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1. WO1999003459 - COMPOSITIONS PHARMACEUTIQUES ANTI-PRURITIQUES CONTENANT DES AGONISTES DE RECEPTEURS KAPPA ET PROCEDE DE TRAITEMENT DU PRURIT A L'AIDE DESDITES COMPOSITIONS

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

WHAT IS CLAIMED IS:

1. A method for the prevention or treatment of pruritus in a mammal in need of such prevention or treatment comprising administering to said mammal an effective antipruritic amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof


wherein
the wavy line bond (~) between the nitrogen in the 2-position and the cyclohexyl ring carbon indicates the bond can be either cis- or trans with respect to each substituent on the cyclohexyl ring;
A is a single chemical bond (-), -(CH2)q, CH(CH3)- or -X(CH2)n
where q is 1 to 4,
n is 1-4 and
x is O or S;
Ar is an aromatic, hetero-aromatic, bicyclic-aromatic, tricyclic-aromatic group or diphenyl methyl each of which may be unsubstituted or substituted with a member selected from the group consisting of H, halo, trifluoromethyl, nitro, CrC3-alkoxy, hydroxy, azido, Cr C3-alkyl, methanesulfonyl, cyano, amino, C,-C -alkoxycarbonyl, Cj-C3-alkanoyloxy, and C1-C3-carboxacylamino of the formula -NHC(O)R7
where R7 is H, C]-C2-alkyl, and aromatic or hetero-aromatic group;
Rj and R2 are independently H, CrC3-alkyl or allyl;
R] and R2, taken together with the nitrogen to which they are bonded, complete a ring selected from the group consisting of azetidinyl, pyrrolidinyl, 3-hydroxypyrrolidinyl, 3- fluoropyrrolidinyl. moφholinyl, piperidinyl, and 3,4-dehydropiperidinyl;
R3, R4, R5, R6 are independently H, hydroxy, OR8 or OC(=O)R9;
R5 and R^ taken together may form the group -E-CH2-CH2-E-;
R5 and R6 taken together may form a ring

where
Z is selected from the group consisting of oxygen (-O-), NR]0, sulfur (-S-), sulfinyl
(-S(O)-), and sulfonyl (-S(O)2-);
E is N~OH, N~OC(O)CH3, O, S, with the proviso that when E is bivalent sulfur or oxygen, R5 and R6 cannot both be hydrogen;
R8 is CrC3-alkyl;
Rg is H or C,-C3-alkyl;
R10 is H, or CrC3-alkyl,

in a pharmaceutically acceptable carrier.

2. The method for the prevention or treatment of pruritus in a mammal in need of such prevention or treatment comprising administering to said mammal an effective anti-pruritic amount of a composition of claim 1 wherein AR is pyridine, thiophene, naphthalene, benzofuran, benzothiophine anthracene or fluorence; and halo is F, Cl, Br or I.

3. The method for the prevention or treatment of pruritus in a mammal in need of such prevention or treatment comprising administering to said mammal an effective anti-pruritic amount of a composition of claim 1 wherein said compound is selected from the group consisting of:
(±)-N-[2-(N,N'-dimethylamino)cyclohexyl]-N-methyl-2-(4-trifluoromethylphenyl)acetamide;
(±)-N-[2-(N',N'-dimethylamino)cyclohexyl]-N-propyl-2-(3-methoxyphenyl)acetamide;
(±)-N-[2-(N',N'-dimethylamino)cyclohexyl]-N-methyl-2-(4-azidopbenyl)acetamide;
(±)-N-[2-(N',N'-dimethylamino)cyclohexyl]-N-methyl-2-(3,4-dichlorophenyl)acetamide;

(±)-N-[2-(N',N'-dimethylamino)cyclohexyl]-N-methyl-2-(4-methoxyphenyl)acetamide;
(±)-N-[2-(N',N'dimethylamino)cyclohexyl]-N-methyl-2-(2-naphthyl)acetamide;
(±)-N-[2-(N-cyclopropyl-N-methylamino)cyclohexyl]-2-(4-azidophenyl)acetamide;
(±)-N-(2-(3 -acetoxy- 1 -pyrrohdiny l)cyclohexyl] -N-methyl-2-(3 ,4-dichlorophenyl)acetamide;

(±)-N-[2-(N-pyrrolidinyl)cyclohexyl]-N-methyl-2-(3,4-dichlorophenyl)acetamide;
(±)-N-[2-(3-hydroxypyrrolidinyl)cyclohexyl]-N-methyl-2-(3,4-dichlorophenyl)acetamide;

(±)-N-[2-[N'-(3-hydroxy-l-azetidinyl]cyclohexyl]methyl-2-(3,4-dichlorophenyl)acetamide;

(±)-N-[2-(N',N'-diethylamino)cyclohexyl]-N-methyl-2-(3,4-dichlorophenyl)acetamide;
(±)-N-[2-(N'-pyrrolidinyl)cyclohexyl]-N-methyl-2-(3,4-dichlorophenyl)propionamide;
(±)-N-[2-(4-methyl-l-piperazinyl)cyclopentyl]-2-(3,4-dichlorophenyl)acetamide;
(±)-N-[2-(N,N-dimethylamino)cyclohexyl]-2-(3,4-dichlorophenyl)acetamide;
(±)-3,4-dichloro-N-methyl-N-[8-(l-pyrrolidinyl)-l,4-dioxaspiro[4.5]dec-7-yl]-benzeneacetamide;
(±)-3,4-dichloro-N-methyl-N-[7-(l-pyrrolidinyl)-l,4-dioxaspiro[4.5]dec-8-yl]- benzeneacetamide;
-46- SUBST1TUTE SHEET (RULE 26) (±)-3,4-dichloro-N-methyl-N-[7-(l-pyrrolidinyl)-l,4-dioxasρiro[4.5]dec-6-yl]-benzeneacetamide;
(±)-4-bromo-N-methyl-N-[7-(l-pyrrolidinyl)-l,4-dioxaspiro[4.5]dec.8.yl]-benzeneacetamide;
(±)-3.fluoro-Nethyl-N-[7-(l-azetidinyl)-l,4-dioxaspiro[4.5]dec-8-yl]benzeneacetamide;

(±)-3,4-dichloro-N-methyl-N-[7-(l-pyrrolidinyl)-l,4-dioxaspiro[4.4]-non-8-yl)-benzeneacetamide;
(±)-3,4-dichloro-N-methyl-N-[7-(l-pyrrolidinyl)-l,4-dioxaspiro[4.6]-undec-8-yl]-benzeneacetamide;
(±)-3,4-dichlor-N-methyl-N-[8-(l -pyrrolidinyl)- l,4-dioxaspiro[4.6]-undec-7-yl]-benzeneacetamide;
(±)-3,4-dichloro-N-methyl-N-[9-(l-pyrrolidinyl)- l,4-dioxaspiro[4.6]-undec-8-yl]-benzeneacetamide;
(±)-3,4-dichloro-N-[4-methoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methylbenzeacetamide; (±)-3,4-dichloro-N-[5-methoxy-2-(l -pyrrolidinyilcyclohexyll-N-methylbenzeneacetamide;

(±)-3,4-dichloro-N-methyl-N-[4-oxo-2-(l-pyrrolidinyl)cyclohexyl]-benzeneacetamide;
(±)-4-bromo-N-methyl-N-[2-(N',N'-dimethylamino)-4-oxo-cyclohexyl]benzeneacetamide;

(±)-N-[4-acetyloxy-2-(l-pyrrolidiny])cyclohexyl]-3,4-dichloro-N-methylbenzeneacetamide;

(±)-N-[4-acetyloxy-2-aminocyclohexyl]-3,4-difluoro-N-methylbenzeneacetarnide;
(±)-3 ,4-dichloro-N-[5-(hydroxyimino)-2-( 1 -pyrrolidinyl)cyclohexyl]-N-methylbenzeneacetamide;
(±)-3,4-dichloro-N-[4,4-dimethoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methylbenzeneacetamide which can also be named:
(±)-3,4-dichloro-N-methyl-N-[4-oxo-2-(l-pyrrolidinyl)cyclohexyllbenzeneacetamide, dimethyl ketal;
(±)-3,4-dichloro-N-[5,5-diethoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methylbenzeneacetamide;

(±)-(lα, 2β)-3,4-dichloro-N-[4,4-dimethoxy-2-(l -pyrrolidinyl )cyclohexyl]-N-methyl benzeneacetamide;
(±)-4-trifluoromethyl-N-[4,4-dimethoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methylbenzeneacetamides ;
(±)-3 -trifluoromethyl -N-[4,4-diethoxy-2- (1 -pyrrolidinyl)-cyclohexyl]-N-methylbenzeneacetamide;
(±)-3-hydroxy-4-methyl-N-[4,4-dimethoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methylbenzeneacetamide;
(±)-4-methanesulfonyl-N-[4,4-dimethoxy-2-(l-piperidinyl)-cyclohexyl ]-N-methylbenzamide;
(±)-4- acetyloxy-N-[4,4-dimethoxy-2- ( 1 -pyrrolidinyl )-cyclohexyl-N-methylbenzeneacetamide;
(±)-N-[4,4-bis(methylthio)-2-(l-pyrrolidinyl)cyclohexyl]-3,4-dichloro-N-methylbenzeneacetamide;
(±)-N- [5 ,5 -bis(ethylthio)-2-(l-pyrrolidinyl)cyclohexyl] -3 ,4-di-chloro-N-methylbenzeneacetamide;
(±)-3,4-dichloro-N-[4-methylthio-2-(l-pyrrolidinyl)cyclohexyl]-N-methylbenzeneacetamide;
(±)-3 ,4-dichloro-N- [5 -ethylthio-2-( 1 -pyrrolidinyl)cyclohexyl] -N- methylbenzeneacetamide;
(±)-3,4-dichloro-N-[6-methylthio-2-(l-pyrrolidinyl)cycloheptyl]-N- methylbenzeneacetamide;
(±)-3,4-dichloro-N-[4-mercapto-2-(l-pyrrolidinyl)cyclohexyl]-N-methylbenzeneacetamide; [lR-(lα,2β,4β,5β)]-N-[4,5-dimethoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methyl-4- benzofuranacetamide;
[lS-(lα,2β,4β,5β)]-N-[4,5-dimethoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methyl-4- benzofuranacetamide;
[lR-(lα,2β,4α,5 )]-N-[4,5-dimethoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methyl-4- benzo furanacetamide;
[lS-(lα,2β,4α,5α)]-N-[4,5-dimethoxy-2-(l-ρyrrolidinyl)cyclohexyl]-N-methyl-4- benzofuranacetamide;

[lR-(lα,2β,4β,5β)]-N-[4,5-dimethoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methyl-benzo[b]thiophene-4-acetamide;
[lS-(lα,2β,4β,5β)]-N-[4,5-dimethoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methyl-benzo [b]thiophene-4-acetamide;
[ 1 R-( 1 α,2β,4α,5α)]-N-[4,5-dimethoxy-2-( 1 -pyrrolidinyl)cyclohexyl]-N-methyl-benzo[b]thiophene-4-acetamide;
[lS-(l ,2β,4α,5α)]-N-[4,5-dimethoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methyl-benzo[b]thiophene-4-acetamide;
[lR-(lα,2β,4β,5β)]-N-[4,5-dimethoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methyl-l-naphthaleneacetamide;
[ 1 S-( 1 α,2β,4β,5 β)]-N-[4,5-dimethoxy-2-(l -pyrrolidinyl)cyclohexyl]-N-methyl- 1 -naphthaleneacetamide;
[lR-(lα,2β,4α,5α)]-N-[4,5-dimethoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methyl-l-naphthaleneacetamide;
[1 S-( lα,2β,4α,5α)]-N-[4,5-dimethoxy-2-( 1 -pyrrolidinyl)cyclohexyl]-N-methyl-l -naphthaleneacetamide;
[lR-(lα,2β,4β,5β)]-3,4-dichloro-N-[4,5-dimethoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methybenzeneacetamide;
[lS-(lα,2β,4β,5β)]-3,4-dichloro-N-[4,5-dimethoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methybenzeneacetamide;
[lR-(lα,2β,4α,5α)]-3,4-dichloro-N-[4,5-dimethoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methybenzeneacetamide;
[lS-(lα,2β,4α,5α)]-3,4-dichloro-N-[4,5-dimethoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methybenzeneacetamide;
[lR-(lα,2β,4β,5β)]-N-[4,5-dimethoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methyl-9H-fluorene-9-carboxamide;
[ 1 S-( 1 α,2β,4β,5β)]-N-[4,5-dimethoxy-2-(l -pyrrolidinyl)cyclohexyl]-N-methyl-9H-fluorene- 9-carboxamide;
[lR-(lα,2β,4α,5α)]-N-[4,5-dimethoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methyl-9H-fluorene-9-carboxamide;
[lS-(lα,2β,4α,5α)]-N-[4,5-dimethoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methyl-9H-fluorene-9-carboxamide;
(±)-(lα,2β,4β)-N-methyl-N-[4-methoxy-2-(l-pyrrolidinyl)cyclohexyl]-4-benzo furanacetamide;
(±)-(lα,2β,4α)-N-methyl- N-[4-methoxy-2-(l -pyrrolidinyl)cyclohexyl]-4-benzofuranacetamide;
(+)-( 1 ,2 β,5 β)-N-methyl-N- [5 -methoxy-2-( 1 -pyrrolidinyl)cyclohexyl] -4-benzofuranacetamide;
(±)-(lα,2β,5α)-N-methyl- N-[5-methoxy-2-(l-pyrrolidinyl)cyclohexyl]-4-benzofuranacetamide;
(±)-(lα,2β,4α)-N-[4-methoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methyl-9H-fluorene-9- carboxamide;
(±)-( 1 α,2 β,5 β)-N- [5 -methoxy-2-( 1 -pyrrolidinyl)cyclohexyl] -N-methyl-9H-fluorene-9- carboxamide;
(±)-N-methyl-2-(l-naphthalenyloxy)-N-[2-(l-pyrrolidinyI)cyclohexyl]acetamide;
(±)-N-methyl-2-(2-naphthalenyoxy)-N-[2-(l-pyrrolidinyl)cyclohexy]jacetamide;
(±)- 1 ,2-dihydro-N-methyl-N-[2-( 1 -pyrrolidinyl)cylohexyl]-l-acenaphthylencarboxamide,

(isomer I, mixture of (lα, 2β) and (lβ,2α) forms);
(±)- 1 ,2-dihydro-N-methyl-N-[2-( 1 -pyrrolidinyl)cyclohexyl]- 1 -acenaphthylenecarboxamide, (isomer II, mixture of (lα, 2β) and (lβ,2α) forms);
(±)-N-[4,5-dimethoxy-2-( 1 -pyrrolidinyl)cyclohexyl] - 1 ,2-dihydro-N-methyl- 1 - acenaphthylenecarboxamide (isomer I, mixture of (lα,2β, 4β, 5β) and (lβ, 2α, 4α, 5α forms);
(±)-N-[4,5-dimethoxy-2-( 1 -pyrrolidinyl)cyclohexyl]- 1 ,2-dihydro-N-methyl-l- acenaphthylenecarboxamide (isomer II, mixture of (lα,2β, 4β, 5β) and (lβ, 2α, 4α, 5α forms);

(±)-l,2-dihydro-N-[4-methoxy-2-(l-pyrrolidinyl)cyclohexyl]-N-methyl-l-acenaphthylenecarboxamide (isomers I and II, mixtures of (lα,2β, 4β) and (l β, 2α, 4α) forms);
(±)- 1 ,2-dihydro-N-[4-methoxy-2-( 1 -pyrrolidinyl)cyclohexyl]-N-methyl-l-acenaphthylenecarboxamide (isomers I and 11, mixtures of (1 β, 2α, 4α) and (lα,2β, 4β) forms);
(±)-trans-N-methyl-N-[2-(l-pyrrolidinyl)cyclohexyl]-9H-fluorene-9-carboxamide;
(±)-trans- 1 ,3-dihydro-N-methyl- 1 -oxo-N-[2-( 1 pyrrolidinyl)cyclohexyl]-4-isobenzofuranacetamide;
(±)-(lα,2β, 4β, 5β)-N-[4,5-dimethoxy-2-(l-pyrrolidinyl)cyclohexyl]-l,3-dihydro-N-methyl- 1 -oxo-4-isobenzo furanacetamide;
(±)-(5α,7α, 8β)-3,4-dichloro-N-methyl-N-[7-(l-pyrrolidinyl)-l-oxasρiro[4.5]dec-8-yl] benzeneacetamide;
(±)-(5α,7α, 8β)-bromo-N-methyl-N-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl] benzeneacetamide;
(±)-(5α,7α, 8β)-4-methoxy-N-methyl-N-[7-(l -pyrrolidinyl)- l-oxaspiro[4.5]dec-8-yl] benzeneacetamide;
(±)-(5α,7α, 8β)-N-methyl-2-nitro-N-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl] benzeneacetamide;
(±)-(5α,7α, 8β)-N-methyl-3-nitro-N-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl] benzeneacetamide;
(±)-(5α,7α, 8β)-N-methyl-4-nitro-N-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl] benzeneacetamide;
(±)-(5α,7α, 8β)-N-methyl-N-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl]-3-(trifluoromethyl)benzeneacetamide;
(±)-(5α,6α, 7β)-3,4-dichloro-N-methyl-N-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-6-yl] benzeneacetamide ;
(±)-(5α,7α, 8β)-3,4-dichloro-N-methyl-N-[7-(l-pyrrolidinyl)-l-thiaspiro[4.5]dec-8-yl] benzeneacetamide;
(±)-(5α,7β, 8α)-3,4-dichloro-N-methyl-N-[8-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-7-yl] benzeneacetamide;
(±)-(5α,7α, 8β)-3,4-dichloro-l,N-dimethyl-[7-(l-ρyrrolidinyl)-l-azaspiro[4.5]dec-8-yl] benzeneacetamide;
(±)-(5α,7α, 8β)-4-bromo-N-methyl-N-[7-(l-pyrrolidinyl)-l-azaspiro[4.5]dec-8-yl] benzamide;
(±)-(5α,7α, 8β)-3,4-dichloro-N-methyl-N-[7-(l-pyrrolidinyl)-l-thiaspiro[4.5]dec-8-yl] benzamide;
(±)-(5 ,7α, 8β)-3,4-dichloro-N-methyl-N-[7-(l-pyrrolidinyl)-l-thiaspiro[4.5]dec-8-yl] benzeneacetamide;
(±)-(5α,7α, 8β)-3,4-dichloro-N-methyl-N-[7-(l-pyrrolidinyl)-l-thiaspiro[4.5]dec-8-yl] benzeneacetamide, 1 -oxide;
(±)-(5α,7α, 8β)-3,4-dichloro-N-methyl-N-[7-(l-p τrolidinyl)-l-thiaspiro[4.5]dec-8-yl] benzeneacetamide, 1,1 -dioxide;
(±)-(5α,7α, 8β)-N-methyl-N-[7-(l -pyrrolidinyl)- l-azaspiro[4.5]dec-8-yl]4-trifluoromethylbenzeneacetamide;
(±)-(5α,7α, 8β)-N-methyl-N-[8-(l -pyrrolidinyl)- 1 -thiaspiro[4.5]dec-7-yl]-3-trifluoromethylbenzeneacetamide;
[5R-(5α,7α,8β)]-N-Methyl-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl]-lH-indene-3-acetamide;
[5S-(5α,7α,8β)]- N-Methyl-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl]-lH-indene-3- [5R-(5α,7β,8α)]- N-Methyl-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl]-lH-indene-3- 3 fit 3 TTΪ 1 π P *
[5S-(5α,7β,8α)]- N-Methyl-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl]-lH-indene-3- [5R-(5α,7α,8β)]-N-Methyl-N-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl]-lH-indole-3- acetamide;
-49- SUBST1TUTE SHEET (RULE 26) [5S-(5α,7α,8β)]-N-Methyl-N-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl]-lH-indole-3-acetamide;
[5R-(5α,7β,8α)]- N-Methyl-N-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl]-lH-indole-3-acetamide;
[5S-(5α,7β,8α)]- N-Methyl-N-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl]-lH-indole-3-acetamide;
[5R-(5α,7α,8β)]-N-Methyl-N-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl]-2-benzofuranacetamide;
[5S-(5α,7α,8β)]-N- Methyl-N-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl]-2-benzo furanacetamide;
[5R-(5α,7β,8α)]-N-Methyl-N-[7-(l -pyrrolidinyl)-l -oxaspiro[4.5]dec-8-yl]-2-benzo [b] furanacetamide;
[5S-(5α,7β,8α)]-N-Methyl-N-[7-(l -pyrrolidinyl)-l -oxaspiro[4.5]dec-8-yl]-2-benzo[b]furanacetamide;
[5R-(5α,7α,8β)]-N-Methyl-N-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl]-3-benzo[b]furanacetamide;
[5S-(5α,7α,8β)]-N- Methyl-N-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl]-3-benzo[b]furanacetamide;
[5R-(5α,7β,8α)]-N-Methyl-N-[7-(l -pyrrolidinyl)-l -oxaspiro[4.5]dec-8-yl]-3-benzo[b]furanacetamide;
[5S-(5α,7β,8α)]-N-Methyl-N-[7-(l -pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl]-3-benzo [b] f ranacetamide;
[5R-(5α,7α,8β)]-N-Methyl-N-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl]-4-benzo[b] furanacetamide;
[5S-(5α,7α,8β)]-N- Methyl-N-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl]-4-benzo[b]furanacetamide;
[5R-(5α,7β,8α)]-N-Methyl-N-[7-(l -pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl]-4-benzo[b]furanacetamide;
[5S-(5α,7β,8α)]-N-Methyl-N-[7-(l -pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl]-4-benzo[b]furanacetamide;
[5R-(5α,7α,8β)]-N-Methyl-N-7-(l-pyrrolidinyl)-l-oxasρiro[4.5]dec-8-yl-4-benzo[b]thiophene-4-acetamide;
[5S-(5α,7α,8β)]- N-Methyl-N-7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl-4-benzo[b]thiophene-4-acetamide;
[5R-(5α,7β,8α)]- N-Methyl-N-7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl-4-benzo[b]thiophene-4-acetamide;
[5S-(5α,7β,8α)]- N-Methyl-N-7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl-4-benzo[b]thiophene-4-acetamide;
(-)-(5α,7α,8β)]-N- Methyl-N-[7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl]-4-benzo[b]furanacetamide;
(-)-(5α,7α,8β)]-N-7-(l-pyrrolidinyl)-l-oxaspiro[4.5]dec-8-yl-4-benzo[b]thiophene-4- acetamide;
(±)-(5α,6α,7β)-3,4-dichloro-N-methyl-N-[7-(l-pyrrolidinyl )-2-oxaspiro[4.5]dec-6-yl] benzeneacetamide;
(±)-(5α,6α,7β)-3,4-dichloro-N-methyl-N-[6-(l-pyrrolidinyl )-2-oxaspiro[4.5]dec-7-yl] benzeneacetamide; and
b(±)-(5α,7α,8β)-3,4-dichloro-N-methyl-N-[8-(l-pyrrolidinyl )-2-oxasρiro[4.5]dec-7-yl] benzeneacetamide.
4. The method of claim 1 wherein said administration is topical administration.

5. The method of claim 1 wherein said administration is parenteral administration.

6. The method of claim 1 wherein said administration is oral administration.
7. The method of claim 1 wherein said administration is rectal administration.

8. The method of claim 2 wherein said administration is topical administration.

9. The method of claim 2 wherein said administration is parenteral administration,

10. The method of claim 2 wherein said administration is oral administration,
11. The method of claim 2 wherein said administration is rectal administration,
12. The method of claim 3 wherein said administration is topical administration,
13. The method of claim 3 wherein said administration is parenteral administration,

14. The method of claim 3 wherein said administration is oral administration,
15. The method of claim 3 wherein said administration is rectal administration.

16. A method for the prevention or treatment of pruritus in a mammal in need of such prevention or treatment comprising administering an effective anti-pruritic amount of a composition comprising a compound of formulae II or Ila or a stable N-oxide pharmaceutically acceptable salt thereof


II


Ila
wherein for the enantiomers and racemic mixtures
n is 0 or 1;
A is
H
C —

R4
or, -CH2CH2- provided that in Formula II, when n is 1, A may also be -O- or -S-;

-51- SUBST1TUTE SHEET (RULE 26) B, C and D are independently selected from the group consisting of H, OH, OCOR5, OCH2CH2OR5, OR6, R6, CH2OR6, CH2COR7, Cl, F, Br, I, NH2, NHR8, NR8R9, SH, SR6, CH,SR6 and OC(S)N(CH3)2; or

two of B, C and D when on adjacent carbon atoms taken together form a fused benzo ring;

X and Y are independently selected from the group consisting of H, OCH3, Cl, F, Br, I, NO2,

CF3, CN, SO2R10, and SO2CF3; or
X and Y taken together with the benzene ring form



R and R independently are selected from the group consisting of H, and alkyl of 1 to 3 carbon atoms;

R2 is H; alkyl of 1 to 6 carbon atoms; CH,CF3; alkenylmethyl of 3 to 6 carbon atoms; hydroxyalkenylmethyl of 2 to 5 carbon atoms; cycloalkyl of 3 to 6 carbon atoms; cyclopropylmethyl; cyclobutylmethyl, or phenylalkyl of 7 to 9 carbon atoms; or R2 can be taken together with R1 and the nitrogen to which they are attached to form 1 -azetidinyl, 1 -pyrrolidinyl optionally substituted at the 3-position by OH, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms or alkanoyloxy of 1 to 3 carbon atoms; 1-piperazinyl optionally substituted at the 4-position by alkyl of 1 to 3 carbon atoms; 1-moφholino; 2,5-dihydro-lH-pyrrol-1-yl; 3-azabicyclo[3.1.0]hexan-3-yl; or 3-azabicyclo[3.2.0]hoptan-3-yl;

R3 is H, but if n is 1 and A is CH2, R3 may also be CH3, CH2OH, CHO, or COR";
R4 is H, alkyl of 1 to 6 carbon atoms, -CH,OH-, CHO, or COR12;
R5 is alkyl of 1 to 6 carbon atoms, phenyl, or mono-substituted phenyl;
R6, R8, R9, R10 and R13 are independently an alkyl group of 1 to 3 carbon atoms; and
R7, R" and R12 independently are selected from the group consisting of H, OH, OR13, NHR13, and NR213;
in a pharmaceutically acceptable vehicle.

17. A method for the prevention or treatment of pruritus in a mammal in need of such prevention or treatment comprising administering an effective anti-pruritic amount of a composition comprising a compound of formulae lib or a stable N-oxide pharmaceutically acceptable salt thereof


wherein
n is 1;
A is -CH,-, -O-, or -S-;
B is OH, OCOR5, OCH2CH2OR5, OR6, CH,OR6, or CH,COR7;
C is H, OH, or OR6;

R1 and R2 independently are selected from H or alkyl of 1 to 3 carbon atoms or are taken together with the nitrogen to which they are attached to form the group 1 -azetidinyl, 1-pyrrolidinyl, l-(2,5-dihydro-lH-pyrrolyl) or 1-piperidinyl;

X and Y taken together with the benzene ring form


R is H, and CrC3 alkyl;
R3 is H; and
R5, R6 and R7 are independently CrC3 alkyl,
in a pharmaceutically acceptable carrier.

18. A method for the prevention or treatment of pruritus in a mammal in need of such prevention or treatment comprising administering an effective anti-pruritic amount of the composition of claim 17 wherein said compound is selected from the group consisting of:

(±)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-l-yl)-5-methoxy-l,2,3,4-tetrahydronaphth- l-yl]-benzeneacetamide hydrochloride or the methansulfonic acid salt;
(±)trans-3 ,4-dichloro-N-methyl-N-[2-(pyrrolidin- 1 -yl)- 1 ,2,3 ,4-tetrahydronaphth- 1 -yl]-benzeneacetamide hydrochloride;
-53- SUBST1TUTE SHEET (RULE 26) (+)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin- 1 -yl)-6-methoxy- 1 ,2,3,4-tetrahydronaphth-1 -yl]-benzeneacetamide hydrochloride;
(±)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin- 1 -yl)-6-hydroxy- 1 ,2,3,4-tetrahydronaphth-1 -yl]-benzeneacetamide hydrochloride;
(±)-trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-l-yl)-l,2,3,4-tetrahydronaphth-l-yl]-benzeneacetamide hydrochloride;
(±)trans-3,4-dichloro-N-methyl-N-[2,3-dihydro-2-(pyrrolidin-l-yl)-lH-inden-l-yl]-benzeneacetamide hydrochloride;
(±)trans-3,4-dichloro-N-methyl-N-[3,4-dihydro-3-(pyrrolidin-l-yl)-2H-benzopyran-4-yl]-benzeneacetamide hydrochloride;
(±)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-l-yl)-5-hydroxy-l,2,3,4-tetrahydronaphth-1 -yl]-benzeneacetamide hydrochloride;
(±)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-l-yl)-5-propionyloxy-l, 2,3,4-tetrahydronaphth- 1 -yl]-benzeneacetamide hydrochloride;
(±)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-l-yl)-5-benzoyloxy- 1,2,3,4-tetrahydronaphth- 1 -yl]-benzeneacetamide hydrochloride;
(±)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin-l -yl)-6,7-dihydroxy- 1,2,3,4-tetrahydronaphth-1 -yl] -benzeneacetamide hydrochloride;
(±)trans-N-methyl-N-[3,4-dihydro-3-(pyrrolidin-l-yl)-2H-benzopyran-4-yl]-benzeneacetamide hydrochloride;
(±)trans-3,4-dichloro-N-methyl-N-[3,4-dihydro-8-methoxy-3-(pyrrolidin-l-yl)-2H-benzopyran-4-yl]-benzeneacetamide hydrochloride;
(±)trans-3,4-dichloro-N-methyl-N-[2-(pyrrolidin- 1 -yl)-5-(N,N-dimethylthiocarbamoyloxy)- 1, 2,3, 4-tetrahydronaphth-l-yl]-benzeneacetamide hydrochloride;
(±)trans-3,4-dichloro-N-methyl-N-[2-(2,5-dihydro-lH-pyrrol-l-yl)-5-methoxy-l,2,3,4-tetrahydronaphth-l-yl]-benzeneacetamide hydrochloride, and
(±)trans-3-nitro-N-methyl-N-[2,3-dihydro-2-(pyrrolidin- 1 -yl)- 1 H-inden- 1 -yl]-benzeneacetamide hydrochloride.

19. The method of claim 16 wherein said administration is topical administration.
20. The method of claim 16 wherein said administration is parenteral administration.

21. The method of claim 16 wherein said administration is oral administration.
22. The method of claim 16 wherein said administration is rectal administration.
23. The method of claim 17 wherein said administration is topical administration.
24. The method of claim 17 wherein said administration is parenteral administration.

25. The method of claim 17 wherem said administration is oral administration.

Z6. The method of claim 17 wherein said administration is rectal administration.
27. The method of claim 18 wherein said administration is topical administration,

28. The method of claim 18 wherein said administration is parenteral administration,

29. The method of claim 18 wherein said administration is oral administration,
30 The method of claim 18 wherein said administration is rectal administration.

31. A method for the prevention or treatment of pruritus in a mammal in need of such prevention or treatment comprising administering to said mammal an effective anti-pruritic amount of a composition comprising a compound of formulae III or a pharmaceutically acceptable salt thereof



III
wherein
n is 0-1;

R is unsubstituted phenyl or phenyl substituted with one to three substituents selected from the group consisting of halogen, C,.6 alkyl, hydroxy, -O-CO-NH,, -O-CO-NHalkyl, -O-CO-N(alkyl),, C,_6 alkoxy, trifluoromethyl, C,.4-alkoxy-C1.4 alkyloxy, carboxy-C,.4 alkyloxy, nitrile, nitro and amino; or mono or dialkyl amino, amide, sulfonamide, carboxamide; or mono or disubstituted carboxamide, ureido, or mono and di-alkylsubstituted ureido; or

R represents an alkyl or cycloalkyl group having up to 7 carbon atoms, wherein the cycloalkyl moiety, where present, can be optionally substituted by one or more substituents selected from the group consisting of from hydroxy, amino, amidino, guanidino, aminocarbonyl, carboxy, C,.6 alkoxy, (C,.6 alkoxy)carbonyl, (C3.6 alkenyloxy)carbonyl, (C3.6 alkynyloxy)carbonyl, C,.6 alkanoyloxy, C,.6 alkylsulfide, CN6 alkylsulfoxide, C,.6 alkylsulfone, C,.6(monoalkylamino)carbonyl, C,.6 acylamino, C1-6 acylmethylamino and C,.6 monoalkylamino; or

R represents the group -B-R7 in which B represents -CH,-, -CH(CH3)- or a single bond and

R7 represents an optionally substituted C6.I0 carbocyclic aryl group with one to three substituents selected from the group consisting of halogen, C,.6 alkyl, hydroxy, -O-CO-NH,, -O-CO-NHalkyl, -O-CO-N(alkyl)2, C,.6 alkoxy, trifluoromethyl, CM-alkoxy-CM alkyloxy, carboxy-C alkyloxy, nitrile, nitro and amino; or mono or dialkyl amino, amide,
sulfonamide, carboxamide; mono or disubstituted carboxamide ureido; and mono or di-alkylsubstituted ureido; or

R represents the group -D-R8 in which D represents a single bond, -CH2-, -CH(CH3)-, -CH2O-, -CH(CH3)O-, -CH-S-, -CH(CH3)S-, -CH2NH- or -CH(CH3)NH- and R8 represents a 4-6 membered heterocyclic ring containing up to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, the heterocyclic ring optionally being substituted on nitrogen or sulfur by oxygen or on nitrogen by hydroxy or C,.3 alkyl and/or the ring optionally being substituted on carbon by one or more substituents selected from the group consisting of amino, hydroxy, thio (and their tautomers), cyano, halogen, C,_3 alkoxy, C,„3 monoalkylamino, C,.3 acylamino, C,.3 acylmethylamino, and C,.3 alkylthio;

R1 and R2 are independently selected from the group consisting of H, C,.6 alkyl, C3.5 alkenyl, C3.5 alkynyl, and C4.7 cycloalkylalkyl group; or R2 can be taken together with R1 and the nitrogen to which they are attached to form a heterocyclic ring which may optionally contain a further heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, said heterocyclic ring selected from the gorup consisting of 1 -azetidinyl and 1 -pyrrolidinyl said 1 -pyrrolidinyl optionally substituted at the 3 -position by OH, -CH,OH, tri(C,-C6
alkyl)silyloxy, acyloxy, C,.6 alkyl, C,.6 alkoxy or C,.6 alkanoyloxy; 1 -piperazinyl optionally substituted at the 4-position by alkyl of 1 to 3 carbon atoms; 1-moφholino; 2,5-dihydro-lH-pyrrol-1-yl; 3-azabicyclo[3.1.0]hexan-3-yl; or 3-azabicyclo[3.2.0]heptan-3-yl;

R3 represents hydrogen, C,_7 alkyl, -CH2 -phenyl or heterocyclic wherein the phenyl or heterocyclic groups may be substituted with one to three substituents selected from the group consisting of halo, C,.4 alkyl, C,.4 alkoxy and methoxycarbonyl; mono-, di- or tri-halomethyl; cyano; COR9, CH=NOR'°, OR10, SR10, CH2CN, CH2OR10, CH2SR10,
CH,S(O)R10, CH,S(O)2R10, CH2N(R10)R", CH2(R10)Rπ, CH2NR'°OH, CH2N(COR10)OH, CH2NR10COR", CH2NR10S(O)2R", or CH2OCOR'°, wherein R9 is hydrogen, hydroxy, amino, NHOH, NHOCH3, pyridylamino, NHN(CH3)2, CM alkoxy, benzyloxy, CM alkylamino, di-C,.4 alkylamino, C,.4 alkyl or C,.4 alkylthio; R10 and R1 ! are each hydrogen, C,.4 alkyl, CM alkoxy or C7.π phenylalkyl), or OR12, wherein R'2 is hydrogen, CM alkyl or a hydroxy protecting group;

X represents -CO-, or -SO2-;

Y represents a single bond wherein only one of R4-R6 is attached, a tetrahedral carbon, -OC-, -SC-, -S(O)C-, -S(O)2C-, or -CH2C-;

R4, R5, and R6 are independently selected from the group consisting of hydrogen, hydroxy, alkoxy, C alkylenedioxy, C,.8 cyclic and acyclic alkyl; substituted or unsubstituted carbocyclic aromatic or heterocyclic aromatic group selected from the group consisting of phenyl, naphthyl, biphenyl, indanyl, l-tetralone-6-yl, furyl, thienyl, pyridyl, thiazolyl, benzofuryl and benzothienyl, each of which may be substituted with one to three substituents selected from the group consisting of halo, cyano, -OCONH2, -OCONHalkyl, -OCON(alkyl)2, -OCOalkyl, -NHCHO, -NHCOalkyl, ureido, -NHCONHalkyl, -NalkylCONHalkyl,-NHCON(alkyl),, -NalkylCON(alkyl)2, -NHSO,alkyl, -COalkyl, -CONH,, -CONHalkyl, -CON(alkyl)2, -CH,CONH,, -CH,CONHalkyl, -CH,CON(alkyl)2, -OCH2CONH2, -OCH2CONHalkyl, -OCH2CON(alkyl)2, CM alkyl, CM alkoxy, amino, hydroxy, nitro, trifluoromethyl, -SO,alkyl, -SOalkyl, and mesyl; or R5 and R6 can together form the following structure


wherein R'3 and R14 are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, mono-, di- or tri-halomethyl, amino, -NHalkyl, -N(alkyl)2, -NHCOalkyl, ureido, nitro, and methylenedioxy; and

D represents -CH2-, -O-, -S-, -NH, -CH,CH2-, -CH=CH-, -CH,NH-, or -CH,Nalkyl-; in a pharmaceutically carrier.

32. The method of claim 31 wherein said compound is selected from the group consisting of:

N-methyl-N-{[lS]-l-phenyl-2-[(3S)-(3-hydroxypyrrolidin-l-yl)]ethyl}-2,2- diphenylacetamide hydrochloride,

3 ,4-dichloro-N-methyl-N-[( 1 S)- 1 -phenyl-2-( 1 -pyrrolidinyl)ethyl]benzeneacetamide hydrochloride,

N-methyl-N-{[lS]-l-phenyl-2-[(3S)-(3-hydroxypyrrolidin-l-yl)]ethyl}-2- aminophenylacetamide hydrochloride,

-57- SUBST1TUTE SHEET (RULE 26) 3,4-dichloro-N-methyl-N-[( 1 S)- 1 -isopropyl-2-( 1 -pyrrolidinyl)ethyl]benzeneacetamide hydrochloride,

3,4-dichloro-N-methyl-N-[(lS)-l-(O-acetic acid-3-hydroxyphenyl)-2-(l-pyrrolidinyl)ethyl]benzeneacetamide hydrochloride, and

N-methyl-N-[(lS)-l-phenyl-2-(l-pyrrolidinyl)ethyl]-2,2-diphenylacetamide hydrochloride.

33. The method of claim 31 wherein said administration is topical administration.
34. The method of claim 31 wherein said administration is parenteral administration.

35. The method of claim 31 wherein said administration is oral administration.
36. The method of claim 31 wherein said administration is rectal administration.
37. The method of claim 32 wherein said administration is topical administration.
38. The method of claim 32 wherein said administration is parenteral administration.

39. The method of claim 32 wherein said administration is oral administration.
40. The method of claim 32 wherein said administration is rectal administration.

41. A method for the prevention or treatment of pruritus in a mammal in need of such prevention or treatment comprising administering to said mammal an effective anti-pruritic amount of a composition comprising a compound of formula IV or a pharmaceutically acceptable salt thereof



wherein:
Rj and R2 are the same or different and are hydrogen, C,_6 alkyl, C3.6 alkenyl, C3.6 cycloalkyl or C4.12 cycloalkylalkyl groups, or Rj and R2 together form a C2.8 branched or linear polymethylene or C2.6 alkenylene group, each of which may be optionally substituted with a hetero-atom; or -NR,R2 forms a 5-membered (optionally containing an oxygen atom adjacent to the nitrogen) or 6-membered ring, which rings optionally contains one unit of
-58- SUBST1TUTE SHEET (RULE 26) unsaturation and which is unsubstituted or substitued with hydroxy, C,.6 acyloxy, oxo, methylene, -COR10 where R,0 represents C,.6 alkyl, -ORn or -NHR, , and Ru represents hydrogen, C,.6 alkyl, aryl, Ar(C,.6)alkyl, or N=NOR,2 (where R,2 represents C,.6 alkyl; R3 is hydrogen, C,.6 alkyl; or phenyl; or R3 together with R, form a -(CH2)3- or -(CH2)4-group;

R4 is C,_6 alkyl, or phenyl;
R5 is hydrogen, or together with R4 forms a C2 5 linear polymethylene group;

R6 represents hydroxy, C,_6 alkyl, C,.6 hydroxyalkyl, C,.6 carboxyalkyl, phenyl, oxo,amino, carboxy, amido, -COR13, -CO2R13 or -COCO2R13 where R13 represents a hydrogen atom or an unsubstituted or substituted C,.,0 hydrocarbon moiety; -NRxCORx where Rx represents

C,.6 alkyl, optionally substituted methylene or R6 together with the E atom to which it is attached, forms a 5 or 6-membered ring containing one or more heteroatoms;

R7 is hydrogen, or together with R6 forms an optionally substituted or unsubstituted single or fused aryl or heterocyclic ring, containing from 5 to 12 ring atoms and comprising up to four heteroatoms in the ring selected from the group consisting of oxygen, nitrogen and sulphur, which may be substituted with hydrogen, C,_6 alkyl, -CH2OR]4, halogen, hydroxy, C,_6 alkoxy, C,_6 alkoxycarbonyl, thiol, C,_6 alkylthio, -OCOR15, -NHCOR,6, -NHSO2R17 or -CH2SO2NR18R,9, in which each of R14 to R19 is independently hydrogen, C,.6 alkyl, aryl or aralkyl;

A is aryl or heteroaryl ring, optionally mono or disubstituted with C,.6 alkyl, C2.6 alkenyl, Cj_6 haloalkyl , C2.6 haloalkenyl, C2-6 haloalkynyl, aryl, aralkyl, hydroxy, C,_6 alkoxy, C,.6 haloalkoxy, thiol, CN6 alkylthio, C,.6 haloalkylthio, halogen, nitro, cyano, carboxy, aryloxy, aralkoxycarbonyl, carbamoyl, sulfonyl or sulfamoyl;

E represents methylene, sulphur, oxygen or an imino group;
R8 is hydrogen or C].6 alkyl; and
R9 is hydrogen or together with R8may form the group -(CRaRa)m-C(=Y)- wherein Ra is hydrogen or C,.6 alkyl having up to a maximum of 3 alkyl groups;
m is 1, 2, or 3; and
Y represents two hydrogens or oxygen,
in a pharmaceutically acceptable vehicle.

-59- SUBST1TUTE SHEET (RULE 26)

42. The method of claim 41 wherein said compound is selected from the group consisting of:
1 -(Pyrrolidin- 1 -yl)methyl-2-(3 ,4-dichlorophenyl)-acetyl-4,4-dimethyl- 1 ,2,3 ,4-tetrahydroisoquinoline;
8-[(3,4-Dichlorophenyl)acetyl]-7-(l-pyrrolidinylmethyl)-l,4-dioxa-8-aza[4.5]spirodecane;

Methyl 4-[3,4-dichlorophenyl)acetyl]-3-(l-pyrrolidinylmethyl)-l-piperazinecarboxylate l-[(3,4-Dichlorophenyl)acetyl]-2-[(3-oxo-l-pyrolidinyl)methyl]-piperidine.
[S-(RR)]-(-)5-[(3,4-Dichlorophenyl)acetyl]-4,5,6,7-tetrahydro-4[(3-hydroxy-l-pyrolidinyl)methyl]furo[3,2-c]pyridine;

[S-(RS)]-4-Acetyl-l-[(3,4-dichlorophenyl)acetyl]-2-[(3-hydroxy-l-pyrolidinyl)methyl]pyridine;
2-[(3,4-Dichlorophenyl)acetyl]-l,2,3,4-tetrahydro-l-(l-pyrolidinyl)methyl)-5-isoquinolinol;

4-(Pyrolidin-l-yl)methyl-5-(3,4-dichlorophenyl)acetyl-4,5,6,7-tetrahydrothieno[3,2,-c]pyridine;
1 -[(5,6-Dichloro-3-oxoindan- 1 -carbonyl)-2-pyrrolidin- 1 -ylmethyl)piperidine;

2-(3,4-Dichlorophenyl)acetyl-3-(pyridin-l-yl)methyl-decahydroisoquinoline;
1 -(4-Trifluoromethylphenyl)acetyl-2-(3-hydroxypyrolidin- 1 -yl)methyl-4,4-dimethyl piperidine;

4-Acetyl-l-[(3,4-dichlorophenyl)acetyl]-2-[(S)-3-hydroxy-l-pyrrolidinyl)methyl]piperazine; 4-Acetyl-l-[(4-methylsulphonylphenyl)acetyl]-2-[(S)-3-hydroxy-l-pyrrolidinyl)methyl]piperazine;
4-(2-Ethanol)-l-[(3,4-dichlorophenyl)acetyl]-2-[(S)-3-hydroxy-l-pyrrolidinyl)methyl]piperazine;
4-Spirohydantoin-l-[(3,4-dichlorophenyl)acetyl]-2-[(pyrrolidinyl)methyl]piperazine; and

4-[(S)-3-hydroxy-l-pyrrolidinyl)methyl]-5-[3,4-dichlorophenyl)acetyl]-4,5,6,7-tetrahydroimidazo [4,5 -c]pyri dine.

43. The method of claim 41 wherein said administration is topical administration.
44. The method of claim 41 wherein said administration is parenteral administration. 45. The method of claim 41 wherein said administration is oral administration.
46. The method of claim 41 wherein said administration is rectal administration.

47. The method of claim 42 wherein said administration is topical administration.
48. The method of claim 42 wherein said administration is parenteral administration. 49. The method of claim 42 wherein said administration is oral administration.
50. The method of claim 42 wherein said administration is rectal administration.

51. A method for the prevention or treatment of pruritus in a mammal in need of such prevention or treatment comprising administering to said mammal an effective anti-pruritic amount of a composition comprising a compound of formula V or a pharmaceutically acceptable salt thereof


wherein
represents a single or double bond;
R1 represents an alkyl group having 1-5 carbon atoms, a cycloalkylalkyl group having 4-7 carbon atoms, a cycloalkenylalkyl group having 5-7 carbon atoms, an aryl group having 6-12 carbon atoms, an aralkyl group having 7-13 carbon atoms, an alkenyl group having 4-7 carbon atoms, an allyl group, a furan-2-ylalkyl group having 1 -5 carbon atoms, or a thiophen-2-ylalkyl group having 1-5 carbon atoms;

R2 represents a hydrogen atom, a hydroxy group, a nitro group, an alkanoyloxy group having 1-5 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkyl group having 1-5 carbon atoms, or -NR9R10 wherein R9 represents a hydrogen atom or an alkyl group having 1-5 carbon atoms, and R10 represents a hydrogen atom; an alkyl group having 1-5 carbon atoms, or -C(=O)R" wherein Ru represents a hydrogen atom, a phenyl group or an alkyl group having 1-5 carbon atoms;

R3 represents a hydrogen atom, a hydroxy group, an alkanoyloxy group having 1-5 carbon atoms, or an alkoxy group having 1-5 carbon atoms;

-61- SUBST1TUTE SHEET (RULE 26) A represents -XC(=Y>, -XC(=Y)Z-, -X-, -XSO2-, or -OC(OR4)R4- where, X, Y and Z each independently represent NR4, S or O wherein R4 represents a hydrogen atom, a straight-chain or branched chain alkyl group having 1-5 carbon atoms or an aryl group having 6-12 carbon atoms, and wherein R4 may be identical or different;

B represents a valence bond, a straight-chain or branched chain alkylene group having 1-14 carbon atoms which may be substituted with at least one substituent selected from the group consisting of an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, a hydroxy group, fluorine, chlorine, bromine, iodine, an amino group, a nitro group, a cyano group, a trifluoromethyl group and a phenoxy group, and wherein 1 to 3 methylene groups may be replaced with carbonyl groups, an acyclic unsaturated hydrocarbon containing from 1 to 3 double bonds and/or triple bonds and having 2-14 carbon atoms which may be substituted with at least one substituent group selected from the group consisting of an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, a hydroxy group, fluorine, chlorine, bromine, iodine, an amino group, a nitro group, a cyano group, a trifluoromethyl group and a phenoxy group, and wherein from 1 to 3 methylene groups may be replaced with carbonyl groups, or a straight-chain or branched chain saturated or unsaturated hydrocarbon group containing from 1 to 5 thioether, ether and or amino bonds and having 1-14 carbon atoms wherein hetero atoms are not bonded directly to A, and 1 to 3 methylene groups may be replaced with carbonyl groups;

R5 represents a hydrogen atom or an organic group (which may be substituted with at least one or more substituent groups selected from the group consisting of an alkyl group having 1-5 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, a hydroxy group, fluorine, chlorine, bromine, iodine, an amino group, a nitro group, a cyano group, an isothiocyanate group, a trifluoromethyl group and a methylenedioxy group); or

R5 is



wherein
Q is N, O or S;
T is CH, N, S or O;
1 is 0-5;
m and n are > 0
m + n < 5;

R6 represents a hydrogen atom;
R7 represents a hydrogen atom, a hydroxy group, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, or R6 and R7 together represent -O-, -CH2-or -S-;
R8 represents a hydrogen atom, an alkyl group having 1-5 carbon atoms, or an alkanoyl group having 1-5 carbon atoms in a pharmaceutically acceptable carrier.

52. The method of claim 51 wherein
R1 is an alkyl group having 1-5 carbon atoms, a cycloalkylmethyl group having 4-7 carbon atoms, a cycloalkenylmethyl group having 5-7 carbon atoms, a phenylalkyl group having 7- 13 carbon atoms, an alkenyl group having 4-7 carbon atoms, an allyl group, a furan-2-yl-alkyl group having 1-5 carbon atoms and a thiophen-2-yi-alkyl group having 1-5 carbon atoms;

R2 is hydrogen, hydroxy, nitro, acetoxy, methoxy, methyl, ethyl, propyl, amino, dimethylamino, acetylamino or benzoylamino groups; or

R4 is


Formula V-l
wherein
Q is N, O or S;
T is CH, N, S or O;
m and n are > 0 and
m + n < 5;
B is -(CH2)n- wherein n = 0-6, -(CH2)n-C(= O)- wherein n = 1-4, -CH = CH-(CH2)n- wherein n = 0-4, -C≡C-(CH2)n- wherein n=0-4, -CH,-O-, -CH2-S-, -CH2-O-(CH2),-O-(CH2)2-, -CH,-O-CH2-NH-CH,-O-CH2- and -CH2-O-CH2-S-CH2-O-CH2-;

R5 is hydrogen or an organic group of Formula V-l said organic group may be substituted with at least one substituent group selected from the group consisting of an alkyl group having 1-5 carbon atoms, an alkoxy group having 1-5 carbon atoms, an alkanoyloxy group having 1-5 carbon atoms, a hydroxy group, fluorine, chlorine, bromine, an amino group, a nitro group, a cyano group, an isothiocyanate group and a trifluoromethyl group, in a pharmaceutically acceptable carrier.

53. The method of claim 62 wherein
R1 is methyl, ethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopentenylmethyl, cyclohexenylmethyl, benzyl, phenethyl, trans-2-butenyl, 2-methyl-2-butenyl, allyl, furan-2-yl-methyl or thiophen-2-yl-methyl;

R is hydrogen, hydroxy, nitro, acetoxy, methyl or dimethylamino;

R3 is -NR4C(=O)-, -NR4C(=S)-, -NR4C(=O)O-, -NR4C(=O)NR4-, -NR4C(=S)NR4- or -NR4 SO2-;

R4 is a straight-chain or branched alkyl group having 1-5 carbon atoms;

B is -(CH,)„- wherein n=0-6, -CH=CH(CH2)n- wherein n=0-4, -C≡C-(CH2)n- wherein n=0-4, -CH2-O- or -CH2-S-; and

R5 is hydrogen, phenyl, 3,4-dichlorophenyl, 4-chlorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4bromophonyl, 3-bromophenyl, 2-bromophenyl, 4-nitrophenyl, 3-nitrophenyl, 2-nitrophenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-trifluoromethylphenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-mothoxy, 3-furanyl, 2-furanyl, 3 -thienyl, 2-thienyl, cyclopentyl or cyclohexyl, in a pharmaceutically acceptable carrier.

54. The method of claim 51 wherein said compound is selected from the group consisting of:

17-cyclopropylmethyl-4,5a-epoxy-3,14b-dihydroxy-6b-(N-methyl-3-phenylpropionamido)moφhinan;
17-cyclopropylmethyl-4,5a-epoxy-3,14b-dihydroxy-6b-(N-methyl-trans-3-(3-furyl)acrylamido)moφhinan;
17-cyclopropylmethyl-4,5 a-epoxy-3 , 14b-dihydroxy-6b-(N-methyl-trans-3 -cyclohexylacrylamido)moφhιnan;
17-cyclopropylmethyl-4,5a-epoxy-3 , 14b-dihydroxy-6b-(N-methyl-trans-3-(4-trifluoromethylphenyl)acrylamido)moφhinan;
17-cyclopropylmethyl-4,5a-epoxy-3,14b-dihydroxy-6a-(N-methyl-trans-3-(3-thiophenyl)acrylamido)moφhinan;
17-cyclopropylmethyl-4,5a-epoxy-3,14b-dihydroxy-6b-(N-methyl-trans-3-phenylacrylamido)moφhinan;
17-cyclopropylmethyl-4,5a-epoxy-3,14b-dihydroxy-6b-(N-methyl-trans-2-hexenamido)moφhinan; and
17-cyclopropylmethyl-4,5a-epoxy-3, 14b-dihydroxy-6b-(N-methyl-phenylpropiolamido)moφhinan.

55. The method of claim 51 wherein said administration is topical administration.
56. The method of claim 51 wherein said administration is parenteral administration.

57. The method of claim 51 wherein said administration is oral administration.
58. The method of claim 51 wherein said administration is rectal administration.

59. The method of claim 52 wherein said administration is topical administration.
60. The method of claim 52 wherein said administration is parenteral administration.

61. The method of claim 52 wherein said administration is oral administration.

62. The method of claim 52 wherein said administration is rectal administration.