The present invention relates to benzoxazole and benzothiazole derivatives as 5-hydroxytryptamine-6 ligands
FIELD OF THE INVENTION
This invention relates to benzoxazole and benzothiazole denvatives as 5-hydroxytr/ptamine-6 ligands, to processes for prepanng them, methods of using them and pharmaceutical compositions containing them
BACKGROUND OF THE INVENTION
Serotonin (5-hydroxytryptamine) (5-HT) receptors play a cntical role in many physiological and behavioral functions in humans and animals. These functions are mediated through vanous 5-HT receptors distnbuted throughout the body. There are now approximeiteiy fifteen different human 5-HT receptor subtypes that have been cloned, many with well-defined roles in humans One of the most recently identified 5-HT receptor subtypes is the 5-HT6 receptor, first cloned from rat tissue in 1993 (Monsma, F. J , Shen, Y., Ward, R P, Hamblin, M W Molecular Pharmacology 1993, 43, 320-327) and subsequently from human tissue (Kohen, R , Metcalf, M. A.; Khan, N.; Druck, T , Huebner, K.; Sibley, D R Journal of Neurochemistry 1996, 66, 47-56) The receptor is a G-protein coupled rfjceptor (GPCR) positively coupled to adenylate cyclase (Ruat, M , Traiffort, E , An-ang, J~M ; Tardivel-Lacombe, L , Diaz, L., Leurs, R., Schwartz, J-C. Biochemical Biophysical Research Communications 1993, 193, 268-276). The receptor is found almost exclusively in the central nervous system (CNS) areas both in rat and in human In situ hybndization studies of the
5-HT6 receptor in rat brain using mRNA indicate pnncipal localization m the areas of 5-HT projection including striatum, nucleus accumbens, olfactory tubercle, and hippocampal formation (Ward, R. P; Hamblin, M W , Lachowicz, J E , Hoffman, B J , Sibley, D. R., Dorsa, D M. Neuroscience 1995, 64,1105-1111).
There are many potential therapeutic uses for 5-HT6 ligands in humans based on direct effects and on indications from available scientific studies. These studies provided information including the localization of the receptor, the affinity of ligands with known in VIVO activity, and results obtained from vanous animal studies conducted so far (Woolley, M. L., Marsden, C A, Fone, K C F Current Drug Targets: CNS & Neurological Disorders 2004, 3(1), 59-79)
One therapeutic use of modulators of 5-HT6 receptor function is in the enhancement of cognition and memory in human diseases such as Alzheimer's The high levels of receptor found in important structures in the forebrain, including the caudate/putamen, hippocampus, nucleus accumbens, and cortex indicate a role for the
receptor in memory and cognition since these areas are known to play a vital role in memory (Gerard, C ; Martres, M -P , Lefevre, K , Miquel, M C , Verge, D., Lanfumey, R , Doucet, E.; Hamon, M, El Mestikawy, S Brain Research, 1997, 746, 207-219) The ability of known 5-HT6 receptor ligands to enhance cholinergic transmission also supported the cognition use (Bentley, J C , Boursson, A; Boess, F G ; Kone, F C, Marsden, C A., Petit, N , Sleight, A J British Journal of Pharmacology, 1999, 126(7), 1537-1542). Studies have demonstrated that a known 5-HT6 selective antagonist significantly increased glutamate and aspartate levels in the frontal cortex without elevating levels of noradrenaline, dopamine, or 5-HT This selective elevation of neurochemicals known to be involved in memory and cognition indicates the role 5-HT6 ligands play in cognition (Dawson, L A, Nguyen, H. Q; Li, P. British Journal of Pharmacology, 2000, 130(1), 23-26). Animal studies of memory and learning with a known selective 5-HTe antagonist found positive effects (Rogers, D. C ; Hatcher, P. D ; Hagan, J.J. Society of Neuroscience, Abstracts 2000, 26, 680) More recent studies have supported this finding in several additional animal models of cognition and memory including in a novel object discnmination model (King, M V.; Sleight, A J.; Wooley, M L., Topham, I A., Marsden, C A., Fone, K. C F Neuropharmacology 2004, 47(2), 195-204 and Wooley, M. L., Marsden, C. A , Sleight, A J., Fone, K. C F Psychopharmacology, 2003, 170(4), 358-367) and in a water maze model (Rogers, D. C, Hagan, J J Psychopharmacology, 2001, 158(2), 114-119 and Foley, A. G , Murphy, K. J.; Hirst, W D., Gallagher, H. C; Hagan, J J, Upton, N.; Walsh, F S., Regan, C. M. Neuropsychopharmacology 2004, 29(1), 93-100).
A related therapeutic use for 5-HT6 ligands is the treatment of attention deficit disordeirs (ADD, also known as Attention Deficit Hyperactivity Disorder or ADHD) in both children and adults Because 5-HT6 antagonists enhance the activity of the nigrostnatal dopamine pathway and because ADHD has been linked to abnormalities in the caudate (Ernst, M, Zametkin, A. J ; Matochik, J H , Jons, P A.; Cohen, R. M Journal of Neuroscience 1998, 18(15), 5901-5907), 5-HTe antagonists attenuate attention deficit disordere
Early studies examining the affinity of vanous CNS ligands with known therapeutic utility or a strong structural resemblance to known drugs implicates 5-HT6 ligands in the treatment of schizophrenia and depression For example, clozapine (an effective clinical antipsychotic) has high affinity for the 5-HTe receptor subtype Also, several clinical antidepressants have high affinity for the receptor as well and act as antagonists at this site (Branchek, T. A , Blackburn, T P Annual Reviews in Pharmacology and Toxicology 2000,40,319-334).

Further, recent in vivo studies in rats indicate that 5-HT6 modulators are useful in the treatment of movement disorders including epilepsy (Stean, T , Routledge, C , Upton, N. British Journal of Pharmacology 1999, 127 Proc Supplement 131P and Routledge, C , Bromidge, S M, Moss, S F ; Price, G W , Hirst, W , Newman, H , Riley, G , Gager, T , Stean, T.; Upton, N , Clarke, S E , Brown, A M. British Journal of Pharmacology 2000, 130(7), 1606-1612).
Therefore, it is an object of this invention to provide compounds which are useful as therapeutic agents in the treatment of a vanety of central nervous system disorders related to or affected by the 5-HT6 receptor
It is another object of this invention to provide therapeutic methods and pharmaceutical compositions useful for the treatment of central nervous system disorders related to or affected by the 5-HT6 receptor
It is a feature of this invention that the compounds provided may also be used to further study and elucidate the 5-HT6 receptor
SUMMARY OF THE INVENTION
The present invention provides a benzoxazole or benzothiazole compound of formula I
(Formula Removed)
wherein
X is O or SOn;
n is 0 or an integer of 1 or 2,
Ri is an aryl or heteroaryl group each group optionally substituted or an optionally
substituted 8- to 13-membered bicyclic or tncyclic nng system having a N atom
at the bridgehead and optionally containing 1, 2 or 3 additional heteroatoms
selected from N, O or S, R2 is H or an alkyl, cycloalkyi or aryl group each group optionally substituted; R3 and R4 are each independently H or an optionally substituted alkyl group; R5 is H, halogen, NR6R7 or an alkyl, alkoxy, alkenyi, alkynyl or cycloalkyi, group each
group optionally substituted. R6 is an alkyl or cycloalkyi group each group optionally substituted; and R7 is H or an alkyl or cycloalkyi group each group optionally substituted, or
a stereoisomer thereof or a pharmaceutically acceptable salt thereof
The present invention also provides methods and compositions useful for the therapeutic treatment of central nervous system disorders related to or affected by the 5-HT6 receptor
DETAILED DESCRIPTION OF THE INVENTION
The 5-hydroxytryptamine-6 (5-HT6) receptor has been identified by molecular cloning. Its ability to bind a wide range of therapeutic compounds used in psychiatry, coupled with its intnguing distnbution in the brain has stimulated significant interest in new compounds which are capable of interacting with or affecting said receptor Significant efforts are being made to understand the role of the 5-HT6 receptor in psychiatry, cognitive dysfunction, motor function and control, memory, mood and the like To that end, compounds which demonstrate a binding affinity for the 5-HT6 receptor are earnestly sought both as an aid in the study of the 5-HT6 receptor and as potential therapeutic agents in the treatment ot central nervous system disorders, for example see C Reavill and D. C Rogers, Current Opinion in Investigational Drugs, 2001, 2(1):104-109, Pharma Press Ltd and Woolley, M L ; Marsden, C A., Fone, K C. F. Current Drug Targets. CNS & Neurological Disorders 2004, 3(1), 59-79
Surprisingly, it has now been found that benzoxazole and benzothiazole compounds of formula I demonstrate 5-HT6 affinity along with significant sub-type selectivity Advantageously, said formula I compounds are effective therapeutic agents for the treatment of central nervous system (CNS) disorders associated with or affected by the 5-HT6 receptor. Accordingly, the present invention provides a benzoxazole or benzothiazole compound of formula I
(Formula Removed)
wherein
X is O or SOn;
n is 0 or an integer of 1 or 2,
Ri is an aryl or heteroaryl group each group optionally substituted or an optionally substituted 8- to 13-membered bicyclic or tricyclic nng system having a N atom at the bridgehead and optionally containing 1, 2 or 3 additional heteroatoms selected from N, O or S,
R2 is H or an alkyl, cycloalkyi or aryl group each group optionally substituted,
R3 and R4 are each independently H or an optionally substituted alkyl group, and
R5 is H, halogen, NR6R7 or an alkyl, aikoxy, alkenyl, alkynyi or cycloalkyi, group each
group optionally substituted, R6 is an alkyl or cycloalkyi group each group optionally substituted; and R7 is H or an alkyl or cycloalkyi group each group optionally substituted, or
a stereoisomer thereof or a pharmaceutically acceptable salt thereof
Preferred compounds of the invention are those compounds of formula I wherein X
is O Another group of preferred compounds is those formula I compounds wherein R2 is
H or an optionally substituted alkyl group Also preferred are those formula I compounds
wherein R1 is an optionally substituted phenyl or naphthyl group. Preferred substituents
include halo, alkyl, haloalkyi and aikoxy
More preferred comp)ounds of the invention are those compounds of formula I
wherein X is O and the SO2-R1 moiety is attached to the benzoxazole nng in the 4- or 7-
position. Another group of more preferred compounds is those compounds of formula I
wherein X is O and R2 is H or C1-C4alkyl A further group of more prefen-ed compounds
are those compounds of fomriula I wherein X is O; R1 is an optionally substituted phenyl or
naphthyl group, and R2 is H or C1-C4alkyl
Among the preferred compounds of the invention are
4-(1-naph1hylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole;
7-(1-naph1hylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole;
5-(1-naph1hylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole,
6-(1-naph1hylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole,
6-(1-naphthylsulfonyl)-2-piperazin-1-ylbenzothiazole
4-(1-naph1hylsulfonyl)-2-piperazin-1-ylbenzothiazole,
7-(1-naph1hylsulfonyl)-2-piperazin-1-ylb)enzothiazole
4-(2,5-dichlorophenylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole;
7-(2,5-dichlorophenylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole,
5-(2,5-dichlorophenylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole,
2-(4-isopropylpiperazin-1 -yl)-4-(1 -naphthylsulfonyl)-1,3-benzoxazole;
2-(4-methylpiperazin-1 -yl)-4-( 1 -naphthylsulfonyl)-1,3-benzoxazole;
2-(4-ethylpiperazin-1-yl)-4-(1 - naphthylsulfonyl)-1,3-benzoxazole,
2-(4-isopropylpiperazin-1-yl)-7-(1-naphthylsulfonyl)-1,3-benzoxazole;
2-(4-methylpiperazin-1 -yl)-7-( 1 -naphthylsulfonyl)-1,3-benzoxazole;
2-(4-ethylpiperazin-1-yl)-7-(1 -naphthylsulfonyl)-1,3-benzoxazole;
2-(4-isopropylpiperazin-1-yl)-5-(1-naphthylsulfonyl)-1,3-benzoxazole,
2-(4-methylpiperazin-1 -yl)-5-( 1 -naphthylsulfonyl)-1,3-benzoxazole.

2-(4-ethylpiperazin-1-yl)-5-(1-naphthylsulfonyl)-1,3-benzoxazole, 4-(phenylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole, 7-(phenylsuifonyl)-2-piperazin-1 -yi-1,3-benzoxazole, 5-(phenylsulfonyl)-2-piperazin-1 -yl-1,3-benzoxazole, 4-{3-fluorophenylsulfonyl)-2-piperazin-1 -yl-1,3-benzoxazole, 7-(3-fluorophenylsulfonyl)-2-piperazin-1 -yl-1,3-benzoxazole, 4-(4-fluoirophenylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole; 7-(4-fluorophenylsulfonyl)-2-piperazin-1 -yl-1,3-benzoxazole; 4-(3-chlorophenylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole, 7-{3-chlorophenylsulfonyl)-2-piperazin-1 -yl-1,3-benzoxazole, 4-(4-isopropylphenylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole; 7-(4-isopropylphenylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole; 2-(piperazin-1-yl)-4-{3-(tnfluoromethyl)phenylsulfonyl}-1,3-benzoxazole, 2-(piperazin-1-yl)-7-{3-(trifluoromethyl)phenylsulfonyl}-1,3-benzoxazole; 4-(3-methoxyphenylsulfonyl)-2-piperazin-1 -yl-1,3-benzoxazole, 7-(3-methoxyphenylsulfonyl)-2-piperazin-1 -yl-1,3-benzoxazole; 4-(1 -naphthylsulfonyl)-2-(4-propyl-piperazin-1 -yl)-1,3-benzoxazole 2-(4-/T-butylpiperazin-1-yl)-4-(1-naphthylsulfonyl)-1,3-benzoxazole; 2-(4-f-butylpiperazin-1-yl)-4-(1-naphthylsulfonyl)-1,3-benzoxazole, 2-(4-cycl obutylpiperazi n-1 -yl)-4-( 1 -na phthylsu Ifonyl)-1,3-benzoxazole, 2-(4-cyclobutylpiperazin-1 -yl)-7-(1 -naphthylsulfonyl)-1,3-benzoxazole, a stereoisomer thereof; or a pharmaceutically acceptable salt thereof.
An optionally substituted moiety may be substituted with one or more substituents The substituent groups, which are optionally present, may be one or more of those customarily employed in the development of pharmaceutical compounds or the modificalion of such compounds to influence their structure/activity, persistence, absorption, stability or other beneficial property Specific examples of such substituents include halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl, haloalkyi, alkoxy, haloalkoxy, ammo, alkylamino, dialkylamino, fonnyl, alkoxycarb)onyl, carboxyl, alkanoyl, alkylthio, alkylsuphinyl, alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, tjenzyloxy, heterocyclyl or cycloalkyi groups, preferably halogen atoms or lower alkyl, or lowerhaloalkyi groups. Unless otherwise specified, typically, 1-3 substituents may be present. In certain embodiments, substituents may be for example halogen, CN, OH, phenyl, carbamoyl, carbonyl, alkoxy or aryloxy
The term "halo" or "halogen", as used herein, whether used alone or as part of another group, designates fluonne, chlonne, bromine, and iodine

As used herein, the term "alkyl", includes both (C1-C10) straight chain and (C3-C12) branched-chain monovalent saturated hydrocarbon moiety. An example of alkyl is lower alkyl, I e , C1-C6 straight-chain alkyl or C3-C6 branched-chain alkyl, for example C1-C4 straight-chain alkyl or C3-C4 branched-chain alkyl Examples of saturated hydrocarbon alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, terf-butyl, isobutyl, sec-butyl; higher homologs such as n-pentyl, n-hexyl, and the like Specifically included within the definition of "alkyl" are those alkyl groups that are optionally substituted Suitable alkyl substitutions include, but are not limited to, halogen, CN, OH, phenyl, carbamoyl, carbonyl, alkoxy or aryloxy
The term "alkoxy" as used herein, whether used alone or as part of another group, refers to the group R-O- where R is an alkyl group as defined herein As used herein, the term "haloalkyi" designates a CnH2n+1 group having from one to 2n+1 halogen atoms which may be the same or different Examples of haloalkyi groups include CF3, CH2CI, C2H3BrCI, C3H5F2, or the like
The term "alkenyl", as used herein, refers to either a (C2-C8) straight chain or (C3-C10) branched-chain monovalent hydrocarbon moiety containing at least one double bond Such hydrocarbon alkenyl moieties may be mono or polyunsaturated, and may exist in the E or Z configurations. The compounds of this invention are meant to include all possible E and Z configurations. Examples of mono or polyunsaturated hydrocarbon alkenyl moieties include, but are not limited to, chemical groups such as vinyl, 2-propenyl, isopropenyl, crotyl, 2-isopentenyl, butadienyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), or the like.
Similarly, the term "alkynyl", as used herein, refers to either a (C2-C8) straight chain or (C3-C10) branched-chain monovalent hydrocarbon moiety containing at least one tnple bond Such hydrocartx>n alkenyl moieties may be mono or polyunsaturated, and may exist in the E or Z configurations The compounds of this invention are meant to include all possible E and Z configurations Examples of mono or polyunsaturated hydrocarbon alkynyl moieties include, but are not limited to, chemical groups such as 2-propynyl, 3-pentynyl, or the like.
The term "cycloalkyl", as used herein, refers to a monocyclic, bicyclic, tricyclic, fused, bridged, or spiro monovalent saturated hydrocarbon moiety of 3-10 carbon atoms Examples of cycloalkyl moieties include, but are not limited to, chemical groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, spiro[4.5]decanyl, or the like
The term "aryl", as used herein, refers to an aromatic carbocyclic moiety of up to 20 carbon atoms, which may be a single nng (monocyclic) or multiple nngs (bicyclic, up to
three nngs) fused together or linked covalently Examples of aryl moieties include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, biphenyl, anthryl, phenanthryl, fluorenyl, indanyl, biphenylenyl, acenaphthenyl, acenaphthylenyl, and the like A preferred aryl group is phenyl. Another preferred aryl group is naphthyl The term "heteroaryl" as used herein designates an aromatic heterocyclic nng system, which may be a single ring (monocyclic) or multiple rings (bicyclic, up to three rings) fused together or linked covalently and having for example 5 to 20 nng members Preferably, heteroaryl is a 5- to 6-membered nng. The nngs may contain from one to four hetero atoms selected from N, O or S, wherein the nitrogen or sulfur atom is optionally oxidized, or the nitrogen atom is optionally quarternized Preferred heteroaryl groups are mono- or bi- cyclic aromatic nngs having 5 to 10 nng members and from 1 to 3 heteroatoms the same or different selected from N, O and S Examples of heteroaryl moieties include, but are not limited to, furan, thiophene, pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, tnazole, pyndine, pynmidine, pyrazine, pyndazine, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzofuran, benzothiophene, thianthrene, dibenzofuran, dibenzothiophene, indole, indazole, quinoline, isoquinoline, quinazoline, quinoxalme, purine, or the like
Exemplary of the 8- to 13-membered bicyclic or tncyclic nng systems having a N atom at the bridgehead and optionally containing 1, 2 or 3 additional heteroatoms selected from N, O or S included in the temn as designated herein are the following ring systems wherein W is NR', O or S, and R" is H or an optional substituent as descnbed hereinbelow
(Formula Removed)
While shown without respect to stereochemistry, compounds of formula I include all stereochemical forms of the structure; i e., the R and S configurations for each asymmetric center Therefore, single stereochemical isomers as well as enantiomeric and diastereomenc mixtures of the present compounds are within the scope of the invention The compounds of this invention may contain one or more asymmetric centers and may thus give nse to optical isomers and diastereomers The present invention includes such optical isomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof Where a stereoisomer is preferred, it may in some esmbodiments be provided substantially free of the corresponding enantiomer. Thus, an enantiomer substantially free of the corresponding enantiomer refers to a compound that is isolated or separated via separation techniques or prepared free of the corresponding enantiomer. "Substantially free", as used herein, means that the compound is made up of a significantly greater proportion of one stenosomer, preferably less than about 50%, more preferably less than about 75%, and even more preferably less than about 90%.
Formula I structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically ennched atoms For example,
compounds having the present structure except for the replacement of a hydrogen by a deutenum or tntium, or the replacement of a carbon by a 13C- or 14C-ennched carbon are Within the scope of this invention
The compounds of the present invention may be converted to salts, in particular pharmaceutically acceptable salts using art recognized procedures. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morphoiine, thiomorpholine, pipendine, pyrrolidine, a mono-, di- or tn-lower alkylamine, for example ethyl-tert-butyl-, diethyl-, diisopropyl-, tnethyl-, tnbutyl- or dimethylpropylamine, or a mono-, di-, or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. Internal salts may furthermore be formed. The term "pharmaceutically acceptable salt", as used herein, refers to salts denved from organic and inorganic acids such as, for example, acetic, propionic, lactic, citric, tartanc, succinic, fumanc, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitnc, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids when a compound of this invention contains a basic moiety
Compounds of the invention include esters, carbamates or other conventional prodrug forms, which in general, are functional denvatives of the compounds of the invention and which are readily converted to the inventive active moiety in vivo. Correspondingly, the method of the invention embraces the treatment of the vanous conditions descnbed hereinabove with a compound of fonnula I or with a compound which is not specifically disclosed but which, upon administration, converts to a compound of formula I in vivo.
Advantageously, the present invention also provides a convenient and effective process for the preparation of a compound of formula I wherein R2 is other than H (la) which comprises reacting a compound of formula II with at least two molar equivalents of an oxidizing agent, optionally in the presence of a solvent, to give the compound of fonnula la The process is shown hereinbeiow in flow diagram I wherein R2 is other than H
FLOW DIAGRAM I

(Formula Removed)
Oxidizing agents suitable for use in the process of the invention include potassium peroxymonosulfate, peracetic acid, m-chloroperbenzoic acid, chromium tnoxide, t-butylperoxide, preferably An-chloroperbenzoic acid, or the like, or a mixture thereof
Solvents suitable for use in the process of the invention include solvents such as alkanols, i e., methanol, ethanol, propanol or the like, water, acetone, chloroform, methylene chloride or the like, or a mixture thereof, preferably chloroform or methylene chloride
Compounds of formula II may be prepared using conventional synthetic methods and, if required, standard isolation or separation techniques For example, compounds of formula II may be prepared by sequentially diazotizing an aminobenzoxazole or -benzothiazole of fonnula III with NaNO2 and reacting the diazotized product with potassium iodide to give the iodo compound of formula IV; coupling the formula IV compound with a thiol of formula V in the presence of a coupling agent, such as Cul, to give the desired compound of formula II The reaction is shown in flow diagram II
FLOW DIAGRAM II
(Formula Removed)

Compounds of fomriula III wherein X is O (Ilia) may be prepared by reacting a 2-aminophenol of formula VII with CS2 in the presence of a base, such as KOH, or with CSCI2 in the presence of K2CO3 to give the mercaptobenzoxazole or -benzo- thiazole compound of formula Vlli; reacting the formula Vill compound with a piperazme of formula IX to give the compound of formula X, and reducing the formula X compound to give the desired compound of formula Ilia The reaction is shown in flow diagram III
FLOW DIAGRAM III
(Formula Removed)
Compounds of fonnula II wherein X is S (Ha) may be prepared by reacting an isothiocyanate of formula XI with a piperazine of formula IX to give the thiourea of formula XII; reacting the formula XII thiourea with bromine to give the iodobenzothiazole compound of formula XIII, and coupling said compound XIII with a thiol of formula V in the presence of a coupling agent, such as Cul, to give the desired compound of formula Ha The reaction is shown in flow diagram IV
FLOW DIAGRAM IV
(Formula Removed)
Compounds of formula I wherein R2 is H (lb) may be prepared by employing a protected piperazine compound of formula XIV in the reactions shown hereinabove in flow diagrams III or IV to give the protected formula II compound; oxidizing said formula II compound, as shown in flow diagram I, and deprotecting the oxidized compound using
standard deprotection procedures, such as HBr and acetic acid, to give the desired compound of formula la The reaction is shown in flow diagram V wherein P represents a protecting group such as benzyloxycarbonyl, Nbutoxy- carbonyl, benzyl, acetyl, or any conventional group known to protect a basic nitrogen in standard synthetic procedures (i e. T W Greene and PGM Wuts, Protective Groups in Organic Synthesis. 3"^ ed, John Wiley & Sons, publisher).
FLOW DIAGRAM V
(Formula Removed)

The compound of formula lb may be alkylated using conventional alkylation techniques, such as reductive amination or simple aikylaton with an alkylating agent, to give compounds of formula I wherein R2 is other than H (la) The reaction is shown in flow diagram VI wherein Z represents CI, Br or I and Ac represents acetyl.
FLOW DIAGRAM VI
(Formula Removed)
Advantageously, the formula I compounds of the invention are useful for the treatment of CNS disorders related to or affected by the 5-HT6 receptor including motor, mood, personality, behavioral, psychiatnc, cognitive, neurodegenerative, or the like disorders, for example Alzheimer's disease, Parkinson's disease, attention deficit disorder, anxiety, epilepsy, depression, obsessive compulsive disorder, sleep disorders, neurodegenerative disorders (such as head trauma or stroke), feeding disorders (such as anorexia or bulimia), schizophrenia, memory loss, disorders associated with withdrawal from drug or nicotine abuse, or the like or certain gastrointestinal disorders such as irritable bowel syndrome. Accordingly, the present invention provides a method for the treatment of a disorder of the central nervous system related to or affected by the 5-HT6 receptor in a patient in need thereof which compnses providing said patient a therapeutically effective amount of a compound of fonnula I as descnbed hereinabove The compounds may be provided by oral or parenteral administration or in any common manner known to be an effective administration of a therapeutic agent to a patient in need thereof.
The term "providing" as used herein vwth respect to providing a compound or substance embraced by the invention, designates either directly administenng such a compound or substance, or administenng a prodrug, denvative or analog which forms an equivalent amount of the compound or substance within the body
The inventive method includes a method for the treatment of schizophrenia, a method for the treatment 0I a disease associated with a deficit in memory, cognition, and/or learning or a cognitive disorder such as Alzheimer's disease or attention deficit disorder; a method for the treatment of developmental disorders such as schizophrenia, Down's syndrome. Fragile X syndrome, autism or the like, a method for the treatment of behavioral disorders, e.g., anxiety, depression, or obsessive compulsive disorder, a method for the treatment of motion or motor disorders such as Parkinson's disease or epilepsy; a method for the treatment of a neurodegenerative disorder such as stroke or head trauma or withdrawal from drug addiction including addiction to nicotine, alcohol, or other substances of abuse, or any other CNS disease or disorder associated with or related to the 5-HT6 receptor
In one embodiment, the present invention provides a method for treating attention deficit disorders (ADD, also known as Attention Deficit Hyperactivity Disorder or ADHD) in both children and adults. Accordingly, in this embodiment, the present invention provides a method For treating attention deficit disorders in a pediatnc patient
The present invention therefore provides a method for the treatment of each of the conditions listed above in a patient, preferably in a human, said method compnses providing said patient a therapeutically effective amount of a compound of formula I as descnbed hereinabove The compounds may be provided by oral or parenteral administration or in any common manner known to be an effective administration of a therapeutic agent to a patient in need thereof
The therapeutically effective amount provided in the treatment of a specific CNS disorder may vary according to the specific condition(s) being treated, the size, age and response pattern of the patient, the severity of the disorder, the judgment of the attending physician and the like. In general, effective amounts for daily oral administration may be about 0 01 to 1,000 mg/kg, preferably about 0 5 to 500 mg/kg and effective amounts for parenteral administration may be about 0 1 to 100 mg/kg, preferably about 0 5 to 50 mg/kg
In actual practice, the compounds of the invention are provided by administenng the compound or a precursor thereof in a solid or liquid form, either neat or in combination with one or more conventional pharmaceutical carriers or excipients Accordingly, the present invention provides a pharmaceutical composition which comprises a pharmaceutically acceptable earner and an effective amount of a compound of formula I as descnbed hereinabove.
In one embodiment, the invention relates to compositions compnsing at least one compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable camers, excipients, or diluents. Such compositions include pharmaceutical compositions for treating or controlling disease states or conditions of the central nervous system In certain embodiments, the compositions compnse mixtures of one or more compounds of fonnula I
In certain embodiments, the invention relates to compositions compnsing at least one compound of formula I, or a pharmaceutically acceptable salt thereof, and one or more phannaceutically acceptable earners, excipients, or diluents. Such compositions are prepared in accordance with acceptable pharmaceutical procedures Pharmaceutically acceptable carriers are those earners that are compatible with the other ingredients in the formulation and are biologically acceptable
The compounds of formula I may be administered orally or parenterally, neat, or in combination with conventional pharmaceutical earners. Applicable solid carriers can
include one or more substances that can also act as flavonng agents, lubncants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet-disintegrating agents, or encapsulating matenals In powders, the earner is a finely divided solid that is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a earner having the necessary compression properties in suitable proportions and compacted in the shape and size desired The powders and tablets preferably contain up to 99% of the active ingredient Suitable solid earners include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextnn, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
In certain embodiments, a compound of formula I is provided in a disintegrating tablet formulation suitable for pediatnc administration.
Liquid carriers can be used in prepanng solutions, suspensions, emulsions, syrups and elixirs The active ingredient can be dissolved or suspended in a pharmaeeutically acceptable liquid earner such as water, an organic solvent, a mixture of both, or a pharmaeeutically acceptable oil or fat. The liquid earner can contain other suitable pharmaceutical additives such as, for example, solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavonng agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators Suitable examples of liquid earners.for oral and parenteral administration include water (particularly containing additives as above, e.g. cellulose denvatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydnc alcohols and polyhydnc alcohols e.g. glycols) and their denvatives, and oils (e g fractionated coconut oil and arachis oil) For parenteral administration, the earner can also be an oily ester such as ethyl oleate and isopropyl mynstate. Stenle liquid earners are used in stenle liquid form compositions for parenteral administration The liquid earner for pressunzed compositions can be halogenated hydrocarbon or other pharmaeeutically acceptable propellant.
In certain embodiments, a liquid pharmaceutical composition is provided wherein said composition is suitable for pediatnc administration In other emtx)diments, the liquid composition is a syrup or suspension
Liquid pharmaceutical compositions that are stenle solutions or suspensions can be administered by, for example, intramuscular, intraperitoneal or subcutaneous injection Stenle solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form
The compounds of fomriula I may be administered rectally or vaginally in the form of a conventional suppository For administration by intranasal or intrabronchial inhalation or insufflation, the compounds of formula I can be formulated into an aqueous or partially
aqueous solution, which can then be utilized in the form of an aerosol The compounds of formula I can also be administered transdennally through the use of a transdermal patch containing the active compound and a earner that is inert to the active compound, is nontoxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin The earner can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices The creams and ointments can be VisCOUS liquid or semisolid emulsions of either the oil-in-water or water-in-oil type Pastes compnsed of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient can also be suitable A vanety of occlusive devices can be used to release the active ingredient into the blood stream such as a semipermeable membrane covenng a reservoir containing the active ingredient with or without a earner, or a matrix containing the active ingredient Other occlusive devices are known in the literature
F'referably the pharmaceutical composition is in unit dosage form, e g as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositones In such fonn, the composition is sub-divided in unit dose containing appropnate quantities of the active ingredient, the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled synnges or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropnate number of any such compositions in package form.
The therapeutically effective amount of a compound of formula I provided to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compounds of formula I are provided to a patient suffering from a condition in an amount sufficient to treat or at least partially treat the symptoms of the condition and its complications. An amount adequate to accomplish this is a "therapeutically effective amount" as descnbed previously herein The dosage to be used in the treatment of a specific case must be subjectively detennined by the attending physician. The variables involved include the specific condition and the size, age, and response pattern of the patient. The treatment of substance abuse follows the same method of subjective drug administration under the guidance of the attending physician Generally, a starting dose is about 5 mg per day with gradual increase in the daily dose to about 150 mg per day, to provide the desired dosage level in the patient
The present invention also provides the use of a compound of formula I as descnbed herein in the manufacture of a medicament for treating a central nervous system disorder related to or affected by the 5-HT6 receptor receptor including motor,
mood, personality, behavioral, psychiatnc, cognitive, neurodegenerative, or the like disorders, for example Alzheimer's disease, Parkinson's disease, attention deficit disorder, anxiety, epilepsy, depression, obsessive compulsive disorder, sleep disorders, neurodegenerative disorders (such as head trauma or stroke), feeding disorders (such as anorexia or bulimia), schizophrenia, memory loss, disorders associated with withdrawal from drug or nicotine abuse, or the like or certain gastrointestinal disorders such as irntable bowel syndrome
The inventive use includes the use of a compound of formula I as descnbed herein in the manufacture of a medicament for treating schizophrenia; a disease associated with a deficit in memory, cognition, and/or learning or a cognitive disorder such as Alzheimer's disease or attention deficit disorder, a developmental disorder such as schizophrenia; Down's syndrome, Fragile X syndrome, autism or the like; a behavioral disorder, e.g., anxiety, depression, or obsessive compulsive disorder; a motion or motor disorder such as Parkinson's disease or epilepsy, a neurodegenerative disorder such as stroke or head trauma or withdrawal from drug addiction including addiction to nicotine, alcohol, or other substances of abuse, or any other CNS disease or disorder associated with or related to the 5-HT6 receptor
In one embodiment, the present invention provides the use of a compound of formula I as descnbed herein in the manufacture of a medicament for treating attention deficit disorders (ADD, also known as Attention Deficit Hyperactivity Disorder or ADHD) in both children and adults.
In certain embodiments, the present invention is directed to prodrugs of compounds of fonnula I. The tenn "prodrug," as used herein, means a compound that is convertible in vivo by metabolic means (e g. by hydrolysis) to a compound of formula I. Vanous fonns of prodrugs are known in the art such as those discussed in, for example, Bundgaard, (ed ), Design of Prodrugs, Elsevier (1985), Widder, et al. (ed ), Methods in Enzymology, vol. 4, Academic Press (1985), Krogsgaard-Larsen, et al., (ed). "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991), Bundgaard, et al.. Journal of Drug Delivery Reviews, 8-1-38(1992), Bundgaard, J of Phamnaceutical Sciences, 77285 et seq (1988); and Higuchi and Stella (eds) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975)
For a more clear understanding, and in order to illustrate the invention more clearly, specific examples thereof are set forth hereinbelow. The following examples are merely illustrative and are not to be understood as limiting the scope and underlying principles of the invention in any way. The term HNMR designates proton nuclear magnetic resonance. The term MS desigates mass spectrum. The terms THF, EtOAc and DMSO designate tetrahydrofuran, ethyl acetate and dimethyisulfoxide, respectively.
All chromatography is perfonned using S1O2 as support Unless otherwise noted, all parts are parts by weight. In the chemical drawings, the term Cbz represents benzyloxycarbonyl
EXAMPLE 1
Preparation of 4-Benzoxazol-2-ul-piperazine-1-carboxulic acid benzyl ester
(Formula Removed)
A mixture of 2-chlorobenzoxazole (100 g, 6 51 mmol), benzyl 1-piperazinecarboxylate (1.43 g, 6 51 mmol), and K2CO3 (1.80 g, 13 0 mmol) in DMF (13 mL) was stirred at 100 °C overnight, cooled, diluted with water, and extracted with EtOAc The extracts were combined, washed with water and brine, dned over Na2SO4 and concentrated in vacuo to provide the title compound (1.70 g, 77%), characterized by NMR and mass spectral analyses.

EXAMPLE 2
Preparation of 4-(5-lodobenzoxazol-2-ul)piperazine-1-carboxulic acid benzyl ester
(Formula Removed)
A mixture of 4-benzoxazol-2-yl-piperazine-1-carboxylicacid benzyl ester (0 50 g, 1 48 mmol) and lodme monochlonde (0 265 g, 1 63 mmol) in acetic acid (4 94 mL) was stin-ed at 60 °C overnight, cooled, and concentrated in vacuo to provide the title compound, which was used without further purification, in Example 3.
EXAMPLE 3
Preparation of 4-r5-f1-naphthulsulfanvhbenzoxazol-2-vnpiperazine-1-carboxulic acid
benzyl ester
(Formula Removed)
A mixture of 4-(5-iodobenzoxazol-2-yl)piperazine-1-carboxylic acid benzyl ester, prepared in Example 2 (1 48 mmol theory), 1-napthalenethiol (0 237 g, 1 48 mmol), Cul (0 042 g, 0 22 mmol), and K2CO3 (0 409 g, 2 96 mmol) in isopropanol was heated at 90 °C overnight, diluted with 20% MeOH in CH2CI2, and filtered through a pad of silica gel The filtrate was concentrated to dryness The resultant residue was purified by chromatography with 5% MeOH in CH2CI2 to provide the title compound (230 mg, 31% overall yield from 4-benzoxazol-2-yl-piperazine-1-carboxylic acid benzyl ester), characten2:ed by NMR and mass spectral analyses
EXAMPLE 4
Preparation of 4-r5-(1-Naphthulsulfonul>benzoxazol-2-vnpiperazine-1-carboxulic
acid benzyl ester
(Formula Removed)
A mixture of 4-[5-(1-naphthylsulfanyl)benzoxazol-2-yl]piperazine-1-carboxylic acid
benzyl ester (0 110 g, 0.22 mmol) and meta-chloroperbenzoic acid (mCPBA) (0.096 g,
0.55 mmol) in CHCI3 was stirred at room temperature for 3 h and concentrated in vacuo
.The resultant residue was purified by chromatography with CH2CI2 to provide the title
compound (120 mg, 100%), charactenzed by NMR and mass spectral analyses.
EXAMPLE 5
Preparation of 5-f1-Naplithulsulfonul)-2-piperazin-1-ulbenzoxazole Dihydrochloride
(Formula Removed)
A solution of 4-[5-(1-naphthylsulfonyl)benzoxazol-2-yl]piperazine-1-carboxylic acid benzyl ester (0 110 g, 0.19 mmol) in 33 wt % of HBr in HOAc (1.3 mL) was stin-ed at rt for 40 mm and diluted with Et20 The precipitate was filtered, washed with Et20, and purified with Gilson reverse phase HPLC The purified matenal was treated with a solution of HCl in ether, stirred at room temperature for 5 minutes and concentrated to dryness to give the title compound (60 mg, 68%), charactenzed by NMR and mass spectral analyses MS (ES+) m/e 394 (MH+).

EXAMPLE 6
Preparation of 4-Nitro-3H-benzoxazole-2-thione
(Formula Removed)
A solution of KOH (3 31 g, 59 0 mmol) in EtOH and water was treated with carbon disulfide (10 4 g, 136 3 mmol) followed by 2-amino-3-nitrophenol (7.00 g, 45 4 mmol) The mixture was heated at reflux temperature overnight, cooled, concentrated, acidified with 1M HCI and filtered The filtercake was washed with water and dried in vacuo to provide the title compound (7 0 g, 79%), charactenzed by NMR and mass spectral analyses
EXAMPLE 7
Preparation of 4-(4-Nitrobenzoxazol-2-ul)piperazine-1-carboxulic acid benzyl ester
(Formula Removed)
A mixture of 4-nitro-3H-benzoxazole-2-thione (7.00 g, 35 7 mmol) and t)enzyl 1-piperazinecarix)xylate (15.72 g, 71.36 mmol) in xylenes was heated at reflux temperature overnight, cooled and concentrated in vacuo to provide the title compound which //as used, without further purification, in Example 8
EXAMPLE 8
Preparation of 4-(4-Aminobenzoxazol-2-vHpiperazine-1-carboxviic acid benzvt ester

(Formula Removed)

A mixture of 4-(4-nitrobenzoxazol-2-yl)piperazine-1-carboxylic acid benzyl ester, from Example 7 (35.7 mmol theory), SnCl2 (40.25 g, 178 4 mmol), and concentrated HCI solution (4.46 mL) in EtOH was heated at 70 °C overnight, cooled, diluted with 20% MeOH in CH2CI2, neutralized with NaOH to pH 8-10 and extracted with CHCI3 The
extracts were combined, dned over Na2SO4, concentrated, and purified by chromatography with 1-5% MeOH in CH2CI2 to provide the title compound (3 0 g, 24% overall yield from 4-nitro-3H-benzoxazole-2-thione), charactenzed by NIVIR and mass spectral analyses
EXAMPLE 9
Preparation of 4-(4-lodobenzoxazol-2-ul)piperazine-1-carboxulic acid benzyl ester
(Formula Removed)
A mixture of NaNOj (0 881 g, 12 8 mmol) in IN HCI (31 mL) and MeOH (62 mL) at 0 °C was treated dropwise with a solution of 4-(4-aminobenzoxazol-2-yl)piperazine-1-carboxylic acid benzyl ester (3.00 g, 8 51 mmol) in MeOH, stirred for 30 mm, treated slowly with a solution of Kl (3.53 g, 21 3 mmol) in water, stirred at room temperature for an additional 30 mm, concentrated and extracted with EtOAc. The extracts were combined, dned over Na2SO4, concentrated and purified by chromatoraphy with 1-3% MeOH in CH2CI2 to provide the title compound (2 05 g, 52%), characterized by NMR and mass spectral analyses
EXAMPLE 10
Preparation of 4-r4-(1-Naphthulsulfanul)benzoxazol-2-vnpiperazine-1-carboxulic
acid benzyl ester
(Formula Removed)
A mixture of 4-(4-iodobenzoxazol-2-yl)piperazine-1-carboxylic acid benzyl ester (0.80 g, 1 73 mmol), 1-naphthyithiol (0 276 g, 1 73 mmol), Cul (0 066 g, 0.35 mmol), ethylene glycol (0.214 g, 3.45 mmol), and K2CO3 (0 477 g, 3 45 mmol) in isopropanol was heated at 90 °C overnight, cooled, diluted with 20% MeOH in CH2CI2 and filtered through a pad of silica gel The filtrated was concentrated and purified by chromatography with 1-
3% MeOH in CH2CI2 to provide the title compound (0 856 g, 93%), charactenzed by NMR and mass spectral analyses
EXAMPLE 11
Preparation of 4-r4-(1-NaphthulsulfonvHbenzoxazol-2-vnpiperazine-1-carboxulic
acid benzyl ester
(Formula Removed)
A mixture of 4-[4-(1-naphthylsuifanyl)t>enzoxazoi-2-yi]piperazine-1-carboxyiic acid benzyl ester (0 297 g, 0.60 mmol) and meta-chloroperbenzoic acid (mCPBA) (0 311 g, 1 80 mmol) in CHCI3 was stirred at room temperature for 30 mm and concentrated in vacuo to provide the title compound which was used, without further purification, in Example 12.
EXAMPLE 12
Preparation of 4-(1-Naphthulsulfonul)-2-piperazin-1-ulbenzoxazole Dihydrochloride
(Formula Removed)
A solution of 4-[4-(1-naphthylsulfonyl)benzoxazol-2-yl]piperazine-1-carboxylic acid benzyl ester obtained in Example 11 (0 60 mmol theory) in 33 wt.% of HBr in HOAc (1 3 mL) was stirred at room temperature for 40 mm, diluted with Et2O and filtered. The fittercake was washed with Et20 and purified by Gilson reverse phase HPLC. The purified material was treated with a solution of HCI in ether, stirred at room temperature for 5 minutes and concentrated to dryness to afford the title compound (58 mg, 21% overall yield from 4-[4-(1-naphthylsulfanyl)benzoxazol-2-yl]piperazine-1-carboxylic acid benzyl ester), charactenzed by NMR and mass spectral analyses MS (ES+) m/e 394 (MH+)
EXAMPLES 13-21
Preparation of 4-(Arylsulfonul)-2-piperazin-1-ulbenzoxazole Dihydrochloride Compounds

(Formula Removed)
Using essentially the same procedures descnbed in Examples 10, 11 and 12 and employing the desired thiol, RiSH, in step 1, the compounds shown in Table I were obtained and identified by HNMR and mass spectral analyses
Table 1

(Table Removed)
EXAMPLE 22
Preparation of 2-(4-Methulpiperazin-1-ul)-4-(1-naphthulsulfonul>benzoxazole
Dihydrochloride
(Formula Removed)
A mixture of 4-(1-naphthylsulfonyl)-2-piperazin-1-ylbenzoxazole (0 050 g, 0 127 mmol), methyl iodide (0.018 g, 0 127 mmol) and K2CO3 (0 017 g, 0 127 mmol) in DMF was stin-ed at room temperature overnight, concentrated and purified by Gilson reverse phase HPLC The purified matenal was treated with a solution of HCI in ether, stirred at room temperature for 5 minutes and concentrated to dryness to afford the title compound (20 mg, 33%), charactenzed by NMR and mass spectral analyses. MS (ES+) m/e 408 (MH+)
EXAMPLE 23
Preparation of 2-(4-Ethylpiperazin-1-yl)-4-(1-naphthylsulfonyl)benzoxazole
Dihydrochloride

(Formula Removed)
A mixture of 4-(1-napiithylsulfonyl)-2-piperazin-1-ylbenzoxazole (0 070 g, 0 18 mmol), acetaideliyde (0.016 g, 0.36 mmol), NaBH(OAc)3 (0.075 g, 0 36 mmol), and acetic acid (0.021 g, 0.36 mmol) in 1,2-dichloroetliane was stirred at room temperature overnigtit, diluted with 20% MeOH in CH2CI2 (with 0 5% NH4OH) and filtered through a pad of silica gel. The filtrate was concentrated and purified by Gilson reverse phase HPLC The purified matenal was treated with a solution of HCI in ether, stirred at room temperature for 5 minutes and concentrated to dryness to five the title compound (17 mg, 19%), characterized by NMR and mass spectral analyses. MS (ES+) m/e 422 (MH+)
EXAMPLES 24-31
Preparation of 2-(4-Alkylpiperazin-1-yl)-4-(1-naphthylsulfonyl)benzoxazole
Dihydrochloride Compounds
(Formula Removed)
Using essentially the same procedure described in Example 23 and employing the appropnate aldehyde, R-CHO, or cyloalkyl ketone, the compounds shown in Table II were obtained and identified by NMR and mass spectral analyses.
Table II
(Table Removed)
EXAMPLE 32
Preparation of 2.6-Diamlnophenol

(Formula Removed)
A mixture of 2,6-dinitrophenol (2 50 g, 13 6 mmol) and 10% Pd/C (300 mg) in MeOH was shaken under H2 (40 psi) overnight and filtered. The filtrate was concentrated in vacuo to provide the title compound (1 50 g, 89%), characterized by NMR and mass spectral analyses.
EXAMPLE 33
Preparation of 7-Arnino-3H-benzoxazole-2-thione
(Formula Removed)
A solution of KOH (0.875 g, 15 6 mmol) in EtOH (14 3 mL) and water (2 6 mL) was treated with carbon disulfide (0 828 g, 10 9 mmol), followed by of 2, 6-diaminophenol (1.50 g, 12.1 mmol) The mixture was heated at reflux temperature for 3 h, concentrated, neutralized with 1M HCI to pH 7, and extracted with EtOAc. The extracts were combined, dned over Na2SO4 and concentrated in vacuo to afford the title compound (0 90 g, 45%), characterized by NMR and mass spectral analyses
EXAMPLE 34
Preparation of 7-(1-naphthulsulfonul)-2-piperazin-1-ulbenzoxazole Dihydrochloride
(Formula Removed)
Using essentially the same procedures descnbed in Examples 7, 9, 10, 11 and 12 and employing 7-amino-3H-benzoxazole-2-thione as starting matenal, the title compound was obtained and identified by HNMR and mass spectral analyses MS (ES+) m/e 394 (MH+)
EXAMPLE 35
Preparation of 6-(1-naphthulsulfonul)-2-piperazin-1-ulbenzoxazole Dihydrochloride
(Formula Removed)
Using essentially the same procedures described in Examples 6, 7, 8, 9, 10, 11 and 12 and employing 2-amino-5-nitrophenol as starting matenal, the title compound was obtained and identified by HNMR and mass spectral analyses MS (ES+) m/e 394 (MH+)
EXAMPLE 36
Preparation of 2-Chloro-6-nitrobenzothiazole
(Formula Removed)
A solution of NaNO2 (3 18 g, 46 1 mmol) in water was slowly added to a solution of 2-amino-6-nitro-benzothiazole (3 00 g, 15 4 mmol) in 85% H3PO4 over a penod of 30 mm at 0 °C. The reaction solution was stirred for 1 hour and was gradually added to a solution of CUSO4 (7.61 g, 76.8 mmol) and NaCI (13 5 g, 230 mmol) in water over a 30 mm period at 0 °C. The resultant suspension was allowed to wann to room temperature, stirred until gas evolution ceased, diluted with water and extracted with CH2CI2. The extracts were combined, dned over Na2SO4 and concentrated in vacuo to provide the title compound (3 15 g, 95%), characterized by NMR and mass spectral analyses.
EXAMPLE 37
Preparation of 4-(6-Nitrobenzothiazol-2-yl)piperazine-1-carboxulic acid benzyl ester
(Formula Removed)

A mixture of 2-chloro-6-nitrobenzothiazole (1 OOg, 4 66 mmol), benzyl 1-piperazinecarboxylate (1 03g, 4 66 mmol), and NaHCOa (0 783 g, 9 32 mmol) in EtOH was heated at reflux temperature for 2 h, concentrated, and extracted with EtOAc The combined extracts were dried over Na2SO4 and concentrated in vacuo to provide the title compound (1 13 g, 61%), charactenzed by NMR and mass spectral analyses
EXAMPLE 38
Preparation of 4-(6-Aminobenzothiazol-2-ul)piperazine-1-carboxulic acid benzyl
ester
(Formula Removed)
A mixture of 4-(6-nitrobenzothiazol-2-yl)piperazine-1-carboxylic acid benzyl ester (1.13 g, 2 84 mmol), SnClz (2.56 g, 11 3 mmol), and cone. HCI (0.35 mL, 4 25 mmol) in EtOH was heated at 70 °C overnight, diluted with water, neutralized with 1 N NaOH to pH 10, and extracted with CH2CI2 The combined extracts were filtered through a pad of silica gel The filtrate was concentrated in vacuo to provide the title compound (0.80 g, 77%), characterized by NMR and mass spectral analyses
EXAMPLE 39
Preparation of 4-(6-lodobenzothiazol-2-ul)piperazine-1-carboxulic acid benzyl ester
(Formula Removed)
A solution of 1 N HCI (8 mL) and MeOH (16 mL) was treated with NaNO2 (0 224 g, 3 26 mmol) at 0 °C followed by slow addition of a solution of 4-(6-amino-benzothiazol-2-yl)piperazine-1-carboxylic acid benzyl ester (8 OOg, 2 17 mmol) in MeOH. The reaction mixture was stirred for 30 mm, treated with a solution of Kl (0.901 g, 5 43 mmol) in water, stirred for an additional 30 mm, concentrated and extracted with CH2CI2 The extracts were combined, dned over Na2SO4 and concentrated in vacuo to provide the title compound (0 74 g, 71%), charactenzed by NMR and mass spectral analyses.

EXAMPLE 40
Preparation of 4-[6-(1 -naphthulsulfanvnbenzothiazol-2-yl]piperazine-1-carboxylic
acid benzyl ester

(Formula Removed)
A mixture of 4-(6-iodobenzothiazol-2-yl)piperazine-1-carboxylic acid benzyl ester (0 370 g, 0.77 mmol), 1-napthalenethiol (0 124 g, 0 77 mmol), Cul (0 015 g, 0.08 mmol), and K2CO3 (0.213 g, 0.77 mmol) in isopropanol was heated at 90 °C overnight, cooled to 25° C, diluted with 20% MeOH in CH2Cl2, and filtered through a pad of silica gel The filtrate was concentrated in vacuo to provide the title compound which used in Example 41 without further purification.
EXAMPLE 41
Preparation of 6-(1-Naphthulsulfonvn-2-piperazin-1-ulbenzothiazoie Dihydrochloride
(Formula Removed)
A mixture of 4-[6-(1-naphthylsulfanyl)benzothiazol-2-yl]piperazine-1-carboxylic acid benzyl ester obtained in Example 40 (0 77 mmol theory) and meta-chloroperbenzoic acid (mCPBA) (0.399 g, 2 31 mmol) in CHCI3 was stirred at room temperature for 2 h and concentrated in vacuo. The resultant residue was dissolved in 33 wt % of HBr in HOAc (3.9 mL), stirred at room temperature for 40 mm, diluted with Et20 and filtered The filtercake was washed with Et2O and purified with Gilson reverse phase HPLC. The purified material was treated with a solution of HCL in ether, stirred for 5 minutes and concentrated to dryness to afford the title compound (315 mg, 85% overall yield from 4-(6-
iodobenzothiazol-2-yl)piperazine-1-carboxylic acid benzyl ester), charactenzed by NMR and mass spectral analyses MS (ES+) m/e 410 (MH+)
Example 42
Evaluation of 5-HT6 Binding Affinity of Test Compounds
The affinity of test compounds for the serotonin 5-HT6 receptor was evaluated in the following manner. Cultured Hela cells expressing human cloned 5-HT6 receptors were harvested and centrifuged at low speed (1,000 x g) for 10 0 minutes to remove the culture media. The harvested cells were suspended in half volume of fresh physiological phosphate buffered saline solution and recentnfuged at the same speed This operation was repeated The collected cells were then homogenized in ten volumes of 50 mM Tns MCI (pH 7.4) and 0 5 mM EDTA The homogenate was centrifuged at 40,000 x g for 30 0 mm and the precipitate was collected The obtained pellet was resuspended in 10 volumes of Tris.HCI buffer and recentnfuged at the same speed The final pellet was suspended in a small volume of Tns HCI buffer and the tissue protein content was determined in aliquots of 10-25 µl volumes. Bovine Serum Albumin was used as the standard in the protein determination according to the method descnbed in Lowry et al, J_ Biol. Chem.. 193: 265 (1951) The volume of the suspended cell membranes was adjusted 1o give a tissue protein concentration of 1.0 mg/ml of suspension The prepared membrane suspension (10 times concentrated) was aliquoted in 1 0 ml volumes and stored at -70° C until used in subsequent binding expenments.
Binding expenments were performed in a 96 well microtiter plate format, in a total volume of 200 pi To each well was added the following mixture: 80 0 pi of incubation buffer made in 50 mM Tns HCI buffer (pH 7 4) containing 10.0 mM MgCl2 and 0 5 mM EDTA and 20 pi of [^H]-LSD (S A , 86 0 Ci/mmol, available from Amersham Life Science), 3 0 nM The dissociation constant, KD of the [^H]LSD at the human serotonin 5-HT6 receptor was 2.9 nM, as determined by saturation binding with increasing concentrations of [^H]LSD. The reaction was initiated by the final addition of 100.0 pi of tissue suspension. Nonspecific binding was measured in the presence of 10 0 pM methiothepin The test compounds were added in 20 0 pi volume.
The reaction was allowed to proceed in the dark for 120 minutes at room temperature, at which time, the bound ligand-receptor complex was filtered off on a 96 well unifilter with a Packard Filtermate® 196 Harvester The bound complex caught on the filter disk was allowed to air dry and the radioactivity is measured m a Packard TopCount® equipped with six photomultiplier detectors, after the addition of 40.0pl Microscmt®-20
scintillant to each shallow well The unifilter plate was heat-sealed and counted in a PackardTopCount® with a tntium efficiency of 31 0%
Specific binding to the 5-HT6 receptor was defined as the total radioactivity bound less the amount bound in the presence of 100µM unlabeled methiothepin Binding in the presence of varying concentrations of test compound was expressed as a percentage of specific binding in the absence of test compound The results were plotted as log % bound versus log concentration of test compound Nonlinear regression analysis of data points with a computer assisted program Pnsm® yielded both the IC50 and the K, values of test compounds with 95% confidence limits A linear regression line of data points was plotted, 1rom which the IC50 value is determined and the K, value is determined based upon the following equation K, = IC50 / (1 + L/KD)
where L was the concentration of the radioactive ligand used and KD IS the dissociation constant of the ligand for the receptor, both expressed in nM
Using this assay, the following Ki values were determined The data are shown in Table III, below.
TABLE I I I

(Table Removed)

WE CLAIM:
1. A compound of formula I
(Formula Removed)
wherein
X is O or SOn;
n is 0 or an integer of 1 or 2;
R1 is an aryl or heteroaryl group each group optionally substituted or an optionally
substituted 8- to 13-membered bicyclic or tricyclic ring system having a N atom
at the bridgehead and optionally containing 1, 2 or 3 additional heteroatoms
selected from N, O or S; R2 is H or an alkyl, cycloalkyi or aryl group each group optionally substituted; R3 and R4 are each independently H or an optionally substituted alkyl group; and R5 is H, halogen, NR6R7 or an alkyl, alkoxy, alkenyl, alkynyl or cycloalkyi, group each
group optionally substituted; Re is an aIkyl or cycloalkyi group each group optionally substituted; and R7 is H or an alkyl or cycloalkyi group each group optionally substituted; or a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
2. A compound as claimed in claim 1 wherein X is O.
3. A compound as claimed in claim 1 or claim 2 wherein R2 is H or an
optionally substituted alkyl group.
4. A compound as claimed in any one of claims 1-3 wherein R1 is an
optionally substituted phenyl or naphthyl group.
5. A compound as claimed in any one of claims 2-4 wherein the SO2-R1 moiety is attached to the benzoxazole ring in the 4- or 7-position.
6. A compound as claimed in any one of claims 2-5 wherein R2 is H or C1-C4alkyl.
7. A compound as claimed in any one of claims 1-6 wherein R3, R4 and R5 are H.
8. The compound according to claim 1 selected from the group consisting essentially of:
4-(1-naphthylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole; 7-(1-naphthylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole; 5-(1-naphthylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole; 6-(1-naphthylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole; 6-(1-naphthylsulfonyl)-2-piperazin-1-ylbenzothiazole 4-(1-naphthylsulfonyl)-2-piperazin-1-ylbenzothiazole ; 7-(1-naphthylsulfonyl)-2-piperazin-1-ylbenzothiazole 4-(2,5-dichlorophenylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole; 7-(2,5-dichlorophenylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole; 5-(2,5-dichlorophenylsulfonyl)~2-piperazin-1-yl-1,3-benzoxazole; 2-(4-isopropylpiperazin-1-yl)-4-(1-naphthylsulfonyi)-1,3-benzoxazole; 2-(4-methylpiperazin-1-yl)-4-(1-naphthylsulfonyl)-1,3-benzoxazole; 2-(4-ethylpiperazin-1-yl)-4-(1-naphthylsulfonyl)-1,3-benzoxazole; 2-(4-isopropylpiperazin-1 -yl)-7-(1 -naphthylsulfonyl)-1,3-benzoxazole; 2-(4-methylpiperazin-1-yl)-7-(1-naphthylsulfonyl)-1,3-benzoxazole; 2-(4-ethylpiperazin-1-yl)-7-(1-naphthylsulfonyl)-1,3-benzoxazole; 2-(4-isopropylpiperazin-1-yl)-5-(1-naphthylsulfonyl)-1,3-benzoxazole; 2-(4-methylpiperazin-1-yl)-5-(1-naphthylsulfonyl)-1,3-benzoxazole; 2-(4-ethylpiperazin-1-yl)-5-(1-naphthylsulfonyl)-1,3-benzoxazole; 4-(phenylsulfonyl)-2-piperazin-1 -yl-1,3-t5enzoxazole; 7-(phenylsulfonyl)-2-piperazin-1 -yl-1,3-benzoxazole; 5-(phenylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole; 4-(3-fluorophenylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole; 7-(3-fluorophenylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole; 4-(4-fluorophenylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole; 7-(4-fluorophenylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole; 4-(3-chlorophenylsulfonyl)-2-piperazin-1 -yl-1,3-benzoxazole; 7-(3-chlorophenylsulfonyl)-2-piperazin-1 -yl-1,3-benzoxazole; 4-(4-isopropylphenylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole; 7-(4-isopropylphenylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole; 2-(piperaziin-1-yl)-4-{3-(trifluoromethyl)phenylsulfonyl}-1,3-benzoxazole;
2-(piperazin-1-yl)-7-{3-(trifluoromethyl)phenylsulfonyl}-1,3-benzoxazole;
4-(3-methoxyphenylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole;
7-(3-methoxyphenylsulfonyl)-2-piperazin-1-yl-1,3-benzoxazole;
4-(1-naphthylsulfonyl)-2-(4-piopyl-piperazin-1-yl)-1,3-benzoxazole
2-(4-n-butylpiperazin-1-yl)-4-(1-naphthylsulfonyl)-1,3-benzoxazole;
2-(4-t-butylpiperazin-1-yl)-4-(1-naphthylsulfonyl)-1,3-benzoxazole;
2-(4-cyclobutylpiperazin-1-yl)-4-(1-naphthylsulfonyl)-1,3-benzoxazole;
2-(4-cyclobutylpiperazin-1-yl)-7-(1-naphthylsulfonyl)-1,3-benzoxazole;
a stereoisomer thereof; and
a pharmaceutically acceptable salt thereof.
9. A method for the treatment of a central nervous system disorder related to or affected by the 5-HT6 receptor in a patient in need thereof which comprises providing to said patient a therapeutically effective amount of a compound of formula I as described in any one of claims 1-8.
10. A method as claimed in claim 9 wherein said disorder is a cognitive disorder, a developmental disorder or a neurodegenerative disorder.
11. A method as claimed in claim 10 wherein said disorder is a cognitive disorder.
12. A method as claimed in claim 10 wherein said disorder is selected from the group consisting of: a learning disorder; attention deficit disorder; Down's syndrome; Fragile X syndrome; and autism.
13. A method as claimed in claim 10 wherein said disorder is stroke or head trauma.
14. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I as described in any one of claims 1-8.
15. A process for the preparation of a compound of fonnula la
(Formula Removed)

wherein
X is O or SOn;
n is 0 or an integer of 1 or 2;
R1 is an aryl or heteroaryl group each group optionally substituted or an optionally
substituted 8- to 13-membered bicyclic or tricyclic ring system having a N atom
at the bridgehead and optionally containing 1, 2 or 3 additional heteroatoms
selected from N, O or S; R2 is H or an alkyl, cycloalkyi or aryl group each group optionally substituted; R3 and R4 are each independently H or an optionally substituted alkyl group; and R5 is H, halogen, NR6R7 or an alkyl, alkoxy, alkenyl, alkynyl or cycloalkyi, group each
group optionally substituted; Re is an alkyl or cycioalkyi group each group optionally substituted; and R7 is H or an alkyl or cycloalkyi group each group optionally substituted which process comprises reacting a compound of formula II
(Formula Removed)
wherein Ri, R2, R3, R4 and R5 are as described for formula I with at least two molar equivalents of an oxidizing agent optionally in the presence of a solvent.
16. The use of a compound of formula I as described in any one of claims 1-8 in the manufacture of a medicament for treating a central nervous system disorder related to or affected by the 5-HT6 receptor.
17. Benzoxazole and benzothiazole derivatives of general compound of formula 1, its composition and application are substantially as herein described with reference to the examples.