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(11) | EP 1 592 680 B9 |
| (12) | CORRECTED EUROPEAN PATENT SPECIFICATION |
| Note: Bibliography reflects the latest situation |
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| (54) |
2-PHENYLPYRAN-4-ONE DERIVATIVES AS SELECTIVE COX-2 INHIBITORS 2-PHENYLPYRAN-4-ON-DERIVATE ALS SELEKTIVE COX-2 INHIBITOREN DERIVES DE 2-PHENYLPYRAN-4-ONE EN TANT QU'INHIBITEURS DE COX-2 SELECTIFS |
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| Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). |
[0001] This invention relates to new therapeutically useful 2-phenylpyran-4-one derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use as medicaments.
[0002] It is known that non-selective inhibition of the enzyme cyclooxygenase (COX) prevents the overproduction of prostaglandins associated with inflammation, which is mediated by cyclooxygenase-2 (COX-2) but, at the same time, deprives tissues of basal levels of prostaglandins necessary for the health of certain tissues mediated largely by cyclooxygenase-1 (COX-1). Non steroidal anti-inflammatory drugs are non-selective inhibitors of COX and for that reason, have side effects of decreased renal blood flow, decreased platelet function, dyspepsia and gastric ulceration.
[0003] WO 00/18753 discloses 2-phenylpyran-4-one derivatives with a sulfonyl group bound to the phenyl moiety as inhibitors of COX-2.
[0004] We have now found that certain 2-phenylpyran-4-one derivatives with a sulfinyl group bound to the phenyl moiety selectively inhibit COX-2 in preference to COX-1 and are useful in the treatment of COX-2 mediated diseases and their symptoms, such as inflammation, pain, fever, and asthma with fewer side effects.
[0005] Accordingly the present invention provides a 2-phenylpyran-4-one compound of formula (I):
wherein:
R1 represents an alkyl group;
R2 represents an alkyl, C3-C7 cycloalkyl, pyridyl, thienyl, naphthyl, tetrahydronaphthyl or indanyl group, or a phenyl group which may be unsubstituted or substituted by one or more halogen atoms or alkyl, trifluoromethyl, hydroxy, alkoxy, methylthio, amino, mono-ordialkylamino, hydroxyalkyl or hydroxycarbonyl groups;
R3 and R4, which may be the same or different represent a hydrogen atom, or an alkyl,
alkenyl or alkynyl group which may be unsubstituted or substituted by one or more halogen atoms; and
X represents a single bond, an oxygen atom or a methylene group more preferably an oxygen atom;
said alkyl groups, said C3-C7 cycloalkyl group, said alkoxy group and the alkyl groups contained in said monoalkylamino and dialkylamino groups are each independently unsubstituted or substituted with 1, 2 or 3 substitutents which may be the same or different and are selected from halogen atoms, hydroxyl groups and alkoxy groups having from 1 to 4 carbon atoms, which alkoxy groups having from 1 to 4 carbon atoms are unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different and are selected from halogen atoms and hydroxyl groups; and
said hydroxyalkyl groups are hydroxyl(C1-C10)alkyl groups and may be substituted with one or more hydroxyl radicals;
enantiomers thereof mixtures thereof and pharmaceutically acceptable salts thereof.
[0006] Typically, the alkyl groups are C1-C20 alkyl groups, the alkoxy groups are C1-C10 alkoxy groups, the mono- or dialkylamino groups are mono- or di(C1-C10)alkylamino groups, the alkenyl groups are C2-C20 alkenyl groups and the alkynyl groups are C2-C20 alkynyl groups.
[0007] The compounds of formula (I) have a chiral center at the sulfur atom of the sulfinyl group, shown by an asterisk (*) in the formula, and consequently exist in the form of the two different enantiomers if there are no other chiral centers in the compounds or in the form of various diastereomers should there be other chiral centers in the compounds. All these stereoisomeric compounds and their mixtures are encompassed in the present invention. The formulas used in the present description are intended to represent all possible stereoisomers or any mixture thereof. Compounds of formula (I) may have the (R) or (S) configuration at the sulphur atom of the sulfinyl group.
[0008] In a preferred embodiment the invention provides a compound of formula (I) wherein R1 represents an unsubstituted alkyl group, more preferably a methyl group.
[0009] In another embodiment the present invention provides a compound of formula (I) wherein X represents a single bond or an oxygen atom, more preferably an oxygen atom.
[0010] In still another embodiment the present invention provides a compound of formula (I) wherein R3 and R4 represent a hydrogen atom or an unsubstituted C1-3 alkyl group, preferably a hydrogen atom.
[0011] In yet another embodiment the present invention provides a compound of formula (I) wherein R2 represents a branched alkyl, C3-C7cycloalkyl, naphthyl, tetrahydronaphthyl or indanyl group, an unsubstituted phenyl group or a phenyl group substituted by one or more halogen atoms, alkyl groups and/or alkoxy groups; more preferably an unsubstituted phenyl group or a phenyl group substituted by 1, 2 or 3 substituents independently selected from halogen atoms, methoxy group or methyl groups; still more preferably a phenyl group substituted by 1 or 2 substituents independently selected from halogen atoms and methyl groups.
[0012] Most preferably R2 represents an optionally substituted phenyl group of formula:
wherein Ra and Rb are selected from the group consisting of hydrogen atoms, halogen atoms, alkyl groups and/or alkoxy groups, more preferably halogen atoms and still more preferably R2 is a 2,4-difluorophenyl, 4-chloro-2-fluorophenyl or 4-bromo-2-fluorophenyl group.
[0013] Unless otherwise specified the term alkyl as used herein embraces optionally substituted, linear or branched radicals having 1 to 20 carbon atoms or, preferably 1 to 12 carbon atoms. More preferably alkyl radicals are "lower alkyl" radicals having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms.
[0014] Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl and tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, n-hexyl or 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dirnethylbutyl, 2,3-dimethylbutyl, 2-methylpentyl, 3-methylperityl; iso-hexyl radicals.
[0015] A said optionally substituted alkyl group is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. The substituents are preferably selected from halogen atoms, preferably fluorine atoms, hydroxy groups and alkoxy groups having from 1 to 4 carbon atoms. Typically, substituents on an alkyl group are themselves unsubstituted.
[0016] When it is mentioned that alkyl radicals may be optionally substituted it is meant to include linear or branched alkyl radicals as defined above, which may be unsubstituted or substituted in any position by one or more substituents, for example by 1, 2 or 3 substituents. When two or more substituents are present, said substituents may be the same or different.
[0017] As used herein, the term alkenyl embraces linear or branched, mono or polyunsaturated radicals having 2 to 20 carbon atoms or, preferably, 2 to 12 carbon atoms. More preferably alkenyl radicals are "lower alkenyl" radicals having 2 to 8, preferably 2 to 6 and more preferably 2 to 4 carbon atoms. In particular it is preferred that the alkenyl radicals are mono or diunsaturated.
[0018] Examples include vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl; 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl and 4-pentenyl radicals.
[0019] When it is mentioned that alkenyl radicals may be optionally substituted it is meant to include linear or branched alkenyl radicals as defined above, which may be unsubstituted or substituted in any position by one or more specified substituents, for example by 1, 2 or 3 substituents. When two or more substituents are present, said substituents may be the same or different.
[0020] A said optionally substituted alkenyl group is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. The substituents are selected from halogen atoms, preferably fluorine atoms.
[0021] As used herein, the term alkynyl embraces linear or branched, mono or polyunsaturated radicals having 2 to 20 carbon atoms or, preferably, 2 to 12 carbon atoms. More preferably, alkynyl radicals are "lower alkynyl" radicals having 2 to 8, preferably 2 to 6 and more preferably 2 to 4 carbon atoms. In particular, it is preferred that the alkynyl radicals are mono or diunsaturated.
[0023] When it is mentioned that alkynyl radicals may be optionally substituted it is meant to include linear or branched alkynyl radicals as defined above, which may be unsubstituted or substituted in any position by one or more specified substituents, for example by 1, 2 or 3 substituents. When two or more substituents are present, said substituents may be the same or different.
[0024] A said optionally substituted alkynyl group is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. The substituents are selected from halogen atoms, preferably fluorine atoms.
[0025] As used herein, the term alkoxy (or alkyloxy) embraces optionally substituted, linear or branched oxy-containing radicals each having alkyl portions of 1 to 10 carbon atoms. More preferred alkoxy radicals are "lower alkoxy" radicals having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms.
[0026] An alkoxy group is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. The substituents are preferably selected from halogen atoms, preferably fluorine atoms, hydroxy groups and alkoxy groups having from 1 to 4 carbon atoms.
[0027] Preferred alkoxy radicals include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, sec-butoxy, t-butoxy, trifluoromethoxy, difluoromethoxy, hydroxymethoxy, 2-hydroxyethoxy or 2-hydroxypropoxy.
[0028] As used herein, the term monoalkylamino embraces radicals containing an optionally substituted, linear or branched alkyl radical of 1 to 10 carbon atoms attached to a divalent-NH- radical. More preferred monoalkylamino radicals are "lower monoalkylamino" radicals having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms.
[0029] A monoalkylamino group typically contains an alkyl group which is unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. The substituents are preferably selected from halogen atoms, preferably fluorine atoms, hydroxy groups and alkoxy groups having from 1 to 4 carbon atoms.
[0030] Preferred optionally substituted monoalkylamino radicals include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, sec-butylamino, t-butylamino, trifluoromethylamino, difluoromethylamino, hydroxymethylamino, 2-hydroxyethylamino or 2-hydroxypropylamino.
[0031] As used herein, the term dialkylamino embraces radicals containing a trivalent nitrogen atom with two optionally substituted, linear or branched alkyl radicals of 1 to 10 carbon atoms attached thereto. More preferred dialkylamino radicals are "lower dialkylamino" radicals having 1 to 8, preferably 1 to 6 and more preferably 1 to 4 carbon atoms in each alkyl radical.
[0032] A dialkylamino group typically contains two alkyl groups, each of which is unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. The substituents are preferably selected from halogen atoms, preferably fluorine atoms, hydroxy groups and alkoxy groups having from 1 to 4 carbon atoms.
[0033] Preferred optionally substituted dialkylamino radicals include dimethylamino, diethylamino, methyl(ethyl)amino, di(n-propyl)amino, n-propyl(methyl)amino, n-propyl(ethyl)amino, di(i-propyl)amino, i-propyl(methyl)amino, i-propyl(ethyl)amino, di(n-butyl)amino, n-butyl(methyl)amino, n-butyl(ethyl)amino, n-butyl(i-propyl)amino, di(sec-butyl)amino, sec-butyl(methyl)amino, sec-butyl(ethyl)amino, sec-butyl(n-propyl)amino, sec-butyl(i-propyl)amino, di(t-butyl)amino, t-butyl(methyl)amino, t-butyl(ethyl)amino, t-butyl(n-propyl)amino, t-butyl(i-propyl)amino, trifluoromethyl(methyl)amino, trifluoromethyl(ethyl)amino, trifluoromethyl(n-propyl)amino, trifluoromethyl(i-propyl)amino, trifluoromethyl(n-butyl)amino, trifluoromethyl(sec-butyl)amino, difluoromethyl(methyl)amino, difluoromethyl(ethyl)amino, difluoromethyl(n-propyl)amino, difluoromethyl(i-propyl)amino, difluoromethyl(n-butyl))amino, difluoromethyl(sec-butyl)amino, difluoromethyl(t-butyl)amino, difluoromethyl(trifluoromethyl)amino, hydroxymethyl(methyl)amino, ethyl(hydroxymethyl)amino, hydroxymethyl(n-propyl)amino, hydroxymethyl(i-propyl)amino, n-butyl(hydroxymethyl)amino, sec-butyl(hydroxymethyl)amino, t-butyl(hydroxymethyl)amino, difluoromethyl(hydroxymethyl)amino, hydroxymethyl(trifluoromethyl)amino, hydroxyethyl(methyl)amino, ethyl(hydroxyethyl)amino, hydroxyethyl(n-propyl)amino, hydroxyethyl(i-propyl)amino, n-butyl(hydroxyethyl)amino, sec-butyl(hydroxyethyl)amino, t-butyl(hydroxyethyl)amino, difluoromethyl(hydroxyethyl)amino, hydroxyethyl(trifluoromethyl)amino, hydroxypropyl(methyl)amino, ethyl(hydroxypropyl)amino, hydroxypropyl(n-propyl)amino, hydroxypropyl(i-propyl)amino, n-butyl(hydroxypropyl)amino, sec-butyl(hydroxypropyl)amino, t-butyl(hydroxypropyl)amino, difluoromethyl(hydroxypropyl)amino, hydroxypropyl(trifluoromethyl)amino.
[0034] As used herein, the term hydroxyalkyl embraces linear or branched alkyl radicals having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, any one of which may be substituted with one or more hydroxyl radicals.
[0035] Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl.
[0036] As used herein, the term cycloalkyl embraces saturated carbocyclic radicals and, unless otherwise specified, a cycloalkyl radical typically has from 3 to 7 carbon atoms.
[0037] A cycloalkyl radical is typically unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different. The substituents are preferably selected from halogen atoms, preferably fluorine atoms, hydroxy groups and alkoxy groups having from 1 to 4 carbon atoms. When a cycloalkyl radical carries 2 or more substituents, the substituents maybe the same or different.
[0038] Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. It is preferably cyclopropyl, cyclopentyl or cyclohexyl. When a cycloalkyl radical carries 2 or more substituents, the substituents may be the same or different.
[0039] As used herein, the term halogen atom embraces chlorine, fluorine, bromine or iodine atom typically a fluorine, chlorine or bromine atom, most preferably chlorine or fluorine. The term halo when used as a prefix has the same meaning.
[0040] As used herein, the term pharmaceutically acceptable salt embraces salts with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid and organic acids, for example citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkaline earth metal (e.g. calcium cr magnesium) hydroxides and organic bases, for example alkyl amines, arylalkyl amines and heterocyclic amines.
[0041] In a phenyl group substituted by one or more halogen atoms or alkyl, trifluoroalkyl, hydroxy, alkoxy, methylthio, amino, mono- or dialkyl amino, hydroxyalkyl or hydroxycarbonyl groups, the phenyl ring may be substituted by 1, 2, 3, 4 or 5 substituents, preferably 1, 2 or 3 substituents, each being independently selected from the possible substituents set out above. That is to say, the phenyl group (attached to X or the pyran-4-one ring through its 1-position) may be substituted at any of the remaining positions, that is to say the 2, 3, 4, 5 or 6-positions. A phenyl group having more than one substituent may be substituted at any combination of positions. For example a phenyl group having two substituents may be substituted at the 2 and 3, 2 and 4, 2 and 5, 2 and 6, 3 and 4 or3 and 5 positions.
[0042] Specific examples of the 2-phanylpyran-4-one derivatives of the present invention include:
3-(2,4-Difluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one
3-(4-Chloro-2-fluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one
3-(4-Bromo-2-fluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one
3-(2,4-difluorophenoxy)-6-ethyl-5-methyl-2-[(4-(methylsulfinylphenyl)]-4H-pyran-4-one;
3-(4-fluoro-2-methylphenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;
3-(4-chloro-2-methylphenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;
3-(2-chloro-4-methylphenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;
3-(2-bromophenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;
3-(3-bromophenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;
3-(4-bromo-2-chlocophenoxy)-6-methyt-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;
3-(2,4-dibromophenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;
3-(2,4-difluorophenoxy)-6-methyl-2-[(4-(ethylsulfinyl)phenyl]-4H-pyran-4-one;
6-methyl-3-(2-methylphenoxy)-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;
6-methyl-3-(3-methylphenoxy)2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;
3-(2-fluoro-4-methylphenoxy)- 6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;
[0043] in the form of all possible enantiomers and mixtures thereof and pharmaceutically acceptable salts thereof.
[0044] Of outstanding interest are compounds of formula:
| Example | R3 | Ra | Rc | Configuration |
| 1 | Me | F | F | Racemic |
| 2 | Me | F | F | Enantiomer 1a |
| 3 | Me | F | F | Enantiomer 1b |
| 4 | Me | F | CI | Racemic |
| 5 | Me | F | CI | Enantiomer 4a |
| 6 | Me | F | CI | Enantiomer 4b |
| 7 | Me | F | Br | Racemic |
| 8 | Me | F | Br | Enantiomer 7a |
| 9 | Me | F | Br | Enantiomer 7b |
[0045] The present invention also provides processes for preparing a compound of formula (I)
wherein R1, R2, R3, R4 and X are as defined above by reacting a mercapto derivative of formula (II):
wherein R1, R2, R3, R4 and X are as defined above with an oxidizing agent, preferably sodium metaperiodate when it is desired to obtain racemic mixtures of compounds or using a mixture of titanium tetraisopropoxide, t-butyl hydroperoxide and either the (R,R) or the (S,S) forms of diethyl tartrate when it is desired to obtain mixtures of compounds of formula (I) enriched with compounds having a specific configuration at the sulfinyl chiral center, namely (R) or (S) configuration.
[0046] The reaction between the mercapto derivative of formula (II) and the oxidizing agent is preferably carried out in an organic solvent, preferably a chlorinated solvent or a mixture of chlorinated solvents and C1-C4 alcohols at a temperature of from -25°C to 40°C. It is preferred that the chlorinated solvent is selected from the group consisting of 1,2-dichloroethane, methylene chloride, chloroform and mixtures thereof . The C1-C4 alcohol is preferably selected from methanol and ethanol. Preferred solvent systems are 1,2-dichloroethane or a mixture of methylene chloride with methanol or ethanol.
[0047] The mercapto derivatives of formula (II) are known and can be prepared following the teachings of WO 01/68633 A1.
[0048] The 2-phenylpyran-4-one derivatives of formula (I) in which a basic group is present can be converted by methods known per se into pharmaceutically acceptable salts, preferably acid addition salts by treatment with organic or inorganic acids such as fumaric, tartaric, succinic or hydrochloric acid.
COX-1 and COX-2 activities in human whole blood
[0050] Fresh blood from healthy volunteers who had not taken any non-steroidal anti-inflammatory drugs for at least 7 days prior to blood extraction was collected in heparinized tubes (20 units of heparin per ml). For the COX activity determination, 500 µl aliquots of blood were incubated with either 5 µl vehicle (dimethylsulphoxide) or 5 µl of a test compound for 24 h at 37°C. Calcium ionophore A23187 (25 µM) was added 20 min before stopping the incubation. Plasma was separated by centrifugation (10 min at 13000 rpm) and kept at -30°C until TXB2 levels were measured using an enzyme immunoassay kit (EIA).
[0051] The effect of the compounds was evaluated by incubating each compound at five to six different concentrations with triplicate determinations. IC50 values were obtained by non-linear regression using InPlot, GraphPad software on an IBM computer.
[0052] For the COX-2 activity determination, 500 µl aliquots of blood were incubated in the presence of LPS (10 µg/ml) for 24 h at 37°C in order to induce the COX-2 expression (Patriagnani et al., J. Pharm. Exper. Ther. 271; 1705-1712 (1994)). Plasma was separated by centrifugation (10 min at 13000 rpm) and kept at-30°C until PGE2 levels were measured using an enzyme immunoassay kit (EIA). The effects of inhibitors were studied by incubating each compound (5 µl aliquots) at five to six different concentrations with duplicate determinations in the presence of LPS for 24 hours. IC50 values were obtained by non-linear regression using InPlot, GraphPad software on an IBM computer.
[0053] The results obtained from the biological assays are shown in Table 1.
| Example | COX-1 IC50 (µM) |
COX-2 IC50 (µM) |
Ratio COX-1/COX 2 |
| 1 | 100 | 0.96 | 104 |
| 2 | 100 | 2,1 | 48 |
| 3 | 86.6 | 0.27 | 321 |
| 4 | 81,1.3 | 0.37 | 219 |
| 5 | 72,9 | 2,47 | 30 |
| 6 | 100 | 0,25 | 400 |
| 7 | 77.0 | 0 57 | 135 |
| 8 | 32,1 | 1, 58 | 20 |
| 9 | 73,1 | 0,17 | 430 |
[0054] As shown in Table 1, the 2-phanylpyran-4-one derivatives of formula (I) are potent and selective COX-2 inhibitors. Thus the compounds of the invention are preferably selective inhibitors of mammalian COX-2, for example human COX-2.
[0055] The compounds of the invention also preferably have low inhibitory activity toward mammalian COX,1, for example human COX-1. Inhibitory activity can typically be measured by in vitro assays, for example as described above. Some of the compounds of the present invention have also shown an unexpected pharmacokinetic profile.
[0056] Preferred compounds of the invention have an IC50 value for COX-2 of less than 50 µM, preferably less than 10µM more preferably less than 5µM, still more preferably less than 2,5µM. Preferred compounds of the invention also have an IC50 value for COX-1 of greater than 10µM preferably greater than 20µM. As an indicator of selectivity for inhibition of COX-2 over COX 1, the ratio of COX-1/COX-2 IC50 values is preferably greaterthan 10, more preferably greater than 20, still more preferably greater than 50.
[0057] The present invention further provides a compound of formula (I) for use in a method of treatment of the human or animal body by therapy, in particular for the treatment of pain, fever or inflammation, to inhibit prostanoid-induced smooth muscle contraction or for the prevention or treatment of colorectal cancer or neurodegenerative diseases, for example, Alzheimer's disease.
[0058] The present invention further provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment of pain, fever or inflammation, to inhibit prostanoid-induced smooth muscle contraction or for the prevention or treatment of colorectal cancer or neurodegenerative diseases for example, Alzheimer's disease.
[0059] The compounds of formula (I) are useful for relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhoea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, bursitis, tendinitis, injuries, following surgical and dental procedures and arthritis including rheumatoid arthritis, osteoarthritis, gouty arthritis, spondyloarthopathies, systemic lupus erythematosus and juvenile arthritis. They may also be used in the treatment of skin inflammation disorders such as psoriasis, eczema, burning and dermatitis. In addition, such compounds may be used for the prevention ortreatment of colorectal cancer or neurodegenerative diseases, for example, Alzheimers disease.
[0060] The compounds of formula (I) will also inhibit prostanoid-induced smooth muscle contraction and therefore may be used in the treatment of dysmenorrhoea, premature labour, asthma and bronchitis.
[0061] The compounds of formula (I) can be used as alternative to conventional non-steroidal anti-inflammatory drugs, particularly where such non-steroidal anti-inflammatory drugs may be contraindicated such as the treatment of patients with gastrointestinal disorders including peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, Crohn's disease, inflammatory bowel syndrome and irritable bowel syndrome, gastrointestinal bleeding and coagulation disorders, kidney disease (e.g. impaired renal function), those prior to surgery or taking anticoagulants, and those susceptible to non-steroidal anti-inflammatory drugs induced asthma.
[0062] The compounds can further be used to treat inflammation in diseases such as vascular diseases, migraine headaches, periarteritis nodosa, thyroiditis, aplastic anaemia, Hodgkin's disease, scleroderma, type I diabetes, myasthenia gravis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, hypersensitivity, conjunctivitis, gingivitis and myocardial ischaemia.
[0063] Compounds of the present invention are inhibitors of cyclooxygenase-2 enzyme and are thereby useful to treat the cyclooxygenase-2 mediated diseases enumerated above.
[0064] Accordingly, the compounds of the present invention and pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising such compounds and/or salts thereof, may be used in a method of treatment of disorders of the human body which comprises administering to a patient requiring such treatment an effective amount of such a compound or a pharmaceutically acceptable salt thereof.
[0065] The present invention also provides pharmaceutical compositions, which comprise, as an active ingredient, at least a 2-phenylpyran-4-one derivative of formula (I) or a pharmacologically acceptable salt thereof in association with a pharmaceutically acceptable excipient such as a carrier or diluent. The active ingredient may comprise 0.001 % to 99% by weight, preferably 0.01 % to 90% by weight of the composition depending upon the nature of the formulation and whether further dilution is to be made prior to application.
[0066] Preferably the compositions are made up in a form suitable for oral, topical, nasal, inhalation, rectal, percutaneous or injectable administration.
[0067] The pharmaceutically acceptable excipients that are admixed with the active compound or salts of such compound, to form the compositions of this invention are known per se and the actual excipients used depend inter alia on the intended method of administering the compositions.
[0068] Compositions of this invention are preferably adapted for injectable and per os administration. In this case, the compositions for oral administration may take the form of tablets, retard tablets, sublingual tablets, capsules or liquid preparations, such as mixtures, elixirs, syrups or suspensions, all containing the compound of the invention; such preparations may be made by methods well-known in the art.
[0069] The diluents that may be used in the preparation of the compositions include those liquid and solid diluents that are compatible with the active ingredient, together with colouring or flavouring agents, if desired. Tablets or capsules may conveniently contain between 2 and 500 mg of active ingredient or the equivalent amount of a salt thereof.
[0070] The liquid composition adapted for oral use may be in the form of solutions or suspensions. The solutions may be aqueous solutions of a soluble salt or other derivative of the active compound in association with, for example, sucrose to form a syrup. The suspensions may comprise an insoluble active compound of the invention or a pharmaceutically acceptable salt thereof in association with water, together with a suspending agent or flavouring agent.
[0071] Compositions for parenteral injection may be prepared from soluble salts, which may or may not be freeze-dried and which may be dissolved in pyrogen free aqueous media or other appropriate parenteral injection fluid.
[0072] Effective doses are normally in the range of 10-600 mg of active ingredient per day. Daily dosage may be administered in one or more treatments, preferably from 1 to 4 treatments, per day.
[0073] The invention is illustrated by the following Preparations and Examples, which do not limit the scope of the invention in any way.
PREPARATION 1
3-(2,4-Difluorophenoxy)-6-methyl-2-[4-(methylthio)phenyl]-4H-pyran-4-one
[0074]
- a) To a solution of 2,4-difluorophenol (1.04 g; 8 mmol) and 2-bromo-1-[4-(methylthio)phenyl]ethanone (1.96 g, 8 mmol) in methylene chloride (13 ml) was added a solution of potassium carbonate (1.66 g) and tetrabutylammonium hydrogensulfate (0.14 g) in water (5 ml). The mixture was stirred at room temperature for 16 hours. Water (100 ml) was added, the organic phase was decanted, and the basic phase was extracted with methylene chloride (2 x 100 ml). The organic solution was dried (Na2SO4) and the solvent removed under reduced pressure. The resulting solid was washed with ethyl ether. 2-(2,4-Difluorophenoxy)-1-[4-(methyfthio)phenyl]ethanone was obtained (1.69 g, 72%) as an off-white solid.
- b) The above compound (1.68 g, 5.7 mmol) was added to a solution of polyphosphoric
acid. (19 g) in acetic anhydride (8.5 ml), pre-heated at 95-100°C. The mixture was
heated at the same temperature for 5 hours. After cooling, the reaction was poured
into ice-water, extracted with ethyl acetate (3 x 100 ml), the organic solution was
washed with saturated sodium bicarbonate (2x100 ml), water and brine, dried (Na2SO4), and the solvent removed under reduced pressure. The residual oil was purified by
column chromatography with silica gel and ethyl acetate/n-hexane (1/1) as eluent.
3-(2,4-Difluorophenoxy)-6-methyl-2-[4-(methylthio)phenyl]-4H-pyran-4-one (0.37 g,
17%) was obtained as an off-white solid.
δ (DMSO): 2.41 (s, 3H), 2.50 (s, 3H), 6.40 (s, 1 H), 6.94 (m, 2H), 7.39 (m, 3H), 7.76 (d, J=8.4 Hz, 2H).
PREPARATION 2
3-(4-Chloro-2-fluorophenoxy)-6-methyl-2-[4-(methylthio)phenyl]-4H-pyran-4-one
[0076] Obtained as an off white solid (16% overall) from 2-bromo-1-[4-(methylthio)phenyl]-ethanone and 4-chloro-2-fluorophenol by the procedure described in Preparation 1.
δ (DMSO): 2.42 (s, 3H), 2.50 (s, 3H), 6.30 (s, 1H), 6.73 (dd, JHH=JHF=9.0 Hz, 1 H), 6.94 (m, 1H), 7.14 (dd, J=10.5, 2.4 Hz, 1H), 7.27 (d, J=8.7 Hz, 2H), 7.82 (d, J=8.7 Hz, 2H).
PREPARATION 3
3-(4-Bromo-2-fluorophenoxy)-6-methyl-2-[4-(methylthio)phenyl]-4H-pyran-4-one
[0078] Obtained as an off-white solid (17% overall) from 2-bromo-1-[4-(methylthio)phenyl]-ethanone and 4-bromo-2-fluorophenol by the procedure described in Preparation 1:
δ (DMSO): 2.42 (s, 3H), 2.50 (s, 3H), 6.31 (s, 1H), 6.68 (dd, JHH=JHF=8.7 Hz, 1 H), 7.07 (m, 1 H), 7.26-7.30 (m, 3H), 7.82 (d, J=8.7 Hz, 2H).
EXAMPLE 1
3-(2,4-Difluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one
[0080] To a solution of the title compound of Preparation 1 (1.36 g, 3.8 mmol) in methanol (17 ml) was added dropwise a solution of sodium metaperiodate (0.80 g) in water (10 ml) at 0°C and this mixture was stirred at this temperature for 2 h and 3 d at r.t. Then, the reaction was poured into water, extracted with ethyl acetate (3 x 100 ml), the organic solution dried (Na2SO4), and the solvent removed under reduced pressure. The residue was purified by column chromatography with silica gel and dichloromethane/ethyl acetate/methanovacetic acid (78/17/3/2) as eluent. 3-(2,4-Difluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H pyran-4-one (1.09 g, 77%) was obtained as an off-white solid.
m.p.: 158-159°C
δ (DMSO): 2.44 (s, 3H), 2.76 (s, 3H), 6.32 (s, 1H), 6.67-6.92 (m, 3H), 7.74 (d, J=6.8 Hz, 2H), 8.08 (d, J=6.8 Hz, 2H).
EXAMPLE 2
3-(2,4-Difluorophenoxy)-6-methyl-2-[4(methylsulfinyl)phenyl]-4H-pyran-4-one-Enantiomer 1a
[0081] To a stirred solution of titanium tetraisopropoxide (1.05 ml, 3.5 mmol) and (R,R)-diethyl tartrate (2.45 ml, 14.2 mmol) in dry 1,2-dichloroethane (25 ml) cooled to 20°C were added successively t-butyl hydroperoxide 5.5 M in nonane (1.29 ml, 7.1 mmol) and the title compound of Preparation 1 (1.26 g, 3.5 mmol). The mixture was stirred at 20°C for 5 h, then washed with a 5% aqueous solution of sodium sulfite (50 ml) and brine. The organic layer was dried (Na2SO4) and the solvent removed under reduced pressure. The residue was purified by flash chromatography and ethyl acetate/methanol (95/5) as eluent. 3-(2,4-Difluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one (0.18 g, 17%, 100% ee) was obtained as an off-white solid.
[α]D22 = +82.3 (c 0.25, MeOH)
m.p.: 158-159°C
δ (DMSO): 2.44 (s, 3H), 2.76 (s, 3H), 6.32 (s, 1H), 6.67-6.92 (m, 3H), 7.74 (d, J=6.8 Hz. 2H), 8.08 (d, J=6.8 Hz, 2H).
EXAMPLE 3
3-(2,4-Difluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one - Enantiomer 1b
[0082] Obtained as an off-white solid (57%, 88.4% ee) from the title compound of Preparation 1 and (S,S)-diethyl tartrate by the procedure described in Example 2.
[α]D22 = -71.5 (c 0-25, MeOH)
m.p.: 158-159°C
δ (DMSO): 2.4.4 (s, 3H), 2.76 (s, 3H), 6.32 (s, 1H), 6.67-6.92 (in, 3H), 7.74 (d, J=6.8 Hz, 2H), 8.08 (d, J=6.8 Hz, 2H)..
EXAMPLE 4
3-(4-Chloro-2-fluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one
[0084] Obtained as an off-white solid (55%) from the title compound of Preparation 2 and sodium metaperiodate by the procedure described in Example 1.
m.p.: 186-188°C
δ (DMSO): 2.43 (s, 3H), 2.78 (s, 3H), 6.47 (s, 1H), 7.03-7.15 (m, 2H), 7.56 (dd, J=10.8, 2.4 Hz, 1H), 7.84 (d, J=8.6 Hz, 2H), 7.99 (d, J=8.6 Hz, 2H).
EXAMPLE 5
3-(4-Chloro-2-fluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one-Enantiomer 4a
[0085] Obtained as an off-white solid (48%, 100% ee) from the title compound of Preparation 2 and (R,R)-diethyl tartrate by the procedure described in Example 2.
[α]D22= +77.7 (c 0.25, MeOH)
m.p.: 186-188°C
δ (DMSO): 2.43 (s, 3H), 2.78 (s, 3H), 6.47 (s, 1H), 7.03-7.15 (m, 2H), 7.56 (dd, J=10.8, 2.4 Hz, 1H), 7.84 (d, J=8.6 Hz, 2H), 7.99 (d, J=8.6 Hz, 2H).
EXAMPLE 6
3-(4-Chloro-2-fluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one-Enantiomer 4b
[0086] Obtained as an off-white solid (49%, 98.4% ee) from the title compound of Preparation 2 and (S,S)-diethyl tartrate by the procedure described in Example 2.
[α]D22 = -77.0 (c 0.25, MeOH)
m.p.: 186-188°C
δ (DMSO): 2.43 (s, 3H), 2.78 (s, 3H), 6.47 (s, 1H), 7.03-7.15 (m, 2H), 7.56 (dd, J=10.8, 2.4 Hz, 1H), 7.84 (d, J=8.6 Hz, 2H), 7.99 (d, J=8.6 Hz, 2H).
EXAMPLE 7
3-(4-Bromo-2-nuorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one
[0088] Obtained as an off-white solid (43%) from the title compound of Preparation 3 and sodium metaperiodate by the procedure described in Example 1.
m.p.: 201 °C
δ (DMSO):. 2.43 (s, 3H), 2.78 (s, 3H), 6.47 (s, 1H), 7.01 (dd, JHH=JHF=9-0 Hz, 1H), 7.24 (m, 1H), 7.66 (dd, J=10.8, 2.1 Hz, 1H), 7.84 (d, J=8.7 Hz, 2H), 7.98 (d, J=8.7 Hz, 2H).
EXAMPLE 8
3-(4-Bromo-2-fluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one-Enantiomer 7a
[0089] Obtained as an off-white solid (48%, 98.8% ee) from the title compound of Preparation, 3 and (R,R)-diethyl tartrate by the procedure described in Example 2.
[α]D22 = +68.0 (c 0.5, MeOH)
m.p.: 201°C
δ (DMSO): 2.43 (s, 3H), 2.78 (s, 3H), 6.47 (s, 1H), 7.01 (dd, JHH=JHF=9.0 Hz, 1 H), 7.24 (m, 1H), 7.66 (dd, J=10.8, 2.1 Hz, 1H), 7.84 (d, J=8.7 Hz, 2H), 7.98 (d, J=8.7 Hz, 2H).
EXAMPLE 9
3-(4-Bromo-2-fluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one-Enantiomer 7b
[0090] Obtained as an off-white solid (53%, 98.2% ee) from the title compound of Preparation 3 and (S,S)-diethyl tartrate by the procedure described in Example 2.
[α]D22= -71.3 (c 0.5, MeOH)
m.p.: 201°C
δ (DMSO): 2.43 (s, 3H), 2.78 (s, 3H), 6.47 (s, 1H), 7.01 (dd, JHH=JHF=9.0 Hz, 1H), 7.24 (m, 1 H), 7.66 (dd, J=10.8, 2.1 Hz, 1H), 7.84 (d, J=8.7 Hz, 2H), 7.98 (d, J=8.7 Hz, 2H).
EXAMPLE 10
Capsules
[0091] 25,000 capsules each containing 100 mg of 3-(2,4-Difluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one (active ingredient) were prepared according to the following formulation:
| Active ingredient | 2.5 | Kg |
| Lactose monohydrate | 5 | Kg |
| Colloidal silicon dioxide | 0.05 | Kg |
| Com starch | 0.5 | Kg |
| Magnesium stearate | 0.1 | Kg |
Procedure
[0092] The above ingredients were sieved through a 60 mesh sieve, and were loaded into a suitable mixer and filled into 25,000 gelatine capsules.
EXAMPLE 11
Tablets
[0093] 100,000 Tablets each containing 50 mg of 3-(2,4-Difluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one (active ingredient) were prepared from the following formulation:
| Active ingredient | 5 | Kg |
| Spray dried lactose | 1 9.9 | Kg |
| Microcrystalline cellulose | 3.9 | Kg |
| Sodium stearyl fumarate | 0.2 | Kg |
| Colloidal silicon dioxide | 0.2 | Kg |
| Carboxymethyl starch | 0.8 | Kg |
Procedure
wherein
• R1 represents an alkyl group;
• R2 represents an alkyl, C3-C7 cycloalkyl, pyridyl, thienyl, naphthyl, tetrahydronaphthyl or indanyl group, or a phenyl group which may be unsubstituted or substituted by one or more halogen atoms or alkyl, trifluoromethyl, hydroxy, alkoxy, methylthio, amino, mono- or dialkylamino, hydroxyalkyl or hydroxycarbonyl groups;
• R3 and R4, which may be the same or different represent a hydrogen atom, or an alkyl, alkenyl or alkynyl group which may be unsubstituted or substituted by one or more halogen atoms;
• X represents a single bond, an oxygen atom, or a methylene group;
• said alkyl groups, said C3-C7 cycloalkyl group, said alkoxy group and the alkyl groups contained in said monoalkylamino and dialkylamino groups are each independently unsubstituted or substituted with 1, 2 or 3 substitutents which may be the same or different and are selected from halogen atoms, hydroxy groups and alkoxy groups having from 1 to 4 carbon atoms, which alkoxy groups having from 1 to 4 carbon atoms are unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different and are selected from halogen atoms and hydroxy groups; and
• said hydroxyalkyl groups are hydroxy(C1-C10)alkyl groups and may be substituted with one or more hydroxyl radicals;
enantiomers thereof mixtures thereof and pharmaceutically acceptable salts thereof.wherein Ra and Rb are selected from the group consisting of hydrogen atoms, halogen atoms, alkyl groups and/or alkoxy groups.
3-(2.4-Difluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one
3-(4-Chloro-2-fluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one
3-(4-Bromo-2-fluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one
3-(2,4-difluorophenoxy)-6-ethyl-5-methyl-2-[(4-(methylsulfinylphenyl)]-4H-pyran-4-one;
3-(4-fluoro-2-methylphenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;
3-(4-chloro-2-methylphanoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;
3-(2-chloro-4-methylphenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;
3-(2-bromophenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;
3-(3-bromophenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;
3-(4-bromo-2-chlorophenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;
3-(2,4-dibromophenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;
3-(2,4-difluorophenoxy)-6-methy)-2-[(4-(ethytsu)finyl)phenyl]-4H-pyran-4-one;
6-methyl-3-(2-methylphenoxy)-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;
6-methyl-3-(3-methylphenoxy)-2-[(4-(methylsulflnyl)phenyl]-4H-pyran-4-one;
3-(2-fluoro-4-methylphenoxy)- 6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-one;
enantiomers thereof, mixtures thereof and pharmaceutically acceptable salts thereof.3-(2,4-Difluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-one
3-(4-Chloro-2-fluorophenoxy)-6-methyl-2-[4-(methylsulflnyl)phenyl]-4H-pyran-4-one
3-(4-Bromo-2-fluorophenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran4-one
in the form of the (-) configuration enantiomers, mixtures thereof and pharmaceutically acceptable salts thereof.(a) reacting a mercapto derivative of formula (II):
(a) sodium metaperiodate when racemic sulfinyl mixtures are to be obtained; or
(b) a mixture of titanium tetraisopropoxide, t-butyl hydroperoxide and either the (R,R) or the (S,S) forms of diethyl tartrate when it is desired to obtain an enantiomerically enriched compound of formula (I).
worin
• R1 eine Alkylgruppe verkörpert;
• R2 eine Alkyl-, C3-C7-Cycloalkyl-, Pyridyl-, Thienyl-, Naphthyl-, Tetrahydronaphthyl- oder Indanylgruppe oder eine Phenylgruppe, die unsubstituiert oder durch ein oder mehrere Halogenatome oder Alkyl-, Trifluormethyl-, Hydroxy-, Alkoxy-, Methylthio-, Amino-, Mono- oder Dialkylamino-, Hydroxyalkyl- oder Hydroxycarbonylgruppen substituiert sein kann, verkörpert;
• R3 und R9, die gleich oder verschieden sein können, ein Wasserstoffatom oder eine Alkyl-, Alkenyl- oder Alkinylgruppe verkörpern, die unsubstituiert oder substituiert sein kann durch ein oder mehrere Halogenatome;
• X eine Einfachbindung, ein Sauerstoffatom oder eine Methylengruppe verkörpert;
• die genannten Alkylgruppen, die genannte C3-C7-Cycloalkylgruppe, die genannte Alkoxygruppe und die in den genannten Monoalkylamino- und Dialkylaminogruppen enthaltenen Alkylgruppen sind jeweils unabhängig unsubstituiert oder substituiert mit 1, 2 oder 3 Substituenten, die gleich oder unterschiedlich sein können und ausgewählt sind aus Halogenatomen, Hydroxygruppen und Alkoxygruppen mit 1 bis 4 Kohlenstoffatomen, wobei die Alkoxygruppen 1 bis 4 Kohlenstoffatome besitzen, die unsubstituiert oder substituiert sind mit 1, 2 oder 3 Substituenten, die gleich sein können oder unterschiedlich und die ausgewählt sind aus Halogenatomen und Hydroxygruppen; und
• die genannten Hydroxyalkylgruppen sind Hydroxy(C1-C10)alkylgruppen und können mit einem oder mehreren Hydroxylresten substituiert sein;
Enantiomere davon, Mischungen davon und pharmazeutisch verträgliche Salze davon.verkörpert, wobei Ra und Rb ausgewählt sind aus der Gruppe, bestehend aus Wasserstoffatomen, Halogenatomen, Alkylgruppen und/oder Alkoxygruppen.
3-(2,4-Difluorphenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-on;
3-(4-Chlor-2-fluorphenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-on;
3-(4-Brom-2-fluorphenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-on;
3-(2,4-Difluorphenoxy)-6-ethyl-5-methyl-2-[(4-(methylsulfinylphenyl)]-4H-pyran-4-on;
3-(4-Fluor-2-methylphenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-on;
3-(4-Chlor-2-methylphenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-on;
3-(2-Chlor-4-methylphenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-on;
3-(2-Bromphenoxy)-6-methyl-2-[(4-methylsulfinyl)phenyl]-4H-pyran-4-on;
3-(3-Bromphenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-on;
3-(4-Brom-2-chlorphenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-on;
3-(2,4-Dibromphenoxy)-6-methyl-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-on;
3-(2,4-Difluorphenoxy)-6-methyl-2-[(4-ethylsulfinyl)phenyl]-4H-pyran-4-on;
6-Methyl-3-(2-methylphenoxy)-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-on;
6-Methyl-3-(3-methylphenoxy)-2-[(4-(methylsulfinyl)phenyl]-4H-pyran-4-on;
3-(2-Fluor-4-methylphenoxy)-6-methyl-2-[(4-methylsulfinyl)phenyl]-4H-pyran-4-on;
Enantiomere davon, Mischungen davon und pharmazeutisch verträgliche Salze davon.3-(2,4-Difluorphenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-on;
3-(4-Chlor-2-fluorphenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-on;
3-(4-Brom-2-fluorphenoxy)-6-methyl-2-[4-(methylsulfinyl)phenyl]-4H-pyran-4-on
in Form der Konfiguration der (-)-Enantiomere, Mischungen davon und pharmazeutisch verträgliche Salze davon.(a) Umsetzen eines Mercaptoderivats der Formel (II):
(a) entweder Natriummetaperiodat ist, sofern racemische Sulfinylmischungen erhalten werden sollen; oder
(b) eine Mischung von Titantetraisopropoxid, t-Butylhydroperoxid und entweder der (R,R)- oder der (S,S)-Form von Diethyltartrat, wenn es erwünscht ist, eine enantiomerangereicherte Verbindung der Formel (I) zu erhalten.
dans laquelle
• R1 représente un groupe alkyle;
• R2 représente un groupe alkyle, cycloalkyle en C3-C7, pyridyle, thiényle, naphtyle, tétrahydronaphtyle ou indanyle, ou un groupe phényle qui peut être non substitué ou substitué par un ou plusieurs atomes d'halogène ou groupes alkyles, trifluorométhyles, hydroxy, alcoxy, méthylthio, amino, mono- ou dialkylamino, hydroxyalkyles ou hydroxycarbonyles ;
• R3 et R4, qui peuvent être identiques ou différents, représentent un atome d'hydrogène, ou un groupe alkyle, alcényle ou alcynyle qui peut être non substitué ou substitué par un ou plusieurs atomes d'halogène ;
• X représente une liaison simple, un atome d'oxygène ou un groupe méthylène ;
• lesdits groupes alkyles, ledit groupe cycloalkyle en C3-C7, ledit groupe alcoxy et les groupes alkyles contenus dans lesdits groupes monoalkylamino et dialkylamino sont chacun indépendamment non substitués ou substitués par 1, 2 ou 3 substituants qui peuvent être identiques ou différents et sont choisis parmi les atomes d'halogène, les groupes hydroxy et les groupes alcoxy ayant de 1 à 4 atomes de carbone, lesquels groupes alcoxy ayant de 1 à 4 atomes de carbone étant non substitués ou substitués par 1, 2 ou 3 substituants qui peuvent être identiques ou différents et sont choisis parmi les atomes d'halogène et les groupes hydroxy ; et
• lesdits groupes hydroxyalkyles sont des groupes hydroxyalkyle(C1-C10) et peuvent être substitués par un ou plusieurs radicaux hydroxyles ;
les énantiomères de celui-ci, les mélanges de celui-ci et des sels pharmaceutiquement acceptables de celui-ci.dans laquelle Ra et Rb sont choisis dans le groupe constitué par les atomes d'hydrogène, les atomes d'halogène, les groupes alkyles et/ou les groupes alcoxy.
la 3-(2,4-difluorophénoxy)-6-méthyl-2-[4-(méthylsulfinyl)phényl]-4H-pyran-4-one
la 3-(4-chloro-2-fluorophénoxy)-6-méthyl-2-[4-(méthylsulfinyl)phényl]-4H-pyran-4-one
la 3-(4-bromo-2-fluorophénoxy)-6-méthyl-2-[4-(méthylsulfinyl)phényl]-4H-pyran-4-one
la 3-(2,4-difluorophénoxy)-6-éthyl-5-méthyl-2-[(4-(méthylsulfinylphényl)]-4H-pyran-4-one ;
la 3-(4-fluoro-2-méthylphénoxy)-6-méthyl-2-[(4-(méthylsulfinyl)phényl]-4H-pyran-4-one ;
la 3-(4-chloro-2-méthylphénoxy)-6-méthyl-2-[(4-(méthylsulfinyl)phényl]-4H-pyran-4-one ;
la 3-(2-chloro-4-méthylphénoxy)-6-méthyl-2-[(4-(méthylsulfinyl)phényl]-4H-pyran-4-one ;
la 3-(2-bromophénoxy)-6-méthyl-2-[(4-(méthylsulfinyl)-phényl]-4H-pyran-4-one ;
la 3-(3-bromophénoxy)-6-méthyl-2-[(4-(méthylsulfinyl)-phényl]-4H-pyran-4-one ;
la 3-(4-bromo-2-chlorophénoxy)-6-méthyl-2-[(4-(méthylsulfinyl)phényl]-4H-pyran-4-one ;
la 3-(2,4-dibromophénoxy)-6-méthyl-2-[(4-(méthylsulfinyl)phényl]-4H-pyran-4-one ;
la 3-(2,4-difluorophénoxy)-6-méthyl-2-[(4-(éthylsulfinyl)phényl]-4H-pyran-4-one ;
la 6-méthyl-3-(2-méthylphénoxy)-2-[(4-(méthylsulfinyl)-phényl]-4H-pyran-4-one ;
la 6-méthyl-3-(3-méthylphénoxy)-2-[(4-(méthylsulfinyl)-phényl]-4H-pyran-4-one ;
la 3-(2-fluoro-4-méthylphénoxy)-6-méthyl-2-[(4-(méthylsulfinyl)phényl]-4H-pyran-4-one ;
les énantiomères de celui-ci, les mélanges de celui-ci et les sels pharmaceutiquement acceptables de celui-ci.la 3-(2,4-difluorophénoxy)-6-méthyl-2-[4-(méthylsulfinyl)phényl]-4H-pyran-4-one
la 3-(4-chloro-2-fluorophénoxy)-6-méthyl-2-[4-(méthylsulfinyl)phényl]-4H-pyran-4-one
la 3-(4-bromo-2-fluorophénoxy)-6-méthyl-2-[4-(méthylsulfinyl)phényl]-4H-pyran-4-one
sous la forme des énantiomères de configuration (-), de mélanges de celui-ci et de sels pharmaceutiquement acceptables de celui-ci.(a) la réaction d'un dérivé mercapto de formule (II) :
(a) du métaperiodate de sodium lorsque des mélanges sulfinylés racémiques doivent être obtenus ; soit
(b) un mélange de tétraisopropoxyde de titane, d'hydroperoxyde de t-butyle et des formes soit (R,R) soit (S,S) du tartrate de diéthyle lorsque l'on souhaite obtenir un composé de formule (I) enrichi énantiomériquement.
REFERENCES CITED IN THE DESCRIPTION
This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.
Patent documents cited in the description
Non-patent literature cited in the description
- PATRIAGNANI et al.J. Pharm. Exper. Ther., 1994, vol. 271, 1705-1712 [0052]