Methods of treating non-inflammatory gastrointestinal tract disorders using Cav2.2 subunit calcium channel modulators

Abstract

A method is provided for using Cav2.2 subunit calcium channel modulators to treat non-inflammatory gastrointestinal tract disorders.

1 . A method for treating a symptom of a non-inflammatory GI tract disorder, comprising administering a therapeutically effective ammount of a Cav2.2 subunit calcium channel modulator selected from the group consisting of: 
 a. ω-conotoxin CNVIIA;    b. ω-conotoxin CVIID;    c. ω-conotoxin AM336;    d. Cilnidipine;    e. Amlodipine;    f. L-cysteine derivative 2A;    g. ω-agatoxin IVA;    h. N,N-dialkyl-dipeptidylamines;    i. Levetiracetam;    j. (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide according to the following structure,    k. A substituted peptidylamine according to the following structure,                           wherein X is selected selected from the group consisting of OR, NR 1 R 2 , and COOR 1 , and R 1  and R 2  are selected from the group consisting of hydrogen, and C 1 -C 8  alkyl, aryl and heteroaryl optimally substituted with one to three substituents;    l. A compound according to the following structure,                          m. A reduced dipeptide analogue according to the following structure,                           wherein X is selected from the group consisting of OR, NR 1 R 2 , and COOR 1 , and R 1  and R 2  are selected from the group consisting of hydrogen and C 1 -C 8  alkyl, aryl, and heteroaryl optimally substituted with one to three substituents;    n. A compound according to the following structure,                          o. A compound according to the following structure,                          p. An amino acid derivative according to the following structure,                           wherein R is selected from the group consisting of hydrogen and C 1 -C 6  alkyl, aryl, and heteroaryl optionally substituted with one to three substituents;    q. A compound according to the following structure,                          r. A benzazepine derivative according to the following structure,                           wherein Ar is selected from the group consisting of aryl and heteroaryl optimally substituted with one to three substituents, and X is selected from the group consisting of hydrogen and C 1 -C 6  alkyl and alkoxy;    s. A compound according to the following structure,                          t. A compound according to the following structure,                           wherein X is selected from the group consisting of R 1  and NHR 1 , R 1  is selected from the group consisting of hydrogen and C 1 -C 6  alkyl, aryl, and                      
heteroaryl optimally substituted with one to three substituents, and R 2  is C 1 -C 4  alkyl or alkoxy;    u. A compound according to the following structure,                          v. A compound according to the following structure,                          w. A compound according to the following structure,                           wherein X is selected from the group consisting of hydrogen and halogen, and R is selected from the group consisting of C 1 -C 6  alkyl, aryl, and heteroaryl optimally substituted with one to three substituents;    x. A compound according to the following structure,                          y. A compound according to the following structure;                          z. A compound according to the following structure,                          aa. A compound according to the following structure,                          bb. A dihydropyridine derivative according to the following structure,                           wherein X is selected from the group consisting of hydrogen and C 1 -C 4  alkyl and alkoxy, R 1  is selected from the group consisting of hydrogen and C 1 -C 4  alkyl, and R 2  is selected from the group consisting of C 1 -C 6  alkyl, alkoxy, alkylamino, and aryl-substituted alkyl,;    cc. A compound according to the following structure,                          dd. A compound according to the following structure,                          ee. A diarylalkene or diarylalkane derivative according to the following structure,                           wherein X is selected from the group consisting of CHCH, CH 2 CH 2 , CH 2 —Y, O, and S, Y is selected from the group consisting of O and S, R 1  is selected from the group consisting of C 1 -C 4  alkyl and alkoxy, and R 2  is selected from the group consisting of hydrogen, COOR 1 , and C 1 -C 4  alkyl and alkoxy;    ff. A compound according to the following structure,                          gg. A compound according to the following structure,                          
     
     
         2 . The method of  claim 1 , wherein said Cav2.2 subunit calcium channel modulator is contained within a pharmaceutical formulation.  
     
     
         3 . The method of  claim 1 , wherein said Cav2.2 subunit calcium channel modulator is administered on an as-needed basis.  
     
     
         4 . The method of  claim 3 , wherein said Cav2.2 subunit calcium channel modulator is administered prior to commencement of an activity wherein suppression of the symptoms of a non-inflammatory GI tract disorder would be desirable.  
     
     
         5 . The method of  claim 4 , wherein said Cav2.2 subunit calcium channel modulator is administered from about 0 to about 5 hours prior to commencement of an activity wherein suppression of said symptoms would be desirable.  
     
     
         6 . The method of  claim 4 , wherein said Cav2.2 subunit calcium channel modulator is administered from about 0 to about 3 hours prior to commencement of an activity wherein suppression of said symptoms would be desirable.  
     
     
         7 . The method of  claim 1 , wherein said Cav2.2 subunit calcium channel modulator is administered orally, transmucosally, sublingually, buccally, intranasally, transurethrally, rectally, by inhalation, topically, transdermally, parenterally, or intrathecally.  
     
     
         8 . The method of  claim 1 , wherein the symptom of a non-inflammatory GI tract disorder is associated with a functional GI tract disorder selected from the group consisting of functional dysphagia, non-ulcer dyspepsia, irritable bowel syndrome, slow-transit constipation, and an evacuation disorder.  
     
     
         9 . The method of  claim 1 , wherein the symptom of a non-inflammatory GI tract disorder is associated with a motor disorder of the esophagus selected from the group consisting of achalasia and diffuse esophageal spasm.  
     
     
         10 . The method of  claim 1 , wherein the symptom of a non-inflammatory GI tract disorder is associated with a non-inflammatory structural GI disorder selected from the group consisting of hiatal hernia, stricture, esophageal web, Schatzki's ring, esophageal diverticulum, and esophageal scleroderma.  
     
     
         11 . The method of  claim 2 , wherein the pharmaceutical formulation further comprises an additional active agent.  
     
     
         12 . The method of  claim 11 , wherein the additional active agent is selected from the group consisting of: an antiulcerative, an antidiarrheal, a peristaltic colon stimulant, an antispasmodic, an antinauseant/prokinetic, an anti-inflammatory bowel drug, a tricyclic antidepressant, a ketolaric, duloxetine, venlafaxine, an SSRI, an SNRI, a spasmolytic, an anticholinergic, gabapentin, pregabalin, a substituted aminomethyl-phenyl-cyclohexane derivative, a 5-HT 3  antagonist, a 5-HT 4  antagonist, a β3 adrenergic agonist, a neurokinin receptor antagonist, a bradykinin receptor antagonist, and a nitric oxide donor.  
     
     
         13 . A pharmaceutical composition comprising a Cav2.2 subunit calcium channel modulator in a therapeutically effective amount sufficient to treat a symptom of a non-inflammatory GI tract disorder, wherein said Cav2.2 subunit calcium channel modulator is selected from the group consisting of: 
 a. ω-conotoxin CNVIIA;    b. ω-conotoxin CVIID;    c. ω-conotoxin AM336;    d. Cilnidipine;    e. Amlodipine;    f. L-cysteine derivative 2A;    g. ω-agatoxin IVA;    h. N,N-dialkyl-dipeptidylamines;    i. Levetiracetam;    J. (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide according to the following structure,                          k. A substituted peptidylamine according to the following structure,                           wherein X is selected selected from the group consisting of OR, NR 1 R 2 , and COOR 1 , and R 1  and R 1  are selected from the group consisting of hydrogen, and C 1 -C 8  alkyl, aryl and heteroaryl optimally substituted with one to three substituents;    l. A compound according to the following structure,                          m. A reduced dipeptide analogue according to the following structure,                           wherein X is selected from the group consisting of OR, NR 1 R 2 , and COOR 1 , and R 1  and R 2  are selected from the group consisting of hydrogen and C 1 -C 8  alkyl, aryl, and heteroaryl optimally substituted with one to three substituents;    n. A compound according to the following structure,                          o. A compound according to the following structure,                          p. An amino acid derivative according to the following structure,                           wherein R is selected from the group consisting of hydrogen and C 1 -C 6  alkyl, aryl, and heteroaryl optionally substituted with one to three substituents;    q. A compound according to the following structure,                          r. A benzazepine derivative according to the following structure,                           wherein Ar is selected from the group consisting of aryl and heteroaryl optimally substituted with one to three substituents, and X is selected from the group consisting of hydrogen and C 1 -C 6  alkyl and alkoxy;    s. A compound according to the following structure,                          t. A compound according to the following structure,                           wherein X is selected from the group consisting of R 1  and NHR 1 , R 1  is selected from the group consisting of hydrogen and C 1 -C 6  alkyl, aryl, and heteroaryl optimally substituted with one to three substituents, and R 2  is C 1 -C 4  alkyl or alkoxy;    u. A compound according to the following structure,                          v. A compound according to the following structure,                          w. A compound according to the following structure,                           wherein X is selected from the group consisting of hydrogen and halogen, and R is selected from the group consisting of C 1 -C 6  alkyl, aryl, and heteroaryl optimally substituted with one to three substituents;    x. A compound according to the following structure,                          y. A compound according to the following structure;                          z. A compound according to the following structure,                          aa. A compound according to the following structure,                          bb. A dihydropyridine derivative according to the following structure,                           wherein X is selected from the group consisting of hydrogen and C 1 -C 4  alkyl and alkoxy, R 1  is selected from the group consisting of hydrogen and C 1 -C 4  alkyl, and R 2  is selected from the group consisting of C 1 -C 6  alkyl, alkoxy, alkylamino, and aryl-substituted alkyl,;    cc. A compound according to the following structure,                          dd. A compound according to the following structure,                          ee. A diarylalkene or diarylalkane derivative according to the following structure,                           wherein X is selected from the group consisting of CHCH, CH 2 CH 2 , CH 2 —Y, O, and S, Y is selected from the group consisting of O and S, R 1  is selected from the group consisting of C 1 -C 4  alkyl and alkoxy, and R 2  is selected from the group consisting of hydrogen, COOR 1 , and C 1 -C 4  alkyl and alkoxy;    ff. A compound according to the following structure,                          gg. A compound according to the following structure,                          
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein said Cav2.2 subunit calcium channel modulator is formulated for oral, transmucosal, sublingual, buccal, intranasal, transurethral, rectal, inhalable, topical, transdermal, parenteral, or intrathecal administration.  
     
     
         15 . The pharmaceutical composition of  claim 13 , wherein the symptom of a non-inflammatory GI tract disorder is associated with a functional GI tract disorder selected from the group consisting of functional dysphagia, non-ulcer dyspepsia, irritable bowel syndrome, slow-transit constipation, and an evacuation disorder.  
     
     
         16 . The pharmaceutical composition of  claim 13 , wherein the symptom of a non-inflammatory GI tract disorder is associated with a motor disorder of the esophagus selected from the group consisting of achalasia and diffuse esophageal spasm.  
     
     
         17 . The pharmaceutical composition of  claim 13 , wherein the symptom of a non-inflammatory GI tract disorder is associated with a non-inflammatory structural GI disorder selected from the group consisting of hiatal hernia, stricture, esophageal web, Schatzki's ring, esophageal diverticulum, and esophageal scleroderma.  
     
     
         18 . The pharmaceutical composition of  claim 13 , wherein the pharmaceutical formulation further comprises an additional active agent.  
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the additional active agent is selected from the group consisting of: an antiulcerative, an antidiarrheal, a peristaltic colon stimulant, an antispasmodic, an antinauseant/prokinetic, an anti-inflammatory bowel drug, a tricyclic antidepressant, a ketolaric, duloxetine, venlafaxine, an SSRI, an SNRI, a spasmolytic, an anticholinergic, gabapentin, pregabalin, a substituted aminomethyl-phenyl-cyclohexane derivative, a 5-HT 3  antagonist, a 5-HT 4  antagonist, a β3 adrenergic agonist, a neurokinin receptor antagonist, a bradykinin receptor antagonist, and a nitric oxide donor.  
     
     
         20 . A packaged kit for use in the treatment of a symptom of a non-inflammatory GI disorder, comprising a Cav2.2 subunit calcium channel modulator, a container housing said Cav2.2 subunit calcium channel modulator during storage and prior to administration, and instructions for carrying out drug administration of said Cav2.2 subunit calcium channel modulator in a manner effective to treat said symptom of a non-inflammatory GI disorder, and wherein said Cav2.2 subunit calcium channel modulator is selected from the group consisting of: 
 a. ω-conotoxin CNVIIA;    b. ω-conotoxin CVIID;    c. ω-conotoxin AM336;    d. Cilnidipine;    e. Amlodipine;    f. L-cysteine derivative 2A;    g. ω-agatoxin IVA;    h. N,N-dialkyl-dipeptidylamines;    i. Levetiracetam;    j. (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide according to the following structure,                          k. A substituted peptidylamine according to the following structure,                           wherein X is selected selected from the group consisting of OR, NR 1 R 2 , and COOR 1 , and R 1  and R 2  are selected from the group consisting of hydrogen, and C 1 -C 8  alkyl, aryl and heteroaryl optimally substituted with one to three substituents;    l. A compound according to the following structure,                          m. A reduced dipeptide analogue according to the following structure,                           wherein X is selected from the group consisting of OR, NR 1 R 2 , and COOR 1 , and R 1  and R 2  are selected from the group consisting of hydrogen and C 1 -C8 alkyl, aryl, and heteroaryl optimally substituted with one to three substituents;    n. A compound according to the following structure,                          o. A compound according to the following structure,                          p. An amino acid derivative according to the following structure,                           wherein R is selected from the group consisting of hydrogen and C 1 -C 6  alkyl, aryl, and heteroaryl optionally substituted with one to three substituents;    q. A compound according to the following structure,                          r. A benzazepine derivative according to the following structure,                           wherein Ar is selected from the group consisting of aryl and heteroaryl optimally substituted with one to three substituents, and X is selected from the group consisting of hydrogen and C 1 -C 6  alkyl and alkoxy;    s. A compound according to the following structure,                          t. A compound according to the following structure,                           wherein X is selected from the group consisting of R 1  and NHR 1 , R 1  is selected from the group consisting of hydrogen and C 1 -C 6  alkyl, aryl, and heteroaryl optimally substituted with one to three substituents, and R 2  is C 1 -C 4  alkyl or alkoxy;    u. A compound according to the following structure,                          v. A compound according to the following structure,                          w. A compound according to the following structure,                           wherein X is selected from the group consisting of hydrogen and halogen, and R is selected from the group consisting of C 1 -C 6  alkyl, aryl, and heteroaryl optimally substituted with one to three substituents; x. A compound according to the following structure,                          y. A compound according to the following structure;                          z. A compound according to the following structure,                          aa. A compound according to the following structure,                          bb. A dihydropyridine derivative according to the following structure,                           wherein X is selected from the group consisting of hydrogen and C 1 -C 4  alkyl and alkoxy, R 1  is selected from the group consisting of hydrogen and C 1 -C 4  alkyl, and R 2  is selected from the group consisting of C 1 -C 6  alkyl, alkoxy, alkylamino, and aryl-substituted alkyl,;    cc. A compound according to the following structure,                          dd. A compound according to the following structure,                          ee. A diarylalkene or diarylalkane derivative according to the following structure,                           wherein X is selected from the group consisting of CHCH, CH 2 CH 2 , CH 2 —Y, O, and S, Y is selected from the group consisting of O and S, R 1  is selected from the group consisting of C 1 -C 4  alkyl and alkoxy, and R 2  is selected from the group consisting of hydrogen, COOR 1 , and C 1 -C 4  alkyl and alkoxy;    ff. A compound according to the following structure,                          gg. A compound according to the following structure,