U.S. patent application number 09/748153 was filed with the patent office on 2001-07-19 for therapeutic agents.
Invention is credited to Birch, Alan Martin, Bradley, Paul Anthony.
Application Number | 20010008903 09/748153 |
Document ID | / |
Family ID | 10808998 |
Filed Date | 2001-07-19 |
United States Patent
Application |
20010008903 |
Kind Code |
A1 |
Birch, Alan Martin ; et
al. |
July 19, 2001 |
Therapeutic agents
Abstract
Compounds of formula I 1 and pharmaceutically acceptable salts
thereof in which A is methylene or --O--; B is methylene or --O--;
G.sub.1-G.sub.2-G.sub.3 form a heteroaromatic or heteroaliphatic
chain; g is 0, 1 or 2; U is an alkylene chain optionally
substituted by one or more alkyl; Q represents a divalent group
containing nitrogen atoms; and T is an optionally substituted aryl
or heteroaryl group, have utility 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.
Inventors: |
Birch, Alan Martin;
(Nottingham, GB) ; Bradley, Paul Anthony;
(Nottingham, GB) |
Correspondence
Address: |
Herbert B. Keil
KEIL & WEINKAUF
1101 Connecticut Avenue, N.W.
Washington
DC
20036
US
|
Family ID: |
10808998 |
Appl. No.: |
09/748153 |
Filed: |
December 27, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09748153 |
Dec 27, 2000 |
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09380375 |
Sep 1, 1999 |
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6201004 |
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09380375 |
Sep 1, 1999 |
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PCT/EP98/00946 |
Feb 19, 1998 |
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Current U.S.
Class: |
514/411 ;
514/359; 514/366; 514/387; 514/443 |
Current CPC
Class: |
A61P 9/06 20180101; A61P
25/24 20180101; A61P 25/22 20180101; A61P 25/30 20180101; A61P 1/10
20180101; C07D 495/04 20130101; A61P 9/00 20180101; A61P 25/28
20180101; A61P 43/00 20180101; A61P 9/12 20180101; C07D 491/04
20130101; A61P 15/00 20180101; A61P 25/08 20180101; A61P 3/10
20180101; C07D 493/04 20130101; A61P 25/16 20180101; A61P 3/04
20180101 |
Class at
Publication: |
514/411 ;
514/359; 514/366; 514/387; 514/443 |
International
Class: |
A61K 031/425; A01N
043/78; A61K 031/415; A01N 043/52; A61K 031/40; A01N 043/38 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 11, 1997 |
GB |
9704948.0 |
Claims
1. Compounds of formula I 27including pharmaceutically acceptable
salts thereof in the form of individual enantomers, racemates, or
other mixtures of enantiomers, in which A is methylene or --O--; B
is methylene or --O--; G.sub.1-G.sub.2-G.sub.3 represent
--N(R')--C(R").dbd.N--, --N.dbd.C(R")--N(R')--,
--N(R')--C(R").dbd.C(R'")--, --C(R'").dbd.C(R")--N(R')--,
--N(R')--N.dbd.C(R")--, --C(R").dbd.N--N(R')--, --N(R')--N.dbd.N--,
--N.dbd.N--N(R')--, --N.dbd.C(R")--O--, --N.dbd.C(R")--S--,
--O--C(R").dbd.N--, --S--C(R").dbd.N--, --O--N.dbd.C(R")--,
--S--N.dbd.C(R")--, --C(R").dbd.N--O--, --C(R").dbd.N--S--,
--S--C(R").dbd.C(R'")--, --C(R").dbd.C(R'")--S--,
--O--C(R").dbd.C(R'")--, --C(R").dbd.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.sub.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.sub.1 being the same or different when g is 2;
R.sub.2 is H or an alkyl group containing 1 to 3 carbon atoms;
R.sub.3 and R.sub.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 28in which V is
(CH.sub.2).sub.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.sub.5 and R.sub.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]oxadiazoly1, 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, 2,3dihydro-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, 1,2,4triazol-2-yl, 5-tetrazolyl,
2-4-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 substituted by one
or two alkyl groups each containing 1 to 3 carbon atoms, 1) 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.
2. Compounds as claimed in claim I in which both A and B are
--O--.
3. Compounds as claimed in either claim 1 or claim 2 in which g is
0 or 1.
4. Compounds as claimed in any preceding claim in which R.sub.1 is
halo or an alkyl group containing 1 to 3 carbon atoms.
5. Compounds as claimed in any preceding claim in which
G.sub.1-G.sub.2-G.sub.3 are --N(R')-C(R").dbd.C(R'")--;
--S--C(R").dbd.C(R'")--, --N(R')--N.dbd.C(R")--,
--O--C(R").dbd.C(R")--, or --O--C(R')(R")--O--
6. Compounds as claimed in any preceding claim in which R.sub.2 is
H.
7. Compounds as claimed in any preceding claim in which R.sub.3 and
R.sub.4, are both H.
8. Compounds as claimed in any preceding claim in which U is
methylene.
9. Compounds as claimed in any preceding claim in which Q is a
group of formula IIa in which V is methylene, E and E' are both
ethylene and R.sub.5 is H.
10. Compounds as claimed in any preceding claim in which 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.
11. Compounds as claimed in any preceding claim in which
G.sub.1-G.sub.2-G.sub.3 are --O--CH.dbd.CH--.
12. Compounds of formula I, as claimed in claim 1, selected from:
N-(9Chloro-2,3-dihydrothieno[3,2-f]-1,4-benzodioxin-2-ylmethyl)-1-[1-(2-m-
ethoxyphenyl)piperid-4-yl]methylamine;
N-(2,3-Dihydrothieno[3,2-f]-1,4-ben-
zodioxin-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine;
Ethyl
2,3-dihydro-2-(N-{[1-(2-methoxyphenyl)piperid-4-yl]methyl}aminomethyl)-7H-
-1,4-dioxino[2,3-e]indole-8-carboxylate;
N(2,3-Dihydro-7H1,4-dioxino[2,3-e-
]indol-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine;
N(2,3-Dihydro-7H-1,4-dioxino[2,3-e]indazol-2-ylmethyl)-1-[1-(2-methoxyphe-
nyl)piperid-4-yl]methylamine;
N(2,3-Dihydrofuro[3,2-f]-1,4-benzodioxin-2-y-
lmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine;
2-{4-[(2,3-Dihydrofuro[3,2-f]-1,4-benzodioxin-2-ylmethyl)aminomethyl]pipe-
ridino}-phenol;
N-(7,8-Methylenedioxy-2,3-dihydro-1,4-benzodioxin-2-ylmeth-
yl)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine; and
pharmaceutically acceptable salts thereof in the form of individual
enantiomers, racemates, or other mixtures of enantiomers.
13. Compounds of formula I as claimed in claim 1 selected from
(S)-N-(9-Chloro-2,3-dihydrothieno[3,2-f]-1,4-benzodioxin-2-ylmethyl)-1-[1-
-(2-methoxyphenyl)piperid-4-yl]methylamine;
(S)-N-(2,3-Dihydrothieno[3,2-f-
]-1,4-benzodioxin-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylami-
ne; Ethyl
(S)-2,3-dihydro-2-(N-{[1-(2-methoxyphenyl)piperid-4-yl]methyl}am-
inomethyl)-7H-1,4-dioxino[2,3-e]indole-8-carboxylate;
(S)-N-(2,3-Dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethyl)-1-[1-(2-methoxy-
phenyl)-piperid-4-yl]methylamine;
(S)-N-(2,3-Dihydro-7H-1,4-dioxino[2,3-e]-
indazol-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine
(S)-N-(2,3-Dihydrofuro[3,2-f]-1,4-benzodioxin-2-ylmethyl)-1-[1-(2-methoxy-
phenyl)piperid-4-yl]methylamine
(S)-2-{4-[(2,3-Dihydrofuro[3,2-f]-1,4-benz-
odioxin-2-ylmethyl)aminomethyl]-piperidino}phenol;
(S)-N-(7,8-Methylenedio-
xy-2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-
-yl]methylamine and pharmaceutically acceptable salts thereof.
14. A pharmaceutical composition comprising a compound of formula
I, as claimed in any one of claims 1-13, in conjunction with a
pharmaceutically acceptable diluent or carrier.
15. A compound of formula I, as claimed in one of claims 1-13, for
use as a medicament.
16. A compound of formula I, as claimed in any one of claims 1-13,
for use in the treatment of depression, anxiety, psychoses, 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, anorexia, cardiovascular and cerebrovascular
disorders, non-insulin dependent diabetes mellitus, hyperglycaemia,
constipation, arrhythmia, disorders of the neuroendocrine system,
stress, and spasticity.
17. A compound of formula I, as claimed in claim 16, for use in the
treatment of psychoses.
18. Use of a compound of formula I, as claimed in any one of claims
1-13, in the manufacture of a medicament for treating depression,
anxiety, psychoses, 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, or spasticity.
19. A method of treating depression, anxiety, psychoses, 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, or spasticity in human beings, which comprises the
administration of a therapeutically effective amount of a compound
of formula I, as claimed in any one of claims 1-13, to a patient in
need thereof.
20. A process for the preparation of compounds of formula I, as
claimed in claim 1, in which Q is a group of formula IIa,
comprising the reaction of a compound of formula III 29in which m
is 0, 1 or 2, with a compound of formula IV 30in which Z is a
leaving group, optionally in the presence of a base, and optionally
in a solvent.
Description
[0001] The present invention relates to novel dioxinoindole and
thienobenzodioxin compounds which have affinity for 5-HT.sub.1A
and/or D.sub.2-like (D.sub.2, D.sub.3 and/or D.sub.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.
[0002] WO9507274 discloses compounds of the general formula 2
[0003] in which R.sub.1 is selected from a number of substituents
or two adjacent R.sub.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: 3
[0004] 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.
[0005] The present invention provides compounds of formula I 4
[0006] including pharmaceutically acceptable salts thereof in the
form of individual enantiomers, racemates, or other mixtures of
enantiomers, in which
[0007] A is methylene or --O--;
[0008] B is methylene or --O--;
[0009] G.sub.1-G.sub.2-G.sub.3 represent --N(R')--C(R").dbd.N--,
--N.dbd.C(R")--N(R')--, --N(R')--C(R").dbd.C(R'")--,
--C(R'").dbd.C(R")--N(R')--, --N(R')--N.dbd.C(R")--,
--C(R").dbd.N--N(R')--, --N(R')--N.dbd.N--, --N.dbd.N--N(R')--,
--N.dbd.C(R')--O--, --N.dbd.C(R")--S--, --O--C(R').dbd.N--,
--S--C(R').dbd.N--, --O--N.dbd.C(R")--, --S--N.dbd.C(R')--,
--C(R").dbd.N--O, --C(R').dbd.N--S--, --S--C(R').dbd.C(R'")--,
--C(R").dbd.C(R'")--S--, --O--C(R').dbd.C(R'")--,
--C(R").dbd.C(R'")--O-- or --O--C(R')(R')--O-- wherein
[0010] R' is H or an alkyl group containing 1 to 3 carbon atoms;
and
[0011] 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;
[0012] g is 0, 1 or 2;
[0013] R.sub.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.sub.1 being the same or different when g is 2;
[0014] R.sub.2 is H or an alkyl group containing 1 to 3 carbon
atoms;
[0015] R.sub.3 and R.sub.4, which are the same or different, are H,
or an alkyl group containing 1 to 3 carbon atoms;
[0016] 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;
[0017] Q represents a divalent group of formula IIa, IIb or IIc
5
[0018] in which V is (CH.sub.2).sub.n, wherein n is 0, 1, 2 or 3,
optionally substituted by one or more alkyl groups each containing
1 to 3 carbon atoms;
[0019] 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;
[0020] 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
[0021] R.sub.5 and R.sub.6, which may be the same or different, are
H or an alkyl group containing 1 to 4 carbon atoms; and
[0022] T represents phenyl, 1- or 2-naphthyl,
1-naphth[2,1-d][1,2,3]oxadia- zolyl, 2-, 3- or 4-pyridyl, 2-, 4- or
5-pyrimidinyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 3- or
benzo[b]furanyl, 2,3-dihydro-7-benzo[b]furanyl, 2-, 3- or
7-benzo[b]thiophenyl, 3-, 4-5-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 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, I) 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.
[0023] In preferred compounds of formula I, A is --O--.
[0024] In preferred compounds of formula I, B is --O--.
[0025] In more preferred compounds of formula I, both A and B are
--O--.
[0026] In preferred compounds of formula I, g is 0 or 1. When g is
1, R.sub.1 is preferably halo or an alkyl group containing 1 to 3
carbon atoms. In more preferred compounds of formula I, g is 0.
[0027] In preferred compounds of formula I, G.sub.1-G.sub.2-G.sub.3
are --N(R')-C(R").dbd.C(R'")--; --S--C(R").dbd.C(R'")--,
--N(R')--N.dbd.C(R")--, --O--C(R").dbd.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.sub.1-G.sub.2-G.sub.3 are --O--C(R").dbd.C(R'")-- and R" and R'"
are both H.
[0028] In preferred compounds of formula I, R.sub.2 is H.
[0029] In preferred compounds of formula I, R.sub.3 and R.sub.4,
are both H.
[0030] In preferred compounds of formula I, U is methylene.
[0031] 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.sub.5
is H.
[0032] 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.
[0033] In one group of preferred compounds of formula I, both A and
B are --O--; g is 0, G.sub.1-G.sub.2-G.sub.3 are --NH--CH.dbd.CH--;
--NH--C(CO.sub.2C.sub.2H.sub.5).dbd.CH--; --S--CH.dbd.CH--;
S--CH.dbd.C(Cl)--; --NH--N.dbd.CH--; --O--CH--CH--; or
--O--CH.sub.2--O--; R.sub.2 is H; R.sub.3 and R.sub.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.sub.5 is H; and T is phenyl
optionally substituted by hydroxy or by one or more alkoxy groups
each containing 1 to 3 carbon atoms. More preferably,
G.sub.1-G.sub.2-G.sub.3 are --S--CH.dbd.CH-- or --O--CH.dbd.CH--.
Most preferably G.sub.1-G.sub.2-G.sub.3 are --O--CH.dbd.CH--.
[0034] In another group of preferred compounds of formula I, both A
and B are --O--; g is 0; G.sub.1-G.sub.2-G.sub.3 are
--N(R')--C(R").dbd.C(R'")-- - wherein R' is H, R" is H or
alkoxycarbonyl in which the alkoxy group contains 1 to 3 carbon
atoms, and R" is H or halo; R.sub.2, R.sub.3 and R.sub.4 are each
H; U is methylene; Q is a group of formula IIa in which V is
methylene, E and E' are both ethylene and R.sub.5 is H; and T is
phenyl optionally substituted by hydroxy or one or more alkoxy
groups.
[0035] In another group of preferred compounds of formula I, both A
and B are --O--; g is 0; G.sub.1-G.sub.2-G.sub.3 are
--S--C(R").dbd.C(R'")-- wherein R" is H or alkoxycarbonyl in which
the alkoxy group contains 1 to 3 carbon atoms, and R'" is H or
halo; R.sub.2, R.sub.3 and R.sub.4 are each H; U is methylene; Q is
a group of formula IIa in which V is methylene, E and E' are both
ethylene and R.sub.5 is H; and T is phenyl optionally substituted
by hydroxy or one or more alkoxy groups.
[0036] In another group of preferred compounds of formula I, both A
and B are --O--; g is 0; G.sub.1-G.sub.2-G.sub.3 are
--O--C(R").dbd.C(R'")-- wherein R" is H or alkoxycarbonyl in which
the alkoxy group contains 1 to 3 carbon atoms, and R'" is H or
halo; R.sub.2, R.sub.3 and R.sub.4 are each H; U is methylene; Q is
a group of formula IIa in which V is methylene, E and E' are both
ethylene and R.sub.5 is H; and T is phenyl optionally substituted
by hydroxy or one or more alkoxy groups.
[0037] In another group of preferred compounds of formula I, both A
and B are O; g is 0; G.sub.1-G.sub.2-G.sub.3 are
--O--C(R')(R')--O-- wherein R' is H, R.sub.2, R.sub.3 and R.sub.4
are each H; U is methylene; Q is a group of formula IIa in which V
is methylene, E and E' are both ethylene and R.sub.5 is H; and T is
phenyl optionally substituted by hydroxy or one or more alkoxy
groups.
[0038] Compounds of formula I may exist as salts with
pharmaceutically acceptable acids. The present invention includes
all such salts. Examples of such salts include hydrochlorides,
hydrobromides, sulphates, methanesulphonates, nitrates, maleates,
acetates, citrates, fumarates, tartrates [eg (+)-tartrates,
(-)-tartrates or mixtures thereof including racemic mixtures],
succinates, benzoates and salts with amino acids such as glutamic
acid.
[0039] It will be understood that any group mentioned herein which
contains a chain of three or more atoms signifies a group in which
the chain may be straight or branched. For example, an alkyl group
may comprise propyl, which includes n-propyl and isopropyl, and
butyl, which includes n-butyl, sec-butyl, isobutyl and tert-butyl.
The term `halo` as used herein signifies fluoro, chloro, bromo and
iodo.
[0040] Compounds of formula I and intermediates in their
preparation contain one or more chiral centres, and exist in
different optically active forms. When compounds of formula I and
intermediates in their preparation contain one chiral centre, the
compounds exist in two enantiomeric forms and the present invention
includes both enantiomers and mixtures of enantiomers. The
enantiomers may be resolved by methods known to those skilled in
the art, for example by formation of diastereoisomeric salts which
may be separated, for example, by crystallisation; formation of
diastereoisomeric derivatives or complexes which may be separated,
for example, by crystallisation, gas-liquid or liquid
chromatography; selective reaction of one enantiomer with an
enantiomer-specific reagent, for example enzymatic esterification;
or gas-liquid or liquid chromatography in a chiral environment, for
example on a chiral support for example silica with a bound chiral
ligand or in the presence of a chiral solvent. It will be
appreciated that where the desired enantiomer is converted into
another chemical entity by one of the separation procedures
described above, a further step is required to liberate the desired
enantiomeric form. Alternatively, specific enantiomers may be
synthesised by asymmetric synthesis using optically active
reagents, substrates, catalysts or solvents, or by converting one
enantiomer into the other by asymmetric transformation.
[0041] When a compound of formula I contains more than one chiral
centre it may exist in diastereoisomeric forms. The
diastereoisomeric pairs may be separated by methods known to this
skilled in the art, for example chromatography or crystallisation
and the individual enantiomers within each pair may be separated as
described above. The present invention includes each
diastereoisomer of compounds of formula I and mixtures thereof.
[0042] Certain compounds of formula I and their salts may exist in
more than one crystal form and the present invention includes each
crystal form and mixtures thereof. Certain compounds of formula I
and their salts may also exist in the form of solvates, for example
hydrates, and the present invention includes each solvate and
mixtures thereof.
[0043] Specific compounds of formula I are:
[0044]
N-(9-Chloro-2,3-dihydrothieno[3,2-f][1,4]-benzodioxin-2-ylmethyl)-1-
-[1-(2-methoxyphenyl)piperid-4-yl]methylamine;
[0045]
N-(2,3-Dihydrothieno[3,2-f]-1,4-benzodioxin-2-ylmethyl)-1-[1-(2-met-
hoxyphenyl)piperid-4-yl]methylamine;
[0046] Ethyl
2,3-dihydro-2-(N-{[1-(2-methoxyphenyl)piperid-4-yl]methyl}ami-
nomethyl)-7H-1,4-dioxino[2,3-e]indole-8-carboxylate;
[0047]
N-(2,3-Dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethyl)-1-[1-(2-metho-
xyphenyl)piperid-4-yl]methylamine;
[0048]
N-(2,3-Dihydro-7H-1,4-dioxino[2,3-e]indazol-2-ylmethyl)-1-[1-(2-met-
hoxyphenyl)piperid-4-yl]methylamine;
[0049]
N-(2,3-Dihydrofuro[3,2-f]-1,4-benzodioxin-2-ylmethyl)-1-[1-(2-metho-
xyphenyl)piperid-4-yl]methylamine;
[0050]
2-{4-[(2,3-Dihydrofuro[3,2-f]-1,4-benzodioxin-2-ylmethyl)aminomethy-
l]piperidino}-phenol;
[0051]
N-(7,8-Methylenedioxy-2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-1-[1--
(2-methoxyphenyl)piperid-4-yl]methylamine;
[0052] and pharmaceutically acceptable salts thereof in the form of
individual enantiomers, racemates, or other mixtures of
enantiomers.
[0053] Specific enantiomeric forms of compounds of formula I
include:
[0054]
(S)-N-(9-Chloro-2,3-dihydrothieno[3,2-f]-1,4-benzodioxin-2-ylmethyl-
)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine;
[0055]
(S)-N-(2,3-Dihydrothieno[3,2-f]-1,4-benzodioxin-2-ylmethyl)-1-[1-(2-
-methoxyphenyl)piperid-4-yl]methylamine;
[0056] Ethyl
(S)-2,3-dihydro-2-(N-{[1-(2-methoxyphenyl)piperid-4-yl]methyl-
}aminomethyl)-7H-1,4-dioxino[2,3-e]indole-8-carboxylate;
[0057]
(S)-N-(2,3-Dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethyl)-1-[1-(2-m-
ethoxyphenyl)-piperid-4-yl]methylamine;
[0058]
(S)-N-(2,3-Dihydro-7H-1,4-dioxino[2,3-e]indazol-2-ylmethyl)-1-[1-(2-
-methoxyphenyl)piperid-4-yl]methylamine
[0059]
(S)-N-(2,3-Dihydrofuro[3,2-f]-1,4-benzodioxin-2-ylmethyl)-1-[1-(2-m-
ethoxyphenyl)piperid-4-yl]methylamine
[0060]
(S)-2-{4-[(2,3-Dihydrofuro[3,2-f]-1,4-benzodioxin-2-ylmethyl)aminom-
ethyl]-piperidino}phenol;
[0061]
(S)-N-(7,8-Methylenedioxy-2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-1-
-[1-(2-methoxyphenyl)piperid-4-yl]methylamine
[0062] and pharmaceutically acceptable salts thereof.
[0063] The present invention also includes pharmaceutical
compositions containing a therapeutically effective amount of a
compound of formula I or a salt thereof together with a
pharmaceutically acceptable diluent or carrier.
[0064] As used hereinafter, the term "active compound" denotes a
compound of formula I or a salt thereof. In therapeutic use, the
active compound may be administered orally, rectally, parenterally
or topically, preferably orally. M Thus the therapeutic
compositions of the present invention may take the form of any of
the known pharmaceutical compositions for oral, rectal, parenteral
or topical administration. Pharmaceutically acceptable carriers
suitable for use in such compositions are well known in the art of
pharmacy. The compositions of the invention may contain 0.1-99% by
weight of active compound. The compositions of the invention are
generally prepared in unit dosage form. Preferably the unit dosage
of active ingredient is 1-500 mg. The excipients used in the
preparation of these compositions are the excipients known in the
pharmacists art.
[0065] Compositions for oral administration are the preferred
compositions of the invention and these are the known
pharmaceutical forms for such administration, for example tablets,
capsules, syrups and aqueous or oil suspensions. The excipients
used in the preparation of these compositions are the excipients
known in the pharmacist's art. Tablets may be prepared by mixing
the active compound with an inert diluent such as calcium phosphate
in the presence of disintegrating agents, for example maize starch,
and lubricating agents, for example magnesium stearate, and
tableting the mixture by known methods. The tablets may be
formulated in a manner known to those skilled in the art so as to
give a sustained release of the compounds of the present invention.
Such tablets may, if desired, be provided with enteric coatings by
known methods, for example by the use of cellulose acetate
phthalate. Similarly, capsules, for example hard or soft gelatin
capsules, containing the active compound with or without added
excipients, may be prepared by conventional means and, if desired,
provided with enteric coatings in a known manner. The tablets and
capsules may conveniently each contain 1 to 500 mg of the active
compound. Other compositions for oral administration include, for
example, aqueous suspensions containing the active compound in an
aqueous medium in the presence of a non-toxic suspending agent such
as sodium carboxymethyl- cellulose, and oily suspensions containing
a compound of the present invention in a suitable vegetable oil,
for example arachis oil.
[0066] The active compound may be formulated into granules with or
without additional excipients. The granules may be ingested
directly by the patient or they may be added to a suitable liquid
carrier (for example water) before ingestion. The granules may
contain disintegrants (for example a pharmaceutically acceptable
effervescent couple formed from an acid and a carbonate or
bicarbonate salt) to facilitate dispersion in the liquid
medium.
[0067] Compositions of the invention suitable for rectal
administration are the known pharmaceutical forms for such
administration, for example, suppositories with cocoa butter or
polyethylene glycol bases.
[0068] Pharmaceutical compositions may also be administered
parenterally (for example subcutaneously, intramuscularly,
intradermally and/or intravenously [such as by injection and/or
infusion]) in the known pharmaceutical dosage forms for parenteral
administration (for example sterile suspensions in aqueous and/or
oily media and/or sterile solutions in suitable solvents,
preferably isotonic with the blood of the intended patient).
Parenteral dosage forms may be sterilised (for example by
micro-filtration and/or using suitable sterilising agents [such as
ethylene oxide]). Optionally one or more of the following
pharmaceutically acceptable adjuvants suitable for parenteral
administration may be added to parenteral dosage forms: local
anaesthetics, preservatives, buffering agents and/or mixtures
thereof. Parenteral dosage forms may be stored in suitable sterile
sealed containers (for example ampoules and/or vials) until use. To
enhance stability during storage the parenteral dosage form may be
frozen after filling the container and fluid (for example water)
may be removed under reduced pressure.
[0069] Pharmaceutical compositions may be administered nasally in
known pharmaceutical forms for such administration (for example
sprays, aerosols, nebulised solutions and/or powders). Metered dose
systems known to those skilled in the art (for example aerosols
and/or inhalers) may be used.
[0070] Pharmaceutical compositions may be administered to the
buccal cavity (for example sub-lingually) in known pharmaceutical
forms for such administration (for example slow dissolving tablets,
chewing gums, troches, lozenges, pastilles, gels, pastes,
mouthwashes, rinses and/or powders).
[0071] Compositions for topical administration may comprise a
matrix in which the pharmacologically active compounds of the
present invention are dispersed so that the compounds are held in
contact with the skin in order to administer the compounds
transdermally. A suitable transdermal composition may be prepared
by mixing the pharmaceutically active compound with a topical
vehicle, such as a mineral oil, petrolatum and/or a wax, for
example paraffin wax or beeswax, together with a potential
transdermal accelerant such as dimethyl sulphoxide or propylene
glycol. Alternatively the active compounds may be dispersed in a
pharmaceutically acceptable cream or ointment base. The amount of
active compound contained in a topical formulation should be such
that a therapeutically effective amount of the compound is
delivered during the period of time for which the topical
formulation is intended to be on the skin.
[0072] The compounds of the present invention may also be
administered by continuous infusion either from an external source,
for example by intravenous infusion or from a source of the
compound placed within the body. Internal sources include implanted
reservoirs containing the compound to be infused which is
continuously released for example by osmosis and implants which may
be (a) liquid such as a suspension or solution in a
pharmaceutically acceptable oil of the compound to be infused for
example in the form of a very sparingly water-soluble derivative
such as a dodecanoate salt or ester or (b) solid in the form of an
implanted support, for example of a synthetic resin or waxy
material, for the compound to be infused. The support may be a
single body containing all the compound or a series of several
bodies each containing part of the compound to be delivered. The
amount of active compound present in an internal source should be
such that a therapeutically effective amount of the compound is
delivered over a long period of time.
[0073] In some formulations it may be beneficial to use the
compounds of the present invention in the form of particles of very
small size, for example as obtained by fluid energy milling.
[0074] In the compositions of the present invention the active
compound may, if desired, be associated with other compatible
pharmacologically active ingredients.
[0075] The present invention also comprises a compound of formula I
for use as a medicament.
[0076] The compounds of formula I or salts thereof or
pharmaceutical compositions containing a therapeutically effective
amount of a compound of formula I or a salt thereof may be used to
treat 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, anorexia, cardiovascular and cerebrovascular
disorders, non-insulin dependent diabetes mellitus, hyperglycaemia,
constipation, arrhythmia, disorders of the neuroendocrine system,
stress, and spasticity in human beings. Preferably, the compounds
of formula I are used to treat psychoses, for example
schizophrenia. Whilst the precise amount of active compound
administered in such treatment will depend on a number of factors,
for example the age of the patient, the severity of the condition
and the past medical history and always lies within the sound
discretion of the administering physician, the amount of active
compound administered per day is in the range 1 to 1000 mg
preferably 5 to 500 mg given in single or divided doses at one or
more times during the day.
[0077] A further aspect of the present invention provides the use
of a compound of formula I in the manufacture of a medicament for
treating 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, or spasticity in human beings.
Preferably, there is provided a compound of formula I for use in
the manufacture of a medicament for treating psychoses, for example
schizophrenia.
[0078] The present invention also provides a method of treating
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, or spasticity in human beings which comprises the
administration of a therapeutically effective amount of a compound
of formula I to a patent in need thereof, Preferably, the method is
a method of treating psychoses, for example schizophrenia.
[0079] Processes for the preparation of compounds of formula I will
now be described. These processes form a further aspect of the
present invention. The processes are preferably carried out at
atmospheric pressure, at a temperature in the range minus
80.degree. C. to 300.degree.C. more preferably in the range
0-200.degree. C., and most preferably in the range 20-150.degree.
C. The substituents are as defined for formula I above unless
otherwise stated.
[0080] Compounds of formula I in which Q is a group of formula IIa
in which R.sub.5 is H, and V is (CH.sub.2).sub.n wherein n is 1, 2
or 3 may be prepared by reaction of a compound of formula III 6
[0081] in which m is 0, 1 or 2, with a compound of formula IV 7
[0082] in which Z is a leaving group, for example
toluene-4-sulphonyloxy, optionally in the presence of a suitable
solvent, for example acetonitrile, optionally in the presence of a
base, for example potassium carbonate, and optionally in the
presence of a catalyst, for example potassium iodide.
[0083] Compounds of formula I in which U is methylene and Q is a
group of formula IIa in which R.sub.5 is H, and V is
(CH.sub.2).sub.n wherein n is 1, 2 or 3, and R" and R'" are other
than formyl may be prepared by reaction of a compound of formula V
8
[0084] with a compound of formula II, followed by reduction of the
intermediate imine with a suitable reducing agent, for example
sodium borohydride.
[0085] Compounds of formula III and methods for their preparation
are known (for example in WO95/07274).
[0086] Compounds of formula IV in which Z is toluene-4-sulphonyloxy
may be prepared by reaction of a compound of formula VI 9
[0087] with toluene-4-sulphonyl chloride, optionally in the
presence of a base, for example pyridine or
4-dimethylaminopyrdine.
[0088] Compounds of formula VI in which A and B are both --O--,
R.sub.2, R.sub.3 and R.sub.4 are all H, and U is methylene may be
prepared by reaction of a compound of formula VII 10
[0089] in which Z is a leaving group, for example chloro or
toluene-4-sulphonyloxy, with a compound of formula VIII 11
[0090] in a suitable solvent, for example water or
dimethylformamide in the presence of a base, for example sodium
hydroxide. When the appropriate enantiomerically pure form of a
compound of formula VlI, for example (R)-glycidyl
4-toluenesulphonate, is used, the single (S)-enantiomer of a
compound of formula VI can be prepared.
[0091] Compounds of formula VI in which A and B are both --O--, U
is methylene, and R.sub.2, R.sub.3 and R.sub.4 are all H, may also
be prepared by cyclisation of a compound of formula IX 12
[0092] in which R is H or an alkyl group containing 1 to 4 carbon
atoms, using a base, for example potassium carbonate.
[0093] Compounds of formula IX may be prepared by oxidation of
compounds of formula X 13
[0094] in which R is H or an alkyl group containing 1 to 4 carbon
atoms, with a peroxyacid, for example 3-chloroperoxybenzoic
acid.
[0095] Compounds of formula X may be prepared by alkylating
compounds of formula XI 14
[0096] in which R is H or an alkyl group containing 1 to 4 carbon
atoms, with compounds of formula VII, in which Z is a leaving
group, for example chloro or toluene-4-sulphonyloxy, in a suitable
solvent, for example dimethylformamide, in the presence of a base,
for example potassium carbonate. When the appropriate
enantiomerically pure form of a compound of formula VII, for
example (R)-glycidyl 4-toluenesulphonate, is used, the single
(S)-enantiomer of a compound of formula VI can be prepared.
[0097] Compounds of formula VI in which A and B are both --O--, U
is methylene, R.sub.2, R.sub.3 and R.sub.4 are all H, and the group
-G.sub.1-G.sub.2-G.sub.3- contains the group R" which is as stated
below, may be prepared as follows:
[0098] when R" is H or CO.sub.2Et, the compound of formula VI may
be prepared by cyclisation of the appropriate compound of formula
IX in the presence of potassium carbonate;
[0099] when R" is CO.sub.2H, the compound of formula VI may be
prepared by hydrolysis of the corresponding compound of formula VI
in which R" is CO.sub.2Et;
[0100] when R" is H, the compound of formula VI may also be
prepared by decarboxylation of the corresponding compound of
formula VI in which R" is CO.sub.2H;
[0101] when R" is CONH.sub.2, the compound of formula VI may be
prepared by reaction of the corresponding compound of formula VI in
which R" is CO.sub.2Et, CO.sub.2H, CO.Cl or CO.O.CO.sub.2Et with
ammonia, in the presence, where appropriate, of an amide coupling
agent such as carbonyl diimidazole;
[0102] when R" is CONMe.sub.2, the compound of formula VI may be
prepared by reaction of the corresponding compound of formula VI in
which R" is CO.sub.2Et, CO.sub.2H, CO.Cl or CO.O.CO.sub.2Et with
dimethylamine, in the presence, where appropriate, of an amide
coupling agent such as carbonyl diimidazole;
[0103] when R" is CHO, the compound of formula VI may be prepared
by reduction of the corresponding compound of formula VI in which
R" is CO.sub.2Et;
[0104] when R" is COMe, the compound of formula VI may be prepared
by reaction of the corresponding compound of formula VI in which R"
is CO.sub.2H with methyl lithium; and
[0105] when R" is CN, the compound of formula VI may be prepared by
dehydration of the corresponding compound of formula VI in which R"
is CONH.sub.2.
[0106] Compounds of formula VI in which A and U are methylene, B is
--O--, R.sub.2 is H and R" and R'" are H or cyano, may be prepared
by reduction of a compound of formula XII 15
[0107] with a reducing agent, for example borane-dimethyl sulphide
complex
[0108] Compounds of formula XII may be prepared by reduction of a
compound of formula XIII 16
[0109] in which L is H with a reducing agent, for example hydrogen
in the presence of a palladium-on-carbon catalyst.
[0110] Compounds of formula XIII in which L is H may be prepared by
acid or base-catalysed hydrolysis of a compound of formula XIII in
which L is an alkyl group containing 1 to 6 carbon atoms.
[0111] Compounds of formula XIII in which L is an alkyl group may
be prepared by reaction of a compound of formula XI in which R is H
with a compound of formula XIV 17
[0112] in which L is an alkyl group containing 1 to 6 carbon atoms,
in the presence of a base, for example
1,4-diazabicyclo[2.2.2]octane (DABCO).
[0113] Compounds of formula V may be prepared by oxidation of a
compound of formula VI in which U is methylene with a suitable
oxidising agent, for example pyrdinium chlorochromate or by
reduction of a compound of formula XV 18
[0114] with a suitable reducing agent, for example sodium
bis(2-methoxyethoxy)aluminium hydride in a solvent, for example
toluene.
[0115] Compounds of formula XV in which A and B are both --O-- may
be prepared by reaction of a compound of formula XVI 19
[0116] in which Y is a leaving group, for example bromo, and L is
an alkyl group containing 1 to 6 carbon atoms with a compound of
formula VIII, in the presence of a base, for example potassium
carbonate.
[0117] Compounds of formula XV in which A is methylene, B is --O--,
R.sub.2 is H and L is an alkyl group containing 1 to 6 carbon atoms
may be prepared by reduction of a compound of formula XIII in which
L is an alkyl group containing 1 to 6 carbon atoms, with a suitable
reducing agent, for example hydrogen in the presence of a
palladium-on-carbon catalyst.
[0118] Compounds of formula I in which Q is a group of formula IIb
may be prepared by reaction of a compound of formula IV in which Z
is a leaving group, for example toluene-4-sulphonyloxy, with a
compound of formula XVII 20
[0119] in which D' is H, optionally in the presence of a base, for
example potassium carbonate, and optionally in a solvent, for
example acetonitrile.
[0120] Compounds of formula XVII in which D' is H may be prepared
by deprotection of a compound of formula XVII in which D' is a
protecting group, for example tert-butoxycarbonyl, for example by
hydrolysis in the presence of an acid, for example trifluoroacetic
acid.
[0121] Compounds of formula XVII in which D' is a protecting group
may be prepared by reaction of a compound of formula XVIII 21
[0122] in which D' is a protecting group, for example
tern-butoxycarbonyl, with a haloaromatic compound, for example a
2-halopyridine such as 2-chloropyridine, optionally in the presence
of a base, for example triethylamine, in a suitable solvent such as
dichloromethane.
[0123] Compounds of formula I in which Q is a group of formula IIc
in which V is (CH.sub.2).sub.n wherein n is 1, 2, or 3 may be
prepared by reaction of a compound of formula XIX 22
[0124] in which D' is H and m is 0, 1 or 2, with a compound of
formula IV in which Z is a leaving group, for example
toluene-4-sulphonyloxy, optionally in the presence of a base, for
example potassium carbonate, and optionally in a solvent, for
example acetonitrile.
[0125] Compounds of formula XIX in which D' is H may be prepared by
deprotection of a compound of formula XIX in which D' is a
protecting group, for example tert butoxycarbonyl, for example by
hydrolysis in the presence of an acid, for example trifluoroacetic
acid.
[0126] Compounds of formula XIX in which D' is a protecting group
may be prepared by reaction of a compound of formula XX 23
[0127] in which D' is a protecting group, for example
tert-butoxycarbonyl, and m is 0, 1 or 2, with a haloaromatic
compound, for example a 2-halopyridine such as 2-chloropyridine,
optionally in the presence of a base, for example triethylamine, in
a suitable solvent such as dichloromethane.
[0128] Compounds of formula IV in which G.sub.1-G.sub.2-G.sub.3 are
--NH--CH.dbd.CH-- are known (J.Med.Chem.,1992,35, pg 3058).
[0129] Compounds of formula IV in which G.sub.1-G.sub.2-G.sub.3 are
other than --NH--CH.dbd.CH-- may be prepared by methods analogous
to that described above.
[0130] Compounds of formula I in which R.sub.5 is an alkyl group
and R" and R'" are other than formyl may be prepared by alkylation
of a compound of formula I in which R.sub.5 is H with for example
formaldehyde and formic acid, or an aldehyde and a reducing agent
such as sodium cyanoborohydride.
[0131] Compounds of formula XI in which R is H may be prepared by
reaction of a compound of formula XXI 24
[0132] with an N-arylformimidate ester of formula XXII 25
[0133] in which R.sup.a is H, an alkyl group containing 1 to 3
carbon atoms, an alkoxy group containing 1 to 3 carbon atoms, or
halo, and R.sup.b is an alkyl group containing 1 to 3 carbon atoms,
for example ethyl N-(4-methoxyphenyl)formimidate, followed by
hydrolysis of the intermediate imine in the presence of an
acid.
[0134] Compounds of formula XI in which R.dbd.H and
G.sub.1-G.sub.2-G.sub.3 represents --O--C(R').sub.2--O-- may be
prepared by reaction of a compound of formula XXIII 26
[0135] with a lithiating agent, for example sec-butyllithium,
followed by a formylating agent, for example N,N-dimethylformamide,
followed by hydrolytic work-up.
[0136] Compounds of formula XXIII may be prepared by reaction of
compounds of formula XXI with diethylcarbamoyl chloride in the
presence of a base, for example sodium hydride.
[0137] Compounds of formula I in which the group T bears a hydroxy
substituent may be prepared by dealkylation of a corresponding
alkoxy substituted compound, by reaction with a dealkylating agent,
for example pyridine hydrochloride.
[0138] Compounds of formula I in which G.sub.1-G.sub.2-G.sub.3
represents --S--CH.dbd.CH-- may be prepared by dechlorination of a
corresponding compound in which G.sub.1-G.sub.2-G.sub.3 represents
--S--CH.dbd.CCl-- by, for example, reaction with hydroiodic
acid.
[0139] The ability of compounds of formula I to interact with
5-hydroxytryptamine (5-HT) receptors has been demonstrated by the
following test which determines the ability of the compounds to
inhibit tritiated ligand binding to 5-HT receptors in vitro and in
particular to 5-HT.sub.1A receptors.
[0140] Hippocampal tissue from the brains of male Charles River CD
rats weighing between 150-250 g were homogenised in ice-cold 50 mM
Tris-HCl buffer (pH 7.7) when measured at 25.degree.C., 1:40 w/v)
and centrifuged at 30,000 g at 40.degree.C. for 10 minutes. The
pellet was rehomogenised in the same buffer, incubated at
37.degree.C. for 10 minutes and centrifuged at 30,000 g at
4.degree.C. for 10 minutes. The final pellet was resuspended in 50
mM Tris-HCl buffer (pH 7.7) containing 4 mM CaCl.sub.2, 0.1%
L-ascorbic acid and 10 .mu.M pargyline hydrochloride (equivalent to
6.25 mg wet weight of tissue/ml) and used immediately in the
binding assay. Aliquots (400 .mu.l; equivalent to 2.5 mg wet weight
of tissue/tube) of this suspension were added to tubes containing
the ligand (50 .mu.l; 2 nM) and distilled water (50 .mu.l; total
binding) or 5-HT (50 .mu.l; 10 .mu.M; non-specific binding) or test
compound (50 .mu.l; at a single concentration of 10.sup.-6 M or at
10 concentrations ranging from 10.sup.-11-10.sup.-3 M). The ligand
was [.sup.3H]8-hydroxy-2-(dipropylamino)tetralin
([.sup.3H]8-OH-DPAT) and the mixture was incubated at 25.degree.C.
for 30 minutes before the incubation was terminated by rapid
filtration.
[0141] The filters were washed with ice-cold Tris-HCl buffer and
dried. The filters were punched out into vials, scintillation fluid
added and radioactivity determined by liquid scintillation
counting. The percentage displacement of specific binding of the
trtiated ligand was calculated for the single concentration
(10.sup.-6 M) of test compound. Displacement curves were then
produced for those compounds which displaced .gtoreq.50% of
specific binding of the tritiated ligand at 10.sup.-6 M using a
range of concentrations of the compound. The concentration which
gave 50% inhibition of specific binding (IC.sub.50) was obtained
from the curve. The inhibition coefficient Ki was then calculated
using the formula 1 K i = IC50 1 + ( [ ligand ] / K D )
[0142] in which [ligand] is the concentration of the tritiated
ligand used and K.sub.D is the equilibrium dissociation constant
for the ligand.
[0143] The ability of compounds of formula I to interact with
dopamine receptors has been demonstrated by the following test
which determines the ability of the compounds to inhibit tritiated
ligand binding to dopamine receptors in vitro and in particular to
the D.sub.2-like dopamine receptors.
[0144] Striatal tissue from the brains of male Charles River CD
rats weighing between 140-250 g were homogenised in ice-cold 50 mM
Tris-HCl buffer (pH 7.7 when measured at 25.degree.C.) and
centrifuged at 40,000 g for 10 minutes. The pellet was resuspended
in Tris salts buffer (50 mM Tris-HCl buffer containing 120 mM NaCl,
5 mM KCl, 2 mM CaCl.sub.2 and 1 mM MgCl.sub.2 with the addition of
6 mM ascorbic acid; pH 7.7 when measured at 25.degree. C.), and
again centrifuged at 40,000 g for 10 minutes. The final pellet was
stored at -80.degree.C. Before each test the pellet was resuspended
in Tris salts buffer (equivalent to 2 mg wet weight of tissue/ml).
Aliquots (720 .mu.l; equivalent to 1.44 mg wet weight of
tissue/tube) of this suspension were then added to tubes containing
the ligand (40 .mu.l; 1 nM) and Tris salts buffer (40 .mu.l; total
binding) or spiroperidol (40 .mu.l; 10 nM; non-specific binding) or
test compound (40 .mu.l; at a single concentration of 10.sup.-6M or
at 6 concentrations ranging from 10.sup.-11-10.sup.-4M). The ligand
was tritiated (S-sulpiride and the mixture was incubated at
4.degree. C. for 40 minutes before the incubation was terminated by
rapid filtration.
[0145] The filters were washed with ice-cold Tris-HCl buffer and
dried. The filters were punched out in to vials, scintillation
fluid added and were left for about 20 hours before being counted
by scintillation spectrophotometry. The percentage displacement of
specific binding of the tritiated ligand was calculated for the
single concentration (10.sup.-6M) of test compound. Displacement
curves were then produced over a range of concentrations for those
compounds which displaced .gtoreq.50% of specific binding of the
tritiated ligand at 10.sup.-6M. The concentration which gave a 50%
inhibition of specific binding (IC50) was obtained from the curve.
The inhibition coefficient Ki was then calculated using the formula
2 K i = IC50 1 + ( [ ligand ] / K D )
[0146] in which [ligand] is the concentration of the tritiated
ligand used and K.sub.D is the equilibrium dissociation constant
for the ligand.
[0147] The K.sub.i values obtained in the above tests for
5-HT.sub.1A and D.sub.2-like binding for each of the final products
of the Examples hereinafter are given in Table I below.
1TABLE 1 Example Ki (nM) value for Number 5-HT.sub.1A D.sub.2-like
1 36 76.9 2 9.7 40.4 3 99% 106 4 99% 8.96 5 1.2 7.1 6 1.7 22.1 7
3.6 11.7 8 1.1 6 The % figures in Table 1 are for % displacement at
10.sup.-6 M.
[0148] Advantageous compounds of the present invention have a Ki of
less than 100 nM for 5-HT.sub.1A or a binding affinity for
5-HT.sub.1A of greater than 90% at 10.sup.-6M and a Ki of less than
100 nM for D.sub.2-like receptors or a binding affinity for
D.sub.2-like receptors of greater than 90% at 10.sup.-6M.
[0149] The invention is illustrated by the following Examples which
are given by way of example only. The final product of each Example
was characterised by one or more of the following procedures:
gas-liquid chromatography; high performance liquid chromatography;
elemental analysis, nuclear magnetic resonance spectroscopy,
infrared spectroscopy and spectroscopy.
EXAMPLE 1
[0150] A stirred solution of ethyl
3-chloro-5-methoxybenzo[b]thiophene-2-c- arboxylate (20.0 g) in
dichloromethane (80 ml) at -20.degree. C. under an atmosphere of
nitrogen was treated with boron tribromide (1 M solution in
dichloromethane; 90 ml) and the solution allowed to warm up to room
temperature slowly. After 2 hours the mixture was carefully poured
into ethanol (400 ml) and left to stand for 10 minutes. The solvent
was evaporated under reduced pressure and the residue dissolved in
ethyl acetate (500 ml). The resulting solution was washed with
water (300 ml), dried over sodium sulphate and the solvent
evaporated under reduced pressure to give ethyl
3-chloro-5-hydroxybenzo[b]thiophene-2-carboxylate (18.68 g) as an
off-white solid; m.p. 160-161.degree. C.
[0151] A round bottomed flask containing a mixture of the product
from the previous reaction (6.04 g) and ethyl
N-(4-methoxyphenyl)formimidate (4.50 g) was submerged rapidly in an
oil bath pre-heated to 160.degree.C., and the mixture stirred at
160-80.degree. C. for 4 hours, the ethanol produced in the reaction
being removed by distillation. More of the formimidate (0.80 g) was
then added and the mixture heated at 180-90.degree. C. for a
further 1 hour. The cooled mixture was then treated with boiling
methanol (100 ml) and the resulting light brown solid collected by
filtration, washed with methanol (100 ml) and dried to give ethyl
3-chloro-5-hydroxy-4-[N-(4-methoxyphenyl)iminomethyl]benzo[b]t-
hiophene-2-carboxylate (4.03 g); m.p. 162-163.degree. C.
[0152] A stirred mixture of the product from the previous reaction
(3.82 g) and hydrochloric acid (4M; 130 ml) was heated at
50-60.degree. C. for 4 hours and then left to stand at room
temperature overnight. The mixture was then heated at 60-70.degree.
C. for 3 hours. The cooled mixture was poured into water (350 ml)
and extracted with ethyl acetate (2.times.250 ml). The combined
organic extracts were washed with water (200 ml), dried over sodium
sulphate and evaporated under reduced pressure to give ethyl
3-chloro-4-formyl-5-hydroxybenzo[b]thiophene-2-carboxylate (2.80 g)
as a pale-green solid; m.p. 128-130.degree. C.
[0153] Potassium carbonate (2.62 g) was added to a stirred solution
of ethyl 3-chloro-4-formyl-5-hydroxybenzo[b]thiophene-2-carboxylate
(4.90 g, prepared as described above) in dry dimethylformamide (50
ml) and then a solution of (R)-glycidyl tosylate (4.12 g) in dry
dimethyl formamide (50 ml) was added slowly. The mixture was then
stirred at 60.degree. C. for 3 hours, cooled and poured into water
(1200 ml). The resulting pale-green solid was collected by
filtration, washed with water (200 ml) and dried to give ethyl
(R-3-chloro-5-(2,3-epoxypropoxy)-4-formylbenzo[b]thiophene--
2-carboxylate (5.15 g).
[0154] A stirred solution of the product from the previous reaction
(1.0 g) in dichloromethane (20 ml) was treated with
3-chloroperoxybenzoic acid (85%; 0.75 g) and the mixture cooled to
0.degree. C. A solution of trifluoroacetic acid (0.335 g) in
dichloromethane (5 ml) was then added and the solution stirred at
0.degree.C. for 5 minutes and then at room temperature for 1 hour.
The mixture was poured into saturated aqueous sodium bisulphite
solution (100 ml) and extracted with dichloromethane (2.times.100
ml). The combined organic extracts were washed with saturated
aqueous sodium bicarbonate solution (2.times.150 ml), dried over
sodium sulphate and evaporated under reduced pressure to give a
brown oil. Purification by flash chromatography on silica using a
1:1 mixture of petroleum ether (b.p. 60-80.degree. C.) and ethyl
acetate as eluant gave ethyl
(R)-3-chloro-5-(2,3-epoxypropoxy)-4-formyloxybenzo[b]th-
iophene-2-carboxylate (0.52 g) as a pale-yellow solid.
[0155] Saturated aqueous potassium carbonate solution (20 ml) was
added to a stirred solution of ethyl
(R)-3-chloro-5-(2,3-epoxypropoxy)-4-formyloxy-
-benzo[b]thiophene-2-carboxylate (1.85 g, prepared as described
above) in tetrahydrofuran (20 ml) and the mixture stirred for 24
hours at room temperature. The reaction mixture was poured into
water (200 ml) and extracted with ethyl acetate (2.times.100 ml).
The combined extracts were dried over sodium sulphate and
evaporated under reduced pressure to give a yellow solid.
Purification by flash chromatography on silica using a 1:1 mixture
of petroleum ether (b.p. 60-80.degree. C.) and ethyl acetate as
eluant gave ethyl
(S)-9-chloro-2,3-dihydro-2-(hydroxymethyl)thieno[3,2-
-f]-1,4-benzodioxin-8-carboxylate (1.44 9) as a pale-yellow solid;
m.p. 165-166.degree.C.
[0156] A stirred solution of the product from the previous reaction
(1.30 g) in methanol (20 ml) was treated with a solution of lithium
hydroxide monohydrate (0.17 g) in water (10 ml) and the mixture
heated at 60.degree. C. for 1 hour. The solution was evaporated
under reduced pressure to remove methanol and then diluted with
water (50 ml). The aqueous solution was acidified with hydrochloric
acid (2 M) and the resulting suspension collected by filtration,
washed with water and dried to give
(S)-9-chloro-2,3-dihydro-2-(hydroxymethyl)thieno[3,2-f]-1,4-benzo-
dioxin-8-carboxylic acid (1.15 g) as an off-white solid, m.p.
236-7.degree.C.
[0157] A round bottomed flask containing a mixture of the product
from the previous reaction (0.80 g) , copper powder (0.17 g) and
quinoline (10 ml) was rapidly submerged in an oil bath pre-heated
to 190.degree.C., and the mixture heated with stirring at this
temperature for 30 minutes. The mixture was cooled to room
temperature and poured into hydrochloric acid (2M; 300 ml). The
mixture was extracted with ethyl acetate (2.times.150 ml) and the
combined extracts washed with hydrochloric acid (2M; 150 ml) ,
water (150 ml), then dried over sodium sulphate and evaporated
under reduced pressure to give a dark brown oil (0.781 g).
Purification by flash chromatography on silica using a 3:10 mixture
of ethyl acetate and petroleum ether (b.p. 60-80.degree. C.) as
eluant gave
(S)-9-chloro-2,3-dihydro-2-(hydroxymethyl)thieno[3,2-f][1,4-benzodioxin
(0.70 g) as a white solid, m.p. 92-3.degree. C.
[0158] 4-Dimethylaminopyridine (0.26 g) then 4-toluenesulphonyl
chloride (0.40 g) were added to a stirred solution of
(S)-9-chloro-2,3-dihydro-2-(-
hydroxymethyl)thieno[3,2-f][1,4]-benzodioxin (0.49 g) in
dichloromethane (20 ml), and the mixture then stirred at ambient
temperature for 24 hours. The resulting solution was poured into
water (100 ml) and extracted with dichloromethane (150 ml). The
resulting organic solution was then washed successively with
saturated copper sulphate solution (2.times.100 ml) and water (100
ml). The solution was dried over sodium sulphate and the solvent
evaporated under reduced pressure to give
(S)-9-chloro-2,3-dihydrothieno[3,2-f]-1,4-benzodioxin-2-ylmethyl
4-toluene-sulphonate (0.7 g) as a white solid m.p.
169-70.degree.C.
[0159] A stirred mixture of the product from the previous reaction
(0.63 g), potassium carbonate (3.0 g) and
1-[1-(2-methoxyphenyl)piperid-4-yl]me- thylamine (0.40 g) in dry
acetonitrile (25 ml) was heated under reflux for 24 hours. The
mixture was cooled, filtered and then evaporated under reduced
pressure. The residue was dissolved in dichloromethane (150 ml),
washed with water (100 ml), dried over sodium sulphate and the
solvent evaporated under reduced pressure to give a pale-yellow oil
(1.08 g). Purification by flash column chromatography on silica
eluting with a 20:1 mixture of dichloromethane and methanol gave a
colourless oil (0.47 g). The oil was dissolved in warm ethanol (2
ml) and a solution of fumaric acid (122 mg) in warm ethanol (2 ml)
then added. The resulting white solid was collected by filtration
and dried to give
(S)-N-(9-chloro-2,3-dihydrothieno[3,2-f]-1,4-benzodioxin-2-ylmethyl)-1-(1-
-(2-methoxyphenyl)piperid-4-yl]methylamine 0.5 fumarate (0.40 g)
m.p. 171-172.degree. C., [.alpha.].sub.D-30.41 (c=0.237, MeOH).
EXAMPLE 2
[0160] A stirred mixture of
(S)-(-)-N-(9-chloro-2,3-dihydrothieno[3,2-f][1-
,4]-benzodioxin-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine-
, prepared by the method described above (2.64 9) and hydroiodic
acid (57%; 100 ml) was heated at 60-70.degree.C. for 6 hours and
then allowed to stand at room temperature for 18 hours. The mixture
was poured into aqueous ammonia (250 ml) and extracted with ethyl
acetate (3.times.150 ml). The combined extracts were then washed
with brine (200 ml), dried over sodium sulphate and the solvent
evaporated under reduced pressure to leave a brown oil (2.72 g).
Purification by flash column chromatography on silica eluting with
a 95:5 mixture of dichloromethane and methanol, followed by repeat
chromatography eluting with a 98:2 mixture of dichloromethane and
methanol, gave a colourless oil (0.65 g). Fumaric acid (0.178 g) in
ethanol (10 ml) was then added to a solution of the oil in ethanol
(5 ml) and the solvent then removed under reduced pressure to give
(S)-N-(2,3-dihydrothieno[3,2-f]-1,4-benzodioxin-2-ylmethyl)-1-[1-(2--
methoxyphenyl)piperid-4-yl]methylamine monofumarate (0.78 g) as an
off-white solid; m.p. 180-182.degree.C.,
[.alpha.].sub.D-28.1.degree. (c=0.498, DMSO)
EXAMPLE 3
[0161] Potassium carbonate (0.89 g) was added under nitrogen to a
stirred solution of ethyl 4-formyl-5-hydroxyindole-2-carboxylate
(1.50 g) in dry dimethylformamide (40 ml). A solution of
(R)-glycidyl 4-toluenesulphonate (1.47 g) in dry dimethylformamide
(30 ml) was then added and the mixture stirred at ambient
temperature for 10 minutes, then at 60.degree. C. for 3 hours. The
mixture was poured into water (400 ml) and extracted with ethyl
acetate (3.times.200 ml). The combined extracts were washed with
brine (6.times.200 ml), dried over magnesium sulphate and the
solvent evaporated under reduced pressure. The brown solid residue
was purified by flash column chromatography on silica eluting with
a 1:1 mixture of petroleum ether (b.p. 40-60.degree.C.) and ethyl
acetate to give ethyl
(R)-5-(2,3-epoxypropoxy)-4-formylindole-2-carboxylate (1.07 g) as
an off-white solid; m.p. 152-154.degree.C.
[0162] A stirred solution of ethyl
(R)-5-(2,3-epoxypropoxy)-4-formylindole- -2-carboxylate (1.95 g;
prepared by the method described above) in dichloromethane (40 ml)
was cooled to 0.degree.C. 3-Chloroperoxybenzoic acid (85%; 1.75 g)
was then added in one portion followed by a solution of
trifluoroacetic acid (0.77 g) in dichloromethane (10 ml), in
portions. The mixture was stirred at 0.degree.C. for 10 minutes and
then at ambient temperature for 1 hour. The reaction mixture was
diluted with dichloromethane (300 ml) , washed successively with
saturated aqueous sodium bisulphite solution (100 ml), saturated
aqueous sodium bicarbonate solution (3.times.150 ml), dried over
sodium sulphate and the solvent evaporated. The solid residue was
purified by flash chromatography on silica eluting with a 1:1
mixture of petroleum ether (b.p. 40-60.degree.C.) and ethyl acetate
to give ethyl (R)-5-(2,3-epoxypropoxy)-
-4-formyloxyindole-2-carboxylate (1.55 g) as a pale yellow
crystalline solid; m.p. 123-125.degree.C.
[0163] Saturated aqueous potassium carbonate solution (200 ml) was
added to a stirred solution of ethyl
(R)-5-(2,3-epoxypropoxy)-4-formyloxyindole- -2-carboxylate (22.0 g;
prepared in a similar manner to that described above) in
tetrahydrofuran (250 ml) and the mixture was stirred at room
temperature for 72 hours. The mixture was poured into water (1000
ml) and extracted with ethyl acetate (4.times.400 ml). The combined
extracts were dried over sodium sulphate and the solvent evaporated
under reduced pressure to give ethyl
(S)-2,3-dihydro-2-(hydroxymethyl)-7H-1,4-dioxino[2-
,3-e]indole-8-carboxylate (17.65 g) as a pale purple solid; m.p.
152-153.degree. C. 4-Toluenesulphonyl chloride (2.23 g) was added
in one portion to a stirred solution of ethyl
(S)-2,3-dihydro-2-(hydroxymethyl)--
7H-1,4-dioxino[2,3-e]indole-8-carboxylate (2.65 g) in dry
dichloromethane (120 ml) at 0.degree.C. 4-Dimethylaminopyridine
(1.52 g) was then added and the cooling bath removed. The resulting
solution was stirred at ambient temperature for 72 hours, then
diluted with dichloromethane (150 ml) and washed successively with
water (80 ml), saturated aqueous copper sulphate solution
(2.times.100 ml), and then dried over sodium sulphate. Evaporation
of the solvent under reduced pressure gave a purple foam which was
purified by flash column chromatography on silica eluting with a
1:1 mixture of petroleum ether (b.p. 40-60.degree.C.) and ethyl
acetate, to give ethyl
(S)-2,3-dihydro-2-[(4-toluenesulphonyloxy)methyl]--
7H-1,4-dioxino[2,3-e]indole-8-carboxylate (3.71 g) as a colourless
oil which solidified on standing.
[0164] A mixture of the product from the previous reaction (1.0 g),
potassium carbonate (3.0 g) and
1-[1-(2-methoxyphenyl)piperid-4-yl]methyl- amine (0.80 g) in dry
acetonitrile (50 ml) was heated under reflux with stirring for 24
hours. The cooled mixture was filtered and then evaporated under
reduced pressure to give a yellow oil. The crude material was
dissolved in dichloromethane (200 ml), washed with water (150 ml),
dried over sodium sulphate and evaporated under reduced pressure to
give a, yellow oil (1.65 g). Purification by flash column
chromatography on silica eluting with a 20:1 mixture of
dichloromethane and methanol gave ethyl
(S)-2,3-dihydro-2-(N-{[1-(2-methoxyphenyl)piperid-
-4-yl]methyl}aminomethyl)-7H-1,4-dioxino[2,3-e]indole-8-carboxylate
0.05 dichloromethane solvate (0.34 g) as an off-white solid m.p.
105-107.degree. C., [.alpha.].sub.D-24.degree.(c=0.409, MeOH).
EXAMPLE 4
[0165] A solution of lithium hydroxide monohydrate (0.94 g) in
water (25 ml) was added to a stirred solution of the product from
the previous reaction (2.95 g) in methanol (50 ml) under nitrogen
and the resulting solution stirred at 60.degree. C. for 1 hour. The
methanol was then removed by evaporation and water (80 ml) added.
Hydrochloric acid (2M) was then added until the mixture was pH 2,
and the resulting precipitate collected by filtration, washed with
water and dried to give
(S)-2,3-dihydro-2-(hydroxymethyl)-7H-1,4-dioxino[2,3-e]indole-8-carboxyli-
c acid (2.61 g) as a solid; m.p. 216-217.degree. C.
[0166] A flask containing the product from the previous reaction
(2.60 g) was plunged into a pre-heated isomantle at 250.degree. C.
under nitrogen and the material heated at 250-60.degree.C. for 30
minutes. The residue was cooled to ambient temperature,
pre-absorbed from a methanol solution onto silica and purified by
flash column chromatograhy on silica eluting with 1:1 mixture of
petroleum ether (b.p. 40-60.degree.C.) and ethyl acetate to give
(S)-2,3-dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethanol (0.69 g) as
a colourless syrup.
[0167] A solution of
(S)-2,3-dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethan- ol (0.75 g;
prepared by the method described above) in dichloromethane (50 ml)
was stirred with cooling in an ice bath. 4-(Dimethylamino)pyridine
(0.59 g) and 4-toluenesulphonyl chloride (0.84 g) were then added
and the solution stirred at ambient temperature overnight. The
mixture was diluted with dichlromethane (200 ml), washed
sucessively with water (50 ml), saturated aqueous copper(II)
sulphate solution (2.times.50 ml) and water (50 ml), then dried
over sodium sulphate and the solvent evaporated to give
(S)-2,3-dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethyl
4-toluenesulphonate (1.04 g) as a pale brown oil which solidified
on standing.
[0168] A mixture of
(S)-2,3-dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethyl
4-toluenesulphonate (2.76 g; prepared in a similar manner to that
described above), potassium carbonate (8.0 g) and
1-[1-(2-methoxyphenyl)p- iperid-4-yl]methylamine (1.86 g) in dry
acetonitrile (60 ml) was heated under reflux with stirring for 24
hours. The cooled mixture was filtered, the solid washed with
dichloromethane (100 ml) and the filtrate then evaporated under
reduced pressure. The residue was dissolved in dichloromethane (250
ml) and the resulting solution washed with water (100 ml), dried
over sodium sulphate and evaporated under reduced pressure to give
a fawn solid (4.51 g). Purification by flash column chromatography
on silica eluting with a 20:1 mixture of dichloromethane and
methanol gave
(S)-N-(2,3-dihydro-7H-1,4-dioxino[2,3-e]indol-2-ylmethy-
l)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine 0.1 hydrate (1.34
g) as an off-white crystalline solid m.p. 162-163.degree.C.,
[.alpha.].sub.D-18.5.degree.(c=0.541, CH.sub.2Cl.sub.2).
EXAMPLE 5
[0169] A round bottomed flask containing a mixture of
5-hydroxy-1H-indazole (28.5 g) and ethyl N-phenylformimidate (35 g)
was submerged rapidly in an oil bath pre-heated to 175.degree. C.
and the mixture stirred at 160-180.degree. C. for 30 minutes, the
ethanol produced in the reaction being removed by distillation. The
cooled mixture was then treated with boiling methanol (500 ml) and
the resultant brown solid collected by filtration, washed with
methanol (100 ml) and dried to give
5-hydroxy-4-(N-phenyliminomethyl)-1H-indazole (32 g) as a yellow
solid. The solid was dissolved in hydrochloric acid (5 M; 500 ml)
and heated at 50-60.degree.C. with stirring for 2 hours. The
mixture was diluted with water (500 ml) and extracted with ethyl
acetate (2.times.500 ml). The combined extracts were washed with
water (500 ml), dried over magnesium sulphate and the solvent
evaporated under reduced pressure to give
5-hydroxy-1H-indazole-4-carboxaldehyde (15.48 g) as a yellow
solid.
[0170] A mixture of potassium carbonate (11 g), the product from
the previous reaction (12.5 g) and (R)-glycidyl tosylate (20 g) in
dimethylformamide (250 ml) was stirred and heated at 50.degree. C.
under an atmosphere of nitrogen for 3 hours. The mixture was poured
into water (1000 ml) and extracted with ethyl acetate (3.times.300
ml). The combined extracts were washed with water (2.times.300 ml),
dried over magnesium sulphate and the solvent evaporated under
reduced pressure. The yellow solid residue was then purified by
flash column chromatography on silica eluting with a 1:1 mixture of
petroleum ether (b.p. 60-80.degree. C.) and ethyl acetate to give
(R)-5-(2,3-epoxypropoxy)-1H-indazole-4-carboxaldehy- de (2.58 g) as
a pale yellow solid.
[0171] A solution of the product from the previous reaction (2.58
g) and 3-chloroperoxybenzoic acid (56-87%; 12.2 g) in
dichloromethane (300 ml) was stirred at 0.degree. C. for 2 hours.
The mixture was then evaporated to dryness and the residue
dissolved in sodium hydroxide solution (2.5 M ; 200 ml). The navy
blue solution was then heated on the steam bath for 1 hour with a
resultant colour change to deep orange. The cooled reaction mixture
was diluted with water (200 ml) and extracted with ethyl acetate
(3.times.250 ml). The combined extracts were washed with brine (250
ml), dried over magnesium sulphate and the solvent evaporated under
reduced pressure to afford
(S)-2-hydroxymethyl-7H-1,4-dioxino[2,3-e]indazole (0.97 g) as a
cream solid.
[0172] A solution of 4-toluenesulphonyl chloride (2 g) in
dichloromethane (100 ml) was added dropwise to a stirred solution
the product from the previous reaction (0.95 g) and
4-dimethylaminopyridine (1.2 g) in dichloromethane (100 ml) at
0-5.degree. C. The mixture was allowed to warm to room temperature
and stirred for 18 hours. The solution was diluted with
dichloromethane (30 ml) and washed successively with water (100
ml), dilute aqueous sodium hydrogen carbonate solution (5M;
2.times.100 ml), brine (2.times.100 ml) and then dried over
magnesium sulphate. Evaporation of the solvent under reduced
pressure gave a white solid residue which was then purified by
flash column chromatography on silica using a 99:1 mixture of
dichloromethane and ethyl acetate as eluant. The
(S)-7-(4-toluenesulphonyl)-2,3-dihydro-7H-1,4-dioxino[2,3-e]i-
ndazol-2-ylmethyl 4-toluenesulphonate produced which was dissolved
in a mixture of 48% hydrobromic acid (2 ml) and phenol (0.4 g) and
heated under reflux for 30 minutes. The cooled mixture was basified
with sodium hydroxide (5M) and extracted with dichloromethane
(3.times.25 ml). The combined extracts were washed with water (25
ml), dried over magnesium sulphate and the solvent removed under
reduced pressure. The residue was purified by flash column
chromatography on silica eluting with a 10:1 mixture of petroleum
ether (b.p. 60-80.degree.C.) and ethyl acetate to give
(S)-2,3-dihydro-7H-1,4-dioxino[2,3-e]indazol-2-ylmethyl
4-toluenesulphonate (0.53 g) as a white solid.
[0173] A mixture of the product from the previous reaction (0.25
g), potassium carbonate (2 g) and
1-[1-(2-methoxyphenyl)piperid-4-yl]methylam- ine (0.3 g) in a
mixture of dimethylformamide (5 ml) and toluene (10 ml) was heated
at reflux temperature for 8 hours. The cooled mixture was poured
into water (100 ml) and extracted with ethyl ether (2.times.100
ml). The combined extracts were then dried over magnesium sulphate
and the solvent removed under reduced pressure to yield a yellow
oil. Purification by flash column chromatography on silica eluting
with a 20:1 mixture of dichloromethane and methanol afforded
(S)-N-(2,3-dihydro-7H-1,- 4-dioxino[2,3-e]indazol-2-ylmethyl)-l
-[1-(2-methoxyphenyl)piperid-4-yl]me- thylamine (0.04 g) as a gummy
solid.
EXAMPLE 6
[0174] Potassium carbonate (2.85 g) and a solution of (R)-glycidyl
4toluensulphonate (4.50 g) in dry dimethylformamide (10 ml) were
added to a stirred solution of
5-hydroxybenzo[b]furan-4-carboxaldehyde (3.04 g) in dry
dimethylformamide (30 ml). The mixture was heated at 60.degree.C.
for 2 hours and then poured into water (500 ml). The mixture was
extracted with dichloromethane (3.times.300 ml) and the combined
extracts washed with water (8.times.200 ml), dried over sodium
sulphate and the solvent evaporated under reduced pressure to give
a red oil. Purification by flash column chromatography on silica
eluting with a 3:7 mixture of ethyl acetate and petroleum ether
(b.p. 40-60.degree.C.) gave
(R)-5-[2-(2,3-epoxypropoxy)]benzo[b]furan-4 carboxaldehyde (3.11 g)
as a yellow solid m.p. 64-65.degree.C.
[0175] 3-chloroperoxybenzoic acid (85%; 3.88 g) and a solution of
trifluroacetic acid (1.61 g) in dichloromethane (5 ml) were added
to a stirred solution of the product from the previous reaction
(3.08 g) in dichloromethane (40ml). The mixture was stirred at room
temperature for 30 minutes and poured into saturated aqueous sodium
bisulphite solution (200 ml) then extracted with dichloromethane
(2.times.150 ml). The combined extracts were washed with saturated
aqueous sodium bicarbonate solution (3.times.150 ml), dried over
sodium sulphate and the solvent evaporated under reduced pressure
to give (R)-5-[2-(2,3-epoxypropoxy)]ben- zo[b]furan-4-yl formate
(3.10 g) as a red oil.
[0176] Saturated aqueous potassium carbonate solution (15 ml) was
added to a stirred solution of the product from the previous
reaction (3.09 g) in tetrahydrofuran (30 ml) and the mixture
stirred vigorously at room temperature for 72 hours. The mixture
was poured into water (200 ml) and extracted with ethyl acetate
(2.times.150 ml). The combined extracts were dried over sodium
sulphate and the solvent evaporated under reduced pressure to give
an orange oil. Purification by flash column chromatography on
silica eluting with a 2:3 mixture of ethyl acetate and petroleum
ether (b.p. 60-80.degree.C.) gave (S)-2,3-dihydro-2-(hydroxymet-
hyl)furo[3,2-f]-1,4-benzodioxin (1.90 g) as a pale yellow oil.
[0177] 4-Toluenesulphonyl chloride (1.89 g) was added to a stirred
solution of the product from the previous reaction (1.86 g) in
dichloromethane (40 ml) . 4-Dimethylaminopyridine (1.21 g) was then
added and the resulting solution stirred at room temperature for 18
hours. The mixture was diluted with dichloromethane (200 ml) and
washed sucessively with water (100 ml), saturated copper sulphate
solution (2.times.100 ml) and water (100 ml). The organic solution
was then dried over sodium sulphate and the solvent evaporated
under reduced pressure to give
(S)-2,3-dihydrofuro[3,2-f]-1,4-benzodioxin-2-ylmethyl
4-toluenesulphonate (3.01 g) as a colourless oil.
[0178] A mixture of the product from the previous reaction (2.80
g), potassium carbonate (10.0 g) and
1-[(2-methoxyphenyl)piperid-4-yl]methyla- mine (1.88 g) in dry
acetonitrile (100 ml) was heated under reflux with stirring for 90
hours. The cooled mixture was filtered and the filtrate evaporated
under reduced pressure to leave a pale-yellow oil. Purification by
flash column chromatography on silica eluting with a 19:1 mixture
of dichloromethane and methanol gave a pale-yellow oil which was
then dissolved in ethanol (5 ml) and treated with a solution of
fumaric acid (0.70 g) in ethanol (5 ml). The solvent was evaporated
from the resulting solution under reduced pressure to give
(S)-N-(2,3-dihydrofuro[-
3,2-f]-1,4-benzodioxin-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl]meth-
ylamine monofumarate monohydrate (3.06 g) as a pale-yellow solid
m.p. 95-6.degree. C., [.alpha.].sub.D=-38.5.degree. (C=0.301,
MeOH)
EXAMPLE 7
[0179] A flask containing a mixture of the product from the
previous reaction (1.14 g) and pyridine hydrochloride (10 g) was
submerged in a pre-heated oil bath at 180.degree.C. and the
resulting solution heated with stirring at 180-200.degree.C. for 2
hours. The cooled reaction mixture was dissolved in water (200 ml),
basified with aqueous ammonia, and then extracted with
dichloromethane (3.times.100 ml). The combined extracts were washed
with water (100 ml), dried over magnesium sulphate and the solvent
evaporated under reduced pressure to leave a brown oil (0.90 g).
Purification by flash column chromatography on silica eluting with
a 19:1 mixture of dichloromethane and methanol gave a pale orange
oil (0.23 g). A portion of this oil (0.2 g) was dissolved in
ethanol (1 ml) and then treated with a solution of fumaric acid (60
mg) in ethanol (5 ml). The resulting solution was evaporated under
reduced pressure to give
(S)-2-{4-[(2,3-Dihydrofuro[3,2-f]-1,4-benzodioxin-2-ylmethyl)-aminom-
ethyl]piperidino}phenol monofumarate 1.1 hydrate, 0.25 ethanol
solvate (0.27 g) as an orange solid m.p. 88-9.degree. C.,
[.alpha.].sub.D=-37.7.d- egree. (C=0.257, EtOH)
EXAMPLE 8
[0180] A solution of 3,4-methylenedioxyphenol (40 g) in diethyl
ether (350 ml) was added dropwise to a stirred suspension of sodium
hydride (12.9 g) in a mixture of dimethylformamide (110 ml) and
diethyl ether (470 ml) at room temperature. The mixture was stirred
until the evolution of hydrogen had ceased, then a solution of
diethyl carbamoyl chloride (47 g) in diethyl ether (110 ml) was
added and the mixture was stirred for 1 hour, then left to stand at
room temperature for 17 hours.
[0181] The reaction mixture was poured into water (600 ml) and the
product was extracted with diethyl ether (3.times.300 ml). The
ethereal layers were combined, washed with 10% aqueous sodium
hydroxide solution (2.times.200 ml), dried over magnesium sulphate
and evaporated under reduced pressure to give
3,4-methylenedioxyphenyl N,N-diethylcarbamate (59 g) as a white
solid.
[0182] N,N,N'N'-Tetramethylethylenediamine (4 ml) was added to a
stirred solution of sec-butyllithium (1.3 M solution in
cyclohexane; 21 ml) in tetrahydrofuran (25 ml) at -78.degree. C.
The mixture was stirred for 30 minutes then added via a cannula to
a stirred solution of the product from the previous reaction (5 g)
in tetrahydrofuran (70 ml) at -78.degree. C. The mixture was
stirred for 2 hours and then dimethylformamide (10 ml) was added.
The reaction mixture was allowed to warm to room temperature over 1
hour and the resulting deep red solution was poured into saturated
aqueous ammonium chloride solution (500 ml) and extracted with
diethyl ether (3.times.200 ml). The combined extracts were dried
over magnesium sulphate, and the solvent was evaporated under
reduced pressure to leave a brown oil. Purification by flash column
chromatography on silica eluting with a 9:1 mixture of petroleum
ether (b.p. 40-60.degree. C.) and ethyl acetate afforded
5,6-methylenedioxysalicaldehyde (1.1 g) as a yellow solid.
[0183] A mixture of potassium carbonate (2.8 g),
5,6-methylenedioxysalical- dehyde, prepared by the method given
above, (3.1 g) and (R)-glycidyl tosylate (4.2 g) in
dimethylformamide (85 ml) was stirred and heated at 60.degree. C.
under an atmosphere of nitrogen for 18 hours. The mixture was
poured into water (700 ml) and extracted with diethyl ether
(4.times.300 ml). The combined extracts were washed with brine
(3.times.400 ml), dried over magnesium sulphate and the solvent
evaporated under reduced pressure. The yellow solid residue was
purified by flash column chromatography on silica eluting with a
2:1 mixture of petroleum ether (b.p. 40-60.degree. C.) and ethyl
acetate to give
(R)-2-(2,3-epoxypropoxy)-5,6-methylenedioxybenzaldehyde (1.6 g) as
a pale yellow solid.
[0184] A stirred solution of the product from the previous reaction
(1.5 g) and 3-chloroperoxybenzoic acid (56-87%; 4.3 g) in
dichloromethane (100 ml) was stirred and heated at reflux
temperature for 6.5 hours then left to stand at room temperature
for 72 hours. More 3-chloroperoxybenzoic acid (56-87%; 1 g) was
then added and the solution was heated for a further 2 hours. The
mixture was allowed to cool, washed with saturated aqueous sodium
bicarbonate solution (4.times.400 ml), water (2.times.400 ml),
brine (2.times.400 ml) and dried over magnesium sulphate. The
solvent was evaporated under reduced pressure to afford crude
(R)-2-(2,3-epoxypropoxy)-5,6-methylenedioxyphenyl formate (1 g) as
a red oil.
[0185] Saturated aqueous potassium carbonate solution (13 ml) was
added to a solution of the product from the previous reaction (1 g)
in tetrahydrofuran (16 ml) and the mixture was stirred at room
temperature for 18 hours. The mixture was poured into water (100
ml) and extracted with ethyl acetate (3.times.60 ml). The combined
extracts were dried over magnesium sulphate and the solvent
evaporated under reduced pressure to give a brown oil. Purification
by flash column chromatography on silica eluting with a 2:1 mixture
of petroleum ether (b.p. 40-60.degree.C.) and ethyl acetate
afforded (S)-7,8-methylenedioxy-2,3-dihydro-1,4-benzodioxin-
-2-ylmethanol (0.3 g) as a clear oil.
[0186] A solution of 4-toluenesulphonyl chloride (0.29 g) in
dichloromethane (10 ml) was added dropwise to a stirred solution of
the product from the previous reaction (0.3 g) and
4-dimethylaminopyridine (0.21 g) in dichloromethane (10 ml) at
0-5.degree. C. The mixture was allowed to warm to room temperature
and stirred for 18 hours. The solution was diluted with
dichloromethane (30 ml) and washed successively with water (100
ml), dilute aqueous hydrochloric acid (5M, 3.times.100 ml), brine
(2.times.100 ml) and then dried over magnesium sulphate.
Evaporation of the solvent under reduced pressure gave
(S)-7,8-methylenedioxy-2,3-dihydro-1,4-benzodioxin-2-ylmethyl
4-toluenesulphonate (0.45 g) as a colourless solid.
[0187] A mixture of the product from the previous reaction (0.45
g), potassium carbonate (0.32 g) and
1-[1-(2-methoxyphenyl)piperid-4-yl]methy- lamine (0.51 g) in
dimethylformamide (4.5 ml) and toluene (10 ml) was heated at reflux
temperature for 6 hours, then left to stand at room temperature for
72 hours and then heated at reflux temperature for a further 4
hours. The cooled mixture was poured into water (300 ml) and
extracted with ethyl acetate (3.times.40 ml). The combined organic
extracts were extracted with dilute aqueous hydrochloric acid (5M;
3.times.30 ml) and the combined aqueous extracts basified by the
addition of sodium hydroxide solution (5M). The aqueous phase was
extracted with ethyl acetate (3.times.300 ml), dried over magnesium
sulphate and the solvent removed under reduced pressure to yield a
yellow oil. Purification by flash column chromatography on silica
eluting with a 95:5 mixture of ethyl acetate and methanol afforded
(S)-N-(7,8-methylenedioxy--
2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl-
]methylamine (0.3 g) as a clear oil. Citric acid (0.14 g) in
ethanol (20 ml) was added to a solution of the oil in ethanol (20
ml) and the solvent was removed under reduced pressure to afford
(S)-N-(7,8-methylenedioxy-2,-
3-dihydro-1,4-benzodioxin-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl]m-
ethyl- amine monocitrate (0.3 g) as a fawn solid; m.p
120-22.degree.C., [.alpha.].sub.D-35.9.degree.(c=0.575,MeOH)
EXAMPLE 9
[0188] The use of compounds of the present invention in the
manufacture of pharmaceutical compositions is illustrated by the
following description. In this description the term "active
compound" denotes any compound of the invention but particularly
any compound which is the final product of one of the preceding
Examples.
[0189] a) Capsules
[0190] In the preparation of capsules, 10 parts by weight of active
compound and 240 parts by weight of lactose are de-aggregated and
blended. The mixture is filled into hard gelatin capsules, each
capsule containing a unit dose or part of a unit dose of active
compound.
[0191] b) Tablets
[0192] Tablets are prepared from the following ingredients.
2 Parts by weight Active compound 10 Lactose 190 Maize starch 22
Polyvinylpyrrolidone 10 Magnesium stearate 3
[0193] The active compound, the lactose and some of the starch are
de-aggregated, blended and the resulting mixture is granulated with
a solution of the polyvinyl-pyrrolidone in ethanol. The dry
granulate is blended with the magnesium stearate and the rest of
the starch. The mixture is then compressed in a tabletting machine
to give tablets each containing a unit dose or a part of a unit
dose of active compound.
[0194] c) Enteric coated tablets
[0195] Tablets are prepared by the method described in (b) above.
The tablets are enteric coated in a conventional manner using a
solution of 20% cellulose acetate phthalate and 3% diethyl
phthalate in ethanol:dichloromethane (1:1).
[0196] d) Suppositories
[0197] In the preparation of suppositories, 100 parts by weight of
active compound is incorporated in 1300 parts by weight of
triglyceride suppository base and the mixture formed into
suppositories each containing a therapeutically effective amount of
active ingredient.
* * * * *