S-Isomer of 2- piperidine and Other Dermal Anesthetic Agents

Abstract

The present invention relates to the S-isomers of anesthetic compounds, the methods of treatment therewith, the compounds being useful for inducing local anesthesia, analgesia and sleep.

1 . A substantially pure S-isomer of a compound having the formula: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, base, or mixture thereof, wherein n is equal to 0, 1, 2, or 3, Z represents two hydrogen atoms or an oxygen atom, the (CH 2 ) n  group having a straight or branched chain, B represents hydrogen, an alkoxy radical containing 1 to 3 carbon atoms or a group of the formula 
     
       
         
         
             
             
         
       
     
     in which R 3  and R 4  may independently be selected from the group consisting of methoxy, ethoxy, a lower alkyl or hydroxyalkyl radical containing 1 to 3 carbon atoms, whereby R 3  may also represent hydrogen, A is a 2-pyridyl radical, an unsubstituted phenyl radical or a phenyl radical substituted by at least one substituent in the ortho, meta and/or para position, and R 1  represents a hydrogen, or a lower alkyl or hydroxyalkyl containing 1 to 4 carbon atoms and the piperidine nucleus is attached at the 2-, 3-, or 4-position, wherein the compound is useful for inducing anesthesia and analgesia in a patient in need thereof. 
   
   
       2 . The compound of  claim 1 , wherein the compound comprises more than 95% or more S-isomer. 
   
   
       3 . The compound of  claim 1 , wherein the compound comprises more than 97% or more S-isomer. 
   
   
       4 . The compound of  claim 1 , wherein the compound comprises more than 99% or more S-isomer. 
   
   
       5 . The compound of  claim 1 , wherein the compound is S-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine (S-LAC-34). 
   
   
       6 . The compound of  claim 1 , wherein the pharmaceutically acceptable salt is selected from the group consisting of the monohydrochloride, dihydrochloride, mesylate, lactate, acetate, and sulfamate. 
   
   
       7 . A pharmaceutical formulation for providing anesthesia and analgesia in a patient in need thereof, comprising:
 a therapeutically effective amount of substantially pure S-isomer of a compound of formula   
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salt, base, or mixture thereof, wherein n is equal to 0, 1, 2, or 3, Z represents two hydrogen atoms or an oxygen atom, the (CH 2 ) n  group having a straight or branched chain, B represents hydrogen, an alkoxy radical containing 1 to 3 carbon atoms or a group of the formula 
     
       
         
         
             
             
         
       
     
     in which R 3  and R 4  may independently be selected from the group consisting of methoxy, ethoxy, a lower alkyl or hydroxyalkyl radical containing 1 to 3 carbon atoms, whereby R 3  may also represent hydrogen, A is a 2-pyridyl radical, an unsubstituted phenyl radical or a phenyl radical substituted by at least one substituent in the ortho, meta and/or para position, and R 1  represents a hydrogen, or a lower alkyl or hydroxyalkyl containing 1 to 4 carbon atoms and the piperidine nucleus is attached at the 2-, 3-, or 4-position, and a pharmaceutically acceptable excipient. 
   
   
       8 . The formulation of  claim 7 , wherein the compound is S-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine (S-LAC-34). 
   
   
       9 . The formulation of  claim 7 , wherein the compound comprises 95% or more S-isomer. 
   
   
       10 . The formulation of  claim 9 , wherein the therapeutically effective amount is an amount effective for inducing anesthesia in a patient in need thereof upon administration. 
   
   
       11 . The formulation of  claim 9 , wherein the therapeutically effective amount is an amount effective for providing analgesia or alleviating pain in a patient in need thereof upon administration. 
   
   
       12 . The formulation of  claim 9 , wherein the formulation is suitable for oral, sublingual, parenteral, topical, transdermal, ocular, intranasal, aural, intrarespiratory, rectal, vaginal, and urethral administration. 
   
   
       13 . The formulation of  claim 12 , wherein the formulation is suitable for parenteral administration and the parenteral administration is selected from the group consisting of intravenous, intra-arterial, intracardiac, intraspinal, intraosseous, intra-articular, intrasynovial, subcutaneous, intradermal, and intramuscular injection, implantation, infiltration or infusion. 
   
   
       14 - 43 . (canceled) 
   
   
       44 . A method of relieving neuropathic pain in a patient in need thereof, comprising administering to a discrete site in a patient in need thereof a neuropathic pain-relieving effective amount of the compound S-2-{2-[N-(2-indanyl)-N-phenylamino]ethyl}piperidine: 
     
       
         
         
             
             
         
       
       wherein administration of the compound to the discrete site provides a duration of action that is longer than that of the corresponding racemate and the corresponding R-isomer, and said compound is co-administered with at least one additional active agent. 
     
   
   
       45 . The method of  claim 44 , wherein the additional active agent is selected from the group consisting of vasoconstrictor, a n analgesic, a glucocorticosteroid, an antihistamine, a local anesthetic, phenol, a capsaicinoid, a spreading or diffusing agent and a viscoelastic agent. 
   
   
       46 - 68 . (canceled) 
   
   
       69 . A method of improving sleep in a patient in need thereof, comprising:
 administering to a discrete site in a patient in need thereof an anesthetic inducing amount of a substantially pure S-isomer of a compound of formula:   
     
       
         
         
             
             
         
       
     
     or pharmaceutically acceptable salt, base, or mixture thereof, wherein n is equal to 0, 1, 2, or 3, Z represents two hydrogen atoms or an oxygen atom, the (CH 2 ) n  group having a straight or branched chain, B represents hydrogen, an alkoxy radical containing 1 to 3 carbon atoms or a group of the formula 
     
       
         
         
             
             
         
       
       in which R 3  and R 4  may independently be selected from the group consisting of methoxy, ethoxy, a lower alkyl or hydroxyalkyl radical containing 1 to 3 carbon atoms, whereby R 3  may also represent hydrogen, A is a 2-pyridyl radical, an unsubstituted phenyl radical or a phenyl radical substituted by at least one substituent in the ortho, meta and/or para position, and R 1  represents a hydrogen, or a lower alkyl or hydroxyalkyl containing 1 to 4 carbon atoms and the piperidine nucleus is attached at the 2-, 3-, or 4-position, 
       wherein administration of the compound to the discrete site provides a duration of action longer than that of lidocaine administration to the discrete site, 
       wherein administration of the compound alleviates pain experienced by the patient and provides for improved sleep resulting from the alleviation of pain. 
     
   
   
       70 - 75 . (canceled) 
   
   
       76 . A method of preparing an S-isomer of a compound of formula 1: 
     
       
         
         
             
             
         
       
     
     comprising:
 a) by reacting a compound of formula 2 
 
     
       
         
         
             
             
         
       
     
     with an S-enantiomer of a compound of formula 3, 
     
       
         
         
             
             
         
       
     
     wherein R 1  represents a lower alkyl or hydroxyalkyl containing 1 to 4 carbon atoms or a substituted or unsubstituted phenyl and X is a halogen (bromo, chloro, fluoro, iodo) or a reactive esterified hydroxyl group, to form a compound of formula 1; and
 b) hydrogenating a compound of formula 1, wherein R 1  is a residue removable by means of hydrogenolysis to give a compound of formula 1, wherein R 1  is hydrogen; and 
 c) hydrolyzing a compound of formula 1, wherein R 1  is a residue removable by means of hydrolysis, to form a compound of formula 1, wherein R 1  is hydrogen; and 
 d) transforming free bases obtained into their salts or transforming salts into their free bases.