Claims for Patent: 6,919,350

Summary for Patent: 6,919,350

Title:	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.
Inventor(s):	Chang; Kwen-Jen (Chapel Hill, NC), McNutt, Jr.; Robert W. (Durham, NC), Pettit; Hugh O. (Cary, NC), Bishop; Michael J. (Durham, NC)
Assignee:	Ardent Pharmaceuticals, Inc. (Durham, NC)
Application Number:	09/974,004
Patent Claims:	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 .delta. receptor activating agent effective for combating said side effect. 2. The pharmaceutical composition of claim 1, wherein the .delta. receptor activating agent comprises a diarylmethylpiperazine or a diarylmethylpiperdine compound. 3. The pharmaceutical composition of claim 1, wherein the .delta. receptor activating agent comprises a diarylmethylpiperazine compound. 4. The pharmaceutical composition of claim 1, wherein the .delta. receptor activating agent comprises 3290W93. 5. The pharmaceutical composition of claim 1, wherein the .delta. receptor activating agent comprises BW373U86. 6. The pharmaceutical composition of claim 1, wherein the .delta. receptor activating agent comprises an agent selected from the group consisting of: I. diarylmethylpiperazine compounds; II. diarylmethylpiperidine compounds; III. deltorphin I; and IV. deltorphin II. 7. The pharmaceutical composition of claim 1, wherein the .delta. receptor activating agent comprises an agent selected from the group consisting of: I. .delta. agonist compounds of the formula: ##STR11## 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.sup.1 ; Y is selected from the group consisting of: hydrogen; halogen; C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl; C.sub.1 -C.sub.6 haloalkyl; C.sub.1 -C.sub.6 alkoxy; C.sub.3 -C.sub.6 cycloalkoxy; sulfides of the formula SR.sup.8 where R.sup.8 is C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, arylalkyl having a C.sub.5 -C.sub.10 aryl moiety and an C.sub.1 -C.sub.6 alkyl moiety, or C.sub.5 -C.sub.10 aryl; sulfoxides of the formula SOR.sup.8 where R.sup.8 is the same as above; sulfones of the formula SO.sub.2 R.sup.8 where R.sup.8 is the same as above; nitrile; C.sub.1 -C.sub.6 acyl; alkoxycarbonylamino (carbamoyl) of the formula NHCO.sub.2 R.sup.8 where R.sup.8 is the same as above; carboxylic acid, or an ester, amide, or salt thereof; aminomethyl of the formula CH.sub.2 NR.sup.9 R.sup.10 where R.sup.9 and R.sup.10 may be the same or different, and may be hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.2 C.sub.6 hydroxyalkyl, C.sub.2 -C.sub.6 methoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, or C.sub.5 -C.sub.10 aryl, or R.sup.9 and R.sup.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.sup.9 R.sup.10 where R.sup.9 and R.sup.10 are the same as above, or C.sub.2 -C.sub.30 peptide conjugates thereof; and sulfonamides of the formula SO.sub.2 NR.sup.9 R.sup.10 where R.sup.9 and R.sup.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.sup.1 is hydrogen, halogen, or C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkynyl; R.sup.2 is hydrogen, halogen, or C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkynyl; R.sup.3, R.sup.4 and R.sup.5 may be the same or different, and are independently selected from hydrogen and methyl, and wherein at least one of R.sup.3, R.sup.4 or R.sup.5 is not hydrogen, subject to the proviso that the total number of methyl groups does not exceed two, or any two of R.sup.3, R.sup.4 and R.sup.5 together may form a bridge of 1 to 3 carbon atoms; R.sup.6 is selected from the group consisting of: hydrogen; C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl; C.sub.3 -C.sub.6 cycloalkyl; arylalkyl having C.sub.5 -C.sub.10 aryl and C.sub.1 -C.sub.6 alkyl moieties; alkoxyalkyl having C.sub.1 -C.sub.4 alkoxy and C.sub.1 -C.sub.4 alkyl moieties; C.sub.2 -C.sub.4 cyanoalkyl; C.sub.2 -C.sub.4 hydroxyalkyl; aminocarbonylalkyl having a C.sub.1 -C.sub.4 alkyl moiety; and R.sup.12 COR.sup.13, where R.sup.12 is C.sub.1 -C.sub.4 alkylene, and R.sup.13 is C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy; and R.sup.7 is hydrogen or fluorine, or a pharmaceutically acceptable ester or salt thereof; II. delta agonist compounds of the formula: ##STR12## in which, R.sub.1 and R.sub.2, which can be the same or different, are each hydrogen, linear or branched C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkenyl, C.sub.4-6 cycloalkylalkyl, C.sub.3-6 alkenyl, C.sub.3-5 alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or may form together a C.sub.3-7 alkyl ring which may be interrupted by oxygen; R.sub.3 and R.sub.4, which can be the same or different, are each hydrogen, linear or branched C.sub.1-6 alkyl, or R.sub.4 is oxygen forming with the carbon atom to which is attached a C.dbd.O group; R.sub.5 is hydrogen, hydroxy, C.sub.1-3 alkoxy, thiol or alkylthio; R.sub.6 is phenyl, halogen, NH.sub.2 or a para or meta --C(Z)-R.sub.8 group, in which Z is oxygen or sulphur; R.sub.8 is C.sub.1-8 -alkyl, C.sub.1-8 -alkoxy or NR.sub.9 R.sub.10, wherein R.sub.9 and R.sub.10, which may be the same or different, are hydrogen, straight or branched C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.4-6 cycloalkylalkyl, C.sub.3-6 alkenyl, aryl or aralkyl, or R.sub.6 is a para or metal --N--C(Z)-R.sub.12 ##STR13## in which R.sub.11 and R.sub.12 which may the same or different are hydrogen, straight or branched C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.4-6 cycloalkylalkyl, C.sub.3-6 alkenyl, aryl, aralkyl or an optionally substituted heterocyclic ring, and Z is as defined above; and, R.sub.7 is hydrogen, straight or branched C.sub.1-8 alkyl or halogen; and III. delta agonist compounds of the formula: ##STR14## in which, R.sub.1 and R.sub.2, which can be the same or different, are each hydrogen, linear or branched C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.3-7 cycloalkenyl, C.sub.4-6 cycloalkylalkyl, C.sub.3-6 alkenyl, C.sub.3-5 alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or may form together a C.sub.3-7 alkyl ring which may be interrupted by oxygen; R.sub.3 and R.sub.4, which can be the same or different, are each hydrogen, linear or branched C.sub.1-6 alkyl; R.sub.5 is hydroxy, C.sub.1-6 alkoxy, thiol or alkylthio; R.sub.6 is a --C(Z)-Rg group, in which Z is oxygen or sulphur, R.sub.8 is C.sub.1-8 -alkyl, C.sub.1-8 -alkoxy or NR.sub.9 R.sub.10, wherein R.sub.9 and R.sub.10, which may be the same or different, are hydrogen, straight or branched C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, C.sub.1-6 cycloalkylalkyl, C.sub.3-6 alkenyl, aryl or aralkyl, or R.sub.6 is a ##STR15## group in which R.sub.11 and R.sub.12 have the same meaning as R.sub.9 and R.sub.10 or together form an optionally substituted heterocyclic ring and Z is as defined above, and R.sub.7 is hydrogen, straight or branched C.sub.1-8 alkyl or halogen. 8. The pharmaceutical composition of claim 1, in a form suitable for injectable or spinal administration. 9. A pharmaceutical composition comprising: (a) an effective amount of a bioactive compound mediating respiratory depression; and (b) an effective amount of a non-polypeptide o receptor activating agent effective for combating said respiratory depression. 10. A pharmaceutical composition comprising an effective amount of a bioactive composition mediating respiratory depression, and an effective amount of a compound for reducing, treating or preventing respiratory depression, of the formula: ##STR16## 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.sup.1 ; Y is selected from the group consisting of: hydrogen; halogen; C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl; C.sub.1 -C.sub.6 haloalkyl; C.sub.1 -C.sub.6 alkoxy; C.sub.3 -C.sub.6 cycloalkoxy; sulfides of the formula SR.sup.8 where R.sup.8 is C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.3 -C.sub.6 cycloalkyl, arylalkyl having a C.sub.5 -C.sub.10 aryl moiety and an C.sub.1 -C.sub.6 alkyl moiety, or C.sub.5 -C.sub.10 aryl; sulfoxides of the formula SOR.sup.8 where R.sup.8 is the same as above; sulfones of the formula SO.sub.2 R.sup.8 where R.sup.8 is the same as above; nitrile; C.sub.1 -C.sub.6 acyl; alkoxycarbonylamino (carbamoyl) of the formula NHCO.sub.2 R.sup.8 where R.sup.8 is the same as above; carboxylic acid, or an ester, amide, or salt thereof; aminomethyl of the formula CH.sub.2 NR.sup.9 R.sup.10 where R.sup.9 and R.sup.10 may be the same or different, and may be hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl, C.sub.2 -C.sub.6 hydroxyalkyl, C.sub.2 -C.sub.6 methoxyalkyl, C.sub.3 -C.sub.6 cycloalkyl, or C.sub.5 -C.sub.10 aryl, or R.sup.9 and R.sup.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.sup.9 R.sup.10 where R.sup.9 and R.sup.10 are the same as above, or C.sub.2 -C.sub.30 peptide conjugates thereof; and sulfonamides of the formula SO.sub.2 NR.sup.9 R.sup.10 where R.sup.9 and R.sup.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.sup.1 is hydrogen, halogen, or C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkynyl; R.sup.2 is hydrogen, halogen, or C.sub.1 -C.sub.4 alkyl, C.sub.2 -C.sub.4 alkenyl, C.sub.1 -C.sub.4 alkynyl; R.sup.3, R.sup.4 and R.sup.5 may be the same or different, and are independently selected from hydrogen and methyl, and wherein at least one of R.sup.3, R.sup.4 or R.sup.5 is not hydrogen, subject to the proviso that the total number of methyl groups does not exceed two, or any two of R.sup.3, R.sup.4 and R.sup.5 together may form a bridge of 1 to 3 carbon atoms; R.sup.6 is selected from the group consisting of: hydrogen; C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl; C.sub.3 -C.sub.6 cycloalkyl; arylalkyl having C.sub.5 -C.sub.10 aryl and C.sub.1 -C.sub.6 alkyl moieties; alkoxyalkyl having C.sub.1 -C.sub.4 alkoxy and C.sub.1 -C.sub.4 alkyl moieties; C.sub.2 -C.sub.4 cyanoalkyl; C.sub.2 -C.sub.4 hydroxyalkyl; aminocarbonylalkyl having a C.sub.1 -C.sub.4 alkyl moiety; and R.sup.12 COR.sup.13, where R.sup.12 is C.sub.1 -C.sub.4 alkylene, and R.sup.13 is C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy; and R.sup.7 is hydrogen or fluorine, or a pharmaceutically acceptable ester or salt thereof. 11. The pharmaceutical composition according to claim 10, wherein Ar is a 6-member carbocyclic aromatic (benzene) ring and R.sup.1 is hydrogen. 12. The pharmaceutical composition according to claim 10, wherein Y is a carboxamide of the formula CONR.sup.9 R.sup.10. 13. The pharmaceutical composition according to claim 10, wherein R.sup.9 and R.sup.10 together form a ring of five or six atoms, thereby forming a pyrrolidinyl or piperdine ring. 14. The pharmaceutical composition according to claim 10, wherein R.sup.9 and R.sup.10 are the same or different and are each independently selected from hydrogen, C.sub.1 alkyl and C.sub.2 alkyl. 15. The pharmaceutical composition according to claim 10, wherein Y is hydrogen. 16. The pharmaceutical composition according to claim 10, wherein Y is a sulfone of the formula SO.sub.2 R.sup.8 and R.sup.8 is C.sub.1 -C.sub.6 alkyl. 17. The pharmaceutical composition according to claim 10, wherein G is N, R.sup.7 and R.sup.2 are each hydrogen, and Z is hydroxyl. 18. The pharmaceutical composition according to claim 10, wherein R.sup.6 is selected from the group consisting of hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 C.sub.6 alkenyl and C.sub.2 -C.sub.6 alkynyl. 19. The pharmaceutical composition according to claim 10, wherein R.sup.3, R.sup.4 and R.sup.5 are hydrogen or methyl, where the total number of methyl groups is one or two. 20. The pharmaceutical composition according to claim 10, wherein R.sup.3 and R.sup.5 are both methyl, and R.sup.4 is hydrogen. 21. The pharmaceutical composition according to claim 1, wherein the .delta. receptor activating agent comprises a compound selected from the group consisting of: (-)-4-((.alpha.R)-.alpha.-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hy droxybenzyl)-N,N-diethyl-benzamide; (-)-4-((.alpha.R)-.alpha.-((2R,5R)-2,5-dimethyl-4-propyl-1-piperazinyl)-3-h ydroxybenzyl)-N,N-diethyl-benzamide; 4-((.alpha.R)-.alpha.-(2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxy benzyl)benzamide; (.+-.)-3-((.alpha.R*)-.alpha.-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl )-3-hydroxybenzyl)benzamide; N,N-diethyl-4-((.alpha.R)-3-hydroxy-.alpha.-((2R,5R)-2,5-dimethyl-1-piperaz inyl)benzyl)benzamide; 4-((.alpha.R)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydrox ybenzyl)-N-ethyl-N-methyl-benzamide; 3-((.alpha.R)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)ph enol; (.+-.)-N,N-diethyl-4-((.alpha.R*)-3-hydroxy-.alpha.-((2R*,5S*)-2,4,5-trimet hyl-1-piperazinyl)benzyl)-benzamide; (+)-4-((.alpha.S)-.alpha.-((2S,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hy droxybenzyl)-N,N-diethyl-benzamide; 3-((.alpha.R)-4-(piperidinocarbonyl)-.alpha.-((2S,5S)-2,4,5-trimethyl-1-pip erazinyl)benzyl)phenol; 3-((.alpha.R)-4-(1-pyrrolidinylcarbonyl)-.alpha.-((2S,5S)-2,4,5-trimethyl-1 -piperazinyl)benzyl)phenol; (.+-.)-3-((.alpha.R*)-.alpha.-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl )-4-(methylsulfonyl)benzyl)-phenol; (+)-4-((.alpha.R*)-.alpha.-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3 -hydroxybenzyl)-N,N-dimethylbenzenesulfonamide; (+)-4-((.alpha.R)-.alpha.-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hy droxybenzyl)-N,N-dimethylbenzenesulfon-amide; or (-)-4-((.alpha.R)-.alpha.-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hy droxybenzyl)-N,N-dimethylbenzenesulfonamide; (.+-.)-3-((.alpha.R*)-.alpha.-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl )benzyl)phenol; (.+-.)-4-((.alpha.R*)-.alpha.-((2S*,5R*)-4-allyl-2,5-dimethyl-1-piperazinyl )-3-hydroxybenzyl)benzamide; (.+-.)-4-((.alpha.R*)-.alpha.-((2R*,5S*)-2,5-dimethyl-1-piperazinyl)-3-hydr oxybenzyl)-N,N-diethyl-benzamide; (+)-cis-4-(.alpha.-(4-allyl-3,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N, N-diethylbenzamide; cis-4-(.alpha.-(3,5-dimethyl-4-(methylallyl)-1-piperazinyl)-3-hydroxybenzyl )-N,N-diethylbenzamide; and pharmaceutically acceptable salts thereof. 22. The pharmaceutical composition of claim 1, wherein the .delta. receptor activating agent comprises (-)-4-((.alpha.R)-((2R,5R)-4-ally-2,5-dimethyl-1-piperazinyl)-3-hydroxybenz yl)-N,N-diethylbenzamide or a pharmaceutically acceptable salt thereof. 23. The pharmaceutical composition of claim 1, wherein the bioactive compound comprises an opiate compound. 24. The pharmaceutical composition of claim 1, wherein the bioactive compound comprises an opiate analgesic compound. 25. The pharmaceutical composition of claim 1, wherein the bioactive compound comprises a .mu. opiate compound. 26. 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. 27. 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, with the proviso that said bioactive compound is not morphine; and (2) a delta receptor agonist. 28. A pharmaceutical composition comprising: (1) an effective amount of a bioactive compound mediating an unwanted side effect thereof; and (2) a non-polypeptide .delta. receptor activating agent effective for combating said side effect. 29. The pharmaceutical composition of claim 28, wherein the .delta. receptor activating agent comprises a diarylmethylpiperazine or a diarylmethylpiperdine compound.

Details for Patent 6,919,350

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Clinigen, Inc.	PROLEUKIN	aldesleukin	For Injection	103293	05/05/1992		2013-02-02