Substituted phenethylamines

Abstract

Disclosed herein are substituted phenethylamine alpha adrenergic receptor modulators of Formula I, process of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.

1 . A compound having structural Formula I 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein:
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13  are independently selected from the group consisting of hydrogen and deuterium; 
 at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13  is deuterium; 
 if R 5  and R 6  are deuterium, then at least one of R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13  is deuterium; 
 if R 7 , R 8 , and R 9  are deuterium, then at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 10 , R 11 , R 12 , and R 13  is deuterium; and 
 if R 10 , R 11 , and R 13  are deuterium, then at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 12  is deuterium. 
 
     
   
   
       2 . The compound as recited in  claim 1 , wherein said compound is substantially a single enantiomer, a mixture of about 90% or more by weight of the (−)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−)-enantiomer, substantially an individual diastereomer, or a mixture of about 90% or more by weight of an individual diastereomer and about 10% or less by weight of any other diastereomer. 
   
   
       3 . The compound as recited in  claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13  independently has deuterium enrichment of no less than about 98%. 
   
   
       4 . The compound as recited in  claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13  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 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13  independently has deuterium enrichment of no less than about 50%. 
   
   
       6 . The compound as recited in  claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13  independently has deuterium enrichment of no less than about 20%. 
   
   
       7 . The compound as recited in  claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13  independently has deuterium enrichment of no less than about 10%. 
   
   
       8 . The compound as recited in  claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13  independently has deuterium enrichment of no less than about 5%. 
   
   
       9 . The compound as recited in  claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13  independently has deuterium enrichment of no less than about 1%. 
   
   
       10 . The compound as recited in  claim 1 , wherein the compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 
     
   
   
       11 . The compound as recited in  claim 10 , wherein said compound is substantially a single enantiomer, a mixture of about 90% or more by weight of the (−)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−)-enantiomer, substantially an individual diastereomer, or a mixture of about 90% or more by weight of an individual diastereomer and about 10% or less by weight of any other diastereomer. 
   
   
       12 . The compound as recited in  claim 10 , wherein each of said positions represented as D have deuterium enrichment of at least 98%. 
   
   
       13 . The compound as recited in  claim 10 , wherein each of said positions represented as D have deuterium enrichment of at least 90%. 
   
   
       14 . The compound as recited in  claim 10 , wherein each of said positions represented as D have deuterium enrichment of at least 50%. 
   
   
       15 . The compound as recited in  claim 10 , wherein each of said positions represented as D have deuterium enrichment of at least 20%. 
   
   
       16 . The compound as recited in  claim 10 , wherein each of said positions represented as D have deuterium enrichment of at least 10%. 
   
   
       17 . The compound as recited in  claim 10 , wherein each of said positions represented as D have deuterium enrichment of at least 5%. 
   
   
       18 . The compound as recited in  claim 10 , wherein each of said positions represented as D have deuterium enrichment of at least 1%. 
   
   
       19 . The compound as recited in  claim 1 , wherein the compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 
     
   
   
       20 . The compound as recited in  claim 19 , wherein said compound is substantially a single enantiomer, a mixture of about 90% or more by weight of the (−)-enantiomer and about 10% or less by weight of the (+)-enantiomer, a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−)-enantiomer, substantially an individual diastereomer, or a mixture of about 90% or more by weight of an individual diastereomer and about 10% or less by weight of any other diastereomer. 
   
   
       21 . The compound as recited in  claim 19 , wherein each of said positions represented as D have deuterium enrichment of at least 98%. 
   
   
       22 . The compound as recited in  claim 19 , wherein each of said positions represented as D have deuterium enrichment of at least 90%. 
   
   
       23 . The compound as recited in  claim 19 , wherein each of said positions represented as D have deuterium enrichment of at least 50%. 
   
   
       24 . The compound as recited in  claim 19 , wherein each of said positions represented as D have deuterium enrichment of at least 20%. 
   
   
       25 . The compound as recited in  claim 19 , wherein each of said positions represented as D have deuterium enrichment of at least 10%. 
   
   
       26 . The compound as recited in  claim 19 , wherein each of said positions represented as D have deuterium enrichment of at least 5%. 
   
   
       27 . The compound as recited in  claim 19 , wherein each of said positions represented as D have deuterium enrichment of at least 1%. 
   
   
       28 . A pharmaceutical composition comprising the compound as recited in  claim 1  and one or more pharmaceutically acceptable carriers. 
   
   
       29 . A pharmaceutical composition as recited in  claim 28 , further comprising one or more release-controlling excipients. 
   
   
       30 . The pharmaceutical composition as recited in  claim 28 , further comprising one or more non-release controlling excipients. 
   
   
       31 . The pharmaceutical composition as recited in  claim 28 , wherein the composition is suitable for oral, parenteral, or intravenous infusion administration. 
   
   
       32 . The pharmaceutical composition as recited in  claim 31 , wherein the oral dosage form is a tablet or capsule. 
   
   
       33 . The pharmaceutical composition as recited in  claim 31 , wherein the compound is administered in a dose of about 0.5 milligram to about 1,000 milligram. 
   
   
       34 . The pharmaceutical composition as recited in  claim 28 , further comprising another therapeutic agent. 
   
   
       35 . The pharmaceutical composition as recited in  claim 34 , wherein the therapeutic agent is selected from the group consisting of calcium channel blockers, adenosine, Beta-blockers, digitoxin, anti-arrhythmic agents, sympathomimetic drugs, steroidal drugs, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, anesthetics, mydriasis agents, anti-histamines, decongestants, expectorants, anti-tussives, sepsis agents, anti-bacterials, anti-fungals, anti-coagulants, thrombolytics, endothelin converting enzyme (ECE) inhibitors, thromboxane enzyme antagonists, potassium channel openers, thrombin inhibitors, growth factor inhibitors, platelet activating factor (PAF) antagonists, anti-platelet agents, Factor VIIa Inhibitors, Factor Xa Inhibitors, renin inhibitors, neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, fibrates, bile acid sequestrants, anti-atherosclerotic agents, MTP Inhibitors, potassium channel activators, alpha-PDE5 agents, beta-PDE5 agents, diuretics, anti-diabetic agents, PPAR-gamma agonists, mineralocorticoid enzyme antagonists, aP2 inhibitors, protein tyrosine kinase inhibitors, antiinflammatories, antiproliferatives, chemotherapeutic agents, immunosuppressants, anticancer agents, cytotoxic agents, antimetabolites, farnesyl-protein transferase inhibitors, hormonal agents, microtubule-disruptor agents, microtubule-stabilizing agents, topoisomerase inhibitors, prenyl-protein transferase inhibitors, cyclosporins, TNF-alpha inhibitors, cyclooxygenase-2 (COX-2) inhibitors, gold compounds, antalarmin, Z-338 and platinum coordination complexes. 
   
   
       36 . The pharmaceutical composition as recited in  claim 35 , wherein the therapeutic agent is a calcium channel blocker. 
   
   
       37 . The pharmaceutical composition as recited in  claim 36 , wherein the calcium channel blocker is selected from the group consisting of amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nhisoldipine, nitrendipine, lacidipine, nilvadipine, manidipine, barnidipine, lercanidipine, cilnidipine, benidipine, mibefradil, verapamil, gallopamil, diltiazem, fendiline, bepridil, lidoflazine, and perhexiline 
   
   
       38 . The pharmaceutical composition as recited in  claim 35 , wherein the therapeutic agent is adenosine. 
   
   
       39 . The pharmaceutical composition as recited in  claim 35 , wherein the therapeutic agent is a Beta-blocker. 
   
   
       40 . The pharmaceutical composition as recited in  claim 39 , wherein the Beta-blocker is selected from the group consisting of alprenolol, oxprenolol, pindolol, propranolol, timolol, sotalol, nadolol, mepindolol, carteolol, tertatolol, bopindolol, bupranolol, penbutolol, cloranolol, practolol, metoprolol, atenolol, acebutolol, betaxolol, bevantolol, bisoprolol, celiprolol, esmolol, epanolol, s-atenolol, nebivolol, talinolol, labetalol, and carvedilol. 
   
   
       41 . The pharmaceutical composition as recited in  claim 35 , wherein the therapeutic agent is an anti-arrhythmic agent. 
   
   
       42 . The pharmaceutical composition as recited in  claim 41 , wherein the anti-arrhythmic agent is selected from the group consisting of quinidine, procainamide, disopyramide, sparteine, ajmaline, prajmaline, lorajmine, lidocaine, mexiletine, tocainide, aprindine, propafenone, flecainide, lorcainide, encainide, amiodarone, bretylium tosilate, bunaftine, dofetilide, ibutilidem, moracizine, and cibenzoline. 
   
   
       43 . The pharmaceutical composition as recited in  claim 35 , wherein the therapeutic agent is an opioid. 
   
   
       44 . The pharmaceutical composition as recited in  claim 43 , wherein the opioid is selected from the group consisting of morphine, codeine, thebain, diacetylmorphine, oxycodone, hydrocodone, hydromorphone, oxymorphone, nicomorphine, fentanyl, 3-methylfentanyl, alfentanil, sufentanil, remifentanyl, carfentanyl, ohmefentanyl, pethidine, ketobemidone, propoxyphene, dextropropoxyphene, methadone, loperamide, pentazocine, buprenorphine, etorphine, butorphanol, nalbufine, levorphanol, naloxone, naltrexone, and tramadol. 
   
   
       45 . The pharmaceutical composition as recited in  claim 35 , wherein the therapeutic agent is a sympathomimetic drug. 
   
   
       46 . The pharmaceutical composition as recited in  claim 45 , wherein the sympathomimetic drug is selected from the group consisting of cyclopentamine, ephedrine, phenylephrine, oxymetazoline, tetryzoline, xylometazoline, naphazoline, tramazoline, metizoline, tuaminoheptane, fenoxazoline, tymazoline, epinephrine, phenylpropanolamine, and pseudoephedrine. 
   
   
       47 . The pharmaceutical composition as recited in  claim 35 , wherein the therapeutic agent is a mydriasis agent. 
   
   
       48 . The pharmaceutical composition as recited in  claim 47 , wherein the mydriasis agent is selected from the group consisting of atropine, scopolamine, methylscopolamine, cyclopentolate, homatropine, and tropicamide. 
   
   
       49 . The pharmaceutical composition as recited in  claim 35 , wherein the therapeutic agent is a steroidal drug. 
   
   
       50 . The pharmaceutical composition as recited in  claim 49 , wherein the steroidal drug is selected from the group consisting of aldosterone, beclometasone, betamethasone, deoxycorticosterone acetate, fludrocortisone acetate, hydrocortisone (cortisol), prednisolone, prednisone, methylprenisolone, dexamethasone, and triamcinolone. 
   
   
       51 . A method for the treatment, prevention, or amelioration of one or more symptoms of an alpha adrenergic receptor-mediated disorder, in a subject, comprising administering a therapeutically effective amount of a compound having structural Formula II: 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein:
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13  are independently selected from the group consisting of hydrogen and deuterium; and 
 at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , and R 13  is deuterium. 
 
     
   
   
       52 . The method as recited in  claim 51 , wherein the alpha adrenergic receptor-mediated disorder is selected from the group consisting of nasal congestion, migraine, asthma, chronic obstructive pulmonary disorders, ischemic heart disorder, and hypotension. 
   
   
       53 . The method as recited in  claim 51 , wherein the alpha adrenergic receptor-mediated disorder can be lessened, alleviated, or prevented by administering an alpha adrenergic receptor modulator. 
   
   
       54 . The method as recited in  claim 51 , wherein said compound has at least one of the following properties:
 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.   
   
   
       55 . The method as recited in  claim 51 , wherein said compound has at least two of the following properties:
 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.   
   
   
       56 . The method as recited in  claim 51 , wherein the method affects a decreased metabolism of the compound per dosage unit thereof by at least one polymorphically-expressed cytochrome P450 isoform in the subject, as compared to the corresponding non-isotopically enriched compound. 
   
   
       57 . The method as recited in  claim 56 , wherein the cytochrome P 450  isoform is selected from the group consisting of CYP2C8, CYP2C9, CYP2C19, and CYP2D6. 
   
   
       58 . The method as recited in  claim 51 , 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. 
   
   
       59 . The method as recited in  claim 58 , 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 . 
   
   
       60 . The method as recited in  claim 51 , wherein the method affects the treatment of the disease while reducing or eliminating a deleterious change in a diagnostic hepatobiliary function endpoint, as compared to the corresponding non-isotopically enriched compound. 
   
   
       61 . The method as recited in  claim 60 , 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.