Compounds useful in therapy

Details Compounds useful in therapy Compounds useful in therapy

2000-05-18

2002-08-27

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...

C546S199000

Reexamination Certificate

active

06441000

ABSTRACT:

This application claims priority under 35 U.S.C. 119 of GB 9912413.3, filed May 28, 1999.
FIELD OF THE INVENTION
This invention relates to pharmaceutically useful compounds, in particular compounds that bind to opiate receptors (e.g. mu, kappa and delta opioid receptors).
BACKGROUND OF THE INVENTION
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.
SUMMARY OF THE INVENTION
According to the invention there is provided compounds of formula I:
wherein Het
1
represents a 5-, 6- or 7-membered heterocyclic ring containing at least one nitrogen atom, and optionally one or more heteroatoms selected from oxygen or sulfur, and which heterocyclic ring is fully saturated, partially unsaturated or aromatic in character;
T represents one or more optional substituents selected from H, halo, OH, ═O, C
1-6
alkyl, C
1-6
alkoxy, C
3-6
cycloalkyl (which latter three groups are optionally substituted by one or more halo atoms), aryl(C
1-6
)alkyl (the aryl part of which is optionally substituted by one or more substituents selected from halo, C
1-4
alkyl and C
1-4
alkoxy (which latter two groups are optionally substituted by one or more halo atoms)), —N(R
4a
)(R
5
), —N(R
4b
)S(O)
m
R
6
, —N(R
4c
)C(O)R
7a
and —N(R
4d
)C(O)OR
7b
, provided that when Het
1
contains less than three C-atoms (i.e. where the only two C-atoms are those provided by the fused benzene ring) and at least one heteroatom selected from oxygen and sulfur, then T does not represent halo or C
1-6
alkoxy (which latter group is optionally substituted by one or more halo atoms);
R
4a
to R
4d
and R
5
independently represent H, C
1-6
alkyl (which latter group is optionally substituted by one or more halo atoms), or R
4a
and R
5
, together with the nitrogen 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
1-4
alkyl, C
1-4
alkoxy, OH, ═O, nitro, amino or halo);
R
6
represents C
1-6
alkyl or aryl, which two groups are optionally substituted by one or more substituents selected from halo, C
1-4
alkyl or nitro;
R
7a
and R
7b
independently represent C
1-6
alkyl, C
1-6
alkoxy, C
3-6
cycloalkyl, aryl (which four groups are optionally substituted by one or more substituents selected from halo, C
1-4
alkyl or nitro), or R
7a
represents H;
m is 0, 1 or 2;
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
8a
)(R
8b
)), 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
8c
, S(O)
n
R
8d
, 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
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
1-4
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
9b
)(R
9c
);
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
9b
)(R
9c
) is not directly attached to an unsaturated carbon atom;
p is 0, 1 or 2;
R
8a
to R
8d
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
3
;
provided that R
8d
does not represent H when n represents 1 or 2;
R
9a
to R
9c
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
4
, or R
9b
and R
9c
together represent unbranched C
2-6
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
1-4
alkyl groups;
R
10
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
11
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
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
1-4
alkyl, C
1-4
alkoxy and C
1-5
alkanoyl (which latter three groups are optionally substituted by one or more halo atoms);
X represents one or two optional substituents on the benzene ring, which substituents are selected from halo, C
1-4
alkyl, C
1-4
alkoxy (which latter two groups are optionally substituted by one or more halo atoms);
or pharmaceutically, or veterinarily, acceptable derivatives thereof;
which compounds are referred to together hereinafter as “the compounds of the invention.”
DETAILED DESCRIPTION OF THE INVENTION
In the definitions used herein, alkyl, alkylene, alkoxy, alkoxy carbonyl, alkanoyl, alkanoyloxy, alkenyl, alkynyl and the alkyl parts of alky

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