Nitric Oxide Amino Acid Esters for Improving Vascular Circulation, and Prophylaxis or Treatment of a Condition Associated with Impaired Blood Circulation

Abstract

The present document describes transdermal compositions comprising effective amounts of a nitric oxide amino acid ester compound, a skin penetration enhancer is association with a pharmaceutically acceptable carrier. Also described are methods of use for improving vascular circulation, and prophylaxis or treatment of a condition associated with impaired blood circulation, including peripheral vascular diseases.

1 . A method of improving vascular circulation, and prophylaxis or treatment of a condition associated with impaired blood circulation in a patient which comprises:
 (a) treating said patient with a therapeutically effective amount of a compound of formula (I)   
       
         
           
           
               
               
           
         
         
           wherein n =1 to 10; 
           wherein R 1  is an amino acid side chain group (D or L configuration), 
           wherein R 2  is a hydrogen atom, or an amino acid (D or L configuration) forming a 
           peptide bond, or any pharmaceutically acceptable salts thereof 
         
       
     
     
         2 . The method as claimed in  claim 1 , wherein said compound of formula (I) is (2-nitrooxy)-2-ethylamino-3-methylbutanoate: 
       
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salts thereof. 
     
     
         3 . The method as claimed in  claim 1  wherein said compound of formula (I) is valine butylene glycol nitrate: 
       
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salts thereof. 
     
     
         4 . The method as claimed in  claim 1 , wherein said compound of formula (I) is: 
       
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salts thereof. 
     
     
         5 . The method as claimed in  claim 1 , wherein said compound of formula (I) is 2′-nitrooxyethyl 2-amino-pentanoate: 
       
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salts thereof. 
     
     
         6 . The method as claimed in  claim 1 , wherein said compound of formula (I) is 4′-nitrooxybutyl 2-amino-pentanoate: 
       
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salts thereof. 
     
     
         7 . (canceled) 
     
     
         8 . The method as claimed in  claim 1 , wherein R 1  is chosen from: 
       
         
           
           
               
               
           
         
       
       wherein when R 1  is 
       
         
           
           
               
               
           
         
       
       said R 1  is also linked to an NH 2  of said Formula (I) to form a proline or hydroxyproline amino acid side chain. 
     
     
         9 . (canceled) 
     
     
         10 . The method according to  claim 1 , wherein said treating is transdermally or topically. 
     
     
         11 . The method as claimed in  claim 1 , wherein said condition associated with impaired blood circulation is chosen from a skin ulcer, a decubitus ulcer, a mouth ulcer, a diabetic foot ulcer, a venous insufficiency ulcer, a venous ulcer, an arterial insufficiency ulcer, a neuropathic ulcer, a genital ulcer, a sore, a wound, a peripheral vascular disease, an atherosclerosis, Raynaud's phenomenon, an erythromelalgia and a gangrene. 
     
     
         12 . The method according to  claim 11 , wherein said peripheral vascular disease is associated with diabetes. 
     
     
         13 . The method as claimed in claim 1 , wherein said patient has a normotensive blood pressure, a hypertensive blood pressure, or a hypotensive blood pressure. 
     
     
         14 . The method as claimed in  claim 13 , wherein when blood pressure is a normotensive blood pressure or a hypotensive blood pressure, said treating said patient results in a stable blood pressure, or wherein when said blood pressure is a hypertensive blood pressure, said treating said patient results in a decreased blood pressure or a normotensive blood pressure. 
     
     
         15 .- 30 . (canceled) 
     
     
         31 . A topical composition for improving vascular circulation and prophylaxis or treatment of peripheral vascular disease and a condition associated with impaired blood circulation comprising:
 an effective amount of a compound of formula (I):   
       
         
           
           
               
               
           
         
         wherein n =1 to 10; 
         wherein R 1  is an amino acid side chain group (D or L configuration), 
         wherein R 2  is a hydrogen atom, or an amino acid (D or L configuration) forming a 
         peptide bond, or any pharmaceutically acceptable salts thereof; and 
         at least one topical antimicrobial, in association with a pharmaceutically acceptable topical carrier. 
       
     
     
         32 . The composition as claimed in  claim 31 , wherein said compound of formula (I) is (2-nitrooxy)-2-ethylamino-3-methylbutanoate: 
       
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salts thereof. 
     
     
         33 . The composition as claimed in  claim 31 , wherein said compound of formula (I) is valine butylene glycol nitrate: 
       
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salts thereof. 
     
     
         34 . (canceled) 
     
     
         35 . The composition as claimed in  claim 31 , wherein said compound of formula (I) is 2′-nitrooxyethyl 2-amino-pentanoate: 
       
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salts thereof. 
     
     
         36 . The composition as claimed in  claim 31 , wherein said compound of formula (I) is 4′-nitrooxybutyl 2-amino-pentanoate: 
       
         
           
           
               
               
           
         
       
       or any pharmaceutically acceptable salts thereof. 
     
     
         37 . (canceled) 
     
     
         38 . The composition as claimed in  claim 31 , wherein R 1  is chosen from: 
       
         
           
           
               
               
           
         
       
       wherein when R 1  is 
       
         
           
           
               
               
           
         
       
       said R 1  is also linked to an NH 2  of said Formula (I) to form a proline or hydroxyproline amino acid side chain. 
     
     
         39 . (canceled) 
     
     
         40 . The composition as claimed in  claim 31 , wherein said topical antimicrobial is at least one of a topical antibiotic chosen from amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, geldanamycin, herbimycin, loracarbef, ertapenem, doripenem, imipenem/cilastatin, meropenem, cefadroxil, cefazolin, cefalotin, cefalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftobiprole, teicoplanin, vancomycin, telavancin, clindamycin, lincomycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spectinomycin, aztreonam, furazolidone, nitrofurantoin, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin g, penicillin v, piperacillin, temocillin, ticarcillin, amoxicillin and clavulanate, ampicillin and sulbactam, piperacillin and tazobactam, ticarcillin and clavulanate, bacitracin, colistin, polymyxin b, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin, mafenide, sulfonamidochrysoidine, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole, sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, trimethoprim-sulfamethoxazole, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin, rifabutin, rifapentine, streptomycin, arsphenamine, chloramphenicol, fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin, platensimycin, quinupristin/dalfopristin, rifaximin, thiamphenicol, and tinidazole,
 a topical antifungal chosen from natamycin, rimocidin, filipin, nystatin, amphotericin b, candicin, hamycin, miconazole, ketoconazole, clotrimazole, econazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole, terconazole, abafungin, terbinafine, amorolfine, naftifine, butenafine, anidulafungin, caspofungin, micafungin, benzoic acid, ciclopirox, tolnaftate, undecylenic acid, 5-fluorocytosine, griseofulvin, haloprogin, and sodium bicarbonate,   
       and combinations thereof. 
     
     
         41 .- 42 . (canceled) 
     
     
         43 . The composition of  claim 31 , further comprising a skin penetration enhancer chosen from a C 8 -C 22  fatty acid, a C 8 -C 22  fatty alcohol, a lower alkyl ester of a C 8 -C 22  fatty acid, a di(lower)alkyl ester of C 6 -C 22  diacid, a monoglyceride of C 8 -C 22  fatty acid, tetrahydrofurfuryl alcohol polyethylene glycol ether, polyethylene glycol, propylene glycol, 2-(2-ethoxyethoxy)ethanol (transcutol), diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, an alkylaryl ether of polyethylene oxide, a polyethylene oxide monomethyl ether, a polyethylene oxide dimethyl ether; dimethyl sulfoxide (DMSO), glycerol, ethyl acetate, acetoacetic ester, N-alkylpyrrolidone, a terpenes, dimethyl formamide (DMF), N,N-dimethylacetamide (DMA), methyl laurate, glycerol monolaurate, a fatty acid ester of a C 2  to C 4  alkanediol having a fatty acid portion of said ester from about 8 to 22 carbon atoms, a fatty alcohol ether of a C 2  to C 4  alkanediols having a fatty acid portion of said ether from about 8 to 22 carbon atoms, triglycerides of coconut oil, isopropyl palmitate, isopropyl myristate, laurocapram, and combinations thereof. 
     
     
         44 .- 69 . (canceled)