Synthesis of functionalized octahydro-isoquinolin-1-one-8-carboxylic esters and analogs, and therapeutic methods

Abstract

A functionalized polycyclic compound can have a structure of Formula 1 or salt, prodrug, analog, or derivative thereof, which compound can be prepared by providing a diene; reacting the diene with a dienophile under sufficient conditions for a combined Diels-Alder/acylation reaction so as to provide a polycyclic compound having a carboxylic acid; and coupling the carboxylic acid with an amine-containing compound or a hydroxyl-containing compound so as to form an amide or an ester and producing a compound having a structure of Formula 1. The compound can be used for modulating an opioid receptor, which can be conducted by administering to an opioid receptor a functionalized polycyclic compound as described herein in an effective amount to modulate the functionality of the opioid receptor. Such opioid modulation can provide a biological benefit to a subject.

1 . A functionalized polycyclic compound comprising:
 a structure of Formula 1 or salt, prodrug, analog, enantiomer, or derivative thereof, wherein:   
       
         
           
           
               
               
           
         
       
       R1 and R3 are independently nothing, hydrogen, halogen, hydroxyl, straight or branched substituted or unsubstituted alkoxy, amine, straight or branched substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, branched or unbranched or cyclic substituted or unsubstituted arylalkyl, or combinations thereof; 
       R2, R4, R5, R6, R11, R12, R13, R14, R15, R16, R17, and R18 are independently a hydrogen, halogen, hydroxyl, straight or branched substituted or unsubstituted alkoxy, amine, straight or branched substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, branched or unbranched or cyclic substituted or unsubstituted arylalkyl, or combinations thereof, or one or more of R4 and R5 together, R11 and R12 together, R13 and R14 together, and R15 and R16 together form a bond or a ring therebetween; 
       R7 and R8 are both a hydrogen or together form a bond therebetween, or R7 and R8 together are O; 
       R9 and R10 are each independently an O or two separate hydrogen atoms; 
       X1 and X2 independently are O, N, or S; 
       n is from 0 to 5; 
       when X1 is N and R1 is nothing, then R2 is a ring with the N; 
       when X1 is O and R1 is nothing, then R2 is as defined; and 
       when X2 is N, R3 is a something. 
     
     
         2 . A compound as in  claim 1 , when any of R1-R3 includes an aryl, the aryl is substituted with one or more electron withdrawing groups. 
     
     
         3 . A compound as in  claim 2 , wherein the electron withdrawing groups are selected from Br, Cl, I, and CF3. 
     
     
         4 . A compound as in  claim 1 , wherein the compound has a structure of one of Formulas 2-16. 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . A compound as in  claim 1 , wherein X1 and X2 are both N. 
     
     
         6 . A compound as in  claim 1 , wherein X1 is N and X2 is O. 
     
     
         7 . A compound as in  claim 1 , wherein X1 is O and X2 is N. 
     
     
         8 . A compound as in  claim 1 , wherein X1 and X1 are both O. 
     
     
         9 . A compound as in  claim 1 , wherein one or more of R1, R2, R3, R4, R5, R6, R11, R12, R13, R14, R15, R16, R17, and R18 is one of the following side chains (side chains 1-16): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . A compound as in  claim 1 , where the compound is selected from the Compounds of Tables 4, 5, 8, and 9. 
     
     
         11 . A method for preparing a functionalized polycyclic compound, the method comprising:
 providing a hydroxyl-containing diene or an amine-containing diene;   reacting the diene with a dienophile under sufficient conditions for a combined Diels-Alder/acylation reaction so as to provide a polycyclic compound having a carboxylic acid; and   conjugating the carboxylic acid with an amine-containing compound or a hydroxyl-containing compound so as to form an amide or an ester and producing a compound having a structure of Formula 1 or derivative thereof, wherein:   
       
         
           
           
               
               
           
         
       
       R1 and R3 are independently nothing, hydrogen, halogen, hydroxyl, straight or branched substituted or unsubstituted alkoxy, amine, straight or branched substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, branched or unbranched or cyclic substituted or unsubstituted arylalkyl, or combinations thereof; 
       R2, R4, R5, R6, R11, R12, R13, R14, R15, R16, R17, and R18 are independently a hydrogen, halogen, hydroxyl, straight or branched substituted or unsubstituted alkoxy, amine, straight or branched substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, branched or unbranched or cyclic substituted or unsubstituted arylalkyl, or combinations thereof, or one or more of R4 and R5 together, R11 and R12 together, R13 and R14 together, and R15 and R16 together form a bond or a ring therebetween; 
       R7 and R8 are both a hydrogen or together form a bond therebetween, or R7 and R8 together are O; 
       R9 and R10 are each independently an O or two separate hydrogen atoms; 
       X1 and X2 independently are O, N, or S; 
       n is from 0 to 5; 
       when X1 is N and R1 is nothing, then R2 is a ring with the N; 
       when X1 is O and R1 is nothing, then R2 is as defined; and 
       when X2 is N, R3 is a something. 
     
     
         12 . A method as in  claim 11 , wherein the Diels-Alder/acylation is conducted at a temperature of at least about 25 degrees C. for a duration of at least about 5 minutes. 
     
     
         13 . A method as in  claim 11 , wherein the combined Diels-Alder/acylation reaction is performed in an organic solvent. 
     
     
         14 . A method as in  claim 13 , wherein the solvent is dichloroethane. 
     
     
         15 . A method as in  claim 11 , wherein the combined Diels-Alder/acylation reaction is at least near-neat. 
     
     
         16 . A method as in  claim 11 , wherein the conjugation of the carboxylic acid is catalyzed with a catalyst. 
     
     
         17 . A method as in  claim 16 , wherein the catalyst is DMAP and/or EDC-HCl. 
     
     
         18 . A method as in  claim 11 , wherein the diene is an amine-containing diene. 
     
     
         19 . A method as in  claim 11 , wherein the diene is a hydroxyl-containing diene. 
     
     
         20 . A method as in  claim 11 , wherein the dienophile is a maleic anhydride or citraconic anhydride. 
     
     
         21 . A method for preparing a functionalized polycyclic compound having a carboxylic acid, the method comprising:
 providing a hydroxyl-containing diene or an amine-containing diene; and   reacting the diene with a dienophile under sufficient conditions for a combined Diels-Alder/acylation reaction so as to provide a polycyclic compound having a carboxylic acid having Formula 17:   
       
         
           
           
               
               
           
         
       
       R3, R4, R5, and R6 are independently a hydrogen, halogen, hydroxyl, straight or branched substituted or unsubstituted alkoxy, amine, straight or branched substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, branched or unbranched or cyclic substituted or unsubstituted arylalkyl, or combinations thereof, or R4 and R5 together form a ring therebetween; 
       X is an O, N, or S; and 
       n is from 0 to 5. 
     
     
         22 . A method as in  claim 22 , further comprising preparing the hydroxyl-containing diene or the amine-containing diene. 
     
     
         23 . A method as in  claim 22 , therein the aminodiene component is prepared from 3,5-hexadien-1-ol. 
     
     
         24 . A pharmaceutical composition comprising:
 a pharmaceutically acceptable carrier; and   the functionalized polycyclic compound in accordance with  claim 1 .   
     
     
         25 . A method of modulating an opioid receptor, the method comprising:
 administering to an opioid receptor the functionalized polycyclic compound in accordance with  claim 1  in an effective amount to modulate the functionality of the opioid receptor.   
     
     
         26 . A method as in  claim 25 , wherein the opioid receptor is selected from a delta, mu, kappa, or nociceptin opioid receptor. 
     
     
         27 . A method as in  claim 25 , wherein the functionalized polycyclic compound agonizes the opioid receptor. 
     
     
         28 . A method as in  claim 25 , wherein the functionalized polycyclic compound antagonizes the opioid receptor. 
     
     
         29 . A method of providing a therapy to a subject, the method comprising:
 administering to the subject having an opioid receptor the functionalized polycyclic compound in accordance with  claim 1  in a therapeutically effective amount to modulate the functionality of the opioid receptor so as to provide a biological benefit to the subject.   
     
     
         30 . A method as in  claim 29 , wherein the biological benefit is one or more of the following: treatment for alcoholism; treatment for drug addiction; reversing side effects or overdose of a MOR agonist or opioid; treatment for obesity; treatment for Parkinson-induced tardive dyskinesia; providing analgesic treatment; providing antidepressant treatment; providing an anorectic treatment; providing weight loss; treatment for a mood disorder; treatment for bipolar disorders; treatment for drug seeking behavior; treatment for stress-induced drug seeking behavior; providing spinal analgesia; providing sedation; providing miosis; inhibiting ADH release; providing respiratory depression; providing euphoria; providing reduced GI motility; treatment of heart failure; treatment of migraines; treatment of a variety of inflammatory disorders; treatment of renal disorders; treatment of cardiovascular disorders; treatment of psychotic disorders and combinations thereof.