CA2340702A1 - Pyrrolidine derivatives for vision and memory disorders - Google Patents

Abstract

This invention relates to pharmaceutical compositions and methods for treating a vision disorder, improving vision, treating memory impairment, or enhancing memory performance using pyrrolidine derivatives.

Description

PYRROLIDINE DERIVATIVES FOR VISION AND MEMORY DISOF~ERS
BACKGROUND OF THE INVENTION
1. Field of Invention This ,~nvent.ien relates to pharmaceutical compositions and methods f:~r tl:~eating v'_sion loss, preventing vision degeneration, and promoting ~; ision regeneration (":~ecpsis" ;
using l~~w molecu:l_ar weight, ;:mall. molecule derivatives.

2. Descrix~tion of Related Art The visu~:~7. system is composed of the eyes, ocular adnexa and the visual pathways. Dysfunction of t:he visua l system may lead to perrr,~~ne~t or temp:~rar~y~ visual impairment, i . e. a deviatic;n from n:~rma.1 i_n one or more runct.ions of the eve.
Visual impairment manifests itself= in various wa~.~s and includes a ~:rc;ad range ~;f visual. dysfunctions and disturbances. 4~'ii=;~out limi~aticn, these dysfunct..ions and disturbances include partial or total loss of vi~sio:o, the need for correction of visual. acuity for objects near and far, loss of visual field, in~.paired ocular motility without diplopia (dcubl.~~ ~~rision) , i_mpaired or_ skewed color perception, l~mir.ed adaptation to light and dark, diminished accommo<~atior,_, rr,E-tan~.orphopsic distortion, impaired bivnocular vision, paresi:~ of ~~ccommodatioru, i.ridoplegia, entropion, ectropion, epiprw,ora, Lagoph~.~halmo, and scarrin~a. See Physicians' Gesk Reference (PDR) f-or Ophthalmology, 16th Edition, 6:47 ~;1a8~). The visual system may be adversely affected by ~,~arious ephtha:LmclogicJ disorders, diseases, injuries, and e:onupl=.c:ation~, including, wit=bout limitation, genetic d;:.sor,_ier~~; [non-genetic disorders; ] disorders associated wvto u:~ing or degenerative diseases; disorders correlat=ing t,~ ~;hysical injury to :he eye, head, or ether parts oj= the :~c:d~_, r~»su'yting from external forces; disorders resultin~~ l:rcJrn ~::,~~:~ircv:Zmental fac:Z~or-s; disorders r:-~sultina SCJBSTI'TUTE SrIEET (RULE 26) WO 00/09124 P~~T/1IS99/18233 from a broad ran~_~e o:C diseases; and combinations c>f ,any of the above.
The: visual sy:~t;em is <; ~~cmplex system com.oot.ed of numerous components. Visua'~ impasrment can involve the entire visual sy~>tem, any one component, or any combination of components, dept=nding upon the precise nature c>f the circumstances. The eye is composed of a lens, which is suspendE:d in the zonules of Zinn and is focused by the ciliary body. Thf= ci:liary body ai.so secretes aqueous :-rumor, which fills the ~~oster.iom chamber, passes through the pupil into the anterior chamber, then drains primarily vi.a the canal of Schlemrn. 'Ihe iris regulates the quantity of sight entering the eyEe by ad;iust~ng the size of its central opening, the pupil. A visual. ~mac~e is f=ocused onto the retina, the fovea c:entralibeing the retinal area of sharpest, visual acu_Lty. The ~:rnjunctiva is the mucus membrane which l i_ne_~ the e~,~e:.~ ids an<~ the eyeball, anc~ ends abruptl.~Y~ at the 1 imbus corn j unct i aae, the edge of the conjunctiva overlapp inch time c; c;rnea. The cornea is the ~Jlear, transparent antei:ior p:>rtion ~::f the ::fibrous coat of the eye;
it is important __n ~~_ght refia.ct,~on and is covered with an epithelium that: differs n many respects from the conjunctival epithelium.
The re~~ina i..s t:~~e i n:~ermc~st, light sensitive portion of the eye, containi°ig t:wo types :~.f photoreceptors, cones, which are responsible f~:~r color ~r s;~on in bvrighter light, and rods, which are essenr_i<~l for vision i_n dim light but do not perceive colors. After light ,gasses through the cornea, lens system, and the v i.treous rumor , i.t enters the retina from the inside; that i>, it. passes t i:r ough the ganglion cel~_s and nerve fibers, the inner anci gayer ulexiform .Layers, the inner and outer nuclear Layer.-= , ~~nd t:_~w ~ nterr_al and exr_ernal limiting membranes i~efore it finally reaches the layer of photoreceptors located near t:'o:e outside of the retina,, just inside the outermos:: w~_gmen- :~ithel i_~.zm layer. The cell s of SU13STITI1TE SI-IEET (RULE 26) the pigrr,ent epithelium layer uct ~:s an anatomical barrier to liquids and substances located outs__cle of the eye, forming the "blood-reti;oa" barrier, and orovi de nourishment, oxygen, a source of functionally useful ~~ubstances like ;Titamin A, and phagocy-~osis ci= decomposition produ.ts to photoreceptor cells . 'There is no anatomical cone=~ct.ion between the p=_gment epithelium and thra photoreceptor layer, permitting separation of the layers ire some patholc,~ical situations.
When rods on cones are excited by light, signals are transmitted througt: successive neurons in the retina itself, into the optic :~e.r~~e fibers, <~nd ~.~:l.timateiy to the cerebral cortex . F3otr~ rods; and cones ec:ntain rnolec:ules that decompose on exposure to light and, in the process, excite the nerve fibers leading from the eye. 'Che molecule in rods is rhodopsin. The three light-sensitive molecules in cones, collectively ca~.lc.~d .i.odopsin, :lave compositions only slightly different from th~:t of rhodopsin and are maximally excit=ed by red, blue, or g:r~~er. light, re:;pectivc~ly.
Neiti~er rc:~d:ncr cones generte action potentials.
Rather, the l.i.gr~t:-induced membrane hyperpo:lariz:ation generated in th~.~ outer, photc:sensi.t;~ve segment of a rod or cone cel:1 i s tr:~nsmi.tted from tre cover segment throuch the inner segment to the synaptic body 'oy direct condu~~tion of the electrical ~~~o_Lt:agE: i_tses_f, a process called electrotonic conduction. At. i=.he synaptic body, the membrane potential controls the re1_e<:~se c;f an unknoc.m transmitter molecule. In low light, rod and cone cell me:r!:nrar~es are depolarized and the rate of transmitter relea:>e i:~ g:~eatest. Light-induced hyperpolarization causes a marF_ed e,~rease in the release of transmitter mo,~c~~c.~ 1 es .
The ~ransmi~t=ers releasec-i by roe: and cone cells induce signals in the bipolar nauron:~ ,~:va rs:~rizor.tal cells. The signals in bor_h '~.'rese _~:LLs are also transmitted by electrotonic cor,:da~_t ion a::d nrvt .~.y~ "~tion potential .
SUBSTITUTE SHEhT (RLfLE 26) 4 PnT/1JS99/18233 The rod bipolar neurons connect with as many as i~0 rod cells, while the c:~wa_ f and di ft':use bid>ol ar ce:lls connect. with one cr several cone cells. t?, depolarizing bipolar cell is stimulated when its connecting rods or cones are exposed to light . The re_l e<.lse of transmitter mol ecul_es inhibits the depolarizing bipolar cell. Therefore, in the dark, when the rods and cones Urc: :~~ creti.ng large cru,antities of transmitter molecules, the clef:polarizing bipolar cells are inhibited. In the light, t:he de:grease in release of transmitter molecules from the rods and ~~c>nes reduce:, the inhibition of the bipolar cell, allowing it too become excited. Tn this manner, both positive and negaltive signal~~ ~~an be transmitted through different bipolar c~s.lls from: the Nods and cones to the amacrine and ganglion cells.
As their n,~me suggest;_, horizontal cells project horizont,~lly in the retina, where they may synapse with rods, cones, other hor~~_zont.al cells, er a combination of cells types. The :Euncticn ~f hot izor:t:al ce:1 l s is unclear, although Borne mechanism in the convergence of photoreceptor signaling has been post:ulat~~c:.
All t=ypes of bipolar cells connect with ganglion cells, which are of twc: primary t;~pes. A-type gangiicn cells predominately conne:ct with rod bipolar cel~_s, while B-type ganglion cells precaominately connect with dwarf and diffuse bipolar cells. I:t appears that A-type ganglion cells are sensitive to contrast, light intensity, and perception of movement, while B--type ganglion cells appear more concerned with color vision and visual acuity.
Lik~_ horizont=al cells, trie Amacrine cells horizontally synapse ~.~ith several to man~;~ other cells, in this case bipolar cells, gang=lion cells, and ot~uer Nmacrsne cells. The function of Funacr_ne cells is also urlciear.
The axons of ganglion cell s c~~rr~; signals into the nerve f fiber ' a'.~er cf t_h~~ f~ye, where ':=he <_..n :~ 7 ~~onverge into f i bets J w::iCrl f'.lrT filer c~c%i_'JerGe at t~lC'_ ? ~T lc C~' X Sc, lvnE:re I:rle'V eXl ~ trle SLJI3ST1T'UTE SHEET (RULE 2G) WO 00/09124 P~CT/US99/18233 G, eye as the opr_ic nerve. The ganglion cells transmit their signals througr_ ;_:he optic: .~:e::-~e fibF~rs to the brain in the form of actic;n potentials. These cells, even when unstimu7_ated, tran:_mit= continuous nerve impulses at an average, baseli.nEe ra~=a of ab::~ut '> per. second. The Visual signal i_s superimposed onto t=his baseline 1_evel of ga:~glion cell stimulation. It can be either an excitatory signal, with the numbeo of impulses increasing above the baseline rate, or an inh:i_bitory signal, with the number of nerve impulse~> decreasing below the b<~seline rate.
As part ofthe central nervous system, the eye is in some ways an c:x~~en:~_~on cf fhe brain; as such, it has a limited capacit~~~ for regeneration. This l.im:ited regeneration capacit~~ furttv:er_ c:omplicatc~s the challenging task of improving vision, resolving dysfunction of the visual system, and/or treating or preventing ~pt:thalmologic disorders. Many disorders of the ~~ye, such as ret.ina7_ photic~ injury, retinal ischemi~i-induced eye in',ury, age-related macular degeneration, free radical-induced eye diseases, a~: well as numerous other ~,~isorders, ave considered to be en-irely untreatable. C_~t:hfer c~phthalmo_cg:ic disorders, e.g., disorders causing permanent ~ ~sua1 impa:~irment, are corrected only by the use of <_>pht:ha~ lm:ic device~~ and/or surgery, with. varying degrees of sscc:e~ss.
The irrmur.o~~up~:~ressant drugs FK506, rapamyc:in, and cyclosporin are well )~:nowr~ as potent T-cell sp~=cific immunosuppressant:s, and are effective against autoi.mm~~nity, transp=~ar:t or :~raf' rejection, inflammation, allergic responses, other autoimmune o., immune-mediated diseases, and infectic,u~~ ~i sea_ e:~ . rt has l:;een disclosed tha t apr;l : ~~ation of Cyclosporin, FK--506, Rapemycin, Buspirone, Spiperone, and/or rhea :~ cie:v~v~it:ives arF~ ef_fec:tive in treating some ophthalrnouogic d~.sorders c:f these types. Several ophthalr-u_;locic di: orders ~~r -risicn ~~robl_em;> are :mown to be associa 'F>d witr: a~.it.oimmu:~.e and immunologicall ;%-me~~i ated SUBSTITUTE SHEET (RULE 2G) activities; hence'', immunomodu latory a:ompeunds are expec:ted to demonstrate efi_icac:y for t:reatinq those types of ophthalmologic d:isor_ders or ~~vsicn preblem:~.
The effects of FK506, R_~.pamyc;i:n, and related agents in the treatment of ophthalmolcgi.c diseases are disclosed in several U.S. patents (Goulet. et al., U.S. Paten.t No.

5, 532, 248; Mocr::i.~uk_i_ et al. , ':J. S. Patent No. 5, 514, 686; Luly et al., U.S. Patent No. 5,457,111; Russo et al., U.S. Patent No. 5, 4~~1, 937; h:u:Li<.arni, U. S. Patent No. 5, 387, 589; Asakura et al., U.S. Patent: No. 5,368,E365; Goulet et. al., U.S. Patent No. 5, 258, 389; A:_-mi:~t:ead et a ~-. , U. S. Patent No. 5,, 192, 773;
Goulet et al. , C). ~. fatent_ Jo. ,, 7_89, 042; and Fehr, U. S.
Patent No. 5, 0~1, ~:~44) . These patents claim FK506 or Rapamyc:in relat:~=:~ compounds arrd di.~?cl ose the known ase of FK506 or Rapamyc:in related c~ompcunds in the treatment of ophthalmologic cisc>rders ir. association with the known immunosuppressi_ve Effects oi- FK50E~ and Rapamycin. The compounds disc i o_~ed in thesF~ patents are relative~_y large.
Further, the c::itec3 patent:: relat:e to immunomodulatory compounds limit:f:ed t:o r_reating autoimmunity or related disease:, or immuno_~cgica ~~ly-mediated diseases, for which the efficacy of FK.'_>06 a:~d Rapamy: in is wel~_ known.
Other U. S. patents dis::lost, the use of cyc:Losporin, Spiperone, Bus~:~irone, their derivatives, and other immunosuppress~.ve . cmpou;:ds Lor use in t=he treatmE:nt of ophthalmologic diseases (:~~,-rrpe et al. , U. S. Patent No.
5,703,088; Shar~~e et. al., U.S. Patent No. 5,693,645;
Sullivan, U.S. Patient T7c. 'x,688,765; Sullivan, U.S. Patent No. 5, 620, 921; >>harpe et al. , U.S. Patent No. 5,. 574, 041;
E.berie, U.S. PaLent CJo. '~,20~?,326; Sharpe et: al., U.S. Patent No. 5,294,902; Chic.l et al., U.S. Patent Nos. 5,198,454 and 5, 194, 434; and E~::a:~~...a,,, ...::. :rate.?t: No. 4, 839, 342) . These patents also rf.~' ate t~~ <l~rnpovr:d~s useful for treating autoimmane disea~=w; grid vile the ~:r.own use of c~~closporin, Spiperone, Bl':s~_>vr~>r:e, their der~vati_ves, and other SL)BSTI'rUT E SHEF;T (RULE 2fi) WO 00/09124 P~T/IIS99/18233 immunosuppressave compounds in treat=.ina ocular inflammation and other immunol.ogically-mediated c;phtha:lrnologic caiseases.
The immunostappressi~ie c~_;.mpound=. disclosed in the prior art suppress t:.hEe immune s~~stem, by definition, and also S exhibit other toxic side e.ff~:~~ots. Accordingly, there is a need for non-imrnunosappressan~ , small molecule compounds, and composit=ions arid methods for ~.zse of such compounds, that a.re useful in improminc:~ vision; preventing, treating, and/or repairing visu<~l impairment or dysfunction of the visual system; and preventing, treat=ing, and/or resolving ophthalmologic ci. sorciers .
There are al~~o « r umber of patents on non-immunosuppres:~ivt:: compounds disclosing methods of use for permitting or promot=ing wound healing (whether from injury or surgery',; contra=_linc~ intraocu~.ar pressure (often resulting from glaucoma) ; cont~rollinq nce.~rcdegenerative eye d~_sorders, including dama:~e or injury ;.o retinal neurons, damage or injury t:o retiraa_. gar~glior~ c<_:l.ls, ar.d macular degeneration;
stimulating n~.'u:rit~.~ outgro~.;th; preventing or reducing oxidative damage caused i-~v free radicals; and treating impaired o~:ygeiu and nutr_venT: sur~pl~,~, as well as impaired waste product rerr;o~~al, result ~ng from low blood flow. These non-immurvosuppre:si~.~e substana~es fal:~ into one of two general categor=_es: naturally occurring molecules, such as proteins, glycoproteins, pept ides, :;orrT~ones, and growth factor:; and synthetuc molec:u=_es.
Within the group of naturally occurring non-immunosuppressi.ve molecules, several hormones, growth factors, and si gnalir:g molect.les hare been patented for use as supplements ~~ natvrW '_~,~ occurring quantities of: such molecule", as v:~e= ~~ a~ fat: t~r:~e:-ing of specific ce~_ls where the particular_ molf.:~ule doer :mt: naturally occur in a :mature individual. These ~~at~-nts der:era~~ly claim methods of use for reducir,~,~ or prm,>enting t:rae , y~mptoms of ocular disease, or 3~ arresting cr .revers i_r:g vvslor~ =ass.
S11I3STI'TUTE SHEET (RULE 2G) WO 00/09124 P~CT/iJS99/18233 Specificall~;~, Louis et ai.. , U. S. Patent Nos. '>, 736, 516 and 5,641,749, disclose the u_~e of a glial cJell line derived neurotrophic ~a~tor (GDNF) to stop or reverse the degeneration. of retinal neurons (i.e. photoreceptors) and retinal ganglion; ,ells caused by glaucoma, or other degenerative or tratzmati;_ retinal diseases or injuries.
0' Briers, et a:l . , U.:~. Patent Nos. 5, 714, 459 and 5, 70~~, 909, disclose the use of a qlycoprotein, Saposin, and its derivatives for ~;ti.mulating ne_>urite outgrowth and increasing myelinat.ion. 'io stop or reverse degeneration of retinal neurons, LaVai1 et al.., U.S. Patent No. 5,667,968, ciisc~loses the use of a ~rariety of neurotrophic proteins, inc:Luding brain-dE:rived ::eu.r~:~trophic factor, ciliary neurot rophic factor, neurotrophirz-3 or neurotrophin-4, acidic or basic fibroblast growth factors, interleukin, tumor necrosis factor-a, insulin-like growth factor-2 and other growth factors. Wong ei: :~1.., U.S. Patent No. 5, 6t'~'>, 984, discloses the use of int:e.rf-erons, especially interferon a-2a, for treating the sym.;~toms of mac.zlar degeneration by reducing hemorrhage and -',.i rni.t_ng neovas.:ularization. F mall y,. Wallace et al., U.S. Patent No. 5,441,937, discloses the use of a lung-derived nei.zrotrophi.c fz~stor (NTF) ' o maint:aiz the functiorvality of ci.l iany gang~.ion anci parasympathetic neuron cells.
A Icey charac:tea-istic of factor; derived 'nom specific cell lines is their localizat,_on to specific cell lines or tissues; systemic, treatment w:i_th these mo'iecJules would run a substantial risk of unintenda:d, and potentially dangerous, effects in cell. lines where the genes encoding these rr~olecu~.~es are inactive. Similarly, :~ormorms and growth factors c,'ten act i~Ja to a large number of genes in man~l cell lines; ~~:qair:, Iron-localised ~cpplic;a".ion ; i: these molecules would run a substantial risk rf proVOkinc~ ~.1~ inapprop,~iate, and potentially dangerous, response.
SUBSTITUTE SHEET (RULE 26) WO 00/09124 fCT/US99/18233 Within the ~~ate~ory of syrv:thetic: molecules, moat of the patented compour:d~~ a~~e imm.:nesuppressive and disclos~= uses in treating infiamrnat:cr:,~,, autoimrnune, and allergic responses, as discussed above. A fecv other: are non-immunosuppre~:sive and claim the ability to treat: cel Lul.ar degeneration, and ir: some cases promote c;~l.lml_ar regenerati.en, most often in the context cf their_ antio::idant properties.
Specif:ical~~y, 'J'so et a1. , U. S. Patent. No. 5, 52'7, 533, discloses the use of astax.anthin, a carotenoid antiox _dant, for preventing or reducing F.~hotcreceptor damage resulting from the presence-~ oi~ free ,: a~"=:.cai s. Similarly, Babcock et al. , U. S. Patent I~o. 5, 25a, 31 9, discloses the u:~e of antioxidant arninosteroids fc~r treating eye disease and injury, by increasing resi:~tance to oxidative damage.
Freeman, U. S. P<ter.t I~Io. 5, 46~~, 752, discloses the use of the antiviral phos~honylmethoxyalkvlcytosines to reduce abnormally increased intraocular ~;ressure.
Harr~iito:~ :~r.c~ :~~einer c isclose in C1.S. Pateni_ No.
5, 614, 54, noT~el pyrr:~' i dine carboxylate compounds ~~hich bind to the immunof,:r: _ ~!.i_n FKF3P:~:: ar.d stimulate nerve growtr:~, but which lack imrr.unosuppressve effects. Dnexpectedly, =_t has been di~~coverec: t:r~at: ~.hese neon-i.rnmunosuppressant compounds promote improvem~,:nt:=; in visi:~n and resolve ophthalmologic disorders . Yet, t:~:ei_~ novel sm<~11. molecule s tructure and non-immunosuppressive pr-cpertz.es differentiate them from FK506 and rel~rted irr~muoost.rppressi_~.~e compoa;nds found in the prior art.
Further, thesE: compounds may be differentiated from the non-immunos«~press _ve compov.;nds used to treat «ision disorder:; by t.:oe_i r r:ovel smal~~ molecule structure and their lack of ge::er~;., sy.stemi c <.ff~~cts. Naturally occurring hormone., g~-~;~,atz f;~ct~~rs, cvt=c:kines, and signals_ng molecules are generally molt:i1=unctional and activate many genes in diverse gel-. lines. The present= compounds do nit, thus avoiding t'~e unex~~~~c~ed, anc:i potentially dangerous, side SUBSTITUTE SHEET (RULE 26) ~0 effects of syst:ern.i~~ use. ~inu:ilar 1 y, the present com~~ounds also avoid tree p~:~tential unexpected side effects of introducing ce~_1 _~ine-specific molE:cules into otiner cell lines were they do not natura'~1~~ occur.
SUMMARY OF THE INVENTION
The present invention relates to a method for treating a vision disorder, improving vision, treating rnemory impairment, or enhancing mem;ry performance in an animal, which comprises adm:i.ni.sterincr to said animal an effective amount of a pyrrol_di_ne deriv,ntive.
The present v~nvention further relates 1=o a pharmaceutical composition which comprises:
(i) an effective amoum_ of a pyrrolidine derivative for treat-ing a vision disorder, improving vision, treating memory impairment, or enhancing memory perfcyrrr.ance in an animal; and (ii) a pharrr.aceutically acceptable carrier.
Brief Descrit~tion of the Drawings Figure .L A, B and ~ show that vPI 1046 protects retinal ganglion cell, against lec:eneratuon following rei i nal ischemia.
Figure ~ shows that. GPI 1046 Nrevents degeneration of optic nerve axons and r~~,yF~:l;_~~ following retinal ischemia.
Figure 3 shows that: ~,=~I i04r; provides moderate protection against retinal ~~;~:ng-Lion cell de4:tn after optic nerve transection.
Figure 4 shows that ~;=~I IG46 t=Batmen;, durat~_on significantly affects the proves > ,~r cpti-:: nerve a,~::onal dc~generati_on after_ transe-::t ion .
SUBSTITUTE SHEET (RULE 26) WO 00/09124 PI~T/L1S99/18233 Figure '_~ shows gnat GPI 104r> treatment produces a greater effect on opr_i~: nerve axons t;:an ganglion cell bodies.
Figure E> shows that: GPI 104F, treatment fcr 28 days after optic nerve trans~~ction prevents myelin degeneration in the proximal stump.
Figure 7 shows that FKBP-la immunohistoc:hemistry 7_abels oligodendroglia (large dark cells wroth fibrous proc:esses), the cells whi ch produce myelin, located between the fascicles of optic nerve fibers, and also some optic nerve axons>.
Figure ~' show:> G1'I 1046 trear_ment for 28 days after optic nerve transecti:~n prevents myelin deceneration in the distal stump.
Figure 9 shows ;:h,_~t a?8 day treatment: caith GfI 1046 treatment beginning 8 weeks after onset cf streptozotocin induced diabetes decreases t:r:e e:~tent of neovascul arizatio:a in the inner and oaten retina and F;rotects neurons in the inner nuclear layer ( 7WL' and ganglion cell- layer (GC:L) from degeneration.
DETAILED DESCRIPTION OF THE INVENTION
Definitions "Eye" refers to the anar_crnica:L structure respon~>ible for vision in humans and other animals, and encompasses the followir_g anatomi_ca1 structures, ~frit_hout limitation: 1 ens, vitreous body, ciliary b~;d~;, posterior chamber, ant:erior chamber, pupil, c~ornea, __~_s, ~~anal of Schlemm, zonu7_es of Zinn, li.mbus, cc~r.'unctiva, choroi~, retina, central vessel s of the retina, o~~tic, nervF~, ~ove« centralis, macula __utea, and sclera.
SUIiSTI'TU'rF: SHEET (ROLE 26) WO 00/09124 PC'T/U 599/18233 i. ~' "GPI 1096" refers to the relates. neuroimmunophi.lin FKBP
ligand 3-(3-pyric~~-l)-1-propyl (2s)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate of formula ~N
()~ /
N
() O
() "GfI 1239" refers to the related neuroimmunophili FKBP
ligand c>f formula.
.,~
o. ! o 'o GI'I 1234 "GP I 1 31'?" refers to the rel ated neurolmmunoph__lin FKBP
ligand of formul<-_i /
N
i c~-s-o 0 "GF?I 138U" r_erers to the related neuroimmunophilin FKBP
ligand of fcrmul.a N
n ., N
0. _ ~() Gl'I 1389 SUBSTITUTE SHEET (RULE 26) "GF?I 1511" re:_ers to the related neuro:immunoph:ilin F'KBP
ligand of formula o~ o i "G PI 1572" refers to the .related neuroimmunophilin FKBP
ligand of_ formula N
s c,,~
i I

~-o GPI I 572, "GPI 1F~05" refers to the related neuroimmunophilin FKBP
ligand of formul<r s~ ~ i N
U
f-iN ~ O

"Lsomers" refer to dif~erent ~sompounds that have the same molecular formula. "Stereoisorners" are isomers that differ only in the way the atoms are arranged in space.
"Enan~.iomers" are a pair or stereoisomers that are non-superimposable mirror images of each other.
"Diast~reo~somer~'" are s~ereoisomers which are not mirror images _f each ether. "Rac:emic mixture" means a mixture containing eaua7_ pares of indimi ,.zal enantiomers. "Noi:-.
raCe1T11 r' mlXture= 1p d mlXi-uCe COntal i:li:g l:Tlegll~tl parts Of individual ~anantiomers cr stereoiso:mers.
SUBSTITUTE SHEET (RUL,E 26) WO 00109124 PC'TlUS99/18233 1 ~l "Enhancing memory performance" refers to improving or increasing the rnenta ~_ faculty ~y ;.~iziclz to register, retain or recall past experiences, klowl.edg~~, ideas, sensat=ions, thoughts or impress>ions .
S "Memory impairment" ee; ers to a diminished rental registration, ~~~ter.tion or recall of past experiences, knowledge, ideas, sensations, thoughts or impressions.
Memory impairment rr,ay affect ~~i-~ort and 1_ong-term information retenticn, facv~lit:y with spatial relationships, memory (rehearsal) strategies, and v~,-rbal. _retrieval and production.
Common causes of memory impairment are age, severe head trauma, brain anoxia co _schemia, alcoholic-nutrit=,tonal diseases, and dr_v,~a _intoxic~:tior.s. Examples of rnemory impairment includee, r; it.hout liruitation, benign forget fu=_ness, amnesia and any disorder ir~ whic'r: memory defic_~ency is present, such as l~or:~akcff's amnesic psychosis, dementia and learninc disorders.
"Necpsic ~~ac~ters" or "r.eopsic:>" refers to compounds useful in :.renting vision loss, preventing vision degeneration, .~ promoting vision regeneration.
"Neopsis" refers to tare ~;rocess c~f trea~ing vision loss, preventing vision degeneration, or promoting vision regenerGtion.
"Ophthalmclogical" refs=.rs tc anything about or concerning tt:E: eye, withoc:t= 1 imitation, and is used interchangeably with "ocelar," "ophthalmic,"
"ophthal.mologic," and other such terms, without limitation.
"Pharmaceut i.cai l y accept able salt, ester, or solvate"
refers ?_o a salt , este:r, or ~;olvate of a subject compound which possesses; the ~_iesired pharmacological activity and which is neither_ bi~loaicall~,r nor otherwise undesirable. A
salt, ; ,vter , _ , ~ol-ra r.e ~.an ,>~a f ~rm~ad with inoraar i~~; acids such as acet<te~, ariipate, alginate, aspartate, benzoate, benzenes~.~lfonat_" cis.ulfate, butyrate, citrate, camphorate, camphorsultcr:are, cyclo~ en -.ar.et:~ropionate, digluc ;::ate, SUI3STI'TUTE SHEET (I2ULI26) WO 00/09124 PC'T/Ur99/18233 l .'.;
dodecylsulfate, et.harlesulfonate, -umarate, glucohept:an~~ate, gluconate, gey~~er:~pl~~ospnatEe, hemisulfate, hept:anoate, hexanoate, hydroc:h.Loricie, hydrobromide, r~ydroiodi.de, 2-hydroxyet.hanesulfonat.e, lactate, maleate, methanesul.fonate, naphthylate, 2-naptut:~~a~.enes..rlton.ate, nicot:inate, oxalate, sulfate, thiocyanate, tosy,~ate and undecanoate. Examples of base salts, esters, or ;solvates in~~lude ammonium salts;
alkali metal salts, such as sodium and potassium salts;
alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, such as di.cyclohex:ylamine salts; N-methyl-J-gl.ucamine; a.~ d salts with amino acids, such as arginine, lysine, ,:nd so f<_;r:r:. Also, the basic ni.tr«gen-contai ning groups can be c;uarrernized with such agents as lower alkyl halides, :such as me,~hyl, er_hyl, propyl, and butyl chlorides, bromides,, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, any diamyl sulfates; long ~:hain halides, such as cl~~cJyl, ! a,~ryl, myristy-~ , and stearyl chlorides>, bromides, and iodi:les; aralkyl halides, such as benzyl and phenet:nyl bromides; and others. Water or oil-soluble or disper:_~ibl.e ~~roduct:~ are thereby obtained.
"Preventi.ng vision degele:-ation" refers to the ability to prevent degener,ztion of visi:~n i.; patients newly diagnosed as having a degene:ratrve disease affecting vision, or at risk of developing <~ new :~egenerat_ve d:is~sase affecting vision, and for preventing fu.rt:r,:er c;eger~eration of vision in patients who are already su=.= erii:g ~ rpm or have symptoms of a degenerat:ive diseas,affec:tina vision.
"Promoting vl_sir~r. regeneration" refers to maint:ai:zing, improving, stimular_ir~a or a:~releratincx recovery of, or revitalizing one cr ~re~~r« components of the visual system in a manner which impro~.~es or enhances vision, either in the presence or absence of =::ly -]p~;t:halmologic disorder, dis=ase, or injury.
SUBS'ftTUTE SHEEN' (RULE 26) i_ h "Treating" refers to:
(v) preventing a disease and/or condition from occurring in a subject which may be predisposed to the disease and%or_ c.~>nd~.t.ion but has note yet been diagnosed as having it;
(i.i) inhibiti.nc~ the disease and/or condition, i.e., arresting its development; cr (iii) re-!ieving the disease a:~nd/or condition, i.e., causing regression of the disease and/or condition.
"Vision" refers to the ability of 1-..umans and other animals to process images, and is used interchangeably with "sight", "seeing", and other :uch terms, without limitation.
"Vision disorder" refers t.o anv disorder that af=fects or involves, vision, includir,a :,rit:hout limitation ',usual impairment, or~~i~al disorder,, disorders of the lacrimal apparatus, disorders of thEe eyelids, disorders of the conjunctiva, disorders of the e,ornea, cataracts, disorders of the uveal tract=, disorders of the retina, disorders of the optic nerve or teisl.ial pa .:n,'ra;ys, free radical induced eye disorders and diseases, i.mmu:lo3.ogical~y-mediated eye disorders and c~i~iseases, ey~~ inj.~ries, and symptoms and complications cf eye disease, eye disorder, or eye injury.
"Visual impairment" refe =s tc any dysfunction i.n vision including without: lirnita-i or; disturbances or diminution in vision (e.g., b__noc:ular, central, peripheral, sc:otopic), visual acuity fm: objects near and far, visual field, ;ocular motility, color perc~sption, adaptation to light and dark, accommodation;, refraction, and lacrimation. See Physiclian' s Uesk Re:Eerence (I?DFe.) for O~:hthalmo~~ogy, 16'" Edition, 6:97 (1988).
Methods of the Present Invention Thc: present in,~ent~ior: L~-sates ro a method of treating a vision disorder, irnprovi.~,:: ~.~ision, treating memory impairment, or enhancing ir.c~,~,?w-y performance in an animal, SU BS'fITUTE SI-IE ET (RULE 26 j which comprise: administerin:~ to said animal an effective amount of a pyrrol.idine derivative.
The inventive methods are particularly useful for treating various eye disorders including but not limited to visual disorders, ~:~iseases, injuries, and complications, genetic disorders; disorders associated with aging or degenerative vision diseases; vision disorders correlating to physical injury to the eye, h«ad, or other parts of the body resulting from e:>;~e:~nal forcces; vision disorders resulting from environmental factors; vis:icn disorders resulting from a broad range of c~.iseases; and combinations of any of the above.
In particular-, the compositions and method; of the present invention are usef~,r1 nor improving vision, or correcting, treating, or preventing visual (ocular) impairment or dysf:unc~.ion of the visual. system, including permanent and t:empcrary visual i.mpa:irment, withou', limitation. The present wnventicn i.s also useful in preventing an,i treating ophthalmologic: diseases and disorders, treatv:.ny damaged a;zd i~.jured eyes, and preventing and treating ds~~ases, disorders, and injuries which result in vision defiolenc:y, vision ~.oss, or .reduced capacity to see or process imaqe:~, and the symptoms and complications resulting from s_~me. The ey~~ diseases and disorders which may be treated co prevented '.:;y the compositions and methods of the present irment:ion are not limited with regard to the cause of said diseases or disorders. Accordingly, said compositions a~w:d me~=hods are appl.i.cable whether the disease or disorder is ~a,~sed by genetic or environmental factors, as well as any o~he~ i:ltluences . The compositions and methods of the preser:t. _r:v~n+io-, arF~ part~cular.l~,~ useful for eye problems or -,-~~_:::~ joss or deficiency associated with a' 1 of the fol l ows_nr" v.~i'~hout ,~imita'.iorl: aging, cellular or ppysiological dec~ene_fation, c~e_~tra1 nervous system or r:eurologica~ ~~s:~;rc~er, vascular detects, muscui.ar defects, SUBSTITUTE SHEET {RULE 26) and exposu_Ne to adverse env:ircnmental conditions or substan~~es .
The compositions and meohods of the present .invention are particularly usefu:L in correctin:, treating, or .improving visual impairment:, v~ithout limitation. Visual impairment in varying degree: occurs in the presence of a deviation from normal in one or more functions of the eye, including (1) visual acuity for objects at distance and near; (2) visual fields; and (:~) oc:ular mot v~lity v~aithout diplopi_a. See Physicians' Desk Reference (PDR) for Ophthalmology; 16th Edition, 6:47 (:L~88). V.is:ion i.s imperfect without the coordinated funci::ion of al:L tr:ree . Id.
Said ccmpc:>s:_tion s and methods of use are also useful in correcting, trea~i.ng, or imX:roving other ocular .=unctions including, withol.it _imitati.or~, color perception, adaptation to light and caarl<, accommodation, metamorphopsia, and binocular vision. The compo:~it.i~ns and methods of use are particularly useful in t,:-eat in J., correcting, or preventing ocular c~isturbanc:es inclt:ding,, ~N~ithout limitation, paresis of accommodation, irid~:~pleg:ia, ::n~ropion, ectropion, epiphora, lagophthalmos, scarring, :~itreous opacities, nom-reactive pupil, light sc:a::ter___ng disttrbances of the cornea or other media, and permanent= deformit;-es of the orbit.
The compositions and metL;ods of use of the present invention are a~_so hi_ghly~ a ;efui in improving vision and treating vision .Loss. Vision. loss ranging from slight loss to absolute los:_> rnay be tr=sated or prev~anted using said compositions and methods of ~,,se. Vision may be improved by the treatment of eye disorder, diseases, and injuries using the compositions and mewio~~:~ of the invention. However, improvements in visi.c;n us~.ng the compositicns and metr.ods of use are not sc .lirr~i.vc~cJ, ~: d r~~.ay ;~cc~.:r in t:nc absence of any such disorder, dise_3se, _ ic:;urv.
The comp~.si t .cm:~ arl;a rne~ tJ-c~ds ~_.L r_he present invention are also useful i:~ the -r~~atme-:r ;:r prevention of the SL1BST1TUTE S~IEIi.T (RULE 26) WO 00/0912:1 1'C"T/US99/18233 1 ~3 following non-1_irraiting exemplary diseases and disorders, and symptoms and complications re:~~alting therefrom.
Vision d,is:onders include, but are not limited to the following:
~.~isual impair_rr:ent, such as diminished visual acuit=y for objects near and far, visual i=fields, <~nd ocular motility;
orbital disorders, such as orbital cellul_itis, periorbital ceilulitis, cavernous sinus thrombosis,. and exophthalmos (propt.osis);
disorders of the lacri.mal appar<~tus, such as dacryostenosis, conga:r_ital dac~-yostenosi s, and dacryocystitis (acute or chron.ic);
disorders c;f the eyelids, such as lid edema, blepharitis, ptosi~>, Bell's palsy, blepharospasm, hordeolum (styei , external hc.~_rdeolum, int=ernal hordeolum (meibomian stye) , chal.azion, entropion ( i_r.versi_on of the eyelid) , ectropion (ever-s:ion of the eyel;.~dj, tumors (benign and malignant), xanth=~la.srna, basil cell carcinoma, squamou:~ cell carcinoma, rneibom.ian gland carcinoma, and melanoma;
disorders o' +~r~e conjunctiva, such as pinguecula, pterygium, and ot~ue:r neoplasms, acute conjunctivitis, chronic conjunctivitis, du_I_t: gonocc:~cal ~;vnjunct-:.vitis, neonatal conjunctivii~is, t=_~acnoma (granular conjunctivitis or Egyptian ophthalmic), incl.u;:,~on conjunctivitis (inclusion blenorrhea or swimming pool conjunctivitis), neonatal inclusion conjunctivitis, adult inclusion conjunctivitis, vernal keratoconjunctivi.ti:~, keratoc~.~nJuncti_~~litis sicca (ker~:titis sicca or dry eye syndromej, ep_iscleritis, scleritis, cicatricial pemplnig~:~_d (ocular cicatriciapemphi_goid or benign mucous rnc-~mbrar,e pemp~hi.gcici) , and subconjunc:tival hemorrhage;
disorders of t~:e cornea, suc:u as superficial punctate keratitis, corneal ~.~lcer, indolent ulcer, recurrent corneal erosion, corneal ~Jr~itrielial oaserr.e:~t membrane dystrophy, cc;rnealendoth~~l_i~~l ~iell <lystmophy, r.erpes ~;impl_ex keratitis SUBSTI'fLTE S~IEI:T (RULE 26) WO 00/09124 PC.'T/US99/18233 (herpes simplex k~~rat~conjuncc~ivitis), dendritic kerat:itis, disciform keratit..i;>, ophthalm:_~: herpes zoster, phlyctenular keratoconjunct::i_v_t;i:~ (phl;~~tenular or ec~err.atous conjunctivitis), i-:terstitial ker~.~titis (parenchymatous 5 keratitis), peripheral uLct~rative kerat:itis (marginal keratolysis or periphera~_ rheumatoid ulcerat:ion), keratomalacia (xerotic keratitis), xerophthalmia, keratoconus, bullous keratopa':hy;
cataracts, i:nc:luding ~aevel_oprnental or congenital 1C cataracts, juvenile or adult cataracts, nuclear cataract, posterior subca;~sular cataract:s;
disorders cf the uveal tract, such as uveitis (inflammation ~:~f t1e uveal tract or retina) , ant.erior uveitis, i ntermec:i.iate uveiti:;, posterior uveitis, iritis, 15 cyclitis, chore:>ic~i.t:is, anky~.osing spondylitis, Rei.ter's syndrome, pays i~l.anitis, tc.~xcp1_asrnosis, cytomegalovirus (CMV) , acute r~~t.inal necrosis, t:oxocariasis, birdshot choroidopathy, r:istoF>lasmosis (presumed ocular histopla~~mosis syndrome), Behcet'~ syndrome, sympathetic ophthalmic, Vogt-20 Koyanagi-Harada syrndrome, :<~rco~~dosis, reticulum cell sarcoma, large cell l~,~mphoma, syphilis, tuberculosis, juvenile rheumat:.ou.cJ ar_t:~ritis, endopht:halmitis, and malignant melanoma of the ;:horoid;
disorders ~f tre retina, such as vascular ret:inop~.thies (e.g., arteri~:~s~;ierotic retinopathy and hypertensive retinopathy) , central and branch retinal artery occlusion, central and i:~r_anc:w; rer_ina ~ vein occlusion, ~~~i~.betic retinopathy (e. G., proliferative retinopathy and non proliferativc~ r._~inopathy) , macular c.egeneration of r_he aged (age=related macular degeneration or senile macular degeneration), .c-ov-ascular macular degeneration, retinal detachment, ret~i=nit.~s pigmentosa, retinal photi~c injury, retinal ischemia-indr.zced e,,~e injury, and glaucoma !e.g., primary glau<-_orn,a, _:hroni:, open-angle glaucoma, acua or SUBS'ffTUTE SHEET (RULE 26) chronic angle-c:l_osvzre, congenital (infantile) glaucoma, secondary glauc:orna, and absolute glaucoma) ;
di:~orders ~~f the optic nerve or visual pathways, such as papilledema (chokes disk), papill.itis (optic neuritis), retrobu:Lbar neur_lti>>, ,lschem-~c: optic neuropathy, toxic amblyopia, optic: at=rophy, higher ~~~isual pathway lesions, disorders of oc:.ilar rnotilit.~ (e.g", thiz:d cranial nerve palsies, fourth ::ran.ial nerv~: palsies, sixth cranial nerve palsies, internuclear opht:halmoplegia, and gaze palsies);
free radic:a=_ irrciuced eye disorders and diseases; and immuno7 ogic:al l ;~-~med;~ateceye disorders and diseases, such as Graves' ~~prlthalmopat:'Iy, conical cornea, dystrophia epithelialis corne<3e, corne~:.-~ leukoma, ocular pemphigus, Mooren's ul_cer,. sc:leritis, arid sarc:oidosis (See Z.ne Merck Manual, Sixteer:tt~ Ec:lition, 217:2365-2397 0_992) and The Eye Book, c:assel, E_~il~_ig, and Randall, The ,Tohns Hopkins Dniversity Press ;1998)).
The corrrpo»'::icn:~ and met:zods of the present =_nvention are also usefu~ _r: the treatment of the following non limiting eye iruju;~i.es, anct symptoms and comp~_ications resulting t.herelrorr,: c:onjunct:ival a:~d corneal foreign body injuries, corneal abrasion, intraocular foreign body injuries, lacer~.t:icns, l.id lacerations, contusions, lid contusions (blaci<: ev,~e) , trauma to the globe, laceration of the iris, ~::a;.:ract, dislocated lens, glaucoma, ,vitreous hemorrhage, orb=i::al--floor fr~rctures, retinal hemorrh<~ge or detachment, an:~ ra~~ture of the eyeball, anterior chamber hemorrhage (traurr,atic hyphema, burns, eyelid burns, chemical burns, chemica'~ bur:ws of tr:c~ cornea and conjunctiva, and ultraviolet lv~ght burns (sunburn). See The Merck Manual, Sixteen ~h Ecli t ~ on, .. ~' 7: 236-i'365 ( 1992 ) .
The compo~~i~_icr;s and mer_hods of the present -;mention are also usefv~. _~r~ Treating <.md/cr prevent=Ana the ,~ollowing non-limit=ine~ exernL;lar~;~ symp~om:~ and comp_Licati~~ns ;:' eye disease, e~;~f~ iL~~or~_~er or eye injury: subconjunctival SI:~BSTITUTL SHECT' (RULE 26) ~: 2 hemorrhages, vitreous hemorrhages, retinal hemc>rriZages, floater~~, reti:-cal detachments, Nhotophobia, ocular pain, scotoma~> (nega~ive and pes,itive), errors of refraction, emmetropia, ametrop.ia, hyperopia (farsightedness), myopia (nearsightedness', ~~stigmatis-n, anisometropia, ani~,ei:ionia, presbyopia, b~~e:ding, recurrent bleeding, sympathetic ophthalmia, in:Elarrunat;~on, swelling, redness of the eye, irritation of tide eye, corneal ulceration and s.ca:rring, iridocyc:litis, perforation or_ the globe, lid deformities, IO exophthalmos, impaired mobil:i_ty of the eye, lid swelling, chemosi~;, loss o_~ vision, including partial or total blindness, opti:; neuritis, fever, malaise, thrombopt-.lebitis, cavernous sinus t:;~urornbosis, panophthalmitis, infection of the meninge~; and b_~a:ir:, papilledema, severe cerebral symptoms (headache, decrreased level of consciousness, and convulssons) , _-r<ani<~~ nerve pa=Lsies, epiphora (chronic or persistE:nt tearing), copious. reflux ef mucus or pus, follicular subccn;,unct~_.va.1 hyperplasia, cc>rneal vascularizatior, cic:atrization of the conjunctiva, cornea, and lids, panr.u::, hypopyoi:, lagophthalmoa, phlyctenules, rubeosi:; i_ridis, c~itemporal hem~~anopia, and hc~monymous hemianopia. ;>ee The Merci: Manual, Sixteenth Edition, 217:2362-2363 (1~~9:~) .
The pyrrolid:_nP derivative may be administ:er~d in combinat:icn with an effective amount of one or more fac~_or (s) useful in r~rea~.in:, vision. disorder, improving vision, treating memory impairment, o:~~ enhanc:ing memory performance.
In a preferred e-nbodimenr_, the factor (.s) to be combined with the pyrrcllcine derivative is/are selected from the group consisting of immunosuppressants for treating autoimmune, irWl~~ramatory, and immunologically--me~~i ated disorder,:; wound healing agentr~ for treating ~~aounds resulting from injury c~- L~rger_y; anriglaucomatous medications for treating Gbl::~rmal ~y ele~~~~ted intraocul.ar pressure;
neurotr«phic ~~3::tcvs and .~,rowth factors for tr~sating SUBSTITUTE SHEET (RIiLE 26) WO 00/09124 PC'T/U;S99/18233 a3 neurodegenerative disorders or ;stimulating neurite outg_=owth;
compounds effective in limiting or preventing hemorrhage or neovascularization t:or treating macular degeneration; and antioxidants for_ treating oxidative damage to eye tissues.
Pharmaceutical Compositions of the Present Invention The present: invention also relaxes to a pharmaceutical composition comprising:
(i) an effective amount. of a pyrrolidine derivative for t.reat:ing a vision disorder, improving vision, treating memory impairment:, or enhancing memory performance in an arl:imai; and (ii) a pha:rm<~c:eutically <~cceptable carrier.
The pyrrol:i~:iine derivat;_ve may be administerE:d in combination faith ~3n effective amount of one or more factor (s) useful in treat_i.ng vision disorders, improving vision, treating memory _rnpa~::ment=, or enhancing memory performance.
PYRROLIDINE DERIVATIVES
The pyrrolidin~ der:ivat~ves used i.n the methods and pharmaceutical compositions of the present invention are low molecular weight, small mo.lecu:Le compounds having an affinity for an FKBP-type immunophilin, such as fKBPl2. When a pyrrolidine derivati-.Te binds t~:> arl ~'KBP-type immunophi 1=_n, it has been found t=o inhibit the prolyl-pe~~tidyl cis-traps isomerase, or I:o::amase, activity of the k>inding protein.
Unexpectedly, t:hc-use compounds have also been found +o successfully treat vision loss and promote vision regeneration. '~'h~ compounds are devoid of any significant immunosuppressi_-~e ac:::i_T,~ity.
SL1BST1TUTE SHEET (RULE 26j WO 00/09124 PCT/U:S99/18233 FORMULA I
The pyrroli.d=.ne derivative: may be a compound of formula I
N~ Y-Z
z \~ O
Ri or a pharmaceuti-tally accept;.~ble salt, ester, or solvate thereof, wherein:
R1 is C.';-C; straight or brancr:,ed chain alkyl, C,-C~
straight or branched chain alkeny:L, C_j-C~ c:ycloalkyl, C"-C, cycloalkenyl or Ar., wherein said R: is unsubstituted or substituted wi-th c>ne or more substituents independently selected from t=he ~~:roup consisting of C,-C'_, alkyl, C.,-C6 alkenyl, C~-f.,-, cyc:loa.lkyl, C,.,-C; cycl.oalkenyi, hydroxy, and Are;
Ar, ~:nd Ar.; are ir:de~endE_:ntly s~=lected from the group consisting of 1-naphthyl_, ?-nab thyl_, ?-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2---th~yer.yl, 3-thienyl, 2-pyr:idyl, 3-pyridyl, 4-pyridyi and pheny7_, wherein said Arl is unsubstit:uted or substituted wit':1 one or more substituent(_:) independently selected from the group consisting of hydrogen, halo, hydroxy, nit:ro, tri-fluoromethyl, ~~~-Cf; straight or branched chain alkyl, C-~C:,, straight or branched chain alkenyl, C;-C~
alkoxy, -C; all<_enylo:x;Y, phenc:>xy, benzyloxy, and amine;
X is 0, S, Cf-i-. cr H->;
Y is 0 or NR_, wherein R-, is hydrogen or C,-C~ alkyl; and Z is C~-C,. sr~-aight or branched chain alkyl, or C;-C"
straigh~ or branched chaff-n alkeny~_, wherein said ? is substi-tut,~d ~.~it-: on~~ c:r more s~abstituent (r>) indep~indently selected from the group consi::ting of Ar" C~-,-C: cycioalkyl, and C;-~" straight or branched ct~ai.n alkyl or- C,,-C::~trai ght SUBST1T'UTE SHEET (RULE 26) WO 00/09124 PC.'T/US99/18233 -; r or branched cha_Ln alkenyl sub: tituted with !:,-C~ cycloalkyl;
or Z is fragment O
i _C,f ~~ X; Ra R~
wherein:
R3 is Cl-Ca t;t:raight or koranched chain alkyl which is unsubstituted on _>>-ibstituted ~~;ith C,-C;, cycloalkyl cr Fir.;
X~ is 0 or_ IVR~, wherein R_ is selected from the group consisting of i~y;~rc>gen, C,- , straight or branched chain alkyl, and C -C~ straight or branched chaff-n alkenyl; and R9 is select=ed f=rom the croup consisting of phenyl, benzyl, c.,-C; stra:i.gh;_ or branched chain alkyl, C_-C:, straight or branched chain a_Lkenyl, C,--C~, straight or branched chain alkyl substituted u.~it.h phenyl, and C--C, straight or 'oranched chain alkenyl s,~b:~ti=uteri ~~ait~u pheny~_.
In a preferred embodiment. of formula I, 2 and R~ are lipophilic.
In a~ more preferred embodiment of formula I, the compound is selected From the c~rou~ consisting of:
3-phenyl.-1--propyl (2S) -1- ; ?, 3-dimethyl-1, 2-dioxoper.tyl ) -2-pyrrolidinecarboxy late;
3-phenyl-1--prop--<~- (~,) -ens,~l (2S) -1- ( 3, 3-dimet:hyl-l, 2-dioxopentyl) -2-pyrro.L:idinecarboxylate;
3- ( 3, 4, 5-trirnethox.yphen~~~1 ) -_-propyl ( 2S) --1- ( 3, 3-dimethyl-l, 2-d.io:~~:~pe~n~.:~~1 ) -~-p1,-.rro~~ id__necarboxylate;
3- ( 3, 9, 5-trirnethoxyp:neny-, -1-prop-2- (E) -enyl (2S) -1-(3, 3-dimethyl-1, 2--di o::oper_t~;~l? -2-pyrrolidinecarboxylate;
3- ( 4 , 5-dict:lor cpt:enyl ) -1--propyl ( 2S) -1- ( 3, 3-d; methyl-1, 2-dioxopen tyl a -~_ --py% rrol i dinF~ca r;ooxwl ate ;
SUBSTITUTE SHEF;'C (RULE 26j WO 00/09124 PCT/U~99/18233 L~
3- (4, 5-dichlorcphenyl) -1--prop-2- (E) -enyl (2S) -1-- (3, 3-dimethyi -l, '?-di;~::opent~w;~l ) -2-pyrrolidinecarbcxylate;
3- (9, 5-methylenedioxyphenyl) -1-propyl (2S) -1-- (3, 3-dimethyl-1,2-dio~;opentyl)-2-p;~rrolidinecarboxylate;
3- (4, 5-methyler:edioxyphenyl_) -1-prep-2- (E) -enyl (2S) -1-(3,3-dirr.ethyl-1,2-dioxopentyll-2-pyrrolidinecarboxylat=e;
3-c:yclchexy:L-7_-propyl (2S) -1- ( 3, 3-dimethyl-l, 2-dioxopentyl)-2-oyrrclidinecar't~oxylat~~;
3-cyclohexyl---1.-~:~rop-2- (E) -enyl (2S) -1- ( 3, 3-dimet:hy:L-l, 2-dioxopentyl) -2-pyrrolidinecar'r~cxylat~=;
( 1F:) -l, 3-d;~phF:r.y i -1-prop~,~l (2S) -1 - ( 3, 3-dimethy~_-l, 2-dioxopentyl;-3-pyr~-clidinecar~oxylat~~;
( 1.F') -l, 3-di~~henyl-1-prep-2- (E) -enyl (2S) -1- ( 3, 3-dimethyl-1,2-dioxopentyl)-2-p~~~rrolidinecarboxylate;
(IR) -1-cyc:lohexyl-3-ohe::yl-1.-propyl (2S) -1- (3, 3-dimethyl.-l,'?-di.oxopentyl)-2-p~~rrolidinecarboxylate;
(1F') -1-cyclohexyl-3-phenyl-1--prop-2- (E) -enyl (a?S) -1-(3, 3-dirr~ethyl-l, 2-c~ioxopentyl I -2-pyrrolidinecarboxylat:e;
(1R)-1-(4,5-dv~chlorophenyl)-3-phenyl-1-propyl (2S)-1-(3,3-dimethyl.-1,2-dioxopentyl'-2-pyrrolidine-carboxyl~ite;
3-phenyl-1-propyl (2Sj-1-(1,2-dioxo-2-cyclohexyl)ethyl-2-pyrrolidinecarbox,alate;
3-phenyl-1-propyl (2S) -1-- f l, 2-dy.oxo-4--cyclohexyl) butyl-2-pyrrolidinecarboxylate;
3-phenyl-i-~.ropyl (2S) -1- ( 1, 2-dic~xo-2- [ 2-furanyl_] ) E:thyl-2-pyrrolidinecarboxylate;
3-phenyl-l-prepy=L (2S) -1- (l, 2-dioxo--2- [a-thienyl.] ) ethyl-2-pyrrol idinecarboxy late;
3-phenyl--i-propyl (2S)-1-(i,2-dioxo-2-[2-thiazoly,~] ) ethyl--2--pyrrolidin~~carboxylate;
?-phenyl-1-~:~rc~pyl (2S) -~:_- (l, 2-dio~_o-2-phenyl) ethyl-2-pyrrolidinecarbcxyla~.e;
l, ~-dipheny l-- ?-heptyl ( 2S-1- ' 3, 3-di met:-~yl-l, 2-dioxopentyl)-~-pyrrc;lidinecarnoxylate;
SUBS1'ITU'rE SHEET (RULE 26) WO 00/09124 PC'T/U;s99/18233 a: 7 3-~>henyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxo-9-hydroxy~>utyl ) --2-~~~yr rol idi neca r boxylate ;
3-phenyl-1 -;~r~,p~y_1 (2 5) -1- ( 3, 3-c-~imethyl-l, 2-dioxope:~tyl) -2-pyrrolidinecark:~oaamide;
1- [ 1- ( 3, 3~-c:imE:>t:hyl-1, 2-dioxooentyl) -L-pro~_inel, -L--phenylalanine ethyl ester;
1- [1- (3, 3-dimethyl-l, 2-dioxopentyl) -L-proline] -h-leucine ethyl ester;
1-[1-(3,3-ci.met;hyl-1,2-dioxopentyl)-L-proline]-L-phenylglycine ethyl ester;
1-[1-(3,3-di.methyl-l,'-dioxopentyl)-L-proi_ine]-L-phenylalanine phenyl ester;
1- [ 1- ( 3, 3-ca.imc:et:hyl-l, 2-diox.opentyl ) -L-prol.ine] -L-phenylalanine benzyl ester;
1- [ 1- ( 3, 3-c~imet~hyl-1 , 1-dioxopentyl ) -L-prol.ine ] -L-isoleucine ethyl ester; and phGrmaceutic_al_:ly~ acceptable salt=s, esters, and so_~_vates thereof.
FORMULA II
They pyrro~i:zine derivat~.~ne may also be a compound of formula II
~I
\\ ~ O
N
() I I
R~
or a prarmaceutically acceptable salt, ester, or solvate thereof , where r~
R, is ~~' -c~- ~>t might or ~>ranched chain alkyl, C,;-C:, straight. or br:n :he,~ chain alkenyl, C--CZ cycloalkl-l, C~,-C-cycloalkenyl :~:~ A=,, wherein sa-~d F,-, is unsubsti~wte~~ cr substituted ~~:i:r. cne or mo--e :>ub;;tituen~~s indeF~endentlv;
SUBSTI'fUTFJ SHEET (RULE 26) selected from the group consisting of C1-C~ alkyl, C~-Cn alkenyl, C,-C,,, c:,~els~.~lkyl, C~-C, cycloalkenyl, hydroxy, and Ar2;
Ar; and Ar:, are independently selected from the group consisting of 1-naphthyl, ~-nax:thyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, '?--th_ienyl, 3-i..hienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and pheny l , wherein said Ar, is unsubstit=uted or substituted with one cr more substituent(~~) independently selected from the group consisting of hydrogen, halo, hydroxy, vitro, t.rifluoromethyl, C1-CE straight or branched chain alkyl, C,,-~Cf straight or branched chain alkenyl, C.,-C~
alkoxy, C;-C; al'Kenyloxy, phen<~xy, benzyloxy, and amino;
Z is Ci-C~ st=ra:ight or branched chain alkyl, or C,-C6 straight or branched chain alkenyl, wherein said Z is substituted wit:n one or more substituent(s) independently selected from tree group consist=ing o= Arl, C3--Cr cyc.Loalkyl, and C1-C~ straight. or branched chain alkyl or C,-C" straight or branched chain alkenyl substituted with C~--C:, cyc.Loalkyl;
or 2 is fragment:
- -wherein:
R, is C~-C9 ~;t:raight or toranchec~ chain alkyl which is unsubstituted or substituted i~;ith C3-Cf cyclcalkyl or F,r,;
X, is C: or_ I~IR;, wherein R:; is selected from the group consisting c:f hydrogen, C,-C, straight. or branched chain alkyl, and C -C~ straight or branched chain alkenyl; and Rq is selected from the group consisting cf phenyl, benzyl , ~'-.-C; straight cr branched chain alkyl, C--C~, straight or branched chair. a.l.kenyl, C_--~~', straight o-r branched chain SUBSTITUTE SHEh;T (RULE. 26) WO 00/09124 PCT/U!i99/18233 L
alkyl substituted with phenyl, and C_--C~ straight or branched chain alkeny~~ substi~uted witYa phenyl.
In a preferrf:d embodiment: of formula II, R, is selected from the grcup consi~.ting of C'--Cstraight or branched chain alkyl, 2-cyc:lohc:~yl, ~~-cy~olohe_::~yl, 2--furanyl, 2-thienyl, 2 thiazolyl, and 4-:nydroxybutyl.
In another p_-eferred embcd.iment of formula II, 2 and R, are lipophilic.
FORMULA III
The pyrrolidine derivative may also be a compound of formula III
H
\r,_\ O --Z' N
O III
\ \o O
or a pharmac.eui-.wc_al.y accept<~ble salt, ester, or solvate thereof, wherein:
Z' is f~aamen O
I I
R
wherein:
R; ..s C,-_ , s~~raight ~~r branched chain alkyl or unsubstituted <~~-" ~.~herein s«id alkyl is unsubsti t=oted or substitwt~~d ~.ai'.'~: ~' <:ycloali<yl or Ar,;
SUBSTITUTE SHEEP (RULE 26) WO 00/09124 PC.'T/US99/18233 X, is 0 or RJR;, wherein R,_ is ~selecte<~ from the group consisting of hyd_~ogen, C;-C,; straight or branched chain alkyl, and C~-C~ ~~t:raight or branched chain alkenyl;
R~ is selFect=.ed from the group consisting of phenyl, benzyl, C;-C~ st.r~.ic~ht or branched chair. alkyl, C~-C:; straight or branched chair ,~l.kenyl, C,-C, straight or branched chain alkyl substitutE=d ~;vith phenyl, and C;,--C, straight or br~~nched chain alkenyl substituted with phenyl; and Arl is as de:f:inc~d in formula II.
In a prefer_rE~,~ embodirruent of formula III, a' is lipophilic.
FORMULA IV
Additionally, t_~e pyrr~~-:idine derivative may be a compound of formula IV
Y~Z
N~
\ \ IOI Iv ~X
R~
wherein:
R; is C,-C'6 straight or branched chain alkyl, C,-CE
straight or branched chain alkenyl, ~~,-C,; cycloalkyl or Ar"
wherein said a:Lk:y=_ or alkenyl _~.s unsubstituted or substituted with C;-CE; cycloalkyl or Ar~;
Arl and Ar, :ire independently selected from the group consisting of 2-furyl, 2-thienyl, anc~ phenyl;
X is selected from the group consisting of oxygen and sulfur;
Y is oxygen;
2 i s C;-C;, straight or x;ranchecJ chain alkyl, or C ~-CF
st=might or braruchec? ct-aain alkenyl, wherein said I is substituted wit:n one o- more ~~~ubstituent(,s; independently SUBSTITUTE SHEET (RULE. 26) selected from the group consi:_~ting of 2-furyl, 2-thienyl, C,-C6 cycloalkyl, ~~yr.icyl., and pl-:eny7_, each having one or more substituent(s) independentl~.~ selected from th.e group consisting of tuycir_oc~en and C,-Cq al_koxy.
In a preferred embodiment of formula IV, Z and R1 are lipophi:Lic .
In another_ preferred eir,bod~ment of formula IV, the compound is selec=:ted from the group consisting of:
3- (2, 5-dime t:hoxyphenyl) -1.-oropyl (2S) -1- ( 3, 3-dimethyl-1, 2-dio<~opentyi ) --2-~:~yrrolidinecarboxylate;
3- (2, 5-dimet:ho:~,yphenyl) -1-prop-2- (E) -enyl (2S) -1- (3, 3-dimethy:L--l, 2-dioxopE~ntyl', -2-~;yrrclic.inecarL>oxylate;
2- ( 3, 4, 5-t.:rimethoxypheny:l ) -1-et'riyl (2S) -1- ( 3, 3-dimethyl-l, 2-dioxopentyl ) --2-pyrroli_dirv.ecarboxylate;
3- ( 3-pyridy:l ) -1-oropyl ( 2 >) -1-- ( 3, 3-dimethy:L-l, 2-dioxopentyl ) -2-pyrrolidinecarboxy'~ate;
3- (2-pyri dy1) -1-propyl (2S) -_- (3, 3-dimethy:L-1, 2-dioxopentyl ) -2-pyrrc>l.idinecarboxylate;
3- (9-pyridyl) -1-propyl ;? ~~) -1- (3, 3-dimethy:_-1, 2-dioxopentyl)-2-pyrrc>lidirlecarboxy~ate;
3-phenyl-1-~-~ropyl (2S) -1-- ;?-te,r;:-but~,~l --l, 2-dioxoethyl) -2-pyrro=_i dinecarbox~.~l.ate;
3-phenyl-~-propyl (2S)-1-(2-cyclohexylethy_L-1,2-dioxoethyl ) -2-~:~yr: roi.i.dinecarboxylate;
3- ; 3-pyridy~-) -1.-propyl ( 2 S) -_L- (2-cycl.ohex.ylet:hyl -1, 2-dioxoethyl) -2-pyrrol.i.dinecarbo~;v~late;
3- ( 3-pyri:~y.1) --1-propyl. (2~~) -1- (2-tert-buty=_-l, 2-dioxoethyl)-2-pyrroli.dinecarboxylate;
3, 3-diphe:;ryl--1-propyl ~ ?S) -1 - ( 3, 3-dimethy~.-l, 2-dioxopentyl)-~-p~rrrc>lidinecarbo:;~;~late;
3- ( 3-pyricayl) -1-propyl i a ~) -1- ( 2-cyclohexyl-i, 2-dioxoethyl ) -2-pyr~ro_:.idineca r~:c~::y~ La ~e;
3- ( 3-pyri<:.yl ) -1-prop yl ; 2 S ) -N- ( [ 2-thienyl ]
glyoxyi; pyrrolidin°c:arboxylat:";
SUBS'TI'TUTE SHEET (RULI~ 26) WO 00/09124 PC.'T/US99/18233 -.', 2 3, 3-dipheruy.l_-1-propyl- (2S) -1- ( 3, 3-dimethyl-l, 2-dioxobutyl)-2-pyr.roiid;~necarboxylate:
3,3-diphenyl-l--oropyl (2.:~)-1- cyclohexylglyoxyl-2-pyrrolidineca:roox:yl ate;
3, 3-diphenyl-l-propyl (2~) -1- (2--thienyl) glyoxyl-2-pyrrolidineca_rboxylate; and pharmaceut:i~c:~ll_y accepta);:~le salts, esters, and solvates thereof.
In a more lpreferred embodiment of Formula IV, the compound is selected from the group consisting of:
3-(3-pyridyl)-~-propyi (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3- (2-pyridyl_) -7.-~propyl (2S) ~-1- (3, 3-dimethyl -1, 2-dioxopentyl) -2-hyrrolidinecark>oxylatE=;
3- ( 3-pyri.dya ) -y-propyl (2S) -1.-- (2-cyclohexyl-l, 2-dioxoethyl) -'?-pyrrolic~~.necarbc->;~tylate; and pharmaceut:ical.ly acceptar:~le salts, esters, and solvates thereof .
In the mo:~t~ preferred embodiment of formula IV, the compound is 3- (~-pyri-dyl) -1-propyl (2.S) -1- (3, 3-dimethyl-1, 2-dioxopentyl)-2-1,>yrrolidinecarl:~oxylat«, and pharmaceutically acceptable sa.lt:~, c:st~~rs, and solvates thereof.
FORMULA V
Additionally, she pyrrc>lidine derivative may be a compound of ~ormu.La vl A
V v (),~ ~ O
x SUI3STI7.'UTE SHEET (RULE 26) WO 00/09124 PC.'T/US99/18233 ::. 3 or a pharmaceutically acceptable sa~'~t, ester, or solvate thereof, wherein:
V is C, N, cr S;
A and B, ta~;en t:oget~her with V and the carbon atom to which they are rf=spectively att:ached, foul a 5-7 mernbered saturated or unsaturated heterocyclic ring containing, in addition to V, one c>r more heteroatom ( s ) selected from the group ccnsisting of 0, S, S0, SO-, N, Nfl, a:zd NR;
R is either t:,--C, straight or branched chain alkyl, C?-C~
straight or branched chain a:'~kenyl, Cj-Cy ~~ycloalkyl, C;-C., cycloaikenyl, cr Ar;, wherein R i=s either unsubstitut.ed of substituted with cne or rnorc~ sub stituent ( s) independently selected from thle grou~> consisting of halo, haloalkyl, carbonyl, carboxyl, hydroxy, vitro, trifluoromethyl, C1-C6 straight or branched chain alkyl., C,,--C,; straight or branched chain alkenyl, C,-Ca alkoxy, C,-C, alkenyloxy, phE:noxy, benzyloxy, thicalkyl, alkylthio, sulfhydryl, ~~mino, alkylamino, ami_nc:a«k:yl, amino-:arboxyl , and Ar,;
R, is Cc-C', straight o-r branched chain alkyl, C~-Ca, straight or branched chaff n ,~ ~ kenyl, C,-C,, ~~yeloalkyl, C;-C., cycloalkenyl or Ar" ;wherein said R, is unsubstit:uted or substituted with one or r~uo~e ~ub~~tituent.s indepen<~ently selected from tl-~e group consisting of C.-CE alkyl, Cl-Cb alkenyl, C3-Cr cycl.oalkyl, c' ---C-, c:ycloal.kenyl, hydroxy, and Are;
Arl and A.r, are independent_~y an alicyclic or aromatic, mono-, bi- or tric:ycl-i-c, c.arbo- c>r het:erocycLic ring, wherein the ring is either unsubsti~u'ed or substituted with one or more substituent (s) ; where:. r: ~ ze ;~~ndi~~-idual ring size :is 5-8 members; wherein ~>aid ~~et=~~~~ocycl_c ring contains 1-6 heteroatom(s) indeoendenCl,~ selected from the group consisting of 0, N, an:i ;
X is 0, S, C:H, ~r f-t~;
Y is O or N~." V::~:erei.r: E~.., is r;ydrogen on C=-C;, alkyl; and SUBSTITUTE SHEET (RULE 26) WO 00/09124 PC.'T/US99/18233 Z is C,-C;; straight or branched chain alkyl, or C-Ch straight or branched chain n:L~:eny~., ~,,~herein said Z is substitui_ed with once: cr more substituent (s~) independently selected frcm the group consi:'t=inct of Ar" C:;-C;; cyc=Loalkyl, and C,-C~ straight. or branched chain alkyl or C,-C;, straight or branched chain al~:enyl substituted with CJ,-C~, cycloalkyl;
or Z is fragment.

-CH XL R~

wherein:
R3 is C1-C~ straight or 1_: ranched chain alkyl which is unsubstit~uted or sub:>t:ituted t,~~i.th C.-C;, cycloalkyl o:r Ar,;
Xz is C or I~dRS, wherein R.; is selected from the group consisting of hydrogen, C,-C, straight or branched chain alkyl, and C,-Cf, straight or br anched chain alkenyl; and R~ is sele~sted from the a=oup consisting of phenyl, benzyl, C'.1-C., st=rai.ght: or brancined chain alkyl, C;,-C~ straight or branched c:ha=~n alkc=nyl, _-i:, straight or branched chain alkyl substituted with phenyl, <~nd : , -C., straight or ;;>ranched chain alkenyl sub:>tituted wv~th phenyl.
All the compounds of ~oT-mulas I-V possess asymmetric centers and thus can be producFd as mixtures cf stereoisomers or as individual R-- and ;=~- slv.ereoisomers . The individual stereoisomers may be obtained by using an optically active starting material., t:>y resolvi.ng a racemic or non--racemic mixture of an int~cermediat,~ at= some appropriate stage of the synthesis, or by resc:lW.ng t°le compounds of Formulas I-t,'. It is understood that t_he comoou:Id~~ ~~~f F'crmul.Gs I-V encompass individual stereoisomers as well as mixtures (racemic and non-racemic) of s ~er~~oi sornf~rs . Preferably, S-stereoisomers SUF3STITUTE SHEET (RULE 26) WO 00/09124 PC'1'/US99/18233 are used in the pharmaceuti~:a~_ compositions and methods of the present invent_iou.
Synthesis of P~Srrolidine Derivatives The com~;ourud~ oi_ formula,: I to V may be prepared by a variety of :::ynt_hc=_ti:' seauences that utilize established chemical transformations. 'The general pathway to the present compounds is described in :>cheme I . T~-glyoxy7_prol ine derivatives may rye p:repared oy reac:ting L-proline methyl ester wit=h methyl o:~alyl chlorv_de as ahown in Scheme I. The resultincx oxamate~ may be rea-::ted with a variety of: carbon nucleophiles tc> obtain :Lnt~:rmediat.e compounds. These intermediates are thel; reactec:~ with a variety of a=_cohols, amides, or protertec:~ ami no acid residues to obtain the propyl esters and amide->s of the _irmernt=ion.
SCHEME I
O
,~ OCf-i:
C' I
<)Cf-I~ « ~ OCH3 RI_i orRMeX
1 ~ - -; N
O r)~ O
O
R
OCH, L~H OCI-I, y MeOf I/I-(,O ~ Coupling _ O~ ~.> O~ O Method ,~ \O
R fZ
(>~ () () R
The substitutE:d aicohols may be prepared ~oy a number of methods known ro :,hose sk,~lled i_~ the arr_ cf organic SUBSTITUTE SHEI~T' (RULE: 26) WO 00/09124 PCT/U >99/18233 synthesis. As described ir. Scheme II, alkyl or aryl aldehyde,s may be hom~~logated to phenyl propanols by .reaction with met::~yl(triphE=ny:Lphosphoranyli.dene)acetate to provide a variety ~~f t:rans-c:.innamates; these hatter may be reduced to 5 the saturated alcohols by reactioru with excess lithium aluminum hydride, or sequentially by reduction of the double bond by catalyt:i_c hydrogen~:t~ioru and reduction of the saturated ester by appropriate reducing agents.
Alternatively, t'ze r_rans-cinn_~mate.- may be reduced to (E)-10 allylic alcohols J:~y the use of diisobutylaluminum hydride.
SCHEME II
I,'dhium alurr>mum P ft3P=C HC_' OOCH3 hydrtle R-CHO -.---r~ R~ (:'OOCH~ _-~ R!~/\ OHf 'rHF
Diisobutylalurninum ~ p-(~ Lithium aluminum hydride ~ I ~C hydride or Diisobutylalurninum hydride R~~OEI R~'~~JOCH:
15 Longer chain alc:ohols rnay bt~ prepared by homologat__on of benzylic and higher aldehydes. A-~.ter:~atively, these aldehydes may b<: ~-repared by conversion of the corresponding phenylacetic and oigher acids, and phenethyl and higher alcohols.
Affinitv for FKBP12 The compounds used in the inventive methods and pharmaceutical compositions ha«can af_finivy for the FK506 binding protein, part icular ly F KBP12 . The i.nhibitic>n of the prolyl p~ept.idyl c_~is--traps isomerase activity of FKBP ray be measured as an induc:ator of t:~i~ affinity.
SUBSTI'TU'TE SHEET (RULE 26) WO 00/09124 PC'T/U~i99/18233 Ki Test Procedure Inhibition of t_he peptidy=L-proll~l. isomerase (rotG.mase) activity of the c:~mpounds used in the inventive methods and pharmaceutical compositions can be evaluated by known mE:thods described in the literature lHardi.ng et al., Nature, 1989, 391:58-760; Holt et al. J. Are. Ch em. Soc., 115:9923-9938) .
These values are obta~..ned as apparent. K;'s and are presented for representative compounds in TABLE A.
The cis-tr:~n.s isomeri.zation of an alanine-proline bond in a model :substrate, IV-succ:inyl-Aia-Ala-Pro-Phe-p nitroanilide, i_s monitored spectr«photometrically in a chymotrypsin--coupled assay, wr;icln releases para-nitroaniiide from the traps fo~:m cf the sub:>trate. The inhibition of_ this reaction caused b:y the addition of different concentrations of inhibitor i s determined, ~~nd the data i_s analy zed as a change in first-order rate constant as a function of inhibitor concentration to yield the apparent K: values.
In a plast::i~~ cuvette are added 950 ml c>f ice co'~d assay buffer (25 mM HE~PI~, pH 7.8, 100 mM NaCl, 10 m1 of F'KBI? (2.5 mM in 10 mM 'T'ris-C1 pH 7.5, 100 mM NaCl, 1 mM
dithiothrei'_.ol ; , :?5 rnl of chymrtrypsin (50 mg/ml. in 1 mL~l HCl) and 1.0 ml of ~es' compound at various concentrations in dimethyl sulfo:~cide. The reaction is initiated b;~ the addition of 5 ml of substrate (.:;uccinyl--Ala-Fhe-Pro-Fhe--para-nitroanilide, ~ mg!ml in 2.35 mM LiCl in trifluoroethanol).
The absorbance at 390 nm versus 'time is monitored for 90 seconds using a spectrophotometer and the rate const.anvs are determined from the absorbance versus time data files..
~UBS'Tl'TUTE SHEET (RULE 26) WO 00/09124 PCT/U~~99/18233 In V? r-_ro T:~:~t Results - Formulas I to V
TABLE A
O-Z
N
\ \
\() ~) R~
TABLE A

In y'.it=r~~ Test Results - ~ormul_as L to V

No. 2 F;1 K;

1 1, 7- ~-phenylpropyl 9a?

dimethyl-propyl.

2 " 3-phenyl--prop-2- (E) -enyl 1:?5 3 " _.- (3, 4, 5- 200 trimetnoxyphenyl)propyl 4 " _.- ( 3, 4 , 5-t. rimethoxyphenyl65 ) prop-_-(E)-enyl 5 " _.- (9, 5- 1'70 methylenedio:~y)phenylpropyi 6 " 3- (4, 5- l00 mE:thy7_enedioxy) phenylprop-2-f E; ) -enyl 7 " 3-cyclohexylpropyl 200 8 " 3-cyclone: yl prop-2.- (E) -E:nyl600 9 " ; 1R) -1 , :~-di.phe:~yl-1- propyl52 10 2-zuranyl 3--phenylpropy.l 4000 11 ?-thien~ul " 9?

12 ~--tr:i_a~o-! " 100 .~!

SUBSTITUTE SHEET (RULE 26) WO 00/09124 PC'T/US99/18233 TABLE A ( ,_ ont i aaad ) In V.it-~o Test Results - Formulas I to V

No . 2 Iil K;

13 phenyl " 1070 14 l, 1- ?- (?., 5-dims-Jthoxy ) phenylpropyl2.'p0 dimethyl-propyl " 3- (2, 5-dim~~thoxy) phenylprop-2-450 ( E) -enyl 16 " :%- (3, 4, 5-trimethoxyphenyl) 1a?0 ethyl 17 " ~-(3-pyridyl)propyl 5 18 " ?-(2-pyrid yl)propyl 195 10 19 " ~-(9-pyridyl)propyl 23 cyc:lohexyl _-phenylpropyl 8a?

21 tent-butyl 22 cyc:lohexyl- " 1025 ethyl 23 cyc:lohexyl.- _- ( ?-pyridyl) propyl 1400 ethyl 15 24 ter_t_-butyl ~-(3-pyridyl)propyl 3 1, . , 3-diphenylprcpyl 5 dimethyl.-propyl 26 cy<:loher.y~. ~- ( 3-pyridyl; propyl 9 27 2-t:hienyl 3-(3-pyridyl.;propyl 1000 28 tent-butyl ?,3-diphenylpropyl 5 20 29 cyclohexyi " 20 2-thieny~_ " 150 SU13STITLJTE SFIEET (RULE; 26) Route of Administration To effective:Ly treat vision loss or promote vision regeneration, the compounds used i_n the inventive methods and pharmaceutical corr,positions mu:~t readily affect the targeted areas.
Other routes of administration known in the pharmaceutical art. are also contemplated by this invention.
Dosage Dosage level: on the order of about 0.1 mg to about 10, 000 mg of the active ingredienr_ compound are useful in the treatment. of the ~:boz~e condit;ons, with pref=erred levels of about 0.1 mg to about 1,000 mg.. The specific dose level for any particular patient will vary depending upon a va__iety of factors, including tre activ~ty of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the rage of excretion; drug combination; she severity of the particular disease being treated; and the form of administration.
Typically, in ~.~i~_:rc dosage-E fect results provide useful guidance on the proo~~r_ closes for patient adminisi~ration.
Studies in animal models are also helpful. The considerations for :determining the proper dose levels are well kno~,an in the art., The compound: can be administered with other agents for treating vision Loss, preventing vision degeneration, or promoting vision. regeneration. Specific dosE: levels for such other agents will depend ~mon the factors previously stated and the effectiveness of the ~lr ug combination.
The followin:~ exarr:pl es a~ve illustrative of the present i nvention and are rot ~ ntendecA to be l.imi tations thereon.
SUI3S'TITUTE SHEET (RULE 26) WO 00/09124 PC'C/US~99/18233 4i Unless otherwise indicated, a:11 percentages are based upon 1000 by weight of the final cr_:mposition.

Synthesis of 3-phenyl-1-propyl (2S) -1- (3 , 3-dimethyl-7.~2-dioxopentyl)-2-pyrrolidinecarboxylate (1) Methyl ( 2 S) -1- ( 1, 2-d:ioxo--%-methoxyethyl )-2_-pyrrolidinecarboxylate A solution of L-proline methyl ester hydrochloride (3.08 g; 18.60 mmol) in. dry methylene chlc>ride was cooled t.o 0°C
and treated with t:riethylamine (_5.92_ g; 38.74 mmol; 2.1 eq) .
After starring t:he f~~rmed slurry under a nitrogen atmosphere for 15 min, a :.;oluti_on of methyl oxalyl chloride ;3.20 g;
?_6.12 mmo,!_) in me t:hylene chloride (45 ml) was added d:ropwise.
The resulting mixture was stirred a~ 0°C for 1.5 hour. After filtering tc remove solids, thc: organ~_c phase was washed with water, dried oVer_ MgSC)~ and concentrated. The crude residue was purified on a silica gel column, eluting with 50% ethyl acetate in hex.ar~e, t.o obtai:: .52 ~l (88'-a) of the product as a reddish oil. I~lixt:ure of cis-t:rans amide rctamers; data for trans rotamer g:iven. 'H NMR. ;~:'DC1.,) : d 1.93 (dm, 21~) ; 2.17 (m, 2H); 3.62 (m, ?H); 3.71 (s, 3H); 3.79, 3.84 (:~, 3H
total) ; 4.86 (dd, 1H, .~ = 8.4, 3. 3) .
Methyl_ (2S-1-':L, 2-dioxo-~?, 3-dimethvlpent~y7.)2-pyrrolidinecarbox~l.
A solution of: methyl (2S) -1- ( 1, 2--dioxo-2-methoxyethyl) -2-pyrrolidineca.r.bo~;ylate (2.35 g; 10.90 mmol) in 30 ml of tetrahydrofuran (THF) was cooled t~~ -78°C and treated with 19.2 ml of a 1.0 M solution <:= l, ~~-di_methylpropylmagr_esium chloride in TI-IF. ?~~:t.er stirrn:; the resulting homogeneous mixture at -78"C 1_oi_ three hnv,~-:~, tl-:e mixture was poured into saturated anunonium chloride (=_'~0 ml; and extracted into ethyl acetate. The organic: phase wa:~ washed with water, dried, and concentrated, and the crude ma'~.~;-~~a1 obtained upon remo~ral of the solvent was purifs.ed on a >ili~~a qel column, eluting with SiJ>E3STITLITE SHEET (RULE; 26) WO 00/09124 PC'T/US99/18233 >?
25 o ethyl acetate in hexane, '=o obtain 2 . 10 g (75 0 ) c~f the oxamate as a colorless oil. =H. NMR (CDCl,,): d 0.88 (t, 3H);
1.22, 1..26 (s, 3f-i e;~ch) ; 1.7'; (dm, 2H) ; 1.87-2.10 (m,. 3H) ;
2.23 (m, lEi) ; 3. '.~4 (m, 2H) ; _..76 (s, 3H) ; 4. 52 (dm, 1H, 8.4, 3.4).
Synthesis of~- ;2S)-1.-(1,2-dioxo-3,3-di-methylpentyl)2-2-pyrrolic~inecarbo::y,lz-c acid A mixture of methyl (2S) -7.- ( l, 2-di.oxo-3, 3 dimethyl_pentyl)-2-pyrrolidine::;~rboxylate (2.10 g; 8.:23 mmol), 1 N LiOH (15 ml) , an:~ methanol_ (50 ml) was stirred at C°C for 30 minutes and at room temperature overnight. The mixture was acidified t:o pH 1 with 1 N HC1, diluted with water, and extracted into _1Ge) ml of methylene chloride. The organic extract was washed with brine and concentrated to deliver 1.73 g (87°) of snow-white solid which did not r~~quire further purifv~ca~:iorv. 'H NMR (CDCI-,) : d 0.87 (t, 3H} ; 1.22, 1.25 (s, 3H each); 1.'77 (dm, 2H); 2.02 (m, 2H); 2.17 (m, 1H);
2.25 (m, 1H); 3.'v3 (dd, 2H, . - 10.9, 7.3); 4.55 (dd, =_H, 8.6, 4..L) .
3-Phenyl-1-propy_= ;2S) -1 - (3, 3-dimet.hyl- 1 , < -dioxopenr_yl1 -2-wrrolidinecarbo:~vlate (1) A mixture c_~f ;2S) -1- ( 1 , 2.-dioxo-3, 3-d~methylpE:ntyl) -2-pyrrolidine-carboxy_'~ic acid (500 mg; 2.49 mrnol), 3-phenyl-1-propano:l. ( 508 rng; 3 .. % mmol ) , dicycl_ohexylcarbodiir~ide ( 822 mg; 3. 98 mmoi ) , camphorsulfonic acid ( 190 rng; 0 . 8 rnmol) and 4-dimetilylaminop~,~r. idine ( 100 mg; 0 . 8 mmol ) in rnethylene chloride (20 ml) was stirrEd overnight under a nitrogen atmosphere. The react-on mz.xture was filterecx through Celite to remove solids ar;d concentrated in vacuo, and t-:he crude material ~faas pur i f ied on a flesh column (25a ethyl acetate in hexane) ~o obtain ?20 mg (80=x) of Example i as a colorless oil. 'H NMR, (CDC:l,) : d 0.84 ; ~, 3H) ; 1.19 (s, 3H) ; 1 .23 (s, 3H); i.7J (dm, 2l-f); 1.98 (m, 5H); %.22 (m, 1H); 2.~9 (m, 2H);
3.47 (m, 2H); ~1.1~ im, 2H); 4.5:~ (d, 1H); 7.16 (m, 3H); 7.26 (m, 2H) .
SLBST'ITUTE SHEET (RULE 26) WO 00/09124 PC'T/U~~99/18233 Example 2 The method ~:~f r;xample 1. was utilized to prepare the followinc illustrati,~e compounds:
Compound 3-phenyl--I--prop-2 - (E) y.1 (2S) -~_- ( 2 : -en 3, 3-di-mevhyl-1,2-dioxopentyl)-2-pyrrolidinecarbox ylate, 800. 'H
(360 I\IMR

MHZ, CDCi~) : d 0.86 (t, 3H); 1.21 (s, 3H); 1.25 (s, 3H);

1.54-2. 10 (m, 5H) ; a'.-~0-2.37 (m, 3.52-3.55 (m, 2H) 4.56 1H) ; ;

(dd, 1H, .~ = 3.8, 8.91 ; 9.78-4.'33 a'.H) ; 6.27 (m, 6.
(m, 1H) ; 67 (dd, 1H, = 15. 9j ; 7..13-7.50 (m, ) .
.~ 5H

Compound 3 : 3- ( 3, 4 , 5--trimethoxyphenyl ( ) -1-propyl ( 2 S) -1- 3, dimethyl--1 , 2-dioxcpentyl) pyrrolidine- carboxylate, 61 -2- 0.

'-H NMR (CDC13) : d 0.89 (L, H) ; 1.15 3H) ; 1.24 3H) 3 (s, (s, ;

I5 I.71 (dm, 2H); 1.98 (m, 5H);2.29 (m, 1H);2.63 (m, 2f3);3.51 (t, 2H); 3.79 (s, 3H); 3.83 (s, 3H); 4.14(m, 2H); 9.5 2 (m, 1H); 6.36 (s, 2H).

Compound 4 : ~- ~; 3, ~, 5-t ri-metroxyphenyl ) -1--prop-2- ( E ) --enyl (2S)-1-(3,3-dimethyl-1,2-d~cxopentyl)-2-pyrrclidine carboxylate, 66a. '-H NMR (CDC.:~~) : d 0.85 (t, 3H) ; 1..22 (s, 3H); 1.25 (s, 3Hi; 1.50-2.11 (m, 5H); 2.11-2.40 (m, 1H); 3.55 (m, 2H) ; 3. 85 (s, 3H1 ; 3. 88 (s, 6H) ; ~1 . 56 (dc~, 1H) ; 4. 81 (m, 2H) ; 6.22 (m, 1~?) ; 6.58 (c:, 1H, .~ = 16) ; F>.63 (s, 2H) .
Compound -1-propyi ) 5 : ( -1-3- ( 2 9 , S
5-rr.ethylene dioxyphenyl ) ( 3, -dimethyl-J_, 2--dic>opentyl;l -2-pyrrolidine- carboxyl ate, 820. H NMR (360 MHZ, CDC.L,) : d 0.86 3H) 1.22 (s, 3H) (t, ; ;

1.25 (s, 3H); 1.60-2.10 (m, 5H); 3.36-3.79(:r.,2_H); 4.53(dd, 1H, = 3.8, 8.6); 9.61-4.89 (m, 2H); 5.96(s, 2H); E3.i0(m, .~

1H) ; 6. 57 (dd, 1H, .~ _:. 6.2, 15. f3) lf~,.~ = 8.0) 6.83 ; 6.75 (d, ;

(dd, IH, .~ = 1.3, 8.0;. ; 6. 93 (;, 1H) .

Compound 6: 3-(9,5-mE~thylenedioxyphenyl)-l-prep-2-(E)-enyl ( 2 S ) - 1 - ( 3 , 3 -- d i m a t h y 1 - 1 , ?_ - d i c ~. o ~ a n t y 1 ; -SU13ST'ITUTE SHEET (RULE 26) WO 00/09124 PC'i'/US99/18233 4 ,~:
pyrrolidi-necarboxylate, 820.'H NMR (:360 MHZ, CDC13) d 0.86 :

(t, 3H); 1.22 (s, 3H); .25(s, 3H); 1.60-2.10 (m, 2.10-1 5H);

2.39 (m, 1H); 3.36-3.79 (m,'?E~); 4.53 (dd, 1H, ~ 3.6);
= 3.8, 4.61-4.8~j (m, 2H); 5.96 (s,2H;; 6.10 (m, 1H; 6.57 d, (d 1H, .~ = 6.2, 15.8) ; 6.'75 1H, (d, .l = 1.3, , = 8.0) ; 6.83 (dd, 1H, 8.0); 6.93 (s, 1H).

Compound 8 3-cyc -ohexyl--1--prop-2- (E) -enyl (2S) : --1- (3, 3-dimethyl--l, 2-dicxoperatyl ) -2-pyrrolidinecarboxylate, 92'-, . --H

NMR (360 MHZ, C:DClj): d 0.86 (t, 3H) ; 1.13-1.40 (m + 2 singlets, 9H ot=al)1.50-1.8'' (m, 8H) ; 1.87-2.94 (m, t ; 6H) ;

3.34-3.8a? (m, 2H); 4.40-4.76 (m, 3H); 5.35-5.60 (m, 1H);

5. 60-5. 8a? (dd, 1H, = 6. 5, 16 i .
.~

Compound 9: (1R) -7-, ~3-biphenyl- -propyl (2S) -:L- (3, 3-dimethyl 1, 2-dioxopentyl ) -2-p5~rrolidinecarbox_ylate, 90 0 . ~H NMR ( 360 MHZ, CDC13): d 0.85 (t, 3H); 1.20 s, 3H); 1.23 (s, 3H);
1.99-2.39 (m, 7H); 2.46-2.86 (m, 2H); 3.25-3.80 (m, 2H);
4.42-4.8:? (m, iH) ; '3.82 (td, 13:, .~ = 1..8, 6.7) ; 7.05-'7.21 (m, 3H) ; -7.?_-:L-7.46 ;m,. 7L~) .
Compound 10: 3-phenyl-1-propyl (2S) -1- (1, 2-dioxo-2- [2-furanyl ] ) ethyl-<'_-~:>yr.rolidinecarboxylate, 99% . 1H I~IMR ( 300 MHZ, CDCl~) : d 7-. E>6-?.41 (m, 6,-i) ; 2.72 (t, 2H, ~ = 7. 5) ; 3.75 (m, 2H); 4.21 (rr., 2H); 4.51 (m, 1H); 5.58 (m, 1H); 7.16-7.29 (m, 5H) ; 7.73 y:,, 2H;: ..
Compound 11: 3-phenyl-1-propyl (2S)-1-(1,2-dio:~o-2-[2-thienyl])ethyl-~%-~yrrol_-idinecarboxylate, 810. 1H NMR (300 MHZ, CDClj) : d 1.8E3-a?.41 m, 6H) ; 2.72 (dm, 2H) ; 3.72 (m, 2H); 4.05 (m, 1H); 4.'2 (m, 1H); 4.69 (m, 1H); 7.13-7.29 (m, 6H) ; 7 . 75 (dm, 1~-ly ; ~ . ~~5 (m, '. H) .
Compound 13: _-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-phenyl)ethyl-2-~~yrro~~ldinecar'~oxylate, 990. 'H NMR. (300 MHZ, SLIBST(TUTE SHEF~T (RULE 26) WO 00/09124 PC'T/U~;99/18233 CDC13) : d 1. 97-2. ~;2 (m., 6H) ; 2.74 (t, 2H, ~ = 7. 5) ; 3. 57 (m, 2H); 4.24 (m, 2H); 4.67 (m, 1H); 6.95-7.28 (rr;, 5H); 7.51-7.64 (m, 3H) ; 8.03-8.0':~ (rn, 2H) .
5 Compound 14: 3-(?,5-dimethoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl -1, 2 -diox~~pentyl ) -2-p~,~rrolid~_ne-carboxylat.e, 99 .

1H NMR (_300 MHZ, C:DC13) : d 0. <37 (t, 1.22 (s, 3H) 1.26 3I-f) ; ;

(s, 3H); 1.69 (rn, 2H); 1.96 (m, 5H); 2.29 (m, 1H); 2.68(m, 2H); 3.55 (m, 2f-I); 3.75 (s, 3H); 3.77 3H); 4.17 (m, 2H);
(s, 10 4.53 (d, 1H) ; 6.72 (m, 3H) .

Compound 15: ~-(2,5-dime::hoxyphenyl)-1-prop-2-(E)-enyl (2S)-1- (3,3-dimet=hy~~-1,2-dioxopentyl)-2-pyrrolidine-carboxylate, 99s. 'H NMR (300 MHZ, CDCl,): 0.87 (t, 3H);
d 15 1.22 3H); 1.2~:~ (::~, 3H); 1.67 (m, 2H); (m, 1H); 2.07 (s, 1.78 (m, 2H); 2.26 (m, 1.H); 3.52 (rn, 2H); 3.78 3H); 3.80 (s, (s, 3H) ; 4. 4 ~-H') ; 4.81 (m, 2H; ; 6.29 (dt,1H, 5~ (m, .) .- 75 .
9 ) ;

6.98 (s, 1H).

20 Compound 16: 2- (3,, 4, 5--trimethoxyphenyl-) -1-et:hyi (2S) -1-- (3, 3-dimethyl-l, :?-dio~;opentyl ) -2-pyrrolidine- carboxylat:e, 97 0 .
=H NMR (300 MH?, CDC~~) : d 0. 84 (t, 3H) ; 1. 15 (s, 3H) ; 1.24 (s, 3H); 1.71 (dm, 21-i); 1.98 (m, 5H); 2.24 rm, 1H); 2.63 (m, 2H) ; 3. 51 (t, 2f4) ; ~ .79 (s, 3H) ; 3. 83'~ (s, 3~f) ; 4 . 19 (m,. 2H) ;
25 4.52 (m, 1H); 6.36 (s, 2H).
Compound 17: 3-(~~-Pyridyl)-_:-propy:l (2S)-1-(3,3-dimethyl-l, 2-dio~:opent~-~l) -2--pyrrolidinecarboxylate, 80 0 . '-EF NMR
(CDCl" 300 fHHZ) : c~ 0.85 (t, 3H) ; 1..23, 1.26 (s, 3H each) ;
30 1 . 63-1. E!9 (m, 2H) ; 1. 9C-2. 30 (m, 4f) ; ~'. 30-2. 50 (m, 1H) ; 2.72 (t, 2H) ; 3.53 (m, :?H) ; 4.19 (m, 2f-i) ; 9.53 fm, 1H) ; 7.22 (m, 1H); 7.'_~3 (dd, 1H); 8.45.
Compound 18 : 3-- ('2--Pyridyl ) --1-F>ro:>yl. ( 2S) --1- ( 3, 3-dim~=thyl -35 l, 2-dioxopentyi) --2-pyrrol_idir.F~c~~rbo;:y late, 88 0 . 1H NMR
SUBSTITUTE SHEET (RULI~. 26) WO 00/09124 PC'T/U~>99/18233 4p (CDC13, 300 MHZ) : d 0.84 (t, ~H; ; 1.22, 1.27 (s, 3Fi each) ;
1.68-2.32 (m, 8H) ; 2.8'8 (t, 2H, . - 7.5) ; 3. 52 (m, 2H) ; 4.20 (m, 2H) ; 4. 51 (m, 1H) ; 7. 09-7. 19 (rn, 2H) ; 7. 59 (m, 11:) ; 8 . 53 (d, 1H, .~ = 9.9) .
Compound 19: 3-(4-Pyridyl)-1-propyl (2S)-1-(3,3-d_imethyl-1, 2-dioxopentyl) -~.-pyrrolidinecarboxylate, 91% . 1H NMR (C:DC1_"
300 MHZ) : d 6. 92--6. 80 (m, 4H) ; 5.28 (m, 1H) ; 5.25 (d, 1H, .~
- 5.7) ; 4.12 (m, 1~-I) ; 4.08 (s, 3H) ; 3.79 (s, 3H) ; 3.30 (m, 2H); 2.33 (m, 7H); 1.85-1.22 (rn, 7H); 1.25 (s, 3H); 1.23 (s, 3H) ; 0.89 (t., 3F~, .~ = 7. 5) .
Compound 20: 3-phenyl-1-propy-~ (2:~)-1-(2-cyclohe:~yl-1,2-dioxoethyl)-2-pyrrolidinecarbc:xylate, 910. 'H NMR (CDCl-" 300 MHZ): d 1.09-1.3;~ (r.~, 5H); 1.62-2.33 (m, 12H); 2.69 (t, 2H, = 7.5) ; 3. 15 (dm, 1H) ; 3. 68 (m, 2H) ; 4. 16 (m, 2H) ; 4.53, 4.84 (d, 1H total; ; 7. 19 (m, :3H) ; 7.'<?9 (m, 2H) .
Compound 21 : ~--phi-~ryl-1-propy_L (2:~) -1- (2-tert-butyl-1, 2-dioxoethyl) -2-pyrrolidinecar bc.~:~ylate,. 92° . 'H NMR (CDC1:, 300 MHZ): d 1.29 (s, 9H); 1.94-2.03 (m, 5H); 2.21 (m, 1H); 2.69 (m, 2H); 3.50-3.~? (:n, 2H); 4.16 (m, 2H); 4.53 (m, 1H); 7.19 (m, 3H) ; 7 . 30 (in, 2I~) .
Compound 22: 3-phenyl.-1-propyl(2S)-1-(2-cyclohexyl-ethyl-1, 2-dioxoethy l j --2-pyrrolidinec;arboxylate, 97 0 . 1H NMR (CDCl i, 300 MHZ): d 0.88 (rn, 2H); (m, 4H); 1.43-1.51 (m, 2H);
1..16 1.67 (m, 5H); 1.94-2. O1 (m, 2.66--2.87(m, 4H); 3.62-3.77 6H;~;

(m, 2H) ; 4. 15 (rn, 2I-~) ; 4.86 1H) ; -7.32 (m, 5H) .
(rn, 7. 17 Compound 23: 3-- ( 3-pyri_dyl ) -1-m:-opyl (2S) -1- (?-cyclo-hexylethyl-l, 2-~~?i.oxoethyl) -2-,ayrrolidinecarboxylate, 70° . 'H
NMR (CDClj, 3001 !~~?2) : d 0.87 (m, 2H) ; 1.16 (m, 4H) ; 1.49 (m, 2H); 1.66 (m, 4~~); ~-.95-2.32 gym, 7H); 2.71 (m, 2H); 2.'35 (m, SUBSTITUTE SHEET (RULE 26) WO 00/09124 PC'T/U;599/18233 2H) ; 3.63-3.78 (m, 2ff) ; 4.19 (rr~, 2H) ; 5.30 (m, 1H) ; 7.c3 (m, 1H) ; 7.53 (m, 1-H) ; 8.46 (m, 2f-!) .
Compound 24 : :=I- 3-pyridyl) -1-propyi.(2S) -1-; (2-tert-)v~utyl-l, 2-dioxoethy_L pyrrolidinec:arboxylate, 83 -H NMR (CDCl~, ) -2- 0 .

300 MHZ) : d 1. (s, 9H) ; l.':~5-2.09(m, 5H) 2.31 (m, 1H) 29 ; ;

2. 72 (t, 2H, .~ . 5) ; 3.52 (r-v, 9 . 18 2H) ; 4. 52 --- ~i 2H) ; (m, (m, 1H); 7.19-7.25 (m, 1H); 7.53 m, LH); 8.46 (m, 2H).

Compound 25 : 3, 3-Biphenyl-1-propyl- ( 2S) -1- ( 3, 3-dimethy~_-l, 2-dioxopentyl)-2-py:rrolidinecarboxylate, 990. vH NMR. (CDCl_"
300 MHZ): d 0.85 (t=, 3H); 1.2:i., 126 (s, 3H each); 1.68-2.04 (m, 5H); 2.31 (m, 1H); 2.40 (rn, 2H); 3.51 (m, 2H); 4.08 (m, 3H) ; 4. 52 (m, l:~l) ; ~7. 18-7. 31 (m, lOH) .
Compound 26: 3-y3-pyridyl) -1~-propyl -cyclo- hexyl-(2S) -1- (2 1,2-dioxoethy l)-~-pyrrolidine,;arboxylate,88~. 'H NMR (CDC1;, 300 MHZ) : d l.a?4--i.28 5H) ; i.88-2.35(m, 11H) ; 2.'72 (m, (t, 2H, ~ = 7.5); 3.00-3.33 (dm,1H); 3.6(~ 2H); 4.19 (m,.
(m, 2H);

4. 55 (m, 7.20-7. 24 1f-I;~ ; , 1I-1)8. 47 (m,, 1H) ; (m, .5~~ (m, ; 2H) .

Compound 27: _.-(3-Pyridyl)-i-propyl (2~~)-N-([2-thienyl]
glyoxyl)pyrrolidinecarboxylate, 49~. ~H NMR (CDCl" 300 MHZ):
d 1 . 81-2 . 39 (m, F_sH) ; 2. 7 2 (dm, 2H) ; 3. 73 (m, 2H) ; 4 . a?1 (m, 2H); 9.95 (m, 1H); 1.19 (m, 2H); ?.67. (m, 1H); 7.80 (d, 1H);
8.04 (d, 1H); 8.46 (m, 2H).
Compound 28 : 3, 3-Di phenyl-1-p=opyl (2S) -1- (3, 3-dimet.hy.1-1, 2-dioxobutyl) -2-py.rro-~ idinecarboxyiate, 99 0 . IH NMR (CDC__., 300 MHZ) : c~ 1.27 (s, 9fi) ; 1. 96 (m, 2Ea) ; 2.44 ~;m, 4H) ; 3. 49 (m, 1H) ; 3.64 (m, 1f-I) ; 4.08 (m, 4H) ; 4.53 (dd, 1H) ; 7.24 (m, lOH) .
Compound ?9: ', 3-Dipheny; 1-1 -propyl (2S) -1-cyclohexyl alyoxyl-:?-pyrr~_~l:idi=.zecarboxy;:a~e, 91° . 'H NMR (CDCl-" 300 SUBSTITUTE SHEET (RULE 26) WO 00/09124 PCT/U!i99/18233 MHZ) : d 1.32 ~;m,, 6H) ; 1.54-?.41 (m, 10H) ; 3.20 (dm, 1H) ;
3.69 (m, 2H); 4.12 (m, 4H); 4.52 (d, 1H); 7.28 (m, 10H).
Compound 30: 3,3--DiphenyL-1-propyl (2S)-1-(2-thienyl) glyoxyl-2-pyrroli.dinecarboxylate, 750. 'H NMR (CDCl;" 300 MHZ) : d 2. 04 (m, 3H) ; 2.26 (rn, 2H) ; 2.48 (m, 1H) ; 3. ; 0 (m, 2H) ; 3. 82-4. I8 (m, ~H total) ; 4 . 64 (m, 1H) ; 7 .25 (m, 11H) ;
7.76 (dd, 1H); 8.03 (m, 1H).
Example 3 General procedure for the synthesis of acrylic esters, exemplified fcr met=hyl (3, 3, 5-trimethoxy) -traps-cinnaraate.
A solution oj_ 3, 4, 5-trimethoxybenzaldehyde ( 5. 0 g; 25. 48 mmol) and methyl (tr.iphenyl- phosphoranylidene)acetate (10.0 g; 29.91 mmo7.) i_n tetrahydrofuran (250 ml) was re;=luxed overnight. After cooling, th~a reaction mixture was diluted with 20C) ml o' e~:.hy:l acet:at:e and washed with 2 x 200 ml of water, dried, anci c~a:ncentrated in vacuo. The crude residue was chromatographed on a silica gel column, eluting with 250 ethy'~ acetate iru hf;:~ane, to obtain 5.63 g (880) cf the cinnamat_e as a white crystalline solid. 'H NMR (300 MHz;
CDCl_~) : d 3.'78 (a, 3H) ; 3.85 (s, 6H) ; 6.32 (d, 1H, ~ -= 16) ;
6.72 (s, 2H) ; 7. 59 ;d, 1H, .~ -_ 16) .
Example 4 General_ procecaure i=or the s~ynthesv.~s of :>aturated alcohols from ~.cr~,~l_ic esters, exempli.f;-ed for (3, 4, 5-trimethoxy) phen~,~lpropano-~..
A =>olution of rn=thyl (3, 3, 5-trimethoxy-traps-cinnamate ( 1 . 81 c~ ; 7 . i'7 mmc_>1 ) in tetrarsydrofunan ( 30 ml ) was added in a dropwise manner to a solut~~on of lithium a~~yumz_nurn hydride (14 mmol) in T.'-~F ~; 35 ml) , wi.th stirring arid ~.~nder an argon atmosphere. F,f tc~r the additi<:;n was complete, the mi.xt~~.re was heated to -".v°C: forhours. After cooling, it was quenched by the careful adcli..ion :~f 1:~ ml of 2 N NaOH followed by 50 SL1~3S'CITUTE SHEET (RULE 26) WO 00/09124 PC'T/U~~99/18233 Ga ml of w~~t~er. The resulting mixture was filtered through Celite t:~~ remove solids, and ti:e filter cake was washed with ethyl acetate. The combined organic fractions were washed with water, dried, concentrated .in vacuo, and purifies. on a silica gel column, eluting witt-: ethyl acetate to obtain 0.86 g ( 53 0 ) of the alcohol as a clear coil . '-H NMR ( 300 MHz;
CDCl,) : d 1.23 (br, 1H) ; 1. 87 (m, 2 H) ; 2. 61 ( t, 2H, .~ = 7.1) ;
3.66 (t, 2H); 3.8c) (s, 3H); 3.83 (s, 6H); 6.40 (s, 2H).
Example 5 General procedure fcr t~~e synthesis c~f trans-al.lylic alcohols from acryli c este_-s, ex~=mplified for (~~, 4, 5-trimethoxy) phenyl.prop-2- (E) -enol .
A solution omethyl (3, 3, 5-trimethoxy}-traps-cinnamate ( 1 . 35 g; 5 . 35 rnmol ) in tcluer~~e ('? 5 ml ) was cooled to -10°C
and treated witlu ~~ solution of diisobutylaluminum hydride in toluene (11.25 mL of a 1.0 i~i solution; 11.25 mmol). The reaction mixture was stirred for 3 hours at 0°C and then quenchea with 3 ml of methanol Coli.owed by =L N HC1 until the pH was 1. The rea~~tion mix,_ure was extracted into ethyl acetate and the c:~rganic phase was washed with water, dried and ccncentr_ated. Purifica Rio n o;1 a silica ge_L column eluting with 2'.~o ethyl acetate in hexane furnished 0.96 g (80%) of a thv~c~: oil. '-H NMR (36Ci MHz; CDCl,) : d 3.85 (s, 5. 6) ; !x.29 (dt,, 1H, 3H) ; 3. E37 (s, E~H;~ ; 4.. 32 (d, <'H, .' -15.8, 5.7) , 6. 54 (~~, 1H, .i = '.:5.8) ; 6.61 (s, 2H) .
Figure 1. GPI ~.04~ protects retinal ganglion cell; against degeneration following retinal ischemia.
Retinal ganglion cells were rett_ogradely labeled in adult rats by bilateral injecti.~~r: :f r:iucrogold in their lateral geniculate nude ~. Label_ed c)anglicn cells in the normal rat retina appear as white prof,~~es agair_st the dark background (Figure 1A) . C'om~~lete r_t_;nal ~:.schemi.a was prcduc:ed by infusing norma'~ sa'_ ine :~~.~1!:t _:.on in~c, the re-tinal vitreous SL1BST1:TUTL Sf-I~;ET (RULE 26) WO 00/09124 PnT/IJS99/18233 ': 0 cavity of each eye until the intraocular pressure exceeded arterial blood pr-s,~sure. 2~ aays after the ischemic ex>isode extensive degener,~tion of retinal ganglion cell was evidenced by massive reduc_t:iorl in the density of fluorogold libeled cells (Figure 15j. Administration of GPI 1046 (lOmg/kg, s.c. ) 1 hour prior t~c~ the ischemic episode and at lOmg/~:g/day for the next fou_~~~ays produced noticeable protection of a large proportion of t:he vulnerable ganglion cell population (Figure 1C).
Figure 2. GPI 1046 prevents degeneration of optic nerve axons and myelin following retinal ischemia Examination of t: he optic nE>:rves f=rom the same rE~tinal ischemia cases rev:als that GPI 1046 produces dramatic protection of optic nerve element from .ischerr.ic degeneration.
Toluidine blue sta~r_ing of: epon embE:dded optic nerve cross sections revea:Le~:~ the detail of myelin sheaths (white circles) and optic: nerve axor.~= (black centers) in the normal rat optic nerve. Opt~_c news from vehicle treated cases examined 2B day: after a 1. hour retinal ischemic episode are characterized bv;~ ~.3 decreased dc~nsi~.y of optic: ner~ne axons and the appearance of numerous degenerating myelin figures (bright white fi_Lled circles). Treatment, with GPI 1046 protected the majc;rit:y of optic: nerve axons from degeneration and also dramatically decreased the density of degenerating myelin figures.
Figure 3. GPI 1046 provides moderate protection against retinal ganglion cell death after optic nerve transect.ion Complete cransect.ion of_ the optic nerve 5 mm from t:ne eyeball produces massi~,ne degeneration of ratinal ganglicn cells, representing Loss r>f >8~7 0 ~.>f the norma~ganglion cell population 90 days after the injury (Table 1). Few spared fluorogold pre ~abel~d gang'~ic:rn ce'~.ls are present in vehicle treated cases l,=irge~ whine f.~:~ures) among a population of SUBSTITUTE SHEET (RULf, 26) WO 00/09124 PfT/i:'S99/18233 small mi.croglia that digest t: he debris of the degene__ating cells and take u~~ the fl~~orogold label (Figure 3A).
Treatment with GPI 1046 fcr 1~ days resulted in a small but not significant increase in tine density of retinal ganglion cells that survived 90 days after transec:tion (Table 1) but treatment with :~PI 1046 fc;r the first 28 days after transaction produced moderate but significant protect__on of 12.60 of the v~;l:;erable ganglion cell population (Table 1, Figure 3B).
Figure 4. GPI 1046 treatment duration significantly affects the process of optic nerve axonal degeneration after transaction.
Examination of opi:ic nerve axon density in the proximal stump of the optic nerve from the same cases revealed a more dramatic protection ~~Eforded k:~y GPI 1046 treatment. 90 days after transaction f=ew ganglicn cell axons remain within the optic nerve (Fictu.~e 4E,) , repre:~enting only 5.6% of tt-.e normal population. fh.e loss of axcns reflects both the death of retinal gang=Liorr :~e1.1:~ and the regression or "dying back" of the axons of ~ ,'0 0 of the >rnall surviving ganglion cell population into the retina itself (Ta.ble 1). Treatment with GPI 1046 for the :f:irst= 14 days after optic nerve transaction produced a sma~~ 1 ~:ut sigr~ifi pant 5.3% protection of optic nerve axons ( Fiqu:~e ~i D, Table 1. ) , but treatment with the same dose of GPI 1046 for 28 days resultE:d in the protection of optic nerve axc.~n;: f~:~r the va:~t majority (E31.4° ) o~ spared retinal ganglion cells (figur<~ 4C, Table 1).
Figure 5. GPI 1046 treatment produces a greater effect on optic nerve axons than ganglion cell bodies This surrunary figr,re shows data from Figure 3 ganglion. cell protection and higher power p:notomicrographs of optic nerve axon protection 'Figure SA~.B, upper panels). 2~3 day ~~1BST1TL1TE SHEI?T (RULE 26) WO 00/09124 P~CT/i1S99/18233 treatment with Gl?I 1046 produced a significant increase in the density o;: large, and particularly medium and small caliber optic nerve axons (Figure 5C:&D, locaer panels) .
Figure 6. GPI 1046 treatment for 28 days after optic nerve transection prevents myelin degeneration in the proximal stump Myelin basic protein imrnunohistochemistry labels fascicles (darker labeled 'islands') of myelinated axons in the normal optic nerve ( F i.gur.e 6A, uc~per left ) . 90 days after transect~ion extensive degene~~ation of myelin is evident in vehicle treatE:d cases, cha=iracter_ized by the lo:~s of fascicular organization and the appearance of numerous large dense de generat.ir:g myelin figures (figure 6B, upper right).
Treatment with GPI 1046 for the first 14 days after optic nerve t.ransection did not alter_ the pattern of myelin degeneration (fic~ur<~ 6C, lower left panel), and yielded an insignificant l_.i>=~ quant.tat:.ve r_ecc~very in myelin density (Table ~). Extending the CPI 1046 treatment course t:~rough the first 28 days after optic nerve transection produced a dramatic: preserv<,.t:ia:n of the t:ascicu=Lar staining pattern for myelin basic prote~.n in the proximal stump of the optic nerve and decreased the density of degenerating myelin figures (Figure 6D, lcwer right panel,, representing a '70o recovery of myelin density (Table ~_).
Figure 7. FKBP-12 immunohistochemistry labels oligodend:roglia (large dark cells with fibrous processes), the cells which produce myelin, located between the fascicles of optic nerve fibers, and also some optic nerve axons.
SUBSTI'TUTI~; SHEET (RULI? 26) WO UO/09124 P~CT/LJS99/18233 '; 3 Figure 8. GPI 1046 treatment for 28 days after optic nerve transaction prevents myelin degeneration in the distal ,tamp.
Complete transect:ion of the optic: nerve leads to degeneration of the distal segments (axon f:ragment.s disconnected from the ganglion: cell bodies), and the degeneration of their myelin sheaths. 90 days after transaction (Figure 8B) myelin basic protein immunch:istochemistry reveals the near total loss of fascicular organization (present in the normal optic nerve, Figure 8A) and t:r:e presence c-f numerous dense degenerating myelin figures. Quantitat.ion reveals that the cross sectional area of the transect:ed distal. stump shrinks by 310 and loses appro:~imately 1/~' of ,its myelin (Tablf~ 1).
Treatment with GF~I 1046 fc;r the first 14 days after transaction did not: protect against shrinkage of the distal stump but did sl.ic~htly increase the density of myelin, though the density of degenerating mye.l.in figures remained high (Figure 8C, Table 7_). GPI IO<~6 treatment through the first 28 days produces: dramatic ~rrotection of the fascicular pattern of myelin labeling, decreased the densit:y of degenerating m:yels.n figures, prevented cross sectional shrinkage of the distal stump of the transacted n~srve and maintained the myelin levels a = ~U9a; of normal levels (Figure 8D, Table 1).
Figure 9. 28 day treatment with GPI 1046 treatment beginning 8 weeks after onset of streptozotocin induced diabetes decreases the extent of neovascularization in the inner and outer retina and protects neurons in the inner nuclear layer (INL) and ganglion cell layer (GCL) from degeneration.
~legative images c>f cresyl vio~et J1=a.ined tangential retinal sections revea_Ls perikarya :.n the three cellular layers (Figure 9A). T.'ne retinae of ,>tre~tozctocin treated animals administered only vetni_cle (F'ig.are 7r:) exhibited loss of cells from the ONL and INL, decreased tnickne~~s of the Outer SUBSTITUTE SHEF,T (RULE 26) WO 00/09124 P~CT/US99/18233 plexiform layer (t=he dark area between ONL and INL) and a dramatic increas:~ l.n the siz~~ and density of retinal blood vessels (large black circular outlines) in the INL, OPL, ONL
and the photorece~~-to:r layer (PR., the gray fuzzy a:=ea above the ONL). GPI 1046 treatment reduced neovascularization (i.e. prevented the proliferation of blood vessel:>) in the PR, ONL, OPL and INL. Although GPI 1046 did not appear to protect agains~: neuronal loss in the ONL, it appeared to decrease the loss of neurons in both the INL and GCL compared to streptozotoc:in/vehicle treated controls.
Example 6 To V~vo Retinal Ganqlion Cell and Optic Nerve Axon Tests The exten?_: ~:~~~= degenerat.v~or. reduction or prevE:ntion in retinal ganglic:~n cells and optic nerve axons was determined in a vision __o;~s model utilizing surgical optic nerve transect=ion to .simulate mecharuical damage to the optic nerve.
The effects cf several neuroimmuncphilin FKBP ligands on retinal gangl;.~cn ce.l.s neuropro-tecticn and optic ner~.~e axon density was detezvmined experimentally, comparing 14 day and 28 day neuroimm~_mophilin ~KBP ligand treatments. The effects of treatment witr~ neuroimmunophilin FKBP .1_gands on retinal ganglion cells and optic nerve axons was correlated.
Suraica-~ Procedures Adult male .'-_~pracxue DawlE:y rats ( 3 months old, 225-250 grams) were anesthetized with a ketamine (87mg/kg) and xylazine (l3mg/kg) mixture. Retina_L ganglicn cells were pre-labeled by bilal=eral ~rtereotax,lc injection of the fluorescent retrogradely 1~_.r:~r,s~orted marker lluoro-gold (FG, 0.5 microliters of 2.5a, solution i.n saline) at the coordinates of the LGNd (4.5 r~i-~lirneters post ~, 3.:~ millimeters lateral, 9 . 6 mi llimeter~> oel ow dura) . Four days later, FC labeled rats underwent a sac:ond :~urgE.~ry for mi crosurgical bilateral SUBSTI'CUTE SHEET (RULE 26) intraorbitai optic: _-~erve tramsectiol 4-5 millimeters behind the orbit.
Experi_ment=al an,~mals were divided into six experimental groups of six vats (:L2 eyes) per group. One group received 5 a neuroimmunop~~i_..in J_'KBP ligand ( 10 milligrams per kg per day sc in PEG vehi~~ a (20 percent propylene g-~ycol, 20 percent ethanol, and 60 percent saline)) for 14 day~~. A second group receive~~ the samf~ nF~uroimmunophil.in FKBP l.igand doae fcr 28 days. Each traated group had a corresponding sham/surgery 10 and transection control group which received corresponding 14 or 28 day dosing with the vehicle only.
Al.L animals were sacrif:Lced 90 days after optic nerve transec~ion and perfused pericardially with formal.in. All eyes and optic nerves stumps were removed. Case;> were 15 excluded from i~hs study if t:~re optic nerve vasculature was damaged or ~.~f FG 1_abeling was absent. in the retina..
Retinal Ganglion Ce-'~ Counts Retinas were removed from eyes and prepared for wholemount anal~.~:~is . For ea::h group, five eyes with dense 20 and intense Fn~ labeling vaere selected for quantitative analysis using a 20 power ot;jecti.ve. Digital ima.ge:~ were obtained from .five fields in the central ret~~~na (3-4 millimeters radial to optic nerve head). FG labeled Large ( >18 um) , medium. ( ~~~2-16 um) , and ~~mall ( <10 um) ganglion 25 cells a:nd mv~.crog_Lia were counted in five 400 um by 400 um fields Jeer case, 5 eases per group.
Examination of Optic: Nerves Proximal and distal optic: nerve stumps were identified, measured, and transferred t.:o 30% sucrose saline. The 30 proximal stump~> c::f five nerves were blocked and affixed to a chuck, and 10 micron cross sections were cut on a cryostat;
one in ten sections were saved per set. Sections including the region 1-2 wm i~ehind the orbit were reacted for RT97 neurofi Lament imn,.unohistocher.istry. Analysis of optic nerve 35 axon density w,~s performed using a 63 power' oil imm~srsion SLJBS'fI'TUTE SHEET (RULE 26) WO 00/09124 P~CT/IJS99/18233 ~6 lens, a Dage E3_ camera, and the Simple Image Analysis program. RT97 ~_>oai.tive optic; nerve: axons were counted in three 200 urn by 200 um fields per nerve. The area of the nerve w<~s also df_:termined for each case at 10 power.
As depicted graphically in Table I&II, the 14 day course of treatment with a neuroimmunophilin FKBP ligand provided moderate neuroprotec:t:ion of retinal ganglion cells observed 28 days after optic nerve transection. However, by 90 days after transecti_on, only 50 01= the ganglion cell population remained viable.
90 days after optic nerve transection the number of axons persisti.rzg ~ n the proximal stump of the optic nerve represented apprcx=~rnately one half of the number of ~~urviving ganglion cells in groups of animal~~ that received vehicle alone or the i4 day ccurse of treatment with a neuroimmunophil.in ff~;EP ligand. These resu7.ts indic:at~= that over half of l~:~e transected ganglion cell axons retract beyond the opti.~:: nerve head., and that treatment with a neuroimmunophilin ~,KBP ligand during the first 14 days after optic nerve transection ,is not sufficient to arrest this retraction.
As depicted graphically -n Tab:Le I&II, more pro:Longed treatment with 3 neuroimmunoph:ilin FKBP ligand during the 28 day course of :reatment prcduced a moderate increase in retinal ganglion ~se'~.l neuroprotection. Approximately 12 0 of the vulnerable retinal ganglion cell population was protected. A simi:Lar proportion 0500) of optic nerve axon density sparing was also observed. These results de:monstate the startling res~.zlt that extending the duration of treatment with a neuroimmunoprlilin FKi3P l igands to 28 da~~s after transect.ion co:~p_etc~ly arrests the regression of damaged axons for essentially the entire surviving copulation of retinal c~angli~~n cells.
Addition<al r.:~s~_ilts are sit forth in Tables III and IV.
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SUI3~STITUTE SHEET (RULE 26) E> 1 Example 7 A patient i:_; ~>uffering from macular degeneration. A
pyrrolidine derimat.ive as identified above, alone or ~n combination w:~th one cr more: other neopsic factors, or a pharmaceutical c::~mposi_tion c_:omprising the same, may be administered to t:he patient. A reduction in vision loss, prevention of vis=.on degeneration, and/or promotion of vision regeneration are/:is expected to occur following treatment.
Example 8 A patient is .suffering from glaucoma, resu-wting in cupping of the optic nerve disc and damage to nerve fibers.
A pyrrol.idine deeivative as identified above, alone or in combination with one or more other neopsic factors, or a pharmaceutical composition comprising the same, may be administered to t:he patient. A reduction in vision loss, prevention of vision degeneration, and/or promotion o.f vision regeneration are/i~~ expected t=o occur following treat=ment.
2 0 Example 9 A patiervt ~ s suffering from cataracts requiring surgery.
Following surgery, a pyrrolidine derivati~~~e as identified above, alone or ir; cc:mbination with one or more other neopsic factors, or a phar_n~iceutical composition comprising the same, may be admini.sterea to the patient. A reduction in vision loss, prevention <.~f ~~~i.sior~ degeneration, and/or promotion of vision regeneratvor. are/is expected to occur following treatment.
3 0 Example 10 A patierut ~~s suffering from an impairment or blockage of retinal ~;lood s~:~ppi_y relat.inc~ to diabet'_.. retinopathy, ischemic op?sic nE:uropathy, or re~inal artery or vein blockage. T: pyrrolicine derivative as identi.Fiec~ above, alone or in combination with one or more other neopsic SU13ST'1'rUTE SHEET (RULE 26) factors, or a pharmaceutical c:ompcsition comprising the same, may be administered to the patient. A reduction in vision loss, p.rever~tion of vision degeneration, and/or promotion of vision regenera~.:ion are/is exp~cted to occur following treatment.
Example 11 A patient is suffering from a detached retina. P
pyrrolidine derivative as identified above, alone or in combination with one or more other neopsic factors, or a pharmaceutical composition comprising the same, may be administ~ereci tc; tie pati.ent~ . A reduction in vision loss, prevention of vision degeneration, and/or promotion ~~f vision regeneration are;'is expected to cccur following treatment.
Example 12 A patient/ is suffering from tissue damage caused by inflammation, associated with uve;~tis cr ccnjunctivitis. A
pyrrolidine derivative as sdentified above, alone or in combination with one or more other neopsic facto.r~;, or a pharmaceutica7_ com.~cs:ition c:ompr.ising the same, may be administ=erect ~o tr-.e patient. A reduct=ion in vision loss, prevention of vis ~~on degeneration, and/or promotion of vision regeneratier~. areiis exper_ted to occur following treatment.
Examt~le 13 A patient is ~~uffering Born photoreceptor damage caused by chronic or acutE: exposure to ultraviolet light. A
pyrrolic~ine der.inat=i_ve as identified above, alone or in combinat=ion wish one or more other neopsic factors, or a pharmaceutical composition :Jomprising the same, may be administ=erect ~-; nr,.e patient. A reduction in vi.sicn loss, prevent-on of ~.~ision ciegenerat;~on, and/or promotion of vision regeneraticr~ a:~:e;'is expected to occur following treatment.
SUt3STITUTE SHEET (RULE 26) Example 14 A patient i,s suffering from optic neuritis. A
pyrrolidine deriv five as identified above, alone or in combination with one or more other neopsic factors, or a pharmaceutical corlposition comprising the same, may be administered to r:hE: patient. A reduction in vision loss, prevention of visor ciegeneration, and/or promotion of vision regeneration are/is expected to occur following treatment.
Example 15 A patient i_~ :suffering from tissue damage associated with a "dry eye" czisorder. A pyrrolidine derivative as identified above, 31.c>ne or ire combination with one or more other neops~c factors, or_ a pharmaceutical composition comprising the same, may be administered to the patient. A
reduction in visior~.Loss, prevention of vision degeneration, and/or promotion of vision regeneration are/is expected to occur fcllowinq tre<~tment.
Examt~le 16 Efficacy of representative compounds from different immunophilin :~iqan;i series in protecting retinal ganglion cell axons frem degenerat:i.on following optic nerve transection i_s set forth in Table V.
SUBSTITUTE SHEI?T (RULE 26) TABLE V
Efficacy of representative compounds from different immunophilin ligand series in protecting retinal ganglion cell axons from degeneration following optic nerve transection RT97+RGC

axon density 14 days after ON transection (% ON
axons Compound Struet:ure Comments rescued) Adamantyl Thioester of urea100.0%

Ki rotamase=149 t5.2%
nM SEM

Clearance=? Itl/min.

--~~ ~ ~' Ester ' ~
~ J

A Ki rotamase=7.5 60.5%
a_,-.~ nM
~

GPI 1046 '~ Clearance=63.8 t3.9 SEM
~rl/min.

~i,~

I
~ Sulfonamide ..s_ Ki rotamase=107 60.4%
nM

2 f, -~- '~ Clearance-31, t3. l 0 I Itl/min. % SEM

Pipecolic sulfonamide o.
Ki rotarnase=nM 58.4%

'~~ Clearance-= ~tl/min.t6.4%
SEM

'~ Ester of pipecolic ~ acid l "

2 ' K i rotamase=20 56.6%
5 ~ ~N'~ nM
~~~ '' P- ~~~~~" ~~ Clearance=41.8 t9.4%
~rl/min. SEM

s " I'roline heterocycle ..~~~ 1 Analog of GPI 55.1 ~0 c>' 1046 ' Ki rotamase=272 X5.9%
~l nM SEM

Clearance=? ~rl/min.

..1 SU13S,T (TOTE SI-~EET (RULE 2G) -'Fable V continued R~1~97+R(;C
axon density 14 days after ON transection Com ound Structure (°~'° ~N ions P Comments rescued) Pipecolic acid N ' o" dimethyl ketone 34.0%
G o ~ ~~ Ki rotamasc> 10,000 nM X4.8% SEM
o Clearance=? yl/min.
i i .~. N"= Ki rotamase= nM 30.3%
o ' c Clearance-- ltl/rnin. t8.0% SEM

Ester of Thiourea ~J Ki rotamase=131 nM 23.8%
I "N~,,s ° ~ J Clearance=8.0 ~tl/min. t5.3 SEM
;.
Ketone analog of GPI 1 U46 15.8%
Ki rotamase=210 nM X4.8% SEM
i ~~.'~~o ~~ Clearance=f.5 ~tl/min.
Pi ecolic acid Thioester (,N ~.-''w.~~ ~~~ Ki rotamase=86 nM 13.0%
K o~ ~'~ ~> ~~ Clearance=4.~ yl/rnm. t4.2% SEM
Prolyl acid " Ki rotamase= >7743 nM 7.8%
o\ ~, o Clearance=5.2 yl/min. X3.0% SEM
. ~; o ~w -~\ ~ Thioester '.n,%~,.-' , _~~ Ki rotarnase=7 nM -6.3%
I
M o\ ;~.o o ,~ Clearance=1?.5 ltl!min. X3.9% SEM
o ~~
.1 SUBS'T1TUTE SHEET (RULE 26) Table V continued RT97+RGC

axon density 14 days after ON transaction Compound Structure Comments (ore cued)ns Ki rotamase=722 nM

Clearance---2t.9 ~tl/min.

n,c _v~~o i <an Example I7 ENHANCES RETINAL GANGLION CELL SURVIVAL
AND ARRESTS AXONAL DYING BACK
FOLLOI~IING OPTIC NERVE TRANSECTION
Transecti.on of the mammalian optic nerve resu.lr_s in a brief period of a:zbortive regeneration, but the majority of axotomia:ed rueurorus d:ie and the axons from many persisting ganglion eel '-s di_e back beyond the optic nerve head. The present Example wa;s designed to examine the neuroprotective effects of GPI-1046 following optic nerve transaction.
Retinal ganglic:n cells ire adult male Sprague Dawley rats were retrogradely la.bel_ed by fluorogold injection in the LGNd and .our days latF:r the optic nerves Vaere transacted 5 mm 2Q behind the globe. Groups of animals received either GPI-1046 lOmg/kgiday s.c. or vehicle for 28 days. All experimental animals anti controls were sacrificed 90 days after transaction.
By 90 days c:mly - l0o or the FG labeled ganglion cell popuJ.ati.on ::orviwed but les:> than half of these neurons maintained axons txlat extended past the optic nerve head, as detec:teci wi_r_h R'T97 rieurofilament immunohistoc':emisty. GPI
1046 treatment ~sroduced a moderate degree cf r~erikaryal neuroprotecr__iori, sparing 25 ~ cf the ganglion cell po~~ul ation, and preserver t::e axons of vi rtual:Ly all pro-ected neurons in SUBSTITUTE SHEET (RULE 26) the proxima:i stump of the transected nerve. These results indicate that: treatment wit:h the FKBP neuroimmunophilin ligand GPI-1046 produces a fundamental alteration. in the pathological proc::ess following injury to CNS tracts.
These results a-~so demor:strate that the small molecule FKBP neuroimmunophilin ligand GPI 1046 enhances neurite outgrowth ir; cultu:=~~, enhance peripheral nerve regeneration, and stimulate s~:~r~aut,ing within the CI~dS following partial deafferentat.ion.
Example 18 NEUROIMMUNOPHILIN LIGANDS PROMOTE RECOVERY
FROM THE PERIPHERAL SENSORY NEUROPATHY ASSOCIATED
WITH STREPTOZOTOCIN-INDUCED DIABETES
Peripheral ne uropathy is a common debilitating complicit:ion of ~!'ype 2 diabetes in some 3C-40 0 of diabetic patients. Neurot:rophic factors such as nerve growth factor (NGF) are kr:own t:o promot:e survival of developing and adult neurons ef the peripheral nervou:~ s~,~stem (PNS) , and have also been evaluated as treatme:~:ts for diabetic peripheral neuropat:hy. Some of the selective ligands of the neuroimmunophiiin F-'KBP-12 such as the small molecule GPI-1096, have also beer.. ~>hown to promote repair and regeneration in the central and peripheral nervous systems (Proc. Nat'1.
Acid. Sc:i. USA 94, 2C19-2024, 1997).
In this-, Examp7_e the potential therapeutic effects of GPI-1096 weza evaluated for its ability to improve sensory function in the st~reptozotocin-induced diabetic rat. The procedure involved using Maie Mist:ar rags which were given a single injection of streptozctoc~.n (65 mg/kg i.v.). Blood glucose levees werE: determined week_lv for the first three weeks and or. tr;e last weed: cf the experiment. Animals were evaluated wE:ekly for signs o:- sensory neuropathy using the conventz.onal hct date arid tail flick apparatus test SUBSTITUTE SHEET (RULE 26) proced;.~r_es. After six weeks, treatment either with GPI-1046 or vehicle was initiated.
The results demonstrated that behavioral testing using the hot: plate anti the ta:ii flick apparatus indicated improvement in la:.~ncy in lesioned animals treated for 6 weeks with GPI-1046 at 10 mg/kg s.c. The results also showed that GPI-1046 ame:Liorates the behavioral sequelae of diabetic sensory neuropathy and may offer some relief for patients suffE:ring from diabetic peripheral neuropathy.
Morris Watexxnaze/Aging and Memory Test Procedure AgE:d rodent::, e:~hibit marked individual differences in performance en a variety of behavioral tasks, including two-choice ~>patial di.s~~rimination in a modified T-maze, spatial discrimination :~.n a circular platform task, passive avoidance, radial. maze tasks, and spatial navigation in a water pc>ol.
In all of these tasks, a proportion of aged rats or mice perform as well as the vast majority of young control animals, while other animals displa~~ severe impairments in memory funct=ion compared to young animals. For example, Fischer and coilf~acues showe,.~ that the proportion of rats displaying significant impairments in spatial navigation increases with age, (Fischer et ai.. 1991.b) with 80 of all 12 month old, 450 of L8 month old, 530 of 24 month old, and 900 of al_1 30 mon;:h cold rats displaying impairments in spatial acquisition of the Morris wat:ermaze task relative to young controls.
Specifically, rodent spatial learning and memor~~ decline during acing has been accepted by m<~ny investigators as an intriguing ccorrel::~ti.ve animal model oz human seni le dementia.
Chol i nergic function in t'r:e hs_ppoc:arnpus has been extensively studied as a com~>onent of spatial fear ni.ng in rodents, and dec 1 ini ng hippocarn~~~zl_ cholinergic fur~c:t .on ryas been noted in parallel. with tr:e development: oi- _~earning and memory SUBSTITUTE SHEET (RULE 26) WO 00/09124 PCT/US99/182~33 ~9 Impairments. In a~~,ydition, other neurotransmitter systems have been shown to contribute to spatial learning, and to decline with age, such as the dopaminerg is and noradrenergic, serot:onergic, and gl_utamatergic systems.
Also, report::s on age-related deficits of hippocampal long-term potentiat:ion (LTP)-.induction, a reduction in theta rhythm frequency, a loss of experience-dependent plasticity of hippocampal pLac.e-units, and reductions in hippocampal protein kinase C ~rr_e in keeping with the concept t=hat no single underlying pathology can be identified as the cause of age-related behavio:=al impairment in rodents. However, the various experiment<~l ther.apeut:i~~ approaches that Nave been undertaken to improve memory function in aged rodents have been somewhat slant:ed towards the cholinergic hypothesis.
I5 The Morris watermaze is widely used for assessing spatial memory fcrmation and retention in experimental animals. The test:. c~~apends on the animal's ability tc> utilize spatial visual. information in order to locate a submerged escape platform in a water tank. It is important that the tank itself be as devoid of specific visual features as possible - thus, it: is always circular in shape, the sides are kept smoe>th and ,ln uniform dull c.~clors, and the water is rendered opaaue with nontoxic wateYcolour pigment or powdered milk. This is tc:~ en sure that: ~,W : animal navigates only by the use of more distant visual. cues, or by the use of intra-maze cues specifi~c~rlly provided by the experimenter.
The tank is filled to a level. which forces the animal to swim actively. Normal mice and rats react aversively to the swimming part of t.re test and will cl-lmb onto, and remain on, an escape platform from whicr: they are removed to a heated resting cage.
If the plat!-orm is visi_~le i~_.e. above the surface) , animals placed in t:he t:ank will q~;ickly learn to home in on tle platform and ci__~,_mb out on~_o iv. Testing with a visible platform will also ensure that th~~ experimental animals are SUBSTITUTE SHEET (RULE 26) WO 00/09124 1'CT/US99/18233 not blind and shc~~,r sufficient motivation and stamina to perform the task, which can be important in experiments involving aged rodents. If t:he platform is invisible (i.e.
submerged just bc:~lcvr the sun race) , normal animals learn to 5 use distant visual ~_~:ues in th~~ test room for orientation in the test= tarnk, arid, when placed in the tank, will quickly home in on the approximate location of the platform and circle in that area until the platform is found.
The animals' ~:ath, speed, and swim time are tracked with 10 a ceiling camera for later computerized analysis. Over the course of sE~ver<~:L successive trials, ~>patial learning can therefore be defined as a drop of distance swum, or time elapsed, from plac:etnent in the tank until escape onto the invisible platform..
15 The test care ~>e adapted to assess several aspects of spatial memory: ~~) acquisiti.on of a cued task, where the animal' = ability t:c link one visua.i cue directly with the escape platform dc~~>E:nds on cortical function ( i . e. a ball is suspended over the E=scape platform and the animal learns to 20 folk>w this cue t:o find the platform); b) acquisition of a spatial task, ~frhere the animal's ability to learn the location, of ~a submerged escape platform based on a combination of :~~_stant visual. cues is dependent: upon hippecampal function (i.e. the animal learns to triangulate 25 its position in tloe yank by visually aligning the paper-tower dispenser with the door and ceiling lamp); c.) retention of a successfully acq~i:_ed spatial task, which is predominantly dependant on cort_:.ca='~ function (i.e. the animal must remember the spatial iocat:ior: of the pl.atfcrm over several- wee;~cs) ; d) 30 a hippocamp_.:~-dependant reversal task where 'he animals must reacquire a r:ew si:aat:ial platfc>rm location (i..e. the platform is moved to ~: ne~,~r location bet:aeen swim trials and the animal must abandon ins previous search strategy and acquire a new one).
SUBSTITUTE SHEET (RULE 26) These different modifications of the Morris watermaze procedure can bEe applied ir: sequence to the same set of experimental animals and allow for a thorough charact~srization of their spatial memory performance and its decline with norma~~ ageing. Moreover, such a series of sequential memory t-ests sheds some light on the functional integri ~y of thc:: :specific:rain: systems involved in the acqu:isi~ion and ~°etention of spatial memory (e.g. rats with chol:inergic ~esions of the hippocam~us may remember a plat:Eorm location: acquired weeks before, but persevere over the old platform location after the platform is moved).
Example 19 ON SPATIAL LEARNING AND MEMORY IN AGED RODENTS
This Example shows the effects of chronic treatment with the systemically a:~railable fKBP-:Ligand GPI-1046 on spatial learnin<~ and memc::ry in aged rodents .
The procedure involved using three-month old (y~~ung) and 18-19 month ol~:l :hale C57BLj 6L~-IVia (aged) mice which habituated to t_he well known and conventiona~_ Morris waterma<~e dt.rring ar 4 trialsiday, 3-4 day visible platform training phase. Subsequent spatial acquisition testing was conducting <~s fc.~llows: All mice were given 4 trials/day (block) , for 5 days. Maximum swim time was 90 seconds,. Aaed mice were allocated to an "aged impaired" group i~ their performance during t~locks 4 oz 5 of the acquisition phase was >1 S.D. above the mean of "young" mice, and to an "aged non-impaired" gr;Jup i f t.'.-:eir performance was < 0. 5 S. D. abo~ne the mean of "your: c" mice. Aged: groups were then split into statisticall~,~ sinw.il~:r "GPI-1096" and "vehicle" grot:ps.
Daily t reatrnen?: with lOrng/kg GPI-1046 was initialed 3 days of~er ehe end of acquisil_ion training, and continued through retent=ion te~;ting. R.etentic;n testing began after 3 weeks o.f do:~ing using the same methods as the acquisition SUBS>TI'CUTE SHEET (RULE 26) phase. Swim Distances (cm) were analyzed in a 7 X 5 ANOVA
including Groups anc~ Blocks (1-5) as factors in the analysis, treating Blocks ::~:_. a repeated measure.
The results showed that planned contrasts revealed that there were signi:fic:ant~ d=ifferences between the "young", and "aged impaired-ve':n--cle and GPI-1046" treated groups at the end of the acquisi.~ion phase, F__56 - 26.75, P=0.0001, and F1.5$ - 17.70, P=0.0001 respectively. While there were no significant differences between the two "aged impaired"
groups, F,,;,, - 0 . F~'', P -- 0. 42. During retention testing, however, "aged i.m~~,aired-vehicle" treated animals performed significant:Ly pocr«r than "aged impaired - GPI-1046", and "young" animals, i' ~;~ -- 8.11, P - 0.006, and F1,~,; - 25.45, P - 0.0001 respectively. There was no longer any statistically sic~nif-~~cant difference between the "young" and "aged impaired" - GPI-1046" treated groups dur,wng ~he retention phase, F'1,~;5 = 3.09, P = 0.08. In summary, systemic treatment with GFI--1046 signi~::Lcantly enhanced spatial memory performance or mi.c:e with age-related spatia?_ memory impairments.
The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to W : regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be i.ncl.uded ~,aithin the scope of the (allowing claims.
SLiB;S'fITUTE SHEET (RULE 26)

Claims (45)

WE CLAIM

1. A method for treating a vision disorder, improving vision in an animal, treating age related memory impairment or enhancing memory performance, which comprises administering to said animal an effective amount of a pyrrolidine derivative.

2. The method of claim 1, wherein the pyrrolidine derivative is immnosuppressive or nor-immunosuppressive.

3. The method of claim 1, wherein the pyrrolidine derivative has an affinity for an FKBP-type immunophilin.

4. The method of claim 3, wherein the FKBP-type immunophilin is FKBP-12.

5. The method of claim 1, wherein the vision disorder is selected from the group consisting of visual impairments;
orbital disorders; disorders of the lacrimal apparatus;
disorders of the eyelids; disorders of the conjunctiva;
disorders of the cornea; cataracts; disorders of the uveal tract; disorders of the retina; disorders of the optic nerve or visual pathways; free radical induced eye disorders and diseases; immunologically-mediated eye disorders and diseases; eye injuries; and symptoms and complications of eye disease, eye disorder, or eye injury.

6. The method of claim 1, which is improving naturally-occuring vision in an animal, in the absence of any ophthalmologic disorder, disease, or injury.

7. The method of claim 1, wherein the pyrrolidine derivative is a compound of formula I
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
R1 is C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl or Ar1 wherein said R1 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl,C5-C7, cycloalkenyl, hydroxy, and Ar2;
Ar1 and Ar2 are independently selected from the group consisting of 1-naphthyl, 2-napthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, wherein said Ar1 is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
X is O, S, CH2 or H2;
Y is O, NR2, or a direct bond; and ~
Z is Ar1, C1-C6 straight or branched chain aklyl, or C2-C6 straight or branched chain alkenyl, wherein said aklyl or alkenyl Z is substituted with one or more substituent(s) independently selected from the group consisting of Ar1, C3-C8 cycloalkyl, and C1-C6- straight or branched chain aklyl or C2-C5 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl; or Z is fragment wherein R3 is C1-C9 straight or branched chain alkyl which is unsubstituted or substituted with C3-C8 cycloalkyl or Ar1;
X2 is O or. NR5, wherein R5 is selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl; and R4 is selected from the group consisting of phenyl, benzyl, C1-C5 straight or branched chain alkyl, C2-C5, straight or branched chain alkenyl, C2-C5 straight or branched chain alkyl substituted with phenyl, and C2-C5 straight or branched chain alkenyl substituted with phenyl.

8. The method of claim 7, wherein Z and R1 are lipophilic.

9. The method of claim 7, wherein the compound is selected from the group consisting of;
3-phenyl-1-propyl (2S) -1-(3, 3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-phenyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(3, 4, 5-trimethoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(3, 4, 5-trimethoxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(4,5-dichlorophenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

3-(4,5-dichlorophenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(4,5-methylenedioxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-cyclohexyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl;-2-pyrrolidinecarboxylate;
3-cyclohexyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
(1R)-1,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
(1R)-1,3-diphenyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
(1R)-1-cyclohexyl-3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2.-dioxopentyl)-2-pyrrolidinecarboxylate;
(1R)-1-cyclohexyl-3-phenyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
(1R)-1-(4,5-dichlorophenyl)-3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-cyclohexyl)ethyl-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl(2S)-1-(1,2-dioxo-4-cyclohexyl)butyl-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thienyl])ethyl-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2.S)-1-(1,2-dioxo-2-phenyl)ethyl-2-pyrrolidinecarboxylate;
1,7-diphenyl-4-heptyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxo-4-hydroxybutyl)-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxamide;
1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine ethyl ester;
1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-leucine ethyl ester;
1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylglycine ethyl ester;
1-1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine phenyl ester;
1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine benzyl. ester;
1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-isoleucine ethyl ester; and pharmaceutically acceptable salts, esters, and solvates thereof.

10. The method of claim 1, wherein the pyrrolidine derivative is a compound of formula II

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
R1 is C1-C9 straight or branched chain alkyl, C2-C9, straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl or Ar1, wherein said R1 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, and Ar2;
Ar1 and Ar2 are independently selected from the group consisting of 1-naphthyl, 2-napthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, wherein said Ar1 is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
Z is Ar1, C1-C6 straight or branched chain aklyl, or C2-C6 straight or branched chain alkenyl, wherein said aklyl or alkenyl Z is substituted with one or more substituent(s) independently selected from the group consisting of Ar1, C3-C8 cycloalkyl, and C1-C6 straight or branched chain aklyl or C2-C6 straight ar branched chain alkenyl substituted with C3-C8 cycloalkyl; or Z is fragment wherein:
R3 is C1-C9 straight or branched chain alkyl which is unsubstituted or substituted with C3-C8 cycloalkyl or Ar1;
X2 is O or NR5, wherein R5 is selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl; and R4 is selected from the group consisting of phenyl, benzyl, C1-C~ straight or branched chain alkyl, C2-C5 straight or branched chairs alkenyl, C2-C5 straight or branched chain alkyl substituted with phenyl, and C2-C5 straight or branched chain alkenyl substituted with phenyl.

11. The method of claim 10, wherein R1 is selected from the group consisting of C1-C9 straight or branched chain alkyl, 2-cyclohexyl, 4-cyclohexyl, 2-furanyl, 2-thienyl, 2-thiazolyl, and 4-hydroxybutyl.

12. The method of claim 10, wherein 2 and R1 are lipophilic.

13. The method of claim 1, wherein the pyrrolidine derivative is a compound of formula III

or a pharmaceutically acceptable salt, ester, or solvate or hydrate thereof, wherein:
Z' is fragment wherein:
R3 is C1-C9 straight or branched chain alkyl or unsubstituted Ar1, wherein said alkyl is unsubstituted or substituted with C3-C8 cycloalkyl or Ar1;
X2 is O or NR5, wherein R5 is selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl;

R4 is selected from the group consisting of phenyl, benzyl, C1-C5 straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, C1-C5 straight or branched chain alkyl substituted with phenyl, and C2-C5 straight or branched chain alkenyl substituted with phenyl; and Ar1 is as defined in claim 10.

14. The method of claim 13, wherein Z' is lipophilic.

15. The method of claim 1, wherein the pyrrolidine derivative is a compound of formula IV

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
R1 is C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C6, cycloalkyl or Ar1, wherein said alkyl or alkenyl is unsubstituted or substituted with C3-C6 cycloalkyl or Ar2;
Ar1 and Ar2 are independently selected from the group consisting of 2-furyl, 2-thienyl, and phenyl;
X is O, S, CH2, or H;
Y is oxygen;
Z is Ar1, C1-C6 straight or branched chain aklyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl Z is substituted with one or more substituent (s) independently selected from the group consisting of 2-furyl, 2-thienyl, C3-C6 cycloalkyl, pyridyl, and phenyl, each having one or more substituent(s) independently selected from the group consisting of hydrogen and C1-C4 alkoxy.

16. The method of claim 15, wherein 2 and R1 are lipophilic.

17. The method of claim 15, wherein the compound is selected from the croup consisting of:
3-(2,5-dimethoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
2- (3,4,5-trimethoxyphenyl)-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(2-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(4-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;
3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;
3-(3-pyridyl)-1-propyl (2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;
3,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;
3-(3-pyridyl)-1-propyl (2S)-N-([2-thienyl]
glyoxyl)pyrrolidinecarboxylate;
3,3-diphenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate;
3,3-diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate;
3,3-diphenyl-1-propyl (2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate; and pharmaceutically acceptable salts, esters, and solvates thereof.

18. The method of claim 15, wherein the compound is selected from the group consisting of:
3-(3-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(2-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate; and pharmaceutically acceptable salts, esters, and solvates thereof.

19. The method of claim 17, wherein the compound is 3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, or a pharmaceutically acceptable salt, ester, or solvate thereof.

20. The method of claim 1, wherein the pyrrolidine derivative is an N-glyoxyl prolyl ester.

21. The method of claim 1, wherein the pyrrolidine derivative is a compound of Formula V

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is C, N, or S;
A and B, taken together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to V, one or more heteroatom(s) selected from the group consisting of O, S, SO, SO2, N, NH, and NR;
R is either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, or Ar1, wherein R is either unsubstituted of substituted with one or more substituent(s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxyl, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar2;
R1 is C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl or Ar1, wherein said R1 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, and Ar2;
Ar1 and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S;
X is O, S, CH2 or H2;
Y is O, NR2, or a direct bond;

is Ar1, C~-C~ straight or branched chain aklyl, or C2-C6, straight or branched chain alkenyl, wherein said aklyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of Ar1 C3-C8 cycloalkyl, and C1-C6 straight or branched chain aklyl or C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl; or Z is fragment wherein:
R3 is C1-C9 straight or branched chain alkyl which is unsubstituted or substituted with C3-C8 cycloalkyl or Ar1;
X, is O or NR5, wherein R5 is selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl; and R4 is selected from the group consisting of phenyl, benzyl, C2-C6, straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, C2-C5 straight or branched chain alkyl substituted with phenyl, and C2-C5 straight or branched chain alkenyl substituted with phenyl.

22. The method of claim 1, wherein the pyrrolidine derivative is administered to said animal in combination with an effective amount of one or more factor(s) useful in treating vision disorders, improving vision, treating memory impairment, or enhancing memory performance in an animal.

23. The method of claim 22, wherein the one or more factor(s) is/are selected from the group consisting of immunosuppressants for treating autoimmune, inflammatory, and immunologically-mediated disorders; wound healing agents for treating wounds resulting from injury or surgery;
antiglaucomatous medications for treating abnormally elevated intraocular pressure; neurotrophic factors and growth factors for treating neurodegenerative disorders or stimulating neurite outgrowth; compounds effective in limiting or preventing hemorrhage or neovascularization for treating macular degenerative; and antioxidants for treating oxidative damage to eye tissues.

24. A pharmaceutical composition which comprises:
(i) an effective amount of a pyrrolidine derivative for treating a vision disorder, improving vision, treating memory impairment, or enhancing memory performance in an animal; and (ii) a pharmaceutically acceptable carrier.

25. The pharmaceutical composition of claim 24, wherein the pyrrolidine derivative is immunosuppressive or non-immunosuppressive.

26. The pharmaceutical composition of claim 29, wherein the pyrrolidine derivative has an affinity for an FKBP-type immunophilin.

27. The pharmaceutical composition of claim 26, wherein the FKBP-type immunophilin is FKBf-12.

28. The pharmaceutical composition of claim 24, wherein the vision disorder is selected from the group consisting of visual impairments; orbital disorders; disorders of the lacrimal apparatus; disorders of the eyelids; disorders of the conjunctiva; disorders of the cornea; cataracts;
disorders of the uveal tract; disorders of the retina;
disorders of the optic nerve er visual pathways; free radical induced eye disorders and diseases; immunologically-mediated diseases; eye injuries; and symptoms and complications of eye disease, eye disorder, or eye injury.

29. The pharmaceutical composition of claim 24 , wherein the pyrrolidine derivative is a compound of formula I

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein R1 is C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl or Ar1, wherein said R1 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, and Ar2;
Ar1 and Ar2 are independently selected from the group consisting of 1-naphthyl, 2-napthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, wherein said Ar1 is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
X is C, S, CH2 or H2;
Y is O, NR2, or a direct bond;
Z is Ar1, C1-C6 straight or branched chain aklyl, or C2-C6, straight or branched chain alkenyl, wherein said aklyl or alkenyl is substituted with cane or more substituent(s) independently selected from the group consisting of Ar1, C3-C8 cycloalkyl, and C1-C6 straight or branched chain alkyl or C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl; or Z is fragment wherein:
R3 is C1-C9. straight or branched chain alkyl which is unsubstituted or substituted with C3-C8 cycloalkyl or Ar1;
X2 is 0 or 'NR5, wherein R5, is selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl; and R4 is selected from the group consisting of phenyl, benzyl, C1-C5 straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, C1-C5, straight or branched chain alkyl substituted with phenyl, and C2-C5 straight or branched chain alkenyl substituted with phenyl.

30. The pharmaceutical composition of claim 29, wherein Z and R1 are lipophilic.

31. The pharmaceutical composition of claim 29, wherein the compound is selected from the group consisting of:
3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-l,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-phenyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3- (3, 4, 5-trimethoxyphenyl)-1-propyl (2S) -1- (3, 3-dimethyl-1, 2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(3,4,5-trimetroxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

3-(4,5-dichlorophenyl)-1-propyl (2S) -1- (3,3-dimethyl-1, 2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(4,5-dichlorophenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(4,5-methylenedioxyphenyl)-1-propyl (2S) -1-(3, 3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3- (4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-cyclohexyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-cyclohexyl-1-prop-2-(E)-enyl (2S) -1- (3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
(1R)-1,3-diphenyl-1-propyl (2S)-1- (3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
(1R)-1,3-diphenyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
(1R)-1-cyclohexyl-3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
(1R)-1-cyclohexy-3-phenyl-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
(1R)-1-(4,5-dichlorophenyl)-3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-cyclohexyl)ethyl-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(1,2-dioxo-4-cyclohexyl)butyl-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(1, 2-dioxo-2-[2-thienyl])ethyl-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-phenyl)ethyl-2-pyrrolidinecarboxylate;

1,7-diphenyl-4-heptyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxo-4-hydroxybutyl)-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxamide;
1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine ethyl ester;
1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-leucine ethyl ester;

1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenyiglycine ethyl ester;
1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine phenyl ester;
1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine benzyl ester;
1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-isoleucine ethyl ester; and pharmaceutically acceptable salts, esters, and solvates thereof.

32. The pharmaceutical composition of claim 24, wherein the pyrrolidine derivative is a compound of formula II

or a pharmaceutically acceptable salt thereof, wherein:
R1 is C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C5 cycloalkyl, C5-C7 cycloalkenyl or Ar1, wherein said R~ is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, and Ar2;

Ar1 and Ar2 are independently selected from the group consisting of 1-naphthyl, 2-napthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, wherein said Ar1 is unsubstituted or substituted with one or more substituent(s) independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6; straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, and amino;
Z is Ar1 C1-C6 straight or branched chain aklyl, or C2-C6 straight or branched chain alkenyl, wherein said aklyl or alkenyl Z is substituted with one or more substituent (s) independently selected from the group consisting of Ar1, C3-C6 cycloalkyl, and C1-C6 straight or branched chain akly or C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl; or Z is fragment wherein:
R3 is C1-C9 straight or branched chain alkyl which is unsubstituted or substituted with C3-C8 cycloalkyl or Ar1;
X2 is O or NR5, wherein R5 is selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl; and R4 is selected from the group consisting of phenyl, benzyl, C1-C5 straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, C~-C5 straight or branched chain alkyl substituted with phenyl, and C2-C5 straight or branched chain alkenyl substituted with phenyl.

33. The pharmaceutical composition of claim 32, wherein R1 is selected from the group consisting of C1-C9 straight or branched chain alkyl, 2-cyclohexyl, 4-cyclohexyl, 2-furanyl, 2-thienyl, 2-thiazolyl, and 4-hydroxybutyl.

34. The pharmaceutical composition of claim 32, wherein Z and R1, are lipophilic.

35. The pharmaceutical composition of claim 24, wherein the pyrrolidine derivative is a compound of formula III
or a pharmaceutically acceptable salt, ester, or solvate or hydrate thereof, wherein:
Z' is fragment.
wherein:
R3 is C1-C4 straight or branched chain alkyl or unsubstituted Ar~, wherein said alkyl is unsubstituted or substituted with C3-C8 cycloalkyl or Ar1;

X2 is O or NR5, wherein R5, is selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl;
R4 is selected from the group consisting of phenyl, benzyl, C1-C5 straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, C~-C5 straight or branched chain alkyl substituted with phenyl, and C1-C5 straight or branched chain alkenyl substituted with phenyl; and Ar1 is as defined in claim 32.

36. The pharmaceutical composition of claim 35, wherein Z' is lipophilic.

37. The pharmaceutical composition of claim 24, wherein the pyrrolidine derivative is a compound of formula IV
or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
R1 is C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C3-C6 cycloalkyl or Ar1, wherein said alkyl or alkenyl is unsubstituted or substituted with C3-C6 cycloalkyl or Ar2;
Ar1 and Ar2 are independently selected from the group consisting of 2-furyl, 2-thienyl, and phenyl;
X is O, S, CH2 or H2;
Y is O, NR2 or a direct bond;
Z is Ar1 C3-C6, straight or branched chain aklyl, or C2-C6 straight or branched chain alkenyl, wherein said alkyl or alkenyl Z is substituted with one or more substituent (s) independently selected from the group consisting of 2-furyl, 2-thienyl, C3-C6 cycloalkyl, pyridyl, and phenyl, each having one or more substituent(s) independently selected from the group consisting of hydrogen and C1-C4 alkoxy.

38 . The pharmaceutical composition of claim 37, wherein Z and R1 are lipophilic.

39. The pharmaceutical composition of claim 37, wherein the compound is selected from the group consisting of:
3-(2,5-dimethoxyphenyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl (2S)-1-(3,3-dimethyl.-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
2-(3, 4, S-tri:nethoxypherryl)-1-ethyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl-)-2-pyrrolidinecarboxylate;
3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(2-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(4-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-l,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(2-tert-butyl-l,2-dioxoethyl) -2-pyrrolidinecarboxylate;
3-phenyl-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;
3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;
3-(3-pyridyl)-1-propyl (2S)-1-(2-tert-butyl-1,2-dioxoethyl)--2-pyrrolidinecarboxylate;
3,3-diphenyl)-1-propyl (2S)-l-(3,3-dimethyl-l,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1, 2-dioxoethyl)-2-pyrrolidinecarboxylate;
3-(3-pyridyl)-1-propyl (2S)-N-([2-thienyl]
glyoxyl) pyrrolidinecarboxylate;

3, 3-diphenyl-1-propyl (2S)-1-(3, 3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate;
3, 3-diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate;
3, 3-diphenyl-1-propyl (2S)-1-(2-thienyl) glyoxyl-2-pyrrolidinecarboxylate; and pharmaceutically acceptable salts, esters, and solvates thereof.

40. The pharmaceutical composition of claim 39, wherein the compound is selected from the group consisting of:
3-(3-pyridyl)-1-propyl (2S)-1-(3, 3-dimethyl-l,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(2-pyridyl)-1-propyl (2S)-1-(3, 3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;
3-(3-pyridyl)-1-propyl (2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate; and pharmaceutically acceptable salts, esters, and solvates thereof.

41. The pharmaceutical composition of claim 39, wherein the compound is 3-(3-pyridyl)-1-propyl (2S)-1-(3, 3-dimethyl-1, 2-dioxopentyl)-2-pyrrolidinecarboxylate, or a pharmaceutically acceptable salt, ester, or solvate thereof.

42. The pharmaceutical composition of claim 24, wherein the pyrrolidine derivative is an N-glyoxyl prolyl ester.

43. The pharmaceutical composition of claim 24, wherein the pyrrolidine derivative is a compound of formula V

or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein:
V is C, N, or S;
A and B, taker: together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to V, one or more heteroatom(s) selected from the group consisting of O, S, SO, SO2, N, NH, and NR;
R is either C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloalkyl, C5-C7 cycloalkenyl, or Ar1, wherein R is either unsubstituted of substituted with one or more substituent(s) independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxyl, hydroxy, nitro, trifluoromethyl, C1-C6 straight or branched chain alkyl, C2-C6 straight or branched chain alkenyl, C1-C4 alkoxy, C2-C4 alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar2;
R1 is C1-C9 straight or branched chain alkyl, C2-C9 straight or branched chain alkenyl, C3-C8 cycloalkyl, C5-C7 cycloalkenyl or Ar1, wherein said R1 is unsubstituted or substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C5-C7, cycloalkenyl, hydroxy, and Ar2;

Ar1 and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted with one or more substituent(s); wherein the individual ring size is 5-8 members; wherein said heterocyclic ring contains 1-6 heteroatom(s) independently selected from the group consisting of O, N, and S;
X is O, S, CH2 or H2;
Y is O, NR2 or a direct bond;
Z is Ar1, C1-C6 straight or branched chain aklyl, or C2-C6 straight or branched chain alkenyl, wherein said aklyl or alkenyl is substituted with one or more substituent(s) independently selected from the group consisting of Ar1, C3-C6 cycloalkyl, and C1-C6 straight or branched chain aklyl or C2-C6 straight or branched chain alkenyl substituted with C3-C8 cycloalkyl; or Z is fragment wherein:
R3 is C1-C9 straight or branched chain alkyl which is unsubstituted or substituted with C3-C9 cycloalkyl or Ar1 ;
X2 is O or NR5, wherein R5 is selected from the group consisting of hydrogen, C1-C6 straight or branched chain alkyl, and C2-C6 straight or branched chain alkenyl; and R4 is selected from the group consisting of phenyl, benzyl, C1-C5 straight or branched chain alkyl, C2-C5 straight or branched chain alkenyl, C1-C5 straight or branched chain alkyl substituted with phenyl, and C2-C5, straight or branched chain alkenyl. substituted with phenyl.

44. The pharmaceutical composition of claim 24, wherein the pyrrolidine derivative is combined with an effective amount of one or more factors useful in treating vision loss, preventing vision degeneration, or promoting vision regeneration in an animal.

45. The pharmaceutical composition of claim 44, wherein the one or more factor(s) is/are selected from the group consisting of immunosuppressants, wound healing agents, antiglaucomatous medications, neurotrophic factors, growth factors, compounds effective in limiting or preventing hemorrhage or neovascularization, and antioxidants.