Dioxino derivatives and their use as therapeutic agents

Details Dioxino derivatives and their use as therapeutic agents Dioxino derivatives and their use as therapeutic agents

1999-09-01

2001-03-13

Lambkin, Deborah C. (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S321000, C514S443000, C514S454000, C548S430000, C546S198000, C546S197000, C549S043000, C549S359000

Reexamination Certificate

active

06201004

ABSTRACT:

The present invention relates to novel dioxinoindole and thienobenzodioxin compounds which have affinity for 5-HT
1A
and/or D
2
-like (D
2
, D
3
and/or D
4
sub-types) receptors, to processes for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of central nervous system disorders, for example depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexual dysfunction, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, senile dementia, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders and anorexia, cardiovascular and cerebrovascular disorders, non-insulin dependent diabetes mellitus, hyperglycaemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress, and spasticity.
WO9507274 discloses compounds of the general formula
in which R
1
is selected from a number of substituents or two adjacent R
1
groups together with the carbon atoms to which they are attached form a fused benz ring, A and B are —O— or methylene, U is an alkylene chain, Q is selected from the following:
and T is an optionally substituted aromatic group optionally containing one or more N atoms. These compounds are described as being useful in the treatment of central nervous system disorders.
The present invention provides compounds of formula I
including pharmaceutically acceptable salts thereof in the form of individual enantiomers, racemates, or other mixtures of enantiomers, in which
A is methylene or —O—;
B is methylene or —O—;
G
1
—G
2
—G
3
represent —N(R′)—C(R″)═N—, —N═C(R″)—N(R′)—, —N(R′)—C(R″)═C(R′″)—, —C(R′″)═C(R″)—N(R′)—, —N(R′)—N═C(R″)—, —C(R″)═N—N(R′)—, —N(R′)—N═N—, —N═N—N(R′)—, —N═C(R″)—O—, —N═C(R″)—S—, —O—C(R″)═N—, —S—C(R″)═N—, —O—N═C(R″)—, —S—N═C(R″)—, —C(R″)═N—O—, —C(R″)═N—S—, —S—C(R″)═C(R′″)—, —C(R″)═C(R′″)—S—, —O—C(R″)═C(R′″)—, —C(R″)═C(R′″)—O— or —O—C(R′)(R′)—O— wherein
R′ is H or an alkyl group containing 1 to 3 carbon atoms; and
R″ and R′″, which are the same or different, are H; halo; an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo; carboxy; an alkanoyl group containing 1 to 6 carbon atoms; an alkoxycarbonyl group in which the alkoxy group contains 1 to 3 carbon atoms; formyl; cyano; or a carbamoyl group or carbamoylmethyl group each optionally N-substituted by one or two alkyl groups, which may be the same or different, each containing 1 to 3 carbon atoms;
g is 0, 1 or 2;
R
1
represents an alkyl group containing 1 to 3 carbon atoms optionally substituted by one or more halo; an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo; halo; or an alkylthio group containing 1 to 3 carbon atoms optionally substituted by one or more halo; the substituents represented by R
1
being the same or different when g is 2;
R
2
is H or an alkyl group containing 1 to 3 carbon atoms;
R
3
and R
4
, which are the same or different, are H, or an alkyl group containing 1 to 3 carbon atoms;
U is an alkylene chain containing 1 to 3 carbon atoms, optionally substituted by one or more alkyl groups each containing 1 to 3 carbon atoms;
Q represents a divalent group of formula IIa, IIb or IIc
in which V is (CH
2
)
n
, wherein n is 0, 1, 2 or 3, optionally substituted by one or more alkyl groups each containing 1 to 3 carbon atoms;
V′ is an alkylene chain containing 2 to 6 carbon atoms, optionally substituted by one or more alkyl groups each containing 1 to 3 carbon atoms;
E is an alkylene chain containing 0 to 2 carbon atoms and E′ is an alkylene chain containing 1 to 4 carbon atoms provided that the total number of carbon atoms in E and E′ amounts to 3 or 4; and
R
5
and R
6
, which may be the same or different, are H or an alkyl group containing 1 to 4 carbon atoms; and
T represents phenyl, 1- or 2-naphthyl, 1-naphth[2,1-d][1,2,3]oxadiazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-thienyl, 2- or 3-furyl, 2- 3- or 7-benzo[b]furanyl, 2,3-dihydro-7-benzo[b]furanyl, 2-, 3- or 7-benzo[b]thiophenyl, 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-2-yl, 5-tetrazolyl, 2- 3- or 4-quinolinyl, 2- or 4-quinazolinyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-oxazolyl, 3- 4- or 5-isothiazolyl or 2-, 4- or 5-thiazolyl each of which may be optionally substituted by one or more substituents selected from a) halo, b) an alkyl group containing 1 to 4 carbon atoms optionally substituted by one or more halo, c) an alkoxy group containing 1 to 3 carbon atoms optionally substituted by one or more halo, d) an alkylthio group containing 1 to 3 carbon atoms optionally substituted by one or more halo, e) hydroxy, f) an acyloxy group containing 1 to 3 carbon atoms, g) hydroxymethyl, h) cyano, i) an alkanoyl group containing 1 to 6 carbon atoms, j) an alkoxycarbonyl group containing 2 to 6 carbon atoms, k) a carbamoyl group or carbamoylmethyl group each optionally N-substituted by one or two alkyl groups each containing 1 to 3 carbon atoms, l) a sulphamoyl or sulphamoylmethyl group each optionally N-substituted by one or two alkyl groups each containing 1 to 3 carbon atoms, m) an amino group optionally substituted by one or two alkyl groups each containing 1 to 5 carbon atoms, n) 1-pyrrolidinyl or 1-piperidinyl, o) nitro or p) acetamido.
In preferred compounds of formula I, A is —O—.
In preferred compounds of formula I, B is —O—.
In more preferred compounds of formula I, both A and B are —O—.
In preferred compounds of formula I, g is 0 or 1. When g is 1, R
1
is preferably halo or an alkyl group containing 1 to 3 carbon atoms. In more preferred compounds of formula I, g is 0.
In preferred compounds of formula I, G
1
—G
2
—G
3
are —N(R′)—C(R″)═C(R′″)—; —S—C(R″)═C(R′″)—, —N(R′)—N═C(R″)—, —O—C(R″)═C(R′″)—, or —O—C(R′)(R′)—O—. Preferably, R′ is H, R″ is H or alkoxycarbonyl (more preferably H or ethoxycarbonyl), and R′″ is H or halo (more preferably H or chloro). In more preferred compounds of formula I, G
1
—G
2
—G
3
are —O—C(R″)═C(R′″)— and R″ and R′″ are both H.
In preferred compounds of formula I, R
2
is H.
In preferred compounds of formula I, R
3
and R
4
, are both H.
In preferred compounds of formula I, U is methylene.
In preferred compounds of formula I, Q is a group of formula IIa in which V is methylene, E and E′ are both ethylene and R
5
is H.
In preferred compounds of formula I, T is phenyl or naphthyl, each of which may be optionally substituted by one or more substituents selected from an alkoxy group containing 1 to 3 carbon atoms, hydroxy, or halo (more preferably the substituent is methoxy). In more preferred compounds of formula I, T is phenyl optionally substituted by one or more substituents selected from an alkoxy group containing 1 to 3 carbon atoms, hydroxy, or halo (more preferably the substituent is methoxy). In especially preferred compounds of formula I, T is 2-methoxyphenyl or 2-hydroxyphenyl.
In one group of preferred compounds of formula I, both A and B are —O—; g is 0, G
1
—G
2
—G
3
are —NH—CH═CH—; —NH—C(CO
2
C
2
H
5
)═CH—; —S—CH═CH—; S—CH═C(Cl)—; —NH—N═CH—; —O—CH═CH—; or —O—CH
2
—O—; R
2
is H; R
3
and R
4
are both H; U is methylene; Q is a group of formula IIa in which V is methylene, E and E′ are both ethylene and R
5
is H; and T is phenyl optionally substituted by hydroxy or by one or more alkoxy groups each containing 1 to 3 carbon at

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