ZA200405804B - Benzenesulfonamide derivatives as antipsychotic agents - Google Patents

Description

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BENZENESULFONAMIDE DERIVATIVES AS ANTIPSYCHOTIC AGENTS

This invention relates to novel compounds, pharmaceutical compositions containing them and their use in therapy, in particular as antipsychotic agents.

WO 98/27081, WO 99/02502, WO 99/37623, WO 99/42465 and WO 01/32646 (SmithKline

Beecham plc) disclose a series of aryl sulfonamide and sulfoxide compounds that are said to be 5-HT, receptor antagonists and which are claimed to be useful in the treatment of various

CNS disorders.

WO 01/62737 discloses amino pyrazole derivatives useful for the treatment of obesity and other disorders associated with the NPY receptor subtype Y5.

EP0937723 discloses sulfonamide compounds useful in the treatment of thrombolytic disorders.

WO 01/85695 discloses tetrahydroisoquinoline analogues useful as growth hormone secretagogues.

US 5,684,195 discloses a method of preparing sulfonamides from sulfones.

WO 02/46164 discloses aryl sulfonamide compounds that are said to be useful as selective

ER-B ligands in the treatment or prophylaxis of Alzheimer’s disease, anxiety disorders, depressive disorders, osteoporosis, cardiovascular disease, rheumatoid arthritis or prostate cancer.

A structurally novel class of compounds has now been found which are useful as antipsychotic agents and for the treatment of other disorders.

According to the invention, there is provided a compound of formula (I): ®") 0.0 AA

NY NMR

R—z—Ar" ON B

I wherein

A and B represent the groups (CHy)- and ~(CH,)a-respectively; R!represents hydrogen or C, alkyl;

R? represents hydrogen, halogen, hydroxy, cyano, nitro, hydroxyC,.salkyl, trifluoromethyl, trifluoromethoxy, Cisalkyl, Cealkoxy, Ci.salkoxyCi.ealkyl, Cs.scycloalkylC, alkoxy, - (CH>),Cs.scycloalkyl, -(CH,),C;.scycloalkyloxy, -COC,ealkyl, -SO,C, alkyl, -SOC, alkyl, -

S-Cyalkyl, C.calkylsulfonyloxy, CyealkylsulfonylCyealkyl, -CO,Cy.calkyl, -CO,NR'R?, -

SONR'R®, C,salkylsulfonamido, C.calkylsulfonamidoC,calkyl, «(CH,),NR'R’, Cis alkylamidoC;.salkyl, -(CH,),NR'COR’, arylsulfonyl, arylsulfonyloxy, arylsulfonylC,.salkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC,¢alkyl, arylcarboxamidoC, salkyl, aroyl, aroylCiealkyl, arylC,alkanoyl, -SO,NR'R®, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl, or a group CONR'R® or SO,NR'R® wherein R’ and R® together may be fused to form a 5- 7-membered aromatic or non-aromatic heterocyclic ring optionally interrupted by an O or S atom;

R? represents hydrogen or C,.salkyl;

Ar represents optionally substituted phenyl or optionally substituted monocyclic heteroaryl group;

R* represents optionally substituted aryl or optionally substituted heteroaryl;

R’ and R® each independently represent hydrogen, Cisalkyl or together form a 5- to 7- membered heterocyclic ring;

Z represents a bond, an oxygen atom or C,_ealkylene:

Y represents hydrogen or C,salkyl; m and n independently represent an integer selected from 1 and 2; p independently represents an integer selected from 0, 1, 2 and 3; qrepresents an integer from 1 to 3; r represents an integer from 1 to 4; or a pharmaceutically acceptable salt or solvate thereof.

As a further aspect of the invention, there is provided a compound of formula (I) wherein A,

B,Y,Z qr, Ar and R' to R* have any of the meanings as hereinbefore described, with the proviso that when R' represents Cy.salkyl and Y represents hydrogen, Ar cannot represent an optionally substituted monocyclic heteroaryl group.

As used herein, the term “alkyl”, either alone or as part of another group, refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. For example,

Cisalkyl means a straight or branched alkyl containing at least 1, and at most 6, carbon atoms. Examples of “alkyl” as used herein include, but are not limited to, methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, isobutyl, isopropyl, t-butyl and 1,1-dimethylpropyl.

As used herein, the term “alkoxy” refers to a straight or branched alkoxy group containing the specified number of carbon atoms. For example, C alkoxy means a straight or branched alkoxy group containing at least 1, and at most 6, carbon atoms. Examples of “alkoxy” as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-0xy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy or hexyloxy.

As used herein, the term “cycloalkyl” refers to a non-aromatic hydrocarbon ring containing the specified number of carbon atoms. For example, Cs.scycloalkyl means a non-aromatic ring containing at least three, and at most seven, ring carbon atoms. Examples of “cycloalkyl” as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. A Ce cycloalkyl group is preferred.

As used herein, the term “halogen” refers to the elements fluorine, chlorine, bromine and jodine. Preferred halogens are fluorine, chlorine and bromine.

As used herein, the term “aryl” refers to a phenyl or a naphthyl ring.

As used herein, the term “heteroaryl” refers to a 5- or 6-membered heterocyclic aromatic ring or a fused bicyclic heterocyclic ring system.

As used herein, the term “heterocyclyl” refers to a 3- to 7-membered monocyclic saturated 40 ring containing at least one heteroatom independently selected from oxygen, nitrogen and sulfur. Examples of suitable heterocyclic rings include, but are not limited to, piperidine and morpholine.

bY

As used herein, the term “5- or 6-membered heterocyclic aromatic ring” refers to a monocyclic unsaturated ring containing at least one heteroatom independently selected from oxygen, nitrogen and sulfur. Examples of suitable 5- and 6-membered heterocyclic aromatic rings include, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, pyrimidinyl, pyrazolyl, isothiazolyl and isoxazolyl.

As used herein, the term “fused bicyclic heterocyclic ring system” refers to a ring system comprising two 5- to 7-membered saturated or unsaturated rings, the ring system containing at least one heteroatom independently selected from oxygen, nitrogen and sulfur. Preferably, eachring has S or 6 ring atoms. Examples of suitable fused bicyclic rings include, but are not limited to, indolyl, indolinyl, benzofuranyl, benzothienyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzodioxanyl, indanyl and tetrahydronapthyl.

As used herein, the term “optionally substituted” refers to optional substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.

As used herein, the term “solvate” refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include water, methanol, ethanol and acetic acid. Most preferably the solvent used is water and the solvate may also be referred to as a hydrate.

It will be appreciated that for use in medicine the salts of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include for example acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Other non-pharmaceutically acceptable salts e.g. oxalates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention. Also included within the scope of the invention are solvates and hydrates of thc compounds of formula (I).

Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms thereof.

Certain compounds of formula (I) may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention.

The present invention also covers the individual isomers of the compounds represented by formula (I) as mixtures with isomers thereof in which one or more chiral centres are inverted.

Likewise, it is understood that compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present 40 invention.

The groups R%, R® and R® may be located on any free position on their respective phenyl rings. The Y group(s) may be located on any free position on the respective ring.

IS

\ 4

When R% R*, R® or R® represent optionally substituted aryl or optionally substituted heteroaryl or R? additionally represents optionally substituted heterocyclyl, the optional substituents may be independently selected from Ci.ealkyl, Ci.calkoxy, halogen, trifluoromethyl, trifluoromethoxy, cyano, nitro, -NRR®, -C,alkylS and —S-C,salkyl. More preferably, the optional substituents for the groups R?, R’, R® and R® are independently selected from chloro, fluoro, bromo, methyl, ethyl, t-butyl, methoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, —S-methyl, —methyl-S and -NRR®.

When Ar represents optionally substituted phenyl or optionally substituted monocyclic heteroaryl, the optional susbtituents are independently selected from hydrogen, halogen, hydroxy, cyano, nitro, hydroxyCi.ealkyl, trifluoromethyl, triflucromethoxy, Cisalkyl, Ci. salkoxy, Ci.ealkoxyCyealkyl, CsicycloalkylC, alkoxy, -(CH,),Cs.scycloalkyl, -(CH;),C;. scycloalkyloxy, -COC,.ealkyl, -SO.Ci.ealkyl, -SOC, alkyl, -S-Ciealkyl, -CiealkylS, Ci. calkylsulfonyloxy, C,.salkylsulfonylCi.alkyl, -CO,Ci-salkyl, -CO,NR'R®, -SO,NR'R?, C,. calkylsulfonamido, C,.ealkylsulfonamidoC;.ealkyl, -(CH,),NR'R?, C,_alkylamidoC,.calkyl, - (CHp,NR'COR’, aryl sulfonyl, arylsulfonyloxy, arylsulfonylC.calkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC.alkyl, arylcarboxamidoC,ealkyl, aroyl, aroylC,_salkyl, arylC,.salkanoyl, -SO,NR'R®, optionally substituted aryl or optionally substituted heteroaryl, or a group CONR'R® or SO,;NR'R® wherein R’ and R® together may be fused to form a 5- to 7.membered aromatic or non-aromatic heterocyclic ring optionally interrupted by an O or S atom.

Preferably, R! represents hydrogen or Cyqalkyl. More preferably, R' represents hydrogen, methyl, ethyl, n-propyl, isopropyl, t-butyl or n-butyl. Even more preferably, R! represents hydrogen, methyl, ethyl, n-propyl or isopropyl. Even more preferably, R! represents hydrogen or methyl.

Preferably, R? represents hydrogen, halogen, C.¢alkyl, C,.¢alkoxy, -Cy.alkylS, —S-Ci.ealkyl, -

NR'R® or optionally substituted heterocyclyl. In particular, R? represents methyl, ethyl, methoxy, ethoxy, isopropoxy, bromo, chloro, dimethylamino, -S-ethyl, -ethyl-S or piperidyl.

More preferably, R? represents hydrogen, halogen, Ci.calkyl or C..salkoxy. Even more preferably, R? represents hydrogen, halogen, Cy4alkyl or C,4alkoxy. Even more preferably, R?represents hydrogen, dimethylamino, methoxy, ethoxy or isopropoxy.

Preferably, R® represents hydrogen or C,,alkyl. More preferably, R® represents hydrogen, methyl, ethyl, n-propyl or isopropyl. Even more preferably, R® represents hydrogen, methyl or isopropyl.

Preferably, R* represents phenyl, naphthyl, thienyl, benzofuranyl, furyl, benzothienyl, pyridyl, isoxazolyl and pyrrolyl, all of which may be optionally substituted. More preferably,

R*? represents phenyl, naphthyl, thienyl, benzofuranyl, furyl or benzothienyl, all of which may be optionally substituted. Even more preferably, R* represents phenyl or thienyl (e.g. 2- thienyl or 3-thienyl).

If R* is optionally substituted, preferably R* is mono- or di-substituted. In particular, when rR 40 is phenyl, the optional substituents may be independently selected from chloro (e.g. 2-, 3- or 4-chloro), bromo (e.g. 4-bromo), fluoro (e.g. 2-, 3- or 4-fluoro), dichloro (e.g. 2,4- or 3,4- dichloro), difluoro (e.g. 2,4-, 3,4- or 3,5-difluoro), trifluoromethyl (e.g. 4-trifluoromethyl), methyl (e.g. 2-, 3- or 4-methyl), t-butyl (e.g. 4-t-butyl), methoxy (e.g. 4-methoxy),

trifluoromethoxy (e.g. 4-trifluoromethoxy), cyano (e.g. 4-cyano), nitro (e.g. 4-nitro), dimethylamino (e.g. 4-dimethylamino), -methyl-S (e.g. 4-methyl-S), or methyl and chloro together (e.g. 2-methyl-4-chloro or 3-methyl-4-chloro). More preferably, when R* is phenyl, one of the optional substituents is located at the 4-position relative to the attachment of R* to 5 the rest of the molecule.

When R? is thienyl, the optional substituents may be independently selected from chloro (e.g. 5-chloro) or methyl (e.g. 4- or S-methyl).

Preferably, R and R® independently represent hydrogen or Cj4alkyl. More preferably, R’ and R® independently represent hydrogen or methyl.

Preferably, Ar represents optionally substituted phenyl.

Preferably, Z represents a bond or oxygen. More preferably, Z represents a bond.

Preferably, Y represents hydrogen.

Preferably, p represents 0.

Preferably, q represents 1.

Preferably, r represents 1.

According to a further aspect of the invention, there is provided a compound of formula (I) wherein Ar represents a phenyl ring, i.e. a compound of formula (IA): (R) y

Qf [Oe

RY NC % (1A)

NE

R® or a pharmaceutically acceptable salt or solvate thereof wherein the groups A, B, R'toR*, Z,

Y, q and r have any of the meanings as given hereinbefore and R® and R® each independently represent hydrogen, halogen, hydroxy, cyano, nitro, hydroxyCi.salkyl, trifluoromethyl, trifluoromethoxy, Cjealkyl, Cisalkoxy, C,.ealkoxyC,sealkyl, C;cycloalkylCy salkoxy, - (CH,),Cs.scycloalkyl, -(CH,),Cs.cycloalkyloxy, -COC, alkyl, -SO.Cy.¢alkyl, -SOCy. alkyl, -

S-Ciealkyl, -C,salkylS, Cisalkylsulfonyloxy, CiealkylsulfonylCy.salkyl, -CO,C,qalkyl, - CO,NR'R®, -SO,NR'R?, Cy.ealkylsulfonamido, Cy alkylsulfonamidoC.salkyl, -(CH,),NR'R’,

C,.¢alkylamidoCy_calkyl, CH2),NR'COR®, aryl sulfonyl, arylsulfonyloxy, arylsulfonylCi. salkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC,.ealkyl, arylcarboxamidoC;. calkyl, aroyl, aroylCi.ealkyl, arylCicalkanoyl, -SO,NR'R®, optionally substituted aryl or optionally substituted heteroaryl, or a group CONR'R? or SO,NR’R® wherein R” and R® together may be fused to form a 5- to 7-membered aromatic or non-aromatic heterocyclic ring optionally interrupted by an O or S atom.

Preferably, R® and R® independently represent hydrogen, methyl, fluoro or chloro.

According to a further aspect of the invention, there is provided a compound of formula (IA) wherein q represents 1, r represents 1 and Y represents hydrogen, i.e. a compound of the formula (IB):

R3 0.0 No

RS \ NTR - 5 (1B) 4 N

R—z [,

R

R® or a pharmaceutically acceptable salt or solvate thereof wherein the groups A, B, R'toR® and

Z have any of the meanings as given hereinbefore.

According to a further aspect of the invention, there is provided a compound of formula (IB) wherein the R? group is located at the para-position relative to the group B, i.e. a compound of formula (IC):

R?

AW \ R’ 5 —R'

R Ly ge’ (IC)

Ri—z I

R

R® or a pharmaceutically acceptable salt or solvate thereof wherein the groups A, B, R!to R®and

Z have any of the meanings as given hereinbefore.

According to a further aspect of the invention, there is provided a compound of formula (IB) wherein the group —Z-R* is located at the para-position relative to the sulfonamide group, i.e. a compound of formula (ID) rR? 0.0 AN

SP JO ATR oy 8

R*” z RS wherein

A and B represent the groups —(CH,)n- and (CHy)y-respectively; R! represents hydrogen or Cy.calkyl;

R? represents hydrogen, halogen, hydroxy, cyano, nitro, hydroxyCi.ealkyl, trifluoromethyl, trifluoromethoxy, Cy.calkyl, Ci.calkoxy, -(CH;),Csscycloalkyl, (CH,),Csscycloalkyloxy, -

COC,qalkyl, -SO,Crealkyl, -SOC,ealkyl, -S-Cisalkyl, -CO,Cisalkyl, -CO.NR'R?, -

SO,NR'R®, CH,),NR'R®, -(CH,),NR'COR’, optionally substituted aryl, optionally substituted heteroaryl, a fused bicyclic heterocyclic ring system or optionally substituted heterocyclyl;

R? represents hydrogen or C, alkyl;

R* represents optionally substituted aryl or optionally substituted heteroaryl;

R® and R®each independently represent hydrogen, halogen, hydroxy, cyano, nitro, hydroxyC,. ealkyl, trifluoromethyl, trifluoromethoxy, C;salkyl, C,.ealkoxy, -(CH),Csccycloalkyl, - (CH,),Cscycloalkyloxy, -COC,.salkyl, -SO,C,.salkyl, -SOC,.calkyl, -8-Cp.ealkyl, -CO,C,.¢alkyl, -CO.NR'R}, -SO,NR'R®, -(CH,),NR'R}, -(CH,),NR'COR’, optionally substituted aryl, optionally substituted heteroaryl or a fused bicyclic heterocyclic ring system;

R’ and R® each independently represent hydrogen or C, salkyl;

Z represents a bond, an oxygen atom or Cy.¢alkylene; m and n independently represent an integer selected from 1 and 2; p independently represents an integer selected from 0, 1, 2 and 3; or a pharmaceutically acceptable salt or solvate thereof.

According to a further aspect of the invention, there is provided a compound of formula (ID) whereinmis 1 and nis 1, i.e. a compound of formula (IE):

Rr? 0.0 . 5 \Y/ N—R

R YL JOS (IE)

N a

R*” z R® or a pharmaceutically acceptable salt or solvate thereof wherein the groups Z and R' to R® have any of the meanings as given hereinbefore.

According to a further aspect of the invention, there is provided a compound of formula (ID) wherein m is 2 and n is 1, i.e. a compound of formula (IF):

R2 0.0

Xe, Ne

Ie

RY” z Re . or a pharmaceutically acceptable salt or solvate thereof wherein the groups Z and R' to R® have any of the meanings as given hereinbefore.

According to a further aspect of the invention, there is provided a compound of formula (ID) wherein m is 1 and n is 2, i.e. a compound of formula (IG):

RY R' ~~ 0 ? N

RY \

N

Ie

RY” Zz 8 or a pharmaceutically acceptable salt or solvate thereof wherein the groups Z and R' to R® have any of the meanings as given hereinbefore.

According to a further aspect of the invention, there is provided a compound of formula (IB) wherein mis 2 and nis 2, i.e. a compound of formula (IH): rR? 0.0 1 5 W/ N—R

R NL CH (IH) n N

R&-2z rR? r® or a pharmaceutically acceptable salt or solvate thereof wherein the groups Z and R' to R® have any of the meanings as given hereinbefore.

According to a further aspect of the invention, there is provided a compound of formula (ID) wherein mis 2 and n is 2, i.e. a compound of formula (IJ):

R3 00 1 5 NY] N—R

R No 0) (19)

N ka

RY z R® or a pharmaceutically acceptable salt or solvate thereof wherein the groups Z and R! to R® have any of the meanings as given hereinbefore.

According to a further aspect of the invention, there is provided a compound of formula (IJ) wherein the R? group is located at the para-position relative to the group B, i.e. a compound of formula (IK):

RZ

0 7 1 5 \ N—R ) 6. po (IK)

N

IB rR z R® or a pharmaceutically acceptable salt or solvate thereof wherein the groups Z and R' to R® have any of the meanings as given hereinbefore.

According to a further aspect of the invention, there is provided a compound of formula (I) wherein R' and R? both represent hydrogen, m and n both represent 2 and Z represents a bond, i.e. a compound of formula (IL): 2

Ra (Y), 0 N—H IL

LOSE “

R—Ar \

H wherein:

R? represents hydrogen, halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy,

Ci. alkyl, trifluoromethanesulfonyloxy, pentafluoroethyl, Cs alkoxy, arylC,.s alkoxy, Cis alkylthio, C,.s alkoxyCi. alkyl, Cs.; cycloalkylC,.s alkoxy, Cy. alkanoyl, Cy alkoxycarbonyl,

C.s alkylsulfonyl, Cys alkylsulfinyl, Cs alkylsulfonyloxy, Cis alkylsulfonylC, alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylCi.s alkyl, Cy alkylsulfonamido, Cy. alkylamido,

C..¢ alkylsulfonamidoC, 6 alkyl, C,.s alkylamidoC. alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC,¢ alkyl, arylcarboxamidoCi. alkyl, aroyl, aroylCs alkyl, arylC¢ alkanoyl, or a group CONR'R® or SO,NR'R’, wherein R’ and R® independently represent hydrogen or C,_ alkyl or together may be fused to form a 3- to 7- membered aromatic or non- aromatic heterocyclic ring optionally interrupted by an O or S atom;

Y represents hydrogen or Cs alkyl; q represents an integer from 1 to 3; rrepresents an integer from 1 to 4;

Ar and R? independently represent phenyl or a monocyclic heteroaryl group each of which may be optionally substituted;

Ar and R* may be optionally substituted by one or more substituents which may be the same or different, and which are selected from those defined for R?; or solvates thereof.

According to a further aspect of the invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof wherein the groups A, B, R'toR*,Y, q and 1 have any of the meanings as given hereinbefore and Z represents oxygen or Cy alkylene.

According to a further aspect of the invention, there is provided a compound of formula (IA) or a pharmaceutically acceptable salt or solvate thereof wherein the groups A, B, R' to R*, Y, q and r have any of the meanings as given hereinbefore and Z represents oxygen or Cis alkylene.

According to a further aspect of the invention, there is provided a compound of formula (IB) or a pharmaceutically acceptable salt or solvate thereof wherein the groups A, B and R'toR® have any of the meanings as given hereinbefore and Z represents oxygen or Ci. alkylene.

According to a further aspect of the invention, there is provided a compound of formula (IC) or a pharmaceutically acceptable salt or solvate thereof wherein the groups A,BandR' to R have any of the meanings as given hereinbefore and Z represents oxygen or Ci.salkylene.

According to a further aspect of the invention, there is provided a compound of formula (ID) ora pharmaceutically acceptable salt or solvate thereof wherein the groups A,BandR' to R® have any of the meanings as given hereinbefore and Z represents oxygen or C.salkylene.

According to a further aspect of the invention, there is provided a compound of formula (IE) or a pharmaceutically acceptable salt or solvate thereof wherein the groups R' to R® have any of the meanings as given hereinbefore and Z represents oxygen or Ci.¢alkylene.

According to a further aspect of the invention, there is provided a compound of formula (IF) or a pharmaceutically acceptable salt or solvate thereof wherein the groups R' to R® have any of the meanings as given hereinbefore and Z represents oxygen or Ci.saliylene.

According to a further aspect of the invention, there is provided a compound of formula (IG) or a pharmaceutically acceptable salt or solvate thereof wherein the groups R' to R® have any of the meanings as given hereinbefore and Z represents oxygen or C..salkylene.

According to a further aspect of the invention, there is provided a compound of formula (IH) or a pharmaceutically acceptable salt or solvate thereof wherein the groups R' to R® have any of the meanings as given hereinbefore and Z represents oxygen or C,.salkylene.

According to a further aspect of the invention, there is provided a compound of formula (IJ) or a pharmaceutically acceptable salt or solvate thereof wherein the groups R' to R® have any of the meanings as given hereinbefore and Z represents oxygen or C;salkylene.

According to a further aspect of the invention, there is provided a compound of formula (IK) or a pharmaceutically acceptable salt or solvate thereof wherein the groups R! to R® have any of the meanings as given hereinbefore and Z represents oxygen or Ci.salkylene.

According to a further aspect of the invention, there is provided a compound of formula (IL) or a pharmaceutically acceptable salt or solvate thereof wherein the groups R! to R® have any of the meanings as given hereinbefore and Z represents oxygen or C.salkylene.

In u preferred aspect of the invention, compounds of formula (I) are of the formulae (IE), (IF), (IH), (IV) and (IX) or a pharmaceutically acceptable salt or solvate thereof wherein the groups 7 and R! to R® have any of the meanings as given hereinbefore.

Particular compounds according to the invention include those incorporated in Tables 1 to 3 and those specifically exemplified and named hereinafter including, without limitation:- 4-(4-Chloro-phenyl)-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesul fonamide; 4-(4-Chloro-phenyl)-N-(3 -methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)- benzenesulfonamide; 4-(4-Chloro-phenyl)-N-methyl-N-(2,3,4,5-tetrahydro-1/-3 -benzazepin-7-yl)- benzenesulfonamide; 40 4-(4-Chloro-phenyl)-N-methyl-N-(3 -methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)- benzenesulfonamide; 4-(3,4-Dichloro-phenyl)-N-(2,3,4,5-tetrahydro-1H-3 -benzazepin-7-yl)-benzenesulfonamide hydrochloride;

4-(4-Chloro-phenyl)-N~(8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)- benzenesulfonamide hydrochloride; 4-(4-Chloro-phenyl)-N~(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)- benzenesulfonamide hydrochloride; 4-(4-Chloro-phenyl)-N~(1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzenesulfonamide; 4-(4-Chloro-phenyl)-N-(2,3-dihydro-1H-isoindol-5-y1)-benzenesulfonamide hydrochloride; 4-(4-Chloro-phenyl)-N-(2-methyl-2,3-dihydro-1H-isoindol-5-yl)-benzenesulfonamide; 4-(4-Chloro-phenyl)-3-methyl-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)- benzenesulfonamide hydrochloride; 4-(4-Chloro-phenyl)-3-methyl-N-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)- benzenesulfonamide; 4-(4-Chloro-phenyl)-3-methyl-N-(8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)- benzenesulfonamide hydrochloride; 4-(4-Chloro-phenyl)-3-methyl-N-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin- 7-yl)-benzenesulfonamide; 4-(5-Chloro-thiophen-2-yl)-N-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7- yD)-benzenesulfonamide; 4-(5-Chloro-thiophen-2-yl)-2-fluoro-N-(8-methoxy-3-methyl-2,3,4,5-tetrahydro- 1 H- benzo[d]azepin-7-yl)-benzenesulfonamide; 4-(4-Chloro-phenyl)-N-(8-dimethylamino-3-methyl-2,3,4,5-tetrahydro-1H-benzazepin-7-yl)- benzenesulfonamide hydrochloride and 4~(4-fluorobenzyl)-N-(3-methyl-2,3,4,5-tetrahydro-1 H-benzo[dJazepin-7-yl)- benzenesulfonamide hydrochloride.

The compounds of the present invention may be in the form of their free base or pharmaceutically acceptable salts thereof, particularly the monohydrochloride salt.

The present invention also provides a general process (A) for preparing compounds of formula (I) which process comprises: reacting a compound of formula (II) >

Ra AA)

Ir MR

HN B

Ls with a compound of formula (III) of

R*—z—ar" cl an) wherein A, B, Z, q and r are as hereinbefore defined and R'-R* and Y’ represent R' to R* and

Y as hereinbefore defined or are groups that may be readily convertible to R! to R%.

This general method (A) can be conveniently performed by mixing the two components in a suitable solvent such as pyridine or dichloromethane (in the presence of a base), at 0°C.

According to a further aspect of the invention, when compounds of the formula (ID) are prepared by method (A), a compound of formula (I) as hereinbefore defined is reacted with a compound of formula (11a) 0.0

R® \Y al

RY—z (Illa)

R® wherein A, B, Z, q and r are as hereinbefore defined and RY-R® and Y’ represent R' to R® and

Y as hereinbefore defined or are groups that may be readily convertible to R' to R.

The present invention also provides a general process (B) for preparing compounds of formula (I) wherein Z is a bond, which process comprises: reacting a compound of formula (IV) (RR), ,

Y)

A

? 7 Xo ]"

NX / wv)

X—Ar N BE

R® wherein X is a leaving group, such as iodo, bromo or triflate, and A, B, q, r and Y are as hereinbefore defined and R'-R* represent R' to R® as hereinbefore defined or are groups that may be readily convertible to R' to R, with an aryl boronic acid of formula (V) '

B Vv)

R*~” OH wherein R* represents R* as hereinbefore defined or is a group that may be readily convertible to R*, under standard Suzuki conditions, e.g. treatment of compound (IV) with 4- chlorobenzeneboronic acid in toluene containing aqueous sodium carbonate and a catalytic amount of Pd (PPh), at reflux under argon.

According to a further aspect of the invention, when compounds of the formula (ID) are prepared by method (B), a compound of formula (IV a) ® (¥)

A

5 R\ 7 x &

R NY 8 (IVa)

N

X | .

RE wherein X is a leaving group, such as iodo, bromo or triflate, and A, B, gq, rand Y are as hereinbefore defined and R'-R? represent R' to R® as hereinbefore defined or are groups that may be readily convertible to R' to R®, with an aryl boronic acid of formula (V) as hereinbefore defined.

The present invention also provides a general process (C) for preparing compounds of formula (I) which process comprises: converting a compound of formula (I)

RY, 0.0 AC

NX ATR

R—z—Ar" ">N B ha wherein A, B, Z, Y, q, r and R' to R? are as hereinbefore defined, into another compound of formula (I) by substituting the group R! or the group R® using conventional techniques.

Interconversion of one of the R" to R* groups to the corresponding R! to R* groups typically arises when one compound of formula (I) is used as the immediate precursor of another compound of formula (I), or when it is easier to introduce a more complex or reactive substituent at the end of a synthetic sequence.

For example, conversion of RY from a t-butoxycarbonyl (BOC) group to hydrogen is conducted by the treatment of the N-BOC protected compound with hydrogen chloride in ethanol or dioxan at room temperature.

Conversion of R" from hydrogen to an alkyl group is conducted by the treatment of the NH compound with the appropriate aldehyde in dichloroethane in the presence of a reducing agent, such as sodium triacetoxyborohydride, or by the treatment of the NH compound with the appropriate alkyl halide, such as iodomethane, under standard alkylation conditions (potassium carbonate in DMF at 60°C).

Conversion of R®" from hydrogen to an alkyl group is conducted by the treatment of the sulfonamide NH compound with the appropriate alcohol, such as methanol, under Mitsunobu conditions i.e. treatment with diisopropyl azodicarboxylate/triphenylphosphine and methanol in tetrahydrofuran at room temperature.

Compounds of formula (I) are known in the literature or may be prepared by known processes, for example, reduction of the corresponding nitro compound as disclosed in WO 99/14197, or by procedures analogous to these procedures. Suitable examples of an RY protecting group are trifluoroacetyl or the t-butoxycarbonyl (BOC) group.

Compounds of formula (TI) are commercially available or may be prepared by established procedures, for example chlorosulfonylation of a suitable substituted aromatic precursor, using chlorosulfonic acid, for example as described in J. Med. Chem. 2000, 43, 156-166.

Compounds of formula (IV) may be prepared from compounds of formula (ID) by the treatment with the appropriate 4-substituted benzenesulfonyl chloride using standard conditions, for example in pyridine or dichloromethane in the presence of a base such as triethylamine at room temperature.

Compounds of formula (V) are commercially available or may be prepared by known methodology, for example lithiation of a suitable substituted bromobenzene at low temperature followed by quenching with tri-isopropylborate and acidic hydrolysis of the reaction product.

Compounds of formula (I) have been found to exhibit affinity for dopamine receptors, in particular the D3 and Dy receptors, and are useful in the treatment of disease states which require modulation of such receptors, such as psychotic conditions. Many of the compounds of formula (I) have also been found to have greater affinity for dopamine D3 than for Dp receptors. The therapeutic effect of currently available antipsychotic agents (neuroleptics) is generally believed to be exerted via blockade of Dj receptors; however this mechanism is also thought to be responsible for undesirable extrapyramidal side effects (eps) associated with many neuroleptic agents. Without wishing to be bound by theory, it has been suggested that blockade of the dopamine D3 receptor may give rise to beneficial antipsychotic activity without significant eps. (see for example Sokoloff et al, Nature, 1990; 347: 146-151; and

Schwartz et al, Clinical Neuropharmacology, Vol 16, No. 4, 295-314, 1993). Additionally, certain compounds of formula (I) have antagonist affinity for the serotonin 5-HTa, 5-HT,c and 5-HT, receptors. These additional properties may give rise to enhanced anti-psychotic activity (e.g. improved effects on cognitive dysfunction) and/or reduced eps. These could include, but are not limited to, attenuation of cognitive symptoms via 5-HTs receptor blockade (see Reavill, C. and Rogers, D.C., 2001, Investigational Drugs 2, 104-109), and reduced anxiety (see for example Kennett et al., Neuropharmacology 1997 Apr-May; 36 (4- 5): 609-20), protection against eps (Reavill et al., Brit. J. Pharmacol, 1999; 126: 572-574) and antidepressant activity (Bristow et al., Neuropharmacology 39:2000; 1222-1236) via 5-

HT, receptor blockade.

Compounds of formula (I) may also exhibit affinity for other receptors not mentioned above, resulting in beneficial antipyschotic activity.

The compounds of formula (I) are of use as antipsychotic agents for example in the treatment of schizophrenia, schizo-affective disorders, schizophreniform diseases, psychotic depression, mania, acute mania, paranoid and delusional disorders. Furthermore, they may have utility as adjunct therapy in Parkinsons Disease, particularly with compounds such as L-DOPA and possibly dopaminergic agonists, to reduce the side effects experienced with these treatments on long term use (e.g. see Schwartz et al., Brain Res. Reviews, 1998, 26, 236-242). From the localisation of D3 receptors, it could also be envisaged that the compounds could also have utility for the treatment of substance abuse where it has been suggested that D3 receptors are involved (e.g. see Levant, 1997, Pharmacol. Rev., 49, 231-252). Examples of such substance abuse include alcohol, cocaine, heroin and nicotine abuse. Other conditions which may be treated by the compounds include dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias; depression; anxiety; agitation; tension; social or emotional withdrawal in psychotic patients; cognitive impairment including 40 memory disorders such as Alzheimer’s disease; psychotic states associated with neurodegenerative disorders, e.g. Alzheimer’s disease; eating disorders; obesity; sexual dysfunction; sleep disorders; emesis; movement disorders; obsessive-compulsive disorders; amnesia; aggression; autism; vertigo; dementia; circadian rhythm disorders; and gastric motility disorders e.g. IBS. Therefore, the invention provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof for use in therapy.

The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in a condition which requires modulation of a dopamine receptor.

The invention also provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of psychotic disorders, Parkinsons disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders.

The invention also provides the use of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of a condition which requires modulation of a dopamine receptor.

The invention also provides the use of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of psychotic disorders, Parkinsons disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive- compulsive disorders, ammesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders.

The invention also provides a method of treating a condition which requires modulation of a dopamine receptor, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof.

In a further aspect, the invention provides a method of treating psychotic disorders,

Parkinsons disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, anmesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt or solvate thereof.

A preferred use for dopamine antagonists according to the present invention is in the treatment of psychotic disorders, Parkinsons disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety and cognitive impairment. "Treatment" includes prophylaxis, where this is appropriate for the relevant condition(s).

For use in medicine, the compounds of the present invention are usually administered as a standard pharmaceutical composition. The present invention therefore provides in a further aspect a pharmaceutical composition comprising a compound of formula (I) as hereinbefore 40 described or a pharmaceutically (i.e. physiologically) acceptable salt thereof and a pharmaceutically (i.e. physiologically) acceptable carrier. The pharmaceutical composition can be for use in the treatment of any of the conditions described herein.

The compounds of formula (I) may be administered by any convenient method, for example by oral, parenteral (e.g. intravenous), buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.

The compounds of formula (I) as hereinbefore described and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.

Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. The aerosol dosage forms can also take the form of a pump-atomiser.

Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin. 40 Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

Compositions suitable for transdermal administration include ointments, gels and patches.

Preferably the composition is in unit dose form such as a tablet, capsule or ampoule.

Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.

The pharmaceutically acceptable compounds of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 500 mg, preferably between 10 mg and 400 mg, e.g. between 10 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.

Biological Test Methods

Binding experiments on cloned dopamine (e.g. D, and D,) receptors

The ability of the compounds to bind selectively to human D,/D; dopamine receptors can be demonstrated by measuring their binding to cloned receptors. The inhibition constants X) of test compounds for displacement of [1251}-Todosulpride binding to human D,/D; receptors expressed in CHO cells were determined as follows. The cell lines were shown to be free from bacterial, fungal and mycoplasmal contaminants, and stocks of each were stored frozen in liquid nitrogen. Cultures were grown as monolayers or in suspension in standard cell culture media. Cells were recovered by scraping (from monolayers) or by centrifugation (from suspension cultures), and were washed two or three times by suspension in phosphate buffered saline followed by collection by centrifugation. Cell pellets were stored frozen at - 80°C. Crude cell membranes were prepared by homogenisation followed by high-speed centrifugation, and characterisation of cloned receptors achieved by radioligand binding.

Preparation of CHO cell membranes: Cell pellets were gently thawed at room temperature, and resuspended in about 20 volumes of ice-cold Extraction buffer; 5SmM EDTA, 50mM

Trizma pre-set crystals (pH7.4@37°C), 1mM MgClp, SmM KCl and 120mM NaCl. The suspension was homogenised using an Ultra-Turrax at full speed for 15 seconds. The homogenate was centrifuged at 18,000 r.p.m for 15 min at 4°C in a Sorvall RC5C centrifuge.

Supernatant was discarded, and homogenate re-suspended in extraction buffer then centrifugation was repeated. The final pellet was resuspended in 50mM Trizma pre-set crystals (pH 7.4 @ 37°C) and stored in 1ml aliquot tubes at —80°C (D2 = 3.0E+08 cells, D3 = 7.0E+07 cells and D4 = 1.0E+08 cells). The protein content was determined using a BCA protocol and bovine serum albumin as a standard (Smith, P. K., et al., Measurement of protein using bicinchoninic acid. Anal. Biochem. 150, 76-85 (1985)).

Binding experiments:

Binding experiments on D3/D, receptors

Crude D,/D; cell membranes were incubated with 0.03nM [1251)-Todosulpride (~2000 40 Ci/mmol; Amersham, U. K., and the test compound in a buffer containing 50mM Trizma pre- set crystals (pH 7.4 @ 37°C), 120mM NaCl, SmM KCl, 2mM CaClp, 1mM MgCl, 0.3% (w/v) bovine serum albumin. The total volume is 0.2ml and incubated in a water bath at 37°C for 40 minutes. Following incubation, samples were filtered onto GF/B Unifilters using a

. +

Canberra Packard Filtermate, and washed four times with ice-cold 50mM Trizma pre-set crystals (pH 7.4 @ 37°C). The radioactivity on the filters was measured using a Canberra

Packard Topcount Scintillation counter. Non-specific binding was defined with 10pM SKF- 102161 (YM-09151). For competition curves, 10 serial log concentrations of competing cold drug were used (Dilution range: 10uM-10pM). Competition curves were analysed using

Inflexion, an iterative curve fitting programme in Excel. Results were expressed as pK; values where pK; = -loglO[Ki].

The exemplified compounds have pK; values within the range of 6.6 — 9.6 at the dopamine

Dj; receptor.

The exemplified compounds have pK; values within the range of 5.3 -9.3 at the dopamine D, receptor.

Binding experiments on cloned 5-HT, receptors

Compounds were tested following the procedures outlined in WO 98/27081. All of the exemplified compounds have pK; values within the range of 7.0 — 8.8 at the serotonin 5-HT receptor.

Binding experiments on cloned 5-HT,c receptors

Compounds were tested following the procedures outlined in WO 94/04533. All of the exemplified compounds have pK; values within the range of 6.6 — 8.4 at the serotonin 5-

HT,creceptor.

Binding experiments on cloned S-HT;, receptors

Compounds can be tested following the procedures outlined in British Journal of

Pharmacology (1996) 117, 427-434. All of the exemplified compounds have pKi values within the range of 6.3 — 8.9 at the serotonin 5-HT:4 receptor.

The invention is further illustrated by the following non-limiting examples:

¢

Description 1 1-(7-Amino-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-2,2,2-trifluoro-ethanone (D1)

COA

H,N CF, 7-Nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (D12a) 1,2,4,5-Tetrahydro-3H-benzazepine (1 g) (See P. Ruggli et al., Helv. Chim. Acta, 18, 1388,

[1935]) was added slowly dropwise to stirred fuming nitric acid (25 ml) at -10°C. Stirring was continued at -10°C for 1 hour and the reaction mixture was then poured onto ice, the precipitate collected by filtration and dried to give the title compound as the nitrate salt, 1.4g.

This salt was suspended in water, cooled to 5°C and neutralised with SM sodium hydroxide.

The precipitate was collected by filtration, recrystallised from water and dried, affording the title compound D1a as a white solid (0.6 g). 1-(7-Nitro-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-2,2,2-trifluoro-ethanone (D1b)

The 7-nitro benzazepine derivative (5 g) was dissolved in dichloromethane (80 ml) and to this was added diisopropylethylamine (5.4 ml) in dichloromethane (20 ml) at 0°C, followed by a solution of trifluoroacetic anhydride (4.3 ml) in dichloromethane (20 ml) at 0°C. The mixture was allowed to warm to room temperature and stirred overnight. Aqueous work up with water and dichloromethane gave the title compound D1b (7.0 g). MH™ 289 1-(7-Amino-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-2,2,2-trifluoro-ethanone D1)

The nitro derivative D1b was hydrogenated in accordance with the procedure described in

D2c to give the title compound D1. MH?' 259

Description 2 7-Amino-1,2,3,4-tetrahydro-2-trifluoracetyl-isoquinoline (D2)

Pew

CF,

N-2-(4-Nitrophenyl)ethyl-trifluoroacetamide (D2a)

A solution of trifluoroacetic anhydride (10.6ml) in dichloromethane (100ml) was added dropwise to a stirred solution of 2,6-lutidine (17.44ml) and 4-nitrophenethylamine hydrochloride (15.2g; 75 mmol) at 0°C. The mixture was stirred at 25°C overnight under argon and then washed with dilute citric acid (2 x ), brine and dried over NapSO4. The material in the organic phase gave the title compound D2a as a pale yellow solid (19.04g). 7-Nitro-1,2,3,4-tetrahydro-2-trifluoracetyl-isoquinoline ({D2b)

The nitro compound D2a (2.26g; 9.15 mmol) and paraformaldehyde (0.45g; 14.4 mmol) in acetic acid (10ml) and conc. H3SO4 (15ml) were stirred at 25°C for 20h according to the procedure of G.E. Stokker., Tet. Lett., 1996, 37, 5453. Work up afforded the title compound

D2b as a white solid (2.17g). 'H NMR (CDCl) 8: 3.10 (2H, m), 3.92 (2H, m), 4.85 + 4.92 (2H, 2xs), 7.38 (1H, 1), 8.10 (2H, m). I, (EI): 274 (M™).

7-Amino-1,2,3,4-tetrahydro-2-trifluoracetyl-isoquinoline (D2)

The 7-nitro compound D2b (0.99g, 3.6 mmol) in ethanol (50 ml) was hydrogenated over 10% palladium on carbon (450 mg) at atmospheric pressure for 4 h. The catalyst was removed by filtration through a pad of celite and evaporation gave the title compound D2 as a colourless solid (840mg). 'H NMR (CDCl) 8: 2.84 (2H, t), 3.23 (2H, bs), 3.82 (2H, m), 4.66 (2H, d), 6.47 (1H, m), 6.57 (1H, m), 6.96 (1H, m).

Description 3 7-Amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (D3)

OX

ALI

The title compound D3 was prepared using a similar methodology to that described in EP 284384. MH 263 -

Description 4 7-Amino-2-(¢-butyloxycarbonyl)-1,2,3,4-tetrahydroisoquinoline (D4)

AT or 7-Nitro-1,2,3,4-tetrahydroisoquinoline (D4a)

The trifluoroacetamide D2b (17.22g; 63 mmol) was hydrolysed at room temperature using a solution of potassium carbonate (46.6g) in 10% aqueous methanol (660ml). Work-up with dichloromethane gave the title compound D4a (11g). 7-Amino-2-(-butyloxycarbonyl)-1,2,3,4-tetrahydroisoquinoline (D4)

The title compound D4 was prepared from the compound D4a using di--butyl dicarbonate in 10% aqueous hydroxide in dioxan at 25°C followed by catalytic hydrogenation according to the procedure described for D2c. MH 249.

Description 5 7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert- butyl ester (DS)

CO

HN 0 7-Methoxy-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (D5a)

To a solution of 7-hydroxy-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (5 g, 19 mmol) in dimethylformamide (50ml) was added potassium carbonate (3.4 g, 25 mmol) and methyl iodide (3.25 ml, 60 mmol). The mixture was heated to 30°C for 12h. The solvent was evaporated and the residue partitioned between dichloromethane (100 ml) and water (100 ml). The organic layer was separated and evaporated to give the crude product

D5a as a colourless oil (5.3 g, 100%). 7-Methoxy-8-nitro-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid fert-butyl ester (D5b)

To a mixture of 7-methoxy-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (D5a) (5.3 g, 19 mmol) in glacial acetic acid (100 ml) and acetic anhydride (10 ml) at 0°C was added a mixture of nitric acid (70% aqueous, 5 g, 55 mmol) dropwise in glacial acetic acid (100 ml) and acetic anhydride (10 ml) maintaining the temperature below 5°C.

The mixture was stirred at room temperature for 2 h and then poured into ice/water (500 ml).

The aqueous was extracted with dichloromethane (2 x 200 ml) and the combined organic portions were neutralised with saturated sodium bicarbonate solution. The dichloromethane layer was evaporated and the residue chromatographed on silica gel (eluent: hexane/dichloromethane (1:1) to dichloromethane) to give the product. D5b as a colourless solid (1.5 g, 25%). 7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid rert-butyl ester

D3)

To a solution of 7-methoxy-8-nitro-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid fert- butyl ester D2b (1.5 g, 4.7 mmol) in ethanol (80 ml) was added palladium on charcoal (10%, 0.5 g). The mixture was stirred under an atmosphere of hydrogen for 2 h and then filtered.

The solvent was evaporated to give the title compound D5 as a colourless solid (1.35 g, 100%).

Mass spectrum APY: Found 193 ((M-Boc]™V). C1gHp4N,O3 requires 292. 'H NMR (CDCl3) 3 1.48 (9H, s), 2.76 (4H, m), 3.51 (4H, m), 3.65 (2H, s), 3.82 (3H, s), 6.50 (1H, m), 6.56 (1H, m).

Description 6. 5-Amino-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (D6) 0]

JCI

H,N o— 5-Nitroisoindoline nitrate (D6a)

Isoindoline (4g, 33.1mmol) was added to 95%. sulphuric acid, the reaction was treated carefully with fuming nitric acid (2.2ml) at 0°C and stirred for 1 h, then the mixture was poured onto ice and the resulting precipitate was collected by filtration and dried in vacuo to afford the title compound D6a (4.1g, 46%); '"H NMR (DMSO0-d%) 8.35 (1H, s), 8.35 (1H, 4, 8.4Hz), 7.70 (1H, d, 8.4Hz), 4.64 (4H,s). 5-Nitro-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (D6b)

The compound Dé6a (3.06g, 13.47mmol) in dichloromethane (50ml) was treated with triethylamine (4.09g, 40.42mmol) followed by di-tertbutyl dicarbonate (3.08g, 14.15mmol) 40 and stimed at room temperature for 3 days. The reaction was then diluted with dichloromethane and washed with 3N citric acid, sodium bicarbonate solution, water and

Claims (10)

Claims

1. A compound of formula (I) (R%), POSS PS 8’ » 8 wherein A and B represent the groups (CH,)- and (CH,),-respectively; R! represents hydrogen or Cy.salkyl; R? represents hydrogen, halogen, hydroxy, cyano, nitro, hydroxyCealkyl, trifluoromethyl, trifluoromethoxy, C,salkyl, C,salkoxy, C,.salkoxyC,.ealkyl, Ci.;cycloalkylC, alkoxy, - (CH,),Cs.scycloalkyl, -(CH,),C;.¢cycloalkyloxy, -COC, alkyl, -SO,Cy.¢alkyl, -SOC, alkyl, - S-C,.ealkyl, C,.qalkylsulfonyloxy, C,salkylsulfonylC,alkyl, -CO,C,.salkyl, -CO,NR'R}, - SO,NR'R®, C,.ealkylsulfonamido, CealkylsulfonamidoCyealkyl, -(CH,),NR'R®, Cs alkylamidoC,_salkyl, ~(CH,),NR'COR?, arylsulfonyl, arylsulfonyloxy, arylsulfonylC,.calkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC,salkyl, arylcarboxamidoC;.salkyl, aroyl, aroylCy.galkyl, arylCyalkanoyl, -SO,NR'R?, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl, or a group CONR'R® or SO,NR'R? wherein R’ and R® together may be fused to form a 5- 7-membered aromatic or non-aromatic heterocyclic ring optionally interrupted by an O or S atom; R? represents hydrogen or C,qalkyl; Ar represents optionally substituted phenyl or optionally substituted monocyclic heteroaryl group; R* represents optionally substituted aryl or optionally substituted heteroaryl; R’ and R® each independently represent hydrogen, C,.salkyl or together form a 5- to 7- membered heterocyclic ring; Z represents a bond, an oxygen atom or Cy_alkyl: Y represents hydrogen or C,salkyl; m and n independently represent an integer selected from 1 and 2; p independently represents an integer selected from 0, 1, 2 and 3; q represents an integer from 1 to 3; r represents an integer from 1 to 4; or a pharmaceutically acceptable salt or solvate thereof.

2. A compound of formula (I) which is 4-(4-Chloro-phenyl)-N~(2,3,4,5-tetrahydro-1H-3 -benzazepin-7-yl)-benzenesulfonamide; 4-(4-Chloro-phenyl)-N~(3-methyl-2,3,4,5-tetrahydro- 1 /-3-benzazepin-7-yl)- benzenesulfonamide; 4-(4-Chloro-phenyl)-N-methyl-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)- benzenesulfonamide;

4-(4-Chloro-phenyl)-N-methyl-N-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)- benzenesulfonamide; 4-(3,4-Dichloro-phenyl)-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-benzenesulfonamide hydrochloride; 444-Chloro-phenyl)-N-(8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)- benzenesulfonamide hydrochloride; 4-(4-Chloro-phenyl)-N-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)- benzenesulfonamide hydrochloride; 4-(4-Chloro-phenyl)-N-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzencsulfonamide; 4-(4-Chloro-phenyl)-N-(2,3-dihydro-1H-isoindol-5-yl)-benzenesulfonamide hydrochloride; 4-(4-Chloro-phenyl)-N-(2-methyl-2,3-dihydro-1H-isoindol-5-yl)-benzenesulfonamide; 4-(4-Chloro-phenyl)-3-methyl-N-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)- benzenesulfonamide hydrochloride; 4-(4-Chloro-phenyl)-3-methyl-N-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)- benzenesulfonamide; ‘ 4-(4-Chloro-phenyl)-3-methyl-N-(8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)- benzenesulfonamide hydrochloride; 4-(4-Chloro-phenyl)-3-methyl-N-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin- 7-yl)-benzenesulfonamide; 4-(5-Chloro-thiophen-2-yl)-N-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7- yl)-benzenesulfonamide; 4-(5-Chloro-thiophen-2-yl)-2-fluoro-N-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H- benzo[d]azepin-7-yl)-benzenesulfonamide; 4-(4-Chloro-phenyl)-N-(8-dimethylamino-3-methyl-2,3,4,5-tetrahydro-1 H-benzazepin-7-yl)- benzenesulfonamide hydrochloride and 4-(4-fluorobenzyl)-N-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)- benzenesulfonamide hydrochloride.

3. A pharmaceutical composition comprising a compound of formula (I) as claimed in claims 1 or 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor.

4. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in claims 1 or 2, for use in therapy.

5. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in claims 1 or 2 for use in a condition which requires modulation of a dopamine receptor.

6. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof according to claim 5 wherein the condition is selected from psychotic disorders, Parkinsons disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement 40 disorders, obsessive-compulsive disorders, ammesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders.

7. Use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in claims 1 or 2 in the manufacture of a medicament for the treatment of a condition which requires modulation of a dopamine receptor.

8. Use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof according to claim 7 wherein the condition is selected from psychotic disorders, Parkinsons disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders.

9. A method of treating a condition which requires modulation of a dopamine receptor, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in claims 1 or 2.

10. A method of treating a condition according to claim 9 wherein the condition is selected from psychotic disorders, Parkinsons disease, substance abuse, dyskinetic disorders, depression, bipolar disorder, anxiety, cognitive impairment, eating disorders, obesity, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders and gastric motility disorders.