Chiral arylketones in the treatment of neutrophil-dependent inflammatory diseases

1 . A method for making a medicament comprising admixing (R,S)-1-Arylethylketone compounds of formula I and their single (R) and (S) enantiomers:

wherein:

Ar represents phenyl, optionally substituted by one to three substituents, which are the same or different from one another, selected from:

halogens, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, hydroxy, C 1 -C 4 -acyloxy, phenoxy, cyano, nitro, amino, C 1 -C 4 -acylamino, halogen-C 1 -C 3 -alkyl, halogen C 1 -C 3 -alkoxy, benzoyl;

or Ar represents 4-thienoyl-phenyl, 4-(1-oxo-2-isoindolinyl)-phenyl, 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)phenyl, 6-methoxy-β-naphthyl, 1 -hydroxy-phenyl-1-methyl;

or Ar represents a residue of formula III:

wherein A is benzyl, phenoxy, benzoyl, benzoyloxime, 1-hydroxy-phenyl-1-methyl, B is hydroxy, C 1 -C 4 -acyloxy or a group of formula —O—C(═S)—N(CH 3 ) 2 , or —S—C(═O)—N(CH 3 ) 2 ;

Ra and Rb are independently chosen in the group of hydrogen, linear or branched C 1 -C 6 alkyl, phenyl, α-or β-naphthyl, 2,3,4-pyridyl, C 1 -C 4 -alkylphenyl, C 1 -C 4 -alkyl(α-or β-naphthyl), C 1 -C 4 -alkyl(2,3,4-pyridyl), cyano (—CN), carboxyamide, carboxyl or carboxyesters of formula CO 2 R″ wherein R″ is the residue of a linear or branched C 1 -C 6 aliphatic alcohol, a phosphonate PO(OR″) 2 wherein R″ is as defined above, a group of formula —X—(CH 2 ) n -Z, wherein X is a CO, SO, SO 2 group; Z is H, tert-butyl, isopropyl, CO 2 R″, CN, phenyl, α-or β-naphthyl, 2,3,4-pyridyl, C 3 -C 6 cycloalkyl, NH-BOC, NH 2 ; n is zero or an integer from 1 to 3;

or Ra and Rb, with the carbon atom to which they are bound, form a cyclic residue 4,6-dioxo-1,3-dioxanyl-2,2-disubstituted of formula II:

wherein R″ is methyl or ethyl, or the two groups R′ form a cyclohexane or cyclopentane ring, in an amount effective for the treatment of diseases that involve IL-8 induced human PMNs chemotaxis, together with a pharmaceutically acceptable carrier.

2 . The method according to claim 1 wherein Ar represents a residue 4-isobutyl-phenyl, 3-benzoyl-phenyl, 5-benzoyl-phenyl, 2-acetoxy-phenyl, 3-phenoxy-phenyl.

3 . The method according to claim 1 or 2 in which the compound is selected from:

methyl (R)(−)-4-[(4′-isobutyl)phenyl]-3-oxopentanoate;

methyl (S)(+)-4-[(4′-isobutyl)phenyl]-3-oxopentanoate;

(R,S) 4-[(4′-isobutyl)phenyl]-3-oxopentanoic acid;

methyl (R)(−)-4-[(3′-benzoyl)phenyl]-3-oxopentanoate;

(R)(−)-3-[(4′-isobutyl)phenyl]butan-2-one;

(S)(+)-3-[(4′-isobutyl)phenyl]butan-2-one;

(R)(−)-3-[(3′-benzoyl)phenyl]butan-2-one;

(R)(−)-dimethyl 3-(4-isobutyl-phenyl)-2-oxobutan-1-phosphonate;

(S)(±)-dimethyl 3-(3′-phenoxy-phenyl)-2-oxo-butyl-1-phosphonate;

(R)(−)-2-(4-isobutylphenyl)-pentan-3-oxopentanoate;

(S)(+) ethyl-4-[(3′-benzoyl)phenyl]-3-oxopentanoate;

(S)(+)-3-[(3′-benzoyl)phenyl]butan-2-one;

(R)(−)-2-(4-isobutylphenyl)-4-phenyl-butan-3-one;

(R)(−)-2-(4-isobutylphenyl)-5 -phenyl-pentan-3 -one;

(R)(−)-2-(4-isobutylphenyl)-5-(pyrid-3-yl)-pentan-3-one;

(R,S) 5-(4′-isobutylphenyl)-hexan-2,4-dione;

(R,S) 1-phenyl-5-(4′-isobutylphenyl)-2 4-hexandione;

(R,S) 1-(pyrid-2-yl)-4-(4′-isobutylphenyl)-1,3-pentadione;

(R) (−) 2-(4-isobutylphenyl)-7-tert-butoxycarbonylamino-heptan-3-one;

(R,S) 2-(4′-isobutylphenyl)-3-oxo-butyl, methyl-sulfoxide;

(R,S) 2-(3′-benzoylphenyl)-3-oxo-butyl, methyl-sulfoxide;

(R,S) 2-(4′-isobutylphenyl)-3-oxo-butyl, methyl-sulfone;

(R,S) 2-(3′-benzoylphenyl)-3-oxo-butyl, methyl-sulfone;

(R,S) 2-(3′-phenoxyphenyl)-3-oxo-butyl, methyl-sulfone;

(R,S) 2-(4′-isobutylphenyl)-3-oxo-butyl, phenyl-sulfone;

(R)(−)-4-(4′-pyridyl)-2-[(4″-isobutyl)phenyl]butan-3-one;

(R) (+)-5-[2-(4-isobutyl-phenyl)-propion-1-yl]-2,2-dimethyl-1,3-dioxan-4,6-dione;

(R) (−)-5-[2-(3′-benzoyl-phenyl)-propion-1-yl]-2,2-dimethyl-1,3-dioxan-4,6-dione.

(R)-2-[4-(1-oxo-2-isoindolinyl)phenyl]-3-oxo-valeramide;

(R)-2-[4-(1-oxo-2-isoindolinyl)phenyl]-3-oxo-valeronitrile;

4 . A method for preparing a medicament comprising admixing:

(R)(−) methyl 4-[(4′-benzoyloxy)phenyl]-3-oxopentanoate,

(R)(−) methyl-4-[(4′-isopropylsulfonyloxy)phenyl]-3-oxopentanoate and

(R)(−) methyl-4-{[4′-(2″-ethyl)phenylsulfonylamino]phenyl}-3-oxopentanoate, in an amount effective for the treatment of diseases that involve IL-8 induced human PMNs chemotaxis, together with a pharmaceutically acceptable carrier.

5 . The method according to claim 1 or 2 , wherein the steric configuration of the carbon atom to which the residue Ar is bound corresponds to the enantiomer (R).

6 . A pharmaceutical composition comprising (R,S)-1-Arylethylketone compounds of formula I and their single (R) and (S) enantiomers:

wherein:

Ar represents phenyl, optionally substituted by one to three substituents, which are the same or different from one another, selected from:

halogens, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, hydroxy, C 1 -C 4 -acyloxy, phenoxy, cyano, nitro, amino, C 1 -C 4 -acylamino, halogen-C 1 -C 3 -alkyl, halogen C 1 -C 3 -alkoxy, benzoyl;

or Ar represents 4-thienoyl-phenyl, 4-(1-oxo-2-isoindolinyl)-phenyl, 3-chloro-4-(2,5-dihydro-1H-pyrrol-1yl)phenyl, 6-methoxy-β-naphthyl, 1-hydroxy-phenyl-1methyl;

or Ar represents a residue of formula III:

wherein A is benzyl, phenoxy, benzoyl, benzoyloxime, 1-hydroxy-phenyl-1-methyl, B is hydroxy, C 1 -C 4 -acyloxy or a group of formula —O—C(═S)—N(CH 3 ) 2 , or —S—C(═O)—N(CH 3 ) 2 ;

Ra and Rb are independently chosen in the group of hydrogen, linear or branched C 1 -C 6 alkyl, phenyl, α-or β-naphthyl, 2,3,4-pyridyl, C 1 -C 4 -alkylphenyl, C 1 -C 4 -alkyl(α-or β-naphthyl), C 1 -C 4 -alkyl(2,3,4-pyridyl), cyano (—CN), carboxyamide, carboxyl or carboxyesters of formula CO 2 R″ wherein R″ is the residue of a linear or branched C 1 -C 6 aliphatic alcohol, a phosphonate PO(OR″) 2 wherein R″ is as defined above, a group of formula —X—(CH 2 ) n -Z, wherein X is a CO, SO, SO 2 group, Z is H, tert-butyl, isopropyl, CO 2 R″, CN, phenyl, α-or β-naphthyl, 2,3,4-pyridyl, C 3 C 6 cycloalkyl, NH-BOC, NH 2 ; n is zero or an integer from 1 to 3;

or Ra and Rb, with the carbon atom to which they are bound, form a cyclic residue 4,6-dioxo-1,3-dioxanyl-2,2-disubstituted of formula II:

wherein R′ is methyl or ethyl, or the two groups R′ form a cyclohexane or cyclopentane ring, in admixture with a suitable carrier thereof.

7 . (canceled)

8 . A method for treatment of a disease selected from the group consisting of psoriasis, rheumatoid arthritis, ulcerative cholitis, acute respiratory distress syndrome (ARDS), idiopathis fibrosis, glomerulonephritis, bollous pemphigo or for the prevention and the treatment of tissue damage caused by ischemia and reperfusion, comprising administering the pharmaceutical composition of claim 6 to a subject requiring treatment for said disease or for ischemia and reperfusion.