dioxane from under cooling to under heating.
- aqueous ammonia or alkylamine or a base such as sodium acetate and ammonium salt such as alkylamine hydrochloride
- an organic solvent such as tetrahydrofuran, ether, toluene, benzene, methylene chloride and dioxane from under cooling to under heating.
- the alkylation can be carried out by the method described in J. Org. Chem., 56: 4974-4976 (1991).
- Compound (I) can be also synthesized by the method of the following Step 10 to Step 15.
- This method is directed to finally introducing sulfonyl group in the last Step 15.
- R′ or R 1 ′ is phenyl of the formula
- R 4 , R 5 , R 6 and R 7 are as defined above, and the other is a group corresponding to one of R and R 1 , cycloalkyl which may be substituted by a substituent such as lower alkyl, heterocyclic group such as thienyl and furyl, which may be substituted by a substituent lower alkyl or halogen atom, or aryl which may be substituted by a substituent such as halogen atom, lower alkyl and lower alkoxy, and R, R 1 , X, X′ and Z are as defined above.
- Compound (IV′) can be synthesized in the same manner as in Step 1, wherein compound (II′) and compound (III′) are reacted in the presence of a metal such as zinc and magnesium in an inert solvent such as 1,2-dimethoxyethane, dioxane, ether, tetrahydrofuran, methylene chloride, benzene and toluene at room temperature.
- a metal such as zinc and magnesium
- an inert solvent such as 1,2-dimethoxyethane, dioxane, ether, tetrahydrofuran, methylene chloride, benzene and toluene at room temperature.
- a catalyst such as palladium(O) complex and copper(I) iodide complex may be added.
- Compound (XI) can be synthesized by refluxing under heating compound (IV′) and hydroxylammine hydrochloride in the presence of a base such as sodium acetate, sodium hydroxide and potassium carbonate in an organic solvent such as methanol, ethanol and tetrahydrofuran, water or a mixed solvent thereof.
- a base such as sodium acetate, sodium hydroxide and potassium carbonate
- an organic solvent such as methanol, ethanol and tetrahydrofuran, water or a mixed solvent thereof.
- Compound (XII) can be synthesized by reacting compound (XI) in the presence of an acylating agent such as acetic anhydride and acetyl chloride, in pyridine, or in the presence of a base such as triethylamine in an organic solvent such as methylene chloride and chloroform from under cooling to under heating.
- an acylating agent such as acetic anhydride and acetyl chloride
- a base such as triethylamine
- organic solvent such as methylene chloride and chloroform
- Compound (XIII) can be synthesized by refluxing under heating compound (XII) in an acidic solvent such as formic acid and acetic acid.
- a dehydrating agent such as magnesium sulfate and sodium sulfate may be added.
- This step is for the synthesis of compound (XIII) from compound (XI) in a single step, and compound (XIII) can be synthesized from compound (XI) and carboxylic acid chloride such as acetyl chloride by the method described in Indian J. Chem., 20B: 322-323 (1981).
- compound (XIII) can be synthesized by reacting compound (XI) and acetic anhydride while heating in acetic acid.
- Compound (I) can be synthesized by reacting compound (XIII) in the presence of a chlorosulfonylating agent such as chlorosulfonic acid in an organic solvent such as chloroform and methylene chloride, or without solvent, and subjecting the resulting product to amination, alkylamination or alkylation by a known method.
- a chlorosulfonylating agent such as chlorosulfonic acid
- organic solvent such as chloroform and methylene chloride
- the amination and alkylamination in Step 15 specifically comprise reacting in the presence of aqueous ammonia, alkylamine or a base such as sodium acetate and ammonium salt such as alkylamine hydrochloride in an organic solvent such as tetrahydrofuran, ether, toluene, benzene, methylene chloride and dioxane from under cooling to under heating.
- aqueous ammonia, alkylamine or a base such as sodium acetate and ammonium salt
- alkylamine hydrochloride in an organic solvent such as tetrahydrofuran, ether, toluene, benzene, methylene chloride and dioxane from under cooling to under heating.
- Compound (XIII) used in Step 15 can be also synthesized by the following route.
- R 1 , R 1 ′, R 2 and Z are as defined above.
- Compound (V′′) can be synthesized in the same manner as in Step 2 wherein compound (IV′) is reacted in the presence of lead tetraacetate in acetic acid solvent, or by heating compound (IV′) in the presence of a complex such as manganese acetate in lower alkanecarboxylic acid such as acetic acid and propionic acid corresponding to R 2 COOH wherein R 2 is as defined above, and benzoic acid and in a solvent such as benzene as necessary.
- a complex such as manganese acetate in lower alkanecarboxylic acid such as acetic acid and propionic acid corresponding to R 2 COOH wherein R 2 is as defined above, and benzoic acid and in a solvent such as benzene as necessary.
- Compound (XIII) can be synthesized in the same manner as in Step 3 wherein compound (V′′) is refluxed under heating in the presence of ammonium salt such as lower alkanecarboxylic acid ammonium (e.g., ammonium acetate and ammonium formate) and inorganic ammonium (e.g., ammonium carbonate) in an acidic solvent of lower alkanecarboxylic acid such as formic acid, acetic acid and propionic acid.
- ammonium salt such as lower alkanecarboxylic acid ammonium (e.g., ammonium acetate and ammonium formate) and inorganic ammonium (e.g., ammonium carbonate) in an acidic solvent of lower alkanecarboxylic acid such as formic acid, acetic acid and propionic acid.
- ammonium salt such as lower alkanecarboxylic acid ammonium (e.g., ammonium acetate and ammonium formate) and inorgan
- Compound (I) can be also synthesized by the method shown in the following Step 18 to Step 21.
- X 2 is halogen atom
- R, R 1 , R′, R 1 ′, R 2 and Z are as defined above.
- Compound (XV) can be synthesized by reacting compound (XIV) with chlorocarbonate such as ethyl chlorocaronate in an inert solvent such as tetrahydrofuran, toluene and ethyl acetate in the presence of a base such as triethylamine, or by heating compound (XIV) in acetic anhydride.
- chlorocarbonate such as ethyl chlorocaronate
- an inert solvent such as tetrahydrofuran, toluene and ethyl acetate
- a base such as triethylamine
- Compound (XVII) can be synthesized by reacting compound (XV) with compound (XVI) or an acid anhydride corresponding to compound (XVI) in an inert solvent such as tetrahydrofuran, acetonitrile, ethyl acetate and toluene in the presence of magnesium salt such as magnesium chloride and a base such as triethylamine, pyridine and potassium carbonate.
- Compound (XVII) can be also synthesized by the method described in Chem. Ber., 102: 883-898 (1969).
- Compound (XVIII) can be synthesized by treating compound (XVII) with an acid such as IN-4N hydrochloric acid, oxalic solid and dilute sulfuric acid in an inert solvent such as tetrahydrofuran, dioxane, methylene chloride and toluene, or heating compound (XVII) in the presence of pyridine and acetic acid.
- an acid such as IN-4N hydrochloric acid, oxalic solid and dilute sulfuric acid in an inert solvent such as tetrahydrofuran, dioxane, methylene chloride and toluene, or heating compound (XVII) in the presence of pyridine and acetic acid.
- Compound (I) is obtained by reacting compound (XVIII) with a chlorosulfonylating agent such as chlorosulfonic acid in an organic solvent such as chloroform and methylene chloride, or without solvent. Then, the obtained product is reacted with aqueous ammonia or alkylamine in an organic solvent such as tetrahydrofuran, ether, toluene, methylene chloride and dioxane, or reacted with ammonium salt such as alkylamine hydrochloride in the presence of a base such as sodium acetate, pyridine and sodium hydroxide.
- a chlorosulfonylating agent such as chlorosulfonic acid
- organic solvent such as chloroform and methylene chloride, or without solvent.
- Compound (I) can be also synthesized from compound (XVIII) by the following Step 22 and Step 23.
- Compound (XIII) can be synthesized by reacting compound (XVIII) with inorganic acid such as concentrated sulfuric acid and polyphosphoric acid in acetic anhydride, or without solvent, at room temperature to under heating.
- inorganic acid such as concentrated sulfuric acid and polyphosphoric acid in acetic anhydride, or without solvent
- Compound (I) can be synthesized by reacting compound (XIII) in the same manner as in the aforementioned Step 15.
- Step 22 and Step 23 alkylsulfonylation or aminosulfonylation in the final Step 23 has been exemplarily discussed. It is possible to subject a compound having R and R 1 instead of R′ and R 1 ′ to the reaction according to Step 18 to Step 20, followed by Step 22 to give an oxazole compound (I). In this case, Step 23 is not necessary.
- the compound (I) thus obtained can be isolated and purified by a known method for separation and purification, such as concentration, concentration under reduced pressure, solvent extraction, crystal precipitation, recrystallization and chromatography.
- Aqueous ammonia (28%) was added to a solution of the obtained compound (10.00 g) in tetrahydrofuran (40 ml) with stirring at room temperature, and the mixture was stirred at room temperature for one hour.
- the solvent was evaporated under reduced pressure and ethyl acetate was added to the residue.
- the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate.
- Triethylamine (8.39 ml) was added to a suspension of DL-N-acetyl-2-cyclohexylglycine (10.00 g) obtained from ⁇ -aminophenylacetic acid according to a known method [Collect. Czeck. Chem. Commun., 31: 4563 (1996)] in ethyl acetate (50 ml).
- Ethyl chlorocarbonate (5.28 ml) was dropwise added to the mixture under ice-cooling. The mixture was stirred under ice-cooling for one hour, added with ethyl acetate (150 ml), and washed successively with water and saturated brine. The ethyl acetate solution was concentrated under reduced pressure to give 9.86 g of the title compound as an oil.
- the enzymatic activity was determined from the percent conversion of 14 C arachidonic acid into prostaglandin H 2 (PGH2) and the decomposed product thereof. That is, a test sample (20 ⁇ l), an enzyme solution (20 ⁇ l) and distilled water (10 ⁇ l) were added to 100 mM Tris-HCl buffer (pH 8, 140 ⁇ l) containing hematin (2 gM) and tryptophan (5 mM), and the mixture was thoroughly stirred, which was followed by preincubation at 24° C. for 5 minutes.
- control compound 1 was 5-(4-aminosulfonylphenyl)-4-cyclohexyl-2-methyloxazole, a patent application to which has been previously filed by us, and control compound 2 was a known analogous compound, 5-(4-aminosulfonylphenyl)-4-(4-fluorophenyl)-2-methyloxazole.
- the compound of the present invention in particular, a compound wherein R 3 is methyl or amino, R 5 is fluorine atom, R 6 is hydrogen atom. or fluorine atom, and R 4 and R 7 are hydrogen atom, and pharmaceutically acceptable salts thereof surprisingly selectively inhibit COX-2 alone, while scarcely inhibiting COX-1. Accordingly, the compound of the present invention possesses superior antipyretic action, analgesic action and anti-inflammatory action that the conventional products cannot afford, and scarcely show side-effects in the digestive tract.
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Abstract
wherein R3 is lower alkyl, amino or lower alkylamino, and R4, R5, R6 and R7 are the same or different and each is hydrogen atom, halogen atom, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy or amino, provided that at least one of R4, R5, R6 and R7 is not hydrogen atom, and the other is an optionally substituted cycloalkyl, an optionally substituted heterocyclic group or an optionally substituted aryl; and R2 is a lower alkyl or a halogenated lower alkyl, and a pharmaceutically acceptable salt thereof. The heterocyclic aromatic oxazole compound and pharmaceutically acceptable salts thereof have antipyretic action, analgesic action, anti-inflammatory action, and particularly, selective inhibitory action on cyclooxygenase-2 (COX-2), and are expected to be useful as anti-inflammatory agents with less side-effects such as digestive tract disorders.
Description
- The present invention relates to novel heterocyclic aromatic oxazole compounds. More particularly, the present invention relates to heterocyclic aromatic oxazole compounds having antipyretic activity, analgesic activity, anti-inflammatory activity, and in particular, selective inhibitory activity against cyclooxygenase-2 (COX-2), pharmaceutically acceptable salts thereof, intermediates for producing them and pharmaceuticals useful as anti-inflammatory agents causing less side-effects such as disorders in the digestive tract, which comprise these heterocyclic aromatic oxazole compounds.
- It has been conventionally known that arachidonic acid metabolites, prostaglandin E2 (PGE2), prostaglandin I2 (PGI2) and thromboxane B2 (TXB2) are deeply involved in inflammations. An important enzyme in this arachidonic acid metabolism is cyclooxygenase. Cyclooxygenase is a synthase which produces prostaglandin H2 (PGH2) from arachidonic acid via prostaglandin G2 (PGG2), and includes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2).
- With respect to COX-1, cDNA cloning was performed in 1988 and its primary structure and induction by various factors have been clarified [Yokoyama, C. et al.: Biochem. Biophys. Res. Commun., 165: 888-894 (1989); Smith, W. L. et al.: Biochim. Biophys. Acta, 1083: 1-17 (1991); DeWitt, D. L.: Biochim. Biophys. Acta, 1083: 121-134 (1991)]. On the other hand, the existence of an isozyme of COX-1, namely, COX-2, was suggested in 1989 [Holtzman, M. J. et al.: J. Biol. Chem., 267: 21438-21445 (1992)], and cDNAs of COX-2 of chicken, mouse and human have been cloned since 1991 [Xie, W. et al.: Proc. Natl. Acad. Sci. USA, 88: 2692-2696 (1991); Kujubu, D. A. et al.: J. Biol. Chem., 266: 12866-12872 (1991); Hla, T. et al.: Proc. Natl. Acad. Sci. USA, 89: 7384-7388 (1992)]. COX-2 is quickly induced by phorbol ester, lipopolysaccharide (LPS) and the like, and the relationship with inflammation and bronchial asthma has been inferred.
- COX-1 systemically and constantly exists in almost all cells and is physiologically concerned with the generation of prostaglandin (PG) necessary for the functions of, for example, stomach and kidney. Therefore, when COX-1 is inhibited, the biosynthesis of PG by vasodilative PGE2 and PGI2, which protect gastric mucosa, is suppressed, and the protective action on the gastric mucosa becomes degraded, as a result of which ulcer is caused. With regard to a symptom associated with a decrease in renal blood flow, in general terms, the renal blood flow can be increased by promoting the production of vasodilative PGE2 in the body, thereby to appropriately maintain glomerular filtration rate. However, if the production of such vasodilative PG is suppressed due to the inhibition of COX-1, the renal blood flow becomes less, so that a side-effect such as the onset of ischemic acute renal insufficiency is sometimes caused.
- On the other hand, COX-2 exists in particular sites such as monocytes, synovial cells, granulosa cells and intravenous endothelial cells, and is topically expressed when inflammation is caused. It is therefore considered that PG generated by COX-2 is deeply concerned with inflammation and tissue disorders.
- Currently, non-steroidal anti-inflammatory drugs (NSAID) such as aspirin, mefenamic acid, diclofenac, indomethacin, ibuprofen and naproxen have been widely used in clinical situations. Most of these NSAIDs are anti-inflammatory drugs which selectively inhibit cyclooxygenase (COX) and are associated with side-effects such as disorders in the digestive tract. Such side-effects are considered to be caused by the fact that they, though certainly selectively inhibit COX, inhibit both COX-1 and COX-2.
- It follows therefrom that selective inhibition, without inhibition of COX-1, of solely COX-2 which is specifically induced at the inflammatory sites, would enable provision of a superior anti-inflammatory drug free of side-effects such as disorders in the digestive tract (e.g., ulcer).
- There are various reports on anti-inflammatory drugs having selective COX-2 inhibitory activity, which aim at reducing side-effects such as disorders in the digestive tract.
- For example, WO94/15932 discloses, as COX-2 inhibitors, 5-membered heterocyclic compounds substituted by bisaryl, such as thiophene, furan and pyrrole, which are specifically exemplified by 3-(4-methylsulfonylphenyl)-4-(4-fluorophenyl)thiophene. However, this publication merely shows a 5-membered heterocyclic compound such as thiophene having aryl or heteroaryl at the 3-position or 4-position.
- Moreover, various reports deal with anti-inflammatory drugs having cyclooxygenase-inhibitory action, prostaglandin synthesis-inhibitory action or thromboxane A2 synthesis-inhibitory action.
- For example, Japanese Patent Unexamined Publication No. 141261/1991 discloses pyrazole derivatives such as ethyl 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxylate; Japanese Patent Unexamined Publication No. 183767/1982 discloses thiazole derivatives such as 2-thylthio-5-phenyl-4-(3-pyridyl)thiazole; and Japanese Patent Unexamined Publication No. 58981/1985 discloses thiazole derivatives such as 2-ethyl-4-(4-methoxyphenyl)-5-(3-pyridyl)-1,3-thiazole. These publications mention that they are useful as anti-inflammatory drugs, whereas they do not disclose if they have selective inhibitory action on COX-2 to reduce side-effects, or any suggestion of it.
- There are other reports on the following heterocyclic aromatic compounds.
- For example, U.S. Pat. No. 4,632,930 discloses oxazole compounds such as 5-cyclohexyl-4-(4-methylsulfonylphenyl)-α,α-bis(trifluoromethyl)oxazole-2-methanol. Yet, the compounds disclosed therein are effective for hypertension and their usefulness as anti-inflammatory drugs or any suggestion to that effect are not included.
- Japanese Patent Application under PCT laid-open under Kohyo No. 500054/1984 discloses oxazole derivatives having heteroaryl or carbon ring aryl at the 4-position or 5-position of oxazole ring and having carboxy, ester or amidized carboxy via lower alkylene at the 2-position thereof, such as ethyl 2-[4-phenyl-5-(3-pyridyl)-oxazol-2-yl]-propionate; and Japanese Patent Application under PCT laid-open under Kohyo No. 500055/1984 discloses imidazole derivatives having heteroaryl and/or carbon ring aryl at the 4-position or 5-position of imidazole ring and having formyl or acetalized formyl via lower alkylene at the 2-position thereof, such as 2-[4-phenyl-5-(3-pyridyl)-imidazol-2-yl]-acetaldehyde dimethyl acetal. These publications teach that these compounds are effective as dermal antiphlogistic or mucosal antiphlogistic for inflammatory dermal diseases, but do not teach or even suggest that they have selective inhibitory action on COX-2.
- Japanese Patent Unexamined Publication No. 70446/1993 discloses N-thiazolylsulfonamide derivatives such as N-[5-cyclohexyl-4-(4-methoxyphenyl)thiazol-2-yl]trifluoromethanesulfonamide; and Japanese Patent Unexamined Publication No. 83372/1990 discloses cyclohexylimidazole derivatives such as 4-cyclohexyl-5-phenyl-2-t-butyl-imidazole. These publications only exemplify cyclohexyl as a substituent and include no suggestion as to the substitution with phenyl substituted by aminosulfonyl, lower alkylaminosulfonyl or lower alkylsulfonyl.
- WO94/27980 discloses oxazole compounds such as 2-phenyl-4-cyclohexyl-5-(4-methylsulfonylphenyl)oxazole as COX-2 inhibitors. However, the compounds described in this publication are mainly characterized by 4-fluorophenyl and 4 methylsulfonylphenyl at the 4-position and 5-position of oxazole ring, and do not suggest the compounds having specific substituents in combination, as in the present invention.
- Not only in COX-2 inhibitors but also in the field of anti-inflammatory drugs, preferable phenyl substituent for 5-membered heterocyclic ring skeleton has been conventionally considered to be monosubstituted phenyl such as 4-methylsulfonylphenyl and 4-methoxyphenyl, and di-substituted phenyl has been barely tried (e.g., UK Patent No. 1206403).
- The present inventors have intensively studied with the aim of providing a novel compound having antipyretic activity, analgesic activity and anti-inflammatory activity, which is free of side-effects such as disorders in the digestive tract. Surprisingly, they have found that a compound having a secondary substituent such as halogen atom, in particular, fluorine atom, introduced into phenyl such as 4-lower alkylsulfonylphenyl, 4-aminosulfonylphenyl or 4-lower alkylaminosulfonylphenyl, as a substituent for oxazole, has superior selective inhibitory action on COX-2, which resulted in the completion of the present invention.
- That is, the present invention relates to heterocyclic aromatic oxazole compounds as shown in the following (1) to (21), pharmaceutically acceptable salts thereof, intermediate compounds for producing such compounds and pharmaceutical compositions comprising such heterocyclic aromatic oxazole compound.
-
- wherein
- Z is an oxygen atom;
-
- wherein R3 is lower alkyl, amino or lower alkylamino, and
- R4, R5, R6 and R7 are the same or different and each is hydrogen atom, halogen atom, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy or amino, provided that at least one of R4, R5, R6 and R7 is not hydrogen atom, and the other is optionally substituted cycloalkyl, optionally substituted heterocyclic group or optionally substituted aryl; and
- R2 is a lower alkyl or a halogenated lower alkyl, and pharmaceutically acceptable salts thereof.
-
- wherein R3′ is lower alkyl or amino, at least one of R4′, R5′, R6′ and R7′ is halogen atom or lower alkyl and the rest is hydrogen atom or halogen atom, and pharmaceutically acceptable salts thereof.
-
- wherein R3″ is methyl or amino, R5″ is fluorine atom and R6″ is hydrogen atom or fluorine atom, and R2 is methyl, and pharmaceutically acceptable salts thereof.
-
- wherein R3″, R5″ and R6″ are as defined in the above (3); R is optionally substituted cycloalkyl having 5 to 7 carbon atoms, optionally substituted thienyl, optionally substituted furyl, optionally substituted pyrrolyl, optionally substituted morpholino, optionally substituted piperazinyl, optionally substituted piperidyl, optionally substituted phenyl, optionally substituted naphthyl or optionally substituted biphenyl, and R2 is methyl, and pharmaceutically acceptable salts thereof.
- (5) Heterocyclic aromatic oxazole compounds of the above (4), wherein R3″ is amino, and pharmaceutically acceptable salts thereof.
- (6) Heterocyclic aromatic oxazole compounds of the above (4), wherein R is optionally substituted cycloalkyl having 5 to 7 carbon atoms, optionally substituted phenyl or optionally substituted thienyl, and pharmaceutically acceptable salts thereof.
- (7) Heterocyclic aromatic oxazole compounds of the above (4), wherein R is cyclohexyl or 4-fluorophenyl, and R1 is 4-aminosulfonyl-3-fluorophenyl, 4-aminosulfonyl-3,5-difluorophenyl, 3-fluoro-4-methylsulfonylphenyl or 3,5-difluoro-4-methylsulfonylphenyl, and pharmaceutically acceptable salts thereof.
- (8) Heterocyclic aromatic oxazole compounds of the above (1), which are selected from the group of:
- 4-cyclohexyl-5-(3-fluoro-4-methylsulfonylphenyl)-2-methyloxazole,
- 5-(4-aminosulfonyl-3-fluorophenyl)-4cyclohexyl-2-methyloxazole,
- 5-(4-aminosulfonyl-3,5-difluorophenyl)-4-cyclohexyl-2-methyloxazole,
- 4-cyclohexyl-5- (3,5-difluoro-4-methylsulfonylphenyl)-2-methyloxazole, and
- 5-(4-aminosulfonyl-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyloxazole,
- and pharmaceutically acceptable salts thereof.
-
- wherein R4, R5, R6 and R7 are as defined in the above (1), and R″ is optionally substituted cycloalkyl or optionally substituted aryl.
- (10) Oxime compounds of the above (9) wherein R1″ is 3-fluorophenyl or 3,5-difluorophenyl, and R″ is cyclohexyl or 4-fluorophenyl.
-
- wherein R1″ and R″ are respectively as defined in the above (9).
- (12) Ketone compounds of the above (11) wherein R1″ is 3-fluorophenyl or 3,5-difluorophenyl, and R″ is cyclohexyl or 4-fluorophenyl.
-
-
- wherein R3′, R4′, R5′, R6′ and R7′ are as defined in the above (2).
- (14) Ketomethylene compounds of the above (13) wherein R′″ is cyclohexyl, and R1′″ is 4-aminosulfonyl-3-fluorophenyl, 4-amino-sulfonyl-3,5-difluorophenyl, 3-fluoro-4-methylsulfonylphenyl or 3,5-difluoro-4-methylsulfonylphenyl.
-
- wherein R, R1, R2 and Z are as defined in the above (1).
- (16) Ester compounds of the above (15) wherein R is cycloalkyl and R2 is lower-alkyl.
-
- wherein R1″ and R″ are respectively as defined in the above (9), and Z and R2 are as defined in the above (1).
- (18) Amide compounds of the above (17) wherein R1″ is 3-fluorophenyl or 3,5-difluorophenyl, R″ is cyclohexyl or 4-fluorophenyl, and R2 is lower alkyl.
- (19) Pharmaceutical compositions comprising a pharmaceutically acceptable carrier, and a heterocyclic aromatic oxazole compound of the above (1) or a pharmaceutically acceptable salt thereof.
- (20) Cyclooxygenase-2 inhibitors comprising a pharmaceutically acceptable carrier, and a heterocyclic aromatic oxazole compound of the above (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
- (21) Anti-inflammatory agents comprising a pharmaceutically acceptable carrier, and a heterocyclic aromatic oxazole compound of the above (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
- As used herein, lower alkyl means an optionally branched alkyl having 1 to 4 carbon atoms, which is exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, with preference given to methyl.
- Lower alkylamino is that wherein amino group is substituted by the above-mentioned lower alkyl, and is exemplified by methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino and tert-butylamino. Preferred are methylamino and dimethylamino.
- Halogen atom means chlorine atom, bromine atom, fluorine atom and the like, with preference given to chlorine atom and fluorine atom. Particularly preferred is fluorine atom.
- Lower alkoxy is an optionally branched alkoxy having 1 to 4 carbon atoms, which is exemplified by methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy, with preference given to methoxy.
- Cycloalkyl means a cycloalkyl having 3 to 8 carbon atoms, which is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, with preference given to cycloalkyl having 5 to 7 carbon atoms, such as cyclopentyl, cyclohexyl and cycloheptyl. Particularly preferred is cyclohexyl.
- Heterocyclic group is a 5- or 6-membered aromatic heterocyclic ring, saturated heterocyclic ring or condensed heterocyclic ring of these heterocyclic rings and benzene ring, all having, besides carbon atom, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom as atom(s) constituting the ring. Examples thereof include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, morpholino, piperazinyl, piperidyl, pyranyl, thiopyranyl, pyridyl, benzothienyl, benzofuranyl, indole, 4,5,6,7-tetrahydroindole, 4,5,6,7-tetrahydrobenzothienyl and 4,5,6,7-tetrahydrobenzofuranyl, with preference given to thienyl, furyl, pyrrolyl, morpholino, piperazinyl and piperidyl, and particular preference given to thienyl.
- Aryl is, for example, phenyl, naphthyl or biphenyl. Preferred is phenyl.
- Halogenated lower alkyl is that wherein lower alkyl is substituted by the above-mentioned halogen atom, and is exemplified by fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, fluoroethyl, chloroethyl, difluoroethyl, dichloroethyl, trifluoroethyl, trichloroethyl, tetrachloroethyl, pentafluoroethyl and fluoropropoyl, with preference given to fluoromethyl, chloromethyl, dichloromethyl, difluoromethyl, trichloromethyl and trifluoromethyl.
- “Optidnally substituted” means that the group may be substituted by 1 to 3 substituents wherein said substituents may be the same or different. The position of the substituents is optional and is not particularly limited. Specific examples include lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl; hydroxy; lower alkoxy such as methoxy, ethoxy, propoxy and butoxy; halogen atom such as fluorine, chlorine and bromine; nitro; cyano; acyl such as formyl, acetyl and propionyl; acyloxy such as formyloxy, acetyloxy and propionyloxy; mercapto; alkylthio such as methylthio, ethylthio, propylthio, butylthio and isobutylthio; amino; alkylamino such as methylamino, ethylamino, propylamino and butylamino; dialkylamino such as dimethylamino, diethylamino, dipropylamino and dibutylamino; carbonyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; amide; trifluoromethyl; alkylsulfonyl such as methylsulfonyl and ethanesulfonyl; aminosulfonyl; cycloalkyl such as cyclopentyl and cyclohexyl; phenyl; and acylamide such as acetamide and propionylamide. Preferred are hydroxy, lower alkyl, lower alkoxy, mercapto, lower alkylthio, halogen atom, trifluoromethyl, alkylcarbonyl, alkoxycarbonyl and acylamide.
- More specifically, optionally substituted aryl means an aryl which may be substituted-by halogen atom, hydroxy, lower alkyl, lower alkoxy, lower alkylsulfonyl and aminosulfonyl, particularly phenyl, and is exemplified by phenyl, fluorophenyl, methylphenyl, methoxyphenyl, methylsulfonylphenyl and aminosulfonylphenyl, with preference given to phenyl and 4-fluorophenyl.
- Optionally substituted heterocyclic group means a heterocyclic group which may be substituted by halogen atom, hydroxy, lower alkyl, lower alkoxy, lower alkylsulfonyl and aminosulfonyl, and particularly means thienyl, furyl, 5-methylthienyl and 5-chlorothienyl. Optionally substituted cycloalkyl means a cycloalkyl which may be substituted by the same substituents as above, with preference given to cyclohexyl.
-
- wherein R3, R4, R5, R6 and R7 are as defined above, with particular preference given to a group wherein R3 is amino or methyl, R4 and R7 are hydrogen atoms and at least one of R5 and R6 is fluorine atom. Specific examples include 4-aminosulfonyl-3-fluorophenyl, 3-fluoro-4-methylsulfonylphenyl, 4-aminosulfonyl-3,5-difluorophenyl and 3,5-difluoro-4-methylsulfonylphenyl, with particular preference given to 4-aminosulfonyl-3-fluorophenyl. Preferred as R2 is methyl.
- Pharmaceutically acceptable salt may be any as long as it forms a non-toxic salt with the oxazole derivative of the formula (I). Alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salt, organic base salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt and N,N′-dibenzylethylenediamine salt, and amino acid salts such as lysine salt and arginine salt are among the examples. It may be a hydrate as the case demands.
- The compound of the present invention has particularly superior selective inhibitory action on COX-2 and is expected to make a therapeutic drug useful for antipyresis, pain relief and anti-inflammation, which is free of side-effects such as digestive tract disorders.
- When the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof is used as a pharmaceutical preparation, it is generally admixed with pharmacologically acceptable carriers, excipients, diluents, extenders, disintegrators, stabilizers, preservatives, buffers, emulsifying agents, aromatics, colorings, sweeteners, thickeners, flavorings, solubilizers and other additives known Per se, such as water, vegetable oil, alcohol such as ethanol and benzyl alcohol, polyethylene glycol, glycerol triacetate gelatin, carbohydrates such as lactose and starch, magnesium stearate, talc, lanolin and petrolatum, and formulated into, by a conventional method, tablets, pills, powders, granules, suppositories, injections, eye drops, liquids, capsules, troches, aerosols, elixirs, suspensions, emulsions, syrups and the like, which can be administered orally or parenterally.
- While the dose varies depending on the kind and severity of the disease, compound to be administered, administration route, and age, sex, body weight etc. of patients, 0.1 mg-1,000 mg, particularly 1 mg-300 mg of compound (I) is generally administered orally to an adult per day.
-
- wherein R2′ is lower alkyl or halogenated lower alkyl wherein R2′ may be the same with or different from R2, X and X′ are the same or different and each is halogen atom such as bromine atom and chlorine atom, X1 is halogen atom or hydroxy, X1′ is halogen atom or hydroxy or alkali metal derivative thereof, and R, R1, R2 and Z are as defined above.
- Step 1
- Compound (IV) can be synthesized by reacting compound (II) with compound (III) in the presence of a metal such as zinc and magnesium in an inert solvent such as 1,2-dimethoxyethane, dioxane, ether, tetrahydrofuran, methylene chloride, benzene and toluene at room temperature. In this case, a catalyst such as palladium(O) complex and copper(I) complex may be added.
- Step 2
- Compound (V) can be synthesized by reacting compound (IV) in acetic acid solvent in the presence of lead tetraacetate, or by refluxing compound (IV) under heating in the presence of a complex such as manganese acetate, in lower alkanecarboxylic acid such as acetic acid and propionic acid corresponding to R2COOH wherein R2 is as defined above and benzoic acid and a solvent such as benzene as necessary.
- Step 3
- Compound (I) can be synthesized by refluxing compound (V) under heating in the presence of ammonium salt (e.g., lower alkanecarboxylic acid ammonium such as ammonium acetate and ammonium formate), and inorganic ammonium such as ammonium carbonate in an acidic solvent such as lower alkanecarboxylic acid (e.g., formic acid, acetic acid and propionic acid). In this reaction, when R or R1 is aromatic heterocycle, isomers may be produced wherein the 4-position R and the 5-position R1 are reversed.
- Compound (I) can be also synthesized by the following route.
- Step 4 Wherein X1 is Hydroxy
- This step, Step 6 and Step 7 are advantageous when R2 (e.g., methyl) is converted to other R2 (e.g., R2′ such as ethyl).
- When X1 is hydroxy, compound (VI) can be synthesized by reacting compound (V) in the presence of a base such as potassium carbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide in an organic solvent such as methanol, ethanol and dioxane, water or a mixed solvent thereof from under cooling to under heating.
- Compound (VI) can be also synthesized by the following Step 5.
- Step 5 Wherein X1 is halogen Atom or Hydroxy
- Compound (VI) can be synthesized by reacting compound (IV) in the presence of a halogenating agent such as bromine, chlorine and N-bromosuccinimide in an inert solvent such as acetic acid, 1,2-dimethoxyethane, dioxane, ether, tetrahydrofuran, methylene chloride, benzene and toluene to give compound (VI) wherein X1 is halogen atom. Compound (VI) wherein X1 is hydroxy can be synthesized by oxidizing compound (IV) with an oxidizing agent such as benzene iodoacetate, or by treating the halogenated compound (VI) obtained above with water in an inert solvent such as acetone, 1,2-dimethoxyethane, dioxane, ether, tetrahydrofuran, benzene and toluene.
- Step 6
- Compound (V′) can be obtained by reacting compound (VI) and compound (VII′) by a known method. Specifically, compound (VI) wherein X1 is hydroxy and compound (VII′) wherein X1′ is halogen atom, or compound (VI) wherein X1 is halogen atom and compound (VII′) wherein X1′ is hydroxy are reacted in pyridine, or in the presence of a base such as triethylamine and sodium hydroxide, in an organic solvent such as methylene chloride, chloroform and ethanol, from under cooling to under heating. When X1 is halogen atom, alkali metal salt such as sodium acetate may be used instead of carboxylic acid compound (VII′). In this case, a base may or may not be added.
- Step 7
- Compound (I′) can be obtained by treating compound (V′) in the same manner as in Step 3.
- When a compound wherein either R or R1 is 4-aminosulfonyl-3-fluorophenyl is desired, the compound can be produced from a compound having 3-fluoro-4-methylsulfonylphenyl corresponding to the objective compound by a known method.
-
-
- wherein R4, R5, R6 and R7 are as defined above, may be used as a starting material to give compound (IV′) according to Step 10, which compound is then converted to aminosulfonyl or methylsulfonyl according to the method of Step 15 to give compound (IV). Alternatively, such starting materials (II′) and (III′) may be used to give a non-sulfonylated oxazole compound (XIII) corresponding to the ultimate compound (I) or (I′) according to Step 1 to Step 7, and the obtained compound (XIII) may be subjected to sulfonylation in the same manner as in Step 15 to give the objective compound (I) or (I′).
-
-
- wherein R4, R5, R6 and R7 are as defined above, and the other is optionally substituted cycloalkyl, optionally substituted heterocyclic group or optionally substituted aryl, and R, R1, X and X′ are as defined above.
- Step 8
- Compound (X) can be synthesized in the same manner as in Step 1, using compound (VIII) and compound (IX).
- Step 9
- When at least one of R and R1 is phenyl having aminosulfonyl or alkylsulfonyl at the 4-position, compound (IV) can be synthesized by heating compound (X) in pyridine, or refluxing compound (X) under heating in the presence of sodium iodide, potassium iodide, lithium iodide and the like, in an organic solvent such as acetone and tetrahydrofuran, after which the obtained compound is reacted with thionyl chloride or oxalyl chloride under heating. Then, the resulting product is aminated or alkylaminated or alkylated by a known method. More specifically, amination or alkylamination is carried out by reacting the resulting product in the presence of aqueous ammonia or alkylamine, or a base such as sodium acetate and ammonium salt such as alkylamine hydrochloride, in an organic solvent such as tetrahydrofuran, ether, toluene, benzene, methylene chloride and dioxane from under cooling to under heating. The alkylation can be carried out by the method described in J. Org. Chem., 56: 4974-4976 (1991).
- Compound (I) can be also synthesized by the method of the following Step 10 to Step 15.
-
-
- wherein R4, R5, R6 and R7 are as defined above, and the other is a group corresponding to one of R and R1, cycloalkyl which may be substituted by a substituent such as lower alkyl, heterocyclic group such as thienyl and furyl, which may be substituted by a substituent lower alkyl or halogen atom, or aryl which may be substituted by a substituent such as halogen atom, lower alkyl and lower alkoxy, and R, R1, X, X′ and Z are as defined above.
- Step 10
- Compound (IV′) can be synthesized in the same manner as in Step 1, wherein compound (II′) and compound (III′) are reacted in the presence of a metal such as zinc and magnesium in an inert solvent such as 1,2-dimethoxyethane, dioxane, ether, tetrahydrofuran, methylene chloride, benzene and toluene at room temperature. In this case, a catalyst such as palladium(O) complex and copper(I) iodide complex may be added.
- Step 11
- Compound (XI) can be synthesized by refluxing under heating compound (IV′) and hydroxylammine hydrochloride in the presence of a base such as sodium acetate, sodium hydroxide and potassium carbonate in an organic solvent such as methanol, ethanol and tetrahydrofuran, water or a mixed solvent thereof.
- Step-12
- Compound (XII) can be synthesized by reacting compound (XI) in the presence of an acylating agent such as acetic anhydride and acetyl chloride, in pyridine, or in the presence of a base such as triethylamine in an organic solvent such as methylene chloride and chloroform from under cooling to under heating.
- Step 13
- Compound (XIII) can be synthesized by refluxing under heating compound (XII) in an acidic solvent such as formic acid and acetic acid. In this case, a dehydrating agent such as magnesium sulfate and sodium sulfate may be added.
- Step 14
- This step is for the synthesis of compound (XIII) from compound (XI) in a single step, and compound (XIII) can be synthesized from compound (XI) and carboxylic acid chloride such as acetyl chloride by the method described in Indian J. Chem., 20B: 322-323 (1981). When R2 is methyl, compound (XIII) can be synthesized by reacting compound (XI) and acetic anhydride while heating in acetic acid.
- Step 15
- Compound (I) can be synthesized by reacting compound (XIII) in the presence of a chlorosulfonylating agent such as chlorosulfonic acid in an organic solvent such as chloroform and methylene chloride, or without solvent, and subjecting the resulting product to amination, alkylamination or alkylation by a known method. The amination and alkylamination in Step 15 specifically comprise reacting in the presence of aqueous ammonia, alkylamine or a base such as sodium acetate and ammonium salt such as alkylamine hydrochloride in an organic solvent such as tetrahydrofuran, ether, toluene, benzene, methylene chloride and dioxane from under cooling to under heating. When alkylsulfonation is carried out, the method described in J. Org. Chem., 56: 4974-4976 (1991) can be used for the synthesis.
- In the above description, alkylsulfonation or aminosulfonation in the final Step 15 has been exemplarily discussed. It is possible to use compound (II) and compound (III) instead of the starting materials (II′) and (III′) to give compound (IV), which is followed by Step 11 to Step 14 to give an oxazole compound (I). In this case, Step 15 is not necessary.
-
- wherein R1, R1′, R2 and Z are as defined above.
- Step 16
- Compound (V″) can be synthesized in the same manner as in Step 2 wherein compound (IV′) is reacted in the presence of lead tetraacetate in acetic acid solvent, or by heating compound (IV′) in the presence of a complex such as manganese acetate in lower alkanecarboxylic acid such as acetic acid and propionic acid corresponding to R2COOH wherein R2 is as defined above, and benzoic acid and in a solvent such as benzene as necessary.
- Step 17
- Compound (XIII) can be synthesized in the same manner as in Step 3 wherein compound (V″) is refluxed under heating in the presence of ammonium salt such as lower alkanecarboxylic acid ammonium (e.g., ammonium acetate and ammonium formate) and inorganic ammonium (e.g., ammonium carbonate) in an acidic solvent of lower alkanecarboxylic acid such as formic acid, acetic acid and propionic acid. In this reaction, when R′ or R1′ is an aromatic heterocycle, isomers may be produced wherein the 4-position R′ and the 5-position R1′ are reversed.
-
- wherein X2 is halogen atom, and R, R1, R′, R1′, R2 and Z are as defined above.
- Step 18
- Compound (XV) can be synthesized by reacting compound (XIV) with chlorocarbonate such as ethyl chlorocaronate in an inert solvent such as tetrahydrofuran, toluene and ethyl acetate in the presence of a base such as triethylamine, or by heating compound (XIV) in acetic anhydride.
- Step 19
- Compound (XVII) can be synthesized by reacting compound (XV) with compound (XVI) or an acid anhydride corresponding to compound (XVI) in an inert solvent such as tetrahydrofuran, acetonitrile, ethyl acetate and toluene in the presence of magnesium salt such as magnesium chloride and a base such as triethylamine, pyridine and potassium carbonate. Compound (XVII) can be also synthesized by the method described in Chem. Ber., 102: 883-898 (1969).
- Step 20
- Compound (XVIII) can be synthesized by treating compound (XVII) with an acid such as IN-4N hydrochloric acid, oxalic solid and dilute sulfuric acid in an inert solvent such as tetrahydrofuran, dioxane, methylene chloride and toluene, or heating compound (XVII) in the presence of pyridine and acetic acid.
- Step 21
- Compound (I) is obtained by reacting compound (XVIII) with a chlorosulfonylating agent such as chlorosulfonic acid in an organic solvent such as chloroform and methylene chloride, or without solvent. Then, the obtained product is reacted with aqueous ammonia or alkylamine in an organic solvent such as tetrahydrofuran, ether, toluene, methylene chloride and dioxane, or reacted with ammonium salt such as alkylamine hydrochloride in the presence of a base such as sodium acetate, pyridine and sodium hydroxide.
- Compound (I) can be also synthesized from compound (XVIII) by the following Step 22 and Step 23.
- Step 22
- Compound (XIII) can be synthesized by reacting compound (XVIII) with inorganic acid such as concentrated sulfuric acid and polyphosphoric acid in acetic anhydride, or without solvent, at room temperature to under heating.
- Step 23
- Compound (I) can be synthesized by reacting compound (XIII) in the same manner as in the aforementioned Step 15.
- In the above Step 22 and Step 23, alkylsulfonylation or aminosulfonylation in the final Step 23 has been exemplarily discussed. It is possible to subject a compound having R and R1 instead of R′ and R1′ to the reaction according to Step 18 to Step 20, followed by Step 22 to give an oxazole compound (I). In this case, Step 23 is not necessary.
- The compound (I) thus obtained can be isolated and purified by a known method for separation and purification, such as concentration, concentration under reduced pressure, solvent extraction, crystal precipitation, recrystallization and chromatography.
- The present invention is described in more detail in the following by illustrative Examples and Experimental Examples, to which the present invention is not limited.
- Synthesis of 5-(2-chloro-4-methylsulfonylphenyl)-4-cyclohexyl-2-methyloxazole (Formula (I′); R=cyclohexyl, R1=2-chloro-4-methyl-sulfonylphenyl, R2′=methyl, Z=oxygen Atom)
-
- To a solution of tetrakis(triphenylphosphine)palladium (1.29 g) and zinc powder (2.19 g) in 1,2-dimethoxyethane (10 ml) was added a solution of cyclohexanecarbonyl chloride (3.60 g) in 1,2-dimethoxyethane (10 ml) at room temperature under a nitrogen atmosphere. A solution of 2-chloro-4-methylsulfonylbenzyl bromide (9.40 g) in 1,2-dimethoxyethane (20 ml) was gradually added dropwise to the mixture at room temperature with stirring. The mixture was further stirred at room temperature for 3 hours. The insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. Then, ethyl acetate (200 ml) was added to the residue, and the mixture was washed with 1N hydrochloric acid, and then with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and ethyl acetate and diisopropyl ether were added. The precipitated solid was collected by filtration to give 3.47 g of the title compound as a white solid.
-
- To a solution of the compound (3.40 g) obtained in the above Step 1) in benzene (20 ml) was dropwise added a solution of bromine (1.73 g) in benzene (20 ml) with stirring under ice-cooling, and the mixture was stirred for one hour. This solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 4.20 g of the title compound. Step 6) 1-(2-Chloro-4-methylsulfonylphenyl)-2-cyclohexyl-2-oxoethyl acetate (formula (V′); R=cyclohexyl, R1=2-chloro-4-methylsulfonylphenyl, R2′=-methyl, Z-oxygen atom)
- Sodium acetate (1.06 g) and ethanol (40 ml) were added to the compound (4.20 g) obtained in the above Step 5). The mixture was refluxed under heating for 4 hours, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give 3.85 g of a crude product of the title compound.
-
- A solution of the compound (3.85 g) obtained in the above Step 6) and ammonium acetate (2.08 g) in acetic acid (40 ml) was refluxed under heating for 5 hours. The solvent was evaporated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 1.95 g of the title compound (yield 53%).
- Synthesis of 5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole (Formula (I); R=cyclohexyl, R1=4-aminosulfonyl-3-fluorophenyl, R2=ethyl, Z=oxygen Atom)
-
- To a solution of tetrakis(triphenylphosphine)palladium (2.00 g) and zinc powder (17.98 g) in 1,2-dimethoxyethane (50 ml) was added a solution of cyclohexanecarbonyl chloride (20.00 g) in 1,2-dimethoxyethane (50 ml) at room temperature under a nitrogen atmosphere. A solution of 3-fluorobenzyl bromide (26.00 g) in 1,2-dimethoxyethane (100 ml) was gradually added dropwise to the mixture with stirring under ice-cooling. The mixture was stirred under ice-cooling for 30 minutes, and at room temperature for 2 hours. The insoluble matter was removed by filtration and the filtrate was concentrated under reduced pressure. Then, ethyl acetate (200 ml) was added to the residue, and the mixture was washed with 1N hydrochloric acid, and then with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give 29.20 g of an oily crude product.
-
- Lead tetraacetate (75.00 g) was added to a solution of the compound (29.20 g) obtained in the above Step 10) in acetic acid (300 ml). The mixture was refluxed under heating for 1.5 hours, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=9:1) to give 18.30 g of the title compound as an oil (yield 50%).
-
- A solution of the compound (18.00 g) obtained in the above Step 16) and ammonium acetate (15.00 g) in acetic acid (100 ml) was refluxed under heating for 5 hours, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 17.20 g of an oily crude product.
-
- To a solution of the compound (17.00 g) obtained in the above Step 17) in chloroform (80 ml) was added dropwise chlorosulfonic acid (27 ml) with stirring under ice-cooling, and the mixture was heated at 100° C. for 3 hours. The reaction mixture was cooled to room temperature, and dropwise added to ice-water (300 ml) with stirring. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 20.31 g of a crude product.
- Aqueous ammonia (28%) was added to a solution of the obtained compound (10.00 g) in tetrahydrofuran (40 ml) with stirring at room temperature, and the mixture was stirred at room temperature for one hour. The solvent was evaporated under reduced pressure and ethyl acetate was added to the residue. The mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was separated and purified by silica gel column chromatography (developing solvent; dichloromethane:ethyl acetate=6:1) to give 5.74 g of the title compound (yield 61%).
- The compound of Example 2 (formula (I); R=cyclohexyl, R1=4-aminosulfonyl-3-fluorophenyl, R2=methyl, Z=oxygen atom) was synthesized according to another synthetic method.
-
- To a solution of the compound (353 g) obtained according to a method similar to that of the above Example 2, Step 10) in ethanol (1300 ml) were added hydroxylamine hydrochloride (123 g) and sodium acetate (158 g). The mixture was refluxed under heating for 2 hours, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product was recrystallized from n-heptane to give 160 g of the title compound (yield 42%).
-
- Acetic anhydride (95 ml) was dropwise added to a solution of the compound (158 g) obtained in the above Step 11) in acetic acid (900 ml) with stirring at room temperature, and the mixture was refluxed under heating for 7 hours. The solvent was evaporated under reduced pressure and n-heptane was added to the residue. The mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution, saturated brine and acetonitrile. The solvent was evaporated under reduced pressure to give 119 g of the title compound as an oil.
- Then, the obtained compound (119 g) was reacted in the same manner as in the above Example 2, Step 15) to give a compound of Example 2 (formula (I); R=cyclohexyl, R1=4-aminosulfonyl-3-fluorophenyl, R2=methyl, Z=oxygen atom).
- Synthesis of 4-cyclohexyl-5-(3-fluoro-4-methylsulfonylphenyl)-2-methyloxazole (Formula (I); R=cyclohexyl, R1=3-fluoro-4-methylsulfonylphenyl, R2=methyl, Z=oxygen atom)
-
- To a solution of the compound (17.00 g) obtained in the above Example 2, Step 17) in chloroform (80 ml) was dropwise added chlorosulfonic acid (27 ml) with stirring under ice-cooling. The mixture was heated at 100° C. for 3 hours. The reaction mixture was cooled to room temperature and dropwise added to ice-water (300 ml) with stirring. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 20.31 g of a crude product.
- Water (25 ml) was added to the obtained compound (3.66 g). To the mixture were added sodium sulfite (1.42 g) and sodium hydrogencarbonate (1.89 g) successively with stirring at room temperature. The mixture was heated at 70° C. for 2 hours. Ethanol (25 ml) and methyl iodide (2.20 g) were added to the mixture, and the mixture was heated at 100° C. for 2 hours. The mixture was cooled to room temperature and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was saparated and purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=2:1) to give 0.82 g of the title compound (yield 24%).
- The compounds of Examples 4-6 were obtained in the same manner as in Examples 1-3 or Example 7 to be mentioned below.
- The structures and properties of the compounds of Examples 1-6 are shown in the following Tables. In the Tables, Me means methyl.
TABLE 1 Ex. Compound m.p. 1H NMR (δ) ppm IR cm−1 MS Elem. analysis 1 119˜121° C. white crystals CDCl3 300 MHz 1.1-1.2(3H, m) 1.6-1.8(7H, m) 2.48(1H, m) 2.51(3H, s) 3.12(3H, s) 7.55(1H, d, J=8.1Hz) 7.88(1H, dd, J=1.8, 8.1Hz) 8.07(1H, d, J=1.8Hz) neat 2928 1578 1317 1155 1100 960 FAB+354 #(MH+) 2 166˜167° C. white crystals CDCl3 300 MHz 1.3-1.5(3H, m) 1.6-1.9(7H, m) 2.51(3H, s) 2.79(1H, tt, J=3.7, 11.3Hz) 5.11(2H, s) 7.36-7.44(2H, m) 7.94(1H, t, J=7.9Hz) neat 3280 2929 1613 1343 1170 FAB+339 (MH+) Calculated # C 56.79% H 5.66% N 8.28% Found C 56.41% H 5.73% N 8.19% 3 111˜112° C. white crystals CDCl3 300 MHz 1.3-1.5(3H, m) 1.6-1.8(7H, m) 2.52(3H, s) 2.80(1H, tt, J=4.0, 11.4Hz) 3.25(3H, s) 7.40(1H, dd, J=1.6, 11.2Hz) 7.48(1H, dd, J=1.6, 8.3Hz) 7.99(1H, dd, J=8.3, 8.4Hz) neat 2929 1612 1320 1161 1144 # 769 FAB+338 (MH+) Calculated C 60.52% H 5.97% N 4.15% Found C 60.70% H 6.10% N 4.12% -
TABLE 2 Ex. Compound m.p. 1H NMR (δ) ppm IR cm−1 MS Elem. analysis 4 200˜201° C. white crystals CDCl3 300 MHz 1.28-1.44(4H, m) 1.62-1.92(6H, m) 2.51(3H, s) 2.72-2.83(1H, m) 5.18(2H, s) 7.53(1H, dd, J=8.4, 4, 1.6Hz) 7.69(1H, d, J=1.6Hz) 8.13(1H, d, J=8.4Hz) KBr 3353 3255 2928 1606 1342 1166 FAB+ # 355(MH+) Calculated C 54.16% H 5.40% N 7.89% Found C 54.11% H 5.45% N 7.78% 5 183.2˜184.2° C. white crystals CDCl3 300 MHz 1.3-1.5(3H, m) 1.7-1.9(7H, m) 2.50(3H, s) 2.73(3H, s) 2.80(1H, m) 4.92(2H, s) 7.43-7.49(2H, m) 8.05(1H, d, J=8.3Hz) KBr 3294 2929 1609 1299 1170 FAB+335 #(MH+) Calculated C 61.05% H 6.63% N 8.38% Found C 61.24% H 6.73% N 8.43% 6 amorphous CDCl3 300 MHz 1.28-1.47(3H, m) 1.57-1.95(7H, m) 2.51(3H, s) 2.68-2.80(1H, m) 5.37(2H, brs) 7.18(2H, ddd, J=9, 9, 1.7, 1.4Hz) KBr 2931 1622 1557 1422 1359 1175 1035 FAB+357(MH+) -
- A solution of 5-(3-fluorophenyl)-4-(4-fluorophenyl)-2-methyl-oxazole (1.10 g) obtained by the method as mentioned above and chlorosulfonic acid (1.6 ml) in chloroform (2 ml) was heated with stirring at 90° C. for 2 hours. The reaction mixture was poured into ice-water and extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 1.06 g of a crude product of 5-(4-chlorosulfonyl-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyloxazole.
- To a solution of this crude product (1.06 g) in tetrahydrofuran (6 ml) was added 28% aqueous ammonia (0.6 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, added with ethyl acetate, and washed with water and saturated brine. The ethyl acetate solution was dried over anhydrous magnesium sulfate, and concentrated to give 981 mg of a crude product. This crude product was recrystallized from ethanol to give 629 mg of the title compound (yield 44%). The structure and properties of this compound are shown in the following Table.
TABLE 3 Ex. Compound m.p. 1H NMR (δ) ppm IR cm−1 MS Elem. analysis 7 208° C. white crystals CDCl3 300 MHz 2.58(3H, s) 5.07(2H, s) 7.14(2H, tt, J=2.2, 8.8Hz) 7.36(1H, dd, J=1.5, 11.0Hz) 7.47(1H, dd, J=1.8, 7.7Hz) 7.59(2H, ddd, J=2.2, 5.5, 8.8Hz) 7.88(1H, t, J=7.7Hz) neat 3278 2359 1613 1562 1510 # 1342 1171 FAB+351 (M+ 1) Calculated C 54.74% H 3.86% N 7.66% Found C 54.40% H 3.74% N 7.59% - The compound of Example 2 (formula (I); R=cyclohexyl, R1=4-aminosulfonyl-3-fluorophenyl, R2=methyl, Z=oxygen atom) was synthesized according to another synthetic method.
-
- Triethylamine (8.39 ml) was added to a suspension of DL-N-acetyl-2-cyclohexylglycine (10.00 g) obtained from α-aminophenylacetic acid according to a known method [Collect. Czeck. Chem. Commun., 31: 4563 (1996)] in ethyl acetate (50 ml). Ethyl chlorocarbonate (5.28 ml) was dropwise added to the mixture under ice-cooling. The mixture was stirred under ice-cooling for one hour, added with ethyl acetate (150 ml), and washed successively with water and saturated brine. The ethyl acetate solution was concentrated under reduced pressure to give 9.86 g of the title compound as an oil.
-
- A solution of the compound (9.86 g) obtained in the above Step 18) in tetrahydrofuran (15 ml) was added to a suspension of magnesium chloride (3.56 g) in tetrahydrofuran (20 ml). Triethylamine (9.49 ml) was added with stirring under ice-cooling, and the mixture was stirred for 15 minutes. 3-Fluorobenzoyl chloride (4.55 ml) was dropwise added to the mixture, and the mixture was stirred under ice-cooling for one hour. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 11.69 g of the title compound as an oil.
-
- To a solution of the compound (527 mg) obtained in the above Step 19) in tetrahydrofuran (3.5 ml) was added 1N hydrochloric acid (0.35 ml). The mixture was stirred at room temperature for one hour, added with ethyl acetate, and washed successively with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 404 mg of the title compound as a solid (yield 84%). The solid was recrystallized from n-heptane to give white crystals, melting point 116-117° C.
-
- Chlorosulfonic acid (0.34 ml) was added to a solution of the compound (200 mg) obtained in the above Step 20) in chloroform (2 ml) with stirring under ice-cooling, and the mixture was refluxed under heating for 5 hours. The reaction mixture was diluted with chloroform and poured into ice-water. The organic layer was separated, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 181 mg of a crude product.
- To a solution of the obtained compound (169 mg) in tetrahydrofuran (2 ml) was added 28% aqueous ammonia (0.1 ml) with stirring at room temperature, and the mixture was stirred for 30 minutes. The solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated brine, which was followed by drying over anhydrous sodium sulfate. The solvent was evaporated, and the residue was separated and purified by silica gel column chromatography (developing solvent; dichloromethane:ethyl acetate=6:1) to give 126 mg of the title compound (yield 55%).
- The compound of Example 2 (formula (I); R=cyclohexyl, R1=4-aminosulfonyl-3-fluorophenyl, R2=methyl, Z=oxygen atom) was synthesized according to another synthetic method.
-
- Concentrated sulfuric acid (30 μl) was added to a suspension of the compound (141 mg) obtained in the above Example, Step 20) in acetic anhydride (2 ml), and the mixture was stirred at 100° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, added with aqueous potassium carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 135 mg of the title compound as an oil.
-
- In the same manner as in the above Example 2, Step 15), the compound obtained in the above Step 22) was reacted to give the compound of Example 2 (formula (I); R=cyclohexyl, R1=4-aminosulfonyl-3-fluorophenyl, R2=methyl, Z=oxygen atom).
- The enzymatic activity was determined from the percent conversion of14C arachidonic acid into prostaglandin H2 (PGH2) and the decomposed product thereof. That is, a test sample (20 μl), an enzyme solution (20 μl) and distilled water (10 μl) were added to 100 mM Tris-HCl buffer (pH 8, 140 μl) containing hematin (2 gM) and tryptophan (5 mM), and the mixture was thoroughly stirred, which was followed by preincubation at 24° C. for 5 minutes. Then, a 14C arachidonic acid solution (10 μl) was added and the mixture was reacted at 24° C., whereafter a solution (40 μl) of ethyl ether/methanol/1M citric acid (30/4/1) ice-cooled to −20° C. was added to stop the reaction. The reaction mixture was centrifuged for 5 minutes at 3,000 rpm to give an ether layer which was placed on a thin plate, and developed with ethyl ether/methanol/acetic acid (90/2/0.1) to determine percent conversion (Å) from arachidonic acid to PGH2 and the decomposed product thereof. The percent conversion (B) without a test sample was also determined, based on which percent inhibition was calculated from the following formula, and a concentration (IC50) necessary for 50% inhibition of the test sample was determined.
- Inhibition (%)=(1−A/B)×100
- An enzyme prepared from human platelets was used as an enzyme solution of cyclooxygenase-1, and an enzyme expressed by a yeast, into which cDNA of human cyclooxygenase-2 had been introduced using a kit of Invitrogen Corp., was used as an enzyme solution of cyclooxygenase-2. As used herein, control compound 1 was 5-(4-aminosulfonylphenyl)-4-cyclohexyl-2-methyloxazole, a patent application to which has been previously filed by us, and control compound 2 was a known analogous compound, 5-(4-aminosulfonylphenyl)-4-(4-fluorophenyl)-2-methyloxazole.
- The results are shown in Table 4.
- As is evident from the comparison of control compound 1 and the compound of Example 2, as well as control compound 2 and the compound of Example 7, a remarkable reduction of the action on COX-1 while retaining the activity on COX-2 has become possible particularly by introducing fluorine atom.
TABLE 4 Experimental Example 1 (inhibitory action on cyclooxygenase) Structural IC50 (μM) Example formula COX-2 COX-1 COX-1/COX-2 2 0.07 >100 >1,428 3 0.3 >100 >333 4 >10 5 >10 6 0.16 >100 >625 7 0.03 37 1,233 Indomethacin 8 0.5 0.063 Control 1 0.07 45 643 Control 2 0.02 5 250 - Carrageenin (1%, 0.05 ml) dissolved in physiological saline was subcutaneously injected to the left hindlimb of male Donryu rats to induce podedema. The degree of podedema was evaluated by measuring the volume of the limb 3 hours after carrageenin administration. A test compound (1, 3, 10 or 30 mg/kg) was orally administered one hour before carrageenin administration, and suppression thereby was studied. Inhibitory activity was expressed by the dose (ED30) of the test compound necessary for inhibiting by 30% relative to the control group. The results are shown in Table 5.
TABLE 5 Experimental Example 2 (effects on carrageenin-induced podedema in rats) carrageenin-induced podedema Example in rats, ED30 (mg/kg p.o.) 2 5.5 indomethacin 2.9 - The compound of the present invention, in particular, a compound wherein R3 is methyl or amino, R5 is fluorine atom, R6 is hydrogen atom. or fluorine atom, and R4 and R7 are hydrogen atom, and pharmaceutically acceptable salts thereof surprisingly selectively inhibit COX-2 alone, while scarcely inhibiting COX-1. Accordingly, the compound of the present invention possesses superior antipyretic action, analgesic action and anti-inflammatory action that the conventional products cannot afford, and scarcely show side-effects in the digestive tract.
- Consequently, the development of a superior anti-inflammatory agent heretofor not existed has been enabled, which in turn produces great expectation of the provision of a practical therapeutic agent for the diseases possibly caused by COX-2 product, such as asthma and rheumatism.
Claims (21)
1. A heterocyclic aromatic oxazole compound of the formula (I)
wherein
Z is an oxygen atom;
one of R and R1 is a group of the formula
wherein R3 is lower alkyl, amino or lower alkylamino, and R4, R5, R6 and R7 are the same or different and each is hydrogen atom, halogen atom, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy or amino, provided that at least one of R4, R5, R6 and R7 is not hydrogen atom, and the other is optionally substituted cycloalkyl, optionally substituted heterocyclic group or optionally substituted aryl; and
R2 is a lower alkyl or a halogenated lower alkyl, or a pharmaceutically acceptable salt thereof.
4. The heterocyclic aromatic oxazole compound of claim 1 , wherein R1 is a group of the formula
wherein R3″, R5″ and R6″ are as defined in claim 3; R is optionally substituted cycloalkyl having 5 to 7 carbon atoms, optionally substituted thienyl, optionally substituted furyl, optionally substituted pyrrolyl, optionally substituted morpholino, optionally substituted piperazinyl, optionally substituted piperidyl, optionally substituted phenyl, optionally substituted naphthyl or optionally substituted biphenyl, and R2 is methyl, or a pharmaceutically acceptable salt thereof.
5. The heterocyclic aromatic oxazole compound of claim 4 , wherein R3″ is amino, or a pharmaceutically acceptable salt thereof.
6. The heterocyclic aromatic oxazole compound of claim 4 , wherein R is optionally substituted cycloalkyl having 5 to 7 carbon atoms, optionally substituted phenyl or optionally substituted thienyl, or a pharmaceutically acceptable salt thereof.
7. The heterocyclic aromatic oxazole compound of claim 4 , wherein R is cyclohexyl or 4-fluorophenyl, and R1 is 4-aminosulfonyl-3-fluorophenyl, 4-aminosulfonyl-3,5-difluorophenyl, 3-fluoro-4-methylsulfonylphenyl or 3,5-difluoro-4-methylsulfonylphenyl, or a pharmaceutically acceptable salt thereof.
8. The heterocyclic aromatic oxazole compound of claim 1 , which is selected from the group consisting of:
4-cyclohexyl-5-(3-fluoro-4-methylsulfonylphenyl)-2-methyloxazole,
5-(4-aminosulfonyl-3-fluorophenyl)-4-cyclohexyl-2-methyloxazole,
5-(4-aminosulfonyl-3,5-difluorophenyl)-4-cyclohexyl-2-methyloxazole,
4-cyclohexyl-5-(3,5-difluoro-4-methylsulfonylphenyl)-2-methyloxazole, and
5-(4-aminosulfonyl-3-fluorophenyl)-4-(4-fluorophenyl)-2-methyloxazole,
or a pharmaceutically acceptable salt thereof.
10. The oxime compound of claim 9 wherein R1″ is 3-fluorophenyl or 3,5-difluorophenyl, and R″ is cyclohexyl or 4-fluorophenyl.
12. The ketone compound of claim 11 , wherein R1″ is 3-fluorophenyl or 3,5-difluorophenyl, and R″ is cyclohexyl or 4-fluorophenyl.
13. A ketomethylene compound of the following formula (IV′″)
wherein R′″ is an optionally substituted cycloalkyl having 5 to 7 carbon atoms, an optionally substituted phenyl or an optionally substituted thienyl, and R1′″ is a group of the formula
wherein R3′, R4′, R5′, R6′ and R7′ are as defined in claim 2 .
14. The ketomethylene compound of claim 13 , wherein R′″ is cyclohexyl, and R1′″ is 4-aminosulfonyl-3-fluorophenyl, 4-aminosulfonyl-3,5-difluorophenyl, 3-fluoro-4-methylsulfonylphenyl or 3,5-difluoro-4-methylsulfonylphenyl.
16. The ester compound of claim 15 , wherein R is cycloalkyl and R2 is lower alkyl.
18. The amide compound of claim 17 , wherein R1″ is 3-fluorophenyl or 3,5-difluorophenyl, R″ is cyclohexyl or 4-fluorophenyl, and R2 is lower alkyl.
19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and a heterocyclic aromatic oxazole compound of claim 1 or a pharmaceutically acceptable salt thereof.
20. A cyclooxygenase-2 inhibitor comprising a pharmaceutically acceptable carrier, and a heterocyclic aromatic oxazole compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
21. An anti-inflammatory agent comprising a pharmaceutically acceptable carrier, and a heterocyclic aromatic oxazole compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
Priority Applications (1)
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US09/906,764 US20020198244A1 (en) | 1994-12-20 | 2001-07-18 | Heterocyclic aromatic oxazole compounds and use thereof |
Applications Claiming Priority (11)
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JP335838/1994 | 1994-12-20 | ||
JP33583894 | 1994-12-20 | ||
JP9309995 | 1995-03-27 | ||
JP93099/1995 | 1995-03-27 | ||
JP164656/1995 | 1995-06-06 | ||
JP16465695 | 1995-06-06 | ||
JP7326571A JP2636819B2 (en) | 1994-12-20 | 1995-11-20 | Oxazole-based heterocyclic aromatic compounds |
JP326571/1995 | 1995-11-20 | ||
US08/693,051 US5994381A (en) | 1994-12-20 | 1995-12-18 | Heterocyclic aromatic oxazole compounds and use thereof |
US09/398,997 US6362209B1 (en) | 1994-12-20 | 1999-09-17 | Heterocyclic aromatic oxazole compounds and use thereof |
US09/906,764 US20020198244A1 (en) | 1994-12-20 | 2001-07-18 | Heterocyclic aromatic oxazole compounds and use thereof |
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US09/398,997 Continuation US6362209B1 (en) | 1994-12-20 | 1999-09-17 | Heterocyclic aromatic oxazole compounds and use thereof |
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US20020198244A1 true US20020198244A1 (en) | 2002-12-26 |
Family
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US08/693,051 Expired - Fee Related US5994381A (en) | 1994-12-20 | 1995-12-18 | Heterocyclic aromatic oxazole compounds and use thereof |
US09/398,997 Expired - Fee Related US6362209B1 (en) | 1994-12-20 | 1999-09-17 | Heterocyclic aromatic oxazole compounds and use thereof |
US09/906,764 Abandoned US20020198244A1 (en) | 1994-12-20 | 2001-07-18 | Heterocyclic aromatic oxazole compounds and use thereof |
US09/906,765 Abandoned US20020115701A1 (en) | 1994-12-20 | 2001-07-18 | Heterocyclic aromatic oxazole compounds and use thereof |
US09/906,761 Abandoned US20020143040A1 (en) | 1994-12-20 | 2001-07-18 | Heterocyclic aromatic oxazole compounds and use thereof |
US09/906,762 Abandoned US20020107270A1 (en) | 1994-12-20 | 2001-07-18 | Heterocyclic aromatic oxazole compounds and use thereof |
US09/906,763 Abandoned US20020107271A1 (en) | 1994-12-20 | 2001-07-18 | Heterocyclic aromatic oxazole compounds and use thereof |
US09/906,766 Abandoned US20020198245A1 (en) | 1994-12-20 | 2001-07-18 | Heterocyclic aromatic oxazole compounds and use thereof |
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US08/693,051 Expired - Fee Related US5994381A (en) | 1994-12-20 | 1995-12-18 | Heterocyclic aromatic oxazole compounds and use thereof |
US09/398,997 Expired - Fee Related US6362209B1 (en) | 1994-12-20 | 1999-09-17 | Heterocyclic aromatic oxazole compounds and use thereof |
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US09/906,765 Abandoned US20020115701A1 (en) | 1994-12-20 | 2001-07-18 | Heterocyclic aromatic oxazole compounds and use thereof |
US09/906,761 Abandoned US20020143040A1 (en) | 1994-12-20 | 2001-07-18 | Heterocyclic aromatic oxazole compounds and use thereof |
US09/906,762 Abandoned US20020107270A1 (en) | 1994-12-20 | 2001-07-18 | Heterocyclic aromatic oxazole compounds and use thereof |
US09/906,763 Abandoned US20020107271A1 (en) | 1994-12-20 | 2001-07-18 | Heterocyclic aromatic oxazole compounds and use thereof |
US09/906,766 Abandoned US20020198245A1 (en) | 1994-12-20 | 2001-07-18 | Heterocyclic aromatic oxazole compounds and use thereof |
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US (8) | US5994381A (en) |
EP (1) | EP0745596B1 (en) |
JP (1) | JP2636819B2 (en) |
KR (1) | KR100201581B1 (en) |
CN (1) | CN1146204A (en) |
AT (1) | ATE180253T1 (en) |
AU (1) | AU695045B2 (en) |
BR (1) | BR9506815A (en) |
CA (2) | CA2183645A1 (en) |
CZ (1) | CZ285476B6 (en) |
DE (1) | DE69509753T2 (en) |
DK (1) | DK0745596T3 (en) |
ES (1) | ES2132751T3 (en) |
FI (1) | FI963238A (en) |
GR (1) | GR3030643T3 (en) |
HU (1) | HUT76541A (en) |
MX (1) | MX9603506A (en) |
NO (1) | NO306778B1 (en) |
NZ (1) | NZ297105A (en) |
SK (1) | SK281468B6 (en) |
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- 2001-07-18 US US09/906,765 patent/US20020115701A1/en not_active Abandoned
- 2001-07-18 US US09/906,761 patent/US20020143040A1/en not_active Abandoned
- 2001-07-18 US US09/906,762 patent/US20020107270A1/en not_active Abandoned
- 2001-07-18 US US09/906,763 patent/US20020107271A1/en not_active Abandoned
- 2001-07-18 US US09/906,766 patent/US20020198245A1/en not_active Abandoned
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Date | Code | Title | Description |
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STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |