Treatment of diseases modulated by a h4 receptor agonist

Abstract

The invention provides a method for the treatment of H4R modulated diseases and/or conditions comprising administering to the subject an effective amount of a H4R agonist. The invention also provides a method for treating COPD comprising administering to the subject an effective amount of a H4R agonist, a H1R antagonist and an anticholinergic drug. Further, the invention provides a pharmaceutical formulation comprising a H4R agonist, a second active agent and a pharmaceutically acceptable carrier.

1 .- 45 . (canceled) 
     
     
         46 . A method for the treatment of a disease modulated by a H4R agonist comprising administering to a subject an effective amount of a H4R agonist to treat the disease. 
     
     
         47 . The method of  claim 46 , wherein the disease modulated by a H4R agonist is an immune system disease. 
     
     
         48 . The method of  claim 47 , wherein the immune system disease is selected from eczema, Crohn's disease, ulcerative colitis, celiac disease, autoimmune gastritis, uveitis and disease conditions in cancer. 
     
     
         49 . The method of  claim 46 , wherein the H4R agonist is selected from a group consisting of Tritoqualine (TRQ), Tritoqualine isomer, 4-methylhistmime (4MeHA) and clobenprobit (CB). 
     
     
         50 . The method of  claim 47 , wherein the Tritoqualine isomer is E1 or E2. 
     
     
         51 . The method of  claim 46 , wherein the effective amount of the H4R agonist is about 200 mg/day, about 1 g/day, about 2 g/day, about 3 g/day, about 1-5 mg/day, about 5-10 mg/day, about 10-15 mg/day, about 15-20 mg/day, about 20-25 mg/day, about 25-30 mg/day, about 30-35 mg/day, about 35-40 mg/day, about 40-45 mg/day, about 45-50 mg/day, about 50-55 mg/day, about 55-60 mg/day, about 60-65 mg/day, about 65-70 mg/day, about 70-75 mg/day, about 75-80 mg/day, about 80-85 mg/day, about 85-90 mg/day, about 90-95 mg/day, about 95-100 mg day, about 100-105 mg/day, about 105-110 mg/day, about 110-115 mg/day, about 115-120 mg/day, about 120-125 mg/day, about 125-130 mg/day, about 130-135 mg/day, about 135-140 mg/day, about 140-145 mg/day, about 145-150 mg/day, about 150-155 mg/day, about 155-160 mg/day, about 160-165 mg/day, about 165-170 mg/day, about 170-175 mg/day, about 175-180 mg/day, about 180-185 mg/day, about 185-190 mg/day, about 190-195 mg/day, about 195-200 mg/day, about 200-205 mg/day, about 205-210 mg/day, about 210-215 mg/day, about 215-220 mg/day, about 220-225 mg/day, about 225-230 mg/day, about 230-235 mg/day, about 235-240 mg/day, about 240-245 mg/day, about 245-250 mg/day, about 250-255 mg/day, about 255-260 mg/day, about 260-265 mg/day, about 265-270 mg/day, about 270-275 mg/day, about 275-280 mg/day, about 280-285 mg/day, about 285-290 mg/day, about 290-295 mg/day, about 295-300 mg/day, about 300-305 mg/day, about 305-310 mg/day, about 310-315 mg/day, about 315-320 mg/day, about 320-325 mg/day, about 325-330 mg/day, about 330-335 mg/day, about 335-340 mg/day, about 340-345 mg/day, about 345-350 mg/day, about 350-355 mg/day, about 355-360 mg/day, about 360-365 mg/day, about 365-370 mg/day, about 370-375 mg/day, about 375-380 mg/day, about 380-385 mg/day, about 385-390 mg/day, about 390-395 mg/day, about 395-400 mg/day, about 400-405 mg/day, about 405-410 mg/day, about 410-415 mg/day, about 415-420 mg/day, about 420-425 mg/day, about 425-430 mg/day, about 430-435 mg/day, about 435-440 mg/day, about 440-445 mg/day, about 445-450 mg/day, about 1 mg/day-1 g/day, about 1 mg/day-2 g/day or about 1 mg/day-3 g/day. 
     
     
         52 . The method of  claim 46 , further comprising administering to the subject an effective amount of one or more of an anti-H1, anti-H2 and anti-H3 drug. 
     
     
         53 . The method of  claim 46 , further comprising administering to the subject an effective amount of an anti-H1 drug. 
     
     
         54 . The method of  claim 46 , further comprising administering to the subject an effective amount of an anti-H2 drug. 
     
     
         55 . The method of  claim 46 , further comprising administering to the subject an effective amount of an anti-H3 drug. 
     
     
         56 . The method of  claim 46 , further comprising administering to the subject an effective amount of an anti-H1, anti-H2 and anti-H3 drug. 
     
     
         57 . The method of  claim 52 , wherein the anti-H1 drug is selected from a group consisting of brompheniramine, cetirizine, fexofenadine, cyproheptadine, dexchlorpheniramine, hydroxizine, ketotifen, loratadine, mequitazine, oxotomide, mizolastine, ebastine, astemizole, carbinoxamide, alimemazine, buclizine, cyclizine hydrochloride, doxylamine, mepyramine, antazoline, diphenhydramine, carbinoxamine, clemastine, dimenhydrinate, pheniramine, chlorphenamine, triprolidine, chlorcyclizine, hydroxyzine, meclizine, promethazine, and azatadine. 
     
     
         58 . The method of  claim 57 , wherein the effective amount of anti-H1 drug is about 10.0 mg/day, about 120.0 mg/day, about 0.1 to 1.0 mg/day, about 1.0 to 2.0 mg/day, about 2.0 to 3.0 mg/day, about 3.0 to 4.0 mg/day, about 4.0 to 5.0 mg/day, about 5.0 to 6.0 mg/day, about 6.0 to 7.0 mg/day, about 7.0 to 8.0 mg/day, about 8.0 to 9.0 mg/day, about 9.0 to 10.0 mg/day, about 10.0 to 11.0 mg/day, about 11.0 to 12.0 mg/day, about 12.0 to 13.0 mg/day, about 13.0 to 14.0 mg/day, about 14.0 to 15.0 mg/day, about 15.0 to 16.0 mg/day, about 16.0 to 17.0 mg/day, about 17.0 to 18.0 mg/day, about 18.0 to 19.0 mg/day, about 19.0 to 20.0 mg/day, about 20.0 to 21.0 mg/day, about 21.0 to 22.0 mg/day, about 22.0 to 23.0 mg/day, about 23.0 to 24.0 mg/day, about 24.0 to 25.0 mg/day, about 25.0 to 26.0 mg/day, about 26.0 to 27.0 mg/day, about 27.0 to 28.0 mg/day, about 28.0 to 29.0 mg/day, about 29.0 to 30.0 mg/day, about 30.0 to 31.0 mg/day, about 31.0 to 32.0 mg/day, about 32.0 to 33.0 mg/day, about 33.0 to 34.0 mg/day, about 34.0 to 35.0 mg/day, about 1 mg/day to about 35 mg/day, 1.0 to 30.0 mg/day, about 30.0 to 50.0 mg/day, about 50.0 to about 70.0 mg/day, about 70.0 to 90.0 mg/day, about 90.0 to 110.0 mg/day, about 110.0 to 130.0 mg/day, about 130.0 to 150.0 mg/day, about 150.0 to 170.0 mg/day, about 170.0 to 190.0 mg/day, about 190.0 to 210.0 mg/day, about 210.0 to 230.0 mg/day, about 230.0 to 250.0 mg/day, about 250.0 to 270.0 mg/day, about 270.0 to 290.0 mg/day, about 290.0 to 310.0 mg/day, about 310.0 to 330.0 mg/day, about 330.0 to 350.0 mg/day, about 350.0 to 370.0 mg/day, about 370.0 to 390.0 mg/day, about 390.0 to 410.0 mg/day, about 410.0 to 430.0 mg/day, about 430.0 to 450.0 mg/day, about 450.0 to 470.0 mg/day, about 470.0 to 490.0 mg/day, about 490.0 to 510.0 mg/day or about 1 mg/day to 510 mg/day. 
     
     
         59 . (canceled) 
     
     
         60 . The method of  claim 52 , wherein the effective amount of anti-H2 drug is about 150.0 mg/day, about 1.0 to 20.0 mg/ml, about 20.0 to 40.0 mg/ml, about 40.0 to 60.0 mg/ml, about 60.0 to 80.0 mg/ml, about 80.0 to 100.0 mg/ml, about 100.0 to 120.0 mg/ml, about 120.0 to 140.0 mg/ml, about 140.0 to 160.0 mg/ml, about 160.0 to 180.0 mg/ml, about 180.0 to 200.0 mg/ml, about 200.0 to 220.0 mg/ml, about 220.0 to 240.0 mg/ml, about 240.0 to 260.0 mg/ml, about 260.0 to 280.0 mg/ml, about 280.0 to 300.0 mg/ml, about 300.0 to 320.0 mg/ml, about 320.0 to 340.0 mg/ml, about 340.0 to 360.0 mg/ml, about 360.0 to 380.0 mg/ml, about 380.0 to 400.0 mg/ml, about 400.0 to 420.0 mg/ml, about 420.0 to 440.0 mg/ml, about 440.0 to 460.0 mg/ml, about 460.0 to 480.0 mg/ml, about 480.0 to 500.0 mg/ml, about 500.0 to 520.0 ing/ml, about 520.0 to 540.0 mg/ml, about 540.0 to 560.0 mg/ml, about 560.0 to 580.0 mg/ml, about 580.0 to 600.0 mg/ml, about 600.0 to 620.0 mg/ml, about 620.0 to 640.0 mg/ml, about 640.0 to 660.0 mg/ml, about 660.0 to 680.0 mg/ml, about 680.0 to 700.0 mg/ml, about 700.0 to 720.0 mg/ml, about 720.0 to 740.0 mg/ml, about 740.0 to 760.0 mg/ml, about 760.0 to 780.0 mg/ml, about 780.0 to 800.0 mg/ml, about 800.0 to 820.0 mg/ml, about 820.0 to 840.0 mg/ml, about 840.0 to 860.0 mg/ml, about 860.0 to 880.0 mg/ml, about 880.0 to 900.0 mg/ml or about 1 mg/ml to about 900 mg/ml. 
     
     
         61 . The method of  claim 52 , wherein the anti-H3 drug is selected from a group consisting of betahistine (N-methyl-2-pyridin-2-ylethanamine), ABT-239 (4-(2-{2-[(2R)-2-Methylpyrrolidin-1-yl]ethyl}-benzofuran-5-yl)benzonitrile), Cipralisant(1R,2R)-4-(2-(5,5-dimethylhex-1-ynyl)cyclopropyl)imidazole, Ciproxifan cyclopropyl 4-(3-(1H-imidazol-4-yl)propyloxy)phenyl ketone, Clobenpropit N′-[(4-chlorophenyl)methyl]-1-[3-(3H-imidazol-4-yl)propylthio]formamidine, Thioperamide N-Cyclohexyl-4-(1H-imidazol-4-yl)-1-piperidinecarbothioamide. 
     
     
         62 . The method of  claim 61 , wherein the effective amount of anti-H3 drug is about 0.1 to 1.0 mg/day, about 1.0 to 2.0 mg/day, about 2.0 to 3.0 mg/day, about 3.0 to 4.0 mg/day, about 4.0 to 5.0 mg/day, about 5.0 to 6.0 mg/day, about 6.0 to 7.0 mg/day, about 7.0 to 8.0 mg/day, about 8.0 to 9.0 mg/day, about 9.0 to 10.0 mg/day, about 10.0 to 15.0 mg/day, about 15.0 to 20.0 mg/day, about 20.0 to 25.0 mg/day, about 25.0 to 30.0 mg/day, about 30.0 to 35.0 mg/day, about 35.0 to 40.0 mg/day, about 45.0 to 50.0 mg/day, about 50.0 to 60.0 mg/day, about 60.0 to 70.0 mg/day, about 70.0 to 80.0 mg/day, about 80.0 to 90.0 mg/day, about 90.0 to 100.0 mg/day, about 100.0 to 150.0 mg/day, about 150.0 to 200.0 mg/day, about 200.0 to 250.0 mg/day, about 250.0 to 300.0 mg/day, about 300.0 to 350.0 mg/day, about 350.0 to 400.0 mg/day, about 400.0 to 450.0 mg/day, about 450.0 to 500.0 mg/day, about 500.0 to 550.0 mg/day, about 550.0 to 600.0 mg/day, about 600.0 to 650.0 mg/day, about 650.0 to 700.0 mg/day, about 700.0 to 750.0 mg/day, about 750.0 to 800.0 mg/day, about 800.0 to 850.0 mg/day, about 850.0 to 900.0 mg/day, about 900.0 to 950.0 mg/day, about 950.0 to 1000.0 mg/day, about 1000.0 to 1100.0 mg/day, about 1100.0 to 1200.0 mg/day, about 1200.0 to 1300.0 mg/day, about 1300.0 to 1400.0 mg/day, about 1400.0 to 1500.0 mg/day, about 1500.0 to 1600.0 mg/day, about 1600.0 to 1700.0 mg/day, about 1800.0 to 1900.0 mg/day or about 1900.0 to 2000.0 mg/day. 
     
     
         63 . The method of  claim 46 , wherein the subject is suffering from eczema, Crohn's disease, ulcerative colitis, celiac disease, autoimmune gastritis, uveitis and disease conditions in cancer. 
     
     
         64 . The method of  claim 46 , wherein the subject is a mammal. 
     
     
         65 .- 69 . (canceled) 
     
     
         70 . A pharmaceutical formulation comprising a combination of
 (a) a H4R agonist,   (b) one or more of an anti-H1, anti-H2 and anti-H3 drug, and   (c) a pharmaceutically acceptable carrier.   
     
     
         71 .- 100 . (canceled) 
     
     
         101 . The method of  claim 46 , wherein the H4R agonist does not inhibit Organic Cation Transporter-3 (OCT-3) and/or Serotonin Transporter (SERT).