Antipsychotic indolyl derivatives

Details Antipsychotic indolyl derivatives Antipsychotic indolyl derivatives

2001-10-12

2004-02-10

Bernhardt, Emily (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S322000, C514S323000, C514S338000, C514S339000, C546S174000, C546S177000, C546S199000, C546S201000, C546S273400, C546S277400, C546S277700

Reexamination Certificate

active

06689792

ABSTRACT:

This invention concerns a series of novel &bgr;-hydroxy aryloxypropylamines which are effective pharmaceuticals for the treatment of conditions related to or affected by the dopamine D2 receptor and also by the serotonin 1A receptor subtype. The compounds are particularly useful for the treatment of schizophrenia and related psychotic disorders and other conditions such as Parkinson's disease and Alzheimer's disease.
BACKGROUND TO THE INVENTION
In their letter to the editor, TINS, Vol. 17, No. 4, 1994, Bowen et al. note that the cognitive impairment characteristics of Alzheimer's disease may be ameliorated by antagonists at the inhibitory 5-HT
1A
receoptor, or by activation of the phospholipase-C-linked cholinergic M
1
receptor.
SUMMARY OF THE PRESENT INVENTION
This invention relates to novel indolyl derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in therapy. The compounds are useful for the treatment of psychotic disorders, particularly schizophrenia, by virtue of their ability to antagonize the dopamine D2 receptor. Furthermore, the present invention also provides compounds that are antagonists and agonists at the 5-HT1A receptor subtype and thus compounds of this invention may be used to treat Alzheimer's Disease, Parkinson's Disease, depression and anxiety.
Compounds of the present invention are represented by the general formula (1):
wherein
R
1
and R
2
are each independently selected from H, OH, F, Cl, Br, I, 1 to 6 carbon alkyl or alkenyl, 1 to 6 carbon alkoxy, aryl, OR
5
, nitro, amino, CF
3
and when R
1
and R
2
are taken together, form a fused ring at the 2,3- or 3,4-positions providing a fused phenyl group or a benzodioxane group, or a 4- or 7-substituted indole group, or a 5- or 8-substituted quinoline group;
the group formed by the fusion of R
1
and R
2
being taken together is further optionally substituted by from 1 to 3 groups selected from H, COOH or the C
1
to C
6
alkyl esters thereof, OH, F, Cl, Br, I, 1 to 6 carbon alkyl or alkenyl, 1 to 6 carbon alkoxy, OR
5
, —C(O)NR
6
R
7
, nitro, amino, or CF
3
;
R
3
represents a group selected from hydrogen, 1 to 6 carbon alkyl, 1 to 4 carbon alkoxy or halogen;
R
4
represents a group selected from hydrogen, 1 to 6 carbon alkyl or R
5
;
R
5
is CH
2
Ph in which the phenyl ring can be optionally substituted by a group selected from OMe, halogen, CF
3
;
R
6
and R
7
are independently selected from H or C
1
to C
6
alkyl;
X is selected from a group represented by CR
4
, CHR
4
and CHCH;
A is selected from a group represented by N, NIH, CH and CH
2
;
B is selected from a group represented by ═O, ═S, H and H
2
;
or A and B may be concatenated together to form indole, benzimidazole, indolone or indoline moieties; or a pharmaceutically acceptable salt thereof.
It will be understood that the type of substitution indicated by B in the generic groups herein will be controlled by whether A is N, NH, CH or CH
2
.
The moieties in which A and B may be concatenated together in formula (1) may be represented by the formula:
which includes moieties selected from the group of:
wherein the substituents indicated by R
3
and R
4
are as defined above.
In the description above, when R
1
and R
2
are taken together to form a fused phenyl group at the 2,3- or 3,4-positions, the two fused phenyl rings are understood to form a napthyl moiety, optionally substituted by from 1 to 3 groups described above.
The description above states the fusion of R
1
and R
2
with their corresponding phenyl ring may form a 4- or 7-substituted indole group, or a 5- or 8-substituted quinoline group. In this description, the 4- or 7-positions indicated for the indole group and 5- or 8-positions indicated for the quinoline group indicate the position at which the relevant indole or quinoline moiety is bound to the remainder of the molecule of Formula (1).
The term “aryl” as used in the definitions of R
1
and R
2
indicates phenyl, benzyl, benzyloxy or pyridine groups, optionally substituted by from 1 to 3 substitutents selected from halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, —S—C
1
-C
6
alkyl, —CN, —OH, —NO
2
or —CF
3
. The most preferred aryl group is phenyl, optionally substituted as just described.
A subset of compounds of this invention includes those of the formula:
wherein
R
1
and R
2
are each independently selected from H, OH, F, Cl, Br, I, 1 to 6 carbon alkyl or alkenyl, 1 to 6 carbon alkoxy, OR
5
, nitro, amino, CF
3
, phenyl, benzyl, benzyloxy or pyridyl, the aromatic rings of which are optionally substituted by from 1 to 3 substitutents selected from halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, —S—C
1
-C
6
alkyl, —CN, —OH, —NO
2
or —CF
3
; or R
1
and R
2
are taken together to form, in conjunction with the phenyl ring to which they are bound, a fused ring at the 2,3- or 3,4-positions providing a fused phenyl group or a benzodioxane group, or a 4- or 7-substituted indole group, or a 5- or 8-substituted quinoline group;
the group formed by the fusion of R
1
and R
2
being taken together is further optionally substituted by from 1 to 3 groups selected from H, COOH or the C
1
to C
6
alkyl esters thereof, OH, F, Cl, Br, I, 1 to 6 carbon alkyl, alkenyl or alkoxy, —C(O)NR
6
R
7
, nitro, amino, or CF
3
;
R
3
represents a group selected from hydrogen, a 1 to 6 carbon alkyl, a 1 to 4 carbon alkoxy or a halogen;
R
4
represents a group selected from hydrogen, 1 to 6 carbon alkyl or R
5
;
R
5
is CH
2
Ph in which the phenyl ring can be optionally substituted by a group selected from OMe, halogen, CF
3
;
R
6
and R
7
are independently selected from H or C
1
to C
6
alkyl;
A is selected from a group represented by N, NH, CH and CH
2
;
B is selected from a group represented by ═O, ═S, H and H
2
;
or A and B may be concatenated together such that the moiety in formula (1) represented by the formula:
is selected from the group of:
or a pharmaceutically acceptable salt thereof.
The pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable inorganic acid such as phosphoric, sulfuric, hydrochloric, hydrobromic citric, maleic, fumaric, acetic, lactic or methanesulfonic acid.


REFERENCES:
patent: 4335126 (1982-06-01), Kleemann et al.
patent: 4737505 (1988-04-01), Guillaume et al.
patent: 5342845 (1994-08-01), Chokai et al.
patent: 5565447 (1996-10-01), Forner et al.
patent: 5607960 (1997-03-01), Wythes
patent: 5607961 (1997-03-01), Cipollina et al.
patent: 5614523 (1997-03-01), Audia et al.
patent: 5639752 (1997-06-01), Macor
patent: 5639772 (1997-06-01), Hammarberg et al.
patent: 5641794 (1997-06-01), Booher et al.
patent: 5654320 (1997-08-01), Catlow et al.
patent: 5654324 (1997-08-01), Booher et al.
patent: 5670511 (1997-09-01), Marz et al.
patent: 5693655 (1997-12-01), Bottcher et al.
patent: 5708008 (1998-01-01), Audia et al.
patent: 5792763 (1998-08-01), Fritz et al.
patent: 9748698 (1997-12-01), None
Gueremy et al., J. Med. Chem, 1980, 23, 1306-1310.
Malleron et al., J. Med. Chem., 1993, 36, 1194-1202.
Bergman, J. Heterocyclic Chem., 1970, 1071-1076.
Guillaume et al., Eur. J. Med. Chem., 1987, 22(1), 33-34.
Cheetham et al., Neuropharmacol. 32: 737, 1993.
Cheng and Prusoff, Biochem. Pharmacol., 22, 3099, 1973.
Bowen et al., TINS, vol. 17, No. 4, 1994.
Freter et al., Arzneim.-Forsch. 35 (1), 272-276, 1985.
Rastogi et al.,J. Med. Chem., 15 (3), 1972, p. 286-91.

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