Compositions and methods for reducing respiratory depression and attendant side effects of mu opioid compounds

Abstract

A method of reducing, treating or preventing drug-mediated respiratory depression, muscle rigidity, or nausea/vomiting in an animal, incident to the administration to said animal of a mixed delta/mu opioid agonist or a respiratory depression-mediating drug, comprising administering to the animal receiving said drug an effective amount of a delta receptor agonist compound. Preferred examples of such delta receptor agonist compound include diarylmethyl piperazine compounds and diarylmethyl piperidine compounds, and pharmaceutical compositions thereof, having utility in medical therapy for reducing respiratory depression associated with certain analgesics, such as mu opiates.

1 . A screening method to determine the level of respiratory depression caused by an opioid receptor agonist test compound having mu, delta or mixed mu/delta receptor activity, the method comprising:
 (a) providing a test model mammal implanted with a catheter for introduction of a testing compound;   (b) placing an electrode on an outer surface of the mammal, wherein the electrode monitors O 2  and CO 2  levels;   (c) administering a first control compound exhibiting suppression of respiratory depression to the mammal and determining the level of respiratory depression;   (d) administering a second control compound that exhibits anti-suppression of respiratory depression relative to the first control compound to the mammal, wherein the second control compound is a mixed mu/delta receptor opioid agonist, wherein the mixed mu/delta opioid receptor agonist is selected from compounds of the formula:   
       
         
           
           
               
               
           
         
         
           wherein: 
           Ar is a 5- or 6-member carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur, and having on a first carbon atom thereof a substituent Y and on a second ring carbon thereof a substituent R 1 ;
 Y is selected from the group consisting of: 
 
           hydrogen; 
           halogen; 
           C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl; 
           C 1 -C 6  haloalkyl; 
           C 1 -C 6  alkoxy; 
           C 3 -C 6  cycloalkoxy; 
           sulfides of the formula SR 8  where R 8  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, arylalkyl having a C 5 -C 10  aryl moiety and an C 1 -C 6  alkyl moiety, or C 5 -C 10  aryl; 
           sulfoxides of the formula SOR 8  where R 8  is the same as above; 
           sulfones of the formula SO 2 R 8  where R 8  is the same as above; 
           nitrile; 
           C 1 -C 6  acyl; 
           alkoxycarbonylamino (carbamoyl) of the formula NHCO 2 R 8  where R 8  is the same as above; 
           carboxylic acid, or an ester, amide, or salt thereof; 
           aminomethyl of the formula CH 2 NR 9 R 10  where R 9  and R 10  may be the same or different, and may be hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 2 -C 6  hydroxyalkyl, C 2 -C 6  methoxyalkyl, C 3 -C 6  cycloalkyl, or C 5 -C 10  aryl, or R 9  and R 10  together may form a ring of 5 or 6 atoms, the ring atoms selected from the group consisting of N and C; 
           carboxamides of the formula CONR 9 R 10  where R 9  and R 10  are the same as above, or C 2 -C 30  peptide conjugates thereof, and 
           sulfonamides of the formula SO 2 NR 9 R 10  where R 9  and R 10  are the same as above;
 Z is selected from the group consisting of: 
 
           hydroxyl, and esters thereof; 
           hydroxymethyl, and esters thereof; and 
           amino, and carboxamides and sulfonamides thereof;
 G is nitrogen; 
 R 1  is hydrogen, halogen, or C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 1 -C 4  alkynyl; 
 R 2  is hydrogen, halogen, or C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 1 -C 4  alkynyl; 
 
           R 3 , R 4  and R 5  may be the same or different, and are independently selected from hydrogen and methyl, and wherein at least one of R 3 , R 4  or R 5  is not hydrogen, subject to the proviso that the total number of methyl groups does not exceed two, or any two of R 3 , R 4  and R 5  together may form a bridge of 1 to 3 carbon atoms;
 R 6  is selected from the group consisting of: 
 
           hydrogen; 
           C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl; 
           C 3 -C 6  cycloalkyl; 
           arylalkyl having C 5 -C 10  aryl and C 1 -C 6  alkyl moieties; 
           alkoxyalkyl having C 1 -C 4  alkoxy and C 1 -C 4  alkyl moieties; 
           C 2 -C 4  cyanoalkyl; 
           C 2 -C 4  hydroxyalkyl; 
           aminocarbonylalkyl having a C 1 -C 4  alkyl moiety; and 
           R 12 COR 13 , where R 12  is C 1 -C 4  alkylene, and R 13  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy; and
 R 7  is hydrogen or fluorine, 
 
           or a pharmaceutically acceptable ester or salt thereof; 
         
         (e) determining level of respiratory depression reversal for use as a comparative combined control; 
         (f) providing a test compound; 
         (g) repeating steps a to c and then administering the test compound to a mammal to determine the level of respiratory depression and compare to the level determined for the comparative combined control. 
       
     
     
         2 . The screening method according to  claim 1 , wherein the second control compound is (+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide. 
     
     
         3 . The screening method according to  claim 1 , wherein the first control compound is alfentanil. 
     
     
         4 . The screening method according to  claim 1 , wherein the first and second control compound are administered simultaneously and the level of respiratory depression is determined and compared to that of the first control compound alone. 
     
     
         5 . The screening method according to  claim 1 , wherein the first control compound is selected from the group consisting of alcohol, aldesleukin, alfentanil, bremazocine, buprenorphine, butorphanol, chloropromazine, clozapine, codeine, dantrolene, diazepam, dihydrocodeine, etorphine, fentanyl, flurazepam, heroin, hydrocodone, hydromorphone, ketamine, larazepam, levallorphen, levorphanol, meperidine, methadone, methohexital, mitomycin, morphine, nalbuphine, opium, oxazepam, oxycodone, oxymorphone, pentazocine, phenobarbital, porfimer, propoxyphene, resperidone, sufentanil, temazepam, thiopental, thiorzadine, tramadol, trimethaphan, and zolpidem. 
     
     
         6 . The screening method according to  claim 1 , wherein the second control compound is (−)-4-((αR)-α-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The screening method according to  claim 1 , wherein the second control compound is selected from the group consisting of: 
       (−)-4-((αR)-α-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide; 
       (−)-4-((αR)-α-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide; 
       4-((αR)-α-(2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)benzamide; 
       (±)-3-((αR*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1 piperazinyl)-3-hydroxybenzyl)benzamide; 
       N,N-diethyl-4-((αR)-3-hydroxy-α-((2R,5R)-2,5-dimethyl-1-piperazinyl)benzyl)benzamide; 
       4-((αR)-α-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-ethyl-N-methyl-benzamide; 
       3-((αR)-α-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)phenol; 
       (±)—N,N-diethyl-4-((αR*)-3-hydroxy-α-((2R*,5S*)-2,4,5-trimethyl-1-piperazinyl)benzyl)-benzamide; 
       (+)-4-(((αS)-α-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide; 
       3-((αR)-4-(piperidinocarbonyl)-α-((2S,5S)-2,4,5-trimethyl-1-piperazinyl)benzyl)phenol; 
       3-((αR)-4-(1-pyrrolidinylcarbonyl)-α-((2S,5S)-2,4,5-trimethyl-1-piperazinyl)benzyl)phenol; 
       (±)-3-((αR*)-α-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-4-(methylsulfonyl)benzyl)-phenol; 
       (±)-4-((αR*)-α-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide; 
       (+)-4-(((αR)-α-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide; 
       (−)-4-(((αR)-α-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-dimethylbenzenesulfonamide; 
       (±)-3-((αR*)—((2S*, 5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)phenol; 
       (±)-4-((αR*)-α-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxbenzyl)benzamide; 
       (±)-4-((αR*)—((2R*,5S*)-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide; 
       (±)-cis-4-(α-(4-allyl-3,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide; 
       cis-4-(α-(3,5-dimethyl-4-(methylallyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide;
 and pharmaceutically acceptable salts thereof. 
 
     
     
         8 . The screening method according to  claim 1 , wherein the second control compound is selected from the group consisting of: 
       (−)-4-((αS)-α-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide; 
       (−)-4-((αS)-α-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide; 
       cis-4-(α-(4-((Z)-2-butenyl)-3,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethyl-benzamide; and
 acceptable salts thereof. 
 
     
     
         9 . A screening method to determine the level of respiratory depression caused by an opioid receptor agonist test compound having mu, delta or mixed mu/delta receptor activity, the method comprising:
 (a) administering a first control compound exhibiting suspression of respiratory depression to a mammal and determining the level of respiratory depression;   (b) administering a second control compound that exhibits anti-suspression of respiratory depression relative to the first control compound to the mammal, wherein the second control compound is a mixed mu/delta receptor opioid agonist, wherein the mixed mu/delta opioid receptor agonist is selected from compounds of the formula:   
       
         
           
           
               
               
           
         
         
           wherein: 
           Ar is a 5- or 6-member carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur, and having on a first carbon atom thereof a substituent Y and on a second ring carbon thereof a substituent R 1 ;
 Y is selected from the group consisting of: 
 
           hydrogen; 
           halogen; 
           C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl; 
           C 1 -C 6  haloalkyl; 
           C 1 -C 6  alkoxy; 
           C 3 -C 6  cycloalkoxy; 
           sulfides of the formula SR 8  where R 8  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl, arylalkyl having a C 5 -C 10  aryl moiety and an C 1 -C 6  alkyl moiety, or C 5 -C 10  aryl; 
           sulfoxides of the formula SOR 8  where R 8  is the same as above; 
           sulfones of the formula SO 2 R 8  where R 8  is the same as above; 
           nitrile; 
           C 1 -C 6  acyl; 
           alkoxycarbonylamino (carbamoyl) of the formula NHCO 2 R 8  where R 8  is the same as above; 
           carboxylic acid, or an ester, amide, or salt thereof; 
           aminomethyl of the formula CH 2 NR 9 R 10  where R 9  and R 10  may be the same or different, and may be hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 2 -C 6  hydroxyalkyl, C 2 -C 6  methoxyalkyl, C 3 -C 6  cycloalkyl, or C 5 -C 10  aryl, or R 9  and R 10  together may form a ring of 5 or 6 atoms, the ring atoms selected from the group consisting of N and C; 
           carboxamides of the formula CONR 9 R 10  where R 9  and R 10  are the same as above, or C 2 -C 30  peptide conjugates thereof; and 
           sulfonamides of the formula SO 2 NR 9 R 10  where R 9  and R 10  are the same as above;
 Z is selected from the group consisting of: 
 
           hydroxyl, and esters thereof; 
           hydroxymethyl, and esters thereof; and 
           amino, and carboxamides and sulfonamides thereof;
 G is nitrogen; 
 R 1  is hydrogen, halogen, or C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 1 -C 4  alkynyl; 
 R 2  is hydrogen, halogen, or C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 1 -C 4  alkynyl; 
 
           R 3 , R 4  and R 5  may be the same or different, and are independently selected from hydrogen and methyl, and wherein at least one of R 3 , R 4  or R 5  is not hydrogen, subject to the proviso that the total number of methyl groups does not exceed two, or any two of R 3 , R 4  and R 5  together may form a bridge of 1 to 3 carbon atoms;
 R 6  is selected from the group consisting of: 
 
           hydrogen; 
           C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl; 
           C 3 -C 6  cycloalkyl; 
           arylalkyl having C 5 -C 10  aryl and C 1 -C 6  alkyl moieties; 
           alkoxyalkyl having C 1 -C 4  alkoxy and C 1 -C 4  alkyl moieties; 
           C 2 -C 4  cyanoalkyl; 
           C 2 -C 4  hydroxyalkyl; 
           aminocarbonylalkyl having a C 1 -C 4  alkyl moiety; and R 12 COR 13 , where R 12  is C 1 -C 4  alkylene, and R 13  is C 1 -C 4  alkyl or C 1 -C 4  alkoxy; and
 R 7  is hydrogen or fluorine, 
 
           or a pharmaceutically acceptable ester or salt thereof, 
         
         (c) determining level of respiratory depression reversal for use as a comparative combined control; 
         (d) providing a test compound; 
         (e) repeating step a and then administering the test compound to a mammal to determine the level of respiratory depression and compare to the level determined for the comparative combined control.