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US 5,686,419 AGranted
Basic .alpha.-aminoalkylphosphonate derivatives
AssigneeGeorgia Tech Research Corporation
InventorsJames C. Powers, Bogdan Boduszek, Jozef Oleksyszyn
Life of this patent
Estimating the term…
Abstract
Peptidyl derivatives of diesters of .alpha.-aminoalkylphosphonic acids with basic substitutents, their use in inhibiting serine proteases with trypsin-like specificity and their roles as anti-inflammatory agents, anticoagulants, and anti-tumor agents.
Claims8
A compound of the formula:
- ##STR6## or a pharmaceutically acceptable salt, wherein:
- R is selected from the group consisting of phenyl substituted with B, benzyl substituted with B on the phenyl ring, and C.sub.1-6 alkyl substituted with B,
- B is selected from the group consisting of amidino {--C(.dbd.NH)NH.sub.2 }, guanidino {--NH--C(.dbd.NH)NH.sub.2 }, isothiureido {--S--C(.dbd.NH)NH.sub.2 }, and amino,
- Z and Z.sup.1 are the same or different and are selected from the group consisting of C.sub.1-6 perfluoroalkyl, phenyl, phenyl substituted with J, phenyl disubstituted with J, and phenyl trisubstituted with J,
- J is selected from the group consisting of halogen, C.sub.1-6 alkyl, C.sub.1-6 perfluoroalkyl, C.sub.1-6 alkoxy, NO.sub.2, CN, OH, CO.sub.2 H, amino, C.sub.1-6 alkylamino, C.sub.2-12 dialkylamino, C.sub.1-6 acyl, C.sub.1-6 alkoxy--CO--, and C.sub.1-6 alkyl--S--,
- AA.sup.2 is selected from the group consisting of
- (a) a blocked or unblocked amino acid residue with the L or D configuration at the .alpha.-carbon selected from the group consisting of alanine, valine, leucine, isoleucine, proline, methionine, methionine sulfoxide, phenylalanine, tryptophan, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, phenylglycine, norleucine, norvaline, alpha-aminobutyric acid, citrulline, hydroxyproline, ornithine, and homoarginine, and
- (b) glycine, sarcosine, epsilon-aminocaproic acid, and beta-alanine,
- AA.sup.3 is selected from the group consisting of
- (a) a single bond, and
- (b) a blocked or unblocked amino acid residue with the L or D configuration at the .alpha.-carbon selected from the group consisting of alanine, valine, leucine, isoleucine, proline, methionine, methionine sulfoxide, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, phenylglycine, norleucine, norvaline, alpha-aminobutyric acid, citrulline, hydroxyproline, ornithine, and homoarginine, and
- (c) glycine, sarcosine, epsilon-aminocaproic acid, and beta-alanine,
- AA.sup.4 is selected from the group consisting of:
- (a) a single bond,
- (b) a blocked or unblocked amino acid residue with the L or D configuration at the .alpha.-carbon selected from the group consisting of alanine, valine, leucine, isoleucine, proline, methionine, methionine sulfoxide, phenylalanine, tryptophan, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine,. histidine, phenylglycine, norleucine, norvaline, alpha-aminobutyric acid, citrulline, hydroxyproline, ornithine, and homoarginine, and
- (c) glycine, sarcosine, epsilon-aminocaproic acid, and beta-alanine, except that if AA.sup.3 is a single bond, AA.sup.4 is not tryptophan or phenylalanine,
- X is selected from the group consisting of H, NH.sub.2 --CO--, NH.sub.2 --CS--, NH.sub.2 --SO.sub.2 --, Y--NH--CO--, Y--NH--CS--, Y--NH--SO.sub.2 --, Y--CS--, Y--SO.sub.2 --, Y--O--CO--, Y--O--CS--, and U--CO--,
- Y is selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 fluoroalkyl, C.sub.1-6 alkyl substituted with K, C.sub.1-6 fluoroalkyl substituted with K, 9-fluorenylmethyl, phenyl, phenyl substituted with J, phenyl disubstituted with J, phenyl trisubstituted with J, naphthyl, naphthyl substituted with J, naphthyl disubstituted with J, naphthyl trisubstituted with J, C.sub.1-6 alkyl with an attached phenyl group, C.sub.1-6 alkyl with two attached phenyl groups, C.sub.1-6 alkyl with an attached phenyl group substituted with J, and C.sub.1-6 alkyl with two attached phenyl groups substituted with J, and
- U is selected from the group consisting of C.sub.1-6 fluoroalkyl, C.sub.1-6 alkyl substituted with K, C.sub.1-6 fluoroalkyl substituted with K, 9-fluorenylmethyl, phenyl, phenyl substituted with J, phenyl disubstituted with J, phenyl trisubstituted with J, naphthyl, naphthyl substituted with J, naphthyl disubstituted with J, naphthyl trisubstituted with J, C.sub.1-6 6 alkyl with an attached phenyl group, C1-6 alkyl with two attached phenyl groups, C.sub.1-6 6 alkyl with an attached phenyl group substituted with J, and C.sub.1-6 alkyl with two attached phenyl groups substituted with J, and
- K is selected from the group consisting of halogen, COOH, OH, CN, NO.sub.2, NH.sub.2, C.sub.1-6 alkoxy, C.sub.1-6 alkylamine, C.sub.1-6 dialkylamine, C.sub.1-6 alkyl--O--CO--, C.sub.1-6 alkyl--O--CO--NH, and C.sub.1-6 alkyl--S--.
17 more elements
A compound selected from the group consisting of:
- (a) H-(4-AmPhGly).sup.P (OPh).sub.2,
- (b) Cbz-(4-AmPhGly).sup.P (OPh).sub.2,
- (c) H-(3-AmPhGly).sup.P (OPh).sub.2,
- (d) Cbz-(3 -AmPhGly).sup.P (OPh).sub.2,
- (e) Cbz-Pro-(4-AmPhGly).sup.P (OPh).sub.2,
- (f) D-Phe-Pro-(4-AmPhGly).sup.P (OPh).sub.2,
- (g) Boc-D-Phe-L-Pro-(4-AmPhGly).sup.P (OPh).sub.2,
- (h) 2-NpSO.sub.2 -Gly-(4-AmPhGly).sup.P (OPh).sub.2,
- (i) Boc-Phe-Phe-(4-AmPhGly).sup.P (OPh).sub.2,
- (j) Benzoyl-NHCH(4-NH.sub.2 -C.sub.6 H.sub.4)PO(OPh).sub.2,
- (k) H-(4-AmPhe).sup.P (OPh).sub.2,
- (l) Cbz-(4-AmPhe).sup.P (OPh).sub.2,
- (m) Cbz-Pro-(4-AmPhe).sup.P (OEt).sub.2,
- (n) Boc-D-Phe-Pro-(4-AmPhe).sup.P (OPh).sub.2,
- (o) D-Phe-Pro-(4-AmPhe).sup.P (OPh).sub.2,
- (p) Cbz-Thr-(4-AmPhGly).sup.P (OPh).sub.2,
- (q) Boc-Leu-Thr-(4-AmPhGly).sup.P (OPh).sub.2,
- (r) H-(4-AmPhGly).sup.P (OPh-4-Cl).sub.2, and
- (s) Cbz-(4-AmPhGly).sup.P (OPh-4-Cl).sub.2.
16 more elements
Dependencies are inferred from the claim text.