CA2116213A1 - Pyrrolo-pyridine derivatives - Google Patents

Abstract

ABSTRACT

PYRROLO-PYRIDINE DERIVATIVES

A class of pyrrolo[2,3-b]pyridine derivatives, substituted at the 3-position by a substituted piperazinylmethyl moiety, are antagonists of dopamine receptor subtypes within the brain, having a selective affinity for the dopamine D4 receptor subtype over other dopamine receptor subtypes, and are accordingly of benefit in the treatment and/or prevention of psychotic disorders such as schizophrenia whilst manifesting fewer side-effects than those associated with classical neuroleptic drugs.

Description

2:~6213 PYE2ROLO--PYRIDINE DERIVATIVE~:

This invention relates to the use of a particular class of heteroaromatic compounds. More particularly, the invention is concerned with the use of substituted pyrrolo[ 2, 3 -b]pyridine derivatives which are antagonists of dopamine receptor subtypes within the brain and are therefore of bene~it in the treatment and/or prevention of psychotic disorders such as schizophrenia.
~ he "dopamine hypothesis" of schizophrenia predicts an increased activity of dopamine neurotransmission in the disease. The hypothesis is supported by early observations that drugs, such as amphetamine, with dopamine agonist or dopamine-releasing properties are capable of eliciting a psychosis indistinguishable from acute paranoid schiæophrenia.
Schizophrenia is a disorder which is conventionally treated with drugs known as neuroleptics.
In the majori~y of cases, the symptoms of schizophrenia can be treated successfully with so-called "classical"
neuroleptic agents such as haloperidol. Classical neuroleptics generally are antagonists at dopamine D2 receptors. The fact that classical neuroleptic drugs have an action on dopamine receptors in the brain thus lends credence to the "dopamine hypothesis" of schizophrenia.
Molecular biological techniques have revealed the existence o~ several subtypes of the dopamine receptor. The dopamine Dl receptor subtype has been shown to oc~ur in at least two discrete forms. Two ~orms of the D2 receptor subtype, and at least one form of the D3 receptor subtype, have also been discovered. More . , ::

2~l6~2~

recently, the D4 (Van Tol et al., Nature (London), 1991, 350, 610) and D5 (Sunahara et al., Nature (London), 1991, 350, 6143 receptor subtypes have been described.
Notwithstanding their beneficial antipsychotic effects, classical neuroleptic agents such as haloperidol are frequently responsible for eliciting acute extrapyramidal symptoms and neuroendocrine disturbances.
These side-effects, which clearly detract from the clinical desirability o~ classical neuroleptics, are lo believed to be attri~utable to D2 receptor blockade in the striatal region of the brain. It is considered (Van Tol et al., supra) that compounds which can interact selectively with the dopamine D4 receptor subtype, whilst having a less-pronounced action at the D2 subtype, might be free from, or at any rate less prone to, the side-effe~ts associated with classical neuroleptics, whilst at the same time maintaining a beneficial level of antipsychotic activity.
The compounds of use in the present invention, being antagonists of dopamine receptor subtypes within the brain, are accordingly of benefit in the treatment and/or prevention of psychotic disorders such as schizophrenia. Moreover, the compounds of use in the invention have a selective affinity for the dopamine D4 receptor subtype over other dopamine receptor subtypes, in particular the D2 subtype, and can therefore be expected to manifest fewer side-effects than those associated with classical neuroleptic drugs.
US Patents 3362956 and 3511~41 describe certain 1-[(heterocyclyl)-lower-alkyl]-4-substituted-piperazines, in which the heterocyclyl moiety represents inter alia a pyrrolo[2,3-b]pyridine group (referred to therein as a 7-azaindole group). These compounds are alleged therein to possess a panoply of depressant actions on the autonomic 2~6~13 nervous system, the cardiovascular system and the skeletal muscular system (including psychomotor depressant, sedative, adrenolytic, rectal temperature lowering, anticonvulsant, blood pressure lowering and heart force increasing activities), and are consequently alleged to be useful as tranquilizers, sedatives, adrenolytic agents, hypothermic agents, anti-convulsants, hypotensive agents and cardiovascular agents. There is, however, no precise suggestion in US Patents 3362956 or 3511841 that the compounds described therein would be of any benefit in the treatment and/or prevention of psychotic disorders such as schizophrenia, still less that in doing so they might be expected to manifest fewer side-effects than those exhibited by classical neuroleptic agents.
The present invention accordingly provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof or a prodrug thereo~:

~ N ~ R2 wherain R represents hydrogen or Cl_6 alkyl;
Rl represents hydrogen, or an optionally substituted Cl_6 alkyl, Cl_6 alkoxy, C2_6 alkenyl, C2_6 alkynyl, aryl, aryl~Cl_6)alkyl, aryloxy(Cl_6)alkyl, :

21~62~3 aryltCl_6)alkoxy, aryl(C2_6)alkenyl, aryl(C2_6)alkynyl, C3_7 heterocycloalkyl(Cl_6)alkyl, heteroaryl, heteroaryl(Cl_6)alkyl, heteroaryl(C2_6)alkenyl or heteroaryl(C2_6)alkynyl group; or Rl represents a straight or branched alkylene chain containing from 1 to 4 carbon atoms, and optionally incorporating an oxygen atom, which links the piperazine moiety to the group R2;
R2 represents an optionally substituted Cl_6 alkyl, C1_6 alkoxy, C2_6 alkenyl, C2_6 alkynyl, aryl, aryl(Cl_6)alkyl, aryloxy(Cl_6~alkyl, aryl~Cl_~)alkoxy, aryl(C2_6)alkenyl, aryl(C2_6)alkynyl, C3_7 heterocycloalkyl(Cl_6)alkyl, heteroaryl, heteroaryl(Cl_6)alkyl, heteroaryl(C2-6)alkenyl or heteroaryl(C2_6)alkynyl group;
R3, R4 and R5 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -ORa, -SRa, -SORa, -SO2Ra, -SO2NRaRb -NRaRb, -NRaCORb, -NRaCO2Rb, -CORa, ~CO2Ra or -CONRaRb; and 2V Ra and Rb independently represent hydrogen, hydrocarbon or a heterocyclic group;
for the manufacture of a medicament for the treatment and~or prevention of psychotic disorders such as schizophrenia.
Also of use in accordance with the present inventisn are the compounds of formula I above wherein is other than a straight or branched alkylene chain containing from 1 to 4 carbon atoms, and optionally incorporating an oxygen atom, which links the piperazine moieky to the group R2; and the remaining substituPnts :
are as defined with reference to formula I above. ~.
For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts.
Other salts may, however, be useful in the preparation of , . , ~ ':,-:;-. '-: : ' '' - -`~ -the compounds of use in the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts o~ the compounds of use in this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of use in the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
Furthermore, where the compounds of use in the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
The term "hydrocarbon" as used herein includes straight-chained, branched and cyclic groups containing up to 18 carbon atoms, suitably up to 15 carbon atoms, and conveniently up to 12 carbon atoms. Suitable hydrocarbon groups include C1_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C3_7 cycloalkyl(Cl_6)alkyl, aryl, aryl(C1_6)alkyl, aryl(C2_6)alkenyl and "~
aryl(C2_6)alkynyl.
The expression "a heterocyclic group" as used herein includes cyclic groups containing up to 18 carbon atoms and at least one heteroatom preferably selected from oxygen, nitrogen and sulphur. The heterocyclic group suitably contains up to 15 carbon atoms and conveniently up to 12 carbon atoms, and is preferably linked through carbon. Examples of suitable heterocyclic groups include C3_7 heterocycloalkyl, C3_7 heterocycloalkyl(Cl_6)alkyl, heteroaryl, i- - : : : , , :
.~ - ::
,: .
: ., ;.
~-21~21~

heteroaryl(Cl_6)alkyl, heteroaryl(C2_6)alkenyl and heteroaryl(C2_6)alkynyl groups.
Suitable alkyl groups within the scope of the term "hydrocarbon" and within the definition of the substituents R, Rl and R2 include straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples include methyl and ethyl group~, and straight-chained or branched propyl and butyl groups.
Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl.
Suitable alkenyl groups within the scope of the term "hydrocarbon" and within the definition of the substituent~ Rl and R2 include straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl and allyl groups.
Suitable alkynyl groups within the scope of the term "hydrocarbon" and within the definition o~ the substituents Rl and R2 include straight-chained and branched alkynyl ~roups containing from 2 to 6 carbon atoms. Typical examples include ethynyl and propargyl groups.
Suitable cycloalkyl groups include groups containing from 3 to 7 carbon atoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl.
Parti¢ular aryl groups within the scope of the ~
term "hydrocarbon" and within the definition of the ~-substituents Rl and R2 include phenyl and naphthyl.
Particular aryl(Cl_6)alkyl groups within the s~ope of the term "hydrocarbon" and within the definition of the substituents Rl and R2 include benzyl, naphthylmethyl, phenethyl and phenylpropyl.
Suitable heterocycloalkyl groups include azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl and tetrahydrofuryl groups.

A particular C~_7 heterocycloalkyl(Cl_6)alkyl group within the scope of the expression "a heterocyclic group" and within the definition of the substituents and R is tetrahydro~urylethyl.
Suitable heteroaryl groups within the scope of the expression "a heterocyclic group" and within the definition of the substituents R1 and R2 include pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, indolyl~ indazolyl, imidazolyl, ben~imidazolyl, oxadiazolyl and thiadia~olyl groups.
Particular heteroaryl(Cl_6)alkyl groups within the scope of the expression "a heterocyclic group" and within the definition of the substituents Rl and R2 include thienylmethyl, pyridylmethyl, pyrimidinylmethyl and pyrazinylmethyl.
The hydrocarbon and heterocyclic groups, as well as the substituents Rl and R2, may in turn be :~
optionally substituted by one or more groups selected from Cl_6 alkyl, adamantyl, phenyl, aryl(Cl_6)alkyl, :
halogen, halolCl_6)alkyl, amino(Cl_6)alkyl, Cl_6 alkylamino(Cl_6)alkyl, di(Cl_6)alkylamino(Cl_6)alkyl, trifluoromethyl, hydroxy, hydroxy(C1_6)alkyl, C1_6 alko~y, Cl_6 alkoxy(Cl_6)alkyl, aryloxy, keto, Cl_3 alkylenedioxy, nitro, cyano, carboxy, C2_6 alkoxycarbonyl, C2_6 alkoxycarbonyl(Cl_6)alkyl, C2_6 alkylca~bonyloxy, arylcarbonyloxy, C2_6 alkylcarbonyl, arylcarbonyl, C1_6 alkylthio, Cl_6 alkylsulphinyl, Cl_6 alkylsulphonyl, arylsulphonyl, trifluoromethane-sulphonyloxy, -NRVRw, -NRVCORw, -NRVCO2Rw, -NRVSO2Rw, -CH2NRVS02RW, -NHCONRVRw, -PO(ORV)(ORW3, -CONRVRW, : -S02NRVRw and -CH2S02NRVRw, in which RY and Rw independently represent hydrogPn, Cl_6 alkyl, aryl or aryl(Cl_6)alkyl.

2~6213 The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine~ especially chlorine.
The present invention includes within its scope the use of prodrugs of the compounds of formula I above.
In general, such prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in vivo into the required compound of formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H.
Bundgaard, Elsevier, 1985.
h~here the compounds of use in the invention have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the compounds of use in the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that the use of all such isomers and mixtures thereof is encompassed within the scope of the present invention.
Suitably, the substituent ~ represents hydrogen or methyl, especially hydrogen.
Suitably, the substituent R1 represents hydrogen, fluoro or chloro, especially hydrogen.
When Rl represents a straight or branched alkylene chain containing from 1 to 4 carbon atoms, and optionally incorporating an oxygen atom, which links the piperazine moiety to the group R2, this is suitably a methylene, ethylene or oxamethylene chain.
3-0 Suitable values for the substituent R2 include Cl_6 alkyl, aryl, aryl(C1_6)alkyl, aryloxy(Cl_6)alkyl and heteroaryl, any of which groups may be optionally substituted. Examples of optional substituents on the group R2 include Cl_6 alkyl, halogen, trifluoromethyl, ~` ~

2ll~2l3 - g - T1232Y

hydroxy, hydroxy(Cl_6)alkyl, C1_6 alkoxy, C1_6 alkXY(C1-6)alkYl, C1_3 alkylenedioxy, carboxy, C2_6 alkoxycarbonyl, nitro, Cl_6 alkylamino, di(C1_6)alkylamino, C1_6 alkylamino(Cl_6)alkyl and di(C1_6)alkylamino(Cl_6)alkyl.
Particular values of R2 include methyl, ethyl, n-propyl, isopropyl, phenyl, methylphenyl, ethylphenyl, fluorophenyl, chlorophenyl, dichlorophenyl, bromophenyl, iodophenyl, trifluoromethyl-phenyl, hydroxyphenyl, hydroxymethyl-phenyl, methoxyphenyl, ethoxyphenyl, methoxymethyl-phenyl, methylenadioxy-phenyl, carboxyphenyl, methoxycarbonyl-phenyl, ethoxycarbonyl-phenyl, nitrophenyl, dimethylamino-phenyl, dimethylaminomethyl-phenyl, benzyl, chlorobenzyl, phenethyl, phenoxy-ethyl, methylpyridyl, chloropyridyl, isoquinolyl, indolyl, methylindolyl, inda~olyl and benzthienyl. `~`
Suitable values for the substituents R3, R4 and R5 include hydrogen, halogen, cyano, nitro, trifluoromethyl, amino, Cl_6 alkylamino, di(Cl_6)alkylamino, C1_6 alkyl, Cl_6 alkoxy, aryl(Cl_6)alkoxy and C~-6 alkylcarbonyl. Particular values include hydrogen, fluoro, chloro, methyl, methoxy and benzyloxy.
A particular sub-class of compounds of use in the invention is represented by the compounds of formula IIA, and pharmaceutically acceptable salts thereof and prodrugs thereof:

:, : . . -: -::

, 2~62l3 /----\N--~CH2)n~R17 ~ N

N
Rl (IIA) wherein n is zero, 1, 2 or 3;
R10 represents hydrogen or methyl, especially hydroqen;
R13 represents hydrogen, halogen, cyano, nitro, trifluoromethyl, amino, Cl_6 alkylamino, di(Cl_6)alkylamino, Cl_6 alkyl, C1_6 alkoxy, aryl(Cl 6)alkoxy or C2_6 alkylcarbonyl; and R17 represents hydrogen, Cl_6 alkyl, halogen, -~.
trifluoromethyl, hydroxy, hydroxy(Cl_6)alkyl, Cl_6 alkoxy, aryl~Cl_6)alkoxy, Cl_6 alkoxy(Cl_6)alkyl, carboxy, C2_6 alkoxycarbonyl, C2_6 alkylcarbonyl, cyano, nitro, amino, C1_6 alkylamino, di(Cl 6)alkylamino, :~ -; amino(C1_6)alkyl, C1_6 alkylamino(C1_6)alkyl sr : 25 di(Cl_6)alkylamino(C1_6)alkyl.
Particular values of R13 include hydrogen, fluoro, chloro, methyl, ethyl, methoxy and benzyloxy, especially hydrogen.
Particular values of R17 include hydrogen, methyl, ethyl, fluoro, chloro, bromo, iodo, trifluoromethyl, hydroxy, hydroxymethyl, methoxy, ethoxy, methoxymethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, nitro, dimethylamino and dimethylaminomethyl.

2~2l~

~ T1232Y

Another ~ub-class of compounds of use in the invention is represented by the compounds of formula IIB, and pharmaceutically acceptable salts thereof and prodrugs thereof:

/--\N--( CH2)m-0~R 1 7 ~N~J

N
R 1 0 . . .

(I 1~) :
wherein m is 1, 2 or 3; and R10, R13 and R17 are as defined with reference to formula IIA above.
A further sub-class of compounds of use in the invention is represented by the compounds of formula IIC, and pharmaceutically acceptable salts thereof and prodrugs thereof:

N - (CH2)n-w ~ N

Rl3 ~

\R10 (IlC) wherein .... ~ ,. . . ..

;:. : : , : . . .:: :: .. , 2~62~

n, RlO and R13 are as defined with reference to formula IIA above; and W represents a group of formula (i), (ii), (iii) or (iv):

R~7 R17 ~ ~ ' ( i) (T i) ( i I i ) ( i V ) in which V represents nitrogen or CH;
~17 is as d~fined with reference to formula IIA
above;
R18 represents hydrogen or methyl; and R27 represents Cl_6 alkyl, halogen, trifluoromethyl, Cl_6 alkoxy, cyano, nitro, amino, Cl_6 alkylamino or di(C1_6)alkylamino.
Suitably, R27 is C1_6 alkyl or halogen, especially methyl or chloro.
A still further sub-class of compounds of use in the invention is represented by the compounds of formula IID, and pharmaceutically acceptable salts thereof and prodrugs thereof:

21~6~

Rl~ t~? x Y

R 1 o ( I ID) wherein X represents a group of formula -CH2- or -CH2CH2-;
Y represents a chemical bond or an oxygen atom;
and R10, R13 and R17 are as defined with referenc~
to formula IIA above.
Certain compounds falling within the scope of formula I above are novel. Particular sub-classes of novel compounds in accordance with the present invention comprise the rompounds of formula IIB, IIC and IID as defined above, and salts and prodrugs thereof. A
discrete sub-class of novel compounds according to the invention having particularly advantageous properties as selective antagonists of the dopamine D~ receptor subtype relative to the D2 subtype, and hence as agents for the treatment and~or prevention of psychotic disorders such as schizophrenia which manifest fewer side-effects than those associated with classical neuroleptic drugs, comprises the compounds of formula IIE, and salts and prodrugs thereof:

:`
~62:~

N - ~ -R3 N ~
1"'~

( I IE) ~-wherein R13 is as defined with reference to formula IIA
above; and R37 represents fluoro, chloro, bromo, iodo or trifluoromethyl.
The invention further provides a novel compound selected from the following:
3-(4-phenylpiperazin-1-yl~methyl-lH-pyrrolo[2,3-b]-pyridine;
3-[4-(4-methoxyphenyl)piperazin-1-yl]methyl-lH-pyrrolo[2,3-b ? pyridine;
3-(4-benzylpiperazin-1-yl)methyl-lH-pyrrolo[2,3-b]-pyridine;
3-[4-(4-ethylphenyl)piperazin-1-yl]methyl-lH-pyrrolo[2,3-b]pyridine;3-[4-(4-chlorophenyl)piperazin-1-yl]methyl-lH-pyrrolo[2,3-b]pyridine;
3-[4-(4-ethoxyphenyl)piperazin-1-yl]methyl-lH-pyrrolo[2,3-b]pyridine;
3-[4-(4 dimethylaminophenyl)piperazin-1-yl]methyl-lH-pyrrolo[2,3-b]pyridine;
3-[4-(3,4-dichlorophenyl)piperazin-1-yl]methyl-lH-pyrrolo[2,3-b]pyridine, 21~2~ 3 3-[4-(4-methoxyphenyl)piperazin-1-yl]methyl-1-methyl-lH-pyrrolo[2,3-b~pyridine;
3-[4-(5-chloxopyrid-2-yl)piperazin~ yl]methyl-lH-pyrrolo[2,3-b]pyridine;
3-[4-(3-isoquinolyl)piperazin-1-yl]methyl-lH-pyrrolo[2,3-b~pyridine;
3-[4-(5-indolyl)piperazin-1-yl]methyl-lH-pyrrolo[2,3-b]pyridine;
3-[4-(4-iodophenyl)piperazin-1-yl]methyl-lH-pyrrolo[2,3-b]pyridine;
3-[4-(4-trifluoromethylphanyl)piperazin-1-yl]methyl-lH-pyrrolo[2,3-b]pyridine;
3-[4-(2-phenoxyethyl)piperazin-1-yl]methyl-lH~
pyrrolo[2,3-h]pyridine;
3-[4-(4-methylphenyl)piperazin-1-yl]methyl-lH-pyrrolo[2,3-b]pyridine;
3-[4-(4-fluorophenyl)piperazin-1-yl]methyl-lH-pyrrolo[2,3-b]pyridine;
3-[4-(1-methylindol-5-yl)piperazin-1-yl]methyl-lH-pyrrolo[2,3-b]pyridine;
3-[4-(indazol-5-yl)piperazin-1-yl]methyl-lH-pyrrolo~2,3-b]pyridine;
3-[4-(4-ethoxycarbonylphenyl)piperazin-1-yl]methyl-lH-pyrrolo[2 ! 3-b]pyridine;
3-[4-(4~carboxyphenyl)piperazin-1-yl]methyl-lH-pyrrolo[2,3-b]pyridine;
3-[4-(3-methylphenyl~piperazin-1-yl]methyl-lH-pyrrolo[2,3-b]pyridine;
3-[4-(2-methylphenyl)piperazin-1-yl]methyl-lH-pyrrolo[2,3-b]pyridine;
3-~4-(3,4-methylenedioxyphenyl)piperazin-1-yl]methyl-lH-pyrrolo[2,3-b]pyridine;
3-[4-(4-bromophenyl)piperazin-1-yl]methyl-lH-pyrrolo[2,3-b]pyridine; ..

.. , ~, . ~ . . - - .

- . . - . - -2~62~3 ~

3-[4-~4-methoxycarbonylphenyl)piperazin-1-yl]methyl-lH-pyrrolo~2,3-b]pyridine;
3-~4-(4-hydroxymethylphenyl3piperazin-~-yl]methyl-lH-pyrrolo[2,3-b]pyridine;
3-[4-(5-methylpyrid-2-yl~piperazin-1-yl~methyl-lH-pyrrolo[2,3-b]pyridine;
3-[4-(4-hydroxyphenyl)piperazin-1-yl]methyl-lH-pyrrolo r 2,3-b]pyridine;
3-[4-(benzothiophen-2-yl)piperazin-1-yl]methyl-lH-pyrrolo[2,3-b]pyridine;
3-[4-(benzothiophsn-3-yl)piperazin-1-yl]methyl-lH-pyrrolo[2,3-b]pyridine;
3-~(lH-pyrrolot2,3-b]pyridin-3-yl~methyl]-2,3,4,4a,5,6-hexahydro-l(H)-pyrazino[1,2-a]quinoline;
8-chloro-3-[(lH-pyrroloC2,3-b]pyridin-3-yl)methyl]-2,3,4,4a,5,6-hexahydro-l(H)-pyrazino[1,2-a]quinoline;
8-chloro-3-[(lH-pyrrolo[2,3-b]pyridin-3-yl)methyl]-2,3,4,4a,5,6-hexahydro-l(H)-pyrazino[2,1-c]-1,4-benzoxazine;
3-[4-(4-methoxymethylphenyl)pipera in-l-yl]methyl-lH-pyrrolo[2,3-b]pyridine;
3-[4-(4-dimethylaminomethylphenyl)piperazin-1-yl]methyl-lH-pyrrolo[2,3-b]pyridine;
3-(1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-2-yl)methyl-lH-pyrrolo[2,3-b)pyridine;
and salts and prodrugs thereof.
The invention also provides pharmaceutical compositions comprising one or more of the novel compounds according to the invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or . .

21~ 2~ ~

suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
Alternatively, the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage compcnent, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in : : . ~ - :

. .

2~

the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A
variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersiny or suspending agents for aqu~ous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
In the treatment of schizophrenia, a suitable dosage level is about 0.01 to ~50 mg/kg per day, preferably about 0005 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day.
The compounds of formula I above, including the novel compounds according to the present invention, may be prepared by a process which comprises reacting a compound of formula III with a compound of formula IV:

- - . : .~: -:

- \

2 ~ 3 R~ I
'T' ~ H-N N-R2 R5/~N/J--N~

(III) (IV) wherein Rl, R2, R3, R4 and R5 are as dafined above, and RP corresponds to the group R as defined above or represents a suitable protecting group; in the presence of a substantially equimolar amount of ~ormaldehyde;

followed, where required, by removal of the protecting group RP; and subsequently, if necessary, N-alkylation by standard methods to introduce the moiety R.

The reaction is conveniently carried out by stirring the reactants in aqueous acetic acid, ideally in the presence of a buffer such as sodium acetate trihydrate, suitably at room temperature.

The formaldehyde may be utilised in the form of paraformaldehyde; or as a solution of formaldehyde in an inert solvent, e.g. 37~ aqueous formaldehyde.

The protecting group RP, when present, is suitably an acyl moiety such as acetyl, which can conveniently be rèmoved as necessary by treatment under strongly basic conditions, e.g. sodium methoxide in methanol. Alternatively, the protecting group RP may be a carbamoyl moiety such as t-butoxycarbonyl (BOC), which can conveniently be removed as necessary by treatment -under mildly acidic conditions.

21~213 In an alternative procedure, the compounds of formula I above, including the novel compounds according to the present invention, may be prepared by a process which comprises reacting a compound of formula IV as defined above with a compound of formula V~

R

R N
R P

(V~
wherein R3, R4, R5 and RP are as defined above, and L
represents a suitable leaving group; followed, where required, by removal of the protecting group RP; and subsequently, if necessary, N-alkylation by standard methods to introduce the moiety R.
The leaving group L is suitably a halogen atom, e.g. chlorine or bromine; or a dialkylamino group, e~g.
dimethylamino.
When L represents a halogen atom, the reaction between compounds IV and V is conveniently carried out by ~5 ~tirring the reactants under basic conditions in a suitable solvent, for example potassium carbonate in N,N-dimethylformamide, or triethylamine in tetrahydrofuran or acetonitrile. Where L represents a dialkylamino group, the reaction is conveniently effected by heating the reactants in an inert solvent such as toluene, typically at the reflux temperature of the solvent.
Whexe they are not commercially available, the starting materials of formula III, IV and V may be prepared by procedures analogous to those described in 211~2~l3 the accompanying Examples, or by standard methods well known ~rom the art.
It will be appreciated that any compound of formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further desired compound of formula I
using techniques known from the art. For example, a compound of formula I wherein R is hydrogen initially obtained may be converted into a compound of formula I
wherein R represents Cl_6 alkyl by standard alkylation techniques, such as by treatment with an alkyl iodide, e.g. methyl iodide, typically under basic conditions, e.g. sodium hydride in dimethylformamide, or triethylamine in acetonitrila. Moreover, a compound of formula I wherein the R2 moiety is substituted by carboxy may be obtained from the corresponding alkyl ester derivative initially obtained by conventional deesterification procedures, typically by treatment with a base such as sodium hydroxide in a lower alkanol such as ethanol. Similarly, a compound of formula I wherein the R2 moiety is substituted by an alkyl ester or carboxamide moiety initially obtained may be converted into the corresponding hydroxymethyl or aminomethyl derivative respectively by reduction with an appropriate reducing agent, e.g. diisobutylaluminium hydride or lithium aluminium hydride.
Where the above-described processes for the preparation of the compounds of use in the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their .- . ... . ... - . . ..

21~213 - 22 ~ T1232Y

component enantiomers by standard techniques such as preparative HPLC, or the formation of diasteraomeric pairs by salt formation with an optically activa acid, such as ~ di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base. Tha compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973;
and T.W. Greene & P.G.M. Wuts, Protective Groups in organic Synthesis, John Wiley ~ Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The followin~ Examples illustrate the preparation of compounds according to the invention.
The compounds useful in this invention potently inhibit [3H~-spiperone binding to human dopamine D4 receptor subtypes expressed in clonal cell lines.

[ H]-Spiperone Binding Studies Clonal cell lines expressing the human dopamine D4 receptor subtype were harvested in PBS and then lysed in 10 mM Tris-HCl pH 7.4 buffer containing 5 mM MgS04 for 20 min on ice. Membranes were centrifuged at 50,000g for 15 min at 4C and the resulting pellets resuspended in assay buffer (50 mM Tris-HCl pH 7.4 containing 5 mM EDTA, : ~ `

2II~2~ 3 - 23 - Tl232Y

1.5 mM CaCl~, 5 mM MgCl2, 5 mM KCl, 120 mM NaCl, and 0.1%
ascorbic acid) at 20 mg/ml wet weight. Incubations were carried out for 60 min at room temperature (22C~ in the presence of 0.05 2 nM [3H]-spiperone or 0.2 nM for displacemant studies and were initiated by addition of 20-lO0 ~g protein in a final assay volume of 0.5 ml. The incubation was terminated by rapid filtration over GF/B
filters presoaked in 0.3% PEI and washed with 10 ml ice-cold 50 mM Tris-HCl, pH 7.4. Specific binding was determined by 10 ~M apomorphine and radioactivity determined by counting in a LKB beta counter. Binding parameters were determined by non-linear least squares .
regression analysis, from which the inhibition constant Ki could be calculated for each test compound.
The compounds of the accompanying Examples were tested in the above assay, and all were found ko possess a Ki value for displacement of [3H]-spiperone from the human dopamine D4 receptor subtype of below 1.5 ~M.

:

f J~

3-(4-Phenylpi~er~7,in-l-Yl3mçthvl-lH-p~v rolQr2~-121l2vridine 1-Phenylpiperazine (1.63g, 10.0mmol), and sodium acetate trihydrate (1.36g, 10mmol) were dissolved in acetic acid (4ml) 6 and water (2ml3. 37% Aqueous formaldehyde (0.9ml, 12mmol) wa~ addsd and the reaction mixture stir~ed for ~ve ~nin~tes.
1H-Pyrrolo[2,3-b]pyridine (1.18g, 10mmol) was added, and the resulting solution stirred at roorn temperature overnight. The reaction mixture was poured into 2M sodium hydro~ide solution (60ml) and extracted with ethyl acetate (2 ~ 50ml). The e~tracts were washed with brine (50ml), combined and dried (MgSO4).
The ethyl acetate solution was concentrated in vacuo to about one quarter of the original volume and the precipitated yellow solid was collected by filtration and recrystallised ~om toluene to yield the ti~le compound (1.20g), as pale lemon crystals. This mate~al was filr~her recrystallised firom methanol to give pale lemon needles, m.p. 207-209C; (Found: C, 73.91; H, 7.09; N, 19.31. ~l8H20N4 reqtures C, 73.94; H, 6.90; N, 19.16%); SH
(DMSO-dfi) 2.53 (4H, t, J 6Hz, 2 x CH2N), 3.10 (4H, t, J 5Hz, 2 x CH2N), 3.68 (2H, s, indole-CH2N), 6.75 (lH, t, J 7Hz, 4 -E), 6.89 (2H, d, J 8Hz, 2 -H, 6'-H), 7.04 (lH, dd, J 8, 4.6Hz, 5-H), 7.18 (2H, t, J 8Hz, 3 -H, 5 -H), 8.05 (lH, dd, J 8, 1.~Hz, 4-H), 8.19 (lH, dd, J 4.5, 1.6Hz, 6-H), and 11.45 (lH, br s, NH); m/z (CI~, NH3) 293 (M~l)+.

Prepared in an analogous manner were:

.' ~., :' '. ' .. `: :?':. '.

2~ ~62~3 E~AMPLE 2 3-(4-r4-Me~a~xyphenvllpiper~,y~=~
r2~ 2vridin~
M.p. 213-214C (PhMe); (Found: C, 70.84; H, 6.7~; N, 17.14.
Cl9H22N40 req~ures C, 70.78; H, 6.88; N, 17.38%); ~H (DMSO-d6) 2.49-2.~3 (4H, m, 2 x piperazinyl CH2), 2.98 (4H, m, 2 ~ piperazinyl CH2), 3.66-3.67 (5H, m, CH2 ~ OC~3~, 6.77-6.86 (4H, m, ArH), 7.04 (lH, dd, J 7.9, 4.6Hz, ~-H), 7.37 (lH, d, J 1.6Hz, ArH), 8.04 (lEI, dd, J 7.9, 1.5Hz, 4-H), 8.1g (lH, dd, J 4.6,1.5Hz, 6-H), and 11.46 (lH, 10 br s, ~); m/z (CI+, NH3) 323 (M~l)+.

,~-(4-Benzvlpipera3in-l-yl~methyl-lH~yrrolor2,~-blpYridine M.p. 153C (MeOH); (Found: C, 74.35; H, 7.03; N, lB.17.
ClgH22N4 requires C, 74.48; H, 7.24; N, 18.29%); ~H (DMS-2.36 (8H, br s, 4 x CH2), 3.42 (2H, s, CH2), 3.60 (2H, s, CH2), 7.01 (lH, dd, J 7.8, 4.6Hz, 5-H), 7.19-7.31 (6H, m, ArH), 8.01 (lH, dd, J 7.8, 1.6Hz, 4-H), 8.17 (lH, dd, J 4.6, 1.6Hz, 6-H), and 11.41 (lH, br s, NH); m/z (CI+, NH3) 307 (M+l).

3-!4-~4-EthvlphenvllpipQazin-l-y,l)methYl-lH~rolo r2 ~3-blpvridine M.p. 216-217C (MeOH); (Found: C, 76.32; H, 7.36; N, 17.59.
2~ C20H24N4 requires C, 74.97; H, 7.5~; N, 17.48%); ~ (DMSO-d6) 1.12 (3H, t, J 7.6Hz, ArCH2CH3), 2.60 (6H, m, ArCH2CH3 and 2 x = . . ... . . . - - . .................................. . .

~, . . . ~ - ~ - .
. .: ~ :

2~21 ~

piperazinyl CH2), 3.06 (4H, m, 2 x piperazinyl CEI2~, 3.67 (2H, ~, N-C~2Ar), 6.81 (2H, d, J 8.6Hz, ArH), 7.03 (3H, m, ArH), 7.37 (lH, d, J 2.2Hz, 2-H), 8.05 (lH, dd, J 7.8, 1.4Hz, 4-E), 8.19 (lH, dd, J 4.6, 1.4H7. 6-H), and 11.47 (lH, br s, NH); m/z (CI+, NH3) 321 (M+1)+.
EXAMPLE ~i 3-(4-r4-Chlorophenvllpiperazin-l-vl)methvl-lH-pvrrolo r2!3-hlpv~dine M.p. 226-227C (MeOH); (Found: C, 66.77; H, 5.78; N, 17.26.
Cl8HlgN4Cl requires C, 66.15; H, ~i.86; N, 17.14%); ~H (DM~O-d6) 2.63 (4H, m, 2 x piperazinyl CH~), 3.10 (4H, m, 2 g piperazinyl CH2), 3.67 (2H, s, CH2-N), 6.90 (2H, d, J 9.0~Iz, ArH), 7.03 (lH, dd, J 7.8, 4.6Hz, !i-H~, 7.19 (2H, d, J 9.0Hz, ArH), 7.37 (lH, d, J 2.4Hz, 2-H), 8.04 (lH, dd, J 7.8, 1.6Hz, 4-H), 8.19 (lH, dd, J 4.6, 1.6Hz, 6-H), and 11.47 (lH, br s, NH); m/z (CI+, NH3) 327 (M+1)+.

EXAMPLE ~

3-(4-r4-Ethoxvphenvllpiper~zin-l-vl)methYl-lH-pvrrolor2.3-~1 Dvridine Step 1: 1-(tert-Butoxvcarbonvl)-4-(4-hvdroxvphenvl)piperazine Di-tert-butyl dicarbonate (3.13g, 14.3mmol) was added to a suspension of 1-(4-hydroxyphenyl)piperazine (2.40g, 13.~mmol) in dichloromethane (~0ml) and the mixture stirred overnight at room temperature. The reaction mixture was filtered and the filtrate evaporated. Trituration with diethyl ether gave 1-(tert-, - . -- - :

27 21 ~ 6 2 ~ 3 T1232Y
butoxycarbonyl)-4-(4-hydroxyphenyl)piperazine as a buff solid (2.76g, 74%); oH(CDCl3) 1.48 (9H, s, C((~H3)3), 2.9g (4H, m, 2 x piperazinyl CH2), 3.~8 (4H, m, 2 x piperazinyl CH2), ~.18 (lH, br s, ArOH), 6.77 ~2H, m, ArH), and 6.8~ (2H, m, ArH).

Step 2~ -Ethoxy~henvl)pi~erazin~

Bromoethane (0.48ml, 6.43mmol) was added to a mixture of 1-(tert-butoxycarbonyl)-4-(4-hydroxyphenyl)piperazine (1.64g, ~.89mmol) and potassium carbonate (0.9Og, 6.51mmol) in dimethylfiormamide (15ml). The reaetion mixture was s-tirred overnig~t and then more potassium carbonate (1.63g, 11.8mmol) and bromoethane (0.48ml, 6.43mmol) was added. The mixture was stirred at room temperature os7ernight, poured into water (160ml) 16 and extracted with ethyl acetate (2 x 1ûOml). The extracts were washed wi~h brine (1OOml), combined, and dried ~MgSO4).
Evaporation of the solvent gave a buffsolid (1.71g). This was dissolved in dichloromethane (~Oml), tri~uoroacetic acid (~.Oml) added and the reaction mixture stirred at room temperature llnder 20 nitrogen for 30 minutes. The mixture was concentrated in vacuo, the residue dissolved in lM hydrochloric acid (~Oml) and washed wi~h dichloromethane (2 x 26ml). The aqueous phase was basified with 4M sodium hydroxide (3ûml) and ext~acted with e~hyl acetate (~ ~ 50ml). The extracts were washed with brine ~Oml), combined, 25 dried (MgSO4) and concentrated in vacuo to give 1-(4-ethoxyphenyl) piperazine (1.03g, 89%) as a beige solid; ~H (CDCl3) 1.38 (3H, t, J 7.0Hz, ArCH2~3), 1.84 (lH, br s, NH), 3.04 (8H, s, 4 x piperazinyl CH2), 3.98 (2H, q, d 7.0Hz, Ar~;~CH3), and 6.82-6.91 (4H, m, ArH).

. - .. . ~ . ... ~

~1~6213 Step 3: 3-(4-r~-13thoxyphenYll~iperazin-l-yl)mQthyl-1H-l?Vrrolor2^3-~J~2yridine A mixture of 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine [pr0pared by the method of M.M. P~obison and B.L. Robison, J Am. Chem. Soc., 1955, 77, 457] (0.40g9 2.28mmol) and 1-(4-e~oxyphenyl)piperazine (0.495g, 2.40~nol) in toluene (10ml) was heated at reflu~ under nitrogen for 7h. The mi~ture was allowed to cool and the crystallised product collected. Recrystallisation from methanol af~orded the ~itle compound (0.513g, 67%), m.p. 179-180C; (Found: C, 71.27; H, 7.19; N, 16.59. C20H24N4O reqwres C, 71.40; H, 7.19; N, 16.6~%); ~H (DMSO-d6) 1.27 (3H, t, J 7.0Hz, ArOCH2~3), 2.62 (4H, m, 2 x piperazinyl CH2), 2.98 (4H, m, 2 x piperazinyl CH2), 3.67 (2H, s, CH2N), 3.92 (2H, q, J 7.0Hz, ArOCH2CH3), 6.80 (4H, m, ArH), 7.04 (lH, dd, J 7.8, 4.6Hz, ~-H), 7.37 (lH, d, J 2.1Hz, 2-H), 8.04 (lH, dd, J 7.8, 1.3Hz, 4-H), 8.19 (lH, dd, J 4.6, 1.3Hz, 6-H), and 11.46 (lH, br s, ~H); m/z (CI~, NH3) 337 (M+1)+.

3-(4-~4-Di.mQthvlamino~henYllpiperazin-l-vl2,methyl-lH-I!YrrO]Or2 ~$-bl~vridine ., Step 1: 1-(te~-Butoxyçarbonvl~4-(4-dimethvlaminophenvl)piperazine Di-tert-butyl dicarbonate (3.11g, 14.2mmol) was added to a solution of 1-(4-nitrophenyl)pipera~ine (2.96g, 14.3mmol) in dichloromethane (lOOml). The resulting solution was stirred for 3h at room temperature 30 and then concentrated in vacuo to a yellow solid (4.37g). The solid was dissolved in ethanol (200ml), a 37% aqueous solution of formaldehyde 2 ~ 2 1 3 (3.2ml, 43mmol) and 10% palladium on carbon (0.40g) were added and the mixture hydrogenated on a Palr apparatus tmaxim~un 60psi) for 8h.
Further portions of aqueous formaldehyde (1.Oml) and 10% palladillm on carbon (O.lOg) were added and the reaction mixture hydrogenated ovemight. This procedure was repeated to ensure complete formation of the desired product. The reaction mi~ture wa~ filtered and the filtrate concent~ated to an oil which was treated with silica gel in ethyl acetate.
The mixture was iLSltered and concentrated $o give 1-(tert-butoxycar~onyl)-4-(4-dimethylaminoph~nyl)piperazine (4.26g, 98%) as an o~-white crystalline solid; ~iH (DMSO-d6) 1.41 (9H, s, C(CH3)3), 2.78 (6H, 6, N(CH3)2), 2.89 ~4H9 m, 2 x piperazinyl CH2), 3.44 (4H, m, 2 x piperazinyl CH2), 8.68 (2~, m, ArH), and 6.84 (2H, m, ArH).

Step 2: 1-(4-Dimethvlaminophenvl)lpi}2~razine Trilquoroacetic acid (lOml) was added to a solution of 1-(tert-butoxycarbonyl)-4-(4-dime~hylaminophenyl)piperazine (2.01g 6.68mn ol) in dichloromethane (2Qml) and the mi~ture stirred for 30 min at room temperature. The mixture was concentrated in vacuo and saturated 20 aqueous potassium carbonate (1OOml) was cautiou~ly added to the residue. The mixture was extracted with dichloromethane (3 x 100ml), the extracts were washed with brine (50ml), combined and dried (MgSO4).
Concentration of the e~tracts gave 1-(4-dim~thylaminophenyl)piperazine (1.14g, 84~o) as a cream solid; ~H (DMSO-d6) 2.77 (6H, s, N(CH3)2), 2.79 2~ (4H, m~ 2 x piperazinyl CH2), 2.86 (4H, m, 2 x piperazinyl CH2), 6.68 (2H,m, Ar~ nd 6.82 (2H, m, ArH).

-.. ~ . . : ~ - . . -.~ ... .... .,, .. ........ ... , . . i ... . . .

Step 3: 3-(~-L4-DimethvlaminophenYllpiper~zin-1-vl~methvl-lH-~rolor2 ~-bl~Q

A mixture of 3-dimethylaminomethyl-lH-pyrrolo[2,3-b]pyridine (0.4450g, 2.~4~nol) and 1-(4-d;methylaminophenyl)piperazine (0.5~g, 2.68mmol) in toluene (20ml) was hea~d at reflux under nitrogen for 7h.
The mixture was allowed to cool and the solid formed was collected.
Recrystallisation fi om met~anol gave the ti~le compound (0.382g, 45%) as colourless Ileedles, m.p. 199-201C; (Found: C, 71.32; H, 7.37;
N, 20.71. C2oH26N6 requires C, 71.61; H, 7.51; N, 20.88%); ~H (DMSO-dô) 2.62 (4H, m, 2 x piperazinyl CH2), 2.76 (6H, s, N(CH3)g), 2.9~ (4H, m, 2 x piperazinyl CH2), 3.67 (2H, s, CH2N), 6.66 (2H, m, ArH), 6.80 (2H, m, ArH), 7.03 (lH, dd, J 7.8, 4.7Hz), 7.35 (lH, d, J 2.0Hz, 2-H), 8.04 (lH, dd, J 7.8, 1.5Hz, 9~-H), 8.19 (lH, dd, J 4.7, 1.5Hz, 6-H), and 11.41 (lH, br s, NH); m/z (CI+, NH3) 336 (M~1)+.

EXAMPLE

3-(4-r3,4-DiçhlQrop,h~l~ç~zin-l-vl)methvl-lH-pvrrolo r2~3-bl~ridin~

M.p. 219-220C (MeOH); (Found: C, 60.0~; H, 5.18; N, 15.32. Cl8Hl8Cl2N4 requires C, ~9.84; H9 5.02; N, 1~.51%); ~H
(DMSO-d6) 2.60 (4~I, m, 2 x piperazinyl CH2), 3.15 (4H, m, 2 x 26 piperazinyl CH2), 3.67 (2H, s, CH2N), 6.89 (lH, dd, J 2.9,9.0Hz, 6'-H), 7.04 (lH, dd, J 7.8, 4.7Hz, 5-H), 7.09 (lH, d, J 2.9Hz, 2'-H), 7.36 (2H, m, 2-H, 5'-H), 8.0~ (lH, dd, J 7.8, 1.5Hz, 4-H), 8.20 (lH, dd, J 4.7, 1.5Hz, 6-H), 11.48 (lH, br s, NH); m/z (CI+, NH3) 361 [(M+1)+, 35Cl2~.

- - -: . ~ . - ~ , - : . ~ - ~ - - .

21 3 ~21 3 EXAMPLE ~

3-(4-r4-~ thQ2~Zphçn,vll l~m-l-vl)methvl-l-methvl-lH-pvITnlo~3-klpyridine Sodium hydride (80% dispersion in oil; 0.13g, 4.3mmol) was added to a solution of 3-(4-(4-methoxyphenyl)pipera~in-1-yl)methyl-1H-pyrrolo[2,3-b]pyridine ~1.06g, 3.29mmol) in dimet hylfo~mamide (30ml) at 0C. The cooling bath was removed and the mixture st irred at room temperature for an hour. Methyl iodide (0.22ml, 3.53mmol) was added and the reaction mixture stirred for 2h at room temperature. The mixture was poured into water (300ml), ext~acted with ethyl acetate (2 x 150ml), and the extracts washed with b~ne (150ml). The combined extracts were dried (MgSO4) and evaporated to giv~ a yellow snlid. Purification by flash chromatography, eluting with 5% then 7.5% methanol in dichloromethane, gave the title compound (0.87g, 79%).
Recrystallisation from ethyl acetate/petrol (60-80C) gave fine n~edles, m.p. 92 g4Oc; (Found: C, 71.25; H, 7.18; N, 16.49.
C20H24N4O requires C, 71.40; H, 7.19; N, 16.65~ (CDCl3) 2.66 (4E, m, 2 x piperazinyl CH2), 3.09 (4H, m, 2 x pipera~nyl CH2), 3.74 (2H, s, CH2N), 3.75 (3~, s, ArOCH3), 3.87 (3H, s, N-CH3), 6.85 (4H, m, ArH), 7.05 (lH, dd, J 7.8, 4.7Hz, 5-H), 7.15 (1H, br s, 2-H), 8.04 (lH, dd, J 7.8, 1.5Hz, 4-H), and 8.33 (lH3 dd, J 4.7, 1.5Hz, 6-H); m/z (CI+, NH3) 337 (M+1)+.

32 ~ 213 T1232Y
EXAMPLE~0 ~-~4-[~ or~-2-p~dvll;E?i~razin-l-vl)me~h.,rl-l~l-pvrrQlQ
r2 .3-blpvlidine A mixture of 2,5-dichloropyridine (10.Og, 67.6mmol) and piperazine (58.1g, 675mmol) was stirred at 165C for 2h. The mixtur~ was allowed to cool, slurried with dichloromethane (200ml) and ~he solid collected by filtration. The filtrate was concentrated in vacuo and the procedure repeated. The residue after concentration of the filtrate was purified by flash chromatography twice (eluting with 1% ammonia, 10% methanol in dichloromethane~ to give 1-(5-chloro-2-pyridyl)piperazine (12.26g, 92%) as a tan solid. A portion of this solid (0.484g, 2.45mmol) was 1~ added to a solution of 3-dimethylaminomet~yl-lH-pylTolo[~,3-b]
pyridine (0.392g, 2.24mmol) in toluene (1Oml) and the mixture heated at re~ u~der nitrogen for 6h. The mixture was allowed to cool and the crystallised product filtered of~. Recrystallisation from toluene gav~ the title compound (0.229g, 31%), m.p. 196-198C;
(Found: C, 63.16; H, 5.60; N, 21.18. Cl7H,8ClN5. 0.1PhMe requires C, 63.08; H, ~.62; N, 20.78%); ~H (DMSO-d~) 2.46 (4H, t, J 6.0Hz, 2 ~ piperazinyl CH2), 3.45 (4H, t, J 5.0Hz, 2 x piperazinyl CH2), 3.67 (2H, s, CH2N), 6.82 (lH, d, J 9.1Ez, 3 -H), 7.04 (1H, dd, J 7.8, 4.6Hz, ~-H), 7.37 (lH, d, J 2.1Hz, 2-H), 7.66 (lH, dd, 2~ J 9.1, 2.7Hz, 4 -H), 8.05 (lH, dd, J 7.8,1.4Hz, 4~H), 8.08 (lH, d, J 2.7Hz, 6 -H), 8.19 (lH, dd, J 4.6, 1.AHz, 6-E), and 11.46 (lH, br s, ~I); m/z (CI+, NH3~ 328 [(M+H)+, 35Cl].

. "

- 33 - j~ 32Y

~-(4-r3~I~o~,uinolvllpi~er~zin-l-vl)m~thvl-lE-~vrrolo r2~3-blR~

Prepared by the method outlined in the previous example from the trifluoromethanesuliphonate derived from 3-hydro~yisoquinoline.
M.p. 246-248C (dec.) (EtOH); (Found: C, 72,15; H, 6.11;
N, 19.92. C2lH2~N~. 0.35H2O requires C, 72.12; H, 6.25; N, lû 20.02%); ~H (DMSO-dfi) 2.5~ (4H, m, 2 x piperazinyl CH2), 3.~1 ~4H, m, 2 x piperazinyl CH2~, 3.70 (2H, s, CH2N), 6.94 (lH, s, 4'-H), 7.06 (lH, dd, J 7.8, 4.7Hz, 6-H), 7.28 (1H, m, 6'-H or 7'-H), 7.39 (lH, s, 2-H), 7.62 (lH, m, 7'-H or 6'H), 7.64 (lH, m, 5'-H or 8'-H), 7.8~ (lH, mJ 8'-H or 6'-H), 8.08 (lH, dd, J 7.8, 1.~Hz, 4-H), 16 8.20 (lH, dd3 J 4.7, 1.5Hz, 6-H), and 11.48 (lH, br s, NH); m/z (CI+, NH3) 344 (M+1)+.

lEXAMPLE 12 3-(4-r6-Ir dolYlll;~iperazin-1-vl)methyl-lH-p~olo~2!3-bl~yridine Step 1: 1-(~I~olvl)piperazine Bis(2-chloroethyl)amine hydrochloride (3.60g, 20.2mmol) was added to a suspension of 5-aminoindole (2.63g, 19.1mmol) in ethanol (30ml) and the mixture heated at reflux for 16h. The mixture was allowed to cool, sodium carbonate (2.14g, 20.2mmol) was added and the reaction mi~ture heated at reflux for 8h. The mixture was allowed to cool, filtered and the filtrate evaporated. The residue was dissolved in lM hydrochloric acid (100ml) and extracted with dichloromethane (2 x 50ml). The aqueous phase was made basic 2~ 2~3 with 4M sodium hydroxide (30ml) and extracted with ethyl acetate (2 x 100ml). The e~tract~ were washed with bIine (lOOml), combined arld dried ~MgSO4). The residue from evaporation of the extracts was puri~ed by flash chromatography, eluting wi~h dichloromethane/methanol/ammonia, to ~re 1~ indolyl)piperazine (0.71g, 18%), as a cr~am solid; ~ (DMSO-d6) 2.94 (4H, m, 2 ~
piperzinyl CH2), 3.00 (4H, m, 2 x piperazinyl CH2), 6.29 (lH, m, 3-H), 6.84 (lH, dd, 3 9.0,2.0Hz, 6-H), 7.00 (lH, d, J 2.0Hz, 2-H), 7.24 (2H, m, 4-H, 7-H), and 10.82 (lH, br s, NH~.
Step 2: 3-(4-r5-Tndolvllpiperazin-1-vl)methvl-1H-p~rrQlQ
r2,3-blp~ridine A mixture of 3-dimethylaminomethyl-lH-pyrrolo[2,3-b]
pyridine (0.23g, 1.33mmol) and 1-(5-indolyl)piperazine (0.27g3 1.34mmol) in tnluene (20ml) was heated at reflux for 16h under nitrogen. The mixture was allowed to cool and the ~olid pre~ent collected. Purification by flash chromatography, eluting with 90:8:1 dichloromethane/methanol/ammonia, twice gave the title compound (0.14g, 32%) as a white solid. Recrystallisation from methanol af~orded needles, m.p. 232.5-233C; (Folmd: C, 72.14; H, 6.29;
N, 21.07. C2oH2lN6. O.lH20 reql~ires C, 72.09; H, 6.41; N, 21.02%);
~H (DMSO-d6) 2.56 (4H, m, 2 x piperazinyl CH2), 3.02 (4H, m, 2 x piperazinyl CH2), 3.69 (1H, s, CE2N), 6.27 (lH, m, 3 -H), 6.83 (lH, `
dd, J 8.8, 2.1Hz, 6 -H), 6.97 (1H, m, 2 -H), 7.05 (lH, dd, J 7.8, 4.6Hz, 5-H), 7.22 (2H, m~ 4 -H, 7 -H), 7.38 (lH, d, J 2.1Hz, 2-H), 8.06 (lH, dd, J 7.8, 1.4Hz, 4-H), 8.20 (lH, dd, J 4.6, 1.4Hz, 6-H), 10.77 (lH, br s, NH), and 11.46 (lH, br s NH); m/z (CI+, NH3) 322 (M+1)+.

2~ 3 E~L.E~ 13 .~(4-r4-Xod~h ~--r2 ,~3-blpyridine M.p. 223-225C (dec.) (MeOH); (Folmd: C, 61.85; H, 4.~0; N, 13.12. Cl8Hl9N4I requires C, 51.69; H, 4.68; N, 13.39%); ~H (DMS-d6) 2.50 (4H, m, 2 x piperazinyl CH2), 3.10 (4H, m, 2 x piperazinyl CH2), 3.67 (2H, 6, CH2N), 6.74 (2H, d, J 9.0Hz, ArH), 7.04 (lH, dd, J 7.8, 4.7Hz, 5-H), 7.37 (lH, d, J 2.0Hz, 2-H), 7.46 (2H, d, 3 9.0Hz, ArH), 8.05 (lH, dd, J 7.8, 1.4Hz, 4-H), 8.19 (lH, dd, J 4.7, 1.4Hz, 6-H), and 11.47 (lH, br s, NH); m/z (CI+, NH3) 419 (M+1)~.

3-(4-r4-(Trifluoromethvl)phenvllpiperazin-l-vl)methvl-lH-p~olor2.3-blp~dine M.p. 247-2~0C (dec.) (MeOH); (Found: C, 63.44; H, ~.29;
N, 15.38. Cl9HlgF3N4 requires C, 63.32; E, ~.31; N, 1~.~6%);
~DMSO-d6) 2.51 (4H, m, 2 x piperazinyl CH2), 3.26 (4H, m, 2 x piperazinyl CH2~, 3.68 (2H, s, CH2N), 7.04 (3H, m, ~-H + 2 x ArH), 7.38 (lE, br s, 2-H), 7.48 (2H, d, J 8.6Hz, ArH), 8.0~ (1H, br d, 2~ J 8Hz, 4-H), 8.20 (lH, m, 6-H), and 11.47 (lH, br s, NH); m/z CI+, NH3) 361 (M+1)+. ~ -~

E XoiM P ~ E 15 3-(4-r2-~,~Q~hy~ razin-l-vl)-m~hy~ I-pmolo r2!3-b~yridir~

M .p. 143C (EtO Ac); (Fol~nd: C, 71.39; H, 7.19; N, 16.35.
C20H 24N4O req w res C, 71.40; H, 7.19; ~I, 16.6~ %); ~(D M S O-d6) 2.40 (4 H, br s, 2 x C H 2), 2.47 (4 H, br s, 2 x C H 2), 2.66 (2 H, t, J 6.8 H z, N C H 2C H 2O), 3.60 (2 H, s, C E 2), 4-03 (2 H, t, J 5.8 H z, N C H 2~I2O), 6.89 (3 H, m, A r H ), 7.03 (H, dd, J 7.8, 4.7 H z, 5-H ), 7.26 (2 H, t, J 3.4 X z, Ar H), 7.32 (1EI, d, 2.1 H z, 2-H ), 8.00 (H, dd, J 7.8, 1.2 H z, 4-H ), 8.18 (H, dd, J 4.7, 1.~ H z, 6-H ), and 11.4~ (H, br s, N H);
rnlz (CI+, r~H3) 337 ( M +1).

E X~M P L E 1 3-f4-r4-M~hvlphenvll~iperazin-l-vl)me~hvl-lH-pvrr~
r2,~-blpvri~

M .p. 220 222C ( M e O H ); (Fou nd: C, 74.24; H, 7.12; N, 18.32.
ClgH 22 N4 requ~res: C, 74.48; H, 7.24; N, 18.29 %); ~H (D M S O-d6) 2.18 (3 H, s, A rC H 3), 2.04-2.53 (4 H, m, 2 x piperazinyl C H 2), 3.04 (4 H, t, J 4.8 H z, 2 x piperazinyl C H 2), 3.67 (2 H, s, N C H 20~r), 6.79 (2 H, d, J 8.~ H z, ~r H ), 6.99 (2 H, d, J 8.5 H z, ~r H), 7.03 (l H, dd, J 7.8, 4.7 H z, 26 5-H), 7.36 (1 H, d, J 2.2 H z, 2-H ), 8.Q4 (l H, dd, J 7.8, 1.3 H z, 4-H),8.19 (l H, dd, J 4.7, 1.~ H z, 6^H ), an d 11.4~ (l H, br s, N-H ); rn/z (CI+, NH3) 307 ( M ~ 1)+.

, . ~ .

- ., - -. ~ .: . ~ . ................ - . .

. : ~-: , - . -. . -.. - . , ~ - .
- - ~ ~ . .. - . . . . -21 ~

EXAMPT,E 1l 3-(4-r~-Fl~Qro~ H-pyrrQlor2~3 bll?v~dine M.p. 214-216C (MeOH); (Found: C, 69.42; H, 6.29; N, 17.91.
ClôHlgN4F requires C, 69.6~; H, 6.17; N, 18.05%); ~H (DMSO-d6) 2.49-2.53 (4H, m, 2 x piperazinyl CH2), 3.04 (4H, t, J 4.8Hz, 2 x piperazinyl CH2), 3.68 (2H, s, NCH2Ar), 6.88-6.93 (2H, m, ArH), 6.98-7.0~ (3H, m, ArH), 7.37 (lH, d, J 2.3Hz, 2-H), 8.04 (lH, dd, J
7.8, 1.3Hz, 4-H), 8.19 (lH, dd, J 4.7,1.6Hz, 6-H), and 11.47 (lH, br s, N~I); m/z (CI+, NH3) 311 (M+1)~.
.

3-(4-rl-Methvl-~,-in~Qlvll~iperazin-l-vl)me~lH-pvrrolol:2~3-blpvridine Step 1: 1-(t~t-Butoxvcar~L~4-(l-methvl-5 indolvl)piperazin~

Di-te~t-butyldicarbonate (0.46g, 2.11mmol) was added to a solution of 1-(~-indolyl)piperazine (0.41g, 2.04mmol) in dimethylformamide/tetrahydrofuran (1:1; 20ml) and the mixture 2~ stir~ed at room temperature overnight. The mixture was poured into water (2001nl) and extracted wit~ ethyl acetate (2 x 100ml).
The extracts were washed with brine (100ml), combined and dried (MgSO4). The residue after evaporation of the solvent was dissolved in tetrahydrofuran (~ml). Sodium hydride (80% dispersion in oil;
0.068g, 2.27mmol) was added and the mixture stirred at room temperature for thirty minutes. Methyl iodide (0.14ml, 2.25mmol) , -: - --: - - -: - :, - - , ~21~ 6~

was added, the reaction mixture was stirred for 90 minutes then poured into water (50ml) and ~xtracted with ethyl acetate (2 x ~Oml~. The extracts were washed with brine (50ml), combined and dried (MgSO4). Purification of the residue by flash chromatography, 5 eluting with 1:3 then 1:2 ethyl acetate/petrol, gave ~he title compound (0.218g, 34%) as a waxy solid; ~;H (CDC13) 1.49 (9H, s, C(CH3)3), 3.08 (4H, t, J 4.8Hz, 2 x piperazinyl CH2), 3.62 (4H, t, J
4.8Hz, 2 x piperazinyl CH2), 3.76 (3H, s, N-CH3), 6.39 (lH, d, J
3.0Hz, 3'-H), 7.00 (2H, m, 2-H, 5-H), and 7.24 (lE, d, J 9.1Hz, 7-H).

Step 2: 3-(4-[1-Methvl-6-in~olvllpiperazin-1-vl)methyl-1H-pvrroloL2~3-blpyridine Trifluoroacetic acid (5ml) was added to a solution of l-(tert-butoxycarbonyl)-4-(1-methyl-~-indolyl)piperazine (0.2102g, 0.666mmol) in dichloromethane (~ml) and the mixture stirred for 30 minutes at room temperature. The mixture was concentrated in vacuo and saturated aqueous potassium carbonate (20ml) was added to the residue. The mixture was extracted with dichloromethane (2 x 20ml), the extracts washed with brine (20ml), combined and dried (MgSO4). The extracts were concentrated and the residual yellow solidredissolvedintoluene(6ml). 3-Dimethylaminomethyl-lH-pyrrolo[2,3-b]pyridine (0.1136g, 0.648mmol) was added and the mixture heated at reflux under nitrogen ~or 6 hours. The mixture was allowed to cool and the solid present collected. Puri~cation by flash chromatography, aluting with 120:8:1 then 90:8:1 dichloromethane/methanol/ammonia, gave the title compound (0.1433g, 64%) as a yellow solid. Recrystallisation firom methanol aflEorded pale yellow needles, m.p. 222-223C; (Found: C, 72.81; H, 6.81; N, 20.17. C2lH23N5 requires C, 73.02; H, 6.71; N, 20.27~6); ~H
(DMSO-d6) 2.~7 (4H, m, 2 x piperazinyl CH2), 3.03 (4H, m, 2 x - ~ , - ~

piperazinyl CH2), 3.69 (2~I, s, CH2N), 3.71 (3H, s, N-CH3), 6.25 (lH, d, J 2.9Hz, 3'-H), 6.89 (lH, dd, J 8.9, 2.1Hz, 6'-H), 6.98 (lH, d, J
2.0Hz, 2-H or 4'-H), 7.05 (lH, dd, J 7.8, 4.6Hz, 5-H), 7.18 (lH, d, J
2.9H~, 2'-H), 7.26 (lH, d, J 8.9Hz, 7'-H), 7.38 (lH, d, J 2.1Hz, 4'-H or 2-lH), 8.07 (lH, dd, J 7.8, 1.4Hz, 4-H), 8.20 (lH, dd, J 4.6, 1.4Hz, 6-H), and 11.46 (lH, br s, NH); m/z (CI+, NH3) 346 (M+1)~.

3-(4-r~;-IndazQlyl~ çr~zin-l-yl)methyl-lH-pyrrolnr2,3-blpvridine Prepared in an analogous manner to 3-(4-[5-indolyl]piperazin-1-yl)methyl-1H-pyrrolo[2,3-b]pyridine (Example 1~ 12).

M.p. 238-239.5C (dec.) (MeOH); (Found: C, 68.39; H, 6.07; N, 25.34. Cl9H20N6 requires C, 68.65; H, 6.06; N, 25.28%), ~iH (DMSO-d6) 2.67 (4H, m, 2 x piperazinyl CH2), 3.06 (4H, m, 2 x piperazinyl CH2), 3.70 (2H, s, CH2N), 7.05 (2H, m, 5-H, 4'-X), 7.16 (lH, dd, J

9.1, 2.1Hz, 6'-H), 7.38 (2H, m, 2-H, 7'-H), 7.87 (lH, s, 3'-H), 8.06 (lH, dd, J 7.8, 1.4Hz, 4-H), 8.20 (lH, dd, J 4.7, 1.5Hz, 6-H), 11.48 (1H, br s, NH), and 12.77 (lH, br s, NH); m/z (CI+, NH3) 333 (M+1)+.

3-(4-r4-Ethoxycarbonvlphenvllpiperazin-l-yl)methvl-lH-pvrrolor2~-blpYridine M.p. 196-197C (EtOH); (Found: C, 69.04; H, 6.57; N, 15.20.
C2lH24N402 requires C, 69.21; H, 6.64; N, 15.37%); ~iH (DMSO-d6) 1.28 (3H, t, J 7.1Hz, OCH2C~3), 2.~0 (4H, m, 2 x piperazinyl CH2), 3.30 (4H, m, 2 x piperazinyl CH2), 3.69 (2H, s, CH2N), 4.23 (2H, q, J
7.1Hz, OC~52CH9), 6.94 (2H, d, J 9.0Hz, ArH), 7.04 (lH, dd, J 7.8, 4.6Hz, 5-H), 7.38 (lH, d, J 2.2Hz, 2-H), 7.76 (2H, d, J 9.0Hz, ArH), 8.0~ (lH, dd, J 7.8, 1.4Hz, 4-H), 8.20 (lH, dd, J 4.6, 1.4Hz, 6-H), and 11.47 (lH, br s, NH); mlz (CI~, NH3) 365 (M+1)~.

~-(4-r4--~-rbox~h~nyllplp~r~i~ yl)methyl-lH-pvrrolor2~3 blpvridine A suspension of 3-(4-[4-ethoxycarbonylphenyl]piperaæin-1-yl)methyl-1~i[-pyrrolo[2,3-b]pyridine (0.6~94g, 1.81mmol) in ethanol (50ml) containing lM aqueous sodium hydroxide (10.5ml, 10.8mmol) was stirred at room temperature for eight days, during which time the solid slowly dissolved. The reaction mixture was concentrated to a small volume, diluted with water and neutralised (pH 6-7) wit~
acetic acid to give a gum which solidified on standing. The solid was collected, washed with water and dried in vacuo. Recrystallisation ~om dimethylformamide/water gave th~ title compound (0.4069g, 67~o) as a white solid, m.p. >260C (dec.); (Found: C, 66.96; H, 5.88;
N, 16.30. ClgH2oN4O2Ø25H2O requires C, 66.94; H, 6.06; N, 16.44);
~H (DMSO-d63 2.51 (4H, m, 2 x piperazinyl CH2), 3.27 (4H, m, 2 x piperazinyl CH2), 3.68 (2H, s, CH2N), 6.93 (2H, d, J 9.0Hz, ArH), 7.04 (1H, dd, J 7.8, 4.7Hz, 5-H), 7.38 (lH, d, J 2.2Hz, 2-H), 7.57 (2H, d, J 9.0Hz, Ar~I), 8.06 (lH, dd, J 7.8, 1.4Hz, 4-H), 8.20 (lH, dd, J
4.7, 1.4Hz, 6-H), and 11.48 (lH, br s, NH); m/z (CI~, NH3) 337 (M+1)~.

.- ~ -.... ....... ... . .. .. . .. ..
. ~ - .- . ~ . . - . ..

: ~, 2~2~ ~

EX~[PLE ~2 ~ -(4-r3-~thv!~hen~lL~erazin~ y,l~na~hYl lH-~vrrolo[2J~-b~lp~ridine M.p. 156-1~8C (MeOH); (Found: C, 73.73; H, 7.12; N, 17.99.
ClgH22N4Ø2H20 reqllires C, 73.61; H, 7.28; N, 18.07%); ~H ~DMSO-d6) 2.22 (3H, s, ArCH3), 2.51 (4H, m, 2 x piperazinyl CH2), 3.0g (4H, m, 2 x piperazinyl CH2), 3.67 (2H, s, CH2N), 6.~7 (lH, m, ArH), 6.70 ~ :
(2~I, m, ArH), 7.05 (2H, m, 5-H, ArH), 7.38 (lH, d, J 2.3Hz, 2-H), 8.05 (lH, m, 4-H), 8.19 (lH, dd, J 4.6, 1.6Hz, 6-H), and 11.48 (lH, br s, NH); m/z (CI+, NH3) 307 (M+1)+.

~:~[~M~thvlph~nYllpip~razin-l-vl)methvl-lH-;pvlTolor2.3-blpv~line ~.p. 174-176C ~MeOH); (Found: C, 74.29; H, 7.18; N, 18.11.
ClgH22N4 requires C, 74.48; H, 7.24; N, 18.29~o?; ~H (DMSO-d6) ~.21 (3H, s, Al~CH3), 2.55 (4H, br s, 2 x piperazinyl CH2), 2.81 ~4H~ m, 2 x piperazinyl CH2), 3.70 (2H, s, CH2N), 6.92 (1H, m, ArH), 6.99 (lH, m, ArH), 7.04 (1~, dd, J 7.8, 4.7Hz, ~-H), 7.09 (2H, m, ArH), 7.37 (lH, d, J 2.2Hz, 2-H), 8.06 (lH, dd, J 7.8, 1.3Hz~ 4-H), 8.20 (lH, dd, J 4.7, 1.~Hz, 6-H), and 11.46 (lH, br s, NH); m/z (CI+, NH3) 307 (M+1)~.

~(4-r3.4-Methvlenedioxvphenvllpiperazin-1-vl)methYl-1H-p~rrolor2 ~3-blpyridine M.p. 196~199C (PhMe~; (Foulld: C, 67.69; H, 6.03; N, 16.48.
Cl9~I20N4O2 requires C, 67.84; H, 5.99; N, 16.66%); ~H (DMSO-d6) 2.~0 (4H, m, 2 x piperazinyl CH2), 2.98 (4H, m, 2 ~ piperazinyl CH2), 3.67 (2H, s, CH2N), 6.89 (2H, 8, OCH2O, 6.30 (lH, dd, J 8.5, 2.3Hz, 6'-H), 6.62 (1H, d, J 2.3Hz, 2'-H), 6.73 (lH, d, J 8.5Hz, 5'-H), 7.04 (lH, dd, J 7.8, 4.6Hz, 6-H), 7.36 (lH, br B, 2-H), 8.04 (lH, m, 4-H), 8.19 (lH, m, 6-H), and 11.43 (lH, br s, NH); m/~ (CI+, NH3) 337 (M+1)+.
EXA~kl3 2 3-t4-r4-BromQphenyllpipçr~zin-l-vl)me~hvl-lE-pvrrolor2~3-blpvridine M.p. 234-238C (MeOH); (Found: C, 57.8g; H, 5.10; N, 14.86.
Cl8HlgBrN4 requires C, 58.23; H, 5.16; N, 15.09%); ~H ~DMSO-d6) 2.50 (4H, m, 2 x piperazinyl CH2), 3.10 (4H, m, 2 x piperazinyl CH2), 3.67 (l~I, s, CHaN), 6.85 (2H, d, J 9.0Hz, ArH), 7.04 (lH, dd, J 7.8, 4.7Hz, 6-H), 7.31 (2H, d, J 9.0Hz, ArH), 7.37 (lH, d, J 2.3Hz, 2-H), 8.04 (1H, dd, J 7.8, 1.4Hz, 4-H), 8.19 (lH, dd, J 4.7, 1.5Hz, 6-H), and 11.45 (lH, br s, ~I); m/z (CI+, NH3) 373/371 (M+1)+.

3-(4-r4-~ethoxycarbonvlphenyllpipera2in-l-vl)methvl-lH-pvrrolor2~3-blpYridine M.p. 205-207C (dec.) (PhMe); ~Fo~md: C, 67.94; H, 6.27; N, 15.70. C20~I22N4O2Ø16H20 requires C, 68.03; H, 6.37; N, 16.87~);
~ (DMSO-d6) 2.50 (4H, m, 2 x piperazinyl CH2), 3.29 (4H, m, 2 x .

, : :., . : -:
.. ~ - ~ : : -, : -, : -~ `
2~

piperazinyl CH2), 3.68 (2H, s, CH2N), 3.76 (3H, s, CO2CH3), 6.94 (2H, d, J 9.1Hz, ArH), 7.05 (lH, dd, J 7.8, 4.7EIz, 5-H), 7.38 (lH, d, J
2.1Hz, 2-H), 7.76 (2H, d, J 9.1~Iz, ArH)~ 8.06 (lH, br d, J 7.8Hz, 4-H), 8.22 (lH, dd, J 4.7, 1.5Hz, 6-H), and 11.48 (lH, br 8, NH); m/z (CI~, NH3) 351 (M+1)~.

~-(4-r4-~Ivdroxvmethvlphenvllpiperazin-l-Yl)methvl-lH-;~vrroloJ2!3-blpy~.~l~nQ

A solution of diisobutylaluminium hydride in toluene (1.5M, 9.4ml, 14.1mmol) was added to a solution of 3-(4-[4-m~thoxycarbonylphenyl~piperazin-l-yl)methyl-lH-pyrrolo[2,3-b]pyridine (1.64g, 4.68mmol) in tetrahydrofilran (100ml) and the resultant mixture stirred at room temperature for forty minutes.
Methanol (3.3ml) was added, followed by water (2.0ml) and 2M
aqueous sodium hydroxide (2.0ml). The precipitate formed was collected, the filtrate concentrated in vacuo and the solid residue was rec~rstallised from methanol to ~ord the title compound (1.12g, 74%), m.p. 207-209C (dec.); (Found: C, 69.48; H, 7.00; N, 16.61. ClgH22N4OØ3 MeOH requires C, 69.82; H, 7.04; N, 16.87%);
~iH (DMSO-d6) 2.52 (4~I, m, 2 x pip~razinyl CH2), 3.08 (4H, m, 2 ~
piperazinyl CH2), 3.68 (2H, CH2N), 4.36 (2X, d, J 5.6Hz, CH20H), 4.92 (lH, t, J 5.6Hz, CH20H), 6.85 (2H, d, J 8.7Hz, ArH), 7.05 (lH, dd, J 7.9, 4.7Hz, 5-H), 7.13 (2H, d, J 8.7Hz, ArH), 7.37 (lH, d, J
2.2Ez, 2-H), 8.05 (lH, br d, J 7.9Hz, 4-H), 8.19 (lH, dd, J 4.7,1.5Hz, 6-H~, and 11.47 (lH, br s, NH); m/z (CI~, NH3) 323 (M+1)+.

XAM:PLE 28 ~(4-r~~ 2-~Yxi~vllpi~ a n-L-vl)me~l-1H-,~

Bromine (74g, 24ml, 0.46mmol) was added dropwise with vigorous sti~ng to a solution of 2-amino-5-picoline (20.0g, 0.19mol) in 48% hydrobromic acid (300ml) at -10C. Sodium nitrite (32g, 0.46mol) in water (80ml) was added dropwise to the orange suspension, maintaining the temperature below -5C, and the mixture was then stirred at room temperature for 30 minutes. The mixture was recooled to 0C and sodium hydroxide (188g, 4.7mol) in wat~r (160ml) added dropwise. The resulting black suspension was extracted with ether (2 x 500ml), the e~tracts combined, dried (MgSO4), and evaporated to give 2-bromo-6-picoline as a tan solid (24g, 76%); OH (CDCl3) 2.30 (3H, 6, CH3), 7.38 (2H, s, 3-H, 4-H), 8.21 (lH, s, 6-H). This was converted in two steps, using the procedure outlined in Example 10, to the title compound, m.p. 204-205C
(EtOAc); (Found: C, 70.63; H, 6.86; N, 22.86. Cl8H2lN6 requires C, 70.33; H, 6.89; N, 22.78~; OH (DMSO-d6) 2.12 (3H, s, ArCH3), 2.47 (4H, m, 2 x piperazinyl CH2), 3.39 (4 H, m, 2 x piperazinyl CH2), 3.66 (2H, s, CH2N), 6.70 (lH, d, J 8.6Hz, 3'-H), 7.04 (l H, dd, J 7.8, 4.7 H z, 5-H), 7.34 (lH, dd, J 8.6, 2.3H~, 4'-H), 7.36 (l H, d, J 2.3 H z, 2-H ), 7.92 (lH, d, J 2.3 H z, 6'-E ), 8.05 (l H, dd, J 7.8, 1.2 H z, 4-H), 8.19 26 (l H, dd, J 4.7, 1.5Hz, 6-H), and 11.45 (lH, br s, NH); m/z (CI+, NH3) 308 ( M +1)~.

E ~ Il'L E 29 3-!4-r4-H y dro~Yphenvllpipera2in-l-vl)m ethYl-l H
p~nlor2~3-blp~inç

~ ~ ~ . . -. . -;~l ~$2~

- 45 - ~ T1232Y
M.p. 197-200C (EtOAc); (Found: C, 68.16; H, 6.46; N, 17.34. Cl8H20N4OØ~H2O requires C, 68.12; H, 6.67; N, 17.65%); ~H
(DMSO-d6) 2.93 (4H, t, J 4.3Hz, 2 x piperazinyl CH2), 3.30-3.32 (4H, m, 2 x piperazinyl CH2), 3.67 (2H, 6, ArC~I2N), fi.61-6.63 (2H, m, 2',6'-H), 6.73-6.76 (2H, m, 3',5'-H)9 7.04 (lH, dd, J 7.8, 4.7Hz, 5-H), 7.37 (lH, s, 2-H), 8.04 (lH, dd, J 7.8, 1.2Hz, 4-H), 8.19 (lH, dd, J
4.7, 1.2Hz, 6-H), 8.76 ~1H, br s, OH)3 and 11.45 (1H, br s, NH); m/z (CI~, NH3) 309 (M~

3-(4-(Benzothiophçn-2-~)pipçrazin-1-y~)methvl-lH-pvrrolor2!3-blpvridine 1~ Step 1: 1-Benzvl-4-(henzo~hiophen-2-~iperazine To a solution of 2-mercaptobenzothiophene (1.8g, 10.8mmol) in toluene under nitrogen was added N-benzylpiperazine (1.88ml, 10.8mmol) and the mixture heated at reflux for 1.5h. Left to cool, 20 concentrated in vacuo and product recrystallissd ~om diethyl ether-hexane to yield the title compound (1.55g), m.p. 160-161C.

Step 2: 1-(BenzQthi~phen-2-vl)piperazine hvdrochloride To a solution of 1-benzyl-4-(benzothiophen-2-yl)piperazine (1.5g, 4.9mmol) in anhydrous dichloromethane (20ml) at 0C under nitrogen was added 1-chloroethylchloroformate (0.68ml, 6.37mmol).
The mixture was allowed to warm to room temperature, stirred for lh and concentra~ed in vacuo. The crude residue was dissolved in 30 methanol (10ml) and heated to reflux ~or 30 minutes, left to cool and the title compound collected by filtration (0.6g), m.p. 240C (dec.).

=, . ~ ~ . .

'.: - ' ~ '' - ~ ' . ,' ' '' .
: ~ .

Step 3~ 3~ (B~en~i~erazin-1-yl)m~thyl-lH-~olor2!3-bl~in~

The til'le compound was prepared in an analogous manner 5 to Example 6, Step 3 using 1-(benzothiophen-2-yl)piperazine ~180mg, 0.83mmol) and 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (145mg, û.83mmol). Recrystallisation ~om ethyl acetate-hexane af~orded the title compound (155mg, ~4%), m.p. 269C (dec.);
(Folmd: C, 69.10; H, 5.85; N, 16.08. C20H20N4S requires C, 68.94; H, 5.79; N, 16.08%); ~H (DMSO-d6) 2.~5 (4H, t, J 5Hz, 2 x piperazinyl CH2), 3.18 (4H, t, J i~Hz, 2 x piperazinyl CH2), 3.70 (2H, s, indole-CH2N), 6.26 (lH, s, 3-~I-benzothiophene), 7.04 (2H, m, 2 x ArH), 7.19 (1H, m, ArH), 7.05 (2H, m, 2 x ArH), 7.63 (lH, d, 8Hz, ArH), 8.06 (lH, d, 8Hz, ArH), 8.20 (lH, d, 3Hz, ArH), and 11.46 (lH, br s, 16 NH~; m/z ~CI~, N~3) 349 (M~1)+.

E~LE 31 3-14-(BenzQthiQh~n-3-yl~iperazin-1-vl)methvl-lH-~olor2~3-blpYridine Step 1: 1-(BenzQ$hiophen-3-vl)pi}~erazine To a solution of methyl 3-aminobenzothiophene-2-2~ carboxylate ~prepared by the method of J.R. Beck, ~. Qrg. (~hem.
1972, 37, 3224~ (6.5g, 31.4mmol) in N-methylpyrrolidinone (30ml) was added 1-methylpiperazine and the reaction mixture was heated to 17&C for 4h. After cooling the mixture was poured into water and the product extracted with diethyl ether (3 x 100ml), the extracts were washed with water (1 x 100ml) and brine (1 x 100ml), combined and dried (MgSO4). Concentration of the extracts yielded '~ :: ` : : . ` .. '; `, ::: ` .

47 2 ~ 13 T Y
3-aminoben~othioph~ne (5.9g), which was used without pu~ification.
To a solution of 3-aminobenzothiophene (5g, 32mmol) in N-methylpyrrolidinone (~0ml) was added piperazine (8.7g, 102mmol) and the mixture heated to reflux under nitrogen for 14h. Cooled and poured into water and extracted with dichloromethane (4 x lûOml). The ex~acts were washed with brine (50ml), combined and dried (MgSO4). On concentration of ~he e~tracts a white solid came out of solution which was collected by filtration to yield the title compouncl (0.78g, more product left in solution); ~H (DMS-d6 +
TF~A), 3.3 (8H, m, 4 x piperazinyl CH2), 7.08 (lH, s, 3-H), 7.39 (2H, m, 2 x ArH), 7.83 (lH, m, ArH), 7.95 (lH, m, ArH), and 9.30 (lH, br s, N~I).

2: ~(4-(BQnzothiophen-3-vl)~iperazin-1-vl)mQthyl-1H-~vrrolor2.3-blpYridine The title compound was prepared in an analogus manner to Example 6, ~3tep 3 using 1-(benzothiophen-3-yl)piperazine (0.5g, 2.3mmol) and 3-dimethylarninome$hyl-1H-pyrrole[2,3-b]pyridine (0.40g, 2.3mmol). Recrystallisation using ethyl acetate-hexane af~orded the title compound (0.18g, 23%), m.p. 172-173C; (Found:
C, 68.37; H, ~.57; N, 15.90. C20H20N4SØ1H2O requires C, 68.~8; H, 5.81; N, 16.00%~; ~H (DMSO-d6) 2.63 (4H, br s, 2 x piperazinyl CH2), 3.05 (4H, br s, 2 x piperazinyl CH2), 3.74 (2H, s, indole-CH2-N), 6.88 (lH, s, 2-benzothiophene-H), 7.06 (lH, dd, J 8, 2Hz, ArH), 7.39 (3H, m, 3 x ArH), 7.70 (lH, m, Ar~I), 7.88 (lH, m, ArH), 8.07 (lH, d, J
&Hz, ArH), 8.20 (lH, m, ArH), and 11.48 (lH, br s, NH); m/z (CI+, NH3) 349 (M+1)+.

2 ~ t r3 ~2 ~ 2~ H-p-vrr~lQr2~3-b4?-vridin-~-yl)mçthsrl)-2~3~4~4a!5 hexah~dro-1~H)-pvrazinor1,2-al~linoline Using the procedure described for Example 1 replacing 1-phenylpiperazine with 2,3,4,4a,5,6-hexahydro-1(H)-pyrazino[1,2-a]quinoline [V.A. Rao et al. Indian J. C~hemL~ 7, 833 (1969) and . Med Chem., 13, 516 (1970)] the title compound was obtained 0 a6 a colowrless solid, m.p. 181-3C (MeOE~; (Found: C, 7~.27; H, 6.89; N, 17.50. C20H22N4 requires C, 75.44; H, 6.96; N, 17.60~ H (COCl3) 1.66-1.9 (2H, m, CH2CH2Ar), 1.9-2.05 and 2.2-2.35 (~H, 2m9 CH~CH2Ar), 2.6-3.1 (6H, m, 3 x CH2N), 3.65-3.8 (3H, m, indole-CH2N and CH), 6.75 (lH, t, J 8Hz, 9'-H), 6.8 (1~I, d, J 8Hz, 10'-H), 7.0 (lH, d, 8 Hz, 7'-H), 7.05-7.15 (2H, m, 8'-H and 5-H), 7.13 (lH, br s, 2-H), 8.13 (lH, dd, J 8, 1.5 Hz, 4-H), 8.32 (lH, dd, J 4.5, 1.~ Hz, 6-H), and 9.95 (lH, br s, NH).

EX~LE 33 (+)-~ hloro-~((lH-pvrrolor2,3-blpvIi~in-3-yl)methvl)- -2!~4,,4aJ5,~,-,hQxahvdro-l(H)-pvr,~L2inorl,2-al~linnline Step 1: (_)-6-Chloro-2-U1~1-26 dimethvleth~rbonvlamino)m~thvl)-1!2,3~4-~rah~lrQquinoline A solution of 6-chloroquinoline-2-carbonitlile ~3.4 g, 0.018 mol) in methanol (50 ml) was shaken on a Parr hydrogenator at 55 psi ~I2 in the presence of PtO2 (0.1 g) for 18 h. The catalyst was then removed by filtration and the solvent evaporated. The . .

,, . - :- i . .- - . . -~ .. . . . ..
~ .. . . ~ .
-, . : . - - .. - . . .

49 ~6~3 T123 Y
residue was tlissolved in dichloromethane (100 ml), cooled below -5C and di-tert-butyl dicarbonate (4.5 g, û.0~ mol) was added.
After 2h the solvent was evaporated and the residue triturated with hexane to a~ord the title compound as a colourless powder ~i (4.3 g, 80%); ~OH (CDCl3) 1.46 (9H, s, C(CH3)3), 1.6-1.75 and 1.85-1.96 (2H, 2m, CH~CH2Ar), 2.7-2.86 (2H, m, CH2CH2Ar), 3.15-3.2~, 3.25-3.3~, 3.35-3.4~ (3H, 3m, BOCNHCEI2C~:N), 4.88 (lH, br s, NH), 6.48 (lH, d, J 8 Hz, 8-H), 6.91-6.94 (2H, m, 6-H and 7-~).
Step 2: ~+~-~-Chlor~-2~4 4a.6L6-hexah~dro-l(E)-pvrazinorl~2-alquinolin-2-one A solution of bromoacetyl bromide (3.2 g, 0.016 mol) in 15 dichloromethane (10 ml) was added dropwise to a solution of (+)-6-chloro-2-((1,1-dimethylethoxycarbonylamino)methyl)-1,2,3,4-tetrahydroquinoline (4.3 g, 0.014~ mol) in dichloromethane (90 ml) stirring with aqueous sodium hydroxide [NaOH (0.72g, 0.018 mol); H20 (10 ml)] cooled below 6C. After lh the organic phase 20 was separated, dried (MgSO4) and evaporated to give crude bromoacetamide as a colourless solid (6g) which was used as such.
The bromoacetamide was dissolved in dichloromethane (100 ml). TFA (1~ ml) was added and the resulting homogeneous 2~ solution was stirred at room temperature for 3h. Tlc (silica;
CH~Cl2:MeOH:NH3 90:10:1) after this time showed no remaining starting material with product Rf, 0.1. The solvent and excess reagent were removed in v~cuo to give the crude amine which was dissolved in DMF (100 ml), powdered potassium carbonate 30 was then added and the resulting slurry was stirred at 80C
~mder nitrogen for 24h. Tlc (silica; CH2Cl2:MeOH:NH~ 90:10:1) ~ ...... , . ., -50 2~ 3 T1232Y

after this time ~howed product Rf, 0.5 with no remaining starting material. The insolubles were removed by filtration; the mother liquors concentrated in vacuo and the residue purified by column chromatography on silica eluting with CH2Cl2 then 6 CH2Cl2:MeOH (95:5), to a~ord ~he title compound (1.7 g, 46%) as a bui~ coloured solid; ~H (CDC13) 1.7-2.1 (2H, m, CH~CH2Ar), 2.8-3.05 (2H, m, CH2CH2Ar), 3.4-3.8 (5H, m, NCH2CO and NCl~l2CHN), 7.12 (lH, s, 7-H~, 7.15 (lH, d, J 8H, 9-H), and 7.9S
(lH, d, J 8Hz, H-10).
~;tep 3: (+)-~-~hlorQ-2~3,4.4a.$!6-hexahYdro-1(H)-~yrazinQ~,2-alquinnline Borane-tetrahydrofuran complex (lM, 6 rr~) was added dropwise to a solution of 8-chloro-2,3,4,4a,5,6-hexahydro-1(H)-pyrazino[1,2-a]quinolin-2-one (0.5 g, 0.002 mol) in THF (25 ml) stirring at room temperature under nitrogen. The resulting mixture was heated at reflux for lh, cooled in ice and lN HCl (20 ml) was added dropwise. The mi~{ture was heated at reflw~ for lh. The reaction mixture was then concentrated in vacuo, the residue partitioned between CH2Cl2:MeOH [1:1] (3 x 20 ml) and ammonia solution (20 ml). The organic phase was evaporated to giYe crude amine which was purified by column chromatography on silica with CH2Cl2:MeOH (9:1) as eluan$ to afford the ti~le compound as a colourless oil (0.34 g, 71%); ~iH (CDCl3) 1.65-1.9 (2H, m, CH2CH2Ar), 2.6-3.2 (8~I, m), 3.73-3.8 (lH, m), 6.5 (lH, d, J 8Hz, 10-H), 6.94 (lH, d, J 8 Hz, 9-H), and 6.97 (lH, s, H-7~.

Step 4: (+~-~Chloro-3-((1H-pvrrolor2!3-blpvridin-3-vl)methyl)-2"~,4~4a~5,6-hex~hydro-1(H)-pvrazinor1,2-~ inoline `: ~ ` :: :

- 51 - ~ T1232Y
Following the procedure described in Example 6, Step 3 replacing 1-(4-el~hoxyphenyl)piperazine with 8-chloro-2,3,4,4a,5,6-hexahydro-l(H)-pyrazino[1,2-a]quinoline the title compound was prepared as an o~-white solid (24 %)> m.p. 203-5C (MeOH/EtOH); (Found: C, 68.29; H, 6.98; N, 1~.79.
C20H2lClN4 requires C, 68.07; H, 6.00; N, 15.88%); ~H (DMSO-d6) 1.5-1.65, 1.9-2.05 and 2.08-2.15 (4H, 3m, CH~CH~Ar), 2.55-3.0 (6H, m, 3 x CH2N), 3.65-3.8 (3H, m, indole-CH2N and CH), 6.77 (lH, d, J 8Hz, 9'-H), 6.9-7.1 (3H, m, 10'-H, 7'-H and 5-H), 7.36 (lH, br s, 2-H), 8.03 (lH, dd, J 8, 1.~ Hz, 4-H), 8.2 (lH, dd, J
4.5, 1.5 Hz, 6-H), and 11.6 (lH, br s, NH).

8-Chloro-3-(~lH-~vrrolor2.3-blpvri~in-3-v )methvl~-2.3~4,4a!5~6-hex~ydrQ~l~H)-~Zrazinorl~2-alauinoline Enantiomer A

HPLC resolu~ion of the enantiomers of (_)-8-chloro-3-((lH-pyrrolo[2,3-lb]pyridin-3-yl)methyl)-2,3,4,4a,5,6-hexahydro-l(H)-pyrazino[l,2-a]quinoline ~Example 33) was achieved USiIlg a Chiralcel OJ (250x4.6 mm id, 10 micron) column using 10%
isopropanol in hexane (+ 0.~% diethylamine) at a flow rate of 1 ml/min. Enantiomer A was first eluting with a retention time of 26 15.1 min. Preparative HPL(: using the above system enabled the isolation of milligram quantities of ~he title eompound.

.. ~ ~ . , . -- 62 2I ~ ~21 3 T1232Y
~:X4MPLE

(~loro-3-((I!~-I;?~Qlor2.3-bl~din-3-v'l?methyl~-2~3,4!4a~5~hexahvdro-l(H)~ vr~zirlQrl.2-alquinoline 6 Enantiomer B

HPLC resolution of the enantiomers of (:t)-8-chloro-3-((lH-pyrrolo~2,3-b]pylidin-3-yl)methyl)-2,3,4,4a,5,6-he~ahydro-1(H)-pyrazino[1,2-a~quinoline (E~amp~e 33) was achieved using a Chiralcel OJ (2~0x4.6 mm id, 10 micron) column using 10%
isopropanol in hexane (+ 0.~% diethylamine) at a flow rate of 1 ml/min. Enantiomer B was second eluting with a retention time of 21.6 min. Preparat*e HPLC using the above system enabled the isolation of milligram quantities of ~e title compound.
lE~AMPLE 3~

(+)-8-Chloro-~-((lH-pv~rolor2,3-~idin-~-vl)me~hvl)-2,3,4 4a,~.6-hçxa.hvdr~-1(H~;yrazinor2!1-cl-1~4-b~nzQxazinQ
:
Step 1: (+)-~-Chloro-2,~ 4a.5~6-hexahydro-1(H)-pvrazinç[2 1-cL1!4-benzox~zine Following the procedure of Gupta et al. Indian J. (~hem., 139 2~ 462-7 (1976) replacing 2-nitrophenol with 6-chloro-2-nitroph~nol the ti~le compound was obtained as a colourless oil; ~iH (CDCl3) 2.46 (lH, dd, J 12, 12Hz, CH), 2.6 (lH, ddd, J, 12, 12, 3Hz, CH), 2.8-3.15 (4H, m, 4 x CH), 3.~ (lH, dd, J 12, 2Hz, CH), 3.9 (lHI
dd, J 9, 9Xz, CH), 4.08 (lH, dd, J 12, 2Hz, CH), 6.6 tlH, d, J 8 Hz, 10'-H), 6.7 (lH, d, J 2Hz, 7'-E), and 6.72 (lH, dd, J 8, 2H~, 9'-H).

- 63 - ~ ~ 621 3 T1232Y

Step 2~ 8-Chloro~-((l~l-~vrrolor2.3-bl~vridin-3-vllmethvl~-2~ ,4a.$~ ex~ydrQ-l(H)-pvrazi~or2,1~cl-1~4-benzoxazineA

Following the procedure described in E~ample 6, Step 3 replacing 1-(4-ethoxyphenyl)piperazine with (i)-8-Chloro-2,3,4,4a,~,6-he~ahydro-1(H)-pyrazino[2,1-c]-1,4-benzoxazine the title compound was obtained as a colourless solid, m.p.> 200C
(MeOH); (Found: C, 63.98; H, 5.37; N, 15.49. ClgHl9ClN4O
requires C, 64.31; H, 5.39; N, 16.79%); ~H (DMSO-d6) 1.73 (lH, dd, J 11, ~ Hz, CH), 2.14 (lH, dd, J 11, 1.6 Hz, CH), 2.55 (lH, dd, J 11, 2Hz, CH), 2.7~-3.0 (3H, m, 3 x CH), 3.6-3.7 (3H, m, 3 ~
~H), 3.86 (1H, t, J 9Hz, CH), 4.21 (lH, dd, J 10, 3Hz, CH), 6.72 ~lH, s, 7'-E), 6.7~-6.85 (2H, m, 10'-H and 9'-H), 7.04 (lH, dd, J 8, 4.5Hz, 5-H), 7.38 (lH, br s, 2-~), 8.03 (1EI, dd, J 8, 2Hz, 4-H), 8.2 (lH, dd, J 4.5, 2Hz, 6-H), and 11.6 (lH, br 5, NH); m/z (CI~, NH3) 355, 357 (M~1)+.

EXAM:PLE 37 3-(4-r4-Methoxymethylph_nyl~piperazin-l-yl)methvl-lH-~vrrolor2,3-bll~y,ridine Step 1: 1-(tert-Butoxv~arbonyl)-4-(4-trifluoromethanesulfonvlQxy~aQn~rl)pip~razine lriethylamine (0.77ml, 5.62mmol) was added to a suspension of 1-(te~t-buto~ycarbonyl)-4-(4-hydroxyphenyl)piperazine (1.39g, 30 4.99mmol) in dichloromethane and the resulting solution cooled to 0C. Tri~luoromethanesulfionic anhydride (0.92ml, 5.47mmol) was ~: :

- 54 - ~ 21 3 T1232Y
added and the reaction mixture stirred at 0C for 1 hour under nitrogen. The mixture was concentrated in vacuo to a dark brown oil which was redissolved in dichloromethane (50ml) and washed with lM hydrochloric acid (50ml), lM sodium hydroxide solution (50ml) and brine (~Oml). The organic phase was dried (MgSO,~) and concentrated in vacuo to give the title compozmd (1.93g, 94%), a~, a pale amber oil which crystallised on standing; ~iH (CDC13) 1.48 (9H, s, C(CH3)3), 3.16 (4H, m, 2 x piperazinyl CH2), 3.59 (4H, m, 2 x piperazinyl CH2), 6.91 (2H, m, ArH), and 7.16 (2H, m, ArH).
Stel;~ 2~ 1-(tçrt-Butoxyçarbonvl)-4-(4-methQxycarbQnYlphenYl)pip~er~ine A mixture of 1-(te~-butoxycarbonyl)-4-(4-trifluoromethanesulfonylo~yphenyl)piperazine (1.92g, 4.68~nol), palladium (II) acetate (52.5mg, 0.23mmol), 1,1'-bis(diphenylphosphino)ferrocene (325.0mg, 0.59mmol), triethylamine (1.3ml, 9.33mmol), methanol (8ml) and dimethylformamide (20ml) was purged with carbon monoxide for 1~ -minutes, sealed under a balloon of carbon monoxide and stirred at 60C ovelnight (18 hours). The reaction mixture was allowed to cool, concentrated in vacuo to a small volume and the residue triturated with ethyl acetate. The solid was collected, washed with ethyl acetate and dried to give the title compound ~0.6~9g, 44%), as 2~ a pale cream solid. Evaporation of the ethyl acetate mother liquors and purification of the residue by flash chromatography ~eluting with ~% to 10% ethyl acetate in dichloromethane) gave more of the title compound (0.492g, 33~ H (CDCl3) 1.49 (9H, s, C(CH3)3), 3.31 (4H, m, 2 x piperazinyl CH2), 3.60 (4H, m, 2 x piperazinyl CH2), 3.87 (3H, s, C~2CH3), 6.89 (2H, m, Ar~l), and 7.94 (2H, m, ArH).

. ~ . - .

Step 3: l-(tert-B~tQxvcarbo~ -L4-hvdroxy~hvl~henvl)piperazin~

Diisobutylaluminium hydride in toluene (1.5M, 16ml, 5 22.5mmol) was added dropwise to a solution of 1-(te~-butoxycarbonyl)-4-(4-methoxycar~onylphenyl)piperazine (2.90g, 9.05mmol) in THF (116ml) at 0C. The mixture was stirred at 0C
for ~ hours then allowed to warm to room temperature. The solution was recooled to -4C and the reaction quenched by the addition of 10 methanol (6ml), water (3ml) and finally 2M sodium hydro~ide (3ml).
The mixture was allowed to warm to room temperature, the precipitated alumini~n salts collected under suction and washed with dichloromethane. The filtrate was concentra$ed in vacuo and the residue purif;ed by flash chromatography, eluting with 15 dichloromethane~ethyl acetate, to give the title compound (2.30g, 74%); ~ (CDCl3) 1.48 (9H, s, C(CH3)3), 1.60 (lH, v br, CH2OH), 3.13 (4H, m, 2 x piperazinyl CH2), 3.58 (4H, m, 2 ~ piperazinyl CH2), 4.61 (2H, s, CH2OH), 6.92 (2H, m, ArH), and 7.29 (2H, m, ArH).

Step 4; 1-(tert-Butoxycarbonvl~-4-(4-methoxYmethYlphenvl)piper~,zin_ Sodium hydride (80% dispersion in oil; 0.10g, 3.3mmol) was added to a sohltion of (l-t~rt-butoxycarbonyl)-4-(4-hydroxymethylphenyl)piperazine (0.80g, 2.74mmol) in THF (lOml) at 0C. The mi~ture was stirred at 0C for 90 minutes, allowed to warm to room temperature and stirred for a further 30 minutes.
The mixture was recooled to 0C, me-thyl iodide tO.20ml, 3.2mmol) added dropwise and the mi~ture stirred at room temperature overnight. TLC indicated that starting material remained unreacted. A furt~er portion of sodium hydride (0.04g, 1.3mmol) ~, . .. .

- 66 - X ~ T1232Y
was added, the reaction mixture stirred at room temperature for one hour, methyl iodide (0.17ml, 2.73mmol) was added and the mixture stirred overnight. The reaction mixture was poured into water (lOOml) and extracted with ethyl acetate (2 x 50ml). The extracts 5 were washed with brine (50~ , combined, dried (MgSO4) and concen~rated in v~cuo. The residue was purified by flash chromatography eluting with ethyl acetate/petrol (60-80) to give the title compound (0.62g, 74%); ~H (DMSO-d6) 1.42 (9H, s, C(CH3)3), 3.08 (4H, m, 2 x piperazinyl CH2), 3.22 (3H, s, CH20CH3), 3.45 (4H, m, 2 x piperazinyl CH2), 4.28 (2H, s, ArCHgOCH3), 6.92 (2H, m, ArH), and 7.17 (2H, m, A~H).

~teI) 6: 1-(4_Me~hoxymethvl~henvl)piperazine 16 A solution of hydrogen chloride in ether (lOml) was added to a solution of 1-(tert-butoxycarbonyl)-4-(4-metho2 :ymethylphenyl)piperazine (0.62g, 2.02mmol) in ethyl acetate (lOml) and the resulting mixture stirred at room temperature for 16 minutes. The mixture was poured into saturated aqueous 20 potassium carbonate (200ml) and e~tracted with dichloromethane (2 x 100ml). The extracts were washed with brine (1OOml), combined, dried (MgSO4) and concentrated. The residue was purified by flash chromatography, eluting with 90:8:1 then 60:8:1 dichloromethane/methanoVammonia, to give the title compound (0.26g, 62%), a~ a pale brown oil; ~H (CDCl3) 3.03 (4H, m, 2 x piperazinyl CH2), 3.14 (4H, m, 2 x piperazinyl CH2), 3.34 (3H, s, CH20CH3), 4.37 ~2H~ s, ArCH20CH3), 6.90 (2H, m, ArH), and 7.23 (2H, m, ArH).

Step 6: 3-(4-r4-M~Q~ne~lphenvllpiperazin-l-vl)methvl-lH-pvrrolo[2 .3-blp~ridine 2 ~ 3 1-(4-Methoxymethylphenyl)piperazine was converted into the title compound by the method outlined in Example 6, Step 3.

6 M.p. 161 5-163C (MeOH); (Found: C, 71.46; H, 7.07; N, 16-09- C20H24N4O.o.o6 C7H8 requires C, 71.72; H, 7.22; N, 16.38%);
~H (DMSO-d6) 2.62 (4H, m, 2 ~ piperazinyl CH2~, 3.10 (4H, m, 2 x piperazinyl CH2), 3.21 (3H, s, CH2OC~3), 3.68 (2H, s, CH2N), 4.26 (2H, s, ArC~3;2OCH8), 6.87 (2E, d, J 8.6Hz, ArH), 7.04 (lH, dd, J 7.8, 4.6Hz, ~-H), 7.13 (2H, d, J 8.6Hz, ArH), 7.37 (lH, br s, 2-H), 8.06 (lH, br d, J 7.8Hz, 4-H), 8.1~ (lH, dd, J 4.6, 1.4H~, S-H), and 11.47 (lH, br s, NH); m/z (CI-~, NH3) 337 (M+1).

1~
~-(4-r4-Dimethvlaminomethvlphenvllpiperazin-1-vl)methvl-1H-py~olor2 3-blpyr~dine Step li 1-(4-Dime~hylç~rboxamidophenxl)piperazine ~0 A mixture of 1-(te~-butoxycarbonyl)-4-(4-trifluoromethanesulfonylo~yphenyl)piperazine (7.4g, 18mmol), palladium(II) acetate (198mg, 0.88mmol), 1,1'-bis(diphenylphosphino)ferrocene (1.28g, 2.26mmol), triethylamine (17.6ml, 126mmol), dimethylamine hydrochloride (7.3g, 90mmol) and dimethylformamide (7~ml) was purged with carbon monoxide for 16 minutes, sealed under a balloon of carbon monoxide and stirred at 60C overnight (20 hours). The reaction was cooled and concentrated in vacuo to a small volume. Water (50ml) and ethyl acetate (~0ml) were added and the phases were separated. The aqueous was extracted with ethyl acetate (2 x ~0ml). The combined -58- ~l62~3 T1232Y
organics were washed with water (20ml) and brine (20ml), dried (MgSO4) and evaporated in VCICUO to give a purple re6idue. The crude product was chromatographed on silica eluting with 2%
methanol~dichloromethane. The amine W3.8 deprotected by dissolving the compound in ethyl acetate and treatment with ethereal hydrogen chloride. The gum obtained was partitioned between hydrochloric acid (û.5M) and ether, the phase~ were separated and the aqueous washed again with ether. The aqueous was basified with sodium hydroxide (lOM) and extracted with n-butanol (4 x 60ml). The extracts were dried (Na2SO4) and evaporated in vacuo to give the ~itle compound as a brown gum (0.8g, 19%); SH (CDC13) 2.98-3.14 (8H, m, N(CH3)2 and piperazinyl CEI2), 3.18-3.30 (4H, m, 2 x piperaæinyl CH2), 3.56-3.65 (2H, m, piperazinyl CH2), 6.89 (2H, d, J 12.5Hz, ArH), and 7.40 (2H, d, J
12.5Hz, ArH).

Step 2: 3-(4-r4-Dimethvlcarboxamidophenvllpiperazin~
vl)methvl-lH-pyrrolor2!3-blp~idine 1-(4-Dimethylcarboxamidophenyl)piperazine was converted into the titl~ compound by the method outlined in Example 6, Step 3; m.p. 217-219C (MeOH).

Step~ ~4-r4-Dime~hylaminomethYlphenyllpiperazin-l-26 vl)methyl-1H-pv~olor2.3-1~2xridine Lithium aluminium hydride (lM solution in TXF, 2.7ml, 2.7mmol~ was carefully added to a suspension of 3-(4-[4-dimethyl-carboxamidophenyl]piperazin-1-yl)methyl-1H-pyrrolo[2,3-b]pyridine (650mg, 1.79mmol) in tetrahydrofuran (30ml) under a nitrogen - -.. . .- . -. ~ . ~ ,.; . , . ~ . . . - . . . .

2~ 3 atmosphere and the resultant solution was heated at reflux for 2 hours.
The mixture was cooled to room temperature and treated with water (0.1ml), sodium hydroxide (4N, 0.1ml) and water (0.3ml). The mixture was filtered through celite(~) and the filter cake was washed with tetrahydrofuran. The ~ltrate was evaporated in vacuo and the residue triturated with ether. Recrystallisation from ethyl acetate gave the title compound as an offwhite solid (228mg, 36%), m.p.
163-165C; (Found: C, 71.72; H, 7.90; N, 20.02. C2lH27N~Ø2 (H20) requires C, 71.80; H, 7.81; N, 19.93~ H (DMSO-d6) 2.08 (6H, s, N(CH3)2), 2.49-2.53 (4H, m, 2 x piperazinyl CH2), 3.07 (4H, m, 2 x piperazinyl CH2), 3.24 (2H, s, ArCH2N(CH3)2), 3.67 (2H, s, ArCH2N), ff.84 (2H, d, J 8.6Hz, 2 x ArH), 7.02-7.09 (3H, m, ArH), 7.37 (lH, d, J
2.1Hz, 2-H), 8.û4 (lH, dd, J 7.8, 1.2Hz, 4-H), ~.18 (lH, dd, J 4.6, 1.5Hz, 6-H), and 11.47 (lH, br s, NH); m/z (CI+, NH3) 350 (M~1)+.

3~ 2.~,4~1QlOa-Hexahvdropvraæinorl!2-alindol-2-vl)me~hvl-1H pyrroloL2~3-blpyridine ~3tep 1: 1~2,3,4.10`10a-HexahvdropvrazinoL1~2-alindole Palladium on charcoal (10%, 660mg) was carefillly added to a solution of 2-benzyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole hydrochloride (4.2g, 140mmol) (prepared using the method of Freed, U~; Patent 3,317,524~ in methanol (200ml) under a nitrogen atmosphere and the mixture was hydrogenated at 46 psi, 50C for 3.5 hours after which time the hydrogen uptake had ceased. The catalyst was removed by filtration and the filtrate concentrated in vacuo to about ~Oml. Dry ether (lOOml~ was added, the precipitated : -. - .

~1~Bi~l~

pink solid was collected by ~Sltration and dried irl vacuo. This hydrochloride salt was partitioned between sodium hydroxide solution (2N, 100ml) and ethyl acetate (lOOml), the phases were separated and the aqueous e~ctracted with ethyl acetate (lOOml and 50ml). The combined organics were washed with brine (50ml), dried (Na2SO4) and evaporated in vacuo to give a red oil. The oil was puri~ed by column chromatography on silica eluting with 10%
methanol/dichloromethane to give 1,2,3,4-tetrahydropyrazine [1,2-a]indole (1.48g, 61%) and 1,2,3,4,10,10a-hexahydropyrazino[1,2,-a]indole (280mg, 11%); ~H (CDC13) 2.53-2.60 (lH, m, aliphatic CH), 2.78-3.17 (6H, m, 3 x aliphatic CH2), 3.47-3.71 ~2H, m, aliphatic CH2), 6.45 (lH, t, J 7.7Hz, ArH), 6.64-6.68 (lH, m, ArH), and 7.05-7.09 (2H, m, ArH).

~tep 2: 3-(1~2~3,4!1~10a-H~xahvdropvrazinorl,2-~lindol-2-yl2methvl-lH-~yrrolQr2~-blpvridin~

Following the procedure described in Example 6, Step 3 replacing 1-(4-ethoxyphenyl)pipera7ine with 1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indole the title compound was obtained, m.p. 197-198C (EtOAc); (Found: C9 74.53; H, 6.77; N, 17.86.
C1gH20N4 05 (CH3C02C2H~) requires C, 74.68; H, 6.66; N, 18.14%);
~H (DMSO-d6) 1.91-1.98 (lH, m, 1 x aliphatic H), 2.0~ (lH, dt, J 3.0, 11.3Hz, 1 x aliphatic H), 2.43 (1H, m, 1 x aliphatic H), 2.7&-2.90 26 (4H, m, 4 x aliphatic H), 3.42-3.69 (4H, m, 4 x aliphatic H), 6.43-6.53 (2H, m, ArH), 6.92-7.06 (3H, m, ArH), 7.34 (lH, d, J 2.2Hz, 2-H), 8.03 (lH, dd, J 7.8, 1.3Hz, 4-H), 8.18 (lH, dd, J 4.6, 1.4Hz, 6-H), and 11.47 (lH, br s, NH); m/z (CI~, NH3) 305 (M+1)*.

,.. ~ ~ . ... .... . ~ .. .. .

Claims (25)

1. The use of a compound of formula I, or a pharmaceutically acceptable salt thereof or a prodrug thereof:

( I ) wherein R represents hydrogen or C1-6 alkyl;
R1 represents hydrogen, or an optionally substituted C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, aryl, aryl(C1-6)alkyl, aryloxy(C1-6)alkyl, aryl(C1-6)alkoxy, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl heteroaryl(C1-6)alkyl, heteroaryl(C2-6)alkenyl or heteroaryl(C2-6)alkynyl group; or R1 represents a straight or branched alkylene chain containing from 1 to 4 carbon atoms, and optionally incorporating an oxygen atom, which links the piperazine moiety to the group R2;
R2 represents an optionally substituted C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, aryl, aryl(C1-6)alkyl, aryloxy(C1-6)alkyl, aryl(C1-6)alkoxy, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl, heteroaryl(C1-6)alkyl, heteroaryl(C2-6)alkenyl or heteroaryl(C2-6)alkynyl group;

R3, R4 and R5 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -ORa, -SRa, -SORa, -SO2Ra, -SO2NRaRb, -NRaRb, -NRaCORb, -NRaCO2Rb, -CORa, -CO2Ra or -CONRaRb; and Ra and Rb independently represent hydrogen, hydrocarbon or a heterocyclic group;
for the manufacture of a medicament for the treatment and/or prevention of psychotic disorders.

2. The use as claimed in claim 1 wherein represents hydrogen, or an optionally substituted C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, aryl, aryl(C1-6)alkyl, aryloxy(C1-6)alkyl, aryl(C1-6)alkoxy, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl, heteroaryl(C1-6)alkyl, heteroaryl(C2-6)alkenyl or heteroaryl(C2-6)alkynyl group; and R2, R3, R4 and R5 are as defined in claim 1.

3. The use as claimed in claim 1 or claim 2 of a compound represented by formula IIA, and pharmaceutically acceptable salts thereof and prodrugs thereof:

(IIA) wherein n is zero, 1, 2 or 3;
R10 represents hydrogen or methyl;

R13 represents hydrogen, halogen, cyano, nitro, trifluoromethyl, amino, C1-6 alkylamino, di(C1-6)alkylamino, C1-6 alkyl, C1-6 alkoxy, aryl(C1-6)alkoxy or C2-6 alkylcarbonyl; and R17 represents hydrogen, C1-6 alkyl, halogen, trifluoromethyl, hydroxy, hydroxy(C1-6)alkyl, C1-6 alkoxy, aryl(C1-6)alkoxy, C1-6 alkoxy(C1-6)alkyl, carboxy, C2-6 alkoxycarbonyl, C2-6 alkylcarbonyl, cyano, nitro, amino, C1-6 alkylamino, di(C1-6)alkylamino, amino(C1-6)alkyl, C1-6 alkylamino(C1-6)alkyl or di(C1-6)alkylamino(C1-6)alkyl.

4. A method for the treatment and/or prevention of psychotic disorders, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof or a prodrug thereof.

5. The method as claimed in claim 4 wherein R1 represents hydrogen, or an optionally substituted C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, aryl, aryl(C1-6)alkyl, aryloxy(C1-6)alkyl, aryl(C1-6)alkoxy, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl, heteroaryl(C1-6)alkyl, heteroaryl(C2-6)alkenyl or heteroaryl(C2-6)alkynyl group; and R, R2, R3, R4 and R5 are as defined in claim 1.

6. The method as claimed in claim 4 wherein the compound administered is represented by formula IIA
as defined in claim 3, and pharmaceutically acceptable salts thereof and prodrugs thereof.

7. A compound of formula IIB, or a salt thereof or a prodrug thereof:

( I I B ) wherein m is 1, 2 or 3; and R10, R13 and R17 are as defined in claim 3.

8. A compound of formula IIC, or a salt thereof or a prodrug thereof:

(I I C ) wherein n, R10 and R13 are as defined in claim 3; and W represents a group of formula (i), (ii), (iii) or (iv):

( I ) ( I I ) ( I I I ) ( i V ) in which V represents nitrogen or CH;
R17 is as defined in claim 3;
R18 represents hydrogen or methyl; and R27 represents C1-6 alkyl, halogen, trifluoromethyl, C1-6 alkoxy, cyano, nitro, amino, C1-6 alkylamino or di(C1-6)alkylamino.

9. A compound of formula IID, or a salt thereof or a prodrug thereof:

( I I D ) wherein X represents a group of formula -CH2- or -CH2CH2-;
Y represents a chemical bond or an oxygen atom;
and R10, R13 and R17 are as defined in claim 3.

10. A compound of formula IIE, or a salt thereof or a prodrug thereof:

( I I E ) wherein R13 is as defined in claim 3; and R37 represents fluoro, chloro, bromo, iodo or trifluoromethyl.

11. A compound selected from:
3-(4-phenylpiperazin-1-yl)methyl-1H-pyrrolo[2,3-b]-pyridine;
3-[4-(4-methoxyphenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-(4-benzylpiperazin-1-yl)methyl-1H-pyrrolo[2,3-b]-pyridine;
3-[4-(4-ethylphenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine:
3-[4-(4-chlorophenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
and salts and prodrugs thereof.

12. A compound selected from:
3-[4-(4-ethoxyphenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(4-dimethylaminophenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(3,4-dichlorophenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-h]pyridine;
3-[4-(4-methoxyphenyl)piperazin-1-yl]methyl 1-methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(5-chloropyrid-2-yl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(3-isoquinolyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(5-indolyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(4-iodophenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(4-trifluoromethylphenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine:
3-[4-(2-phenoxyethyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(4-methylphenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
and salts and prodrugs thereof.

13. A compound selected from:
3-[4-(4-fluorophenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(1-methylindol-5-yl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(indazol-5-yl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(4-ethoxycarbonylphenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(4-carboxyphenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;

3-[4-(3-methylphenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(2-methylphenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(3,4-methylenedioxyphenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(4-bromophenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(4-methoxycarbonylphenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(4-hydroxymethylphenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(5-methylpyrid-2-yl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(4-hydroxyphenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(benzothiophen-2-yl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(benzothiophen-3-yl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-2,3,4,4a,5,6-hexahydro-1(H)-pyrazino[1,2-a]quinoline;
8-chloro-3-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-2,3,4,4a,5,6-hexahydro-1(H)-pyrazino[1,2-a]quinoline;
8-chloro-3-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]-2,3,4,4a,5,6-hexahydro-1(H)-pyrazino[2,1-c]-1,4-benzoxazine;
3-[4-(4-methoxymethylphenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-[4-(4-dimethylaminomethylphenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine;
3-(1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indol-2-yl)methyl-1H-pyrrolo[2,3-b]pyridine;
and salts and prodrugs thereof.

14. 3-[4-(4-Chlorophenyl)piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine; and salts and prodrugs thereof.

15. A pharmaceutical composition comprising a compound as claimed in any one of claims 7 to 14 in association with a pharmaceutically acceptable carrier.

16. A compound as claimed in any one of claims 7 to 14 for use in therapy.

17. The use of a compound as claimed in any one of claims 7 to 14 for the manufacture of a medicament for the treatment and/or prevention of psychotic disorders.

18. A method for the treatment and/or prevention of psychotic disorders, which comprises administering to a patient in need of such treatment an effective amount of a compound as claimed in any one of claims 7 to 14.

19. A process for the preparation of a compound of formula IA:

( I A ) wherein R, R3, R4 and R5 are as defined in claim 1, and Q
represents a group of formula selected from the moieties of formula Qa, Qb, Qc and Qd:

( Q a ) ( Q b ) ( Q c ) ( Q d ) in which n and R17 are as defined in claim 3, m is as defined in claim 7, W is as defined in claim 8, X and Y
are as defined in claim 9 and R37 is as defined in claim 10; which process comprises:

(A) reacting a compound of formula III with a compound of formula IV:

( I I I ) ( I V ) wherein RP corresponds to the group R or represents a suitable protecting group; in the presence of a substantially equimolar amount of formaldehyde; followed, where required, by removal of the protecting group RP;
and subsequently, if necessary, N-alkylation by standard methods to introduce the moiety R; or (B) reacting a compound of formula IV as defined above with a compound of formula V:

( V ) wherein L represents a suitable leaving group; followed, where required, by removal of the protecting group RP;
and subsequently, if necessary, N-alkylation by standard methods to introduce the moiety R; and (C) subsequently, where required, converting a compound of formula IA initially obtained into a further compound of formula IA by conventional methods.

20. A process as claimed in claim 19 wherein L
represents a halogen atom or a dialkylamino group.

21. A process for the preparation of a pharmaceutical composition which comprises mixing a compound as claimed in any one of claims 7 to 14 with a pharmaceutically acceptable carrier.

22. An anti-psychotic disorder pharmaceutical composition comprising an effective, acceptable anti-psychotic disorder amount of a compound of formula (I) as defined in claim 1 or 2, or a pharmaceutically acceptable salt or prodrug thereof, in association with a pharmaceutically acceptable carrier.

23. An anti-psychotic disorder pharmaceutical composition comprising an effective, acceptable anti-psychotic disorder amount of a compound of formula (IIA) as defined in claim 3, or a pharmaceutically acceptable salt or prodrug thereof, in association with a pharmaceutically acceptable carrier.

24. A dopamine receptor subtype antagonist pharmaceutical composition comprising an effective, acceptable antagonist amount of a compound of formula (I) as defined in claim 1 or 2, or a pharmaceutically acceptable salt or prodrug thereof, in association with a pharmaceutically acceptable carrier.

25. A compound of formula (I) as defined in claim 1 or 2, or a pharmaceutically acceptable salt or prodrug thereof for use in the treatment or prevention of schizophrenia.