7-azoniabicyclo[2.2.1]heptane derivatives, methods of production, and pharmaceutical uses thereof

Abstract

Muscarinic acetylcholine receptor antagonists and methods of using them for the treatment of muscarinic acetylcholine receptor-mediated diseases, such as pulmonary diseases, are provided

1 .- 27 . (canceled) 
     
     
         28 . A method of making a pharmaceutical composition comprising:
 combining
 i. a stereochemically pure compound with a stereochemical purity of at least 80% according to formula (II) 
   
       
         
           
           
               
               
           
         
         
           
             wherein, in the compound of formula (II): 
             R 1  is independently selected from phenyl or thienyl, both optionally substituted with an alkyl, alkoxy, halo, or COOR group; 
             R 2  is independently selected from phenyl, thienyl, cyclopentyl, cyclohexyl, 1-alkylcyclopentyl, 1-alkylcyclohexyl, 1-hydroxycyclopentyl or 1-hydroxycyclohexyl, where phenyl, thienyl, cyclopentyl, cyclohexyl, 1-alkylcyclopentyl, 1-alkylcyclohexyl, 1-hydroxycyclopentyl or 1-hydroxycyclohexyl are optionally substituted with an alkyl, alkoxy, halo, or COOR group; or wherein R 1  and R 2  together are 9-xanthenyl, where 9-xanthenyl is substituted on either or both benzene rings with an alkyl, alkoxy, halo, or COOR group; 
             R 3  is OH; 
             R 4  and R 5  are independently selected from lower alkyl, alkoxycarbonylalkyl, aralkyl, or aryloxyalkyl, where alkoxycarbonylalkyl and/or aralkyl are optionally substituted with an alkyl, alkoxy, halo, or COOR group; or wherein R 4  and R 5  together with the ring to which they are attached form a five- or six-membered ring optionally substituted with aryl or aryloxy; 
             R is a lower alkyl; 
             *, *, and *** are each independently a stereocenter, the stereocenters *, ** and *** are present in one of the following combinations: 
             (i) * is (R), ** is (R), and *** is (S), or 
             (ii) * is (S), ** is (S), and *** is (R), or 
             (iii) * is (R), ** is (S), and *** is (R), or 
             (iv) * is (S), ** is (R), and *** is (S); or 
             (v) * is (S), ** is (R), and *** is (R); or 
             (vi) * is (R), ** is (R), and *** is (R); or 
             (vii) * is (R), ** is (S), and *** is (S); or 
             (viii) * is (S), ** is (S), and *** is (S); wherein, X ⊖  represents a pharmaceutically acceptable anion; and 
           
           ii. at least one pharmaceutically acceptable carrier or excipient. 
         
       
     
     
         29 . The method of  claim 28 , wherein, in the compound of formula (II), R 1  is phenyl, optionally substituted with an alkyl, alkoxy, halo, or COOR group. 
     
     
         30 . The method of  claim 29 , wherein, in the compound of formula (II), R 1  is unsubstituted phenyl. 
     
     
         31 . The method of  claim 28 , wherein, in the compound of formula (II), R 2  is cyclopentyl. 
     
     
         32 . The method of  claim 28 , wherein, in the compound of formula (II), R 4  and R 5  are independently C 1 -C 4  alkyl. 
     
     
         33 . The method of  claim 32 , wherein, in the compound of formula (II), both R 4  and R 5  are methyl. 
     
     
         34 . The method of  claim 28 , wherein, in the compound of formula (II), R 1  is unsubstituted phenyl and R 2  is cyclopentyl. 
     
     
         35 . The method of  claim 28 , wherein, in the compound of formula (II), R 1  is unsubstituted phenyl, R 2  is cyclopentyl, and R 4  and R 5  are independently C 1 -C 4  alkyl. 
     
     
         36 . The method of  claim 28 , wherein, in the compound of formula (II), X −  is selected from the group consisting of acetate, besylate (benzenesulfonate), benzoate, bicarbonate, bitartrate, bromide, calcium edentate, camphorsulfonate (camsylate), carbonate, chloride, chlorotheophyllinate, citrate, edetate, ethanedisulfonate (edisylate), ethanesulfonate (esylate), fumarate, gluceptate (glucoheptonate), gluconate, glucuronate, glutamate, hexylresorcinate, hydroxynaphthoate, hippurate, iodide, isethionate, lactate, lactobionate, lauryl sulfate (estolate), malate, maleate, mandelate, mesylate, methanesulfonate, methylnitrate, methylsulfate, mucate, naphthoate, napsylate, nitrate, octadecanoate, oleate, oxalate, pamoate, pantothenate, phosphate, polygalacturonate, salicylate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, teoclate, toluenesulfonate (tosylate), and trifluoroacetate. 
     
     
         37 . The method of  claim 36 , wherein, in the compound of formula (II), X −  is selected from the group consisting of chloride, bromide, iodide, sulfate, methanesulfonate, benzenesulfonate, and toluenesulfonate. 
     
     
         38 . The method of  claim 37 , wherein, in the compound of formula (II), X −  is bromide. 
     
     
         39 . The method of  claim 28 , wherein the pharmaceutical composition further comprises one or more additional therapeutic agents. 
     
     
         40 . The method of  claim 39 , wherein at least one of the one or more additional therapeutic agents is selected from the group consisting of an anti-inflammatory agent, a bronchodilator, an antihistamine, and an antitussive agent. 
     
     
         41 . The method of  claim 28 , wherein the pharmaceutical composition is formulated for administration by inhalation. 
     
     
         42 . The method of  claim 41 , wherein the pharmaceutical composition is in a form of an inhalable powder. 
     
     
         43 . The method of  claim 41 , wherein the pharmaceutical composition is in a form of an inhalable aerosol. 
     
     
         44 . The method of any one of  claims 41 - 43 , wherein the pharmaceutical composition is suitable for delivery by an inhalation nebulizer. 
     
     
         45 . The method of  claim 28 , wherein the pharmaceutically acceptable carrier or the excipient is selected from one or more of calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-3-cyclodextrin, polyvinylpyrrolidinone, low melting waxes, or ion exchange resin. 
     
     
         46 . The method of  claim 28 , wherein the pharmaceutical composition further comprises a preservative.