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US 6,638,977 B1Granted
Plasminogen activator inhibitor antagonists
AssigneeCorvas International, Inc.
InventorsEdwin L. Madison, Terence K. Brunck, Joseph Edward Semple, Marguerita Lim-Wilby, Kent E. Pryor
Life of this patent
Estimating the term…
Abstract
Compounds and pharmaceutical compositions useful as plasminogen activator inhibitor (PAI) antagonists are provided. In particular, methods of antagonizing PAI with substituted and unsubstituted aryl and heteroaryl ethers and thioethers are provided.
Claims71
A pharmaceutical composition, comprising a compound having the formula:
- or a pharmaceutically acceptable derivative thereof, in a pharmaceutically acceptable carrier, wherein:
- Z and Z′ are each carbon;
- X′ is (CH2)dO or (CH2)dS;
- d is an integer from 1 to 6;
- R1 is halide or pseudohalide;
- m is 2;
- R2, R3, n and p are selected from (i) or (ii) as follows:
- (i) R2 is alkyl, aryl, alkoxy, haloalkyl, haloalkoxy, halide or pseudohalide;
- n is an integer from 1 to 5;
- R3 is hydroxy or alkoxy;
- p is an integer from 0 to 3;
- or
- (ii) n and p are 1;
- and R2 and R3, together form, with the carbon to which each is attached, an aryl, aromatic ring, heteroaromatic ring, carbocyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members;
- R4 and R5 are each independently selected from —SO3−, —NO2, alkyl, hydroxy, alkoxy, halide or pseudohalide;
- q is an integer from 0 to 1;
- r is an integer from 0 to 2;
- X is H, C1-17alkyl-L-, C2-17alkenyl-L-, or C2-17alkynyl-L-;
- L is a direct link, amido, carboxy, carbonyl, carbamoyl, sulfonyl, carbamide, ureido, sulfonamide, hydrazinyl, hydrazide, semicarbazide, carbazate, thiocarbazate, isothiocarbazate or sulfonyl hydrazide;
- Y′ is selected from a direct link, alkylene, a heterocyclylene group, —COO—, —S(O)2O—, —S(O)O—, —P(O)(OH)O—, —P(OH)O— and —B(OH)O—;
- Y is a direcalky link, C1-4alkyl(W)(carboxy), C2-4alkenyl(W)(carboxy), C2-4alkynyl(W)(carboxy), C1-4alkyl(W)(sulfo), C2-4alkenyl(W)(sulfo) or C2-4alkynyl(W)(sulfo);
- where W is H, amino or A-D-E-G, where A is C1-4alkylene, C2-4alkenylene or C2-4alkynylene;
- D is a direct link, amido, ureido, imino, azido, carbamoyl, thio or thionyl;
- E is a direct link, C1-3alkylene, arylene or heteroarylene;
- and G is H, amino, nitro, cyano, hydrazinyl, thio or sulfonamido;
- with the provisos that (i) if m, n or p are not 0, then q and r are 0;
- (ii) if q or r are not 0, then m, n and p are 0;
- (iii) if X is not H, then Y is a direct link;
- (iv) if Y is not a direct link, then Y′ is a direct link;
- (v) if Y′ is not a direct link, then Y is a direct link;
- (vi) if D is not a direct link, then G is H;
- (vii) if D is a single bond and G is not H, then E is a single bond;
- and (viii) if E is not a direct link or C1-3alkylene, then G is H.
30 more elements
The pharmaceutical composition of claim wherein the compound is of formula I with the proviso that X—Y′—Y is not hydrogen.
An article of manufacture, comprising packaging material, a compound of formula:
- or a pharmaceutically acceptable derivative thereof, wherein:
- Z and Z′ are each carbon;
- X′ is (CH2)dO or (CH2)dS;
- d is an integer from 1 to 6;
- R1 is halide or pseudohalide;
- m is 2;
- R2, R3, n and p are selected from (i) or (ii) as follows:
- (i) R2 is alkyl, aryl, alkoxy, haloalkyl, haloalkoxy, halide or pseudohalide;
- n is an integer from 1 to 5;
- R3 is hydroxy or alkoxy;
- p is an integer from 0 to 3;
- or
- (ii) n and p are 1;
- and R2 and R3, together form, with the carbon to which each is attached, an aryl, aromatic ring, heteroaromatic ring, carbocyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members;
- R4 and R5 are each independently selected from —SO3−, —NO2, alkyl, hydroxy, alkoxy, halide or pseudohalide;
- q is an integer from 0 to 1;
- r is an integer from 0 to 2;
- X is H, C1-17alkyl-L-, C2-17alkenyl-L-, or C2-17alkynyl-L-;
- L is a direct link, amido, carboxy, carbonyl, carbamoyl, sulfonyl, carbamide, ureido, sulfonamide, hydrazinyl, hydrazide, semicarbazide, carbazate, thiocarbazate, isothiocarbazate or sulfonyl hydrazide;
- Y′ is selected from a direct link, alkylene, a heterocyclylene group, —COO—, —S(O)2O—, —S(O)O—, —P(O)(OH)O—, —P(OH)O— and —B(OH)O—;
- Y is a direct link, C1-4alkyl(W)(carboxy), C2-4alkenyl(W)(carboxy), C2-4alkynyl(W)(carboxy), C1-4alkyl(W)(sulfo), C2-4alkenyl(W)(sulfo) or C2-4alkynyl(W)(sulfo);
- where W is H, amino or A-D-E-G, where A is C1-4alkylene, C2-4alkenylene or C2-4alkynylene;
- D is a direct link, amido, ureido, imino, azido, carbamoyl, thio or thionyl;
- E is a direct link, C1-3alkylene, arylene or heteroarylene;
- and G is H, amino, nitro, cyano, hydrazinyl, thio or sulfonamido;
- with the provisos that (i) if m, n or p are not 0, then q and r are 0;
- (ii) if q or r are not 0, then m, n and p are 0;
- (iii) if X is not H, then Y is a direct link;
- (iv) if Y is not a direct link, then Y′ is a direct link;
- (v) if Y′ is not a direct link, then Y is a direct link;
- (vi) if D is not a direct link, then G is H;
- (vii) if D is a single bond and G is not H, then E is a single bond;
- and (viii) if E is not a direct link or C1-3alkylene, then G is H;
- which is effective for antagonizing PAI or for treatment, prevention or amelioration of one or more symptoms of thrombotic disorders or cancer, and a label that indicates that the compound or pharmaceutically acceptable derivative thereof is used for antagonizing PAI, or for treatment, prevention or amelioration of one or more symptoms of thrombotic disorders or cancer.
31 more elements
A method of treating, preventing, or ameliorating one or more symptoms of cancer, comprising administering a compound of formula:
- or a pharmaceutically acceptable derivative thereof, wherein:
- Z and Z′ are each carbon;
- X′ is (CH2)dO or (CH2)dS;
- d is an integer from 1 to 6;
- R1 is halide or pseudohalide;
- m is 2;
- R2, R3, n and p are selected from (i) or (ii) as follows:
- (i) R2 is alkyl, aryl, alkoxy, haloalkyl, haloalkoxy, halide or pseudohalide;
- n is an integer from 1 to 5;
- R3 is hydroxy or alkoxy;
- p is an integer from 0 to 3;
- or
- (ii) n and p are 1;
- and R2 and R3, together form, with the carbon to which each is attached, an aryl, aromatic ring, heteroaromatic ring, carbocyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members;
- R4 and R5 are each independently selected from —SO3−, —NO2, alkyl, hydroxy, alkoxy, halide or pseudohalide;
- q is an integer from 0 to 1;
- r is an integer from 0 to 2;
- X is H, C1-17alkyl-L-, C2-17alkenyl-L-, or C2-17alkynyl-L-;
- L is a direct link, amido, carboxy, carbonyl, carbamoyl, sulfonyl, carbamide, ureido, sulfonamide, hydrazinyl, hydrazide, semicarbazide, carbazate, thiocarbazate, isothiocarbazate or sulfonyl hydrazide;
- Y′ is selected from a direct link, alkylene, a heterocyclylene group, —COO—, —S(O)2O—, —S(O)O—, —P(O)(OH)O—, —P(OH)O— and —B(OH)O—;
- Y is a direct link, C1-4alkyl(W)(carboxy), C2-4alkenyl(W)(carboxy), C2-4alkynyl(W)(carboxy), C1-4alkyl(W)(sulfo), C2-4alkenyl(W)(sulfo) or C2-4alkynyl(W)(sulfo);
- where W is H, amino or A-D-E-G, where A is C1-4alkylene, C2-4alkenylene or C2-4alkynylene;
- D is a direct link, amido, ureido, imino, azido, carbamoyl, thio or thionyl;
- E is a direct link, Cl13alkylene, arylene or heteroarylene;
- and G is H, amino, nitro, cyano, hydrazinyl, thio or sulfonamido;
- with the provisos that (i) if m, n or p are not 0, then q and r are 0;
- (ii) if q or r are not 0, then m, n and p are 0;
- (iii) if X is not H, then Y is a direct link;
- (iv) if Y is not a direct link, then Y′ is a direct link;
- (v) if Y′ is not a direct link, then Y is a direct link;
- (vi) if D is not a direct link, then G is H;
- (vii) if D is a single bond and G is not H, then E is a single bond;
- and (viii) if E is not a direct link or C1-3alkylene, then G is H.
30 more elements
A method of modulating the activity of a plasminogen activator inhibitor (PAI), comprising contacting the PAI with a compound of formula Ar1—X′—Ar2, or pharmaceutically acceptable derivatives thereof, wherein:
- X′ is O, S, (CH2)dO or (CH2)dS where d is an integer from 1 to 6;
- Ar1 and Ar2 are each independently selected from monocyclic or fused bicyclic aryl and heteroaryl, and are substituted with at least one acidic group selected from a carboxylic acid, sulfonic acid, sulfinic acid, phosphonic acid, phosphinic acid or boronic acid group;
- and may be further substituted with one or more substituents independently selected from halide, pseudohalide, nitro, hydroxy, alkoxy, aryl, heteroaryl, heterocyclyl, alkyl or cycloalkyl;
- wherein the aryl, heteroaryl, heterocyclyl and cycloalkyl substituents may be further substituted with C1-20alkyl-L-, C2-20alkenyl-L-, or C2-20alkynyl-L-, where L is a direct link, amido, carboxy, carbonyl, carbamoyl, sulfonyl, carbamide, ureido, sulfonamide, hydrazinyl, hydrazide, semicarbazide, carbazate, thiocarbazate, isothiocarbazate or sulfonyl hydrazide.
1 more element
A method of modulating the interaction of a plasminogen activator (PA) with a plasminogen activator inhibitor (PAI), comprising contacting the PAI with a compound of formula Ar1—X′—Ar2, or pharmaceutically acceptable derivatives thereof, wherein:
- X′ is O, S, (CH2)dO or (CH2)dS where d is an integer from 1 to 6;
- Ar1 and Ar2 are each independently selected from monocyclic or fused bicyclic aryl and heteroaryl, and are substituted with at least one acidic group selected from a carboxylic acid, sulfonic acid, sulfinic acid, phosphonic acid, phosphinic acid or boronic acid group;
- and may be further substituted with one or more substituents independently selected from halide, pseudohalide, nitro, hydroxy, alkoxy, aryl, heteroaryl, heterocyclyl, alkyl or cycloalkyl;
- wherein the aryl, heteroaryl, heterocyclyl and cycloalkyl substituents may be further substituted with C1-20alkyl-L-, C2-20alkenyl-L-, or C2-20alkynyl-L-, where L is a direct link, amido, carboxy, carbonyl, carbamoyl, sulfonyl, carbamide, ureido, sulfonamide, hydrazinyl, hydrazide, semicarbazide, carbazate, thiocarbazate, isothiocarbazate or sulfonyl hydrazide;
- wherein the contacting is effected simultaneously with, prior to, or subsequent to contacting the PA with the PAI.
2 more elements
A method of attenuating metastasis, comprising administrating to a patient suffering from a metastatic disorder a compound of formula Ar1—X′—Ar2, or pharmaceutically acceptable derivatives thereof, wherein:
- X′ is O, S, (CH2)dO or (CH2)dS where d is an integer from 1 to 6;
- Ar1 and Ar2 are each independently selected from monocyclic or fused bicyclic aryl and heteroaryl, and are substituted with at least one acidic group selected from a carboxylic acid, sulfonic acid, sulfinic acid, phosphonic acid, phosphinic acid or boronic acid group;
- and may be further substituted with one or more substituents independently selected from halide, pseudohalide, nitro, hydroxy, alkoxy, aryl, heteroaryl, heterocyclyl, alkyl or cycloalkyl;
- wherein the aryl, heteroaryl, heterocyclyl and cycloalkyl substituents may be further substituted with C1-20alkyl-L-, C2-20alkenyl-L-, or C2-20alkynyl-L-, where L is a direct link, amido, carboxy, carbonyl, carbamoyl, sulfonyl, carbamide, ureido, sulfonamide, hydrazinyl, hydrazide, semicarbazide, carbazate, thiocarbazate, isothiocarbazate or sulfonyl hydrazide.
1 more element
A method of treating, preventing or ameliorating one or more symptoms of a thrombotic disorder or haemostatic disorder, comprising administrating a compound of formula Ar′—X′—Ar2, or pharmaceutically acceptable derivatives thereof, wherein:
- X′ is O, S, (CH2)dO or (CH2)dS where d is an integer from 1 to 6;
- Ar1 and Ar2 are each independently selected from monocyclic or fused bicyclic aryl and heteroaryl, and are substituted with at least one acidic group selected from a carboxylic acid, sulfonic acid, sulfinic acid, phosphonic acid, phosphinic acid or boronic acid group;
- and may be further substituted with one or more substituents independently selected from halide, pseudohalide, nitro, hydroxy, alkoxy, aryl, heteroaryl, heterocyclyl, alkyl or cycloalkyl;
- wherein the aryl, heteroaryl, heterocyclyl and cycloalkyl substituents may be further substituted with C1-20alkyl-L-, C2-20alkenyl-L-, or C2-20alkynyl-L-, where L is a direct link, amido, carboxy, carbonyl, carbamoyl, sulfonyl, carbamide, ureido, sulfonamide, hydrazinyl, hydrazide, semicarbazide, carbazate, thiocarbazate, isothiocarbazate or sulfonyl hydrazide.
1 more element
A method of antagonizing a plasminogen activator inhibitor PAI), comprising contacting the PAI with a compound of formula Ar1—X′—r2, or pharmaceutically acceptable derivatives thereof, wherein:
- X′ is O, S, (CH2)dO or (CH2)dS where d is an integer from 1 to 6;
- Ar1 and Ar2 are each independently selected from monocyclic or fused bicyclic aryl and heteroaryl, and are substituted with at least one acidic group selected from a carboxylic acid, sulfonic acid, sulfinic acid, phosphonic acid, phosphinic acid or boronic acid group;
- and may be further substituted with one or more substituents independently selected from halide, pseudohalide, nitro, hydroxy, alkoxy, aryl, heteroaryl, heterocyclyl, alkyl or cycloalkyl;
- wherein the aryl, heteroaryl, heterocyclyl and cycloalkyl substituents may be further substituted with C1-20alkyl-L-, C2-20alkenyl-L-, or C2-20alkynyl-L-, where L is a direct link, amido, carboxy, carbonyl, carbamoyl, sulfonyl, carbamide, ureido, sulfonamide, hydrazinyl, hydrazide, semicarbazide, carbazate, thiocarbazate, isothiocarbazate or sulfonyl hydrazide.
1 more element
A method of modulating angiogenesis, comprising administering a compound of formula Ar′—X′—Ar2, or pharmaceutically acceptable derivatives thereof, wherein:
- X′ is O, S, (CH2)dO or (CH2)dS where d is an integer from 1 to 6;
- Ar1 and Ar2 are each independently selected from monocyclic or fused bicyclic aryl and heteroaryl, and are substituted with at least one acidic group selected from a carboxylic acid, sulfonic acid, sulfinic acid, phosphonic acid, phosphinic acid or boronic acid group;
- and may be further substituted with one or more substituents independently selected from halide, pseudohalide, nitro, hydroxy, alkoxy, aryl, heteroaryl, heterocyclyl, alkyl or cycloalkyl;
- wherein the aryl, heteroaryl, heterocyclyl and cycloalkyl substituents may be further substituted with C1-20alkyl-L-, C2-20alkenyl-L-, or C2-20alkynyl-L-, where L is a direct link, amido, carboxy, carbonyl, carbamoyl, sulfonyl, carbamide, ureido, sulfonamide, hydrazinyl, hydrazide, semicarbazide, carbazate, thiocarbazate, isothiocarbazate or sulfonyl hydrazide.
1 more element
A compound that has the formula:
- and pharmaceutically acceptable derivatives thereof, wherein:
- X′ is (CH2)dO or (CH2)dS;
- d is an integer from 1 to 6;
- Z and Z′ are each carbon;
- R1 is Br or I;
- m is 2;
- R2, R3, n and p are selected from (i) or (ii) as follows:
- (i) R2 is halide, pseudohalide, alkyl, aryl, heteroaryl, cycloalkyl, alkoxy, aryloxy, heteroaryloxy, cycloalkoxy, haloalkyl or haloalkoxy;
- n is an integer from 1 to 5;
- R3 is OH or alkoxy;
- p is an integer from 0 to 3;
- or
- (ii) n and p are 1;
- and R2 and R3 together form, with the carbon to which each is attached, an aryl, aromatic ring, heteroaromatic ring, carbocyclic or heterocyclic ring, which is saturated or unsaturated, containing from about 3 to about 16 members;
- R4 and R5 are each independently selected from —SO3−, —NO2, alkyl, hydroxy, alkoxy, halide or pseudohalide;
- q is an integer from 0 to 1;
- r is an integer from 0 to 2;
- X is H, C1-17alkyl-L-, C2-17alkenyl-L-, or C2-17alkynyl-L-;
- L is a direct link, amido, carboxy, carbonyl, carbamoyl, sulfonyl, carbamide, ureido, sulfonamide, hydrazinyl, hydrazide, semicarbazide, carbazate, thiocarbazate, isothiocarbazate or sulfonyl hydrazide;
- Y′ is selected from a direct link, alkylene, a heterocyclylene group, —COO—, —S(O)2O—, —S(O)O—, —P(O)(OH)O—, —P(OH)O— and —B(OH)O—;
- Y is a direct link, C1-4alkyl(W)(carboxy), C2-4alkenyl(W)(carboxy), C2-4alkynyl(W)(carboxy), C1-4alkyl(W)(sulfo), C2-4alkenyl(W)(sulfo) or C2-4alkynyl(W)(sulfo);
- where W is H, amino or A-D-E-G, where A is C1-4alkylene, C2-4alkenylene or C2-4alkynylene;
- D is a direct link, amido, ureido, imino, azido, carbamoyl, thio or thionyl;
- E is a direct link, C1-3alkylene, arylene or heteroarylene;
- and G is H, amino, nitro, cyano, hydrazinyl, thio or sulfonamido;
- with the provisos that (i) if m, n or p are not 0, then q and r are 0;
- (ii) if q or r are not 0, then m, n and p are 0;
- (iii) if X is not H, then Y is a direct link;
- (iv) if Y is not a direct link, then Y′ is a direct link;
- (v) if Y′ is not a direct link, then Y is a direct link;
- (vi) if D is not a direct link, then G is H;
- (vii) if D is a single bond and G is not H, then E is a single bond;
- (viii) if E is not a direct link or C1-3alkylene, then G is H.
30 more elements
Dependencies are inferred from the claim text.