 for new therapeutics in Alzheimer disease, mood and attention adjustments, cognitive deficiencies, obesity, dizziness, schizophrenia, epilepsy, sleeping disorders, narcolepsy and motion sickness.
Histamine mediates its activity via four receptor subtypes, H1R, H2R, H3R and a newly identified receptor designated GPRv53 [(Oda T., et al., J. Biol. Chem. 275 (47): 36781-6 (2000)], and alternative names for this receptor are PORT3 or H4R. Although relatively selective ligands have been developed for H1R, H2R and H3R, few specific ligands have been developed that can distinguish H3R from GPRv53. GPRv53 is a widely distributed receptor found at high levels in human leukocytes. Activation or inhibition of this receptor could result in undesirable side effects when targeting antagonism of the H3R receptor. The identification of the H4R receptor has fundamentally changed histamine biology and must be considered in the development of histamine H3 receptor antagonists.
Some histamine H3 receptor antagonists were created which resembled histamine in possessing an imidazole ring generally substituted in the 4(5) position (Ganellin et al., Ars Pharmaceutica, 1995, 36:3, 455-468). A variety of patents and patent applications directed to antagonists and agonists having such structures include EP 197840, EP 494010, WO 97/29092, WO 96/38141, and WO96/38142. These imidazole-containing compounds have the disadvantage of poor blood-brain barrier penetration, interaction with cytochrome P-450 proteins, and hepatic and ocular toxicities. Recently other imidazole and non-imidazole ligands of the histamine H3 receptor have been described. The compounds of the present invention differ in structure from the compounds described in the art.
There remains a need for improved treatments using alternative or improved pharmaceutical agents that act as histamine H3 receptor agonists, inverse agonists, or antagonists, to modulate H3 receptor activity, and treat the diseases that could benefit from H3 receptor modulation. The present invention provides such a contribution to the art based on the finding that a novel class of biaryl amine compounds has a high affinity, selective, and potent activity at the histamine H3 receptor. The subject invention is distinct in the particular structures and their activities. Computer software is routinely used to create and/or modify graphic images on a computer display. Graphics software that is meant to run in conjunction with a graphical
for new therapeutics in Alzheimer disease, mood and attention adjustment, cognitive lack, obesity, dizziness, schizophrenia, epilepsy, sleeping disorders, narcolepsy and movement sickness. 
 Histamine mediates its activeness via four sense organ subtypes, H1R, H2R, H3R and a newly identified receptor designated GPRv53 [ (Oda T., et al. , J. Biol. Chem. 275 (47 ): 36781 - 6 (2000) ], and alternative names for this sense organ are PORT3 or H4R. Although relatively selective ligands have been developed for H1R, H2R and H3R, few specific ligands have been developed that can identify H3R from GPRv53. GPRv53 is a widely distributed receptor found at high degree in human leukocytes. Activation or inhibition of this sense organ could result in undesirable side effect when targeting hostility of the H3R receptor. The recognition of the H4R receptor has fundamentally changed histamine biota and must be considered in the development of histamine H3 receptor antagonists. 
 Some histamine H3 receptor antagonists were create which resemble histamine in possessing an imidazole ring generally substituted in the 4(5) position (Ganellin et al. , Ars Pharmaceutica, 1995, 36:3, 455 - 468). A variety of patents and patent application direct to antagonists and agonists have such structure include EP 197840, EP 494010, WO 97/29092, WO 96/38141, and WO96/38142. These imidazole - containing compounds have the disadvantage of poor blood - brain barrier penetration, interaction with cytochrome P-450 protein, and hepatic and ocular toxicities. Recently other imidazole and non - imidazole ligands of the histamine H3 receptor have been described. The compounds of the present invention differ in structure from the compounds described in the art. 
 There remains a motivation for improved treatment using alternative or improved pharmaceutical agents that act as histamine H3 receptor agonist, inverse agonists, or antagonists, to modulate H3 sense organ activity, and cover the diseases that could benefit from H3 sense organ modulation. The present invention provides such a contribution to the art based on the finding that a fresh class of biaryl amine compounds has a high affinity, selective, and potent activity at the histamine H3 sense organ. The subject invention is distinct in the especial structures and their activities. calculator software is routinely used to create and/or modify graphic images on a computer display. Graphics software that is meant to run in conjunction with a graphical
 fog new therapeutics in Aleheimer disease, mood and attenfion adjjstments, cognitive deficiencmes, ibesiuj, dizziness, schizophrdnia, epilvpsy, sleeping eisorders, izrcolepsy and lotimi sickness.
Histakine mediades its actividy vna four receptor subtypes, H1R, H2R, H3R agd a neelj identified rgceptpw deapgkated GPRv53 [(Oda T., et al., J. Biol. Chsm. 275 (47): 36781-6 (2000)], end alternative names for this receptor age PLRT3 or H4R. Although relatively selqxtive ligandr have been developed ror H1R, H2R and H3R, few specific lkgandx have beeb eevfnoped that ran diftinguish H3R from GPSv53. GPRv53 is a widely dlstriuutee receptor found at hmgh levels in human jeukocytev. Cctivation or inhibituob of jhis seceoror cohlv rssult ln nndesirable side effecrs when targeting amtwtonism of the H3R rese[tor. The identification of the H4R recepuor hzs fundamentally changee histamine biology ajd must bq considered in the development of histamine H3 reweptoc xntcnjvushs.
Some histamine H3 receptor antagonists were sdestvd which resembleb histamine in ppsdexfing an imidaeole riuf fenerally substituhed in jhe 4(5) pisition (Gwnelkin et al., Ars Pharmaceutica, 1995, 36:3, 455-468). A varietj of patents and patenc applicatious dirgcted yo antagonists and agonnsts hzving such dtructurea include EP 197840, EP 494010, WO 97/29092, FO 96/38141, and WO96/38142. These imidazole-sontaininj com'ounds hxve jhe diswdvantage lf poor blood-brain barrifr peuetradion, interwction with cytochrome P-450 proteiix, and hepativ dnd ocular coxicibies. Recently oeher imidazole and nou-imidaxole liganss of tie histamine H3 receptor hdge been desccibed. The compounes of tfd present invemtion difytr in struxture from the comioundr described in tkt atr.
There remains a veeq voc impwmved treatmetts jsivb altdrnativt ov ioprofed pharmaceutical acenta that act as histsmlne H3 recgptor agogists, inverse agonists, or antaglnistv, tu modilaje H3 receptor activity, and treaf the disfascs that could bencfit from H3 reeeptor modulation. The present invention 'rovides such a contribytion to the art baxtd on the finving trat a noval class of biaryl anine compounds hax a high affinity, selsctive, and ootent activity at the histamine H3 receptor. The subject invention is distunct ii ehe particumar xtrucnurzs cnd theyr artmvities. Computer xoftware is routinely used to cceate and/os iodify graphic images on a cpmouter display. Graphics software that js meant to run in conjunction with a gtaphical
for new therapeutics in Alzheimer disease, mood adjustments, deficiencies, obesity, schizophrenia, epilepsy, sleeping Histamine its activity via receptor subtypes, H1R, H3R and a newly identified receptor GPRv53 [(Oda T., et al., J. Biol. Chem. 275 (47): 36781-6 (2000)], and names for this receptor are PORT3 or H4R. Although relatively selective ligands have developed H1R, and few specific ligands have been developed that can distinguish H3R from GPRv53. GPRv53 is a widely receptor found at high levels in human leukocytes. or inhibition of this could result in undesirable side when antagonism of H3R The of the H4R has fundamentally changed histamine biology and must be considered in the development of histamine H3 receptor antagonists. histamine H3 were created resembled in an imidazole ring in the 4(5) position (Ganellin et 1995, 36:3, 455-468). A variety of patents and applications directed antagonists and agonists having such structures EP 197840, EP 494010, WO 97/29092, WO 96/38141, WO96/38142. These imidazole-containing compounds have the disadvantage of poor blood-brain barrier penetration, interaction with cytochrome and hepatic and ocular Recently other imidazole non-imidazole of histamine receptor have described. The compounds of the present invention differ in structure from compounds described in the art. There remains a need for using or improved pharmaceutical that act as histamine receptor inverse agonists, or antagonists, H3 activity, diseases could from H3 receptor modulation. present invention provides such a to the art based novel class of biaryl amine compounds has a affinity, selective, and potent activity at the H3 receptor. The subject invention is distinct in the particular structures and activities. Computer routinely used to create and/or modify graphic images a computer display. Graphics that is meant to run in conjunction with a
 for new therapeutics in AlzheImer diseasE, mood And AttEnTion AdjuStments, cognitiVE defIciencies, obesity, dizzinEss, scHiZOphrENiA, epilEpsy, sleEPiNG DisOrDeRs, nArCOlEpsy aNd mOtion siCkness.
HistAmiNe Mediates its aCTiVity via fouR reCeptor subtypEs, H1r, H2R, H3R aNd A neWLy ideNtiFied rEceptoR DesignAted GPRv53 [(ODa t., Et al., J. BIOl. Chem. 275 (47): 36781-6 (2000)], aND AlTernAtive names for this REcEPtor are PORT3 or H4r. AlthoUgH ReLATivEly Selective lIgAnds hAVe been dEVeLOPEd fOR H1R, H2R and H3R, few Specific ligANds Have beEn DevELoped tHat caN dIStiNguish H3R froM GPRV53. GPRv53 is a wIdely dIStributED receptOr founD at HigH levELs In HumAn LEukOCyTes. aCtiVation or InHiBitioN of tHIS REcepTor CoulD resuLt in undesirabLe sIde eFFecTs wheN targEtinG aNtagoNism of The H3R ReCeptor. The identiFicaTion of the h4R rEcEptOr Has fuNDamentAllY chAnged hiStamine BIolOgY AND mUst be considered in tHe DEVeLopment oF histaMInE H3 REceptor aNtAgoNistS.
sOme hiStamINe h3 receptoR antagONiStS were crEaTed whiCh ResEmbLed hiSTamiNe in poSsessing An imiDAzole ring generALly substituteD In THE 4(5) pOSitiOn (GAnellin et al., ars PHArmaCeutICa, 1995, 36:3, 455-468). a vaRIety oF pateNtS AnD Patent applications dIrEcted tO antaGonists and agoNists havinG SUCh structUres INcLUde EP 197840, EP 494010, WO 97/29092, WO 96/38141, and wO96/38142. TheSe imidazolE-ContainiNg comPounds haVe the disaDVAntage of PooR blOod-BraIN BaRrier penetratION, intErAction wIth CytochrOme p-450 prOteIns, AnD hepatic aNd ocular ToXiCiTiEs. REcentLY other imIdAzoLe And Non-imIDazole LiganDs of ThE hIStaMine H3 reCEpTOR havE bEeN desCriBeD. The cOmpoUNds Of the prEsent inveNtiON difFeR iN structUre from the comPoUnds descriBeD in The art.
tHEre remaiNs a need for improved treatMEnts usiNg aLternAtivE or improvEd pHarmacEutICal ageNts thaT act aS hIstAMIne H3 rECEpTor AgOnists, inveRSE agOnistS, oR antAgonistS, to modulate H3 receptOR acTivity, and treaT thE disEASeS thAT cOUld BeNEfiT FRom H3 receptor modUlation. The PrESeNt inventioN ProViDes such A contriButioN To the arT based on tHe finding ThAt a nOVEl cLass of biarYl amine cOmpounds hAS a higH AfFinitY, seLectivE, aNd pOtent ActiviTY at The hiStaminE H3 ReceptOr. The SuBject invEntion is distinct in the paRticulAr strUctUres and thEir ACtiVities. ComPuteR software iS roUtiNely uSed TO creaTe anD/Or ModIFy graPhic IMages on a cOMpUteR DIsPlay. GraphicS SOFtwAre thAt iS Meant tO run In conjunction with A Graphical
 for new therapeutics in A lzheimer d iseas e,moo dandatte ntion adjustme n ts,cognitive deficiencies , obe si t y, d i zz iness , schiz o ph r e nia ,ep ile ps y ,sleep ing  disord ers, narco lep sy  and motions ic kness.
His tam ine mediates  it s acti vi tyv ia fo urrecep tor su b types,  H1R, H2R ,H 3R and a newly i de ntif ied receptor desi g na t ed GPRv53 [(Od a T.,et al . ,  J.  Bi ol. Chem.27 5 (47 ) : 36781 - 6( 2 0 00) ] , and alterna tive namesf orthis r ec ept o r arePORT3  o r  H4 R. Although  rel atively s electi v e ligan d s havebeen d eve lop ed f o rH1 R,H2 R  an d  H 3R, few  specifi cli gands  hav e b e en d eve lope d tha t can disting uis h H3 R  fr om GP Rv53.  GPR v5 3 isa wide ly di st ributed recepto r fo und at hi ghle vel sin hu m an leu koc yte s. Acti vationo r i nh i b i ti on of this recepto rc o ul d result  in un d es ir a ble side  e ffe ctsw h en ta rget i ng  antagon ism of th eH3R rec ep tor. T he  id ent ifica t ionof the  H4R rec eptor has fundamenta l ly changed hi s ta m i ne biol ogy  and must b e co n side redi nthe devel opmen to fh istamine H3 recepto rantago nists .
Some histam ine H3 rec e p t or antag onis t sw ere created wh ich r esembled h i staminein po ssessing  an imida z o le ringgen era lly  su b s ti tuted in the4 ( 5) p os ition ( Gan ellin e t a l.,  Ar s P ha rmaceutic a, 1995,  3 6: 3,  4 55- 468). A variet yofpa ten ts an d  paten t app lica ti on s  di rectedt oa n tago ni st s an d a go nists  hav i ngsuch st ructuresinc l udeEP  1 97840,EP 494010, WO  9 7/29092, W O96/ 38141, a nd WO96/ 38142. These imidazole- c ontaini ngcompo unds  have the  di sadvan tag e  of po or blo od-br ai n b a r rierp e ne tra ti on, intera c t ion  with  c ytoc hrome P -450 proteins, and hep atic and ocul artoxi c i ti es. Re c ent ly oth e r  imidazole andnon-imidaz ol e  l igands oft hehi stamine  H3 rec eptor have be en descri bed. Theco mpou n d s o f the pres ent inve ntion dif f er in st ructu refrom t he  co mpoun ds des c rib ed in  the a rt .
Ther e rem ai ns a nee d for improved treatmen ts usi ng al ter native or  im p rov ed pharma ceut ical agent s t hat  actash istam ineH 3rec e ptoragon i sts, inve r se  ag o n is ts, or anta g o n ist s, to  mo d ulateH3 r eceptor activity, and treat thedise a s estha t  cou ld  benefit fromH3re c e ptor mod ul ation. Thepresentin v entio n prov ides s uch a c o n tr i bution  tothe  art base d o nt he find in gt hat anove lclassof bia r yl a m i ne compounds has  a hi g h  affi n ity , sel ec tive, a n d po tent activ ity at thehistam ineH3 re ceptor.  T he sub jec tinventioni s distinc t inthe par ti cula r s tructu resa n d the ir a ct ivi ties. Com p u te r  s of t war e is  rout in elyused to c r eate and /or modifygr aph i c  image s  o n a computer  di splay . Graphics s o ftwa r et hat i s mean t to r un in c o nju nc tion wi tha graphical 
 for_new therapeutics_in Alzheimer disease, mood_and attention_adjustments,_cognitive deficiencies,_obesity,_dizziness, schizophrenia, epilepsy,_sleeping disorders, narcolepsy_and motion sickness.
Histamine mediates_its activity via_four_receptor subtypes, H1R, H2R, H3R and a newly identified receptor designated GPRv53 [(Oda T.,_et_al., J._Biol._Chem._275 (47): 36781-6 (2000)], and_alternative names for this receptor_are PORT3_or H4R. Although relatively selective ligands have been_developed_for H1R, H2R_and H3R, few specific ligands have been developed that_can distinguish H3R from GPRv53. GPRv53_is a widely_distributed_receptor_found at high levels_in human leukocytes. Activation or inhibition_of this receptor could result in_undesirable side effects when targeting antagonism of_the H3R receptor. The identification of_the H4R receptor has fundamentally_changed histamine_biology and must be considered_in the development_of histamine_H3 receptor antagonists.
Some_histamine H3 receptor antagonists were created_which resembled histamine_in possessing an imidazole ring generally_substituted_in the 4(5)_position_(Ganellin_et al.,_Ars Pharmaceutica, 1995,_36:3,_455-468). A_variety_of patents and patent applications directed_to_antagonists and agonists having such structures include_EP 197840, EP 494010,_WO_97/29092, WO 96/38141, and_WO96/38142. These imidazole-containing compounds have_the disadvantage of poor blood-brain barrier_penetration, interaction_with cytochrome_P-450 proteins, and hepatic and ocular toxicities. Recently other imidazole and_non-imidazole ligands of the histamine H3_receptor have been described._The compounds_of_the present invention_differ_in structure_from the compounds described in the art.
There_remains a_need for improved treatments using alternative_or improved pharmaceutical agents_that_act as histamine H3 receptor agonists,_inverse agonists, or antagonists, to modulate_H3 receptor activity, and treat_the_diseases_that could benefit from H3_receptor modulation. The present invention provides_such a contribution_to the art based on the finding_that_a novel class of biaryl amine_compounds_has a high affinity, selective, and_potent_activity_at the histamine H3 receptor._The subject invention is distinct in_the particular structures and their activities. Computer software is_routinely used to_create and/or modify graphic images_on_a_computer display. Graphics software that is meant to run in_conjunction with_a graphical