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

2002-03-19

2004-06-15

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...

C546S207000, C546S208000, C546S209000, C546S210000, C546S211000, C546S212000

Reexamination Certificate

active

06750231

ABSTRACT:

This invention relates to pharmaceutically useful compounds, in particular compounds that bind to opiate receptors (e.g. mu, kappa and delta opioid receptors).
Compounds that bind to such receptors are likely to be useful in the treatment of diseases mediated by opiate receptors, for example irritable bowel syndrome; constipation; nausea; vomiting; and pruritic dermatoses, such as allergic dermatitis and atopy in animals and humans. Compounds that bind to opiate receptors have also been indicated in the treatment of eating disorders, opiate overdoses, depression, smoking and alcohol addiction, sexual dysfunction, shock, stroke, spinal damage and head trauma.
There is a particular need for an improved treatment of itching. Itching, or pruritus, is a common dermatological symptom that can give rise to considerable distress in both humans and animals. Pruritus is often associated with inflammatory skin diseases which may be caused by hypersensitivity reactions, including reactions to insect bites, such as flea bites, and to environmental allergens, such as house dust mite or pollen; by bacterial and fungal infections of the skin; or by ectoparasite infections.
Existing treatments that have been employed in the treatment of pruritus include the use of corticosteroids and antihistamines. However, both of these treatments are known to have undesirable side effects. Other therapies that have been employed include the use of essential fatty acid dietary supplements, though these have the disadvantages of being slow to act, and of offering only limited efficacy against allergic dermatitis. A variety of emollients such as soft paraffin, glycerine and lanolin are also employed, but with limited success.
Thus, there is a continuing need for alternative and/or improved treatments of pruritus.
Certain 4-arylpiperidine-based compounds are disclosed in inter alia European patent applications EP 287339, EP 506468, EP 506478 and
J. Med. Chem
. 1993, 36, 2833-2850 as opioid antagonists. In addition, International Patent Application WO 95/15327 discloses azabicycloalkane derivatives useful as neuroleptic agents.
According to the invention there is provided compounds of formula I:
wherein Het
1
represents a 5- or 6-membered heterocyclic ring comprising at least one atom selected from nitrogen, oxygen and sulfur, which ring is optionally fused to a 5- or 6-membered ring, which latter ring optionally contains one or more heteroatoms selected from nitrogen, oxygen and/or sulfur, and which heterocyclic ring system (Het
1
) is optionally substituted by one or more substituents selected from halo, nitro, —OH, ═O, Si(R
4a
)(R
4b
)(R
4c
), N(R
5a
)(R
5b
), SR
6a
, N(R
6b
)S(O)
2
R
7a
, N(R
6c
)C(O)OR
7b
, N(R
6d
)C(O)R
7c
, C
1
-C
6
alkyl, C
1
-C
6
alkoxy or C
3
-C
6
cycloalkyl (which latter three groups are optionally substituted by one or more halo atoms); R
4a
to R
4c
independently represent C
1
-C
6
alkyl or aryl;
R
5a
and R
5b
independently represent H, C
1
-C
6
alkyl, C
1
-C
4
alkylphenyl, aryl (which latter three groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, C
1
-C
4
alkyl or C
1
-C
4
alkoxy (which latter two groups are optionally substituted by one or more halo atoms)) or, together with the N-atom to which they are attached, form a 4- to 6-membered heterocyclic ring (which ring is optionally substituted by one or more substituents selected from C
1
-C
4
alkyl, C
1
-C
4
alkoxy, OH, ═O, nitro, amino or halo);
R
6a
to R
6d
each independently represent H, C
1
-C
6
alkyl, C
1
-C
4
alkylphenyl or aryl (which latter three groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, C
1
-C
4
alkyl or C
1
-C
4
alkoxy (which latter two groups are optionally substituted by one or more halo atoms));
R
7a
to R
7c
independently represent C
1
-C
6
alkyl, C
1
-C
4
alkylphenyl or aryl, which four groups are all optionally substituted by one or more substituents selected from OH, nitro, amino, halo, C
1
-C
4
alkyl or C
1
-C
4
alkoxy (which latter two groups are optionally substituted by one or more halo atoms);
R
1
and R
2
are each independently H or C
1
-C
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
-C
4
alkyl, C
1
-C
4
alkoxy, C
1
-C
5
alkanoyl (which latter three groups are optionally substituted by one or more halo atoms) and —N(R
8
a)(R
8
b)), C
1
-C
10
alkyl, C
3
-C
10
alkenyl or C
3
-C
10
alkynyl wherein said alkyl, alkenyl or alkynyl groups are optionally substituted and/or terminated by one or more substituents selected from OR
8c
, S(O)
p
R
8d
, CN, halo, C
2
-C
6
alkanoyl, C
1
-C
6
alkoxy carbonyl, C
2
-C
6
alkanoyloxy, C
3
-C
8
cycloalkyl, C
4
-C
9
cycloalkanoyl, N(R
9a
)S(O)
2
R
10
, Het
2
, 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
-C
4
alkyl, C
1
-C
4
alkoxy and C
1
-C
5
alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)), or —W—A
1
—N(R
9b
)(R
9c
);
p is 0, 1 or 2;
W represents a single bond, C(O) or S(O)
q
;
A
1
represents a single bond or C
1
-C
10
alkylene;
provided that when both W and A
1
represent single bonds, then the group —N(R
9b
)(R
9c
) is not directly attached to an unsaturated carbon atom;
q is 0, 1 or 2;
R
8a
to R
8d
each independently represent H, C
1
-C
10
alkyl, C
3
-C
10
alkenyl, C
3
-C
10
alkynyl, C
3
-C
8
cycloalkyl, C
1
-C
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
-C
4
alkyl, C
1
-C
4
alkoxy and C
1
-C
5
alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)) or Het
3
;
provided that R
8d
does not represent H when p represents 1 or 2;
R
9a
to R
9c
each independently represent H, C
1
-C
10
alkyl, C
3
-C
10
alkenyl, C
3
-C
10
alkynyl, C
3
-C
8
cycloalkyl, C
1
-C
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
-C
4
alkyl, C
1
-C
4
alkoxy and C
1
-C
5
alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)), Het
4
, or R
9b
and R
9c
together represent unbranched C
2
-C
6
alkylene which alkylene group is optionally interrupted by O, S and/or an N(R
11
) group and is optionally substituted by one or more C
1
-C
4
alkyl groups;
R
10
represents C
1
-C
6
alkyl, C
3
-C
8
cycloalkyl, C
1
-C
4
alkylphenyl or aryl, which four groups are optionally substituted by or one or more substituents selected from C
1
-C
4
alkyl, C
1
-C
4
alkoxy, OH, nitro, amino or halo;
R
11
represents H, C
1
-C
6
alkyl, C
3
-C
8
cycloalkyl, A
2
—(C
3
-C
8
cycloalkyl) or
A
2
-aryl;
A
2
represents C
1
-C
6
alkylene;
Het
2
, Het
3
and Het
4
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
-C
4
alkyl, C
1
-C
4
alkoxy and C
1
-C
5
alkanoyl (which latter three groups are optionally substituted by one or more halo atoms);
X is H, halo, C
1
-C
4
alkyl or C
1
-C
4
alkoxy (which latter two groups are optionally substituted by one or more halo atoms);
n is 0, 1 or 2;
or pharmaceutically, or veterinarily, acceptable derivatives thereof;
which compounds are referred to together hereinafter as “the compounds of the invention.”
In the definitions used herein, alkyl, alkylene, alkoxy, alkoxy carbonyl, alkanoyl, alkanoyloxy, alkenyl, alkynyl and the alkyl parts of alkylphenyl and aryl alkoxy groups may, when there is a sufficient number of carbon atom

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