Amide of R-2-(aminoaryl)-propionic acid for use in the prevention of leucocyte activation

1. Process for the preparation of an amide of the (R)—enantiomers of 2-arylpropionic acids of formula (1):

and pharmaceutically acceptable salts thereof, wherein:

q is zero or the integer 1;

Ph represents a phenylene group linked to the group —(CH 2 ) q -A in its position 2, 3 or 4 and optionally substituted in the remaining positions by one or more substituents, same or different, chosen from C 1 –C 3 -alkyl, halogens, C 1 –C 3 -alkoxy, hydroxy, SH, C 1 –C 3 -alkylthio, nitro, haloalkyl,

R is hydrogen, C 1 –C 3 -alkyl or the residue of a C 1 –C 3 -alkanoic acid, or an amino acid;

A is:

a N—C 1 –C 5 -alkylamino group, a N,N— C 1 –C 5 -dialkylamino group, a N— C 1 –C 8 -alkanoyl(cycloalkanoyl, arylalkanoyl)-N—C 1 –C 5 -alkylamino group;

a heterocyclic ring selected from the group consisting of: piperazine, pyrroline, thiomorpholine, morpholine, quinoline and piperidine;

a residue of formula (2a)

wherein R c is:

—H; —SO 2 —CH 3 ; C 1 –C 3 -alkyl, a residue of formula —CH 2 –CH 2 —X—(CH 2 –CH 2 O) n —P where P is H, methyl, ethyl, isopropyl; —CH 2 CO 2 R 1 , wherein R 1 is H or C 1 –C 3 ; n is an integer from 0 to 5, X is O or S;

a residue of formula (3)

—(CH 2 ) m -Φ  (3)

wherein, when m is an integer from 2 to 3, Φ represents an unsubstituted or substituted phenylene as defined above, 2-(1-methyl-pyrrolidyl), 2-pyridyl, 4-pyridyl, 1-imidazolyl, 4-imidazolyl, 1-methyl-4-imidazolyl, 1-methyl-5-imidazolyl, or a group —NRa,Rb wherein each of Ra and Rb, same or different, represents C 1 –C 5 -alkyl or hydroxyalkyl-(CH 2 ) mi —OH wherein m i is an integer from 2 to 3; when m is zero, Φ is selected from the group of 2- or 4-pyridyl, 2- or 4-pyrimidinyl, 2-pyrazinyl, 5-methyl-2-pyrazinyl, 1-1,2,4-thiadiazolyl, 3-1,2,4-triazolyl, 3-1-benzyl-1,2,4-triazolyl, 2-1,3-thiazolidinyl, 2-1,3-thiazolyl, 3-isoxazolyl, dihydro-isoxazol-4-yl, 5-methyl-isoxazol-4-yl, 2-imidazolyl, imidazol-4-yl-5-carboxyamide, imidazol-2-yl-4,5-dicarbonitrile, 5-indanyl, 5-indazolyl, 7-aza-indol-3-yl, indol-3-yl, 2- or 3- or 4-quinolyl;

a residue of an α-amino acid selected from the group of alanine, valine, leucine, isoleucine, nor-leucine, phenylalanine, p-fluoro-phenylalanine, tyrosine, biphenylalanine, 2′-methoxy-biphenylalanine, tryptophan, 7-azatryptophan, histidine, S-methylcysteine, carboxy-methylcysteine, methionine, O-methyl-serine, O-ethyl-serine, glycine, phenyl- or p-fluorophenyl-glycine;

a residue of an acid chosen from the group of β-alanine, γ-aminobutyric, δ-aminovaleric, cis-4-amino-cyclohexanecarboxylic, trans-4-amino-methylcyclohexanecarboxylic and 3-amino-1,5-pentadioic acid;

a residue of formula (3a)

wherein B represents H; a straight or branched C 1 –C 5 -alkyl; (CH 2 ) ni —NH 2 ; (CH 2 ) ni —NH-t-butoxycarbonyl; —(CH 2 ) ni —NH-benzyloxycarbonyl; —(CH 2 ) ni —CO 2 H wherein n i is an integer between 1 and 3; benzyl; p-fluorobenzyl; p-phenyl-benzyl; p-(2-methoxy-phenyl)-benzyl; —CH 2 O—C 2 H 5 ; —CH 2 —S—CH 3 ; —CH 2 —S—CH 2 —CO 2 H; indolyl-3-methyl; 7-aza-indolyl-3-methyl;

provided that when q is zero, R is SO 2 CH 3 and Ph is 3-chloro-1,4-phenylene, A is other than 1-2,5-dihydro-pyrrolidino, comprising:

reacting an activated acid derivative of Formula (4)

wherein A and q are as defined above and AT is a moiety activating the carbonyl group, with an amine R—NH 2 , wherein R is hydrogen, C 1 –C 3 alkyl, a halogen, a residue of a C 1 –C 3 alkanoic acid, or an amino acid.

2. A method of inhibiting chemotaxis of neutrophils induced by interleukin-8 in vitro, wherein said method comprises contacting said neutrophils with an effective amount of a compound comprising amides of the (R)—enantiomers of 2-arylpropionic acids of formula (1):

and pharmaceutically acceptable salts thereof, wherein:

q is zero or the integer 1;

Ph represents a phenylene group linked to the group —(CH 2 ) q -A in its position 2, 3 or 4 and optionally substituted in the remaining positions by one or more substituents, same or different, chosen from C 1 –C 3 -alkyl, halogens, C 1 –C 3 -alkoxy, hydroxy, SH, C 1 –C 3 -alkylthio, nitro, haloalkyl;

A is:

a N—C 1 –C 5 -alkylamino group, a N,N— C 1 –C 5 -dialkylamino group, a N— C 1 –C 8 -alkanoyl(cycloalkanoyl, arylalkanoyl)-N—C 1 –C 5 -alkylamino group;

a heterocyclic ring selected from the group consisting of: piperazine, pyrroline, thiomorpholine, morpholine, quinoline and piperidine;

a residue of formula (2a)

wherein R c , is hydrogen, C 1 –C 3 -alkyl or the residue of a C 1 –C 3 -alkanoic acid;

R is:

—H; —SO 2 —CH 3 ; C 1 –C 3 -alkyl, a residue of formula —CH 2 –CH 2 —X—(CH 2 —CH 2 O) n -P where P is H, methyl, ethyl, isopropyl; —CH 2 CO 2 R 1 , wherein R 1 is H or C 1 –C 3 ; n is an integer from 0 to 5, X is O or S;

a residue of formula (3)

—(CH 2 ) m -Φ  (3)

wherein, when m is an integer from 2 to 3, Φ represents an unsubstituted or substituted phenylene as defined above, 2-(1-methyl-pyrrolidyl), 2-pyridyl, 4-pyridyl, 1-imidazolyl, 4-imidazolyl, 1-methyl-4-imidazolyl, 1-methyl-5-imidazolyl, or a group —NRa,Rb wherein each of Ra and Rb, same or different, represents C 1 –C 5 -alkyl or hydroxyalkyl-(CH 2 ) mi —OH wherein m i is an integer from 2 to 3; when m is zero, Φ is selected from the group of 2- or 4-pyridyl, 2- or 4-pyrimidinyl, 2-pyrazinyl, 5-methyl-2-pyrazinyl, 1-1,2,4-thiadiazolyl, 3-1,2,4-triazolyl, 3-1-benzyl-1,2,4-triazolyl, 2-1,3-thiazolidinyl, 2-1,3-thiazolyl, 3-isoxazolyl, dihydro-isoxazol-4-yl, 5-methyl-isoxazol-4-yl, 2-imidazolyl, imidazol-4-yl-5-carboxyamide, imidazol-2-yl-4,5-dicarbonitrile, 5-indanyl, 5-indazolyl, 7-aza-indol-3-yl, indol-3-yl, 2- or 3- or 4-quinolyl;

a residue of an α-amino acid selected from the group of alanine, valine, leucine, isoleucine, nor-leucine, phenylalanine, p-fluoro-phenylalanine, tyrosine, biphenylalanine, 2′-methoxy-biphenylalanine, tryptophan, 7-azatryptophan, histidine, S-methylcysteine, carboxy-methylcysteine, methionine, O-methyl-serine, O-ethyl-serine, glycine, phenyl- or p-fluorophenyl-glycine;

a residue of an acid chosen from the group of β-alanine, γ-aminobutyric, δ-aminovaleric, cis-4-amino-cyclohexanecarboxylic, trans-4-amino-methylcyclohexanecarboxylic and 3-amino-1,5-pentadioic acid;

a residue of formula (3a)

wherein B represents H; a straight or branched C 1 –C 5 -alkyl; (CH 2 ) ni —NH 2 ;(CH 2 ) ni —NH-t-butoxycarbonyl; —(CH 2 ) ni —NH-benzyloxycarbonyl; —(CH 2 ) ni —CO 2 H wherein n i is an integer between 1 and 3; benzyl; p-fluorobenzyl; p-phenyl-benzyl; p-(2-methoxy-phenyl)-benzyl; —CH 2 O—C 2 H 5 ; —CH 2 —S—CH 3 ; —CH 2 —S—CH 2 —CO 2 H; indolyl-3-methyl; 7-aza-indolyl-3-methyl;

provided that when q is zero, R is SO 2 CH 3 and Ph is 3-chloro-1,4-phenylene, A is other than 1-2,5-dihydro-pyrrolidino; and

wherein said compound inhibits chemotaxis of neutrophils due to interleukin-8.

3. A method for treating a disease selected from the group consisting of psoriasis, ulcerative colitis, glomerulonephritis, acute respiratory failure, idiopathic fibrosis, rheumatoid arthritis and injury caused by ischemia and reperfusion, comprising administering to a subject presenting said disease an effective amount of a compound comprising an amide of the (R)—enantiomers of 2-arylpropionic acids of formula (1):

and pharmaceutically acceptable salts thereof, wherein:

q is zero or the integer 1;

Ph represents a phenylene group linked to the group —(CH 2 ) q -A in its position 2, 3 or 4 and optionally substituted in the remaining positions by one or more substituents, same or different, chosen from C 1 –C 3 -alkyl, halogens, C 1 –C 3 -alkoxy, hydroxy, SH, C 1 –C 3 -alkylthio, nitro, haloalkyl;

A is:

a N—C 1 –C 5 -alkylamino group, a N,N— C 1 –C 5 -dialkylamino group, a N— C 1 –C 8 -alkanoyl(cycloalkanoyl, arylalkanoyl)-N—C 1 –C 5 -alkylamino group;

a heterocyclic ring selected from the group consisting of: piperazine, pyrroline, thiomorpholine, morpholine, quinoline and piperidine;

a residue of formula (2a)

wherein R c , is hydrogen, C 1 –C 3 -alkyl or the residue of a C 1 –C 3 -alkanoic acid;

R is:

—H; —SO 2 —CH 3 ; C 1 –C 3 -alkyl, a residue of formula —CH 2 —CH 2 —X—(CH 2 —CH 2 O) n —P where P is H, methyl, ethyl, isopropyl; —CH 2 CO 2 R 1 , wherein R 1 is H or C 1 –C 3 ; n is an integer from 0 to 5, X is O or S;

a residue of formula (3)

—(CH 2 ) m -Φ  (3)

wherein, when m is an integer from 2 to 3, Φ represents an unsubstituted or substituted phenylene as defined above, 2-(1-methyl-pyrrolidyl), 2-pyridyl, 4-pyridyl, 1-imidazolyl, 4-imidazolyl, 1-methyl-4-imidazolyl, 1-methyl-5-imidazolyl, or a group —NRa,Rb wherein each of Ra and Rb, same or different, represents C 1 –C 5 -alkyl or hydroxyalkyl-(CH 2 ) mi —OH wherein m i is an integer from 2 to 3; when m is zero, Φ is selected from the group of 2- or 4-pyridyl, 2- or 4-pyrimidinyl, 2-pyrazinyl, 5-methyl-2-pyrazinyl, 1-1,2,4-thiadiazolyl, 3-1,2,4-triazolyl, 3-1-benzyl-1,2,4-triazolyl, 2-1,3-thiazolidinyl, 2-1,3-thiazolyl, 3-isoxazolyl, dihydro-isoxazol-4-yl, 5-methyl-isoxazol-4-yl, 2-imidazolyl, imidazol-4-yl-5-carboxyamide, imidazol-2-yl-4,5-dicarbonitrile, 5-indanyl, 5-indazolyl, 7-aza-indol-3-yl, indol-3-yl, 2- or 3- or 4-quinolyl;

a residue of an α-amino acid selected from the group of alanine, valine, leucine, isoleucine, nor-leucine, phenylalanine, p-fluoro-phenylalanine, tyrosine, biphenylalanine, 2′-methoxy-biphenylalanine, tryptophan, 7-azatryptophan, histidine, S-methylcysteine, carboxy-methylcysteine, methionine, O-methyl-serine, O-ethyl-serine, glycine, phenyl- or p-fluorophenyl-glycine;

a residue of an acid chosen from the group of β-alanine, γ-aminobutyric, δ-aminovaleric, cis-4-amino-cyclohexanecarboxylic, trans-4-amino-methylcyclohexanecarboxylic and 3-amino-1,5-pentadioic acid;

a residue of formula (3a)

wherein B represents H; a straight or branched C 1 –C 5 -alkyl; (CH 2 ) ni —NH 2 ;(CH 2 ) ni —NH-t-butoxycarbonyl; —(CH 2 ) ni —NH-benzyloxycarbonyl; —(CH 2 ) ni —CO 2 H wherein n i is an integer between 1 and 3; benzyl; p-fluorobenzyl; p-phenyl-benzyl; p-(2-methoxy-phenyl)-benzyl; —CH 2 O—C 2 H 5 ; —CH 2 —S—CH 3 ; —CH 2 —S—CH 2 —CO 2 H; indolyl-3-methyl; 7-aza-indolyl-3-methyl;

provided that when q is zero, R is SO 2 CH 3 and Ph is 3-chloro-1,4-phenylene, A is other than 1-2,5-dihydro-pyrrolidino; and

wherein said compound inhibits chemotaxis of neutrophils due to interleukin-8.

4. The method according to claim 3 wherein R is a residue of an amino acid selected from the group consisting of glycine, aminomalonic acid, benzyl- and p-fluorobeuzyl-aminomelonic acid, or a residue of a monocarboxylic acid or bicarboxylic α-amino acid.

5. The method according to claim 3 wherein R is a residue of L-alanine, L-phenylalanine, L-p-fluoro-phenylalanine, L-methionine and L-p-(2′-methoxyphenyl)-phenylalanine.

6. The method according to claim 3 wherein R is H, a —SO 2 —CH 3 group, a polyoxyethylene residue of formula —(CH 2 —CH—O) 2 —P wherein P represents H, methyl, ethyl, isopropyl or CH 2 —CO 2 R 1 wherein R 1 is H or C 1 –C 3 alkyl.

7. The method according to claim 3 wherein R is a substituent of formula (3), and wherein, when m is an integer from 2 to 3, Φ is a basic residue selected from the group of substituents consisting of: N,N-diethyl-amine, 4-morpholyl, 1-piperidyl, 1-(4-benzyl)piperazinyl, 1-(4-diphenylmethyl)-piperazinyl, 1-(4-(4′,4″-difluoro-diphenyl)methyl-piperazinyl; or wherein, when m is zero, Φ is an heteroarylic residue such as 2- or 4-pyridyl, 2- or 4-pyrimidinyl, 2-pyrazinyl, 2-1,3-thiazolyl, 2-1,3-thiazolidinyl, 2-imidazolyl and 4-pyridyl.

8. The method according to claim 3 wherein the condition to be treated is psoriasis.

9. The method according to claim 3 wherein the condition to be treated is ulcerative colitis.

10. The method according to claim 3 wherein the condition to be treated is glomerulonephritis.

11. The method according to claim 3 wherein the condition to be treated is acute respiratory failure.

12. The method according to claim 3 wherein the condition to be treated is idiopathic fibrosis.

13. The method according to claim 3 wherein the condition to be treated is rheumatoid arthritis.

14. The method according to claim 3 wherein said chemotaxis of neutrophils follows injury caused by ischaemia and reperfusion.