Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-10-23
1998-06-02
Russel, Jeffrey E.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514 20, 546193, 546196, 546205, 548518, 548524, 548525, 548537, A61K 3805, C07K 5078
Patent
active
057602352
DESCRIPTION:
BRIEF SUMMARY
This invention relates to new peptide derivatives of the general formula (I), group, furthermore an acyl group of the general formula 2-naphthylmethyl, 9-fluorenyl, benzhydryl, cyclohexyl, cyclohexylmethyl, 2-pyridyl, 3-pyridyl or 4-pyridyl group, and L-arginine residue as Arg is in accordance with the prior art, e.g. Biochem. J. 126, 773 (1972); Biochemistry 14, 449 (1975)!.
The invention furthermore relates to a process for preparing the new peptide derivatives of the general formula (I) and pharmaceutical compositions containing these compounds.
The compounds of the invention have valuable therapeutic, particularly anticoagulant properties.
Preferred representatives of the compounds having the formula (I) are those described in the Examples.
Particularly preferred representatives of the compounds according to the invention are the following derivatives:
It is known that the aldehyde, derived from the tripeptide D-phenylalanyl-L-prolyl-L-arginine (Hungarian patent specification No. and Tarnus: Thrombos Haemostas 65, 1290 (1991)!, and the boro-arginine anticoagulants exerting activity both in vitro and in vivo. However, these compounds are rather unstable and are converted in neutral aqueous (1990)!. No. 4,478,475 and Kettner et al.: J. Biol. Chem. 265, 18289 (1990)) or alkylating (U.S. Pat. No. 4,703,036) the D-phenylalanine moiety, or by exchanging it for analogue amino or imino acids such as N-methylphenylglycine or 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid Symposium (Eds. J. A. Smith and J. E. Rivier), ESCOM, Leyden, pp. 801-802, 1992!. It is a characteristic feature of highly active anticoagulant peptides that they are tripeptide derivatives, and the N-terminal residue, linked to the central L-proline moiety, is an amino or imino acid residue. These tripeptides correspond to the general formula (I) only if A stands for a D-phenylalanine residue, and acylated or alkylated derivative an amino acid or imino acid analogue thereof.
It is the objective of the present invention to provide novel peptide derivatives of improved stability and bioavailability compared to known compounds.
It was unexpectedly found that the tripeptide structure is not a prerequisite of anticoagulant activity, a carboxylic acid group containing advantageously substituted for the N-terminal amino acid or imino acid moiety of the known compounds.
Furthermore it has also been found that the compounds of the general formula (I) according to the invention, wherein A, A', Xaa and Arg have the same meaning as above, and their acid-addition salts are stable in aqueous solution, exert strong anticoagulant activity both in vitro and in vivo, and have favorable bioavailability.
According to the invention the compounds of general formula (I) and their acid-addition salts formed with an organic or inorganic acid are prepared by a process which comprises condensing an acid, containing an acyl radical A, wherein A has the above meaning, and L-proline or L-pipecolinic acid, converting the thus-obtained acyl-L-proline or acyl-L-pipecolinic acid by a method known in the art by acylating an arginine lactam protected at the guanidino group with the said acyl-L-proline or acyl-L-pipecolinic acid, reducing the protected acyl-arginine lactam to the protected acyl-arginine aldehyde and removing the protecting groups, and, if desired, finally converting the resulting compound of the general formula (I) with an inorganic or organic acid to an acid-addition salt.
Compounds of the general formula (I), wherein A, A', Xaa and Arg have the same meaning as in the introduction, are prepared from the new acyl-L-proline or acyl-L-pipecolinic acid synthesized by the first step of the process of the invention, according to the method as described in the U.S. Pat. No. 4,703,036 disclosing compounds of similar structure.
According to a preferred embodiment of the process according to the invention DL-isochroman-1-carboxylic acid is condensed with L-proline t-butyl ester, the ester group is removed by acidolysis from the DL-acyl-L-proline t-butyl ester formed, th
REFERENCES:
patent: 4316889 (1982-02-01), Bajusz et al.
patent: 4703036 (1987-10-01), Bajusz et al.
patent: 5380713 (1995-01-01), Balasubramanian et al.
patent: 5416093 (1995-05-01), Shuman
patent: 5430023 (1995-07-01), Gesellchen et al.
Copy of U.S. Patent Application Serial No. 07/756,091, filed Sep. 6, 1991, Which is the Parent to U.S. 5,430,023.
Aranyosi Katalin Palne
Bagdy Daniel
Bajusz Sandor
Barabas Eva
Feher Andras
Gyogyszerkutato Intezet Kft.
Russel Jeffrey E.
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