ZA200602756B - Novel tetraydrospiro{piperidine-2,7'-pyrrolo[3,2-b]pyridine derivatives and novel indole derivatives useful in the treatment of 5-HT6 receptor-related disorders - Google Patents

Description

‘Novel tetrahydrospiro{piper?dine-2,7’ ~pyrrolo[3,2-b] pyridine} derivatives and novel indole derivatives useful in the treatment of 5-HT6 receptor -related disorders

TECHNICAL FIELD

The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for their preparation, as well as to the use of the compounds for the preparation of a medicament against 5-HT¢ receptor-related disorders.

BACKGROUND OF THE INVENTION

Obesity is a condition characterized by an increase in body fat content resulting in excess body weight above accepted norms. Obesity is the most important nutritional disorder in the western world and represents a major health problem in all industrialized countries. This disorder leads to increased mortality due to increased incidences of diseases such as cardiovascular disease, digestive disease, respiratory disease, cancer and type 2 diabetes. Searching for compounds, which reduce body weight has been going on for many decades. One line of research has been activation of serotoninergic systems, either by direct activation of serotonin receptor subtypes or by inhibiting serotonin reuptake. The exact receptor subtype profile required is however not known.

Serotonin (5-hydroxytryptamine or 5-HT), a key transmitter of the peripheral and central nervous system, modulates a wide range of physiological and pathological functions, including anxiety, sleep regulation, aggression, feeding and depression. Multiple serotonin receptor subtypes have been identified and cloned. One of these, the 5-HTg receptor, was cloned by several groups in 1993 (Ruat, M. et al. (1993) Biochem. Biophys.

Res. Commun.193: 268-276; Sebben, M. et al. (1994) NeuroReport 5: 2553-2557). This receptor is positively coupled to adenylyl cyclase and displays affinity for antidepressants such as clozapine. Recently, the effect of 5-HTg antagonist and 5-HTg antisense oligonucleotides to reduce food intake in rats has been reported (Bentley, J.C. et al. (1999)

Br J Pharmacol. Suppl. 126, P66; Bentley, J.C. et al. (1997) J. Psychopharmacol. Suppl.

A64,255; Woolley M.L. et al. (2001) Neuropharmacology 41: 210-219).

Compounds with enhanced affinity and selectivity for the 5-HT¢ receptor have been identified, e.g. in WO 00/34242 and by Isaac, M. et al. (2000) 6-Bicyclopiperazinyl-1- arylsulphonylindoles and 6-Bicyclopiperidinyl-1-arylsulphonylindoles derivatives as novel,

potent and selective 5-HT receptor antagonists. Bioorganic & Medicinal Chemistry

Letters 10: 1719-1721 (2000), Bioorganic & Medicinal Chemistry Letters 13: 3355-3359 (2003), Expert Opinion Therapeutic Patents 12(4) 513-527 (2002).

It has surprisingly been found that the compounds according to the present invention show affinity for the 5-HTg receptor as antagonists at nanomolar range. Compounds according to the present invention and their pharmaceutically acceptable salts have 5-HTg receptor antagonist, agonist and partial agonist activity and are believed to be of potential use in the treatment or prophylaxis of obesity and type 2 diabetes, to achieve reduction of body weight and of body weight gain, as well as in the treatment or prophylaxis of disorders of the central nervous system such as anxiety, depression, panic attacks, memory disorders, cognitive disorders, epilepsy, sleep disorders, migraine, anorexia, bulimia, binge eating disorders, obsessive compulsive disorders, psychoses, Alzheimer’s disease,

Parkinson’s disease, Huntington’s chorea and/or schizophrenia, panic attacks, Attention

Deficit Hyperactive Disorder (ADHD), withdrawal from drug abuse, neurodegenerative diseases characterized by impaired neuronal growth, and pain. The reduction of body - weight and of body weight gain (e.g. treating body-weight disorders) is achieved inter alia by reduction of food intake. As used herein, the term “body weight disorders” refers to the ++ disorders caused by an imbalance between energy intake and energy expenditure, resulting in abnormal (e.g., excessive) body weight. Such body weight disorders include obesity.

INFORMATION DISCLOSURE

WO 99/42465 discloses sulphonamides derivatives that bind to the 5-HT¢ receptor and that can be used for the treatment of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, cognitive disorders, ADHD, anorexia and bulimia, schizophrenia, and drug abuse.

WO 01/32646 Al discloses compounds that bind to the 5-HT¢ receptor and that are used for the treatment of CNS disorders and which inter alia may be used for the treatment of eating disorders.

WO 99/37623 A2 discloses compounds that bind to the 5-HTg receptor and that are used for the treatment of CNS disorders and which inter alia may be used for the treatment of eating disorders.

used for the treatment of CNS disorders and which inter alia may be used for the treatment of eating disorders.

EP 0815 861 Al discloses compounds that bind to the 5-HTg receptor and that are used for the treatment of CNS disorders.

WO 99/02502 A2 discloses compounds that bind to the 5-HT¢ receptor and that are used for the treatment of CNS disorders and which inter alia may be used for the treatment of eating disorders.

WO 98/27081 Al discloses compounds that bind to the 5-HT¢ receptor and that are used for the treatment of CNS disorders and which inter alia may be used for the treatment of eating disorders.

EP 0701819 discloses compounds that bind to the 5-HT} p receptor and that are used for the treatment of CNS disorders and obesity.

US 6,191,141 and WO 01/12629 disclose compounds that bind to the 5-HT¢g receptor and that are used for the treatment of CNS disorders.

WO003/072198 disclose benzenesulphonamide derivatives for the treatment of ‘ obesity.

No publications disclose the compounds and their use according to the present - invention against 5-HTg receptor-related disorders.

DISCLOSURE OF THE INVENTION

One object of the present invention is a compound of the Formula (I) u m' (R™) we EY

Way N 3 \

P MD wherein: vis 1 or 2 and P is selected from a substituent of Formula (II) and Formula (III);

Kaoz© To $36 o NJ

Rr! R $=0

R' (nm (1) or P may also be selected from H or Cy .-alkyl provided that R™ is selected from _NHSO,R"., -SO,NR®R"! or -S(O).R"!, wherein R'" is selected from aryl and heteroaryl 5 and whereeis0,1,20r3,vis 1 and R™ is H; — represents a single bond or a double bond, with the proviso that both — represent double bonds or that both — represent single bonds;

W,, W,, W3, Z and Y are each a carbon atom; or one of Wy, W2, Wj, Z and Y is a nitrogen atom, while the remainder being carbon atoms, provided that both ~— in Formula (D) represent single bonds;

U is selected from CHR?, CR* and CR*R¥, provided that when the dotted line connecting

W, and U is a double bond, then U is CR* and further provided that when the dotted line 1S connecting W, and U is a single bond, then U is selected from CHR* and CRR*; a.

R! is selected from: (@) C1-6-alkyl, (b) C,.s-alkoxy-C,.¢-alkyl, (c) Ci-alkenyl, (d) hydroxy-Cj-¢-alkyl, (e) halo-Cy-s-alkyl, (f) aryl, (g) arylcarbonylmethyl, (h) aryl-Cy¢-alkenyl, (i) aryl-Ci6-alkyl, (j) Cs.7-cycloalkyl, (k) heteroaryl, (1) 4-piperidinyl,

(m) N-substituted 4-piperidinyl, wherein the substituents are selected from C,-¢-alkyl, aryl, heteroaryl, aryl-C,-s-alkyl and heteroaryl-C-¢-alkyl, (n) heteroaryl-Cy.s-alkyl, wherein any heteroaryl or aryl residue, alone or as part of another group, is optionally substituted, independently, in one or more positions with substituents having the values as defined for R™ andR™;

R™ and R™ are each independently selected from: (a) hydrogen, (b) halogen, (c) Ci6-alkyl, (d) hydroxy, (e) Ci¢-alkoxy, (f) C,.6-alkenyl, (g) phenyl, (h) phenoxy, (i) benzyloxy, (j) benzoyl, (k) -OCF;, . (CN, (m) hydroxy-C,.¢-alkyl, (n) halo-C, ¢-alkyl, ©) _NRI®R'?, (p) -NO, (q) -CONR'R", (r) -NHSOR', (s) -NRECOR'', (t) -SO;NR’R"", (u) -C=OR", (v) Ci-¢-alkoxycarbonyl,

Ww) -S(0)R', whereineis 0, 1,2 or 3, (x) SCF, (y) -CHF=CH_, (aa) -OCF2H, or

(ab) ethynyl; and with the proviso that, R™ is attached to a carbon atom in ring B; and with the further proviso that when one of W,, W3 and W; in Formula (I) is a nitrogen atom and both — represent single bonds the said nitrogen atom is attached to R", wherein R™ is selected from hydrogen or Cy-s-alkyl and vis 1; and with the further proviso that when Wi, W; and W3 in Formula (I) are each a carbon atom and both — represent single bonds, R™ is selected from hydrogen or methyl; and with the further proviso that when R™ or R™, as substituents on ring A and B in

Formula (I), are selected from phenyl, phenoxy, benzyloxy and benzoyl, the phenyl or aryl ring thereof may be optionally substituted by C;-4-alkyl, halogen, C;-s-alkoxy, Ci-4- alkylthio, trifluoromethyl, hydroxymethyl or cyano; wherein R™and R* may be linked to each other to form a fused substituent of Formula (IV) provided that R™ is attached to W;: 8 ; [ T TR q=00r1 (wv) when U is CR? or CHR?, R* is a group selected from:

4 x 8 I .

R | ax pS [ X il

N s ONS

I

R* Jo x D lo 7 Y

RO R

RN “Nr rT t- 4 "e Rr ox 1,0) <S o J Vo oN 0 R* 0 I. N, oN

R R

. a ~-

ANS T A re je

RR N—( JN AN

SE. 0 07 n X R 0

R 10/7 N10 [

N MN ] R R of 10 N

Rr R® p N-R RY rR" “T° .

Yo . XY Ld

C 1s Cr o 0

N o N o

R® ) )

R® R®

Clk XK I [ R'" N R R® 1) R' lo Is N”

N-R™ \ R in

Lio rR"

RGA i. -t-- .

N RN RA, A

XD N

ES px] | r®

R® = nN" NR "7 } 8

R

N I re-N~ge N Pr

R wherein: n=0,1,0r2, o=1lor2, p=1,2,3,0r4, r=2or3,

s=1,20r3; when U is CHR*, R* is additionally selected from the following groups: f-- id tT 7) LN N 3 Oo 0} 0 DO oN hs of nN Rd

R ]® RS R \ | - . | pe | pe | )

R r Ir 0 oil ef b ] 7 N 9g Be 10

R* t J RD Js ls R VR

R wherein: n=01or2, o=1lor2, t=2,3o0r4, r=2or3, s=1,20r3; wherein X is selected from O, NR®and S; wherein R® is independently a group selected from: (a) hydrogen, (®) Ci-¢-alkyl, (c) 2-cyanoethyl, (d) hydroxy-Cs-¢-alkyl, (e) C;-¢-alkenyl, (f) Cy-¢-alkynyl, (g) C3-7-cycloalkyl, (h) Cs-7-cycloalkyl-Ci-¢-alkyl, (i) Cy-¢-alkoxy-Cz-¢-alkyl, (j) aryl-Cy-¢-alkyl, (k) heteroaryl-C,-¢-alkyl,

(1) 3,3,3-trifluoropropyl, wherein any aryl and heteroaryl residue may be optionally substituted with C,-s-alkyl, halogen, C;-s-alkoxy, Cs-s-alkylthio, trifluoromethyl or cyano;

R°® is selected from: (a) hydrogen, (b) Cy-s-alkyl, (c) hydroxy-C,-4-alkyl, (d) Ci-s-alkoxy-C-4-alkyl, (e) halo-C;-4-alkyl, (f) -NR®R?, provided that the said ~NR®R® group is not attached to a carbon atom adjacent to a ring nitrogen atom, (g) -CO-NR'R®, (h) hydroxy, provided that the said hydroxy group is not attached to a carbon atom adjacent to a ring nitrogen atom,

R’ is selected from: (a) hydrogen, (b) Ci-4-alkyl, (c) hydroxy-C,-s-alkyl, or (d) Ci-s-alkoxy-C,-4-alkyl, (e) hydroxy, provided that the said hydroxy group is not attached to a carbon atom adjacent to a heterocyclic ring nitrogen atom and that the said hydroxy group is attached to a heterocyclic ring not substituted with oxo;

R® is each independently selected from: (a) hydrogen, or (b) Cy-¢-alkyl,

R’ is selected from: (a) hydrogen, (b) Ci-4-alkyl, wherein one or two groups may be present at any carbon atom, or when two groups are present at the same carbon atom they may together form a cyclopropane ring,

(c) hydroxy-Ci-s-alkyl, (d) Ci-s-alkoxy-Ci-s-alkyl, (e) halo-C;-4-alkyl,

Ss R'is each independently selected from: (a) hydrogen, (b) C,-¢-alkyl, (c) hydroxy-C,-s-alkyl, (d) Cs-7-cycloalkyl, or (e) C)-4-alkoxy-Cz-s-alkyl, wherein the two R'° groups together with the nitrogen to which they are attached form a heterocyclic ring; and when the two R'® groups form a piperazine ring, the nitrogen of the piperazine ring that allows the substitution may be substituted with a group selected from

R>;

R" is selected from: (a) Cr¢-alkyl, (b) aryl, or (c) heteroaryl, wherein aryl and heteroaryl may be optionally substituted with C;-4-alkyl, halogen, Ci-4- alkoxy, C)-s-alkylthio, trifluoromethyl, hydroxymethyl or cyano;

R'? is selected from: (a) hydrogen, or (b) methyl; when U is R‘R*,R* and R* are linked to each other to form a heterocyclic ring selected from pyrrolidine or piperidine, wherein the N atom may be substituted by a group selected from R®; and pharmaceutically acceptable salts, hydrates, solvates, geometrical isomers, tautomers, optical isomers, and prodrug forms thereof.

It is preferred in Formula (I) that:

P is selected from

*s2° io (i) cach of W,, Wa, Ws, Z and Y is a carbon atom provided that both “= in Formula (I) represent double bonds; or one of Wy, Wa, W3, Z and Y is a nitrogen atom, while the remainder being carbon atoms, provided that both —— in Formula (I) represent single bonds;

U is selected from CHR*, CR* and CR*R?, provided that when the dotted line connecting

W, and U is a double bond, then U is CR"; and further provided that when the dotted line connecting W; and U is a single bond, then U is selected from CHR* and CR'RY;

R! is selected from: (f) ary}, (h) aryl-C;¢-alkenyl, (1) aryl-C,¢-alkyl, (j) Cs.s-cycloalkyl, : (k) heteroaryl, (n) heteroaryl-C, s-alkyl, wherein any heteroaryl or aryl residue, alone or as part of another group, is optionally substituted, independently, in one or more positions with substituents having the values as defined for R™andR™;

R™ and R™ are each independently selected from: (a) hydrogen, (b) halogen, (c) Cig-alkyl, (d) hydroxy, (e) Ci¢-alkoxy, (f) Cy.¢-alkenyl, (k) -OCF3, (1)-CN,

(m) hydroxy-C,s-alkyl, (n) halo-C,.¢-alkyl, (0) -NR'R", (q) -CONR'’R", (r)-NHSOR", (s) -NR®COR", (t) -SONR'R", (u) -C(=O)R", (w) -S(O).R", wherein e is 0, 1,2 or 3, (x)-SCF, (y) -CHF=CH,, (aa) ~OCF,H, or (ab) ethynyl; and with the proviso that, R™ is attached to a carbon atom in ring B; and with the further proviso that when one of Wy, W, and W3 in Formula (I) is a nitrogen atom and both — represent single bonds the said nitrogen atom is attached to R™, wherein

R™ is selected from hydrogen or C,-4-alkyl and v is 1; and with the further proviso that when W;, W> and W3 in Formula (I) are each a carbon atom and both —— represent single bonds, R™ is selected from hydrogen or methyl; and with the further proviso that when R™ and R™ are substituents on ring A and B, R" and

R™ are independently selected from: hydrogen, halogen, methyl, methoxy, trifluoromethyl, hydroxymethyl or cyano; when U is CR? or CHR? R*is a group selected from:

RS < rd N~ge rR . N~R®

Ry Jo | buf (

N N ke RY R® a

Ry \ . 8 Pa N T

A <A

N 107 N\,10

RS’ Jp R R . 3 . PY SN

RAL pa RN NT JY pa.

N = | = rR

XN rR? R ~ _R N Fl . ZZ R® NZ N N rR® RNR ) NG 8 § A .R®

R X 0 N R% 12 . we Ao I Ya 0 -—

Lo ve ne

R Rr" R' wherein n=0,1,or2, o=1or2, : © p=1,2,3,0r4, when U is CHR? R? is additionally selected from the following groups: ——pam rR’ f= ) 1

A N N , (0) N

Oo

N N N N is is °) 1s

R R® / X | 1 [ . FX 1 ; [ : X

R N r sN A rR R’ N Bt 10

R R N—R

Oo o R wherein : n=01or2,

o=1lor2, t=2,30r4, r=2or3, wherein X is selected from O and NR?

S wherein R® is independently a group selected from: (a) hydrogen, (b) Ci-6-alkyl, (c) 2-cyanoethyl, (d) hydroxy-C,-s-alkyl, (e) Cs-¢-alkenyl, (h) Cs-7-cycloalkyl-C-¢-alkyl, or (i) C;-4-alkoxy-Cz-s-alkyl,

Ris selected from: (a) hydrogen, (b) Cy-a-alkyl, (c) hydroxy-C;-2-alkyl, or (d) C;-2-alkoxy-Ci-2-alkyl;

R® is each independently selected from: (a) hydrogen, or (b) Ci-¢-alkyl,

Ris selected from: (a) hydrogen, (b) C)-4+-alkyl, wherein one or two groups may be present at any carbon atom, or when two groups are present at the same carbon atom they may together form a cyclopropane ring, (c) hydroxy-C-;-alkyl, (d) Ci--alkoxy-C,-2-alkyl, (e) halo-C,-;-alkyl,

R' is each independently selected from: (a) hydrogen,

(b) Ci-s-alkyl, (c) hydroxy-C»-s-alkyl wherein the two R'? groups together with the nitrogen to which they are attached form a heterocyclic ring; and when the two R'® groups form a piperazine ring, the nitrogen of the piperazine ring that allows the substitution may be substituted with a group selected from

RS;

R'! is selected from: (a) Cy4-alkyl

RZ is selected from: (a) hydrogen, or (b) methyl; when Uis R‘R*, R*and R* are linked to each other to form a heterocyclic ring selected from pyrrolidine or piperidine, wherein the N atom may be substituted by a group R® selected from: (a) hydrogen, (b) Cy-s-alkyl, (d) hydroxy-C;-s-alkyl, (i) Ci-4-atkoxy-Cor-4-alkyl, (k) 2-cyanoethyl.

Preferred compounds are: 4’-Methyl-1’-(2-naphthylsulphonyl)-1°,4°,5 ’ 6’-tetrahydrospiro {piperidine-2,7’- pyrrolo[3,2-b]pyridine} hydrochloride, 4’-Methyl-1’-(4-bromophenylsulphonyl)-1°,4’,5 * 6’-tetrahydrospiro{piperidine-2,7’- pyrrolo[3,2-b]pyridine} hydrochloride, 4’-Methyl-1°-(5-bromo-2-thienylsulphonyl)-1°,4°,5’,6’ -tetrahydrospiro {piperidine-2,7’- pyrrolo[3,2-b}pyridine} hydrochloride, 4’-Methyl-1’-(2-thienylsulphonyl)-1’,4’,5’,6’-tetrahydrospiro {piperidine-2,7’-pyrrolo(3,2- b]pyridine} hydrochloride,

N-(1-Benzenesulfonyl-1H-indol-4-yl)-2-(2-hydroxy-ethylamino)-acetamide,

1-Benzenesulfonyl-1H-indol-4-yl)-pyridin-4-yl-amine,

N-(4-Piperazin-1-yl- 1H-indol-1-yl)benzenesulfonamide hydrochloride, and 3-{(4-Methylphenylsulfony1)-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine trifluoroacetate

Another object of the present invention is a process for the preparation of a compound as mentioned above, comprising the following steps: 1) reaction of 2-(2-ethylamino)pyrrole and 1-methylpiperazine-4-one to give 4'- methyl-1',4",5",6 -tetrahydrospiro {piperidine-2,7-pyxrolo[3 ,2-b]pyridine} ; and 2) reaction of the product from step a) with an arylsulphonyl chloride in the presence of a base.

Another object of the present invention is a process for the preparation of a compound as mentioned above, by reaction of 1-benzensulfonyl-1H-indol-4-ylamine and bromoacetyl bromide and further reaction with ethanolamine.

Another object of the present invention is a process for the preparation of a compound as mentioned above, by reductive amination of 3-(toluene-4-sulfonyl)-6,9- dihydro-3H, 7H-benzo[e]indol-8-one in the presence of sodium cyanoborohydride and ammonium acetate.

Another object of the present invention is a compound as mentioned above for use in therapy, especially for use in the treatment or prophylaxis of a 5-HTg receptor-related disorder, to achieve reduction of body weight and of body weight gain.

Another object of the present invention is a pharmaceutical formulation comprising a compound as mentioned above as active ingredient, in combination with a pharmaceutically acceptable diluent or carrier, especially for use in the treatment or prophylaxis of a 5-HT receptor-related disorder, to achieve reduction of body weight and of body weight gain.

Another object of the present invention is a method for treating a human or animal subject suffering from a S-HTg receptor-related disorder, to achieve reduction of body weight and of body weight gain. The method can include administering to a subject (e.g., a human or an animal, dog, cat, horse, cow) in need thereof an effective amount of one or more compounds of any of the formulae herein, their salts, or compositions containing the compounds or salts.

The methods delineated herein can also include the step of identifying that the subject is in need of treatment of the 5-HT receptor-related disorder, to achieve reduction of body weight and of body weight gain. Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).

Another object of the present invention is a method for the treatment or prophylaxis of a 5-HT¢ receptor-related disorder, to achieve reduction of body weight and of body weight gain, which comprises administering to a subject in need of such treatment an effective amount of a compound as mentioned above.

Another object of the present invention is a method for modulating 5-HT¢ receptor activity, which comprises administering to a subject in need of such treatment an effective amount of a compound as mentioned above.

Another object of the present invention is the use of a compound as mentioned above for the manufacture of a medicament for use in the prophylaxis or treatment of a 5-HTg receptor-related disorder, to achieve reduction of body weight and of body weight gain.

The compounds as mentioned above may be agonists, partial agonists or antagonists for the 5-HT¢ receptor. Preferably, the compounds act as partial agonists or antagonists for the 5-HTg receptor.

Examples of 5-HTg receptor-related disorders are obesity; type 11 diabetes; disorders of the central nervous system such as anxiety, depression, panic attacks, memory disorders, cognitive disorders, epilepsy, sleep disorders, migraine, anorexia, bulimia, binge eating disorders, obsessive compulsive disorders, psychoses, Alzheimer's disease, Parkinson's disease, Huntington's chorea, schizophrenia, attention deficit hyperactive disorder (ADHD), withdrawal from drug abuse, neurodegenerative diseases characterized by impaired neuronal growth, and pain.

The compounds and compositions are useful for treating diseases, to achieve reduction of body weight and of body weight gain. The diseases include obesity; type Il diabetes; disorders of the central nervous system such as anxiety, depression, panic attacks, memory disorders, cognitive disorders, epilepsy, sleep disorders, migraine, anorexia, bulimia, binge eating disorders, obsessive compulsive disorders, psychoses, Alzheimer’s disease, Parkinson's disease, Huntington's chorea, schizophrenia, attention deficit hyperactive disorder (ADHD), withdrawal from drug abuse, neurodegenerative diseases characterized by impaired neuronal growth, and pain. In one aspect, the invention relates to a method for treating or preventing an aforementioned disease comprising administering to a subject in need of such treatment an effective amount or composition delineated herein.

Another object of the present invention is a cosmetic composition comprising a compound as mentioned above as active ingredient, in combination with a cosmetically

S acceptable diluent or carrier, especially for use in the prophylaxis or treatment of a 5-HTg receptor-related disorder, to achieve reduction of body weight and of body weight gain.

Definitions

The following definitions shall apply throughout the specification and the appended claims.

Unless otherwise stated or indicated, the term “Cy.¢-alkyl” denotes a straight or branched alkyl group having from 1 to 6 carbon atoms. Examples of said Cy.¢-alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched-chain pentyl and hexyl. For parts of the range “C,¢-alkyl” all subgroups thereof are contemplated such as C.s-alkyl, C,4-alkyl, C;3-alkyl, C,2-alkyl, C¢-alkyl, C,.s-alkyl,

C,4-alkyl, Ca.3-alkyl, Cy.¢-alkyl, C,.s-alkyl, etc. “Halo-Cy.¢-alkyl” means a C,.s-alkyl group substituted by one or more halogen atoms. Examples of said halo-C;¢-alkyl include 2- fluoroethyl, fluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl. Likewise, “aryl-Ci.¢- alkyl” means a C.¢-alkyl group substituted by one or more aryl groups.

Unless otherwise stated or indicated, the term “hydroxy-C;.¢-alkyl” denotes a straight or branched alkyl group that has a hydrogen atom thereof replaced with OH.

Examples of said hydroxy-C,.¢-alkyl include hydroxymethyl, 2-hydroxyethyl, 2- hydroxypropyl and 2-hydroxy-2-methylpropyl.

Unless otherwise stated or indicated, the term “C)c-alkoxy” denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms. Examples of said C,.- alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t- butoxy and straight- and branched-chain pentoxy and hexoxy. For parts of the range “Ci .4- alkoxy” all subgroups thereof are contemplated such as C,.s-alkoxy, Cj4-alkoxy, C;.3- alkoxy, Ciz-alkoxy, Cy¢-alkoxy, Ca s-alkoxy, Cz4-alkoxy, C,.3-alkoxy, C;¢-alkoxy, Ca.s- alkoxy, etc.

Unless otherwise stated or indicated, the term C,¢-alkoxy-Ci.¢-alkyl denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms connected to an alkyl group having from 1to 6 carbon atoms. Examples of said C,¢-alkoxy-Ci.¢-alkyl include methoxymethyl, ethoxymethyl, iso-propoxymethyl, n-butoxymethyl, t-butoxymethyl and straight- and branched-chain pentoxymethyl. For parts of the range “C) ¢-alkoxy-Ci.¢- alkyl” all subgroups thereof are contemplated such as C,.s-alkoxy-C, -alkyl, Ci4-alkoxy-

Csalkyl, Cia-alkoxy-Cie-alkyl, C,.z-alkoxy-Ci.¢-alkyl, C,¢-alkoxy-C) s-alkyl, Ca-s- alkoxy-C,.¢-alkyl, Ca4-alkoxy-C.¢-alkyl, C,.3-alkoxy-Cj¢-alkyl, Cs.¢-alkoxy-Ci.¢-alkyl,

Ca.s-alkoxy-Cy.¢-alkyl, C,¢-alkoxy-Cy.s-alkyl, C,¢-alkoxy-C,4-alkyl, etc.

Unless otherwise stated or indicated, the term “C,¢-alkenyl” denotes a straight or branched alkenyl group having from 2 to 6 carbon atoms. Examples of said Cz.s-alkenyl include vinyl, allyl, 2,3-dimethylallyl, 1-butenyl, 1-pentenyl, and 1-hexenyl. For parts of the range “C,.¢-alkenyl” all subgroups thereof are contemplated such as Ca.s-alkenyl, Cz.4- alkenyl, C,.3-alkenyl, C3¢-alkenyl, Cas-alkenyl, etc. Likewise, “aryl-C,.¢-alkenyl” means a

C,¢-alkenyl group substituted by one or more aryl groups. Examples of said aryl-Cz.6- alkenyl include styryl and cinnamyl.

The term "oxo" denotes =0 15 .

Unless otherwise stated or indicated, the term “Cs.¢-alkynyl” denotes a straightor branched alkynyl group having from 3 to 6 carbon atoms. Examples of said C3.¢-alkynyl include 1-propynyl, 1-butynyl, and 1-hexynyl. For parts of the range “C¢-alkynyl” all subgroups thereof are contemplated such as C;.s-alkynyl, C4-alkynyl, Cs.¢-alkynyl, Cas- alkynyl, etc.

Unless otherwise stated or indicated, the term “Cj.7-cycloalkyl” denotes a cyclic alkyl group having a ring size from 3 to 7 carbon atoms. Examples of said cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl, and cycloheptyl. For parts of the range “Cj.7-cycloalkyl” all subgroups thereof are contemplated such as Cy.¢-cycloalkyl, Cs.s-cycloalkyl, C;4-cycloalkyl, C4.7-cycloalkyl, Cs. ¢-cycloalkyl, Cs.s-cycloalkyl, Cs.-cycloalkyl, Cs7-cycloalkyl, etc.

Unless otherwise stated or indicated, the term “aryl” refers to a hydrocarbon ring system having at least one aromatic ring. Examples of aryls are phenyl, pentalenyl, indeny}, indanyl, 1,2,3,4-tetrahydronaphthyl, 1-naphthyl, 2-naphthyl, fluorenyl and anthryl.

The aryl rings may be optionally substituted. Likewise, phenoxy refers to a phenyl group bonded to an oxygen atom.

The term "heteroaryl" refers to a mono- or bicyclic aromatic ring system, only one ring need be aromatic, and the said heteroaryl moiety can be linked to the remainder of the molecule via a carbon or nitrogen atom in any ring, and having from § to 10 ring atoms (mono- or bicyclic), in which one or more of the ring atoms are other than carbon, such as nitrogen, sulphur, oxygen and selenium. Examples of such heteroaryl rings include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, chromanyl, quinazolinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, indazoly), pyrazolyl, pyridazinyl, quinolinyl, isoquinolinyl, benzofuranyl, dihydrobenzofuranyl, benzodioxolyl, benzodioxinyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, and benzotriazolyl groups. If a bicyclic heteroaryl ring is substituted, it may be substituted in any ring.

Unless otherwise stated or indicated, the term “heterocyclic” refers to a non- aromatic (i.¢., partially or fully saturated) mono- or bicyclic ring system having 4 to 10 ring atoms with at least one heteroatom such as O, N, or S, and the remaining ring atoms are carbon. Examples of heterocyclic groups include piperidyl, tetrahydropyranyl, tetrahydrofuranyl, azepinyl, azetidinyl, pyrrolidinyl, morpholinyl, imidazolinyl, thiomorpholinyl, pyranyl, dioxanyl, and piperazinyl groups. When present, the sulfur atom may optionally be in an oxidized form (i.e., S=0 or 0=S=0). Examples of heterocyclic groups containing sulfur in oxidized form include octahydrothieno[3,4b]pyrazine 6,6- dioxide and thiomorpholine 1,1-dioxide.

Unless otherwise stated or indicated, the term “halogen” shall mean fluorine, chlorine, bromine or iodine.

The term -S(O)R' ! wherein e is 0, 1, 2 or 3, has the meaning as illustrated by

Formula (V) — (VII): 0 0 ‘—s—R" ‘—s—R" LR" 8

DEERE EERE DE

V) (VD (VID) (VII)

The term “leaving group” refers to a group to be displaced from a molecule during a nucleophilic displacement reaction. Examples of leaving groups are iodide, bromide, chloride, methanesulphonate, hydroxy, methoxy, thiomethoxy, tosyl, or suitable protonated forms thereof (e.g., H:0, MeOH), especially bromide and methanesulphonate. “Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.

“pharmaceutically acceptable” means being useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes being useful for veterinary use as well as human pharmaceutical use. “Treatment” as used herein includes prophylaxis of the named disorder or condition, or amelioration or elimination of the disorder once it has been established. “An effective amount” refers to an amount of a compound that confers a therapeutic effect on the treated subject. The therapeutic effect may be objective (i.e, measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).

The term “prodrug forms” means a pharmacologically acceptable derivative, such as an ester or an amide, which derivative is biotransformed in the body to form the active drug. Reference is made to Goodman and Gilman's, The Pharmacological basis of

Therapeutics, 8™ ed., Mc-Graw-Hill, Int. Ed. 1992, “Bjotransformation of Drugs”, p. 13- 15; and “The Organic Chemistry of Drug Design and Drug Action” by Richard B.

Silverman. Chapter 8, p 352. (Academic Press, Inc. 1992. ISBN 0-12-643730-0).

The following abbreviations have been used:

CV means Coefficient of Variation,

DMSO means dimethyl sulphoxide,

EDTA means ethylenediamine tetraacetic acid,

EGTA means ethylenebis(oxyethylenenitrilo)tetraacetic acid,

HEPES means 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid,

HPLC means high performance liquid chromatography,

LSD means lysergic acid, diethylamide,

MeCN means acetonitrile,

SPA means Scintillation Proximity Assay, t-BuOK means potassium tert-butoxide, and

THF means tetrahydrofuran.

All isomeric forms possible (pure enantiomers, diastereomers, tautomers, racemic mixtures and unequal mixtures of two enantiomers) for the compounds delineated are within the scope of the invention. Such compounds can also occur as cis- or trans-, E- or Z- double bond isomer forms. All isomeric forms are contemplated.

The compounds of the Formula (I) may be used as such or, where appropriate, as pharmacologically acceptable salts (acid or base addition salts) thereof. The pharmacologically acceptable addition alts mentioned above are meant to comprise the therapeutically active non-toxic acid and base addition salt forms that the compounds are able to form. Compounds that have basic properties can be converted to their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid. Exemplary acids include inorganic acids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulphuric acid, phosphoric acid; and organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulphonic acid, toluenesulphonic acid, methanesulphonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, ascorbic acid and the like. Exemplary base addition salt forms are the sodiurn, potassium, calcium salts, and salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzathine, and amino acids, such as, e.g. arginine and lysine. The term addition salt as used herein also comprises solvates which the compounds and salts thereof are able to form, such as, for example, hydrates, alcoholates and the like. :

For clinical use, the compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other mode of administration. Pharmaceutical formulations are usually prepared by mixing the active substance, or a pharmaceutically acceptable salt thereof, with conventional pharmaceutical excipients. Examples of excipients are water, gelatin, gum arabicum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talcum, colloidal silicon dioxide, and the like. Such formulations may also contain other pharmacologically active agents, and conventional additives, such as stabilizers, wetting agents, emulsifiers, flavouring agents, buffers, and the like. Usually, the amount of active compounds is between 0.1-95% by weight of the preparation, preferably between 0.2-20% by weight in preparations for parentral use and more preferably between 1-50% by weight in preparations for oral administration.

The formulations can be further prepared by known methods such as granulation, compression, microencapsulation, spray coating, etc. The formulations may be prepared by conventional methods in the dosage form of tablets, capsules, granules, powders, syrups, suspensions, suppositories or injections. Liquid formulations may be prepared by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules may be coated in a conventional manner.

In a further aspect the invention relates to methods of making compounds of any of the formulae herein comprising reacting any one or more of the compounds of the formulae delineated herein, including any processes delineated herein. The compounds of the formula (I) above may be prepared by, or in analogy with, conventional methods.

The processes described above may be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. A pharmaceutically acceptable acid addition salt may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Examples of addition salt forming acids are mentioned above.

The compounds of formula (I) may possess one or more chiral carbon atoms, and they may therefore be obtained in the form of optical isomers, e.g. as a pure enantiomer, or : as a mixture of enantiomers (racemate) or as a mixture containing diastereomers. The separation of mixtures of optical isomers to.obtain pure enantiomers is well known in the art and may, for example, be achieved by fractional crystallization of salts with optically - active (chiral) acids or by chromatographic separation on chiral columns.

The chemicals used in the synthetic routes delineated herein may include, for : example, solvents, reagents, catalysts, and protecting group and deprotecting group reagents. The methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compounds. In addition, various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.

Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic

Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wauts, Protective

Groups in Organic Synthesis, 3" Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, J ohn Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and

Sons (1995) and subsequent editions thereof.

The necessary starting materials for preparing the compounds of formula (I) are either known or may be prepared in analogy with the preparation of known compounds.

The dose level and frequency of dosage of the specific compound will vary depending on a variety of factors including the potency of the specific compound employed, the metabolic stability and length of action of that compound, the patient's age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the condition to be treated, and the patient undergoing therapy. The daily dosage may, for example, range from about 0.001 mg to about 100 mg per kilo of body weight, administered singly or multiply in doses, e.g. from about 0.01 mg to about 25 mg each. Normally, such a dosage is given orally but parenteral administration may also be chosen.

The invention will now be further illustrated by the following non-limiting Examples.

The specific examples below are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. All publications cited herein are hereby incorporated by reference in their entirety.

TABLE 1 :

OsgcR!

NE

—Eewr_[® © 2 o H lel

SN

Br

SF

Methods 'H nuclear magnetic resonance (NMR) and '>C NMR were recorded on a Bruker s Advance DPX 400 spectrometer at 400.1 and 100.6 MHz, respectively. All spectra were recorded using residual solvent or tetramethylsilane (TMS) as internal standard. Infra red (IR) spectra were recorded on a Perkin-Elmer Spectrum 1000 FT-IR spectrophotometer.

Tonspray mass spectrometry (MS) spectra were obtained on a Perkin-Elmer API 150EX mass spectrometer. Accurate mass measurements were performed on a Micromass LCT dual probe. Preparative HPLC/MS was performed on a Waters/Micromass Platform ZQ system equipped with System A: ACE 5 C8 column (19x50mm), eluents: MilliQ water,

MeCN and MilliQ/MeCN/0.1%TFA and system B: Xterra MS C18, 5pm column (19x50mm), eluents: MilliQ water, MeCN and NH,HCO; (100mM). Analytical HPLC were performed on Agilent 1100, column: ACE 3 C8 (system A) or column: YMC-Pack (system B), eluents: MilliQ/0.1%TFA and MeCN. Elemental analyses were performed on a

Vario Fl instrument. Preparative flash chromatography was performed on Merck silica gel 60 (230-400 mesh).

EXPERIMENTAL

Synthesis of 4’-methyl-1°,4,5°,6*-tetrahydrospiro{piperidine-2,7°-pyrrolo[3,2- b]pyridine} \

On { es:

N CT a

CH,OH, H,SO, y

H

A mixture of 2-(2-ethylamino)pyrrole (Herz W. J. Am. Chem. Soc. 75, 483, 1953;

Wasley J.W.F, EP 338989 B, 1989) (9.6 g, 87 mmol) and 1-methylpiperazin-4-one (9.85 g, 87 mmol) in benzene (100 mL) was completely evaporated under vacuo. The dry residue was dissolved in methanol (50 mL). H,SO; (43 mL) in methanol (107 mL) was added to the methanol solution at 0 °C (ice). The cooling bath was removed and the mixture was stirred for 2 hours at room temperature. It resulted in the appearance of a white dense precipitate. Then the mixture was held overnight at —20 °C. The precipitate was filtered and dissolved in minimal amount of NaOH in water (30 %). The organic material was extracted with ethyl acetate (100 mL x 4). The organic phases were combined and dried by

K,CO; followed by filtration. The volatiles were eliminated under vacuo. The residue was trturated with cold ethyl acetate, filtered and washed by minimal amount of cold ethyl acetate to yield 7.6 g (44%) of product.

General method for the synthesis of 4’-methyl -1°.4°.5".6-tetrahydrospito {piperidine- 2.7’-pyrrolo[3,2-blpyridine} sulphonamides \ \ N 7 \ N t-BuOK, THF / N \

N Ar=8=0 (0) : A suspension of t-BuOK (160 mg, 1.4 mmol) in anhydrous THF (3 mL) was added to the mixture of 4’-methyl -1°,4’,5’,6’-tetrahydrospiro {piperidine-2,7’-pyrrol[3,2- b]pyridine} (205 mg, 1 mmol) in THF. The mixture was heated under stirring (complete dissolution was observed at 40 °C) followed by the addition of the corresponding sulfonyl chloride (1.2 mmol) in THF (3 mL). The mixture was papidly heated to the boiling point and then cooled. The reaction mixture was poured into water, extracted with ethyl acetate, dried (K2COs) and evaporated. The product was isolated by column chromatography on silica gel (CHCly/MeOH :10/1). The yields of compounds synthesized by this method vary from 18 to 62%.

EXAMPLE 1 4°>-Methyl-1’-(2-naphthylsulphonyl)-1 *4°,5°,6-tetrahydrospiro{piperidine-2,7’- pyrrolo[3,2-b]pyridine} hydrochloride 28.3 mg of material was isolated. 'H NMR (270 MHz, Methanol-ds) 5 2.25-2.50 (m, 4H), 2.96 (s, 3H), 3.19 (app. t., 2H), 3.52- 5.65 (m, 6H), 7.56 (d, 1H, J=3.22Hz),7.72 (dq, 1H,

J = 1.48 Hz), 7.83 (dd, 1H, J = 1.86 Hz, J = 8.98 Hz), 7.99-8.02 (m, 1H), 8.09 (d,2H,J= 8.98 Hz), 8.11-8.15 (m,1H), 8.67 (d, 1H, J = 1.73Hz). HPLC purity 96 %.

EXAMPLE 2 4’-Methyl-1’-(4-bromophenylsulphonyl)-1 4 5,6’-tetrahydrospiro{piperidine- 2,7°-pyrrolo[3,2-b]pyridine} hydrochloride 29.8 mg of material was isolated. 'H NMR (270 MHz, DMSO-d¢) & 1.45-1.50 (bd, 2H)

Hz), 1.71-1.83 (dt, 2H, J = 4.21 Hz), 2.15 (s, 3H), 2.36 (app.t, 2H), 2.45-2.55 (m, 2H), 2.59 (app.t, 2H), 2.88 (app.t, 2H), 2,86 (appt, 2H), 6.32 (d, 1H, J = 3.46 Hz), 7.15(d, 1H,J= 3.46 Hz), 7.43 (4, 1H, I= 3.96 Hz), 7.71 (4, 1H, J = 3.96 Hz). HPLC purity 95 %.

EXAMPLE 3 4’-Methyl-1°-(5-bromo-2-thienylsulphonyl)-1 '4°,5°,6’- tetrahydrospiro{piperidine-2,7>-pyrrolo[3,2-b]pyridine} hydrochloride 254 mg of material was isolated. 'H NMR (270 MHz, DMSO-ds) 5 1.40-1.44 (bd, 2H, J = 12.62 Hz), 1.72 (dt, 2H, J = 4.21 Hz), 2.22 (s, 3H), 2.25 (bt, 2H, J = 10.89 Hz ), 2.45-2.55 (m, 2H), 2.42-2.46 (m, 2H), 2.83 (app.t, 2H), 2,86 (app.t, 2H), 6.29 (d, 1H, J = 3.46 Hz), 7.15(d, 1H, J =3.22 Hz), 7.23 (dd, 1H, J =4.95 Hz, = 3.96 Hz), 7.83 (dd, 1H, J=3.84

Hz, J = 1.36 Hz), 8.10 (dd, 1H, J=4.95Hz, J =1.24 Hz). HPLC purity 95 %.

EXAMPLE 4 . 4-Methyl-1°-(2-thienylsulphonyl)-1°,4°,5’,6-tetrahydrospiro{piperidine-2,7- Cor pyrrolo[3,2-b]pyridine} hydrochloride 67.6 mg of material was isolated. 'H NMR (270 MHz, Methanol-d.) 6 1.45 (d, 2H J = 13.11 Hz), 1.75 (dt, 2H, J = 3.96 Hz), 2.18 (s, 3H), 2.25-2.40 (m, 2H), 2.40-2.65 (m, 4H), 2.59 (app. t, 2H), 2,86 (app.t, 2H), 6.29 (d, 1H, J = 3.46 Hz), 7.15 (d, 1H, J =3.22 Hz), 7.23 (dd, 1H, J = 4.95 Hz, J = 3.96 Hz), 7.83 (dd, 1H, J =3.84 Hz, J = 1.36 Hz), 8.10 (dd, 1H, J =4.95Hz, J = 1.24 Hz). HPLC purity 95 %.

TABLE 2

R4

N

R1

N-(1-Benzenesulfonyl-1H-indol-4- 2 Jo OH H y1)-2-(2-hydroxy-ethylamino)- oS § acetamide ; HN =

NH

Ny, 1-Benzenesulfonyl-1H-indol-4-y1)- Qo OQ H .y- . \ 7 Z pyridin-4-yl-amine. sl. pe 7 N-(4-Piperazin-1-yl-1H-indol-1- A 0 @ H yhbenzenesulfonamide al H N hydrochloride 9) \-- 3-[(4-Methylphenyl)sulfonyl]- Q Io) 6,7,8,9-tetrahydro-3H-benzo[e]indol- pf NH, 8-amine trifluoroacetate < > ®

H,C >

N'-(1-Benzenesulfonyl-1H-indol-4- Q 0 ~n" ylmethyl)-N,N-dimethy}-ethane-1,2- NZ ’ diamine trifluoroacetate O) / - : Scheme 1 . : _

H

0 jal - - B 0:0 O:y° NH, NA r fo) NH OH

N N N

N N «=0 Vo \

H 025° 7 0=5°° 07570

S Legend to Scheme 1: i) N,N-diisopropylethylamine, acetonitrile, heat; ii) Hy, Pd/C methanol, ammonium formate, room temperature; iii) bromoacetyl bromide, NaHCO, CH,Cl; iv) ethanolamine, KI, ethanol, heat.

INTERMEDIATE 1 4-Nitro-1H-indole p-Toluenesulfonic acid monohydrate (0.10 kg) was added to triethyl orthoformate (8.00 kg) at 111 °C. The mixture was stirred for 5 min and then 3-nitro-o-toluidine (4.10 kg) was added portion wise. The addition is slightly exothermic and the speed of addition was adjusted to avoid letting the temperature al below 111°C. The addition time was 65 min.

During the addition, formed ethanol starts to distill off. After the addition was completed, the reaction mixture was distilled at atmospheric pressure for 70 min at 125 °C. In total 4.5

L of ethanol was distilled off. When the distillation speed slowed down, vacuum (800 mbar — 140 mbar) was applied to finalize the distillation. The distillation was aborted when approx. 6L remained in the reactor. The reaction mixture was diluted with N,N- dimethylformamide (DMF) (15 L) and cooled to 43 °C. Diethyl oxalate (4.20 kg) was added. To the resulting mixture, potassium tert-butoxide (4.08 kg) was added portionwise while keeping the temperature between 38-45 °C. The addition time was 55 min. After completed addition, the reaction was stirred at 40-45 °C for 10 min. The reaction mixture was then added to water (90 L) at 50-60 °C. The product crystallized during the addition.

After cooling to 20 °C, the product was isolated on a nutsche filter. The resulting product cake was washed with 25 L of water and dried at 80 °C while applying full vacuum. The product weighed 2.90 kg (66%) after drying. "H NMR (400 MHz, DMSO-d¢) 3 ppm 7.05 (d,J=2.93 Hz, 1 H) 7.28 (t, /=7.93 Hz, 1 H) 7.75 (d, J=2.93 Hz, 1 H) 7.89 (d, /=7.32 Hz, 1

H) 8.04 (d, J=8.06 Hz, 1 H) 11.96 (s, 1 H). 13C NMR (101 MHz, DMSO-ds) 8 ppm 101.11 (s,1C) 116.79 (s,1 C) 119.13 (s, 1 C) 120.06 (s, 1 C) 121.26 (s, 1 C) 130.65 (s, 1 C) 138.13 (s, 1 C) 139.09 (s, 1 C).

INTERMEDIATE 2 1-Benzenesulfonyl-4-nitro-1H-indole

A solution of 4-nitro-1H-indole (9.49 kg) in acetonitrile (69.5 kg) was heated to 81°C.

N,N-Diisopropylethylamine (Hilnigs base) (8.98 kg) was added followed by a portion wise addition of benzenesulfonyl chloride. The exotermic addition of benzenesulfonyl chloride was done with such speed that the temperature was kept between 75-81 °C. The addition time was 45 min. after stirring the reaction mixture for 30 min at 80 °C, analysis showed the disappearance of the starting material. Water (8.2 L) was added to the reaction mixture at 80°C. (NOTE! A serious error was made, as the recipe called for the addition of 16 L of water). The reaction mixture was kept at 80 °C for 50 min. Upon cooling, the product started to crystallize at approximately 74 °C. The resulting slurry was cooled to 10 °C. The product was isolated on a nutsche filter and washed with a mixture of acetonitrile (21.9 kg) and water (9.1 L). Drying at 70 °C and full vacuum gave 12.71 kg (72%) of the title compound. 'H NMR (400 MHz, DMSO-d) 8 ppm 7.34 (d, J=3.91 Hz, 1 H) 7.55- 7.65 (m,

3H) 7.69 - 7.76 (m, 1 H) 8.05 - 8.09 (m, 2 H) 8.18 - 8.23 (m, 2 H) 8.42 (dd, J=8.30,0.73

Hz, 1 H). °C NMR (101 MHz, DMSO-ds) 3 ppm 107.64 (s, 1 C) 119.75 (s, 1 C) 120.18 (s, 1C) 124.20 (s, 1 C) 124.66 (s, 1 C) 126.78 (s,2 C) 129.94 (5,2 C) 131.17 (s, 1C) 135.07 (s,1C) 135.36 (5,1 C) 136.34 (s, 1 C) 139.96 (s, 1 C).

INTERMEDIATE 3 1-Benzenesulfonyl-1H-indol-4-ylamine

To a solution of 4-nitro-1H-indole (1 g, 3.3 mol) in MeOH (7 mL) under argon Pd/C (150 mg) and ammonium formate (3 g, 47 mmol) were added. The obtained mixture was heated to reflux temeprature for 1.5 h until complete disappearance of the starting nitro compound. The catalyst was filtered off, and the residue was washed with methanol. Then the solution was concentrated and purified by flash chromatography to give 0.72 g (80 %) of the title compound. '"H NMR (400 MHz, DMSO-ds) 8 ppm 5.57 (s, 2 H) 6.39 (d, /=7.81

Hz, 1 H) 6.95 - 7.05 (m, 2 H) 7.12 (d, J=8.06 Hz, 1 H) 7.50 - 7.58 (m, 3 H) 7.59 - 7.67 (m, 1 H) 7.91 (d, J=7.57 Hz, 2 H). 13C NMR (101 MHz, DMSO-dg) 8 ppm 101.49 (s, 1 0) 107.29 (s, 1 C) 108.26 (s,1 C) 118.55 (5, 1 C) 124.12 (s, 1 C) 126.61 (s,1 C) 127.19 (s, 2

C) 130.25 (5,2 C) 134.91 (5, 1 C) 136.11 (5, 1 C) 137.86 (s, 1 C) 142.91 (s, 1 C).

INTERMEDIATE 4

N-(1 -Benzenesulfonyl-1H-indol-4-yl)-2-bromo-acetamide

The solution of 1-benzenesulfonyl-1H-indol-4-ylamine (0.6 g, 2.2 mmol) in CHCl; (10 mL) the solution of NaHCO; (0.84g, 10 mmol) in water (10 mL) was added dropwise.

Then bromoacetyl bromide (0.21 mL, 2.4 mmol) was added to the resulting mixture with simultaneous stirring. The reaction mixture was stirred for 30 min, and then the organic layer was separated and concentrated. The yield of product was 0.78g (90%). The formation of the product was monitored by TLC (Thin Layer Chromatography). The compound was taken to the next step without further analysis.

EXAMPLE 5

N-(1 -Benzenesulfonyl-1H-indol-4-y1)-2-(2-hydroxy-ethylamino)-acetamide

To N-(1-benzenesulfonyl-1H-indol-4-yl)-2-bromo-acetamide (0.78 g, 2 mmol) dissolved in

EtOH (5 mL) KI (0.07 g, 0.4 mmol) and ethanolamine (0.6 mL, 10 mmol) were added. The reaction mixture was heated to reflux temperature for 10 min until the completion of the reaction as indicated by TLC. The product was purified by column chromatography (eluent system CHCly/CH30H 5:1). The yield of product was 0.52 g (70 %).Yield; 0.52 g (70 %) of material was isolated; HPLC purity 95 %; 'H NMR (400 MHz, DMSO-de) 5 ppm 262 (t, J=5.40 Hz, 2 H) 3.47 (q, J=5.44 Hz, 2 H) 4.65 (1, J=5.27 Hz, 2 H) 6.99 (d, J=3.51 Hz, 1

H) 7.29 (t, J/=8.16 Hz, 1 H) 7.59 (t, J=1.78 Hz, 2 H) 7.69 (t, J=7.53 Hz, 2 H) 7.78 - 7.85 (m,2H)7.94-8.00 (m, 2 H); MS (posEL-DIP) m/z 374 (M+H).

EXAMPLE 6 1-Benzenesulfonyl-1H-indol-4-yl)-pyridin-4-yl-amine

To the solution of 1-benzenesulfonyl-1H-indol-4-ylamine (0.5 g, 1.8 mmol) in DMF (4 mL) 4-bromopyridine hydrochloride (0.36 g, 1.8 mmol) and KI (0.07 g, 0.40 mmol) were added. The reaction mixture was heated to reflux temperature for 2 h. The reaction was monitored by TLC. The organic layer was concentrated and final compound was purified by flash-chromatography (eluent: CHCLs). The yield of product was 0.175 g (35%). HPLC purity 98%; 'H NMR (270 MHz, DMSO-d) & 6.77-6.87 (m, 1H), 6.96-7.10 (m, 2H), 7.23- 7.32 (m, 1H), 7.36-7.50 (m, 1H), 7.55-7.78 (m, 4H), 7.82-7.93 (m, 2H), 7.98-8.01 (m, 2H), 8.18-8.30 (m, 2H), 10.45 (brs, 1H); MS (posEI-DIP) m/z 350 (M+H).

INTERMEDIATE 5 tert-Butyl 4-(1-amino-1H-indol-4-yl)piperazine-1 -carboxylate x

To a solution of tert-butyl 4-(1H-indol-4-yl)piperazine-1-carboxylate (0.56 g, 1.9 mmol) (

WO 02/32863) in DMF (30 mL) at 0 °C was added KOH (1.04 g, 18.6 mmol), followed by hydroxylamine-O-sulfonic acid (0.42 g, 3.7 mmol), added portionwise over 30 min.

After stirring at ambient temperature for 1 h, the mixture was filtered, and the filtrate was poured into ice water (200 mL) and extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with water and brine, dried (MgSOa), and filtered, and the filtrate was concentrated under reduced pressure. The resultant oil was purified by column chromatography on silica using gradient elution CHCl; —»CHCl; +5% MeOH—>CHCI; + 10% MeOH as eluent to yield 0.536 g of the product. HPLC purity 91%; MS (posEI-DIP) m/z 317 (M+H). ( Larry Davies et al. J. Med. Chem, 1996, 39, 582-587).

EXAMPLE 7

N-(4-Piperazin-1-yl-1H-indol-1-yl)benzenesulfonamide hydrochloride

To a suspension of of NaH (0.05 g, 2.0 mmol; 50% oil dispersion) in 5 mL DMF at 0 °C, was added a solution of tert-butyl 4-(1-amino-1H-indol-4-yl)piperazine-1-carboxylate (0.54 g, 1.7 mmol) in DMF (5 mL). After warming to 50 °C for 30 min, the solution was cooled to 0 °C, and a solution of benzenesulfonyl chloride 0.30 g, 1.7 mmol) in DMF (3

S mL) was slowly added. The mixture was stirred at room temperature over night and then concentrated under reduced pressure. Column chromatography on silica using CHCl; + 5%

MeOH as eluent gave a crude intermediate which was dissolved in MeOH and HCl in ether (1M) was added. The mixture was stirred over 16 hours at room temperature and then concentrated to give 0.223 g crude product. The crude product was purified by preparative

HPLC, converted to its HCl-salt and then lyophilized to give 0.010g of the pure product as a brown solid. The solid was dried under vacuo at 60 °C for 5 days to remove all the solvent. Yield; 10 mg of material was isolated; HPLC purity 95%; 'H NMR (270 MHz,

Methanol-ds) 5 ppm 3.37 - 3.53 (m, 8 H) 6.46 (appd, J=3.46 Hz, 1 H) 6.66 (appd, J=7.55

Hz, 1 H) 6.70 - 6.75 (m, 1 H) 6.79 (appd, J=8.16 Hz, 1 H) 6.89 - 7.02 (m, 1 H) 7.50 (appt,

J=7.67 Hz, 2H) 7.61 - 7.77 (m, 3 H); MS (posEI-DIP) m/z 357 (M+H). (Larry Davies et al. J. Med. Chem, 1996, 39, 582-587). (Ishibashi, Hiroyuki; Akamatsu, Susumu; Iriyama,

Hiroko; Ikeda, Masazumi. Convenient synthesis of 4-alkyl, alkenyl, and alkynyl : substituted N-(phenylsulfonyl)indoles. Chemical & Pharmaceutical Bulletin (1994), 42(10), 2150-3. Ishibashi, Hiroyuki; Tabata, Takashi; Hanaoka, Kyoko; Iriyama, Hiroko; Akamatsu, Susumu; Ikeda, Masazumi. A new, general entry to 4-substituted indoles.

Synthesis of (S)-(-)-pindolol and (+)-chuangxinmycin. Tetrahedron Letters (1993), 34(3), 489-92).

EXAMPLE 8 3-[(4-Methylphenylsulfonyl]-6,7,8,9-tetrahydro-3H-benzo[e]indol-8-amine trifluoroacetate

To a suspension of 3-(toluene-4-sulfonyl)-6,9-dihydro- 3H,7H-benzo[elindol-8-one (0.017g, 0.1 mmol) in dry methanol (2 mL) at room temperature was added first ammonium acetate (0.0387g, 0.5mmol) and then after 2 mins, sodium cyanoborohydride (0.0157 g, 0.03 mmol). The mixture was heated to 70°C. After 16h, the sample was allowed to cool and then was treated with conc. aq. HCI until pH 2 was achieved. The mixture was washed with diethyl ether (2x20 mL) and then the aqueous phase was treated with SM aq. NaOH. The resulting suspension was extracted with diethyl ether (2x20 mL), washed with brine (1x1 0 mL) and dried over anhydrous magnesium sulfate The solvent was removed under reduced pressure and purification by preparative

HPLC gave the desired product as a white solid (0.0027g, 15%).HPLC 100%, Rt = 2.828min (system A, 5-60%MeCN over 3 min); 100%, Rt = 2.451 min (system B, 5- 60%MeCN over 3min); 1H NMR (270 MHz, METHANOL-D4) & ppm 1.21 - 1.39 (m, 2

H) 2.08 - 2.24 (m, 1 H) 2.33 (5, 3H) 2.77 - 3.07 (m, 2 H) 3.55 (d, J=1.48 Hz, 2 H) 6.71 (d,

J=3.71 Hz, 1 H) 7.09 (d, J=8.41 Hz, 1 H) 7.29 (4, J=8.16 Hz, 2 H) 7.64 (d, 3.46 Hz, 1

H) 7.70 - 7.88 (m, 3 H); MS (ESI+) for CoH20N20,S m/z 341 (M+H). The preparation of 3-(toluene-4-sulfonyl)-6,9-dibydro-3H,7H-benzo{ e}indol-8-one is descibed in J. Med.

Chem. 1995, 38, 2217-30.

INTERMEDIATE 6 4-Methyl-1-(phenylsulfonyl)-1H-indole

The material was prepared according to the literature method. HPLC purity 99 %; 'H NMR (400 MHz, DMSO-ds) § ppm 2.41 (s, 3 H) 6.88 (d, J=3.76 Hz, 1 H) 7.04 (d, J<7.53 Hz, 1

H) 7.18 - 7.26 (m, 1 H) 7.57 (¢, /=7.65 Hz, 2 H) 7.67 (1, J=7.40Hz, 1H) 7.72 - 7.81 (m, 2

H) 7.92 - 7.98 (m, 2 H); MS (ESI+) for CisH13NO2S m/z 272 (M+H)* - (Chemical &

Pharmaceutical Bulletin (1994), 42(10), 2150-3, Tetrahedron Letters (1993), 34(3), 489-92).

INTERMEDIATE 7 4-(Bromomethyl)-1-(phenylisulfonyl)-1H-indole

Br

O

0257° 0} keo 8) (PhCOOQO)2 OY) cca

The compound was obtained using N-bromosuccinimide (1.2 equiv.), as bromination agent, and benzoyl peroxide (0.25 equiv.), as initiator, in CCl. The final product was purified by flash chromatography (using CCl, as eluent and obtained as white crystals (Yield: 3.5 g (61.6%); eluent-system chloroform- hexane 1:1). HPLC purity 92%;'H NMR (400 MHz, DMSO-ds) & ppm 4.94 (s, 2 H) 7.04 (4, /<3.76 Hz, 1H) 7.28 -7.37 (m,2 H)

7.59 (t, J=7.78 Hz, 2 H) 7.69 (t, J=7.53 Hz, 1 H) 7.89 - 7.94 (m, 2 H) 8.00 (d, J=8.03 Hz,2

H); MS (ESI+) for CisHi2BrNOS m/z 351 M+H)* (WO 9602502 Al 19960201).

EXAMPLE 9

N'-(1 _Benzenesulfonyl-1H-indol-4-ylmethyl)-N,N-dimethyl-ethane-1,2-diamine

The compound was prepared from Intermediate 7 and dimethylethylamine. Yield:184 mg (98%); RT=1.44 HPLC (System A. 10-97% MeCN over 3 min) and 99% R1=1.31 (System B. 10-90% MeCN over 3 min). 'H NMR (400 MHz, MeOD) & ppm 2.93 (s, 6 H) 3.44 - 3.61 (m, 4 H) 4.51 (s, 2H) 7.05 (d, /~3.51 Hz, 1 H) 7.42 (d, J=3.76 Hz, 2 H) 7.50 (%

J=7.65Hz, 2 H) 7.61 (t, J=7.40 Hz, 1 H) 7.80 - 7.85 (m, 1 H) 7.96 (d, /=8.03 Hz, 2 H) 8.09-8.15(m, 1 H), (ESI+) for C19H2:N30,S m/z 358 (M+H)+

BIOLOGICAL TESTS

The ability of a compound according to the invention to bind to a 5-HT¢ receptor, and to "be pharmaceutically useful, can be determined using in vivo and in vitro assays known in the art. : (a) 5-HTs receptor binding Assay :

Binding affinity experiment for the human 5-HT¢ receptor are performed in HEK293 cells transfected with 5-HT¢ receptor using [*H]-LSD as labeled ligand according to the general method as described by Boess F.G et al. Neuropharmacology 36(4/5) 713-720, 1997.

Materials

Cell culture

The HEK-293 cell line transfected with the human 5-HT¢ receptor was cultured in

Dulbeccos Modified Eagles Medium containing 5 % dialyzed foetal bovine serum, (Gibco

BRL 10106-169), 0.5 mM sodium pyruvate and 400 ug/ml Geneticin (G-418) (Gibco

BRL10131-019). The cells were passaged 1:10, twice a week.

Chemicals

The radioligand [*H] LSD 60-240 Ci/mmol, obtained from Amersham Pharmacia Biotech, (Buckinghamshire, England) was in ethanol and stored at -20°C. The compounds were dissolved in 100% DMSO and diluted with binding buffer.

Disposable

Compounds were diluted in Costar 96 well V-bottom polypropylene plates (Coming Inc.

Costar, NY, USA). Samples were incubated in Packard Optiplate (Packard Instruments

B.V., Groningen, The Netherlands). The total amount of added radioligand was measured in Packard 24-well Barex plates (Packard Instruments B.V., Groningen, The Netherlands) inthe presence of Microscint™ 20 scintillation fluid (Packard Bioscience, Meriden, CT,

USA).

Buffer

The binding buffer consisted of 20 mM HEPES, 150 mM NaCl, 10 mM MgCl; and 1 mM,

EDTA,pH 74.

Methods

Membrane preparation

Cells were grown to approximately 90% confluence on 24.5 x 24.5 mm culture dishes. The medium was aspirated, and after rinsing with ice-cold PBS, the cells were scraped off using 25 mi Tris buffer (50 mM Tris-HCl, 1 mM EDTA, 1 mM EGTA, pH 7.4) and a window scraper. The cells were then broken with a Polytron homogeniser, and remaining particulate matter was removed by low-speed centrifugation, 1000x g for 5 min. Finally, the membranes were collected by high-speed centrifugation (20 000x g), suspended in binding buffer, and frozen in aliquots at -70°C.

Radioligand binding

Frozen cell membranes were thawed, immediately rehomogenized with a Polytron homogenizer, and coupled to SPA wheat germ agglutinin beads (Amersham Life Sciences,

Cardiff, England) for 30 min under continuous shaking of the tubes. After coupling, the beads were centrifuged for 10 minutes at 1000 g, and subsequently suspended in 20 ml of binding buffer per 96-well plate The binding reaction was then initiated by adding radioligand and test compounds to the bead-membrane suspension. Following incubation at room temperature, the assay plates were subjected to scintillation counting.

The original SPA method was followed except for that membranes were prepared from

HEK?293 cells expressing the human 5-HTg receptor instead of from HeLa cells (Dinh

DM, Zaworski PG, Gill GS, Schlachter SK, Lawson CF, Smith MW. Validation of human 5-HT¢ receptors expressed in HeLa cell membranes: saturation binding studies, pharmacological profiles of standard CNS agents and SPA development. (The Upjohn

Company Technical Report 7295-95-064 1995;27 December). The specific binding of [’H]-LSD was saturable, while the non-specific binding increased linearly with the concentration of added radioligand. [*H)-LSD bound with high affinity to 5-HT¢ receptors. The Kg value was estimated to 2.6% 0.2 nM based on four separate experiments.

The total binding at 3 nM of [*H]-LSD, the radioligand concentration used in the competition experiments, was typically 6000 dpm, and the specific binding more than 70%. 5-HT caused a concentration dependent inhibition of ’H]-LSD binding with an over all average Ki value of 236 nM when tested against two different membrane preparations.

The inter assay variability over three experiments showed a CV of 10% with an average K; values of 173 nM (SD 30) and a Hill coefficient of 0.94 (SD 0.09). The intra assay variation was 3% (n=4). All unlabelled ligands displaced the specific binding of *H]-LSD in a concentration-dependent manner, albeit at different potencies. The rank order of affinity for the 5-HTs receptor of reference compounds was methiothepin (Ki 2 nM) >mianserin (190 nM) =5-HT (236 nM) >methysergide (482 nM) > mesulergine (1970 nM).

Protein determination

Protein concentrations were determined with BioRad Protein Assay (Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 1976;72:248-54). Bovine serum albumin was used as standard.

Scintillation counting

The radioactivity was determined in a Packard TopCount™ scintillation counter (Packard

Instruments, Meriden, CT, USA) at a counting efficiency of approximately 20 %. The counting efficiency was determined in separate sets of experiments.

Saturation experiments

At least 6 concentrations in duplicates of radioligand (0.120 nM of [*H]-LSD) were used in saturation experiments. The specific binding was calculated as the difference between total binding and non-specific binding, which was determined as the binding of radioligand inthe presence of 5 uM lisuride. Bmax and the dissociation constant, K;, were determined from the non-linear regression analysis using equation 1. Ly is the unbound concentration of radioligand, and is y is the amount bound. y= Som (equation 1)

Competition experiments

Total- and non-specific binding of radioligand was defined in eight replicates of each.

Samples containing test compound were run in duplicate at 11 concentrations. Incubations were carried out at room temperature for 3 hours. The ICs value, i.e. the concentration of test compound that inhibited 50% of the specific binding of radioligand, was determined with non linear regression analysis and the K; value was calculated using equation 2 [Cheng Y.C. Biochem. Pharmacol. 22, 3099-3108, 1973]. : Ki= Se : (equation 2)

Co "x

L = concentration of radioligand

Kg= Affinity of radioligand (b) 5-HTg Intrinsic Activity Assay

Antagonists to the human 5-HT¢ receptor were characterized by measuring inhibition of 5-

HT induced increase in cAMP in HEK 293 cells expressing the human 5-HTg receptor (see Boess et al. (1997) Neuropharmacology 36: 713-720). Briefly, HEK293/5-HTg cells were seeded in polylysine coated 96-well plates at a density of 25,000 / well and grown in

DMEM (Dulbecco’s Modified Eagle Medium) (without phenol-red) containing 5% dialyzed Foetal Bovine Serum for 48 hat 37°C ina 5% CO; incubator. The medium was then aspirated and replaced by 0.1 ml assay medium (Hanks Balance Salt Solution containing 20 mM HEPES, 1.5 mM isobutylmethylxanthine and 1 mg/ml bovine serum albumin). After addition of test substances, 50 ul dissolved in assay medium, the cells were incubated for 10 min at 37°C in a 5% CO; incubator. The medium was again aspirated and the cAMP content was determined using a radioactive cAMP kit (Amersham Pharmacia

Biotech, BIOTRAK RPA559). The potency of antagonists was quantified by determining the concentration that caused 50% inhibition of 5-HT (at [5-HT]= 8 times ECso) evoked increase in cAMP, using the formula ICs0,cor=1C50/ (1 +{SHT}/ECs0).-

The compounds in accordance with the invention have a selective affinity to human 5-HTg receptors with Kj and ICsp corr values between 0.5 nM and 5 uM or display a % inhibition of [’H]-LSD = 20 % at 50 nM and are antagonists, agonists or partial agonists at 5-HTg .

The compounds show good selectivity over human cloned 5-HT 1a, 5-HT 1p, 5-HT 24, 5-H, and 5-HT,. receptors.

TABLE 3

Binding affinity (Ki) at the h 5-HT¢ receptor

EATS rw

I

(c) In vivo assay of reduction of food intake

For a review on serotonin and food intake, see Blundell, J.E. and Halford, J.C.G. (1998)

Serotonin and Appetite Regulation. Implications for the Pharmacological Treatment of

Obesity. CNS Drugs 9:473-495.

Obese (ob/ob) mouse is selected as the primary animal model for screening as this mutant mouse consumes high amounts of food resulting in a high signal to noise ratio. To further substantiate and compare efficacy data, the effect of the compounds on food consumption is also studied in wild type (C57BL/6J) mice. The amount of food consumed during 15 hours of infusion of compounds is recorded.

Male mice (obese C57BL/6JBom-Lep™ and lean wild-type C57BL/6JBom;

Bombholtsgaard, Denmark) 8-9 weeks with an average body weight of 50 g (obese) and 25 g (lean) are used in all the studies. The animals are housed singly in cages at 2311°C, 40- 60 % humidity and have free access to water and standard laboratory chow. The 12/12-h light/dark cycle is set to lights off at 5 p.m. The animals are conditioned for at least one week before start of study.

The test compounds are dissolved in solvents suitable for each specific compound such as cyclodextrin, cyclodextrin/methane sulphonic acid, polyethylene glycol/methane sulphonic acid, saline. Fresh solutions are made for each study. Doses of 30, 50 and 100 mg kg'day’ are used. The purity of the test compounds is of analytical grade.

The animals are weighed at the start of the study and randomized based on body weight. Alzet osmotic minipumps (Model 2001D; infusion rate 8 l/h) are used and loaded essentially as recommended by the Alzet technical information manual (Alza Scientific

Products, 1997; Thecuwes, F. and Yam, S.I. Ann. Biomed. Eng. 4(4). 343-353, 1976).

Continuous subcutaneous infusion with 24 hours duration is used. The minipumps are. either filled with different concentrations of test compounds dissolved in vehicle or with only vehicle solution and maintained in vehicle pre-warmed to 37°C (approx. 1h). The minipumps are implanted subcutaneously in the neck/back region under short acting anesthesia (metofane/enflurane). This surgical procedure lasts approximately 5S min.

The weight of the food pellets are measured at 5 p.m. and at 8 p. m. for two days before (baseline) and one day after the implantation of the osmotic minipumps. The weigh-in is performed with a computer assisted Mettler Toledo PR 5002 balance. Occasional spillage is corrected for. At the end of the study the animals are killed by neck dislocation and trunk blood sampled for later analysis of plasma drug concentrations.

The plasma sample proteins are precipitated with methanol, centrifuged and the supernatant is transferred to HPLC vials and injected into the liquid chromatography /mass spectrometric system. The mass spectrometer is set for electrospray positive ion mode and

Multiple Reaction Monitoring. A linear regression analysis of the standards forced through the origin is used to calculate the concentrations of the unknown samples.

Food consumption for 15 hours is measured for the three consecutive days and the percentage of basal level values is derived for each animal from the day before and after treatment. The values are expressed as mean + SD and + SEM from eight animals per dose group. Statistical evaluation is performed by Kruskal-Wallis one-way ANOVA using the percent basal values. If statistical significance is reached at the level of p<0.05, Mann-

Whitney U-test for statistical comparison between control and treatment groups is performed.

The compounds according to the invention show an effect (i.e., reduction of food intake) in the range of 5-200 mg/kg/d.

Claims (24)

Claims

1. A compound of the Formula (I) VU z_R" WEN RM—t A BY Wass. N WwW, \ Pw wherein: vis 1 or 2 and P is selected from a substituent of Formula (II) and Formula (III); LO ) T ) O $s 8. N< 4 kt © R $=0 rR’ (1) (ny) or P may also be selected from H or C¢-alkyl provided that R™ is selected from NHSO,R", -SO,NR®*R"' or -S(O).R*, wherein R"! is selected from aryl and heteroaryl and where eis 0, 1,2 or 3,vis 1 and R™ is H; — represents a single bond or a double bond, with the proviso that both — represent double bonds or that both — represent single bonds; Wi, Wy, W3, Zand Y are each a carbon atom; or one of Wy, Wz, Wi, Z and Y is a nitrogen atom, while the remainder being carbon atoms, provided that both “in Formula (I) represent single bonds; Uis selected from CHR®, CR* and CR*R*, provided that when the dotted line connecting W, and U is a double bond, then U is CR? and further provided that when the dotted line connecting Wy and U is a single bond, then U is selected from CHR® and CR'R*; R' is selected from: (a) Cy-¢-alkyl, (b) C;.s-alkoxy-Ci.¢-alkyl,

(c) Ci¢-alkenyl, (d) hydroxy-Cy.g-alkyl, (e) halo-C,-¢-alkyl, (f) aryl, (g) arylcarbonylmethyl, (h) aryl-Cy¢-alkenyl, (i) aryl-C¢-alkyl, (j) Cs.9-cycloalkyl, (k) heteroaryl, ' (1) 4-piperidinyl, (m) N-substituted 4-piperidinyl, wherein the substituents are selected from Cj-¢-alkyl, aryl, heteroaryl, aryl-C,-¢-alkyl and heteroaryl-C;-¢-alkyl, (n) heteroaryl-C,.¢-alkyl, : wherein any heteroaryl or aryl residue, alone or as part of another group, is optionally substituted, independently, in one or more positions with substituents having the values as defined for R™ and R™; : R™ and R™ are each independently selected from: . (a) hydrogen, . (b) halogen, (c) Ci6-alkyl, (d) hydroxy, (e) Cs-alkoxy, (f) Ca¢-alkenyl, (g) phenyl, (h) phenoxy, (i) benzyloxy, (j) benzoyl, (k) -OCFs3, ()-CN, (m) hydroxy-C,.s-alkyl, (n) halo-Cy.¢-alkyl, (0) -NR'R, (p) -NO,

(q) -CONR'’R", (r) -NHSOR", (s) -NR®COR", (t) -SO,NR*R", (u)-C(=O)R", (v) C-s-alkoxycarbonyl, (w) -S(O).R'', wherein eis 0, 1,2 or 3, (x) SCF, (y) -CHF=CH,, (aa) -OCF:H, or (ab) ethynyl; and with the proviso that, R™ is attached to a carbon atom in ring B; and with the further proviso that when one of W;, Wz and W3 in Formula (I) is a nitrogen atom and both —— represent single bonds the said nitrogen atom is attached to R™, wherein R™is selected from hydrogen or C;-s-alkyl and v is 1; and with the further proviso that when Wy, W; and W3 in Formula (I) are each a carbon atom andboth —— represent single bonds, R™ is selected from hydrogen or methyl; and with the further proviso that when R™ or R™, as substituents on ring A and B in Formula (I), are selected from phenyl, phenoxy, benzyloxy and benzoyl, the phenyl or aryl ring ~~ thereof may be optionally substituted by C;-4-alkyl, halogen, C-s-alkoxy, C-s-alkylthio, trifluoromethyl, hydroxymethyl or cyano; wherein R™ and R* may be linked to each other to form a fused substituent of Formula (IV) provided that R™ is attached to Wy: : a Rr q=0o0r1 av) when U is CR? or CHR®, R*is a group selected from:

1-- + 8 pA . R Lx Pa | de Ld rfp) ON © Re Jo Xb low ° R* 0 R

RA. ay “t- + NS ( be ol . R ae | YY ] ON O° \ WN 0 R*“%o0 0 JJ o N N RY R R eT Ae SY RX “ N— BY (0) NR ” a N “8 lo) 0” °N R R 0 R ] R17 “RY [ ( N 0 es RY p N-R" oh RY I Lt POO NOU. Cf ve WT °

RE . R® LL 1 _— - L Ox Neos N Nes eo C0 Or 12 a [ R 10 N ~-R 0 R ~ Jo [1 N N-R'® \ R r° Lo Rr" rR PY — -1-" . NT : 8 x RN x 8 ~ | R® RY R / _R? N ZZ NN ug " \ N N oF Re rR?” “R® wherein: n=0,1,o0r2, o=1lor2, p=1,2,3,0r4, r=2o0r3,

s=1,20r3; when U is CHR? R* is additionally selected from the following groups: .. R® “t si ol eRe Ie [ " oe | le ls A NEO PIP: SE NR R d PEs 0 oll 8 "t ] 7 N 9 3 10 RS” t ef | 0 rb IN 0 I, R N—R R Rr wherein: n=201or2, o=1or2, t=2,3 or4, r=2or3, s=1,20r3; wherein X is selected from O, NR®and S; wherein R’ is independently a group selected from: (a) hydrogen, (b) Ci-¢-alkyl, (¢) 2-cyanoethyl, (d) hydroxy-Ca-¢.alkyl, (e) Cs-¢-alkenyl, (f) Cs¢-alkynyl, (g) Cs-7-cycloalkyl, (h) C3-7-cycloalkyl-C;-¢-alkyl, (i) C,-s-alkoxy-Ca-¢-alkyl, (j) aryl-C,-¢-alkyl, (k) heteroaryl-C;-¢-alkyl,

(1) 3,3,3-trifluoropropyl, wherein any aryl and heteroaryl residue may be optionally substituted with C-¢-alkyl, halogen, C,-4-alkoxy, C,-4-alkylthio, trifluoromethyl or cyano; RSis selected from: (a) hydrogen, (b) Cy-4-alkyl, (c) hydroxy-C;-4-alkyl, (d) C-4-alkoxy-Ci-s-alkyl, (e) halo-C;-4-alkyl, ® ~NR®R?, provided that the said —-NR®R® group is not attached to a carbon atom adjacent to a ring nitrogen atom, (8) -CO-NR’R%; (h) hydroxy, provided that the said hydroxy group is not attached to a carbon atom adjacent to aring nitrogen atom, R’ is selected from: (a) hydrogen, (b) Ci-s-alkyl, (c) hydroxy-Ci-4-alkyl, or (d) C;-4-alkoxy-C,-s-alkyl, (e) hydroxy, provided that the said hydroxy group is not attached to a carbon atom adjacent to a heterocyclic ring nitrogen atom and that the said hydroxy group is attached to a heterocyclic ring not substituted with oxo;

R? is each independently selected from: (a) hydrogen, or (b) Cy-s-alkyl, R’is selected from: (a) hydrogen, (b) Ci-4-alkyl, wherein one or two groups may be present at any carbon atom, or when two groups are present at the same carbon atom they may together form a cyclopropane ring, (c) hydroxy-Ci-4-alkyl,

(d) Ci-4-alkoxy-C,-s-alkyl, (e) halo-C,-4-alkyl, R'is each independently selected from: (a) hydrogen, (b) Ci-s-alkyl, (c) hydroxy-C,-4-alkyl, (d) Cs-7-cycloalkyl, or (€) Ci-s-alkoxy-Ca-s-alkyl, wherein the two R'® groups together with the nitrogen to which they are attached form a heterocyclic ring; and when the two R' groups form a piperazine ring, the nitrogen of the piperazine ring that allows the substitution may be substituted with a group selected from R>; R" is selected from: (a) Ci¢-alkyl, (b) aryl, or (c) heteroaryl, wherein aryl and heteroaryl may be optionally substituted with C,-¢-alkyl, halogen, Cy-4- alkoxy, C,-s-alkylthio, trifluoromethyl, hydroxymethyl or cyano; R'is selected from: (a) hydrogen, or (b) methyl; when U is R'R¥, R* and R* are linked to each other to form a heterocyclic ring selected from pyrrolidine or piperidine, wherein the N atom may be substituted by a group selected from R®; and pharmaceutically acceptable salts, hydrates, solvates, geometrical isomers, tautomers, optical isomers, and prodrug forms thereof.

2. The compound according to claim 1, wherein P is selected from s2° fo (n) each of W,, W,, W3, Z and Y is a carbon atom provided that both —— in Formula 4) represent double bonds; or one of Wj, W,, Ws, Z and Y is a nitrogen atom, while the remainder being carbon atoms, provided that both —— in Formula (I) represent single bonds; U is selected from CHR, CR* and CR*R*, provided that when the dotted line connecting W, and U is a double bond, then U is CR*; and further provided that when the dotted line connecting W, and U is a single bond, then U is selected from CHR" and CRRY;

R! is selected from: (f) aryl, (h) aryl-C,¢-alkenyl, (i) aryl-Cys-alkyl, (j) Csg-cycloalkyl, (k) heteroaryl, (n) heteroaryl-Cy.¢-alkyl, wherein any heteroaryl or aryl residue, alone or as part of another group, is optionally substituted, independently, in one or more positions with substituents having the values as defined for R™ andR™; R™ and R™ are each independently selected from: (a) hydrogen, (b) halogen, (c) Cis-alkyl, (d) hydroxy, (e) Ci¢-alkoxy, (f) C2¢-alkenyl, (k) -OCF;, (1)-CN,

(m) hydroxy-C,.c-alkyl, (n) halo-C,¢-alkyl, (0) -NR"R", (q) ~-CONR'R", (r)-NHSOR', (s)-NR®COR', (t) -SONR*R", (u) -C(=O)R", (w) -S(O).R", whereine is 0, 1,2 or 3, (x)-SCFs, (y) -CHF=CH;, (aa) -OCF,H, or (ab) ethynyl; and with the proviso that, R™ is attached to a carbon atom in ring B; and with the further proviso that when one of Wi, W» and W3 in Formula (I) is a nitrogen atom and both —— represent single bonds the said nitrogen atom is attached to R™, wherein R™ is selected from hydrogen or C;-s-alkyl and v is 1; and with the further proviso that when W;, Wz and W3 in Formula (I) are each a carbon atom and both — represent single bonds, R™ is selected from hydrogen or methyl; and with the further proviso that when R™ and R™ are substituents on ring A and B, then R" and R™ are independently selected from: hydrogen, halogen, methyl, methoxy, trifluoromethyl, hydroxymethyl or cyano; when U is CR? or CHR", R*is a group selected from:

N A ow FH | ~ RA here Ry Jo hut S N MN \e RY R oh a 8 A NH od lo} py i Jo RR" 8 s -d-e RL pa RS cee N x Ny Rf | R® \ x 8 rR: pr = Re NP NF R N N n, N R RY ~R® N 8 ° “RE § on I” R" R R'W lo [ 3) ° \ N-R" N-R" rR" Lio R10 wherein n=0,1,0r2, o=1or2, oo : 7 p=1,2,3,0r4, Co : when U is CHR? R* is additionally selected from the following groups: open R® “f= 1 AN N AO N OY J N N N N N ls t 0 R R® 5 R® R RS St SN A Rr aX a [ : X N ] 8 N N BY rR t ef ) “Lyf R'"? N—R'® 0) o R10 wherein : n=01or2,

S2 o=1lor2, : t=2,30r4, r=2or3, wherein X is selected from O and NR”;

wherein R® is independently a group selected from: (a) hydrogen, (b) Ci-¢-alkyl, (c) 2-cyanoethyl, (d) hydroxy-Cz-s-alkyl, (e) Cs-¢-alkenyl, (h) C3+-cycloalkyl-Cy-4-alkyl, or (i) Ci-s-alkoxy-Ca-s-alkyl, Ris selected from: (a) hydrogen, : (b) Ci-s-alkyl, (c) hydroxy-C;-2-alkyl, or oo : (d) C-2-alkoxy-C;-2-alkyl; Co

R? is each independently selected from: (a) hydrogen, or (b) Ci-s-alkyl, R’is selected from: (a) hydrogen, (b) Cy-s-alkyl, wherein one or two groups may be present at any carbon atom, or when two groups are present at the same carbon atom they may together form a cyclopropane ring, (c) hydroxy-C;-;-alkyl, (d) Cy—-alkoxy-Cy--alkyl, (e) halo-C,-z-alkyl, R'? is each independently selected from: (a) hydrogen,

() Cy-s-alkyl, (c) hydroxy-C;-s-alkyl wherein the two R' groups together with the nitrogen to which they are attached form a heterocyclic ring; and when the two R'® groups form a piperazine ring, the nitrogen of the piperazine ring that allows the substitution may be substituted with a group selected from rR R" is selected from: (a) Ci4-alkyl R'? is selected from: (a) hydrogen, or (b) methyl; when U is R‘R*, R* and R* are linked to each other to form a heterocyclic ring selected from pyrrolidine or piperidine, wherein the N atom may be substituted by a group R’ : selected from: (a) hydrogen, (b) Ci-s-alkyl, (d) hydroxy-C,-s-alkyl, (1) Cy-s-alkoxy-Cr-4-alkyl, (k) 2-cyanoethyl.

3. The compound according to claim 1 or 2, wherein Aris selected from phenyl, naphthyl, and thienyl, which group Ar is optionally substituted by halogen, methyl, methoxy.

4. The compound according to any one of claims 1 to 3, which is selected from 4’-Methyl-1’-(2-naphthylsulphonyl)-1°,4°,5 ’ 6’-tetrahydrospiro {piperidine-2,7’- pyrrolo[3,2-b]pyridine} hydrochloride, 4’-Methyl-1’-(4-bromophenylsulphonyl)-1°,4’,5’ ,6’-tetrahydrospiro {piperidine-2,7’- pyrrolof3,2-blpyridine} hydrochloride,

4’-Methyl-1 ’-(5-bromo-2-thienylsulphonyl)-1 > 4’,5 6’ -tetrahydrospiro {piperidine-2,7’- pyrrolo[3,2-b]pyridine} hydrochloride, 4’-Methyl-1’-(2-thienylsulphonyl)-1°,4’,5 ’ 6’ -tetrahydrospiro {piperidine-2,7°-pyrrolo[3,2- blpyridine} hydrochloride N-(1-Benzenesulfonyl-1H-indol-4-y1)-2-(2-hydroxy-ethylamino)-acetamide, and 1-Benzenesulfonyl-1H-indol-4-yl)-pyridin-4-yl-amine, N-(4-Piperazin-1-yl-1H-indol-1 -yl)benzenesulfonamide hydrochloride, and 3-(Phenylsulfonyl)-6,7,8,9-tetrahydro-3H-benzo[elindol-8-amine trifluoroacetate.

5. A process for the preparation of a compound according to claim 1, comprising the following steps: (a) reaction of 2-(2-ethylamino)pyrrole and 1-methylpiperazine-4-one to give 4’ methyl-1",4',5",6 -tetrahydrospiro {piperidine-2,7 ’-pyrrolo[3,2-b]pyridine}; and (b) reaction of the product from step a) with an arylsulphonyl chloride in the presence of a base.

6. A process for the preparation of a compound according to claim 1, comprising the following steps: (c) reaction of 1-benzensulfonyl-1H-indol-4-ylamine and bromoacety! bromide and further reaction with ethanolamine.

7. A process for the preparation of a compound according to claim 1, comprising the following steps: (d) reductive amination of 3-(toluene-4-sulfonyl)-6,9-dihydro-3H, 7H-benzo[e}indol- 8-one in the presence of sodium cyanoborohydride and ammonium acetate.

8. A compound according to any one of claims 1 to 4 for use in therapy.

9. A compound according to any one of claims 1 to 4 for use in the treatment or prophylaxis of a 5-HTg receptor-related disorder, to achieve reduction of body weight and of body weight gain.

10. A compound according to claim 9, wherein the disorder is selected from obesity; type II diabetes; disorders of the central nervous system selected from anxiety, depression, panic attacks, memory disorders, cognitive disorders, epilepsy, sleep disorders, migraine, anorexia, bulimia, binge eating disorders, obsessive compulsive disorders, psychoses, Alzheimer's disease, Parkinson's disease, Huntington's chorea, schizophrenia, attention deficit hyperactive disorder, withdrawal from drug abuse, neurodegenerative diseases characterized by impaired neuronal growth, and pain.

11. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 4 as active ingredient, in combination with a pharmaceutically acceptable diluent or carrier. ‘

12. The pharmaceutical formulation according to claim 11 for use in the prophylaxis or treatment of a 5-HT receptor-related disorder, to achieve reduction of body weight and of body weight gain.

13. The pharmaceutical formulation according to any one of claim 11 or 12, wherein the disorder is selected from obesity; type II diabetes; disorders of the central nervous system selected from anxiety, depression, panic attacks, memory disorders, cognitive disorders, epilepsy, sleep disorders, migraine, anorexia, bulimia, binge eating disorders, obsessive compulsive disorders, psychoses, Alzheimer's disease, Parkinson's disease, Huntington's chorea, schizophrenia, attention deficit hyperactive disorder, withdrawal from drug abuse, neurodegenerative diseases characterized by impaired neuronal growth, and pain.

14. A compound according to any one of claims 1 to 4 for use in modulating 5-HTs receptor activity.

15. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for use in the prophylaxis or treatment of a 5-HT receptor-related disorder, to achieve reduction of body weight and of body weight gain.

16. The use according to claim 15, wherein the disorder is selected from obesity; type II diabetes; disorders of the central nervous system selected from anxiety, depression, panic attacks, memory disorders, cognitive disorders, epilepsy, sleep disorders, migraine, anorexia, bulimia, binge eating disorders, obsessive compulsive disorders, psychoses, Amended sheet: 8 March 2007

Alzheimer's disease, Parkinson's disease, Huntington's chorea, schizophrenia, attention deficit hyperactive disorder, withdrawal from drug abuse, neurodegenerative diseases characterized by impaired neuronal growth, and pain.

17. A cosmetic composition comprising a compound according to any one of claims 1 to 4 as active ingredient, in combination with a cosmetically acceptable diluent or carrier.

18. The cosmetic composition according to claim 17 for use in the prophylaxis or treatment of a 5-HT, receptor-related disorder, to achieve reduction of body weight and of body weight gain.

19. Use of a compound according to anyone of claims 1 to 4 for the manufacture of a medicament for use in modulating 5-HTg receptor activity.

20. A compound according to claim 1 substantially as herein illustrated and exemplified with reference to the accompanying examples.

21. A process according to any one of claims 5 to 7 substantially as herein illustrated and exemplified with reference to the accompanying examples.

22. A pharmaceutical composition according to claim 11 substantially as herein illustrated and exemplified with reference to the accompanying examples.

23. Use of a compound according to claim 15 or claim 19 substantially as herein illustrated and exemplified with reference to the accompanying examples.

24. A cosmetic composition according to claim 17 substantially as herein illustrated and exemplified with reference to the accompanying examples. Amended sheet: 8 March 2007