Organosulfur inhibitors of tyrosine phosphatases

• US 20050065118A1
• Filed: 10/16/2002
• Published: 03/24/2005
• Est. Priority Date: 10/16/2001
• Status: Abandoned Application

• Current Assignee: Metabasis Therapeutics, Inc. (Ligand Pharmaceuticals, Inc.), Cengent Therapeutics, Inc. (Long-E International, Inc.)
• Original Assignee: Metabasis Therapeutics, Inc. (Ligand Pharmaceuticals, Inc.)
• Inventors: Loweth, Colin, Brady, Thomas P., ElAbdellaoui, Hassan, Fung, Leah, Wang, Jing, Wu, Feiyue, Rideout, Darryl, Tsai, Chung-Ying, Yalamoori, Venkatachalapathi V., Ramnarayan, Kalyanaraman
• Application Number:
  US10/493,113
• Publication Number:
  US 20050065118A1
• Time in Patent Office: Days
• US Class Current: 514/114
• CPC Class Codes: A61K 31/325 Carbamic acids; Thiocarbamic acids; Anhydrides or salts thereof thiurams A61K31/145
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/428 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/429 condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/433 Thidiazoles
• CPC Class Codes: A61K 31/542 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives

Abstract

Organosulfur modulators of tyrosine phosphatases and their use in the treatment of disease are disclosed.

Claims

1. A method of inhibiting protein tyrosine phosphatase activity which comprises administering to a mammal an effective amount of a compound having the formula:

2. A method as recited in claim 1 wherein R1 and R2 are taken together with the core unit to which they are attached (formula I) to form a heterocyclic group having formula (II) as follows:

3. A method as recited in claim 2 wherein R3 is

(1) a phenyl group unsubstituted or substituted with one to three of the following and their combinations:

halogen, hydroxy, aryloxy, nitro, carboxylic acid, CF₂P═

O(OH)₂, NHCOCOOH, alkyl (C1-C10) or alkoxy (C1-C10) (unsubstituted or substituted with NR1R2, COOH, cycloheteroalkyl), alkylthio (C1-C4), 2′

-hydroxyethoxy, alkoxycarbonylmethoxy (C1-C4), dialkylamino (C1-C4 where the two alkyls can form a heteroalicyclic ring), 2-(dialkylamino)-2-oxoethoxy (C1-C7 where the two alkyls can form a heteroalicyclic ring), difluoromethoxy, perfluoroallyl (C1-C4), perfluoroalkylthio (C1-C4), perfluoroalkoxy (C1-C4), 2-carboxyvinyl, alkanoyl (C1-C5), alkoxycarbonyl (C1-C4), alkanoylamino (C1-C8), benzoylamino (unsubstituted or substituted with one or more perfluoroalkyl group (C1-C4) and/or CF₂P═

O(OH)₂, NHCOCOOH,), aryl, aryloxy, arylcarbonyl, arylmethoxy, arylmethyl in which the methyl group is substituted with hydroxyl, O(CH₂)_nCOOH (n=1-5), S(CH₂)_nCOOH (n=1-5), (4-carboxy)benzyloxy, (3-carboxybenzyloxy), or the group ═

N—

O—

CH₂R in which R is carboxyl, alkoxycarbonyl (C1-C4), hydrogen, or phenyl (unsubstituted or substituted with one or more halogens), or the group ═

N—

NHAr in which Ar is a phenyl (unsubstituted or substituted with one or more alkyl groups (C1-C4), and/or a carboxyl group, and/or CF₂P═

O(OH)₂, NHCOCOOH), or the group-Y—

(CH₂)_n-Z, where Y is O or S, n is 1, 2, or 3, and Z is hydrogen, methyl, branched alkyl (C3-C5), cycloalkyl (C3-C6), phenyl (unsubstituted or substituted with one or more of the following;

halogen, trifluoroalkyl, carboxy, alkoxycarbonyl (C1-C4), CF₂P═

O(OH)₂, NHCOCOOH, or carboxyl;

or

(2) a pyridylthio group unsubstituted or substituted with one or more halogen and/or one or more nitro groups, methylenedioxyphenyl, benzo[3,4-c]1,2,5-oxadiazol-5-yl, 4-oxo-3-hydroquinazolin-2-yl, or a group having formula (III) as follows;

in which the imidazole ring is unsubstituted or substituted with one or more halogens.

4. A method as recited in claim 1 wherein R1 and R2 are taken together with the core unit to which they are attached (formula I) to form a heterocyclic group having formula (IV as follows:

5. A method as recited in claim 1 wherein R1 and R2 are linked through an aromatic ring, and taken together with the N═

CR3—

S unit to which they are attached, form a tricyclic heterocyclic group having formula (V) as follows;

6. A method as recited in claim 1 wherein R1 and R2, taken together with the N═

CR3—

S unit to which they are attached, form a heterocyclic group having formula (VI) as follows;

7. A method as recited in claim 1 wherein R1 and R3, taken together with the N═

C—

SR2 unit to which they are attached, form a heterocyclic group having formula (VII) as follows;

8. A method as recited in claim 1 wherein R1 and R3, taken together with the N═

C—

SR2 unit to which they are attached, form a bicylic heterocyclic group having formula (VII) as follows;

9. A method as recited in claim 1 wherein R1, R2 and R3, taken together with the N═

C—

S unit to which they are attached, form a bicyclic heterocyclic group having formula (IX) as follows;

10. A method as recited in claim 1 wherein R1, R2 and R3, taken together with the N═

C—

S unit to which they are attached, form a bicyclic heterocyclic group having formula (X) as follows;

11. A pharmaceutical composition which comprises an effective amount of a compound having the formula:

12. A pharmaceutical composition as recited in claim 11 wherein R1 and R2 are taken together with the core unit to which they are attached (formula I) to form a heterocyclic group having formula (II) as follows:

13. A pharmaceutical composition as recited in claim 12 wherein R3 is

(1) a phenyl group unsubstituted or substituted with one to three of the following and their combinations:

halogen, hydroxy, aryloxy, nitro, carboxylic acid, CF₂P═

O(OH)₂, —

NHCOCOOH, alkyl (C1-C10) or alkoxy (C1-C10) (unsubstituted or substituted with NR1R2, COOH, cycloheteroalkyl), alkylthio (C1-C4), 2′

-hydroxyethoxy, alkoxycarbonylmethoxy (C1-C4), dialkylamino (C1-C4 where the two alkyls can form a heteroalicyclic ring), 2-(dialkylamino)-2-oxoethoxy (C1-C7 where the two alkyls can form a heteroalicyclic ring), difluoromethoxy, perfluoroalkyl (C1-C4), perfluoroalkylthio (C1-C4), perfluoroalkoxy (C1-C4), 2-carboxyvinyl, alkanoyl (C1-C5), alkoxycarbonyl (C1-C4), alkanoylamino (C1-C8), benzoylamino (unsubstituted or substituted with one or more perfluoroalkyl group (C1-C4) and/or CF₂P═

O(OH)₂, NHCOCOOH,), aryl, aryloxy, arylcarbonyl, arylmethoxy, arylmethyl in which the methyl group is substituted with hydroxyl, O(CH₂)_nCOOH (n=1-5), S(CH₂)_nCOOH (n=1-5), (4-carboxy)benzyloxy, (3-carboxybenzyloxy), or the group ═

N—

O—

CH₂R in which R is carboxyl, alkoxycarbonyl (C1-C4), hydrogen, or phenyl (unsubstituted or substituted with one or more halogens), or the group ═

N—

NHAr in which Ar is a phenyl (unsubstituted or substituted with one or more alkyl groups (C1-C4), and/or a carboxyl group, and/or CF₂P═

O(OH)₂, NHCOCOOH), or the group-Y—

(CH₂)_n-Z, where Y is O or S, n is 1, 2, or 3, and Z is hydrogen, methyl, branched alkyl (C3-C5), cycloalkyl (C3-C6), phenyl (unsubstituted or substituted with one or more of the following;

halogen, trifluoroalkyl, carboxy, alkoxycarbonyl (C1-C4), CF₂P═

O(OH)₂, NHCOCOOH, or carboxyl;

or

(2) a pyridylthio group either unsubstituted or substituted with one or more halogen and/or one or more nitro groups, methylenedioxyphenyl, benzo[3,4-c]1,2,5-oxadiazol-5-yl, 4-oxo-3-hydroquinazolin-2-yl, or a group having formula (III) as follows;

in which the imidazole ring is unsubstituted or substituted with one or more halogens.

14. A pharmaceutical composition as recited in claim 11 wherein R1 and R2 are taken together with the core unit to which they are attached (formula I) to form a heterocyclic group having formula (IV) as follows:

15. A pharmaceutical composition as recited in claim 11 wherein R1 and R2 are linked through an aromatic ring, and taken together with the N═

CR3—

S unit to which they are attached, form a tricyclic heterocyclic group having formula (V) as follows;

16. A pharmaceutical composition as recited in claim 11 wherein R1 and R2, taken together with the N═

CR3—

S unit to which they are attached, form a heterocyclic group having formula (VI) as follows;

17. A pharmaceutical composition as recited in claim 11 wherein R1 and R3, taken together with the N═

C—

SR2 unit to which they are attached, form a heterocyclic group having formula (VII) as follows;

18. A pharmaceutical composition as recited in claim 11 wherein R1 and R3, taken together with the N═

C—

SR2 unit to which they are attached, form a bicylic heterocyclic group having formula (VIII) as follows;

19. A pharmaceutical composition as recited in claim 11 wherein R1, R2 and R3, taken together with the N═

C—

S unit to which they are attached, form a bicyclic heterocyclic group having formula (IX) as follows;

20. A pharmaceutical composition as recited in claim 11 wherein R1, R2 and R3, taken together with the N═

C—

S unit to which they are attached, form a bicyclic heterocyclic group having formula (X) as follows;