Benzimidazole compounds for regulating IgE

• US 20050277686A1
• Filed: 06/28/2005
• Published: 12/15/2005
• Est. Priority Date: 05/22/1998
• Status: Abandoned Application

• Current Assignee: Jagadish C. Sircar, Mark L. Richards, Michael G. Campbell, Michael W. Major
• Original Assignee: Jagadish C. Sircar, Mark L. Richards, Michael G. Campbell, Michael W. Major
• Inventors: Campbell, Michael G., Major, Michael W., Sircar, Jagadish C., Richards, Mark L.
• Application Number:
  US11/168,711
• Publication Number:
  US 20050277686A1
• Time in Patent Office: Days
• US Class Current: 514/394
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07D 235/02 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 235/18 with aryl radicals directly attached in position 2
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

This invention relates to a family of phenylbenzimidazole analogs, which are inhibitors of the IgE response to allergens. These compounds are useful in the treatment of allergy and/or asthma or any diseases where IgE is pathogenic.

Claims

1. A compound selected from Formula A or B:

wherein X and Y are independently selected from the group consisting of H, alkyl, alkoxy, aryl, substituted aryl, hydroxy, halogen, amino, alkylamino, nitro, cyano, CF₃, OCF₃, CONH₂, CONHR, NHCOR₁, benzo, COPh, COOCH₃, and NHCONHCR₁;

wherein R is selected from the group consisting of H, CH₃, C₂H₅, C₃H₇, C₄H₉, CH₂Ph, and CH₂C₆H₄—

F(p-);

wherein R₁ and R₂ are independently selected from the group consisting of alkyl, substituted alkyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, multi-ring cycloalkyl, fused-ring aliphatic, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl, substituted cyclohexyl, cycloheptyl, substituted cycloheptyl, bicycloheptyl, substituted bicycloheptyl, bicyclooctyl, bicyclononyl, bicycloalkenyl, substituted bicycloalkenyl, adamantyl, substituted adamanyl, heterocyclic rings, and substituted heterocyclic rings; and

wherein the substituents on R₁ or R₂ are selected from the group consisting of alkyl, acyl, aryl, carbonyl, CF₃, CH₃, OCH₃, OH, CN, COOR, COOH, COCF₃, and heterocyclic rings;

wherein R₁ and R₂ cannot both be methyl.

11. The compound of claim 1, further comprising at least one additional ingredient which is active in reducing at least one symptom associated with said allergic reaction.

12. The compound of claim 11, wherein said at least one additional ingredient is selected from the group consisting of a short-acting β

₂-adrenergic agonist, a long-acting β

₂-adrenergic agonist, an antihistamine, a phosphodiesterase inhibitor, an anticholinergic agent, a corticosteroid, an inflammatory mediator release inhibitor and a leukotriene receptor antagonist.

13. A method for treating or preventing an allergic reaction in a mammal wherein said reaction is caused by an increase in IgE levels comprising administering an IgE-suppressing amount of at least one compound of claim 1.

14. The method of claim 13, further comprising administering at least one additional ingredient which is active in reducing at least one symptom associated with said allergic reaction.

15. The method of claim 14, wherein said additional ingredient is selected from the group consisting of a short-acting β

₂-adrenergic agonist, a long-acting β

₂-adrenergic agonist, an antihistamine, a phosphodiesterase inhibitor, an anticholinergic agent, a corticosteroid, an inflammatory mediator release inhibitor and a leukotriene receptor antagonist.

16. A method for treating or preventing asthma in a mammal comprising administering an IgE-suppressing amount of at least one compound of claim 1.

17. The method of claim 16 further comprising administering at least one additional ingredient which is active in reducing at least one symptom associated with said allergic reaction.

18. The method of claim 17, wherein said additional ingredient is selected from the group consisting of a short-acting β

₂-adrenergic agonist, a long-acting β

₂-adrenergic agonist, an antihistamine, a phosphodiesterase inhibitor, an anticholinergic agent, a corticosteroid, an inflammatory mediator release inhibitor and a leukotriene receptor antagonist.

2. A compound of Formula A:

wherein X and Y are independently selected from the group consisting of H, alkyl, alkoxy, aryl, substituted aryl, hydroxy, halogen, amino, alkylamino, nitro, cyano, CF₃, OCF₃, CONH₂, CONHR and NHCOR₁;

wherein R is selected from the group consisting of H, CH₃, C₂H₅, C₃H₇, C₄H₉, CH₂Ph, and CH₂C₆H₄—

F(p-);

wherein R₁ and R₂ are independently selected from the group consisting of alkyl, substituted alkyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, multi-ring cycloalkyl, fused-ring aliphatic, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl, substituted cyclohexyl, cycloheptyl, substituted cycloheptyl, bicycloheptyl, substituted bicycloheptyl, bicyclooctyl, bicyclononyl, bicycloalkenyl, substituted bicycloalkenyl, adamantyl, and substituted adamantyl, wherein said substituents are not heterocyclic rings; and

wherein the substituents on R₁ or R₂ are selected from the group consisting of alkyl, aryl, carbonyl, CF₃, CH₃, OCH₃, OH, CN, COOR, and COOH.

3. The compound of claim 2 selected from the group consisting of:

4. A compound selected from Formula A or B:

wherein X and Y are independently selected from the group consisting of H, alkyl, alkoxy, aryl, substituted aryl, hydroxy, halogen, amino, alkylamino, nitro, cyano, CF₃, OCF₃, CONH₂, CONHR, and NHCOR₁;

wherein R is selected from the group consisting of H, CH₃, C₂H₅, C₃H₇, C₄H₉, CH₂Ph, and CH₂C₆H₄—

F(p-);

wherein R₁ and R₂ are independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, multi-ring cycloalkyl, fused-ring aliphatic, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl, substituted cyclohexyl, cycloheptyl, substituted cycloheptyl, bicycloheptyl, bicyclooctyl, bicyclononyl, substituted bicycloalkenyl, adamantyl, substituted adamantyl, heterocyclic rings, and substituted heterocyclic rings;

wherein R₁ and R₂ cannot both be methyl groups;

wherein the substituents on R₁ or R₂ are selected from the group consisting of alkyl, acyl, aryl, CF₃, CH₃, OCH₃, OH, CN, COOR, COOH, COCF₃, and heterocyclic rings; and

wherein at least one of R₁, R₂ or said substituents is a heterocyclic ring; and

wherein X is selected from the group consisting of mono, di, tri, and tetra substituted H, alkyl, alkoxy, aryl, substituted aryl, hydroxy, halogen, amino, alkylamino, nitro, cyano, CF₃, OCF₃, CONH₂, CONHR, and NHCOR₁;

wherein R is selected from the group consisting of H, CH₃, C₂H₅, C₃H₇, C₄H₉, CH₂Ph, and CH₂C₆H₄—

F(p-);

wherein Y is selected from the group consisting of mono, di, tri, and tetra substituted H, alkyl, alkoxy, aryl, benzo, substituted aryl, hydroxy, halogen, amino, alkylamino, nitro, cyano, CF₃, OCF₃, COPh, COOCH₃, CONH₂, CONHR, NHCONHR₁, and NHCOR₁; and

wherein R₁ is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, multi-ring cycloalkyl, fused-ring aliphatic, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl, substituted cyclohexyl, cycloheptyl, substituted cycloheptyl, bicycloheptyl, bicyclooctyl, bicyclononyl, substituted bicycloalkenyl, adamantyl, substituted adamantyl, heterocyclic rings containing one or more heteroatoms, and substituted heterocyclic rings; and

wherein the substituents on R₁ are selected from the group consisting of alkyl, aryl, CF₃, CH₃, OCH₃, OH, CN, COOR, COOH, and heterocyclic rings.

5. The compound of claim 4, wherein the compound is from Formula A.

6. The compound of claim 4, wherein the compound is selected from the group consisting of:

7. The compound of claim 4, wherein the compound is from Formula B.

8. The compound of claim 4, wherein the compound is selected from the group consisting of:

9. A compound having the formula:

10. A compound having the formula: