Novel Salts of Fumaric Acid Monoalkylesters and Their Pharmaceutical Use
The present invention relates to novel amino acid salts of fumaric acid monoalkylesters. The salts are suitable for use as active substances in the treatment of e.g. psoriasis or other hyperproliferative, inflammatory or autoimmune disorders.
1 . A compound of the general formula (I)
wherein
R 1 is: C 1-5 alkyl and
X + is a protonated form of an amino acid, and any enantiomers or racemic mixtures thereof.
2 . The compound according to claim 1 selected from the group consisting of
amino acid salts of monomethylester of fumaric acid,
amino acid salts of monoethylester of fumaric acid,
amino acid salts of monopropylester of fumaric acid,
amino acid salts of monobutylester of fumaric acid, and
amino acid salts of monopentylester of fumaric acid.
3 . The compound according to claim 1 , wherein the amino acid is selected from the group consisting of natural amino acids.
4 . The compound according to claim 3 , wherein the amino acid is selected from the group consisting of lysine, arginine, glutamine, histidine, ornithine and tryptophan.
5 . The compound according to claim 1 , which is an amino acid salt of the monomethylester of fumaric acid.
6 . The compound according to claim 1 , which compound is selected from the group consisting of:
(S)-2-hydro-2,6-diaminohexanal-(E)-methoxy-4-oxobut-2-enoate(lysine monomethylfumarate),
(S)-6-hydro-2,6-diaminohexanal-(E)-methoxy-4-oxobut-2-enoate(lysine monomethylfumarate),
2-hydro-amino-((E)-methoxy-4-oxobut-2-enoate)-3-hydroxybutanoic acid (threonine monomethylfumarate),
hydro-pyrrolidine-((E)-methoxy-4-oxobut-2-enoate)-2-carboxylic acid (proline monomethylfumarate),
(S)-2-hydro-amino-((E)-methoxy-4-oxobut-2-enoate)-3-(IH-imidazol-5-yl)propanoic acid (histidine monomethylfumarate),
2-hydro-((E)-methoxy-4-oxobut-2-enoate)-aminopropanoic acid (alanine monomethylfumarate),
2-hydro-amino-((E)-methoxy-4-oxobut-2-enoate)-acetic acid (glycine monomethylfumarate),
2-hydro-amino-((E)-methoxy-4-oxobut-2-enoate)-3-hydroxypropanoic acid (serine monomethylfumarate),
2-hydro-amino-((E)-methoxy-4-oxobut-2-enoate)-5-guanidinopentanoic acid (arginine monomethylfumarate),
2-hydro-amino-((E)-methoxy-4-oxobut-2-enoate)-3-mercaptopropanoic acid (cystein monomethylfumarate),
2-hydro-2,4-diamino-((E)-methoxy-4-oxobut-2-enoate)-4-oxobutanoic acid (asparagine monomethylfumarate), and
4-hydro-2,4-diamino-((E)-methoxy-4-oxobut-2-enoate)-4-oxobutanoic acid (asparagine monomethylfumarate).
7 . A compound according to claim 5 , which is a lysine salt of the monomethylester of fumaric acid.
8 . A composition comprising a compound according to claim 1 in combination with di(C 1-5 )alkylester of fumaric acid,
9 . A composition comprising a compound according to claim 1 in combination with a mono(C 1-5 )alkylester of fumaric acid, optionally in the form of a pharmaceutically acceptable salt.
10 - 18 . (canceled)
19 . A pharmaceutical composition comprising a compound as defined according to claim 1 .
20 . The pharmaceutical composition according to claim 19 in the form of a controlled release composition.
21 . A method of treating and/or preventing one or more conditions selected from the group consisting of psoriasis, psoriatic arthritis, neurodermatitis, atopic dermatitis, inflammatory bowel disease, autoimmune diseases, pain, organ transplantation (prevention of rejection), sarcoidosis, necrobiosis lipoidica, granuloma annulare, lupus nephritis, myasthenia gravis, uveitis, refractory uveitis, vernal conjunctivitis, pemphigus vulgaris, and/or scleroderma, which method comprises administering orally to a patient in need thereof, an effective dosage of a compound according to claim 1 .
22 . The method according to claim 21 , wherein the autoimmume disease is multiple sclerosis.
23 . The method according to claim 21 , wherein the condition is psoriasis.
24 . The method according to claim 21 , wherein the condition is psoriatic arthritis.