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US 5,892,112 AGranted
Process for preparing synthetic matrix metalloprotease inhibitors
AssigneesGlycomed Incorporated, University of Florida
InventorsDaniel E. Levy, Damian Grobelny, Cho Tang, Kevin R. Holme, Richard E. Galardy, Gregory S. Schultz, Asaad Nematalia, John H. Musser
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Abstract
Synthetic mammalian matrix metalloprotease inhibitors are disclosed that are useful for treating or preventing diseases wherein said diseases are caused by unwanted mammalian matrix metalloprotease activity and include skin disorders, keratoconus, restenosis, rheumatoid arthritis, wounds, cancer, angiogenesis and shock.
Claims14
A process for the synthesis of an N-acyl-L-amino acid carboxamide which process comprises the steps of
- (a) acylating the .alpha.-amino group of an L-amino acid with a acylating agent selected from the group consisting of
- (i) carboxylic acid anhydrides and
- (ii) compounds comprising two carboxylic acid derivatives
- (A) wherein the first carboxylic acid derivative is an activated acyl, and
- (B) wherein the second carboxylic acid derivative is selected from the group consisting of carboxylic acids and carboxylic esters to yield an N-acyl-L-amino acid comprising a carboxylic acid or carboxylic eater derived from said acylating agent;
- (b) amidating the C-terminal carboxylic acid of said N-acyl L-amino acid with an amine to yield an intermediate N-acyl-L-amino acid carboxamide comprising a carboxylic acid or carboxylic ester derived from said acylating agent;
- (c) converting said carboxylic acid or carboxylic ester to a hydroxamic acid;
- or
- (d) hydrolyzing said carboxylic ester.
6 more elements
A process for the synthesis of racemic 2-isobutyl-3-(methoxycarbonyl)propanoic acid which process comprises the steps of
- (a) reacting maleic anhydride with 2-methylpropene to yield .beta.-methallylsuccinic anhydride;
- (b) reducing the carbon-carbon double bond of said .beta.-methallylsuccinic anhydride to yield isobutylsuccinic anhydride;
- and
- (c) treating said isobutylsuccinic anhydride with anhydrous methanol to yield racemic 2-isobutyl-3-(methoxycarbonyl)propanoic acid;
- and
- (d) recovering said racemic 2-isobutyl-3-(methoxycarbonyl)propanoic acid.
3 more elements
A process for resolving and isolating racemic 2-isobutyl-3-(methoxycarbonyl)propanoic acid comprising the steps of
- (a) reacting racemic 2-isobutyl-3-(methoxycarbonyl)propanoic acid with a resolving agent to form a diastereomeric mixture;
- (b) separating from said diastereomeric mixture at least one stereochemically pure diastereomer through a difference in physical properties;
- (c) releasing said resolving agent from said stereochemically pure diastereomer;
- and
- (d) isolating enantiomerically pure 2-isobutyl-3-(methoxycarbonyl)propanoic acid.
2 more elements
A process for the synthesis of an N-acyl-L-amino acid carboxamide derivatives which process comprises the steps of
- (a) amidating the C-terminal carboxylic acid of an L-amino acid with an amine to yield an L-amino acid carboxamide;
- (b) acylating the .alpha.-amino group of said L-amino acid carboxamide with an acylating agent selected from the group consisting of
- (i) carboxylic acid anhydrides
- (ii) compounds comprising two carboxylic acid derivatives
- (A) wherein the first carboxylic acid derivative is an activated acyl, and
- (B) wherein the second carboxylic acid derivative is selected from the group consisting of carboxylic acids and carboxylic esters to yield an intermediate N-acyl-L-amino acid carboxamide comprising a carboxylic acid or carboxylic ester derived from said acylating agent;
- (c) converting said carboxylic acid or carboxylic ester into a hydroxamic acid;
- or
- (d) acid hydrolysis of said ester.
6 more elements
A process for the synthesis of an N-acyl-L-tryptophan carboxamide of the formula:
- ##STR31## wherein R.sup.1 is selected from the group consisting of H and alkyl;
- R.sup.2 is selected from the group consisting of H, alkyl, and --NHZ, wherein
- Z is selected from the group consisting of --R.sup.11, --COR.sup.11, and --COOR.sup.11 where R.sup.11 is alkyl,
- or wherein the R.sup.1 and R.sup.2 taken together are --(CH.sub.2).sub.p --, wherein p is 3-5;
- R.sup.3 is selected from the group consisting of H and C.sub.1-4 alkyl;
- R.sup.4 is selected from the group consisting of --CH.sub.3 and fused or conjugated, optionally substituted bicycloaryl methylenes;
- n is 0, 1 or 2;
- X is selected from the group consisting of --OR.sup.5, --NHR.sup.5, --NR.sup.5 R.sup.5, --NH(CH.sub.2).sub.q and --M, wherein R.sup.5 is independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted aryl, and optionally substituted aryl alkyl;
- q is 1-8;
- M is selected from the group consisting of amino acids, amides of amino acids, cyclic amines, and heterocyclic amines;
- R.sup.6 is selected from the group consisting of H and lower alkyl;
- and
- R.sup.7 is selected from the group consisting of H, lower alkyl, and acyl;
- which process comprises the steps of
- (a) acylating the .alpha.-amino group of an L-amino acid with a carboxylic acid derivative selected from the group consisting of ##STR32## to yield an N-acyl-L-amino acid of the formula:
- ##STR33## (b) amidating the C-terminal carboxylic acid of said N-acyl-L-amino acid with an amine to yield an N-acyl-L-amino acid carboxamide of the formula:
- ##STR34## and followed by the step of (c) converting said --COOR group to a hydroxamic acid group;
- or
- (d) acid hydrolyzing said --COOR group to a carboxylic acid wherein said --COOR group is an ester.
16 more elements
A process for the synthesis of a compound of the formula:
- ##STR35## wherein R.sup.1 is selected from the group consisting of H and alkyl;
- R.sup.2 is selected from the group consisting of H, alkyl, and NHZ, wherein
- Z is selected from the group --R.sup.11, --COR.sup.11, and --COOR.sup.11 where R.sup.11 is alkyl,
- or wherein the R.sup.1 and R.sup.2 taken together are --(CH.sub.2).sub.p --, wherein p is 3-5;
- R.sup.3 is selected from the group consisting of H and C.sub.1-4 alkyl;
- R.sup.4 is selected from the group consisting of --CH.sub.3 and fused or conjugated, optionally substituted bicycloaryl methylene;
- n is 0, 1 or 2;
- X is selected from the group consisting of --OR.sup.5, --NHR.sup.5, --NR.sup.5 R.sup.5, --NH(CH.sub.2).sub.q and --M, wherein
- R.sup.5 is independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted aryl, and optionally substituted aryl alkyl;
- q is 1-8;
- M is selected from the group consisting of amino acids, amides of amino acids, cyclic amines, and heterocyclic amines;
- R.sup.6 is selected from the group consisting of H and lower alkyl;
- and
- R.sup.7 is selected from the group consisting of H, lower alkyl, and acyl;
- which process comprises the steps of
- (a) amidating the C-terminal carboxylic acid of an L-amino acid with an amine to yield an L-amino acid carboxamide of the formula:
- ##STR36## (b) acylating the .alpha.-amino group of said L-amino acid carboxamide with a carboxylic acid derivative selected from the group consisting of ##STR37## to yield an N-acyl-L-amino acid carboxamide of the formula:
- ##STR38## and followed by the step of (c) converting said --COOR group to an hydroxamic acid group;
- or
- (d) acid hydrolyzing of said --COOR group to a carboxylic acid wherein said --COOR group is an ester.
17 more elements
Dependencies are inferred from the claim text.