4-Arylpiperidine derivatives for the treatment of pruritus

Details 4-Arylpiperidine derivatives for the treatment of pruritus 4-Arylpiperidine derivatives for the treatment of pruritus

2000-05-23

2003-02-11

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S192000

Reexamination Certificate

active

06518282

ABSTRACT:

This application claims priority under 35 U.S.C. 119 from application GB 9912415.8, filed May 28, 1999.
FIELD OF THE INVENTION
This invention relates to novel 4-phenylpiperidines having utility in the treatment of pruritic dermatoses including allergic dermatitis and atopy in animals and humans, and processes for the preparation of and intermediates used in the preparation of such compounds.
BACKGROUND OF THE INVENTION
Itching or pruritus is a common dermatological symptom which can give rise to considerable distress, in both humans and animals. Pruritus is often associated with inflammatory skin disease which can commonly be caused by hypersensitivity reactions, such as reaction to insect bites e.g. flea bites, or to environmental allergens such as house dust mite or pollen; or by bacterial and fungal infections of the skin or ectoparasite infections. Previous treatments for pruritus include the use of corticosteroids and antihistamines, however both have undesired side effects. Other therapies include the use of essential fatty acid dietary supplements which are slow to act and offer only limited efficacy against allergic dermatitis. A variety of emollients such as soft paraffin, glycerine and lanolin are also employed but with limited success and there is a continuing need for an effective remedy.
Certain 1,3,4-trisubstituted 4-aryl-piperidine derivatives are disclosed in GB-A-1525584 as potent narcotic antagonists which also display analgesic properties. These compounds are also claimed in EP-B-0287339 as opioid antagonists which block the effect of agonists at the mu or kappa receptors having potential utility in treating a variety of disorders associated with these receptors such as eating disorders, opiate overdose, depression, smoking, alcoholism, sexual dysfunction, shock, stroke, spinal damage and head trauma; utility as an appetite suppressant for weight loss has also been suggested. Further related 1-N-substituted-4-aryl piperidines are disclosed in EP-A-0506468 and EP-A-0506478. Potential utility is suggested in preventing peripherally mediated undesired opiate effects and in relieving the symptoms of idiopathic constipation and irritable bowel syndrome.
SUMMARY OF THE INVENTION
According to the present invention we provide novel 4-phenylpiperidines which are potent and effective antipruritic agents.
Thus, the present invention provides compounds of formula I:
wherein
R
1
and R
2
are each independently H or C
1-4
alkyl;
R
3
represents aryl (optionally substituted by one or more substituents selected from OH, nitro, halo, CN, CH
2
CN, CONH
2
, C
1-4
alkyl, C
1-4
alkoxy, C
1-5
alkanoyl (which latter three groups are optionally substituted by one or more halo atoms) and —N(R
5a
)(R
5b
)), C
1-10
alkyl, C
3-10
alkenyl or C
3-10
alkynyl wherein said alkyl, alkenyl or alkynyl groups are optionally substituted and/or terminated by one or more substituents selected from OR
5c
, S(O)
n
R
5d
, CN, halo, C
1-6
alkoxy carbonyl, C
2-6
alkanoyl, C
2-6
alkanoyloxy, C
3-8
cycloalkyl, C
4-9
cycloalkanoyl, N(R
6a
)S(O)
2
R
7
, Het
1
, aryl, adamantyl (which latter two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH
2
CN, CONH
2
, C
1-4
alkyl, C
1-4
alkoxy and C
1-5
alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)), or —W—A
1
—N(R
6b
)(R
6c
);
n is 0, 1 or 2;
W represents a single bond, C(O) or S(O)
p
;
A
1
represents a single bond or C
1-10
alkylene;
provided that when both W and A
1
represent single bonds, then the group —N(R
6b
)(R
6c
) is not directly attached to an unsaturated carbon atom;
p is 0, 1 or 2;
R
5a
to R
5d
each independently represent H, C
1-10
alkyl, C
3-10
alkenyl, C
3-10
alkynyl, C
3-8
cycloalkyl, C
1-4
alkylphenyl, aryl (which latter six groups are optionally substituted by or one or more substituents selected from OH, nitro, amino, halo, CN, CH
2
CN, CONH
2
, C
1-4
alkyl, C
1-4
alkoxy and C
1-5
alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)) or Het
2
;
provided that R
5d
does not represent H when n represents 1 or 2;
R
6a
to R
6c
each independently represent H, C
1-10
alkyl, C
3-10
alkenyl, C
3-10
alkynyl, C
3-8
cycloalkyl, C
1-4
alkylphenyl, aryl (which latter six groups are optionally substituted by or one or more substituents selected from OH, nitro, amino, halo, CN, CH
2
CN, CONH
2
, C
1-4
alkyl, C
1-4
alkoxy and C
1-5
alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)), Het
3
, or R
6b
and R
6c
together represent unbranched C
2-6
alkylene which alkylene group is optionally interrupted by O, S and/or an N(R
8
) group and is optionally substituted by one or more C
1-4
alkyl groups;
R
7
represents C
1-6
alkyl, C
3-8
cycloalkyl, C
1-4
alkylphenyl or aryl, which four groups are optionally substituted by or one or more substituents selected from C
1-4
alkyl, C
1-4
alkoxy, OH, nitro, amino or halo;
R
8
represents H, C
1-6
alkyl, C
3-8
cycloalkyl, A
2
-(C
3-8
cycloalkyl) or A
2
-aryl;
A
2
represents C
1-6
alkylene;
Het
1
, Het
2
and Het
3
independently represent 3- to 8-membered heterocyclic groups, which groups contain at least one heteroatom selected from oxygen, sulfur and/or nitrogen, which groups are optionally fused to a benzene ring, and which groups are optionally substituted in the heterocyclic and/or fused benzene ring part by one or more substituents selected from OH, ═O, nitro, amino, halo, CN, aryl, C
1-4
alkyl, C
1-4
alkoxy and C
1-5
alkanoyl (which latter three groups are optionally substituted by one or more halo atoms); and
R
4
represents H, C
1-5
alkyl, C
1-12
alkanoyl, (pyridin-3-yl)carbonyl or (pyridin-4-yl)carbonyl (which latter two groups are optionally in the pyridine N-oxide form);
or pharmaceutically, or veterinarily, acceptable derivatives thereof;
provided that, when the group OR
4
is attached to the benzene ring at the meta-position relative to the piperidine ring and the piperidine is not in the N-oxide form, then:
(a) when R
1
and R
2
both represent C
1-4
alkyl, then R
3
does not represent:
C
1-8
alkyl (optionally terminally substituted by C
4-8
cycloalkyl);
unsubstituted C
3-8
alkenyl;
unsubstituted C
3-8
alkynyl;
C
1-3
alkyl, terminally substituted by phenyl, phenoxy, —S-phenyl, —N(H)-phenyl or —N(C
1-4
alkyl)-phenyl, furan-2-yl or thiophen-2-yl;
C
1-4
alkyl, terminally substituted by an OH group and a further group selected from phenyl, furan-2-yl and thiophen-2-yl; or
C
3-5
alkenyl, terminally substituted by phenyl, furan-2-yl or thiophen-2-yl, where the position of unsaturation is at the carbon atoms that are &agr;,&bgr; to the phenyl, furan-2-yl or thiophen-2-yl group;
all of which phenyl, phenoxy and phenylthio groups are optionally substituted by one or two substituents selected from OH, C
1-3
alkyl, C
1-3
alkoxy, halo, nitro, amino and CF
3
; and
all of which furanyl and thiophenyl groups are optionally substituted by a methyl group; and
(b) when R
1
represents methyl, and:
(i) R
2
represents C
1-4
alkyl and R
4
represents H or C
1-4
alkanoyl, then R
3
does not represent:
unsubstituted C
3-8
alkyl;
unsubstituted C
4-8
alkenyl;
C
3-8
alkyl, substituted by an unsubstituted C
4-8
cycloalkyl group;
C
2
alkyl, terminally substituted by an unsubstituted C
5-9
cycloalkanoyl, an unsubstituted C
2-6
alkanoyl group or an unsubstituted thiophenyl group;
C
4-9
alkyl (optionally substituted at 4- to 9-C position by C
4-8
cycloalkyl) or C
5-9
alkenyl, which alkyl or alkenyl groups are substituted at the 3-C position by OH, C
1-6
alkoxy, oxy-C
1-3
-alkylphenyl or C
2-5
alkanoyloxy (which latter three groups are all unsubstituted); or
C
3
alkyl, terminally substituted by (1) OH, C
1-6
alkoxy, oxy-C
1-3
-alkylphenyl or C
2-5
alkanoyloxy (which latter three groups are all unsubstituted) and (2) C
4-8
cycloalkyl, thiophenyl (which latter two groups are both unsubstituted); or
(ii) R
2
represents H or C
1-4
alkyl and R
4
represents H or C
1-5
alkyl, then

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