MXPA99011155A - Peripherally acting anti-pruritic opiates - Google Patents

Abstract

Composiciones antipruríticas y métodos de uso de las composiciones para la prevención y tratamiento de pruritus que comprende la formula (I), en donde M es (a)(b)ó(c), R, R2, R3, R4, R7, Ar1 y Ar2 son como se definieron en la especificación en un portador farmacéuticamente aceptable.

Description

ANTI-PRIURITIC OPIATES THAT ACT IN A PERIPHERAL FORM DESCRIPTION OF THE INVENTION This invention relates to anti-pruritic opiates that act peripherally, having substantially no effects on the central nervous system and method of topical treatment of pruritic conditions thereof. The prior art has investigated the physiology and treatment of pruritis as illustrated in the following. _ Pruritus is a well-known sensitive state associated with the desire to scratch. As with pain, pruritus can be produced by a variety of chemical, mechanical, thermal or electrical stimuli. In addition to the difference in the sensitive quality of pruritus and pain, they also differ in that (1) itching, unlike pain can only be evoked from the superficial layers of the skin, mucosa, and conjunctiva, and (2) pruritus and Pain usually does not occur simultaneously from the same dermal region; in fact, moderate painful stimuli, such as scratching, are effective in eliminating pruritus. In addition, the application of histamine to the skin produces itching but not pain. The pruritus and pain are also dissociated pharmacologically: pruritus appears to be insensitive to opiate and treatment with non-spheroidal anti-inflammatory (NSAID), which are effective in the treatment of pain.

Although the pruritus and pain are of a class in which both are modalities of nociception transmitted by small C fibers without myelomas, they show that pruritus is not only a variety of low threshold pain that is overwhelming. Pruritus leads to reflex or urgency of scratching; the pain leads to elimination. Removal of the epidermis eliminates itching but causes pain. Analgesics, particularly opioids, alleviate pain but often cause itching (see, eg, J. Es. Acad. Derm. 24: 309-310, 1991). There can be no doubt that pruritus is of primary clinical importance; Most systemic and skin diseases are accompanied by persistent or recurrent pruritus attacks. Current knowledge suggests that the pruritus has several. features in common with pain but also exhibits disconcerting differences (see, for example, W. Magerl, IAS7P Newslet ter, pp.-4-7, Sept / Oct 1996). McMahon et al (TINS, Vol., 15, No., 12, pp.-497 501, 1992) provides a description of the stimuli (Table a) and a comparison of the established characteristics of pruritus and pain (Table b) : Table to Stimuli that can excite or increase the itching Mechanical Physicists. Touch light, pressure, suction. Thermal Heating. Electric . Focal transcutaneous repetitive stimulation, transcutaneous constant current stimulation, intraneural microstimulation. Chemical Irri so non-specific te. Acids, alkalis. Inflammatory mediators. Histamine, kallikrein, bradykinin, prostaglandins. His substances that liberate his tamina. Compound-48/80, protamine, C3a. Peptidase Mucunain, papain, trypsin, mast cell chymase Neuropeptides. Substance P, vasoactive intestinal polypeptide, neurotensin, secretin. Opioídes. Morphine, (β-endorphin, encephalitis analogs.

Table b Comparison of established characteristics of pruritus and pain PRURITY PAIN Psychophysiology Skin tissue. Mucous membranes Most tissues Stimuli See Table at Many stimuli Intraneural micro-stimulation Occasionally Yes Secondary sensations oquinesis (skin With pruritus) Hyperalgesia Modification Psychogenic Pronounced Present Contrastimulus Scratching, pain, cooling Stimuli tactile cooling Neurophysiology - Primary afferent neurons C- and P &C fibers - C- and Ad-size fibers Irritation size Large Small Spinal trajectory Anterolateral funiculum Funiculum - anterolateral Protective reflexes, Scratching, sneezing Flexion, preservation Autonomic reflexes Yes Yes Pharmacology Capsaicin sensitivity Yes Pain _ chemogenic; yes NSAID sensitivity Probably not Yes Sense of morphine No Yes Abbreviation: NSAID, non-spheroidal anti-inflammatory drugs.

The experimental focal pruritus stimuli are surrounded by a halo of apparently unaffected tissue where light tactile stimuli are capable of producing similar pruritus sensations. The term irritated skin or alochinesis have been coined for these secondary sensations that are reminiscent of the characteristics of secondary hyperalgesia that evolves around a painful focus. A crucial observation is that itching and pain do not normally coexist in the same region of the skin and a moderate noxious stimulus such as scratching is in fact the most efficient individual form to eliminate itching. This abolition of pruritus can be prolonged by producing an 'antipruritic state'. Although moderate scratching is often not painful, microneurographic records of humans have directly determined that such stimuli are among the most effective ways to stimulate nociceptive afferents without cutaneous myeloma. (See, for example: Shelly, WB and Arthur, RP (1957) Arch. Derma tol. 76, 296-323; Simone, DA et al. (1987) Soma tosens, Res. 5, 81-92; Graham, DT , Goodell, H. and Wolff, HG (1951) J. Clin.Research 30, 37-49; Simone, DA, Alreja, M., and LaMotte, RH (1991) Soma tosens, Mot. Res. 8, 271 279; Torebjdrk, E. (1985) Philos. Trans. R. Soc. London Ser. B 30a, 227-234; and Vallbo, A.B., Hagbarth, K.E., Torebjdrk, H.E. and Wallin, B.G. (1979) Physiol. Rev. 59, 919-957) Physiologically, there is evidence that the substance P released from the nociceptors terminals can cause the release of histamine from mast cells. Activation of mast cells, with release of pruritrogen histamine, occurs in immediate-type hypersensitive diseases, such as anaphylactic reactions and urticaria. Urticarial rashes are distinctly pruritic and can involve any portion of the body, and have a variety of causes beyond hypersensitivity, including physical stimuli such as cold, solar radiation, exercise, and mechanical irritation. Other causes of prutitus include: tick, the larval form of which secretes the substance that creates a red papule that causes intense pruritus; secondary hyperparathyroidism associated with chronic kidney disease; migrans cutaneous larva, caused by larva excavator of animal hookworms; dermal myiasis, caused by horsefly worms that can affect riders; onchocerciasis ("river blindness") caused by filarial nematodes; pediculosis, caused by lice infestations; enterobiasis (intestinal worm) infestations that affect approximately 40 million Americans, particularly children of school age; schistosome dermatitis (swimmer's itch); psoriasis; poison ivy and astheatotic eczema ("winter pruritus"). The role of histamine or other endogenous pruritógenes in mediating pruritus associated with these and other pruritus conditions, such as atopic dermatitis, is not yet well established. For atopic dermatitis, in particular, it seems that pruritus not inhibited by antihistamines, but by cyclosporin A, a drug that inhibits the production of cytokines that have been proposed as potential pruritogens. Current therapies for the treatment of pruritus include a variety of topical and systemic agents, such as steroids, antihistamines, and some psychotherapeutic tricyclic compounds, such as doxepin hydrochloride. Many such agents are listed in PDR Generics (see Second Edition, 1996, p., Cv for a listing of such agents). The limitations of these agents are well known in medical practitioners, and are summarized in the "Warnings" and "Precautions" sections for the individual agents listed in PDR Generics. In particular, the total ineffectiveness of antihistamines is well known, but antihistamines are frequently used in dermatology to treat pruritis due to urticaria, atopic dermatitis, contact dermatitis, psoriasis, and a variety of other conditions. Although sedation has been a common side effect of conventional ahtihistamines administered systemically, a new generation of antihistamines has been developed to be nonsedating, apparently due to their inability to cross the blood-brain barrier. Intravenous administration of opiate analgesics, such as morphine and hydromorphone, has been associated with prutitus, urticaria, other skin rashes, and hives and inflammation on the vein that is injected. It is believed that these pruritus and pruritus-related reactions are due to a property of histamine release from these opiates, by degranulation of mast cells. These opiates are thought to act in the mu subtype of the opiate receptor, but the possibility of interactions in the other major opiate receptor subtypes (delta and kappa) can not be excluded since these and other pruritogenic analgesics are not purely agonists. Cell sites of the receptor type or types that mediate the effect of pruritus are unknown, although the mast cell is a possible candidate since opiates cause histamine release from these cells. However, some researchers have suggested that the frequent inability of antihistamines to block morphine-induced pruritus suggests a non-histaminergic mediation of the opiate-induced pruritus mechanism - which could involve central opiate receptors. Although intravenous morphine results only occasionally in generalized pruritus (in approximately 1% of patients), pruritus is more prevalent in opiate analgesia with epidural (8.5%) or intraspinal (45.8%) administration. (See, for example: Bernstein et al., "Antipruritic Effect of an Opiate Antagonist, Naloxone Hydrochoride," The Journal of Investigation of Dermatology, 78: 82-83, 1982.; Ballantyne et al., "Itching after epidural and spinal opiates", Pain, 33: 149-160, 1988.) To date, treatment with opiates has not only proven to be useless in the treatment of pruritus, but it seems to exacerbate the itching in mammals. The compatible breakthroughs from studies in humans indicate that either by central or peripheral mechanisms, opiates seem to promote rather than prevent pruritus, and that opiate antagonists have antipruritic activity. _ Clinical studies in humans have generally shown that opiates cause pruritus and there is evidence that these effects can be reproduced in animal models, where the pruritus sensations themselves can not be reported, but the scratching behavior can be observed. (See, for example: Tomas et al., "Microinjection of morphine into the rat medullary dorsal horn produces a dose dependent increase in facial-scratching", Bra in Research, 695: 267 270, 1996; Tomas et al., "Effects of central administration of opioids on facial scratching in monkeys ", Bra ins Res., 585: 315-317, 1992, and Tomas et al.," The Medullary dorsal horn: A site of action of opioids "producing facial scratching in monkeys" , Anes thesiology, 79: 548 554, 1993) Certain opiates, such as loperamide [ie, 4- (chlorophenyl) -4-hydroxy-NN-dimethyl-a, a-diphenyl-1-piperidinbutyramide hydrochloride] and its analogs were reported to lack CNS effects that are thought to be due to the failure of opiates to cross the blood-brain barrier.Loperamide hydrochloride has been used for a long time in antidiarrheal formulations and has been completely free of the effects of undesirable SNC. It has now been discovered in an amazing way that certain opiates, which lack, substantially of effects on the central nervous system, possess antipluritic activity. "In one aspect, the present invention provides compositions containing one or more compounds that exert antipluritic activity by peripheral opiate receptors although they do not exhibit substantial CNS-mediated analgesic or systemic effects In another aspect, the present invention provides methods comprising administration The compositions for use in the compositions and methods herein possess peripheral antipruritic activities and substantially no CNS because they do not cross the blood-brain barrier. to cross the blood-brain barrier prevents the presence or occurrence of systemic collateral CNS effects, so that there is no potential for abuse Compounds intended for use in the methods and compositions provided herein include any compound that in rtud of their interaction, either directly or indirectly, with peripheral opioid receptors improves the peripheral hyperalgesic state, but do not exhibit analgesic activity mediated by CNS or side effects, including heaviness of the limbs, pale or flushed appearance, congestion of the ducts nasal, vertigo, depression, respiratory depression, sedation and constipation. These compounds include antidiarrheals that act as antidiarrheals by means of the interaction, with μ, d or k receptors, and opiate agonists, such as methefamide and related enkephalin analogues. The compounds of the present invention, the description of which is shown below, have been reported in all prior art patents of which are incorporated herein by reference: (a) Loperamide, its analogs, and related compounds , metabolites and prodrugs thereof reported in U.S. Patents Nos. 3,714,159 4,125,531 3,884,916 4,194,045 3,996,214 4,203,920 4,012,393 4,277,605 4,013,668 4,326,074 4,025,652 4,326,075 4,060,635 4,533,739 4,066,654 4,824,853 4,069,223 4,990,521 4,072,686 5,236,947 4,115,564 5,242,944 4,116,963 Such compounds include compounds of Formula I; its N-oxide or a pharmaceutically acceptable salt or acid: where is where: -N ^^^ is an azabicycloalkyl containing from 6 to 9 carbon atoms with at least 5 atoms in each ring and is substituted or unsubstituted with OR18 in which R18 is hydrogen or lower alkanoyl which contains from 2 to 7_ carbons and OR18 is in position 5 in the 5-member rings or position 5 or 6 in the 6-member rings and joins in the endo or exo configuration; Ar1 and Ar2 are either (i) or (ii) as follows: (i) each is independently selected from aryl and heteroaryl groups containing from 5 to 7 members in the ring, each substituted or unsubstituted with one or more substituents selected from halo, halalkyl, hydroxy, alkyl, alkyloxy, aminosulfonyl, "alkylcarbonyl, nitro, haloalkyl, trifluoromethyl, amino, aminocarbonyl, phenylcarbonyl or thienyl, wherein the alkyl groups are straight or branched chain lower alkyl containing 1 to 6 carbon atoms, or (ii) Ar1 and Ar2 are each independently phenyl or pyridyl groups and with the carbon to which they normally join they form a combined ring so that the compounds of the formula (I) have the structure: where n is 0 to 3; R2 is any alkyl in which the alkyl group is a straight or branched chain having 1 to 12 carbon atoms, or is alkylene having 1 to 6 carbon atoms with one or two double bonds; R3 is Ar3, -Y-Ar3, where Y is alkylene or alkyl having carbon atoms, or R is hydrogen or alkyl which is a straight or branched chain containing from 1 to 6 carbon atoms; Ar3 is aryl or heteroaryl containing from 5 to 1_ members in the ring that is substituted or unsubstituted with one or more halo substituents, lower alkyl lower alkyl tr; Ar4 is either: (i) is a heterocycle containing one to three rings combined or which is substituted or unsubstituted with one or more substituents selected from halo, lower haloalkyl or lower alkyl, or (ii) Ar4 is a radical of the formula: wherein R 10, R 11 and R 12 are each independently selected from hydrogen, alkyl, alkyloxy alkoxyalkyl, halo, haloalkyl, hydroxy, cyano, nitro, amino, alkylamino, di (alkyl) amino, aminocarbonyl, halocarbonylamino, alkylcarbonylamino, alkylcarbonyl , alkylcarbonyloxy, aminosulfonyl, alkylsulfinyl, "alkylsulphonyl, alkylthio, mercapto, C-? -C &" alkenyloxy, arylalkyloxy, aryloxy, or alkyl in which each group is substituted or unsubstituted with one or more halo atoms, haloalkyl, or alkyl, and the alkyl groups are straight or branched chains which are lower alkyl, R is hydrogen, alkyl, halo, haloalkyl or OR9, R9 is selected from alkyl, arylalkyl, alkylcarbonyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl in which alkyl groups they are "of linear or branched chains containing from 1 to 12 carbon atoms; R4 is selected from: (i) 5 to 7 membered aryl groups which are substituted or unsubstituted with lower alkyl, halo lower alkyl or halo, or (ii) heterocyclic rings, contain from one to three heteroatoms which are substituted or unsubstituted with halo, lower haloalkyl or lower alkyl, or (iii) alkyl containing from 1 to 8 carbon atoms, alkenyl containing from 3 to 6 carbon atoms, cycloalkyl containing from 3 to 6 carbon atoms, cycloalkylalkyl in which the first alkyl contains 3 to 6 carbons and the second contains 1 to 3 carbons, or cycloalkenyl containing 4 to 7 carbons, or wherein R5 and R6 are either: (i) independently selected from hydrogen, alkyl, which is a straight or branched chain containing from 1 to 12 carbon atoms, alkenyl which is straight or branched chain and contains from 1 to 12 carbon atoms and one or two double bonds, or aryl containing from 5 to 7 carbon atoms or _ (ü) R5 and R6 are selected from carbon chains, heteroatoms, and carbon chains containing one or more heteroatoms, so that with the nitrogen atoms to which each one binds they form a 3- to 7-membered heterocyclic ring containing from one to three heteroatoms which are substituted or unsubstituted with halo, lower alkylamino lower alkyl; and R7 is selected from: H; OH; R140R13 in which R13 is hydrogen or lower alkyl, alkanoyl containing from 2 to 5 carbon atoms, and Ri4 is lower alkenyl or lower alkyl; -CH2NR15Rld in which R15 is hydrogen, lower alkyl or lower alkanoyl and R16 is hydrogen or lower alkyl; OR15; R22OR13 wherein R22 is lower alkyl; -C (0) OR17 wherein R17 is hydrogen, alkyl containing from 1 to 7 carbons or alkenyl having from 3-7 carbon atoms, aryl or heteroaryl; or an alkali metal or alkaline earth metal salt. It is understood that the nomenclatures have the meaning generally known to those skilled in the art as defined herein: "Halogen" or "halide" or "halo" refers to F, Cl, Br or I, and also pseudohalides. In preferred embodiments the halo refers to F, Cl, Br and I. Pseudohalides are radicals that behave substantially similar to halides. Such radicals can be used in the same way and can be treated in the same way as halides (X, in which X is a halogen, such as Cl or Br). Pseudohalides include, but are not limited to cyanide, cyanate, thiocyanate, selenocyanate, azide and trifluoromethyl. As used herein, the carbon chains and the carbon chains with heteroatoms may be linear or branched or, if they contain 3 or more members, they may be cyclic.The alkyl, alkenyl and carbon chains d ^ alkynyl, if not specified contain from 1 to 20 carbons, preferably from 1 to 12 carbons and are linear or branched.The lower alkyl, lower alkenyl, - lower alkynyl refers to carbon chains having from one to about 6 carbons. Preferred embodiments of the compounds provided herein that include alkyl, alkenyl, or alkynyl portions include lower alkyl, lower alkenyl, and lower alkynyl portions. Preferred among the lower carbon chains are those having 1-3 carbons.

Aryl refers to cyclic groups containing from 3 to 15 or 16 carbon atoms, preferably from 5 to 10, more preferably from 5 to 7 carbons. Aryl groups include, but are not limited to, groups such as phenyl, substituted phenyl, naphthyl, substituted naphthyl in which the substituent is lower alkyl, halo, halo lower alkyl, or lower alkoxy. Preferred aryl groups are lower aryl groups that contain less than 7 carbons in the ring structure. Cycloalkyl refers to saturated cyclic carbon chains; cycloalkienyl and cycloalkynyl refer to cyclic carbon chains that include at least one triple unsaturated bond. The cyclic portions of the carbon chains can include a ring or two or more rings combined. The carbocyclic group is a ring containing at least three carbons; a heterocyclic group is a ring containing one carbon and at least one or more heteroatoms, preferably selected from 0, S and N, more preferably N and 0. A heteroaryl group is an unsaturated ring structure containing 1 or more , preferably from 1 to 3 heteroatoms in the ring. The rings can be single or of two or more combined rings. The heteropole is used interchangeably with the heterocycle.

The heterocycle refers to ring structures that include at least one carbon atom and one or more atoms, such as N, S, and O. Alkyl refers to non-aromatic carbon chains containing one or more carbons; the chains can be linear or branched or they can include cyclical portions or be cyclical. The alicyclic refers to aryl groups that are cyclic. Haloalkyl refers to an alkyl radical, preferably lower alkyl, wherein one or more of the hydrogen atoms are replaced by halogen including, but not limited to, chloromethyl, trifluoromethyl, l-chloro-2-fluoroethyl, and others groups The "lower haloalkyl" refers to lower alkyl substituted with one or more halo substituents, and is preferably trichloromethyl or trifluoromethyl. Haloalkoxy refers to RO- wherein R is a haloalkyl group. Aminocarbonyl refers to C (0) NH2-. Alkylaminocarbonyl refers to -C (0) NHR wherein R is hydrogen, alkyl, preferably lower alkyl or aryl, preferably lower aryl. Dialkylaminocarbonyl refers to C (0) NR'R wherein R 'and R are independently selected from alkyl or aryl, preferably lower alkyl or lower aryl; carboxamide: refers to the groups of the formula NR'COR. Alkoxycarbonyl as used in the present invention refers to C (0) 0R in which R is alkyl, preferably lower alkyl or aryl, preferably lower aryl, Alkoxy and thioalkoxy refer to RO and RS wherein R is alkyl, preferably alkyl lower or aryl, preferably lower aryl When a particular group, such as phenyl or pyridyl is specified, this means that the group is substituted or unsubstituted The compounds can be made as described in the aforementioned patents and incorporated herein by reference. which is preferred as follows: ~ - 2- [4- (4-hydroxy-4-phenylpiperidin) -2, 2-diphenylbutyryl] -piperidine; 4- { 4- [4-hydroxy-4- (3- trifluoromethylphenyl; piperidin! -2,2-diphenylbutyryl, morpholine; l-. {4- [4-hydroxy-4- (3-trifluoromethyl-phenyl) piperidin] -2,2-diphenylbutyl} piperidine; 4- (p-chlorophenyl) -4-hydroxy-NN-trimethyl-a, a-diphenyl-pyridin-1-butyramide; 4- (p-chlorophenyl) -4-hydroxy-NN-dimethyl-a, a-diphenyl pipe-ridin-1-butyramide [loperamide]; 4- (p-chlorophenyl) -4-hydroxy-N-N-dimethyl-a, a-diphenylpipe-ridine-butyramide-1-N-oxide; 4- (3,4-dichlorophenyl) -N-N-diethyl-4-hydroxy-a, a-diphenylpipe-ridin-1-butyramide; 4- (3, 4-dichlorophenyl) -4-hydroxy-N-N-dimethyl-a, a-diphenylpipe-ridine-1-butyramide; 4- (4-chloro-3-trifluoromethylphenyl) -4-hydroxy-N-N-dimethyl-a, a-diphenylpiperidine-1-butyramide; 4- (p-fluorophenyl) -4-hydroxy-N-N-trimethyl-a, a-diphenylpipe-ridine-1-butyramide; 4- (p-bromophenyl) -4-hydroxy-N-N-dimethyl-a, a-diphenylpipe-ridine-1-butyramide; 1- . { 4- [4- (3,4-dichlorophenyl) -4-hydroxypiperidin] -2,2-diphenylbutyryl} pyrrolidine; 4- (p-chlorophenyl) -N-ethyl-4-hydroxymethyl-a, a, -diphenylpipe-ridine-1-butyramide; 5- [1, l-diphenyl-3- (exo-5-hydroxy-2-azabicyclo [2,2,2] oct-2-yl) propyl] -2-methyl-1,3,4-oxadiazole; 5- [1, 1-diphenyl-3- (exo-5-acetoxy-2-azabicyclo [2.2-2] oct-2-yl) propyl] -2-methyl-1,3,4-oxadiazole; 5- [1, 1-diphenyl-3- (endo-5-acetoxy-2-azabicyclo [2.2-2] oct-2-yl) -propyl] -2-methyl-1,3-oxadiazole; 5- [1,1-diphenyl-3- (endo-5-hydroxy-2-azabicyclo [2.2-2] oct-2-yl) -propyl] -2-methyl-1,3,4-oxadiazole; - [1, 1-diphenyl-3- (endo-6-acetoxy-2-azabicyclo [2.2.-2] oct-2-yl) -propyl] -2-methyl-1,3,4-xadiazole; 5- [1,1-di-phenyl-3- (endo-6-hydroxy-2-azabicyclo [2.2.-2] oct-2-yl-) propyl] -2-methyl-1,3,4-oxadiazole; 5- [1, 1-diphenyl-3- (exo-6-acetoxy-2-azabicyclo [2.2.-2] oct-2-yl) -propyl] -2-methyl-1,3,4-oxadiazole; 5- [1, 1-diphenyl-3- (exo-6-hydroxy-2-azabicyclo [2.2.-2] oct-2-yl) -propyl] -2-methyl-1,3,4-oxadiazole; 1- (3,3,3-Triphenylpropyl) -4-phenyl-4-piperidinecarboxylic acid hydrochloride; ethyl 1- (3, 3, 3-triphenylpropyl) -4-phenyl-4-piperidinecarboxylate; potassium 1- (3, 3, 3-triphenylpropyl) -4-phenyl-4-piperidinecarboxylate; sodium 1- (3, 3, 3-triphenylpropyl) -4-phenyl-4-piperidinecarboxylate; 1- [3,3-diphenyl-3- (2-pyridyl) propyl] -4-phenyl-4-piperidinecarboxylic acid hydrochloride; sodium-1- [3, 3-diphenyl-3- (2-pyridyl) propyl] -4-phenyl-4-piperidinecarboxylate; ethyl 1- [3,3-diphenyl-3- (2-pyridyl) -propyl] -4-phenyl-4-piperazinecarboxylate; potassium 1- [3, 3-diphenyl-3-pyridyl-2-pyridyl] -4-phenyl-4-pyridinecarboxylate; 1- (3, 3, 3-triphenylpropyl) -4-phenyl-4-piperidinemethanol; 1- [3, 3-diphenyl-3- (2-pyridyl) -propyl-4-phenyl-4-piperidine-methanol; 1- (3, 3, 3-triphenylpropyl) -4-phenyl-4-acetoxymethyl-piperidine; 1- (3, 3, 3-triphenylpropyl) -4-phenyl-4-methoxymethyl-piperidine; 1- (3, 3, 3-triphenylpropyl) -4- (4-chlorophenyl) -4-piperidinemethanol; 1- [3- (p-chlorophenyl) -3,3-diphenyl-propyl] -4- (phenyl) -4-piperidinemethanol; l- [3- (p-Tolyl) -3,3-diphenylpropyl] -4- (phenyl) -4-piperidinemethanol; 1- [3- (p-bromophenyl) -3,3-diphenylpropyl] -4- (phenyl) -4-piperidinemethanol; 1- [3, 3-diphenyl-3- (4-pyridyl) -propyl] -4-phenyl-4-piperidinemethanol; 1- [3, 3-dipheny1-3- (3-pyridyl) propyl] -4-phenyl-4-iperidinemethanol; 1- (3, 3, 3-triphenylpropyl) -4-phenyl-4-hexoxymethyl-piperidine; 1- (3,3,3-triphenylpropyl) -4- (p-tolyl) -4-pipendinmethanol; 1- (3, 3, 3-triphenylpropyl) -4- (p-trifluoromethyl) -4-piperidinemethanol; 1- (3, 3, 3-triphenylbutyl) -4- (phenyl) -4-piperidinemethanol; 1- (3, 3, 3-triphenylpropyl) -4- (phenyl) -4-piperidinemethanol; 1- (3, 3, 3-triphenylpropyl) -4- (phenyl) -4-methoxyethylpiperidine; 1- [3, 3-diphenyl-3- (2-pyridi1) propyl] -4-phenyl-4-methoxyethyl-piperidine; 1- (3, 3, 3-triphenylpropyl) -4-phenyl-4-piperidinemethanol; l- [3,3-Diphenyl-3- (2-pyridyl) propyl] -4-phenyl-4-piperidinemethanol; 1- (3, 3, 3-triphenylpropyl) -4-phenyl-4-acetoxymethylpiperidine; 1- (3, 3, 3-triphenylpropyl) -4-phenyl-4-methoxymethylpiperidine; 1- (3, 3, 3-triphenylpropyl) -4- (chlorophenyl-4-piperidinemethanol; 1- (3, 3, 3-triphenylpropyl) -4-hydroxy-4-benzylpiperidine and 1- (3,3,3-triphenylpropyl) -4-hydroxy-4-benzylpiperidine; hydrochloride; 1- (3, 3, 3-triphenylpropyl) -4-hydroxy-4- (p-chlorobenzyl) piperidine; 1- (3, 3, 3-triphenylpropyl) -4-hydroxy-4- (p-methylbenzyl) -piperidine; l- (3,3,3- (2-pyridyl) propyl-] -4-benzyl-4-hydroxypiperidine; oidophenylamidinourea; p-chlorophenylamidinourea; 3-dichlorophenylamine, m-bromophenylamidinourea; p-bromophenylamidinourea; 3-dibromo-phenylamidineourea; 3-Chloro-4-bromophenylamine, 3-bromo-chlorophenylamine, 3-chloro-4-fluorophenylamine, 3-bromo-4-fluoro-phenylamide, 3-fluoro-4-chlorophenylamine, 2,6-dimethylphenylamine. 2,6-diethylphenylamidinourea; 2-methyl-6-ethylphenylamidinourea; 2-methyl-6-methoxyphenylamidinourea; 2-methyl-6-ethoxyphenylamine; 2-ethyl-6-methoxyphenylamidoinourea; 2-ethyl-6-ethoxyphenylamine; 3, 4-dimethoxyphenylamine; 3, 4-dihydroxyphenylamidoinourea; 3,4,5-trimethoxyphenylamine in urease; 3,4,5-trihydroxyphenylamidinourea; 2- [(2-methyl-3-aminophenyl) amino] -1-pyrroline, dihydrochloride; 2- [(2-methyl-3-acetamidophenyl) amino] -1-pyrroline, hydrochloride; 2- [(2-methyl-3- (ethoxycarbonylamino) phenyl) amino] -1-pyrroline, hydrochloride; 2- (2, 2-diphenylpentyl) -1-azabicyl [2.2.2] octane; 2- (2, 2-diphenylhexyl) -1-azabicyl [2.2.2] octane; 2- (2, 2-diphenylpropyl) -1-azabicyl [2.2.2] octane; 2- (2, 2-diphenyloctyl) -1-azabicyl [2.2.2] octane; and "" 2- (2, 2-diphenylheptyl) -1-azabicyl [2.2.2] octane. Of these compounds, loperamide, [4- (p-chlorophenyl) -4-hydroxy-N-N-dimethyl-a, a-diphenyl-1-piperidenebutyramide monochloride] and the N-oxides of loperamide they are more preferred. FORMULATIONS OF THE PRESENT INVENTION The effective concentrations of one or more of the compounds of the present invention or pharmaceutically acceptable derivatives thereof are mixed with a carrier or pharmaceutical carrier suitable for systemic, topical or local administration. The compounds are included in an amount effective to reduce the pruritic symptoms for which treatment is contemplated. The concentration of the active compound in Xa composition will depend on the absorption, inactivation, ranges of excretion of the active compound, the dosing schedule, and the amount administered as well as other factors known to those skilled in the art. For topical and local administration, the dosages are higher, typically at least about 5 to about 10, more than the amount delivered when administered systèmically in oral form. 8 The dosage of the compounds used in the compositions of the present invention is approximately 0. 001 to approximately 20 mg / kg patient body weight.

Preferred unit dosages are from 0.05 to 10 mg / kg body weight of the patient. The compounds contained in a pharmaceutically acceptable carrier are administered orally, parenterally, rectally and topically. Suitable carriers or pharmaceutical carriers for the administration of the compounds and for the methods provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration. a) Systemic Formulations The formulations of the present invention are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable amounts of a compound of Formula I or pharmaceutically acceptable salts thereof. The dosage unit dosage forms are given from about 0.05 mg to about 50 ~ D mg and preferably from about 1.0 to about 200 mg of the essential active ingredient or a combination of essential ingredients per unit dosage form. The oral pharmaceutical dosage forms are either solid or liquid. The solid dosage forms are tablets, capsules, granules, and powders in volume. Types of oral tablets include dragees and compressed, chewable tablets that may be enteric, sugar or film coated. The capsules can be hard or soft gelatin capsules, while the granules and powders can be supplied in an effervescent or non-effervescent form with the combination of other ingredients known to those skilled in the art.The pharmaceutically acceptable carriers used in tablets are binders, lubricants , diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents Tablets "coated with enteric coating, due to their enteric coating, resist the action of stomach acid and dissolve or disintegrate in the intestines with neutral or alkaline characteristics. Sugar coated tablets are compressed tablets to which different layers of pharmaceutically acceptable substances have been applied. The film coated tablets are compressed tablets that have been coated with water soluble polymers.

Multiple compressed tablets are compressed tablets made by more than one compression cycle using pharmaceutically acceptable substances mentioned above. Coloring agents can also be used in the form of the above dosage. Flavoring agents or sweeteners are used in compressed tablets, sugar coated tablets, compressed multiple and chewable. Flavoring or sweetening agents are especially useful in the formation of chewable tablets and lozenges. Examples of binders include glucose solution, acacia mucilage, gelatin solution, starch paste and sucrose. Lubricants include talcum, starch7"magnesium or calcium stearate, lycopodic and stearic acid, eg, diluents include lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.The disintegrating agents include corn starch, starch potato, bentonite, methylcellulose, agar and carboxymethylcellulose For example, the coloring agents include any of the approved and certified water soluble dyes FD and C, mixtures thereof, and dyes "FD and C insoluble in water suspended in alumia hydrate. ._ Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as sodium cyclamate and saccharin, and any number of dry spray flavorings. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds that produce a pleasant sensation. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene laural ether. The enteric layers include fatty acids, fats, waxes, shellac, ammoniated lacquer and cellulose acetate phthalates. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules and reconstituted effervescent preparations from effervescent granules. For example, aqueous solutions include elixirs and syrups. The emulsions are either oil in water or water in oil. The elixirs are hydroalcoholic, transparent sweetened preparations. The pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of sugar, for example, sucrose, and may contain a preservative. An emulsion is a two-phase system in which a liquid is dispersed in the form of small globules through another liquid. The pharmaceutically acceptable carriers used in the emulsions are non-aqueous liquids, emulsifying agents and preservatives. The suspensions use pharmaceutically acceptable and conservative suspending agents. The pharmaceutically acceptable substances used in the non-effervescent granules, to be reconstituted in oral, liquid dosage form, include diluents, sweeteners and wetting agents. The pharmaceutically acceptable substance used in effervescent granules, to be reconstituted in a liquid oral dosage form, includes organic acids and a source of carbon dioxide. The coloring and flavoring agents are used in all the above dosage forms. Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia. The diluents include lactose and sucrose. Sweetening agents include sucrose, syrups, glycerin and antifungal sweetening agents such as sodium cyclamate and saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate.The coloring agents include any of the approved water-soluble dyes and FD and C dyes, and mixtures thereof Flavoring agents include natural flavors extracted from plantings such as fruits1, and synthetic mixtures of compounds that produce a pleasant taste sensation Parenteral administration of the formulations of the present invention includes intravenous, hypodermic and intramuscular administration Preparations for parenteral administration include ready sterile solutions prepared for -the-injection , sterile dry soluble products prepared to be combined with a solvent prepared before use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just before use and emulsifiers. Sterile ions Solutions can be aqueous or non-aqueous. The pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents, pH regulators, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances. Examples of aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Ringers Injection with Dextrose and Lactate. Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations should be added to parenteral preparations packed in multiple-dose containers that include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl esters of methyl and propyl p-hydroxybenzoic acid thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. PH regulators that include phosphate ^ and citrate. Loa antioxidants that include sodium bisulfate. Local anesthetics that include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (Tween 80). A metal ion chelating or sequestering agent includes EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for vehicles miscible in water and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for Ph adjustment. The concentration of the pharmaceutically active compound is adjusted so that the injection provides an effective amount to produce the pharmacological-desired effect. The dose depends on the age, weight and condition of the patient or animal as is known in the art. Parenteral preparations of unit doses are packaged in a vial or syringe with a needle. All preparations for parenteral administration must be sterile as known and practiced in the art. Illustratively, intravenous or intraarterial infusion of a sterile aqueous infusion containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an injected active material conformed! is necessary to produce the desired pharmacological effect.

The pharmacological dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories as used herein, represent solid bodies for insertion into the rectum that melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients. The pharmaceutically acceptable substances used in rectal suppositories are bases or vehicles and agents for raising the melting point. Examples of the bases include cocoa butter (theobroma oil), glycerin ^ gelatin, carbowax, (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. The combinations of several bases can be used. Agents for raising the melting point of suppositories include whale whit and ceraz rectal suppositories can be prepared either by the compressed method or by molding. The typical weight of a rectal suppository is approximately 2 to 3 grams. Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and through the same methods as for oral administration formulations.

The pharmaceutically and therapeutically active compounds of the Formula I are administered orally, parenterally or rectally in the form of unit doses or in the form of multiple doses. The unit dose forms as used herein refer to physically discrete units suitable for human and animal subjects and are packaged individually as is known in the art. Each unit dose contains a predetermined quantity of therapeutically active compound sufficient to "produce the desired therapeutic effect in association with the required pharmaceutical carrier, vehicle or diluent." Examples of unit dosage forms include individually packed ampoules and syringes, tablets or capsules. The unit dosage forms can be administered in fractions or multiple fractions thereof A unit dosage form is a plurality of identical unit dose forms packaged in a single container to be administered in the form of a segregated unit dose. examples of multiple dosage forms include bottles, bottle capsules or bottles of different capacities.Therefore, the multiple dose form is a multiple of the unit doses that are not segregated in the packaging.) b) Local and Topical Formulations Normally, a therapeutically effective dose is form to contain r a concentration of at least 0.1% w / w up to about 50% w / w or more preferably, more than 1% w / w of the active compound for the treated tissue. The active ingredient can be administered at one time, or it can be divided into a number of smaller doses to be administered at intervals. It is understood that the precise dosing and duration of treatment is a function of the tissue being treated and can be determined empirically using test protocols - or by screening in addition to in vivo or in vitro test data. It should be noted that the concentrations and dose values may also vary with the age of the individual treated. It should also be understood that for any particular subject, the specific dose regimens must be adjusted over time in accordance with the individual need and professional judgment of the person administering or supervising the administration of the formulations, and that the established concentration ranges they are only illustrative here and are not intended to limit the scope or practice of the formulations claimed. The compound can be suspended in micronized or other suitable form or can be derivatized to produce a more soluble active product or to produce a pro-drug. The form of the resulting mixture depends on a number of factors, including the intended mode of administration and the solubility of the compound in the carrier or vehicle selected.The effective concentration is sufficient to ameliorate the pruritic condition and can be determined empirically. - The compounds are usually included in "concentrations of 0.001% w / w more than 1% w / w up to 50% w / w or more.The concentration is generally higher than the concentration for systemic administration of the compound. range of 0.01 .__ p / pa approximately 25% w / w, more preferably 1% w / w 25% - w / w, even more preferably more than about 1% w / w approximately 10% w / w, and more preferably greater than 1% w / w up to about 5% w / w The suspensions and aqueous formulations contain 1% w / w more The resulting mixture can be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments , emulsions, solutions, elixirs, lotions, suspensions, dyes, pastes, foams, sprays, irrigates, sprays, suppositories, bandages or any other formulation suitable for topical or local administration.The administration route in the present is the administration t pica or local and the compositions are formulated in a manner suitable for each route of administration. Preferred modes of administration include topical administration to the skin, eyes or mucosa and local application to the joints, such as intra-articular injections. Therefore, typical vehicles are those suitable for pharmaceutical or cosmetic application to body surfaces or for local injection. The pharmaceutical carriers and vehicles suitable for the administration of the compounds provided herein include any carriers known to those known in the art to be suitable for the particular mode of administration. In addition, the compounds can be formulated as the sole pharmaceutically active ingredient in the composition or can be combined with other active ingredients. The active compound is included in the carrier in an amount sufficient to exert a therapeutically useful effect in "absence of serious toxic effects on the treated individual." The effective concentration can be determined empirically by testing the compounds using in vitro systems. In vivo For the topical administration, the compounds can be formulated into compositions in the form of gels, creams, lotions, solids, solutions or suspensions, or aerosols.The compositions for the treatment of human skin are formulated for topical application with an amount effective antripuritics of one or more of the selected compounds as described herein, in an effective concentration range [by weight] between about 0.1% and 80%, preferably 0.1 to 50%, more preferably more than about 1% up to about 50% or more in a cream, ointment, lotion, gel, solution or solid base or vehicle known in the art to be non-toxic and dermatologically acceptable or suitable for application to the mucosa. Aqueous suspensions are preferably formulated in concentrations greater than about 1% w / w, more preferably 2% w / w To formulate a composition, the weight fraction of the compound is dissolved, suspended or dispersed, otherwise The mixture is mixed in a selected vehicle at an effective concentration so that the hyperalgesic condition is relieved or improved. Generally, emollient or lubricant vehicles that can help hydrate the skin are more preferred than volatile vehicles, such as ethanol, which dries the skin. Examples of suitable bases or vehicles for preparing compositions for use with human skin are petrolatum, petrolatum plus volatile silicones, lanolin, [USP], hydrophilic ointment [USP]. The choice of an acceptable vehicle is determined to a large extent by the mode of application and the fabric to be treated. Pharmaceutically and determatologically acceptable vehicles for topical application include those suitable for use that include lotions, creams, solutions, gels, tapes and the like. Generally, the vehicle is organic in nature or an aqueous emulsion and capable of having the selected compound or compounds that can be micronized, dispersed, suspended or dissolved therein. The vehicle can include pharmaceutically acceptable emollients, skin penetration enhancers, coloring agents, fragrances, emulsifiers, thickening agents and solvents. For local internal administration, such as intra-articular administration, the compounds are preferably formulated as a suspension in an aqueous-based medium, such as isotonicly-regulated salt solution or combined with a biocompatible or bioadhesive support intended for internal administration. Lotions Lotions contain an effective concentration of one or more of the compounds. The effective concentration is preferably effective to deliver an anthropytic amount, typically a concentration of between about 0.1-50% w / w or more than one or more of the compounds provided herein. The lotions also contain from 1% to 50% w / w, preferably from 3% to 15% w / w of an emollient and the remainder water, a suitable regulator, a C2 or C3 alcohol, or a water mixture of the pH regulator and alcohol. Any emollients known to those skilled in the art as have been suitable for application to human skin can be used. These include, but are not limited to the following: (a) Hydrocarbon and paraffin oils, which include mineral oil, petrolatum, paraffin, ceresin, ozokerite, microcrystalline wax, polyethylene, and perhydrosqualene. (b) Silicone oils that include dimethylpolysiloxanes, methylphenylpolysiloxanes, water soluble and silicone-soluble silicone-glycol copolymers. (c) Triglyceride fats and oils including those derived from plant, animal and marine sources. Examples include, but are not limited to, castor oil, safflower oil, cottonseed oil, corn oil, olive oil, cod liver oil, almond oil, avocado oil, sesame oil and oil. of soybeans. (d) Acetoglyceride esters such as "acetylated monoglycerides. (e) Ethoxylated glycerides such as ethoxylated glyceryl monostearate. (f) Alkyl esters of fatty acids having from 10 to 20 carbon atoms. Methyl, isopropyl and butyl esters of fatty acids are useful herein. Examples include, but are not limited to, hexyl laurate, isohexyl laurate, isohexyl palmitate, isopropyl palmitate, isopropyl myristate, decyl oleate, isodecyl oleate, hexadecyl stearate, decyl stearate, isopropyl isostearate diisopropyladipate, adipate. of diisohexyl, dihexyldecyl adipate, diisopropyl sebacate, lauryl lactate, myristyl lactate, and cetyl lactate. (g) Alkenyl esters of fatty acids having from 10 to 20 carbon atoms. Examples thereof include, but are not limited to, oleyl myristate, oleyl stearate and oleyl oleate. (h) fatty acids having from 9 to 22 carbon atoms. Suitable examples include, but are not limited to, pelargonic, lauric, myristic, palmitic, stearic, isostearic, hydroxystearic, oleic, linoleic, ricinoleic, arachidonic, behenic, and erucic acids. (i) Fatty alcohols having from 10 to 20 carbon atoms, such as, but not limited to, lauryl, myristyl, cetyl, hexadecyl, stearyl, isostearyl, hydroxystearyl, oleyl, ricinoleilic, behenyl, erucyl and 2-octyl dodecyl alcohol. (j) Fatty alcohol ethers, including, but not limited to, ethoxylated fatty alcohols of 10 to 20 carbon atoms, such as, but not limited to, laurylcetyl, stearyl, isostearyl, oleyl and cholesterol alcohols having attached to the same from 1 to 50 ethylene oxide groups or from 1 to 50 propylene oxide groups or mixtures thereof. (k) Ether esters such as fatty acid esters such as ethoxylated fatty alcohols (1) Lanolin and derivatives, including but not limited to lanolin, lanolin oil, lanolin wax, lanolin alcohols, lanolin fatty acids, isopropyl lanolate , ethoxylated lanolin, ethoxylated lanolin alcohols, ethoxylated cholesterol, propoxylated lanolin alcohols, acetylated lanolin, acetylated lanolin alcohols, lanolin alcohol linoleate, lanolin alcohol ricinoleate, lanolin alcohol ricinoleate acetate, alcohol ester alcohol ethoxylates, lanolin hydrogenolysis, ethoxylated hydrogenated lanolin, ethoxylated sorbitol lanolin, and liquid and semisolid lanolin absorption bases. (m) Polyhydric alcohols and polyether derivatives, including, but not limited to, propylene glycol, dipropylene glycol, polypropylene glycol, [M.W. 2000-4000], polyoxyethylenepolyoxypropylene glycols, polyoxypropylene polyoxyethylene glycols, glycerol, ethoxylated glycerol, sorbitol, ethoxylated sorbitol, hydroxypropyl sorbitol, polyethylene glycol [M. W. 200 6000], methoxypolyethylene glycols, 350, "550, 750, 2000, 5000, poly) ethylene oxide) homopolymers [MW 100,000 5,000,000], polyalkylene glycols and derivatives, hexylene glycol (2-methyl-2, -pentanediol), 1, 3 -butylene glycol, 1,2,6-hexanetriol, ethohexadiol USP (2-ethyl-l, 3-hexanediol), vicinal glycol of Cis-Cig and polyoxypropylene derivatives of trimethylolpropane. (n) Polyhydric alcohol esters, including, but are not limited to esters of diethylene glycol mono- and di-fatty acid esters of diethylene glycol mono and di-fatty acids, polyethylene glycol [MW 20Q-6000], mono- and di-fatty esters, acid esters of propylene glycol mono- and di- -, propylene glycol monooleate 2000, propylene glycol 2000 stearate, ethoxylated propylene glycol monostearate, glyceryl mono- and di-fatty acid esters, polyglycerol polyglyc acid esters, ethoxylated glyceryl monostearate, 1,3-butylene glycol monostearate, distearate of 1, 3-butylene glycol, fatty acid ester of polyoxyethylene polyol polyol, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters. (o) Wax esters, including, but not limited to, beeswax, whale white, myristyl myristate and stearyl stearate and beeswax derivatives, including, but not limited to, polyoxyethylene sorbitol beeswax, which are products of the reaction of beeswax with ethoxylated sorbitol - with content variable ethylene oxide forming a mixture of ether-esters. (p) Vegetable waxes, including, but not limited to carnauba and candelilla waxes. "" (q) Phospholipids, such as lecithin and derivatives, (r) Esterols, including, but not limited to, cholesterol and esters of Fatty acid is cholesterol. (s) Amides, such as fatty acid amides, ethoxylated fatty acid amides and solid fatty acid alkanolamides. The lotions preferably further contain from 1% w / w to 10% w / w, more preferably from 2% w / w to 5% w / w of an emulsifier. The emulsifiers can be nonionic, anionic, or cationic. Examples of "satisfactory nonionic emulsifiers include, but are not limited to, fatty alcohols having from 10 to 20 carbon atoms, fatty alcohols having 10 to 20 carbon atoms, condensed with 2 to 20 moles of ethylene oxide or propylene, alkylphenols with 6 to 12 carbon atoms in the alkyl chain condensed with 2 to 20 moles of ethylene oxide, mono- and di-fatty acid esters of ethylene oxides of mono- and di-fatty acid esters of ethylene glycol wherein the fatty acid moiety contains from 10 to 20 carbon atoms, diethylene glycol, polyethylene glycols of molecular weight from 200 to 6000, propylene glycols of molecular weight from 200 to 3000, glycerol, sorbitol, sorbitan, polyoxyethylene sorbitol, polyoxyethylene sorbitan and esters of hydrophilic wax Suitable anionic emulsifiers include, but are not limited to, fatty acid soaps, for example, sodium, potassium and triethanolamine soaps, wherein the acid portion is satin contains from 10 to 20 carbon atoms, other suitable anionic emulsifiers, but not limited to, alkali metal, ammonium or substituted ammonium sulfates, alkylaryl sulphonates, and alkyl ethoxyether sulfonates having from 10 to 30 carbon atoms in the alkyl portion . Alkylethoxyether sulfonates contain from 1 to 50 ethylene oxide units. Among the satisfactory cationic emulsifiers are quaternary ammonium, morpholinium and pyridinium compounds. Some of the emollients described in the preceding paragraphs also have emulsifying properties. When formulating a lotion containing such an emollient, an additional emulsifier is not necessary although it may be included in the composition.

The rest of the lotion is water or a C-alcohol or C3, or a mixture of water or alcohol. Lotions are formulated by simply mixing all the components together. Preferably, the compound is dissolved, suspended or otherwise dispersed in the mixture. Other conventional components of such lotions may be included. Such an additive is a thickening agent at a level from 1% to 10% w / w of the composition. Examples of suitable thickening agents include, but are not limited to: crosslinked carboxymethylene polymers, ethylcellulose, polyethylene glycols, gum, tragacanth, karaya gum, xanthan gum and bentonite, hydroxyethylcellulose and hydroxypropylcellulose. Creams The creams are formulated to contain effective concentration to deliver an effective antipruritic amount of the compound to the treated tissue, typically between about 0.1%, preferably greater than 1% up to and greater than 50%, preferably between about 3% and 50%, more preferably between about 5% and 15% of one or more of the compounds provided herein. The creams also contain from 5% to 50%, preferably from 10% to 25% of an emollient and the remainder is water or another suitable non-toxic carrier, such as an isotonic pH regulator. The emollients, as described above for the lotions, can be used in the cream compositions. The cream may also contain a suitable emulsifier as described above. The emulsifier is included in the composition at a level from 3% to 50%, preferably from 5% to 20%. Solutions and suspensions for topical and local administration The solutions are formulated to contain an amount of one or more effective compounds to be delivered. an antipruritic amount, typically at a concentration of between about 0.1 to 50% w / w, preferably at least more than 1% w / w, more preferably more than 2% w / w of one or more of the compounds provided herein. The rest is water, a suitable organic solvent or another suitable solvent or pH regulator. Suitable organic materials useful as the solvent or a part of the solvent system are the following: propylene glycol, polyethylene glycol, [M.W. 200-600], polypropylene glycol [M.W. 425-2025], glycerin, sorbitol esters, 1, 2, 6-hexanetriol, etane, isopropanol, diethyl tartrate, butanediol and mixtures thereof. Such solvent systems may also contain water. The solutions or suspensions used for the local application may include any of the following. components: a sterile diluent, such as water for "injection, saline, fixed oil, polyethylene glycol, glycerin, propylene glycol or other synthetic solvent, agents, antimicrobials, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid, [EDTA], pH regulators such as acetates, citrates and phosphates, and agents for the tonicities such as sodium chloride or dextrose.The liquid preparations can be enclosed in ampoules, disposable syringes or containers Multiple doses made of glass, plastic or other suitable material Suitable carriers may include physiological saline solution or phosphate buffered saline [PBS], and suspensions and solutions may contain thickening and solubilizing agents, such as glucose, polyethylene glycol and polypropylene glycol and mixtures thereof. liposomal, may also be suitable as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. These compositions which are formulated as solutions or suspensions may be applied to the skin, or they may be formulated as an aerosol or foam and applied to the skin as a spray. The aerosol compositions typically contain from 25% up to 80% w / w, preferably from 30% to 50% w / w of a suitable propellant. Examples of such propellants are low molecular weight, chlorinated, fluorinated and chlorofluorinated hydrocarbons. Nitrous oxide, carbon dioxide, butane and propane are also used as propellant gases. These propellants are used as known in the art in an amount and under a suitable pressure to expel the contents of the container. Solutions and suspensions prepared in a suitable manner can also be applied topically to the eyes and mucosa. Solutions, particularly those intended for ophthalmic use, can be formulated as isotonic solutions of 0.01% -10% w / w, pH of about 5-7, with appropriate salts and preferably contain one or more of the present compounds in a concentration of 0.1% w / w preferably greater than 1% w / w, up to 50% w / w more. Suitable ophthalmic solutions are known [See for example, US Patent No. 5,116,868, which describes typical compositions of ophthalmic irrigation solutions and solutions for topical application]. Such solutions, which have a pH adjusted to about 7.4, contain for example 90-100 mM sodium chloride, 4-6 mM dibasic potassium phosphate, 4-6 mM dibasic sodium phosphate, 8-12 mM citrate sodium, 0.5-1.5 mM magnesium chloride, 1.5-2.5 M calcium chloride, 15-25 mM sodium acetate, 5 -20 mM of D.L. sodium ß-hydroxybutyrate and -5.5 mM glucose. The active compounds of the present invention can also be mixed with other active materials, those that do not deteriorate the desired action, or with materials that complement the desired action, including viscoelastic materials, such as hyaluronic acid, which is sold under the HEALON brand [ solution of a high molecular weight fraction (MW of about 3 million) of sodium hyaluronate, manufactured by Pharmacia, Inc. See for example, US Patents Nos. 5,292,362, 5,282,851, 5,273,056, 5,229,127, 4,517,295 and 4,328.8"03 ], VISCOAT [fluorine-containing methacrylates, such as 1H, 2H, 2H-heptadecafluorodecylmethacrylate, see for example, U.S. Patent Nos. 5,278,126, 5,273,751 and 5,214,080, commercially available from Alcon Surgical, Inc.], ORCOLON [see for example, U.S. Patent No. 5,273,056, commercially available from Optical Radiation Corporation], methyl cellulose, methyl hyaluronate, polyacrylamide and pol imetacrilamide; [see for example, U.S. Patent No. 5,273,751]. Viscoelastic materials are generally present in amounts ranging from about 0.5 to 5.0 °, w / w, preferably from 1% to 3% w / w of the conjugate material and serve to coat and protect the treated tissues. The compositions may also include a colorant, such as methylene blue or other inert dye, so that the composition can be seen when it is injected into the eye or brought into contact with the surgical site during surgery. Gels The gel compositions can be formulated by simply mixing a suitable thickening agent to the solution or suspension composition previously described. The. Examples of suitable thickening agents have been previously described with respect to lotions. The gelled compositions contain an effective amount of one or more antipruritic amount, usually at a concentration between about 0.1-50% w / w or more than one of the compounds provided therein; from 5% to 75% w / w, preferably from 10% to 50% w / w, of an organic solvent as previously described; from 0.5% to 20% "w / w, preferably from 1% to 10% w / w of the thickening agent, the remainder being water or other aqueous carrier Solids The solid form compositions can be formulated as adhesive-like compositions intended for application to the lips or other body parts Such compositions contain an effective amount of one or more of the compounds provided herein The amount is usually an amount effective to deliver an antipruritic amount, typically at a concentration of between about 0.1-50% w / w more than one or more of the compounds provided herein.The solids also contain from about 40% to 98% w / w, preferably from about 50% to 90% w / w of the emollients described above The composition can also contain from 1% to 20% w / w, preferably from 5% to 15% w / w, from a thickening people, and, if desired or needed, emulsifiers and water or regulators of pH. Other ingredients such as preservatives, including methylparaben or ethylparaben, perfumes, colorants or the like, which are known in the art to provide stability, fragrance or desirable color, or other desirable properties, such as protection from the sun's acinic rays, to Compositions for application to the skin can also be used in a composition for topical application. The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention. Example 1 - Capsules Active compound 2.5 gm Corn starch 23.0 gm Lactose 145.0 gm Talc 15.0 gm Magnesium stearate 3.0 gm The ingredients are mixed and encapsulated using techniques known in the art. Example 2 - Tablet Active compound 150 gm Lactose 125 gm Corn starch 50 grn Magnesium stearate 2.0 gm PPeettrroollaattoo llííqquididao 2.0 gm The ingredients were mixed, then they were placed in American standard sieves to produce fine granules. The granules were compressed into the tablets, each tablet containing about 150 mg of an active compound of the present invention. Example 3 - Active compound syrup 25 gm Lemon oil 2 mi Sucrose 650 gm Citric acid 4 gm Benzoic acid 3 gm Tragacanth 16 gm Deionized water qs 1000 ml The ingredients without the active compound are dispersed in water to form approximately 800 to 900 ml of -solution. The active compound is then added and the solution is stirred in a syrup. Then the water is added to form 1000 ml of syrup. Example 4 - Parenteral Solution Active compound 30 gm Methylparaben 3 gm Propylparaben 1 gm Lidocaine 5 gm Deionized water q.s. 1000 ml The ingredients were dissolved in water to provide a solution followed by sterilization by filtration. Example 5 - Rectal suppository Active compound "80 gm Propylene glycol 95 gm Polyethylene glycol 4000 1800 gm The active compound is added to the propylene glycol and milled until a uniform finely divided mixture is formed.The polyethylene glycol 4000 is melted and the propylene glycol dispersion is added with stirring to obtain a suspension The suspension is poured into molds allowing it to solidify and removed from the packing molds Example 6 - Ointment washable with water Active compound 1.4% w / w Lanolin alcohol 0.1% w / w Emulsifying wax NF 7.5% w / w Glycerides PEG-20 5.0% w / w Petrolatum 86.0% w / w The ingredients are melted together and mixed until the resulting ointment is coagulated Example 7 - Oil-in-water cream Active compound 10.0% w / o p Benzyl alcohol 4.0% w / w Propylene glycol 10.0% w / w Polyethylene glycol-400 10.0% w / w Petrolatum 20.0% w / w Stearyl alcohol 10.0% w / w Poloxamer 10.0% w / w Water qs 100 Regulator for pH 7.0% w / w In the Preparation of the oil cream in water, water, glycol and propylene glycol 400 are heated to approximately 70 to 80 ° C, followed by the addition of a mixture of petrolatum, stearyl alcohol and poloxamer and the mixture is stirred until be homogeneous. The pH "" is then adjusted with a regulator to about 7.0. Example 8 - Aqueous Gel _ _ _ Active compound 10.0% w / w Benzyl alcohol 4.0% w / w 3.0% w / w hydroxyethyl cellulose Water q.s. 100 Regulator for pH 7.0% p / p PROOF OF FILM FORMAT COMPOSITIONS FOR ANTIPRURITIC ACTIVITY The test was executed in a pattern scraping model under blind conditions. In the test groups of 8-10 male Swiss albino mice (Hilltop Lab Animáis, Inc., Scottsdale, PA), weighing 2.5-2.6 g were used. They were housed under controlled temperature of 23-25 ° C. Food and water were freely available. Before the experiments, the mice were weighed, placed in individual boxes and allowed to acclimate for 30 minutes. Materials The vehicle used to dissolve the test compounds: cremophor EL 20% w / w. To induce the scraping compound 48/80 (Sigma, St. Louis, USA) was used which showed that it produced a sensation of itching in humans (Armstrong et al., J. Of Physiol., 120: 326, 1953) . The compound to be tested for activity, antipruritic was dissolved in the cremophor EL vehicle of 20% w / w. Method 100 μl of the vehicle (3-5 doses, n = 8-10) was injected into the back of the neck of the mice 20 minutes before testing with 100 μl of Compound 48/80 (2 mg / ml; 50 μg) ) injected into the back of the neck. One minute later the mice were observed for 30 minutes and the number of scraping movements directed to the neck was counted. The mouse with injected vehicle was scratched 79 ± 16 times in the 30 minutes after the standard challenge with Compound 48/80. Each mouse from a group of 8-10 mice was previously subjected to the standard challenge of several doses of the compounds to be tested for antipruritic activity, which was administered to the back of the neck. One minute later the mice were observed for 30 minutes and the number of scraping movements directed towards the neck was counted. _ For each group of 8-10 mice, the average values for scraping were normalized to a "relative scratch antagonism" and then plotted against the dose of the test compounds.The interval estimates of the average A50 were determined by linear ns_ regression analysis (Kaleida Graph) and the mean percentage inhibition of scratching was calculated.

The following compounds were tested: (1) hydrochloride _ 1- [3, 3-diphenyl-3- (2-pyridyl) propyl] -4-phenyl-4-piperidinecarboxylic acid; (2) 1- (3, 3, 3-triphenylpropyl) -4-hydroxy-4-p-chlorobenzylpiperidine; and (3) 4- (p-chlorophenyl-4-hydroxy-N-N-dimethyl-a, a-diphenylpiperidine-1-butyramide [loperamide].

Each compound (1, 2, 3) was opposed to Compound 48/80 induced by scraping in a dose-related manner. The results are shown in Table C. TABLE C% Scrape Inhibition Medium Compound Dose (mg / kg, sc)% Inhibition medium (i: 2.5 32 5.0 65 1-0.0 83 2) - 1.0 35 2.5 68 5.0 94 0.5 18 1.0 47 2.5 65 Other tested compounds have shown similar antipruritic activity in response to dose scale from about 15 to about 95% based on the dosage form of about 0.5 to 10.0 mg / kg, sc Those skilled in the art should understand that, while the previous invention has been described and illustrated in relation to certain specific embodiments, many variations and "modifications" may be used without departing from the scope of the invention.

Claims (3)

CLAIMS 1. A method for preventing or treating a non-respiratory and non-anilic pruritic condition in a mammal in need of such prevention or treatment comprising administration in topical, oral or parenteral form to the mammal in an effective antipruritic amount of a pharmaceutical composition that stimulates opiate receptors in peripheral sensory neurons in the skin comprising a compound of formula I where M is where: - T77 > is an azabicycloalkyl containing from 6 to 9 carbon atoms with at least 5 atoms in each ring and is substituted or unsubstituted with OR18 in which R18 is hydrogen or lower alkanoyl containing from 2 to 7 carbons and OR18 is in the position 5 in the 5-member rings or position 5 or 6 in the 6-member rings and join in the endo or exo configuration; Ar1 and Ar2 are either (i) or (ii) as follows: (i) each is independently selected from aryl and heteroaryl groups containing from 5 to 7 members in the ring, each substituted or unsubstituted with one or more substituents selected from halo, halalkyl, hydroxy, alkyl, alkyloxy, aminosulfonyl, alkylcarbonyl, nitro, haloalkyl, trifluoromethyl, amino, aminocarbonyl, phenylcarbonyl or thienyl, wherein the alkyl groups are straight or branched chain lower alkyl containing 1 to 6 carbon atoms; or (ii) Ar1 and Ar2 are independently each one phenyl or pyridyl groups and with the carbon to which they normally join they form a combined ring so that the compounds of the formula (I) have the structure: where n is 0 to 3; R2 is any alkyl in which the alkyl group is a straight or branched chain having 1 to 12 carbon atoms, or is alkylene having 1 to 6 carbon atoms with one or two double bonds; R3 is Ar3, -Y-Ar3, where Y is alkylene or alkyl having carbon atoms, or R is hydrogen or alkyl which is a straight or branched chain containing from 1 to 6 carbon atoms; Ar3 is aryl or heteroaryl containing from 5 to 7 members in the ring that is substituted or unsubstituted with one or more halo substituents, lower haloalkyl or, lower alkyl; - - Ar4 is either: (i) is a heterocycle containing one to three rings combined or which is substituted or unsubstituted with one or more substituents selected from halo, lower haloalkyl or lower alkyl, or (ii) Ar 4 is a radical of the formula: wherein R10, R11 and R12 are each independently selected from hydrogen, alkyl, alkyloxy, alkoxyalkyl, halo, haloalkyl, hydroxy, cyano, nitro, amino, alkylamino, di (alkyl) amino, aminocarbonyl, arylocarbonylamino, alkylcarbonylamino, alkylcarbonyl, alkylcarbonyloxy, aminosulfonyl, alkylsulfinyl, alkylsulfonyl, alkylthio, mercapto, Cj-C6 alkenyloxy, arylalkyloxy, aryloxy or alkyl in which each group is substituted or unsubstituted with one or more halo, haloalkyl or alkyl atoms, and the alkyl groups are of linear or branched chains that are lower alkyl; R is hydrogen, alkyl, halo, haloalkyl or OR9; Rs is selected from alkyl, arylalkyl, alkylcarbonyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl in which the alkyl groups are straight or branched chains containing from 1 to 12 carbon atoms; R 4 is selected from: (i) 5 to 7 membered aryl groups, which are substituted or unsubstituted with lower alkyl, halo lower alkyl or halo, or (ii) heterocyclic rings, contain from one to three heteroatoms which are substituted or unsubstituted with halo, lower haloalkyl or lower alkyl, or (iii) alkyl containing from 1 to 8 carbon atoms, alkenyl containing from 3 to 6 carbon atoms, cycloalkyl containing from 3 to 6 carbon atoms, cycloalkylalkyl wherein the first alkyl contains from 3 to 6 carbons and the second contains from 1 to 3 carbons, or cycloalkenyl containing from 4 to 7 carbons, or wherein R and R are either: (i) independently selected from hydrogen, alkyl, which is a straight or branched chain containing from 1 to 12 carbon atoms, alkenyl which is straight or branched chain and contains from 1 to 12 carbon atoms and one or two double bonds, or aryl containing from 5 to 7 carbon atoms or (ii) R5 and R6 are selected from carbon chains, heteroatoms, and carbon chains containing one or more heteroatoms , so that with the nitrogen atoms to which each binds they form a 3- to 7-membered heterocyclic ring containing from one to three heteroatoms which are substituted or unsubstituted with halo, lower alkyl halo or lower alkyl; and R7 is selected from: H; OH; R140R13 in which R13 is hydrogen or lower alkyl, alkanoyl containing from 2 to 5 carbon atoms, and R14 is lower alkenyl or lower alkyl; -CH2NR15R16 in which R15 is hydrogen, lower alkyl or lower alkanoyl and R16 is hydrogen or lower alkyl; OR15; R2 ~ OR13 wherein R22 is lower alkyl; -C (0) OR17 wherein R17 is hydrogen, alkyl containing from 1 to 7 carbons or alkenyl having from 3-7 carbon atoms, aryl or heteroaryl; or an alkali metal or alkaline earth metal salt. 2. The method according to claim 1, characterized in that the compound is selected from the group consisting of: 2- [4- (4-hydroxy-4-phenylpiperidin) -2, 2-diphenylbutyryl] -piperidine; 4- . { 4- [4-hydroxy-4- (3-trifluoromethylphenyl) piperidin] -2,2-diphenylbutyryl} morpholine; 1- . { 4- [4-hydroxy-4- (3-trifluoromethylphenyl) piperidin] -2,2-diphenylbutyl} piperidine; 4- (p-chlorophenyl) -4-hydroxy-N-N-trimethyl-a, a-diphenylpipe-ridine-1-butyramide; 4- (p-chlorophenyl) -4-hydroxy-N-N-dimethyl-a, a-diphenylpipe-ridin-1-butyramide [loperamide]; 4- (p-chlorophenyl) -4-hydroxy-N-N-dimethyl-a, a-diphenylpipe-ridine-butyramide-1-N-oxide; 4- (3,4-dichlorophenyl) -N-N-diethyl-4-hydroxy-a, a-diphenyl-pyl-ridin-1-butyramide; 4- (3,4-dichlorophenyl) -4-hydroxy-N-N-dimethyl-a, a-diphenyl-piperamido-1-butyramide; 4- (-chloro-3-trifluoromethylphenyl) -4-hydroxy-N-N-dimethyl-a, a-diphenylpiperidine-1-butyramide; 4- (p-fluorophenyl) -4-hydroxy-N-N-trimethyl-a, a-diphenylpipe-ridirta-1-butyramide; 4- (p-bromophenyl) -4-hydroxy-N-N-dimethyl-a, a-diphenylpipe-ridine-1-butyramide; 1- . { 4- [4- (3,4-dichlorophenyl) -4-hydroxypiperidin] -2,2-diphenylbutyryl} pyrrolidine; 4- (p-chlorophenyl) -N-ethyl-4-hydroxy-methyl-a, a, -diphenylpipe-ridine-1-butyramide; 5- [1, l-diphenyl-3- (exo-5-hydroxy-2-azabicyclo [2,2,2] oct-2-yl) propyl] -2-methyl-1,3,4-oxadiazole; 5- [1, 1-diphenyl-3- (exo-5-acetoxy-2-azabicyclo [2.2-2-oxy-2-yl) -propyl] -2-methyl-1,3,4-oxadiazole; 5- [1,1-diphenyl-3- (endo-5-acetoxy-2-azabicyclo [2.2-2] oct-2-yl) -propyl] -2-methyl-1,3,4-oxadiazole; 5- [1,1-diphenyl-3- (endo-5-hydroxy-2-azabicyclo [2.2-2] oct-2-yl) -propyl] -2-methyl-1,3,4-oxadiazole; 5- [1, 1-diphenyl-3- (endo-6-acetoxy-2-azabicyclo [2.2.-2] oct-2-yl) -propyl] -2-methyl-1,3,4-xadiazole; 5- [1, 1-diphenyl-3- (endo-6-hydroxy-2-azabicyclo [2.2.-2] oct-2-yl-) propyl] -2-methyl-1,3,4-oxadiazole; 5- [1, 1-diphenyl-3- (exo-6-acetoxy-2-azabicyclo [2.2.-2] oct-2-yl) -propyl] -2-methyl-1,3,4-oxadiazole; 5- [1,1-diphenyl-3- (exo-6-hydroxy-2-azabicyclo [2.2.-2] oct-2-yl) -propyl] -2-methyl-1,3,4-oxadiazole; 1- (3,3,3-Triphenylpropyl) -4-phenyl-4-: piperidinecarboxylic acid hydrochloride 1- (3,3-, 3-triphenylpropyl) -4-phenyl-4-piperidinecarboxyl-potassium ethyl ester of 1- (3, 3, 3-trifenylpropyl) -4-phenyl-4-piperidine-carboxylate, sodium of 1- (3,3,3-triphenylpropyl) -4-phenyl-4-piperidinecarboxylate, hydrochloride acid 1- [3, 3-diphenyl-3- (2-pyridyl) propyl] -4-phenyl-4-piperidinecarboxylic acid, sodium-1- [3, 3-di-phenyl-3- (2-pyridyl) propyl] -4-phenyl -4-piperidinecarboxylate; ethyl 1- [3, 3-diphenyl-3- (2-pyridyl) -propyl] -4-phenyl-4-piperazinecarboxylate-potassium l- [3, 3-diphenyl-3- (2-pyridyl) propyl] -4-phenyl-4-pipe-ridincarboxylate; 1- (3, 3, 3-triphenylpropyl) -4-phenyl-4-piperidinemethanol; 1- [3, 3-diphenyl-3- (2-pyridyl) -propyl-4-phenyl-4-piperidine-methanol; 1- (3, 3, 3-triphenylpropyl) -4-phenyl-4-acetoxymethyl-piperidine; 1- (3, 3, 3-triphenylpropyl) -4-phenyl-4-methoxymethyl-piperidine; 1- (3, 3, 3-triphenylpropyl) -4- (4-chlorophenyl) -4-piperidinemethanol; 1- [3- (p-chlorophenyl) -3,3-diphenyl-propyl] -4- (phenyl) -4-piperidinemethanol; 1- [3- (p-tolyl) -3,3-diphenylpropyl] -4- (phenyl) -4-piperidinemethanol; 1- [3- (p-bromophenyl) -3,3-diphenylpropyl] -4- (phenyl) -4-piperidinemethanol; 1- [3, 3-diphenyl-3- (4-pyridyl) -propyl] -4-phenyl-4-piperidinemethanol; 1- [3, 3-diphenyl-3- (3-pyridyl) propyl] -4-phenyl-4-iperidinemethanol; 1- (3, 3, 3-triphenylpropyl) -4-phenyl-4-hexoxymethyl-piperidine; 1- (3, 3, 3-triphenylpropyl) -4- (p-tolyl) -4-pipendinmethanol; 1- (3, 3, 3-triphenylpropyl) -4- (p-trifluoromethyl) -4-piperidinemethanol; 1- (3, 3, 3-triphenylbutyl) -4- (phenyl) -4-piperidinemethanol; 1- (3, 3, 3-triphenylpropyl) -4- (phenyl) -4-piperidinmethanol; 1- (3, 3, 3-triphenylpropyl) -4- (phenyl) -4-methoxyethylpiperidine; 1- [3, 3-diphenyl-3- (2-pyridyl) propyl] -4-phenyl-4-methoxyethyl-piperidine; 1- (3, 3, 3-triphenylpropyl) -4-phenyl-4-piperidinemethanol; 1- [3, 3-diphenyl-3- (2-pyridyl) propyl] -4-phenyl-4-piperidine-methanol; 1- (3, 3, 3-triphenylpropyl) -4-phenyl-4-acetoxymethylpipe idine; 1- (3, 3, 3-triphenylpropyl) -4-phenyl-4-methoxymethylpiperidine; 1- (3, 3, 3-triphenylpropyl) -4- (chlorophenyl-4-piperidinemethanol;

1- (3, 3, 3-triphenylpropyl) -4-hydroxy-4-benzylpiperidine and 1- (3,3,3-triphenylpropyl) -4-hydroxy-4-benzylpiperidine; hydrochloride; 1- (3, 3, 3-triphenylpropyl) -4-hydroxy-4- (p-chlorobenzyl) piperidine; 1- (3, 3, 3-triphenylpropyl) -4-hydroxy-4- (p-methylbenzyl) -piperidine; 1- (3, 3, 3 (2-pyridyl) propyl-] -4-benzyl-4-hydroxypiperidine; nielorophenylamidinourea; p-chlorophenylamidinourea; 3-dichlorophenylamidinourea; m-bromophenylamidinourea; p-bromophenylamidinourea; 3,4-dibromo- phenylamidinourea; 3-chloro-4-bromophenylamidinourea; 3-bromo- -chlorophenylamidinourea; 3-chloro-4-fluorophenylamidourea; 3-bromo-4-fluorophenylamidourea; 3-fluoro-4-chlorophenylamidoinourea; 2, 6-dimethylphenylamidinourea; 2,6-diethylphenylamidinourea; 2-methyl-6-ethylphenylamidinourea; 2-methyl-6-methoxyphenylamidinourea; 2-methyl-6-ethoxyphenylamine din; 2-ethyl-6-methoxyphenylamidine; 2-ethyl-6-ethoxyphenylamine; 3, 4-dimethoxyphenylamine; 3, 4-dihydroxyphenylamidoinourea; 3,4,5-trimethoxyphenylamine in urease; 3,4,5-trihydroxyphenylamidinourea; 2- [(2-methyl-3-aminophenyl) amino] -1-pyrrone, dihydrochloride; 2- [(2-methyl-3-acetamidophenyl) amino] -1-pyrroline, hydrochloride;

2- [(2-methyl-

3- (ethoxycarbonylamino) phenyl) amino] -1-pyrroline, hydrochloride; 2- (2, 2-diphenylpentyl) -1-azabicyl [2.2.2] octane; 2- (2,2-diphenylhexyl) -l-azabicyclo [2.2.2] octane; 2- (2, 2-diphenylpropyl) -1-azabicyl [2.2.2] octane; 2- (2,2-diphenyloctyl) -1-azabicyl [2.2.2] octane; and 2- (2, 2-diphenylheptyl) -l-azabicyl [2.2.2] octane. 3. The method according to claim 1, characterized in that the non-respiratory pruritic condition is selected from the group consisting of urticaria, dermatitis, psoriasis, eczema, dermal myiasis, pediculosis, enterobiasis, onchocersiasis and alcochinesis.