Amides, useful in the inhibition of IL-8-induced chemotaxis of neutrophils

1. A method for the treatment of psoriasis, ulcerative cholitis, glomerular nephritis, acute respiratory insufficiency, idiopathic fibrosis, and rheumatoid arthritis in a mammal, comprising administering to a mammal in need thereof, a therapeutically effective amount of a compound of an isolated (R)-enantiomer of a 2-aryl-propionic amide of formula (I)

and pharmaceutically acceptable salts thereof,

wherein:

Aryl represents a substituted or unsubstituted aryl group;

R represents H, C 1 -C 4 -alkyl, allyl, propargyl, CH 2 —CO 2 H or (CH 2 ) 2 —CO 2 H;

R′ is:

straight or branched C 1 -C 6 -alkyl, alkenyl, cycloalkyl, or phenylalkyl substituted with one or more carboxy groups CO 2 H;

straight or branched C 1 -C 6 -alkyl, alkenyl, cycloalkyl, or phenylalkyl substituted with one or more carboxy groups CO 2 H and with a heteroatom selected from oxygen or sulphur;

a residue of formula —CH 2 —CH 2 —X—(CH 2 —CH 2 O) n R wherein R is hereinbefore defined, n being an integer from 0 to 5, whilst X is oxygen or sulphur;

a residue of formula (R) or (S)—CH(CH 3 )CH 2 —O—CH 2 —CH 2 —OH;

a residue of formula OR, wherein R is hereinbefore defined;

a residue of formula (III)

wherein

Φ represents 2-(1-methyl-pyrrolidyl), 2-pyridyl, 4-pyridyl, 1-imidazolyl, 4-imidazolyl, 1-methyl-4-imidazolyl, 1-methyl-5-imidazolyl or a NRaRb group wherein each Ra and Rb, which may be the same or different, represent C 1 -C 6 alkyl or —(CH 2 ) m —OH hydroxyalkyl wherein m is an integer from 2 to 3, and, alternatively, Ra and Rb together with the atom of N to which they are bound, constitute a heterocycle from 3 to 7 members of formula (IV)

wherein

Y represents a single bond, CH 2 , O, S or N-Rc, Rc being H, C 1 -C 6 alkyl, (CH 2 ) m —OH hydroxyalkyl, a —(CH 2 ) m —Ar′ residue wherein Ar′ is an aryl, heteroaryl, cycloaliphatic and/or heterocycloaliphatic residue, m′ is zero or an integer from 1 to 3, p and q, each independently, is an integer from 1 to 3; or

a heteroaryl selected from the group consisting of, 2-pyridyl or 4-pyridyl, 2-pyrimidinyl or 4-pyrimidinyl; 2-pyrazinyl, 5-methyl-2-pyrazinyl; 3-1,2,4-thiazinyl 3-1,2,4-thiazolyl, 3-1-benzyl-1,2,4-thiazolyl 2-1,3-thiazolidinyl, 2-1,3-thiazolyl, 1,3-oxazolyl, 3-isoxazolyl, 4-dihydro-3-oxo-isoxazolyl, 5-methyl-isoxazol-4-yl, 2-imidazolyl, 4-imidazolyl-5-carboxyamide and 2-imidazolyl-4,5-dicarbonitrile, 5-indanyl, 5-indazolyl, 7-aza-indol-3-yl, 2- or 3- or 4-quinolinyl;

wherein the compounds of formula I inhibit the chemotaxis of neutrophils induced by interleukin-8.

2. A method for the inhibition and the treatment of damages caused by ischaemia and reperfusion in a mammal comprising, administering to a mammal in need thereof, a therapeutically effective amount of an isolated (R)-enantiomer of a 2-aryl-propionic amide of formula (I)

and pharmaceutically acceptable salts thereof,

wherein:

Aryl represents a substituted or unsubstituted aryl group;

R represents H, C 1 -C 4 -alkyl, allyl, propargyl, CH 2 —CO 2 H or (CH 2 ) 2 —CO 2 H;

R′ is:

straight or branched C 1 -C 6 -alkyl, alkenyl, cycloalkyl, or phenylalkyl substituted with one or more carboxy groups CO 2 H;

straight or branched C 1 -C 6 -alkyl, alkenyl, cycloalkyl, or phenylalkyl substituted with one or more carboxy groups CO 2 H and with a heteroatom selected from oxygen or sulphur;

a residue of formula —CH 2 —CH 2 —X—(CH 2 —CH 2 O) n R wherein R is hereinbefore defined, n being an integer from 0 to 5, whilst X is oxygen or sulphur;

a residue of formula (R) or (S)—CH(CH 3 )CH 2 —O—CH 2 —CH 2 —OH;

a residue of formula OR, wherein R is hereinbefore defined;

a residue of formula (III)

wherein

Φ represents 2-(1-methyl-pyrrolidyl), 2-pyridyl, 4-pyridyl, 1-imidazolyl, 4-imidazolyl, 1-methyl-4-imidazolyl, 1-methyl-5-imidazolyl or a NRaRb group wherein each Ra and Rb, which may be the same or different, represent C 1 -C 6 alkyl or —(CH 2 ) m —OH hydroxyalkyl wherein m is an integer from 2 to 3, and, alternatively, Ra and Rb together with the atom of N to which they are bound, constitute a hetero cycle from 3 to 7 members of formula (IV)

wherein

Y represents a single bond, CH 2 , O, S or N—R c , Rc being H, C 1 -C 6 alkyl, (CH 2 ) m —OH hydroxyalkyl, a —(CH 2 ) m —Ar′ residue wherein Ar′ is an aryl, heteroaryl, cycloaliphatic and/or heterocycloaliphatic residue, m′ is zero or an integer from 1 to 3, p and g, each independently, is an integer from 1 to 3: or

a heteroaryl selected from the group consisting of, 2-pyridyl or 4-pyridyl, 2-pyrimidinyl or 4-pyrimidinyl: 2-pyrazinyl, 5-methyl-2-pyrazinyl 3-1,2,4-thiazinyl 3-1,2,4-thiazolyl, 3-1-benzyl-1,2,4-thiazolyl 2-1,3-thiazolidinyl, 2-1,3-thiazolyl, 1,3-oxazolyl, 3-isoxazolyl, 4-dihydro-3-oxo-isoxazolyl, 5-methyl-isoxazol-4-yl, 2-imidazolyl, 4-imidazolyl-5-carboxyamide and 2-imidazolyl-4,5-dicarbonitrile, 5-indanyl, 5-indazolyl, 7-aza-indol-3-yl, 2- or 3- or 4-quinolinyl:

wherein the compounds of formula I inhibit the chemotaxis of neutrophils induced by interleukin-8.

3. The method of claim 1

wherein:

Aryl represents a substituted or unsubstituted aryl group;

R represents H, C 1 -C 4 -alkyl, allyl, propargyl, CH 2 —CO 2 H or (CH 2 ) 2 CO 2 H; and

R′ is an (L) amino acid.

4. The method of claim 1 wherein:

Aryl represents a substituted or unsubstituted aryl group;

R represents H, C 1 -C 4 -alkyl, allyl, propargyl, CH 2 —CO 2 H or (CH 2 ) 2 —CO 2 H; and

R′ is a residue of an L-amino acid selected from the group consisting of alanine, valine, leucine, isoleucine, nor-leucine, phenylalanine, tyrosine, histidine, S-methylcysteine, S-carboxymethylcysteine, S-2-hydroxyethylcysteine, methionine, O-methylserine, O-2-hydroxyethylserine, or a residue of glycine, phenylglycine, β-alanine, γ-amino-butyric acid, δ-amino-valeric acid, cis-4-amino-cyclohexancarboxylic acid, trans-4-aminomethyl-cyclohexancarboxylic acid, 3-amino-1,5-pentandioic acid, or a residue of formula (II),

wherein the A substituent represents H, straight or branched C 1 -C 6 -alkyl, (CH 2 ) ni CO 2 H wherein n is an integer between 1 and 3, benzyl, p-hydroxy-benzyl, —CH 2 —O—C 2 H 5 , —CH 2 —S—CH 3 , —CH 2 —S—CH 2 —CO 2 H, wherein the residues of the acids indicated above are in the form of a free acid or of a salt.

5. The method of claim 1 wherein:

Aryl represents a substituted or unsubstituted aryl group; and

wherein R is hydrogen; and

R′ is the residue of L-alanine, L-carboxymethylcysteine, L-phenylalanine, L-leucine, L-methionine, L-O-methylserine, L-alanyl-glycine.

6. The method of claim 1 wherein the compound of formula (I) is selected from the group consisting of:

(R)(−)-2-(4′-isobutyl-phenyl)-N-methylpropionamide;

(R)(−)-2-[4′-isobutyl)phenyl]-N-carboxymethyl propionamide;

cis-(R)-2-[(4′-isobutyl)phenyl]-N-(4′carboxy-cyclohexyl)propionamide;

trans-(R)-2-[(4′-isobutyl)phenyl]-N-(4′carboxymethyl-cyclohexyl)propionamide;

(R,S′)-2-[(4′-isobutyl)phenyl]-N-(2-carboxyethyl)propionamide;

(R,S′)-2-[(4]-methoxy)phenyl]-N-(2-carboxyethyl)propionamide;

(R)—N-[2′-(4″-isobutylphenyl)propanoyl]-2-amino acrylic acid;

(R)(−)-2-[(4′-isobutyl)phenyl]-N-(2″-hydroxyethoxyethyl)propionamide;

(R,S′)-2-[(4″-isobutyl)phenyl]-N-[1′methyl-2′-(2″″-hydroxyethoxy)ethyl]propionamide;

(R,R′)-2-[(4″-isobutyl)phenyl]-N-[1′-methyl-2′-(2″″-hydroxyethoxy)ethyl]propionamide;

(R)(−)-2-(4′-isobutyl-phenyl)-N-(2″-pyridyl)propionamide and its hydrochloride;

(R)(−)-2-(4′-isobutyl-phenyl)-N-(4″-pyridyl)propionamide and its hydrochloride;

(R)(−)-2-[(3′-benzoyl)phenyl]-N-(2″-pyridyl)propionamide and its hydrochloride;

(R)(−)-2-[(2′-hydroxy-5′-benzoyl)phenyl]-N-(2″-pyridyl)propionamide and its hydrochloride;

(R)(−)-2-[(2′-hydroxy-5′-benzoyl)phenyl]-N-(4″-pyridyl)propionamide and its hydrochloride;

(R)(−)-2-[(2′-hydroxy-5′-benzoyl)phenyl]-N-carboxymethyl propionamide;

(R)(−)-2-(4′-isobutyl-phenyl)-N-(2″-pyrazinyl)propionamide and its hydrochloride;

(R)(−)-2-(4′-isobutyl-phenyl)-N-(2″-pyrimidinyl)propionamide and its hydrochloride;

(R)(−)-2-(4′-isobutyl-phenyl)-N-(4″-pyrimidinyl)propionamide and its hydrochloride;

(R)(−)-2-[(3′-isopropyl)phenyl]-N-carboxymethyl propionamide;

(R,S′)(−)-2-[(3′-α-methylbenzyl)phenyl]-N-carboxymethyl propionamide; and

(R,R′)(−)-2-[(3′-α-methylbenzyl)phenyl]-N-carboxymethyl propionamide.

7. The method of claim 2 wherein:

Aryl represents a substituted or unsubstituted aryl group

R represents H, C 1 -C 4 -alkyl, allyl, propargyl, CH 2 —CO 2 H or (CH 2 ) 2 —CO 2 H; and

R′ is an (L) amino acid.

8. The method of claim 2 wherein:

Aryl represents a substituted or unsubstituted aryl group;

R represents H, C 1 -C 4 -alkyl, allyl, propargyl, CH 2 —CO 2 H or (CH 2 ) 2 —CO 2 H; and

R′ is an L-amino acid selected from the group consisting of alanine, valine, leucine, isoleucine, nor-leucine, phenylalanine, tyrosine, histidine, S-methylcysteine, S-carboxymethylcysteine, S-2-hydroxyethylcysteine, methionine, O-methylserine, O-2-hydroxyethylserine, or a residue of glycine, phenylglycine, β-alanine, γ-amino-butyric acid, δ-amino-valeric acid, cis-4-amino-cyclohexancarboxylic acid, trans-4-aminomethyl-cyclohexancarboxylic acid, 3-amino-1,5-pentandioic acid, or a residue of formula (II),

wherein the A substituent represents H, straight or branched C 1 -C 6 -alkyl, (CH 2 ) ni CO 2 H wherein n is an integer between 1 and 3, benzyl, p-hydroxy-benzyl, —CH 2 —O—C 2 H 5 , —CH 2 —S—CH 3 , —CH 2 —S—CH 2 —CO 2 H, wherein the residues of the acids indicated above are in the form of a free acid or of a salt or in the form of methyl, ethyl and allyl esters thereof.

9. The method of claim 2 wherein:

Aryl represents a substituted or unsubstituted aryl group;

R is hydrogen; and

R′ is the residue of L-alanine, L-carboxymethylcysteine, L-phenylalanine, L-leucine, L-methionine, L-O-methylserine, L-alanyl-glycine.

10. The method of claim 2 wherein the compound of Formula (I) is selected from the group consisting of:

(R)(−)-2-(4′-isobutyl-phenyl)-N-methylpropionamide;

(R)(−)-2-[(4′-isobutyl)phenyl]-N-carboxymethyl propionamide;

cis-(R)-2-[(4′-isobutyl)phenyl]-N-(4′carboxy-cyclohexyl)propionamide;

trans-(R)-2-[(4′-isobutyl)phenyl]-N-(4′-carboxymethyl-cyclohexyl)propionamide;

(R,S′)-2-[(4′-isobutyl)phenyl]-N-(2-carboxyethyl)propionamide;

(R, S′)-2-[(4]-methoxy)phenyl]-N-(2-carboxyethyl)propionamide;

(R)—N-[2′-(4″-isobutylphenyl)propanoyl]-2-amino acrylic acid;

(R)(−)-2-[(4′-isobutyl)phenyl]-N-(2″-hydroxyethoxyethyl)propionamide;

(R,S″)-2-[(4″-isobutyl)phenyl]-N-[1′methyl-2′-(2″″-hydroxyethoxy)ethyl]propionamide;

(R,R′)-2-[(4″-isobutyl)phenyl]-N-[1′-methyl-2′-(2″″-hydroxyethoxy)ethyl]propionamide;

(R)(−)-2-(4′-isobutyl-phenyl)-N-(2″-pyridyl)propionamide and its hydrochloride;

(R)(−)-2-(4′-isobutyl-phenyl)-N-(4″-pyridyl)propionamide and its hydrochloride;

(R)(−)-2-[(3′-benzoyl)phenyl]-N-(2″-pyridyl)propionamide and its hydrochloride;

(R)(−)-2-[(2′-hydroxy-5′-benzoyl)phenyl]-N-(2″-pyridyl)propionamide and its hydrochloride;

(R)(−)-2-[(2′-hydroxy-5′-benzoyl)phenyl]-N-(4″-pyridyl)propionamide and its hydrochloride;

(R)(−)-2-[(2′-hydroxy-5′-benzoyl)phenyl]-N-carboxymethyl propionamide;

(R)(−)-2-(4′-isobutyl-phenyl)-N-(2″-pyrazinyl)propionamide and its hydrochloride;

(R)(−)-2-(4′-isobutyl-phenyl)-N-(2″-pyrimidinyl)propionamide and its hydrochloride;

(R)(−)-2-(4′-isobutyl-phenyl)-N-(4″-pyrimidinyl)propionamide and its hydrochloride;

(R)(−)-2-[(3′-isopropyl)phenyl]-N-carboxymethyl propionamide;

(R,S′)(−)-2-[(3′-α-methylbenzyl)phenyl]-N-carboxymethyl propionamide; and

(R,R′)(−)-2-[(3′-α-methylbenzyl)phenyl]-N-carboxymethyl propionamide.

11. The method of claim 1 wherein:

Aryl represents a substituted or unsubstituted aryl group;

R represents H, and

R′ represents H, —CH2-CH3, L-CH2-(CH3)-CO2H, (CH2-CH2O)2H, 2-pyridyl or 4-pyridyl.

12. The method of claim 2 wherein:

Aryl represents a substituted or unsubstituted aryl group;

R represents H, and

R′ represents H, —CH2-CH3, L-CH2-(CH3)-CO2H, (CH2-CH2O)2H, 2-pyridyl or 4-pyridyl.

13. The method of claim 2 , wherein Aryl represents a phenyl group substituted with a group selected from isopropyl, acetyl, (2″,6″-dichlorophenyl)amino, α-hydroxyisopropyl, (R,S) α-hydroxyethyl and its single R and S isomers, (R,S)-α-hydroxybenzyl and its single R and S isomers, and (R,S)-α-methylbenzyl and its single R and S isomers; (R,S)-α-hydroxy-α-methylbenzyl and its single R and S isomers.

14. The method of claim 2 , wherein Aryl is selected from phenyl, 4-methyl-phenyl, 3-isopropyl-phenyl, 4-methoxy-phenyl, 4-acetoxy-phenyl, 4-benzoyloxyphenyl, 4-hydroxyphenyl, 4-isobutylphenyl, 4-(2,2-dimethyl)vinylphenyl, (CH 3 ) 2 C═CH—C 6 H 4 —, 4-(2-methyl)-allyl-phenyl, 3-benzoyl-phenyl, 3-phenoxy-phenyl, 3-benzyl-phenyl, 3-C 6 H 5 —CH(OH)-phenyl, 5-benzoyl-thien-2-yl, 4-thienoyl-phenyl, 1-oxo-2-isoindolinyl-phenyl, 2-fluoro-4-biphenylyl, 6-methoxynaphthyl, 5-benzoyl-2-acetoxy-phenyl, 5-benzoyl-2-hydroxy-phenyl, 3-α-methylbenzyl-phenyl, 3-hydroxypropyl-phenyl, 3-hydroxyethyl-phenyl.

15. The method of claim 1 , wherein Aryl represents a phenyl group substituted with a group selected from isopropyl, acetyl, (2″,6″-dichlorophenyl)amino, α-hydroxyisopropyl, (R,S) α-hydroxyethyl and its single R and S isomers, (R,S)-α-hydroxybenzyl and its single R and S isomers, and (R,S)-α-methylbenzyl and its single R and S isomers; (R,S)-α-hydroxy-α-methylbenzyl and its single R and S isomers.

16. The method of claim 1 , wherein Aryl is selected from phenyl, 4-methyl-phenyl, 3-isopropyl-phenyl, 4-methoxy-phenyl, 4-acetoxy-phenyl, 4-benzoyloxyphenyl, 4-hydroxyphenyl, 4-isobutylphenyl, 4-(2,2-dimethyl)vinylphenyl, (CH 3 ) 2 C═CH—C 6 H 4 —, 4-(2-methyl)-allyl-phenyl, 3-benzoyl-phenyl, 3-phenoxy-phenyl, 3-benzyl-phenyl, 3-C 6 H 5 —CH(OH)-phenyl, 5-benzoyl-thien-2-yl, 4-thienoyl-phenyl, 1-oxo-2-isoindolinyl-phenyl, 2-fluoro-4-biphenylyl, 6-methoxynaphthyl, 5-benzoyl-2-acetoxy-phenyl, 5-benzoyl-2-hydroxy-phenyl, 3-α-methylbenzyl-phenyl, 3-hydroxypropyl-phenyl, 3-hydroxyethyl-phenyl.