MXPA98010024A - Treatment of the prur - Google Patents

Abstract

The use of certain known 1,3,4-trisubstituted 4-aryl-piperidines for the treatment of pruritus in humans and animals is described

Description

TREATMENT OF PRURITE This invention concerns the use of certain 4-phenylpiperidines in the treatment of pruritus, including allergic dermatitis and atopy, in animals and humans. Itching or pruritus is a common dermatological symptom that can cause considerable discomfort, both in humans and animals. Pruritus is often associated with an inflammatory skin disease, which can usually be caused by hypersensitive reactions (such as reaction to insect bites, for example, flea bites, or reaction to environmental allergens, such as house dust mites). , or pollen), bacterial and fungal infections of the skin, or infections by ectoparasites. Previous treatments for pruritus include the use of corticosteroids and antihistamines, but nevertheless both have undesirable side effects. Other therapies include the use of dietary supplements of essential fatty acids, which are slow acting, and offer only limited efficacy against allergic dermatitis. Documents O84 / 00889 and US 4,181,726 describe the use of the opioid antagonist naloxone in the treatment of pruritus, but nevertheless naloxone has not been commercially exploited for the control of pruritus, and there is a continued need to have a cheap and effective remedy. In GB-A-1525584 certain 1,3,4-trisubstituted 4-arylpiperidine derivatives are described, as potent narcotic antagonists, which also have analgesic properties. These compounds are also claimed in EP-A-10 0287339 as opioid antagonists, which block the effect of agonists on mu or kappa receptors, and which have a potential utility for treating a variety of disorders associated with these receptors. , such as eating disorders, overdose of opiates, depression, smoking, alcoholism, sexual dysfunctions, shock, cerebrovascular accidents, spinal cord injuries, and traumatic brain injury. The relationships between activity and structure of this series of compounds are indicated in J. Medicinal Chemistry, 1993, 36, 2833, and its effect on feed intake in obese Zuker rats is described in J. Medicinal Chemistry, 1993, 36, 2842. It is suggested its potential utility as an appetite suppressant for weight loss. Other 4- related 1-N-substituted arylpiperidines are described as peripherally selective opioid antagonists in EP-A-0506468 and EP-A-0506478. Its potential utility is suggested to prevent undesirable effects mediated peripherally, and to mitigate the symptoms of idiopathic constipation and irritable bowel syndrome. We have now discovered unexpectedly that these compounds also possess activity as antipruritic agents. Thus, the present invention provides the use of a compound for the preparation of a medicament for use in the treatment of pruritus in a human being, or in an animal, wherein said compound is: (i) a compound of formula I Formula I in which in formula I above Ri is C? -C8 alkyl, C3-C8 alkenyl, alkynyl C3-C8, (cycloalkyl) C4-C8 alkyl, wherein: n is 1, 2 or 3; m is O or 1; X is C (= 0), CH (OH), CH = CH, S, O, or NR8, wherein: R8 is H, C1-C4 alkyl, or C1-C4 alkanoyl; Z is C (= 0), CH (OH), or CH = CH; W is 0 or S; R5 is (C 1 -C 3 alkyl) thio, nitro, amino, trifluoromethyl, hydroxy, or R 6; R6 is H, C1-C3 alkyl, C1-C3 alkoxy, or halogen; R7 is H or methyl; R2 is H, C1-C4 alkyl, or C2-C6 alkenyl; R3 is C1-C4 alkyl or C2-C6 alkenyl; and R 4 is H, hydroxy, C 1 -C 3 alkoxy, C 1 -C 2 alkanoyloxy or or a pharmaceutically or veterinarily acceptable salt thereof; with the limitation that when X or Z is CH (OH) or C (= 0), n is different from 3; or (ii) a compound of formula 2: formula 2 wherein in formula 2 above R1 is H or C? -C4 alkanoyl; R2 is H, C1-C4 alkyl, or C2-C6 alkenyl; R3 is C4-C8 cycloalkyl, C4-C8 cycloalkenyl / C? -C6 alkyl, C-C8 cycloalkyl substituted with Ci-C4 alkyl, C4-C8 cycloalkenyl substituted with C? -C4 alkyl, or thiophene; Z is CH (OR 4), (C = 0), or a link R 4 is hydrogen, Ci-Cß alkyl, R5 is C? -C4 alkyl, or And n is 1, 2 or 3; or a pharmaceutically or veterinarily acceptable salt thereof; or (iii) a compound of formula 3 Formula 3 wherein in the above formula 3 R1 is H, or C? -C5 alkyl; R 2 is H, C 1 -C 5 alkyl, or C 2 -C 6 alkenyl; R3 is H, Ci-Cio alkyl, C3-C8 cycloalkyl, C3-C3 alkenyl, (C3-C8 cycloalkyl) - (C?-C3 alkyl), phenyl, C5-C8 cycloalkenyl, (C5-C8 cycloalkenyl) - (C 1 -C 3 alkyl), or phenyl- (C 1 -C 3 alkyl); R 4 is H, C 3 -C 8 cycloalkyl, C 1 -C 10 alkyl, C 3 -C 0 alkenyl, (C 3 -C 8 cycloalkyl) - (C 3 -C 3 alkyl), phenyl, or phenyl- (C 1 -C 3 alkyl); R5 is H, Cx-Cio alkyl, Cx-Cio alkanoyl, C (0) CH- [(CH2) 3NHC (NH) NHN02] -NHC (0), C (0) NH (Ci-Cio alkyl), [( C (0) - (CH2) mC (0)] qR6, or [(C (0) - (CH2) mNHC (0)] qR6; is Ci-Cio alkyl, O (C? -C? O alkyl), (C 1 -C 4 alkyl) -NHC (O) (C 1 -C 6 alkyl), or (C 1 -C 4 alkyl) C (O) NHB, wherein B is Ci-Cι alkyl, phenyl, or phenyl- ( C3-C3 alkyl); R6 is OR7, NHR7, OCH2C (O) NR8R9, O- (Ci- C4 alkyl) OC- (0) R10, C? -C10 alkyl, or NHCHRnC (0) R12; R7 is H, C1-C10 alkyl, C3-C8 cycloalkyl, (C3-C8 cycloalkyl) - (C1-C3 alkyl), or (CH2) mC (O) NR8R9; R8 is H, or C? -C? 0 alkyl; R9 is H, or C1-C10 aikyl; R10 is C1-C10 alkyl, C3-C8 cycloalkyl, or R11 is H, C1-C10 alkyl, or phenyl- (C1-C3 alkyl); R12 is OR13 or NR13R14; R13 is H, or C1-C10 alkyl; R14 is H, or C1-C10 alkyl; n = 1-3; m = 1-3; q = 1-3; or a veterinarily acceptable pharmaceutical salt thereof; or (iv) a compound of formula 4 Formula 4 wherein in the above formula 4: Ri is H, or C? -C5 alkyl; R2 is H, C1-C5 alkyl, or C2-Cd alkenyl; R3 is H, C1-C10 alkyl, C1-C10 alkenyl, phenyl, cycloalkyl, Cs-Cs cycloalkenyl, C1-C3 alkyl substituted with cycloalkyl, C1-C3 alkyl substituted with C5-C8 cycloalkenyl, or C1-C3 alkyl substituted with phenyl; A is OR4 or NR5R6; wherein: R 4 is H, (C 1 -C 10 alkyl) - (C 2 -C 0 alkenyl), cycloalkyl, C 5 -C 8 cycloalkenyl, C 1 -C 3 alkyl substituted with cycloalkyl, C 1 -C 3 alkyl substituted with C 5 -C 9 cycloalkenyl, or C1-C3 alkyl substituted with phenyl; R5 is H, or C? -C3 alkyl; R6 is H, C? -C10 alkyl, C3-C10 alkenyl, cycloalkyl, phenyl, C1-C3 alkyl substituted with cycloalkyl, C5-C8 cycloalkenyl, C1-C3 alkyl substituted with C5-C8 cycloalkenyl, C1-C3 alkyl substituted with phenyl , or (CH2) qB; or R5 and R6 are each CH2 that together with N form a heterocyclic ring of 4 to 6 links; where: B is or NR7R8 wherein: R7 is H, or C? -C3 alkyl; R6 is H, Ci-Cio alkyl, C3-C? Alkenyl, alkyl C1-C3 substituted with cycloalkyl, cycloalkyl, C5-C8 cycloalkenyl, C1-C3 alkyl substituted with C5-C8 cycloalkenyl, phenyl, or C1-C3 alkyl substituted with phenyl; or R7 and R8 are each CH2 which together with N form a heterocyclic ring of 4 to 6 links; W is OR9, NR10Rn, or OE; wherein: R9 is hydrogen, C1-C10 alkyl, C2-C30 alkenyl, cycloalkyl, C5-Cs cycloalkenyl, C1-C3 alkyl substituted with cycloalkyl, C1-C3 alkyl substituted with C5-C8 cycloalkenyl, or C1-6 alkyl C3 substituted with phenyl; R10 is hydrogen, or C1-C3 alkyl; R11 is hydrogen, C1-C10 alkyl, C3-C10 alkenyl, phenyl, cycloalkyl, C5-C8 cycloalkenyl, C1-C3 alkyl substituted with cycloalkyl, C1-C3 alkyl substituted with phenyl, or ff (CH2) CY; OR R10 and R11 are each CH2 which together with N form a heterocyclic ring of 4 to 6 links; E is wherein: R12 is methylene substituted with C1-C3 alkyl; R 13 is C 1 -C 0 alkyl; D is OR14 or NR15R16; wherein: R14 is H, C1-C10 alkyl, C2-C10 alkenyl, cycloalkyl, C5-C8 cycloalkenyl, C1-C3 alkyl substituted with cycloalkyl, C1-C3 alkyl substituted with Cs-C8 cycloalkenyl, or C3-C3 alkyl substituted with phenyl; R15 is H, C1-C10 alkyl, C3-C10 alkenyl, phenyl, C1-C3 alkyl substituted with phenyl, cycloalkyl, C5-C8 cycloalkenyl, C1-C3 alkyl substituted with cycloalkyl, or C1-C3 alkyl substituted with C5-C8 cycloalkenyl; R16 is H, or C? -C3 alkyl; R15 and R16 are each CH2 that together with N form a heterocyclic ring of 4 to 6 links; And it is OR17 or NR18R19; wherein: R 17 is H, C 1 -C 10 alkyl, C 2 -C 0 alkenyl, cycloalkyl, C 5 -C 8 cycloalkenyl, C 1 -C 3 alkyl substituted with cycloalkyl, C 1 -C 3 alkyl substituted with C 5 -C 8 cycloalkenyl, or C 1 -C 8 alkyl C3 substituted with phenyl; R18 is hydrogen, or C? -C3 alkyl; R19 is hydrogen, C1-C10 alkyl, C3-C10 alkenyl / phenyl, cycloalkyl, C5-C8 cycloalkenyl, C1-C3 alkyl substituted with cycloalkyl, C1-C3 alkyl substituted with C5-C8 cycloalkyl, or C1-C3 alkyl substituted with phenyl; R18 and R19 are each CH2 which together with N form a heterocyclic ring of 4 to 6 links; n is 0-4; q is 1-4; m is 1-4; or a pharmaceutically or veterinarily acceptable salt thereof. A particularly preferred group of compounds for use in the present invention are the compounds of formula 5: Formula 5 (I) and pharmaceutically or veterinarily acceptable salts thereof, wherein in formula 5 above: R20 is H, or Cx-C4 alkanoyl; R21 is C? -C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, (C3-C8 cycloalkyl) - (C? -C6 alkyl), (C5-C8 cycloalkenyl) - (cycloalkyl d-C6), or a group of formula - (CH2) n- G-Ar; wherein n is l, 2 or 3; G is C = 0, CH (OH), O, or a direct bond; and Ar is C3-C8 cycloalkyl, phenyl, which may optionally be substituted with one or more substituents, independently selected from halo, C1-C4 alkyl and C6-4 alkoxy, or A1 is thienyl, furyl or pyridyl. The invention also provides a method for treating pruritus, in a human or animal, which includes administering a therapeutically or prophylactically effective amount of a compound of formula 1, 2, 3, 4 or 5 as defined above, or a pharmaceutically or veterinarily acceptable salt thereof. The piperidines of this invention form pharmaceutically or veterinarily acceptable acid addition salts, with a wide variety of inorganic and organic acids. The concrete acid that is used in the formation of the salt is not critical; however, the corresponding salt that is formed must be substantially non-toxic to the animals. Typical acids used generally include sulfuric, hydrochloric, hydrobromic, phosphoric, iodhydric, sulfamic, citric, acetic, maleic, malic, succinic, tartaric, cinnamic, benzoic, ascorbic, and related acids. In addition, the piperidines form quaternary ammonium salts, for example, with a variety of organic esters of the sulfuric, halohydric and aromatic sulfonic acids. The compounds of the invention contain one or more asymmetric centers, and can therefore exist as enantiomers and diastereoisomers. The invention includes the use of the separate individual isomers, as well as mixtures of isomers.

The compounds defined above for use in the present invention can be prepared according to the methods described in the publications mentioned above. Particularly preferred compounds for use in the treatment of pruritus include the compounds of formula (5) above in which R20 is H or COCH3, and wherein R21 is C2-C8 alkyl, in particular n-hexyl or 2-methylpentyl , or C 1 -C 6 alkyl substituted with C 3 -C 8 cycloalkyl, in particular cyclohexylethyl. Although it is possible to administer a compound of the invention directly without any formulation, the compounds are preferably employed in the form of a pharmaceutical or veterinary formulation, which includes a pharmaceutically or veterinarily acceptable carrier, diluent or excipient, and a compound of the invention. These compositions will contain from 0.1% by weight to 90.0% by weight of the active ingredient. The methods by which the compounds can be administered for veterinary use include oral administration by capsules, boluses, tablets or potions, topical administration by ointments, formulations for pouring or spraying, washes, powders, foams, shampoos, collars or a Formulated in powder, or alternatively, can be administered by the invention directly without any formulation, the compounds are preferably employed in the form of a pharmaceutical or veterinary formulation, which includes a pharmaceutically or veterinarily acceptable carrier, diluent or excipient, and a compound of the invention. These compositions will contain from 0.1% by weight to 90.0% by weight of the active ingredient. The methods by which the compounds can be administered for veterinary use include oral administration by capsules, boluses, tablets or potions, topical administration by ointments, formulations for pouring or spraying, washes, powders, foams, shampoos, collars or a formulated in powder, or as an alternative, they can be administered by injection (for example, subcutaneously, intramuscularly or intravenously), or as an implant. These formulations are prepared in a conventional manner, according to conventional veterinary practice. Thus, the capsules, or tablets can be prepared by mixing the active ingredient with a diluent or finely divided vehicle in a suitable manner, further containing a disintegrating agent and / or a binder such as starch, lactose, talc, magnesium stearate, etc. Oral potions are prepared by dissolving or suspending glycerides such as triacetin, esters such as benzyl benzoate, isopropyl myristate, and fatty acid derivatives of propylene glycol, as well as organic solvents such as pyrrolidin-2-one and glycerol. formal. The formulations are prepared by dissolving or suspending the active ingredient in the liquid vehicle, so that the final formulation contains from 0.1 to 10% by weight of the active ingredient. These formulations vary with respect to the weight of the active compound contained therein, depending on the animal species to be treated, the severity and type of infection, and the animal's body weight. For parenteral, topical and oral administration, the typical dose ranges of the active ingredient are from 0.01 to 100 mg per kg of body weight of the animal. Preferably, the range is from 0.1 to 10 mg per kg. The compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 to about 500 mg, more typically from about 5 to about 300 mg of the active ingredient. The term "unit dosage form" refers to physically discrete units, which are suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active material, calculated to produce the desired therapeutic effect, in association with a pharmaceutically acceptable vehicle. For veterinary use, the compounds of the invention are of particular value in treating pruritus in domestic animals, such as cats and dogs, and in horses. Therefore, the invention also provides a veterinary formulation that includes a compound of formula 1, 2, 3, 4 or 5, as defined above, together with a veterinarily acceptable diluent or carrier. These formulations include in particular ointments, formulated for pouring, formulated for spraying, washing, spraying, foams, poos, collars and powder formulations. As an alternative for treating animals, the compounds can be administered with the animal feed, and for this purpose a concentrated feed additive or pre-mix can be prepared to mix with the animal's normal feed. For use in humans, the compounds are administered as a pharmaceutical formulation containing the active ingredient, together with a pharmaceutically acceptable diluent or carrier. The compounds of the invention are prepared using the methods described in GB-A-1525584, EP-A-0287339, EP-A-0506468, EP-A-0506478, or in J. Medicinal Chemistry, 1993, 3_6, 2833 The following examples are illustrative of the preparation of the typical examples. The melting points were determined using a Gallenkamp melting point determination apparatus, and are uncorrected. Nuclear magnetic resonance (NMR) spectrum data were obtained using a Bruker AC300 or AM300 spectrometer, the observed chemical shifts (d) being consistent with the proposed structures. The mass spectrum (MS) data were obtained in a Finnigan Mat spectrometer. TSQ 7000 or Fisons Instruments Trio 1000. The calculated and observed ions indicated refer to the lower mass isotopic composition. HPLC means high performance liquid chromatography. Ambient temperature means 20 to 25 ° C.

EXAMPLES EXAMPLE 1 (±) -N- (n-hexyl) -4- (3-hydroxyphenyl) -trans-3,4-dimethylpiperidine hydrochloride (i) To a stirred solution of 3-bromoanisole (12.83 g, 0.069 mol) in dry tetrahydrofuran (70 ml) at -50 ° C under a nitrogen atmosphere, sec-butyllithium (1.3 M) was added. in hexanes, 68.5 ml, 0.089 mol) dropwise, making sure that the temperature in the reaction vessel did not exceed -50 ° C. After the addition of sec-butyllithium was complete, a white precipitate formed, and the reaction was stirred for 1 hour at -50 ° C. N-ethyl-4- (3-methoxyphenyl) piperidine (10.5 ml, 0.079 mol) in dry tetrahydrofuran (50 ml) was added dropwise, at a rate such as to maintain the reaction temperature below - 40 ° C, resulting in an orange solution. The reaction mixture was allowed to warm up to reach. -20 ° C for 1.5 hours, and then to room temperature for another hour. After this time, the reaction mixture was quenched by the addition of saturated brine (21 ml), and water (30 ml). The quenched reaction was stirred for a further 30 minutes, and then the two phases were separated, and the organic phase was retained. The aqueous phase was extracted with dichloromethane (3 x 75 ml), and the two organic phases were combined and washed with hydrochloric acid (1 N, 2 x 50 ml). The aqueous layer was separated, basified with ammonium hydroxide to a pH of 10, and extracted with dichloromethane (3 x 40 ml). The dichloromethane extracts were concentrated to provide a thick oil, which was triturated in cold hexane until a solid was obtained. This crude solid was stirred in hot hexane, allowed to cool, and filtered to give N-ethyl-4-hydroxy-4- (3-methoxyphenyl) piperidine (5.5 g, 33.7%) as a solid of color White. P.f. = 8β, 7-91, 1 ° C. MS (thermospray): M / Z [MH +] 236.4; C14H2oN02 + H requires 236.2. (ii) p-Toluenesulfonic acid (0.56 g, 2.98 mmol) was added to a suspension of the above product (0.5 g, 1.49 mmol) in toluene, and heated to reflux for 2.5 hours , using a Dean and Stark device. After this time, the reaction mixture was allowed to cool to room temperature, then water (4 ml) was added, and the resulting biphasic system was stirred vigorously for several minutes. The two phases were separated, and the toluene layer was washed with water (2 x 3 ml). The aqueous portions were combined, made basic by the addition of sodium hydroxide (1 M, 0.2 ml), after which a white precipitate formed. The aqueous suspension was extracted with hexane (3 x 5 mL), dried (Na2SO4), and concentrated to yield 1,2,3,6-tetrahydro-4- (3-methoxyphenyl) -N-ethylpyridine, as an oil (0.31 g), which was used without further purification. MS (thermospray): M / Z [MH +] 218.3; C? 4H19NO + H requires 218.2. (iii) The above product was converted to (±) -N-ethyl-4- (3-methoxyphenyl) -trans-3,4-dimethylpiperidine hydrochloride following the procedures described by Zimmerman et al. , J. Org. Chem., 1991, 5_6, 1660, for the corresponding N-methyl compound, except that the hydrochloride salt was used in the crystallization step with 2-propanol. The product was obtained as a white crystalline solid, which was used immediately in the next step. NMR (CDC13) (data selected for the free base): 0.8 (d, 3H), 1.05 (t, 3H), 1.3 (s, 3H), 1.6-1.8 (m, 2H), 3.8 (s, 3H), 2.3-2.65 (m, 6H), 6.7-7.3 (m, 4H). MS (thermospray): M / Z [MH +] 248.3; Ci6H25 O + H requires 248, 3. (iv) The free base of (±) -N-ethyl-4- (3-methoxyphenyl) -trans-3,4-dimethylpiperidine was prepared by the addition of 5 N NaOH to an aqueous solution until that the pH reached 9-10 (test paper). The resulting basic suspension was extracted into dichloromethane, the organic fractions were dried (Na2SO4), and concentrated in vacuo to provide a thick oil. The resulting free base (3.93 g, 0.016 mol) was combined with a-chloroethyl chloroformate (3, 35 ml, 0.032 mol), and heated to reflux for 5 hours. After this time, the excess reagent was removed under vacuum, to produce a dark oil, which was suspended in methanol (15 ml), and heated to reflux for 1 hour. After this time the methanol was removed in vacuo, and the resulting (±) -4- (3-methoxyphenyl) -trans-3,4-dimethylpiperidine (3.5 g), in the form of a dark oil, was used without subsequent purification. NMR (CDC13) (free base): 0.95 (d, 3H), 1.4 (s, 3H), 1.85 (m, 2H), 2.2 (br, 1H), 2.5 (t , 1H), 3.2 (ta, 2H), 3.4 (m, 2H), 3.8 (s, 3H), 6.7-7.3 (m, 4H). MS (thermospray): M / Z [MH +] 219.9; C? 4H21N0 + H requires 220.2. (v) The above product was heated to reflux in HBr / glacial acetic acid, following the procedure described by Zimmerman et al., J. Org. Chem., 1991, 56, 1660, to produce (±) -4- (3-hydroxyphenyl) -3,3,4-dimethylpiperidine, as a pale brown solid (4.09 g), m.p. = 179-180 ° C. NMR (CDCl 3) (data selected for the free base): 0.75 (d, 3H), 1.40 (s, 3H), 6.7-7.2 (m, 4H). MS (thermospray): M / Z [MH +] 206.5; C13H19NO + H requires 206.2. (vi) To a solution of (±) -4- (3-hydroxyphenyl) -tjrans-3,4-dimethylpiperidine (3 g, 15 mmol) in tetrahydrofuran (115 ml) was added (in order) acetic acid (0). , 84 ml, 15 mmol), hexanal (1.93 ml, 16 mmol), and finally sodium triacetoxyborohydride (4.92 g, 22 mmol) in ten equal portions for 5 minutes. The resulting mixture was stirred for 5.5 hours, filtered to remove a precipitate, and the collected solid was washed with ethyl acetate. The combined organic fractions were washed with water (100 ml), a saturated solution of aqueous sodium bicarbonate (2 x 75 ml), and dried over sodium sulfate. Filtration and removal of the solvent in vacuo yielded a thick brown solid, which was purified by silica column chromatography (150 g), eluting with ethyl acetate: hexane (1: 1) + 0.5 ammonia. %. Concentration of the appropriate fractions gave a pale oil, which was dissolved in dry ether (60 ml). The addition of 2 mol equivalents of a 1 N ethereal hydrogen chloride solution gave a precipitate which was collected by filtration, and dried in a vacuum oven to produce (±) -N- (n-hexyl) -4 hydrochloride. - (3-hydroxyphenyl) -trans-3,4-dimethylpiperidine (2.2 g, 45%) as a white solid, mp = 140, 3-143, 7 ° C. NMR (CDC13) (data selected for the free base): 0.75 (d, 3H), 0.85 (t, 3H), 1.15-1.25 (m, 6H), 1.3 (s, 3H), 2.0 (m, 1H), 2.35 (, 4H), 2.6 (, 2H), 6.55-7.2 (m, 4H). MS (thermospray): M / Z [MH +] 290.2; C19H31NO + H requires 290.3.

EXAMPLE 2 Resolution of the enantiomers of (+) - N- (n-hexyl) -4- (3-hydroxyphenyl) -trans-3,4-dimethylpiperidine The (±) -N- (n-hexyl) -4- (3-hydroxyphenyl) -trans-3,4-dimethylpiperidine enantiomers were separated by preparative HPLC on a 25 cm x 2.0 cm ChiralpakTD AD column, with a flow of 9 ml min "1, using UV detection at 220 nm, eluting with hexane: propan-2-ol (91: 9) + 1% diethylamine (w / v).

The enantiomeric purity was determined using a Chiralpak10 AD 25 cm x 0.46 cm column, with a flow of 1 ml min-1, using UV detection at 254 nm, eluting with hexane: propan-2-ol (90:10) + 1% diethylamine (w / v). Fraction 1 provided the (R, R) - (+) - enantiomer (retention time: 4.02 min, 94.9% excess enantiomer), NMR (CDC13) (data selected for the free base): 0, 75 (d, 3H), 0.85 (t, 3H), 1.15-1.25 (m, 6H), 1.3 (s, 3H), 2.0 (m, 1H), 2.35 (m, 4H), 2.6 (m, 2H), 6.55-7.2 (m, 4H) ). MS (Cl): M / Z [MH +] 290.3; C19H31 O + H requires 290.3. Fraction 2 provided the (S, S) - (-) - enantiomer (retention time: 4.82 min, 91.2% enantiomer excess), NMR (CDC13) (data selected for the free base): 0, 75 (d, 3H), 0.85 (t, 3H), 1.15-1.25 (m, 6H), 1.3 (s, 3H), 2.0 (m, 1H), 2.35 (m, 4H), 2.6 (m, 2H), 6.55-7.2 (m, 4H). MS (Cl): M / Z [MH +] 290.3; C? 9H31NO + H requires 290.3.

EXAMPLE 3 (+) -4- (3-Hydroxyphenyl) -trans-3,4-dimethyl-N- (4-me-ilpentyl) piperidine hydrochloride The experiment was carried out by the reaction of (+) -4- (3-hydroxyphenyl) -3,3-dimethylpiperidine with 4-methylvaleric acid and oxalyl chloride, in direct analogy with Zimmerman et al. , J. Med. Chem., 1993, 36, 2842. The product was obtained as an oil which was converted to the hydrochloride salt as previously described in example l (vi), and isolated as a solid of color whitish, p.'f. = 176-178 ° C. NMR (CDC13) (data selected for the free base): 0.8 (d, 3H), 0.9 (d, 6H), 1.3 (s, 3H), 6.6-7.2 (m, 4H). MS (thermospray): M / Z [MH +] 290.4; C19H31NO + H requires 290.4.

EXAMPLE 4 (+) -4- (3-Hydroxy enyl) -trans-3,4-dimethyl-N- [3- (thien-3-yl) prop-1-yl-piperidine To a solution of (±) -4- (3-hydroxyphenyl) -3,3-dimethylpiperidine (0.2 g, 0.97 mmol) in pyridine (5 mL), a solution of thiophene chloride was added. -2-propionyl (187 mg, 10.7 mmol) prepared from thiophen-3-propionic acid (prepared by the method of Mihialo, Mihailovic and Tot (J. Org. Chem., 1957, 22, 653)) and chloride of thionyl in pyridine (5 ml). The resulting mixture was allowed to stir overnight at room temperature. The pyridine was removed in a rotary evaporator, and the product was dissolved in ethyl acetate (20 ml). This solution was washed with 20% w / v aqueous citric acid (5 ml), water (5 ml), brine (5 ml), and finally dried over sodium sulfate. The solvent was removed on a rotary evaporator to yield an amber gum (135 mg). MS (thermospray): M / Z [MH +] 344.1; C20H25N02-S + H requires 344.1. The gum was dissolved in tetrahydrofuran (5 ml). To this solution, purged with dry nitrogen, and stirred at room temperature, a 1.0 M solution (in diethyl ether) of lithium aluminum hydride (390 μL, 0.39 mmol) was carefully added, and the stirring for 30 minutes. A TLC of the reaction mixture (silica plate eluting with dichloromethane containing 10% v / v methanol) indicated the absence of starting material. The reaction mixture was quenched with ethyl acetate (10 ml), and after 5 minutes with water (10 ml).

After filtration to remove the emulsifying solids, the layers were separated and the aqueous layer was back extracted with ethyl acetate (10 ml). The combined extracts were washed with water (5 ml), then with brine (5 ml), and the solvent was removed on a rotary evaporator. The product was purified by column chromatography on silica, eluting with dichloromethane containing 5% methanol, to provide the title compound (22 mg, 7% in two steps). NMR (CDCI3) (data selected for the base (free): 0.8 (d, 3H), 1.3 (s, 3H), 1.65 (broad d, 1H), 1.9 (m, 2H), 2.05 (broad m, 1H) , 2.9 (broad m, 1H), 6.6-7.3 (m, 7H). MS (thermospray): M / Z [MH +] 330.4; C20H27NOS + H requires 330.18.

EXAMPLE 5 (+) - N- (2-Cyclohexylethyl) -4- (3-hydroxyphenyl) -3,3-dimethylpiperidine hydrochloride The experiment was carried out by the reaction of (±) -4- (3-hydroxyphenyl) -trans-3,4-dimethylpiperidine with cyclohexane acetic acid and oxalyl chloride, in direct analogy with Zimmerman et al. , J. Med.

Chem., 1993, 3_6, 2842. The product was obtained as an oil which was converted to the hydrochloride salt as previously described in example 1 (vi), and isolated as a white solid, m.p. = 204-207 ° C. NMR (CDC13) (data selected for the free base): 0.8 (d, 3H), 0.9-2.8 (m, 13H), 2.0 (m, 1H), 2.3 (m, 2H), 2.5 (m, 2H), 2.8 (, 2H), 6.6-7.2 (m, 4H). MS (thermospray): M / Z [MH +] 316.4; C21H33NO + H requires 316.4.

EXAMPLE 6 (±) -4- (3-Hydroxyphenyl) -trans-3,4-dimethyl-N- [3- (thien-2-yl) prop-1-yl-piperidine Joint 3- (2-thiophene) propanoic acid (220 mg, 1.4 mmol) [prepared in direct analogy with Toth et al. , Synth. Commun., 1995, 25, 3067], 1-hydroxybenzo-triazole (204 mg, 1.5 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (320 mg, 2.0 mmol) and dimethylformamide ( 50 ml), at room temperature, until all the solids had dissolved. (±) -4- (3-Hydroxyphenyl) -3,3-dimethylpiperi-dine (300 mg, 1.5 mmol) was added, and the reaction mixture was allowed to stir at room temperature for 18 hours. After this time, the reaction mixture was diluted with water (25 ml), and extracted with diethyl ether (25 ml). The diethyl ether extract was dried (Na2SO4) and concentrated in vacuo to yield a clear colorless oil. The crude product was purified by chromatography on a silica column (10 g), eluting with ethyl acetate. The appropriate fractions were combined, and concentrated in vacuo to yield 300 mg of a white solid. This solid was then dissolved in anhydrous tetrahydrofuran (25 ml), and a 1 M solution of lithium aluminum hydride in diethyl ether (10 ml) was added to the solution. The reaction was allowed to stand at room temperature for 15 minutes, then diluted with water (25 ml), and extracted with ethyl acetate (25 ml). The ethyl acetate extract was dried (Na 2 SO 4), and concentrated in vacuo to yield the title compound as a clear brown oil (310 mg, 64% in two steps). NMR (CDC13) (data selected for the free base): 0.85 (d, 3H), 1.30 (s, 3H), 6.65 (d, 1H), 6.8 (s, 1H), 6 , 85 (d, 1H), 6.90 (dd, 1H), 7.10-7.20 (m, 3H). MS (thermospray): M / Z [MH +] 330.4; C20H27NOS + H requires 330.18.

EXAMPLE 7 (±) -4- (3-Hydroxy enyl) -trans-3,4-dimethyl-N- (3-phenylpropi1) piperidine To a stirred solution of (±) -4- (3-hydroxyphenyl) -3,3-dimethylpiperidine (0.15 g, 0.731 mmol) in dimethylformamide (5 mL) was added sodium bicarbonate (0.068 g, 0.804 mmol) and l-bromo-3-phenylpropane (0.16 g, 0.804 mmol). The stirred reaction mixture was heated to reflux for 1.5 hours, then quenched with water (20 ml), and extracted with diethyl ether (2 x 20 ml). The organic fractions were washed with saturated brine (20 ml), dried (Na 2 SO 4), filtered and concentrated in vacuo to give the crude product, which was purified by chromatography on a column of silica (15 g), eluting with dichloromethane. , followed by dichloromethane: ethanol: 0.880 ammonia (100: 8: 1), to yield the title compound as a brown oil (209 mg, 88%). NMR (CDC13) (free base): 0.8 (d, 3H), 1.3 (s, 3H), 1.6 (m, 1H), 1.7-1.9 (m, 2H), 1.9-2.1 (m, 2H), 2.2-2.5 (m, 4H) , 2.5-2.7 (, 4H), 2.9 (m, 1H), 6.5-6.6 (m, 1H), 6.7-6.8 (, 2H), 7.1 -7.3 (m, 6H). MS (thermospray): M / Z [MH +] 324, 2; C22H29NO + H requires 324.23.

EXAMPLE 8 (+) -4- (3-Hydroxyphenyl) -trans-3, -dimethyl-N- (2-xylene) piperidine A dry round bottom flask, equipped with a reflux condenser and a nitrogen inlet, was charged with (±) -4- (3-hydroxyphenyl) -3,3-dimethylpiperidine (82 mg, 0.4 mmol) , 2- (phenoxy) ethyl bromide (88 mg, 0.44 mmol), sodium bicarbonate (37 mg, 0.44 mmol) and dimethylformamide (5 mL). The stirred reaction mixture was heated at 50 ° C for 36 hours, then cooled to room temperature, and diluted with dichloromethane (30 ml). The resulting solution was washed with a saturated solution of aqueous sodium bicarbonate (30 ml), and the organic layer was retained. The aqueous layer was back extracted with more dichloromethane (2 x 30 ml), and the organic fractions were combined, washed with brine (25 ml), dried (Na 2 SO 4), filtered and concentrated in vacuo to give an oil of brown color. This was purified by silica column chromatography (1: 98.9: 0.1 to 2: 97.8: 0.2, methanol: dichloromethane: ammonia), to afford the title compound as a yellow oil pale (33 mg, 25%). NMR (C6D6) (data selected for the free base): 0.9 (d, 3H), 1.15 (s, 3H), 3.9 (t, 2H), 6.6-7.1 (m, 9H). MS (API +): M / Z [MH +] 326.2; C2? H27N02 + H requires 326.43.

EXAMPLE 9 (+) - N- (2-Cyclohexylpropyl) -4- (3-hydroxyphenyl) -trans-3,4-dimylpiperidine A dry round bottom flask, equipped with a reflux condenser and a nitrogen inlet, was charged with (±) -4- (3-hydroxyphenyl) -trans-3, -dimethylpiperidine (82 mg, 0.4 mmol), 3- (cyclohexyl) chloropropane (71 mg, 0.4 mmol), sodium bicarbonate (37 mg, 0.44 mmol), sodium iodide (3 mg, 0.02 mmol) and dimethylformamide (5 mL). The stirred reaction mixture was heated at 70 ° C for 8 hours, then cooled to room temperature, and quenched with water (30 ml). The resulting mixture was extracted with dichloromethane (30 ml), and the organic layer was retained. The aqueous layer was back extracted with dichloromethane (2 x 20 ml), and the organic fractions were combined, washed with brine (40 ml), dried (Na2SO4), filtered and concentrated in vacuo to give a crude material .

This was purified by chromatography on a silica column, eluting with a gradient system 1: 98.9: 0.1 to 2: 97.8: 0.2, methanol: dichloromethane: ammonia, to produce the title compound as a viscous, colorless oil (56 mg, 42%). NMR (C6D6) (data selected for the free base): 0.9 (d, 3H), 1.2 (s, 3H), 1.8 (m, 1H), 2.8 (m, 1H), 6 , 6-7.1 (m, 4H). MS (API +): M / Z [MH +] 330.3; C22H35N0 + H requires 330.49.

EXAMPLE 10 (+) -4- (3-Hydroxyphenyl) -N- ((R) -3-hydroxy-3-phenylpropyl) -trans-3, -dimethylpiperidine A dry round bottom flask, equipped with a reflux condenser and a nitrogen inlet, was charged with (+) -4- (3-hydroxyphenyl) -t.rans-3, 4-dimethylpiperidine (82 mg, 0.4 mmol), R- (+) - 1-chloro-3-hydroxy-3 phenylpropane (75 mg, 0.44 mmol), sodium bicarbonate (37 mg, 0.44 mmol), sodium iodide (6 mg, 0.04 mmol) and dimethylformamide (5 ml). The stirred reaction mixture was heated at 80 ° C for 16 hours, then cooled to room temperature, and quenched with water (20 ml). The resulting mixture was extracted with ethyl acetate (10 ml), and the organic layer was retained. The aqueous layer was back extracted with ethyl acetate (3 x 10 ml), and the organic fractions were combined, washed with water (3 x 15 ml), and brine (20 ml), dried (Na2SO4), filtered and concentrated in vacuo to provide a crude material. This was purified by chromatography on a silica column (1: 98.9: 0.1 to 2: 97.8: 0.2, methanol: dichloromethane: ammonia). The appropriate fractions were concentrated in vacuo to yield the title compound as a 1: 1 mixture of diastereoisomers, as a colorless oil (47 mg, 35%). NMR (C6D6) (data selected for the free base): (1: 1 mixture of diastereoisomers) 0.75 and 0.8 (2xd, 3H), 1.0 and 1.05 (2xs, 3H), 4.9 and 4.95 (m, 1H), 6.6-7.5 (m, 9H). MS (API +): M / Z [MH +] 340.3; C22H29NO2 + H requires 340.45.

EXAMPLE 11 (±) -4- (3-Hydroxyphenyl) -N- ((S) -3-hydroxy-3-phenylpropyl) -3,3-dimethylpiperidine The procedure of Example 10 was followed, but using S- (-) - 1-chloro-3-hydroxy-3-phenylpropane instead of R- (+) - 1-chloro-3-hydroxy-3-phenylpropane, to produce 51 mg, 38% of a 1: 1 mixture of diastereoisomers. NMR (C6D6) (data selected for the free base): (1: 1 mixture of diastereoisomers) 0.8 and 0.85 (2xd, 3H), 1.0 and 1.05 (2xs, 3H), 4.9 and 4.95 (m, 1H), 6.6-7.5 (m, 9H). MS (API +): M / Z [MH +] 340.2; C22H29NO2 + H requires 340.45.

EXAMPLE 12 (±) -N- ((S) -3-Cyclohexyl-3-hydroxypropyl) -4- (3-hydroxyphenyl) -frans-3,4-dimethylpiperidine To a stirred solution of (±) -4- (3-hydroxyphenyl) -3,3-dimethylpiperidine (0.2 g, 0.97 mmol) in 1,2-dimethoxyethane (10 mL), bicarbonate was added. of sodium (0.122 g, 1.455 mmol) and (4-bromobenzenesulfonate) of (S) -3-cyclohexyl-3-hydroxypropyl [prepared in direct analogy with Werner et al. , J. Org.

Chem., 1996, 61, 587] (0.368 g, 0.97 mmol). The stirred reaction mixture was heated to reflux for 16 hours, cooled to room temperature, and stirred for 1 hour at 0 ° C. The resulting white precipitate was removed by filtration through celite, and washed with tetrahydrofuran (5 ml). The filtrate was washed with a saturated aqueous solution of potassium carbonate (2 x 10 ml) and brine (10 ml). The resulting organic phase was dried (MgSO 4), filtered and concentrated in vacuo to yield the crude material, which was purified by chromatography on a silica column (10 g), eluting with dichloromethane, followed by dichloromethane: ethyl acetate ( 1: 1), to provide the title compound as a brown oil (87 mg, 26%). NMR (CDC13) (data selected for the free base): 0.6 (d, 3H), 1.3 (s, 3H), 1.5 (, 2H), 1.7-1.9 (m, 2H) ), 1.6-1.75 (m, 5H), 1.9 (m, 2H), 2.85 (m, 1H), 6.5-6.6 (m, 1H), 6.65 ( m, 2H), 7.05 (m, 6H). MS (thermospray): M / Z [MH +] 346.3; C22H35NO2 + H requires 346.28.

EXAMPLE 13 (+) - (3-Acetoxyphenyl) -N- (n-hexyl) -trans-3, -dimethylpiperidine hydrochloride A dry round bottom flask was charged with (±) -N- (n-hexyl) -4- (3-hydroxyphenyl) -3,3-dimethylpiperidine hydrochloride (114 mg, 0.39 mmol), triethylamine ( 1 ml), and dichloromethane (5 ml). The stirred reaction mixture was cooled to 0 ° C, and acetyl chloride (0.055 ml, 0.78 mmol) was added dropwise. After 4 hours the reaction mixture was diluted with water (10 ml), and extracted with dichloromethane (3 x 25 ml). The organic fractions were dried (Na 2 SO), filtered and concentrated in vacuo to provide the crude product. This was purified by chromatography on a silica column (5 g), eluting with ethyl acetate: hexane (3: 7) + 1% ammonia, to yield the title compound as an oil (79 mg, 56%). The oil was dissolved in dry ether (2 ml), and 1.1 mol equivalents of a 1 N ethereal hydrogen chloride solution were added, to produce a precipitate which was collected by filtration, and dried in a vacuum oven, to provide the title compound as a white solid, mp = 165-167 ° C. NMR (CDC13) (data selected on the hydrochloride salt): 0, 8 (d, 3H), 2, 3 (s, 3H), 3, 7 (m, 2H), 6, 9-7, 4 (m, 4H), 11, 5 and 12, 3 (2xse, 1H). MS (thermospray): M / Z [MH +] 332, 3; C21H33NO2 + H requires 332, 5.

BIOLOGICAL ACTIVITY The compounds of the invention are evaluated to observe their activity as antipruritic agents, measuring their ability to inhibit the scratching behavior of the hind paw, induced in rats by the administration of a known pruritogenic agent. These studies are based on the procedure described by Berendsen and Broekkamp in European Journal of Pharmacology, 1991, 194, 201. The test is carried out in the following way. Male Wistar rats (approximately 150 g of body weight) were treated with a pruritogen by subcutaneous injection of 5-methoxytryptamine hydrochloride (4 mg / 3 ml / kg), dissolved in physiological saline, in the neck. With this dose a constant and quantifiable rear leg scraping response is obtained, which lasts up to 90 minutes. The test compound is administered to the test animals by subcutaneous injection into an aqueous micelle formulation. The test compound is prepared in the following manner. The compound is dissolved in a vehicle (% v / v composition: glycerol formal, 24, tween 80, 17, benzyl alcohol, 1.5, and purified water to 100), then seven parts of purified water are added to three parts of vehicle, to produce the aqueous micelle formulation. The compounds can be administered before or after the administration of the pruritogen, or can be co-administered with it. After the administration of pruritogen, scraping of the hind paw is scored for each animal by registering the presence or absence of scratching during each 30 second interval, with a score of 0 or 1, respectively. The score for each animal is added after 25 minutes (maximum score 50). The efficacy of the compounds is evaluated by their ability to significantly reduce the score in the treated groups, compared to the control group, whose score was approximately 30. The antipruritic activity of the test compounds is expressed as the percentage of the reduction of scratching of the hind paw, using the following formula: (ab) x 100, where a is the average scratching score of the hind paw of untreated rats treated with pruritogen. b is the average scratching score of the hind paw of rats treated with compound and treated with pruritogen. Using the previous test, the following results were obtained.

COMPUES: ro DOSES (mg / kg)% RETRACTION% Example 1 10 90 Example 2 (+) - 10 95 enantiomer Example 2 (-) - 10 82 enantiomer Example 3 10 92 Example 4 10 75 Example 5 10 82 Example 6 10 69 Example 7 10 54 Example 8 10 94 Example 9 10 80 Example 10 10 77 Example 11 10 85 Example 12 10 81 Example 13 10 90 Antipruritic activity was also demonstrated in dogs suffering from allergic dermatitis caused by fleas . The administration of a subcutaneous injection significantly reduced the scraping behavior at a dose level of 1-10 mg / kg.

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a compound for the preparation of a medicament for use in the treatment of pruritus in a human being, or in an animal, wherein said compound is: (i) a compound of formula I Formula I wherein in the above formula I Rx is C 1 -C 8 alkyl, C 3 -C 8 alkenyl, C 3 -C 8 alkynyl, C 4 -C 8 (cycloalkyl) alkyl, wherein: n is 1, 2 or 3; m is 0 or 1; X is C (= 0), CH (OH), CH = CH, S, O, or NR8, wherein: R8 is H, C? -C4 alkyl, or C? -C4 alkanoyl; Z is C (= 0), CH (OH), or CH = CH; W is O or S; R5 is (C1-C3 alkyl) thio, nitro, amino, trifluoromethyl, hydroxy, or R6; R6 is H, C1-C3 alkyl, C1-C3 alkoxy, or halogen; R7 is H or methyl; R2 is H, C1-C4 alkyl, or C2-C6 alkenyl; R 3 is C 1 -C 4 alkyl or C 2 -C 6 alkenyl; and R 4 is H, hydroxy, C 1 -C 3 alkoxy, C 1 -C 12 alkanoyloxy, or or a pharmaceutically or veterinarily acceptable salt thereof; with the limitation that when X or Z is CH (OH) or C (= 0), n is different from 3; or (ii) a compound of formula 2: formula 2 wherein in the above formula 2 R1 is H or C-C alkanoyl; R2 is H, C1-C4 alkyl, or C2-C6 alkenyl; R3 is C4-C8 cycloalkyl, C-C8 cycloalkenyl, C? -C6 alkyl, C4-C8 cycloalkyl substituted with C? -C4 alkyl, C4-C8 cycloalkenyl substituted with Cx-C alkyl, or thiophene; Z is CH (OR4), (C = 0), or a bond; R4 is hydrogen, alkyl C? ~ Ce, R5 is C1-C4 alkyl, or and n is 1, 2 or 3; or a pharmaceutically or veterinarily acceptable salt thereof; or (iii) a compound of formula 3: Formula 3 wherein in the above formula 3 R1 is H, or Ci- C5 alkyl; R2 is H, C1-C5 alkyl, or C2-C6 alkenyl; R3 is H, C1-C10 alkyl, C3-C8 cycloalkyl, C3-C10 alkenyl, (C3-C8 cycloalkyl) - (C1-C3 alkyl), phenyl, cycloalkenyl C5-C8, (C5-C8 cycloalkenyl) - (C1-C3 alkyl), or phenyl- (C1-C3 alkyl); R4 is H, C3-C8 cycloalkyl, C1-C10 alkyl / C3-C10 alkenyl, (C-C8 cycloalkyl) - (C1-C3 alkyl), phenyl, or phenyl- (C1-C3 alkyl); R5 is H, C1-C10 alkyl / C alkanoyl? -C? 0 C (0) CH- [(CH2) 3NHC (NH) NHN02] -NHC (0) W, C (0) NH (d-Cio alkyl), [(C (0) - (CH2) mC (0)] qR6, or [(C (0) - (CH2) mNHC (0)] qR6; W is alkyl C1-C10, O (C1-C10 alkyl) / (C1-C4 alkyl) -NHC (0) (C? -C6 alkyl), or (Ci-C4 alkyl) C (0) NHB, wherein B is alkyl C1-C10, phenyl, or phenyl- (C1-C3 alkyl); R6 is OR7, NHR7, 0CH2C (0) NR8R9, 0- (alkyl C? -C4) 0C- (0) R10, C? -C10 alkyl, or NHCHR? C (0) R12; R7 is H, C1-C10 alkyl, C3-C8 cycloalkyl, (C3-C8 cycloalkyl) - (C1-C3 alkyl) or (CH2) mC (0) NR8R9; R8 is H, or C? -C10 alkyl; R9 is H, or C1-C10 alkyl; R 10 is C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl, or R is H, C1-C10 alkyl, or phenyl- (C1-C3 alkyl); R12 is OR13 or NR13R14; R13 is H, or C1-C10 alkyl; R14 is H, or C? -C10 alkyl; n = 1-3; m = 1-3; q = 1-3; or a pharmaceutically or veterinarily acceptable salt thereof; or (iv) a compound of formula 4 Formula 4 wherein in the above formula 4: R_ is H, or alkyl d-C5; R 2 is H, C 1 -C 5 alkyl, or C 2 -C 6 alkenyl; R3 is H, Ci-Cio alkyl, Ci-Cio alkenyl, phenyl, cycloalkyl, C5-C8 cycloalkenyl, C1-C3 alkyl substituted with cycloalkyl, C1-C3 alkyl substituted with C5-C8 cycloalkenyl, or C1-C3 alkyl substituted with phenyl; A is OR4 or NR5R6; wherein: R4 is H, (C1-C10 alkyl) - (C2-C10 alkenyl) cycloalkyl, C5-C8 cycloalkenyl, C1-C3 alkyl substituted with cycloalkyl, C1-C3 alkyl substituted with C5-C8 cycloalkenyl, or C1 alkyl -C3 substituted with phenyl; R5 is H, or C? -C3 alkyl; R6 is H, C1-C10 alkyl, C3-C10 alkenyl, cycloalkyl, phenyl, C1-C3 alkyl substituted with cycloalkyl, C5-C8 cycloalkenyl, C1-C3 alkyl substituted with C5-C8 cycloalkenyl, C1-C3 alkyl substituted with phenyl, or (CH2) qB; or R5 and R6 are each CH2 which together with N form a heterocyclic ring of 4 to 6 links; where: B is or NR7R8 wherein: R7 is H, or C? -C3 alkyl; R6 is H, Ci-C3 alkyl, C3-C10 alkenyl, C1-C3 alkyl substituted with cycloalkyl, cycloalkyl, C5-C8 cycloalkenyl / C?-C3 alkyl substituted with C5-C8 cycloalkenyl, phenyl, or C1-C3 alkyl substituted with phenyl; or R7 and R8 are each CH2 that together with N form a heterocyclic ring of 4 to 6 links; W is OR9, NR ^ R11, or OE; wherein: R9 is hydrogen, C1-C10 alkyl, C2-C2 alkenyl, cycloalkyl, Cs-C8 cycloalkenyl, dC3 alkyl substituted with cycloalkyl, C3-C3 alkyl substituted with C5-C8 cycloalkenyl, or C-alkyl ? -C3 substituted with phenyl; R10 is hydrogen, or C? -C3 alkyl; R 11 is hydrogen, C 1 -C 10 alkenyl, C 3 -C 0 alkenyl, phenyl, cycloalkyl, C 5 -C 8 cycloalkenyl, C 1 -C 3 alkyl substituted with cycloalkyl, C 1 -C 3 alkyl substituted with phenyl, or fl (CH2) mCY; or R, 10 and R > n are each CH2 which together with N form a heterocyclic ring of 4 to 6 links; E is wherein: R12 is methylene substituted with C? -C3 alkyl; R 13 is C 1 -C 0 alkyl; D is OR14 or NR15R16; wherein: R14 is H, Ci-Cio alkyl, C2-C? alkenyl, cycloalkyl, C5-C8 cycloalkenyl, C?-C3 alkyl substituted with cycloalkyl, C1-C3 alkyl substituted with C5-C8 cycloalkenyl, or alkyl C? ~ C3 substituted with phenyl; R15 is H, Ci-Cio alkyl, C3-C3 alkenyl, phenyl, C?-C3 alkyl substituted with phenyl, cycloalkyl, Cs-C8 cycloalkenyl, C?-C3 alkyl substituted with cycloalkyl, or substituted C?-C3 alkyl with Cs-C8 cycloalkenyl; R16 is H, or Ci-C3 alkyl; R15 and R16 are each CH2 which together with N form a heterocyclic ring of 4 to 6 links; And it is OR17 or NR18R19; wherein: R17 is H, Ci-Cio alkyl, C2-Cio alkenyl, cycloalkyl, C5-C8 cycloalkenyl, C? -C3 alkyl substituted with cycloalkyl, C? -C3 alkyl substituted with C5-C8 cycloalkenyl, or C-alkyl? -C3 substituted with phenyl; R18 is hydrogen, or C1-C3 alkyl; R19 is hydrogen, C1-C10 alkyl, C3-C10 alkenyl, phenyl, cycloalkyl, C5-C8 cycloalkenyl, C1-C3 alkyl substituted with cycloalkyl, C1-C3 alkyl substituted with Cs-Cs cycloalkyl, or C1-C3 alkyl substituted with phenyl; R18 and R19 are each CH2 which together with N form a heterocyclic ring of 4 to 6 links; n is 0-4; q is 1-4; m is 1-4; or a pharmaceutically or veterinarily acceptable salt thereof.

2. The use of a compound according to claim 1, wherein said compound is a compound of formula 5: Formula 5 and pharmaceutically or veterinarily acceptable salts thereof, wherein in formula 5 above: R20 is H, or C? -C alkanoyl; R21 is C? -C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl / (C3-C8 cycloalkyl) - (C? -C6 alkyl), (C5-C8 cycloalkenyl) - (C? -C6 cycloalkyl), or a group of formula - (CH2) n-G-Ar; wherein n is 1, 2 or 3; G is C = 0, CH (OH), O, or a direct bond; and Ar is C3-C8 cycloalkyl, phenyl, which may optionally be substituted with one or more substituents, independently selected from halo, C? -C4 alkyl and C? -C alkoxy, or A1 is thienyl, furyl or pyridyl.

3. The use of a compound according to claim 2, wherein R20 is H or COCH3, and R21 is C2 to C8 alkyl, or d-C6 alkyl substituted with C3-C8 cycloalkyl.

4. The use of a compound according to claim 3, wherein R21 is n-hexyl, 2-methylpentyl, or cyclohexylethyl.

5. The use of a compound according to claim 2, wherein said compound is: (±) -N- (n-hexyl) -4- (3-hydroxyphenyl) -3,3-dimethylpiperidine hydrochloride; (±) -4- (3-hydroxyphenyl) -3,3-dimethyl-N- (4-methylpentyl) piperidine hydrochloride; (±) -4- (3-hydroxyphenyl) -trans-3,4-dimethyl-N- [3- (thien-3-yl) prop-1-yl] piperidine; (±) -N- (2-cyclohexylethyl) -4- (3-hydroxyphenyl) -3,3-dimethylpiperidine hydrochloride; (+) -4- (3-hydroxyphenyl) -trans-3,4-dimethyl-N- [3- (thien-2-yl) prop-1-yl] piperidine; (±) -4- (3-hydroxyphenyl) - trans-3,4-dimethyl-N- (3-phenylpropyl) piperidine; (±) -4- (3-hydroxyphenyl) -3,3,4-dimethyl-N- (2-phenoxyethyl) piperidine; (±) -N- (2-cyclohexylpropyl) -4- (3-hydroxyphenyl) -3,3-dimethylpiperidine; (±) -4- (3-hydroxyphenyl) -N- ((R) -3-hydroxy-3-phenylpropyl) -3,3-dimethylpiperidine; (±) -4- (3-hydroxyphenyl) -N- ((S) -3-hydroxy-3-phenylpropyl) -trans-3,4-dimethylpiperidine; (±) -N- ((S) -3-cyclohexyl-3-hydroxypropyl) -4- (3-hydroxyphenyl) -3,3-dimethylpiperidine; or (±) - (3-acetoxyphenoxy) -N- (n-hexyl) - trans-3,4-dimethylpiperidine hydrochloride.

6. The use of a compound according to any of claims 1 to 5, wherein said medicament is for the treatment of pruritus in cats, dogs or horses.

7. A veterinary formulation for the treatment of pruritus in animals, which includes a compound of formula 1, 2, 3 or 4, as defined in claim 1, or of formula 5 as defined in claim 2, together with a diluent or veterinarily acceptable vehicle.

8. A veterinary formulation according to claim 7 for topical application, wherein said formulation is in the form of an ointment, formulated for pouring, formulated for spraying, bathing, spraying, lathering, shampooing, collaring, or powdering.

9. The use of a compound of formula 1, 2, 3 or 4 according to claim 1, or of formula 5 as defined in claim 2, or a pharmaceutically or veterinarily acceptable salt thereof for manufacturing of a medicine to treat pruritus in humans and animals.