4,6-diaminopyrimidine stimulators of soluble guanylate cyclase

Abstract

The present invention relates to new 4,6-diaminopyrimidine stimulators of soluble guanylate cyclase, pharmaceutical compositions thereof, and methods of use thereof.

What is claimed is: 
     
         1 . A compound of structural Formula I 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein:
 R 1 -R 19  are independently selected from the group consisting of hydrogen and deuterium; and 
 at least one of R 1 -R 19  is deuterium. 
 
     
     
         2 . The compound as recited in  claim 1  wherein at least one of R 1 -R 19  independently has deuterium enrichment of no less than about 10%. 
     
     
         3 . The compound as recited in  claim 1  wherein at least one of R 1 -R 19  independently has deuterium enrichment of no less than about 50%. 
     
     
         4 . The compound as recited in  claim 1  wherein at least one of R 1 -R 19  independently has deuterium enrichment of no less than about 90%. 
     
     
         5 . The compound as recited in  claim 1  wherein at least one of R 1 -R 19  independently has deuterium enrichment of no less than about 98%. 
     
     
         6 . The compound as recited in  claim 1  wherein said compound has a structural formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . The compound as recited in  claim 1  wherein said compound has a structural formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound as recited in  claim 7  wherein each position represented as D has deuterium enrichment of no less than about 10%. 
     
     
         9 . The compound as recited in  claim 7  wherein each position represented as D has deuterium enrichment of no less than about 50%. 
     
     
         10 . The compound as recited in  claim 7  wherein each position represented as D has deuterium enrichment of no less than about 90%. 
     
     
         11 . The compound as recited in  claim 7  wherein each position represented as D has deuterium enrichment of no less than about 98%. 
     
     
         12 . The compound as recited in  claim 7  wherein said compound has the structural formula: 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound as recited in  claim 7  wherein said compound has the structural formula: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound as recited in  claim 7  wherein said compound has the structural formula: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound as recited in  claim 7  wherein said compound has the structural formula: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The compound as recited in  claim 7  wherein said compound has the structural formula: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound as recited in  claim 7  wherein said compound has the structural formula: 
       
         
           
           
               
               
           
         
       
     
     
         18 . A pharmaceutical composition comprising a compound as recited in  claim 1  together with a pharmaceutically acceptable carrier. 
     
     
         19 . A method of treatment of a soluble guanylate cyclase-mediated disorder comprising the administration of a therapeutically effective amount of a compound as recited in  claim 1  to a patient in need thereof. 
     
     
         20 . The method as recited in  claim 19  wherein said disorder is selected from the group consisting of chronic thromboembolic pulmonary hypertension, pulmonary arterial hypertension, asthma, hypertension, atherosclerosis, osteoporosis, thromboembolism, genitourinary disorders, bronchoconstriction, chronic obstructive pulmonary disease, acute respiratory distress syndrome, pulmonary vasoconstriction, migraine, migraine with vertigo, optic nerve damage, glaucoma cerebrovascular disorders, cerebrovasospasm, stroke, transient ischemic attacks, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, fibrotic disorders, renal disorders, non-alcoholic hepatosteatosis, hepatitis, diabetic nephropathy, idiopathic pulmonary fibrosis. 
     
     
         21 . The method as recited in  claim 19  further comprising the administration of an additional therapeutic agent. 
     
     
         22 . The method as recited in  claim 21  wherein said additional therapeutic agent is selected from the group consisting of antihypertensives and PDE5 inhibitors. 
     
     
         23 . The method as recited in  claim 22  wherein said antihypertensive is selected from the group consisting of metoprolol, hydrochlorothiazide, aliskiren, valsartan, candesartan, amlodipine, olmesartan, medoxomil, azelnidipine, azilsartan, azilsartan medoxomil potassium, chlorthalidone, darusentan, fimasartan, olmesartan medoxomil, pratosartan, telmisartan, ADX-415, AR-9281, angiotensin vaccine/CoVaccine HT, cholecalciferol, daglutril, flavangenol, INT-001, LCI-699, LCZ-696, lisinopril, MK-0736, PL-3994, PS-433540, rostafuroxine, S-(+)-mecamylamine, SLx-2101, SPP-635, sapropterin, TBC-3711, udenafil, MC-4262, mirodenafil, NV-04, SPP-1148, SPP-676, TAK-591, VNP-489, rhACE2, allisartan, BNP-054, CGEN-856, CGEN-857, INT-002, QGC-001, SLV-316, tempol, urocortin 2, and XL-550. 
     
     
         24 . The method as recited in  claim 22  wherein said PDE5 inhibitor is selected from the group consisting of vardenafil, sildenafil, and tadalafil. 
     
     
         25 . The method as recited in  claim 19 , further resulting in at least one effect selected from the group consisting of:
 a. decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound;   b. increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;   c. decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;   d. increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; and   e. an improved clinical effect during the treatment in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.   
     
     
         26 . The method as recited in  claim 19 , further resulting in at least two effects selected from the group consisting of:
 a. decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound;   b. increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;   c. decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound;   d. increased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound; and   e. an improved clinical effect during the treatment in said subject per dosage unit thereof as compared to the non-isotopically enriched compound.   
     
     
         27 . The method as recited in  claim 19 , wherein the method effects a decreased metabolism of the compound per dosage unit thereof by at least one polymorphically-expressed cytochrome P 450  isoform in the subject, as compared to the corresponding non-isotopically enriched compound. 
     
     
         28 . The method as recited in  claim 27 , wherein the cytochrome P 450  isoform is selected from the group consisting of CYP2C8, CYP2C9, CYP2C19, and CYP2D6. 
     
     
         29 . The method as recited  claim 19 , wherein said compound is characterized by decreased inhibition of at least one cytochrome P 450  or monoamine oxidase isoform in said subject per dosage unit thereof as compared to the non-isotopically enriched compound. 
     
     
         30 . The method as recited in  claim 29 , wherein said cytochrome P 450  or monoamine oxidase isoform is selected from the group consisting of CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, CYP51, MAO A , and MAO B . 
     
     
         31 . The method as recited in  claim 19 , wherein the method reduces a deleterious change in a diagnostic hepatobiliary function endpoint, as compared to the corresponding non-isotopically enriched compound. 
     
     
         32 . The method as recited in  claim 31 , wherein the diagnostic hepatobiliary function endpoint is selected from the group consisting of alanine aminotransferase (“ALT”), serum glutamic-pyruvic transaminase (“SGPT”), aspartate aminotransferase (“AST,” “SGOT”), ALT/AST ratios, serum aldolase, alkaline phosphatase (“ALP”), ammonia levels, bilirubin, gamma-glutamyl transpeptidase (“GGTP,” “γ-GTP,” “GGT”), leucine aminopeptidase (“LAP”), liver biopsy, liver ultrasonography, liver nuclear scan, 5′-nucleotidase, and blood protein. 
     
     
         33 . A compound as recited in  claim 1  for use as a medicament. 
     
     
         34 . A compound as recited in  claim 1  for use in the manufacture of a medicament for the prevention or treatment of a disorder ameliorated by the stimulation of soluble guanylate cyclase.