N-(2-aryl-propionyl)-sulfonamides and pharmaceutical preparations containing them
The compounds of formula 1 wherein R and R 2 are as defined in the disclosure, are useful in the prevention and treatment of tissue damage due to exacerbated recruitment of polymorphonuclear neutrophils (PMN leukocytes) at the inflammatory sites.
1. A compound of formula 1
in which
R is an aryl group,
R is a straight or branched C 1 -C 16 -alkyl, trifluoromethyl, cyclohexyl, o-tolyl, 3-pyridyl, 2-pyridyl-ethyl, p-cyanophenylmethyl, p-aminophenylmethyl, 3-cyano-1-propyl, 4-aminobutyl group, an alkoxyethylene CH 3 —(CH 2 ) ni —(OCH 2 CH 2 ) mi — group in which n i is zero or 1 and m i is an integer 1 to 3, or a P 1 P 2 N—CH 2 —CH 2 — group in which P 1 and P 2 are independently H, C 1 -C 3 -alkyl, benzyloxy-carbonyl, α-, β- or γ-pyridocarbonyl, carboxycarbonyl or carbalkoxycarbonyl, or P 1 and P 2 , when joined to the N atom which they are linked to, form a phthalimido, piperidino, morpholino residue;
R′ is H or straight or branched C 1 -C 3 -alkyl and salts thereof with strong and medium bases.
2. The compound of claim 1 wherein R′ is hydrogen.
3. The compound of claim 1 or 2 in which R 2 is selected from the group consisting of: 4-isobutylphenyl, 3-benzoylphenyl, 5-benzoyl-2-acetoxyphenyl, 3-phenoxyphenyl, 5-nenzoyl-thien-2-yl, 4-thienoylphenyl, 1-oxo-2-isoindolinyl-phenyl, 3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)phenyl, methoxyethane-naphthyl, 1-hydroxyphenyl or a residue of formula
in which A is benzyl, benzoyl or benzoyl-oxime, 1-hydroxyphenyl-1-methyl, B is hydrogen, hydroxy, C 1 -C 3 -acyloxy or amino.
4. The compound of claim 1 in which the asymmetric carbon substituted with methyl has absolute configuration R.
5. The compound of claim 1 , which is R(−)-N-2-[(4-isobutylphenyl)propionyl]-methanesulfonamide and its L(+)-lysine salt.
6. The compound of claim 1 , which is R(−)-N-2-[3-(benzoylphenyl)-propionyl]-methanesulfonamide.
7. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
8. A method for treating a disease selected from the group consisting of: psoriasis, rheumatoid arthritis, ulcerative colitis, acute respiratory insufficiency, idiopathic fibrosis, and glomerulonephritis in a patient in need thereof, comprising the step of administering the compound of claim 1 to said patient.
9. The method according to claim 8 , wherein the compound is R(−)-N-2-[(4-isobutylphenyl)propionyl]-methanesulfonamide or its L(+)-lysine salt.
10. A method for inhibiting the chemotaxis and degranulation of neutrophils induced by interleukin 8 in a mammal, comprising the step of administering the compound of claim 1 to said mammal.
11. A process for the preparation the compound of claim 1 , comprising the steps of:
reacting equimolecular amounts of an acid of formula (2)
in which R 2 ′ has the same meanings as the group R 2 defined in claim 1 , or is a group which can be transformed into R 2 by removing any protecting groups, with equimolecular amounts of a sulfonamide of formula (3):
in which R and R′ have the meanings defined in claim 1 , in the presence of a condensing agent in an inert solvent.
12. A method for preparing the compound of claim 1 , comprising the steps of:
reacting a sulfonamide anion of formula (3′):
in which R and R′ have the meanings defined in claim 1 , in the presence an inert solvent, with the chlorides of acids of formula (2)
in which R 2 ′ has the same meanings as the group R 2 defined in claim 1 .