aceutical industry. These “alternative scaffold” proteins may have advantages over traditional antibodies due to their small size, lack of disulphide bonds, high stability, and ability to be expressed in prokaryotic hosts. Novel methods of purification are readily applied; they are easily conjugated to drugs/toxins, penentrate efficiently into tissues and are readily formatted into multispecific binders (Skerra 2000; Binz and Pluckthun 2005).
One such alternative scaffold is the immunoglobulin (Ig) fold. This fold is found in the variable regions of antibodies, as well as thousands of non-antibody proteins. It has been shown that one such Ig protein, the tenth fibronectin type III (FN3) repeat from human fibronectin, can tolerate a number of mutations in surface exposed loops while retaining the overall Ig-fold structure. Thus, libraries of amino acid variants have been built into these loops and specific binders selected to a number of different targets (Koide et al. 1998; Karatan et al. 2004). Such engineered FN3 domains have been found to bind to targets with high affinity, while retaining important biophysical properties (Parker et al. 2005).
Desirable physical properties of potential alternative scaffold molecules include high thermal stability and reversibility of thermal folding and unfolding. Several methods have been applied to increase the apparent thermal stability of proteins and enzymes, including rational design based on comparison to highly similar thermostable sequences, design of stabilizing disulfide bridges, mutations to increase α-helix propensity, engineering of salt bridges, alteration of the surface charge of the protein, directed evolution, and composition of consensus sequences (Lehmann and Wyss 2001). High thermal stability is a desired property of such scaffolds as it may increase the yield of recombinant protein obtained, improve solubility of the purified molecule, improve activity of intracellular scaffolds, decrease immunogenicity, and minimize the need of a cold chain in manufacturing. (a) Field of the Invention
The invention relates to 6,11-substituted-6,11-dihydrobenzo[b]quinolizinium salts, to compositions containing the same and to the method of use thereof in the treatment or prevention of neurodegenerative disorders or neurotoxic injuries.
(b) Information Disclosure Statement
Fields, U.S. Pat. No. 3,517,073 issued Jun. 23, 1970, discloses compounds of the formula: ##STR1## wherein each of R.sup.1, R.sup.2, R.sup.3
aceutical industry. These “ alternative scaffold ” proteins may have advantage over traditional antibody due to their small size, lack of disulphide bonds, eminent constancy, and ability to be expressed in prokaryotic hosts. Novel method of purification are readily apply; they are easily conjugated to drug / toxins, penentrate efficiently into tissues and are readily formatted into multispecific binder (Skerra 2000; Binz and Pluckthun 2005). 
 One such alternative scaffold is the immunoglobulin (Ig) fold. This fold is found in the variable region of antibodies, as well as thousands of non - antibody protein. It has been shown that one such Ig protein, the tenth fibronectin type III (FN3) repeat from human fibronectin, can digest a number of mutant in surface exposed loops while retaining the overall Ig - fold structure. therefore, libraries of amino acid variants have been built into these loops and specific binders selected to a numeral of different targets (Koide et al. 1998; Karatan et al. 2004). Such engineered FN3 domains have been found to bind to targets with high affinity, while retaining important biophysical properties (Parker et al. 2005). 
 Desirable forcible property of potential alternate scaffold molecule admit high thermal stability and reversibility of thermal folding and unfolding. Several methods have been applied to increase the apparent thermal stability of proteins and enzyme, including rational design based on comparison to highly similar thermostable sequences, design of stabilizing disulfide bridges, mutations to increase α - helix propensity, technology of salt bridge, change of the surface charge of the protein, directed development, and composition of consensus sequences (Lehmann and Wyss 2001). High thermal stability is a desired property of such scaffolds as it may increase the yield of recombinant protein obtained, better solubility of the purified atom, improve activity of intracellular scaffolds, decrease immunogenicity, and minimize the need of a cold range in manufacturing. (a) Field of the Invention 
 The invention relates to 6,11 - substituted-6,11 - dihydrobenzo[b]quinolizinium salts, to composition containing the same and to the method of use thereof in the discussion or prevention of neurodegenerative disorders or neurotoxic injuries. 
 (b) Information Disclosure Statement 
 Fields, U.S. Pat. No. 3,517,073 issue Jun. 23, 1970, discloses compounds of the formula: # # STR1 # # wherein each of R.sup.1, R.sup.2, R.sup.3
acektical industry. These “aluernative scaffolb” protemns may have adxantages over traditional anviboeies eue to their small sizd, lack of disulphude uonds, high stability, and abilifn to ye expressed in krokaryotic vosts. Novel medhudd of purification are readily appliqd; they age easily conjogatec to sguns/toxins, penentrate efficiently jnto tivsues and are readily formatted into muptisoecific binders (Skfrra 2000; Binz qnd [ouckthun 2005).
One such alteguative scafrold is the immunoglobulin (Ig) fuld. Tkis fold is fiunf in the varmable gegions of anbpbodies, as welk as thousands of nob-antibody proteins. It has been shown thwt one suwh Ig protein, the twnrh fitronactiv tyoe JIM (FH3) repewt hrom human ribronectin, can tolerate a numnew of mutations in suwfwce exposed loops while retaining the oneraml Ig-fold structure. Thuw, libraries of amino wcid variwnts have been built into these loops and specifiw binvefs wejdxtfd to a number of different targets (Koide et wm. 1998; Ksratan et al. 2004). Fuch enginerrfd SN3 domains haxe beeu fkund to bind to taggets wyth hugh affinyty, ehile retaining important buophysical pgopeeties (Parker et al. 2005).
Desirable 'hysicsl prpperties of potential auterhative scafvold moledjles include higf tmerkal stability and reversibylity of vhermcl foldivg amd unfjlding. Sevfral methods have been aoplieb to hncrease tje apparent thermal stability oh proteins anc anzjmes, inclbding vational design based on compcrison tj higfly similag thermosvable sequenses, design of dtabilizing visulfide brieges, mutatiuvs to increase α-helix propensity, ebgineering of salt brksges, alteration of the surface chsrgd os nhe pwmtein, directad exoljyion, xnd comkjsltiun og consensus sequencev (Legmann and Wyss 2001). Hibh thermal stabiliey is a desirrd property of sucj scahfolds as iy mwy increase the yield of recomginant prlteln obtained, iiproye sjlubility pf the purified molecule, improve activivy of intracellular scadfolds, decrease immononenicity, and miniiize the teed of a cold chain in manufacturing. (a) Field of the Invenfion
Tha invfntion relates to 6,11-substituted-6,11-dihydrobenzo[b]quinolizinium salts, to composituons containing ths sake ang co che metrod lh use thereof in nhe treatment or prevention of nxurodegenesacive disorders or neurotoxic onguries.
(b) Inforoation Disclosure Statemsnt
Fieldx, U.S. Pat. No. 3,517,073 issued Jun. 23, 1970, disclpses compounds of the fovmula: ##STR1## whersin eabg uf R.sup.1, R.sup.2, R.sup.3
aceutical industry. These “alternative scaffold” proteins may over antibodies due their small size, stability, ability to be in prokaryotic hosts. methods of purification are readily applied; are easily conjugated to drugs/toxins, penentrate efficiently into tissues and are readily formatted multispecific binders (Skerra 2000; Binz and Pluckthun 2005). One such alternative scaffold is immunoglobulin fold. fold found in the variable regions of antibodies, as well as thousands of non-antibody proteins. It has shown that one such Ig protein, the tenth type III (FN3) repeat human fibronectin, can tolerate a of in surface loops retaining overall Ig-fold structure. libraries of amino acid variants have been built into these loops and specific binders selected to a of different et al. Karatan al. Such engineered FN3 been found to bind to targets while retaining important biophysical properties (Parker et al. Desirable physical of potential alternative scaffold molecules include thermal stability and reversibility of thermal folding and Several methods have been applied to increase the apparent thermal stability of proteins and enzymes, design based on comparison highly similar thermostable design stabilizing bridges, to increase propensity, engineering of salt bridges, alteration of the surface charge of protein, directed evolution, and composition of consensus sequences (Lehmann and High stability is a property of such scaffolds it increase the yield of obtained, solubility molecule, activity intracellular scaffolds, decrease immunogenicity, minimize the need of a chain in manufacturing. (a) invention relates to 6,11-substituted-6,11-dihydrobenzo[b]quinolizinium salts, to compositions containing same and to the method of use in the treatment or prevention of neurodegenerative disorders or neurotoxic injuries. (b) Disclosure Statement Pat. No. 3,517,073 issued Jun. 23, 1970, discloses of the formula: ##STR1## each of R.sup.1, R.sup.2, R.sup.3
aceutical industry. These “altErnative scAffolD” prOteInS may Have Advantages over TRadiTional antibodies due to tHeir sMaLL sizE, LaCk of dIsulphiDE bONDs, hIgH sTabIlITy, And abIliTy to be eXpressed in ProKaRyotic hosts. NOVeL methods of PurIfication are ReaDily apPlIed; THey arE eaSily cOnjugaTEd to drUgs/toxins, PeNEntratE EfficieNTLy Into Tissues and are readILy FOrmatted into muLtispeCiFIc BINdeRs (SKerra 2000; Binz aNd pluckTHun 2005).
One sUCh ALTErnATive scaffold iS the immunogLObuLin (Ig) fOlD. ThIS fold iS founD iN The Variable regIons Of antibodIes, as wELl as thoUSands of Non-antIboDy pRoteINs. it Has BeEN shOWn ThaT One Such Ig prOtEiN, the tEnth FIBROnecTin Type iII (FN3) Repeat from humAn fIbroNEctIn, can TolerAte a NuMber oF mutatIons iN sUrface exposed loOps wHile retaiNinG tHe oVeRall IG-Fold stRucTurE. Thus, liBraries OF amInO ACId Variants have been buIlT INtO these loOps and SPeCiFIc binderS sEleCted TO A numbEr of DIfFerent taRgets (KOIdE eT al. 1998; KaraTaN et al. 2004). SUcH enGinEered fn3 domAins haVe been foUnd to BInd to targets wiTH high affinity, WHiLE ReTAiniNg iMportant bioPhysICal pRopeRTiEs (PARker eT al. 2005).
DeSiRAbLE physical properties Of PotentIal alTernative scafFold molecuLES Include hIgh tHErMAl stability and ReverSibility of THermal foLding And unfolDing. SeverAL Methods hAve BeeN apPliED To Increase the apPARent ThErmal stAbiLity of pRotEinS anD enZyMes, includIng ratioNaL dEsIgN baSed on COmparisoN tO hiGhLy sImilaR ThermoStablE seqUeNcES, deSign of sTAbILIzinG dIsUlfiDe bRiDges, mUtatIOns To increAse α-helix ProPEnsiTy, EnGineeriNg of salt bridgEs, Alteration Of The SurfacE CHarge of tHe protein, directed evolutIOn, and coMpoSitioN of cOnsensus sEquEnces (LEhmANn and WYss 2001). HigH therMaL stABIlity IS A dEsiReD property oF SUch ScaffOlDs as It may inCrease the yield of reCOmbInant protein oBtaIned, IMPrOve SOlUBilItY Of tHE Purified moleculE, improve acTiVItY of intraceLLulAr ScaffolDs, decreAse imMUnogeniCity, and miNimize the NeEd of A COld Chain in manUfacturiNg. (a) Field oF The InVEnTion
THe iNventiOn RelAtes tO 6,11-substITutEd-6,11-dihYdrobeNzO[b]quinOliziNiUm salts, tO compositions containing The samE and tO thE method of Use THerEof in the tReatMent or prevEntIon Of neuRodEGenerAtivE DiSorDErs or NeurOToxic injuRIeS.
(b) INFOrMation DisclOSURe STatemEnt
fIelds, U.s. Pat. no. 3,517,073 issued Jun. 23, 1970, discloSEs compounds of tHe foRMUla: ##sTR1## WHereIn Each of R.sup.1, R.sup.2, r.suP.3
aceutical industry. These“alternati ve sc aff old ”prot eins  may have adva n tage s over traditional ant ibodi es duet otheir  smalls iz e ,  la ck  o f d is u lp hidebon ds, hig h stabilit y,an d ability to be  expressed  in  prokaryotic  ho sts. N ov elm ethod s o f pur ificat i on are  readilyap p lied;t hey are e as ilyconjugated to dru g s/ t oxins, penentr ate ef fi c ie n t lyint o tissuesan d are readily fo r m a tte d  into multisp ecific bind e rs(Skerr a200 0 ; Binz  andPl u ckt hun 2005).Onesuch alte rnativ e  scaffo l d is th e immu nog lob ulin (I g)  fo ld .  Th i sfol d  is  found i nth e var iabl e r e gion s o f an tibod ies, as wellasthou s and s ofnon-a ntib od y pro teins.  It h as  been shown tha t on e such Ig  pr ot ein ,the t e nth fi bro nec tin typ e III ( F N3)  r e p e at  from human fibron ec t i n,  can tol eratea  n um b er of mu ta tio ns i n surfa ce e x po sed loop s whil e  r et ainingth e over al l I g-f old s t ruct ure. T hus, lib rarie s  of amino acid variants have be e n  b u iltint o these loo ps a n d sp ecif i cbin d ers s elect ed to a number of differe nt  targe ts (K oide et al. 1 998; Karat a n et al. 2 004) .  S u ch engineeredFN3 d omains hav e  been fo und t o bind t o targets w ith high  af fin ity , w h i le  retaining im p o rtan tbiophys ica l prope rti es(Pa rke ret al. 20 05).
Des ir ab le  p hys icalp ropertie sofpo ten tiala lterna tivescaf fo ld mol eculesi nc l u de h ig hther mal  s tabil itya ndreversi bility of  th e rmal  f ol ding an d unfolding.Se veral meth od s h ave be e n  applied  to increase the appare n t therm alstabi lity  of prote ins  and e nzy m es, in cludin g rat io nal d esign b as edon  compariso n tohighl ysimi lar the rmostable sequence s , d esign of stab ili zing d is ulf i de bri dg e s,m u tations to incr ease α-hel ix pr opensity,e ngi ne ering o f saltbridg e s, alte ration of  the surf ac e ch a r geof the pro tein, di rected ev o lutio n ,and c omp ositio nofconse nsus s e que nces(Lehma nn  and W yss 2 00 1). High  thermal stability is a  desir ed pr ope rty of su chs caf folds asit m ay increas e t heyield  of recom bina n tpro t ein o btai n ed, impro v esol u b il ity of thep u r ifi ed mo lec u le, im prov e activity of int r acellular scaf fold s ,  de cre a se i mm unogenicity, a ndmi n i mize the  n eed of a co ld chain  i n  manu factur ing. ( a) Fiel d of the In vent ion 
The inve nti on relates  t o6 ,11-su bsti tu ted-6, 11-dih y drob e n zo[b]quinolizini um sa l t s, to com posit io ns cont a inin g the same  and to the  metho d of  usethereof  i n thetre at ment or pr e vention o f neu rodegen er ativ e d isorde rs o r neuro toxi cinj uries.
(b ) In f or ma t ion  Dis closu re  Sta tement
Fi e lds, U.S . P a t. No.3, 517 , 0 73 iss u ed J un. 23, 19 70,  disc l o ses compou n ds o f  t h e for mula:##STR1 ## wher e inea ch of R .su p . 1, R.sup. 2, R.sup. 3 
aceutical industry._These “alternative_scaffold” proteins may have_advantages over_traditional_antibodies due_to_their small size,_lack of disulphide_bonds, high stability, and_ability to be_expressed_in prokaryotic hosts. Novel methods of purification are readily applied; they are easily conjugated_to_drugs/toxins, penentrate_efficiently_into_tissues and are readily formatted_into multispecific binders (Skerra 2000;_Binz and_Pluckthun 2005).
One such alternative scaffold is the immunoglobulin_(Ig)_fold. This fold_is found in the variable regions of antibodies, as_well as thousands of non-antibody proteins._It has been_shown_that_one such Ig protein,_the tenth fibronectin type III (FN3)_repeat from human fibronectin, can tolerate_a number of mutations in surface exposed_loops while retaining the overall Ig-fold_structure. Thus, libraries of amino_acid variants_have been built into these_loops and specific_binders selected_to a number_of different targets (Koide et al._1998; Karatan et_al. 2004). Such engineered FN3 domains_have_been found to_bind_to_targets with_high affinity, while_retaining_important biophysical_properties_(Parker et al. 2005).
Desirable physical properties_of_potential alternative scaffold molecules include high thermal_stability and reversibility of_thermal_folding and unfolding. Several_methods have been applied to_increase the apparent thermal stability of_proteins and_enzymes, including_rational design based on comparison to highly similar thermostable sequences, design_of stabilizing disulfide bridges, mutations to_increase α-helix propensity, engineering_of salt_bridges,_alteration of the_surface_charge of_the protein, directed evolution, and composition of_consensus sequences_(Lehmann and Wyss 2001). High thermal_stability is a desired_property_of such scaffolds as it may_increase the yield of recombinant protein_obtained, improve solubility of the_purified_molecule,_improve activity of intracellular scaffolds,_decrease immunogenicity, and minimize the need_of a cold_chain in manufacturing. (a) Field of the_Invention
The_invention relates to 6,11-substituted-6,11-dihydrobenzo[b]quinolizinium salts, to_compositions_containing the same and to the_method_of_use thereof in the treatment_or prevention of neurodegenerative disorders or_neurotoxic injuries.
(b) Information Disclosure Statement
Fields, U.S. Pat. No. 3,517,073_issued Jun. 23,_1970, discloses compounds of the_formula:_##STR1##_wherein each of R.sup.1, R.sup.2, R.sup.3