Indole and indoline derivatives as 5-HT6 selective ligands

Details Indole and indoline derivatives as 5-HT6 selective ligands Indole and indoline derivatives as 5-HT6 selective ligands

1999-09-09

2001-02-13

Lambkin, Deborah C. (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S414000, C514S323000, C514S235200, C514S253030, C548S469000, C548S491000, C548S467000, C546S201000, C544S143000, C544S373000

Reexamination Certificate

active

06187805

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to classes of indole derivatives which bind selectively to 5-HT
6
receptors, and hence are potentially useful in the treatment of a number of clinical conditions believed to be sensitive to the selective agonism or antagonism of the 5-HT
6
receptors. Certain of the compounds are novel.
BACKGROUND OF THE INVENTION
The actions of the neurotransmitter 5-hydroxytryptamine (5-HT) are mediated through a number of receptor families termed 5-HT
1
, 5-HT
2
, 5-HT
3
, 5-HT
4
, 5-HT
5
, 5-HT
6,
and 5-HT
7
(see D. Hoyer et al.,
Pharmacol. Rev.,
1994, 46, 157-204). Although the functions of the 5-HT
5
, 5-HT
6
and 5-HT
7
receptors are less well understood than the functions of the other 5-HT receptors, it is generally accepted that compounds which selectively interfere with 5-HT-mediated signal transduction are important novel drug targets. In particular, 5-HT
6
selective ligands have been identified as potentially useful in the treatment of certain CNS disorders such as Parkinson's disease, Huntingdon's disease, anxiety, depression, manic depression, psychosis, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease (enhancement of cognitive memory), sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. Such compounds are also expected to be of use in the treatment of certain GI (gastrointestinal) disorders such is IBS (Irritable Bowel Syndrome). (See WO98/27058, WO98/27081, Drug News Perspectives, 1997, 10, 214 and A. J. Sleight et al.,
Serotonin ID Research Alert,
1997, 2(3), 115-8).
A wide variety of 5-HT analogues incorporating an indole nucleus have been prepared and tested for pharmacological effects, but hitherto none has been shown to be a selective ligand for 5-HT
6
receptors. WO-A-98/27058 and WO-A-98/27081 disclose, respectively, sulphonamides and carboxamides which are 5-HT
6
receptor antagonists, but none of the compounds disclosed comprises an indole or indoline nucleus. Similarly, certain benzenesulphonamides of non-indole nature are disclosed as selective 5-HT
6
antagonists in EP-A-815861 and in
Br.J.Pharinacol.,
1998, 124, 556-562.
Many analogues of 5-HT are known, comprising a 1-acyl- or 1-arylsulphonyl-3-(2-aminoethyl) indole nucleus (see, for example, U.S. Pat. Nos. 3,481,953 and 3,489,429). Fused-ring analogues, such as trans-4-dimethylamino-1-(4-methylbenzenesulphonyl)-1,3,4,5-tetrahydrobenz[cd]indol-5-ol, are also known (
J.Chem.Soc., Perkin Trans. I,
1973, 438-42). Analogues comprising a 4-(2-N,N-dialkylaminoethyl)indole nucleus, unsubstituted in the 1-position, have been shown to be dopamine agonists (
Eur. J. Med. Chem.,
1991, 26, 473-5;
J. Med. Chem.,
1984, 27, 386-9). However, the 1-substituted derivatives disclosed herein are believed to be novel.
SUMMARY OF THE INVENTION
The present invention, in a first aspect, provides the use of a compound, or a pharmaceutically acceptable salt or prodrug thereof, for the manufacture of a pharmaceutical composition for the treatment and/or prevention of clinical conditions for which selective agonism or antagonism of 5-HT
6
receptors is indicated, said compound being an indole or indoline derivative having a structure in accordance with Formula I, II or III:
wherein
n is 1 or 2;
p is 0,1,2 or 3;
q is 0,1,2,3 or 4;
R
1
and R
2
independently represent hydrogen, C
1-6
alkyl or aryl (C
1-6
)alkyl, or together represent the atoms necessary to complete a heterocycloalkyl group comprising the nitrogen atom to which R
1
and R
2
are attached;
R
3
represents hydrogen, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, aryl(C
1-6
)alkyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl or C
1-6
alkylcarbonyl;
R
4
represents arylsulphonyl, heteroarylsulphonyl, C
1-6
alkylsulphonyl, di(C
1-6
)alkylaminosulphonyl, arylcarbonyl, C
1-6
alkylcarbonyl, heteroarylcarbonyl or C
1-6
alkoxycarbonyl;
each R
5
independently represents hydroxy, C
1-6
alkoxy, aryl(C
1-6
)alkoxy, nitrile or halogen;
R
6
represents hydrogen, hydroxy or C
1-6
alkoxy; and
-A-B- represents —C═C— or —CH—CH—.
Also in its first aspect, the invention further provides a method for the treatment and/or prevention of clinical conditions for which selective agonism or antagonism of 5-HT
6
receptors is indicated comprising administering to a patient in need of such treatment an effective amount of a compound in accordance with Formulae I, II or III, or a pharmaceutically acceptable salt or a prodrug thereof.
Compounds of Formula I wherein n,p, and R
1
-R
5
are defined as before, and salts and prodrugs thereof, are novel and constitute a second aspect of the invention.
In its second aspect, the invention also provides a pharmaceutical composition comprising one or more compounds of Formula I, or pharmaceutically acceptable salts or prodrugs thereof, in association with a pharmaceutically-acceptable carrier.
Also in its second aspect, the invention further provides a compound of Formula I or a pharmaceutically acceptable salt or a prodrug thereof for use in therapy.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of Formulae I-III are selective ligands for 5-HT
6
receptors, having a 5-HT
6
receptor (rat or human) binding affinity (Ki), when measured in cell lines expressing cloned recombinant 5-HT
6
receptors, of less than 1 &mgr;M, typically less than 100 nM, and in preferred embodiments less than 10 nM, and having a selective affinity for 5-HT
6
receptors relative to 5-HT
5
and/or 5-HT
7
receptors of at least 3-fold, typically at least 10-fold, and in preferred embodiments at least 100-fold.
In Formulae I-III, one or more substituents may be present on any alkyl or aryl group represented by any of R
1
-R
5
, or on any alkyl or aryl moiety of a group represented by anyi of R
1
-R
5
. Preferred substituents include C
1-6
alkyl, halogen, hydroxy and C
1-6
alkoxy.
As used herein, the expression “C
1-6
alkyl” includes methyl and ethyl groups, and straight-chained, branched or cyclic propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and tert-butyl. Derived expressions such as “C
1-6
alkoxy”, “C
1-6
alkylthio” and “C
1-6
alkylamino” are to be construed accordingly.
The expression “C
2-6
alkenyl” as used herein refers to straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl, allyl, dimethylallyl and butenyl groups.
The expression “C
2-6
alkynyl” as used herein refers to straight-chained and branched alkynyl groups containing from 2 to 6 carbon atoms. Typical examples include ethynyl and propargyl groups.
Typical aryl groups include phenyl and naphthyl.
The expression “aryl(C
1-6
)alkyl” as used herein includes benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
Suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl groups.
Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.
The term “halogen” as used herein includes fluorine, chlorine, bromine and iodine, especially chlorine or fluorine.
For use in medicine, the salts of the compounds of Formulae I-III will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of Formulae I-III or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of Formulae I-III include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid s

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