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US 2003/0120073 A1Published application
Alpha-ketocarboxylic acid based inhibitors of phosphoryl tyrosine phosphatases
OwnerChristopher T. Setoinventor
Life of this patent
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Abstract
Protein tyrosine phosphatases (PTPs) are implicated in a number of disease processes, including autoimmune diseases, glucose intolerance, diabetes, obesity and certain types of proliferative diseases such as cancer and psoriasis. The present invention discloses novel α-ketocarboxylic acid inhibitors of PTPs, methods for synthesizing said inhibitors, and methods for using pharmaceutical compositions of the inhibitors to treat PTP-mediated disorders, diseases or dysfunctions. The compositions described herein can also be used as diagnostic and screening tools to elucidate complex signal transduction pathways involving PTPs or to identify PTP-mediated disease states.
Claims40
A compound having the general structure shown in Formula 1:
- 37
- wherein, as valence and stability permits,
- A represents an alkyl or heteroalkyl, or a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or polycycle;
- V, independently for each occurrence, is absent or represents a group selected from lower alkyl, alkoxy, arylalkyl, or a group with up to 10 heavy atoms;
- R1, independently for each occurrence, represents one or more of hydrogen, halogen, hydroxyl, alkoxyl, silyloxyl, amino, nitro, sulfhydryl, alkylthio, imine, amide, cyano, carbonyl, carboxyl, carboxamide, silyl, sulfamoyl, sulfinyl, thioalkyl, alkylsulfonyl, arylsulfonyl, ketone, aldehyde, ester, isocyano, guanidine, amidine, acetal, ketal, amine oxide, azide, carbamate, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbonate, urea, thiourea, or a substituted or unsubstituted alkyl or heteroalkyl, alkenyl, alkynyl, aryl or heteroaryl or —(CH2)m-R3;
- R3 represents a substituted or unsubstituted aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycle, or polycycle;
- m, independently for each occurrence, represents an integer from 0 to 6;
- and
- n is an integer from 1 to 4, or
- a salt, an ester or amide derivative thereof.
7 more elements
A compound having the general structure shown in Formula II:
- 38
- wherein, as valence and stability permits,
- A represents an a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or polycycle;
- V, independently for each occurrence, is absent or represents a group selected from lower alkyl, alkoxy, arylalkyl, or:
- a group with up to 10 heavy atoms;
- Y, independently for each occurrence, represents,
- 39
- A′, independently for each occurrence, represents an alkyl or heteroalkyl, or a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or polycycle;
- X′, independently for each occurrence, represents an O, NR5, or S;
- R1 and R2, independently for each occurrence, represent one or more of hydrogen, halogen, hydroxyl, alkoxyl, silyloxyl, amino, nitro, sulfhydryl, alkylthio, imine, amide, cyano, carbonyl, carboxyl, carboxamide, silyl, sulfamoyl, sulfinyl, thioalkyl, alkylsulfonyl, arylsulfonyl, ketone, aldehyde, ester, isocyano, guanidine, amidine, acetal, ketal, amine oxide, azide, carbamate, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbonate, urea, thiourea, or a substituted or unsubstituted alkyl or heteroalkyl, alkenyl, alkynyl, aryl or heteroaryl or —(CH2)m-R3;
- R3 represents a substituted or unsubstituted aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycle, or polycycle;
- R5 represents a hydrogen or a group with up to 10 heavy atoms;
- m, independently for each occurrence, represents an integer from 0 to 6;
- and
- n is an integer from 1 to 4,
- a salt, an ester or amide derivative thereof.
13 more elements
A method for synthesizing a compound with a general structure shown in Formula III,
- 40
- wherein, as valence and stability permits,
- A represents an alkyl or heteroalkyl, or a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or polycycle;
- P represents a ketone protecting group or an optionally protected amine or hydroxyl;
- P′ represents a protecting group for a carboxylic acid;
- V′, independently for each occurrence, is absent or represents alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, or a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or polycycle;
- m, independently for each occurrence, represents an integer from 1 to 4;
- comprising,
- Reacting G with one or more equivalents of H in the presence of a base, wherein, as valence and stability permit,
- G represents
- 41
- A represents alkyl or heteroalkyl, or a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or polycycle;
- V, independently for each occurrence, is absent or represents lower alkyl, alkenyl, alkynyl, alkoxy, or a group with up to 10 heavy atoms;
- X is a leaving group preferably selected from halides, permethylated amines, acetates or sulphonate esters, such as a tosylate or mesylate;
- and
- n represents a integer in the range of 1 to 4;
- and
- H is represented by the general structure:
- 42
- A′ represents an alkyl or heteroalkyl, or a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or polycycle;
- Z represents an OH, NR5H, or SH;
- R5 represents a hydrogen or a group with up to 10 heavy atoms;
- P′ represents a carboxyl protecting group;
- and
- P represents a ketone protecting group or an optionally protected amine or hydroxyl.
22 more elements
A method for synthesizing a compound with a general structure shown in Formula IV,
- 43
- wherein, as valence and stability permits,
- A represents an alkyl or heteroalkyl, or a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or polycycle;
- V, independently for each occurrence, is absent or represents a linking group selected from lower alkyl, alkenyl, alkynyl, alkoxy, or a group with up to 10 heavy atoms;
- and
- m, independently for each occurrence, represents an integer from 1 to 4;
- comprising the acts of
- converting P to an oxo, and P′ to a hydrogen in the structure represented by formula IVa,
- 44
- wherein, as valence and stability permits,
- A represents an alkyl or heteroalkyl, or a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or polycycle;
- V, independently for each occurrence, is absent or represents a linking group selected from lower alkyl, alkenyl, alkynyl, alkoxy, or a group with up to 10 heavy atoms;
- P represents a ketone protecting group or an optionally protected amine or hydroxyl;
- P′ represents a protecting group for a carboxylic acid;
- and
- m, independently for each occurrence, represents an integer from 1 to 4.
13 more elements
A method for synthesizing a compound with a general structure shown in Formula V,
- 45
- wherein, as valence and stability permits,
- A represents an alkyl or heteroalkyl, or a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or polycycle;
- V, independently for each occurrence, is absent or represents a linking group selected from lower alkyl, alkenyl, alkynyl, alkoxy, or a group with up to 10 heavy atoms;
- m, independently for each occurrence, represents an integer from 1 to 4;
- comprising the act of converting P to an oxo in the compound represented by Formula Va:
- 46
- wherein, as valence and stability permits,
- A represents an alkyl or heteroalkyl, or a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or polycycle;
- P represents a ketone protecting group;
- V, independently for each occurrence, is absent or represents a linking group selected from lower alkyl, alkenyl, alkynyl, alkoxy, or a group with up to 10 heavy atoms;
- and
- m, independently for each occurrence, represents an integer from 1 to 4.
10 more elements
A method for synthesizing a compound with a general structure shown in Formula VI,
- 47
- wherein, as valence and stability permits,
- A represents an alkyl or heteroalkyl, or a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or polycycle;
- V, independently for each occurrence, is absent or represents a linking group selected from lower alkyl, alkenyl, alkynyl, alkoxy, or a group with up to 10 heavy atoms;
- m, independently for each occurrence, represents an integer from 1 to 4;
- comprising the act of converting P′ to a hydrogen in the compound represented by Formula VIa:
- 48
- wherein, as valence and stability permits,
- A represents an alkyl or heteroalkyl, or a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or polycycle;
- P′ represents a carboxy protecting group;
- V, independently for each occurrence, is absent or represents a linking group selected from lower alkyl, alkenyl, alkynyl, alkoxy, or a group with up to 10 heavy atoms;
- and
- m, independently for each occurrence, represents an integer from 1 to 4.
10 more elements
Dependencies are inferred from the claim text.