MXPA00000195A - Compositions and methods for reducing respiratory depression and attendant side effects of mu opioid compounds - Google Patents

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. The figure shows the effect of the positive isomer of the delta agonist BW373U86 on analgesia and respiratory depression induced by the mu agonist, alfenta. The delta agonist compound may comprise a compound of formula (I), wherein the variables of Ar, G, Z, R2, R3, R4, R5, R6 and R7 are herein described in the description.

Description

COMPOSITIONS AND METHODS TO REDUCE DEPRESSION RESPIRATORY AND SIDE EFFECTS OF THE OPIOID COMPOUNDS MU This invention generally relates to methods for reducing, treating, reversing or preventing drug-mediated respiratory depression, which may be caused directly or indirectly by the use of various bioactive compositions, including anesthetics, barbiturates, analgesics, etc. This invention further relates to diaryiimethyl piperazine compounds and diaryiimethyl piperidine compounds and pharmaceutical compositions thereof, which have utility in medical therapy especially for reducing respiratory depression associated with certain analgesics, such as mu opiates. This invention additionally relates to diaryiimethyl piperazine compounds and diaryiimethyl piperidine compounds which have utility in analysis for determining the respiratory reduction characteristics of other bioactive compounds, including other diamimethyl piperazine compounds and other diarymethyl piperidine compounds. In the study of opioid biochemistry, a variety of endogenous opioid compounds and non-endogenous opioid compounds have been identified. In this effort, significant research has focused on the understanding of the mechanism of action of opioid drugs, particularly if they are related to differentiated cell tissue opiate receptors.

Opioid drugs are normally classified in their binding selectivity with respect to cellular and differentiated tissue receptors to which specific drug species bind as a ligand. These receptors include mu (μ), delta (d), sigma (s) and kappa () receptors. Well-known narcotic opiates, such as morphine and its analogues, are selective for the mu receptor opiate. Analgesics mediated by mu receptors, respiratory depression and gastrointestinal transit inhibition. Analgesics and sedation mediated by kappa receptors. Several biological activities mediated by Sigma receptors. The diaryiimethyl piperazine compounds and the compounds of the diarymethyl piperidine compounds which have utility, for example, as analgesics, are described in International Publication WO93 / 15062, which is incorporated herein by reference in its entirety. The present application provides the use of compounds of said general type to treat and prevent respiratory depression. Campa, M. J, et al., "Characterization of d Opioid Receptors in Lung Cancer Using a Novel Nonpeptidic Ligand," Cancer Research 56, 1965-1701, April 1, 1996, describes the binding of [3H] (+) - 4- [(aR) -a - ((2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-dietyl-ilbenzamide with membranes prepared from several small cell lung cancer cells. There is a necessary continuation in the matter for methods of prevention or treat respiratory depression associated with the use of bioactive compositions, v.gr, certain analgesics, anesthetics and barbiturates, that affect respiratory depression, either directly or indirectly. It is also a necessary continuation for improved opioid compounds, particularly compounds that can reduce respiratory depression associated with the use of certain analgesics, such as mu opiate analgesic compounds, when said improved opioid compounds are administered contemporaneously with or sequentially in the administration of the analgesic mediated by respiratory depression. It is an object of the present invention to provide a bioactive compound that when administered contemporaneously with analgesics, anesthetics, barbiturates and other drugs that cause respiratory depression, act to markedly attenuate said lateral effects of respiratory depression. COMPENDIUM OF THE INVENTION The present invention relates to methods for treating, reducing, or preventing respiratory depression in an animal, v.gr, a human or non-human mammal, comprising administering to said animal an effective amount of a composition comprising a delta receptor antagonist, optionally further including an agonist compound from mu receiver. Illustrative examples of suitable delta receptor agonist compounds that can be co-administered according to the invention include, but are not limited to: (+) - 4 - ((aR) -a - ((2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-d -I-I-benzamide; [D-Pen2, D-Pen5] - (enkephalin); deltorphine I; deltorphine II; the compounds described in the Application Publication of International Patent WO96 / 36620 published on November 21, 1996 for "Diaryldiamine Derivatives and Their Use as Delta Opioid (ant) -anonists", the description of which is incorporated herein by reference; and The compounds described in International Patent Application Publication WO97 / 10230 published March 20, 1997 for "Diarylalkenylamine Derivatives", the disclosure of which is incorporated herein by reference. Particularly preferred delta agonist compounds among the illustrative compounds mentioned above include (+) - 4 - ((aR) -a - ((2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide, and (±) -4 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-pperazinyl) -3-hydroxybenzyl) -N, N-dimethylbenzenesulfonamide (e, independently, each of the isomers of the component thereof, viz, (+) - 4 - ((aR) -a - ((2S, 5R) -4-aIiI-2,5-dimethyl-1-piperazinyl) - 3-hydroxybenzyl) -N, N-dimethylbenzenesulfonamide and (+) - 4 - ((aR) -a - ((2S, 5R) -4-al-l-2,5-d-methyl- 1 - piperazinyl) -3-hydroxybenzyl) -N, N-dimethylbenzenesulfonamide). The composition that is co-administered with the bioactive agent mediated by respiratory depression further includes a mu receptor agonist such as morphine, fentanyl, alfentanil and its analogs, or the mu receptor agonists described in U.S. Pat. 08 / 284,445, and the United States Patent Application No. 08 / 285,313, the descriptions of which are incorporated herein by reference, including those compounds that predominantly exhibit the character of the mu receptor agonist, as well as disclosed compounds that exhibit the mu / delta receptor agonism mixture. Examples of display compounds such as the mu / delta agonistic character are included by the example form of the following compounds: Compounds mediated by respiratory depression, as mentioned above, include various analgesics, anesthetics, barbiturates, such as for example morphine, fentanyl, midazolam, meperidine, sufentanil and codeine. Therefore, the invention contemplates co-administration with drug agents mediated by respiratory depression, delta receptor agonist compounds, optionally with additional co-administration of mu receptor agonists, or simply display compounds mixed the agonist character of the mu receptor / delta receptor, in an effective amount to combat, v.gr, significantly attenuate, and preferentially substantially eliminate, respiratory depression incident to the use of the respiratory depression mediating agent. The invention, therefore, has wide utility in surgical or clinical care applications, to combat the incidence of Lateral effects of unwanted respiratory depression due to the use of such commonly used drugs as morphine and fentanyl. Illustrative of a preferred class of delta agonist compounds that can be readily employed in a broad practice of the present invention are the delta agonist compounds of the formula: (I) wherein Ar is a 5- or 6-membered carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur and having a first carbon atom thereof, a Y substituent, and a second carbon ring thereof and a substituent R1, Y is selected from the group consisting of: hydrogen; halogen; C6-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; Haloalkyl of C ^ Ce; Ci-Ce alkoxy; C3-C6 cycloalkoxy; sulphides of the formula SR8 wherein R8 is C6-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, arylalkyl having a C6-C10 aryl portion and an alkyl portion of C? -C6, or C5-C10 aryl; sulfoxides of the formula SOR8 wherein R8 is the same as described above; sulfones of the formula SO 2 R 8 wherein R 8 is the same as described above; nitrile; Acyl of C? -C6; alkoxycarbonylamino (carbamoyl) of the formula NHCO2R8 wherein R8 is the same as described above; carboxylic acid, or an ester, amide or salt thereof; aminomethyl of the formula CH 2 NR 9 R 10 wherein R 9 and R 10 may be the same or different, or may be hydrogen, C 1 -C 6 alkyl, C 2 -C 2 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 hydroxyalkyl, C 2 -C 6 methoxyalkyl , C3-C6 cycloalkyl or C5-C10 aryl, or R9 and R10 together can form a ring of 5 or 6 atoms, the ring atoms selected from the group consisting of N And C; carboxyamides of the formula CORN9R10 wherein R9 and R10 are the same as described above, or peptide conjugates of C2-C3o thereof; Y sulfonamides of the formula SO 2 NR 9 R 10 wherein R 9 and R 10 are the same as described above; Z was selected from the group consisting of: hydroxyl, and esters thereof; hydroxymethyl, and esters thereof; and amino and carboxyamides 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 alkenyl, C 1 -C alkynyl; R3, R4 and R5 may be the same or different and are independently selected from hydrogen and methyl and wherein at least one of R3, R4 or R5 are not hydrogen, subject to the proviso that the total number of methyl groups does not exceed of two, or either of the two of R3, R4 and R5 together may form a bridge of 1 to 3 carbon atoms; R6 is selected from the group consisting of: hydrogen; C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; C3-C6 cycloalkyl; arylalkyl having portions of C5-C10 aryl and C6-C6 alkyl; alkoxyalkyl having portions of C5-C10 aryl and C6-C6 alkyl; cyanoalkyl of C2-C; C2-C4 hydroxyalkyl aminocarbonylalkyl having an alkyl portion of R 1 COOR, wherein R, 112"is C 1 -C 4 alkylene, and R 'is C 1 -C 4 alkyl or C 1 -C alkoxy; and R7 is hydrogen or fluoride, or a pharmaceutically acceptable ester or salt thereof. In addition to methods for treating, reducing or preventing respiratory depression, the present invention also contemplates methods for screening and characterizing opioid compounds that reduce, treat or prevent respiratory depression. Methods for screening said opioid compounds (ie, opioid compounds that reduce, treat or prevent respiratory depression, hereinafter referred to as "respiratory depression suppression compounds") which comprise inverse analyzes of the driving activity of the compounds that suppress candidate respiratory depression in the recipient tissue to determine whether said candidate compounds mediated by transduction in a respiratory depression effect in response to a respiratory depression composition. Said analyzes of reverse activity are carried out comparatively, in the absence and in the presence of an anti-suppression compound of the formula (I), that is, a compound to combat the effect of suppressing respiratory depression and allowing said respiratory depression to be Watch instead. If the activity of the candidate compound is markedly reversed in the receptor system by the presence of the anti-suppression compound of the formula (I), the analysis is positive for the candidate respiratory depression suppression compound, indicating its potential bioefficacy. for the effects of respiratory suppression depression with the use of other therapeutic agents. The anti-suppression compound of the formula (I) used in the sieving analysis described above is preferably selected from those groups consisting of: (-) - 4 - ((aS) - - ((2R, 5R) -4- allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethyl-benzamide; (-) - 4 - ((aS) -a - ((2R, 5R) -2,5-dimethyl-4-propyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethyl-benzamide; c / s-4- (a- (4 - ((Z) -2-buten-yl) -3,5-di-methi-1-piperazin-yl) -3-hydroxy-benzyl) -N, N-diethyl-benzam gives; and acceptable salts thereof. In this context, the term "acceptable" refers to suitable salt species of the particular identified compounds, meaning salts that are effective in mediating the suppression of the effects of respiratory depression. In addition, the present invention provides pharmaceutical compositions comprising a combination of an effective amount of an opiate analgesic and an effective amount of an compositions to combat the effect of respiratory depression of an agent mediated by respiratory depression. The agent for combating respiratory depression comprises at least one delta receptor agonist compound. The delta agonist compound employed in the invention can also exhibit the mu receptor agonism (i.e., said compound can be mixed with the agonist character of the mu / delta receptor) or the composition for combating respiratory depression of the invention can include the different compounds, one or more of which exhibit the delta receptor agonist character, and one or more different onas of which exhibit the receptor agonist character. As yet a further alternative, the composition for combating respiratory depression of the invention may utilize one or more compounds, each of which has a mutant delta receptor agonist activity character varying. In a specific embodiment, the invention contemplates the compound for combating respiratory depression, a compound of formula (I) for reducing, treating or preventing respiratory depression that could otherwise be affected by an administered opiate analgesic. Additionally, the present invention provides the following particularly preferred compounds, which may be included, for example, in a pharmaceutical composition containing a compound and a pharmaceutically acceptable carrier and may used, for example, in a form suitable for injectable or spinal administration, to combat the incidence of respiratory depression by the use of analgesic or anesthetic agents. Particularly preferred compounds are the following: (-) - 4 - ((aR) -a - ((2R, 5R) -4-allyl-2,5-dimethyl-4-propyl-1-piperazinyl) -3-hydroxybenzyl ) -N, N-diethyl-benzamide; (-) - 4 - ((aR) -a - ((2 R, 5 R) -2,5-dimethyl-4-propi 1-1 -piperazin-yl) -3-hydroxybenzyl) -N, N-diethyl- benzamide; (-) - 4 - ((aR) -a - ((2S, 5S) -4-allyl-2,5-dimethyl-4-1-piperazinyl) -3-hydroxybenzyl) benzamide; (+) - 3 - ((aR *) - a - ((2S *, 5R *) - 4-al? I-2,5-1-piperazinyl) -3-h idroxy benz I) benzamide; N, N-diethyl-4 - ((aR) -3-hydroxy-a - ((2R, 5) -2,5-dimethyl-1-piperazinyl) benzyl) benzamide; 4 - ((aR) -a - ((2R, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N-ethyl-N-methyl-benzamide; 3 - ((aR) -a - ((2S, 5S) -4-allyl-2,5-d i methyl-1-piperazinyl) benz l) f enol; 3 - ((aS) - - ((2S, 5S) -4-allyl-2,5-d i methyl-1-piperazinyl) benz l) f enol; (+) - 4 - ((R *) - a - ((2R *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-dimethylbenzenesulfonamide; 4 - ((aR) -a - ((2 R, 5S) -4-al i I-2, 5-d imethyl-1-piperazin i 1) -3-h id roxybenzyl) - N, N-dimethylbenzenesulfonamide); (+) - N, N -d-ethyl-4 - ((aR *) - 3-hydroxy-a - ((2R, 5S *) - 2,4,5-trimethyl-1-piperazinyl) benzyl) -benzamide; (+) - 4 - ((aS) -a - ((2S, 4S) -4-al-l-2,5-di-methy1-1-piperazin-yl) -3-hydroxybenzyl) -N, N-diethyl -benzamide; and pharmaceutically acceptable salts thereof. These preferred compounds of the invention have utility in medical therapy, in particular for resorting to, treating, or avoiding respiratory depression associated with certain analgesics, such as mu opiates. Various aspects, features and embodiments of the invention will be more fully apparent from the appended description and claims below. DETAILED DESCRIPTION OF THE INVENTION AND MODALITIES PREFERRED OF THE SAME The vast majority of currently used high-potency analgesics, including morphine, fentanyl, meperidine, sufentanil, codeine and naltrindol, are the mu receptor binding compounds. These compounds have been established, while highly effective in mediating the analgesic, which has the side effects attached, including respiratory depression. The use of delta agonist compounds according to the present invention can prevent, reduce, attenuate or even eliminate inverse conditions in which analgesic-induced respiratory depression, such as the lateral effects of respiratory depression normally attenuate the use of the compounds binding of the mu receptor. The present invention therefore provides, among other things, methods to reduce, treat or prevent respiratory depression using agents that fight respiratory depression including delta agonist compounds. Such as the delta agonist compounds may be mentioned which exhibit the mixture of the mu / delta receptor agonist character or be provided with other receptor binding agents that exhibit the mu receptor agonism. The compositions of the invention can therefore be co-administered with drugs or other bioactive agents that mediate respiratory depression, so that the effects of respiratory depression of said drug or bioactive agent are at least partially attenuated. The delta agonist compounds that can be usefully employed in such compositions include delta agonist compounds and pharmaceutical compositions comprising a combination of an effective amount of an opiate analgesic and an amount of a delta agonist compound effective to reduce, treat or prevent respiratory depression. The use of the delta agonist compounds to combat respiratory depression and in combination with pharmaceutical compositions are more fully described below. Preferably, delta agonist compounds reduce, treat or prevent respiratory depression without affecting the desired analgesic of opiate analgesic agents, such as mu opiate analgesic agents. Delta compounds potentially useful in the broad practice of the present invention include: I. [D-Pen2-D-Pen5] - (encef aliña); deltorphine I; deltorphine II; IV. agonist compounds of the formula: (D where Ar is a 5- or 6-membered carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur and having a first carbon atom thereof, a Y substituent, and a second carbon ring thereof and a substituent R1, Y is selected from the group consisting of: hydrogen, halogen, C? -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl; C? -C6; C3-C6 cycloalkoxy; sulphides of the formula SR8 wherein R8 is Ci-Cß alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, arylalkyl having a C6-C10 aryl portion and an alkyl C ? -C6, or C5-C10 aryl; sulfoxides of the formula SOR8 wherein R8 is the same as described above; sulfones of the formula SO 2 R 8 wherein R 8 is the same as described above; nitrile; Acyl of C? -C6; alkoxycarbonylamino (carbamoyl) of the formula NHCO2R8 wherein R8 is the same as described above; carboxylic acid, or an ester, amide or salt thereof; aminomethyl of the formula CH 2 NR 9 R 10 wherein R 9 and R 10 may be the same or different, or 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 , C3-C6 cycloalkyl or C5-C10 celery, or R9 and R0 together can form a ring of 5 or 6 atoms, the ring atoms selected from the group consisting of N and C; carboxyamides of the formula CORN9R10 wherein R9 and R10 are the same as described above, or conjugates of C2-C3o peptides thereof; and sulfonamides of the formula SO 2 NR 9 R 10 wherein R 9 and R 10 are the same as described above; Z is selected from the group consisting of: hydroxyl, and esters thereof; hydroxymethyl, and esters thereof; and amino and carboxyamides and sulfonamides thereof; G is carbon or nitrogen; R1 is hydrogen, halogen or C1-C alkyl, C2-C4 alkenyl, C? -C alkynyl; R 2 is hydrogen, halogen or C 1 -C 4 alkyl, C 2 -C 4 alkenyl, d-C 4 alkynyl; R3, R4 and R5 may be the same or different and are independently selected from hydrogen and methyl and wherein at least one of R3, R4 or R5 are not hydrogen, subject to the proviso that the total number of methyl groups does not exceed of two, or either of the two of R3, R4 and R5 together may form a bridge of 1 to 3 carbon atoms; R6 is selected from the group consisting of: hydrogen; C 1 -C 2 alkyl, C 2 -C 6 alkenyl, C 2 -C 4 alkynyl; C3-C6 cycloalkyl; Arylalkyl having portions of C5-C10 aryl and alkyl alkoxyalkyl having portions of C5-C10 aryl and Ci-Cß alkyl! cyanoalkyl of C2-C4; C2-C4 hydroxyalkyl aminocarbonylalkyl having an alkyl portion of R 12 COR 13, wherein R 12 is C 1 -C 4 alkylene, and R 13 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy; and R7 is hydrogen or fluoride, or a pharmaceutically acceptable ester or salt thereof, V. delta agonist compounds of the formula: wherein, R1 and R2, which may be the same or different, are each hydrogen, linear or branched C6-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C4-6 cycloalkylalkyl, alkenyl C3-6, C3-5 alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or can together form a C3-7 alkyl ring that can be interrupted by oxygen.

R3 and R4, which may be the same or different, are each hydrogen, linear or branched C? -6 alkyl, or R is the formation of oxygen formed with the carbon atom to which a C = O, R5 group is attached is hydrogen, hydroxy, C? -3 alkoxy, thiol or alkylthio; R6 is phenyl, halogen, NH2 or a group for or meta -C (Z) -R8, in which Z is oxygen or sulfur; R8 is C2-8 alkyl, C?-8 alkoxy or NR9R10, wherein R9 and R10, which may be the same or different, are hydrogen, linear or branched C ?_6 alkyl, C3.7 cycloalkyl, cycloalkylalkyl C4-6, C3-6 alkenyl, C3-6 alkenyl, aryl or aralkyl, or R6 is a group for or metal of -N-C (Z) -R 2 wherein Rn and R12 which may be the same or different are hydrogen, straight or branched C? -? 6 alkyl, C3.7 cycloalkyl, C6 cycloalkylalkyl, C3-6 alkenyl, aryl, aralkyl or a ring optionally substituted herocyclic and Z is as defined above; and, R7 is hydrogen, straight or branched C? -8 alkyl or halogen; and I saw. Delta agonistic compounds of the formula: wherein, Ri and R2, which may be the same or different, are each hydrogen, linear or branched C-6 alkyl, C3- cycloalkyl, C3-7 cycloalkenyl, C-6 cycloalkylalkyl, C3- alkenyl 6, C3.5 alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or can together form an alkyl ring of C3.7 which can be interrupted by oxygen. R3 and R4, which may be the same or different, are each hydrogen, linear or branched C_6 alkyl; R5 is, hydroxy, C? -3 alkoxy, thiol or alkylthio; R6 is a group -C (Z) -Rg, in which Z is oxygen or sulfur, R8 is C? _8 alkyl, C1-8 alkoxy or NR9R10, wherein R9 and R10, which may be the same or different, are hydrogen, straight or branched C? -6 alkyl, C3-7 cycloalkyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, aryl or aralkyl, Rr or R6 is a group -NC (Z) -R12 in which Rn and R12 have the same meaning as R9 and R10 or together form an optionally substituted heterocyclic ring and z is as defined above and, R7 is hydrogen, C-alkyl -8 straight or branched or halogen. An exemplary delta agonistic compound among the illustrative compounds mentioned above is: (+) - 4 - ((aR) -a - ((2S, 5R) -4-allyl-2,5-di methyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide, and The composition that is co-administered with the bioactive agent mediated by respiratory depression further includes a mu agonist receptor such as the mu receptor agonists in U.S. Patent Application No. 08 / 284,445, and the Patent Application.

No. 08 / 285,313, including the mu receptor agonists and the mixture of the mu / delta receptor agonist compounds such as: when the compound for combating respiratory depression used in the practice of the invention does not affect the analgesic, it can be used in combination with an analgesic opiate agent, so that the opiate agent produces its desired analgesic effect, worse without the occurrence of respiratory depression otherwise (ie, in the absence of the compound of formula (I)) could be produced by the analgesic opiate agent. The invention therefore contemplates the use of the compounds that combat respiratory depression that mediate analgesia by themselves, as well as the compounds that combat respiratory depression that do not mediate analgesia. In said combination of the opiate agent (or other compound mediated by respiratory depression) and the compound for combating respiratory depression, the dose of the opiate agent to induce the analgesic and the dose of the compound of the formula (I) to recur, Treating, or avoiding respiratory depression, can be determined independently. The separate dose control of these two functions is provided for greater flexibility to treat individual patients. This separate control is one of the advantages of the combination of the pharmaceutical compositions of the present invention. The combination of the pharmaceutical compositions of the invention therefore comprises a combination of (1) an effective amount of a therapeutic agent having a (lateral) effect of respiratory depression, v.gr, an analgesic opiate, and (2) an effective amount of a compound, v. g, a compound of the formula (I) below, to reduce, treat or prevent respiratory depression. The compounds of the formula (I) are as follows: (I) wherein Ar is a 5- or 6-membered carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur and having a first carbon atom thereof, a Y substituent, and a second carbon ring thereof and a substituent R1, Y is selected from the group consisting of: hydrogen; halogen; C-i-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; Ci-Cß haloalkyl; alkoxy C3-C6 cycloalkoxy; sulphides of the formula or the SR8 wherein R8 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, arylalkyl having one aryl moiety of Ce-Cio and an alkyl portion of C? -C6, or C5-C10 aryl; sulfoxides of the formula SOR8 wherein R8 is the same as described above; sulfones of the formula SO R8 where R8 is the same as described above; nitrile; Acyl of C? -C6; alkoxycarbonylamino (carbamoyl) of the formula N HCO2R8 wherein R8 is the same as described above; carboxylic acid, or an ester, amide or salt thereof; aminomethyl of the formula CH2N R9R1 0 wherein R9 and R10 may be the same or different, or may be hydrogen, d-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C2 hydroxyalkyl, C2 methoxyalkyl -C6, C3-C6 cycloalkyl or C5-C0 aryl, or R9 and R1 0 together can form a ring of 5 or 6 atoms, the ring atoms selected from the group consisting of N and C; carboxyamides of the formula CORN9R1 0 wherein R9 and R10 are the same as described above, or conjugates of C2-C3o peptides thereof; and sulfonamides of the formula SO 2 N R 9 R 1 0 wherein R 9 and R 1 0 are the same as described above; Z is selected from the group consisting of: hydroxyl, and esters thereof; hydroxymethyl, and esters thereof; and amino and carboxyamides 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 4 C alkynyl; R 2 is hydrogen, halogen or C 1 -C 4 alkyl, C 2 -C alkenyl, C 1 -C 4 alkynyl; R3, R4 and R5 may be the same or different and are independently selected from hydrogen and methyl and wherein at least one of R3, R4 or R5 are not hydrogen, subject to the proviso that the total number of methyl groups does not exceed of two, or either of the two of R3, R4 and R5 together may form a bridge of 1 to 3 carbon atoms; R6 is selected from the group consisting of: hydrogen; C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; C3-C6 cycloalkyl; arylalkyl having portions of C5-C10 aryl and C6-C6 alkyl; alkoxyalkyl having portions of C5-C10 aryl and Ci-Cß alkyl; cyanoalkyl of C2-C; hydroxyalkyl of C2-C aminocarbonylalkyl having an alkyl portion of R12COR13, wherein R12 is C? -C4 alkylene, and R13 is C? -C4 alkyl or C? -C4 alkoxy; and R7 is hydrogen or fluoride, or a pharmaceutically acceptable ester or salt thereof. In preferred methods and pharmaceutical compositions of the present invention, substituents of the compound of formula (I) for reducing, treating or preventing respiratory depression in the following manner. Preferably, Ar is a 6-membered carbocyclic aromatic benzene ring and R1 is hydrogen. In certain preferred methods, Y is carboxyamide of the formula CONR9R10, and R9 and R10 are preferably the same or different and each is hydrogen, C1 alkyl or C2 alkyl, or together they form a ring of five or six atoms, so that it is formed by a pyrrolidinyl or piperidino ring. In other preferred methods, Y is hydrogen or a sulfone of the formula SO 2 R 8 and R 8 preferably is C 1 -C 6 alkyl. In addition, in the preferred methods, G is N, R7 and R2 are each hydrogen, and Z is hydroxyl. Preferably, R6 is selected from the group consisting of hydrogen, C?-C6 alkyl, C2-C6 alkenyl and C2-C alqu alkynyl and more preferably, R6 is selected from the group consisting of hydrogen, methyl, propyl, allyl and butenyl, and more preferably, R is allyl. In the preferred methods, R3, R4 and R5 are hydrogen or methyl, wherein the total number of methyl groups is one or two, and more preferably, R3 and R5 are both methyl, and R4 is hydrogen. Preferably, the compound for reducing, treating or preventing respiratory depression is selected from the group consisting of: (-) - 4 - ((aR) -a - ((2 R, 5 R) -4-allyl-2,5 -di-methyl-4-pro? il-1-piperazin-yl) -3-hydroxy-benzyl) -N, N-diethyl-benzamide; (-) - 4 - ((aR) -a - ((2R, 5R) -2,5-dimethyl-4-propyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethyl-benzamide; (-) - 4 - ((aR) -a - ((2S, 5S) -4-allyl-2,5-dimethyl-4-1-piperazinyl) -3-hydroxybenzyl) benzamide; (+) - 3 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-1-piperazinyl) -3-hydroxybenzyl) benzamide; N, N-diethyl-4 - ((aR) -3-hydroxy-a - ((2R, 5R) -2,5-dimethyl-1-piperazinyl) benzyl) benzamide; 4 - ((aR) -a - ((2 R, 5 R) -4-allyl-2,5-di methyl-1-piperazinyl) -3-h-idroxybenzyl) -N-ethyl-N-methyl-benzamide; 3 - ((aR) -a - ((2S, 5S) -4-allyl-2,5-di methyl-1-piperazinyl) benzl) f enol; 3 - ((aS) -a - ((2S, 4S) -4-al-l-2,5-dimeti 1-1 -piperazinyl) benzyl) f enol; (+) - N, N-diethyl-4 - ((aR *) - 3-hydroxy-a - ((2R *, 5S *) - 2,4,5-trimethyl-1-piperazinyl) benzyl) -bezamide; (±) -4 - ((aS) - - ((2S, 5S) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide; 3 - ((aR) -4- (piperidinocarbonyl) -a - ((2S, 5S) -2,4,5-trimethyl-1-piperazinyl) benzyl) phenol; 3 - ((aR) -4- (1-pyrrolidinylcarbonyl) -a - ((2S, 5S) -2,4,5-trimethyl-1-pipe razinyl) benzyl) phenol; (+) - 3 - ((aR *) - a - ((2R *, 5S *) - 4-allyl-2,5-d-methyl-1-piperazinyl) -4- (methylsulfonyl) benzyl) phenol); (±) -4 - ((aR *) - a - ((2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-dimethylbenzenesulfonamide (e , independently, each of the isomers of the components thereof); (+) - 3 - ((aR *) - - ((2S *, 5 R *) - 4-allyl-2,5-dimeti 11-1 -piperazinyl) benzyl) f enol; (±.}. -4 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) benzamide; (+) - 4 - ((aR *) - a - ((2R *, 5S *) - 4-allyl-2,5-dimethyl-1-p-piperazinyl) -3-hydroxybenzyl) -N, N-diethyl-benzamide; + _) - cis-4 - ((a- (4-allyl-3,5-dimethyl-1-pyrrazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide; cis-4- (a- (3.5 -dimethyl-4- (methylalkyl) -1-piperazinyl) -3-h idroxybenzyl) -N, N-diethyl-benzamide, and pharmaceutically acceptable salts thereof More preferably, the compound is (-) - 4 - ((aR) -a - ((2R, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-d iethyl benzamide; (+) - 4 - ((aR *) - a - ((2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-dimethylbenzenesulfonamide; 4 - ((R) -a - ((2 R, 5S) -4-allyl-2,5-dimeti-1-1-piperazinyl) -3-hydroxy-benzyl) -N-dimethylbenzenesulfon-amide; or 4 - ((aS *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxy-benzyl) - N, N-d i -methylbenzenesulfonamide; or a pharmaceutically acceptable salt thereof. In addition to the methods of treating, resorting to, or preventing respiratory depression, the present invention also provides methods for screening and characterizing respiratory depression suppression compounds, which comprise analysis of reverse activity of candidate respiratory pressure suppression compounds that in the receptor tissue mediated transductionally by an effect of respiratory depression in responses with the composition of respiratory depression. The inverse activity analyzes are carried out comparatively, in the absence and in the presence of an anti-suppression compound of the formula (I), to determine whether the suppression activity (respiratory depression) of the candidate compound is markedly reversed in the receptor system by the presence of an anti-suppression compound of the formula (I). If so, the analysis indicates that the candidate respiratory depression suppression compound may have potential bioefficacy to suppress the effects of respiratory depression incidental to the use of other therapeutic agents. Preferred anti-suppression compounds of the formula (I) which can be usefully employed in the screening assay described above include: (-) - 4 - ((aS) -a - ((2R, 5R) -4- allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethyl-benzamide; (-) - 4 - ((aS) -a - ((2 R, 5 R) -2,5-dimeti I-4-propi 1-1 -piperazin-yl) -3-hydroxybenzyl) -N, N- diethylbenzamide; c / s-4- (a (4 - ((Z) -2-butenyl) -3,5-dimethyl-1-piperazin-yl) -3-h-idroxybenzyl) -N, N-diethyl-benzamide; and acceptable salts thereof. Additionally, the present invention provides the following preferred compounds of formula (I), which may be included, for example, in a pharmaceutical composition containing the compound and a pharmaceutically acceptable carrier. The pharmaceutical compositions can be used, for example, in a form suitable for injectable or spinal administration. The preferred compounds referred to above are the following. (-) - 4 - ((aR) -a - ((2 R, 5 R) -4-allyl-2,5-dimeti 1-1 -piperazinyl) -3-hydroxybenzyl) -N, N-diethyl- benzamide; (-) - 4 - ((aR) -a - ((2R, 5) -2,5-dimethyl-4-propyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide; 4 - ((aR) -a- (2R, 5S) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -benzamide; (+) - 3 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -benzamide; N, N-diethyl-4 - ((R) -3-hydroxy-a - ((2R, 5R) -2,5-di-methyl-1-piperazinyl) benzyl) benzamide; 4 - ((aR) -a - ((2S, 5S) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N-ethyl-N-methyl-benzamide; 3 - ((aR) -a - ((2S, 5S) -4-allyl-2,5-d i meti 1-1 -piperazin i I) benzl) f enol; (+) - N, N-diethyl-4 - ((R *) - 3-hydroxy-a - ((2R *, 5S *) - 2,4,5-trimethyl-1-piperazinyl) benzyl) benzamide; (+) - 4 - ((aR *) - a - ((2 R *, 5S *) - 4-allyl-2,5-di methyl-1-1-piperazinyl) -3-hydroxybenzyl) -N, N - tell me useful benzene his I fonamide; 4 - ((aR) -a - ((2 R, 5S) -4-al i-l, 2,5-dimeti 1-1 -piperazin il) -3-h idroxy benzyl) - N, N-dimethylbenzene nosul fonamida; 4 - ((S) -a - ((2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) - N, N-dimetyl Iben ce nosul fonamide, (+) -4 - ((aS) - - ((2S, 5S) -4-allyl-2,5-di-methyl-1-piperazin-yl) -3-hydroxy-benzyl) -N, N-diethyl-benzamide; and pharmaceutically acceptable salts thereof. These preferred compounds of the invention have utility in medical therapy, in particular to reduce, treat or prevent respiratory depression associated with drugs mediated by respiratory depression, including hundreds of analgesics such as mu opiate analgesics.

The compositions for combating respiratory depression of the present invention can be formulated with the respiratory depression mediating agent, as a unitary composition. Alternatively, the compositions for combating respiratory depression of the present invention may be administered separately or independently to a patient in need thereof, to combat the effects of respiratory depression otherwise obtained in the use of the mediation agent of the patient. respiratory depression, v.gr, a respiratory depressant such as morphine, fentanyl or the like. The invention contemplates the use of any means and / or mode of administration of the compositions for combating respiratory depression of the invention, in conjunction with the drug or bioactive agent that mediates respiratory depression. The compounds of the above general formula (I) exhibit the binding selectivity for the receptors. Depending on the structure and stereospecificity of the compounds of the particular formula (I), said compounds may exhibit binding capacity to the receptors selected from the group consisting of delta receptors, mu receptors, kappa receptors, sigma receptors, and combinations of said receptors. . Several compounds within the general formula (I) exhibit the delta receptor agonist activity including reducing, treating or preventing respiratory depression. Other compounds of the formula (I) exhibit the antagonist activity of the delta receptor which are useful as agonist conjugates for the analytical applications, example, for the identity of agonist species. Still other compounds within the general formula exhibit the activity of the mu receptor and more particularly, in some cases, the mu receptor / delta receptor activity mixture. In the case of delta receptor agonists, activity is generally distinguished and measured by activity in the electrically stimulated mouse against difference analysis. Additionally, empirical determinations using the compounds of the present invention give us ample evidence of the existence of a delta receptor subtype in the brain that is different from the delta receptor in the mouse vas deferens. As a consequence of the existence of said delta receptor subtypes, other receptor binding assays or screening techniques can be employed as an additional predictor of agonist or antagonist activity for the specific compounds of the present invention. The compounds used in the methods and compositions of the present invention preferably have the following in vitro profile according to the delta receptor IC50 and the deferent channel of the mouse DE50 described in Example 12. Preferably, the IC50's are between about 0.01 and about 100 nM; more preferably, IC50's are less than about 100 nM; even more preferably, IC50's are less than about 10 nM; even more preferably, the IC50's are less than about 2 nM, and more preferably, the IC50's are less that approximately 1 mM. Preferably, the deferent channels of mice of the ED50 are as high as possible, preferably, greater than about 10 nM; more preferably, greater than about 30 nM; even more preferably, greater than about 50 nM; and more preferably, greater than about 30 nM; even more preferably, greater than about 50 nM; and more preferably, greater than about 100 nM. In general, it is preferred that they have an IC5o: ED5o ratio of about 1:10; and more preferably, about 1: 100. As used herein, with reference to the present invention, the term "alkyl" is understood to be broadly constructed to encompass: (i) straight chain alkyl groups as well as branched chain character; (ii) unsubstituted as well as substituted alkyl groups may include any spherically acceptable substituent which is compatible with said alkyl groups and which does not exclude the efficacy of the diaryiimethyl piperazine compound for its intended utility (examples of substituents for substituted alkyl groups include halogen ( v.gr, fluoride, chlorine, bromine and iodine), amino, amido, C? -C4 alkyl, C? -C4 alkoxy, nitro, hydroxy, etc.); (iii) saturated alkyl groups as well as unsaturated alkyl groups, the latter including groups such as alkyl groups substituted with alkenyl (v. gr, allyl, methallyl, propyl, butenylmethyl, etc.), alkyl groups substituted with alkynyl and any other alkyl groups containing spherically unsaturated which is compatible with the alkyl groups and which does not exclude the efficacy of the diaryiimethyl piperazine compound for its intended utility; and (iv) alkyl groups including the linking or bridging portions, v.gr, heteroatoms such as nitrogen, oxygen and sulfur, etc. As used herein, with reference to the present invention, the term "arid" is understood to be broadly construed with reference to carbocyclic (v.gr, phenyl, naphthyl) as well as heterocyclic aromatic groups (v.gr, pyridyl, thienyl, furanyl, etc.) and encompass unsubstituted as well as substituted aryl groups, wherein the substituents of the substituted aryl groups can include any spherically suitable substituent that is compatible with the aryl groups and does not exclude the efficacy of the diamimethyl piperazine compound for its intended utility. Examples of the substituents of the substituted aryl groups include one or more of halogen (v.gr, fluoride, chlorine, bromine, and iodine), amino, amido, C? -C4 alkyl, C1-C alkoxy, nitro, trifluoromethyl, hydroxy, hydroxyalkyl containing an alkyl portion of C? -C4, etc. The compounds contemplated by the invention include those of the formula (I) per se, as well as physiologically functional derivatives thereof. By "physiologically functional derivative" is meant a salt, ether, ester or salt of a pharmaceutically acceptable ether or ester of the composed of the formula (I) or any other compound which is administered to the recipient, is capable of being provided (directly or indirectly) to the compound of the formula (I) or a metabolite or active residue thereof. The phenolic d-Cß alkyl ethers are the subclass of physiologically functional derivatives of the compounds of the formula (I). Enantiomeric forms, the compounds of the invention include enantiomers of the compounds of the formula (I) in simple species forms substantially free of the corresponding enantiomer as well as a mixture (in mixture of enantiomer pairs and / or mixtures of multiple enantiomeric species) .

A subclass of the compounds within the scope of formula (I) are the esters and pharmaceutically acceptable salts thereof. Examples of pharmaceutically acceptable esters of the invention include carboxylic acid esters of hydroxy groups in the compounds of formula (I) in which the carbonyl-free portion of the carboxylic acid moiety of the ester group is selected from straight-chain alkyl or branched (v.gr, n-propyl, t-butyl, n-butyl), alkoxyalkyl (v.gr, methoxymethyl), arylalkyl (v.gr, benzyl), aryloxyalkyl (v.gr, phenoxymethyl) and aryl (v. gr, phenyl); alkyl-aryl-, or arylkylsulfonyl (v. gr, methanesulfonyl), amino acid esters (v.gr, L-valyl or L-isoleucyl); esters of dicarboxylic acid (v.gr, hemisuccinate); carbonate esters (v.gr, ethoxycarbonyl); esters of carbamate (v.gr, dimethylaminocarbonyl, (2-aminoethyl) aminocarbonyl); and inorganic esters (v.gr, mono-, di- or triphosphate). Examples of pharmaceutically acceptable salts of the compounds of the formula (I) and physiologically functional derivatives thereof include salts derived from an appropriate base, such as an alkali metal (e.g., sodium, potassium), an alkaline earth metal (e.g., calcium, magnesium), ammonium and NX4 + (wherein X is C? -C4 alkyl). The pharmaceutically acceptable salts of an amino group include salts of: organic carboxylic acids such as acetic, lactic, tartaric, malic, lactobionic, fumaric and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, isothionic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric and sulfamic acids. The pharmaceutically acceptable salts of a compound having a hydroxy group consisting of the anion of the compound in combination with a suitable cation such as Na +, NH4 + or NX4 + (where X is for example an alkyl group of C? -4). For therapeutic use, the salts of the compounds of the formula (I) may be pharmaceutically suitable, that is, they may be salts derived from a pharmaceutically acceptable acid or base. However, salts of acids or bases that are not pharmaceutically acceptable also find use, for example, in the preparation or purification of a compound pharmaceutically. acceptable. All salts, whether or not derived from a pharmaceutically acceptable acid or base, are within the scope of the present invention. As used herein, with reference to the present invention, the term "hydrocarbyl" is understood to encompass a continuation of the group solely of carbon and hydrogen atoms, which may contain double or triple bonds that may be cyclic or aromatic in the nature. The compounds of the invention when used in convenient diagnostic applications, are prepared in substantially pure enantiomeric form, with an enantipure of at least 90% enantiomeric excess (EE), preferably at least 95% EE, more preferably at least 98% EE and even more preferably at least 99% EE The values of enantiomeric excess provide a quantitative measure of the excess of the percentage amount of a major isomer over the percentage amount of a major isomer that is present therein, and can be easily determined by suitable well-known methods and established in the art, such as for example chiral high pressure liquid chromatography (CLAP), chiral gas chromatography (GC), nuclear magnetic resonance (RM N) using the chiral change reagents, etc. The subjects can be treated by the methods of the present invention which includes both human and non-human animals (v.gr, birds, dogs, cats, goats, horses) subjects and subjects preferably mammals, and more preferably human subjects.

Depending on the specific condition to be treated, the animal subjects can be administered the compounds of the formula (I) at any therapeutically effective and safe dose, as well as easily determine within the skin of the material and without undue experimentation. In vitro tests for agonist / antagonist activity, such as receptor binding binding tests and inhibition of electrically stimulated motion tests, compounds of the present invention exhibit power on a scale of nanomolar forms at micromolar concentrations, depending of the specific compound used. In general, while the effective dose of the compounds of the invention for therapeutic use may vary widely in the broad practice of the invention, depending on the application, condition or disease state involved, specific to easily determine within the skin of the subject . Suitable therapeutic doses of the compounds of the formula (I), for each of the related compositions described herein, and to achieve therapeutic benefit in the treatment of each of the conditions described herein, could be in the scale of 10 micrograms (μg) to 100 milligrams (mg) per kilogram of container body weight per day, preferably in the range of 50 μg to 75 mg per kilogram of body weight per day, and even more preferably on the scale of 100 μg to 50 mg per kilogram of body weight per day. The dose is preferably presented as two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. These sub-doses in unit dosage forms, for example, containing from 100 μg to 1000 mg, preferably from 50 μg to 500 mg, more preferably from 50 μg to 250 mg, and even more preferably from 50 μg to 10 mg of ingredient active per unit dose form. Alternatively, if the condition of the recipient requires, the doses may be administered as a continuous infusion. The mode of administration and dosage forms of the effect of the course of the therapeutic amounts of the compounds that are desirable and effective to give the application treatment. For example, orally administered doses are usually at least twice, v.gr, 2-10 times, the dose levels used for parenteral administration methods, for the same active ingredient. In oral administration, the dose levels for the delta receptor binding compounds of the invention may be in the order of 5-200 mg / 70 kg. by body weight / day. In tablet dosage forms, normally the dose levels of the active agent are in the order of 10-100 mg per tablet. The compounds of the formula (I) can be administered by themselves as is known in the form of pharmaceutically acceptable ethers, esters, salts and other physiologically functional derivatives thereof.

The present invention also contemplates pharmaceutical formulations, both for the veterinary and for the use of human medicine, which comprise as the active agent one or more compounds of the invention. In such pharmaceutical formulations, the active agent is preferably used together with one or more pharmaceutically acceptable carriers thereof and optionally any other therapeutic ingredient. The vehicles may furthermore be pharmaceutically acceptable in the sense that they are compatible with other ingredients of the formulation and unduly deteriorate the container thereof. The active agent is provided in an amount effective to achieve the desired pharmacological effect, as described above and in an appropriate amount to achieve the desired daily dose. Formulations include those suitable for parenteral administration as well as non-parenteral administration, and specific administration modalities including oral, rectal, topical, sub-lingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular, intravenous, transdermal, spinal administration , intrathecal, intra-articular, intra-arterial, sub-araconoid, bronchial, lymphatic and intra-uterine. Formulations suitable for parenteral administration are preferred. When the active agent is used in a formulation comprising a liquid solution, the formulation can advantageously be administered parenterally. When the active agent is employed in a liquid suspension formulation or as a powder in a biocompatible vehicle formulation, the formulation can be advantageously administered orally, rectally or bronchially. When the active agent is used directly in the form of a solid powder, the active agent can be advantageously orally administered. Alternatively, it can be administered bronchially, via the nebulization of the powder in a carrier gas, to form the gaseous dispersion of the powder that is inspired by the patient from a breathing circuit comprising a suitable nebulizer device. In some applications, it may be advantageous to use the active agent in a "vectorized" form, such as by encapsulating the active agent in a liposome or other encapsulating medium, or by fixing the active agent, v. Gr, by covalent attachment, chelation or associated coordination, in a suitable biomolecule, such as that selected from proteins, lipoproteins and polysaccharides. The formulations comprising the active agent of the present invention can be conveniently presented in unit dosage forms and can be prepared by any of the methods well known in the pharmacy field. Such methods generally include the step of binding the active compounds in association with a vehicle that constitutes one or more accessory ingredients. Usually. The formulations are prepared by the uniformly and intimately binding the active compounds in association with a liquid carrier, a finely divided solid carrier or both, and then, if necessary, forming the product in dosage forms of the desired formulation. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, troches, tablets or lozenges, each containing a predetermined amount of active ingredients such as a powder or granules; or a suspension in an aqueous liquor or a non-aqueous liquid, such as a syrup, an elixir, an emulsion or a beverage. A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compression in a suitable machine, with the active compound being in a free-flowing form such as a powder or granules which optionally are mixed with a binder, disintegrant, lubricant, inert diluent, surface active agent or unloading agents. Compressed molded tablets of a mixture of the active compound powder with a suitable vehicle can be made by molding in a suitable machine. A syrup can be made by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose, to which any accessory ingredient is also added. These accessory ingredients may include flavorings, preservatives suitable, agents for retarding the crystallization of sugar and agents for increasing the solubility of any ingredient, such as polyhydroxy alcohol, for example glycerol or sorbitol. Formulations suitable for administration conveniently comprise a sterile aqueous preparation of the active compound, which is preferably isotonic with the blood of the container (v.gr, physiological saline). Such formulations may include suspending agents and thickening agents and liposomes or other microparticle systems that are designed to target the compound in the blood components or one or more organs. The formulations may be presented in the form of a dose or multiple doses. Nasal spray formulations comprise purified aqueous solutions of the active compounds with preservatives and isotonic agents. Said formulations are preferably adjusted to pH and isotonic state compatible with the membranes of the nasal mucosa. Formulations for rectal administration may be presented as a suppository with a suitable vehicle such as buffer solution of cocoa butter, hydrogenated fats or hydrogenated fatty carboxylic acids. Ophthalmic formulations are prepared by a method similar to nasal spray, except that the pH and isotonic factors are preferably adjusted to match that of the eye.

Topical formulations comprise the active compound dissolved or suspended in one or more media, such as mineral oil, petroleum, polyhydroxy alcohols, or other bases used for pharmaceutical formulations. Transdermal formulations can be prepared by incorporating the active agent into a thixotropic or gelatinous vehicle such as a cellulose medium, v. Gr, methyl cellulose or hydroxyethyl cellulose, with the resulting formulation being packaged in a transdermal device adapted to ensure dermal contact with the skin. skin or a person. In addition, in the ingredients mentioned above, the formulations of this invention may further include one or more accessory ingredients selected from diluents, buffer solutions, flavoring agents, binders, disintegrants, surface active agents, thickeners, lubricants, preservatives (including antioxidants) and Similar. The compounds of the formula (I) and the pharmaceutically acceptable esters, salts and other physiologically functional derivatives thereof can be formed by the illustrative synthetic techniques described in International Publication No. WO93 / 15062 mentioned above. The compositions that combat respiratory depression of the present invention can advantageously also attenuate the side effects of drug agents other than respiratory depression. For example, fentanyl also reduces the stiffness of the I mumble through the mu receptor activation. Such pheantyl-induced muscle rigidity can be inhibited by an agonist compound such as (+) - 4 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1 -piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide. However, said combination of mu agonist and delta agonist compounds are synergistic, selectively antagonizing one another with adverse side effects. The compound (+ _) - 4 - ((aR *) - a - ((2S *, 5 R *) - 4-a I il-2,5-di methyl-1-piperazin il) -3-h id roxibencil) -N, N-diethylbenzamide at high doses can induce the activity taken via the activation of the delta receptor. Fentanyl of the mu agonist, for example, has been shown to antagonize said given high dose effect, while the delta agonist antagonizes respiratory depression and male stiffness of the side effects of fentanyl. At the same time, the combination of said agonist compounds result from an additive analgesic effect. The effects of nausea / vomiting of opioid analgesics are also attenuated by delta opioid agonists. The combination of mu and delta opioid agonists or compounds that have both mu and delta opioid receptor activity may produce less nausea and vomiting compared to the mu opioid analgesics currently used. The invention is further illustrated by the following examples without limitation.

Certain specifications and common methods for many of the following examples in relation to chemical synthesis are described in the following paragraph. The melting points are determined with a Thomas-Hoover apparatus and are not in correct form. All chemical reagents are sold by Aldrich Chemical Company, Milwaukee, Wisconsin, under another specific mode. Commercial solvents are used without further purification except tetrahydrofuran, which is distilled from the potassium metal. The nuclear magnetic resonance (NMR) spectrum was obtained variously with R-24 spectrometers from Perkin-Elmer, Varian XL-200 or XL-300. The CLAP analyzes were carried out with a liquid chromatography system from Waters equipped with a System Controller 700 Satellite WISP, 6003 and a detector 991 Photodiode Array, with a column of Cyclounion I (4.6 x 250 mm, Advenced Separations Technologies, Whippany, New Jersey) or a μ-Bondapack C-18 column (125 Á, 3.9 x 300 mm, Waters Chromatography Division, Millipore Corporation, Milford, Massachusetts) at a flow rate of 1 ml / min. Analytical gas chromatography was carried out using a Hewlett-Packard Series II Instrument, Model 5890 with flame ionization detector using helium as the carrier gas (injector temperature, 225 ° C, detector temperature, 250 ° C) C). Optical rotations are obtained with a Perkin-Elmer 241 polarimeter. The mass spectrum was carried out by Oneida Research Services, Whitesboro, New York. X-ray crystallography was carried out by the Molecular Structure Corporation, College Station, Texas. Analytical thin-layer chromatography was carried out on Analtech glass plates pre-coated with silica gel GF (250micras) and preparative thin layer chromatography on Analtech Uniplacas pre-coated with silica gel GF (1000 and 200 microns). ). Elemental analyzes were carried out by Atlantic Microlab, Norcross, Georgia. EXAMPLE 1 (-) - 4 - ((aR *) - a - ((2R, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxy benzyl) -N, N- di ethylbenzamide A mixture of 4-carboxybenzaldehyde (100 g, 0.66 mol), 1 liter of dimethylformamide and 2 liters of dichloromethane was cooled in an ice bath. Thionyl chloride (53 mL, 0.73 mol) was added dropwise while stirring. After 18 hours at room temperature, the mixture was cooled again and diethylamine (275 mL, 2.6 moles) was added dropwise. After stirring at room temperature for one hour the solvent was evaporated and the residue was dissolved in aqueous 0.1M sodium hydroxide and extracted with ethyl acetate. The organic layers were washed with water and brine, dried over sodium sulfate and evaporated to give a yellow oil. Chromatography on silica gel with ethanol (0-2%) in dichloromethane gave 44.2 g (32%) of 4-formyl-N, N-diethylbenzamide as a yellow oil. A solution of 3-bromophenol (500 g, 2.89 moles), tert-butylchlorodimethylsilane (436 g, 2.89 moles) and imidazole (500 g, 7.22 g) moles) in 500 mL of dimethylformamide was stirred overnight at room temperature. The reaction solution was poured into 3000 mL of water and extracted with two 2000 mL portions of diethyl ether. The combined ether extracts were dried over sodium sulfate and the solvent was removed to give 846 g of 3- (bromophenoxy) -tert-butyldimethylsilane as a pale yellow liquid. NMR (300 MHz, CDC13): d 0.2 (s, 6H); 1.0 (s, 9H), 6.75 (m, 1H), 7.0 (br s, 1H); 7.1 (m, 2H). 3- (Bromophenoxy) -tert-butyldimethylsilane (61.7 g, 0.21 mol) was dissolved in 500 mL of dry tetrahydrofuran under nitrogen and cooled to -78 ° C. A solution of 1.6 M n-butyllithium in hexane (132, 0.21 mol) was added dropwise at a rate to maintain the temperature below -70 ° C. The reaction was stirred for thirty minutes after the addition was complete and the solution was cooled and transferred via cannula to another vessel containing a cold solution (-78 ° C) of 4-formyl-N, N-diethylbenzamide (44.1 g)., 0.21 moles), from the foregoing, in 500 mL of dry tetrahydrofuran under nitrogen. The transfer rate was monitored to keep the temperature below -70 ° C. After stirring for one hour at -78 ° C, the reaction was washed with saturated aqueous ammonium chloride, warmed to room temperature and diluted with diethyl ether. The ether layer was washed with water and brine, dried over sodium sulfate and evaporated to give a yellow oil. Chromatography on silica gel with ethanol (0-1%) in dichloromethane gave 45.4 g (52%) of 4- (3- (tert-butylidimethylsilyloxy) -ahydroxybenzyl) -N, N-diethylbenzamide as a white solid. NMR (200 MHz, CDCl 3) d: 0.15 (s, 6H); 1.0 (s, 9H), 1.2 (br m, 6H); 2.8 (br s, 1H); 3.25 (br m, 2H), 3.5 (br m, 2H); 5.75 (s, 1H); 6.75 (d, J = 8Hz, 1H), 6.85 (s, 1H); 7.95 (d, J = 8 Hz, 1H), 7.2 (t, J = 8Hz, 1H); 7.35 (AB q, J = 8 Hz, 4H). Thionyl chloride (5.3 mL, 0.075 mole) was added to a solution of benzohydryl alcohol from the above (19.75 g, 0.048 mole) in 350 mL of dichloromethane. After stirring at room temperature overnight the solvent was evaporated, the residue redissolved in toluene and again vaporized to drive excess thionyl chloride to give 4- (3- (tert-butyldimethylsilyloxy) -a- chlorobenzyl) -N, N-diethylbenzamide. Crude benzohydril chloride (approximately 0.047 mol), (2R-5R) -2,5-dimethylpiperazine (6.0 g, 0.53 mol), prepared from L-Ala-L-Ala-diketopiperazine (Bachem Chemicals, Philadelphia, Pennsylvania) as is described in J. Org. Chem. 50: 4909-13 (1985), sodium iodide (9.0 g, 0.06 moles) and diisopropylethylamine (14.19 g, 0.11 moles) was heated to reflux in acetonitrile (300 mL) under nitrogen for four hours. The acetonitrile was evaporated. The residue was dissolved in ethyl acetate (0.5 L) and washed with water. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in dichloromethane and purified on a short column of silica gel with ethanol (5%) in dichloromethane to give provide a 1: 1 mixture of two diastereomers of benzohydri Ipiperazine. The mixture of the benzohydrylpiperazine epimers (7.6 g, 14.9 mmol) was dissolved in 50 mL of dry tetrahydrofuran with 1.6 mL (18.6 mmol) of allyl bromide and 5.1 g (36.9 mmol) of sodium carbonate and stirred at room temperature. under nitrogen for 2 days. The reaction solution was poured into ice water / ethyl acetate and separated. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in a small amount of dichloromethane and placed on a column of silica. The diastereomers were separated by elution with a gradient step of ethanol in dichloromethane. The first isomer was eluted with 1.3% ethanol in dichloromethane and the second isomer was obtained with 1.6% ethanol in dichloromethane. The fractions containing the second isomer were combined and the solvent was removed in vacuo to give 1.44 g of 4- (aR) -a - ((2R-5R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-tert-butyldimethylsiloxy) benzyl) -N, N-diethylbenzamide as a brown oil. NMR (300 MHz, DMSO-d6) d: 0.12 (s, 6H); 0.89 (m, 12H); 0.93 (d, J = 6.5 Hz, 3H); 1.05 (br s, 6H); 2.12 (app t, J = 10.4 Hz, 1H), 2.25-2.37 (m, 3H); 2.55 (dd, partially obscure by DMSO, 1H); 2.71 (dd, J1 = 8.2 Hz, J2 = 14.2 Hz, 1H); 2.82 (br d, J = 6.2 Hz, 1H); 3.12 (br s, 2H); 3.19 (m, obscured by water, 1H); 3.36 (br s, 2H); 4.55 (s, 1H), 5.08 (d, J = 10.8 Hz, 1H), 5.14 (d, J = 21.4 Hz, 1H), 5.72-5.83 (m, 1 HOUR); 6.62 (d, J = 8.7 Hz, 1H), 6.99 (s, 1H); 7.00 (d, J = (.1 Hz, 1H), 7.12 (t, J = 7.9 Hz, 1H), 7.12 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H). The brown oil (1.05 g, 1.9 mmol) was dissolved in 8 mL of acetonitrile with 0.53 g (2.9 mmol) of tetraethylammonium fluoride dihydrate and stirred for 30 minutes at room temperature.After evaporation of the solvent, the residue The mixture was redissolved in 1N hydrochloric acid and diethyl ether, the aqueous phase was separated and neutralized to pH 8 with 1N sodium hydroxide solution, the product was extracted using dichloromethane and washed with brine, and the organic phase was dried over sodium sulfate. sodium and the solvent was removed to give 0.69 g of (-) 4- (R) -a - ((2R-5R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-tert-butyldimethylsilyloxy) benzyl) -N, N-diethylbenzamide. NMR (300 MHz, DMSO-d6) d 0.94 (d, J = 5.4 Hz, 3H); 1.00 (d, J = 5.4 Hz, 3H); 1.13 (br s, 6H); 2.19 (app t, J = 10.0 Hz, 1H); 2.26-2.41 (m, 3H), 2.55 (m, partially dark by DMSO, 1H); 2.81 (dd, J1 = 7.9 Hz, J2 = 14.1 Hz, 1H); 2.89 (br d, J = 6.2 Hz, 1H); 3.21 (br s, 2H); 3.21 (m, dark, 1H); 3.39 (br s, 2H); 4.54 (s, 1H); 5.17 (d, J = 11.3 Hz, 1H), 5.22 (d, J = 19.6 Hz, 1H); 5.82-5.96 (m, 1H); 6.60 (d, J = 7.8 Hz, 1H); 6.93 (m, 2H); 7.11 (t, J = 7.9 Hz, 1H); 7.31 (d, J = 7.9 Hz, 2H); 7.52 (d, J = 7.9 Hz, 2H); 9.39 (s, 1H). Mass spectrum (CI-CH4) m / z: 436 (M + 1.12%), 282 (100%), 153 (3%). [a] 20D = -17.8 ° C (ethanol, c = 1.2). A portion of the free amine (0.100 g) was dissolved in ethanol and triturated with ethanolic hydrogen chloride at pH 4.0, followed by precipitation with dichloromethane diethyl ether to give 0.089 g of the monohydrochloride salt as a hygroscopic beige powder. Calculated for C27H3 N3O2 HCl 0.75 H2O: C, 66.78, H, 8.20; N, 8.65 Cl, 7.30. Found: C, 66.90; H, 8.05; N, 8.69; Cl, 7.13. EXAMPLE 2 (-) - 4 - ((aS) -a - ((2R, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethyl-benzamide obtained the first isomer to be eluted from the column of Example 1, as 1.39 g of a brown oil. NMR (300 MHz, DMSO-d6) d: 0.11 (s, 6H); 0.86 (d, J = 6.8 Hz, 3H); 0.88 (m, 9H), 0.94 (d, J = 6.8 Hz, 3H); 1.02 (br s, 6H); 2.14 (app t, J = 10.7 Hz, 1H); 2.215-2.38 (m, 3H); 2.55 (dd, partially obscure by DMSO, 1H); 2.73 (dd, J1 = 7.4 Hz, J2 = 13.9 Hz, 1H); 2.84 (br s, 1H); 3.13 (br s, 2H); 3.28 (m, obscured by water, 1H); 3.34 (br s, 2H); 4.55 (s, 1H); 5.09 (d, J = 11.3 Hz, 1H); 5.14 (d, J = 19.9 Hz, 1H); 5.74-5.84 (m, 1H); 6.63 (d, J = 7.8 Hz, 1H); 6.90 (s, 1H); 7.02 (d, J = 7.6 Hz, 1H); 7.13 (t, J = 7.8 Hz, 1H); 7.23 (d, J = 8.1 Hz, 2H); 7.47 (d, J = 8.1 Hz, 2H). The brown oil (0.95 g, 1.73 mmol) was dissolved in 8 mL of acetonitrile with 0.48 g (2.6 mmol) of tetramethylammonium fluoride dihydrate and stirred for 30 minutes at room temperature. After evaporation of the solvent, the residue was redissolved in 1N hydrochloric acid and diethyl ether. The aqueous phase was separated and neutralized to pH 8 with 1N sodium hydroxide solution. The product was extracted using dichloromethane and washed with brine. The organic phase was dried over sodium sulfate and the solvent was removed to give 0.64 g of (-) - 4- (aS) -a - ((2R-5R) -4-allyl-2,5-dimeti I-1 -piperazinyl) -3-h id roxybenzyl) -N, N-diethyl benzamide. NMR (300 MHz, DMSO-d6) d 0.89 (d, J = 5.8 Hz, 3H); 0.98 (d, J = 5.8 Hz, 3H); 1.08 (br s, 6H); 2.10-2.43 (m, 4H); 2.56 (m, partly dark by DMSO, 1H); 2.78 (dd, J1 = 7.7 Hz, J2 = 14.4 Hz, 1H); 2.97 (br d, J = 6.0 Hz, 1H); 3.17-3.43 (m, 5H), 4.51 (s, 1H), 5.13 (d, J = 8.6 Hz, 1H), 5.19 (d, J = 15.6 Hz, 1H); 5.75-5.88 (m, 1H); 6.57 (d, J = 6.8 Hz, 1H); 6.88 (m, 2H); 7.04 (t, J = 7.7 Hz, 1H); 7.27 (d, J = 8.0 Hz, 2H); 7.50 (d, J = 8.0 Hz, 2H); 9.34 (s, 1H). Mass spectrum (CI-CH4) m / z: 436 (M + 1.23%), 282 (100%), 153 (4%). [a] 20D = -17.3C (ethanol, c = 1.2). A portion of the free amine (0.100 g) was dissolved in ethanol and triturated with ethanolic hydrogen chloride at pH 4.0, followed by precipitation with dichloromethane diethyl ether to give 0.075 g of the monohydrochloride salt as a hygroscopic whitish powder. Calculated for C27H37N3O2 HCl 0.5 H2O: C, 67.41, H, 8.17; N, 8.73 Cl, 7.37. Found: C, 67.16; H, 8.18; N, 8.81; Cl, 7.26. EXAMPLE 3 (-) - 4 - ((aR) -a - ((2R, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide (-) -4 - ((aR) -a - ((2R, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide (0.075 g, 0.17 mmol, Example 1) was dissolved in toluene (10 mL), added to a three neck flask containing the Lindlar catalyst (0.071 g, ca. 0.033 mmol Pd) and stirred for 3.5 hours under a hydrogen atmosphere. The solution was filtered through celite, the solvent was evaporated under vacuum and the residue was purified on silica gel with 5% ethanol in dichloromethane to give 0.065 g of (-) - 4 - ((aR) -a- ( (2R, 5R) -2,5-dimethyl-4-propyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide as a light brown solid. NMR (300 MHz, DMSO-d6) 5: 0.76-1.41 (m, 17H); 2.10-243 (m, 4H); 2. 56 (m, partially obscure by DMSO, 1H); 2.87 (m, 1H), 3.03-3.43 (m, 6H); 4.50 (s, 1H); 6.57 (d, J = 7.4 Hz, 1H); 6.91 (m, 2H); 7.07 (t, J = 7.9 Hz, 1H), 7.27 (d, J = 7.7 Hz, 2H); 7.48 (d, J = 7.7 Hz, 2H); 9. 33 (s, 1H). Mass spectrum (CI-CH4) m / z: 438 (M + 1, 5%), 282 (100%), 155 (4%). [a] 20D = -37.5 ° C (ethanol, c = 1.2). A portion of the free amine (0.05 g) was dissolved in ethanol and triturated with ethanolic hydrogen chloride at pH 4.0, followed by precipitation with dichloromethane diethyl ether to give 0.045 g of the monohydrochloride salt as a hygroscopic beige powder.

Calculated for C27H39N3O2 HCl 0.5 H2O: C, 67.13, H, 8.55; N, 8.70.

Found: C, 67.23; H, 8.55; N, 8.49. EXAMPLE 4 (-) - 4 - ((aS) -a - ((2R, 5R) -2,5-Dimethyl-4-propyl-1-pi? Erazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide dissolved (-) - 4 - ((aS) -a - ((2R, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide (0.200) g, 0.46 mmoles, Example 2) in toluene (10 mL) and stirred for 4 hours under a hydrogen atmosphere. The solution was filtered through celite to give 0.182 g of the crude product. The phenol was again protected in the following manner to provide chromatographic resolution. A mixture of the course product (0.18 g), tert-butylchlorodimethylsilane (0.93 g) and imidazole (0.079 g) in 10 mL of acetonitrile was stirred overnight at room temperature. The reaction solution was poured into 100 mL of water and extracted with two 50 mL portions of dichloromethane. The combined extracts were dried over sodium sulfate and the solvent was removed. The residue was purified on a column of silica gel with ethanol (0-4%) in dichloromethane to give 0.085 g of 4 - ((aS) -a - ((2R, 5R) -2,5-dimethyl-4- propyl-1 -piperazinyl) -3- (tert-butyldymethylsilyloxy) benzyl) -N, N-diethylbenzamide as a light brown solid. The material (0.080 g) was dissolved in acetonitrile (5 mL) and treated with tetraethylammonium fluoride dihydrate (0.040 g). After 30 minutes the solvent was removed under reduced pressure. The residue was dissolved in 1N hydrochloric acid (5 mL) and washed twice with diethyl ether. The aqueous phase was then adjusted to pH 9 with 1N sodium hydroxide solution and extracted with dichloromethane. The dichloromethane extracts were combined, dried over sodium sulfate and the solvent was removed under reduced pressure to give 0.056 g of (-) - 4 - ((aS) -a - ((2R, 5R) -2.5- dimethyl-4-propyl-1-piperazinyl) -3-hydroxy-benzyl) -N, N-methylphenylbenzamide as a light brown solid.

NMR (300 MHz, DMSO-d6) d 0.72-1.41 (m, 17.4); 1.95-2.34 (m, 4H), 2.56 (m, partially obscured by DMSO, 1H); 2.91 (m, 1H); \\ 3.02-3.48 (m, 6H); 4.47 (s, 1H); 6.56 (br s, 1H); 6.83 (m, 2H); 7.05 (m, 1H); 7.24 (d, J = 6.5 Hz, 2H); 7.46 (d, J = 6.5 Hz, 2H); 9.31 (s, 1H). Mass spectrum (CI-CH4) m / z: 438 (M + 1.12%), 282 (100%), 155 (4%). [A] 20D = -36.7 ° (ethanol, c = 1.3). The free amine (0.044 g) was dissolved in ethanol and triturated with ethanolic hydrogen chloride at pH 4.0, followed by precipitation with dichloromethane diethyl ether to give 0.031 g of the monohydrochloride salt as a hygroscopic white powder. Calculated for C27H39N3O2 HCl H2O: C, 65.90, H, 8.60; N, 8.54. Found: C, 65.72; H, 8.41; N, 8.42. EXAMPLE 5 4 - ((a4) -a - ((2S, 5R) -4-AI i-2,5-Dimethyl-1-piperazinyl) -3-h id roxybenzyl) -benzamide 3- (bromophenoxy) was dissolved -tert-butyldimethylsilane (146 g, 0.51 moles, Example 1, infra) in dry tetrahydrofuran under nitrogen and cooled to -78 ° C. A solution of 1.6 M n-butyllithium in hexane (3.18 ml, 0.51 moles) was added dropwise at a rate to keep the temperature below -70 ° C. The reaction was stirred for 30 minutes after the addition was terminated and the cold solution was transferred to another vessel containing a cold solution (-78). ° C) of 4-bromobenzaldehyde (94.3 g, 0.51 mol) in 1000 mL of tetrahydrofuran under nitrogen.The transfer rate was monitored to keep the reaction temperature below -70 ° C.

The reaction mixture was stirred for an additional 45 minutes at -78 ° C and washed with 100 mL of saturated aqueous sodium chloride. After warming to room temperature, the mixture was diluted with 2000 mL of diethyl ether and washed with 2000 mL of water followed by 500 mL of saturated sodium chloride. The ether solution was washed over sodium sulfate and the solvent was removed to give 197.2 g of crude a- (4-bromophenyl) -3- (tert-butyldimethylsilyloxy) benzyl alcohol as a yellow oil. NMR (200 MHz, CDCl 3) d 0.2 (s, 6H); 0.9 (s, 6H); 5.7 (s, 1H), 6.75 (dd, J1 = 2Hz, J2 = 8 Hz, 1H); 6.8 (br s, 1H); 6.9 (d, J = 8 Hz, 1H); 7.15 (t, J = 8 Hz, 1H); 7.25 and 7.45 (AB q, J = 8 Hz, 4H). Crude benzohydryl alcohol (53.2 g, 135 mmol) was dissolved in 1000 mL of dichloromethane and 14.7 mL (202 mmol) of thionyl chloride was added dropwise. The solution was stirred overnight at room temperature and the solvent was removed under vacuum. The crude product was dissolved in 500 mL of toluene and the solvent was again removed under vacuum to remove excess thionyl chloride, providing a- (4-bromophenyl) -3- (tert-butyldimethylsilyloxy) benzyl chloride as a dark oil. NMR (200 MHz, CDCl 3) d 0.2 (s, 6H); 1.0 (s, 9H), 6.0 (s, 1H); 6.78 (dd, J1 = 1 Hz, J2 = 8 Hz, 1H); 6.9 (m, 2H); 7.2 (t, J = 8Hz, 2H); 7.27 and 7.47 (AB q, J = 8 Hz, 4H). The crude benzohydride chloride (approximately 42 mmol) was combined with 9.55 g (84 mmol) of (+) - (2S, 5S) -2,5-dimethylpiperazine, prepared from L-Ala-L-Ala-diketopiperazine (Bachem Chemicals, Philadelphia, Pennsylvania) as described in J. Org. Chem. 50: 4909-13 (1985) and 30 mL of toluene and heated to reflux overnight under nitrogen. The toluene was removed under vacuum and the residue redissolved in diethyl ether and washed with 1.0 M sodium hydroxide followed by saturated aqueous sodium chloride. The ether solution was dried over sodium sulfate and the solvent was removed to give a dark oil. The product was purified by chromatography on silica gel (Waters Prep 500) with 0.5-0.7% ethanol in dichloromethane with 0.1% triethylamine to give 8.01 g (39%) of (2S, 5S) -1- (4-bromine α- (3- (tert-butyldimethylsilyloxy) phenyl) benzyl) -2,5-dimethylpiperazine as a 1: 1 mixture of diastereomers. The purified benzohydrylpiperazine (1.51 g, 3.1 mmol) was dissolved in 20 mL of dry tetrahydrofuran with 0.27 mL (3.2 mmol) of allyl bromide and 1.6 g (15.5 mmol) of sodium carbonate and heated to reflux overnight under nitrogen. . The cooled reaction solution was filtered and the solvent was removed to give (2S, 5S) -1-allyl-4- (4-bromo-a- (3- (tert-butyldimethylsilyloxy) phenyl) benzyl) -2.5- dimethylpiperazine as a yellow oil. NMR (200 MHz, CDCl 3) d 0.15 (s, 6H); 0.95-1.1 (m, 12H); 1.45 (m, 1H); 2.2-2.55 (m, 4H); 2.6 (m, 1H); 2.75-3.1 (m, 2H); 3.4 (m, 1H); 4.45 (s, 1H), 5.1-5.25 (m, 3H); 5.85 (m, 1H); 6.75 (d, J = 8 Hz, 1H); 6.8-6.95 (m, 2H); 7.1 (m, 1H); 7.2-7.5 (m, 4H).

The product of the above (1.40 g, 2.6 mmol) was dissolved in 10 mL of dry tetrahydrofuran and cooled to -78 ° C under nitrogen. A solution of n-butyl-lithium 1.6M in hexane (1.6 mL, 2.6 mmol) was added dropwise at a rate to maintain the temperature below -70 ° C. After the orange solution was stirred for an additional 30 minutes at low temperature, anhydrous carbon dioxide gas was introduced into the reaction solution at a rate to keep the temperature below -60 ° C. The addition of carbon dioxide was stopped when the color of the reaction solution turned a pale yellow. The reaction was allowed to warm to room temperature with stirring and the solvent was removed under vacuum. The residue was redissolved in 50 mL of toluene and the solvent was again removed under vacuum in order to remove residual n-bromobutane. The reaction yielded 1.39 g of lithium salt of 4- (aR) -a - ((2S, 5S) -4- al i 1-2,5-di meti 1-1 -piperazin il) -3-ter- butyldimethylsilyloxy) benzoic acid. The lithium benzoate salt (1.39 g, 2.8 mmol) was dissolved in dichloromethane and cooled to 0 ° C. Thioyl chloride (0.3 mL, 4.2 mmol) was added dropwise. After stirring for two hours at 0 ° C, concentrated ammonium hydroxide (6.0 mL) was added. The resulting dark yellow slurry was allowed to warm to room temperature and stirred for another hour. The reaction solution was washed with water and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography on silica gel with 1-3% methanol in dichloromethane to give 0.10 g from 4- (aR) -a - ((2S-5S) -4-al i I-2, 5-di methyl-1-piperazinyl) -3- (tert-butyldimethylsilyl-oxy) benzyl) benzamide as a resin yellow. NMR (200 MHz, CDCl 3) d 0.15 (s, 6H); 0.95 (s, 9H); 0.97 (d, J = 6 Hz, 3H); 1.05 (d, J = 6 Hz, 3H); 2.2-2.5 (m, 4H); 2.65 (m, 1H); 2.8 (m, 1H); 3.0 (m, 1H); 3.5 (m, 1H); 4.55 (s, 1H); 5.1 (d, J = 10 Hz, 1H); 5.2 (d, J = 1ß Hz, 1H); 5.85 (m, 1H); 6.1 (br s, 2H); 6.65 (d, J = 8 Hz, 1H); 6.9 (s, 1H); 6.95 (d, J = 8 Hz, 1H); 7.1 (t, J = 8 Hz, 1H); 7.55 and 7.7 (AB q, J = 8 Hz, 4H). The benzamide of the above (0.10 g, 0.20 mmol) was dissolved in 2 mL of acetonitrile with 60 mg (0.3 mmol) of tetraethylammonium fluoride hydrate and stirred for 1 hour at room temperature. After evaporation of the solvent, the residue was redissolved in dichloromethane and washed with water (pH = 8), then dried over sodium sulfate and the solvent was removed to give 90 mg of the beige solid. The monohydrochloride salt was prepared by trituration at pH 4.3 with ethanolic hydrogen chloride (approximately 0.2 M) followed by precipitation with diethyl ether to give 49 mg of 4- (aR) -a - ((2S-5R) - hydrochloride - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxy-benzyl) benzamide as a hygroscopic white powder. Calculated for C23H29N3O2 HCl 1.5 H2O: C, 62.36; H, 7.51; N, 9.49; Cl, 8.00. Found: C, 62.38; H, 7.42; N, 9.41; Cl, 8.10. Mass spectrum (CI-CH4): m / z (M + 1, 100%). EXAMPLE 6 (+) - 3 - ((aR *) - a - ((2S *, 5R *) - 4-AIl-2,5-D-methi 1-1 -piperazin-yl) -3-hydroxybenzyl) benzamide A 12-liter 3-necked round bottom flask was charged with trans-2,5-dimethylpiperazine (767 g, 6.72 mol), recrystallized from toluene at mp = 115-119 ° C and 600 mL of water. The flask was cooled in an ice bath and a solution of methanesulfonic acid (1290 g, 13.4 moles) in 600 mL of water was added slowly with stirring and cooling to maintain the temperature above 40 ° C. The solution was cooled to 20 ° C and 800 mL of ethane were added. A 400 mL addition funnel was filled with 60% aqueous potassium acetate from a 2 liter container of the solution, and potassium acetate was added to the reaction flask to adjust the pH to 4.0. the second addition funnel was charged with a solution of ethyl chloroformate (642 mL, 6.71 mol) in 360 mL of tetrahydrofuran. The solutions of ethyl chloroformate and potassium acetate were added simultaneously by dropping at a rate to maintain the reaction solution at pH 4.0 + 0.1, with cooling as necessary to maintain the temperature at 25 ° C. After the addition of ethyl chloroformate was terminated, the reaction was stirred for 1 hour with continuous addition of potassium acetate solution to maintain the pH at 4.0. The organic solvents were removed by distillation under vacuum. The remaining aqueous solution was washed with 1500 mL of ethyl acetate to remove any impurity of bis-carbamate. The ethyl acetate was extracted with two portions of 400 mL of 1M hydrochloric acid to recover the desired product. The acid extracts were combined with original aqueous solution and the pH was adjusted to 11 by the addition of 10M sodium hydroxide, with cooling to keep the temperature below 40 ° C. The aqueous solution was extracted with two portions of 1500 mL of ethyl acetate, the combined extracts were dried over magnesium sulfate and the solvent was removed to give 937 g (74%) of trans-2,5-dimethyl-1-piperazinecarboxylate. of ethyl as a yellow oil. A mixture of ethyl trans-2,5-dimethyl-1-piperazinecarboxylate (643 g, 3.45 mol), allyl bromide (328 mL, 3.80 mol) and sodium carbonate (440 g, 4.15 mol) in 2500 mL of acetonitrile it was heated to reflux for 1.5 hours. The reaction was cooled to room temperature, filtered and the solvent removed under vacuum. The residue was dissolved in 4000 mL of dichloromethane and washed with two 500 mL portions of 1M sodium hydroxide. The dichloromethane solution was dried over magnesium sulfate and the solvent was removed to give 630 g (81%) of ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate as an oil. Ethyl trans-4-allyl-2,5-dimethyl-1-piperazinecarboxylate (630 g, 2.78 moles) was added to a solution of 87% potassium hydroxide pellets (2970 g, 46 moles) in 4300 mL of 95 % ethanol and heated to reflux for 1.5 hours. The evolution of carbon dioxide was observed during the first 0.5-1 hours of heating. The reaction was cooled below the reflux temperature and 2000 mL of toluene was carefully added. The ethanol was removed by azeotropic distillation at 105 ° C, while an additional 400 mL of toluene was added to the reaction flask during the course of distillation. After recovery of 9000 mL of the distillate, the reaction was cooled to 100 ° C and 1000 mL of toluene were carefully added. The solution was slowly cooled to 5 ° C and kept at 5 ° C for 30 minutes. The solution was filtered, washing the filter cake with 1500 ml of toluene added. The filtrate was washed with 1000 mL of water, dried over magnesium sulfate and the solvent was removed to give 296 g (69%) of trasn-1-allyl-2,5-dimethylpiperazine as a dark liquid. 3- (Bromophenoxy) -tert-butyldimethylsilane (155.2 g, 0.54 mole, Example 1, infra) was dissolved in 600 mL of dry tetrahydrofuran, further dried over the molecular sieves, then transferred to a reaction flask and diluted to a 1200 mL with dry tetrahydrofuran and cooled to -78 ° C. N-Butylithium (310 mL of a 1.6M solution in hexane) was added while stirring under nitrogen, to a regime to keep the temperature below -70 ° C. Stirring was continued at -78 ° C for 45 minutes a solution of 3-bromobenzaldehyde (100.0 g, 0.54 mole) in 900 mL of dry tetrahydrofuran was added at a certain rate to keep the reaction temperature below -70 ° C. After stirring for 30 minutes at -78 ° C, the reaction was washed with 500 mL of saturated aqueous ammonium chloride and allowed to warm to room temperature. The mixture was diluted with water and diethyl ether and the ether layer was washed with brine, dried over sodium sulfate and evaporated to give 216.2 g of a yellow oil. Chromatography on silica gel with hexane: acetate ethyl (4-25%) gave 98.86 g (51%) of - (3-bromophenyl) - (3- (tert-butyldimethylsilyloxy) benzyl alcohol, NMR (CDCl3, 200 MHz) d: 0.2 (s, 6H). ), 0.95 (s, 9H), 2.3 (br s, 1H), 5.7 (s, 1H), 6.75 (d, J = (Hz, 1H), 6.8 (s, 1H), 6.9 (d, J = 8Hz , 1H), 7.2 (m, 2H), 7.3 (d, J = 8 Hz, 1H), 7.4 (d, J = 8 Hz, 1H), 7.5 (s, 1H). Thionyl chloride (27.5 mL) was added. 0.38 moles) was dripped to a benzohydryl alcohol solution of the above (98.9 g, 0.25 moles) in 500 mL of dichloromethane and the mixture was stirred overnight at room temperature.The solvent was removed under vacuum, the residue became to dissolve in toluene and the solvent was again removed under vacuum to remove excess thionyl chloride to give 154 g of a- (3-bromophenyl) -3- (tert-butyldimethylsilyloxy) benzyl chloride as a brown oil. (CDCl 3, 200 MHz) d 0.2 (s, 6H), 0.95 (s, 9H), 6.0 (s, 1H), 6.8-7.0 (m, 3H), 7.2-7.6 (m, 5H), a mixture of chloride of benzohydril of the above (103.5 g, 0.25 moles) and trans -1-allyl-2,5-dimethylpiperazine (96.9 g, 0.63 mol) in 50 mL of toluene was heated to reflux overnight. Acetonitrile (350 mL) and tetraethylammonium fluoride hydrate (75 g, 0.38 mol) were added in a cooled reaction mixture. After stirring at room temperature for 30 minutes. The solvent was removed under vacuum to give 344 g of a crude mixture of diatereomers as a dark brown oil. Chromatography on silica gel with dichloromethane: ethanol (99: 1) gave 31.15 g of a brown solid containing 95% less mobile diastereomer (RF = 0.42. on silica gel with dichloromethane: ethanol: ammonium hydroxide / 95: 5.1). crystallization from isopropanol gave 28.6 g (55% theory of a diastereomer) of (+) - 3 - ((aR *) - a - ((2R *, 5S *) - 4-allyl-2,5-dimethyl- 1-piperazinyl) -3-bromobenzyl) phenol as a white solid, mp 186-189 ° C. NMR (DMSO-d6, 200 MHz) d: 0.95 (d, J = 6 Hz, 3H); 1.03 (d, J = 6 Hz, 3H); 1.8 (dd, J1 = 6 Hz, J2 = 10 Hz, 1H); 2.1 (dd, J1 = 6 Hz, J2 = 10 Hz, 1H); 2.4-2.6 (m, 3H); 2.7 (d, J = 11 Hz, 1H); 2.8 (dd, J1 = 7 Hz, J2 = 14 Hz, 1H); 3.2 (dd, J1 = 6 Hz, J2 = 13 Hz, 1H); 4.9 (s, 1H); 5.1 (d, J = 10 Hz, 1H); 4.2 (d, J = 18 Hz, 1H); 5.7-5.9 (m, 1H); 6.6-6.8 (m, 3H); 7.0-7.4 (m, 4H); 7.55 (s, 1H); 9.35 (s, 1H). Bromobenzene was dissolved from the above (3.22 g, 7.75 mmol) in 25 mL of dimethylformamide with copper cyanide (1.39 g, 15.5 mmol) and the reaction was refluxed for 3 days. The reaction was cooled to room temperature and poured into 300 mL of 30% aqueous sodium cyanide. The mixture was extracted with 250 mL of ethyl acetate. The solvent was removed and the residue was purified by chromatography on silica gel with ethanol (0-20%) in dichloromethane to give 1.3 g (45%) of (+) - 3 - ((aR *) - a - (( 2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) benzonitrile, mp 169-171 ° C. Calculated for C 23 H 27 N 3 O: C, 76.42; H, 7.53: N, 11.62. Found: C, 76.35; H, 7.54; N, 11.62. Hydrogen peroxide (0.5 mL of 30% by weight of the solution) was added to a mixture of benzonitrile (0.50 g, 1.4 mmol), 0.7 mL of 10N sodium hydroxide and 3 mL of ethanol. The reaction was exothermic with the evolution of gas and the formation of a white precipitate. After a few minutes, the mixture was carefully heated under a reflux condenser in an oil bath at 60 ° C for three hours. After cooling to room temperature, the 6N aqueous hydrochloric acid was added to adjust the pH to 8. The mixture was evaporated to dryness under vacuum, and the residue was extracted between the ethyl acetate and the pH 8 buffer. organic was washed with pH 8 buffer solution and brine, dried over sodium sulfate and the solvent was evaporated to give 0.42 g (79%) of (+) - 3 - ((aR *) - a - ((2S * , 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) benzamide as a bright yellow solid. NMR (200 MHz, DMSO-d6) d: 0.95 (d, J = 6 Hz, 3H); 1.05 (d, J = 6 Hz, 3H); 1.9 (m, 1H); 2.1 (m, 1H); 2.5-2.8 (m, 3H); 2.9 (m, 1H); 3.1 (m, 1H), 3.3 (br m, 1H); 4.9 (s, 1H); 5.1 (d, J = 11Hz, 1H); 5.2 (d, J = 18 Hz, 1H); 5.8 (m, 1H); 6.6-6.8 (m, 3H); 7.1 (t, J = 8 Hz, 1H); 7.2-7.45 (m, 2H); 7.55 (d, J = 8 Hz, 1H); 7.65 (d, J = 8Hz, 1H); 7.9 (m, 2H), 9.3 (br m, 1H). The product was dissolved in absolute ethanol and converted to the monohydrochloride salt by trituration at pH 3 with ethanolic hydrogen chloride. The salt was precipitated with diethyl ether, and dried under vacuum to give 93 mg of a white powder. Calculated for C23H29N3O2 HCl 0.6 H2O: C, 64.73; H, 7.37; N, 9.85; Cl, 8.31. Found: C, 64.81; H, 7.26; N, 9.46; Cl, 8.09. Mass spectrum (CI-CH4) m / z: 380 (M + 1, 76%); 379 (M +, 9%); 226 (39%), 153 (100%). 1? EXAMPLE 7 N, N-Diethyl-4 - ((aR) -3-hydroxy-a - ((2R, 5R) -2,5-Dimethyl-1-piperazinyl) benzyl) benzamide Thionyl chloride (2.9 mL; 40.2 mmole) to a solution of 4- (3- (tert-butyldimethylsilyloxy) -a-hydroxybenzyl) -N, N-diethylbenzamide (11.0 g, 26.8 mmol, Example 1, infra) in 150 mL of dichloromethane. After stirring for one hour at room temperature, the solvent was removed under vacuum. The residue was dissolved in toluene and the solution was evaporated under vacuum again to remove excess thionyl chloride, repeated once more. The crude product was dissolved in toluene (50 mL) and (2R, 5R) -2,5-dimethylpiperazine, prepared from D-Ala-D-Ala-diketopiperazine (Bachem Chemicals, Philadelphia, Pennsylvania) as described in J. Org. . Chem. 50: 4909-13, (1985), were added. The mixture was refluxed overnight under nitrogen. The solvent was removed under vacuum and the residue was redissolved in ethyl acetate and washed with 1.0 m of 1.0M sodium hydroxide. the organic layer was dried over sodium sulfate and the solvent was removed to give a dark oil. The course product was dissolved in 100 mL of acetonitrile, tetraethyl ammonium fluoride hydrate (8.07 g, 39.6 mmol) were added and the mixture was stirred at room temperature for 30 minutes. The solvent was removed under vacuum. The residue was dissolved in 100 mL of 1N hydrochloric acid and 200 mL of diethyl ether. The aqueous layer was adjusted to pH 8 with 5M sodium hydroxide and extracted with dichloromethane (two portions of 300 mL). The phase of Dichloromethane was dried over sodium sulfate and evaporated to dryness to give 8.03 g of a brown solid. Recrystallization from ethanol-hexane gave 1.37 g of N, N-diethyl-4 - ((aR) -3-hydroxy-a - ((2R-5R) -4-allyl-2,5-dimethyl-1-piperazinyl) benzyl) benzamide (26% theory giving one diastereomer). NMR (200 MHz, CDCl 3) d: 0.95 (d, J = 6Hz, 3H); 1.05 (d, J = 6Hz, 3H); 1.0-1.3 (br m, 6H); 2.1 (t, J = 11 Hz, 1H); 2.65 (dd, J1 = 3 Hz, J2 = 11 Hz, 1H); 2.75 (d, J = 13 Hz, 1H); 3.0-3.4 (br m, 5H), 3.5 (br m, 2H); 4.5 (s, 1H); 6.65 (d, J = 8 Hz, 1H); 6.8 (d, J = 8 Hz 1H); 6.9 (s, 1H); 7.1 (t, J = 8 Hz, 1H); 7.3 (d, J = 8 Hz, 2H); 7.5 (d, J = 8 Hz, 2H). Mass spectrum (CI-CH4) m / z 395 (M, 26%); 282 (100%); 113 (21%). Calculated for C24H33N3O2 0.5 H2O: C, 71.26; H, 8.47; N, 10.39. Found: C, 71.32; H, 8.46; N, 10.18. EXAMPLE 8 4 - ((aR) -a - ((2S, 5S) -4-Allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N-ethyl-N-methyl I-benzamide Chloride was added Thionyl (26 mL, 0.36 mol) was added dropwise to a solution of 4-carboxylbenzaldehyde (50.0 g, 0.33 mol) in 2000 mL of dichloromethane: N, N-dimethylformamide (4: 1 mixture). The mixture was stirred overnight at room temperature. Ethylmethylamine (75.0 g, 1.3 moles) was added dropwise and stirring was continued at room temperature for 90 minutes. The solvent was removed under vacuum, the residue was dissolved in 500 mL of 0.1M sodium hydroxide and extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and evaporated under vacuum give 23.8 g (38%) of N-ethyl-4-formyl-N-methylbenzamide as a yellow oil. NMR (300 MHz, CDCl 3) d: 1.1 (m 3 H); 1.2 (m, 3H), 3.2 (m, 2H); 3.5 (m, 2H); 7.5 (d, J = 8 Hz, 2H); 7.9 (d, J = 8 Hz, 2H); 10.0 (s, 1H). N-ethyl-4-formyl-N-methylbenzamide (23.8 g, 0. 12 moles) with 3- (bromophenoxy) -tert-butyldimethylsilane and n-butyllithium as described in Example 5 to give 19.6 g (40%) of 4- (3- (tert-butyldimethylsilyloxy) - a- hydroxybenzyl) -N-ethyl-N-methylbenzamide as a colorless oil. NMR (200 MHz, CDCl3) d: 0.1 (s, 6H); 0.95 (s, 9H); 1.1 (m, 3H); 2.9 and 3.0 (s, 3H); 3.05 (d, J = 3 Hz, 1H); 3.3 (m, 1H); 6.95 (d, J = 8 Hz, 1H); 7.1 (t, J = 8 Hz, 1H); 7.25 (AB quartet, J = 8 Hz, 4H). The benzohydryl alcohol (19.5 g, 0.049 mol) was treated with thionyl chloride and (2S, 5S) -2,5-dimethylpiperazine as described in Example 7 to give 8.13 g (34% 9 of a mixture of 1: 1 of 4 - ((aR) -a - ((2S-5S) -2,5-dimeti 1-1 -piperazin-yl) -3-hydroxybenzyl) -N-ethyl-N-methylbenzamide and 4 - ((aS) -a - ((2S-5S) -2, 5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N-ethyl-N-methylbenzamide as an off-white solid. After chromatography on silica gel (Waters Prep 500) with dichloromethane: ethanol: triethylamine (100: 0.5: 0.1), 0.95 g of 4 - ((aR) -a - ((2S-5S) -2.5- dimethyl-1-piperazinyl) -3-h id roxybenzyl) -N-ethi I- N-methylbenzamide, the least mobile diastereomer was obtained. The product (0.77 g, 1.55 mmol) was treated with allyl bromide (0.14 mL, 1.6 mmol) as described in Example 5 to give 0.71 g of a light beige solid which was dissolved in 25 mL of acetonitrile and treated with tetraethylammonium fluoride hydrate (0.40 g) at room temperature for 30 minutes. The solvent was evaporated under vacuum and the residue was dissolved in diethyl ether and 1N aqueous hydrochloric acid. The aqueous layer was adjusted to pH 8 with 10N sodium hydroxide and extracted with dichloromethane, dried over sodium sulfate and evaporated under vacuum to give 0.51 g of 4 - ((aR) - - ((2S-5S) - 4-allyl-2,5-di methyl-1-piperazinyl) -3-h idroxybenzyl) -N-ethyl-N-methylbenzamide as a white solid. NMR (200 MHz, CDC | 3) d: 0.95 (d, J = 6 Hz, 6H); 1.2 (br m, 3H); 2.1-2.5 (m, 4H); 2.6 (m, 1H); 2.7-2.95 (m, 2H); 3.25 (br m, 1H); 3.4 (m, 1H); 3.55 (br m, 1H), 4.45 (s, 1H); 5.1-5.2 (m, 2H); 5.8 (m, 1H), 6.6 (d, J = 8 Hz, 1H); 6.9 (d, J = 8 Hz, 1H); 6.95 (s, 1H); 7.05 (t, J = 8 Hz, 1H); 7.25 (d, J = 8 Hz, 2H); 7.35 (d, J = 8 Hz, 2H). The conversion to the monochlorhydrate salt is as described in Example 6 to give 0.42 g of a white solid. Calculated for C26H35N3O2 HCl 0.75 H2O: C, 66.22, H, 8.02; Cl, 7.52; N, 8.91. found: C, 65.96; H, 8.02; Cl, 7.54; N, 8.92 [] 20D = + 9.8 ° C (absolute ethanol, c = 1.5). Mass spectrum (CI-CH4) m / z: 422 (M + 1, 53%), 268 (25%); 153 (100%). EXAMPLE 9 3 - ((aR) -a - ((2S, 5S) -4-Allyl-2,5-dimethyl-1-piperazinyl) -benzyl) phenol and 3 - ((aS) -a - (( 2S, 5S) -4-Allyl-2,5-dimeti 1-1 -piperazinyl) benzyl) folol A solution of (2S, 5S) -1-allyl-4- (4-bromo-a- (3- tert-butyldimethyl-silyloxy) phenyl) -benzyl) -2,5-dimethylpiperazine (0.37 g, 0.7 mmol), Example 5 Infra) in 50 mL of dry tetrahydrofuran was cooled to -78 ° C. N-Butyllithium (0.44 mL of a 1.6M solution in hexanes) was added dropwise. After stirring at -78 ° C for 10 minutes, saturated aqueous ammonium chloride (10 mL) was added. The mixture was warmed to room temperature and diluted with diethyl ether and water. The ether layer was dried over sodium sulfate and evaporated to give a light yellow oil, which was purified by preparative tin layer chromatography to give 0.23 g of a yellow glass. The product was dissolved in acetonitrile and treated with tetraethylammonium fluoride hydrate for 30 minutes. The solvent was evaporated under vacuum and the residue was dissolved in 1N hydrochloric acid and extracted with diethyl ether. The aqueous layer was adjusted to pH 8 with aqueous sodium hydroxide, extracted with dichloromethane, the organic layer was dried over sodium sulfate and the solvent was removed to give 0.16 g of an isomeric mixture of 1: 1 of 3 - (( aR) -a - ((2S-5S) -4-allyl-2,5-dimethyl-1-piperazinyl) benz l) -f enol and 3 - ((aS) -a - ((2S-5S) -4 -alyl-2,5-dimethyl-1-piperazinyl) benzyl) -phenol as a yellow oil. NMR (200 MHz, CDCl 3) d 0.9-1.2 (m, 6H), 2.2-2.8 (m, 5H); 2.8-3.2 (m, 2H), 3.4 (m, 1H); 4.5 (s, 0.5H), 4.6 (s, 0.5 H); 5.1-5.25 (m, 2H); 5.8 (M, 1H); 6.6 (d, J = 8 Hz, 1H), 6.7-7.5 (m, 8H): a portion of the product (40 mg) was dissolved in absolute ethanol and triturated at pH 4 with ethanolic hydrogen chloride. Diethyl ether was added to precipitate the monohydrochloride salt as a white solid. After drying under vacuum at 65 ° C overnight, 25 mg of 7 * 6 salt. Calculated for C22H28N2O HCl 0.75 H2O: C, 68.12; H, 7.58; N, 7.16. Found: C, 68.38; H, 7.95; N, 7.25. EXAMPLE 10 (+) - N, N-Diethyl-4 - ((aR *) - 3-hydroxy-a - ((2R *, 5S *) - 2,4,5-trimethyl-1-piperazinyl) benzyl) - benzamide. 4- (3- (tert-Butyldymethylsilyloxy) -a-hydroxybenzyl) -N, N-diethylbenzamide (Example 1, infra) was treated with thionyl chloride and trans-2,5-dimethylpiperazine as described in Example 5 The crude mixture of diastereomers was purified by chromatography on silica gel (Waters Prep 500) with dichloromethane: ethanol: triethylamine (100: 0.25: 0.1). The less mobile isomer (1.28 g, 2.5 mmol) was dissolved in acetonitrile and treated with tetraethylammonium fluoride hydrate (0.6 g, 4.0 mmol) as in Example 7 to give (+) - N, N-diethyl-4- (R *) - 3-hydroxy-a - ((2R *, 5S *) - 2,5-dimethyl-1-piperazinyl) benzyl) benzamide as a white solid, mp 175-177 ° C. NMR (300 MHz, DMSO-d6) d: 0.85 (d, J = Hz, 3H); 1.1-1.2 (m, 9H); 1.45 (m, 1H); 2.2 (m, 2H); 2.5 (m, 1H); 2.6 (m, 1H); 2.8 (m, 2H); 32-3.6 (m, 4H); 5.25 (s, 1H); 6.6 (d, J = 8 Hz, 1H); 6.75 (d, J = 8 Hz, 1H); 6.8 (s, 1H); 7.1 (t, J = 8 Hz, 1H); 7.25 (d, J = 8 Hz, 2H); 7.4 (d, J = 8 Hz, 2H); 9.25 (s, 1H): A mixture of the product (0.31 g, 0.78 mmol) 96% formic acid (0.12 mL, 3.1 mmol) and 37% aqueous formaldehyde (0.06 mL, 2.3 mmol) was heated in an oil bath at 80 ° C overnight. The cooled reaction mixture was dissolved in 3 mL of 6N hydrochloric acid and extracted with diethyl ether. The aqueous layer is adjusted to pH 8 with 10N sodium hydroxide and extracted with dichloromethane. The organic layer was dried over sodium sulfate and evaporated to give a brown oil. The crude product was purified by preparative thin layer chromatography with dichloromethane: ethanol: ammonium hydroxide (95: 5: 1) to give 0.160 g of a yellow oil. Crystallization from ethyl acetate gave 0.105 g of (+) - N, N-diethyl-4 - ((aR *) - a - ((2R *, 5S *) - 2,4,5-trimethyl-1-piperazinyl benzyl) benzamide as a white solid, mp 220-221 ° C. NMR (200 MHz, CDCl 3) d: 0.9 (d, J = 6 Hz, 3H); 1.15 (d, J = 6 Hz, 3H); 1.2 (br m, 6H); 1.85 (m, 1H); 2.0-2.3 (m, 2H), 2.2 (s, 3H); 2.5-2.8 (m, 3H); 3.3 (br m, 2H); 3.6 (br m, 2H); 5.25 (s, 1H); 6.6 (d, J = 8 Hz, 1H); 6.8 (d, J = 8 Hz, 1H); 6.85 (s, 1H); 7.05 (t, J = 8 Hz, 1H); 7.15 (d, J = 8 Hz, 2H); 7.35 (d, J = 8Hz, 2H). Mass spectrum (CI-CH4) m / z 4101 (M + 1). Calculated for C 25 H 35 N 2 O 2: C, 73.31; H, 8.61; N, 10.26. Found: C, 73.11; H, 8.65; N, 10.25. EXAMPLE 11 (+) -4 - ((aS) -a - ((2R, 5R) -4-AMI-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide The process described in Example 1, (2S, 5S) -2,5-dimethylpiperazine was continued to give 4 - ((aS) -a - ((2S-5S) -4-allyl-2,5-di methyl-1-piperazin i I) - 3- (tert-bu ti Id i methylsilyloxy) benz l) -N, N-diethylbenzamide (1.51 g). Chromatography on silica gel with diclomethane: ethanol (1-2%) gave 0.27 g (27% in theory for a diastereomer) of the less mobile isomer. Treatment with tetraethylammonium fluoride in acetonitrile as in Example 1, gave 0.18 g (85%) of (+) - 4 - ((aS) - - ((2S-5S) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide as a white solid. NMR (200 MHz, DMSO-d6) d 0.85 (d, J = 6 Hz, 3H), 0.95 (d, J = 6 Hz, 3H); 1.1 (br m, 6H); 2.1-2.6 (m, 5H), 2.6-2.95 (m, 2H), 3.0-3.5 (br m, 5H); 4.5 (s, 1H); 5.1 (d, J = 8 Hz, 1H); 5.2 (d, J = 14 Hz, 1H); 5.85 (m, 1H); 6.8 (d, J = 8 Hz, 1H); 6.9 (m, 2H); 7.1 (t, J = 8 Hz, 1H); 7.25 (d, J = 8 Hz, 2H); 7.5 (d, J = 8 Hz, 2H); 9.25 (s, 1H). Mass spectrum (Cl) m / z: 436 (M + 1.74%); 282 (100%); 153 (7%). [a] 20D = + 21.6 ° (absolute ethanol, c = 1.1). The monohydrochloride salt was prepared as in Example 1 to give 0.148 g of a white powder. Calculated for C27H37N3O2 HCl H2O: C, 66.17; H, 8.24; N, 8.57; Cl, 7.23. Found: C, 66.36; H, 8.16; N, 8.66; Cl, 7.33. The mobile isomer of the chromatography was also isolated (0.22 g, 22% theoretically for a diastereomer) and treated with tetraethylammonium fluoride to give 0.090 g (53%) of (+) - 4 - ((aR) -a- ((2S-5S) -4-al-I-2, 5-di-methyl-1-piperazin-yl) -3-hydroxy-benzyl) -N, N-di-I-benzamide as a white solid. NMR (200 MHz, DMSO-d6) d: 0.86 (d, J = 6 Hz, 3H); 0.95 (d, J = 6 Hz, 3H); 1.1 (br m, 6H); 2.1-2.5 (m, 5H); 2.8 (m, 1H); 3.0 (m, 1H); 3.05-3.5 (br m, 5H); 4.5 (s, 1H); 5.1 (d, J = 10 Hz, 1H); 5.2 (d, J = 15 Hz, 1H); 5.8 (m, 1H); 6.6 (d, J = 8 Hz, 1H); 6.85 (s, 1H); 6.9 (d, J = 8 Hz, 1H); 7.1 (t, J = 8 Hz, 1H); 7.3 (d, J = 8 Hz, 2H); 7.5 (d, J = 8 Hz, 2H); 9.25 (s, 1H). Mass spectrum (Cl) m / z: 436 (M + 1, 3.7%), 282 (100%); 153 (3%). [a] 20D = + 28.7 ° (absolute ethanol, c = 2.3).

The monohydrochloride salt was prepared as in Example 1 to give 0.061 g of a white powder. Calculated for C27H37N3O2 HCl 0.75 H2O: C, 66.78; H, 8.20; N, 8.65; Cl, 7.30. Found: C, 66.55; H, 8.07; N, 8.63; Cl, 7.35. EXAMPLE 12 Delta In Vitro Opioid Receptor Activity The selected compounds of the present invention, identified below with reference to the opening synthesis examples thereof, were evaluated for delta opioid receptor affinity in vitro in brain membranes of rats (Delta Receiver IC50). The analysis procedures used for such determinations of delta receptor activity are mentioned below. In vitro bioassays: the vast difference was removed from mice and suspended between platinum electrodes with 0.5 g of tension in the bath chambers of organs containing a modified Krebs buffer of the following composition (millimolar): NaCl, 118; KCI, 4.75; CaCl2, 2.6; KH2PO4, 1.20; NaHCO, 24.5; and glucose, 11. The buffer solution was saturated with 95% O2 / 5% CO2 and maintained at 37 ° C. The tissues were stimulated at a maximum voltage with pulse succession of 10 Hz for 400 msec. The succession interval is 10 seconds; The duration of the impulse is 0.5 msec. Percent inhibition of electrically induced masculine concentrations was determined for the compounds by varying to cumulative concentrations. The values of ED5o are they extrapolated from the curves showing the dose concentration against the response (Lord, et al., Nature 267, 495, (1977)). Inhibition of receptor binding: rat brain membrane (Sprague-Dawley) was prepared and binding analyzes were carried out at 24 ° C for 90 minutes as described by Chang, et al., (J. Biol. Chem. .254, 2610 (19789) and Mol.Pharmacol., 16, 91 (1979)) with a filtration method (filtered (GF / C) .The delta receptor binding assays were carried out with (3H) - (+ ) -4 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide (0.1 nM) , having an activity of -48 Ci / mmoles, or with 3H- [D-Pen2, D-Pen5- (enkephalin)] (3H-DPDPE, 0.1 nM) having an activity of -59 Ci / mmoles). The non-specific binding was determined in the presence of 1 mM of the unlabeled ligand. The potency of the compounds in inhibiting the binding of (3H) - (+) - 4 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1 -piperazinyl) -3-hydroxy-benzyl) -N, N-diethylbenzamide or 3H-DPDPE was determined as the concentration that reduces the binding of the labeled compounds by 50 percent (IC50 of the Delta Receptor). The following compounds of the invention were also tested. Compound 12: 3 - ((aR) -4- (piperidinocarbonyl) - - ((2S, 5S) -2,4,5-trimethyl-piperazinyl) benzyl) phenol Compound 13: 3 - ((R) -4- (1-pyrrolidin i Icarbon I) -a - ((2S, 5S) -2,4,5-trimethyl-piperazinyl) benzyl) phenol Compound 14: (+) N, N-Diethyl-4- (3-hydroxy- (aS) -a - ((2S, 5S) -2,4,5-trimethyl-piperazinyl) benzyl) -benzamide Compound 15: N, N-diethyl-4- ( 3-hydroxy- (aR) -4- (2R, 54) -2,4,5-trimethyl-piperazinyl) benzyl) benzamide (see, for example, Publication International WO 93/15062, of Example 13 for the synthesis of the compound) Compound 16: N, N-diethyl-4- (3-hydroxy- (aR) -4 - ((2S, 5S) -2,4,5- trimethyl-piperazinyl) benzyl) -N-methyl-benzamide Compound 17: c / s-4- (a- (4 - ((Z) -2-butenyl) -3,5-dimeti 1-1 -piperazin ) -3-h-hydroxybenzyl) -N, N-diethyl-benzamide (see, for example, WO International Application 93/15062, Example 11 for the synthesis of this compound). Compound 18: (+) - 3 - ((aR *) - a - ((2R *, 5S *) - 4-al i-2,5-d-methyl-1-piperazin-il) -4- (methylsulfon L) benzyl) -phenol (see, for example, Publication International WO 93/15062, Example 55 for the synthesis of this compound). Compound 19: (+) - 4 - ((aR *) - a - ((2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-dimethylbenzenesulfonamide (see, for example, International Publication WO 93/15062, Example 56 for the synthesis of this compound). Compound 20: (+) - 3 - ((aR *) - a - ((2R *, 5S *) - 4-alI-2,5-dimethyl-1-piperazinyl) -benzyl) phenol (see, for example, International Publication WO 93/15062, Example for the synthesis of this compound). Compound 21: (+) - 4 - ((aR *) - a - ((2S *, 54 *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) benzamide (see , for example, International Publication WO 93/15062, Example 4 for the synthesis of this compound). Compound 22: (±) -4 - ((aR *) - a - ((2R *, 5S *) - 2,5-Dimeti 1-1 -piperazin-yl) -3-hydroxy-benzyl) -N, N-diethylbenzamide (see, for example, WO International Publication 93/15062, Example 15 for the synthesis of this compound). Compound 23: (+) - cis-4- (a- (4-Allyl-3,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide Compound 24: cis-4- ( a- (3,5-Dimethyl-4- (methylallyl) -1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide The results are shown in Table A below, with the compounds described in Examples 1-11 being listed as Compounds 1-11, respectively.

Table A Delta In Vitro Opioid Receptor Activity of the Compounds of the Invention Delta Receptor Ductable Conduit Compound ICso (nM) DE50 (nM) 1 2a 43 2, 1a 3 4 > 1,000 5 1.6 260 6 4.0 25 7 1.1 560 8 0.86 30 9 1.5 450 10 1.1 90 11 12 1.2 250 13 0.8 200 15 2 pA2 = 7., 1b 15 2.8 pA2 = 7., 0b 16 3.1 pA2 = 7., 2b 17 1.5 pA2 = 8. .2 ° 18 1.3 250 19 2.6 37 20 1.3 78 21 1.6 44 22 0.7 4400 23 3.3 42 24 2.8 20 a Compounds 1 and 2 were analyzed against (3H) - (+) - 4 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N- Diethylbenzamide. Compounds 5.24 were analyzed against 3H- [D-Pen2, D-Pen5] - (enkephalin). b '° Antagonist potency (pA2 value) was determined by Schild analysis, according to Arunlakshana et al., Brit. J. Pharmacol. 14: 48-58 (1979), of the blockade data of the inhibitory effect of [D-Ala2, D-Leu5] enkephalin (b) or (+) - 4 - ((aR *) - a - ((2S * , 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide (c) in electrically stimulated muscle contraction in the vas deferens of mice. EXAMPLE 13 Effects of the Compounds of Example 1 and Example 2 on Analgesia and Respiratory Depression Induced by Alfentanil in Rats Analgesia was analyzed in rats using the tail puncture test with simultaneous monitoring of capillary blood gases (pCO2 and pO2) using an electrode transcutaneous Male Sprague Dawley rats (groups of six animals) were anesthetized with 25 isofuran (J. A. Webster, Inc. Sterling, Massachusetts) and a cannula was implanted into the right external jugular vein. A small skin patch was animal razor and a fixation ring was attached using VetBond adhesive (3M Corp, Minneapolis, Minnesota). The transcutaneous electrode of a blood gas monitor system of TCM3 TINATM (Radiometer-Copenhagen, Copenhagen, Denmark) was attached to the fixation ring and the rats were left to recover the anesthetic for 1 hour. The analgesic alfentanil of opoid mu (Janssen Pharmaceuticals, Inc., Titusville, New Jersey) was administered by continuous infusion via cannula i.v. at a dose of 6 μg / kg. / min. with concurrent administration of delta opioid test compounds. Analgesia was analyzed before and during dosing using the tail puncture test. An artery forceps was placed in the tail at 2.54 cm from the tail from the tip a maximum of 20 seconds. Rats were observed for nociceptive responses of vocal or painful body movements. The time elapsed to give a pain response was recorded as the latency of the tail puncture in seconds. The blood gases were continuously monitored through the test session. After 15 minutes of infusion, the dose of alfentanil of 6 μg / kg. / min. produced from a maximum analgesic effect was indicated by a tail puncture latency of 20 seconds. Respiratory depression was measured at an average 30% increase in pCO2 level (before preinfusion of the baseline). The concurrent infusion of the compound of Example 1 at a dose of 60 μg / kg. / min partially inverse of respiratory depression at a pCO2 level of 22% from the previous baseline. Increasing the dose of the compound of Example 1 to 120 μg / kg. / min produced from an additional improvement in respiratory depression at 17% of the baseline. The puncture latency of the remaining glue was not affected by the treatment with the compound of Example 1. When the compound of Example 2 was fused at a dose of 60 μg / kg. / min concurrently with alfentanil (6 μg / kg. / min) and the compound of Example 1 (60 μg / kg. / min), the effects of the compound of Example 1 were blocked and the respiratory depression was increased to a pCO2 level of 33% of the previous baseline. The remaining analgesic was not affected, with the latency of the tail puncture continuing a maximum of 20 seconds. In separate experiments, administration of the compound of Example 1 alone or the compound of Example 2 only produced without analgesic effect and without effect on blood levels of pCO2. EXAMPLE 14 A series of experiments were carried out to determine the effects of delta agonists on respiratory depression and the analgesic induced by i.v. infusions. of encourages or fentanyl, mu agonists very powerful. Two different methods were used to measure the effects of respiratory depression. The first method analyzed the blood gases of rats for pCO2 levels. The blood samples from rats were tightened and analyzed for the CO2 content following an i.v. infusion. continuous of encouragement (6 mg / min.) and an injection of i.v. of several doses of selective delta agonists, BW373U86: (+) - 4 - ((aR) -a - ((2S-5R) -4-allyl-2,5-d i methyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide. As an indication of respiratory depression, it was observed that blood levels of CO2 increase as a result of the administration of alfenta. The key in the experiment, however, was the reduced dose of BW373U86 depending on the level of pCO2 observed in the next alfenta infusion. The results are described in Figure 1. Figure 1 shows the effect of the positive isomer of the delta agonist BW373U86 on analgesia and respiratory depression induced by the mu agonist, alfenta. Blocks (+) 373U86 of respiratory depression, but not alfenta-induced analgesia. The negative isomer of 373U86 has no significant effect on alfenta-induced respiratory depression (data not shown).

All doses of BW373U86 were plotted in the analgesia paragraph, however, some points can not be observed because the symbols were translatable. Analgesia was also evaluated with a tail puncture method ("PC"). More importantly, BW373U86 does not significantly affect the analgesia produced by alfenta (Figure 1, lower panel). Global data indicate that BW373U86, or other delta agonists, are clinically useful intraoperatively, post-operatively and chronically to attenuate respiratory depression and maintain the analgesic effects of mu opioid receptor analgesics. A second method was used to quantify the effects of respiratory depression in subsequent studies. These studies used a non-invasive monitoring system for transcutaneous pO2 / pCO2 (Radiometer Copenhagen). The systemic monitors the levels of O2 and CO2 through an electrode that adheres to the surface of the outer skin. These systems are commonly used in infants in hospitals of critical core centers and are adapted to be used with rats for current studies. The rats were implanted with a catheter in the right external jugular vein under 2% isofuran anesthesia. The subjects were allowed to recover for 1 hour and then placed in remaining plastic cages. The tests started after baseline measurements of pCO2 and pO2 were obtained over a period of 15 minutes.

Both fentanyl (an analgesic agent of the strong mu receptor) and 3290W93 (a compound with the mixture of receptor activity delta and mu), whose chemical structure is as follows.

It was found to produce high levels of analgesia. The results are described in Figure 2. Figure 2 shows the analgesics and comparative respiratory depression effects of 3290W93 and fentanyl in rats. Effects were plotted at 4 (upper panel) and 8 (lower panel) minutes of time, the points at which peak effects were observed after drug administration. A greater separation between the analgesic and respiratory depression effects occurs after the administration of 3290W93 that was observed after the administration of fentanyl.

However, while fentanyl produced high levels of respiratory depression, 3290W93 did not substantially increase respiratory depression except at high doses. The ED50 values in fentanyl and 3290W93 rats to produce analgesia were 0.0031 and 0.08 mg / kg. (i.v.), respectively. The ED50 values for fentanyl and 3290W93 to produce respiratory depression are 0.014 and 2.0 mg / kg. (i.v.), respectively. The therapeutic relationship (respiratory depression of ED50 divided by the ED50 analgesia) for fentanyl and 3290W93 are 4.5 and 25, respectively. These data indicate that the 3290W93 mixture of delta agonist / mu has a greater than five-fold separation between the analgesic and respiratory depression effects that are not affected by fentanyl. As shown in Figures 1 and 2, a delta receptor agonist may be selectively blocked effects produced by the alfenta and fentanyl agonists of the mu opioid receptor. Usually, mu agonists produce a substantially beneficial effect of analgesia and many adverse side effects, such as respiratory depression, nausea, addiction and dependence. The ability to use delta receptor compounds to block side effects in such a way that mu agonists allow physicians to increase the administration of analgesics because they reduce respiratory depression. Patients with less experience after an operation and require less postoperative care by hospital staff. The global lifestyle of patients taking mu opioids can improve significantly with the concurrent use of delta receptor compounds. In addition to the delta agonist compounds specifically described above, the compounds described in International Patent Applications WO 96/36620 and WO97 / 10230 are advantageously employed in the broad practice of the present invention to antagonistically modulate the effects of respiratory depression incident on the use of morphine, fentanyl and other analgesics, aesthetics and barbiturates, as well as any other therapeutic agent of the opioid receptor that mediates respiratory depression as an effect of its physiological activity. Industrial Applicability The present invention provides pharmaceutically active agents useful for the treatment or prevention of respiratory depression so that they can be experienced by a patient with a side effect of common drug compositions such as anesthetics, analgesics, barbiturates and other medications that mediate depression. respiratory The pharmaceutically active agents of the invention can be co-administered with drugs having said side effects of respiratory depression, to improve or suppress the respiratory effect. The therapeutic agent of the invention therefore have utility in co-administration with drugs such as morphine and fentanyl.

Claims (64)

1. CLAIMS 1. A method for reducing, treating or preventing drug-mediated respiratory depression in an animal, incident to the administration to said animal of a drug mediated by respiratory depression, which comprises administering to an animal receiving said drug an effective amount of a delta receptor agonist compound.
2. 2. The method according to claim 1, wherein the delta agonist also exhibits mu receptor agonist character.
3. 3. The method according to claim 1, wherein the delta receptor agonist is administered with a mu receptor agonist compound separately.
4. The method according to claim 1, wherein the delta agonist is selected from the group consisting of (-) - 4 - ((aR) -a - ((2S-5R) -4-allyl-2,5 -dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide; (+) - 4 - ((aR *) - a - ((2 R * -5S *) - 4-al l-2,5-di methyl-1-piperazinyl) -3-h idroxy benzyl) - N, Nd i meti I benzenesulfonamide; 4 - ((aR) - - ((2R-5S) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-h id roxybenzyl) -N, N-dimethyl benzene its I fonamide; 4 - ((aS) -a - ((2S-5R) -4-al-l-2,5-d i methyl-1-piperazin i l) -3-hydroxybenzyl) -N, N-dimethylbenzenesulfonamide, deltorphine I; deltorphine II; and [D-Pen2-D-Pen5] -encef aliña.
5. 5. A method according to claim 1, wherein the delta agonist comprises a compound of the formula: wherein, Ri and R2, which may be the same or different, are each hydrogen, linear or branched C6-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C-β cycloalkylalkyl, alkenyl C3-6, C3-5 alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or can together form a C3-7 alkyl ring that can be interrupted by oxygen. R3 and R, which may be the same or different, are each hydrogen, linear or branched C6-6 alkyl, or R is the formation of oxygen formed with the carbon atom to which a C = O group is attached; R5 is hydrogen, hydroxy, C1-3 alkoxy, thiol or alkylthio; R6 is phenyl, halogen, NH2 or a group for or meta -C (Z) -R8, in which Z is oxygen or sulfur; R8 is C2-8 alkyl, C?-8 alkoxy or NR9R10, wherein R9 and Rio, which may be the same or different, are hydrogen, linear or branched C6-6 alkyl, C3-7 cycloalkyl, cycloalkylalkyl of C4-6, C3-6 alkenyl, C3-6 alkenyl, aryl or aralkyl, R 11 or R6 is a group for or metal of -N-C (Z) -R? 2 wherein Rn and R12 which may be the same or different are hydrogen, straight or branched C1-16 alkyl, C3-7 cycloalkyl, C6 cycloalkylalkyl, C3-6 alkenyl, aryl, aralkyl or a herocyclic ring optionally substituted and Z is as defined above; and, R7 is hydrogen, straight or branched C? -8 alkyl or halogen.
6. 6. A method according to claim 1, wherein the delta agonist comprises a compound of the formula: in which, Ri and R2, which may be the same or different, are each hydrogen, linear or branched C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, alkynyl of C3-5, aryl, aralkyl or furan-2 or 3-alkyl or can together form a C3-7 alkyl ring which can be interrupted by oxygen; R3 and R4, which may be the same or different, are each hydrogen, linear or branched C? -6 alkyl; R5 is, hydroxy, C3-alkoxy, thiol or alkylthio; R6 is a group -C (Z) -Rg, in which Z is oxygen or sulfur, R8 is C? -8 alkyl, C? -8 alkoxy or NR9R10, wherein R9 and Rio, which may be the same or different, are hydrogen, straight or branched C? -6 alkyl, C3-7 cycloalkyl, C -6 cycloalkylalkyl, C3-6 alkenyl, aryl or aralkyl, or R6 is a group -N-C (Z) -R? 2 wherein R-n and R? 2 have the same meaning as R9 and R or together form an optionally substituted heterocyclic ring and z e as defined above and, R7 is hydrogen, straight or branched C? -8 alkyl or halogen.
7. 7. A method for reducing, treating, or avoiding drug-mediated respiratory depression in an animal, which comprises administering to an animal an effective amount of a compound of the formula: wherein Ar is a 5- or 6-membered carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur and having a first carbon atom thereof, a Y substituent and a second carbon ring thereof and a substituent R1, 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; haloalkyl of d-C6; d-C6 alkoxy; C3-C6 cycloalkoxy; sulphides of the formula SR8 wherein R8 is d-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryalkyl having an aryl portion of Ce-Cio and an alkyl portion of d -C6, or aryl of C5-C? 0; sulfoxides of the formula SOR8 wherein R8 is the same as described above; sulfones of the formula SO 2 R 8 wherein R 8 is the same as described above; nitrile; acyl of d-C6; alkoxycarbonylamino (carbamoyl) of the formula NHCO2R8 wherein R8 is the same as described above; carboxylic acid, or an ester, amide or salt thereof; aminomethyl of the formula CH2NR9R10 wherein R9 and R10 may be the same or different, or may be hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 hydroxyalkyl, C2-C6 methoxyalkyl , C3-C6 cycloalkyl or C5-C10 aryl, or R9 and R10 together can form a ring of 5 or 6 atoms, the ring atoms selected from the group consisting of N and C; carboxyamides of the formula CORN9R10 wherein R9 and R10 are the same as described above, or conjugates of C2-C3o peptides of the same; and sulfonamides of the formula SO 2 NR 9 R 10 wherein R 9 and R 10 are the same as described above; Z is selected from the group consisting of: hydroxyl, and esters thereof; hydroxymethyl, and esters thereof; and amino and carboxyamides and sulfonamides thereof; G is carbon or nitrogen; R1 is hydrogen, halogen or C? -C alkyl, C2-C alkenyl, C? -C4 alkynyl; R 2 is hydrogen, halogen or C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkynyl; R3, R4 and R5 may be the same or different and are independently selected from hydrogen and methyl and wherein at least one of R3, R4 or R5 are not hydrogen, subject to the proviso that the total number of methyl groups does not exceed of two, or either of the two of R3, R4 and R5 together may form a bridge of 1 to 3 carbon atoms; R6 is selected from the group consisting of: hydrogen; C6-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; C3-C6 cycloalkyl; arylalkyl having portions of C5-C10 aryl and alkyl alkoxyalkyl having portions of C5-C10 aryl and C6-C6 alkyl; cyanoalkyl of C2-C4; hydroxyalkyl of C2-C; aminocarbonylalkyl having an alkyl portion of R 12 COR 13, wherein R 12 is alkylene of d-C 4, and R 13 is C 1 -C 4 alkyl or d-C alkoxy; and R7 is hydrogen or fluoride, or a pharmaceutically acceptable salt or ester thereof.
8. 8. A method according to claim 7, wherein Ar is a carbocyclic (benzene) aromatic ring and R1 is hydrogen.
9. 9. A method according to claim 7, wherein Y is carboxyamide of the formula CONR9R10.
10. 10. A method according to claim 9, wherein R9 and R10 together form a ring of five or six atoms, whereby they form a pyrrolidinyl or piperidino ring.
11. 11. A method according to claim 9, wherein R9 and R10 are the same or different and each is independently selected from hydrogen, Ci alkyl and C2 alkyl.
12. 12. A method according to claim 8, wherein Y is hydrogen.
13. 13. A method according to claim 8, wherein Y is a sulfone of the formula SO2R8; and R8 is d-C6 alkyl.
14. 14. A method according to claim 8, wherein G is N; R7 and R2 are each hydrogen and Z is hydroxyl.
15. 15. A method according to claim 8, wherein R6 is selected from the group consisting of hydrogen, Ci- C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl.
16. 16. A method according to claim 9, wherein R6 is selected from the group consisting of hydrogen, methyl, propyl, allyl and butenyl.
17. 17. A method according to claim 14, wherein R3, R4 and R5 are hydrogen or methyl, wherein the total number of methyl groups is one or two.
18. 18. A method according to claim 7, wherein R3 and R5 are methyl, and R4 is hydrogen.
19. 19. A method according to claim 7, wherein the compound is selected from the group consisting of: (-) - 4 - ((aR) - - ((2 R, 4R) -4-al i-2 , 5-di methyl-4-propyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide; (-) - 4 - ((aR) -a - ((2R, 5R) -2,5-dmethyl-4-propyl-1-1-piperazinyl) -3-hydroxybenzyl) -N, N- diethylbenzamide; (-) - 4 - ((aR) - - ((2S, 5S) -4-allyl-2,5-dimethyl-4-1-piperazinyl) -3-hydroxybenzyl I) benzamide; (+) - 3 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-1-piperazinyl) -3-hydroxybenzyl) benzamide; N, N-diethyl-4 - ((aR) -3-hydroxy-a - ((2R, 4R) -2,5-dimethyl-1-piperazinyl) benzyl) benzamide; 4 - ((aR) -a - ((2S, 5S) -4-al 1-2,5-di methyl-1-piperazinyl) -3-h id roxybenz I) - N-ethyl-N-methyl -benzamide; 3 - ((aR) -a - ((2S, 5S) -4-al i-2,5-d-methyl-1-piperazin i I) benzl) f enol; (+) - N, N-diethyl-4 - ((aR *) - 3-hydroxy-a - ((2R *, 5S *) - 2,4,5-trimethyl-1-piperazinyl) benzyl) -bezam gives; (+) - 4 - ((aS) -a - ((2S, 5S) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethyl-benzamide; 3 - ((aR) -4- (piperidinocarbonyl) -a - ((2S, 5S) -2,4,5-trimethyl-1-p yperazinyl) benzyl) phenol; 3 - ((aR) -4- (1-pyrrolidinylcarbonyl) -a- ((2S, 5S) -2,4,5-tri-methyl-1-pipe-razynyl) benzyl) phenyl; (+ -3 - ((aR *) - a - ((2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -4- (me thsulphonyl) benzyl) phenol); (±) -4 - ((aR *) - a - ((2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-dimethylbenzenesulfonamide; (-) - 4 - ((aR *) - a - ((2R, 5S) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-dimethylbenzenesulfonamide; (-) - 4 - ((S) -a - ((2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-dime thi Iben ce nosul fonamida; (+) - 3 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-d i metill-1-piperazinyl) benzyl) phenyl; (+) - 4 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-pi? -zinzinyl) -3-hydroxybenzyl) benzamide; (±) -4 - ((aR *) - - ((2R *, 5S *) - 2,5-dimeti 11-1 -piperazin-yl) -3-hydroxy-benzyl) - N, N-diethyl-benzamide; (+) - cis-4 - ((a- (4-allyl-3,5-di methyl-1-piperazinyl) -3-h id roxybenzyl) -N, N-diethylbenzamide, cis-4- (a- (3,5-Dimethyl-4- (methylallyl) -1-piperazinyl) -3-h idroxy benzyl) - N, N-diethyl-benzamide, and pharmaceutically acceptable salts thereof
20. 20. A method according to Claim 19, wherein the compound is (-) - 4 - ((aR) -a - ((2R, 5R) -4-allyl-2,5-dimetill-1- piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide or a pharmaceutically acceptable salt thereof.
21. 21. A method for screening compounds that suppress opioid respiratory depression, comprising the conduction activity of inverse analyzes of a candidate respiratory depression suppressant compound in the recipient tissue to determine whether the compound that suppresses candidate respiratory depression mediated transductionally by an effect of respiratory depression in the recipient tissue, in response with a respiratory depression composition, where the analysis of inverse activity is carried out comparatively, in the absence and in the presence of an anti-suppression compound of the formula: wherein Ar is a 5- or 6-membered carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur and having a first carbon atom thereof, a Y substituent and a second carbon ring thereof and a substituent R1, 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; haloalkyl of d-C6; d-C6 alkoxy; C3-C6 cycloalkoxy; sulphides of the formula SR8 wherein R 8 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, aryalkyl having an aryl portion of Ce-Cι and an alkyl portion of d-C6, or C5-C10 aryl; sulfoxides of the formula SOR8 wherein R8 is the same as described above; sulfones of the formula SO 2 R 8 wherein R 8 is the same as described above; nitrile; acyl of d-C6; alkoxycarbonylamino (carbamoyl) of the formula NHCO2R8 wherein R8 is the same as described above; carboxylic acid, or an ester, amide or salt thereof; aminomethyl of the formula CH2NR9R10 wherein R9 and R10 may be identical or different, or may be hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-CK alkynyl, C2-C6 hydroxyalkyl, C2-methoxyalkyl C6, C3-C6 cycloalkyl or Cedo aryl, or R9 and R10 together can form a ring of 5 or 6 atoms, Ring atoms selected from the group consisting of N and C; carboxyamides of the formula CORN9R10 wherein R9 and R10 are the same as described above, or peptide conjugates of C2-C30 thereof; and sulfonamides of the formula SO 2 NR 9 R 10 wherein R 9 and R 10 are the same as described above; Z is selected from the group consisting of: hydroxyl, and esters thereof; hydroxymethyl, and esters thereof; and amino and carboxyamides 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 alkenyl, C 1 -C 4 alkynyl; R3, R4 and R5 can be identical or different and are independently selected from hydrogen and methyl and wherein at least one of R3, R4 or R5 are not hydrogen, subject to the proviso that the total number of methyl groups is not exceeding two, or either of the two of R3, R4 and R5 together may form a bridge of 1 to 3 carbon atoms; R6 is selected from the group consisting of: hydrogen; C6-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; d-Cß cycloalkyl; arylalkyl having portions of C5-C10 aryl and C6-C6 alkyl; alkoxyalkyl having portions of C5-C10 aryl and C6-C6 alkyl; cyanoalkyl of C2-C4; C2-C4 hydroxyalkyl aminocarbonylalkyl having an alkyl portion of R 12 COR 13, wherein R 12 is C 1 -C 4 alkylene, and R 13 is C 1 -C 4 alkyl or C 1 -C 4 alkoxy; and R7 is hydrogen or fluoride, or a pharmaceutically acceptable ester or salt thereof, to determine whether the activity of the candidate compound is substantially reversed at the tissue site by the presence of the anti-suppression compound of the formula (I), thus indicating that the candidate respiratory depression suppression compound has potential bioefficacy for suppressing the effects of respiratory depression incidents for the use of other therapeutic agents.
22. 22. A method according to claim 21, wherein the anti-suppression compound of the formula (I) is selected from the group consisting of (-) - 4 - ((aS) -a - ((2 R, 5 R) -4-allyl-2,5-dimethyl-11-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethyl-benzamide; (-) - 4 - ((aS) -a - ((2R, 5R) -2,5-Dimethyl-4-propyl-1-piperazinyl) -3-hydroxy-benzyl) - N, N-d-ethyl-benzamide; c / s-4- (a (4 - ((Z) -2- bu ten il) -3,5-di meti 1-1 -piperazin il) -3-h id roxi benci I) - N, N- diethyl-benzamide; and acceptable salts thereof.
23. 23. A pharmaceutical composition comprising: (1) an effective amount of a bioactive compound mediating respiratory depression, muscle stiffness and / or nausea / vomiting as an undesired side effect thereof; and (2) a delta receptor agonist.
24. 24. A pharmaceutical composition comprising: I. [D-Pen2-D-Pen5] - (enkephalin); II. deltorphine I; III. deltorphine II; IV. agonist compounds of the formula: wherein Ar is a 5- or 6-membered carbocyclic or heliccyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur and having a first carbon atom thereof, a Y substituent and a second carbon ring thereof and a substituent R1, 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; haloalkyl of C? -C6; C6-C6 alkoxy; C3-C6 cycloalkoxy; sulphides of the formula SR8 wherein R8 is C6-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, arylalkyl having a C6-C6 aryl portion and a portion C? -C6 alkyl, or C5-C10 aryl; sulfoxides of the formula SOR8 wherein R8 is the same as described above; sulfones of the formula SO 2 R 8 wherein R 8 is the same as described above; nitrile; Acyl of C? -C6; alkoxycarbonylamino (carbamoyl) of the formula NHCO2R8 wherein R8 is the same as described above; carboxylic acid, or an ester, amide or salt thereof; aminomethyl of the formula CH2NR9R10 wherein R9 and R10 may be the same or different, or they may be hydrogen, C1-6 alkyl, C6, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 hydroxyalkyl, C2-C6 methoxyalkyl, C3-C6 cycloalkyl or C5-C10 aryl, or R9 and R10 together can form a ring of 5 or 6 atoms, the ring atoms selected from the group consisting of N and C; carboxyamides of the formula CORN9R10 wherein R9 and R10 are the same as described above, or peptide conjugates of C2-C3o thereof; and sulfonamides of the formula SO 2 NR 9 R 10 wherein R 9 and R 10 are the same as described above; Z is selected from the group consisting of: hydroxyl, and esters thereof; hydroxymethyl, and esters thereof; and amino and carboxyamides and sulfonamides thereof; G is carbon or nitrogen; R 1 is hydrogen, halogen or C 1 -C 4 alkyl, C 2 -C 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 alkynyl; R3, R4 and R5 may be the same or different and are independently selected from hydrogen and methyl and wherein at least one of R3, R4 or R5 are not hydrogen, subject to the proviso that the total number of methyl groups does not exceed of two, or either of the two of R3, R4 and R5 together may form a bridge of 1 to 3 carbon atoms; R is selected from the group consisting of: hydrogen; C6-C6 alkyl, C2-C6 alkenyl, d-Ce alkynyl; C3-Ce cycloalkyl; arylalkyl having portions of C5-C10 aryl and alkyl alkoxyalkyl having portions of C5-C10 aryl and d-C6 alkyl; cyanoalkyl of C2-C4; hydroxy alkyl of C2-C aminocarbonylalkyl having an alkyl portion of C? -C4; and R 1 COR 13, wherein R 12 is C 1 -C alkylene, and R 13 is C 1 -C 4 alkyl or C 1 -C alkoxy; and R7 is hydrogen or fluoride, or a pharmaceutically acceptable ester or salt thereof, delta agonist compounds of the formula: wherein Ri and 2, which may be identical or different, are each hydrogen, linear or branched C? -6 alkyl, C3 cycloalkyl, C3-7 cycloalkenyl, C -6 cycloalkylalkyl, alkenyl C3-6, C3-s alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or can together form a C3-7 alkyl ring that can be interrupted by oxygen. R3 and R, which may be the same or different, are each hydrogen, linear or branched d-6 alkyl, or R4 is the formation of oxygen formed with the carbon atom to which a C = O group is attached R5 is hydrogen , hydroxy, C1.3 alkoxy, thiol or alkylthio; R6 is phenyl, halogen, NH2 or a group for or meta -C (Z) -R8, in which Z is oxygen or sulfur; R8 is C2-8 alkyl, C? -8 alkoxy or NR9R? 0, wherein R9 and R10, which may be the same or different, are hydrogen, Linear or branched C? -6, C3-7 cycloalkyl, C4 cycloalkylalkyl. 6, C3-6 alkenyl, C3-6 alkenyl, aryl or aralkyl, R11 or R6 is a group for or metal of -N-C (Z) -R12 wherein Rn and R12 which may be the same or different are hydrogen, straight or branched C1-16 alkyl, C3-7 cycloalkyl, C6 cycloalkylalkyl, C3-6 alkenyl, aryl, aralkyl or a herocyclic ring optionally substituted and Z is as defined above; and, R7 is hydrogen, straight or branched C? -8 alkyl or halogen; and I saw. Delta agonistic compounds of the formula: in which, Ri and R2 > which may be the same or different, are each hydrogen, linear or branched C? -6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C-6 cycloalkylalkyl, C3-6 alkenyl, C3- alkynyl 5, aryl, aralkyl or furan-2 or 3-yl alkyl or can together form a C3-7 alkyl ring that can be interrupted by oxygen. R3 and R4, which may be the same or different, are each hydrogen, linear or branched C? -6 alkyl; R5 is, hydroxy, d-3 alkoxy, thiol or alkylthio; R6 is a group -C (Z) -Rg, in which Z is oxygen or sulfur, R8 is C? -8 alkyl, C? -8 alkoxy or NR9R10, wherein R9 and R10, which may be the same or different, are hydrogen, straight or branched d.β alkyl, C3-7 cycloalkyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, aryl or aralkyl, or R6 is a group -N-C (Z) -R12 wherein R n and R 2 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.
25. 25. A pharmaceutical composition according to claim 24, in a form suitable for injectable or spinal administration.
26. 26. A pharmaceutical composition comprising: (1) an effective amount of a bioactive compound mediating respiratory depression; and (2) an effective amount of a compound to reduce, treat or prevent respiratory depression, of the formula: wherein Ar is a 5- or 6-membered carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur and having a first carbon atom thereof, a Y substituent and a second carbon ring thereof and a substituent R1, Y is selected from the group consisting of: hydrogen; halogen; C6-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; haloalkyl of C? -C6; Ci-Cß alkoxy; C3-C6 cycloalkoxy; sulfides of the formula SR8 wherein R8 is C6-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, arylalkyl having an aryl portion of Ce-Cι and an alkyl portion of d-C 6, or C 5 -C 10 aryl; sulfoxides of the formula SOR8 wherein R8 is the same as described above; sulfones of the formula SO 2 R 8 wherein R 8 is the same as described above; nitrile; acyl of d-C6; alkoxycarbonylamino (carbamoyl) of the formula NHCO2R8 wherein R8 is the same as described above; carboxylic acid, or an ester, amide or salt thereof; aminomethyl of the formula CH2NR9R10 wherein R9 and R10 may be the same or different, or may be hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 hydroxyalkyl, C2-C6 methoxyalkyl , C3-C6 cycloalkyl or C5-C10 aryl, or R9 and R10 together can form a ring of 5 or 6 atoms, the ring atoms selected from the group consisting of N and C; carboxyamides of the formula CORN R wherein R and R, are the same as described above, or conjugates of peptides of C2-C3o thereof; and sulfonamides of the formula SO 2 NR 9 R 10 wherein R 9 and R 10 are the same as described above; Z is selected from the group consisting of: hydroxyl, and esters thereof; hydroxymethyl, and esters thereof; and amino and carboxyamides and sulfonamides thereof; G is carbon or nitrogen; R1 is hydrogen, halogen or d-C4 alkyl, C2-C4 alkenyl, C? -C4 alkynyl; R 2 is hydrogen, halogen or C 1 -C 4 alkyl, C 2 -C alkenyl, C 1 -C alkynyl; R3, R4 and R5 may be the same or different and are independently selected from hydrogen and methyl and wherein at least one of R3, R4 or R5 are not hydrogen, subject to the proviso that the total number of methyl groups does not exceed of two, or either of the two of R3, R4 and R5 together may form a bridge of 1 to 3 carbon atoms; R6 is selected from the group consisting of: hydrogen; C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; C3-C6 cycloalkyl; arylalkyl having portions of C5-C10 aryl and alkyl alkoxyalkyl having portions of C5-C10 aryl and C6-C6 alkyl; cyanoalkyl of C2-C4; C2-C4 hydroxyalkyl aminocarbonylalkyl having an alkyl portion of C? -C4; Y R12COR13, wherein R12 is C? -C4 alkylene, and R13 is C? -C4 alkyl or C? -C alkoxy; and R7 is hydrogen or fluoride, or a pharmaceutically acceptable ester or salt thereof.
27. 27. A pharmaceutical composition according to claim 26, wherein Ar is a carbocyclic (benzene) aromatic ring and R1 is hydrogen.
28. 28. A pharmaceutical composition according to claim 26, wherein Y is carboxyamide of the formula CONR9R10.
29. 29. A pharmaceutical composition according to claim 26, wherein R9 and R10 together form a ring of five or six atoms, so they form a pi rol rol idinyl or piperidino.
30. 30. A pharmaceutical composition according to claim 26, wherein R9 and R10 are the same or different and each is independently selected from hydrogen, Ci alkyl and C2 alkyl.
31. 31. A pharmaceutical composition according to claim 26, wherein Y is hydrogen.
32. 32. A pharmaceutical composition according to claim 26, wherein Y is a sulfone of the formula SO2R8; and R8 is C6-C6 alkyl.
33. 33. A pharmaceutical composition according to claim 26, wherein G is N; R7 and R2 are each hydrogen and Z is hydroxyl.
34. 34. A pharmaceutical composition according to claim 26, wherein R6 is selected from the group consisting of hydrogen, d-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl.
35. 35. A pharmaceutical composition according to claim 26, wherein R3, R4 and R5 are hydrogen or methyl, wherein the total number of methyl groups is one or two.
36. 36. A pharmaceutical composition according to claim 26, wherein R3 and R5 are methyl, and R4 is hydrogen.
37. 37. A pharmaceutical composition according to claim 26, wherein the compound is selected from the group consisting of: (-) - 4 - ((aR) -a - ((2R, 4R) -4-allyl-2, 5-dimethyl-4-propyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethyl-benzamide; (-) - 4 - ((aR) -a - ((2R, 5R) -2,5-dimethyl-4-propyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide; (-) - 4 - ((aR) -a - ((2S, 5S) -4-al i I-2, 5-di methyl-4-1-piperazinyl) -3-hydroxy-benzyl) benzamido; (+) - 3 - ((aR *) - a - ((2S *, 5R *) - 4-allyl-2,5-1-pi? Erazinyl) -3-hydroxybenzyl) benzamide; N, N-diethyl-4 - ((aR) -3-hydroxy-a - ((2R, 4R) -2,5-dimethyl-1-piperazinyl) benzyl) benzamide; 4 - ((R) -a - ((2S, 5S) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N-ethyl-N-methyl-benzamide; 3 - ((aR) -a - ((2S, 5S) -4-allyl-2,5-dimethyl-1-piperazinyl) benzl) f enol; (+) - N, N-diethyl-4 - ((aR *) - 3-hydroxy-a - ((2R *, 5S *) - 2,4,5-trimethyl-1-piperazinyl) benzyl) -bezamide; (+) - 4 - ((aS) -a - ((2S, 5S) -4-allyl-2,5-di methyl-1-1-piperazin-yl) -3-hydroxy-benzyl) - N, N-diethyl- benzam ida; 3 - ((aR) -4- (piperidinocarbonyl) - - ((2S, 5S) -2,4,5-trimethyl-1-piperazinyl) benzyl) phenol; 3 - ((aR) -4- (1-pyrrolidinylcarbonyl) -a - ((2S, 5S) -2,4,5-trimethyl-1-piperazinyl) benzyl) phenyl; (+) - 3 - ((aR *) - a - ((2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -4- (me t -lsulfonyl) benzyl) phenol); (+) - 4 - ((aR *) - a - ((2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-dimethylbenzenesulfonamide; (-) - 4 - ((aR *) - a - ((2R, 5S) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-dimethylbenzenesulfonamide; (-) - 4 - ((aS) -a - ((2S, 5R) -4-allyl-2,5-dimetill-1-pperazinyl) -3-hydroxybenzyl) -N, N- di methylbenzenesu I fonamide; (+) - 3 - ((R *) - a - ((2S *, 5R *) - 4-allyl-2,5-dimethyl-1-piperazinyl) benzyl) phenyl; (+) - 4 - ((aR *) - - ((2S *, 5 R *) - 4-allyl-2,5-dimethyl-1-1-piperazinyl) -3-hydroxybenzyl) benzamide; (+) - 4 - ((R *) - a - ((2R *, 5S *) - 2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) - N, N-diethyl-benzamide; (+ J-cis-4 - ((- (4-allyl-3,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide; cis-4- (a- (3, 5-dimethyl-4- (methylallyl) -1-piperazinyl) -3-hydroxybenzyl) -N, N-diethyl-benzamide; and pharmaceutically acceptable salts thereof.
38. 38. A pharmaceutical composition according to claim 37, wherein the compound is (-) - 4 - ((aR) -a - ((2R, 5R) -4-ali 1-2, 5-di metill- 1 -piperazinyl) -3-hydroxybenzyl) -N, N-diethylbenzamide or a pharmaceutically acceptable salt thereof.
39. 39. A pharmaceutical composition according to claim 26, wherein the bioactive compound comprises an opiate compound.
40. 40. A pharmaceutical composition according to claim 26, wherein the bioactive compound comprises an opiate analgesic compound.
41. 41 A pharmaceutical composition according to claim 26, wherein the bioactive compound comprises a mu opiate compound.
42. 42. A method for treating a patient in need thereof with fentanyl while attenuating fentanyl-induced muscle rigidity and fentanyl-induced respiratory depression, which comprises administering to a patient a delta-agonist compound in an effective amount to attenuate induced muscle rigidity. by fentanyl and respiratory depression induced by fentanyl.
43. 43. A method to treat a patient who needs it with a therapeutic agent of the opioid receptor, while attenuating the respiratory depression incident in the administration thereof, which comprises administering to the patient the therapeutic agent of the opioid receptor, a delta agonist compound selected from the group consisting of: I. [D-Pen2-D-Pen5] - (enkephalin); II. deltorphine I; III. deltorphine II; IV. agonist compounds of the formula: (I) wherein Ar is a 5- or 6-membered carbocyclic or heterocyclic aromatic ring with atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur and having a first carbon atom thereof, a Y substituent and a second carbon ring thereof and a substituent R1, Y is selected from the group consisting of: hydrogen; halogen; C6-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl; haloalkyl of C? -C6; C-C6 alkoxy; d-C6 cycloalkoxy; sulphides of the formula SR8 wherein R8 is C? -C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, dd cycloalkyl, aryalkyl having an aryl portion of d-Cio and an alkyl portion of C? -C6, or C5-C10 aryl; sulfoxides of the formula SOR8 wherein R8 is the same as described above; sulfones of the formula SO 2 R 8 wherein R 8 is the same as described above; nitrile; acyl of d-C6; alkoxycarbonylamino (carbamoyl) of the formula NHCO2R8 wherein R8 is the same as described above; carboxylic acid, or an ester, amide or salt thereof; aminomethyl of the formula CH2NR9R10 wherein R9 and R10 may be the same or different, or may be hydrogen, C1-d alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-d hydroxyalkyl, C2-C6 methoxyalkyl , dd cycloalkyl or d-C10 aryl, or R9 and R10 together can form a ring of 5 or 6 atoms, the ring atoms selected from the group consisting of N and C; carboxyamides of the formula CORN9R10 wherein R9 and R10 are the same as described above, or peptide conjugates of C2-do of the same; Y sulfonamides of the formula SO 2 NR 9 R 10 wherein R 9 and R 10 are the same as described above; Z is selected from the group consisting of: hydroxyl, and esters thereof; hydroxymethyl, and esters thereof; and amino and carboxyamides and sulfonamides thereof; G is carbon or nitrogen; R1 is hydrogen, halogen or C? -C alkyl, C2-C4 alkenyl, C? -C alkynyl; R 2 is hydrogen, halogen or C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkynyl; R3, R4 and R5 may be the same or different and are independently selected from hydrogen and methyl and wherein at least one of R3, R4 or R5 are not hydrogen, subject to the proviso that the total number of methyl groups does not exceed of two, or either of the two of R3, R4 and R5 together may form a bridge of 1 to 3 carbon atoms; R6 is selected from the group consisting of: hydrogen; C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl; C3-d cycloalkyl; arylalkyl having portions of C5-C10 aryl and C6-C6 alkyl; alkoxyalkyl having portions of C5-C10 aryl and C6-C6 alkyl; cyanoalkyl of C2-C4; C2-C4 hydroxyalkyl aminocarbonylalkyl having an alkyl portion of C? -C4; and R12COR13, wherein R12 is C1-C4 alkylene, and R13 is C? -C alkyl or C? -C alkoxy; and R7 is hydrogen or fluoride, or a pharmaceutically acceptable ester or salt thereof. V. Delta agonist compounds of the formula: wherein Ri and R2, which may be the same or different, are each hydrogen, linear or branched C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, C4-6 cycloalkylalkyl, alkenyl C3-5 alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or can together form a C3-7 alkyl ring that can be interrupted by oxygen. R3 and R4, which may be the same or different, are each hydrogen, linear or branched d-6 alkyl, or R is the formation of oxygen formed with the carbon atom to which a C = O group is attached R5 is hydrogen , hydroxy, C -3 alkoxy, thiol or alkylthio; R6 is phenyl, halogen, NH2 or a group for or meta -C (Z) -R8, in which Z is oxygen or sulfur; R8 is C2-8 alkyl, d-8 alkoxy or NR9R10, wherein R9 and Rio, which may be the same or different, are hydrogen, linear or branched C6-6 alkyl, C3 cycloalkyl, C4 cycloalkylalkyl - 6, C3-6 alkenyl, C3-6 alkenyl, aryl or aralkyl, R11 I or R6 is a group for or metal of -N-C (Z) -R? 2 wherein Rn and R12 which may be the same or different are hydrogen, straight or branched C? -? 6 alkyl, C3-7 cycloalkyl, C4-6 cycloalkylalkyl, C3-6 alkenyl, aryl, aralkyl or a ring optionally substituted herocyclic and Z is as defined above; and, R7 is hydrogen, straight or branched C? -8 alkyl or halogen; and I saw. Delta agonistic compounds of the formula: wherein Ri and 2, which may be the same or different, are each hydrogen, linear or branched C? -6 alkyl, C3- cycloalkyl, C3-7 cycloalkenyl, C4-6 cycloalkylalkyl, alkenyl C3-5 alkynyl, aryl, aralkyl or furan-2 or 3-yl alkyl or can together form an alkyl ring of d-7 which can be interrupted by oxygen. R3 and R4, which may be the same or different, are each hydrogen, linear or branched C? _6 alkyl; R5 is, hydroxy, C1-3 alkoxy, thiol or alkylthio; R6 is a group -C (Z) -Rg, in which Z is oxygen or sulfur, R8 is C? -8 alkyl, C? -8 alkoxy or NR9R 0, wherein R9 and R10, which may be the same or different, are hydrogen, straight or branched C? _6 alkyl, C3-7 cycloalkyl, C -6 cycloalkylalkyl, d-6 alkenyl, aryl or aralkyl, or R6 is a group N-C (Z) - R 12 wherein R n and R 2 have the same meaning as R 9 and Rio or together form an optionally substituted heterocyclic ring and z is as defined above and, R 7 is hydrogen, straight or branched C 8 -alkyl or halogen.
44. 44. A method for reducing, treating or preventing drug-mediated respiratory depression in an animal, incident to the administration to said animal of a respiratory depression mediating drug, which comprises administering to an animal receiving said drug an effective amount of a compound selected from: (+) - 4 - ((aR *) - a - ((2R *, 5S *) - 4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-dimethylbenzene nosul fonamide; (-) - 4 - ((aR) -a - ((2R, 5S) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-hydroxybenzyl) -N, N-dimethylbenzenesulfonamide; and (-) - 4 - ((aS) -a - ((2S, 5R) -4-allyl-2,5-d imetill-1-piperazinyl) -3-hydroxybenzyl) -N, N-dimethylbenzenesulfonamide; and pharmaceutically acceptable salts thereof.
45. 45. A method for reducing, treating or preventing drug-mediated respiratory depression, muscle stiffness or nausea / vomiting in an animal, incident to the animal's administration of a respiratory depression mediating drug, which comprises administering to the recipient animal drug one effective amount of a delta agonist receptor or mixing the delta / mu opioid agonist composition.
46. 46. A method according to claim 1, wherein the delta receptor agonist compound comprises.
47. 47. A method according to claim 7, wherein the compound comprises:
48. 48. A method according to claim 21, wherein the compound comprises:
49. 49. A pharmaceutical composition according to claim 23, wherein the delta receptor agonist comprises:
50. 50. A pharmaceutical composition according to claim 26, wherein the compound for reducing, treating or preventing respiratory depression, comprises:
51. 51 A method according to claim 42, wherein the delta agonist compound comprises:
52. 52. A method according to claim 43, wherein the delta agonist compound comprises:
53. 53. A method according to claim 45, wherein the effective amount of a mixture of the delta / mu opioid agonist composition comprises:
54. 54. A method according to claim 1, wherein the respiratory depression mediating drug comprises a mu opiate selected from the group consisting of alfentanil, buprenorphine, butorphanol, codeine, dihydrocodeine, etorphine, fentanyl, heroin, hydrocodon, hydromorphone, levorphanol, meperidine, methadone, morphine, opium, oxycodone, oxymorphone, pentazocine, propoxyphenol and sufentanil.
55. 55. A composition comprising the respiratory depression mediation compound and (+) - 3 - ((aR) -a - ((2S, 5R) -4-allyl-2, 5-di metill-1-piperazin il) -3-hydroxybenzyl) -N, N- (3-f luorofenyl) -N-methylbenzamide.
56. 56. A method for mediating the analgesic in an animal in need thereof, in a therapeutic relationship of respiratory depression DE50 which is substantially in excess of a therapeutic ratio of fentanyl, said method comprising administering to the animal an amount of (+) - 3 - ((aR) -a - ((2S, 5R) -4-allyl-2, 5-di meti 11-1 -pipe razin il) -3-h id roxibencil) -N, N- (3-f luorof enyl) -N-methylbenzamide which is effective to produce analgesia in an animal at said therapeutic relationship.
57. 57. The method according to claim 54, wherein the therapeutic ratio is substantially greater than 4.5.
58. 58. A pharmaceutical composition comprising (i) a mu receptor agonist therapeutic agent that mediates a respiratory, muscular or nausea side effect and (ii) an effective amount to reduce, treat or prevent the side effect of a receptor agonist. delta comprising (+) - 3 - ((aR) -a - ((2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-h id roxybenzyl) -N, N- (3-f luorof in yl) -N-methylbenzamide.
59. 59. A pharmaceutical composition comprising a mu receptor agonist of opiates selected from the group consists of fentanyl or alfentanil and a delta receptor agonist comprising (+) - 3 - ((aR) -a - ((2S, 5R) -4-allyl-2,5-dimetill-1-pi? erazinyl) - 3-hydroxybenzyl) -N, N- (3-f luorof in I) -N-methyl benzamide.
60. 60. A pharmaceutical composition comprising (1) a mu receptor agonist therapeutic agent mediated by a respiratory, muscular or nausea side effect, selected from the group consisting of alfentanil, bruprenorphine, butorphanol, codeine, dihydrocodeine, etorphine, fentanyl, heroin , hydrocodon, hydromorphone, levorphanol, meperidine, methadone, morphine, opium, oxycodone, oxymorofin, pentazocine, propoxyphenol and sulfentanil and (2) (+) - 3 - ((R) -a - ((2S, 5R) -4 -alyl-2, 5-di meti 11-1 -piperazin-yl) -3-h-idroxy-benzyl) -N, N- (3-fluorophenyl) -N-methyl-benzamide.
61. 61. A method of antagonistically modulated respiratory depression incident to the use of a mu receptor agonist in a patient receiving said agonist, comprising administering to said patient an effective amount of (+) - 3 - ((aR) -a- ((2S, 5R) -4-allyl-2, 5-dimethyl-1-piperazyl-1) -3-hydroxybenzyl) -N, N- (3-f luorofenyl) -N-methylbenzamide.
62. 62. A method according to claim 1, wherein the animal is being a human being.
63. 63. A method according to claim 61, wherein the patient is a human being.
64. 64. A method according to claim 61, wherein the mu receptor agonist comprises a mu receptor agonist selected from the group consisting of alfentanil, buprenorphine, butorphanol, codeine, dihydrocodeine, etorphine, fentanyl, heroin, hydrocodon, hydromorphone, levorphanol, meperidine, methadone, morphine, opium, oxycodone, oxymorphone, pentazocine, propoxyphenol and sufentanil.