ZA200409417B - Compounds. - Google Patents

Description

Compounds

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

International patent application WO 01/62737 discloses amino pyrazole derivatives which ) are ligands for the neuropeptide Y subtype 5 receptor and are said to be useful in the treatment of disorders and disease associated with this receptor including, inter alia, obesity, anxiety, depression, pain and schizophrenia.

International patent application WO 01/85695 discloses tetrahydroisoquinoline analogues useful as growth hormone secretagogues. Such analogues are also said to be useful in the treatment of disorders including inter alia, obesity, schizophrenia, depression and

Alzheimer's disease.

We have now found a novel group of phenylsulfonyl compounds which are useful particularly as antipsychotic agents.

According to the invention, there is provided a compound of formula (1): 4 2

R R A

NTR 0)

R*—2 Sa ® oO O wherein

A and B represent the groups (CH,),- and |(CH,),- respectively;

R' represents hydrogen or C,salkyl;

R? represents hydrogen, halogen, hydroxy, cyano, nitro, hydroxyC, salkyl, trifluoromethyl, trifluoromethoxy, Cisalkyl, Cisalkoxy, Cisfluoroalkoxy, -(CH,),Csecycioalkyl, -(CH,),0Cs scycloalkyl, -COC,salkyl, -SO,C,salkyl, -SOC,salkyl, -S-C,galkyl, -CO,C,salkyl, -

CONR°R®, -SONR°R®, -(CH,),;NR°R®, -(CH,),NR°COR®, optionally substituted ary} ring, optionally substituted heteroaryl! ring or optionally substituted heterocyclyl ring;

R’represents optionally substituted aryl ring or optionally substituted heteroaryl ring;

R* represents hydrogen, hydroxy, Cigalkyl, C,salkoxy, trifluoromethyl, trifluoromethoxy, halogen, -OSO,CF3, -(CH),Cs cycloalkyl, -(CH,),0C,.salkyl or -(CH,),OC; cycloalkyl;

R® and R® each independently represent hydrogen, Cgalkyl or, together with the nitrogen : or other atoms to which they are attached, form an azacycloalkyl ring or an oxo- substituted azacycloaikyl ring; . Z represents —(CH,),X- wherein the -(CH,)- group is attached to R®, or —=X(CH,)- wherein

X is attached to R®, and wherein any of the -CH,- groups may be optionally substituted by one or more C, alkyl groups;

X represents oxygen, -NR’ or —CH,- wherein the -CH, group may be optionally substituted by one or more C, alkyl groups;

R’ represents hydrogen or C,salkyl; ] m and n independently represent an integer selected from 1 and 2; pindependently represents an integer selected from 0, 1, 2 and 3; q independently represents an integer selected from 1, 2 and 3; ) r independently represents an integer selected from 0, 1, and 2; or a pharmaceutically acceptable salt or solvate thereof. tis to be understood that the present invention covers all combinations of particular and preferred groups described herein above.

As used herein, the term “alkyl” refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. For example, C,salkyl 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-pentyi, 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,salkoxy 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-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy or hexyloxy.

As used herein, the term “C,¢fluoroalkoxy " refers to a straight or branched alkoxy group containing the specified number of carbon atoms wherein any of the carbon atoms may be substituted by one or more fluorine atoms.

As used herein, the term “cycloalkyl” refers to a non-aromatic hydrocarbon ring containing the specified number of carbon atoms. For example, C; ;cycloalkyl 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 Cg cycloalkyl group is preferred.

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

As used herein, the term “aryl” refers to a phenyl or a naphthyl ring. ) 40 As used herein, the term “heteroaryl” refers to a 5- or 6-membered heterocyclic aromatic ring or a fused bicyclic heteroaromatic ring system.

As used herein, the term “heterocyclyl” refers to a 3- to 7-membered monocyclic saturated 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.

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, fury, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyi, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrazolyl, isothiazolyl and isoxazolyl.

As used herein, the term “fused bicyclic heteroaromatic ring system” refers to a ring system comprising one six-membered unsaturated ring and one 5- or 6-membered unsaturated or saturated ring fused together, the ring system containing at least one heteroatom independently selected from oxygen, nitrogen and sulfur. Examples of suitable fused bicyclic heteroaromatic ring systems include, but are not limited to, indolyl, benzofuranyl, quinolyl and benzothienyl. Further examples include but are not limited to, isoquinolyl, quinolizinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, isoindolyl, indolizinyl, indazolyl, pyrrolopyridinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, dihydrobenzothienyl, dihydrobenzofuranyl, benzodioxolanyl, methylenedioxyphenyl, dihydrobenzodioxinyl and the like.

As used herein, the term “azacycloalkyl ring” refers to a 4- to 7-membered monocyclic saturated ring containing one nitrogen atom. Examples of suitable azacycloalkyl rings are azetidine, pyrrolidine, piperidine and azepine.

As used herein, the term “oxo-substituted azacycloalkyl ring” refers to an azacycloalkyl ning as defined above substituted by one oxo group. Examples of suitable oxo-substituted azacycloalky! rings include, but are not limited to, azetidinone, pyrrolidinone, piperidinone and azepinone.

When Z represents —(CH,),X- wherein the -(CH,)- group is attached to R® examples of Z include —O-, -CH;0-, -(CH;);0-, -NR’-, -CH,NR’, -(CH,);NR’-, -CH,-, ~(CH,),, -(CH,)s-, —

NH-, -CH,NH-, -(CH,).NH, -CH,N(C, salkyl) and -(CH,).N(C,.salkyl).

When Z represents —X(CH,), wherein X is attached to R®, examples of Z include —O-, —OCHj, -O(CH;)2, -NR’-, -NR'CH,, =NR’(CH,);, -CHz-, -(CH,)2, -(CH,)s-, —NH-, -NHCH,-, - ) 40 NH(CHy.)., -N(C.ealkyl)-, -N(C,salkyl)CH,- and -N(C;alkyl)(CH2).-.

As used herein, the term “substituted” refers to 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 physiologically (i.e. pharmaceutically) acceptable. Suitable physiologically 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, malic, mandelic, acetic, fumaric, glutamic, lactic, citric, tartaric, benzoic, benzenesulfonic, p-toluenesulfonic, methanesulfonic or naphthalenesuifonic acid. Other non-physiologically 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 the compounds of formula (1).

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 stereocisomeric 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 invention.

The groups R? R3-Z- and R* may be located on any position on their respective phenyl rings.

When R? represents optionally substituted aryl ring, optionally substituted heteroaryl ring or optionally substituted heterocyclyl ring, the optional substituents may be independently ) 40 selected from C,salkyl, C,galkoxy, halogen, trifluoromethyl, triffuoromethoxy, cyano, —S-

Cisalkyl, -CONR®R® and -NR’COR®, wherein R® and R® have any of the meanings given hereinbefore.

When R?® represents optionally substituted aryl ring or optionally substituted heteroaryl ring, the optional substituents may be independently selected from C,salkyl, C,¢alkoxy, . halogen, trifluoromethyl, trifluoromethoxy, cyano, -S-C,salkyl, di(Cssalkyl)amino, C,. ealkanoyl and C,_alkoxyC,salkyl. ) Preferably, R' represents hydrogen or C,_alkyl. More preferably, R' represents hydrogen, methyl, ethyl, n-propyl or isopropyl. Even more preferably, R' represents methyl.

Preferably, R? represents hydrogen, halogen, C,salkyl, C,salkoxy, C,salkyithio or diC,. salkylamino. More preferably, R? represents hydrogen, halogen, Ci4alkyl, Ci4alkoxy or diC,esalkylamino. Even more preferably, R? represents methyl, methoxy, ethoxy, dimethylamino or isopropoxy.

Equally preferably, R? represents hydrogen, halogen, Cisalkyl or C,salkoxy. More preferably, R? represents hydrogen, halogen, Ci.alkyl or C,jalkoxy. Even more preferably, R? represents hydrogen, methoxy or bromo.

Preferably, when R? represents an optionally substituted aryl ring, an optionally substituted heteroaryl ring, or an optionally substituted heterocyclyl ring, the optional substituents are independently selected from chloro, fluoro, bromo, methyl, ethyl, t-butyl, methoxy, trifluoromethyl, trifluoromethoxy, cyano, —S-methyi, -CONH, and -NHCOMe.

Preferably, R® represents phenyl, pyridyl (e.g. 2-, 4- or 5-pyridyl), isoxazolyl (e.g. isoxazol- 3-yl), thienyl (e.g. 2-thienyl), furyl (e.g. 2- or 3-furyl), thiazolyl (e.g. 2-thiazolyl), benzofuranyl (e.g. 1-benzofuranyl, 2-benzofurany! or 5-(2,3-dihydrobenzofuranyt), benzothienyl (e.g. 2- or 3-benzothienyl), naphthyl (e.g. 2-naphthyl), benzodioxinyl (e.g. 2,3-dihydrobenzo[1,4]dioxin-6-yl or 2,3-dihydrobenzo[1,4}dioxin-2-yl) or benzodioxolanyi (e.g. 1.4-benzodioxolanyl) or methylenedioxyphenyl (e.g. 3.4-methylenedioxyphenyl), all of which may be optionally substituted. Most preferably, R® represents phenyl! or optionally substituted phenyl.

Preferably, when R® represents optionally substituted phenyl, the optional substituents are independently selected from chloro (e.g. 4-chloro), fluoro (e.g. 4-fluoro), bromo, methyl, ethyl, t-butyl, methoxy, trifluoromethyl, triffuoromethoxy, cyano and —S-methyl. More preferably, the optional substituents are selected from chloro and fluoro.

Equally preferably when R® represents optionally substituted phenyl, the optional ) substituents are independently selected from chloro (e.g. 4-chloro, 24-, 3,4-, 2,6- 40 dichloro), fluoro (e.g. 3- or 4-fluoro, 2,3-, 2,4- or 3,4-difluoro), methyl (e.g. 4-methyl), methoxy (e.g. 2-, 3- or 4-methoxy, 3,4-dimethoxy or 3,4,5-trimethoxy), bromo (e.g. 4- bromo), trifluoromethyl (e.g. 3- or 4-trifluoromethyl), i-propyl (e.g. 4-i-propyl), cyano (e.g.

5-cyano), dimethylamino (e.g. 3-dimethylamino), methoxymethylene (e.g. 4- methoxymethylene), acetyl (e.g. 4-acetyl) or any combination thereof (e.g. 2-chloro-4- fluoro).

Preferably when R® represents optionally substituted pyridyl, the optional substituent is methyl (e.g. 6-methyl).

Preferably when R® represents optionally substituted isoxazolyl, the optional substituent is methyl (e.g. S-methyl).

Preferably when R’ represents optionally substituted thienyl, the optional substituents are independently selected from methyl (e.g. 5-methyl) or chloro (e.g. 5-chloro).

Preferably when R® represents optionally substituted furyl, the optional substituents are independently selected from methyl (e.g. 5-methyl or 4,5-dimethyl), trifluoromethyl (e.g. 2- trifluoromethyl or ethyl (e.g. 2-ethyl).

Preferably when R® represents optionally substituted benzothienyl, the optional substituents are independently selected from methyl (e.g. 3-methyl) or chloro (e.g. 5- chloro).

When Z represents ~(CH,),X- or -X(CH,),-, preferably X is —O- or -NR’-. More preferably,

X is =O- or —-N(Me)-.

When Z represents —(CH,)X- or =X(CH,),-, preferably ris 0 or 1.

When Z represents —(CH,),O-, preferably ris O or 1.

More preferably, when Z represents —{(CH,)X- or —X(CH,),, X is —O- or —=NR’- and ris 0 or 1. Even more preferably, when Z is -{(CH,),X- or =X(CH,),-. X is =O- or -N(Me)- and ris 0 or 1.

Preferably, Z represents —CH,0-, -OCH_-, -NHCH,-, CH;NH-, -O- or —N(Me)-. More preferably, Z represents —O- or -CH,O-. Even more preferably, Z represents —CH,0O-.

Preferably, when r represents 0 or 1, R® represents phenyl or optionally substituted phenyl.

Preferably, when r represents 0 or 1 and R® represents phenyl or optionally substituted 40 phenyl, the optional substituents on the phenyl ring are independently selected from chloro, fluoro, bromo, methoxy, trifluoromethyl, trifluoromethoxy and cyano.

Preferably, R* represents hydrogen, C,.alkyl or Cisalkoxy. More preferably, R* represents hydrogen, methyl or methoxy. Even more preferably, R* represents hydrogen.

Preferably, R® and R® independently represent hydrogen or Cialkyl. More preferably, R® andR® independently represent hydrogen or methyl. ) Preferably, R’ represents hydrogen or C,salkyl. More preferably, R’ represents hydrogen.

Preferably, p represents 0.

In a first embodiment of the invention, the R? group is located at the para-position relative to the group B i.e. a compound of formula (IA)

RA Rr? A \ 1

N—R a)

R>—2Z aN ® © © or a pharmaceutically acceptable salt or solvate thereof wherein groups A, B, Z and R' to

R* have any of the meanings as given hereinbefore.

When R? is located in the para-position i.e. compounds of formula (lA), R? is preferably hydrogen, methoxy, ethoxy, isopropoxy or dimethylamino.

In another embodiment of the invention, Z is located at the meta-position relative to the sulfone group i.e. a compound of formula (IB) rR? z

RY A

\ 1 9} IX Mm

R* Sa ®

Oo oO or a pharmaceutically acceptable salt or solvate thereof wherein groups A, B, Z and R' to

R* have any of the meanings as given hereinbefore.

When the R3-Z- group is located in the meta-position i.e. compounds of formula (IB), and . 30 Z represents —(CH,),X- or =X(CH,).-, r is preferably 0 or 1 and R? is preferably phenyl or optionally substituted phenyl. When the R>-Z group is located in the meta-position, and Z represents —{CH_).X- or —=X(CH,),-, ris 0 or 1 and R® is phenyl or optionally substituted phenyl, the optional substituents on the phenyl ring are preferably independently selected from chloro or fluoro.

When R3-(CH,),0- is located in the meta-position and Z is (CH,)O-, r is preferably 0 or 1 } and R® is preferably phenyl! or optionally substituted phenyl. When R*-(CH,),0- is located in the meta-position, r is 0 or 1 and R? is phenyl or optionally substituted phenyl, the optional substituents on the phenyl ring are preferably independently selected from chloro ) or fluoro.

In another embodiment of the invention, the R>-Z- group is located at the para-position relative to the sulfone group i.e. a compound of formula (IC)

RZ RY A

\ 1

NR wo

R* Za ®

Oo O or a pharmaceutically acceptable salt or solvate thereof wherein groups A, B, Z and R' to R* have any of the meanings as given hereinbefore.

When the R*-Z- group is located in the para-position i.e. compounds of formula (IC), and Z represents ~(CH,).X- or =X(CH_)-, r is preferably 0 or 1 and R® is preferably phenyl or optionally substituted phenyl. When the R®Z- group is located in the para-position, and Z represents |CH,)X- or —=X(CHy)-, r is preferably 0 or 1 and R? is preferably phenyl or optionally substituted phenyl, the optional substituents on the phenyl ring are preferably chloro or fluoro.

When R3-(CH,),O- is located in the para-position and Z is (CH,),0-, r is preferably 0 or 1 and R®is preferably phenyl or optionally substituted phenyl. When R>-(CH,)O- is located in the meta-position, r is 0 or 1 and R® is phenyl or optionally substituted phenyl, the optional substituents on the phenyl ring are preferably independently selected from chioro or fluoro.

In another embodiment of the invention, the R>-Z- group is located at the meta-position relative to the sulfone group and the R? group is located at the para-position relative to the group B i.e. a compound of formula (ID)

rR’

R? A \

Re Tr land ID

Ss B (1D) o’ ~o or a pharmaceutically acceptable sait or solvate thereof wherein groups A, B, Z and R' to

R* have any of the meanings as given hereinbefore.

In another embodiment of the invention, the R>-Z- group is located at the para-position relative to the sulfone group and the R? group is located at the para-position relative to the group B i.e. a compound of formula (IE)

R—z R? A \ 1

N—R 6) n S B

R IN

Oo 0] or a pharmaceutically acceptable salt or solvate thereof wherein groups A, B, Z and R' to

R* have any of the meanings as given hereinbefore.

In another embodiment of the invention, mis 1 and nis 1 and the invention is a compound of formula (IF):

RY RA

N—R' (IF)

R—2z Sa

O 0 or a pharmaceutically acceptable salt or solvate thereof wherein groups Z and R' to R* have any of the meanings as given hereinbefore.

In another embodiment of the invention, m is 2 and n is 1 and the invention is a compound of formula (IG): 1 I»® b I N (1G) . Ry PE SR! 8) 0] or a pharmaceutically acceptable salt or solvate thereof wherein groups Z and R' to R* have any of the meanings as given hereinbefore.

In another embodiment of the invention, mis 1 and n is 2 and the invention is a compound of formula (1H): 2

RY R R'

N~ (1H)

RZ SS

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

In another embodiment of the invention, m is 2 and n is 2 and the invention is a compound of formula (1J):

RY R

N—R'

J)

R¥=—2Z o> or a pharmaceutically acceptable salt or solvate thereof wherein groups Z and R' to R* have any of the meanings as given hereinbefore.

In another embodiment of the invention, m is 2 and n is 2, the R? group is located at the para-position relative to the group B, the R>Z- group is located at the meta-position relative to the sulfone group and the invention is a compound of formula (IK):

R3 4

RZ

R® N—R' (IK) 2S

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

In another embodiment of the invention, m is 2 and n is 2, the R? group is located at the para-position relative to the group B, the R®-Z- group is located at the para-position relative to the sulfone group and the invention is a compound of formula (IL): : R-—2z RY

N—R' (IL)

Re 0”

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

In a preferred embodiment of the invention, for any of the compounds of the formulae (ID), (IE), (JF), (1G), (IH), (J), (IK), and (IL), Z is -(CH2)O-.

In another embodiment of the invention, Z is —(CH,),X- wherein X is oxygen and there is provided a compound of formula (IM): 4 2 [IPE

N—R d (IM) 0 S B

RE-(CH,) 0” Yo # wherein

A and B represent the groups —(CH;)- and «(CH;),- respectively,

R' represents hydrogen or C, alkyl;

R? represents hydrogen, halogen, hydroxy, cyano, nitro, hydroxyC, alkyl, trifluoromethyl, trifluoromethoxy, Ciealkyl, Ciealkoxy, -(CH,),Csecycloalkyl, -(CH,),OC;ecycloalkyl, -

COC, alkyl, -SO.,C, alkyl, -SOC,salkyl, -S-C,ealkyl, -CO,C,salkyl, -CONR’RS, -

SO,NR°R®, -(CH,),NR°R®, -(CH,),NR’COR®, optionally substituted aryl ring, optionally substituted heteroaryl ring or optionally substituted heterocyclyl ring;

R® represents optionally substituted aryl ring or optionally substituted heteroaryl ring;

R* represents hydrogen, hydroxy, C,galkyl, C,salkoxy, trifluoromethyl, trifluoromethoxy, halogen, -OSO,CF3;, -(CH;),Csscycloalkyl, -(CH;),0C,salkyl or -(CH,),0C; cycloalkyl;

R® and R® each independently represent hydrogen, C,.salkyl or, together with the nitrogen or other atoms to which they are attached, form an azacycloalkyl ring or an oxo- substituted azacycloalkyl ring; mand n independently represent an integer selected from 1 and 2; p independently represents an integer selected from 0, 1, 2 and 3; q independently represents an integer selected from 1, 2 and 3; r independently represents an integer selected from 0, 1, and 2; or a pharmaceutically acceptable salt or solvate thereof.

In another embodiment of the invention, the R? group is located at the meta-position relative to the group B and the invention is a compound of formula (IN):

R? tC . \ 1

N—R

CL

RI—Z 2S ® 0 oO wherein groups Z, A, B and R to R* have any of the meanings as given hereinbefore. in another embodiment of the invention, there is provided a compound of formula (IP):

RA RY A

\ 1

APSE

R™—Z aN 8 0] 0 wherein

A and B represent the groups —(CH;)n- and —(CH.),- respectively;

R' represents hydrogen or C,.salkyl;

R? represents hydrogen, halogen, hydroxy, cyano, nitro, hydroxyC alkyl, trifluoromethyl, trifluoromethoxy, C,salkyl, Cigalkoxy, -(CH.),Csecycloalkyl, -(CH,),OC;scycloalkyl, -

COC, salkyl, -SO,Cicalkyl, -SOC,salkyl, -S-Cialkyl, -CO,Cigalkyl, -CO.NR’R®, -

SONR°R®, -(CH2),NR’R®, -(CH,),NR®COR®, optionally substituted aryl ring, optionally substituted heteroaryl ring or optionally substituted heterocyclyl! ring; R® represents optionally substituted aryl ring or optionally substituted heteroaryl ring;

R* represents hydrogen, hydroxy, C,ealkyl, C,salkoxy, trifluoromethyl, trifluoromethoxy, halogen, -OSO,CF3;, -(CH;),Csscycloalkyl, -(CH,),OCsalkyl or -(CH,),0C;scycloalkyt;

R® and R® each independently represent hydrogen, C,salkyl or, together with the nitrogen or other atoms to which they are attached, form an azacycloalkyl ring or an oxo- substituted azacycloalkyl ring;

Z represents —(CH,),X- wherein the -(CH,)- group is attached to R®, or —X(CH,)- wherein

X is attached to R®, and wherein any of the -CH,- groups may be optionally substituted by one or more C,galkyl groups,

X represents oxygen, -NR’ or —CH,- wherein the -CH group may be optionally substituted by one or more C,ealkyl groups;

R’ represents hydrogen or C, alkyl; 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 independently represents an integer selected from 1, 2 and 3; rindependently represents an integer selected from 0, 1, and 2, or a pharmaceutically acceptable salt or solvate thereof.

Particular compounds according fo the invention include those incorporated in Tables 1 to 7 and those specifically exemplified and named hereinafter including, without limitation:- 7-Methoxy-8-(3-phenoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-3-benzazepine, . 7-Methoxy-3-methyl-8-(3-phenoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-3- benzazepine;

St ryloxyphenyisulfonyl)-2,3,4,5-tetrahydro-3-benzazepine; ., = = .

7-[4-(4-Chloro-benzyloxy)-benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine; (4-Fluoro-benzyl)-[4-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7- sulfonyl)-phenyi}-amine; [4-(8-Methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl)-phenyl}-phenyl- amine; 7-[4-(4-Chloro-phenoxymethyl)-benzenesulfonyl}-8-methoxy-3-methyl-2,3,4,5-tetrahydro- 1H-3-benzazepine; 4-Chioro-pheny)-[4-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7- sulfonyl)-benzyl}-amine; 7-[4-(4-Fluorobenzyl)benzenesulfonyl}-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1 H-3- benzazepine; 7-{4-(3-Fluoro-benzyloxy)-benzenesulfonyl]-6-methoxy-1,2,3,4-tetrahydro-isoquinoline, and 5-Methoxy-2-methyl-6-[4-(3-trifluoromethyl-benzyloxy)-benzenesulfonyl]-2,3-dihydro-1 H- isoindole; (2-Methoxy-benzyi)-[4-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7- sulfonyl)-phenyf]-amine; 7-{4-(4-Chloro-phenoxymethyl)-benzenesulfonyl]-8-ethoxy-3-methyl-2,3,4,5-tetrahydro- 1H-3-benzazepine; [4-(8-Ethoxy-3-methyl-2,3 4,5-tetrahydro- 1H-3-benzazepine-7-sulfonyl)-benzyl}-(2- methoxy-phenyl)-amine; {8-[4-(4-Fluoro-phenoxymethyl)-benzenesulfonyl]-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepin-7-yl}-dimethyl-amine; 6-Ethoxy-7-[4-(4-fluoro-benzyloxy)-benzenesulfonyl}-1,2,3,4-tetrahydro-isoquinoline hydrochloride; (3-Methoxy-benzyl)-[4-(6-methoxy-1,2,3 4-tetrahydro-isoquinoline-7-sulfonyl}-phenyi}- methyl-amine hydrochioride; 7-[4-(4-Chlorophenoxymethyl)benzenesulfonyl]-6-methoxy-1,2,3 4-tetrahydroisoquinoline hydrochloride salt; and 3-Methyl-7-{(4-(2-methoxybenzyloxy)-phenylsulfonyl}-S-phenyl-1,2 4, 5-tetrahydro-3- benzazepine.

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

The present invention also provides a general process (A) for preparing compounds of formula (I) which process comprises: 40 reacting a compound of formula (il)

R% A \ .

L N—R \ Bg’ an / S \S 7 N\ : oO 0 : with a compound of formula (lll)

R* M 2

R——z wherein L is a leaving group, such as fluoro, chloro, alkoxy or aryloxy, M is a metal, such as lithium or magnesium, and R'-R* represent R' to R* as hereinbefore defined or are groups that may be readily convertible to R' to R*, and Z, A and B are as hereinbefore defined.

This general method (A) can be conveniently performed by mixing the two components at preferably —70°C to room temperature in a suitable solvent such as tetrahydrofuran or ether for 10 minutes to 18 hours. Removal of certain R' protecting groups e.g. trifluoroacetyl, can also take place simultaneously during this process.

The present invention also provides a general process (B) for preparing compounds of formula (1), which process comprises: reacting a compound of formula (IV)

Ww z

R A

\ .

RY ES B

0 0) with a compound of formula (V)

LN _—

R (CH)—Y (V) wherein W is OH or NHR’, and Y is a leaving group, such as bromo, iodo, chloro, fluoro, hydroxy, mesylate or triflate; or Y is OH, NHR’, CHO, MgBr or ZnCl and W is a leaving group, such as fluoro, chloro, bromo or triflate and r, A, B and R’ 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*.

Examples of general process (B) include:

a) WisOH ,YisBrandris 1 which can be conveniently performed by heating the two reactants in an inert solvent e.g. dimethylformamide or dimethylsulfoxide, under basic conditions e.g. potassium carbonate } or sodium hydride, optionally at elevated temperature e.g. 100°C.

b)WisOH,YisOHand ris 1 which can be conveniently carried out using Mitsunobu conditions in the presence of triphenylphosphine and diisopropyl azodicarboxylate in tetrahydrofuran at room temperature.

c)Wis NHR’, Yis CHO and ris 0 which can be conveniently carried out using reductive alkylation conditions e.g. sodium triacetoxyborohydride in dichloroethane at room temperature. d) WisF,YisOHandris 1 which can be conveniently carried out under basic conditions e.g. in the presence of sodium hydride in dimethylsufoxide, optionally at elevated temperature. e) WisF,YisOHandris 0 which can be conveniently carried out under basic conditions e.g. in the presence of sodium hydride in dimethylisulfoxide, optionally at elevated temperature. f)/Wis F, YisNHR and ris 1 which can be conveniently carried out by heating the reactants in an inert solvent e.g. dimethyisulfoxide at elevated temperature. g)WisF,YisNHR and ris 0 which can be conveniently carried out under basic conditions e.g. in the presence of sodium hydride or lithium hexamethyidisilazide in an inert solvent, at room temperature.

hYWisBr,Yis ZnCland ris 1 which can be conveniently out in an inert solvent e.g. tetrahydrofuran in the presence palladium tetrakis(triphenylphosphine) optionally at elevated temperature e.g. 60°C. )WisNHR’ YisBrandris0 which can be conveniently carried out in an inert solvent using palladium catalysed : conditions as published by Buchwald (J.

Org.

Chem. 1997, 1264). j)W is OTf, Yis NHR” and ris 0 40 which can be conveniently carried out in an inert solvent using palladium catalysed conditions as published by Buchwald (J.

Org.

Chem. 1997, 1264).

k) Wis NHR’, Yis Brand ris1 which can be conveniently performed by heating the 2 reactants in an inert solvent e.g. dimethylformamide or dimethylsulfoxide, under basic conditions e.g. potassium carbonate i or sodium hydride, optionally at elevated temperature e.g. 100°C.

The present invention also provides a general process (C) for preparing compounds of formula (1), which process comprises: reacting a compound of formula (VI)

W(CH,), >

R A

\ .

RY 58 B oO (6) with a compound of formula (VIt) - wherein W is OH, NHR’ or CHO and Y is a leaving group, such as bromo, iodo, chloro, fluoro, hydroxy, mesylate or triflate, or Y is OH or NHR” and r, A, B and R’ 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®.

Examples of general process (C) include: a) WisOH, ris 1and Y is OH which can be conveniently carried out using Mitsunobu conditions in the presence of triphenylphosphine and diisopropyl azodicarboxylate in tetrahydrofuran at room temperature. b)WisOH,ristand Yis F which can be conveniently carried out using standard aromatic nucleophilic substitution conditions e.g. in an inert solvent in the presence of base such as sodium hydride c) Wis CHO, ris 0 and Y is NHR’ : which can be conveniently carried out using reductive alkylation conditions e.g. sodium triacetoxyborohydride in dichloroethane at room temperature d) WisBr,ris1andYis OH which can be conveniently performed by heating the two reactants in an inert solvent e.g. dimethylformamide or dimethylsulfoxide, under basic conditions e.g. potassium carbonate or sodium hydride, optionally at elevated temperature e.g. 100°C. e) WisBr, ris 1andY is NHR’ which can be conveniently performed by heating the two reactants in an inert solvent e.g. dimethylformamide or dimethylsulfoxide, under basic conditions e.g. potassium carbonate or sodium hydride, optionally at elevated temperature e.g. 100°C.

The present invention also provides a general process (D) for preparing compounds of formula (I) which process comprises: reacting a compound of formula (Vill) ry

R A

\ .

Ir NTR (vi)

B

M with a compound of formula (IX)

OO

« \//

R S<_

Lr 0

R——2Z wherein L is a leaving group, such as fluoro, chloro, alkoxy or aryloxy, M is a metal, such as lithium or magnesium, or M is hydrogen. Z, A and B 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*. This general method (D) can be conveniently performed by mixing the two components at preferably -70°C to room temperature in a suitable solvent such as tetrahydrofuran or ether for 10 minutes to 18 hours. Alternatively, where M is H, this general method can be conveniently performed by treating (VIII) and (IX) with a Lewis acid under Friedel-Crafts conditions at elevated temperature in a suitable solvent.

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

R A

\ .

Ir MTR "~ B (X) (0); with a compound of formula (XI) ¢

R L

R——7z wherein L is a leaving group, such as halogen (e.g. fluoro or bromo or iodo) or triflate, j is 0, 1 or 2, and Z, A and B 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*. This general method (E) can be conveniently performed by mixing the two components in a suitable solvent such as dimethylfformamide, in the presence of base e.g. sodium hydride, in the presence of copper iodide at elevated temperature e.g. 120°C or palladium catalysed cross coupling as described in Tetrahedron 2001, 3069, and where necessary oxidising, the intermediate sulfide or sulfoxide.

The present invention also provides a general process (F) for preparing compounds of formula (I) which process comprises: reacting a compound of formula (XII) 2

R A

\ . or NTR (XI)

B

L with a compound of formula (XIII) ©) .

R Ss, (Xn)

R—2 wherein L is a leaving group, such as halogen e.g. ( bromo or iodo) or triflate, j is 0, 1 or 2, and Z, A and B 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*. This general method (F) can be conveniently performed by palladium catalysed cross coupling as described in

Tetrahedron 2001, 3069, and where necessary oxidising, the intermediate sulfide or sulfoxide.

Interconversion of one of the R" to R® groups to the corresponding R' to R* groups typically arises when one compound of formula (!) 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 R" 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).

Compounds of formula (Il) are known in the literature or may be prepared by known processes, for example, chiorosulfonation of the aromatic ring using chlorosulfonic acid.

Conversion to the sulfonyl fluoride can be achieved, if required, by reaction with potassium fluoride in acetonitrile at room temperature. Suitable examples of an R" protecting group are trifluoroacety! or the t-butoxycarbonyl (BOC) group.

Compounds of formula (lil) are commercially available or may be prepared by established procedures, for example lithiation of the corresponding bromobenzene in tetrahydrofuran at low temperature, with for example t-butyl lithium or formation of the Grignard reagent from the appropriate bromobenzene.

Compounds of formula (IV) may be prepared using a similar process to general process

A, using a suitably functionalised Grignard or organolithium reagent, where necessary utilising protection or interconversion of the functional group W. For example, compounds of formula (IV) in which W is 4-NH, can be prepared from the corresponding 4-fluoro analogue by displacement with the anion of trifluoroacetamide followed by hydrolysis, or alternatively by hydrolysis of a protected amine function e.g. bis(trimethylsityl)N.

Compounds of formula (IV) in which W is OH can be prepared by hydrolysis of the : corresponding t-butyldimethylsilyl ether.

Compounds of formula (V) are commercially available or readily prepared from 40 commercially available starting materials.

Compounds of formula (VI) may be prepared using a similar process to general process

A, using a suitably functionalised Grignard or organolithium reagent, where necessary utilising protection or interconversion of the functional group W. For example, compounds of formula (VI) in which W is CHO and r is 0 can be prepared by hydrolysis of the corresponding diethyl acetal. Compounds of formula (VI) in which ris 1 and W is OH can be prepared by NaBH, reduction of the corresponding aldehyde. Compounds of formula (V1) in which r is 1 and W is Br can be prepared from the corresponding alcohol by treatment with CBr, and triphenylphosphine.

Compounds of formula (VH) are commercially available or readily prepared from commercially available starting materials.

Compounds of formula (Vill) can be prepared by halogenation (e.g. iodination or bromination) of compounds of formula (Vil) where M is H, followed by formation of the lithium or Grignard reagent.

Compounds of formula (IX) may be prepared by chlorosulfonylation of the aromatic ring, or by oxidation of the corresponding thiol or disulfide. Conversion to the sulfonyl fluoride can be achieved, if required, by reaction with potassium fluoride in acetonitrile at room temperature.

Compounds of formula (X) may be prepared by reduction of compounds of formula (Il) using for example lithium aluminium hydride in tetrahydrofuran to give the thiol, or using sodium bisulphite and sodium bicarbonate in tetrahydrofuran/water to give the sulfinic acid.

Compounds of formula (XI) are commercially available or readily prepared from commercially available starting materials.

Compounds of formula (XH) can be prepared by halogenation (e.g. iodination or bromination) of compounds of formula (XII) where L is H, or conversion of L is OH to triflate using standard methodology.

Compounds of formula (XIII) may be prepared by reduction of compounds of formula (1X) using for example lithium aluminium hydride in tetrahydrofuran to give the thiol, or using sodium bisulphite and sodium bicarbonate in tetrahydrofuran/water to give the sulfinic acid.

Compounds of formula (I) have antagonist affinity for the serotonin 5-HTo¢, 5-HTop and 5-HTg receptors. These properties may give rise to anti-psychotic activity (e.g. improved 40 effects on cognitive dysfunction) activity with reduced extrapyramidal side effects (eps), and/or anxiolytic/antidepressant activity. These could include, but are not limited to, attenuation of cognitive symptoms via 5-HTg 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,c receptor blockade.

Certain compounds of formula (I) have also been found to exhibit affinity for dopamine receptors, in particular the D3 and D2 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 D2 receptors; however this mechanism is also thought to be responsible for undesirable 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).

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, ***e, 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 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 40 disorders, amnesia, aggression; autism; vertigo, dementia; circadian rhythm disorders; convulsions; epilepsy, 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 the treatment of 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, schizophrenia, 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, schizophrenia, 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 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.

The invention also provides a method of treating psychotic disorders, schizophrenia,

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 which comprises administering to a mammal in need thereof an effective 40 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, schizophrenia, 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).

It will be appreciated by those skilled in the art that the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents such as SHT; antagonists, serotonin agonists, NK-1 antagonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressants, dopaminergic antidepressants, Hs antagonists, 5HT,, antagonists, SHT.g antagonists, SHT,p antagonists, D, agonists, M, agonists and/or anticonvulsant agents.

Suitable 5HT; antagonists which may be used in combination of the compounds of the inventions include for example ondansetron, granisetron, metoclopramide.

Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohimbine, metociopramide.

Suitable SSRIs which may be used in combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine.

Suitable SNRIs which may be used in combination with the compounds of the invention include venlafaxine and reboxetine.

Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, amitriptiline, chiomipramine and nortriptiline.

Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine.

Suitable anticonvulsant agents which may be used in combination of the compounds of the inventions include for example divalproex, carbamazepine and diazepam.

It will be appreciated that the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations), separately or sequentially.

For use in medicine, the compounds of the present invention are usually administered as 40 a standard pharmaceutical composition. The present invention therefore provides in a further aspect a pharmaceutical composition comprising a compound of formula (I) as hereinbefore 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 40 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 fluorochloro- hydrocarbon. 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.

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 phamaceutically 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.

No toxicological effects are indicated/expected when a compound of the invention is administered in the above mentioned dosage range.

Biological Test Methods

Binding experiments on cloned dopamine (e.g. D2 and D3) receptors

The ability of the compounds to bind selectively to human D2/D3 dopamine receptors can be demonstrated by measuring their binding to cloned receptors. The inhibition constants (K;) of test compounds for displacement of [1251)-lodosulpride binding to human

D2/D3 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 40 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; SmM

EDTA, 50mM Trizma pre-set crystals (pH7.4@37°C), 1mM MgCly, 5SmM KCI 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. Supematant 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: Crude D2/D3 cell membranes were incubated with 0.03nM [125])- lodosulpride (~2000 Ci/mmol; Amersham, U. K., and the test compound in a buffer containing S0mM Trizma pre-set crystals (pH 7.4 @ 37°C), 120mM NaCl, 5mM KCI, 2mM

CaCl, 1mM MgCly, 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 10uM 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; = -og10[Ki].

The exemplified compounds have pK; values within the range of 6.3 — 8.9 at the dopamine D; receptor.

The exemplified compounds have pK; values within the range of 56 — 8.5 at the dopamine D; receptor. : Binding experiments on cloned 5-HT¢ receptors

Compounds can be tested following the procedures outlined in WO 98/27081. } The exemplified compounds have pK; values within the range of 7.2 — 10.0 at the 40 serotonin 5-HT¢ receptor.

Binding experiments on cloned 5-HT,, and 5-HT,c receptors

Compounds can be tested following the procedures outlined in WO 94/04533.

The exemplified compounds have pK; values within the range of 7.0 — 9.9 at the ] serotonin 5-HT ,c receptor and 7.5 — 9.9 at the serotonin 5-HT 4 receptor.

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

Description 1 3-Trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl fluoride (D1) (0) aS F = a) 3-Trifluoroacetyi-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl chloride

A solution of 3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine (see W002/40471) (20 g, 80 mmol) in dichloromethane (50 mL) was added dropwise to a solution of chlorosulfonic acid (33 mL, 240 mmol) in more dichloromethane (200 mL) at 0°C. The resulting solution was stirred for 18 h without cooling then poured onto ice (250 g). The resulting organic layer was washed with brine (100 mL), dried (MgSO), and evaporated to give the subtitle compound as a white solid (23 g). b) 3-Trifluoroacetyi-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl fluoride

A mixture of 3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl chloride (23 g, 67 mmol), potassium fluoride (12 g, 200 mmol), 18-crown-6 (0.1 g), and acetonitrile (100 mL) was stirred overnight. Water (200 mL) and ethyl acetate (200 mL) were added and the organic layer was washed with brine (100 mL), dried (MgSQO,), and evaporated to give the title compound D1 as a white solid (21 g). 'H NMR § (de-DMSO) 3.2 (4H, m), 3.7 (4H, m), 7.6 (1H, m), and 8.0 (2H, m).

Description 2 3-Trifluoroacetyi-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl fluoride (D2) b 0

SoG dE

IAN A a) 3-Trifluoroacetyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

To a mixture of 7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (see EP 285287) (5.1 g. 25 mmol), triethylamine (8.4 mL, 60 mmol), and dichloromethane (100 mL) at 0°C, was added dropwise trifluoroacetic anhydride (3.5 mL, 26 mmol). The solution was stirred for 2 h without cooling then washed with saturated aqueous sodium hydrogen carbonate (100 mL), and water (100 mL), dried (MgSO,), and evaporated to give the title compound as a white solid (5.5 g). b) 3-Trifluoroacetyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl chloride

Prepared from 3-trifluoroacetyi-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine using the method of Description 1(a),yield 85%. ¢) 3-Trifluoroacetyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl fluoride

Prepared from 3-trifluoroacetyl-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyt chloride using the method of Description 1(b).yield 80%. 'H NMR & (ds-DMSO) 3.1 (4H, m), 3.7 (4H, m), 4.0 (3H, s), 7.3 (1H, 2s, rotamers), and 7.8 (1H, 2s, rotamers).

Description 3 7-3-Hydroxyphenylisulfonyl)-3-{t-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-3- benzazepine (D3)

QCA

Ho” NTS o—- 00° a) 7-(3-t-Butyldimethysilyloxyphenylsulfonyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

Prepared from 3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl fluoride and 3-t-butyldimethyisilyloxybromobenzene using the method of Example 1, yield 80%. b) 7-(3-t-Butyldimethysilyloxyphenyisulfonyl)-3<{t-butoxycarbonyl)-2,3,4,5- tetrahydro-1H-3-benzazepine

A solution of 7-(3-t-butyldimethysilyloxyphenylsulfonyl)-2,3,4,5-tetrahydro-1H-3- benzazepine (5.0 g, 12 mmol) in dichloromethane (100 mL) was treated with di-t-butyl dicarbonate (2.7 g. 12 mmol). After 30min the solution was evaporated, and chromatography on silica, eluting with 10 to 50% ethyl! acetate in hexane, gave the subtitle compound (5.4 g). c¢) 7-(3-Hydroxyphenyisulfonyt)-3-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-3- benzazepine 7-(3-t-Butyldimethysilyloxyphenylsulfonyt)-3-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-3- : benzazepine (5.4 g, 10.5 mmol) was dissolved in a solution of tetra-n-butylammonium fluoride in tetrahydrofuran (15 mL, 1M, 15 mmol). The solution was stirred for 1h then diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium hydrogen 40 carbonate (100 mL), and brine (100 mL), dried (MgSO,), and evaporated.

Chromatography on silica, eluting with 0 to 10% methanol in dichloromethane containing 0.1M ammonia, gave the title compound D3 (3.5 g). . Description 4 8-Methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl fluoride (D4) 0 (O-

Fo &o a) 7-Methoxy-3-methyi-2,3,4,5-tetrahydro-1H-3-benzazepine

A mixture of 7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (see EP 285287) (25 g, 125 mmol) and 37% formalin (25 mL)in dichloroethane (250 mL) was treated with sodium triacetoxyborohydride (30 g, 250 mmol) keeping the internal temperature below 20°C. After stirring for 2 h, water was added and the pH adjusted to 10 using 50% sodium hydroxide solution. The organic layer was separated, dried over sodium sulfate and evaporated to dryness to afford the product (23 g). b) 8-Methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonic acid

The product from part (a) (23 g) was dissolved in trifluoroacetic acid (125 mL), and then stirred in an ice bath while chlorosuifonic acid (16.5 mL, 250 mmol) was added dropwise.

The solution was stirred for 30 min, then evaporated to dryness to afford the title sulfonic acid which was used directly in the next step. c) 8-Methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl chloride

The sulfonic acid from part (b) was dissolved in thionyl chloride (75 mL) and the solution refluxed for 30 min. After cooling, the solution was evaporated to dryness to afford the title sulfonyl chloride which was used directly in the next step. d) 8-Methoxy-3-methyi-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl fluoride

The sulfonyl chloride from part (c) was dissolved in acetonitrile (500 mL) and potassium fluoride (37 g, 625 mmol) and 18-crown-6 (1 crystal) added. The mixture was stirred for 18 h, then quenched with cold aqueous sodium bicarbonate solution until pH = 8. The mixture was extracted twice with ethyl acetate, washed with bicarbonate solution then brine, dried and evaporated to afford the sulfonyl fluoride D4 (25 g).

Description 5 7<4-Fluoro-benzenesulfonyl)-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine (D5)

QC

&

The sulfonyl fluoride D4 from Description 4 (25 g) was dissolved it dry tetrahydrofuran (250 mL) and 4-fluorophenylmagnesium bromide in tetrahydrofuran (2.5 equivalents) added over 15 min with ice bath cooling, an exotherm only apparent during the first part of the addition. Stirred overnight without cooling then added over 10 min to a solution of sodium potassium tartrate tetrahydrate (250 g) in water (450 mL) with stirring. Diethyl ether was added (400 mL) and the organic layer separated, dried, evaporated, and crystallised from diethyl ether to give crystalline fluorophenyl sulfone D5 17 g (51%).

Description 6 8-(4-Fluoro-benzenesulfonyl)-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-ol hydrobromide salt (D6) f

CO) 0 N—

F

!

A solution of D5 (300 mg, 0.86 mmol) in aqueous 48% HBr (10 mL) was heated at 120°C overnight. The mixture was cooled to room temperature and the solvent removed, azeotroping with toluene. Diethyl ether was added to the residue to yield the title compound D6 as the hydrobromide salt (340 mg). MH' 336. '"H NMR § (DMSO-d) 2.75 (3H, d), 2.88-3.25 (6H, m), 3.50-3.66 (2H, m), 7.35-7.50 (2H. t), 7.76 (1H, s), 7.90-8.03 (2H, m), 9.85 (1H, br.s}), 10.80 (1H, br.s).

Description 7 1,1,1-Trifluoro-methanesulfonic acid 8-(4-fluoro-benzenesulfonyi)-3-methyi-2,3,4,5- tetrahydro-1 H-3-benzazepin-7-yl ester (D7) 0

I

TBC

0 ——

F

F F

F

To an ice bath cooled solution of D6 (340 mg, 0.82 mmol) in acetone (10 mL) was added triethylamine (0.29 mL, 2.1 mmol) followed by trifluoromethanesulfony! chloride (0.13 mL,

1.2 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed and the residue partitioned between dichloromethane and saturated sodium bicarbonate. The organic layer was removed, dried (MgSO,) and evaporated to yield the tite compound D7 as a solid (270 mg). MH 468. 'H NMR & (CDCl;) 2.42 (3H, s), 2.55- 2.70 (4H, m), 2.95-3.15 (4H, m), 7.09 (1H, s), 7.15-7.24 (2H, 1), 7.93-8.04 (3H, m).

Description 8 7-(4-Fluoro-benzenesulfonyl)-3,8-dimethyl-2,3,4,5-tetrahydro-1 H-3- benzazepine (D8) 0

S

SCO

F

A solution of D7 (100 mg, 0.21 mmol) in dry tetrahydrofuran (2 mL) was degassed with argon for 10 minutes. To the solution Pd(PPh;), (30 mg) was added followed by methylzinc chloride (0.22 mL, 0.43 mmol) then heated at reflux for 30 minutes. The mixture was cooled to room temperature and quenched with water. Extraction with dichloromethane followed by purification by SCX and chromatography on silica gave the title compound D8 as a gum (56 mg). MH* 334. 'H NMR & (CDCl) 2.36 (3H, s), 2.38 (3H, s), 2.47-2.66 (4H, m), 2.90-3.05 (4H, m), 6.96 (1H, s), 7.10-7.20 (2H, t), 7.83-7.92 (3H, m).

Description 9 2,2,2-Trifluoro-N-[4-(8-methoxy-3-methyi-2,3,4,5-tetrahydro-1H-3-benzazepine-7- sulfonyl)-phenyl}-acetamiden (D9)

Q.,0 ° Ss

SE

2,2, 2-trifluoroacetamide (9 eq., 51.6 mmol, 5.83 g) was dissolved in dry dimethyisulfoxide (50 mL) and sodium hydride (1.01 eq., 52.1 mmol, 2.1 g) was slowly added at 0 °C; the mixture was stirred at room temperature until no more bubbling was observed. The 4- fluorosulfone D5 (2 g. 5.73 mmol), previously dissolved in dry dimethyisulfoxide (20 mL), was added to the trifluoroacetamide mixture at room temperature; the resulting reaction mixture was heated to 145 °C for 30 hours. The reaction mixture was then cooled to room temperature and it was poured onto water (400 mL); the resulting aqueous mixture was extracted with ethyl acetate (300 mL x 3). The organics were washed with water (300 mL x 2) and brine (200 mL x 2), they were dried over Na,SO,, filtered and the solvent was evaporated to afford the crude product D9, 3.5 g. MH"* 444.

Description 10 4-(8-Methoxy-3-methyi-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyf)- phenylamine (D10) 0

IC

HN

; 7

The crude trifluoroacetamide intermediate D9 (3.5 g) was dissolved in methanol (25 mL) and NaOH (2N solution) (28.5 mmol, 14.3 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 14 hours and it was afterwards poured onto brine-water and the aqueous was extracted with ethyl acetate (200 mL x 3); the organics were dried over Na,SO,, filtered and the solvent was evaporated to afford 2.6 g of crude product as a yellow solid. Chromatography on silica eluting with 0-10%

MeOH-NH; - DCM afforded 1.3 g of the title compound (66 %), as a pale yellow solid D10.

MH" 347.

Description 11 4-(8-Methoxy-3-methyi-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl)- benzaldehyde (D11)

Py ‘oboo- rs

Magnesium turnings (1.4 g) in tetrahydrofuran (10 mL) were stirred under an atmosphere of argon and treated with a solution of 4-bromobenzaldehyde diethyl acetal (15.5 g) in tetrahydrofuran (60 mL) The mixture was stirred for 4 hours then the sulfonyl fluoride D4 (5.46 g) was added and the mixture was stirred for 60 hours. The mixture was poured into a solution of potassium sodium tartrate in water and extracted with ethyl acetate. The residue was purified by column chromatography 0-10% methanol (containing 0.5% aqueous ammonia)-dichloromethane. The product was treated with hydrochloric acid (10 mL) in tetrahydrofuran (100 mL) for 18 hours. The solution was basified and extracted with dichloromethane, and solvent evaporation gave the title compound D11 as a white solid. 'H NMR: 8 CDCi3 2.38 (3H, s), 2.6 (4H, m), 2.9 (4H, m), 3.73 (3H, s) 6.65 (1H, s), 7.86 (1H, s), 8.02 (2H, d) 8.12 (2H, d), 10.12 (1H, s).

Description 12 [4-(8-Methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl)-phenyl}- methanol (D12)

0 oO. - 1 -

A oo

A solution of D11 (2.7 g), tetrahydrofuran (50 mL) and methanol (25 mL) was treated with sodium borohydride (0.76 g). The solution was stirred for 1 hour then treated with dilute hydrochloric acid (20 mL). The mixture was basified and extracted with dichloromethane.

The solvent was evaporated and the residue was purified by column chromatography O- 10% methanol (containing 0.5% aqueous ammonia)-dichloromethane to give the title compound D12 as a white solid. (1.13 g). 'H NMR: § CDCI3 2.36 (3H, s), 2.55 (4H, m), 2.93 (4H, m), 3.73 (3H, s), 4.77 (2H, s) 6.63 (1H, s), 7.47 (2H, d), 7.84 (1H, s) 7.94 (2H, d).

Description 13 7-{4-Bromobenzenesulfonyl)-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine (D13) “CUO do

To a stirred solution of 1,4-dibromobenzene (0.665 g, 2.82 mmol, 2.0 eq) in dry tetrahydrofuran (7 mL) under argon at -78°C was added butyllithium (1.25 mL 2.5M in hexanes, 3.10 mmol, 2.2 eq) dropwise over 10 min. After a further 30 min. a suspension of sulfonyl! fluoride D4 (0.385 g, 1.41 mmol, 1.0 eq) was added portionwise. The resultant mixture was allowed to warm to room temperature then stirred for 2 h. The mixture was quenched with water (40 mL) then extracted twice with ethyl acetate (2 x 40 mL). The organic layer was washed sequentially with water (50 mL) and brine (50 mL) then dned over MgSO, and evaporated to dryness. Purification by Biotage chromatography, eluting with 1-6% MeOH-CH.CI, containing 0.5% NH; afforded the desired product D13 as a solid, 0.289 g (50%). MH* 411. '"H NMR § (CDCl;) 2.37 (3H, s), 2.55 (4H, m), 2.93 (4H, m), 3.75 (3H, s), 6.65 (1H, s), 7.60 (2H, d), 7.80 (3H, m).

Description 14 7-Ethoxy-8-(4-fluoro-benzenesulfonyl)-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine (D14) rb

ICC

00 a) 7-Ethoxy-3-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-3-benzazepine

To a solution of 7-hydroxy-3-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (10 g. 38 mmol) in dimethylformamide (70 mL) was added sodium hydride (60% dispersion in oil, 1.5g) and the resulting mixture stirred for 0.5h. Ethyl! iodide (3.6 mL, 45 mmol) was added and the mixture stimed for 12h at 70°C. The mixture was cooled to room temperature and diluted with diethyl ether (200 mL) and water (200 mL), the layers were separated and the aqueous portion extracted with diethyl ether (200 mL). The combined organic extracts were washed with brine (200 mL) and sodium hydroxide solution (2N, 200 mL) and then evaporated to give a yellow oil. b) 7-Ethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride

The material from part (a) was slurried in ethanol (100 mL) and concentrated hydrochloric acid (10 mL) was added and the mixture stirred for 1h. The solvents were removed in vacuo and the residue was treated with methanol (10 mL) and then diethyl ether (300 mL) and the resulting precipitate was filtered and dried (6.79). c) 7-Ethoxy-3-methyi-2,3,4,5-tetrahydro-1H-3-benzazepine

The material from part (b) was dissolved in aqueous formalin solution (37%, 60 mL) and sodium triacetoxyborohydride (10 g) was added, the mixture was stirred for 2h and then saturated sodium bicarbonate solution (100 mL) was added and the mixture extracted with dichloromethane (2 x 100 mL). The organic layers were evaporated and the residue was purified by column chromatography eluting with 10% methanol/dichloromethane.

MH* 206. d) 7-Ethoxy-8-(4-fluoro-benzenesulfonyl)-3-methyi-2,3,4,5-tetrahydro- 1H-3-benzazepine

The title compound D14 was prepared from part (c) in a manner similar to Descriptions 4 and 5

Description 15 7-Ethyisulfanyl-8-(4-fluoro-benzenesulffonyl)-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine (D15) &o

A suspension of palladium acetate (22 mg, 0.1mmoi), BINAP (92 mg, 0.15mmol) and potassium phosphate (312 mg, 1.5mmol) in 1,4-dioxan (4.0 mL) was sonicated for 30 minutes forming a deep, red complex.

The aryl triflate D7 from Description 7 (458 mg, 1.0mmol) and ethane-thiol (0.25mL, xs) were added and the mixture heated at 160°C for 30 minutes using microwave technology (Emrys Optimizer).

M4

Claims (15)

1. A compound of formula (I): RY R3 . A \ 1 Ju JS 2 : RZ 2S ® Oo 6) wherein A and B represent the groups —{CH;),- and —(CH),- respectively; R' represents hydrogen or C;ealkyl; R? represents hydrogen, halogen, hydroxy, cyano, nitro, hydroxyC,.salkyl, trifluoromethyl, trifluoromethoxy, C,salkyl, C,salkoxy, C,sfluoroalkoxy, -(CH;),Csecycloalkyl, -(CH;),OC,. ecycloalkkyl, -COC,ealkyl, -SO.C,ealkyl, -SOC,salkyl, -S-Cisalkyl, -CO.C,galkyl, -

CO.NR®R®, -SO,NR°R®, -(CH,),NR°R®, -(CH,),NR’COR®, optionally substituted aryl ring, optionally substituted heteroaryl ring or optionally substituted heterocyclyl ring; R® represents optionally substituted aryl ring or optionally substituted heteroaryl ring; R* represents hydrogen, hydroxy, Cisalkyl, Cisalkoxy, trifluoromethyl, trifluoromethoxy, halogen, -OSO,CF,, -(CH.),Cs.scycloalkyl, -(CH,),0C,.ealkyl or {CH_),0C3 cycloalkyl; R® and R® each independently represent hydrogen, C,.salky! or, together with the nitrogen or other atoms to which they are attached, form an azacycloalkyl ring or an oxo- substituted azacycloalkyl ring; Z represents —(CH,),X- wherein the -(CH,)- group is attached to R3, or -X(CH.),- wherein Xs attached to R?, and wherein any of the -CH,- groups may be optionally substituted by one or more C, alkyl groups; X represents oxygen, -NR’ or —CH,- wherein the -CH,- group may be optionally substituted by one or more C, alkyl groups; R’ represents hydrogen or C,salkyt; mand n independently represent an integer selected from 1 and 2; p independently represents an integer selected from 0, 1, 2 and 3; g independently represents an integer selected from 1, 2 and 3, r independently represents an integer selected from 0, 1, and 2; or a pharmaceutically acceptable salt or solvate thereof.

2. A compound of formula (I) according to claim 1 wherein R' represents hydrogen or C.. salkyl.

3. A compound of formula (I) according to claim 1 or claim 2 wherein R? represents hydrogen, halogen, C,salkyl, C,¢alkoxy, C,salkyithio or diC,salkylamino.

4. A compound of formula (I) according to any of claims 1 to 3 wherein R® represents phenyl.

5. A compound of formula (I) according to any of claims 1 to 4 wherein R* represents hydrogen, C,4alkyl or C,4alkoxy.

6. A compound of formula (I) according to any of claims 1 to 5 wherein R® and R® independently represent hydrogen or C,4alkyl.

’ 7. A compound of formula (I) which is 7-Methoxy-8-(3-phenoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-3-benzazepine; 7-Methoxy-3-methyl-8-(3-phenoxy-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-3- benzazepine; 7-(3-Benzyloxyphenylsulfonyl)-2,3,4,5-tetrahydro-3-benzazepine; 7-{4-(4-Chloro-benzyloxy)-benzenesulfonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine; (4-Fluoro-benzyl)-[4-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1 H-3-benzazepine-7- sulfonyl)-phenyl}-amine; [4-(8-Methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl}-phenyi}-phenyl- amine; 7-[4-(4-Chloro-phenoxymethyl)}-benzenesulfonyi]-8-methoxy-3-methyi-2,3,4,5-tetrahydro- 1H-3-benzazepine, 4-Chioro-pheny){4-(8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7- sulfonyl)-benzyl}-amine; 7-{4-(4-Fluorobenzyl)benzenesuifonyl]-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine, 7-[4-(3-Fluoro-benzyloxy)-benzenesulfonyl}-6-methoxy-1,2,3,4-tetrahydro-isoquinoline, and 5-Methoxy-2-methyl-6-[4-(3-trifluoromethyl-benzyloxy)-benzenesulfonyl}-2,3-dihydro-1 H- isoindole; (2-Methoxy-benzyl)-{4-(8-methoxy-3-methyl-2,3,4,5-tetrahydro- 1H-3-benzazepine-7- sulfonyl}-phenyl}-amine, 7-[4-(4-Chioro-phenoxymethyl)-benzenesulfonyl]-8-ethoxy-3-methyi-2,3,4,5-tetrahydro- 1H-3-benzazepine; [4-(8-Ethoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl)-benzyl]-(2- methoxy-phenyl)-amine; {8-[4-(4-Fluoro-phenoxymethyl)-benzenesulfonyl]-3-methyl-2,3,4,5-tetrahydro-1H-3- benzazepin-7-yl}-dimethyl-amine; 6-Ethoxy-7-[4-(4-fluoro-benzyloxy)-benzenesulfonyl]-1,2,3,4-tetrahydro-isoquinoline hydrochloride; (3-Methoxy-benzyl)-{4-(6-methoxy-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl)-phenyl)- methyl-amine hydrochloride; } 40 7-[4-(4-Chiorophenoxymethyl)benzenesulfonyl}-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride salt; and 3-Methyl-7-{(4-(2-methoxybenzyloxy)-phenylsuifonyl}-9-phenyl-1,2 4,5-tetrahydro-3- benzazepine.

8. A pharmaceutical composition comprising a compound of formula (1) as claimed in any of claims 1 to 7 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor.

9. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in any of claims 1 to 7 for use in therapy.

10. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in any of claims 1 to 7 for use in the treatment of a condition which requires modulation of a dopamine receptor.

11. A compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof as claimed in any of claims 1 to 7 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, convulsions, epilepsy and gastric motility disorders.

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

13. Use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as claimed in any of claims 1 to 7 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, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders, convulsions, epilepsy and gastric motility disorders.

14. 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 (1) or a pharmaceutically acceptable salt or solvate thereof as claimed in any of claims 1to 7.

15. 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, . 40 obsessive-compulsive disorders, amnesia, aggression, autism, vertigo, dementia, circadian rhythm disorders, convulsions, epilepsy and gastric motility disorders, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof as claimed in any of claims 1to 7.