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

1 . A pharmaceutical composition comprising:

(1) an effective amount of a bioactive compound mediating respiratory depression, muscle rigidity, and/or nausea/vomiting as an unwanted side effect thereof; and

(2) a non-polypeptide δ receptor activating agent effective for combating said side effect,

wherein the δ receptor activating agent comprises an agent selected from the group consisting of:

I. δ agonist 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 carbon or 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.

II. delta agonist compounds of the formula:

in which,

R 1 and R 2 , which can be the same or different, are each hydrogen, linear or branched C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 4-6 cycloalkylalkyl, C 3-6 alkenyl, C 3-5 alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or may form together a C 3-7 alkyl ring which may be interrupted by oxygen.

R 3 and R 4 , which can be the same or different, are each hydrogen, linear or branched C 1-6 alkyl, or R 4 is oxygen forming with the carbon atom to which is attached a C═O group;

R 5 is hydrogen, hydroxy, C 1-3 alkoxy, thiol or alkylthio;

R 6 is phenyl, halogen, NH 2 or a para or meta —C(Z)-R 8 group, in which Z is oxygen or sulphur;

R 8 is C 1-8 -alkyl, C 1-8 -alkoxy or NR 9 R 10 , wherein R 9 and R 10 , which may be the same or different, are hydrogen, straight or branched C 1-6 alkyl, C 3-7 cycloalkyl, C 4-6 cycloalkylalkyl, C 3-6 alkenyl, aryl or aralkyl, I

or R 6 is a para or metal

in which R 11 and R 12 which may the same or different are hydrogen, straight or branched C 1-6 alkyl, C 3-7 cycloalkyl, C 4-6 cycloalkylalkyl, C 3-6 alkenyl, aryl, aralkyl or an optionally substituted heterocyclic ring, and Z is as defined above; and,

R 7 is hydrogen, straight or branched C 1-8 alkyl or halogen; and

III. delta agonist compounds of the formula:

in which,

R 1 and R 2 , which can be the same or different, are each hydrogen, linear or branched C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 4-6 cycloalkylalkyl, C 3-6 alkenyl, C 3-5 alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or may form together a C 3-7 alkyl ring which may be interrupted by oxygen.

R 3 and R 4 , which can be the same or different, are each hydrogen, linear or branched C 1-6 alkyl;

R 5 is hydroxy, C 1-6 alkoxy, thiol or alkylthio;

R 6 is a —C(Z)-Rg group, in which Z is oxygen or sulphur, R 8 is C 1-8 -alkyl, C 1-8 -alkoxy or NR 9 R 10 , wherein R 9 and R 10 , which may be the same or different, are hydrogen, straight or branched C 1-6 alkyl, C 3-7 cycloalkyl, C 4-6 cycloalkylalkyl, C 3-6 alkenyl, aryl or aralkyl,

or R 6 is a

group

in which R 11 and R 12 have the same meaning as R 9 and R 10 or together form an optionally substituted heterocyclic ring and Z is as defined above, and R 7 is hydrogen, straight or branched C 1-8 alkyl or halogen.

2 . The pharmaceutical composition of claim 1 , in a form suitable for a transdermal patch. i

3 . The pharmaceutical composition of claim 1 , wherein the bioactive compound comprises at least one active ingredient 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.