MXPA01000196A

MXPA01000196A - Compositions and uses for vision and memory disorders

Info

Publication number: MXPA01000196A
Application number: MXPA/A/2001/000196A
Authority: MX
Inventors: S Hamilton Gregory; P Steiner Joseph; Douglas T Ross; Hansjorg Sauer
Original assignee: Guilford Pharmaceuticals Inc
Priority date: 1998-08-14
Filing date: 2001-01-08
Publication date: 2002-07-25

Abstract

This invention relates to novel compositions and uses of non-immunosuppressive FKBP neuroimmunophilin ligands for treating a vision disorder, improving vision, treating memory impairment or enhancing memory performance in an animal.

Description

COMPOSITIONS AND USES FOR DISORDERS OF VISION AND MEMORY BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to pharmaceutical compositions and methods for treating vision loss, preventing vision degeneration and promoting vision regeneration ("neopsis") using small molecule derivatives of low molecular weight.

Description of Related Art The visual system consists of eyes, eye attachments and visual pathways. Visual system dysfunction can lead to permanent or temporary visual damage, that is, deviation from normal in one or more functions of the eye. The visual damage manifests itself in various ways and includes a wide range of dysfunctions and visual disturbances. Without limitation, these dysfunctions and alterations include loss of partial or total vision, the need for visual acuity correction for near and far objects, loss of visual field, impaired ocular motility without Ref: 126246 diplopia (double vision), perception of damaged or deviated color, limited adaptation to light and darkness, diminished adaptation, metamorphosis distortion, damaged binocular vision, adaptation paresis, iridioplegia, entropion, ectropion, epiphora, lagophthalmos and scrapes . See Physi cians' Desk Reference (PDR) for Ophthalmology, 16th Edition, 6:47 (1988). The visual system can be adversely affected by various disorders, diseases, injuries and ophthalmological complications that include, without limitation, genetic disorders; [non-genetic disorders]; disorders associated with age or degenerative diseases; disorders related to physical damage to the eye, head, or other parts of the body that result from external forces; disorders that result from environmental factors; disorders that result from a wide range of diseases; and combinations of any of the foregoing. The visual system is a complex system made up of many components. Visual damage can improve the entire visual system, any component or any combination of components, depending on the precise nature of the circumstances. The eye is made up of a lens, which is suspended in Zinn's zonules and focused by the ciliary body. The ciliary body also secretes aqueous humor which fills the posterior chamber, passes through the pupil to the anterior chamber and then drains mainly via Schlemm's canal. The iris regulates the amount of light that enters the eye by adjusting the size of its central opening, the pupil. A visual image is focused on the retina, the central fovea is the area of the retina with the greatest visual acuity. The conjunctiva is the mucus membrane whose lines constitute eyelids and eyeball, and ends abru in the conjunctiva of the limbus, the edge of the conjunctiva overlaps in the cornea. The cornea is the anterior transparent and clear portion of the fibrous covering of the eye; it is important in the refraction of light and is covered with an epithelium that differs in many aspects from the conjunctival epithelium. The retina is the innermost portion sensitive to the light of the eye, which contains two types of photoreceptors, cones, which are responsible for color vision in the brightest light and rods, which are essential for low-light vision but they do not perceive colors. After the light passes through the cornea, the lens system and the vitreous humor, it enters the retina from the inside; that is, it passes through ganglion cells and nerve fibers to the inner and outer plexiform layers, the inner and outer nuclear layers and the inner and outer limiting membranes before it finally reaches the photoreceptor layer that is located near from the outside of the retina, just inside the outermost pigmented epithelial layer. The cells of the pigmented epithelial layer act as an anatomical barrier for liquids and substances located outside the eye, forming the "hemato-retinal" barrier and providing nutrition, oxygen and a source of functionally useful substances, such as vitamin A, and phagocytoses of breakdown products to photoreceptor cells. There is no anatomical connection between the epithelium of the fragment and the photoreceptor layer, which allows the separation of the layers in some pathological situations. When rods or cones are excited by light, the signals are transmitted through successive neurons in the retina itself, within the fibers of the optic nerve and finally to the cerebral cortex. Both rods and cones contain molecules that break down when exposed to light, and in the process, excite the nerve fibers that leave the eye. The molecule in the rods is rhodopsin. The three light sensitive molecules to the cones, collectively called iodopsin, have compositions only slightly different from that of rhodopsin and are maximally excited by red, blue or green light, respectively. Neither rods nor cones generate action potentials. Instead, membrane hyperpolarization induced by the light generated in the outer photosensitive segment of a rod cell or cone is transmitted from the outer segment through the inner segment to the synaptic body by direct conduction of the electrical voltage itself, a process called electrotonic driving. In the synaptic body, the membrane potential controls the release of an unknown transmitter molecule. In low light, the cell membranes of the rods and cones depolarize and the rate of transmission release is greater. The hyperpolarization induced by light causes a marked decrease in the release of transmitting molecules. The transmitters released by the cells of rods and cones induce signals in bipolar neurons and horizontal cells. The signals in these two cell types are also transmitted by electrotonic conduction and not by action potential. The bipolar neurons of the rods are connected with up to 50 cells of rods, while the short and bipolar diffuse cells are connected with one or more cone cells. A depolarizing bipolar cell is stimulated when its connected rods or cones are exposed to light. The release of the transmitting molecules inhibits the depolarization of the bipolar cell. Therefore, in the dark, when rods and cones secrete large quantities of neurotransmitter molecules, depolarizing bipolar cells are inhibited. In light, the decrease in the release of transmitting molecules from rods and cones reduces the inhibition of the bipolar cell, allowing them to become excited. In this way, positive and negative signals can be transmitted through different bipolar cells from the rods and cones to the amacrine and ganglia cells. As its name suggests, horizontal cells are projected horizontally in the retina, where they can synapse with canes, cones or other horizontal cells, or a combination of cell types. The function of horizontal cells is unclear, although some mechanisms have been postulated in the convergence of photoreceptor signaling. All types of bipolar cells are connected to ganglion cells, which are of two main types. The type A ganglion cells are predominantly connected to the bipolar rod cells, while the B-type ganglion cells are predominantly connected to the diffuse dipolar and dipolar cells. It seems that type A ganglion cells are sensitive to contrast, light intensity and movement perception, while type B ganglion cells seem to relate more with color vision and visual acuity. Like horizontal cells, amacrine cells synapse horizontally with several or with many other cells, in this case, bipolar cells, ganglion cells and other amacrine cells. The function of the amacrine cells is not clear either. The axons of ganglia cells carry signals within the nerve fiber layer of the eye, where the axons converge into fibers which converge additionally on the optic disc, where they exit the eye as the optic nerve. The ganglion cells transmit their signals through the optic nerve fibers to the brain in the form of action potentials. These cells, even when not stimulated, transmit continuous nerve impulses at an average of a baseline rate of about 5 per second. The visual signal is superimposed on this baseline level of ganglion cell stimulation. It can be an exciting signal with many pulses increasing above the baseline rate, or an inhibitory signal, with many nerve impulses decreasing below the baseline rate. As part of the central nervous system, the eye is somehow an extension of the brain; as such, it has a limited capacity for regeneration. This limited capacity for regeneration further complicates the demanding tasks of improving vision, resolving dysfunctions of the visual system or treating or preventing ophthalmological disorders. Many eye disorders, such as retinal phytic damage, eye damage induced by retinal ischemia, age-related macular degeneration, eye diseases induced by free radicals as well as many other disorders are considered to be completely untreatable. Other ophthalmological disorders, for example disorders that cause permanent visual damage, are corrected only by the use of ophthalmic devices or surgery, or both, with varying degrees of success. The immunosuppressant drugs FK506, rapamycin and cyclosporin are well known as potent T cell-specific immunosuppressants and are effective against autoimmunity, graft transplantation or rejection, inflammation, allergic responses, other autoimmune or immune-mediated diseases and infectious diseases. It has been described that the application of ciclosporin, FK-506, rapamycin, buspirone, spiperone, and / or other derivatives are effective in treating some ophthalmological disorders of these types. Several ophthalmological disorders of vision problems are known to be associated with autoimmune and immunologically mediated activities; therefore, immunomodulatory compounds are expected to demonstrate efficacy in treating these types of ophthalmological disorders or vision problems. The effects of FK506, rapamycin and related agents in the treatment of ophthalmic diseases are described in several United States patents (Goulet et al., U.S. Patent No. 5,532,248; Mochizuki et al., U.S. Patent No. 5,514,686; Luly et al., U.S. Patent No. 5,457,111; Russo et al., U.S. Patent No. 5,441,937; Kulkarni, U.S. Patent No. 5,387,589; Asakura et al., U.S. Pat. United States No. 5,368,865; Goulet et al., United States Patent No. 5,258,389; Armistead et al., United States Patent No. 5,192,773; Goulet et al., United States Patent No. 5,189,042; and Fehr , United States Patent No. 5,011,844). These patents claim FK506 or compounds related to rapamycin and write in known use of FK506 or rapamycin related compounds in the treatment of ophthalmological disorders in association with the known immunosuppressive effects of FK506 and rapamycin. The compounds described in these patents are relatively large. In addition, the mentioned patents relate to immunomodulatory compounds limited to treating autoimmunity or related diseases, or immunologically mediated diseases, for which the efficacy of FK506 and rapamycin is well known. Other US patents describe the use of cyclosporin, spiperone, buspirone, its derivatives, and other immunosuppressant compounds for use in the treatment of ophthalmic diseases (Sharpe et al., U.S. Patent No. 5,703,088; Sharpe et al., U.S. Patent No. 5,693,645; Sullivan, U.S. Patent No. 5,688,765; Sullivan, U.S. Patent No. 5,620,921; Sharpe et al., U.S. Patent No. 5,574,041; Eberle, U.S. Patent United States No. 5,284,826; Sharpe et al., United States Patent No. 5,244,902; Chiou et al., United States Patent No. 5,198,454 and 5,194,434; and Kaswan, United States Patent No. 4,839,342). These patents also relate to compounds useful in treating autoimmune diseases and mention the known use of cyclosporin, spiperone, buspirone and its derivatives and other immunosuppressive compounds to treat ocular inflammation and other immunologically mediated ophthalmological diseases. The immunosuppressive compounds described in the prior art suppress the immune system, by definition, and also show other toxic side effects. Accordingly, there is a need for non-immunosuppressive small molecule compounds and compositions and methods for use of such compounds, which are useful for improving vision, preventing, treating or repairing visual damage or dysfunction of the visual system; and prevent, treat or resolve ophthalmological disorders. There are also many patents of non-immunosuppressive compounds that describe methods of use to allow or promote the healing of wounds (either damage or surgery); to control intraocular pressure (which often results from glaucoma); control of neurodegenerative disorders of the eye, including damage or alteration of the retinal neurons, damage or alteration of the cells of the retinal ganglia and macular degeneration; stimulation of outward neurite growth; prevention or reduction of oxidative damage caused by free radicals; and treatment of a damaged supply of oxygen and nutrients, as well as a damaged removal of the waste product, resulting in low blood flow. These non-immunosuppressive substances fall into one of two general categories: molecules that occur naturally, such as proteins, glycoproteins, peptides, hormones, and growth factors; and synthetic molecules. Within the group of non-immunosuppressive molecules that occur naturally, various hormones, growth factors and signaling molecules have been patented for use as supplements to naturally occurring amounts of such molecules, as well as to target specific cells wherein the particular molecule does not occur naturally in a mature individual. These patents generally claim methods of use for reducing or preventing the symptoms of eye diseases, or for suppressing or reversing loss of vision.

Specifically, Louis et al., Patents of the United States Nos. 5,736,516 and 5,641,749 describe the use of a line of glial cells derived from neurotrophic factor (GDNF) to stop or reverse the degeneration of retinal neurons (ie, photoreceptors) and retinal ganglion cells caused by glaucoma, or other diseases or degenerative or traumatic damage to the retina. O'Brien et al., U.S. Patent Nos. 5,714,459 and 5,700,909 disclose the use of a glycoprotein, saposin and its derivatives to stimulate neurite outgrowth and increase myelination. To stop or reverse the degeneration of retinal neurons, LaVail et al., U.S. Patent No. 5,667,968 discloses the use of a variety of neurotrophic proteins, including brain-derived neurotrophic factor, ciliary neurotrophic factor, neurotrophin-3 or neurotrophin. -4, growth factors of acidic or basic fibroblasts, interleukin, tumor necrosis factor a, insulin-like growth factor 2 and other growth factors. Wong et al., U.S. Patent No. 5,632,984 describes the use of interferons especially interferon a-2a to treat the symptoms of macular degeneration by reducing bleeding and limiting neovascularization. Finally, Wallace et al., U.S. Patent No. 5,441,937 describes the use of a lung-derived neurotrophic factor (NTF) to maintain the functionality of the ciliary ganglia and the parasympathetic neuronal cells. A key feature of the factors derived from specific cell lines is their localization in specific cell lines or tissues; Systemic treatment with these molecules leads to a substantial risk of unintended and potentially dangerous effects on cell lines where the genes encoding these molecules are inactive. Similarly, hormones and growth factors often activate a large number of genes in many cell lines, the non-localized application of these molecules represents a substantial risk of provoking an inappropriate and potentially dangerous response. Within the category of synthetic molecules, most of the patented compounds are immunosuppressants and describe uses to treat inflammatory, autoimmune and allergic responses, as discussed in the above. Some others are non-immunosuppressive and claim the ability to treat cellular degeneration and in some cases promote cellular regeneration, most frequently in the context of their antioxidant properties. Specifically, Tso et al., U.S. Patent No. 5,527,533 discloses the use of astaxanthin, a carotenoid antioxidant, to prevent or reduce photoreceptor damage resulting from the presence of free radicals.

Similarly, Babcock et al., U.S. Patent No. 5,252,319 discloses the use of antioxidant aminosteroids to treat diseases and damage to the eyes, by increasing resistance to oxidative damage. Freeman U.S. Patent No. 5,468,752 describes the use of antiviral phosphonylmethoxyalkylcytosines to reduce intraocular pressure abnormally increased. Hamilton and Steiner disclose, in U.S. Pat. No. 5,614,547 novel pyrrolidine carboxylate compounds which bind to the immunophilin FKBP12 and stimulate nerve growth, but which lack immunosuppressive effects. Unexpectedly, it has been discovered that these non-immunosuppressive compounds promote improvements in vision and resolve ophthalmological disorders. Their novel small molecule structure and their non-immunosuppressive properties differentiate them from FK506 and related immunosuppressive compounds found in the prior art. In addition, these compounds can be differentiated from the non-immunosuppressive compounds used to treat vision disorders by their novel small molecule structure and their lack of systemic effects in general. Hormones that occur naturally, growth factors, cytokines and signaling molecules are generally multifunctional and activate many genes in various cell lines. The present compounds do not do so, and therefore avoid the unexpected, and potentially dangerous, side effects of systemic use. Similarly, the present compounds also avoid the potential unexpected side effects of introducing specific molecules for a cell line into other cell lines where they do not occur naturally.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to the surprising discovery that non-immunosuppressive immunophilin ligands, i.e. inhibitors or binding agents, can be useful for treating a vision disorder, improving vision, treating memory damage or improving the functioning of memory in an animal. Accordingly, novel compositions and methods for the use of non-immunosuppressive immunophilin ligands are provided. A preferred feature of the compounds of the present invention is that they do not exert any significant immunosuppressive activity. Preferred embodiments of this invention also include methods and compositions wherein the non-immunosuppressive immunophilin ligand has an affinity for immunophilin of the FKBP type, and in particular by FKBP-12.

Preferred non-immunosuppressive immunophilin ligands of the FKBP type include, without limitation, small molecule heterocyclic ring compounds having a first and second substituent groups attached thereto, wherein the first substituent group comprises: i) an acid portion or ii) an alkyl, alkenyl, alkylaryl, alkenylaryl or group exemplified in some other manner herein which is attached to the heterocyclic ring by an ester, thioester, amide, amine, ketone bond or a variation as described herein, and wherein the second substituent group comprises an alkyl, alkenyl, alkylaryl, alkenylaryl or a group otherwise exemplified herein which is attached to the heterocyclic ring by a diketo, thiocarbonyl, carbamate, urea, sulfonyl bond or a bond as exemplified in I presented. Preferred embodiments of the invention include methods and compositions that utilize a compound selected from formulas (I) - (XXIX).

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 A, B and C shows that GPI 1046 protects retinal ganglion cells against degeneration after retinal ischemia.

Figure 2 shows that GPI 1046 prevents degeneration of optic nerve and myelin actions following retinal ischemia. Figure 3 shows that GPI 1046 provides moderate protection against the death of retinal ganglion cells after transection of the optic nerve. Figure 4 shows that the duration of treatment with GPI 1046 significantly affects the process of axonal degeneration of the optic nerve after transection. Figure 5 shows that treatment with GPI 1046 produces a greater effect on axons of the optic nerve than on the bodies of ganglion cells. Figure 6 shows that treatment with GPI 1046 for 28 days after transection of the optic nerve prevents degeneration of myelin in the proximal bundle. Figure 7 shows that the immunohistochemistry of FKBP-12 oligodendroglia tag (large dark cells with fibrous processes), the cells which produce myelin, located between the fascicles of the optic nerve fibers and also some axons of the optic nerve. Figure 8 shows that treatment with GPI 1046 for 28 days after transection of the optic nerve prevents the degeneration of myelin in the distal bundle.

Figure 9 shows that the treatment of 28 days with GPI 1046 treatment beginning 8 weeks after the onset of streptozotocin-induced diabetes decreases the degree of neovascularization in the inner and outer retina and protects neurons in the inner nuclear layer (INL) and the ganglion cell layer (GCL) of degeneration. Figure 10 shows the neuroreceptor effect of GPI 1046 on retinal ganglion cells after transection of the optic nerve. Figure 11 shows the correlation between the retinal ganglion cell and the axon reserve of the optic nerve at 90 days after the optic nerve transection and 14 or 28 days of treatment with GPI 1046. Figure 2 shows the preservation of the axons of the optic nerve by GPI 1046 in the proximal stump after the transection.

DETAILED DESCRIPTION OF THE INVENTION Definitions The term "eye" refers to the anatomical structure responsible for vision in humans and other animals, and encompasses the following anatomical structures without limitation: crystalline, vitreous body, ciliary body, posterior chamber, anterior chamber, pupil, cornea, iris , Schlemm's canal, Zinn zonulas, limbus, conjunctiva, choroid, retina, central vessels of the retina, optic nerve, central fovea, macula lutea and sclera. The term "GPI 1605" refers to a compound of formula The term "GPI 1046" refers to (2s) -l- (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3- (3-pyridyl) -1-propyl, a compound of formula 11046 The term "GPI 1312" refers to a compound of formula 12 The term "GPI 1572" refers to a compound of formula 1572 The term "GPI 1389" refers to a compound of formula The term "GPI 1511" refers to a compound of formula 1511 The term "GPI 1234" refers to a compound of formula The term "isomers" refers to different compounds that have the same molecular formula. The term "stereoisomers" are isomers that differ only in the manner in which atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are mirror images that do not overlap each other. "Diestereoisomers" are stereoisomers which are not mirror images of each other. "Racemic mixture" means a mixture containing equal parts of individual enantiomers. "Non-racemic mixture" is a mixture that contains different parts of individual enantiomers or stereoisomers.

The term "memory performance enhancer" refers to an improvement or increase in the mental faculty by which past experiences, knowledge, ideas, sensations, thoughts or impressions are recorded, retained or remembered. The term "memory damage" refers to a diminished mental record, retention or reminder of past experiences, knowledge, ideas, sensations, thoughts or impressions. Memory damage can affect short and long-term information retention, ease with spatial relationships, memory test strategies, and verbal recall and production. The common causes of memory damage are age, severe head trauma, cerebral anoxia or ischemia, alcoholic-nutritional diseases and drug poisoning. Examples of memory damage include, without limitation, benign forgetfulness, amnesia, and any disorder in which a memory deficiency is present, such as Korsakoff's amnesic psychosis, dementia, and learning disorders. "Neopsic factors" or "neofysics" refers to compounds useful for treating vision loss, preventing degeneration of vision or promoting vision regeneration.

"Neoplasia" refers to the processes to treat vision loss, prevent degeneration of vision or promote vision regeneration. "Ophthalmological" refers to anything related or connected to the eye, without limitation, and is used interchangeably with the terms "ocular", "ophthalmic", "ophthalmologic" and other similar terms, without limitation. The term "pharmaceutically acceptable salt, ester or solvate" refers to a salt, ester or solvate of an object compound which possesses the desired pharmacological activity and which is not undesirable neither biological nor in any other way. A salt, ester or solvate can be made with inorganic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorrate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, emisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, naphthylate, 2-naphthalenesulfonate, nicotinate, oxalate, sulfate, thiocyanate, tosylate and undecanoate. Examples of basic salts, esters or solvates include 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 dicyclohexylamine salts; N-methyl-D-glucamine; and salts with amino acids, such as arginine, lysine and so on. In addition, groups containing basic nitrogen can form quaternary salts with agents such as lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfate; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides such as benzyl bromide and phenethyl; and others. In this way, soluble or dispersible products are obtained in water or oil. "Prevention of vision degeneration" refers to the ability to prevent vision degeneration in patients who have recently been diagnosed with a degenerative disease that affects vision, or at risk of developing a new degenerative disease that affects vision, and to avoid additional degeneration of vision in patients who already suffer or who have symptoms of a degenerative disease that affects vision. The term "that promotes the regeneration of vision" refers to the maintenance, improvement, stimulation or acceleration of the recovery of, or revitalization of, one or more components of the visual system in a manner which improves or increases vision, whether in Presence or absence of any disorder, disease or ophthalmological damage. The term "treatment" refers to: (i) preventing it from occurring. disease or condition, or both, in a subject who may be predisposed to the disease or condition but has not yet been diagnosed with it; (ii) inhibit the disease or condition, that is, suppress its development; or (iii) alleviating the disease or condition, that is, causing the regression of the disease or condition. The term "vision" refers to the ability of humans and other animals to process images and is used interchangeably with "sight", "observation" and other similar terms, without limitation. The term "vision disorder" refers to any disorder that affects or involves vision, including but not limited to visual impairment, orbital disorders, lacrimal apparatus disorders, eyelash disorders, conjunctival disorders, corneal disorders , cataracts, uveal tract disorders, retinal disorders, disorders of the optic nerve or visual pathways, disorders and diseases of the eyes induced by free radicals, disorders and diseases of the eyes immunologically mediated, damage to the eyes, and symptoms and complications of eye diseases, eye disorders, or damage to the eyes. The term "visual damage" refers to any vision dysfunction that includes, without limitation, alterations or decreases in vision (for example binocular, central, peripheral, scotopic), visual acuity for near and far objects, visual field, ocular motility, color perception, adaptation to light and darkness, accommodation, refraction and tearing. See Physician's Desk Reference (PDR) for Ophthalmology, 16th Edition, 6:47 (1988).

METHODS OF THE PRESENT INVENTION The present invention relates to a method for treating a vision disorder, improving vision, treating damage to memory or improving memory performance in an animal, which comprises administering to the animal an effective amount of a derivative. The methods of the invention are particularly useful for treating various disorders of the eye that include, but are not limited to, disorders, diseases, damages and complications as well as genetic disorders; disorders associated with aging or degenerative vision diseases; vision disorders that correlate with physical damage to the eye, head or other parts of the body resulting from external forces; vision disorders that result from environmental factors; vision disorders resulting from a wide range of diseases; and combinations of any of the foregoing. In particular, the compositions and methods of the present invention are useful for improving vision, or for correcting, treating or preventing damage or visual (ocular) dysfunction in the visual system, including permanent or temporary visual damage, without limitation. The present invention is also useful for preventing and treating ophthalmological diseases and disorders, treating damaged and battered eyes and preventing and treating diseases, disorders and damages which result in vision deficiency, loss of vision or reduced ability to see or process images, and the symptoms and complications that result from them. Diseases and ocular disorders which can be treated or prevented by the compositions and methods of the present invention are not limited with respect to the cause of such diseases or disorders. Accordingly, such compositions and methods are applicable whenever the disease or disorder is caused by genetic or environmental factors, as well as any other influence. The compositions and methods of the present invention are particularly useful for eye problems or loss or deficiency in vision associated with all of the following, without limitation: aging, cellular or physiological degeneration, central nervous or neurological disorder, defects vascular, muscular defects and exposure to environmental conditions or adverse substances. The compositions and methods of the present invention are particularly useful for correcting, treating or improving visual damage, without limitation. Visual damage in varying degrees occurs in the presence of a deviation from normal in one or more functions of the eye, which include: (1) visual acuity for distant objects and near; (2) visual fields; and (3) ocular motility without dipoplia. See Physician's Desk Reference (PDR) for Ophthalmology, 16tb Edi tíon, 6: 41 (1988). The vision is imperfect without the coordinate function of the three. Id. Such compositions and methods of use are also useful for correcting, treating or improving other ocular functions including, without limitation, color perception, adaptation to light and darkness, accommodation, metamorphosis and binocular vision. The compositions and methods of use are particularly useful for treating, correcting or preventing ocular alterations including, without limitation, accommodation paresis, iridioplegia, entropion, ectropion, epiphora, lagophthalmos, scraping, vitreous opacities, non-reactive pupil, alterations in the diffusion of the light of the cornea or other means and permanent deformities of the orbit. The compositions and methods of use of the present invention are also highly useful for improving vision and treating vision loss. The loss of vision varies from a slight loss to an absolute loss and can be treated or prevented using such compositions and methods of use. Vision can be improved by treatment of disorders, diseases and damage to the eye using the compositions and methods of the invention. Nevertheless, improvements in vision using the compositions and methods of use are not limited in this way, and may be presented in the absence of any disorder, disease or damage. The compositions and methods of the present invention are also useful in the treatment or prevention of the following exemplary non-limiting disorders or disorders and symptoms and complications resulting therefrom. Vision disorders include, but are not limited to the following: visual damage, such as diminished visual acuity for near and far objects, visual fields and ocular motility; orbital disorders such as orbital cellulitis, periorbital cellulitis, cavernous sinus thrombosis and exophthalmos (protptosis); disorders of the lacrimal apparatus such as dacryostenosis, congenital dacryostenosis and dacryocystitis (acute or chronic); disorders of the eyelids such as edema in the eyelid, blepharitis, ptosis, Bell's palsy, blepharospasm, hordeolum arzuelo, hordeolum externa, internal hordeolum meibomian arzuelo, calazión, entropion (inversion of the eyelid), ectropion (eversion of the eyelid), tumors ( benign and malignant), xanthelasma, vasal cell carcinoma, squamous cell carcinoma, carcinoma of the meibomian gland and melanoma; Conjunctival disorders such as pinguecula, pterygium and other neoplasms, acute conjunctivitis, chronic conjunctivitis, adult gonococcal conjunctivitis, neonatal conjunctivitis, trachoma (granular conjunctivitis or Egyptian ophthalmia), inclusion conjunctivitis (including blenorrhea or conjunctivitis of the pool), conjunctivitis of neonatal inclusion and adult inclusion conjunctivitis, vernal keratoconjunctivitis, dry keratoconjunctivitis (dry keratitis or dry eye syndrome), episcleritis, scleritis, scar pemfigoid (pemfigoid ocular scar or benign mucosal membrane pemphigoid) and subconjunctival hemorrhage; corneal disorders, such as keratitis with superficial spots, corneal ulcer, indolent ulcer, recurrent corneal erosion, corneal epithelial basement membrane dystrophy, cornea epithelial cell dystrophy, herpes simplex keratitis (keratoconjunctivitis) by herpes simplex), dendritic keratitis, disciform keratitis, ophthalmic herpes zoster, phlyctenular keratoconjunctivitis (flictenular conjunctivitis or eczematose), interstitial keratitis (parenchymal keratitis), peripheral ulcerative keratitis (marginal keratolysis or peripheral rheumatoid ulceration), keratomalacia (xerotic keratitis), xerophthalmia , keratoconus, bullous keratopathy; cataracts that include congenital developmental cataracts, juvenile or adult cataracts, nuclear cataracts, posterior subcapsular cataracts; disorders of the uveal tract such as uveitis (inflammation of the uveal tract or retina), anterior uveitis, intermediate uveitis, posterior uveitis, iritis, cyclitis, choroiditis, ankylosing spondylitis, Reiter's syndrome, pars planitis, toxoplasmosis, cytomegalovirus (CMV), acute retinal necrosis, toxocariasis, choroidopathy of silk iridescent, histoplasmosis (opposite ocular histoplasmosis syndrome), Behcet's syndrome, sympathetic ophthalmia, Vogt-Koyanagi-Harada syndrome, sarcoidosis, reticulum cell sarcoma, large cell lymphoma, syphilis, tuberculosis, juvenile rheumatoid arthritis, endophthalmitis, and melanoma malignant of the choroid; disorders of the retina, such as vascular retinopathy (eg, atherosclerotic retinopathy and hypertensive retinopathy), central retinal artery occlusion and branching, central retinal vein occlusion and branching, diabetic retinopathy (eg, proliferative retinopathy and nonproliferative retinopathy) , macular degeneration of aging (age-related macular degeneration or senile macular degeneration), neovascular macular degeneration, retinal detachment, retinitis pigmentosa, retinal phytic damage, eye damage induced by retinal ischemia and glaucoma (eg primary glaucoma, chronic open-angle glaucoma, acute or chronic closed angle, congenital (infantile) glaucoma, secondary glaucoma and absolute glaucoma); disorders of the optic nerve or visual pathways such as papilledema (shocked disk), papillitis (optic neuritis), retrovulvar neuritis, ischemic optic neuropathy, toxic amblyopia, optic atrophy, lesions in the superior visual pathway, ocular motility disorders (for example, paralysis) of the third cranial nerve, paralysis of the fourth cranial nerve, paralysis of the sixth cranial nerve, internuclear ophthalmoplegia and glare paralysis); disorders and diseases of the eye induced by free radicals; and immunologically mediated disorders and diseases in the eye such as Graves' ophthalmopathy, conical cornea, corneal epithelial dystrophy, corneal leucoma, ocular pemphigoid, Mooren's ulcer, scleritis and sarcoidosis (see The Merck Manual, Sixteenth Edition, 217: 2365-2397 (1992) and The Eye Book, Cassel, Billig and Randall, The John Hopkins University Press (1998)). The compositions and methods of the present invention are also useful in the treatment of the following non-limiting damage to the eye as well as symptoms and complications resulting therefrom: damage by a foreign body to the conjunctiva and cornea, abrasion of the cornea, damage due to an intraocular foreign body, lacerations, lacerations on the lid, contusions, bruises on the lid (black eye), balloon trauma, iris laceration, cataracts, dislocated lenses, glaucoma, vitreous hemorrhage, fractures of the orbital floor, retinal hemorrhage or detachment and rupture of the eyeball, hemorrhage of the anterior chamber (traumatic hyphema), burns, burns of the eyelids, chemical burns, chemical burns of the cornea and conjunctiva and burns by ultraviolet light (sunburn). See The Merck Manual, Sixteenth Edition, 217: 2365-2397 (1992).

The compositions and methods of the present invention are also useful for treating or preventing, or both, the following symptoms and non-limiting exemplary complications of eye diseases, eye disorders or damage to the eyes: subconjunctival hemorrhages, vitreous hemorrhages, retinal hemorrhages, buoys, retinal detachment, photophobia, eye pain, scotomas (negative and positive), refractive errors, emmetropia, ametropia, hyperopia (lack of sight from afar), myopia (lack of near vision), astigmatism, anisometropia, aniseoconia, presbyopia, bleeding, recurrent bleeding, sympathetic ophthalmia, inflammation, swelling, eye redness, eye irritation, corneal ulceration and scraping, iridocyclitis, balloon perforation, layer deformities, exophthalmos, impaired mobility of the eye, swollen of the cap, chemosis, loss of vision that includes partial or total blindness, optic neuritis, fever, headache, thrombophlebitis, cavernous sinus thrombosis, panophthalmitis, infection of the meninges and brain, papilledema, severe cerebral symptoms (headache, decreased level of consciousness and convulsions), paralysis of cranial nerves, epiphora (chronic or persistent lachrymation), copious reflux of mucus or pus, follicular conjunctival hyperplasia, vascularization of the cornea, scarring of the conjunctiva, cornea and lids, pannus, hypopion, lagophthalmos, flictenules, rubeosis iridis, bitemporal hemianopia and homonymous hemianopia. See The Merck Manual, Sixteenth Edition, 217: 2365-2397 (1992). The derivative can be administered in combination with an effective amount of one or more factors useful for treating vision disorders, improving vision, treating damage to memory or improving memory performance. In a preferred embodiment, the factors to be combined with the derivatives are selected from the group consisting of immunosuppressants to treat autoimmune, inflammatory and immunologically mediated disorders; wound healing agents to treat wounds resulting from damage or surgery; antiglucomatoses medications to treat abnormally elevated hydro-ocular pressure; neurotrophic factors and growth factors to treat neurodegenerative disorders or stimulate the outward growth of neurites; effective compounds to limit or prevent hemorrhage or neovascularization to treat macular degeneration; and antioxidants to treat oxidative damage to eye tissues.

PHARMACEUTICAL COMPOSITIONS OF THE PRESENT INVENTION The present invention also relates to a pharmaceutical composition comprising: (i) an effective amount of a derivative to treat a vision disorder, improve vision, treat memory damage or improve memory performance in an animal; and (ii) a pharmaceutically acceptable carrier. The derivative can be administered in combination with an effective amount of one or more factors useful for treating vision disorders, improving vision, treating memory damage or improving memory performance.

LIGANDS OF FKBP OF NEUROINMUNOFILINA NOT IMMUNOSUPPRESSORS The non-immunosuppressive neuroimmunophilin FKBP ligand used in the method and pharmaceutical composition of the present invention is a small molecule, low molecular weight compound that has affinity for FKBP type immunifilin, such as FKBP12. When the compound binds to an immunophilin of the FKBP type, it has been found to inhibit the activity of prolyl-peptidyl cis -trans isomerase, or rotamase, activity of the binding protein. As its name suggests, the compound lacks any significant immunosuppressive activity. Examples of a non-immunosuppressive neuroimmunophilin FKBP ligand that can be used in the method and the pharmaceutical composition of the invention are indicated below.

I. HETEROCYCLIC THYOSETHES AND KETONES FORMULA I The non-immunosuppressive neuroimmunophilin FKBP ligand can be a compound of formula I or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatoms that are independently selected from the group consisting of 0, S, S02, N, NH, and NR2; X is O or S; Z is S, CH2, CUR1 or CRXR3; W and Y are independently 0, S, CH2 or H2; R-. and R3 are independently straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein the alkyl or alkenyl are substituted with one or more substituents that are independently selected from group consisting of (Arj) n, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with (Ar ,,, cycloalkyl of 3 to 8 carbon atoms) carbon, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with cycloalkyl of 3 to 8 carbon atoms, and Ar2; n is 1 or 2; is straight or branched chain alkyl of 1 to 9 carbon atoms, straight or branched chain alkenyl of 2 to 9 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, or Arx, wherein the alkyl, alkenyl, Cycloalkyl or cycloalkenyl is unsubstituted or substituted by one or more substituents which are independently selected from the group consisting of straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl of 2 to 4 carbon atoms and hydroxy; and rL and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted with one or more substituents that are independently selected from the group consisting of halo , hydroxyl, nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 atoms carbon, phenoxy, benzyloxy and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatoms which are independently selected from the group consisting of O, N and S. Useful carbo- and heterocyclic rings include, without limitation, phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolicinyl, furyl, thiophenyl, imidazole, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxydiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trityanil, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and fen oxazinyl.

FORMULA II The non-immunosuppressive neuroimmunophilin FKBP ligand can also be a compound of formula II II or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: n is 1 or 2; X is O or S; Z is selected from the group consisting of S, CH2, CHRX and CR ^; RL and R3 are independently selected from the group consisting of straight or re-chain alkyl of 1 to 5 carbon atoms, straight or branched chain alkenyl of 2 to 5 carbon atoms, and Arlf wherein the alkyl, alkenyl or Arx is unsubstituted or substituted with one or more substituents that are independently selected from the group consisting of halo, nitro, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms , phenoxy, benzyloxy, amino and Ar ^ -R2 is selected from the group consisting of straight or branched chain alkyl of 1 to 9 carbon atoms, straight or branched chain alkenyl of 2 to 9 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, and Ar1; and Ar-L is phenyl, benzyl, pyridyl, fluorenyl, thioindolyl or naphthyl, where r! is unsubstituted or substituted with one or more substituents that are independently selected from the group consisting of halo, trifluoromethyl, hydroxy, nitro, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms, phenoxy, benzyloxy and amino. Preferred compounds of formula II are presented in table A.

TABLE A The preferred compounds of TABLE A are named as follows: (2S) -2- ( { L-oxo-5-f-enyl}. -pentyl-1- (3,3-dimethyl-l, 2-dioxopentyl) pyrrolidine 3, 3-dimethyl-l- [( 2S) -2- (5- (3-pyridyl) pentanoyl) -1- pyrrolidine] -1,2-pentanedione (2S) -2- (. {L-oxo-4-phenyl}. -butyl-1 - (3, 3-dimethyl-l, 2-dioxobutyl) pyrrolidine (2S) -1- (3, 3-dimethyl-l, 2-dioxopentyl) -2- pyrrolidinecarbotioate 2-f-enyl-1-ethyl 1- 1- (3, 3-dimethyl-1,2-diox or pentyl) -2-piperidincarbotioate of 2-f-enyl-1-ethyl 11 (2S) -1- (3,3-dimethyl-1,2-diopentyl) - 2-pyrrolidinecarbothioate (3-thioindole) methyl 12 (2S) -1- (2-cyclohexyl-1, 2-dioxoethyl) -2-pyrrolidinecarbothioate 2-phenyl-1-ethyl 1- (2-phenyl-1-phenyl) , 2-phenyl-1-ethyl-2-pyrrolidinecarbothioate 2 (2S) -1- (1-cyclopentyl-1, 2-dioxoethyl) -2-pyrrolidinecarbothioate 2-phenyl-1-ethyl 2-phenyl-1-ethyl 2-phenylpropionate 3-phenyl-1-propyl (3, 3-d-butyl-1, 2-di oxobutyl) -2-piperidincarbothioate (2S) -1- (3, 3-dimethyl-1,2-dioxopentyl) - 2 pyrrolidinecarbothioate 3- f-enyl-1-propyl 31 (2 S) -1- (3, 3-dime t i 1 - 1, 2-dioxopen t i 1) - 2 pyrrolidinecarbothioate 3- (3-pyridyl) -1-propyl 32 (2S) -l- (2-cyclohexyl-1, 2-dioxoethyl) -2-pyrrolidinecarbothioate 3 -f-enyl-1-propyl 33 (2S) -l- (2-cyclohexyl-1,2-dioxoethyl) -2 4-f-enyl-1-butyl pyrrolidinecarbothiolate 34 (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarbotioate 4-f-enyl-1-butyl 35 (2S) -1 - (3- (3-pyridyl) -1-propyl-3- (2-cyclohexyl-1,2-dioxoethyl) -2-pyrrolidinecarbothioate (2S) -1- (3, 3-dimetho-1, 2-dioxopentyl) 1) - 2 • 3, 3 -difenyl-1-propyl pyrrolidinecarbothioate 37 (2S) -l- (2-cyclohexyl-1,2-dioxoethyl) -2- pyrrolidinecarbothioate 3, 3 -difenyl-1-propyl 38 (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2- pyrrolidinecarbothioate 3- (para-methoxyphenyl) -1- propyl 39 1 - (1,2-di-oxo-3, 3-dime ti lbut il) -2-piperidincarbotioate of 4-p-enyl-1-butyl 0 l- (3,3-dimethyl-1, 2-diox or pentyl) -2-piperidinecarbothioate 1,5-dif enyl-3-pentyl 41 1- (3-phenyl-1,2-dioxoethyl) -2-piperidinecarbothioate 1,5-diphenyl-3-mercaptopentyl 42 1- (1,2-dioxo-3,3-dimethylpentyl) - piperidin-2-carbothioate 3- (para-methoxyphenyl) -1-propyl 43 1- (2-phenyl-1,2-dioxoethyl) -piperidin-2-carbothioate 3- (para-methoxyphenyl) -1-propyl 44 1- (3,3-dimethyl-1, 2-dioxopentyl) -piperidin-2-carbothioate 3- (1-naphthyl) -1-propyl 45 (2S) -1- (3, 3-dimethyl-1, 2-dioxopentyl) -2-pyrrolidine-carbothioate of 3,3-di (para-fluoro) phenyl-1-propyl 46 1- (3,4-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbotioate of 4,4-di (para-fluorophenyl) -butyl 47 (2S) -l- (3,3-dimethyl-2-oxopentanoyl) - 2- 3- (1-naphthyl) propyl pyrrolidincarbothioate 48 (2S) -1- (3,3-dimethyl-2-oxopentanoyl) tetrahydro-1H-2-pyrrolidine-carbothioate 2,4-diphenylethyl ester 49 (2S) - l- (2,3-dimethyl-2-oxopentanoyl) -2- 2, 2-diphenylethylpiperidincarbothioate 50 l - (3,3 -dimethyl-2-oxopentanoyl) -2-piperidincarbothioate 3,3-diphenylpropyl 51 (2S 3 - [4- (trifluoromethyl) phenyl] propyl] -1- (3, 3-dimethyl-2-oxopentanoyl) -2-pyrrolidine-carbothioic acid 52 (2S) -1- (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidin-carbothioic acid 3- (2-naphthyl) propyl 53 (2R, S) -l- (3,3-dimethyl-2) -oxopentanoyl) -2- 3- (2-naphthyl) propyl piperidincarbothioate 54 (2S) -1- (3,3-dimethyl-2-oxopentanoyl) -2- pyrrolidinecarbothioate 3- (3-chlorophenyl) propyl 55 (2S 3 - [3- (trifluoromethyl) phenyl] propyl] -1- (3,3-dimethyl-2-oxopentanoyl) -2-pyrrolidinecarbotioate. 56 (2S) -l- (3, 3-dimethyl-2-oxopentanoyl) -2- pyrrolidinecarbothioate 3- (1-biphenyl) propyl 57 (2S) -l- (3,3-dimethyl-2-oxopentanoyl) - 2-3- (2-fluorophenyl) propyl pyrrolidine-carbothioate 58 (2S) -l- (3,3-dimethyl-2-oxopentanoyl) -2- pyrrolidinecarbothioate 3- (3-fluorophenyl) propyl 59 1- (3 , 3-dimethyl-2-oxopentanoyl) -2-piperidine-carbothioate, 4-phenylbutyl 60 1 - (3, 3-dime ti 1 - 2-oxopent anoi 1) - 2-piperidine-carbothioate 3-phenylpropyl 61 (2S) -l- (3, 3-dimethyl-2-oxopentanoi L) -2-pyrrolidinecarbotioate 3- ( 2-chlorophenyl) propyl 62 1- (3,3-dimethyl-2-oxopentanoyl) -2-piperidine-carbothioic acid 3- (2-chlorophenyl) propyl 63 1- (3,3-dimethyl-2-oxopentanoyl) -2 3- (2-fluorophenyl) propyl 1- (3,3-dimethyl-2-oxopentanoyl) -2-piperidin-carbothioic acid 3- (3-fluorophenyl) propyl 65 (2S) -l- (3- (2-fluorophenyl) propyl) piperidine- carbothioate 3, 3-dimethyl-2-oxopentanoyl) -2- pyrrolidinecarbothioate 3- (3,4-dimethoxyphenyl) propyl 66 (2S) -2- (. {1-oxo-4-phenyl}. -1- (2-cyclohexyl-1, 2-dioxoethyl) pyrrolidine 67 2 - (. {L-oxo-4-phenyl} - butyl-1- (3,3-dimethyl-l, 2-dioxobutyl) pyrrolidine 68 2- (. {l-oxo-6-phenyl} - hexyl -1- (2-cyclohexyl-1, 2-dioxoethyl) piperidine 69 2- (. {l-oxo- [2- {2'-phenyl} ethyl] -4-phenyl} -butyl-1- (3, 3-dimethyl-l, 2-dioxobutyl) piperidine 70 l- { (2S) -2- [5,5-di (4-fluorofe nil) pentanoyl] -2- pyrrolidine} 3, 3-dimethyl-l, 2-pentanedione 71 3, 3-dimethyl-1- [2- (4-phenylpentanoyl) piperidino] -1,2-pentanedione.

FORMULA III In addition, the non-immunosuppressive neuroimmunophilin FKBP ligand can be a compound of formula III III or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A, B, and C are independently CH2, O, S, S02, NH, or NR2; X is 0 or S; Z is S, CH2, CHRX or CR ^; Rx and R3 are independently straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein the alkyl or alkenyl are substituted with one or more substituents that are independently selected of the group consisting of (Ar-, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with (Ar?) n, cycloalkyl of 3 to 8 carbon atoms, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with cycloalkyl of 3 to 8 carbon atoms, and Ar2; n is 1 or 2 R2 is straight or branched chain alkyl of 1 to 9 carbon atoms, straight or branched chain alkenyl of 2 to 9 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, or Arx, wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is unsubstituted or substituted with one or more substituents that are independently selected from the group consisting of straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl of 2 to 4 carbon atoms and hydroxyl; and Ar! and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted with one or more substituents that are independently selected from the group consisting of halo, hydroxyl , nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms , phenoxy, benzyloxy and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatoms which are independently selected from the group consisting of O, N and S. Preferred compounds of formula III are depicted in TABLE B.

TABLE B FORMULA IV Alternatively, the non-immunosuppressive neuroimmunophilin FKBP ligand may be a compound of formula IV IV or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A, B, C, and D are independently CH2, 0, S, SO, S02, NH, or NR2; X is O or S; Z is S, CH2, CHRX or CR ^; Rx and R3 are independently straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein the alkyl or alkenyl are substituted with one or more substituents which are selected independently The group consisting of (Arj), straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with (Ar ,,, cycloalkyl) 3 to 8 carbon atoms, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with cycloalkyl of 3 to 8 carbon atoms, and Ar2; n is 1 or 2, R2 is straight or branched chain alkyl of 1 to 9 carbon atoms, straight or branched chain alkenyl of 2 to 9 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, or Arlf wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is unsubstituted or substituted with one or more substituents that are independently selected from the group consisting of cycloalkyl of 3 to 8 carbon atoms, straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl of 2 to 4 carbon and hydroxyl atoms; and Ar and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted with one or more substituents that are independently selected from the group consisting of halo , hydroxyl, nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 atoms carbon, phenoxy, benzyloxy and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatoms which are independently selected from the group consisting of O, N and S. Preferred compounds of formula IV are presented in TABLE C.

TABLE C FORMULA V The non-immunosuppressive neuroimmunophilin FKBP ligand can be a compound of formula V V or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: V is C, N or S; A, and B together with V and the carbon atom to which they are attached respectively, form a 5-7 membered saturated or unsaturated heterocyclic ring which may contain, in addition to V, one or more heteroatoms which are independently selected from the group that consists of O, S, SO, S02, N, NH, and NR4; R4 is straight or branched chain alkyl of 1 to 9 carbon atoms, straight or branched chain alkenyl of 2 to 9 carbon atoms, cycloalkyl of 3 to 9 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, or Ar 3, wherein R 4 is unsubstituted or substituted with one or more substituents that are independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl and Ar4; Ar3 and Ar4 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms which are independently selected from the group consisting of O, N and S; and R1 # R2, W, X, Y, and Z are as defined in formula I above.

II. ESTERES AND AMETAS HETEROCÍCLICOS OF FORMULA VI Additionally, the non-immunosuppressive neuroimmunophilin FKBP ligand can be a compound of formula VI or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to the nitrogen atom, one or more heteroatoms which are independently selected from the group consists of 0, S, SO, S02, N, NH, and NR ?; X is 0 or S; Z is 0, NH or NR1 # - W and Y are independently O, S, CH2 or H2; Rx is straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, which is substituted with one or more substituents that are independently selected from the group consisting of (Arj), straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with (Ar ,,, cycloalkyl of 3 to 8 carbon atoms, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with cycloalkyl of 3 to 8 carbon atoms carbon, and Ar2; n is 1 or 2, R2 is either straight or branched chain alkyl of 1 to 9 carbon atoms, or straight or branched chain alkenyl of 2 to 9 carbon atoms, cycloalkyl of 3 to 8 atoms of carbon, cycloalkenyl of 5 to 7 carbon atoms, or Ar 1 # wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is unsubstituted or substituted by one or more substituents that are independently selected from the group consisting of straight or branched chain alkyl from 1 to 4 carbon atoms, straight or branched chain alkenyl of 2 to 4 carbon atoms and hydroxyl, and rL and Ar2 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, in the one that the ring is not its substituted or substituted with one or more substituents that are independently selected from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 atoms carbon, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms, phenoxy, benzyloxy and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatoms which are independently selected from the group consisting of O, N and S. Useful carbo- and heterocyclic rings include, without limitation, naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl, and phenyl.

FORMULA VII The non-immunosuppressive neuroimmunophilin FKBP ligand can also be a compound of formula VII B-C N O X OR R- VII or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A, B, and C are independently CH2, O, S, SO, S02, NH, or NR?; Rx is straight or branched chain alkyl of 1 to carbon atoms or straight or branched chain alkenyl of 2 to 5 carbon atoms, which is substituted with one or more substituents which are independently selected from the group consisting of (Ar -., And straight or branched chain alkyl) 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with (Ar,) -, n is 1 or 2, R2 is straight or branched chain alkyl of 1 to 9 carbon atoms , straight or branched chain alkenyl of 2 to 9 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, or Arx; Ar-L is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring in the. that the ring is unsubstituted or substituted with one or more substituents that are independently selected from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl from 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms, phenoxy, benzyloxy and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatoms which are independently selected from the group consisting of O, N and S. In a preferred embodiment of the compounds of formula the heterocyclic ester or amide is the compound GPI 1572, of the formula In a particularly preferred embodiment of the compounds of formula A is CH2; B is CH2 or S; C is CH2 or NH; R. is selected from the group consisting of 3-phenylpropyl and 3- (3-pyridyl) ropyl; and R2 is selected from the group consisting of 1,1-dimethylpropyl, cyclohexyl and tert-butyl. The specific examples of this modality are presented in TABLE D.

TABLE D FORMULA In a further embodiment of this invention, the non-immunosuppressive neuroimmunophilin FKBP ligand can be a compound of formula or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A, B, C, and D are independently CH2, O, S, SO, S02, NH, or NR1 # -R-. is straight or branched chain alkyl of 1 to 5 carbon atoms or straight or branched chain alkenyl of 2 to 5 carbon atoms, which is substituted with one or more substituents which are independently selected from the group consisting of (Ar n , and straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with (Arx) n; n is 1 or 2; R2 is straight chain or rhoimified alkyl from 1 to 9 carbon atoms, straight or branched chain alkenyl of 2 to 9 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, or Arx, and Ar-L is a ring alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic, wherein the ring is unsubstituted or substituted with one or more substituents that are independently selected from the group consisting of halo, hydroxyl, nitro, trifluoromethyl, linear or branched chain from 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms, phenoxy, benzyloxy and amino; wherein the individual ring size is 5-8 members; and wherein the heterocyclic ring contains 1-6 heteroatoms which are independently selected from the group consisting of O, N and S. In a particularly pre-determined form of compounds of formula : A is CH2; C is S, or NH; D is CH2; R-L is selected from the group consisting of 3-phenylpropyl and (3,4,5-trimethoxy) phenylpropyl; and R2 is selected from the group consisting of 1,1-dimethylpropyl, cyclohexyl, tert-butyl, phenyl and 3,4,5-trimethoxyphenyl.

The specific examples of this modality are presented in TABLE E. TABLE E FORMULA IX Additionally, the non-immunosuppressive neuroimmunophilin FKBP ligand can be a compound of formula IX or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: V is C, N or S; A, and B, together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring which may contain, in addition to V, one or more heteroatoms which are independently selected from the group consisting of O, S, SO, S02, N, NH, and NR; R is straight or branched chain alkyl of 1 to 9 carbon atoms, straight or branched chain alkenyl of 2 to 9 carbon atoms, cycloalkyl of 3 to 9 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, or Ar3 , wherein the R is unsubstituted or substituted with one or more substituents that are independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 atoms carbon, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl , aminocarboxyl and Ar4; Ar3 and Ar4 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms which are independently selected from the group consisting of O, N and S; and R1 t R2, W, X, Y, and Z are as defined in formula VI above.

III. N-OXIDES OF ESTERS, AMIDAS, THIOESTERS AND HETEROCYCLIC KETONES FORMULA X The non-immunosuppressive neuroimmunophilin FKBP ligand may also be a compound of formula X or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing one or more heteroatoms which are independently selected from the group consisting of CH2, O, S, SO, S02, N, NH, and NR1; - W is O, S, CH2 or H2; R is straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms or Ar17 on the which is optionally substituted with one or more substituents which are independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, hydroxy, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms and Ar2; Arx and Ar2 are independently selected from the group consisting of 1-naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl , 4-pyridyl, and phenyl, having one or more substituents that are independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, alkenyl straight or branched chain of 2 to 6 carbon atoms, alkenyloxy of 2 to 4 carbon atoms, phenoxy, benzyloxy and amino; X is 0, NH, NRX, S, CH, CRX or CRXR3, Y is a direct bond, straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms; wherein the alkyl or alkenyl is optionally substituted with one or more substituents that are independently selected from the group consisting of straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms , cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, hydroxy, carboniloxygen and Ar; wherein the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar are optionally substituted with straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl of 2 to 4 carbon atoms, hydroxy or carbonyloxygen; wherein any carbon atom of the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with O, NH, NR2, S, SO, or S02; R2 is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl or alkynyl of 3 to 4 carbon atoms, and alkyl forming a bridge of 1 to 4 carbon atoms, wherein a bridge is formed between the hydrogen and the carbon atom of the alkyl or alkenyl chain containing such a hetero atom to form a ring, wherein the ring is optionally fused to an Ar group; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; the aromatic amine is selected from the group consisting of pyridyl, pyrimidyl, quinolinyl or isoquinolinyl, which is unsubstituted or substituted by one or more substituents that are independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, chain alkyl linear or branched of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms, phenoxy, benzyloxy and amino; the tertiary amine is NR4R5R6, wherein R4, R5 and R6 are independently selected from the group consisting of straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms, optionally substituted with one or more substituents that are independently selected from the group consisting of straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 atoms carbon, cycloalkenyl of 5 to 7 carbon atoms, hydroxy, carbonyloxygen and Ar; wherein the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl of 2 to 4 carbon atoms, hydroxy, or carbonyl oxygen; wherein any carbon atom is alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with 0, NH, NRlf S, SO, or S02; Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyriminyl, pyrazol, pyridazyl, quinolinyl and isoquinolinyl; and R-L and R3 are independently hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl or alkynyl of 3 to 4 carbon atoms, or Y-Z.

FORMULA XI In addition, the non-immunosuppressive neuroimmunophilin FKBP ligand may also be a compound of formula XI XI or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F, G and J are independently CH2, O, S, SO, S02, NH, or NRX; W is 0, S, CH2 or H2; R is straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms or Ar1 ( which is optionally substituted with one or more substituents which are independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, hydroxy, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms and Ar1; -rL is selected from the group consisting of 1-naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, having one or more substituents that are independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl from 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms rbono, alkenyloxy of 2 to 4 carbon atoms, phenoxy, benzyloxy and amino; X is 0, NH, NRlf S, CH, CRX or CR ^; Y is a direct bond, straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms; wherein the alkyl or alkenyl is optionally substituted with one or more substituents that are independently selected from the group consisting of straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms , cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, hydroxy, carbonyloxygen and Ar; wherein the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar are optionally substituted with straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl of 2 to 4 carbon atoms, hydroxy or carbonyl oxygen; wherein any carbon atom of the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar are optionally substituted with O, NH, NR2, S, SO, or S02; R2 is selected from the group consisting of: hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl or alkynyl of 3 to 4 carbon atoms, and alkyl forming a 1 to 1-membered bridging 4 carbon atoms, wherein a bridge is formed between the hydrogen and the carbon atom of the alkyl or alkenyl chain containing such heteroatom to form a ring, wherein the ring is optionally fused to an Ar group; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; the aromatic amine is pyridyl, pyrimidyl, quinolinyl and isoquinolinyl, which is unsubstituted or substituted by one or more substituents which are independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms, phenoxy, benzyloxy and amino; the tertiary amine is NR4R5R6, wherein R4, R5 and R6 are independently selected from the group consisting of straight or branched chain alkyl of 1 to 6 carbon atoms, and straight or branched chain alkenyl of 2 to 6 carbon atoms; wherein the alkyl or alkenyl is optionally substituted with one or more substituents that are independently selected from the group consisting of straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms , cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, hydroxy, carbonyloxygen and Ar; wherein the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar are optionally substituted with alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, hydroxy, or carbonyl oxygen; wherein any carbon atom of the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with O, NH, NR1 # S, SO, or S02; Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazil, quinolinyl and isoquinolinyl; and R-L and R3 are independently hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl or alkynyl of 3 to 4 carbon atoms, or Y-Z.

FORMULA XII In addition, the non-immunosuppressive neuroimmunophilin FKBP ligand may also be a compound of formula XII XII or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F, and G are independently CH2, O, S, SO, S02, NH, or NR?; W is 0, S, CH2 or H2; R is straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms or Ar1 ( which is optionally substituted with one or more substituents which are independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, hydroxy, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms and Ar1 # - Arx is selected from the group consisting of 1-naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, having one or more substituents that are independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl from 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms rbono, alkenyloxy of 2 to 4 carbon atoms, phenoxy, benzyloxy and amino; X is 0, NH, NRX, S, CH, CRX or CR ^; Y is a direct bond, straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms; wherein the alkyl or alkenyl is optionally substituted with one or more substituents that are independently selected from the group consisting of straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms , cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, hydroxy, carbonyloxygen and Ar; wherein the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar are optionally substituted with straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl of 2 to 4 carbon atoms, hydroxy or carbonyloxygen; wherein any carbon atom of the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar are optionally substituted with O, NH, NR2, S, SO, or S02; R2 is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl or alkynyl of 3 to 4 carbon atoms, and alkyl forming a bridge of 1 to 4 carbon atoms, wherein a bridge is formed between the hydrogen and the carbon atom of the alkyl or alkenyl chain containing such a hetero atom to form a ring, wherein the ring is optionally fused to an Ar group; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; the aromatic amine is pyridyl, pyrimidyl, quinolinyl and isoquinolinyl, which is unsubstituted or substituted by one or more substituents which are independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms, phenoxy, benzyloxy and amino; the tertiary amine is NR4R5R6, wherein R4, R5 and R6 are independently selected from the group consisting of straight or branched chain alkyl of 1 to 6 carbon atoms, and straight or branched chain alkenyl of 2 to 6 carbon atoms; wherein the alkyl or alkenyl is optionally substituted with one or more substituents that are independently selected from the group consisting of straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms , cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, hydroxy, carbonyl, oxygen and Ar; wherein the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar are optionally substituted with alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, hydroxy, or carboniloxygen; wherein any carbon atom of the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with O, NH, NR1; S, SO, or S02; Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazil, quinolinyl and isoquinolinyl; and R1 and R3 are independently hydrugrene, straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl or alkynyl of 3 to 4 carbon atoms, or Y-Z.

FORMULA XIII The non-immunosuppressive neuroimmunophilin FKBP ligand can also be a compound of formula XIII XIII or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: n is 1, 2 or 3, forming a 5-7 membered heterocyclic ring; W is 0, S, CH2 or H2; R is straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms or Arx, which is optionally substituted with one or more substituents which are independently selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, hydroxy, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms and Ar ,; Arx is selected from the group consisting of 1-naphthyl, 2-naphthyl, 1-indolyl, 2-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, and phenyl, having one or more substituents that are independently selected from the group [consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight chain alkenyl or branched of 2 to 6 carbon atoms, alkenyloxy of 2 to 4 carbon atoms, phenoxy, benzyloxy and amino; X is 0, NH, NR1 # S, CH, CRj. or CR1R3; Y is a direct bond, straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms; wherein the alkyl or alkenyl is optionally substituted with one or more substituents that are independently selected from the group consisting of straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms , cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, hydroxy, carbonyloxygen and Ar; wherein the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar are optionally substituted with straight or branched chain alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, hydroxy or carbonyl oxygen; wherein any carbon atom of the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar are optionally substituted with 0, NH, NR2, S, SO, or S02; R2 is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl or alkynyl of 3 to 4 carbon atoms, and alkyl forming a bridge of 1 to 4 carbon atoms, wherein a bridge is formed between the hydrogen and the carbon atom of the alkyl or alkenyl chain containing such a hetero atom to form a ring, wherein the ring is optionally fused to an Ar group; Z is an aromatic amine or a tertiary amine oxidized to a corresponding N-oxide; the aromatic amine is pyridyl, pyrimidyl, quinolinyl or isoquinolinyl, which is unsubstituted or substituted by one or more substituents that are independently selected from the group consisting of halo, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms, phenoxy, benzyloxy and amino; the tertiary amine is NR4RSR6, wherein R4, R5 and R6 are independently selected from the group consisting of straight or branched chain alkyl of 1 to 6 carbon atoms, and straight or branched chain alkenyl of 2 to 6 carbon atoms; wherein the alkyl or alkenyl is optionally substituted with one or more substituents which are independently selected from the group consisting of straight or branched chain alkyl of L to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms , cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, hydroxy, carboniloxygen and Ar; wherein the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar are optionally substituted with alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, hydroxy, or carbonyl oxygen; wherein any carbon atom of the alkyl, alkenyl, cycloalkyl, cycloalkenyl or Ar is optionally substituted with O, NH, NRlf S, SO, or S02; Ar is selected from the group consisting of pyrrolidinyl, pyridyl, pyrimidyl, pyrazyl, pyridazil, quinolinyl and isoquinolinyl; and R1 and R3 are hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl or alkynyl of 3 to 4 carbon atoms, or Y-Z. The examples of formula XIII when W is O are represented in TABLE III TABLE III Preferred compounds of formula XIII can be selected from the group consisting of: (2S) - (l, l-dimethyl-1,2-dioxopentyl N-oxide) ) -2- pyrrolidinecarboxylic acid 3- (2-pyridyl) -1-propyl; 3 (3-pyridyl) -1-propyl (2S) - (1, ldimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate N-oxide; 3 (4-pyridyl) -1-propyl (2S) - (1, l-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate N-oxide; (2S) - (l, ldimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate 3- (2-quinoline) -1-propyl N-oxide; 3- (3-quinoline) -1-propyl N- (2S) - (1, ldimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate N-oxide; 3- (4-quinoline) -1-propyl N-oxide (3- (4-methyl) -1,2-dioxopentyl) -2-pyrrolidinecarboxylate; and pharmaceutically acceptable salts, esters and solvates thereof.

FORMULA XIV Additionally, the non-immunosuppressive neuroimmunophilin FKBP ligand may be a compound of formula XIV or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: V is C, N or S; A, and B, together with V and the carbon atom to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring which may contain, in addition to V, one or more heteroatoms which are independently selected from the group consisting of 0, S, SO, S02, N, NH, and NR7; R7 is straight or branched chain alkyl of 1 to 9 carbon atoms, straight or branched chain alkenyl of 2 to 9 carbon atoms, cycloalkyl of 3 to 9 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, or Ar3 , wherein R7 is unsubstituted or substituted with one or more substituents that are independently selected from the group consisting of halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms , straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms, phenoxy, benzyloxy, thioalkyl, alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl and Ar4; Ar3 and Ar4 are independently an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms which are independently selected from the group consisting of O, N and S; and R, W, X, Y, and Z are as defined in formula X above.

IV. N-LINKED UREAS AND CARBAMATES OF HETEROCYCLIC TIOESTERS The ligand of FKBP of non-immunosuppressive neuroi nmu nofi 1 ina can also be a compound of formula XV or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring which may contain, in addition to the nitrogen atom, one or more additional heteroatoms that are independently selected from the group consisting of O, S, SO, SO-, \ ", NH and NR ,; X is O or S; Y is a direct bond straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl or oxygen to form a carbonyl, or wherein any carbon atom of the alkyl or alkenyl is optionally substituted with 0, NH, NR3, S, SO or S02; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl or alkynyl of 3 to 6 carbon atoms and alkyl forming a bridge of 1 to 4 atoms carbon, wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing such a hetero atom to form a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted by one or more substituents which are independently selected from the group consisting of alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, straight or branched chain alkyl of 1 to 9 carbon atoms, alkoxy of 1 to 9 carbon atoms, alkenyloxy of 2 to 9 carbon atoms, straight or branched chain alkenyl of 2 to 9 carbon atoms carbon, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, carbonyl, carboxy, cyano, diazo, ester, formanilide, halo, haloalkyl, hydroxy, imino, isocyano, isonitrile, nitrile, nitro, nitroso, phenoxy, sulfhydryl, sulfonylisulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioether, thioformamido, trifluoromethyl and carbocyclic and heterocyclic portions including haliciclic and aromatic structures; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms which are independently selected from the group consisting of 0, N and S; and wherein the aromatic or tertiary alkylamine optionally is oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein any carbon atom of the alkyl or alkenyl is optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, its form or oxygen to form a carbonyl, or wherein any other alkyl or alkenyl carbon is optionally substituted with 0, NH, NR3, S, SO or S02; C and D are independently hydrogen, Ar, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms; wherein the alkyl or alkenyl is optionally substituted with one or more substituents which are independently selected from the group consisting of cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, hydroxy, carbonyl oxygen and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl or sulfonyl; wherein any alkyl or alkenyl carbon atom is optionally substituted at one or more positions with oxygen to form a carbonyl; or wherein any carbon atom of the alkyl or alkenyl is optionally substituted with O, NH, NR3, S, SO or SO:; W is O or S; and U is O or N, with the proviso that: when U is O, then R: is a single pair of electrons and R- is selected from the group consisting of Ar, cycloalkyl of 3 to 8 carbon atoms, alkyl of linear or branched chain of 1 to 6 carbon atoms and straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein the alkyl or alkenyl is optionally substituted with one or more substituents which are independently selected from the group consisting of Ar and cycloalkyl of 3 to 8 carbon atoms; and when U is N, then R: and R: are independently selected from the group consisting of hydrogen, Ar, cycloalkyl of 3 to 8 carbon atoms, straight or branched chain alkyl of 1 to 6 carbon atoms and chain alkenyl linear or branched from 2 to 6 carbon atoms, wherein the alkyl or alkenyl is substituted with one or more substituents which are independently selected from the group consisting of Ar and cycloalkyl of 3 to 8 carbon atoms; or R? and R: are taken together to form a 5- or 6-membered heterocyclic ring which is selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidin, piperidine and piperazine. Useful carbo- and heterocyclic rings include, without limitation, phenyl, benzyl, r.aphthio, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthia zolyl, tet rahidrofurar.i tetrahydropyranyl, pyridyl, pyrrolyl, pyrrole, pyrrolidone, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isokir.olinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolylc, iscxazolyl, isotriazolyl, oxadiazolyl, triazolyl, z-isodiazole. , pyridazinyl, pyrimidinyl, pyrazinyl, triazmyl, trityanil, indolizinyl, pyrazolyl, pyrazolyl, pyrazolidinyl, thienyl, tet rahydroisoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl. In a preferred embodiment of formula XV, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl. , thiazolyl, pyrazolyl and thienyl.

FORMULA XVI In addition, the non-immunosuppressive neuroimmunophilin FKBP ligand can be a compound of formula XVI XVI or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F, G and J are independently CH :, 0, S, SO, S02, NH, or NR3; X is 0 or S; Y is a direct bond, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein any carbon atom of the alkyl or alkenyl is optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl or oxygen to form a carbonyl, or in which any carbon atom of the alkyl or alkenyl is optionally substituted with 0, NH, NR3, S, SO or S0 :; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, alkenyl or straight chain or branched alkyl of 3 to 4 carbon atoms and alkyl forming a bridging 1 to 4 carbon atoms wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing such hetero atom to form a ring, wherein the ring optionally is fused to an Ar group; Ar is an alicyclic or aromatic mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted with one or more substituents that are independently selected from the group consisting of alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, straight or branched chain alkyl of 1 to 9 carbon atoms, alkoxy of 1 to 9 carbon atoms, alkenyloxy of 2 to 9 carbon atoms, straight or branched chain alkenyl of 2 to 9 carbon atoms carbon, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, carbonyl, carboxy, cyano, diazo, ester, formaniiido, halo, haloalkyl, hydroxy, imino, isocyano, isonitrilc, nitrile, nitro, nitroso, phenoxy, sulfhydryl, sulfonyl sulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl and carboxylic and heterocyclic moieties, including alicyclic and aromatic structures; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms which are independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 4 to 6 carbon atoms, wherein any carbon atom of the alkyl or alkenyl is optionally substituted er. one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl or oxygen to form a carbonyl, or wherein any carbon atom of the alkyl or alkenyl is optionally substituted with O, NH, NR ,, S, SO or S02; C and D are independently hydrogen, Ar, straight or branched chain alkyl of 1 to 6 carbon atoms or branched straight chain alkenyl of 2 to 6 carbon atoms; wherein the alkyl or alkenyl are optionally substituted with one or more substituents that are independently selected from the group consisting of cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, hydroxy, carbonyloxygen and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, hydroxy, arimo, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl or sulfonyl; wherein any alkyl or alkenyl carbon atom is optionally substituted at one or more positions with oxygen to form a carbonyl; or wherein any carbon atom of the alkyl or alkenyl is optionally substituted with O, NH, NR3, S, SO or S02; W is O or S; and U is O or N, with the proviso that: when U is O, then R: is a single pair of electrons and R2 is selected from the group consisting of Ar, cycloalkyl of 3 to 8 carbon atoms, chain alkyl linear or branched of 1 to 6 carbon atoms and straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein the alkyl or alkenyl is optionally substituted with one or more substituents that are independently selected from the group consisting of Ar and cycloalkyl of 3 to 8 carbon atoms; and when U is N, then R: and R2 are independently selected from the group consisting of hydrogen, Ar, cycloalkyl of 3 to 8 carbon atoms, straight or branched chain alkyl of 1 to 6 carbon atoms and straight chain alkenyl or branched from 2 to 6 carbon atoms, wherein the alkyl or alkenyl is optionally substituted with one or more substituents which are independently selected from the group consisting of Ar and cycloalkyl of 3 to 8 carbon atoms; or R: and R: uptjs are taken to form a 5- or 6-membered heterocyclic ring which are selected from the group consisting of pyrrolidine, irridazolidin, pyrazolidin, piperidine and piperazine. Useful carbo- and heterocyclic rings include, without limitation, phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, mdazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolium, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazmyl, trityanil, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahidoisoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyldinyl, pteridinyl carbazolyl, acridinyl, phenazyl, f enotiazinyl and phenoxazinyl. In a preferred embodiment of formula XVI, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidiyl, purinyl, quinolinyl, isoquinolinyl, furry, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl.

FORMULA XVII The non-immunosuppressive neuroimmunophilin FKBP ligand can also be a compound of formula XVII or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F and G are independently CH2, 0, S, SO, S02, NH and NR3; X is 0 or S; Y is a direct bond, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein any carbon atom of the alkyl or alkenyl is optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarboxyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl or oxygen to form a carbonyl, or in which any carbon atom of the alkyl or alkenyl is optionally substituted with O, NH, NR3, S, SO or SO; - M --- l ------ Í - É ------------ íifl ---- llll R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl from 1 to 4 carbon atoms, alkenyl or alkynyl of straight or branched chain of 3 to 4 carbon atoms and alkyl forming a bridge of 1 to 4 carbon atoms, where a bridge is formed between nitrogen and an atom carbon of the alkyl or alkenyl chain containing such heteroatom to form a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, in which the ring is unsubstituted or substituted with one or more substituents that are independently selected from the group consisting of alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, straight or branched chain alkyl of 1 to 9 carbon atoms, alkoxy of 1 to 9 carbon atoms, alkenyloxy of 2 to 9 carbon atoms, straight or branched chain alkene 2 to 9 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, carbonyl, carboxy, cyano, diazo, ester, formanilide, halo, haloalkyl, hydroxy, imino, isocyano, isomtplo, nitrile , nitro, nitroso, phenoxy, sulfhydryl, sulphidoxyalkyl, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl and carbocyclic and heterocyclic portions, including alicyclic and aromatic structures; wherein the individual ring size is 5-8 members; where the ring ----------------- The heterocyclic compound contains 1-6 heteroetoms which are independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein any carbon atom of the alkyl or alkenyl is optionally substituted in a or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, suifonyl or oxygen to form a carbonyl, or in which any carbon atom of the alkyl or alkenyl is optionally substituted with O, NH, NR ,, S, SO or S02; C and D are independently hydrogen, Ar, straight or branched chain alkyl of 1 to 6 carbon atoms or branched straight chain alkenyl of 2 to 6 carbon atoms; wherein the alkyl or alkenyl is optionally substituted with one or more substituents which are independently selected from the group consisting of cycloalkyl of 3 to 8 carbon atoms, c: olcal ienyl of 5 to 7 carbon atoms, hydroxy, carbonyloxygen and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalicynyl is optionally substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy , cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl or sulfonyl; wherein any alkyl or alkenyl carbon atom is optionally substituted at one or more positions with oxygen to form a carbonyl; or wherein any carbon atom of the alkyl or alkenyl is optionally substituted with O, NH, NR3, S, SO or SO:; W is O or S; and U is either 0 or N, with the proviso that: when U is O, then R -_ is a single pair of electrons and R: is selected from the group consisting of Ar, cycloalkyl of 3 to 8 carbon atoms straight or branched chain alkyl of 1 to 6 carbon atoms and straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein the alkyl or alkenyl is optionally substituted with one or more substituents which are independently selected from the group which consists of Ar and cycloalkyl of 3 to 8 carbon atoms; and when U is N, then R_ and R: are independently selected from the group consisting of hydrogen, Ar, cycloalkyl of 3 to 8 carbon atoms, straight or branched chain alkyl of 1 to 6 carbon atoms and straight chain alkenyl or branched from 2 to 6 carbon atoms, wherein the alkyl or alkenyl is optionally substituted with one or more substituents which are independently selected from the group consisting of Ar and cycloalkyl of 3 to 8 carbon atoms; or Rx and R2 are taken together to form a 5- or 6-membered heterocyclic ring which is selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidin, piperidine and piperazine. Useful carbo- and heterocyclic rings include, without limitation, phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isomodolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquininoinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trityanil, indolizinyl , pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinolinyl, phentazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl. In a preferred embodiment of formula XVII, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl. .

FORMULA XVIII The non-immunosuppressive neuroimmunophilin FKBP ligand may also be a compound of formula XVIII XVIII or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: n is 1, 2 or 3; X is O or S; Y is a direct bond, straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein any carbon atom of the alkyl or alkenyl is optionally substituted in a or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenyloxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl or oxygen to form a carbonyl or wherein any carbon atom of the alkyl or alkenyl is optionally substituted with 0, NH, NR3, S, SO or S0:; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl or alkynyl of 3 to 4 carbon atoms and alkyl forming a bridge of 1 to 4 atoms carbon, in which a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing such a hetero atom to form a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted with one or more substituents that are independently selected from the group consisting of alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, straight or branched chain alkyl of 1 to 9 carbon atoms, alkoxy of 1 to 9 carbon atoms, alkenyloxy of 2 to 9 carbon atoms, straight or branched chain alkenyl of 2 to 9 carbon atoms carbon, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, carbonyl, carboxy, cyano, diazo, ester, formanilide, halo, haloalkyl, hydroxy, imino, isocyano, isonitrile, nitrile, nitro, nitroso, E. ---- ---- Phenoxy, sulfhydryl, sulfonyl sulphonium, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl and carbocyclic and heterocyclic portions, including alicyclic and aromatic structures; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms which are independently selected from the group consisting of 0, N and S; and wherein the aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein any carbon atom of the alkyl or alkenyl is optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl or oxygen to form a carbonyl or in which any alkyl carbon atom or alkenyl is optionally substituted with O, NH, NR3, S, SO or SO; C and D are independently hydrogen, Ar, straight or branched chain alkyl of 1 to 6 carbon atoms or branched straight chain alkenyl of 2 to 6 carbon atoms; wherein the alkyl or alkenyl is optionally substituted with one or more substituents which are independently selected from the group consisting of cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, hydroxy, carbonyl oxygen and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, hydroxy, amino, halo, haloalkion, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl or sulfonyl; wherein any carbon atom of the alkyl or alkenyl is optionally substituted in one or more positions with oxygen to form a carbonyl; or wherein any carbon atom of the alkyl or alkenyl is optionally substituted with O, NH, NR3, S, SO or S02; W is O or S; and U is any of O c N, with the proviso that: when U is 0, then R: is a pair only of electrons and R: is selected from the group consisting of Ar, cycloalkyl of 3 to 8 carbon atoms, straight or branched chain alkyl of 1 to 6 carbon atoms and straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein the alkyl or alkenyl is optionally substituted with one or more substituents which are independently selected from the group consisting of of Ar and cycloalkyl of 3 to 8 carbon atoms; and when U is N, then R: and R: are independently selected from the group consisting of hydrogen, Ar, cycloalkyl of 3 to 8 carbon atoms, straight or branched chain alkyl of 1 to 6 carbon atoms and chain alkenyl linear or branched from 2 to 6 carbon atoms, wherein the alkyl or alkenyl is optionally substituted with one or more substituents which are independently selected from the group consisting of Ar and cycloalkyl of 3 to 8 carbon atoms; or R: and R2 are taken together to form a 5- or 6-membered heterocyclic ring which is selected from the group consisting of pyrrolidine, imidazolidine, pyrazolidin, piperidine and piperazine. Useful carbo- and heterocyclic rings include, without limitation, phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazoyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tritaminyl, indolizinyl, pyrazolyl, pyrazole ini lo, pyrazolini lo, thienyl, tet rahydroi soquinol i ni 1, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl. In a preferred embodiment of formula XVIII, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl. . Exemplary compounds of formula XVIII are presented in TABLE VII.

TABLE VII or. n W R2 01 1 O (CH,) 2 CH 3 -pyridyl HH 2-methyl-butyl 02 (CH 2) 2 CH 3 -pyridyl H 1, 1-dimethyl-propyl 103 O (CH 2) 2 CH 4 -methoxy? - H 1,1-dimethyl-propyl ester 104 1 O CH-CH fer.:. 1, 1-dimime 11 i-propyl 105 1 s (CH;);, CH 4 -methoxy? -H cyclohexyl phen 11 or 106 1 0 (CH.): CH 3 -p? r ??? lc H cyclohexyl 1 10077 1 5 ((CCHH2,)) 2- C CHH 3 - pp? Inndd? Lloo HH H cyclohexyl 108 1 S (CH2) 2 CH3-p? Pd lo H H 1-adamantyl 109 1 S (CH2) 2 CH3-p? R? D? HH 1, 1-d? Methylpropyl 110 (CH CH fer.11 or phen l: 1, 1-dime ti 1-propyl 111 (CH ,) 2 CH phenyl 1, 1-dimethylpropyl 112 OO ((CCHH: :)) 22 C CHH ffeerr..liiloo H f emlo 113 0 0 E Ennllaaccee C CHH 2 2 - ffeenn? Ll- 2 2- -ffeenn? ll-- phenyl ddiirreeccttoo eettiilloo eettiilloo 114 0 0 E Ennllaaccee C CHH 2 2 - ffeenn? ll-2 2 - ffeenn? ll-- cyclohexyl direct ethyl ethyl ethyl s CH 2 -f? 2-Phenol-cyclohexyl, direct, ethyl-ethyl-ethyl, 16 (((CCHH: O) 2, C, CHH 4, 4-mmeettooxx: - H, cyclohexyl, phenyl) a -----------_------- Í - ri The most preferred compounds of formula XVIII are selected from the group consisting of: 2S-1- [(2-methylbutyl) carbamoyl ] 3- (3-pyridyl) -1-propyl pyrrolidine-2-carboxylate; 2S-1- [(1 ', 1' -dimethylpropyl) carbamoyl] pyrrolidin-2-carboxylate 3- (3-pyridyl) -1-propyl; 2S-1- [(cyclohexyl) thiocarbamoyl] pi rrolidin-2-carboxylate of 3- (3-pyridyl) -1-propyl; and pharmaceutically acceptable salts, esters and solvates thereof.

FORMULA XIX Additionally, the non-immunosuppressive neuroimmunophilin FKBP ligand can be a compound of formula XIX iÍ - & -U ---- ft-l or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: V is C, N or S; Y is a direct bond, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbol atoms, wherein any carbon atom of the aikyl or alkenyl is optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonic or oxygen to form a carbonyl, or in which any carbon atom of the alkyl or alkenyl is optionally substituted with O, NH, NR3, S, SO or S02; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl or alkynyl of 3 to 6 carbon atoms and alkyl forming a bridge of 1 to 4 atoms carbon wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing such a hetero atom to form a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted with one or more substituents; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms which are independently selected from the group consisting of 0, N and S; and wherein the aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein any carbon atom of the alkyl or alkenyl is optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioaster, alkoxy, alkenoxy, cyano, nitro, iminc, aicylamine, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl or oxygen to form a carbonyl or wherein any carbon atom of the alkyl or alkenyl is optionally substituted with 0, NH, NR3, S, SO or S0:; C and D are independently hydrogen, Ar, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms; wherein the alkyl or alkenyl is optionally substituted with one or more substituents that are independently selected from the group consisting of cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, hydroxy, carbonyl oxygen and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkene is optionally substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl or sulfonyl; wherein any alkyl or alkenyl carbon atom is optionally substituted at one or more positions with oxygen to form a carbonyl; or wherein any carbon atom of the alkyl or alkenyl is optionally substituted with O, NH, NR3, S, SO or S0:; and A, B, R :, R2, U, W, and X are as defined otherwise in formula XV.V. N-UNITED SULFONAMIDES OF HETEROCICLIC TIOESTERS FORMULA XX The non-immunosuppressive neuroimmunophilin FKBP ligand can also be a compound of formula XX XX or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A and B, together with the nitrogen and carbon atoms to which they respectively bind, form a 5-7 membered saturated or unsaturated heterocyclic ring which may contain, in addition to the nitrogen atom, one or more heteroatoms which are independently selected from the group consisting of O, S, SO or S02, N, NH and NR3; X is 0 or S; Y is a direct bond, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein any carbon atom of the alkyl or alkenyl is optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl or oxygenate to form a carbonyl or wherein any carbon atom of the alkyl or alkenyl is optionally substituted with O, NH, NR3, S, SO or SO:; R: is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl or alkynyl of 3 to 4 carbon atoms and alkyl forming a bridge of 1 to 4 carbon atoms wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing such a hetero atom to form a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted with one or more substituents; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms which are independently selected from the group consisting of 0, N and S; wherein an aromatic or tertiary alkylamine is optionally oxidized to the corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein any carbon atom of the alkyl or alkenyl is optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl or oxygen to form a carbonyl, or wherein any alkyl or alkenyl atom it is optionally substituted with 0, NH, NR :, S, SO or SO:; C and D are independently hydrogen, Ar, straight chain or branched alkyl of 1 to 6 carbon atoms or branched straight chain alkenyl of 2 to 6 carbon atoms; wherein the alkyl or alkenyl is optionally substituted with one or more substituents that are independently selected from the group consisting of cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, hydroxy, carboniloxygen and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy. , cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl or sulfonyl; wherein any alkyl or alkenyl carbon atom is optionally substituted at one or more positions with oxygen to form a carbonyl; or wherein any carbon atom of the alkyl or alkenyl is optionally substituted with O, NH, NR3, S, SO or SO:; and R- is selected from the group consisting of Ar, cycloalkyl of 3 to 8 carbon atoms, straight or branched chain alkyl of 1 to 6 carbon atoms and straight or branched chain alkenyl of 2 to 6 carbon atoms, in wherein the alkyl or alkeniion is optionally substituted with one or more substituents that are independently selected from the group consisting of Ar, C3-C8-cycloalkyl, amino, halo, haloalkyl, hydroxy, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl and sulfonyl, wherein any carbon atom of the alkyl or alkenyl is optionally substituted with 0, NH, NR;, S, SO or S02. Useful carbo- and heterocyclic rings include, without limitation, phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl. , pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trityanil, indolizinyl, pyrazolyl , pyrazolinyl, pyrazolidinyl, thienyl, tetinhydroisoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinylc, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl. In a preferred embodiment of formula XX, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolium, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolyl, furyl, - t-l-ai fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl. In another preferred embodiment of formula XX, A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a saturated or unsaturated heterocyclic 6-membered ring; and R; is branched chain annil of 4 to 7 carbon atoms, cycloalkyl of 4 to 7 carbon atoms, phenyl or 3,4,5-trimethoxyphenyl. In the most preferred embodiment of formula XX, the compound is selected from the group consisting of: (2S) -N- (benzenesulfonyl) pyrrolidine-2-carboxylate of 3- (para-methoxyphenyl) -1-propylmercaptyl; (2S) -N- (α-toluenesulfonyl) pyrrolidine-2-carboxylate of 3- (para-methoxyphenyl) -1-propylmercaptyl; (2S) -N- (α-toluenesulfonyl) pyrrolidine-2-carboxylate 3- (para-methoxyphenyl) -1-propylmercaptyl; N- (para-toluenesulfonyl, 1,5-diphenyl-3-pentyl mercaptyl pipecolate, and pharmaceutically acceptable salts, esters and solvents thereof).

FORMULA XXI In addition, the non-immunosuppressive neuroimmunophilin FKBP ligand can be a compound of formula XXI ---- ^ A ---- ttf or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F, G and J are independently CH2, O, S, SO or S02, NH or NR2; X is O or S; Y is a direct bond, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein any carbon atom of the alkyl or alkenyl is optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbon, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl or oxygen to form a carbonyl or in which any other alkyl or alkenyl carbon is optionally sustenuted with O, NH, NR-, S, SO or SO; R: is selected from the group consisting of nitrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl or alkynyl of 3 to 4 carbon atoms and alkyl forming a bridge of 1 to 4 carbon atoms wherein a bridge is formed between the nitrogen and the carbon atom of the alkyl or alkenyl chain containing the heteroatom to form a ring, wherein the ring is optionally fused to an Ar group; Z is a direct bond, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein any carbon atom of the alkyl or alkenyl is optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro., imino, alkylamino ,. aminoalkyl, sulfhydryl, thioalkyl, sulfonyl or oxygen to form a carbonyl, or wherein any alkyl or alkenyl atom is optionally substituted with O, NH, NR_, S, SO or SO:; Ar is an alicyclic or aromatic mono-, bi- or tricyclic, carbo- or heterocyclic ring, in which the ring is unsubstituted or substituted with one or more substituents; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms which are independently selected from the group consisting of O, N and S; wherein an aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide; C and D are independently hydrogen, Ar, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms; wherein the alkyl or alkenyl is optionally substituted with one or more substituents which are independently selected from the group consisting of cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, hydroxy, carbonyl oxygen and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl or sulfonyl; wherein any alkyl or alkenyl carbon atom is optionally substituted at one or more positions with oxygen to form an oarbonyl; or wherein any carbon atom of the alker.iic alkyl is optionally substituted with O, NH, NR3, S, SO c SO_; Y Rx is selected from the group consisting of Ar, cycloalkyl of 3 to 8 carbon atoms, straight or branched chain alkyl of 1 to 6 carbon atoms and straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein the alkyl or alkenyl is optionally substituted with one or more substituents which are independently selected from the group consisting of Ar, C3 to C8 cycloalkyl, amino, halo, haloalkyl, hydroxy, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl and sulfonyl, wherein any carbon atom of the alkyl or alkenyl is optionally substituted with O, NH, NR3, S, SO or S0 :. Useful carbo- and heterocyclic rings include, without limitation, phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, oenzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl. , pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trityanil, indolizinyl , pyrazolyl, pyrazolyl, pyrazol idini lo, thienyl, tetrahydroisoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, ü ^^^^ ^ á? r? á ?? a ?? á ^^^^ í? áu? ^^^^^ i ^^^^^^^^^^^^^^^ ^^^ ^^^^^^^^^^^^^^^^^^^^^^ carbazolyl, acridinyl, phenazinyl, zinyl phenoty phenoxazinyl. In a preferred embodiment of formula XXI, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl. , thiazolyl, pyrazolyl and thienyl.

FORMULA XXII The non-immunosuppressive neuroimmunophilin FKBP ligand may also be a compound of formula XXII or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F and G are independently CH;, O, S, SO, SO ,, NH or NR:; X is any of O or S; Y is a direct bond, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein any carbon atom of the aikyl or alkenyl is optionally substituted in a or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of the alkyl or alkenyl is optionally substituted with O, NH, NR;, S, SO or S02; R, is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl or alkynyl of 3 to 4 carbon atoms and alkyl forming a 1 to 1 4 carbon atoms, wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing the heteroclast-c to form a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic mono-, bi- or tricyclic, carbo- or heterocyclic ring, in which the ring is unsubstituted or substituted with one or more substituents, in «.i *» --.-... -,. . 'r. rrri ....-_... • -. _--- l ----_ where the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms which are independently selected from the group consisting of 0, N and S; wherein an aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein any carbon atom of the aikyl or alkenyl is optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl or oxygen to form a carbonyl, or in which any alkyl or alkenyl is optionally substituted with 0, NH, NR2, S, SO or S0:; R2 is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl or alkynyl of 3 to 4 carbon atoms and alkyl forming a bridge of 1 to 4 atoms carbon wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing the heteroatom to form a ring, wherein the ring is optionally fused to an Ar group; C and D are independently hydrogen, Ar, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein the alkyl or alkenyl is optionally substituted with one or more substituents which are independently selected from the group consisting of cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, hydroxy, carbonyloxygen and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms or hydroxy; wherein any carbon atom of the alkyl or alkenyl is optionally substituted at one or more positions with oxygen to form a carbonyl, or wherein any carbon atom of the alkyl or alkenyl is optionally substituted with O, NH, NR2, S, SO or SW,; R1 is selected from the group consisting of Ar, cycloalkyl of 3 to 8 carbon atoms, straight or branched chain alkyl of 1 to 6 carbon atoms and straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein the alkyl or alkenyl is optionally substituted with one or more substituents which are independently selected from the group consisting of Ar, cycloalkyl of 3 to 8 carbon atoms, amino, halo, haloalkyl, hydroxy, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, carbonyl, thiocarbonyl, ester, thioester, - »> -. - -, .-. ,. - < --.-- > alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl and sulfonyl, wherein any carbon atom of the alkyl or alkenyl is optionally substituted with 0, NH, NR3, S, SO or S0 :. Useful carbo- and heterocyclic rings include, without limitation, phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trityanil, indolizinyl, pyrazolyl, pi ra zol ini 1 o, pi ra zol idini lo, thienyl, tetrahydroisoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl. In a preferred embodiment of formula XXII, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolium, oxazolyl. , thiazolyl, pyrazolyl and thienyl.

FORMULA XXIII Additionally, the non-immunosuppressive neuroimmunophilin FKBP ligand may be a compound of the formula XXIII XXIII or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: n is 1, 2 or 3; X is any of O or S; Y is a direct bond, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein any carbon atom of the alkyl or alkenyl is optionally substituted in one or more positions with amino, ------------------------------------- ^^ m? a? ^ ü ----- Mlii-te-l-IÉIIH --- halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl or oxygen to form a carbonyl, or wherein any carbon atom of the alkyl or alkenyl is optionally substituted with 0, NH, NR2, S, SO or S0:; R, is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl or alkynyl of 3 to 4 carbon atoms and alkyl forming a bridge of 1 to 4 carbon atoms wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing the heteroatom to form a ring, wherein the ring is optionally fused to an Ar group; Z is a direct bond, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein any carbon atom of the alkyl or alkenyl is optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl or oxygen to form a carbonyl, or in which any alkyl or alkenyl is optionally substituted with O, NH, NR :, S, SO or S02; R: is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl or alkynyl of 3 to 4 carbon atoms and alkyl forming a bridge of 1 to 5 4 carbon atoms wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing such a hetero atom to form a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted with one or more substituents; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms that are independently selected from the group consisting of O, N 15 and S; wherein an aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide; C and D are independently hydrogen, Ar, straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein the alkyl or alkenyl is optionally substituted with one or more substituents which are independently selected from the group consisting of cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, hydroxy, carbonyloxygen and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally It is substituted with alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms or hydroxy; wherein any carbon atom of the alkyl or anynyl is optionally substituted at one or more positions with oxygen to form a carbonyl, or wherein any carbon atom of the alkyl or alkenyl is optionally substituted with 0, NH, NR :, S, SO bear,; and R? is selected from the group consisting of Ar, cycloalkyl of 3 to 8 carbon atoms, straight or branched chain alkyl of 1 to 6 carbon atoms and straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein the alkyl or alkenyl is optionally substituted with one or more substituents that are independently selected from the group consisting of Ar, C 3 -C 8 cycloalkyl, amino, halo, haloalkyl, hydroxy, trifluoromethyl, straight or branched chain alkyl from 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl and sulfonyl, wherein any atom carbon of the alkyl or alkenyl is optionally substituted with 0, NH, NR3, S, SO or SO; Useful carbo- and heterocyclic rings include, without limitation, phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trityanil, indolizinyl , pyrazolyl, pyrazolinyl, pyrazolidin, thienyl, Tetrahydroisoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyldinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, f-enotiazinyl and phenoxazinyl. In a preferred embodiment of formula XXIII, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl. The exemplary compounds of formula XXIII are presented in Table IV. - < - * > * - - * • - • TABLE IV n Y z C D 1 CH: CH phenyl H phenyl 1 CH- CH phenyl H a-methyl phenyl CH. CH phenyl 4-methyl phenyl CH 2); CH p-methoxyH phenyl phenyl CH_): CH p-methoxyH a-methyl phenyl phenyl CH,) -. CH p-methoxyH 4-methyl phenyl phenyl CH2) 2 CH phenyl phenyl phenyl CH,);, CH phenyl phenyl a-methyl phenyl •• * •• - • ---------- ÉÉÍ-Í-Í- 125 (CH,) 2 CH phenyl phenyl 4-methyl phenyl 126 2 (CH,) 2 CH phenyl H phenyl 127 2 CH-), CH phenyl H α -methyl phenyl 128 CH-: CH phenylmethyl phenyl 129 (CH,) CH phenyl 3, 4, 5-trimethoxyphenyl 130 2 (CH 2) 3 CH phenyl H cyclohexyl 131 2 CH 3-phenyl-3-phenylphenyl linkage direct propyl propyl 132 CH 3 -phenyl-3-phenyl-methyl-direct propyl-propyl-phenyl linkage 133 CH 3 -phenyl-3-phenyl-4-methyl-direct propyl-propyl-phenyl linkage Link CH 3-4 phenyl-3-phenyl-4-methyl-direct ethyl ethyl phenyl 135 Link CH 3- (4- 3-phenyl-4-methyl-direct me oxypropyl phenyl phenyl) -propyl --H --- ^ ------- É ------- l --- Ík-1-l-IIÍk ----- 136 2 Link CH 3- (2- 3-phenyl) - 4-methyl-direct pyridyl) - propyl phenyl propyl The most preferred compounds of the formula XXIII are selected from the group consisting of: (2 S) -N- (benzenesulfonyl) pyrrolidine-2-carboxylate of 3- (para-methoxyphenyl) -1-propylmercaptyl; (25) -N- (α-toluenesulfonyl) pyrrolidine-2-carboxylate of 3- (para-methoxyphenyl) -1-propylmercaptyl; (25) -N- (α-toluenesulfonyl) pyrrolidin-2-carboxylate of 3- (para-methoxyphenyl) -1-propylmercaptale; N- (para-toluenesulfonyl) 1,5-diphenyl-pentyl mercaptyl pipingcolate; pharmaceutically acceptable salts, esters and solvates thereof.

FORMULA XXIV In addition, the non-immunosuppressive neuroimmunophilin FKBP ligand may be a compound of formula XXIV or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: V is C, N or S; A, B, C, D, Rl r X, Y and Z are as defined in formula XX above.

SAW. PYROLROLIDINE DERIVATIVES FORMULA XXV The nao ligand of non-immunosuppressive neuroimmunofilm FKBP can also be a compound of formula XXV - * •? JI ** or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: R: is straight or branched chain alkylation of 1 to 9 carbon atoms, straight or branched chain alkenium of 2 to 9 carbon atoms, cycloalicyte of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms or Ar :, wherein R: is unsubstituted or substituted with one or more substituents that are independently selected from the group consisting of alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms, hydroxy and Ar:; Ar, and Ar: are independently selected from the group consisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, -pyridyl, 4-pyridyl and phenyl, wherein Ar: is unsubstituted or substituted by one or more substituents that are independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms, phenoxy, benzyloxy and amino; X is 0, S, CH, or H2; Y is a direct bond, 0 or NR :, wherein R, is hydrogen or alkyl of 1 to 6 carbon atoms; and Z is straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein Z is substituted with one or more substituents which are independently selected from the group consisting of of Ar :, cycloalkyl of 3 to 8 carbon atoms and straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with cycloalkyl of 3 to 8 carbon atoms; or Z is the fragment where: R3 is straight or branched chain alkyl of 1 to 9 carbon atoms which is unsubstituted or substituted by cycloalkyl of 3 to 8 carbon atoms or Ar-; X2 is 0 or NR5, wherein R- is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms and straight or branched chain alkenyl of 2 to 6 carbon atoms; and R 4 is selected from the group consisting of phenyl, benzyl, straight or branched chain alkyl of 1 to 5 carbon atoms, straight or branched chain alkenyl of 2 to 5 carbon atoms, straight or branched chain alkyl of 1 to 5 carbon atoms substituted with phenyl and straight-chain or branched alkenyl of 2 to 5 carbon atoms substituted with phenyl. In a preferred embodiment of formula XXV, Z and R are lipophilic. In a more preferred embodiment of formula XXV, the compound is selected from the group consisting of: (2 S) -1- (3, 3-dimethyl-l, 2-dioxopentyl) -2-20 pyrrolidinecarboxylate 3-phenyl-1 -propyl; (25) -1- (3, 3-dimethyl-l, 2-d-oxopentyl) -2-pyrrolidinecarboxylic acid 3-phenyl-1-prop-2- (E) -enyl ester; (2 S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2- pyrrolidinecarboxylic acid 3- (3,4, 5-trimethoxyphenyl) -1-propyl; ------------------- .tM ----------- l ----------------- -------------- ^ ---------- ii - i --- i (25) -1- (3, 3-dimethyl-l, 2- dioxopentyl) -2- pyrrolidinecarboxylate of 3- (3, 4, 5-trimethoxy-enyl) -l-prop-2- (E) enyl; (25) -1- (3,3-dimethyl-l, 2-dioxopentyl-1-pyrrolidinecarboxylate 3- (4,5-dichlorophyl) -1-propyl; (25) -1- (3, 3) dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate of 3- (4,5-dichlorofenyl) -l-prop-2- (E) -enyl; (25) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate of 3- (4,5-methylenedioxyphenyl) -1-propyl; (25) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3- (4,5-methylenedioxyphenyl) -l-prop-2- (E) -enyl ester; (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3-cyclohexyl-1-propyl ester; (25) -l- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3-cyclohexyl-l-prop-2- (E) -enyl ester; (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate of (IR) -1,3-diphenyl-1-propyl; (25) -1- (3,3-dimethyl-1,2-dioxopen) -2-pyrrolidinecarboxylate of (IR) -1,3-difin-1-prop-2- (E) -enyl; (25) -1- (3,3-dimethyl-l, 2-dioxopenil) -2-pyrrolidinecarboxylate of (IR) -l-cyclohexyl-3-phenyl-1-propyl; A.M--------------? - i --- t? -a --- É --- É-í --- (25) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate of (lR) -cyclohexyl-3-phenyl-1-prop-2- (E) -enyl; (25) -l- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate of (IR) -1- (4,5-dichlorophenyl) -3-phenyl-1-propyl; (25) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate of (IR) -1- (4,5-dichlorophenyl) -3-phenyl-1-propyl; (25) -l- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3-phenyl-1-propyl ester; (25) -1- (3, 3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3-phenyl-1-propyl ester; (2S) -l- (1,2-dioxo-2- [2-furanyl]) ethyl-2-pyrrolidinecarboxylic acid 3-phenyl-1-propyl ester; (25) -l- (1,2-dioxo-2- [2-thienyl]) ethyl-2-pyrrolidinecarboxylic acid 3-phenyl-1-propyl ester; (25) -l- (1,2-dioxo-2- [2-thiazolyl]) ethyl-2-pyrrolidinecarboxylic acid 3-phenol-1-propyl ester; (25) -l- (1, 2-d? Oxo-2-phen? L) 3-phenyl-1-propyl ethyl-2-pyrrolidinecarboxylate; (25) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 1,7-diphenyl-4-heptyl ester; (2S) -1- (3,3-dimethyl-l, 2-dioxo-4-hydroxybutyl) -2-pyrrolidinecarboxylic acid 3-phenyl-1-propyl ester; (2S) -l- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxamide of 3-f-enyl-1-propyl; ethyl ester of l- [1- (3,3-d? methyl-l, 2-dioxopentyl) -L-proline] -L-phenylalanine; ethyl ester of 1- [1- (3, 3-dimethyl-1, 2-dioxopentyl) -L-proline] -L-leucine; ethyl ester of 1 - [1 - (3, 3-d-imethyl-1, 2-dioxopentyl) -L-proline] -L-f-enylglycine; phenyl ester of 1- [1- (3, 3-dimethyl-1, 2-dioxopentyl) -L-proline] -L-phenylalanine; benzyl ester of 1- [1- (3, 3-dimethyl-1, 2-dioxopentyl) -L-prolma] -L-phenylalanine; ethyl ester of 1 - [1 - (3, 3 -dimet i 1 -1,2-dioxopentyl) -L-proline-L-isoleucine; and pharmaceutically acceptable salts, esters and solvates thereof.

FORMULA XXVI Additionally, the non-immunosuppressive neuroimmunophilin FKBP ligand can be a compound of formula XXVI or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: Rx is straight or branched chain alkyl of 1 to 9 carbon atoms, straight or branched chain alkenyl of 2 to 9 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkene or from 5 to 7 carbon atoms or Ar:, wherein R1 is unsubstituted or substituted by one or more substituents that are independently selected from the group consisting of alkyl of 1 to 6 carbon atoms, alkenyl from 2 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, cycloalkophenyl of 5 to 7 carbon atoms, hydroxy and Ar:; Arx and Ar: are independently selected from the group consisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-tαnα, 3-thienyl, 2- pyridol, 3-pyridyl, 4-pyridyl and phenyl, wherein Ar: is unsubstituted or substituted with one or more substituents that are independently selected from the group consisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, alkyl straight or branched chain of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, alkoxy of 1 to 5 4 carbon atoms, alkenyloxy of 2 to 4 carbon atoms, phenoxy, benzyloxy and Not me; Z is straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein Z is substituted with one or More substituents which are independently selected from the group consisting of Ar :, cycloalkylc of 3 to 8 carbon atoms and straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms Carbon substituted with cycloalkyl of 3 to 8 atoms carbon; or Z is a fragment in which ^^? g ^^ jgfe ** ^^ R3 is straight or branched chain alkyl of 1 to 9 carbon atoms which is unsubstituted or substituted by cycloalkyl of 3 to 8 carbon atoms or Ar; X: is 0 or NR 5, wherein R 1 is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms and straight or branched chain alkenyl of 2 to 6 carbon atoms; and R- is selected from the group consisting of phenyl, benzyl, straight or branched chain alkyl of 1 to 5 carbon atoms, straight or branched chain alkenyl of 2 to 5 carbon atoms, straight or branched chain alkyl of 1 to 5 carbon atoms substituted with phenyl and straight-chain or branched alkenyl of 2 to 5 carbon atoms substituted with phenyl. In a preferred embodiment of formula XXVI, R. is selected from the group consisting of straight or branched chain alkyl of 1 to 9 carbon atoms, 2-cyclohexyl, 4-cyclohexyl, 2-furan, 2-thienyl , 2-thiazolyl and 4-hydroxybutyl. In another preferred embodiment of formula XXVI, Z and Rj are lipophilic.

FORMULA XXVII The non-immunosuppressive neuroimmunof i 1 ma FKBP ligand can also be a compound of formula XXVII XXVII or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: Z 'is the fragment wherein: R3 is straight or branched chain alkyl of 1 to 9 carbon atoms or Ar: unsubstituted, wherein the alkyl -------- th ----------- ti ------ i ---------------------- The formula is unsubstituted or substituted by cycloalkyl of 3 to 8 carbon atoms or Ar X, is 0 or NR5, wherein R = is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms and straight or branched chain alkenyl of 2 to 6 carbon atoms; R 4 is selected from the group consisting of phenyl, benzyl, straight or branched chain alkyl of 1 to 5 carbon atoms, straight or branched chain alkenyl of 2 to 5 carbon atoms, straight or branched chain alkyl of 1 to 5 carbon atoms substituted with phenyl and straight-chain or branched alkenyl of 2 to 5 carbon atoms substituted with phenyl; and Ar: is as defined in formula XXVI. In a preferred embodiment of formula XXVII, Z1 is lipophilic.

FORMULA XXVIII The non-immunosuppressive neuroimmunophilin FKBP ligand can also be a compound of formula XXVIII XXVIII wherein: Rx is straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms or Ar wherein the alkyl or alkenyl is unsubstituted or substituted by cycloalkyl of 3 to 6 carbon atoms or Ar2; Ar, and Ar: are independently selected from the group consisting of 2-furyl, 2-thienyl, and phenyl; X is O, S, CH: or H;; And it's oxygen; Z is straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, and wherein Z is substituted with one or more substituents which is independently selected from the group consisting of -furyl, 2-t-enyl, cycloalkyl of 3 to 6 carbon atoms, pyridyl and phenyl, each with one or -------- ^ --------- & ----------- --- i -i ---- ^ í-iU-- more substituents that are inde- pendently selected from the group consisting of hydrogen and alkoxy of 1 to 4 carbon atoms. In a preferred embodiment of formula XXVIII, Z and R are lipophilic. In another preferred embodiment of formula XXVIII, the compound is selected from the group consisting of: (25) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3- (2,5-dimethoxyphenyl) ) -1-propyl; (25) -1- (3,3-dimethyl-l, 2-d-oxopentyl) -2-pyrrolidinecarboxylate of 3- (2,5-d-methoxyphenyl) -l-prop-2- (E) -enyl; (25) -l- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 2- (3,4,5-trimethoxyphenyl) -1-ethyl ester; (25) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3- (3-pyridyl) -1-propyl ester; (25) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate 3- (2-pyridyl) -1-propyl; (25) -1- (3,3-dimethyl-l, 2-dioxopenyl) -2-pyrrolidinecarboxylic acid 3- (4-pyridyl) -1-propyl; (2S) -1- (3-phenyl-1-propyl 2- (tert-butyl-1,2-dioxoethyl) -2-pyrrolidinecarboxylate; (25) -l- (2-cyclohexylethyl, 2-dioxoethyl) 3-phenyl-1-propyl pyrrolidinecarboxylate; '- - • ~~~ "(25) -l- (2-cyclohexylethyl-l, 2-dicxoethyl) -2- pyrrolidinecarboxylic acid 3- (3-pyridyl) -1-propyl; (25) -l- ( 3- (3-pyridyl) -1-propyl-tert-butyl-l, 2-dioxoethyl) -2- pyrrolidinecarboxylate; (25) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate 3, 3-diphenyl-1-propyl; (25) -l- (2-cyclohexyl-1,2-dioxoethyl) -2- pyrrolidinecarboxylic acid 3- (3-pipdyl) -1-propyl; (25) -N 3- (3-pyridyl) -1-propyl ((2) -3- (3) -3-ethyl-1, 2-dioxobutyl) -2-pyrrolidinecarboxylate (3-pyrrolidinecarboxylate) , 3-diphenyl-1-propylene; (25) -l-cyclohexyl-1-oxyl-2-pyrroiido; 3-3-diphenyl-1-propyl; (25) -l- (2-thienyl) -glyoxy} -carboxylate; -2-pyrrolidinecarboxylate 3, 3-diphenyl-1-propyl; and pharmaceutically acceptable salts, esters and solvates thereof. In a more preferred embodiment of formula XXVIII, the compound is selected from the group consisting of: (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate 3- (3-pyridyl) -1-propiio; (25) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3- (3-pyridyl) -1-propyium; (25) -1- (3- (3-pyridyl) -1-propyl c-clohexyl-1, 2-d-oxoetyl) -2-pyrrolidinecarboxylate; and pharmaceutically acceptable salts, esters and solvates thereof. In the most preferred embodiment of formula XXVIII, the compound is (25) -1- (3,3-d? Met? Ll, 2-d? Oxopent? L) -2- pyrrolidinecarboxylic acid 3- (3-pyridyl) - 1-propyl and pharmaceutically acceptable salts, esters and solvates thereof.

FORMULA XXIX Additionally, the non-immunosuppressive neuroimmunophilin FKBP ligand can be a compound of formula XXIX or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: unsubstituted or substituted with one or more substituents; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms which are independently selected from the group consisting of 0, N and S; X is 0, S, CH_- or H :; Y is a direct bond, 0 or NR;, wherein R, is hydrogen or alkyl of 1 to 6 carbon atoms; and Z is straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms, wherein Z is substituted with one or more substituents which are independently selected from the group consisting of of? r-. , cycloalkyl of 3 to 8 carbon atoms and straight or branched chain alkyl of 1 to 6 carbon atoms or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted with cycloalkyl of 3 to 8 carbon atoms; or Z is the fragment twenty ---------- tt ----------------------------- ^ --------- -------------- ^ MUariÉaB- üi ---- aitt-ll- where: R3 is straight or branched chain alkyl of 1 to 9 carbon atoms which is unsubstituted or substituted with cycloalkyl of 3 to 8 carbon atoms or Ar; X, is 0 or NR5, where R; is selected from the group consisting of hydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms and straight or branched chain alkenyl of 2 to 6 carbon atoms; and Rr is selected from the group consisting of phenyl, benzyl, straight or branched chain alkyl of 1 to 5 carbon atoms, straight or branched chain alkenyl of 2 to 5 carbon atoms, straight or branched chain alkyl of 1 to 5 carbon atoms substituted with phenyl and straight-chain or branched alkenyl of 2 to 5 carbon atoms substituted with phenyl. All compounds of formula I-XXIX possess asymmetric centers and therefore can be produced as mixtures of stereoisomers or as individual stereoisomers R- and S-. Individual stereoisomers can be obtained by using an optically active starting material, by separating a racemic or non-racemic mixture from an intermediate at some appropriate stage of the synthesis, or by removing the compounds of formulas I-XXIX. It is understood that the compounds of formulas I-XXIX encompass the individual stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers. S stereoisomers are preferably used in the pharmaceutical compositions and methods of the present invention.

Synthesis of non-immunosuppressive neuroinmunophilin FKBP ligands The compounds of formulas XV to XIX can be easily prepared by standard techniques of organic chemistry, using the general synthesis route described in the following. As described by Reaction Scheme I, the cyclic amino acids 1 protected by suitable blocking P groups at the amino acid nitrogen can react with thiols RSH to generate thioesters 2. After removal of the protecting group, the free amine 3 can react with a variety of isocyanates or isothiocyanates to provide the final ureas or thioureas, respectively.

^^^ - REACTION SCHEME I Vulnerability Isocyanates (R'NCO) or isothiocyanates (R'NCS) 4 can be conveniently prepared from the corresponding readily available amines by reaction with phosgene or thiophosgene, as shown in Reaction Scheme II.

REACTION SCHEME II The R-SH thiols can be conveniently prepared from the corresponding readily available alcohols or halides via a two-step substitution of halide for sulfur, as described in Reaction Scheme III. The halides can be reacted with thiourea and the corresponding alkylthiouronium salts are hydrolyzed to provide the RSH thiols. If alcohols are used as starting materials, they must first be converted to the corresponding halides by standard methods.

REACTION SCHEME III R-OH or R Br R-SH CBr4 / Ph3P 2) OH " --------------------------- til Compounds of formula XX to XXIV can be easily prepared by standard techniques of organic chemistry, using the route of general synthesis described in the following. As described in Reaction Scheme IV, cyclic amino acids 1 protected by suitable blocking P groups in the amino acid nitrogen can react with thiols RSH to generate thioesters 2. After removal of the protecting group, the free amine can react with various chlorides of sulfonyl 4 to provide the final product 5 with a good to excellent yield.

REACTION SCHEME IV Vulnerability The R-SH thiols can be conveniently prepared from the corresponding readily available alcohols or halides via the substitution of two halogen steps for sulfur, as described in Reaction Scheme V. The halides can react with thiourea, and the salts of corresponding alkylthiouronium are hydrolyzed to provide RSH thiols. If alcohols are used as starting materials, they must first be converted to the corresponding halides by standard methods. 10 REACTION SCHEME V CBr4 / Ph3P 2) OH The compounds of formulas XXV to XXIX can be prepared by various synthesis sequences using established chemical transformations. The general route for the present compounds is described in Reaction Scheme VI. The N-glyoxylproline derivatives can be prepared by reacting the L-proline methyl ester with sodium chloride.

A - * - E ---- I-I - I -------- I-I-I methyloxalyl, as shown in Reaction Scheme VI. The resulting oxamates can be reacted with various carbon nucleophiles to obtain the intermediate compounds. These intermediates are then reacted with various alcohols, amides or protected amino acid residues to obtain the propyl esters and amides of the invention.

REACTION SCHEME VI 10 The substituted alcohols can be prepared by numerous methods known to those skilled in the art of organic synthesis. As described in Reaction Scheme VII, the alkyl or arylaldehydes can be homologated to phenylpropanol with reaction with methyl (triphenylphosphoranylidene) acetate to provide a variety of trans-cinnamates; the latter can be reduced to the saturated alcohols by reaction with excess of lithium aluminum hydride, or sequentially by reduction of the double bond by catalytic hydrogenation and reduction of the saturated ester by the appropriate reducing agents. Alternatively, the trans-cinnamates can be reduced to (E) -alicylic alcohols by the use of diisobutylaluminum hydride.

REACTION SCHEME VII Lithium hydride Ph3P = CHCOOCH3 --COOCH3 and aluminum R - CHO THF diisobutylaluminum hydride H2, lithium hydride and Pd / C aluminum or diisobutylaluminum hydride OOCH3 ---------- I ------ Longer chain alcohols can be prepared by homologation of benzylic and higher aldehydes. Alternatively, these aldehydes can be prepared by conversion of the corresponding phenylacetic and higher acids, and phenethyl and higher alcohols.

Affinity for FKBP 12 The compounds used in the methods of the invention and the pharmaceutical compositions have an affinity for the FK506 binding protein, particularly FKBP12. Inhibition of the prolylpeptidyl cis-trans isomerase activity of FKBP can be measured as an indicator of this affinity.

Test procedure K.

The inhibition of the activity of the peptidyl-prolyl isomerase (rotamase) of the compounds used in the methods of the invention and the pharmaceutical compositions can be evaluated by known methods described in the literature (Harding et al., Na ture, 1989, 341 : 758-760; Holt et al., J. Am. Chem. Soc., 115: 9923-9938). These values are obtained as apparent K.

The cis-trans isomerization of an alanine-proline bond in a substrate model, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide is monitored spectrophotometrically in an assay coupled to chymotrypsin, which liberates para-nitroanilide from the trans form of the substrate. The inhibition of this reaction caused by the addition of different concentrations of inhibitor is determined, and the data is analyzed as a change of the first order rate constant as a function of the inhibitor concentration to provide the apparent K1 values. In a plastic cuvette, 950 ml of assay buffer cooled with 25 mM H? PES ice, pH 7.8, 100 mM NaCl), 10 ml of FKBP (2.5 mM in 10 mM Tris-Cl, pH 7.5, 100 NaCl are added. mM, 1 mM dithiothreitol), 25 ml of chymotrypsin (50 mg / ml in 1 mM HCl) and 10 ml of test compound at various concentrations in dimethyl sulfoxide. The reaction is initiated by the addition of 5 ml of substrate (succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg / ml in 2.35 mM LiCl in trifluoroethanol). The absorbance is monitored for 90 seconds 390 nm versus time using a spectrophotometer and the rate constants are determined from the absorbance versus the time data files.

TABLE V In vi tro test results - Formulas I to V Compound K: (nM) 1 31 2 210 3 85 9 104 10 12 11 299 12 442 14 313 28 108 29 59 30 11 31 8.7 32 362 33 1698 34 34 35 62 36 7 37 68 38 8.9 39 347 - •• - '•' - - '-. -. .... »* -» 40 1226 41 366 42 28 43 259 44 188 45 31 46 757 47 21 48 127 49 1334 50 55 51 33 52 6 53 261 54 37 55 30 56 880 57 57 58 79 59 962 60 90 61 139 62 196 63 82 64 163 , ^ á ------------------------------------ ---------- 65 68 66 306 67 177 68 284 69 49 70 457 71 788 TABLE VI Results of the in vi tro test - Form VI to IX Compound K1_ nMJ 80 215 81 638 TABLE VII Results of the test in vi tro - Formulas X to XIV Compound Ki Parental (non-oxidized) 7.5 compound of Example 6 95 (Example 6) 225 TABLE VIII Results of the test in vi tro - Formulas XV to XIX Compound K: (nM) 101 +++ 102 ++ 103 ++ 104 ++ 105 ++ 106 + 107 ++ 108 +++ 109 +++ 110 +++ 111 ++ 112 +++ 113 +++ 114 +++ 115 +++ 116 ++ The relative potencies of the compounds are scored according to the following scale: ++++ indicates K. of DE5C < 1 nM; +++ indicates K. of DE5C of 1-50 nM; ++ indicates K. of DE5C of 51-200 nM; + indicates K1 of DE of 201 -500 nM.

TABLE IX Results of the test in vi tro - Formulas XX to XXIV Compound Kx (nM) 117 +++ 118 ++ 119 ++ 120 ++ 121 ++ 122 + 123 ++ 124 +++ 125 +++ 126 +++ 127 ++ 128 +++ 129 +++ 130 +++ 131 +++ 132 ++ The relative potencies of the compounds are graded according to the following scale: ++++ indicates KL or DE50 < 1 nM; +++ indicates K of DE50 of 1-50 nM; ++ indicates K. or DE50 of 51-200 nM; + indicates K. or DE of 201-500 nM.

TABLE X Results of the in vi tro test - Formulas XXV to XXIX No. ZR / _ K, 137 1, 1-dimethylpropyl 3-phenylpropyl 42 138 3-phenyl-prop-2- (E) -125-enyl 139 3- (3, 4,5-trimethoxy-200 phenyl) propyl 140 3 - (3, 4, 5-trimethoxy-65 phenyl) -prop-2-i'E) -enyl 141"3- (4,5-methylenedioxy) -170 phenylpropyl 142" 3- (4, 5-methylenedioxy) - 160 phenylprop-2- (E) -enyl 143"3-cyclohexylpropyl 200 144" 3-cyclohexylprop-2- (E) - 600 enyl 145"(IR) -1,3-diphenyl-1- Propyl 146 2-furanyl 3-phenylpropyl 4000 147 2-thienyl "92 148 2-thiazolyl" 100 149 phenyl "1970 150 1, 1-dimethylpropyl 3- (2,5-dimethoxy) -250 phenylpropyl 151" 3- (2 , 5-dimethoxy) - 450 femlprop-2- (E) -enyl 152"2- (3,4,5-trimethoxy-120 phenyl) ethyl 153" 3- (3-pyridyl) propyl 5 154" 3- (2-pyridyl) propyl 195 155"3- (4-pyridyl) propyl 23 156 cyclohexyl 3-phenylpropyl 82 157 tert-butyl" 95 158 cyclohexylethyl "1025 ^ ÍurilÉ --- i ---- 159 cyclohexylethyl 3- (3-pyridyl) propyl 1400 160 tert-butyl 3- (3-pyridyl) propyl 3 161 1, 1-dimethylpropyl 3, 3-diphenylpropyl 5 162 cyclohexyl 3- (3-pyridyl) propyl 9 163 2-thienyl 3- (3-pyridyl) propyl 1000 164 tert-butyl 3, 3-diphenylpropyl 5 165 cyclohexyl "20 166 2-thienyl "150 Route of administration To effectively treat vision loss or promote vision regeneration, the compounds used in the methods of the invention and the pharmaceutical compositions should easily affect the target areas. Other routes of administration known in the pharmaceutical art are also contemplated by this invention.

Dosage Dosage levels in the order of from about 0.1 mg to 10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels from about 0.1 mg to about 1,000 mg. The specific dose level for any particular patient will vary depending on a variety of factors, including activity of the specific compound used; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; the combination with other medications; the severity of the particular disease being treated as well as the form of administration. Usually, the in vitro dosage-effect results provide a useful guide regarding the appropriate doses for administration to patients. Studies in animal models are also useful. The considerations for determining appropriate dosage levels are well known in the art. The compounds can be administered with other agents to treat vision loss, prevent degeneration of vision or promote vision regeneration. The specific dose levels for such additional agents will depend on previously mentioned factors as well as the infectivity of the drug combination.

------ H ----- I EXAMPLES The following examples are illustrative of the present invention and are not intended to be limitations thereto. Unless indicated otherwise, all percentages are based on 100% by weight of the final composition.

Example 1 Synthesis of (2S) -2- ( { L-oxo-5-phenyl.}. -pentyl-1- (3,3-dimethyl-1,2-dioxopentyl) pyrrolidine (1) (2S-2- { L-oxo-4-phenyl) butyl-N-benzylpyrrolidine Add 1-chloro-phenylbutane (1.78 g, 10.5 mmol) in 20 mL of THF to 0.24 g (10 mmol) of magnesium swarf in 50 mL of refluxing THF. After the addition is complete, the mixture is refluxed for an additional 5 hours, and then slowly added to a refluxing solution of N-benzyl-L-proline ethyl ester (2.30 g (10 mmol) in 100 ml. After 2 hours of further reflux, the mixture is cooled and treated with 5 ml of 2N HCl. The reaction mixture is diluted with 100 ml of ether and washed with saturated NaHCO3, water and brine. The organic phase is dried, concentrated and subjected to chromatography eluting with 5: 1 CH, Cl,: EtOAc to obtain 2.05 g (64%) of the ketone as an oil: H NMR (CDC13, 300 MHz): 1.49-2.18 (m, 8H), 2.32-2.46 (m, 1H), 2.56-2.65 (m, 2H), 2.97-3.06 (m, 1H), 3.17-3.34 (m, 1H), 3.44-3.62 (m, 1H); 4.02-4.23 (m, 2H); 7.01-7.44 (m, 10H). (2S) -2- (l-oxo-4-phenyl) butylpyrrolidine The ketone compound (500 mg) and palladium hydroxide (20% on charcoal, 50 mg) is hydrogenated at 276 kPa (40 psi) on a Parr shaker overnight. The catalyst is removed by filtration and the solvent is removed in vacuo. The free amine is obtained as a yellow oil (230 mg, 100%). lH NMR (CDC13; 300 MHz): 1.75-2.34 (m, 10H); 2.55 (m, 2H); 2.95 (dm, 1H); 3.45-3.95 (m, 1H); 4.05 (m, 1H); 7.37 (m, 5H). (2S) -2- (l-Oxo-4-phenyl) butyl-1- (1,2-dioxo-2-methoxyethyl) -pyrrolidine To a solution of (2S) -2- (1-oxo-4-phenyl) -butylpyrrolidine (230 mg, 1.0 mmol) in 20 ml of CH: C12 at 0 ° C, methyloxalyl chloride (135 ng; 1.1 mmoles). After stirring at 0 ° C for 3 hours, the reaction is suspended with saturated NHC1 and the organic phase is washed with water and brine, and dried and concentrated. The crude residue is purified on a column of silica gel, eluting with CH: C12 20: 1: EtOAc to obtain 300 mg of oxamate as a clear oil (98%). H NMR (CDC13, 300 MHz): 1.68 (m, 4H); 1.91- 2.38 (m, 4H); 2.64 (t, 2H); 3.66-3.80 (m, 2H); 3.77, 3.85 (s, 3H total); 4.16 (m, 2H); 4.90 (m, 1H); 7.16 (m, 3H); 7.27 (m, 2H). (2S) -2- ( { L-oxo-5-phenyl} - pentyl-1- (3,3-dimethyl-l, 2-dioxopentyl) pyrrolidine (1) To a solution of the above oxamate (250 mg; 0. 79 mmoles) in 15 ml of anhydrous ether, cooled to -78 ° C is added 1,1-dimethylpropylmagnesium chloride (0.8 ml of a 1.0 M solution in ether, 0.8 mmoles). After stirring the resulting mixture at -78 ° C for 2 hours, the reaction is suspended by the addition of 2 ml of saturated NH-C1, followed by 100 ml of EtOAc. The organic phase is washed with brine, dried, concentrated and purified on a column of silica gel, eluting with 50: 1 of CH: C1; : EtOAc. Compound 1 is obtained as a clear oil, 120 mg. H NMR (CDC13, 300 MHz): d 0.87 (t, 3H, J = 7.5); 1.22 (s, 3H); 1.25 (s, 3H); 1.67 (m, 4H); 1.70-2.33 (m, 6H); 2.61 (t, 2H, J = 7.1); 3.52 (m, 2H); 4.17 (t, 2H, J = 6.2); 4.52 (m, 1H); 7.16-7.49 (m, 5H). Analysis calculated for C22H31N03-H, 0; C 70.37; H, 8.86; N, 3.73. Found: 70.48; H, 8.35; N, 3.69.

Example 2 Synthesis of 2-phenyl-l-ethyl 1- (3, 3-dimethyl-l, 2-dioxopentyl) -2- piperidincarbothioate (10) (2S) -1- (1,2-dioxo-2-methoxyethyl) -2-pyrrolidinecarboxylate methyl A solution of L-proline methyl ester hydrochloride (3.08 g, 18.60 mmoles) in dry methylene chloride is cooled to 0 ° C and treated with triethylamine (3.92 g, 38.74 mmole, 2.1 eq). After stirring the suspension formed under a nitrogen atmosphere for 15 min, a solution of methyloxalyl chloride (3.20 g, 26.12 mmol) in 45 ml of methylene chloride is added dropwise. The resulting mixture is stirred at 0 ° C for 1.5 hours. After filtering to remove the solids, the organic phase is washed with water, dried over MgSO4 and concentrated. The crude residue is purified on a column of silica gel, eluting with 50% ethyl acetate in hexane to obtain 3.52 g (88%) of the product as a reddish oil. Mixture of cis-trans amide rotamers; Trans rotamer data is provided. : H NMR (CDC1,): d 1.93 (dm, 2H); 2.17 (m, 2H); 3.62 (m, 2H); 3.71 (s, 3H); 3.79, 3.84 (s, 3H, total); 4.86 (dd, 1H, J = 8.4, 3.3). (2S) -l- (1, 2-dioxo-3, 3-dimethylpentyl) -2-pyrrolidinecarboxylate methyl A solution of methyl (2S) -1- (1,2-dioxo-2-methoxyethyl) -2-pyrrolidinecarboxylate (2.35 g, 10.90 mmol) in 30 ml of tetrahydrofuran (THF) is cooled to -78 ° C and treat with 14.2 ml of a 1.0 M solution of 1,1-dimethylpropylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at -78 ° C for 3 hours, the mixture is poured into 100 ml of saturated ammonium chloride and extracted into ethyl acetate. The organic phase is washed with water, dried and concentrated, and the crude material obtained upon removal of solvent is purified on a column of silica gel eluting with 25% ethyl acetate in hexane to obtain 2.10 g (75 g. %) 'of the oxamate as a colorless oil. 1 NMR (CDC13): d 0.88 (t, 3H); 1.22, 1.26 (S, 3H each); 1.75 (dm, 2H); 1.87-2.10 (m, 3H); 2.23 (m, 1H); 3.54 (m, 2H); 3.76 (s, 3H); 4.52 (dm, 1H, J = 8.4, 3.4). (2S) -1- (1, 2-dioxo-3, 3-dimethylpentyl) -2-pyrrolidinecarboxylic acid A mixture of methyl (2S) -1- (1, 2-dioxo-3, 3-dimethylpentyl) -2-pyrrolidinecarboxylate (2.10 g, 8.23 mmol), 15 ml of 1 N LiOH and 50 ml of methanol is stirred at 0 ° C for 30 - • - - '»- fa¿ ^ ~' - ^ minutes and at room temperature during the night. The mixture is acidified to pH 1 with 1 N HCl, diluted with water and extracted in 100 ml of methylene chloride. The organic extract is washed with brine and concentrated to give 1.73 g (87%) of a white solid as snow which does not require further purification. X H NMR (CDC13): 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); 3.53 (dd, 2H, J = 10.4, 7.3); 4.55 (dd, 1H, J = 8.6, 4.1). 1- (3, 3-dimethyl-l, 2-dioxopentyl) -2-piperidincarbotioate 2.-phenyl-1-ethyl (10) To a solution of (2S) -1- (1,2-dioxo-3, 3-dimethylpentyl) -2-pyrrolidinecarboxylic acid (241 mg, 1.0 mmol) in 10 ml of CH: C1: dicyclohexylcarbodiimide (226 mg, 1.1 mmoles). After stirring the resulting mixture for 5 minutes, the solution is cooled to 0 ° C and treated with a solution of phenylmercaptan (138 mg, 1.0 mmol) and 6 mg of 4-dimethylaminopyridine in 5 ml of CH; C1 :. The mixture is allowed to warm to room temperature with stirring overnight. The solids are removed by filtration and the filtrate is concentrated in vacuo; the crude residue is purified by flash chromatography (10: 1 hexane: EtOAc) to obtain 302 mg (84%) of compound 10 as an oil. X H NMR (CDC13; MHz): d 0.85 (t, 3H, J = 7.5); 1.29 (s, 3H); 1.31 (s, 3H); 1. 70-2.32 (m, 6H); 2.92 (t, 2H, J = 7.4); 3.22 (t, 2H, J = 7.4); 3.58 (m, 2H); 4.72 (m, 1H); 7.23-7.34 (m, 5H). Analysis calculated for C20H, 7NO3S-0.4 H: 0: C, 65.15; H, 7.60; N, 3.80. Found: C, 65.41; H, 7.49; N, 3.72.

Example 3 Synthesis of (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2- pyrrolidinecarbothioate 2-phenyl-1-ethyl. (9) 1- (1,2-dioxo-2-methoxyethyl) -2-piperidinecarboxylic acid methyl A solution of methyl pipelhate hydrochloride (8.50 g, 47.31 mmoles) in 100 ml of dry methylene chloride is cooled to 0 ° C and treated with triethylamine (10.5 g, 103 mmol, 2.1 eq). After stirring the suspension formed under a nitrogen atmosphere for 15 minutes, a solution of methyloxalyl chloride (8.50 g, 69.4 mmol) in 75 ml of methylene chloride is added dropwise. The resulting mixture is stirred at 0 ° C for 1.5 hours. After filtering to remove solids, the organic phase is washed with water, dried over MgSO4 and concentrated. The crude residue is purified on a column of silica gel, eluting with 50% ethyl acetate in hexane, to obtain 9.34 g (86%) of the product as a reddish oil. Mixture of cis-trans amide rotamers; the data for the trans rotamer is provided. 1 H NMR (CDC13): d 1.22-1.45 (m, 2H); 1.67-1.78 (m, 3H); 2.29 (m, 1H); 3.33 (m, 3H); 3.55 (m, 1H); 3.76 (s, 3H); 3.85, 3.87 (s, 3H total); 4.52 (dd, 1H). 1- (1,2-dioxo-3, 3-dimethylpentyl) -2-piperidinecarboxylate methyl A solution of methyl 1- (1,2-dioxo-2-methoxyethyl) -2-piperidinecarboxylate (3.80 g, 16.57 mmol) in 75 ml of tetrahydrofuran (THF) is cooled to -78 ° C and treated with . 7 ml of a 1.0 M solution of 1,1-dimethylpropylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at -78 ° C for 3 hours, the mixture is poured into 100 'ml of saturated ammonium chloride and extracted into ethyl acetate. The organic phase is washed with water, dried and concentrated, and the crude material obtained upon removal of the solvent is purified on a column of silica gel, eluting with 25% ethyl acetate in hexane, to obtain 3.32 g (74 g. %) of the oxamate as a colorless oil. : H NMR (CDC13): d 0.88 (t, 3H); 1.21, 1.25 (s, 3H each); 1.35-1.80 (m, 7H); 2.35 (m, 1H); 3.24 (m, 1H); 3.41 (m, 1H); 3.76 (s, 3H); 5.32 (d, 1H).

L- (1, 2-dioxo-3, 3-dimethylpentyl) -2-piperidinecarboxylic acid A mixture of methyl 1- (1,2-dioxo-3, 3-dimethylpentyl) -2-piperidinecarboxylate (3.30 g, 12.25 mmoles) ), 15 ml of 1 N LiOH and 60 ml of methanol are stirred at 0 ° C for 30 minutes and at room temperature overnight. The mixture is acidified to pH 1 with 1 N CHC1, diluted with water and extracted into 100 ml of methylene chloride. The organic extract is washed with brine and concentrated to provide 2.80 g (87%) of a white solid as snow which does not require further purification. X H NMR (CDC13): d 0.89 (t, 3H); 1.21, 1.24 (s, 3H each); 1.42-1.85 (m, 7H); 2.35 (m, 1H), 3.22 (d, 1H); 3.42 (m, 1H); 5.31 (d, 1H). (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 2-phenyl-1-ethyl ester (9) To a solution of 1- (1,2-dioxo-3, 3-dimethylpentyl) -2-piperidinecarboxylic acid (255 mg; 1.0 mmoles) in 10 ml of CH, C12 is added dicyclohexylcarbodiimide (226 mg, 1.1 mmoles). After stirring the resulting mixture for 5 minutes, the solution is cooled to 0 ° C and treated with a solution of phenylmercaptan (138 mg, 1.0 mmol) and 6 mg of 4-dimethylaminopyridine in 5 ml of CH: C1;. The mixture is allowed to warm to room temperature with stirring overnight. The solids are removed by filtration and the filtrate is concentrated in vacuo; the crude residue is purified by --fi-- > ---------? --- - flash chromatography (10: 1 hexane: EtOAc) to obtain 300 mg (80%) of compound 9 as an oil. H NMR (CDC1, 300 MHz): d 0.94 (t, 3H, J = 7.5); 1.27 (s, 3H); 1.30 (s, 3H); 1.34-1.88 (m, 7H); 2.45 (m, 1H); 2.90 (t, 2H, J = 7.7); 3.26 (t, 2H, J = 7.7); 3.27 (m, 1H); 3.38 (m, 1H); 5.34 (m, 1H); 7.24-7.36 (m, 5H). Analysis calculated for C21H29N03S: CV, 67.17; H, 7.78; N, 3.73. Found: C, 67.02; H, 7.83; N, 3.78.

Example 4 Synthesis of (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2- (4-thiazolidin) carboxylate of 3-phenyl-1-propyl (80) 2- (4-thiazolidin) -carboxylic acid 1- (1,2-dioxo-2-methoxyethyl) A solution of L-thioproline (1.51 g, 11.34 mmol) in 40 ml of dry methylene chloride is cooled to 0 ° C and treated with 3.3 ml (2.41 g, 23.81 mmol) of triethylamine. After stirring this mixture for 30 minutes, a solution of methyloxalyl chloride (1.81 g, 14.74 mmoles) is added dropwise. The resulting mixture is stirred at 0 ° C for 1.5 hours, filtered through Celite to remove solids, dried and concentrated. The crude material is purified on a column of silica gel, eluting with 10% MeOH in methylene chloride to obtain 2.0 g of the oxamate as an orange-yellow solid. (2S) -1- (1,2-dioxo-2-methoxyethyl) -2- (4-thiazolidin) carboxylate of 3-phenyl-1-propyl 2- (4-thiazolidin) -carboxylic acid 1- (1,2-dioxo-2-methoxyethyl) (500 mg, 2.25 mmol), 3-phenyl-1-propanol (465 mg, 3.42 mmol), dicyclohexylcarbodiimide (750 mg, 3.65 mmole), 4-dimethylaminopyridine (95%, 0.75 mmole) and camphorsulfonic acid (175 mg, 0.75 mmole) in 30 ml of methylene chloride are stirred together overnight. The mixture is filtered through Celite to remove solids and chromatograph (25% ethyl acetate / hexane) to obtain 690 mg of material. l NMR (CDC13, 300 MHz): d 1.92-2.01 (m, 2H); 2.61-2.69 (m, 2H); 3.34 (m, 1H); 4.11-4.25 (m, 2H); 4.73 (m, 1H); 5.34 (m, 1H); 7.12 (m, 3H); 7.23 (m, 2H). 15 (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2- (4-thiazole-din) -3-phenyl-1-propyl carboxylate (80) A solution of 3-phenyl-1-propyl (2S) -1- (1,2-dioxo-2-methoxyethyl) -2- (4-thiazolidin) carboxylate (670 mg, 1.98 mmol) in 10 ml of tetrahydrofuran it is cooled to -78 ° C and treated with 2.3 ml of a 1.0 M solution of 1,1-dimethylpropylmagnesium chloride in ether. After stirring the mixture for 3 hours, it is poured into saturated ammonium chloride, extracted into ethyl acetate and the organic phase is washed with water, •• -rTittriy it¡¡ ^ "" - ^ > - »- ^ - - • - '•" - * - • * • * • ** - * - - - • Dry and concentrate The raw material is purified on a column of silica gel, eluting with 25% ethyl acetate in hexane to obtain 380 mg of the compound of Example 4 as a yellow oil: H NMR (CDC1, 300 MHz): d 0.86 (t, 3H) 1.21 (s, 3H); 1.26 (s) , 3H), 1.62-1.91 (m, 3H), 2.01 (m, 2H) 2.71 (m, 2H), 3.26-3.33 (m, 2H), 4.19 (m, 2H) m, 4.58 (m, 1H) 7.19 (m, 3H), 7.30 (m, 2H) Analysis calculated for C20H27NO4S C, 63.63; H, 7.23; N, 3.71. Found: C, 64.29; H, 7.39; N, 3.46.10 Example 5 Synthesis of (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2- (4-thiazolidin) carboxylate of 3- (3-pyridyl) -1-propyl (81) The compound of Example 5 is prepared according to the procedure of Example 4, using 3- (3-pyridyl) -1-propanol in the final step to obtain (2S) -1- (3, 3-dimethyl-1, 2-dioxopentyl) -2- (4-thiazolidin) carboxylate of 3- (3-pyridyl) -l, 1-propyl. : H NMR (CDC13, 300 MHz): d 0.89 (t, 3H, J = 7.3); 1.25 (s, 3H); 1.28 (s, 3H); 1.77 (c, 2H, J = 7.3); 2.03 (tt, 2H, J = 6.4, 7.5); 2.72 (t, 2H, J = 7.5); 3.20 (dd, 1H, J = 4.0, 11.8); 3.23 (dd, 1H, J = 7.0, 11.8); 4.23 (t, 2H, J = 6.4); 4.55 (d, 2H, J = 8.9); 5.08 (dd, 1H, J = 4.0, 7.0); 7.24 (m, 1H); 8.48 (m, 2H). Analysis calculated for C19H26N: 04S - 0.5 -------? -------.

H: 0: C, 58.89; H, 7.02; N, 7.23. Found: C, 58.83; H, 7.05; N, 7.19.

Example 6 Synthesis of 3- (3-pyridyl) -1-propyl (2S) -1- (3, 3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate N-oxide (95) (2S) -1- (1,2-dioxo-2-methoxyethyl) -2-pyrrolidinecarboxylate methyl A solution of L-proline methyl ester hydrochloride (3.08 g, 18.60 mmoles) in dry methylene chloride is cooled to 0 ° C and treated with triethylamine (3.92 g, 38.74 mmole, 2.1 eiq). After stirring the suspension formed under a nitrogen atmosphere for 15 minutes, a solution of methyloxalyl chloride (3.20 g, 26.12 mmol) in 45 ml of methylene chloride is added dropwise. The resulting mixture is stirred at 0 ° C for 1.5 hours. After filtering to remove the solids, the organic phase is washed with water, dried over MgSO4 and concentrated. The crude residue is purified on a column of silica gel, eluting with 50% ethyl acetate in hexane, to obtain 3.52 g (88%) of the product as a reddish oil. Mixture of cis-trans amide rotamers; data are provided for the trans rotamer. X H NMR (CDC13): d 1.93 (dm, 2H); 2. 17 (m, 2H); 3.62 (m, 2H) M; 3.71 (s, 3H); 3.79, 3.84 (s, 3H total); 4.86 (dd, 1H, J = 8.4, 3.3). (2S) -l- (1, 2-dioxo-3, 3-dimethylpenti1) -2-pyrrolidine methylcarboxylate A solution of methyl (2S) -1- (1,2-dioxo-2-methoxyethyl) -2-pyrrolidinecarboxylate (2.35 g, 10.90 mmol) in 30 ml of tetrahydrofuran (THF) is cooled to -78 ° C and treat with 14.2 ml of a 1.0 M solution of 1,1-dimethylpropylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at -78 ° C for 3 hours, the mixture is poured into 100 ml of saturated ammonium chloride and extracted into ethyl acetate. The organic phase is washed with water, dried and concentrated, and the crude material obtained by removing the solvent is purified on a column of silica gel, eluting with 25% ethyl acetate in hexane, to obtain 2.10 g (75%). ) of the oxamate as a colorless oil. 1 H NMR (CDC13): d 0.88 (t, 3H); 1.22, 1.26 (s, 3H each); 1.75 (dm, 2H); 1.87-2.10 (m, 3H); 2.23 (m, 1H); 3.54 (m, 2H); 3.76 (s, 3H); 4.52 (dm, 1H, J = 8.4, 3.4). (2S) -1- (1,2-Dioxo-3, 3-dimethylpentyl) -2-pyrrolidinecarboxylic acid A mixture of (2S) -1- (1,2-dioxo-3, 3-dimethylpentyl-2-pyrrolidinecarboxylate) Methyl (2.10 g, 8.23 mmol), 15 ml of 1 N LiOH and 50 ml of methanol are stirred at 0 ° C for 30 minutes and at room temperature overnight The mixture is acidified to pH 1 with 1 N HCl, diluted with water and extracted in 100 ml of methylene chloride The organic extract is washed with brine and concentrated to give 1.73 g (87%) of white solid as snow which does not require further purification: H NMR (CDC13) : d 0.87 (t, 3H), 1.22, 1.25 (s, 3H each), 1.77 (dm, 2H), 2.02 (m, 2H) M, 2.17 (m, 1H), 2.25 (m, 1H), 3.53 (dd, 2H, J = 10.4, 7.3), 4.55 (dd, 1H, J = 8.6, 4.1). (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3- (3-pyridyl) -1-propyl ester A mixture of (2S) -1- (1, 2-dioxo-3, 3-dimethylpentyl) -2-pyrrolidinecarboxylic acid (4.58 g, 19 mmol), 3-pyridinepropanol (3.91 g, 28.5 mmol), dicyclohexylcarbodiimide (6.27 g) 30.4 mmoles), camphorsulfonic acid (1.47 g, 6.33 mmoles) and 4-dimethylaminopyridine (773 mg, 6.33 mmoles) in methylene chloride are stirred overnight under a nitrogen atmosphere. The reaction mixture is filtered through Celite to remove solids and concentrated in vacuo. The crude material is triturated with several portions of ether, and portions of ether are filtered through Celite to remove solids and concentrated in vacuo. The concentrated filtrate is purified on a flash column (elution gradient, 25% ethyl acetate in hexane to pure ethyl acetate) to obtain 5.47 g (80%) of HPI 1046 as a colorless oil (partial hydrate). : H NMR (CDC13, 300 MHz): d 0.85 (t, 3H); 1.23, 1.26 (s, 3H each); 1.63-1.89 (m, 2H); 1.90-2.30 (m, 4H); 2.30-2.50 (m, 1H); 2.72 (t, 2H); 3.53 (m, 2H); 4.19 (m, 2H); 4.53 (m, 1H); 7.22 (m, 1H); 7.53 (dd, 1H); 8.45. Analysis calculated for C, 0H28NO4 - 0.25 H20: C, 65.82; H, 7.87; N, 7.68. Found: C, 66.01; H, 7.85; N, 7.64. 3- (3-pyridyl) -1-propyl (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate N-oxide (95) A solution of 3- (3-pyridyl) -1-propyl (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate (190 mg, 0.52 mmole) and m-acid chloroperbenzoic acid (160 mg of material 57% -86%, 0.53 mmole) is stirred in 20 ml of methylene chloride at room temperature for 3 hours. The reaction mixture is diluted with methylene chloride and washed twice with 1 N NaOH. The organic extract is dried and concentrated, and the crude material is subjected to chromatography, eluting with 10% methanol in ethyl acetate to obtain 130 mg of compound 95 of example 6.: H NMR (CDC13, 300 MHz): d 0.83 (t, 3H); 1.21 (s, 3H); 1.25 (s, 3H); 1.75-2.23 (m, 8H); 2.69 (t, 2H, J = 7.5); &8. .. . . . . . ,, - ,. "». ... - ^ __ H ^ BQ ^^ - ^ 3.52 (t, 2H, J = 6.3); 4.17 (dd, 2H, J = 6.3); 4.51 (m, 1H); 7.16-7.22 (m, 2H); 8.06-8.11 (m, 2H). Analysis calculated for C 20 H 28 N 2 O 5 - 0.75 H, 0: C, 61.60; H, 7.63; N, 7.18. Found: C. 61.79; H, 7.58; N. 7.23.

Example 7 Synthesis of 3- (3-pyridyl) -1-propylmercaptyl 2S-1- [(2-methylbutyl) carbamoyl] pyrrolidin-2-carboxylate (101) 3- (3-pyridyl) -1-propyl chloride To a solution of 3- (3-pyridyl) -1-propanol (10 g, 72.4 mmoles) in 100 ml of chloroform, a solution of thionyl chloride (12.9 g, 108.6 mmol) in 50 ml of chloroform is added dropwise. The resulting mixture is refluxed for 1 hour, and then poured into 150 ml of 50% aqueous potassium hydroxide cooled with ice. The layers are separated and the organic phase is dried, concentrated and purified on a column of silica gel, eluting with 40% ethyl acetate in hexane to obtain 10 g (65%) of the chloride as a clear oil. γ NMR (CDC13, 300 MHz): d 2.02-2.11 (m, 2H); 2.77 (m, 2H); 3.51 (m, 2H); 7.20 (m, 1H); 7.49 (m, 1H); 8.45 (m, 2H). 3- (3-pyridyl) -1-propylmercaptan --------- É-Ü-ÉI A mixture of 3- (3-p-ridyl) -1-propyl chloride (3 g, 19.4 mmol) and thiourea (1.48 g, 19.4 mmol) in 10 ml of ethanol is refluxed for 24 hours. 15 ml of a 0.75 N aqueous sodium hydroxide solution are added and the mixture is refluxed for an additional 2 hours. After cooling to room temperature, the solvent is removed in vacuo. Chromatographic purification of the crude thiol on a column of silica gel eluting with 50% ethyl acetate in hexane provides 1.2 g of 3- (3-pyridyl) -1-propyl mercaptan as a clear liquid. : H NMR (CDC13, 300 MHz): d 1.34 (m, 1H); 1.90 (m, 2H); 2.52 (m, 2H); 2.71 (m, 2H); 7.81 (m, 1H); 7.47 (m, 1H); 8.42 (m, 2H).

N- (tert-butoxycarbonyl) pyrrolidine-2-carboxylate des 3- (3-pyridyl) -1-prpylmercaptyl A mixture of N- (tert-butyloxycarbonyl) -S-proline (3.0 g, 13.9 mmol); 3- (3-pyridyl) -1-propylmercaptan (3.20 g, 20.9 mmol); dicyclohexylcarbodiimide (4.59 g, 22.24 mmol), camphorsulfonic acid (1.08 g, 4.63 mmol) and 4-dimethylaminopyridine (0.60 g, 4.63 mmol) in 100 ml of dry methylene chloride are stirred overnight. The reaction mixture is diluted with 50 ml of methylene chloride and 100 ml of water, and the layers are separated. The organic phase is washed with water (3 x 100 ml), dried over magnesium sulfate and concentrated, and the crude residue is purified on a column of silica gel eluting with ethyl acetate to obtain 4.60 g (95%). of the thioester as a thick oil. -H NMR (CDC13, 300 MHz): d 1.45 (s, 9H); 1.70-2.05 (m, 5H); 2.32 (m, 1H); 2.71 (t, 2H); 2.85 (, 2H); 3.50 (m, 2H), 4.18 (m, 1H); 7.24 (m, 1H); 7.51 (m, 1H); 8.48 (m, 2H). 3- (3-pyridyl) -1-propylmercaptyl pyrrolidine-2-carboxylate A solution of 3- (3-pyridyl) -1-mercaptyl N- (tert-butyloxycarbonyl) -pyrrolidine-2-carboxylate (4.60 g, 13.1 mmol) in 60 ml of methylene chloride and 6 ml of Trifluoroacetic acid is stirred at room temperature for 3 hours. Saturated potassium carbonate is added until the pH is basic, and the reaction mixture is extracted with methylene chloride (3x). The combined organic extracts are dried and concentrated to provide 2.36 g (75%) of the free amine as a thick oil. lH NMR (CDC13, 300 MHz): d 1.87-2.20 (m, 6H); 2.79 (m, 2H); 3.03-3.15 (m, total 4H); 3.84 (m, 1H); 7.32 (m, 1H); 7.60 (m, 1H); 8.57 (m, 2H). 2S-1- [(2-methylbutyl) carbamoyl] pyrrolidine-2-carboxylate 3- (3-pyridyl) -1-propylmercaptyl (101) ^^^^ A solution of 2-methylbutylamine (113 mg, 1.3 moles) and triethylamine (132 mg, 1.3 mmoles) in 5 ml of methylene chloride is added to a solution of triphosgene (128 mg, 0.43 mmol) in 5 ml of methylene chloride. The resulting mixture is refluxed for 1 hour and then cooled to room temperature. 3- (3-Pyridyl) -1-propylmercaptyl pyrrolidine-2-carboxylate (300 mg, 1.3 mmol) in 5 ml of methylene chloride is added and the resulting mixture is stirred for 1 hour and then divided between water and a 1: 1 mixture of ethyl acetate and hexane. The organic phase is dried, concentrated and purified by column chromatography (50% ethyl acetate / hexane) to obtain 250 mg (55%) of the compound of example 7 (compound 101, table VII) as an oil. XH NMR (CDC13, 300 MHz): d 0.89-0.93 (m, 6H); 1.10-1.20 (m, 1H); 1.27 '(s, 1H); 1.36-1.60 (m, 2H); 1.72 (s, 2H); 1.97-2.28 (m, 6H); 2.70-2.75 (m, 2H); 2.92-3.54 (m, 6H); 4.45-4.47 (m, 1H); 7.21-7.29 (m, 1H); 7.53-7.56 (dd, 1H); 8.46-8.48 (s, 2H).

Example 8 Synthesis of 3- (3-pyridyl) -1-propyl 2S-1- [(1 ', 1' -dimethylpropyl) Cyclobamoyl] -pyrrolidinecarboxylate (102) The reaction of 3- (3-pyridyl) pyrrolidine-3-carboxylate ) -1-propylmercaptyl with the isocyanate monomer of ter-amylamine and triphosgene, as described for example 7, gives the compound of example 8 (compound 102, table VII) in 62% yield. : H NMR (CDC13, 300 MHz): d 0.83 (t, 3H); 1.27 (s, 6H); 1.64-1.71 (m, 2H); 1.91-2.02 (m, 7H); 2.66-2.71 (t, 2H); 2.85 (m, 2H); 3.29-3.42 (m, 2H); 4.11 (broad, 1H); 4.37-4.41 (m, 1H).

Example 9 Synthesis of 3- (3-pyridyl) -1-propylmercaptyl 2S-1- [(cyclohexyl) thiocarbamoyl] -pyrrolidin-2-carboxylate (107) A mixture of cyclohexyl isothiocyanate (120 mg; 0. 9 mmol), 3- (3-pyridyl) -1-propylmercaptyl pyrrolidine-2-carboxylate (200 mg, 0.9 mmol) and triethylamine (90 mg, 0.9 mmol) in 20 ml of methylene chloride are stirred for 1 hour and it is then partitioned between water and a 1: 1 mixture of ethyl acetate and hexane. The organic phase is dried, concentrated and purified by column chromatography (50% ethyl acetate / hexane) to obtain 160 mg (47%) of the compound of Example 9 (compound 107, Table VII). XH NMR (CDC13, 300 MHz): d 1.16-1.40 (m, 6H); 1.50-1.71 (m, 4H); 1.95-2.08 (m, 7H); 2. 70-2.75 (t, 2H); 3.03 (m, 2H); 3.40-3.60 (m, 2H); 4.95-4.98 (d, 1H); 5.26-5.29 (d, 1H); 7.17-7.25 (m, 1H).

Example 10 Synthesis of 3- (para-methoxy-enyl) -1-propylmercaptyl (2S) -N- (benzenesulfonyl) pyrrolidine-2-carboxylate (120) 3- (p-methoxyphenyl) -1-propyl bromide 10 To a solution of 3- (p-methoxyphenyl) -1-propanol (16.6 g, 0.1 mol) in 250 ml of toluene, cooled to 0 ° C, 26 ml of phosphorus tribromide (0.27 mol) is added.

After the addition is complete, the reaction is stirred at room temperature for 1 hour, and then refluxed for an additional 1 hour. The reaction is cooled and poured into ice, the layers are separated and the organic phase is washed with saturated sodium bicarbonate (3x) and brine (3x).

The crude material obtained by drying and evaporating the solvent is subjected to chromatography, eluting with EtOAc. % / hexane to obtain 14 g (61%) of 3- (p-methoxyphenyl) -1-propyl bromide. - 3- (p-methoxyphenyl) -1-propylmercaptan ^^^ ^ ^ ^ A mixture of 3- (p-methoxyphenyl) -1-propyl bromide (14 g, 61 mmol) and thiourea (5.1 g, 67 mmol) in 150 ml of ethanol is refluxed for 48 hours. hours. Evaporation of the solvent gives a clear vitreous compound which is dissolved in 50 ml of water and treated with 100 ml of 40% aqueous sodium hydroxide. After stirring the resulting mixture for 2 hours, the product is extracted into ether (3x) and the combined organic extracts are washed with sodium bicarbonate and brine, dried and concentrated. Chromatographic purification of the crude thiol on a column of silica gel eluting with 2% ether in hexane provides 10.2 g of 3- (p-methoxyphenyl) -1-propyl mercaptan as a clear liquid. X H NMR (CDC13, 300 MHz): d 1.34 (t, 1H); 1.88-1.92) m, 2H); 2.49-2.53 (m, 2H); 2.64-2.69 (m, 2H); 3.77 (s, 3H); 6.80-6.84 15 (m, 2H); 7.06-7.24 (m, 2H).

N- (tert-butyloxycarbonyl) pyrrolidine-2-carboxylate of 3- (p-methoxyphenyl) -1-mercaptyl A mixture of N- (tert-butyloxycarbonyl) - (S) -proline (2.0 g, 9.29 mmole), 3- (p-methoxyphenyl) -1-propylmercaptan (1.86 g, 10.22 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide chloride (1.96 g, 10.22 mmol) and 4-dimethylaminopyridine (catalytic) in dry methylene chloride (50 ml) is stirred at night. The reaction mixture is diluted with 50 ml methylene chloride and 100 ml water, and the layers are separated. The organic phase is washed with water (3 x 100 ml), dried over magnesium sulfate and concentrated to provide 3.05 g of the product (100%) as an oil: H NMR (CDC13, 5 300 MHz): d 1.15 (s, 9H); 1.84-2.31 (m, 6H); 2.61 (m, 2H); 2.83 (m, 2H); 3.51 (m, 2H); 3.75 (s, 3H); 6.79 (d, 2H, J = 8.04); 7.05 (m, 2H). 3- (p-Methoxyphenyl) -1-mercaptyl pyrrolidine-2-carboxylate A solution of 3- (p-methoxyphenyl) -mercaptyl N- (tert-butyloxycarbonyl) pyrrolidine-2-carboxylate (3.0 g, 8.94 mmol) in methylene chloride (60 ml) and trifluoroacetic acid (6 ml) are stirred at room temperature for three hours. NMR (CDC13, 300 MHz): d 1.80-2.23 (m, 6H); 2.62 (m, 2H); 2.81 (m, 2H); 3.01 (m, 2H); 3.75 (s, 3H); 3.89 (m, 1H); 6.81 (m, 2H); 7.06 (m, 2H). (2S) -N- (benzenesulfonyl) pyrroiidine-2-carboxylate of 3- (para-20-methoxyphenyl) -1-propylmercaptyl (120) A solution of 3- (p-methoxyphenyl) -1-mercaptyl pyrrolidine-2-carboxylate (567 mq, 2.03 mmol) and benzenesulfonyl chloride (358 mg, 2.03 mmol) in 5 ml of sodium chloride methylene is treated with diisopropylethylamine (290 mg; 2.23 • 'Virí, ip- ia •,? , i go ii r-tnl ia ... • mii T -ii ^^ a- »* ^ Mié - ^» ^ M? ». ^^ iM. ^ M? a ---------- -I-1 mmoles) and stir overnight at room temperature. The reaction mixture is filtered to remove solids and applied directly to the column of silica gel, eluting with 25% ethyl acetate in hexane, to obtain 540 mg of compound 120 (table VIII) as a clear oil. : H NMR (CDC13, 300 MHz): d 1.65-1.89 (m, 6H); 2.61 (t, 2H, J = 7.3); 2.87 (t, 2H, J = 7.6); 3.26 (m, 1H); 3.54 (, 1H); 3.76 (s, 3H); 4.34 (dd, 1H, J = 2.7, 8.6); 6.79 (d, 2H, J = 8.7); 7.06 (d, 2H, J = 8.6); 7.49-7.59 (m, 3H); 7.86 (dd, 2H, J = 1.5, 6.8).

Example 11 Synthesis of (2S) -N- (? -toluensulfonyl) pyrrolidin-2-carboxylate of 3- (para-methoxyphenyl) -1-propylmercaptyl (121) A solution of 3- (p-methoxyphenyl) -1-mercaptyl pyrrolidine-2-carboxylate (645 mg, 2.30 mmol) and a-toluenesulfonyl chloride (440 mg, 2.30 mmol) in 5 ml of methylene chloride is treated with Diisopropylethylamine (330 mg, 2.53 mmol) and stir overnight at room temperature. The purification is described for Example 10 to provide the compound of Example 11 (compound 121, Table VIII) as a clear oil. lH NMR (CDC13, 300 MHz): d 1.65-2.25 (m, 8H); 2.65 (t, 2H); 2.89-2.96 (m, 2H); 3.55-3.73 (, 2H); 3.80 (s, 3H); 4.32 (s, 2H); 4.70-4.81 (m, 1H); 6.83 (d, 2H); 7.09 (d, 2H); 7.14 (m, 3H); 7.26 (m, 2H).

Example 12 Synthesis of (2S) -N- (α-toluenesulfonyl) pyrrolidin-2-carboxylate of 3- (para-methoxyphenyl) -1-propylrnercaptyl (122) A solution of 3- (p-methoxyphenyl) -1-mercaptyl pyrrolidine-2-carboxylate (567 mg, 2.30 mmol) and p-toluenesulfonyl chloride (425 mg, 2.23 mmol) in 5 ml of methylene chloride is stirred for the night at room temperature. The purification described for example 10 provides the compound of example 12 (compound 122, table VIII) as a clear oil. : H NMR (CDC1., 300 MHz): d 1.67-1.94 (m, 6H); 2.40 (s, 3H); 2.61 (t, 2H, J = 7.3); 2.84 (m, 2H, J = 7.2); 3.22 (m, 1H); 3.52 (m, 1H); 3.76 (s, 3H); 4.32 (dd, 1H, J = 2.9, 8.5); 6.70 (d, 2H, J = 6.5); 7.07 (d, 2H, J = 6.5); 7.29 (d, 2H, J = 6.5); 7.74 (d, 2H, J = 6.5).

Example 13 Synthesis of 1,5- diphenyl-3-pentylmercaptyl (134) 3-phenyl-1-propanal N- (para-toluenesulfonyl) pipecolate Oxalyl chloride (2.90 g, 2.29 mmol) is treated in 50 ml of methylene chloride, cooled to -78 ° C, with 3.4 ml of dimethyl sulfoxide in 10 ml of methylene chloride. After stirring for 5 minutes, 3-phenyl-1-propanol (2.72 g, 20 mmol) in 20 ml of methylene chloride is added, and the resulting mixture is stirred at -78 ° C for 15 minutes, treated with water. ml of triethylamine, stir for an additional 15 minutes and pour into 100 ml of water. The layers are separated, the organic phase is dried and concentrated and the crude residue is purified on a column of silica gel eluting with 10% ethyl acetate in hexane, to obtain 1.27 g (47%) of the aldehyde as a clear oil. . X H NMR (CDC13, 300 MHz): d 2.80 (m, 2H); 2.98 (m, 2H); 7.27 (m, 5H); 9.81 (2, 1H). 1, 5-diphenyl-3-pentanol A solution of 2- (bromoethyl) benzene (1.73 g, 9.33 mmol) in 10 ml of diethyl ether is added to a stirred suspension of magnesium turnings (250 mg, 10.18 mmol) in 5 ml of ether. The reaction is started with a heat gun, and after the addition is complete, the mixture is heated in an oil bath for 30 minutes. 3-Phenyl-1-propanal (1.25 g, 9.33 mmol) is added in 10 ml of ether, and the reflux is continued for 1 hour. The reaction is cooled and suspended with saturated ammonium chloride, extracted into 2x ethyl acetate, and the combined organic portions are dried and concentrated. Chromatographic purification on a column of silica gel (10% ethyl acetate in hexane) provides 1.42 g (63%) of the diphenylalcohol. H NMR (CDC13, 300 MHz): d 1.84 (m, 4H); 2.61-2.76 (m, 4H); 3.65 (m, 1H); 7.19-7.29 (m, 10H). 1, 5-diphenyl-3-bromopentane To a solution of 1,5-diphenyl-3-pentanol (1.20 g, 5 mmol) and carbon tetrabromide (1.67 g, 5 mmol) in 20 ml of methylene chloride is added triphenylphosphine (1.31 g, 5 mmol) in portions, 0 ° C. After stirring at room temperature for 18 hours, the mixture is concentrated, triturated with ether and the solids are removed by filtration. The filtrate is passed through a plug of silica gel, eluting with hexane: methylene chloride, 10: 1 to provide 1.35 g (90%) of the bromide as an oil which is used without further purification. 2 H NMR (CDC13, 300 MHz): d 2.11-2.18 (m, 4H); 2.73 (m, 2H); 2.86 (m, 2H); 3.95 (m, 1H); 7.16-7.30 (m, 10H). 1, 5-diphenyl-3-pentyl mercaptan Using the procedure described in Example 10 for the conversion of bromides to thiols, 1,5-diphenyl-3-bromopentane is converted to 1,5-diphenyl-3-pentyl mercaptan with a total return of 35%. lH NMR (CDC13, 300 MHz): d 1.79 (, 2H); 1.98 (m, 2H); 2.71 (m, 3H); 2.80 (m, 2H); 7.16-7.28 (, 10H).

N- (tert-butyloxycarbonyl) pyrrolidine-2-carboxylate 1,5-diphenyl-3-pentyl mercaptide A mixture of N- (tert-butyloxycarbonyl) - (S) -pipecolic acid (2.11 g, 9.29 mmol), 1,5-diphenyl-3-pentyl mercaptan (2.58 g, 10.22 mmol), l- (3-dimethylaminopropyl) hydrochloride ) -3-ethylcarbodiimide (1.96 c, 10.22 mmoles) and 4-dimethylarpinopyridine (catalytic amount) in 50 ml of dry methylene chloride is stirred overnight. The reaction mixture is diluted with 50 ml of methylene chloride and 100 ml of water, and the layers are separated. The organic phase is washed with water (3 x 100 ml), dried over magnesium sulfate and concentrated to give 870 mg (20%) of the product as a thick oil, which is used without further purification.

Pyrrolidine-2-carboxylic acid 1,5-diphenyl-3-pentyl mercaptyl ester ------------------------ ------- ^ --------- ih -------- - A solution of 1,5- diphenyl-3-pentyl mercaptyl N- (tert-butyloxycarbonyl) pyrrolidine-2-carboxylate (850 mg, 1.8 mmol) in 10 ml of methylene chloride and 1 ml of trifluoroacetic acid are added. Stir at room temperature for 3 hours. Saturated potassium carbonate is added until the pH is basic, and the reaction mixture is extracted with methylene chloride. The combined organic extracts are dried and concentrated to provide 480 mg (72%) of the free amine as a thick oil, which is used without further purification.

N- (para-toluenesulfonyl) 1,5-diphenyl-3-pentylmercaptyl pipecolate (134) 1,5-Diphenyl-3-pentylmercaptyl (18) N- (para-toluenesulfonyl) pipecolate is prepared from 1,5-diphenyl-3-pentylmercaptyl pyrrolidine-2-carboxylate and para-toluenesulfonyl chloride, as describes for example 12, with a yield of 65%. : H NMR (CDC13, 300 MHz): d 0.80 (m, 4H); 1.23-1.97 (m, 5H); 2.15 (d, 1H); 2.61-2.69 (m, 4H); 3.23 (m, 1H); 3.44 (dm, 1H); 4.27 (s, 2H); 4.53 (d, 1H, J = 4.5); 5.06 (m, 1H); 7.16-7.34 (m, 15H).

Example 14 ------------- MY Synthesis of (2S) -1- (3, 3-dimethyl-l, 2-dioxopentyl) -2- pyrrolidinecarboxylic acid 3-phenyl-1-propyl (137) (2S) -1- (1,2-dioxo-2-methoxyethyl) -2-pyrrolid? Ncarboxylate of methyl A solution of L-proline methyl ester hydrochloride (3.08 g, 18.60 mmoles) in dry methylene chloride is cooled to 0 ° C and treated with triethylamine (3.92 g; 38.74 mmoles; 2.1 eq). After stirring the suspension which is formed under a nitrogen atmosphere for 15 minutes, a solution of methyloxalyl chloride (3.20 g, 26.12 mmol) in 45 ml of methylene chloride is added dropwise. The resulting mixture is stirred at 0 ° C for 1.5 hours. After filtering 5 to remove the solids, the organic phase is washed with water, dried over MgSO. and concentrates. The crude residue is purified on a column of silica gel, eluting with 50% ethyl acetate in hexane to obtain 3.52 g (88%) of the product as a reddish oil. Mixture of cis-trans amide rotamers; 0 the data for the trans rotamer is provided. lti NMR (CDC13): d 1.93 (dm, 2H); 2.17 (m, 2H); 3.62 (m, 2H); 3.71 (s, 3H); 3.79, 3.84 (s, 3H total); 4.86 (dd, 1H, J = 8.4, 3.3). (2S) -l- (1, 2-dioxo-3, 3-dimethylpentyl) -2-pyrrolidinecarboxylate 5 methyl > - * - '* - "A solution of methyl (2S) -1- (1,2-dioxo-2-methoxyethyl) -2-pyrrolidinecarboxylate (2.35 g, 10.90 mmoles) in 30 ml of tetrahydrofuran (THF) is cooled at -78 ° C and treated with 14.2 ml of a 1.0 M solution of 1,1-dimethylpropylmagnesium chloride in THF.After stirring the resulting homogeneous mixture at -78 ° C for 3 hours, the mixture is poured into 100 ml of saturated ammonium chloride and extracted into ethyl acetate The organic phase is washed with water, dried and concentrated, and the crude material which is obtained after the removal of the solvent is purified on a column of silica gel, eluting with 25% ethyl acetate in hexane to obtain 2.10 g (75%) of the oxamate as a colorless oil.1H NMR (CDC13): d 0.88 (t, 3H); L 1.22, 1.26 (s, 3H each) 1.75 (dm, 2H), 1.87-2.10 (m, 3H), 2.23 (m, 1H), 3.54 (m, 2H), 3.76 (s, 3H), 4.52 '(dm, 1H, J = 8.4, 3.4 ).

Synthesis of (2S) -1- (1, 2-dioxo-3, 3-dimethylpentyl) -2-pyrrolidinecarboxylic acid A mixture of methyl (2S) -1- (1, 2-dioxo-3, 3-dimethylpentyl) -2-pyrrolidinecarboxylate (2.10 g, 8.23 mmol), 15 ml of 1 N LiOH and 50 ml of methanol is stirred at 0 ° C for 30 minutes and at room temperature overnight. The mixture is acidified to pH 1 with 1 N HCl, diluted with water and extracted in 100 ml of methylene chloride. The organic extract is washed with brine and concentrated to give 1.73 g (87%) of a white solid as snow which does not require further purification. X H NMR (CDC13): d 0.08 (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); 3.53 (dd, 2H, J = 10.4, 7.3); 4.55 (dd, 1H, J = 8.6, 4.1). (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrole 3-phenyl-1-propyl idincarboxylate (137) A mixture of (2S) -1- (1, 2-dioxo-3, 3-dimethylpentyl) -2-pyrrolinecarboxylic acid (600 mg, 2.49 mmol), 3-phenyl-1-propanol (508 mg, 3.73 mmol), dicyclohexylcarbodiimide (822 mg, 3.98 mmol), camphorsulfonic acid (190 mg, 0.8 mmol) and 4-dimethylaminopyridine (100 mg, 0.8 mmol) in 20 ml of methylene chloride are stirred overnight under a nitrogen atmosphere. The reaction mixture is filtered through Celite to remove solids and concentrated in vacuo, and the crude material is purified on a flash chromatography column (25% ethyl acetate in hexane) to obtain 720 mg (80%) of the example 14 as a colorless oil. X H NMR (CDC13): d 0.84 (t, 3H); 1.19 (s, 3H); 1.23 (s, 3H); 1.70 (dm, 2H); 1.98 (m, 5H); 2.22 (m, 1H); 2.64 (m, 2H); 3.47 (m, 2H); 4.14 (m, 2H); 4.51 (d, 1H); 7.16 (m, 3H); 7.26 (m, 2H).

Example 15 The method of Example 14 is used to prepare the following illustrative compounds.

Compound 138: (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate 3-phenyl-1-prop-2- (E) -enyl, 80%. 1 NMR (360 MHz, CDC13): d 0.86 (t, 3H); 1.21 (s, 3H); 1.25 (s, 3H); 1.54-2.10 (m, 5H); 2.10 - 2.37 (m, 1H), 3.52 - 3.55 (m, 2H) 4.56 (dd, 1H, J = 3.8, 8.9); 4.78-4.83 (n, 2H); 6.27 (m, 1H) 6.67 (dd, 1H, J = 15.9); 7.13-7.50 (m, 5H).

Compound 139: (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3- (3,4-, 5-trimethoxyphenyl) -1-propyl, 61%. XH NMR '(CDC13) d 0.84 (t, 3H) 1.15 (s, 3H); 1.24 (s, 3.H), 1.71 (dm, 2H); 1.00 (m, 5H), 2.24 (m, 1H); 2.63 (m, 2H); 3.51 (t, 2H); 3.79 (s, 3H); 3.83 (s, 3H); 4.14 (m, 2H); 4.52 (m, 1H); 6.36 (s, 2H) Compound 140: (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate of 3- (3,4-, 5-trimethoxyphenyl) -l-prop-2- (E) -enyl, 66%. X H NMR (CDC13): d 0.85 (t, 3H); 1.22 (s, 3H); 1.25 (s, 3H) 1.50-2.11 (m, 5H); 2.11 - 2.40 (, 1H); 3.55 (m, 2H); 3.85 (s, 3H); 3.88 (s, 6H); 4.56 (dd, 1H) 4.81 (m, 2H) 6.22 (m, 1H) 6.58 (d, 1H, J = 16); 6.63 (s, 2H).

Compound 141: 3- (4,5-methylenedioxyphenyl) -1-propyl, 82% (3S) -1- (3,3-dimethyl-l, -dioxopentyl) -2- pyrrolidinecarboxylate. 2 H NMR (360 MHz, CDC13): d 0.86 (t, 3H); 1.22 (s, 3H); 1.25 (s, 3H); 1.60-2.10 (m, 5H); 3.36-3.79 (m, 2H); 4.53 (dd, 1H, J = 3.8, 8.6); 4.61-4.89 (m, 2H); 5.96 (s, 2H); 6.10 (m, 1H); 6. 5 7 (dd, 1H, J-6.2, 15.8); 6.75 (d, 1H, J = 8.0); 6.83 (dd, 1H, J-1.3, 8.0); 6.93 (s, 1H).

Compound 142: 3- (4,5-methylenedioxyphenyl) -l-prop-2- (E) -enyl, (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate, 82 %. : H NMR (360 MHz, CDC13): d 0.86 (t, 3H); 1.22 (s, 3H); 1.25 (s, 3H); 1.60-2.10 (m, 5H); 2.10-2.39 (m, 1H); 3.36-3.79 (m, 2H) 4.53 (dd, 1H, J-3.8, 8.6); 4.61-4.89 (m, 2H); 5.96 (s, 2H) 6.10 (m, 1H); 6.57 (dd, 1H, J = 6.2, 15.8); 6.75 (d, 1H, J = 8.0); 6.83 (dd, 1H, J = 1. 3, 8.0); 6.93 (s, 1H).

Compound 144: (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3-cyclohexyl-1-prop-2- (E) -enyl, 92%. : H NMR (360 MHz, CDC1.): D 0.86 (t, 3H); 1.13 - 1.40 (m + 2 singles, 9H total); 1.50-1.87 (m, 8H) 1.87-2.44 (m,, 6H) 3.34-3.82 (m, 2H); 4.40-4.76 (m, 3H) 5.35-5.60 (m, 1H) 5.60-5.82 (dd, 1H, J = 6.5, 16), Compound 145: (2S) -1- (3, 3-dimethyl-1,2) -dioxopentyl) -2- pyrrolidinecarboxylate of (IR) -1,3-diphenyl-1-propyl, 90%. : H NMR (360 MHz, CDC13): d 0.85 (t, 3H); 1.20 (s, 3H); 1.23 (s, 3H); 1.49 - 2.39 (m, 7H); 2.46-2.86 (m, 2H); 3.25-3.80 (m, 2H); 4.42-4.82 (m, 1H); 5.82 (td, 1H, J = 1.8, 6.7); 7.05-7.21 (m, 3H); 7.21-7.46 (m, 7H).

Compound 146: (2S) -1- (1,2-d? Oxo-2- [2-furanyl) ethyl-2-pyrrolidinecarboxylic acid 3-phenyl-1-propyl, 99%. : H NMR (300 MHz, CDC13): d 1.66-2.41 (m, 6H); 2.72 (t, 2H, -7.5); 3.75 (m, 2H); 4.21 (m, 2H); 4.61 (m, 1H); 6.58 (m, 1H); 7.16-7.29 (m, 5H); 7.73 (m, 2H).

Compound 147: (2S) -1- (1,2-dioxo-2- [2-thienyl]) ethyl-2-pyrrolidinecarboxylic acid 3-phenyl-1-propyl, 81%. H NMR (300 MHz, CDC1. d 1 -2.41 m, 6H; 2.72 (dm, 2H); 3.72 m, 2H: 4.05 (m, 1H); 4.22 (m, 1H); 4.64 (m, 1H); 7.13-7.29 (m, 6H); 7.75 (dm, 1H); 8.05 (m, 1H).

Compound 149: (2S) -1- (1, 2-d? Oxo-2-phenyl) ethyl-2-pyrrolidinecarboxylic acid 3-phenyl-1-propyl, 99%. : H NMR (30O MHz, CDC13): d 1.97-2.32 (m, 6H); 2.74 (t, 2H, J = 7.5); 3.57 (m, 2H); 4.24 (m, 2H); 4.67 (m, 1H); 6.95-7.28 (m, 5H); 7.51-7.64 (m, 3H); 8.03-8.09 (m, 2H). and?? ? ^^^^^^^^^^^^^^^^^^^^ m ^ ^^^ m m? k ^ Compound 150: (2S) -I- (3, 3-dimethyl-!, 2-dioxopenti 1) -2- pyrrolidinecarboxylic acid 3- (2,5-dimethoxyphenyl) -1-propyl, 99%. l H NMR (300 MHz, CDC13) d 0.87 (t, 3H); 1.22 (S, 3H); 1.26 (s, 3H); 1.69 (m, 2H); 1.96 (m, 5H); 2.24 (m, 1H); 2.68 (m, 2H); 3.55 (m, 2H); 3.75 (s, 3H); 3.77 (s, 3H); 4.17 (m, 2H); 4.53 (d, 1H); 6.72 (m, 3 H).

Compound 151: (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3- (2,5-dimethoxyphenyl) -l-prop-2- (E) -enyl, 99 %. X H NMR (300 MHz, CDC13) d 0. 87 (t, 3 H) 1.22 (s, 3 H): 1.26 (s, 3 H) 1.67 (m 2 H); 1.78 (m, 1H) 2.07 (m, 2H); 2.26 (m, 1H); 3.52 (m, 2H); 3.78 (s, 3H); 3.80 (5, 3H); 4. 54 (m, 1H); 4.81 (m, 2H); 6.29 (dt, 1H, J = 15. 9) d.98 (5, 1H).

Compound 152: (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate of 2- (3,4,5-trimethoxyphenyl) -l-ethyl, 97%. -H NMR (30O MHz, CDC13): d O.8. (t, 3H); 1.15 (s, 3H); 1. 24 (s, 3H); 1.71 (dm, 2H); 1.98 (m, 5H); 2.24 (m, 1H); 2.63 (m, 2H); 3.51 (t, 2H); 3.79 (s, 3H); 3.83 (s, 3H); 4.14 (m, 2H); 4.52 (m, 1H); 6.36 (s, 2H).

Compound 153: (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3- (3-pyridyl) -1-propyl, 80%. 1 H NMR (CDC13, 300 MHz) d 0.85 (t, 3H); 1.23, 1.26 (s, 3H each); 1.63-1.89 (m, 2H); 1.90-2.30 (m, 4H); 2.30-2.50 (m, 1H); 2.72 _i--i ---- (t, 2H); 3. 53 (m, 2H); 4.19 (m, 2H); 4. 53 (ra, 1H); 7.22 (m, 1H); 7.53 (dd, 1H); 8.45.

Compound 154: (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2- pyrrolidinecarboxylic acid 3- (2-pyridyl) -1-propyl, 88%. : H NMR (CDC13, 300 MHz): d 0.84 (t, 3H); 1.22, 1.27 (s, 3H each); 1.68-2.32 (m, 8H), 2.88 (t, 2H, J = 7.5); 3.52 (m, 2H); 4.20 (m, 2H); 4.51 (m, 1H); 7.09-7.19 (m, 2H); 7.59 (m, 1H); 8.53 (d, 1H, J = 4.9).

Compound 155: (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3- (4-pyridyl) -1-propyl, 91%. X H NMR (CDC13 300 MHz): d 6.92-6.80 (m, 4H); 6.28 (, 1H); 5.25 (d, 1H, = 5.7) 4.12 (m, 1H); 4.08 (s, 3H); 3.79 (s, 3H) 3.30 (m, 2 H); 2.33 (m, '1H); 1.85-1.22 (m, 7H); 1.25 (s, 3 H) 1.23 (s, 3H); 0.89 (t, 3H, J = 7.5).

Compound 156: (2S) -1- (2-cyclohexyl-l, 2-dioxoethyl) -2-pyrrolidinecarboxylic acid 3-phenyl-1-propyl, 91%. : H NMR (CDC13 300 MHz): d 1.09-1.33 (m, 5H); 1.62-2.33 (m, 12H); 2.69 (t, 2H, J = 7.5); 3.15 (dm, 1H); 3.68 (m, 2H); 4.16 (m, 2H); 4.53, 4.84 (d, total 1H); 7.19 (m, 3H); 7.29 (m, 2H).

Compound 157: (2S) -1- (2-tert-butyl-l, 2-dioxoethyl) -2-pyrrolidinecarboxylic acid 3-phenyl-1-propyl, 92%. 1 H NMR (CDC13, 300 MHz): d 1.29 (s, 9H); 1.94-2.03 (m, 5H) 2.21 (m, 1H); 2.69 (m, 2H); 3.50-3.52 (m, 2H); 4.16 (m, 2H) 4.53 (m, 1H); 7.19 (m, 3H); 7.30 (m, 2H).

Compound 158: (2S) -1- (2-cyclohexyl-ethyl-l, 2-dioxoethyl) -2-pyrrolidinecarboxylate 3-phenyl-1-propyl, 97%. -H NMR (CDC13, 300 MHz): d 0.88 (m, 2H); 1.16 (m, 4H); 1. 3-1.51 (m, 2H); 1.67 (m, 5H); 1.94-2.01 (m, 6H); 2.66-2.87 (m, 4H); 3.62-3.77 (m, 2H); 4.15 (m, 2H); 4.86 (m, 1H); 7.17-7.32 (m, 5H).

Compound 159: (2S) -1- (2-cyclohexylethyl-l, 2-dioxoethyl) -2-pyrrolidinecarboxylic acid 3- (3-pyridyl) -1-propyl, 70%. lH NMR (CDC13, 300 MHz): d 0.8 7 (m, 2H) 1.16 (m, 4H); 1.49 (m, 2 H 1.68 (m, 4 H); 1.95 - 2.32 (m, 7 H) 2.71 (m, 2 H); 2.85 (m, 2 H 3.63 - 3.78 (m, 2 H); 4.19 (m, 2 H) 5.30 (m 1H), 7.23 (m, 1H 7.53 (m, 1H), 8.46 (m, 2H).

Compound 160: (2S) -1- (2-tert-butyl-l, 2-dioxoethyl) -2-pyrrolidinecarboxylic acid 3- (3-pyridyl) -1-propyl, 83%. H NMR (CDCl 3, 300 MHz): d 1.29 (s, 9H); 1.95-2.04 (m, 5H); 2.31 (, 1H); 2.72 (t, 2H, J = 7.5); 3.52 (m, 2H); 4.18 (m, 2H); 4.52 (m, 1H); 7.19 - 7.25 (m, 1H); 7.53 (m, 1H); 8.4 6 (m, 2H).

Compound 161: (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3, 3-diphenyl-1-propyl, 99%. : H NMR (CDC13, 300 MHz): d 0.85 (t, 3H); 1.21, 1.26 (s, 3H each); 1.68-2.04 (m, 5H); 2.31 (m, 1H); 2.40 (m, 2H); 3.51 (M, 2H) 4.08 (m, 3H); 4.52 (m, 1H); 7.18-7.31 (m, 10H).

Compound 162: (2 S) -1- (2-cyclohexyl-l, 2-d-oxoethyl) -2-pyrrolidinecarboxylic acid 3- (3-pyridyl) -1-propyl, 88%. : H NMR (CDC13, 300 Hz): d 1.24-1.28 (m, 5H); 1.88-2.35 (m, 11H); 2.72 (t, 2H, J = 7..5); 3.00-3.33 (dm, 1H); 3.69 (m, 2H); 4.1 9 (m, 2H); 4.55 (m, 1H); 7.20-7.24 (m, 1H); 7.53 (m, 1H); 8.47 (m, 2H).

Compound 163: (2S) -N - ([2-thienyl] glyoxyl) pyrrolidinecarboxylic acid 3- (3-pyridyl) -1-propyl, 49%. : H NMR (CDC13, 300 MHz): d 1.81-2.39 (m, 6H); 2.72 (dm, 2H); 3.73 (m, 2H); 4.21 (m, 2H); 4.95 (m, 1H); - 7.19 (m, 2H); 7.61 (m, 1H); 7.80 (d, 1H); 8.04 (d, 1H); 5.46 (m, 2H) Compound 164: (2S) -1- (3,3-dimethyl-1,2-dioxobutyl) -2-pyrrolidinecarboxylic acid 3, 3-diphenyl-1-propyl, 99%. H NMR (CDCl 3, 300 MHz): d 1.27 (s, 9H); 1.96 (m, 2H); 2.44 (M, 4H); 3.49 (m, 1H); 3.64 (m, 1H); 4.08 (m, 4H); 4.53 (dd, 1H); 7.24 (m, 10H).

Compound 165: (2S) -l-cyclohexylglyoxyl-2-pyrrolidinecarboxylate 3,3-diphenyl-1-propyl, 91%. X H NMR (CDC13, 300 MHz) d 1.32 (m, 6H); 1.54-2.41 (m, 10H); 3.20 (dm, 1H) 3.69 (m, 2H); 4.12 (m, 4H); 4.52 (d, 1H); 7.28 (m, 10H).

Compound 166: (2S) -1- (2-thienyl) glyoxyl-2-pyrrolidinecarboxylic acid 3, 3-diphenyl-1-propyl, 75%. 1 H NMR (CDC13, 300 MHz): d 2.04 (m, 3H); 2.26 (m, 2H); 2.48 (m, 1H); 3.70 (m, 2H); 3.82-4.18 (m, 3H total); 4.64 (m, 1H); 7.25 (m, 11H); 7.76 (dd, 1H); 8.03 (m, 1H).

Example 16 General procedure for the synthesis of acrylic esters, exemplified for methyl (3, 3, 5-trimethoxy) -trans-cinnamate.

A solution of 3,4-trimethoxybenzaldehyde (5.0 g, 25.48 mmol) and methyl (triphenyl-phosphoranylidene) acetate (10.0 g, 29.91 mmol) in 250 ml of tetrahydrofuran is refluxed overnight. After cooling, the reaction mixture is diluted with 200 ml of ethyl acetate and washed with 2 x 200 ml of water, dried and concentrated in vacuo. The crude residue is subjected to chromatography on a column of silica gel, eluting with 25% ethyl acetate in hexane, to obtain 5.63 g (88%) of the cinnamate as a crystalline solid.

--------------------- ^^^^^^^^^ Maaa ^^^^ rf ------- ME ------ ---- White. X H NMR (CDC13, 300 MHz): d 3.78 (s, 3H); 3.85 (s, 6H); 6.32 (d, 1H, J = 16); 6.72 (s, 2H); 7.59 (d, 1H, J = 16).

Example 17 General procedure for the synthesis of saturated alcohols from acrylic esters, exemplified for (3,4,5-trimethoxy) phenylpropanol.

A solution of methyl (3, 3, 5-trimethoxy) -trans-cinnamate (1.81 g, 7.17 mmol) in 30 ml of tetrahydrofuran is added dropwise to a solution of 14 mmol of lithium aluminum hydride in 35 ml of THF, with stirring and under an argon atmosphere. After the addition is complete, the mixture is heated at 7.5 ° C for 4 hours. After cooling, it is suspended by the careful addition of 15 ml of 2 N NaOH followed by 50 ml of water. The resulting mixture is filtered through Celite to remove solids and the filter cake is washed with ethyl acetate. The combined organic fractions are washed with water, dried, concentrated in vacuo and purified on a column of silica gel eluting with ethyl acetate to obtain 0.86 g (53%) of the alcohol as a clear oil. X H NMR (CDC13, 300 MHz): d 1.23 (broad, 1H); 1.87 (m, 2H); 2.61 (t, 2H, J = 7.1); 3.66 (t, 2H); 3.80 (s, 3H); 3.83 (s, 6H); 6.40 (s, 2H).

Example 18 General procedure for the synthesis of trans-allylic alcohols from acrylic esters, exemplified 5 for (3, 4, 5-trimethoxy) phenylprop-2- (E) -enol.

A solution of methyl (3, 3, 5-trimethoxy) -trans-cinnamate (1.35 g, 5.35 mmol) in 25 ml of toluene is cooled to -10 ° C and treated with a hydride solution of diisobutylaluminum in toluene (11.25 ml of a 1.0 M solution, 11.25 mmoles). The reaction mixture is stirred for 3 hours at 0 ° C and then suspended with 3 ml of methanol followed by 1 N HCl until the pH is 1. The reaction mixture is extracted into ethyl acetate and the organic phase wash with water, dry and concentrate. Purification on a column of silica gel eluting with 25% ethyl acetate in hexane gives 0.96 g (80%) of a thick oil. : H NMR (360 MHz, CDC13): d 3.85 (s, 3H); 3.87 (s, 6H); 4.32 (d, 2H, J = 5.6); 6.29 (dt, 1H, J = 15.8, 5.7); 6.54 (d, 1H, J = 15.8); 6.61 (s, 2H). 20 Example 19 Synthesis of (2S) -1- (3,3-dimethyl-l, 2-dioxopentyl) -2-pyrrolidinecarboxylate 3-phenyl-1-propyl (1) - go "'i? -------- i ?? -----? - i ^^^ - • - • • - *" ** (2S) -1- (1, 2- methyl dioxo-2-methoxyethyl) -2-pyrrolidinecarboxylate A solution of L-proline methyl ester hydrochloride (3.08 g, 18.60 mmoles) in dry methylene chloride is cooled to 0 ° C and treated with triethylamine (3.92 g, 38.74 mmole, 2.1 eq). After stirring the suspension which is formed under a nitrogen atmosphere for 15 min, a solution of methyloxalyl chloride (3.20 g) is added dropwise.; 26.12 mmoles) in 45 ml of methylene chloride. The resulting mixture is stirred at 0 ° C for 1.5 hours. After filtering to remove the solids, the organic phase is washed with water, dried over MgSO4 and concentrated. The crude residue is purified on a column of silica gel, eluting with 50% ethyl acetate in hexane, to obtain 3.52 g (88%) of the product as a reddish oil. Mixture of cis-trans amide rotamers; the data for the trans rotamer is provided. : H NMR (CDC13): d 1.93 (dm, 2H); 2.17 (m, 2H); 3.62 (m, 2H); 3.71 (s, 3H); 3.79, 3.84 (s, 3H total); 4.86 (dd, 1H, J = 8.4, 3.3). (2S) -1- (1, 2-dioxo-3, 3-dimethylpenti1) -2-pyrrolidinecarboxylate methyl A solution of methyl (2S) -1- (1,2-dioxo-2-methoxyethyl) -2-pyrrolidinecarboxylate (2.35 g, 10.90 mmoles) in 40 ml of tetrahydrofuran (THF) is cooled to -78 ° C and treat with 14.2 ml of a 1.0 M solution of 1,1-dimethylpropylmagnesium chloride in THF. After stirring the resulting homogeneous mixture at -78 ° C for 3 hours, the mixture is poured into 100 ml of saturated ammonium chloride and extracted into ethyl acetate. The organic phase is washed with water, dried and concentrated, and the crude material obtained upon removal of the solvent is purified on a column of silica gel, eluting with 25% ethyl acetate in hexane to obtain 2.10 g (75%). ) of the oxamate as a colorless oil. : H NMR (CDC13): d 0.88 (t, 3H); 1.22, 1.26 (s, 3H each); 1.75 (dm, 2H); 1.87-2.10 (m, 3H); 2.23 (m, 1H); 3.54 (m, 2H); 3.76 (s, 3H); 4.52 (dm 1H, J = 8.4, 3.4).

Synthesis of '(2S) -1- (1, 2-dioxo-3, 3-dimethylpentyl) -2-pyrrolidinecarboxylic acid A mixture of methyl (2S) -1- (1, 2-dioxo-3, 3-dimethylpentyl) -2-pyrrolidinecarboxylate (2.10 g, 8.23 mmol), 15 ml of 1 N LiOH and 50 ml of methanol is stirred at 0 ° C for 30 minutes and at room temperature overnight. The mixture is acidified to pH 1 with 1 N HCl, diluted with water and extracted in 100 ml of methylene chloride. The organic extract is washed with brine and concentrated to give 1.73 g (87%) of a white solid as snow which does not require further purification. X H NMR (CDC13): 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); 3.53 (dd, 2H, J = 10.4, 7.3); 4.55 (dd, 1H, J = 8.6, 4.1). (2S) -1- (3, 3-dimethyl-l, 2-dioxopentyl) -2-pyrrole 3-phenyl-1-propyl idincarboxylate (1) A mixture of (2S) -1- (1,2-dioxo-3, 3-dimethylpentyl) -2-pyrrolidinecarboxylic acid (600 mg, 2.49 mmole), 3-phenyl-1-propanol (508 mg, 3.73 mmole), dicyclohexylcarbodiimide) 822 mg; 3.98 mmol), camphorsulfonic acid (190 mg, 0.8 mmol) and 4-dimethylaminopyridine (100 mg, 0.8 mmol) in 20 ml of methylene chloride is stirred overnight under a nitrogen atmosphere. The reaction mixture is filtered through Celite to remove solids and concentrated in vacuo, and the crude material is purified on a flash chromatography column (25% ethyl acetate in hexane) to obtain 720 mg (80%) of the example 1 as a colorless oil. lH NMR (CDC13): d? .84 (t, 3H); 1.19 (s, 3H); 1.23 (s, 3H); 1.70 (dm, 2H); 1.98 (m, 5H); 2.22 (m, 1H); 2.64 (m, 2H); 3.47 (m, 2H); 4.14 (m, 2H); 4.51 (d, 1H); 7.16 (m, 3H); 7.26 (m, 2H).

Figure 1. GPI 1046 protects retinal ganglion cells against degeneration after retinal ischemia ^ -l --- M - J The retinal ganglion cells were labeled retrogradely in adult rats by bilateral injection of fluoro-gold into their lateral geniculate nuclei. The ganglion cells labeled in a normal rat retina appear as white profiles against a black background (Figure 1A). Complete retinal ischemia is produced by infusing normal saline solution into the retinal vitreous cavity of each eye until the intraocular pressure exceeds the arterial blood pressure. At 28 days after the ischemic episode, extensive degeneration of the retinal ganglion cells occurs by massive reduction in the density of the cells marked with fluoro-gold (figure IB). The administration of GPI 1046 (10 mg / kg, sc) 1 hour before the ischemic episode at 10 mg / kg / day for the following four days produces remarkable protection for a large proportion of the vulnerable ganglion cell population (Figure 1C). ).

Figure 2. GPI 1046 prevents the degeneration of optic nerve and myelin axons after retinal ischemia The examination of the optic nerves of the same cases of retinal ischemia shows that GPI 1046 produces a remarkable protection of the optic nerve element preventing ischemic degeneration. Toluidine blue staining of cross sections of the optic nerve embedded epon .UMaa * ^ ...! ^! ---------) shows the detail of the myelin sheaths (white circles) and the optic nerve axons (black centers) in the normal rat optic nerve. The optic nerves of the vehicle-treated cases examined 28 days after 1 hour of retinal ischemic episode are characterized by a decreased density of optic nerve axons and the appearance of numerous degenerative myelin figures (white shiny circles filled). Treatment with GPI 1046 protects most of the optic nerve axons preventing degeneration and also significantly decreases the density of degenerative myelin figures.

Figure 3. GPI 1046 provides moderate protection against the death of retinal ganglion cells after transection of the optic nerve.

Complete transection of the optic nerve 5 mm from the ocular globe produces massive degeneration of the retinal ganglion cells which represents the loss of > 87% of the population of normal ganglion cells 90 days after damage (Table 1). Some ganglion cells pre-labeled with reserved fluoro-gold are present in vehicle-treated cases (large white figures) between a population of small microglia that digests the degenerating cell debris and that capture the fluoro-gold label (Figure 3A) . Treatment with GPI 1046 for 14 days results in a small but not significant increase in the density of retinal cells of the ganglion that survive 90 days after the transection (table 1), but treatment with 5 GPI 1046 for the first 28 days after the transection, it produces a moderate but significant protection of 12.6% of the population of vulnerable ganglion cells (Table 1, Figure 3B).

Figure 4. The duration of treatment with GPI 1046 significantly affects the process of axonal degeneration of the optic nerve after transection.

Examination of density of an axon of an optic nerve in the proximal stump of the optic nerve in the same cases shows a more remarkable protection provided by the GPI 1046 treatment. Within 90 days after the transection some axons of the ganglion cells remain inside the optic nerve (Figure 4B). ) , what represents only 5.6% of the normal population. The loss of axons reflects both the death of retinal ganglion cells and the regression of "retroteño" of the axons of -70% of the small population of surviving ganglion cells within the retina itself (table 1). He treatment with GPI 1046 during the first 14 days after -, Jt. < - ~ - »Sfc • -. of the optic nerve transection produces a small but significant protection of 5.3% of the optic nerve axons (figure 4D, table 1), but treatment with the same dose of GPI 1046 for 28 days results in the protection of the axons of the optic nerve. optic nerve for the great majority (81.4%) of the reserved reticular ganglion cells (Figure 4C, Table 1).

Figure 5. Treatment with GPI 1046 produces a greater effect on optic nerve axons than ganglion cell bodies.

This summary figure shows data of the ganglion cell protection of Figure 3 and photomicrographs of greater magnification of the protection of the optic nerve action (Figures 5A and B, upper panels). Treatment for 28 days with GPI 1046 produces a significant increase in the density of axons of optic nerves of large caliber and particular medium and small (Figure 5C and D, lower panels).

Figure 6. Treatment with GPI 1046 for 28 days after the transection of the optic nerve prevents the degeneration of myelin in the proximal stump.

The fascicles marked by immunohistochemistry of myelin basic protein ("islets" marked darker) of myelinated axons in the normal optic nerve (Figure 6A, top left). At 90 days after the extensive transection, the degeneration of myelin is evident in cases treated with vehicle, characterized by the loss of fascicular organization and the appearance of numerous dense and large degenerative myelin figures (Figure 6B, top right). Treatment with GPI 1046 during the first 14 days after the transection of the optic nerve does not alter the pattern of myelin degeneration (Figure 6A, lower left panel), and provides an insignificant quantitative recovery of 1.6% in myelin density (table 1) . The extension of treatment with GPI 1046 in the course of the first 28 days after the transection of the optic nerve produces a remarkable conservation of the pattern of fascicular staining for the basic myelin protein in the proximal stump of the optic nerve and decreases the density of the degenerative myelin figures (figure 6D, lower right panel), representing a recovery of '70% myelin density (table 1).

Figure 7. Oligodendroglia marked by immunohistochemistry of FKBP-12 (large dark cells with fibrous processes), the cells which produce myelin, are located between the fascicles of the fibers of the optic nerve and also some axons of the optic nerve.

Figure 8. Treatment with GPI 1046 for 28 days after the transection of the optic nerve prevents the degeneration of myelin in the distal stump Complete transection of the optic nerve leads to degeneration of the distal segments (axon fragments disconnected from the bodies of the ganglion cells), and the degeneration of their myelin sheaths. At 90 days after the transection (Figure 8B) immunohistochemistry of myelin basic protein shows that there is an almost total loss of the fascicular organization (present in the normal optic nerve, Figure 8A) and 'the presence of numerous myelin figures dense degenerative The quantification shows that the cross-sectional area of the transected distal stump shrinks by 31% and loses approximately 1/2 of its myelin (Table 1). Treatment with GPI 1046 during the first 14 days after the transection does not protect against distal stump shrinkage but slightly increases myelin density, although the density of degenerative myelin amounts remains high (Figure 8C, Table 1). The treatment with GPI 1046 during the first 28 days produces a remarkable protection of the fasicular pattern of myelin labeling, decreasing the density of degenerative myelin amounts, avoiding a shrinkage in the cross section of the distal stump of the transected nerve and maintaining the levels of myelin at -99% of normal levels (figure 8D, table 1), Figure 9. 28-day treatment with GPI 1046, treatment begins 8 weeks after the onset of streptozotocin-induced diabetes, decreases the degree of neovascularization in the inner and outer retina and protects the neurons in the inner nuclear layer (INL) and the ganglion cell layer (GCL) preventing degeneration.

Negative images of tangential retina sections stained with cresyl violet show pericaria in all three cell layers (Figure 9A). The retinas of animals treated with streptozotocin and those given only vehicle (Figure 9B) show LOS of ONL and INL cells, decreased thickness of the outer plexiform layer (the dark area between ONL and INL), and a marked increase in the size and density of the blood vessels of the retina (large black circular contours) in INL, OPL, ONL, and the photoreceptor layer (PR, gray diffuse area above ONL). Treatment with GPI 1046 reduces neovascularization (ie prevents the proliferation of blood vessels) in PR, ----------- to --------- i ------------------- M ---- &- --- ONL, OPL and INL. Although GPI 1046 does not appear to protect against neuronal loss in the ONL, neuronal loss appears to decrease in both the INL and GCL compared to controls treated with streptozotocin / vehicle.

Example 20 In vivo tests of retinal ganglion and optic nerve axon cells The degree of reduction of degeneration or prevention in retinal ganglion cells and optic nerve axons was determined in a model of vision loss using surgical optic nerve transection to simulate mechanical damage to the optic nerve. This produces that several ligands of FKBP of neuroinmunofilina in the neuroprotection of retinal ganglion cells and in the density of the optic nerve axon is determined experimentally, when comparing the ligand treatments with FKBP of neuroinmunofilina at 14 days and 28 days. The effects of treatment with FKBP ligands of neuroimmunophilin on retinal ganglion cells and on optic nerve axons are correlated.

Surgical Procedures Adult male Sprague Dawley rats are anesthetized (3 months old), 225-250 grams) with a mixture of ketamine (87 mg / kg) and xylasin (13 mg / kg). The retinal ganglion cells are previously labeled by bilateral stereotaxic injection of the retrogradely fluorescent fluoro-gold transported marker (FG, 0.5 microliter of a 2.5% solution in saline) at the LGNd coordinates (4.5 mm posterior, 3.5 mm lateral, 4.6 millimeters below the dura). Four days later, the rats labeled with FG underwent a second surgery for microsurgical bilateral intraorbital optic nerve transection 4-5 millimeters behind the orbit. The experimental animals were divided into six experimental groups of six rats (12 eyes) per group. One group received neurokinmunophilin FKBP ligand (10 milligrams per kg per day, was in PEG vehicle (20 percent propylene glycol, 20 percent ethanol and 60 percent saline)) for 14 days. The second group received the same dose of FKBP ligand of neuroinmunofilin for 28 days. 20 Each treated group had a corresponding control group submitted to false surgery and transection, which received a corresponding dosage of 14 or 28 days only with a vehicle. All the animals were sacrificed 90 days 25 after the transection of the optic nerve and administered by ^ 2 ------------- ¿---------- k ---------------------- -----------------------? perfusion pericardially formalin. All eyes and optic nerve stumps were removed. Cases of the study are excluded if the optic nerve vasculature is damaged or if it is absent marked by FG in the retina.

Retinal Ganglion Cell Accounts The retinas of the eyes are removed and prepared for complete analysis. For each group, five eyes with dense and intense FG marking are selected for quantitative analysis using a 20-magnification objective. Digital images are obtained from five fields in the central retina (3-4 millimeters radial to the tip of the optic nerve). The ganglion cells with large (> 18 μm), medium (12-16 μm) and small (<10 μm) ganglion cells and the microglia are counted in five fields of 400 μm by 400 μm per case, and 5 cases per group.

Optical Nerve Examination Stumps of proximal and distal optic nerve were identified, measured and transcribed to saline solution with 30% sucrose. The proximal stumps of five nerves were blocked and fixed to a mandrel, and cross sections of 10 micrometers were cut in a ciostat; One in ten sections were saved by group. Sections include the 1-2 mm region behind the orbit that reacted for neurofilament immunohistochemistry RT97. An optic nerve axon density analysis was performed using a 63-fold oil immersion lens, a Dage 81 camera and a Simple Image Analysis image analysis program. Optic nerve axons positive to RT97 are counted in three fields of 200 μm by 200 μm, per nerve. The area of the nerve also determines for each case an enlargement of 10. As shown graphically in Table I and Figure 10, the course of 14-day treatment with FKBP ligand of neuroinmunofilin provides moderate neuroprotection of retinal ganglion cells. observed 28 days after the optic nerve transection. However, at 90 days after the transection, only 5% of the ganglion cell population remains viable. At 90 days after the optic nerve transection the number of axons that persist in the proximal stump of the optic nerve represent approximately half of the number of surviving ganglia cells in groups of animals that received only vehicle or in the course of 14 days. days of treatment with a neurokinmunophilin FKBP ligand. These results indicate that more than half of the axons of transected ganglion cells retract past the head of the optic nerve, and that treatment with a FKBP ligand of neuroimmunophilin during the first 14 days after optic nerve transection is not enough to suppress this retraction. As shown graphically in Table I in Figure 10, a longer treatment with FKBP 5 ligand of neuroimmunofilin during the course of 28 days of treatment produces a moderate increase in the neuroprotection of retinal ganglion cells. Approximately 12% of the vulnerable retinal ganglion cell population is protected. A similar proportion (-50%) of the density reserve of the optic nerve axon is also observed. These results demonstrate that the initial result of extending the duration of treatment with FKBP ligands of neuroimmunophilin at 28 days of transection completely suppresses the regression of damaged axons for essentially the entire surviving population of the retinal ganglion cells. Additional results are established in figures 11 and 12. --ie? > a ----- tt-ai-t-- Table I Effect of prolonged treatment with GPI 1046 on survival of retinal ganglion cells, preservation of the optic nerve axon and myelination 90 days after the transection of the optic nerve ro s. * s gn canc to p < 0.001 x Mean density + SEM of retinal ganglion cells (RGC) labeled with fluoro-gold in 400 μm x 400 μm sample grid fields. 2D mean + SEM of optic nerve (ON) axons marked with neurofilament antibody RT97 in regions of interest of 200 μm x 200 μm. 'estimated for a region of 200 μm x 200 μm in normal optical medium assuming 120,000 RGC axons in a rat normal optic nerve, measured which is 0.630 mm2 in a medium cross-sectional area. 3adjusted for the diameter of the optic nerve 4calculated by multiplying the axonal density by the ON area 5determined from a 20X analysis of the% coverage of the cross-sectional area of the optic nerve. t 0 0 Example 21 A patient suffers from macular degeneration. A derivative as identified above may be administered to the patient, alone or in combination with one or more additional neopy factors, or a pharmaceutical composition comprising the same. A reduction of vision loss, prevention of vision degeneration or promotion of vision regeneration is expected after treatment.

Example 22 A patient suffers from glaucoma, resulting in the covering of the optic nerve disc and damage to the nerve fibers. A derivative as identified above, alone or in combination with one or more additional nephous factors, or a pharmaceutical composition comprising the same, can be administered to the same patient. A reduction in vision loss, prevention of vision degeneration or promotion of vision regeneration is expected after treatment.

Example 23 A patient suffers from cataracts that require surgery. After surgery, the patient may be administered a derivative as identified above, alone or in combination with one or more additional neopy factors, or a pharmaceutical composition comprising the same. A reduction in vision loss, prevention of vision degeneration or promotion of vision regeneration is expected after treatment.

Example 24 A patient suffers from damage or blockage of the retinal blood supply in relation to diabetic retinopathy, ischemic optic neuropathy or retinal artery or blockage of the vein. A derivative as identified above, alone or in combination with one or more additional nephous factors or a pharmaceutical composition comprising the same may be administered to the patient. A reduction in vision loss, prevention of vision degeneration or promotion of vision regeneration is expected after treatment.

Example 25 A patient has a detached retina. A derivative as identified above may be administered to the patient, alone or in combination with one or more additional neopy factors or a pharmaceutical composition comprising the same. A reduction in vision loss, prevention of vision degeneration or promotion of vision regeneration is expected after treatment.

Example 26 A patient suffers from tissue damage caused by inflammation associated with uveitis or conjunctivitis. A derivative as identified above, alone or in combination with one or more additional nephous factors or a pharmaceutical composition comprising the same may be administered to the patient. A reduction in vision loss, prevention of vision degeneration or promotion of vision regeneration is expected after treatment.

Example 27 A patient suffers from photoreceptor damage caused by chronic or acute exposure to ultraviolet light. A derivative as identified above may be administered to the patient, alone or in combination with one or more additional neopy factors or a pharmaceutical composition comprising the same. A reduction in vision loss, prevention of vision degeneration or promotion of vision regeneration is expected after treatment.

Example 28 A patient suffers from optic neuritis. A derivative as identified above may be administered to the patient, alone or in combination with one or more additional neopy factors or a pharmaceutical composition comprising the same. It is expected that after the treatment a reduction in vision loss, prevention of vision degeneration or promotion of vision regeneration. ------ i ----------.

Example 29 A patient suffers from tissue damage associated with a "dry eye" disorder. A derivative as identified above may be administered to the patient, alone or in combination with one or more additional neopy factors or a pharmaceutical composition comprising the same. A reduction in vision loss, prevention of vision degeneration or promotion of vision regeneration is expected after treatment.

Example 30 The efficacy of the representative compounds of different immunophilin ligand series to protect axons of the retinal ganglion cell from degeneration after transection of the optic nerve is set forth in Table II.

TABLE II Efficacy of the representative compounds of different immunofilin ligand series in the protection of retinal ganglion cell axons preventing degeneration after transection of the optical medium - "-" • "* Compound Structure Comments Axon density RT96 + TGC 14 days after the ON transection (% of rescued axons ON) Acid dimethyl ketone 34 0% pipecolic + 4 8% SEM Ci rotamase > 10 000 nM Slow Aclaram = ', μl / m? N - ^ - te - É ------- áa- «i-i --- 1 ------- É-ÉÉÉÍÍÉ. ^ ------- «1 -----.

TABLE V continuation Compound Structure Comments Density dtl a.?n RT96 + TGC 14 days after the ON transection (% of axons rescued ON) M I loester -63% Ci rotamasa = 7 nM + 39% GM Clearance = 125 μl / min Ci rotakinase = 722 nM Aclaram? Epto = 2l 9 μl / m? N ------------------- Example 31 THE FKBP NEUROINMUNOFYLIN LIGAND, GPI-1046 IMPROVES THE SURVIVAL OF RETINAL GANGLION CELLS AND ELIMINATES THE AXONAL RETROTEINING AFTER OPTICAL NERVE TRANSDUCTION Transection of the mammalian optic nerve results in a short period of abortive regeneration, but most axotomized neurons die and the axons of many persistent ganglion cells stain in the back beyond the head of the optic nerve. The present example is designed to examine the neuroprotective effects of GPI-1046 after the transection of the optic nerve. The retinal ganglion cells in adult male Spague Dawley rats are retrogradely labeled by fluoro-gold injection in the LNGd and four days later the 5 mM optic nerves are transfected behind the balloon. Groups of animals received GPI-1046, 10 mg / kg '/ day, s.c., or vehicle, for 28 days. All experimental animals and controls were sacrificed 90 days after transection. At 90 days only - 10% of the population of ganglion cells labeled with FG survive, but less than half of these neurons maintain axons that extend past the head of the optic nerve, as detected by filament immunohistochemistry RT97. Treatment with GPI-1046 produces a moderate degree of pericardial neuroprotection, reserving 25% of the population of ganglion cells and retaining the axons of virtually all protected neurons in the proximal stump of the transected nerve. These results indicate that treatment with FKBP's neuroimmunophilin ligand, GPI-1046, produces a fundamental alteration in the pathological processes after damage to the CNS tracts. These results also demonstrate that the small molecule FKBP neuroinmunophilin ligand, GPI 1046, enhances the outgrowth of neurites in culture, improves peripheral nerve regeneration and stimulates outbreaks within the CNS after partial deafferation.

Example 32 THE NEUROINMUNOFILIN LIGANDS PROMOTE THE RECOVERY OF PERIPHERAL SENSORIAL NEUROPATHY ASSOCIATED WITH DIABETES INDUCED BY STREPTOZOTOCINE Peripheral neuropathy is a common debilitating complication of type 2 diabetes in approximately 30-40% of diabetic patients. It is known that neurotrophic factors such as nerve growth factor (NGF) promote developmental survival and adult neurons of the peripheral nervous system (PNS), and have also been evaluated as treatments for diabetic peripheral neuropathy. Some of the selective ligands of the neuroimmunophilin FKBP-12 such as the small molecule of GPI-1046 have also been shown to promote repair and regeneration in the central and peripheral nervous systems (Proc. Nat'l. Acad. Sci. USA 94 , 2019-2024, 1997). In this example, the potential therapeutic effects of GPI-1046 were evaluated to determine its ability to improve sensory function in the diabetic rat induced by streptozotocin. The procedure involves using rats Male Winstar who are given a single injection of streptozotocin (65 mg / kg, i.v.). Weekly blood glucose levels are determined during the first three weeks and in the last week of the experiment. The animals are evaluated weekly for signs of sensory neuropathy using the testing procedures of the conventional hotplate apparatus and the tail tapping apparatus. After six weeks, treatment is started either with GPI-1046 or with vehicle. The results show that behavioral tests using the hot plate and tail tapping apparatus indicate an improvement in latency in injured animals treated for 6 weeks with GPI 1046 at 10 mg / kg, s.c. The results also show that GPI-1046 decreases the sequelae of diabetic sensory neuropathy behavior and may offer some relief for patients suffering from diabetic peripheral neuropathy.

Morris Watermaze test procedure / aging and memory Old rodents that show remarkable individual differences in the performance of a variety of behavioral tasks, including spatial differentiation of two selections in a modified T-maze, spatial differentiation on a circular task platform, passively avoiding, radial maze tasks, and navigation space in a pool. In all these tasks, a proportion of old rats or mice works as well as the vast majority of young control animals, while other animals show severe damage in memory function compared to young animals. For example, Fischer et al have shown that the proportion of rats that show significant damage in space navigation increases with age (Fischer et al., 1991b) with 8% of the total of 12 months of age, 45% of 18 months of age, 53% of 24 months of age and 90% of all 30-month-old rats that show damage in the spatial acquisition of the Morris water maze tasks in relation to the young controls. Specifically, the learning and spatial memory of a rodent decline during aging is accepted by many researchers as an intriguing correlative animal model of human senile dementia. The cholinergic function in the hippocampus has been extensively studied as a component of rodent spatial learning, and a decline in cholinergic function of the hippocampus parallel with the development of learning and memory damage has been noted. In addition, it has been shown that other neurotransmitter systems contribute to spatial learning and that they also decline with age, such as the dopaminergic or noradrenergic, serotonergic and glutamatergic systems. In addition, reports regarding deficiencies related to the age of induction of long-term potentiation (LTP) of the hippocampus, a reduction in the frequency of the theta rhythm, a loss of plasticity dependent on the experience of the hippocampal placement units and reductions in hippocampal protein kinase C coincide with the concept that a single underlying pathology can not be identified as the cause of age-related behavior damage in rodents. However, different experimental therapeutic solutions have been carried out to improve memory function in old rodents and have shown advances towards the cholinergic hypothesis. The Morris water labyrinth is widely used to determine the formation and retention of spatial memory in experimental animals. The test depends on the ability of the animal to use visual spatial information in order to locate an escape platform submerged in a water tank. It is important that the tank itself lacks as much specific visual characteristics as possible 10 - therefore, it is always circular, the sides are kept smooth and of a uniform neutral color, and the water becomes opaque with a pigment soluble in non-toxic water or with powdered milk. This is to ensure that the animal navigates only through the use of more distant visual cues or through the use of cues within the labyrinth that are provided specifically by the experimenter. The tank fills up to a level which forces the animal to actively swim. The normal mice and rats react adversely to the swim portion of the test 20 and prepare or remain on the escape platform from which they are removed to a heated resting cage. If the platform is visible (that is, it is above the surface), the animals placed in the tank will quickly learn to go to the platform and prepare 25 in it. The test with a visible platform also ensures ^ B ^^ i? Mimm? Ám ?? - mm-? ^ - ^ - ^^ - ^ * ^ - ^^ ^ ^ - ^ - ^ ~ ^^^^ - ^ ^ - ^ ~ - ~~~ ~ - l I - f. --r-rrit that the experimental animals are not blind and show enough motivation and histamine to perform the task, which may be important in experiments involving old rodents. If the platform is invisible (that is, it is submerged just below the surface), normal animals learn to use distant visual cues in the test room for orientation in the test tank and, when placed in the tank, They quickly direct to the approximate location of the platform and circle in that area until the platform is located. The trajectory, speed and swim time of the animals are monitored with a camera on the roof for later computer analysis. During the development of several successive tests, spatial learning can be defined as a decrease in swim distance or elapsed time, from its placement in the tank to the escape in the invisible platform. The test can be adapted to determine several aspects of spatial memory: a) acquisition of a key task, where the ability of the animal to relate a visual key directly to the escape platform depends on the cortical function (ie, place a balloon on the escape platform and the animal learns to follow this key to find the platform); b) acquisition of a spatial task, where the animal's ability to learn the position of an escape platform submerged on the basis of a combination of distant visual cues depends on the function of the hippocampus (ie, the animal learns to triangulate its position) in the tank by visually aligning the paper-tower spout with the door and the ceiling lamp); c) retention of a successfully acquired spatial task, which depends predominantly on the cortical function (that is, the animal must remember the spatial location of the platform for several weeks); d) a reverse task dependent on the hippocampus where the animal must reacquire a new spatial platform location (ie, the platform moves to a new position between swimming trials and the animal must abandon its previous search strategy and acquire a new) . The different modifications of the Morris water maze procedure can be applied in sequence to the same set of experimental animals and allow a deep characterization of its spatial memory functioning and its decline with normal aging. In addition, such a series of sequential memory tests diffuses some light regarding the functional integrity of the specific brain systems involved in the acquisition and retention of spatial memory (for example, rats with cholinergic lesions of the hippocampus may recall a platform position acquired weeks before. , but they persevere on the location of the previous platform after the platform moves).

Example 33 EFFECTS OF THE CHRONIC ADMINISTRATION OF GPI-1046 ON SPACE LEARNING AND MEMORY ON OLD RODENTS This example shows the effects of chronic treatment with the ligand of FKBP available systemically, GPI-1046 on spatial learning and memory in old rodents. The procedure involves using male mice of the C57BL / 6N-Nia strain of three months of age (young) and 18-19 months of age (old) which are used to the conventional and well-known Morris water maze during 4 trials / day, with a visible platform training phase of 3-4 days. Subsequent spatial acquisition tests are carried out as follows: All mice are given 4 trials / day (block) for 5 days. The maximum swim time is 90 seconds. Old mice are assigned to an "old damaged" group if their performance during blocks 4 or 5 of the acquisition phase is <1 standard deviation above the mean of the "young" mice and to an "old undamaged" group if its performance is < 0.5 standard deviations above the mean of the "young" mice. The groups of old animals are then divided into statistically similar groups "GPI-1046" and "vehicle". Daily treatment with 10 mg / kg of GPI-1046 starts three days after completing the training acquisition, and continues during the retention test. The retention test begins after three weeks of dosing using the same methods as in the acquisition phase. The swimming distances (cm) were analyzed in a 7 X 5 ANOVA that includes groups and blocks (1-5) as factors in the analysis, treating the blocks as a repeated measure. The results show that the planned contrasts reveal that there are significant differences between the "young" and "old damaged-vehicle and GPI-1046" groups at the end of the acquisition phase, lf = 26.75, P = 0.0001 and F- 58 = 17.70 , P = 0.0001, respectively. Although there is no significant difference between the two "old damaged" groups, F 58 = 0. 67, P = 0.42. However, during the retention test, the treated animals "old damaged-vehicle" performed in a significantly poorer way compared to the "old damaged - GPI-1046" and the young animals, F1-69 = 8. 11, P = 0.006 and F1 69 = 25.45, P = 0.0001 respectively. There is no statistically significant difference between the "young" and "old damaged" groups - GPI-1046"during the retention phase, F1-69 = 3.09, P = 0.08 In summary, the systemic treatment with GPI-1046 significantly improves the performance of spatial memory of mice with age-related spatial memory damage.5 The invention has therefore been described, and it will be apparent that it can vary in many ways.Such variations are not considered as a deviation of the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims.It is noted that in relation to this date, the best method known by the applicant to implement the cited invention, is that which is clear from the present description of the invention. ^ y ^^^ Jgg ^

Claims

CLAIMS Having described the invention as above, the content of the following 5 claims is claimed as property:

1. A method to treat a vision disorder, improve vision, treat damage to memory or improve the functioning of memory in an animal, characterized in that 10 comprises administering to the animal an effective amount of a non-immunosuppressive FKBP neuroimmunophilin ligand.

2. The method according to claim 1, characterized in that the neuroimmunofilin of 15 FKBP is FKBP-123.

A pharmaceutical composition for treating a vision disorder, improving vision, treating damage to memory or improving memory performance in an animal, Characterized in that it comprises: a) an amount effective to treat a vision disorder, improve vision, treat damage to memory or improve memory performance in an animal of a neuroimmunophycin ligand of FKBP not 25 immunosuppressant; Y UM -------- I b) a pharmaceutically acceptable carrier.

4. The pharmaceutical composition according to claim 3, characterized in that the neuroimmunophilin of FKBP is FKBP-12.