Pure heptasulfated disaccharides having improved oral bioavailability

Abstract

Hypersulfated disaccharides with utility in asthma or asthma related disorders are disclosed. The heptasulfated disaccharides administered orally have comparable bioavailability to the intravenous administered dosage form.

1 . A dosage form comprising a substantially pure form of a compound of formula I or pharmaceutically acceptable salts thereof 
       
         
           
           
               
               
           
         
       
       wherein R 1 -R 7  are independently selected from the group consisting of SO 3 H or PO 4 H and a pharmaceutically acceptable excipient wherein the amount of a compound of formula I in said dosage form ranges from 0.3 to 10 mgs/kg. 
     
     
         2 . The formulation according to  claim 1  wherein R 1 -R 7  is selected from SO 3 H. 
     
     
         3 . The formulation according to  claim 1  wherein the salt is a sodium salt. 
     
     
         4 . The formulation according to  claim 1  wherein said formulation is oral. 
     
     
         5 . The formulation according to  claim 1  which is i.v. 
     
     
         6 . The formulation according to  claim 1  in inhalable form. 
     
     
         7 . A method of treating or alleviating an inflammatory condition in a mammal in need of treatment thereof comprising administration of
 (i) a pharmaceutically effective amount of a formulation comprising a compound of formula I   
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof wherein R 1 -R 7  are independently selected from SO 3 H or PO 4 H and 
         (ii) a pharmaceutically acceptable excipient. 
       
     
     
         8 . The method according to  claim 7  wherein the inflammatory condition is selected from pulmonary inflammation such as asthma and/or asthma related pathologies; pneumonia, tuberculosis, rheumatoid arthritis, allergic reactions which impact the pulmonary system, early and late phase responses in asthma and asthma related pathologies, diseases of the small and large airways of the lung, bronchospasm, inflammation, increased mucus production, conditions which involve vasodilation, plasma exudation, recruitment of inflammatory cells such as neutrophils, monocytes, macrophages, lymphocytes and eosinophils and/or release of inflammatory mediators by resident tissue cells (mast cells); conditions or symptoms which are caused by allergens, secondary responses to infections, industrial or occupational exposures, ingestion of certain chemicals or foods, drugs, exercise or vasculitis; conditions or symptoms which involve acute airway inflammation, prolonged airway hyperreactivity, increases in bronchial hyperreactivity, asthmatic exacerbations, hyperresponsiveness; conditions or symptoms which involve the release of inflammatory mediators such as 15-HETE, leukotriene C4, PAF, cationic proteins or eosinophil peroxidases; conditions or symptoms which relate to cutaneous, nasal, ocular or systemic manifestations of late phase allergic responses; clinical diseases of the skin, lung, nose, eye or throat or other organs and which involve allergic mechanisms having an histologic inflammatory component upon antigen challenge; allergic rhinitis, respiratory diseases characterized by seasonal or perennial sneezing; rhinorrhea, conjunctivitis, pharyngitis, intrinsic or extrinsic asthma bronchiale, any inflammatory lung disease, acute chronic bronchitis, pulmonary inflammatory reactions secondary to acute chronic bronchitis, chronic obstructive lung disease (COPD), cystic fibrosis, ARDS, acute lung injury, pulmonary fibrosis, Goodpasture's syndrome, any pulmonary condition in which white blood cells play a role including but not limited to idiopathic pulmonary fibrosis and any other autoimmune lung disease; ear, nose and throat disorders such as acute external otitis, furunculosis and otomycosis of the external ear; respiratory diseases such as traumatic and infectious myringitis, acute eustachian salpingitis, acute serous otitis media, acute and chronic sinitis; extrapulmonary conditions selected from any late-phase reactions and inflammatory response such as allergic rhinitis; allergic dermatitis; allergic conjunctivitis; extrapulmonary diseases where inflammation occurs and/or an inflammatory response plays a major role including inflammatory bowel disease; central nervous system disorders; neuroinflammation; Alzheimer's, the inhibition of β-amyloid aggregation in Alzheimer's disease, rheumatoid arthritis and other collagen vascular diseases; glomerulonephritis; inflammatory skin diseases and sarcoidosis and cardiovascular inflammation. 
     
     
         9 . The method according to  claim 8  wherein the mammal in need of treatment thereof is human. 
     
     
         10 . A process for producing a compound of formula I comprising the steps of (1) reacting a thioglycoside of formula Ia with a mannitol of formula Ib to form a compound of formula Ic; (2) reacting the compound of formula Ic with a sulfating reagent to form a compound of formula I and wherein the thioglycoside Ia was produced using 1,6-anhydro-3-O-benzyl-βL-idopyranose as an intermediate. 
     
     
         11 . The process according to  claim 10  wherein the compound of formula Ia is produced by a process which comprises
 (a) reacting 1,6-anhydro-3-O-benzyl-β-L-idopyranose (3) 
 
       
         
           
           
               
               
           
         
         with a reducing agent and benzoyl chloride to form compound 4: 
       
       
         
           
           
               
               
           
         
         (b) reacting compound 4 with an acetylating agent to form compound 5: 
       
       
         
           
           
               
               
           
         
         (c) thiolating compound 5 with a thiolating reagent to form a compound of formula Ia. 
       
     
     
         12 . The process according to claim  1 I wherein pivaolyl chloride is used as a reagent in place of beyzoyl chloride to form compound 4′ 
       
         
           
           
               
               
           
         
       
       and compound 4′ is acetylated to form compound 5′ 
       
         
           
           
               
               
           
         
       
       which is further reacted with a thiolating reagent to form the pivolated version of a crystalline form of compound Ia. 
     
     
         13 . The process according to  claim 11  wherein the thiolating reagent is selected from thiophenol or thiocresol. 
     
     
         14 . A process for producing a substantially pure compound of formula I comprising the steps of (a) reacting a compound of formula Ia with a compound of formula Ib wherein the protecting group (Pr) in compounds Ia and Ib are identical. 
     
     
         15 . A substantially pure crystalline form of 2,5-anhydro-3-O-(α-L-idopyranosyl)-D-mannitol hepta-O-sulfate salt wherein the salt is substantially free of impurities. 
     
     
         16 . The substantially pure crystalline form according to  claim 15  wherein the salt is a sodium salt and the impurities are acetate salts. 
     
     
         17 . The crystalline form according to  claim 16  having less than 1.4 wt % of sodium acetate as an impurity. 
     
     
         18 . The form according to  claim 17  having less than 1.0 wt % of sodium acetate. 
     
     
         19 . The form according to  claim 17  having less than 0.5 wt % of sodium acetate.