Benzoylecgonine, ecgonine and ecgonidine derivatives

Abstract

The present invention relates to a novel class of covalently coupled benzoylecgonine, ecgonine and ecgonidine derivatives that are useful for alleviating the symptoms of immunoregulatory disorders, neuromuscular disorders, joint disorders, connective tissue disorders, circulatory disorders and pain. Accordingly, this invention also relates to pharmaceutical compositions and methods for their use.

What is claimed is:  
     
         1 . A compound of formula I or II:  
       
         
           
           
               
               
           
         
       
       wherein: 
 each R 1  is independently selected from the group consisting of H; COR 2 ; COBn, alkyl; alkenyl; and alkynyl, said alkyl, alkenyl and alkynyl being optionally substituted with OH, SH, NH 2 , CN, CF 3  or halogen;  
 A is -L—(M)p;  
 B is -L—(M′)p′;  
 each p and p′ is independently selected from the group consisting of 1 or 2;  
 each L is independently a linker which, 
 (a) if linking one M or M′ to the ring system, is selected from the group consisting of —(CR 2 R 2 ) n —CO—Q—; —(CR 2 R 2 ) n —Q—CO—; —(CR 2 R 2 ) n —O—C(OH)—; and —(CR 2 R 2 ) n —Q—; or  
 (b) if linking two M or M′, the same or different, to the ring system is  
                     
 (c) if linking two ring systems chosen from compounds of formulas I and ll, the same or different, to M or M′ is  
                     
 
 each n is independently selected from the group consisting of 0, 1, 2 and 3;  
 each Q is independently selected from the group consisting of —NH—, —O— and —S—;  
 each M and M′ is independently a moiety that, either alone or in combination with other M or M′ moieties, enhance the distribution characteristics, intrinsic activity or efficacy of said compound, provided that M is not a moiety having the formula —CH 2 —CHX—R 3  when B is —O—CO—M′, —O—M′ or when B is not present (i.e., in compounds of formula II);  
 each R 2  is independently selected from the group consisting of H; alkyl; alkenyl; alkynyl; alkoxy; aminoalkyl; haloalkyl; aryl; heterocyclyl; aralkyl, cycloalkyl; cycloalkylallkyl; halogen; aroyl, acyl; and aralkyl; any of said R 2  being optionally substituted with OH, SH, NH 2 , oxo and halogen;  
 X is selected from the group consisting of OH; SH; NH 2 ; and halogen; and  
 R 3  is selected from the group consisting of alkyl, alkenyl and alkynyl, optionally substituted with OH, SH, NH 2  or halogen; COCH 3 ; COPh; and COBn.  
 
     
     
         2 . The compound according to  claim 1 , wherein Q is —O—; M′ is selected from the group consisting of —OH, O—(CH 2 ) n -aryl and O—C(O)-aryl; and n is selected from the group consisting of 0 and 1.  
     
     
         3 . The compound according to  claim 1 , wherein A or B or both are independently selected from the group consisting of —(CR 2 R 2 ) n —O—CO—(CR 2 R 2 ) n -E , —(CR 2 R 2 ) n —CO—O—(CR 2 R 2 ) n -E, —(CR 2 R 2 ) n —O—CH(OH)—(CR 2 R 2 ) n -E and —(CR 2 R 2 ) n —O—(CR 2 R 2 ) n -E, wherein: 
 each R 2  is independently selected from the group consisting of H; alkyl; alkenyl; alkynyl; alkoxy; aminoalkyl; haloalkyl; aryl; heterocyclyl; aralkyl; cycloalkyl; cycloalkylalkyl; halogen; aroyl, acyl; and aralkyl; any of said R 2  being optionally substituted with OH, SH, NH 2 , oxo and halogen,  
 each n is independently selected from the group consisting of 0, 1, 2 and 3; and  
 E is the aromatic ring system of any conventional anti-inflammatory or analgesic agent.  
 
     
     
         4 . The compound according to  claim 3 , wherein E is selected from the group consisting of formulas III-VII:  
       
         
           
           
               
               
           
         
       
       wherein: 
 each R 4  is independently selected from the group consisting of H, alkyl; alkenyl; alkynyl; acyl; aroyl; and halogen, said alkyl, alkenyl, alkynyl and carboalkyl being optionally substituted with OH, SH, NH 2 , oxo and halogen; and  
 each R 5  is independently selected from the group consisting of alkyl; alkenyl; alkynyl; alkoxy; aminoalkyl; haloalkyl; aryl; heterocyclyl; aralkyl; cycloalkyl; cycloalkylalkyl; halogen; aroyl, acyl; and aralkyl; any of said R 5  being optionally substituted with OH, SH, NH 2 , oxo and halogen.  
 
     
     
         5 . The compound according to  claim 3  or 4, wherein A is selected from the group consisting of —CH 2 —O—C(O)-E and —C(O)—O—CH 2 -E and B is O—CO-Ph.  
     
     
         6 . A compound having the structure of any one of formulas VIII-XV:  
       
         
           
           
               
               
           
         
       
     
     
         7 . A pharmaceutical composition comprising a compound according to any one of claims  1 - 6 , or a mixture thereof, and a pharmaceutically acceptable carrier or adjuvant.  
     
     
         8 . The pharmaceutical composition according to  claim 7 , further comprising at least one additional ingredient selected from the group consisting of benzoylecgonine, ecgonine and ecgonidine.  
     
     
         9 . The pharmaceutical composition according to  claim 7  or  8 , wherein the composition comprises at least about 5% of the compound according to any one of claims  1 - 6 , or a mixture thereof  
     
     
         10 . The pharmaceutical composition according to  claim 7  or  8 , further comprising at least one additional ingredient selected from the group consisting of methotrexate, taxol, 5-fluorouracil, cis-platinum, cortisone, nitrogen mustards, thiotepa and nitrosoureas, non-steroidal anti-inflammatory agents, penicillamine, methotrexate, cortisone and gold salts, amantadine, L-DOPA and CNS-anticholinergics.  
     
     
         11 . The pharmaceutical composition according to  claim 7  or  8 , wherein the composition is in an administering dosage form selected from the group consisting of a tablet, capsule, caplet, liquid, solution, suspension, emulsion, lozenges, syrup, reconstitutable powder, granule, suppository and transdermal patch.  
     
     
         12 . A method for alleviating the symptoms of immunoregulatory disorders, neuromuscular disorders, joint disorders, connective tissue disorders, circulatory disorders or pain, comprising the step of administering to a mammal, including a human, a pharmaceutically effective amount of the pharmaceutical composition according to  claim 7  or  8 .  
     
     
         13 . The method according to  claim 12 , wherein the pharmaceutical composition is administered intravenously, intramuscularly, subcutaneously, intra-articularly, intrasynovially, intrathecally, periostally, intratumorally, peritumorally, intralesionally, perilesionally, by infusion, sublingually, buccally, transdermally, orally, topically or by inhalation.  
     
     
         14 . The method according to  claim 12  or  13 , wherein the disorder is selected from the group consisting of pain, inflammation, autoimmune diseases, allergies, poison ivy, poison oak, contact dermatitis, amyotrophic lateral sclerosis, multiple sclerosis, skeletal muscle trauma, spasm post-stroke, loss of sensory acuity, weakness, cerebral edema, Reiter's syndrome, polymyositis, Parkinson's disease, Huntington's disease, angina, acute back strain, frozen shoulder, restricted range of motion, post-fracture contracture, arthritis, bursitis, ankylosing spondylitis, rheumatoid vasculitis, joint rigidity, osteoarthritis, mixed arthritis, psoriatic arthritis, gout, inflammatory gout, juvenile rheumatoid arthritis, systemic lupus, Burger's disease, periarteritis nodosum, proliferative diseases, scleroderma, collagen disorders, angina pectoris, myocardial ischemia, gangrene and diabetes.  
     
     
         15 . The method according to  claim 14 , wherein the disorder is pain, inflammation, Parkinson's disease, acute back strain, restricted range of motion, arthritis, bursitis, ankylosing spondylitis, Burger's disease and myocardial ischemia.  
     
     
         16 . The use of the pharmaceutical composition according to  claim 7  or  8  for alleviating the symptoms of immunoregulatory disorders, neuromuscular disorders, joint disorders, connective tissue disorders, circulatory disorders or pain.  
     
     
         17 . The use according to  claim 16 , wherein the disorder is selected from the group consisting of inflammation, autoimmune diseases, allergies, poison ivy, poison oak, contact dermatitis, amyotrophic lateral sclerosis, multiple sclerosis, skeletal muscle trauma, spasm post-stroke, loss of sensory acuity, weakness, cerebral edema, Reiter's syndrome, polymyositis, Parkinson's disease, Huntington's disease, angina, acute back strain, frozen shoulder, restricted range of motion, post-fracture contracture, arthritis, bursitis, ankylosing spondylitis, rheumatoid vasculitis, joint rigidity, osteoarthritis, mixed arthritis, psoriatic arthritis, gout, inflammatory gout, juvenile rheumatoid arthritis, systemic lupus, Burger's disease, periarteritis nodosum, proliferative diseases, scleroderma, collagen disorders, angina pectoris, myocardial ischemia, gangrene and diabetes.  
     
     
         18 . The use according to  claim 17 , wherein the disorder is inflammation, Parkinson's disease, acute back strain, restricted range of motion, arthritis, bursitis, ankylosing spondylitis, Burger's disease and myocardial ischemia.