US 5,543,396 AGranted

Proline phosphonate derivatives

AssigneeGeorgia Tech Research Corporation

InventorsJames C. Powers, Bogdan Boduszek, Jozef Oleksyszyn

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Abstract

Peptidyl derivatives of diesters of .alpha.-aminoalkylphosphonic acids, particularly those with proline or related structures, their use in inhibiting serine proteases with chymotrypsin-like, trypsin-like, elastase-like, and dipeptidyl peptidase IV specificity and their roles as anti-inflammatory agents, anticoagulants, and anti-tumor agents.

Claims13

Dependent claims

A compound having the following structures:

##STR7## or a pharmaceutically acceptable salt thereof, wherein Z and Z.sup.1 are the same or different and are selected from the group consisting of C.sub.1-6 perfluoralkyl, phenyl, phenyl substituted with J, phenyl disubstituted with J, phenyl trisubstituted with J, and pentafluorophenyl;
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, and C.sub.1-6 alkoxy--CO--, and C.sub.1-6 alkyl--S--;
X is selected from the group consisting of
(a) a single bond,
(b) --CH.sub.2 --,
(c) --CH.sub.2 CH.sub.2 --,
(d) --CH.sub.2 CH.sub.2 CH.sub.2 --,
(e) --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --,
(f) --Y--
(g) --CH.sub.2 --Y--,
(h) --Y--CH.sub.2 --, and
(i) --H, H--,
wherein Y is O or S;
and
AA is attached through the carboxylic end and is selected from the group consisting of
(a) the structure NH.sub.2 --CHR--CO--
where R is selected from the group consisting of C.sub.1-6 alkyl and C.sub.1-6 fluorinated alkyl,
(b) a side chain blocked or unblocked alpha amino acid residue with the L, D or DL configuration at the .alpha.-carbon atom selected from the group consisting of alanine, valine, leucine, isoleucine, proline, methionine, methionine sulfoxide, phenylalanine, tryptophan, serine, threonine, cysteine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, phenylglycine, norleucine, norvaline, alpha-aminobutyric acid, citrulline, hydroxyproline, ornithine, homoarginine, O-methylserine, O-ethylserine, S-methylcysteine, S-ethylcysteine, S-benzylcysteine, [NH.sub.2 --CH(CH.sub.2 CHEt.sub.2)--COOH]NH.sub.2 --CH(CH.sub.2 CHEt.sub.2)--CO--, alpha-aminoheptanoic acid, [NH.sub.2 --CH(CH.sub.2 -1-napthyl)--COOH, NH.sub.2 --CH(CH.sub.2 -2-napthyl)--COOH, NH.sub.2 --CH(CH.sub.2 -cyclohexyl)--COOH, NH.sub.2 --CH(CH.sub.2 -cyclopentyl)--COOH, NH.sub.2 --CH(CH.sub.2 -cyclobutyl) --COOH, NH.sub.2 --CH(CH.sub.2 -cyclopropyl)--COOH,]NH.sub.2 --CH(CH.sub.2 -1-napthyl)--CO--, NH.sub.2 --CH (CH.sub.2 -2-napthyl)--CO--, NH.sub.2 --CH(CH.sub.2 -cyclohexyl)--CO--, NH.sub.2 --CH(CH.sub.2 -cyclopentyl)--CO--, NH.sub.2 --CH(CH.sub.2 -cyclobutyl)--CO--, NH.sub.2 --CH(CH.sub.2 -cyclopropyl)--CO--5,5,5-trifluoroleucine, and hexafluoroleucine,
(c) an amino acid residue selected from the group consisting of beta-alanine, glycine, epsilon-aminocaproic acid, and sarcosine, and
(d) C.sub.6 H.sub.5 CH.sub.2 OCO--.

17 more elements

A compound having the following structures:

##STR8## or a pharmaceutically acceptable salt thereof, wherein Z and Z.sup.1 are the same or different and are selected from the group consisting of C.sub.1-6 perfluoralkyl, phenyl, phenyl substituted with J, phenyl disubstituted with J, phenyl trisubstituted with J, and pentafluorophenyl;
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, and C.sub.1-6 alkoxy--CO--, and C.sub.1-6 alkyl--S--;
X is selected from the group consisting of --CH.sub.2 -- and --CH2CH.sub.2 -- and,
AA is attached through the carboxylic end and is selected from the group consisting of
(a) the structure NH.sub.2 --CHR--CO--
where R is selected from the group consisting of C.sub.1-6 alkyl and C.sub.1-6 fluorinated alkyl,
(b) a side chain blocked or unblocked alpha amino acid residue with the L, D or DL configuration at the .alpha.-carbon atom selected from the group consisting of alanine, valine, leucine, isoleucine, proline, methionine, methionine sulfoxide, phenylalanine, tryptophan, serine, threonine, cysteine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, phenylglycine, norleucine, norvaline, alpha-aminobutyric acid, citrulline, hydroxyproline, ornithine, homoarginine, O-methylserine, O-ethylserine, S-methylcysteine, S-ethylcysteine, S-benzylcysteine, [NH.sub.2 --CH(CH.sub.2 CHEt.sub.2)--COOH]NH.sub.2 --CH(CH.sub.2 CHEt.sub.2)--CO--, alpha-aminoheptanoic acid, [NH.sub.2 --CH(CH.sub.2 -1-napthyl)--COOH, NH.sub.2 --CH(CH.sub.2 -2-napthyl)--COOH, NH.sub.2 --CH(CH.sub.2 -cyclohexyl)--COOH, NH.sub.2 --CH(CH.sub.2 -cyclopentyl)--COOH, NH.sub.2 --CH(CH.sub.2 -cyclobutyl)--COOH, NH.sub.2 --CH(CH.sub.2 -cyclopropyl)--COOH,]NH.sub.2 --CH(CH.sub.2 -1-napthyl)--CO--, NH.sub.2 --CH (CH.sub.2 -2-napthyl)--CO--, NH.sub.2 --CH(CH.sub.2 -cyclohexyl)--CO--, NH.sub.2 --CH(CH.sub.2 -cyclopentyl)--CO--, NH.sub.2 --CH(CH.sub.2 -cyclobutyl)--CO--, NH.sub.2 --CH(CH.sub.2 -cyclopropyl)--CO--5,5,5-trifluoroleucine, and hexafluoroleucine,
(c) an amino acid residue selected from the group consisting of beta-alanine, glycine, epsilon-aminocaproic acid, and sarcosine,
(d) H, and
(e) C.sub.6 H.sub.5 CH.sub.2 OCO--.

7 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound having the following structures:

##STR7## or a pharmaceutically acceptable salt thereof, wherein Z and Z.sup.1 are the same or different and are selected from the group consisting of C.sub.1-6 perfluoralkyl, phenyl, phenyl substituted with J, phenyl disubstituted with J, phenyl trisubstituted with J, and pentafluorophenyl;
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, and C.sub.1-6 alkoxy--CO--, and C.sub.1-6 alkyl--S--;
X is selected from the group consisting of
(a) a single bond,
(b) --CH.sub.2 --,
(c) --CH.sub.2 CH.sub.2 --,
(d) --CH.sub.2 CH.sub.2 CH.sub.2 --,
(e) --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --,
(f) --Y--
(g) --CH.sub.2 --Y--,
(h) --Y--CH.sub.2 --, and
(i) --H, H--,
wherein Y is O or S;
and
AA is attached through the carboxylic end and is selected from the group consisting of
(a) the structure NH.sub.2 --CHR--CO--
where R is selected from the group consisting of C.sub.1-6 alkyl and C.sub.1-6 fluorinated alkyl,
(b) a side chain blocked or unblocked alpha amino acid residue with the L, D or DL configuration at the .alpha.-carbon atom selected from the group consisting of alanine, valine, leucine, isoleucine, proline, methionine, methionine sulfoxide, phenylalanine, tryptophan, serine, threonine, cysteine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, phenylglycine, norleucine, norvaline, alpha-aminobutyric acid, citrulline, hydroxyproline, ornithine, homoarginine, O-methylserine, O-ethylserine, S-methylcysteine, S-ethylcysteine, S-benzylcysteine, [NH.sub.2 --CH(CH.sub.2 CHEt.sub.2)--COOH]NH.sub.2 --CH(CH.sub.2 CHEt.sub.2)--CO--, alpha-aminoheptanoic acid, [NH.sub.2 --CH(CH.sub.2 -1-napthyl)--COOH, NH.sub.2 --CH(CH.sub.2 -2-napthyl)--COOH, NH.sub.2 --CH(CH.sub.2 -cyclohexyl)--COOH, NH.sub.2 --CH(CH.sub.2 -cyclopentyl)--COOH, NH.sub.2 --CH(CH.sub.2 -cyclobutyl) --COOH, NH.sub.2 --CH(CH.sub.2 -cyclopropyl)--COOH,]NH.sub.2 --CH(CH.sub.2 -1-napthyl)--CO--, NH.sub.2 --CH (CH.sub.2 -2-napthyl)--CO--, NH.sub.2 --CH(CH.sub.2 -cyclohexyl)--CO--, NH.sub.2 --CH(CH.sub.2 -cyclopentyl)--CO--, NH.sub.2 --CH(CH.sub.2 -cyclobutyl)--CO--, NH.sub.2 --CH(CH.sub.2 -cyclopropyl)--CO--5,5,5-trifluoroleucine, and hexafluoroleucine,
(c) an amino acid residue selected from the group consisting of beta-alanine, glycine, epsilon-aminocaproic acid, and sarcosine, and
(d) C.sub.6 H.sub.5 CH.sub.2 OCO--.

17 more elements