Substituted (4-sulfonylphenyl)oxazoles and pharmaceutical compositions containing them, as well as intermediates thereof

gvjá-gyizer - ^ - és.d-ímch.vjtk ₍

The present invention relates to a hetero-cyclo aromatic oxazole compound of formula (I): wherein Z is O;

R and R! one of the substituents is a group of formula (a) wherein

R₃ lower alkyl, amino or Low,

R & lt; 1 & gt; alkyl-amino and R₄, R₅, R₆ and R₇ are the same or different and each is independently hydrogen, halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy or amino, provided that R₄, R₅, R₆ and R₇ at least one of the substituents is other than hydrogen, the other substituents being optionally substituted cycloalkyl, optionally substituted heterocyclyl or optionally substituted aryl; and

R₂ denotes a low or unsubstituted haloalkyl group or a pharmaceutically acceptable salt thereof. ^{02 e}-^2e'^juice«^ 'K *^r *- ^ΛΧ°,. A i_THE| THE(_M IcozÍU ^{LKI <r}

THE'^thetefacyclic aromatic oxazole compounds and pharmaceutically acceptable salts thereof have antipyretic, analgesic, anti-inflammatory and, in particular, selective cyclooxygenase-2 (COX-2) activity, and are expected to be used without adverse effects such as anti-inflammatory properties of the gastrointestinal tract.

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FIELD OF THE INVENTION

The present invention relates to novel heterocyclic aromatic oxazole compounds. More particularly, the present invention relates to heterocyclic aromatic oxazole compounds having an antipyretic, analgesic, anti-inflammatory activity, in particular selective cyclooxygenase-2 (COX-2) inhibitory activity, intermediates and pharmaceutical compositions containing them, which are less anti-inflammatory, Thus, they are less likely to cause gastrointestinal disorders.

State of the art

It is well known that arachidonic acid metabolites, prostaglandin E₂, (PGE₂), prostaglandin l₂ (PGI₂) and thromboxane B₂ (TXB₂) play an important role in the prevention of inflammation. Cyclooxygenase is an important enzyme in the metabolism of arachidonic acid. Cyclooxygenase is a synthase enzyme that prostagiandine H₂-t (PGH₂) produces the arachidonic acid prostaglandin G₂(PGG₂) and includes cyclooxygenase-2-1 (COX-1) and cyclooxygenase-2 (COX-2).

The cloning of COX-1 cDNA was carried out in 1988 and its primary structure and its induction by various factors are described in Yokoyama, C. et al., Biochem. Biophys, Slit. Commun

165: 888-894 (1989); Smith, WL, et al., Biochim. Biophys. Acta,

1083: 1-17 (1991); DeWitt, DL: Biochim. Biophys. Acta, 1083: 121-134 (1991)]. On the other hand, the existence of COX-1 isozyme, namely COX-2, was described in 1989 [Holtzman, MJ et al., J. Biol. Chem., 267: 21438-21445 (1992)], the cloning of COX-2 chicken, mouse and human cDNA was described in 1991 by Xie, W. et al., Proc. Natl. Acad. Sci. USA, 88: 2692-2696 (1991), Kujubu, DA, et al., J. Bioi. Chem. 266: 12866-12872 (1991); Hla, T. et al., Proc. Natl. Acad. Sci. USA, 89: 7384-7388 (1991)]. The ester of COX-2 is rapidly induced in its ester and is induced by lipolysaccharides (LPS) and related compounds and has been suggested to be associated with anti-inflammatory and bronchial asthma.

COX-1 is systemically and permanently present in almost all cells and is physiologically related to the production of prostaglandin (PG), which functions for example in the function of the stomach and kidneys. Consequently, if COX-1 is inhibited. the vasodilator PGE₂ and PGI₂ biosynthesis “which protects the digestive mucosa is suppressed and thus the digestive mucosal defense system is degraded resulting in ulceration. Considering the symptom. associated with a decrease in renal blood flow, usually PGE₂ by accelerating its production, kidney blood flow to the body is reduced, thus maintaining the rate of glomerular filtration. However, if such a vasodilator PGE₂ production is reduced due to inhibition of COX-1, renal blood flow is reduced, thus certain side effects such as ischemic acute renal failure may occur.

On the other hand, COX-2 occurs at particulate sites, such as monocytes, synovial cells, granulosa cells, and endothelial cells of intravenous lines, and occurs in the development of topical inflammation. This is to be considered because PG, which is derived from COX-2, is strongly involved in the development of inflammatory and tissue disorders.

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Non-steroidal anti-inflammatory drugs (NSA1D) such as aspirin, mefenamic acid Merckludex 1, 5683, dicofenac, indomethacin, ibuprofen and naproxen are widely used in clinics. The vast majority of NSAID anti-inflammatory drugs selectively inhibit cyclooxygenase (COX) and cause side effects, such as in the digestive tract. Such side effects are caused by the fact. although certain selectivities inhibit COX, both COX-1 and COX-2 are inhibited.

It follows from the foregoing that selective inhibition, without inhibition of COX-1, refers exclusively to COX-2, which is specifically induced at the anti-inflammatory sites, and thus can be used as an anti-inflammatory drug without the development of side effects such as gastrointestinal disorders such as ulcer.

Many anti-inflammatory drugs are known to have selective COX-2 inhibitory activity aimed at reducing side effects such as gastrointestinal disorders.

WO 94/15932, for example, discloses heterocyclic compounds substituted by 5-membered bisaryl groups as COX-2 inhibitors, such as thiophene, furan and pyridine, preferably exemplified by 3- (4-methyl). sulfonylphenyl) -4- (4-fluorophenyl) thiophene can be used. These literature merely disclose that certain 5-membered heterocyclic compounds, such as thiophene, are substituted at the 3- or 4-position with an aryl or heteroaryl group.

Various articles further discuss anti-inflammatory drugs that have cyclooxygenase inhibitory activity by inhibiting prostaglandin synthesis or thromboxane A.₂ inhibition of synthesis.

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Japanese Patent Application Laid-Open No. 141261/1991 includes, for example, pyrazole derivatives such as diethyl I-1- (4-fluorophenyl) -5- [4- (methylsulfonyl) phenyl] ] -pyrazole-3-carboxylate; Japanese Patent Laid-Open No. 183767/1983 describes thiazole derivatives such as 2-methylthio-5-phenyl-4- (3-pyridyl) thiazole; Japanese Unexamined Patent Application No. 58981/1985 discloses thiazole derivatives such as 2-ethyl-4- (4-methoxyphenyl) -5- (3-pyridyl) -1,3-thiazole. These literature mention that these compounds can be used as anti-inflammatory drugs, but do not mention that they have a selective inhibitory effect on COX-2, reducing side effects.

Many literature discloses heterocyclic aromatic compounds.

U.S. Patent 4,632,930 discloses, for example, oxazole compounds such as 5-cyclohexyl-4- (4-methylsulfonylphenyl) - (z, (x-bis (trifluoromethyl) oxazole-2-methanol). The disclosed compounds are effective as antihypertensive agents, but are not useful as anti-inflammatory agents, and the patent does not imply any such effect.

Japanese Patent Application PCT 500054/1984 discloses oxazole derivatives which are substituted at the 4 and 5 position of the oxazole ring with a heteroaryl or carbon ring aryl group and have a carboxyl, ester or amidated carboxyl group at the 2 position. a lower alkylene chain such as ethyl 2- [4-phenyl-5- (3-butyl) oxazol-2-yl] propionate; Japanese Patent Application PCT 500055/1984 discloses imidazole derivatives which are substituted at the 4 or 5 position of the imidazole ring with a heteroaryl and / or carbon ring aryl group and at the 2 position by a formyl or acetylated formyl group. They include an alkylene group 803 / SM, such as 2- [4-phenyl-5- (3-pyridyl) imidazol-2-yl] acetaldehyde dimethyl acetate. These literature teaches that these compounds have dermal antiflogistic or mucosal antiflogistic activity in inflammatory diseases of the female, but do not teach, nor do they suggest that the compounds exhibit selective COX-2 inhibitory activity.

Japanese Patent Application Laid-Open No. 70446/1993 discloses N-thiazolylsulfonamide derivatives such as N- [5-cyclohexyl-4- (4-methoxyphenyl) thiazol-2-yl] trifluoromethane sulfonic acid amide; Japanese Patent Application Laid-Open No. 83372/1990 describes cyclohexylimidazole derivatives such as 4-cyclohexyl-5-phenyl-2-t-butylimidazole. These references provide the cyclohexyl substituent by way of example only, but do not include the assumption that the substitution also applies to phenyl-substituted amino-sulfyl, lower-alkyl-alkylsulfonyl, or lower-carbon-alkylsulfonyl. .

WO 94/27980 discloses oxazole compounds such as 2-phenyl-4-cyclohexyl-5- (4-methylsulfonylphenyl) oxazole as a COX-2 inhibitor. at position 5 or 5 are predominantly characterized by 4-fluorophenyl and 4-methylsulfonylphenyl substituents and it is not believed that specific substituent combinations of the disclosed compounds may occur, as in the present disclosure.

Not only in the field of COX-2 inhibitors, but also in anti-inflammatory drugs, the phenyl substituent on the 5-membered heterocyclic ring backbone is preferred and is conventionally substituted with a monosubstituted phenyl group such as 4-methylsulfonylmethyl and 4-methylsulfonylmethyl. methoxyphenyl, and also disubstituted phenyl, although it has hardly been tried, as disclosed in British Patent No. 1206403.

FIELD OF THE INVENTION

The present inventors have conducted intensive studies to find novel compounds with antipyretic, analgesic and anti-inflammatory activity that are free of side effects and thus do not induce digestive disorders. Surprisingly, it has been found that a compound having a secondary substituent such as halogen, especially fluorine. attached to the phenyl group, thus forming a lower alkylsulfonylphenyl group, a 4-aminosulfonylphenyl group or a 4-lower alkylaminosulfonylphenyl group as a substituent on the oxazole ring, They have COX-2 inhibition.

The present invention relates to the heterocyclic aromatic oxazole compounds as set forth in claims 1-21 and accordingly to the pharmaceutically acceptable salts of the heterocyclic aromatic oxazole compounds, as well as to intermediates and pharmaceutical compositions containing the same.

(1) a heterocyclic aromatic oxazole compound of formula (I) wherein Z is oxygen;

R and R₁ one of the substituents is a group of formula (a) wherein

R₃ is lower alkyl, amino or lower alkylamino, and R₄, R₅, R₆ and R₇ are the same or different and each is independently hydrogen, halo, lower alkyl, lower alkoxy. a trifluoromethyl group, a hydroxyl group or an amino group, provided that when R₄, R₅, R₆ and R₇at least one of the substituents is other than hydrogen, the other substituents being optionally substituted cycloalkyl, optionally substituted heterocyclyl or optionally substituted aryl: and

R₂ represents a lower alkyl group or a halogenated lower alkyl group or a pharmaceutically acceptable salt thereof.

(2) The heterocyclic aromatic oxazole compound according to (1) above wherein R is R (bj where R)₃'is lower alkyl or amino, R₄', R₅', R₆'and R₇at least one of the substituents is halogen or lower alkyl and the other substituents are hydrogen or halogen - or a pharmaceutically acceptable salt thereof.

(3) The heterocyclic aromatic oxazole compound according to (1) above, wherein R 1 in formula (I) is a group of formula (b) wherein R₃"Is methyl or amino, R₅ is fluorine and R₆'Is hydrogen or fluorine and R₂ is a methyl group or a pharmaceutically acceptable salt thereof.

(4) The heterocyclic aromatic oxazole compound according to (1) above, wherein R 1 in formula I is (b'j, wherein R₃", R₅And R₆"Is as defined in point 3: R is optionally substituted C 5-7 cycloalkyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted pyrrolyl, optionally substituted morpholino, desired

622.803 / SM substituted piperazinyl. optionally substituted piperidyl, optionally substituted phenyl, optionally substituted naphthyl or optionally substituted diphenyl, and R₂ is a methyl group or a pharmaceutically acceptable salt thereof.

(5) The heterocyclic aromatic oxazole compound according to (4) above, wherein R₃ is an amino group, or a pharmaceutically acceptable salt thereof.

(6) The heterocyclic aromatic oxazole compound according to (4) above, wherein R is an optionally substituted C 5 -C 7 cycloalkyl group, an optionally substituted phenyl group or an optionally substituted thienyl group, or a pharmaceutically acceptable salt thereof. a pharmaceutically acceptable salt thereof.

(7) The heterocyclic aromatic oxazole compound of (4) above, wherein R is cyclohexyl or 4-fluorophenyl, and R₁ is 4-aminosulfonyl-3-fluorophenyl. 4-aminosulfonyl-3,5-difluorophenyl group. 3-fluoro-4-methylsulfonylphenyl or 3,5-difluoro-4-methylsulfonylphenyl; or a pharmaceutically acceptable salt thereof.

(8) The heterocyclic aromatic oxazole compound of (1) above, which is 4-cyclohexyl-5- (3-fluoro-4-methylsulfonylphenyl) -2-methyl-oxazole, 5- (4-amino) sulfonyl-3-fluorophenyl) -4-cyclohexyl-2-methyl oxazole, 5- (4-aminosulfonyl-3,5-difluorophenyl) -4-cyclohexyl-2-methyl oxazole. 4-cyclohexyl-5- (3,5-difluoro-4-methylsulfonyl-phenyl) -2-methyl-oxazole; and 5- (4-amino-sulfonyl-3-fluoro-phenyl) -4- Any of (4-fluorophenyl) -2-methyloxazole compounds, or a pharmaceutically acceptable salt thereof.

62.803 / SM (9) The oxun compound of formula XIj wherein Rf is a group of formula (c) wherein Rf is₄, R₅. R₆ and R₇ R 1 is as defined in (1) above and R is optionally substituted cycloalkyl or optionally substituted aryl.

(10) The oxime compound according to (9) above, wherein Rf is 3-fluorophenyl or 3,5-difluorenenyl and R is cyclohexyl or 4-fluorophenyl.

(11) A ketone compound of formula (IV). wherein Rf and R 'are as defined in (9) above.

(12) The ketone compound of (11) above, wherein Rf is 3-fluorophenyl or 3,5-difluorophenyl and R 'is cyclohexyl or 4-fluorophenyl -group.

(13) The ketomethylene compound of formula (IV '). wherein R 'is an optionally substituted C 5 -C 7 cycloalkyl group, an optionally substituted phenyl group or an optionally substituted thienyl group, and R f is a group of formula (b) wherein R₃', Rf, Rf, Rf and Rf have the meanings given in (2) above.

(14) The ketomethylene compound of (13) above, wherein R '' is cyclohexyl and Rf 'is 4-aminosulfonyl-3-fluorophenyl, 4-aminosulfonyl -3,5-difluorophenyl, 3-fluoro-4-methylsulfonylphenyl or 3,5-difluoro-4-methylsulfonylphenyl.

(15) The ester compound of formula (V) wherein R, R_1t R₂and Z is as defined in (1) above.

(16) The ester compound according to (15) above, wherein R is cycloalkyl and R is₂ is lower alkyl.

62.803 / SM (17) A compound of general formula (XVIII ') wherein R 1' and R are as defined in (9) above and Z and R₂ has the meaning given in section 1.

(18) The amine compound of (17) above. wherein R 1 is 3-fluorophenyl or 3,5-difluorophenyl. R is cyclohexyl or 4-fluorophenyl;₂ is lower alkyl.

(19) A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a heterocyclic aromatic oxazole compound according to (1) above or a pharmaceutically acceptable salt thereof.

(20) A cyclooxygenase-2 inhibitor comprising a pharmaceutically acceptable carrier and a heterocyclic aromatic oxazole compound according to (1) above, or a pharmaceutically acceptable salt thereof, as active ingredient.

(21) Anti-inflammatory agent. containing a pharmaceutically acceptable diluent and the Heterocyclic Aromatic Oxazole Compound of the above (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

The term "lower alkyl" as used herein, if desired, means a straight chain C 1-4 alkyl such as methyl, ethyl, propyl. isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, preferably methyl.

The term "lower alkylamino" refers to an amino group substituted by a lower alkyl group as described above and, for example, a methylamino group. dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino and tert-62. .803 / SM butylamino. Preferably the lower alkylamino group is a methylamino group and a dimethylamino group.

The term halogen means chlorine, bromine, fluorine and the like, preferably chlorine and fluorine. Fluorine is particularly preferred.

Lower alkoxy optionally includes C1-C4 straight chain alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy. The lower alkoxy group is preferably methoxy.

By cycloalkyl is meant a C3-C8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The cycloalkyl ring preferably contains from 5 to 7 carbon atoms and is thus cyclopentyl, cyclohexyl and cycloheptyl. Particular preference is given to cyclohexyl.

The term heterocyclic group refers to a 5- or 6-membered aromatic heterocyclic ring, which is a saturated heterocyclic ring or a benzene ring fused heterocyclic ring, each ring having from 1 to 3 heteroatoms besides carbon atoms, which heteroatoms are nitrogen , oxygen and sulfur. Heterocyclic groups include, for example, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, morpholino, piperazinyl, piperidyl, pyranyl, thiopyranyl, pyridyl. benzothienyl group, benzofuranyl group, indole group, 4,5,6,7-tetrahydroindole group, 4,5,6,7-tetrahydrobenzene thienyl group and 4,5.6, 7-tetrahydro-benzofuranyl group. Preferably, thienyl is used, furyl is pyrrolyl. the morpholino group. piperazinyl and pipendyl. Particularly preferred is thienyl.

Aryl is, for example, phenyl, naphthyl or diphenyl. Aryl is preferably phenyl.

The term "halogenated lower alkyl" means a lower alkyl substituted by the above halogen, for example fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl. dichloromethyl. trifluoromethyl, trichloromethyl. fluoroethyl, chloroethyl, difluoroethyl, difluoroethyl. dichloroethyl, trifluoroethyl, trichloroethyl, tetrachloroethyl. pentafluoroethyl, fluoropropoyl. Halogenated lower alkyl preferably includes fluoromethyl, chloromethyl, dichloromethyl, difluoromethyl, trichloromethyl and trifluoromethyl.

The term "optionally substituted" refers to a group which may be substituted with 1 or 3 substituents, which may be the same or different. The position of the substituent is not defined but is optional. Examples of lower alkyl include methyl, ethyl, propyl. isopropyl, butyl and tert-butyl; hydroxy: lower alkoxy such as methoxy. ethoxy, propoxy or butoxy-x; halogen such as fluorine, chlorine and bromine; nitro; CN; acyl groups such as formyl, acetyl and propionyl; acyloxy groups such as formyloxy, acetyloxy and propionyloxy; a mercapto group; an alkylthio group such as a methylthio group

62,803 / SM ethylthio, propylthio. the berylthio group. isobutylthio; the amino group; alkylamino groups. Thus the methylamino group. ethylamino, propylamino and butylamino; dialkylamino groups such as dimethylamino. diethylamino, dipropylamino and dibutylamino; carbonyl; alkoxycarbonyl. Thus, the methoxycarbonyl group, the ethoxycarbonyl group and the propoxycarbonyl group are the amides: the irifluoromethyl group; alkylsulfonyl groups such as methylsulfonyl groups and ethanesulfonyl groups; aminosulfonyl: cycloalkyl groups such as cyclopentyl and cyclohexyl; phenyl; acylamides such as acetamide and propionylamide. The hydroxyl group is preferred. lower alkyl, lower alkoxy. the mercapto group, the lower alkylthio group, the halogen atom. trifluoromethyl, alkylcarbonyl, alkoxycarbonyl, and acylamide.

More particularly, the term "optionally substituted aryl" refers to an aryl group which may be substituted by a halogen atom, a hydroxy group, a lower alkyl group, a lower unsaturated alkoxy group, a lower alkylsulfonyl group and an amino sulfonyl group, preferably a phenyl group. Examples of these groups are phenyl, fluorophenyl, methylphenyl, methoxyphenyl, methylsulfonylphenyl and aminosulfonylphenyl, preferably phenyl. and 4-fluorophenyl.

The optionally substituted heterocyclic group means a heterocyclic group which is halogen, hydroxy, lower alkyl. lower alkoxy, lower alkylsulfonyl and aminosulfonyl,

62803 / SM preferably with a thienyl group. furilcsoporrtai. It may be substituted by 5-methylthienyl and 5-chlorothienyl. The term "optionally substituted cycloalkyl" refers to a cycloalkyl group as defined above and preferably represents a cyclohexyl group.

In the heterocyclic aromatic oxazole compounds of the present invention, the substituent R is preferably, for example, cyclohexyl, 4-fluorophenyl and 5-chlorothienyl, particularly preferably cyclohexyl. The R₁is preferably a group (a) wherein R is₃, R₄, R₅,

R₆ and R₇ is as defined above, and particularly preferably R is₃ is an amino group or a methyl group, R₄ es R- is hydrogen and R₅ and R₆at least one of fluorine. Preferred substituents include 4-aminosulfonyl-3-fluorophenyl, 3-fluoro-4-methylsulfonylphenyl, 4-aminosulfonyl-3,5-difluorophenyl and 3,5-difluoro-4-methylsulfonyl-phenyl, particularly preferably 4-aminosulfonyl-3-fluorophenyl. R₂ preferably the substituent is methyl.

The pharmaceutically acceptable salt may be any salt which forms a non-toxic salt with the oxazole derivative of formula (I). Examples of such salts are alkali metal salts such as sodium salt and potassium salt. alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salt, salts of organic bases such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine and the N, N'-dibenzylethylenediamine salt. and salts of amino acids such as lysine salt and arginine salt. If desired, the salts may be in the form of a hydrate.

The compounds of the present invention are expected to be particularly effective for selective inhibition of COX-2 and for their therapeutic use as antipyretic, analgesic and anti-inflammatory, with no adverse effects on the gastrointestinal tract.

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When a compound of formula (I) or a pharmaceutically acceptable salt thereof is used as a pharmaceutical composition, it will generally be in the form of a pharmaceutically acceptable carrier, diluent, diluent, extender, disintegrant, stabilizer, preservative, buffering agent, emulsifier, emulsion, sweeteners, thickeners, flavorings. solubilizers and other additives known per se such as water, vegetable oils, alcohol such as ethanol or benzyl alcohol, polyethylene glycol, glycerol, triacetate gelatin, carbohydrates. Thus, it is mixed with lactose and starch, magnesium stearate, talc, lanolin and petrolatum to form a pharmaceutical composition. Thus, in a manner known per se, such as tablets, pills, powders, granules, suppositories, injections, eye drops, liquids, capsules, wafers, aerosols, elixirs. suspensions, emulsions, syrups and the like, which may be administered orally or parenterally.

Depending on the type and severity of the disease, the compound administered, the route of administration, the age and sex of the patient, and the body weight, the daily dose of the compound of formula I to adults is 0.1-1000 mg, preferably 1-300 mg.

The compounds of the invention may be prepared by the following methods. The present invention is illustrated by the following production methods, but is not limited to these.

In the intermediates and end product of Scheme A, R₂'is lower alkyl or halogenated lower alkyl where R₂'is the same or R₂ other than X, X and X 'are the same or different and each represents

62803 / SM halogen such as bromine. and chlorine. X 1 is halogen or hydroxy, Χ_η 'represents a halogen atom or a hydroxyl group or an alkali metal derivative thereof and R.R._v R₂ and Z is as defined above.

First operation

The compound of formula (IV) may be prepared by reacting a compound of formula (II) with a compound of formula (III) in the presence of a metal such as zinc and magnesium in an inert solvent such as 1,2-dimethoxyethane in 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 is added.

Second operation

The compound of formula (V) is refluxed in the presence of lead tetraacetate in acetic acid solvent or the compound of formula (IV) in the presence of a complex such as manganese tetraacetate in a lower alkane carboxylic acid such as acetic acid and in propionic acid, synthesizing the corresponding R₂Re-COOH. where R₂ is as defined above and the solvent used is benzene.

Third operation

The compound of formula (I) may be prepared by refluxing the compound of formula (V) in the presence of an ammonium salt (e.g. such as lower alkylene carboxylic acid (e.g. formic acid, acetic acid and propionic acid). In this reaction, when R or R 1 is a heterocyclic aromatic group, isomers may be formed where R is reversed at position 4 and Rt at position 5.

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The compound of formula (I) may also be prepared as follows.

4th wherein Xi is hydroxy

In this operation, the use of steps 6 and 7 is preferred provided that R₂ a substituent (e.g., methyl) on another R₂ to a substituent (e.g. R₂such as ethyl).

When X) is hydroxy. the compound of formula (VI) 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 mixture of the above solvents first chilled and then heated.

The compound of formula (VI) may also be prepared according to Step 5.

5th wherein X is halogen or hydroxy

The compound of formula (VI) may be prepared by reacting a compound of formula (IV) in the presence of a halogenating agent such as bromine, chlorine, and N-bromosuccinimide in an organic solvent. Thus, in acetic acid, 1,2-dimethoxyethane, dioxane, ether, tetrahydrofuran, methylene chloride, benzene and toluene, a compound of formula VI ι wherein X 1 is halogen is obtained. Compounds of formula (VI) in which they are hydroxy may be prepared by oxidizing the compound of formula (IV) with an oxidizing agent such as benzene iodoacetate or treating the halogenated compound prepared above with water in an inert solvent such as acetone. In 1,2-dimethoxyethane. dioxane, ether, tetrahydrofuran, benzene and toluene.

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6th operation

The compound of formula (V) is prepared by reaction of the compound of formula (VIi) with the compound of formula (VII '). In particular, the compound of formula (VI) wherein X 1 is hydroxy and the compound of formula (VII') wherein X / is a halogen atom, or a compound of formula (VI) wherein X1 is a halogen atom and a compound of formula (VII ') anoly X7 is a hydroxy group, is reacted in pyridine or an oasis. Thus, in the presence of triethylamine and sodium hydroxide in an organic solvent, such as methylene chloride, chloroform and ethanol, first by cooling and subsequently by heating. If X! is a halogen atom, an alkali metal such as sodium acetate may be used instead of the carboxylic acid of formula VII '. In this case, the base may be used as desired.

7th operation

Formula (I ') can be obtained by treating compound (Vj) as described in Step (3).

If a compound. wherein either R or Rt is 4-aminosulfonyl-3-fluorophenyl. then the desired compound is prepared from the 3-fluoro-4-methylsulfonylphenyl group in a known manner to give the corresponding target compound.

Instead of using the compound of formula (IV) as prepared above, the compound of formula (II) or (III) wherein R or R R is a group of formula (a) wherein R₃, R,. R₃. R_G and R₇ is as defined above, a compound of formula (Hj or (III ') having a substituent of formula (c) and wherein in formula (c) R₄, R₅, R₆ and R₇ as defined above, may be used as starting material and thus proceed to the compound of formula (IVj) according to Step 10.

62.803 / SM is then converted to the aminosulfonyl or methylsulfonyl derivative according to Step 15 to obtain the compound of formula IV. Alternatively, starting from the compound (II j or III j), the unlabeled oxazole compound (XIII) can be obtained according to steps 1-7 to give the final compound (I) or (I). The compound of formula (XIII) is optionally selected from the group consisting of (15). Sulfonylation as described in step (b) above gives the product of formula (I) or (I ').

If it is desired to produce a compound wherein R or R 1 is phenyl substituted with alkylsulfonyl or amino sulfonyl, the compound of formula (X). anol up to R_K, up to R₉ is methoxysulfonylphenyl, subject to Scheme B, Steps 8 and 9, to afford the compound of Formula IV. In Scheme B, for the compounds involved in Steps 8 and 9, R_s or R 'is a methoxysulfonylphenyl group of formula (a') wherein R₄, R₅, R₆ and R₇ the other substituents as defined above are optionally substituted cycloalkyl, optionally substituted heterocyclic or optionally substituted aryl and R, R_b X and X 'are as defined above.

8th operation

Compound (X) can be prepared in the same manner as in Step 1 using (VIII) and (IX).

9th operation

If R and R₁ at least one of the substituents at the 4-position substituted by an amino sulfonyl or amino sulfonyl group, heating a compound of formula (IV) with pyridine, or a compound of formula (X) sodium iodide, potassium; by refluxing iodide, lithium iodide and ha62.303 / SM-like compounds in an organic solvent such as acetone and tetrahydrofuran, then reacting the compound thus obtained with thionyl chloride or oxalyl chloride under heating. The resulting products are then either aminated or alkylated or alkylated by known methods. In particular, the amination or alkyl amination is carried out by reacting the resulting product with aqueous ammonia or alkylamine or a base such as sodium acetate and an ammonium salt such as alkylamine hydrochloride in an organic solvent such as tetrahydrofuran, ether. , toluene, benzene, methylene chloride and dioxane, first by cooling and then heating at the end of the reaction. Alkylation is described in J. Org. Chem. 56; 4974-4976 (1991).

The compound of formula (I) is described in Scheme 10-15. can also be prepared according to the operation.

In this process, the simnyl group is finally introduced in step 15. 10-15. R 'and R' are phenyl or a radical of formula (c) wherein R₄, R₅, R₆ and R₇ is as defined above and the other substituents represent one of the substituents R and R, cycloalkyl, which is optionally substituted. thus, a lower alkyl group, a heterocyclic group such as a thiol group and a furyl group optionally substituted by a lower alkyl group or a halogen atom, or an aryl group optionally substituted by a halogen atom, a lower alkyl group and a lower alkyl group and R, R_b X, X 'and Z are as defined above

62 803 / SM

10th operation

The compound of formula (IV ') is prepared as described in step 1 by reacting the compound of formula (II') and the compound of formula (III ') in a solvent in the presence of a metal such as copper, zinc and magnesium, such as 2-dimethoxyethane, dioxane, ether, mtranidrofuran. methylene chloride, benzene and toluene at room temperature. In this case, a catalyst such as palladium) 0) and copper (I) iodide complex is added to the reaction mixture.

11th operation

The compound (XI) is prepared in a monone by refluxing the compound (IV) and hydroxylamine 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 the like. tetrahydrofuran, water or a mixture of these solvents.

12th operation

The compound of formula (XII) is prepared by reacting a compound of formula (II) 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. started with cooling and finished with heating.

13th operation

The compound of formula (XIII) is prepared by refluxing the compound of formula (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 are added to the reaction mixture.

62 303 / SM

14th operation

In this step, compound (XI) is converted to compound (XIII) and compound (XIII) is synthesized from compound (XI) and a carboxylic acid chloride such as acetyl chloride in Indian J. Chem., 20B: 322 -323 (1981). If R₂ is a methyl group, the compound of formula (XIII) is prepared by reacting the compound of formula (XI) with acetic anhydride by heating in acetic acid.

15th operation

The compound of formula (I) is prepared by reaction of a compound of formula (XIII) with a chlorosulfonylating agent such as chlorosulfonic acid in or without an organic solvent, such as chloroform and methylene chloride, and the resulting product is aminated, alkylated or alkylated. by known methods. The amination and alkyl amination in step 15 are specifically in aqueous ammonia, alkylamine or a base such as sodium acetate and ammonium salt. Thus, the reaction is carried out in the presence of alkylamine hydrochloride in an organic solvent such as tetrahydrofuran, ether, toluene, benzene, methylene chloride and dioxane, starting with cooling and heating. When alkylsulfonylation is performed, J. Org. Chem., 56: 4974-4976 (1991).

In the above description, alkylsulfomylation or aminosulfonylation was studied in the final step 15. It is possible that when using the compounds of formula (II) and (III), the compound of formula (II) is used¹) and (III) to prepare the compound of formula (IV) and then proceeding from step 11 to step 14, whereby the oxazole compound of formula (I) can be prepared. no action is required.

62,803 / SM • ·

Compound (XIII) can also be prepared in Scheme D in step 15, wherein the compound is R ', R /, R₂ and Z is as defined above.

16th operation

The compound of formula (V) may be prepared as described in Step 2 by reacting the compound of formula (IV) with lead tetraacetate in an organic solvent or by heating the compound of formula (IV) with a low carbon atom. alkanecarboxylic acids such as acetic acid and propionic acid provide the corresponding R₂COOH, where R₂ is as defined above, benzoic acid optionally dissolved in benzene, to carry out the reaction.

17th operation

The compound of formula (XIII) is prepared according to the method of art. In a similar manner, the compound of formula (V'j) is prepared in the presence of an ammonium salt such as a lower alkanecarboxylic acid ammonium salt (e.g., ammonium acetate and ammonium formate) and an inorganic ammonium salt (e.g., ammonium carbonate) carboxylic acid is refluxed in an acidic solvent such as formic acid, acetic acid and propionic acid. In this reaction, when R 'or R / is an aromatic heterocyclic group, isomers are obtained in which R' at position 4 and R / position 5 are interchangeable.

Compounds of formula (I) are prepared according to Scheme 18, Scheme 18-28. can also be prepared by the same procedure. In the compounds of Scheme E, X₂ is halogen; and R.R.R., R ', R'₂ and Z is as defined above.

62.803 / SM • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

18th operation

The compound of formula (XV) may be prepared by reacting a compound of formula (XIV) with a chlorocarbonate such as ethyl chlorocarbonate in an inert solvent such as tetrahydrofuran, toluene and ethyl acetate in the presence of a base such as triethylamine. heating the compound of formula (XIV) in acetic anhydride.

19th operation

Compound (XVII) is prepared 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. a magnesium salt such as magnesium chloride and a base such as triethylamine, pyridine and potassium carbonate. Compound (XVII) is prepared according to Chem. 102; 883-898 (1969) may also be synthesized.

20th operation

Compound (XVIII) is prepared by treating Compound (XVII) with an acid such as 1N-4N hydrochloric acid, oxalic acid and dilute sulfuric acid in an inted solvent such as tetrahydrofuran, dioxane, methylene chloride, and toluene. compound is heated in the presence of pyridine and acetic acid.

21st operation

The compound of formula (I) is prepared by reacting a compound of formula (XVIII) with a chlorosulfonating agent such as chlorosulfonic acid in an organic solvent such as chloroform and methylene chloride or performing the reaction in the absence of a solvent. The resulting product is then treated with aqueous ammonia or alkylamine in an organic solvent such as tetrahydrofuran.

62,803 / SM ······ ·······························································eded in ether, toluene, methylene chloride, and dioxane, or with an ammonium salt such as alkylamine. hydrochloride with a base such as sodium acetate, pyridine and sodium hydroxide.

Compounds of formula (I) from compounds of formula (XVI11) are shown in Schemes 22 and 23.

can also be produced according to operations.

22nd operation

Compound (XIII) may be prepared by reading that compound (XVIII) with an inorganic acid. Thus, it is reacted with concentrated sulfuric acid and polyphosphoric acid in acetic anhydride or without solvent at room temperature.

23rd operation

The compound of formula (I) may also be prepared by reaction of compound of formula (XIII) according to Step 15 above.

In Steps 22 and 23 above, alkylsulfonylation or aminosulfonylation is exemplified. Alternatively, a compound which includes R and R in place of R 'and R 1' may be substituted as described in Examples 18-20. The reaction is carried out according to the procedure of Steps 22 to 24, which is followed by Step 22 to obtain an oxazole of formula (I). In this case, step 23 of the operation is not required.

The compound of formula (I) thus obtained is isolated and purified in a manner known per se, for isolation and purification by evaporation under reduced pressure. solvent extraction, crystalline precipitation, recrystallization and chromatography.

The invention is illustrated by the following Examples and Experimental Examples, which are not to be construed as limiting.

62.803 / SM • · · · • · ·

First example

Preparation of 5- (2-chloro-4-methylsulfonyl-phenyl) -4-cyclohexyl-2-methyl-oxazole (Formula I); R = cyclohexyl. R 1 = 2-chloro-4-methylsulfonylphenyl, R_z'= methyl group. Z = oxygen

Step 1) Preparation of 2-chloro-4-methylsulfonylbenzylcyclohexyl ketone (Formula V); R is cyclohexyl. R 1 - 2-chloro-4-methylsulfonyl 1

To a solution of 1.29 g of tetrakis (triphenylphosphine) palladium and 2.19 g of zinc powder in 10 ml of 1,2-dimethoxyethane, 3.60 g of cyclohexanecarbonyl chloride in 10 ml of

A solution of 1,2-dimethoxyethane was added at room temperature under nitrogen. Then, a solution of 2-chloro-4-methylsulfonylmethyl bromide (9.40 g) in 1,2-dimethoxyethane (20 ml) was added dropwise with stirring at room temperature. The reaction mixture was stirred for 3 hours at room temperature. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. Ethyl acetate (200 mL) was added to the residue and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated salt were added 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.

Step 5) Preparation of 2-Bromo-2- (2-chloro-4-methylsulfonyl-phenyl) -1-cyclohexyl-1-ethanone j (Formula VI: R = cyclohexyl) R 1 = 2-chloro -4-methylsulfonylphenyl, Χ_Ί = my bromine!

A solution of 1.73 g of bromine in 20 ml of benzene is added dropwise to a solution of 3.40 g of the compound prepared in Step 1 above in 20 ml of benzene, with ice-cooling and stirring, and the mixture is stirred for 1 hour. The solution was poured into water and extracted with ethyl acetate. The organic phase was saturated

62803 / SM · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · washed with saturated brine and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure afforded 4.20 g of the title compound.

Step 6: Preparation of 1- (2-chloro-4-methylsulfonylphenyl) -2-cyclohexyl-2-oxoethyl acetate f (V '): R - cyclonexyl. R₅ = 2-chloro-4-methylsulfonylphenyl, R ' - methyl. Z - oxygen

To the compound (4.20 g) obtained in Step 5, 1.06 g of sodium acetate and 40 ml of ethyl alcohol are added. After refluxing for 4 hours, the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed with water and brine and dried over anhydrous sodium sulfate. Removal of the solvent gave 3.85 g of crude product.

Step 7: Preparation of 5- (2-chloro-4-methylsulfonyl-phenyl) -4-cyclohexyl-2-methyl-oxazole f (1 '): R = cyclohexyl, R 1 = 2-chloro 4-methylsulfonyl-phenyl, RT - methyl. Z = oxygen]

A solution of 3.85 g of the compound obtained in Step 6) and 2.08 g of ammonium acetate in 40 ml of acetic acid is refluxed for 5 hours. The solvent was removed under reduced pressure and ethyl acetate was added to the residue. The mixture was washed with water, and the wash was repeated with saturated aqueous sodium bicarbonate solution and brine, and then dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave 1.95 g of the title compound. Yield 53%.

62 803 / SM

Second example

Preparation of 5- (4-Aminosulfonyl-3-fluoro-phenyl) -4-cyclohexyl-2-methyl-oxazole (Formula I); R = cyclohexyl. R 1 = 4-aminosulfonyl-3-fluoro,

R? = methyl. Z = oxygen

Step 10: Preparation of cyclohexyl-3-fluorobenzyl ketone Formula F (IV '):

R '= cyclohexyl, R' -3-fluorophenyl

To a solution of 2.00 g of tetrakis (triphenylphosphine) palladium and 17.98 g of zinc powder in 50 ml of 1,2-dimethoxyethane are dissolved in 20.00 g of cyclohexanecarbonyl chloride in 50 ml of 1,2-dimethoxyethane. A solution of 26.00 g of 3-fluorobenzyl bromide in 100 ml of 1,2-dimethoxyethane was added dropwise dropwise with ice-cooling and stirring. The mixture was further stirred for 30 minutes under ice-cooling, and the mixture was continued for 2 hours at room temperature. The insoluble material was collected by filtration and the filtrate was concentrated under reduced pressure. Ethyl acetate (200 µl) was added to the residue and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give 29.20 g of crude oil.

Step 16: Preparation of 2-cyclohexyl-1- (3-fluorophenyl) -2-oxoethyl acetate f Formula V: R '= cyclohexyl. R 3 -fluorophenyl, R 6 ' = methyl. Z = oxygen]

To a solution of 29.20 g of the compound prepared in Step 10 in 300 ml of acetic acid is added 75.00 g of lead tetraacetate. The mixture was refluxed for 1.5 hours and the solvent removed under reduced pressure. Ethyl acetate was added to the residue. The mixture was then washed with water, saturated aqueous sodium bicarbonate, and brine, and then dried over anhydrous sodium 62.803 / SM. The solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column (developing solvent: hexane: ethyl acetate = 9: 1). This gave 18.30 g of the title compound as an oil. Yield 50%.

Step 17) Preparation of 4-cyclohexyl-5- (3-fluorophenyl) -2-methyloxazole (Formula XIII); R '- cyclohexyl. R7 = 3-fluorophenyl; = methyl, Z = oxygen)

A solution of 18.00 g of the compound obtained in Step 16) and 15.00 g of ammonium acetate in 100 ml of acetic acid is refluxed for 5 hours and then the solvent is removed under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed with water, saturated aqueous sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave 17.20 g of crude oil.

Step 15: Preparation of 5- (4-Aminosulfonyl-3-fluoro-phenyl) -4-cyclohexyl-2-methyl-oxazole f; R is cyclohexyl. R₁ - 4-aminosulfonyl-3-fluorophenyl, R_? = methyl. Z = oxygen]

A solution of 17.00 g of the compound obtained in Step 17 in 80 ml of chloroform is added dropwise to 27 ml of chlorosulfonic acid under ice-cooling and stirring, and the mixture is heated to 100 ° C for 3 hours. The reaction mixture was then cooled to room temperature and added dropwise to 300 ml of ice water with stirring. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave 20.31 g of crude product.

10 g of the compound obtained are dissolved in 40 ml of chloroform and added to the solution

28% aqueous ammonia was added while stirring at room temperature,

62.803 / SM and then stirred at room temperature for an additional 1 hour. The solvent was removed under reduced pressure and ethyl acetate was added to the residue. The mixture was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was removed and the residue was separated and purified by silica gel column chromatography (developing solvent; dichloromethane: ethyl acetate = 6: 1). This gave 5.74 g of the title compound. Yield 61%.

Example 2 '

Variant for the preparation of the compound of formula I according to Example 2; R = cyclohexyl. R 1 = 4-aminosulfonyl-3-fluorophenyl,

R₇ = methyl, Z = oxygen

Step 11: Preparation of Cyclohexyl-3-Fluorobenzyl-Ketone-Oxime f (X1);

R '= cyclohexyl, R' = 3-fluorophenyl

353 To a solution of the compound prepared in a similar manner to Example 2 (10) (g) in ethyl alcohol (1300 ml) was added hydroxylamine hydrochloride (123 g) and sodium acetate (158 g). The mixture was refluxed for 2 hours and the solvent removed under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed with water, saturated aqueous sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the crude product was recrystallized from n-heptane to give 160 g of the title compound. Yield 42%.

Step 14: Preparation of 4-cyclohexyl-5- (3-fluorophenyl) -2-methylloxazole

Γ (ΧΙΙΙ); R '= cyclohexyl, R 2 = 3-fluorophenyl, R'; methyl group, Z = oxygen), mg of acetic anhydride was added dropwise to a solution of 158 g of compound (11) in 900 ml of acetic acid. The mixture was stirred at room temperature 62.803 / SM and refluxed for 7 hours. The solvent was removed under reduced pressure and n-heptane was added to the residue. The mixture was washed with water, saturated aqueous sodium bicarbonate solution, saturated brine, and acetonitrile. Removal of the solvent under reduced pressure gave 119 g of the title compound as an oil.

The resulting 119 g / acyl compound was then reacted in a similar manner to Example 2 (15) to give the compound of formula (I) according to Example 2, wherein R = cyclohexyl, R 1 = 4-aminosulfonyl-3. -fluoro, R₂ = methyl, Z = oxygen.

Third example

Preparation of 4-cyclohexyl-5- (3-fluoro-4-methylsulfonyl-phenyl) -2-methyl-oxazole f (1); R = cyclohexyl. R 1 = 3-fluoro-4-methylsulfonyl-phenyl, R_? = methyl, Z = oxygen]

Step 15) Preparation of 4-Cyclohexyl-5- (3-fluoro-4-methylsulfonyl-phenyl) -2-methyl-oxazole Formula (I); R is cyclohexyl. R₁ - 3-fluoro-4-methylsulfonyl-phenyl, R? = methyl. Z = oxygen]

17.00 g of a solution of the compound obtained in Example 2, Step 17) in 80 ml of chloroform are treated dropwise with 27 ml of chlorosulfonic acid under stirring and ice-cooling. The reaction mixture was stirred at 100 ° C for 3 hours. The mixture was then cooled to room temperature and 300 ml of ice water was added dropwise with stirring. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave 20.31 g of crude product.

To the resulting compound (3.66 g) was added water (25 mL). Sodium sulfite (1.42 g) and sodium bicarbonate (1.89 g) were then added sequentially at room temperature with stirring. The mixture was heated to 70 ° C for 2 hours

Stir for 62803 / SM hours. A mixture of ethanol (25 ml) and methyl iodide (2.20 g) was added at 100 ° C, and the mixture was stirred for 2 hours. The reaction mixture was then 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 removed under reduced pressure and the residue was separated and purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 2: 1). Hv^!,% οη gives 0.82 g of the title compound. Yield 24%.

4-6. examples

4-6. Examples 1-3. example or below

7th was synthesized according to example.

1-6. The structure and properties of the exemplary compound are shown in Table 1 below. In the table, Me is methyl.

62.803 / SM + TO CO -rt &lt;LG LL CO c

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<td>CO</td><td>CM</td><td>cn</td><td>co</td><td>CO</td><td>T</td>

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<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>N X X</td>

<td></td><td></td><td></td><td></td><td></td><td> __</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>V</td>

<td></td><td></td><td></td><td></td><td></td><td>N</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>r-</td>

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<td></td><td></td><td></td><td></td><td></td><td></td><td>N</td><td>IM</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>N</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>cn</td>

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<td>She</td><td></td><td></td><td>ω</td><td>· £&gt; σΓ</td><td>X</td><td>X</td><td>X</td><td>She</td><td>X</td><td>X</td><td></td><td>ω</td><td>c</td><td>ω</td><td> '—'</td><td>X</td><td>She</td><td> -—-</td><td></td><td>c</td><td>ω</td><td></td><td>X</td><td>X</td>

<td>θ</td><td>Ό *</td><td>CN</td><td></td><td>co</td><td> -</td><td></td><td> -</td><td>She</td><td>co</td><td>Γ--</td><td></td><td></td><td></td><td> -</td><td>CT</td><td> -</td><td>She</td><td>r-</td><td>SHOOT</td><td> -</td><td> -</td><td>She</td><td> -</td><td> -</td>

<td>co</td><td>X</td><td>σ&gt;</td><td>X</td><td>co X</td><td>X</td><td>X</td><td>X</td><td>co</td><td> —'</td><td> —</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>co</td><td>X</td><td>CT</td><td>X</td><td>X</td><td> 00</td><td>X</td><td>X</td>

<td>CO</td><td></td><td></td><td>co</td><td>CM ™</td><td></td><td>X,</td><td>ΣΞ</td><td></td><td>SHOOT</td><td>cn</td><td>co</td><td>co</td><td>X,</td><td>CM</td><td>X</td><td>X</td><td>CO</td><td>v- "</td><td>X</td><td>co</td><td>co</td><td>cm '</td><td>CM</td><td>CM</td>

<td>SHE</td><td>CO</td><td>CN</td><td> ^_</td><td>CM CO</td><td>CO</td><td>CT</td><td>co</td><td>Ü</td><td>χ</td><td>X</td><td>She</td><td>co</td><td>She</td><td>CM</td><td>co</td><td>SHOOT</td><td>SHE</td><td>co</td><td>r-</td><td> ·&lt;—</td><td> &lt;—</td><td>CO</td><td>S</td><td>co</td>

<td>Q</td><td>CM</td><td>CO</td><td>SHOOT</td><td>r- -r-</td><td>SHOOT</td><td>CO</td><td>v-</td><td> 0</td><td>co</td><td>r-</td><td>SHOOT</td><td>X</td><td>co</td><td>CT</td><td>X</td><td>She</td><td> 0</td><td>CM</td><td>SHOOT</td><td>SHOOT</td><td>SHOOT</td><td>co</td><td>CO</td><td></td>

<td>SHE</td><td>X</td><td>T "</td><td>CN</td><td>CN UO</td><td>X</td><td>X</td><td>CO</td><td>SHE</td><td>T</td><td>X</td><td>dl</td><td>CM</td><td>CM</td><td>X</td><td>X</td><td>co</td><td>SHE</td><td>X</td><td>X</td><td>X</td><td>cm '</td><td>cm '</td><td>Shoot'</td><td>X</td>

o&gt; ·, o

CN

SHE

SHE

CN

-ro ω

'U.

LZ i_

-CD

S

CD «X)

CO

CO _L o

&gt;&gt;

• ra ω

X

1_

-CD

X ω

JD&gt;.

σ) &lt;υ&gt;

CO

C _L:

E ~ ro £

03 XN d?

SHE

N

CO

X o

CD £

o ro x C _! _ &lt;Φ ŐT -L _ o _Z ΰ o ω n P ra TX CM O

LO X

I - I o co

CM c

£ co

CX α) ω o

N co

X o

sci 1 0

L / C = γ =

CO: X

X o

í _z: 'o

7th example

Preparation of 5- (4-Aminosulfonyl-3-fluoro-phenyl) -4- (4-fluoro-phenyl) -2-methyl-oxazole Formula (I); R = 4-fluorophenyl, R₁ = 4-aminosulfonyl-3-fluorophenyl, R? - methyl group, Z = oxygen]

A solution of 3 3 5-β-3-fluorophenyl) -4- (4-fluorophenyl) -2-methyloxazole prepared by the above method and 1.6 ml of chlorosulfonic acid in 3 ml of chloroform was added.

Stir 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, then brine, dried over anhydrous magnesium sulfate and, after evaporation, 5- (4-chlorosulfonyl-3-fluorophenyl) -4- (4-fluorophenyl) - 1.06 g. The crude 2-methyl-oxazole is obtained.

To a solution of the crude mass (1.06 g) in tetrahydrofuran (6 mL) was added 28% aqueous ammonia (0.60 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was evaporated, ethyl acetate added, washed with water and brine. The ethyl acetate solution was dried over anhydrous magnesium sulfate and evaporated to give 981 mg of crude product. The crude product thus obtained was recrystallized from ethyl alcohol to give 629 mg of the title compound. Yield 44%. The structure and properties of the resulting compound are shown in Table 3.

<td></td><td>\ Ο ό-</td><td>° cm</td><td>Ű³SHE '</td><td></td><td>SHE '</td><td>&gt; p SHE '</td><td>·, Σ 6 '·</td>

<td>ο</td><td></td><td>CO</td><td>lake</td><td></td><td>SHE</td><td></td><td>σ&gt;</td>

<td></td><td></td><td>CO</td><td>lake</td><td></td><td></td><td>r ^ -</td><td>tendon</td>

<td>Ε</td><td>'ΤΤ</td><td>CO</td><td></td><td></td><td></td><td>CO</td><td>r-</td>

<td>'CU</td><td>SHOOT</td><td></td><td></td><td>-a</td><td>m</td><td></td><td></td>

<td>Ν ω</td><td>ο</td><td>X</td><td>z</td><td>CC</td><td>She</td><td>X</td><td>X</td>

+ 70ω &lt;m υ_ CO

Third table _COC7) COCMOCM ^ .S ^ cm co to in m co &lt;- r cc (Ί -

N

X co co in

N

X

CO

IM

XN ο X τ- &lt;

<td></td><td></td><td></td><td>CO</td><td></td><td></td><td>CM</td><td>M</td>

<td></td><td></td><td></td><td></td><td>tendon</td><td>co</td><td>CM</td><td></td>

<td></td><td></td><td></td><td></td><td>V "</td><td>r-</td><td>II</td><td>r-</td>

<td></td><td></td><td></td><td>CM</td><td>II</td><td>II</td><td> —)</td><td></td>

<td>N</td><td></td><td></td><td>II</td><td> —&gt;</td><td>-J</td><td></td><td>r ·</td>

<td>X</td><td></td><td></td><td>^—)</td><td></td><td></td><td>tj</td><td> 11 ¹</td>

<td></td><td> ,_,</td><td></td><td></td><td> 70</td><td>Ό</td><td>Ό</td><td></td>

<td>She</td><td>lake</td><td>lake</td><td>you</td><td>u</td><td>Ό</td><td>Ό</td><td></td>

<td>She CO</td><td>x '</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td><td>X</td>

<td></td><td>CO</td><td>CM</td><td>CM</td><td>T ~</td><td>'C</td><td>CM</td><td>T</td>

<td>· _L *</td><td> •---'</td><td> -·—-</td><td> •—</td><td> -—'</td><td> '—'</td><td> —·</td><td> '—-</td>

<td>She</td><td>co</td><td>r-</td><td></td><td>lake</td><td> &gt;-</td><td>CO</td><td>co</td>

<td colspan="2">Q LO</td><td>She</td><td> ·&lt;—</td><td>CO</td><td></td><td>tendon</td><td>CO</td>

<td>She</td><td>CM</td><td>SHOOT</td><td>r-</td><td></td><td></td><td>r-</td><td></td>

o _ &gt;&gt;

S ω

_φ σ&gt;

φ&gt;

o co C _! _ uo

NC ^ ín q = ω 8 ω χ Ο

CM =&gt;

- 37 Example 2

A process for preparing the compound of general formula (ii) of Example 2; R is cyclohexyl. R1 is 4-aminosulfonyl-3-fluorophenyl.

R? = methyl, Z = oxygen

Step 18: Preparation of 4-cyclohexyl-2-methyl-5-oxazolone (Formula XV);

R '= cyclohexyl. Ro = methyl group

8.39 mL of triethylamine was added to hXYL DL-N-acetyl-2-cyclohexylglycine - available from Collect. Czeck. Chem. Commun. 31, 4563 (1996), prepared according to the method described in a suspension of α-aminophenylacetic acid in 50 ml of ethyl acetate. Ethyl chlorocarbonate (5.28 mL) was added dropwise under ice-cooling. After stirring for 1 hour under ice-cooling, ethyl acetate (150 mL) was added and the mixture was washed with water and brine. The ethyl acetate solution was concentrated under reduced pressure to give the title compound as an oil (9.86 g).

Step 19: Preparation of 4-cyclohexyl-4- (3-fluorobenzoyl) -2-methyl-5-oxazolone (Formula XVII: R '= cyclohexyl). RJ = 3-fluorophenyl,

R_? = methyl. Z = oxygen

A solution of 9.86 g of the compound prepared in Step 18 in 15 ml of tetrahydrofuran is added to a suspension of 3.56 g of magnesium chloride in 20 ml of tetrahydrofuran. To the reaction mixture was added triethylamine (9.49 mL) with stirring and ice-cooling, followed by stirring for 15 minutes. 4.55 ml of 3-fluorobenzoyl chloride are then added dropwise and stirring is continued under ice-cooling for 1 hour. The mixture was then diluted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. 11.69 g of the title compound are obtained in the form of an oil.

• ·

Step 20) Preparation of 2-N-acetylamino-2-cyclohexyl-3'-fluoroacetophenone r (XVIII); R '= cyclohexyl, R' = 3-fluorophenyl, R '_? methyl group, Z = oxygen]

To a solution of 527 mg of the compound prepared in Step 19 in 3.5 ml of tetrahydrofuran is added 0.35 ml of 1N hydrochloric acid. The reaction mixture was stirred at room temperature for 1 hour, ethyl acetate was added and the mixture was washed with water, saturated aqueous sodium bicarbonate solution and then brine. The organic layer was dried over anhydrous sodium sulfate and the solvent removed under reduced pressure to give 4.04 mg of the title compound as a solid. Yield 84%. The solid was recrystallized from n-heptane to give the product as white crystals, m.p. 116-117 ° C.

Step 21: Preparation of 5- (4-Aminosulfonyl-3-fluorophenyl) -4-cyclohexyl-2-methyl-oxazole [Formula I: R = Cyclohexyl, R 1 = 4-Aminosulfonyl] 3-fluorophenyl, R? - methyl, Z - oxygen

Chlorosulfonic acid (0.34 mL) was added to a solution of 200 mg (20 mg) in chloroform (2 mL) and the mixture was stirred under ice-cooling and refluxed for 5 hours. The reaction mixture was then diluted with chloroform and poured into ice water. The organic layer was separated, washed with water, brine and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave 181 mg of crude product.

To a solution of the above product (169 mg) in tetrahydrofuran (2 ml) was added 0.1 ml of 28% aqueous ammonia with stirring, and after the addition was complete, the mixture was stirred for 30 minutes. The solvent was removed under reduced pressure and ethyl acetate was added to the residue, and the mixture was washed with water and brine and then

62 803 / SM

Dry over 39. anhydrous sodium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography (developing solvent; dichloromethane: ethyl acetate = 6: 1). 126 mg of the title compound are obtained. Yield 55%.

2 "'example

Process variant for the preparation of the compound of formula I according to Example 2; R = cyclohexyl, R = 4-aminosulfonyl-3-fluorophenyl. R_z - methyl, Z = oxygen

Step 22: Preparation of 4-cyclohexyl-5- (3-fluorophenyl) -2-methyloxazole (Formula XVIII); R '= cyclohexyl, R' -3-fluorophenyl.

R_? = methyl group

To a suspension of 141 mg of the compound obtained in Step 20 above in 2 ml of acetic anhydride, 30 µl of conc. sulfuric acid was added and the mixture was stirred at 100 ° C for 30 minutes. The reaction mixture is then sued under reduced pressure, an aqueous potassium carbonate solution is added to the residue and the mixture is extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under reduced pressure gave 135 mg of the title compound as an oil.

Step 23: Preparation of 5- (4-aminosulfonyl-3-fluorophenyl) -4-cyclohexyl-2-methyl-oxazole (Formula I); R = cyclohexyl. R 4 = 4-aminosulfonyl-3-fluorophenyl, R 6 =. = methyl. Z - Oxygen By following the procedure of Example 2, Step 15, reacting the compound of Step 22, above, gives the compound of Formula I of Example 2, wherein R is cyclohexyl, R is 4-aminosulfonyl. 3-fluorophenyl, R₂ is methyl, Z is oxygen.

62 803 / SM

First pharmacological example (inhibition of cyclooxygenase)

Enzyme activity is a ¹⁴C arahidonic acid prostaglandin H₂ (PGH₂) and its degradation products as a percentage of conversion. Proceed by adding 20 µl of test sample, 20 µg of true enzyme solution and 10 µl of distilled water to 100 mH Tris-HCl buffer, pH 8. 140 µl, containing 2 pmol of hematin and 5 pmol of triprophane. and then reincubated at 24 ° C for 5 minutes. The mixture was then treated with 10 µl^,4A solution of arachidonic acid C was added and the reaction was allowed to proceed at 24 ° C, followed by addition of 40 µl of a mixture of ethyl ether / methanol / 1M nitric acid 30/4/1 in an ice bath and lowering to -20 ° C. for the purpose. The reaction mixture is then centrifuged for 5 minutes at 3,000 rpm and the ether layer thus obtained is placed on a thin plate and developed with ethyl ether / methanol / acetic acid 90/2 / 0.1 to determine the% conversion of (A). v orakidonik from acid PHG₂and degradation products. Conversion% (B) was also determined without the test sample, calculated from the% inhibition calculated using the equation below, IC₅₀ concentration for 50% inhibition of the test sample was also determined.

Inhibition (%) = gl-A / B) X 100

Human platelet enzyme was used as the cyclooxygenase-1 enzyme solution and yeast-expressed enzyme was used as the cyclooxygenase-2 enzyme solution in the cDNA human cyclooxygenase2 (a kit used by Invitrogen Corp.). Control 1 was 5- (4-aminosulfonylphenyl) -4-cyclohexylmethyl-oxazole, which was the subject of a patent application.

62.803 / SM was previously claimed and a known analogue of 5- (4-aminosulfonylphenyl) -4- (4-fluorophenyl) -2-methyloxazole was used as control 2.

The results are shown in Table 4.

Comparison of control compound 1 with the compound of Example 2 and control compound 2 with the compound of example 7 demonstrates that the activity on C0X-1 is greatly reduced while the activity on C0X-2 is maintained, especially when a fluorine atom is introduced into the claimed compound.

62 803 / SM

4th spreadsheet

First experimental example (cyclooxygenase inhibition)

<td rowspan="2">Example</td><td rowspan="2">Formula</td><td colspan="2">IC₅₀ (ΜΜ)</td><td rowspan="2">COX-1 / COX-2</td>

<td>COX-2</td><td>COX-1</td>

<td> 2</td><td>5- (4-amino- sulfonyl-3-fluoro- phenyl (4-cyclohexyl -2-methyl-oxazole</td><td>'4 Ω7 , / /</td><td> 400</td><td> &gt;1,428</td>

<td> 3</td><td>4-cyclohexyl-5- (3 fluoro-4-methyl- sulfonyl-phenyl) -2- methyl-oxazole</td><td> 0.3</td><td> 400</td><td> &gt;333</td>

<td> 4</td><td>5- (4-amino- sulfonyl-3-chloro- phenyl) -4-cyclohexyl -2-methyl-oxazole</td><td>I0</td><td></td><td></td>

<td> 5</td><td>5- (4-amino- sulfonyl-3-methyl- phenyl) -4-cyclohexyl -2-methyl-oxazole</td><td>I 0</td><td></td><td></td>

<td> 6</td><td>5- (4-amino- sulfonylamino of 3.5 -fluorophenyl) -4- -cyclohexyl-2-methyl- oxazole</td><td> 0.16</td><td> 400</td><td> &gt;625</td>

<td> 7</td><td>5- (4-amino- sulfonyl-3-fluoro- phenyl) -4- (4-fluoro- phenyl) -2-methyl- oxazole</td><td> 0.03</td><td> 37</td><td> 1,233</td>

<td>indomethacin</td><td></td><td>SHE</td><td> 0,5</td><td> 0,063</td>

<td>1. Control</td><td></td><td> 0.07</td><td> 45</td><td> 643</td>

<td>2. Inspection</td><td></td><td> 0.02</td><td> 5</td><td> 250</td>

62 803 / SM

Second pharmacological example (effect on Chondrus crispus-induced podema)

0.05 ml of 1% Chondrus crispus saline was injected subcutaneously in the hind paw of male Donryu rats to induce podedema. The degree of podedema development was measured by measuring foot volume 3 hours after administration of Chondrus crispus. The test compound (1, 3, 10 or 30 mg / kg) was administered orally 1 hour before the administration of Choacrus crispus and the suppression induced in this manner was studied. The inhibitory effect is the test compound ED₃₀dose required to develop a 30% relative inhibition relative to the control group. The results are shown in Table 5.

5th spreadsheet

Second experimental example (effect on carrageenin-induced podedema in rats)

<td>Example</td><td>Carrageenin-induced podedema rats, ED_{I ()} (mg / kg po)</td>

<td> 2</td><td> 5.5</td>

<td>indomethacin</td><td> 2,9</td>

Industrial applicability

In particular, the compounds of the present invention are those wherein R₃ is methyl or amino, R₅ R5 is hydrogen or fluorine;₄ and R₇ is hydrogen; and pharmaceutically acceptable salts thereof. surprisingly, they selectively inhibit COX-2 alone while barely inhibiting COX-1. Accordingly, the compounds of the present invention have excellent antipyretic, analgesic, anti-inflammatory and anti-inflammatory activity, which are unremarkable in conventional products and have little side effect in the digestive tract.

According to our invention, it has become possible to develop an excellent anti-inflammatory agent that has not been available so far and we are looking forward to its use as a practical therapeutic agent in the treatment of COX-2-induced diseases such as asthma and rheumatism.

62 803 / SM

PATENT CLAIMS