MXPA00013032A - N-linked urea or carbamate of heterocyclic thioesters for vision and memory disorders - Google Patents

Abstract

This invention relates to pharmaceutical compositions and methods for treating a vision disorder, improving vision, treating memory impairment, or enhancing memory performance using N-linked urea or carbamate of heterocyclic thioesters derivatives.

Description

- > N-LINKED UREA OR CARBAMATE OF HETEROCICLES TIOESTERS FOR DISEASES OF VISION AND THE MEMORY BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to pharmaceutical compositions and methods for treating vision loss, preventing degeneration of vision, and promote the regeneration of vision ("neopsis") using small molecule, low molecular weight derivatives. 2. Description of the Related Art 15 The visual system is composed of the eyes, ocular attachment and visual routes. The dysfunction of the visual system can lead to permanent or temporary visual diminution, that is, a deviation from the normal in one or more functions of the eye. Visual diminution manifests itself in various forms and includes a wide range of dysfunctions and visual disturbances. Without limitation, these dysfunctions and disturbances include partial or total loss of vision, the need to correct visual acuity for near and far objects, loss of visual field, decreased eye mobility without diplopia (double vision), diminished or skewed perception of color, adaptation limited to -,? ..,: - * ...-. A .....? R ..,. .i "iii - naMah ^^^^ M ^^^^^^^ and ^ light and darkness, diminished accommodation, metamorphosis distortion, diminished binocular vision, accommodation paresis, iridoplegia, entropion, ectropion, epiphora, lagophthalmos, and cicatrization. See Physicians' Desk Reference (PDR) for Ophthalmology, 16th Edition, 6:47 (1988). The visual system can be adversely affected by various ophthalmological disorders, diseases, wounds and complications, including without limitation, genetic disorders; [non-genetic disorders] disorders associated with aging or degenerative diseases; disorders that correlate to the physical wound of the eye, head, or other parts of the body resulting from external forces; disorders resulting 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 composed of numerous components. The visual decrease may involve the entire visual system, some component or any combination of components, depending on the precise nature of the circumstances. The eye is composed of a lens, which is suspended in Zinn's zonules and is focused by the ciliary body. The ciliary body also secretes accuse humor, which fills the posterior chamber, passes through the pupil into the anterior chamber, then drains mainly through the Schlemm's canal. The iris regulates the amount of light that enters the eye by adjusting the size of its central opening, the pupil. An image ^ JJKjy visual focuses on the retina, the central fovea being the area of the retina of sharpest visual acuity. The conjunctiva is the mucous membrane which covers the eyelids and the eyeball, and ends abruptly in the limbus of the conjunctivae, the end of the conjunctiva that overlaps the cornea. The cornea is the clear transparent anterior portion of the fibrous covering of the eye; it is important for the refraction of light and is covered with an epithelium that differs in many aspects from the conjunctival epithelium. The retina is the innermost light sensitive portion of the eye, which contains two types of photoreceptors, cones, which are responsible for color vision in brighter light, and rods, which are essential for vision in dim light but does not perceive colors. After the light passes through the cornea, the lens system, and the vitreous humor, enters the retina from the inside; that is, it passes through the cells of the ganglion and nerve fibers, and the plexiform layers, internal and external, the inner and outer nuclear layers, and the internal and external limiting membranes before it finally reaches the layer of photoreceptors located nearby. from the outside of the retina, just inside the outermost pigmented epithelium layer. Cells of the pigment epithelium layer act as an anatomical barrier for liquids and substances located on the outer side of the eye, forming the "blood-retinal" barrier, and provide nutrition, oxygen, a source of functionally useful substances such as vitamin A , and phagocytosis of the decomposition products of the photoreceptor cells. There is no anatomical connection between the pigmented epithelium and the photoreceptor layer, allowing 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 optic nerve fibers, and finally in the cerebral cortex. The rods and cones contain molecules that decompose on exposure to light and, in the process, excite the nerve fibers that advance from the eye. The molecule in the rods is rodoxin. The three light sensitive molecules in the cones, collectively called iodopsin, have compositions only slightly different from those of the rodoxin and are excited maximum by red, blue or green light respectively. Neither rods nor cones generate action potentials. Rather, the hyperpolarization of the membrane induced by light generated in the external photosensitive segment of a rod cell or cone is transmitted from the outer segment to through the internal segment to the synaptic body by direct conduction of the electric voltage itself, a process called electrotonic conduction. In the synaptic body, the potential of the membrane controls the release of an unknown transmitter molecule. In low light, the membranes of the cane cell and cone are depolarized and the speed of "i '" "*" "" * ^' - - "*" "^ j ^ in the release of the transmitter is the largest, the hyperpolarization induced by light causes a marked decrease in the release of transmitting molecules. The cells in the cane and cone induce signals in the bipolar neurons and the horizontal cells.The signals in both cells are also transmitted by electrotonic conduction and not by action potential.The bipolar cane neurons connect with as many as 50 cane cells, While diffuse and dwarf bipolar cells connect one or more cone cells, a depolarizing bipolar cell is stimulated when its connecting rods or cones are exposed to light.The release of transmitting molecules inhibits the depolarizing bipolar cell. When the rods and cones secrete large amounts of transmitting molecules, the depolarizing bipolar cells are inhibited. Decrease in the release of transmitting molecules from rods and cones reduces the inhibition of the bipolar cell, allowing it to become aroused. In this way, positive and negative signals can be transmitted through different bipolar cells from the rods and cones to the amacrine and ganglion cells. As its name suggests, horizontal cells project horizontally into the retina, where they can synapse with canes, cones, other horizontal cells or a combination of cell types. The function of the horizontal cells is not clear, although some mechanism has been postulated in the convergence of the photoreceptor signaling. All types of bipolar cells connect with ganglion cells, which are of two main types. The 5 cells of the type A ganglion connect predominantly with bipolar rod cells, while the cells of the type B ganglion connect predominantly with diffuse and dwarf bipolar cells. It seems that type A ganglion cells are sensitive to contrast, light intensity, and movement perception, while that type B ganglion cells seem more interested in color vision and visual acuity. Like horizontal cells, amacrine cells synapse horizontally with several to many other cells, in this case bipolar cells, ganglion cells, and other cells of amacrine. The function of the amacrine cells is unclear. The axons of the ganglion cells carry signals within the nervous fiber layer of the eye, where the axons converge on fibers which converge additionally on the optic disc, where they leave the eye as the nerve optical. 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 nerve impulses at an average baseline rate of about 5 per second. The visual signal is overlays on this level of baseline stimulation of - * - * - - - - ganglion cell It can be either an excitation signal, with the number of impulses increasing above the baseline rate, or an inhibition signal, with the number of nerve impulses decreasing below As a part of the central nervous system, the eye is in some ways an extension of the brain, as such it has a limited capacity for regeneration.This limited regenerative capacity further complicates the challenging task of improving the addition, resolve the dysfunction of the visual system and / or treat or prevent ophthalmological disorders. Many eye disorders such as photic wound of the retina, eye injury induced by retinal ischemia, age-related macular degeneration, eye diseases induced by free radicals, as well as numerous other disorders, are considered to be completely intractable. Other ophthalmological disorders, for example, disorders that cause permanent visual decline, are corrected only by the use of ophthalmic devices and / or surgery, with varying degrees of success. The immunosuppressant drugs FK506, rapamycin, and Cyclosporin are well known as potent immunosuppressants specific for T cells and are effective against autoimmunity, transplant or graft 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 its derivatives are effective in treating some ophthalmological disorders of these types. It is known that various ophthalmological disorders or vision problems are associated with autoimmune and immunologically mediated activities; in consequence, the immunomodulatory compounds are expected to demonstrate efficiency in treating those types of ophthalmological disorders or vision problems. The effects of FK506, Rapamycin, and related agents in the treatment of ophthalmic diseases are describes in various North American patents (Goulet et al., US Patent No. 5,532,248, Mochizuki et al., US Patent No. 5,514,686, Luly et al., US Patent No. 5,457,111; Russo et al., US Patent No. 5,441,937.; Kulkarni, North American Patent No. 5,387,589; Asakura et al., U.S. Patent No. 5,368,865; Goulet et al., U.S. Patent No. 5,258,389; Armistead et al., U.S. Patent No. 5,192,773; Goulet et al., US Patent No. 5,189,042; and Fehr, U.S. Patent No. 5,011,844). These patents claim the compounds related to FK506 or Rapamycin and describe the known use of compounds related to FK506 or Rapamycin 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. Additionally, the patents cited are "K > ** T-- • *;. ^^^^ A ^ ZyjA ^ V refer to immunomodulatory compounds limited to treating autoimmunity or related diseases, or immunologically mediated diseases, for which the efficiency 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 ophthalmological diseases (Sharpe et al., US Patent No. 5,703,088; Sharpe et al., Patent North American No. 5,693,645, Sullivan, US Patent No. 5,688,765, Sullivan, US Patent No. 5,620,921, Sharpe et al., US Patent No. 5,574,041, Eberle, US Patent No. 5,284,826, Sharpe et al., US Patent No. 5,244,902; Chiou et al., US Patents Nos. 5,198,454 and 5,194,434; and Kaswan, US Patent No. 4,839,342). These patents also refer to compounds for treating autoimmune diseases and cite the known use of cyclosporin, spiperone, buspirone, its derivatives, and other immunosuppressant compounds in the treatment of ocular inflammation and other immunologically mediated ophthalmological diseases. The immunosuppressive compounds described in the prior art suppress the immune system, by definition, and also exhibit other toxic side effects. Accordingly, there is a need for small molecule, non-immunosuppressant compounds, and compositions and methods for use of such compounds that are useful for improving vision; prevent, treat and / or repair the visual decrease or dysfunction of the visual system; and preventing, treating, and / or resolving ophthalmological disorders. There are also a number of patents of non-immunosuppressive compounds that describe methods of use to allow or promote the healing of injuries (whether it is from wounds or surgery); control intraocular pressure (which frequently results from glaucoma); control neurodegenerative disorders of the eye, including damage or injury to retinal neurons, including damage or injury to retinal ganglion cells, and degeneration of the macula; stimulate neurite growth; prevent or reduce damage oxidative damage caused by radicals free; and treating the decreased supply of oxygen and nutrients, as well as the decreased elimination of waste products resulting from 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 the amounts that occur naturally from such r-ritirt-r T 'r * - • -? l - * - * - - - * ----- * molecules, as well as to select specific cells where 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 disease, or stopping or reversing the loss of vision. Specifically, Louis et al., US Patent Nos. 5,736,516 and 5,641,749, describe the use of a glial cell line 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 wounds of the retina. O'Brien, et al., US Patent Nos. 5,714,459 and 5,700,909, describe the use of a glycoprotein, saposin, and its derivatives to stimulate neurite growth and increase myelination. To stop or reverse the degeneration of retinal neurons, LaVail et al., US Patent No. 5,667,968, discloses the use of a variety of neurotrophic proteins, including neurotrophic factor derived from the brain, ciliary neurotrophic factor, neurotrophin 3 or neurotrophin-4, acidic or basic fibroblast growth factors, interleukin, tumor necrosis factor-a, insulin-like growth factor-2, and other growth factors. Wong et al., US Patent No. 5,632,984, describes the use of interferons, especially interferon a-2a, to treat the symptoms of macular degeneration by reducing hemorrhage. • lIiÜ MtfM-1 and limiting neovascularization. Finally, Wallace et al., US Patent No. 5,441,937, describes the use of a lung-derived neurotrophic factor (NTF) to maintain the functionality of ciliary ganglion cells and parasympathetic neurons. A key feature of the factors derived from specific cell lines is their location in specific cell lines or tissues; Systemic treatment with these molecules would run a substantial risk of unwanted, and potentially dangerous, effects on cell lines where the genes encoding these molecules are inactive. Similarly, hormones and growth factors frequently activate a large number of genes in many cell lines; again, the non-localized application of these molecules would run 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 above. Some others are not immunosuppressants and claim the ability to treat cell degeneration; and in some cases it promotes cellular regeneration, more frequently in the context of its antioxidant properties.

Specifically, Tso et al., US Patent No. 5,527,533, describes the use of astaxanthin, an antioxidant carotenoid, to prevent or reduce photoreceptor damage resulting from the presence of free radicals. Similarly, Babcock 5 et al., U.S. Patent No. 5,252,319, discloses the use of antioxidant amlnosteroids to treat eye diseases and wounds, by increasing resistance to oxylative damage. Freeman, US Patent No. 5,468,752, describes the use of antiviral phosphonylmethoxyalkylcytosine to reduce pressure abnormally increased intraocular. Hamilton and Steiner describe in US Pat. No. 5,614,547 novel carboxylated pyrrolidine compounds which bind to the immunophillin 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 structure of small molecule and non-inmusupresor properties differentiates them from the FK506 and the related immunosuppressant compounds found in the prior art. Additionally, these compounds can be differentiated from the non-immunosuppressive compounds used to treat vision disorders because of their novel molecule structure. small and its lack of general systemic effects. The ^^ & ¿^ ^^^ ...-, »-. : z.-.- .-. . .. .. ........ -Ay, y- ~ ITL Hormones, growth factors, cytokines, and signaling molecules that occur naturally are usually multifunctional and activate many genes in various cell lines. The present compounds, in this way, do not 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 cell line molecules into other cell lines where they do not occur naturally.

PREVIOUS ART OF THE INVENTION The present invention relates to a method for treating a disorder of vision, improving vision, treating memory depletion, or increasing memory performance in an animal comprising administering to the animal an effective amount. of an N-linked urea or carbamate of a heterocyclic thioester compound. The present invention additionally relates to a pharmaceutical composition for treating a disorder of vision or improving vision or treating memory depletion or increasing memory performance in an animal comprising (i) an effective amount of a urea or N-linked carbamates of a heterocyclic thioester compound to treat a vision disorder or improve vision or treat memory depletion or increase memory performance in an animal; and (ii) a pharmaceutically acceptable carrier.

Brief Description of the Drawings Figures 1A, B and C show that GPl 1046 protects retinal ganglion cells against degeneration after retinal ischemia. Figure 2 shows that GPl 1046 prevents degeneration of optic nerve and myelin axons after retinal ischemia. Figure 3 shows that GPl 1046 provides moderate protection against death of retinal ganglion cells after transection of the optic nerve. Figure 4 shows that the duration of treatment with GPl 1046 significantly affects the degeneration process of the optic nerve axon after transection. Figure 5 shows that treatment with GPl 1046 produces a larger effect on axons of the optic nerve than bodies of ganglion cells. Figure 6 shows that treatment with GPl 1046 for 28 days after transection of the optic nerve prevents myelin degeneration in the proximal stump. Figure 7 shows that FKBP-12 immunohistochemistry marks oligodendroglia (large dark cells with fibrous processes), cells that produce myelin, located between the fascicles of optic nerve fibers, and also some axons of the optic nerve. Figure 8 shows that treatment with GPl 1046 for 28 days after the transection of the optic nerve prevents the degeneration of myelin in the distal stump. Figure 9 shows that the 28-day treatment with GPl 1046 treatment that started 8 weeks after the onset of diabetes induced by streptozotocin decreases the degree of neovascularization in the internal and external retina and protects the neurons in the inner nuclear layer (INL) and the ganglion cell layer (GCL) of degeneration. Figure 9a: A - External Nuclear layer (ONL) B - Internal Nuclear layer (INL) C - Ganglion Cell layer (GCL) DETAILED DESCRIPTION OF THE INVENTION Definitions "Eye" refers to the anatomical structure responsible for vision in humans and other animals, and encompasses the following anatomical structures, without limitation: lens, vitreous body, ciliary body, posterior chamber, anterior chamber, pupil , cornea, iris, Schlemm's canal, Zinn zonules, limbus, conjunctiva, choroid, retina, central vessels of the retina, optic nerve, central fovea, macula lutea, and sclera. - ^ - & ^ - ^ - > ? - ^ - ^^^^ _ ^ _ ^^^^^^^^^^^^^^^^ - ^^^ - ^^^^^ _ ^^^^^^^^^^^^ ^^ AiB "GPl 1605" refers to a compound of the formula "GPl 1046" refers to (2s) -1- (3,3-dimethyl-1, 2-dioxopentyl) -2-pyrrolidinecarboxylic acid 3- (3-pyrridyl) -1-propyl, a compound of the formula "GPl 1312" refers to a compound of the formula "GPl 1572" refers to a compound of the formula a-ia-Hl- "la-É-Htt? -i? i-aÉ- &. ^ aMMk ^^^ a M | ¡jg | É ^ "GPl 1389" refers to a compound of the formula "GPl 1511" refers to a compound of the formula "GPl 1234" refers to a compound of the formula "Isomers" refers to different compounds that have the same molecular formula. "Esterioisomers" are isomers that differ only in the way that atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are not images superimposed on the mirror of each one. "Diasterioisomers" are stereoisomers that are not mirror images of each other. "Racemic mixture" means a mixture containing equal parts of individual enantiomers. "Non-racemic mixture" is a mixture containing unequal portions of individual enantiomers or stereoisomers. "Improving memory function" refers to improving or increasing the mental faculty by which to record, retain or recall past experiences, knowledge, ideas, sensations, thoughts or impressions. "Decreased memory" refers to a retention or reduced mental recall of past experiences, knowledge, ideas, sensations, thoughts or impressions. The decrease in memory can affect the retention of information in the short and long term, ease with spatial relationships, memory strategies (essay), and verbal recovery and production. The common causes of memory decline are age, severe head trauma, anoxia or cerebral ischemia, nutritional alcoholic diseases, and drug intoxications. Examples of memory depletion include without limitation, benign forgetfulness, amnesia and any disorder in which memory deficiency is present, such as Korsakoff's amnesic psychosis, dementia and learning disorders.

"Neopsic factors" or "neopsic" refers to compounds useful for treating vision loss, preventing vision degeneration or promoting vision regeneration. "Neopsis" refers to processes to deal with loss of vision, prevent degeneration of vision, or promote vision regeneration. "Ophthalmological" refers to anything about or concerning the eye, without limitation, and is used interchangeably with "ocular" "ophthalmic", "ophthalmologic", and other terms, without limitation. "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 neither biologically nor otherwise undesirable. A salt, ester or Solvate can be formed 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, hemisulfate, heptanoate, hexanoate, hydrochloride, bromohydrate, iodohydrate, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, naphthylate, 2-naphthalenesulfonate, nicotinate, oxalate, sulfate, thiocyanate, tosylate and undecanoate. Examples of basic salts, esters or solvates include salts of ammonium; alkali metal salts, such as sodium and potassium salts; ^^^^ g ^ ^ s ^ 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, licina, etc. Also, groups containing basic nitrogen can be quaternized with agents such as lower alkyl halides, such as chlorides, bromides, methyl, ethyl, propyl and butyl iodides; dialkylsulfates, such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides, such as benzyl and phenethyl bromides; and others. Soluble or dispersible products are obtained in water or oil. "Prevent Vision Degeneration" refers to the ability to prevent vision degeneration in newly diagnosed patients such as having a degenerative disease that affects vision, or at risk of developing a new degenerative disease that affects vision and to prevent Additional vision regeneration in patients who already suffer from or have symptoms of a degenerative disease that affects vision. "Promoting vision regeneration" refers to maintaining, improving, stimulating or accelerating the recovery of, or revitalizing one or more components of the visual system in a way that increases or improves vision, whether in the presence or absence of any Ophthalmological disorder, disease or injury.

"Treat" refers to: (i) preventing a disease and / or condition from occurring in a subject who may be predisposed to the disease and / or condition but has not yet been diagnosed as having it. 5 (ii) inhibit the disease and / or condition, ie stop its development; or (iii) Alleviate the disease and / or condition, that is, cause the regression of the disease and / or condition. "Vision" refers to the ability of humans and 10 other animals to process images and is used interchangeably with "sight", "seeing", and other such terms, without limitation. "Vision disorder" refers to any disorder that affects or involves vision, including but not limited to visual decline, orbital disorders, lacrimal apparatus disorders, eyelid disorders, conjunctival disorders, corneal disorders , cataracts, uveal tract disorders, retinal disorders, optic nerve disorders, or visual trajectories, disorders and diseases of the eye induced by 20 free radicals, disorders and diseases of the eye, immunologically mediated, eye injuries, and symptoms and complications of eye disease, eye disorder, or eye injuries. "Visual decline" refers to any vision dysfunction that includes, without limitation, disturbances or diminution in the vision (for example, binocular, central, peripheral, -? i niíi'phiir * 1 »* • * - scotopic), visual acuity for near and far objects, visual field, ocular mobility, color perception, adaptation to light and darkness, accommodation, refraction, and tearing. See Physician's Desk Reference (PDR) for Ophthalmology, 16th Edition, 5 6:47 (1988).

Methods of the Present Invention The present invention relates to a method for treating a vision disorder, improving vision, treating the decrease of memory, or improve memory performance in an animal, which comprises administering to the animal an effective amount of a derivative. The inventive methods are particularly useful for treating various disorders of the eye that include but are not limited to visual disorders, diseases, wounds and complications, genetic disorders; disorders associated with aging or degenerative diseases of vision; vision disorders that correlate to physical injury to the eye, head, or other parts of the body that result from external forces; disorders the vision resulting 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 enhancing vision, or correcting, treat, or prevent visual (ocular) decrease or dysfunction of the ? ^ Lt'te- - ' "IM ^^ - ^^ ^^ ^ ri-ii -. M ^ ^^^ iiÉtf visual system including visual, permanent and temporary decrease without limitation The present invention is also useful for preventing and treating diseases and ophthalmological disorders, treating damaged and injured eyes, and preventing and treating diseases, disorders, and wounds that result in impaired vision, loss of vision, or reduced ability to see or process images, and the symptoms and complications resulting from same. the diseases and disorders of the eye which may be treated or prevented by the compositions and methods of the present invention are not limited with respect to the cause of diseases or disorders. accordingly, the compositions and The methods are applicable whether the disease or disorder is caused by genetic or environmental factors, as well as any other influences.The compositions and methods of the present invention are particularly useful for more of the eye or loss of vision or deficiency associated with all of the following, without limitation: aging, cellular or physiological degeneration, central nervous or neurological disorders, vascular defects, muscle 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 diminution, without limitation. The visual decrease in various degrees occurs in the presence of a deviation from normal in one or more functions of the eye that includes (1) visual acuity for distant and nearby objects; (2) visual fields; and (3) ocular mobility without diplopia. See Physicians' Desk Reference (PDR) for Ophthalmology, 76th Edition, 6:47 (1988). The vision is imperfect without the coordinated 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, metamorphopsia, and binocular vision. The compositions and methods of use are particularly useful for treating, correcting or preventing ocular disturbances including, without limitation, accommodation paresis, iridoplegia, entropion, ectropion, epiphora, lagophthalmos, and scarring, vitreous opacities, non-reactive pupils, dispersion disturbances. of light from 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. Vision loss that varies from light loss to absolute loss can be treated or prevented using the compositions and methods of use. Vision can be improved by the treatment of eye disorders such as diseases, and wounds using the compositions and methods of the invention. However, improvements in vision using the compositions and methods of use are not limited as such, and may Lui ^ aA- occur in the absence of any disorder, illness, or injury. The compositions and methods of the present invention are also useful in the treatment or prevention of the following non-limiting examples of diseases and disorders, and symptoms and complications resulting therefrom. Vision disorders include but are not limited to the following: visual decline, such as decreased visual acuity for near and far objects, visual fields, and ocular mobility; orbital disorders, such as orbital cellulitis, periorbital cellulitis, cavernous sinus thrombosis, and exophthalmos (proptosis); disorders of the lacrimal apparatus, such as dacryostenosis, congenital dacryostenosis, and dacryocystitis (acute or chronic); eyelash disorders, such as eyelid edema, blepharitis, ptosis, Bell's palsy, blepharospasm, stye, external sty, internal stye (meibomian sty), chalazion, entropion (eyelid inversion), ectropion (eversion of the eyelid), tumors (benign and malignant), xanthelasma, basal cell carcinoma, squamous cell carcinoma, carcinoma of the meibomian gland, and melanoma; Conjunctival disorders, such as pinguecula, pterygia, and other neoplasms, acute conjunctivitis, chronic conjunctivitis, adult gonococcal conjunctivitis, neonatal conjunctivitis, trachoma (granular conjunctivitis or Egyptian ophthalmia), inclusion conjunctivitis (inclusion blenorrhea or conjunctivitis of the pool) , neonatal inclusion conjunctivitis, adult inclusion conjunctivitis, spring keratoconjunctivitis, dry keratoconjunctivitis (dry keratitis or dry eyes syndrome), episcleritis, scleritis, scar pemphigoid (ocular scar pemphigoid or benign mucous membrane pemphigoid), and subconjunctival hemorrhage; corneal disorders, such as superficial punctate keratitis, corneal ulcer, indolent ulcer, recurrent corneal erosion, corneal epithelial basement membrane dystrophy, corneal endothelial cell dystrophy, herpes simplex keratitis (keratoconjunctivitis due to herpes simplex) dendritic keratitis, disciform keratitis, ophthalmic herpes zoster, keratoconjunctivitis flictenular (conjunctivitis flictenular or exzematosa) interstitial keratitis (parenchymal keratitis), peripheral keratitis, (marginal keratolysis or peripheral rheumatoid ulceration), keratomalasia (xerotic keratitis), xerophthalmia, keratoconus, bilirubin keratopathy; cataracts, which includes developmental or congenital cataracts, juvenile or adult cataracts, nuclear cataract, posterior subcapsular cataracts; Uveal tract disorders, such as Uveltis (inflammation of the uveal or retinal tract), anterior uveitis, intermediate uveitis, posterior uveitis, iritis, cytis itis, ankylosing spondylitis choroiditis, Reiter syndrome, pars planitis, toxoplasmosis, sitomegalovirus 5 (CMV), acute retinal necrosis, toxocariasis, pelvic heart disease, histoplasmosis (so-called ocular histoplasmosis syndrome), Behcet's syndrome, sympathetic ophthalmia, Vogt-Koyanagi-Harada syndrome, sarcoidosis, reticulum cell sarcoma, large cell lymphoma, syphilis, tuberculosis, arthritis juvenile rheumatoid, endophthalmitis, and malignant melanoma of the choroid; disorders of the retina, such as vascular retinopathies (for example arteriosclerotic retinopathy and hypertensive retinopathy), occlusion of the central retina artery and branched, central and branched retinal vein occlusion, diabetic retinopathy (eg proliferative retinopathy and nonproliferative retinopathy), macular degeneration of the elderly (age-related macular degeneration or senile macular degeneration), neovascular macular degeneration, retinal detachment, retinitis pigmentosa, photic retinal wound, eye injury induced by retinal ischemia, and glaucoma (eg primary glaucoma, chronic open-angle glaucoma, chronic or acute angle closure, congenital (childhood) glaucoma secondary glaucoma, and absolute glaucoma); • *-to ". . "- > . . ^ a ^ »optic nerve disorders or visual trajectories, such as papilledema (drowned disk), papillitis (optic neuritis), retrobulbar neuritis, ischemic optic neuropathy, toxic amblyopia, optic atrophy, higher visual path lesions, 5 ocular mobility (for example, third cranial nerve palsy, fourth cranial nerve palsy, sixth cranial nerve palsy, internuclear ophthalmoplegia, and gaze paralysis); disorders and diseases of the eye induced by free radicals; and immunologically mediated disorders and diseases of 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 Johns Hopkins University Press (1998)). The compositions and methods of the present invention are also useful in the treatment of the following non-limiting eye injuries, and the symptoms and complications that result from them: foreign body injuries of the conjunctiva and cornea, corneal abrasion, intraocular foreign body injuries, lacerations, eyelid lacerations, contusions, eyelid contusions (black eye), trauma on the globe, laceration of the iris, cataract, dislocated lens, glaucoma, "Mai" M '-' AA • - * - - - - - - - -? Í - - --- • - * "^ - vitreous hemorrhage, fractures of the orbital floor, hemorrhage or detachment of the retina and rupture of the eyeball, hemorrhage of the anterior chamber (traumatic hyphema), burns, eyelid burns, chemical burns of the cornea and conjunctiva and burns by ultraviolet light, sunburn.) See The Merck Manual, Sixteenth Edition, 217: 2364- 2365 (1992) The compositions and methods of the present invention are also useful for treating and / or preventing the following non-limiting examples of symptoms and complications of eye disease, eye disorder or eye injury: subconjunctival hemorrhages, vitreous hemorrhages , hemorrhages of the retina, floaters, detachments of the retina, photophobia, eye pain, scotomas (negative and positive), refractive errors, emmetropia, ametropia, hyperopia, (far sight), myopia (near view), astigmatism, anisometropia, Aniseconia, pr eviopia, bleeding, recurrent bleeding, sympathetic ophthalmia, inflammation, swelling, redness of the eye, eye irritation, ulceration and scarring of the cornea, iridocyclitis, perforation of the globe, eyelid deformities, exophthalmos, decreased mobility of the eye, eyelid swelling, conjunctix hydrops, loss of vision, including partial or total blindness, optic neuritis, fever, malaise, thrombophlebitis, cavernous sinus thrombosis, panophthalmitis, infection of the meninges and brain, papilledema, severe cerebral symptoms (headache, decreased level of consciousness, and convulsions), paralysis of the cranial nerves, epiphora (persistent or chronic lachrymation), copious reflux of mucus or pus, follicular subconjunctival hyperplasia, vascularisation of the cornea, scarring of the conjunctiva, cornea, and eyelids, cataract, hypopyon, lagophthalmos, flícténulos, rubeosis of the iris, bitemporal hemianopia, and homonymous hemianopia. See. The Merck Manual Sixteenth Edition, 217: 2362-2363 (1992). The derivative can be administered in combination with an effective amount of one or more useful factors in the treatment of vision disorder, improve vision, treat memory decline, or improve memory performance. In a preferred embodiment, the factor or factors to be combined with the derivative is / are selected from the group that consists of immunosuppressants to treat autoimmune, inflammatory, and immunologically mediated disorders; agents to heal injuries to treat injuries resulting from injury or surgery; antiglaucomatous medications to treat abnormally high intraocular pressure; neurotrophic factors and factors of Growth to treat neurodegenerative disorders or stimulate neurite growth; effective compounds to limit or prevent hemorrhage or neovascularization to treat macular degeneration; and antioxidants to treat oxidative damage to ocular tissues. 25 The present invention also relates to a pharmaceutical composition comprising: (i) an effective amount of a derivative to treat a disorder of vision, improve vision, treat memory decline , or improve the performance of memory 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 in the treatment of disorders of vision, improve vision, treat memory decline, or improve memory performance.

N-LINKED UREASES AND CARBAMATES OF HETEROCICLIC TIOESTERS The N-linked ureas and carbamates of heterocyclic thioesters used in the methods and pharmaceutical compositions of the present invention are small molecule compounds of low molecular weight that have an affinity for an immunophilin type FKBP such as FKBP12. When a N-linked urea or carbamate or a heterocyclic thioester is linked to an FKBP-type immunophilin, it has been found to inhibit the proliferative activity of the cis-trans isomerase, or rotamase of the binding protein. Unexpectedly, these compounds also ^ A ^ -teBfa S? - - • • - < - - - - • - - - - - - - - ** «» * "have been found to stimulate hair growth and are devoid of any significant immunosuppressive activity.

FORMULA I The N-linked urea or carbamate of a heterocyclic thioester can be a compound of the formula I or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A and B, taken 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 O, S, SO, SO2, N, NH, or NR3 additional; X is either O or S; Y is a direct bond, straight or branched chain alkyl of C | -C6, or straight or branched chain alkenyl of C2-C6, 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, ^^^^ j ^ ** ^ u, cyano, nitro, min, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of straight or branched alkenyl or alkynyl of C3-C6, and connecting alkyl of 0, -04, 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; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is already substituted or unsubstituted with one or more substituents independently selected from the group including, but not limited to a, alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, straight or branched chain alkyl of C2-C9 alkenyloxy alkoxy, straight or branched chain alkenyl of C2-C9, cycloalkyl of C3-C8, cycloalkenyl of C5- C7, carbonyl, carboxy, cyano, diazo, ester, formanilide, halo, haloalkyl, hydroxy, imino, isocyano, isonitrile, nitrile, nitro, nitroso, phenoxy, sulfhydryl, sulfonyl sulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, Irifluoromethyl and carboxylic and heterocyclic portions, including alicyclic and aromatic structures; where the individual ring size is "-" "" * - * 5-8 members, wherein the heteroacrylic ring consists of 1-6 heteroatoms independently selected from the group consisting of O, N, and S, and wherein the aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl or straight or branched chain alkenyl of C2-C6, wherein any alkyl or alkenyl carbon atom is optionally substituted on one or more amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl or oxygen positions to form a carbonyl, or wherein any carbon atom of the alkyl or alkenyl is optionally substituted with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl of C C6, or straight or branched chain alkenyl of C2-C6; wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7-cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C2-C6 alkenyl alkyl, 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 alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; W is O or S; and U is either 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, C3-C8 cycloalkyl, alkyl straight or branched chain of and straight or branched chain alkenyl of C2-C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and C3-C8 cycloalkyl; and when U is N, then R., and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl of C, -C6, and straight or branched chain alkenyl of C2-C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and C3-C8 cycloalkyl; or R, and R2 are taken together to form a 5- or 6-membered heterocyclic ring 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, Ddli-l-MI-i anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinone, and , tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trityanil, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl , phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl. In a preferred embodiment of formula I, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolinyl. , oxazolyl, thiazolyl, pyrazolide, and thienyl. In a more preferred embodiment of the compounds of formula I, the N-linked urea or carbamate of a heterocyclic thioester is compound GPl 1605, of the formula FORMULA II ¿¡¡¡¡¡¡¡3¡ ^ The N-linked urea or carbamate of a heterocyclic thioester can also be a compound of the formula II or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F, G and J are independently CH2, O, S, SO, SO2, NH, or NR3; X is either O or S; Y is a direct bond, straight or branched chain alkyl or straight or branched chain alkenyl of C2-C6, wherein any alkyl or alkenyl carbon atom is optionally substituted at one or more positions with amino, halo, haloalkyl , thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, alkyl, alkylamino, ammoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or where any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of 0, -04, alkenyl or alkynyl straight or branched chain C3-C4, and alkyl of connection 0, -04 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; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is already substituted or unsubstituted with one or more substituents, independently selected from the group included, but is not limited to, alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, straight or branched chain alkyl of 0, -Cg, 0, -Cg alkoxy, C2-C9 alkenyloxy, straight or branched chain alkenyl of C2-C9 , C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilide, halo, haloalkyl, hydroxy, imino, isocyano, isonitrile, nitrile, nitro, nitroso, phenoxy, sulfhydryl, sulfonyl sulfoxy, thio , thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl, and carboxylic and heterocyclic portions, including alicyclic and aromatic structures; wherein the size of the individual ring is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of 0, -Cg, straight or branched chain alkenyl of C2-C6, wherein any alkyl or alkenyl carbon atom 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 replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl of 0, -Ce, or straight or branched chain alkenyl of C2-C6; wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C6 alkyl, C2-C6 alkenyl, 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 alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO, or SO2; W is O or S; and U is either 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, C3-C8 cycloalkyl, alkyl straight or branched chain of C ^ Ce, and straight or branched chain alkenyl of C2-C6, wherein alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and cycloalkyl of C3 -C8; and when U is N, then R, and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl of C, -C6, and straight or branched chain alkenyl of C2-C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from from the group consisting of Ar and C3-C8 cycloalkyl; or R, and R2 is taken together to form a 5- or 6-membered heterocyclic ring 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, ? Mii-i-l-M > -k - »« i. ^ _ ^ ^ _ ^ Mda-_i _ ^ __ a ^^ Ea_-M __ ^^ ___ __a - ^ _- MM * -IM »M ^^ oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl , triazinyl, trityanil, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl. In a preferred embodiment of Formula II, 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 III In addition, the N-linked urea or carbamate of a heterocyclic thioester can be a compound of the formula III or a pharmaceutically acceptable salt, ester, or solvate thereof, wherein: E, F and G are independently CH2, O, S, SO, SO2, NH, and NR3; X is either O or S; Ü ^ g Y is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any carbon atom of the alkyl or alkenyl is optionally substituted on one or more amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, amino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C1-C4, alkenyl or alkynyl straight or branched chain of C3-C4, and connecting alkyl of 0, -04, 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; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is already substituted or unsubstituted with one or more substituents independently selected from the group including, but not limited to a, alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, straight or branched chain alkyl of C, -C9, C, -C9 alkoxy, C2-C9 alkenyloxy, straight or branched chain alkenyl of C2-C9, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilide, halo, AA ~ ** mlt # ***. haloalkyl, hydroxy, methoxy, isonic, isonitrile, nitrile, nitro, nitroso, phenoxy, sulfhydryl, sulfonyl sulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl and carboxylic 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 independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any alkyl or alkenyl carbon atom 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 replaced with O, NH, NR3, S, SO or S02; C and D are independently hydrogen, Ar, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6; wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxyl, carbonyl oxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C6 alkyl, C2-C6 alkenyl, 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 alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; 10 W is O or S; and U is either 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, C3-C8 cycloalkyl, alkyl linear or branched chain of C, -C6 and straight or branched chain alkenyl of C2-C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and C3-C8 cycloalkyl; and when U is N, then R, and R2 are selected independently of the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl of C, -C6, and straight or branched chain alkenyl of C2-C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from A group consisting of Ar and C3-C3 cycloalkyl; or R, and R2 is -É-ÍA-S ^ á- & 1-. taken together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of pyrrolidin, imidazoline, 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, isoquinylinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trityanil, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acrldinyl, phenazinyl, phenothiazinyl and phenoxazinyl. In a preferred embodiment of formula III, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazole, oxazolyl, thiazolyl, pyrazolyl. , and thienyl. In a more preferred embodiment of the compounds of the formula III, the N-linked urea or carbamate of a hetrocyclic thioester is the compound GPl 1605, of the formula • - FORMULA IV The N-linked urea or carbamate of a heterocyclic thioester may also be a compound of the formula IV Ri or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: n is 1, 2 or 3; X is either O or S; Y is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, 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 alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or S02; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C, -C4, alkenyl or alkynyl straight or branched chain of C3-C4, and C, -C4 connecting alkyl, 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 a group Ar; Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is already substituted or unsubstituted with one or more substituents independently selected from the group including, but not limited to a, alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, straight or branched chain alkyl of C, -C9, C, -C9 alkoxy, C2-C9 alkenyloxy, straight or branched chain alkenyl of C2-C9, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilide, halo, haloalkyl, hydroxy, imino, isocyano, isonitrile, nitrile, nitro, nitroso, phenoxy, sulfhydryl, sulfonyl sulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl and carboxylic and heterocyclic portions, including alicyclic and aromatic structures; where the individual ring size - «HM-ti - ^ - ^ is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide 5; Z is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any alkyl or alkenyl carbon atom 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 alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6; wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl of C3-C8, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, mino, alkylamino, aminoalkyl, Sulfhydryl, thioalkyl, or sulfonyl; where any atom of MMitiBMM £ H jM, - > • alkyl or alkenyl carbon is optionally substituted at one or more positions with oxygen to form a carbonyl; or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; 5 W is O or S; and U is either 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, C3-C8 cycloalkyl, linear or branched chain of C, -C6 and straight or branched chain alkenyl of C2-C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of Ar and C3-C8 cycloalkyl; and when U is N, then R, and R2 are selected Independently of the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl of C, -C6, and straight or branched chain alkenyl of C2-C6, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from A group consisting of Ar and C3-C8 cycloalkyl; or R, and R2 are taken together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of pyrrolidine, imidazoline, pyrazolidin, piperidine and piperazine. Useful carbo- and heterocyclic rings include limitation phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, - • .TÉiiÉiÉÉtl-if) - »-" * '- - - • - - - -. - - -. &- & amp; anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, ndazolyl, benzimidazolyl , benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoq or in ili nyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, midazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trityanil, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl. Preferred embodiment of the formula IV, Ar is selected from the group consisting of phenyl, benzyl, naphthyl, pyrrolyl, pi rrol id ini lo, pyridini pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl, thiophenyl, imidazole, oxazolyl, thiazolyl, pyrazolyl and thienyl. Exemplary compounds of formula IV are presented in TABLE A. - ^ 1 ^ - ^ U? ÁÉ - ^ - fa TABLE A Ri No. n w Y z C D R, R 2 1 1 O (CH 2) 2 CH 3-Pyridyl H 2-Methylbutyl 2 1 O (CH 2) 2 CH 3 -pyridyl H H 1, -dimethylpropyl 3 1 0 (CH 2) 2 CH 4 -Metoxy H H 1, 1 -dimethylpropyl phenyl 4 1 O CH 2 CH Phenyl, H 1, 1-dimethylpropyl 1 s (CH 2) 2 CH 4 -Metoxy HH Cichlorhexyl phenyl 6 1 O (CH 2) 2 CH 3 -Pyridyl HH Cichlorhexyl 7 1 s (CH 2) 2 CH 3 -Pyridyl HH Cichlorhexyl 8 1 s (CH 2) 2 CH 3 Pyridyl HH 1-Adamantyl 9 1 s (CH 2) 2 CH 3-Pyridyl HH 1, -dimethylpropyl 1 O (CH 2) 2 CH Phenyl Fenll H 1, 1 -dimethylpropyl 0 11 2 O (CH 2) 2 CH Phenyl, H 1, 1 -dimethylpropyl 12 2 O (CH2) 2 CH Phenyl H H Phenyl 13 2 O Link CH 2 -phenyl 2- H Phenyl i raí ¡f • - littfaa-fc-tti -'- ^^.

Direct ethyl Phenyl ethyl 14 2 O Link CH 2 -Phenyl 2- H Cichloroethyl Direct ethyl Phenyl ethyl 15 2 S Link CH 2 -Phenyl 2- H Cichlorhexyl Direct ethyl Phenyl ethyl 16 2 O (CH 2): CH ^ -Metoxy H H Cichlohexyl phenyl The most preferred compounds of Formula IV are selected from the group consisting of: 3- (3-Pi rid i) -1-propyl-2S-1 - [(2-methyl butyl) carbamoyl] pyrrolidi n-2-carboxylate; 3- (3-Pyridyl) -1-propyl-2S-1 - [(1 ', 1'-D-methylpropyl) carbamoyl] pyrrolidine-2-carboxylate; 3- (3-Pyridyl) -1-propyl-2S-1 - [(cyclohexyl) thiocarbamoyl] pyrrolidine-2-carboxylate; and pharmaceutically acceptable salts, esters and solvates thereof.

FORMULA V The N-linked urea or carbamate of a heterocyclic thioester can be a compound of the formula V alfi-Mi-ÜÉ-feM-ta-aiil-il-i HtaMi-iri-N - ^ - 1 - ^^ - b or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: V is C, N, or S; Y is a straight, straight or branched chain alkyl of C, -C6, straight or branched chain alkenyl of C2-C6, 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 alkyl or alkenyl carbon atom it is replaced opclonally with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C, -C6, alkenyl or C3-C6 alkynyl, and C, -C4 connecting alkyl wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing a heteroatom to form a ring, wherein the ring is optionally fused to an Ar group; < - Í-l l l l Í Í Í &&&&&&&&&&&&&&&&&&&&&&&&&&** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** Ar is an alicyclic or aromatic, mono-, bi- or tricyclic carbo- or heterocyclic ring, wherein the ring is already substituted or if substituted with one or more substituents; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring contains 1-6 heteroatoms independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight chain alkyl or Branched C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any alkyl or alkenyl carbon atom 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 alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, C, -C6 straight-chain or branched alkyl, or straight-chain alkenyl or branched C2-C6; wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is Optionally substituted with C, -C6 alkyl, C2-C6 alkenyl, - • --- * ---- "-" "* hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, amino, 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 alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; and A, B, R1, R2, U, W and X are as defined otherwise in formula I. All compounds of formulas IV have asymmetric centers and thus can be produced as mixtures of stereoisomers or as individual R and S stereoisomers The individual stereoisomers can be obtained using an optically active starting material, resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or resolving the compounds of the formulas. The compounds of Formulas I-V will be understood to encompass individual stereoisomers as well as mixtures (racemic and non-racemic) of stereoisomers. Preferably, the S-stereoisomers are used in the compositions and pharmaceutical methods of the present invention. Synthesis of Ureas and Carbamates of N-linked Heterocyclic Thioesters The compounds of Formulas I to V can be easily prepared by standard techniques of organic chemistry, using the general synthetic trajectory represented in the following. As described in Scheme I, the cyclic amino acids 1 protected by appropriate blocking groups P on the amino acid nitrogen can be reacted with thiols of RSH to generate thioesters 2. After removing the protecting group, the free amine 3 can be reactive with a variety of isocyanates or isothiocyanates to provide the final ureas or thioureas, respectively.

SCHEME I Check out 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 depicted in Scheme II. ^ gggjggaj ^ g *** ^^^^ SCHEME II The R-SH thiols can conveniently be prepared from the corresponding alcohols or halides readily available through two halide replacement steps by sulfur, as described in Scheme Ill. The halides can be reacted with thiourea, and the corresponding alkyl thiouronium salts hydrolyzed to provide RSH thiols. If the alcohols are used as the starting materials, they can be first converted to the corresponding halides by standard methods.

SCHEME lll R-OH R-S CBr4 / Ph3P 2) QH- Affinity for FKBP12 The compounds used in the inventive methods and pharmaceutical compositions have an affinity for the FK506 binding protein, particularly FKBP12. The inhibition of the propyl peptidyl cis-trans isomerase activity of FKBP can be measured as an indicator of this affinity.

KL Test Procedure The inhibition of the peptidyl-propyl isomerase (rotamase) activity of the compounds used in the inventive methods and pharmaceutical compositions can be evaluated by known methods described in the literature (Harding et al., Nature, 1989, 341 : 758-760; Holt et al., J. Am. Chem. Soc, 115: 9923-9938). These values are obtained as K, apparent and are presented by representative compounds in TABLE II The cis-trans isomerization of an alanine-proline bond in a model substrate, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide , is verified spectrophotometrically in a coupled assay of chymotrypsin, which releases para-nitroanilide from the trans form of the substrate. The inhibition of this reaction caused by the addition of different concentrations of the inhibitor is determined, and the data is analyzed as a change in the first-order velocity constant as a concentration function to produce the apparent K-values. 950 mL of cold assay regulator (25 mM HEPES, pH 7.8, 100 mM NaCl), 10 mL of FKBP (2.5 mM in 10 mM Tris-Cl pH 7.5, 100 mM NaCl are added in a plastic cuvette). , 1 mM dithiothreitol), 25 mL of chymotrypsin (50 mg / mL in 1 mM HCl) and 10 mL of the test compound at various concentrations in dimethyl sulfoxide. The reaction is initiated by the addition of 5 mL of the substrate (succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg / mL in 2.35 mM LiCl in trifluoroethanol). The absorbance at 390 nm is checked against time for 90 seconds using a spectrophotometer and the rate constants are determined from the absorbance against time of the data files. 10 TABLE II In Vitro Test Results - Formulas I to V Composite Ki (nM) 1 + + + 15 2 + + 3 + + 4 + + 5 + + 6 + 20 7 + + 8 + + + Table II (continued) Compound Ki (nM) 9 + + + 25 10 + + + -d ± ¡-at £ tt2 £ iáts- 11 + + 12 + + + 13 + + + 14 + + + 15 + + + 16 + + The relative powers of compounds are classified according to the following scale: + + + + means K, or ED50 < 1 nM; + + + means K, or ED50 of 1-50 nM; ++ means K, or ED50 of 51-200 nM; + means K, or ED of 201-500 nM.

Route of Administration To effectively treat vision loss or cause vision regeneration, the compounds used in the inventive methods and pharmaceutical compositions can easily affect the target areas. For these purposes, the compounds are preferably administered [topically to the skin.] Other routes of administration known in the pharmaceutical art are also contemplated by this invention. Dosage Dosage levels in the order of about 0.1 mg to about 10,000 mg of the compound of the active ingredient are useful in the treatment of conditions The previous ones, with preferred levels of 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 the activity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; drug combination; the severity of the particular disease that is treated; and the form of administration. Typically, the results of the in vitro dose effect provide useful guidance at the correct doses for administration to the patient. Studies in animal models are also useful. Considerations for determining appropriate dose levels are well known in the art. The compounds can be administered with other agents for treatment of vision loss, prevention of vision degeneration, or to cause vision regeneration. The specific dose levels for other agents will depend on the previously established factors and the effectiveness of the drug combination.

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

EXAMPLE 1 Synthesis of 3- (3-pyridyl) -1-propylmercaptyl (1) 3- (3-Pyridyl) - ((2-methylbutyl) carbamoyl] pyrrolidin-2-carboxylate 1-propylchloride is added dropwise to a solution of 3- (3-pyridyl) -1-propanol (10 g, 72.4 mmol) in chloroform (100 mL) to a solution of thionyl chloride (12.9 g, 108.6 mmol) in chloroform (50 mL). The resulting mixture was refluxed for 1 hour, then vacuum in 50% cold aqueous potassium hydroxide (150 mL). The layers were separated, and the organic phase was dried, concentrated and purified on a column of silica gel, eluting with 40% ethyl acetate in hexane, to obtain 10 g (65%) of chloride as a clear oil. 1 H NMR (300 MHz, CDCl 3): 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-Pi rid i I) -1-propyl mercaptan A mixture of 3- (3-pyridyl) -1-propylchloride (3 g, 19.4 mmol) and thiourea (1.48 g) was refluxed for 24 hours. 19.4 mmol) in ethanol (10 mL). Aqueous sodium hydroxide, 15 mL of a 0.75 N solution was added, and the mixture was refluxed for an additional 2 hours. After cooling to room temperature, the solvent was removed in vacuo. Chromatographic purification of the unpurified thiol on a silica gel column eluting with 50% ethyl acetate in hexane supplying 1.2 g of 3- (3-pyridyl) -1-propyl mercaptan as a clear liquid. 1 H NMR (300 MHz, CDCl 3): 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- (fer-butyloxycarbonyl) pyrrolidine-2-carboxylate of 3- (3-pi ri di I) -1-propyl mercaptyl It was stirred overnight N- (fer-butyloxycarbonyl) - (S) ) -proline (3.0 g, 13.9 mmoles); 3- (3-Pyridyl) -1-propylmercaptan (3.20 g; 20.9 mmole), dicyclohexylcarbodiimide (4.59 g, 22.24 mmole), camphorsulfonic acid (1.08 g, 4.63 mrnol), and 4-dimethylaminopyridine (0.60 g, 4.63 mmole) in dry methylene chloride (100 mL). The reaction mixture was diluted with methylene chloride (50 mL) and water (100 mL), and the layers were separated. The organic phase was washed with water (3 x 100 mL), dried over magnesium sulfate, and concentrated, and the unpurified residue was purified on a column of silica gel, eluting with ethyl acetate to obtain 4.60 g ( 95%) of the thioester as a thick oil. 1 H NMR (300 MHz, CDCl 3): 1.45 (s, 9 H); 1.70-2.05 (m, 5H); 2.32 (m, 1H); 2.71 (t, 2H); 2.85 (m, 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- (N- (rer-butyloxycarbonyl) pyrrolidine-2-carboxylate) was stirred at room temperature for three hours. 3- Pyridyl) -1-mercaptyl (4.60 g, 13.1 mmol) in methylene chloride (60 mL) and trifluoroacetic acid (6 mL). The saturated potassium carbonate was added until the pH was basic, and the reaction mixture was extracted with methylene chloride (3x). The combined organic extracts were dried and concentrated to yield 2.36 g (75%) of the free amine as a thick oil. 1 H NMR (300 MHz, CDCl 3): 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 (rn, 1H); 8.57 (m, 2H). 2S-1 - 3-.3-Pyridyl-1-propylmercaptyl [3-.3-pyridyl-1-propylmercaptyl]. [2-methylbutylcarbamoyl-pyrrolidine-2-carboxylate] A solution of 2-methylbutylamine (113 mg, 1.3 mmol) was added. and triethylamine (132 mg, 1.3 mmol) in methylene chloride (5 mL) to a solution of triphosgene (128 mg, 0.43 mmol) in methylene chloride (5 mL). The resulting mixture was 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 was added and the resulting mixture was stirred for 1 hour and then divided between water and a 1: 1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (ethyl acetate 50% / hexane) to obtain 250 mg (55%) of the compound of Example 1 (Compound 1, Table II) as an oil. 1 H NMR (300 MHz, CDCl 3): d 1 H NMR (CDCl 3, 300 MHz): 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 2 Synthesis of 2S-1 -T (1 '.1'-dimeti I propi hcarbamoyl pyrrolidin-2-carboxylic acid 3- (3-pyridyl) -1-propyl ester (2) The reaction of pyrrolidin-2-carboxylate of 3- (3-pyridyl) -1-propylmercaptyl with the isocyanate generated from ter-amylamine and triphosgene, as described by Example 1, provides the compound of Example 2 (Compound 2, Table II in a yield of 62%). % .1H NMR (CDCl3, 300 MHz): 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 3 Synthesis of 3- (3-pyridyl) -1-propylmercaptyl 2S-1-f (cyclohexyl) thiocarbamoyl-pyrrolidin-2-carboxylate (7) A mixture of cyclohexylisothiocyanate (120 mg, 0.9 mmol) was stirred for 1 hour. 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 and then divided between water and a mixture 1: 1 ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (50% ethyl acetate / hexane) to obtain 160 mg (47%) of the compound of Example 3 (Compound 7, Table II). 1 H NMR (CDCl 3, 300 MHz): 1.16-1.40 (m, 6H); 1.50-171 (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 4 Synthesis of (2S) -1- (3,3-dimethyl-1,2-dioxopentyl) -2-pyrrolidinecarboxylate 3-phenyl-1-propyl (1) (2S) -1- (1,2-d-oxo-2-methoxyethyl) Methyl) -2-pyrrolidinecarboxylate A solution of L-proline methyl ester hydrochloride (3.08 g, 18.60 mmoles) in dry methylene chloride was cooled to 0 ° C and treated with triethylamine (3.92 g, 38.74 mmoles; equivalents). After stirring the suspension formed under a nitrogen atmosphere for 15 minutes, a solution of methyloxalyl chloride (3.20 g, 26.12 mmol) in methylene chloride (45 ml) was added dropwise. The resulting mixture was stirred at 0 ° C for 1.5 hours. After filtering to remove solids, the organic phase was washed with water, dried over MgSO 4, and concentrated. The unpurified residue was purified on a column * iteli ~ of silica gel, eluting with 50% ethyl acetate in hexane, to obtain 3.52 g (88%) of the product as a reddish residue. The mixture of rotamers of cis-trans amide; The data for trans rotamer give. 1 H NMR (CDCl 3): 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, 8.4, 3.3). (2S) -1- (1.2-di oxo-3.3-dim eti I pe ntih-2-pi rrol id i nca methyl ethoxylate) A solution of (2S) -1- (1) was cooled to -78 ° C. Methyl 2-dioxo-2-methoxyethyl) -2-pyrrolidinecarboxylate (2.35 g, 10.90 mmol) in 30 ml of tetrahydrofuran (THF) 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 three hours, the mixture was emptied into saturated ammonium chloride (100 ml) and extracted into ethyl acetate.The organic phase was washed with water, dried, and concentrated, and the unpurified material obtained upon removal of the solvent was 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 (CDCl3): 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; = 8.4, 3.4).

Synthesis of (2S) -1 - (1,2-dioxo-3,3-dimethylpentyn-2-pyrrolidinecarboxylic acid A mixture of (2S) -1 - (1,) was stirred at 0 ° C for 30 minutes and at room temperature overnight. Methyl 2-dioxo-3,3-dimethylpentyl) -2-pyrrolidinecarboxylate (2.10 g, 8.23 mmole), 1 N LiOH (15 ml), and methanol (50 ml) The mixture was acidified to pH 1 with 1 N HCl it was diluted with water and extracted into 100 ml of methylene chloride.The organic extract was washed with brine and concentrated to give 1.73 g (87%) of the white solid as snow which does not require further purification. CDCI3): 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; = 10.4, 7.3); 4.55 (dd, 1H, = 8.6, 4.1). .2S) -1-.3.3-dimethyl-1,2-dioxopenth-2-pyrrolidine carboxylate 3-phenyl-1-propyl (1) A mixture of (2S) acid was stirred overnight under a nitrogen atmosphere. ) -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 methylene chloride (20 ml). The reaction mixture was filtered through Celite to remove solids and concentrated in vacuo, and the unpurified material was purified on a flash column (25% ethyl acetate in hexane) to obtain 720 mg (80%) of Example 1 as a colorless oil. 1 H NMR (CDCl 3): 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).

Figure 1. GPl 1046 protects the retinal ganglion cells against degeneration after retinal ischemia. The retinal ganglion cells were retrogradely labeled in adult rats by bilateral injection of gold fluoride into their lateral geniculate nucleus. The ganglion cells labeled in the normal rat retina appeared as white profiles against the dark background (Figure 1A). Complete retinal ischemia occurred by infusion of normal saline solution into the vitreous retinal cavity of each eye until the intraocular pressure exceeded arterial blood pressure. 28 days after the ischemic episode, the extensive degeneration of the retinal ganglion cell was evidenced by the massive reduction in the density of cells marked with fluorine-gold (Figure 1B). The administration of GPl 1046 (10 mg / kg, sc) 1 hour before the ischemic episode and at 10 mg / kg / day for the next four days produced remarkable protection of a large proportion of the vulnerable ganglion cell population (Figure 1C) .

Figure 2. GPl 1046 prevents degeneration of axons of the optic nerve and myelin after retinal ischemia Examination of the optic nerves of the same cases 5 of ischemia of the retinal revealed that GPl 1046 produces dramatic protection of the optic nerve element of ischemic degeneration. Toluidine blue staining of cross sections of the optic nerve embedded in epon revealed the detail of covers (white circles) and axons of the optic nerve (black centers) in the optic nerve of the normal rat. The optic nerves of the vehicle-treated cases examined 28 days after a 1-hour retinal ischemic episode are characterized by a decreased density of optic nerve axons and the appearance of numerous degenerated myelin figures (circles full bright white). Treatment with GPl 1046 protected most of the optic nerve axons from degeneration and also dramatically decreased the density of the degenerated myelin figures. Figure 3. GPl 1046 provides moderate protection against the death of retinal ganglion cells after the transection of the optic nerve The complete transection of the optic nerve 5 mm from the ocular globe produces massive degeneration of the retinal ganglion cells, representing a loss of > 87% of the population of normal ganglion cells 90 days after the -.JMMJHH. - "*. ... ..zz ... ._. ... ... - t- • ^ J ^^^ L_ iBÍÍtll £ ll_ wound (Table 1). Few preframed ganglion cells left over from fluorine-gold are present in vehicle-treated cases (large white figures) between a population of small microglia that digests the degenerated cell debris and takes the fluorine-gold label (Figure 3A). Treatment with GPl 1046 for 14 days resulted in a small, but not significant increase in the density of retinal ganglion cells that survived 90 days after transection (Table 1) but treatment with 1010 GPl during the first 28 days after the transection produced 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 GPl 1046 significantly affects the process of axonal degeneration of the optic nerve after transection. The axon density examination of the optic nerve in the proximal optic nerve stump of the same cases revealed a more dramatic protection produced by the 1046 GPl treatment. 90 days after the transection a few axons of ganglion cells remain inside the nerve optic (Figure 4B), representing only 5.6% of the normal population. The loss of axons reflects the death of the retinal ganglion cells and the regression or "subsequent death" of the axons of ~ 70% of the small population of surviving ganglion cells within the retina itself (Table 1). Treatment with GPl 1046 during the first 14 days after the transection of the optic nerve produced a small, but significant protection of 5.3% of the axons of the optic nerve (Figure 4D, Table 1), but treatment with the same dose of GPl 1046 for 28 days resulted in the protection of optic nerve axons for the vast majority (81.4%) of the remaining retinal ganglion cells (Figure 4C, Table 1).

Figure 5. Treatment with GPl 1046 produces a greater effect on optic nerve axons than in ganglion cell bodies. This summarized figure shows data of the ganglion cell protection of Figure 3 and photomicrographs of higher power protection of the optic nerve axon (Figure 5A &B, upper panels). The 28 day treatment with GPl 1046 produced a significant increase in axon density of the large caliber optic nerve, and particularly medium and small (Figure 5C &D, lower panels).

Figure 6. Treatment with 1046 GPl for 28 days after optic nerve transection prevents myelin degeneration in the proximal stump Immunohistochemistry of myelin basic protein ('darker marked' insulae) marks axon bundles • ^^ ÉBÉÍUÜaii. myelinated in the normal optic nerve. (Figure 6A, left above). 90 days after the transection, the extensive degeneration of myelin is evident in cases treated with vehicle, characterized by the loss of the fascicular organization and the appearance of numerous dense large myelin figures (Figure 6B, right above). Treatment with GPl 1046 during the first 14 days after the transection of the optic nerve did not alter the myelin degeneration pattern (Figure 6C, lower left panel), and produced a negligible quantitative recovery of 1.6% in myelin density (Table 1). Extending the course of treatment of GPl 1046 through the first 28 days after the transection of the optic nerve produced a dramatic preservation of the fasicular staining pattern for the myelin basic protein in the proximal stump of the optic nerve and decreased the density of the figures of degenerated myelin (Figure 6D, lower right panel), representing a 70% recovery of myelin density (Table 1).

Figure 7. Immunohistochemical marks FKBP-12 oligodendroglia (large dark cells with fibrous processes), the cells that produce myelin, located between bundles of optic nerve fibers, and also some optic nerve axons ..n-- - .. ..,) .., ». zí. ? í JßáabUatßá? t? Figure 8. Treatment with GPl 1046 for 28 days after the transection of the optic nerve prevents the degeneration of myelin in the distal stump. The complete transection of the optic nerve leads to the degeneration of the distal segments (axon fragments disconnected from the ganglion cell bodies), and the degeneration of their myelin sheaths. 90 days after the transection (Figure 8B) the immunohistochemistry of the myelin basic protein reveals the almost total loss of the fascicular organization (present in the normal optic nerve, Figure 8A) and the presence of numerous myelin figures of dense degeneration. The quantification reveals that the cross-sectional area of the transected distal stump shrinks by 31% and loses approximately V-¿of its myelin (Table 1). Treatment with 5 GPl 1046 during the first 14 days after the transection did not protect against shrinkage of the distal stump, but slightly increased myelin density, although the density of the degenerated myelin figures remained high. (Figure 8C, Table 1). Treatment with 1046 GPl during the first 28 days produced dramatic protection of the marked myelin fascicular pattern, decreased the density of the degenerated myelin figures, prevented the shrinkage of the transection of the distal stump of the transected nerve and maintained myelin levels at -99% of normal levels 5 (Figure 8D, Table 1). ^^ gA ^ * Figure 9. Treatment of 28 days with GPl 1046 starting treatment 8 weeks after the onset of streptozotocin-induced diabetes decreased grade 5 neovascularization in the internal and external retina and protected the neurons in the inner nuclear layer ( INL) and the ganglion cell layer (GCL) of degeneration. Negative images of tangential retinal sections stained with cresyl violet revealed pericarions in the three cell layers (Figure 9A). The retina of animals treated with streptozotocin administered only with vehicle (Figure 9B) exhibited cell loss of the ONL and INL, decreased thickness of the outer plexiform layer (the dark area between ONL and INL) and a dramatic increase in size and density of the retinal blood vessels (large black circular profiles) in INL, OPL, ONL and the photoreceptor layer (PR, the gray area above ONL). Treatment with GPl 1046 reduced neovascularization (ie prevented the proliferation of blood vessels) in PR, ONL, OPL and INL. Although GPl 1046 does not seemed to protect against neuronal loss in the ONL, it seems to decrease the loss of neurons in the INL and GCL compared with the controls treated with this rep tozo toe i na / vehicle.

Example 7 r-tmifíiii * '- ** -' **** - »•. - .- ... »«. »». TO .

In vivo Retinal Ganglion Cells and Optic Nerve Axon Tests The degree of reduction or prevention of degeneration in retinal ganglion cells and axons of the optic nerve was determined in a model of vision loss using surgical transection of the nerve optical to simulate the mechanical damage of the optic nerve. The effects of several FKBP ligands of neuroimmunofilin on the neuroprotection of retinal ganglion cells and the density of optic nerve axon were determined experimentally, comparing 14-day and 28-day treatments of FKBP ligand of neuroimmunofilin. The effects of treatment with FKBP ligands of neuroimmunophilin on retinal ganglion cells and axons of the optic nerve were correlated.

Surgical Procedures Adult male Sprague Dawley rats (3 months old, 225-250 grams) were anesthetized with a mixture of ketamine (87 mg / kg) and xylazine (13 mg / kg). The retinal ganglion cells were pre-labeled by bilateral stereotaxic injection of the marker Fluorescent fluorescent-gold transported retrogradely (FG, 0.5 microlitres of 2.5% solution in saline solution) at the LGNd coordinates (4.5 mm post ß, 3.5 mm lateral, 4.6 mm below the dura). Four days later, the rats labeled with FG underwent a second surgery for the '- a-n-iiMt- -,, z ... y..z ... ... ...... i. .. ..: ... z. . . . .. - .. - -_ ^ _ L ___ ^ _ íitífii micro-surgical transection of the bilateral intraorbital optic nerve 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 a FKBP neuroinmunophilin ligand (10 milligrams per kg per day sc in PEG vehicle (20 percent propylene glycol, 20 percent ethanol, and 60 percent saline)) for 14 days. A second group received the same dose of FKBP ligand neuroinmunofilin for 28 days. Each treated group had a corresponding transection and imitation / surgery and transection control group which received a corresponding dosage of 14 or 28 days only with the vehicle. All animals were sacrificed 90 days after the transection of the optic nerve and perfused pericardially with formalin. All eyes and stumps of optic nerves were removed. Cases of the study were excluded if the optic nerve vasculature was damaged or if the FG mark was absent in the retina.

Cell Accounts of the Retinal Ganglia The retinas were removed from the eyes and prepared for full-length analysis. For each group, five eyes were selected with the dense and intense FG mark for quantitative analysis using a 20 power object. Digital images of five fields were obtained in the central retina (3-4 radial millimeters at the head of the optic nerve). Cells of the ganglion and microglia Grande (<18 μm), medium (12-16 μm), and small (<10 μm) labeled FG were counted in five fields of 400 μm by 400 μm per case, 5 cases per group.

Optical Nerve Examination Proximal and distal optic stumps were identified, measured and transferred to 30% sucrose saline. The proximal trunnions of five nerves were blocked and fixed in a jaw clip, and cross sections of 10 microns were cut in a cryostat; One of ten sections per set is saved. Sections including the region 1-2 mm behind the orbit were reacted for neurofilament immunohistochemistry RT97. Axonal density analysis of the optic nerve was performed using a power oil immersion lens 63, a Dage 81 camera, and the Simple Image Analysis program. Optical nerve axons RT97 were counted in three fields of 200 μm per 200 μ per nerve. The area of the nerve was also determined for each case at power 10. As graphically described in Table I & II, the course of treatment of 14 days with a ligand FKBP neuroinmunofilina provided moderate neuroprotection of the retinal ganglion cells observed 28 days after the transection of the optic nerve. However, 90 days after the ---,, ... AA.I. . A ...... AAA * ... ^ z -. A - * A t * transection, only 5% of the ganglion cell population remained viable. 90 days after the optic nerve transection the number of axons that persisted in the proximal stump of the optic nerve accounted for approximately half the number of surviving ganglion cells in groups of animals that received only the vehicle or the 14-day course of the treatment with a ligand FKBP neuroinmunofilina. These results indicate that almost half of the axons of the ganglion cells transected retractions behind the head of the optic nerve, and that treatment with a FKBP ligand neuroimmunophilin during the first 14 days after the transection of the optic nerve is not sufficient to stop this retraction. As graphically described in Table I & II, a Longer treatment with a FKBP ligand neuroimmunofilin during the course of 28 days of treatment produced a moderate increase in the neuroprotection of the retinal ganglion cells. Approximately 12% of the vulnerable population of retinal ganglion cells was protected. A similar proportion (-50%) of axon density of the remaining optic nerve was also observed. These results demonstrate the surprising result that the degree of duration of treatment with FKBP neuroimmunophilin ligands at 28 days after transection completely stops the regression of the axons - - "- -» - * -. »- I M ae-a **» ----- damaged for essentially the entire surviving population of retinal ganglion cells The additional results are set forth in Tables III &IV.

Table 1 Effect of prolonged treatment with GPl 1046 on survival of retinal ganglion cells, preservation of optic nerve axons and myelination 90 days after optic nerve transection * significance p < .001 1 Mean Density + SEM of retinal ganglion cells labeled with fluoro-gold (RGC) in samples of 400 μm x 400 μm grid fields. 2 Mean density + SEM of axons of the optic nerve (ON) marked with antibody neurofilament RT97 in the region of interest of 200 μm x 200 μm 10 * estimated for the region of 200 μm x 200 μm in the normal optic nerve assuming 120,000 axons of RGC in the optic nerve of the normal rat, measured to be 0.630 mm2 from the area of the average cross section. 3 Adjusted for the diameter of the optic nerve 4 Calculated by multiplying the density of the axons by the ON area. 15 5 Determined from the 20X analysis of the coverage percent of the cross-sectional area of the optic nerve Table II Neuroprotective effect of GPl 1046 on the cells of the ganglion of the retina after the transection of the optic nerve Imitation ONT / Veh 0NT / 14d ONT / 28d GPl 1046 GPl 1046 ^? atlltMtjl¡gl ^ ¡m Table lll Correlation between Retinal Ganglion Cells and Optic Nerve Axons Surplus 90 days after the Optic Nerve transection and 14 or 28 days of treatment with GPl 1046 U Imitation 4- ONT / Vehíc? Lo • ONT / 14 days with GPl 104610n A ONT / 28 days with GPl 104610n Retinal Ganglion Cells,% excess Table IV GPl 1046 preserves axons of the optic nerve in the proximal stump after the transection O Imitation 0 ONTVehicle E2 ONT / 14 days with GPl 104610 mg / kg ac. [=] ONT / 28 days with GPl 104610 mg / kg ac.

Row numbers Example 6 A patient suffering from macular degeneration. A derivative as identified above, alone or in combination with one or different neopsic factors, or a pharmaceutical composition comprising the same, can be administered to the patient. A reduction in vision loss, prevention of vision degeneration, and / or promotion of vision regeneration are expected to occur with the following treatment.

Example 7 A patient suffering from glaucoma, which results in application of the optic nerve disc and damage to the nerve fibers. A derivative as identified above, alone or in combination with one or different neopsic factors, or a pharmaceutical composition comprising the same, can be administered to the patient. A reduction in vision loss, prevention of vision degeneration, and / or promotion of vision regeneration are expected to occur with the following treatment. Example 8 A patient suffering from cataracts, who require surgery. Subsequent to surgery, a derivative as identified above, alone or in combination with one or more neopsic factors, or a pharmaceutical composition comprising the same, may be administered to the patient. A reduction in loss The vision, prevention of vision degeneration, and / or promotion of vision regeneration are expected to occur with the following treatment.

Example 9 A patient suffering from a decrease or blockage of retinal blood supply related to diabetic retinopathy, ischemic optic neuropathy or retinal artery or venous block. A derivative as identified above alone or in combination with one or more neopsic factors, or a pharmaceutical composition comprising the same, may be administered to the patient. A reduction in vision loss, prevention of vision degeneration, and / or promotion of vision regeneration are expected to occur with the following treatment.

Example 10 A patient suffering from a retinal detachment. A derivative as identified above alone or in combination with one or more neopsic factors, or a pharmaceutical composition comprising the same, may be administered to the patient. A reduction in vision loss, prevention of vision degeneration, and / or promotion of vision regeneration are expected to occur with the following treatment.

Example 11 A patient suffering from tissue damage caused by inflammation associated with uveitis or conjunctivitis. A derivative as identified above alone or in combination with one or more neopsic factors, or a pharmaceutical composition comprising the same, may be administered to the patient. A reduction in vision loss, prevention of vision degeneration, and / or promotion of vision regeneration are expected to occur with the following treatment.

Example 12 A patient suffering from photoreceptor damage caused by chronic or acute exposure to ultraviolet light. A derivative as identified above alone or in combination with one or more neopsic factors, or a pharmaceutical composition comprising the same, may be administered to the patient. A reduction in vision loss, prevention of vision degeneration, and / or promotion of vision regeneration are expected to occur with the following treatment.

Example 13 A patient suffering from optic neuritis. A derivative as identified above alone or in combination with one or more neopsic factors, or a pharmaceutical composition comprising the same, may be administered to the patient. A reduction in vision loss, prevention of vision degeneration, and / or promotion of vision regeneration are expected to occur with the following treatment.

Example 14 A patient suffering from tissue damage associated with a "dry eye" disorder. A derivative as identified above alone or in combination with one or more neopsic factors, or a pharmaceutical composition comprising the same, may be administered to the patient. A reduction in vision loss, prevention of vision degeneration, and / or promotion of vision regeneration are expected to occur with the following treatment.

Example 15 The efficacy of representative compounds of different immunophilin ligand series in the protection of retinal ganglion cell axons from degeneration after transection of the optic nerve is set forth in Table V.

• ^^ P ^ j ^ ja Table V Efficacy of representative compounds of the different immunophilin ligand series in retinal ganglion cell axons protected from degeneration following the transection of the optic nerve * * »** • ** - Table V below j - "- ** - ^ ^ g« 5 ^^ * Table V continued EXAMPLE 16 THE NEUROINMUNOFILI LIGAND TO FKBP GPI-1046 IMPROVES THE SURVIVAL OF RETINAL GANGLION CELL AND STOPS DEATH AFTER THE OPTICAL NERVE TRANSITION Transection of the mammalian optic nerve results in a brief period of abortive regeneration, but most of the axotomized dead neurons and the axons of many cells MtfiMlliliMlHÉün of persistent ganglion dead behind the head of optic nerve. The present example was designed to examine the neuroprotective effects of GPI-1046 after the transection of the optic nerve. The retinal ganglion cells in male adult rats Sprague Dawley were retrogradely marked by fluorine-gold injection in LGNd and four days later the optic nerves were transected 5 mm behind the globe. The groups of animals already received is GPI-1046 10 mg / kg / day s.c. or vehicle for 28 days. All animals and experimental controls were sacrificed 90 days after the transection. For 90 days only - 10% of the labeled FG ganglion cell population survived, but less than half of these neurons maintained axons that extended before the optic nerve head, as detected by neurofilament immunohistochemistry RT97. Treatment of GPI-1046 produced a moderate degree of neuroprotection pericarions, moderation of 25% of the ganglion cell population, and retained the axons of virtually all protected neurons in the proximal stump of the transected nerve. These results indicate that treatment with the neuroimmunophillic ligand FKBP GPI-1046 produced a fundamental alteration in the pathological process after damage to CNS tracts.

^^ H ^ - These results also demonstrate that the small-molecule neuroinmunophilin ligand GPl 1046 enhances the neurite outbreak in the culture, improves peripheral nerve regeneration, and stimulates outbreaks within CNS after partial 5-partiation.

Example 17 NEUROINMUNOPHYLLINE LIGANDS PROMOTING THE RECOVERY OF NEUROPATHY 10 PERIPHERAL SENSORY ASSOCIATED WITH DIABETES INDUCED BY STREPTOZOTOCIN Peripheral neuropathy is a common complication of type 2 diabetes in some diabetic patients 30-40%. Neurotrophic factors such as factor of Nerve growth (NGF) are known to promote development 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 FKBP-12 of neuroimmunophilin such as small molecule of GPI-1046, have also been shown to cause 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 for their ability to improve A.A ~ .A ".¿ * - ~ ** - * -t? Tax? .t. . . ., "._. . . ... ... . z, - .., ... ... .. - ^ ia¡¡Ba¡s_- sensory function in the diabetic rat induced by streptozotocin. The procedure involved using Wistar male rats to which they were administered a single injection of streptozotocin (65 mg / kg i.v.). Blood glucose levels were determined weekly during the first three weeks and in the last week of the experiment. The animals were evaluated weekly for signs of sensory neuropathy using the conventional hot plate and the tail blow apparatus test procedures. After six weeks, the treatment is already with GPI-1046 or vehicle was started. The results showed that the behavior test using the hot plate and tail blow apparatus indicated improvement in latency in injured animals treated for 6 weeks with GPI-1046 at 10 mg / kg s.c. The results also showed that GPI-1046 decreased the sequela of behavior of diabetic sensory neuropathy and may offer some relief for patients suffering from diabetic peripheral neuropathy.

Morris Water Labyrinth / Evidence of Aging and Memory Test Old rodents exhibited marked individual differences in the functioning of a variety of behavioral tasks, including spatial discrimination of double selection in a modified T-maze, spatial discrimination, in a task of circular platform, passive abstinence, radial maze tasks, and space navigation in a pool. In all these tasks, a proportion of old rats or mice is also defected as the vast majority of young control animals, while other animals show severe decreases in memory function compared with young animals. For example, Fischer and colleagues showed that the proportion of rats that exhibit significant decreases in space navigation increases with age, (Fischer et al., 1991b) with 8% of all rats at 12 months of age, 45% at those of 18 months of age, 53% of those of 24 months of age, and 90% of those of 30 months of age exhibited decreases in spatial acquisition of the Morris water maze task relative to young controls. Specifically, the decline in rodent learning and spatial memory during aging has been accepted by many researchers as an intriguing correlative animal model of human senile dementia. Cholinergic function in the hippocampus has been studied extensively as a component of spatial learning in rodents, and the decline of cholinergic function of the hippocampus has been noted in parallel with the development of decreased learning and memory. In addition, it has been shown that other neurotransmitter systems contribute to spatial learning, and decline with age, such as the dopaminergic and noradrenergic, serotonergic and glutamatergic systems. Also, the reports on deficits of induction of long-term potentiation (LTP), of the hippocampus related to aging, a reduction in the frequency of theta rhythm, a loss of experience dependent on the elasticity of the location units of the hippocampus, and Reductions in hippocampal protein kinase C are in accordance with the concept that an underlying simple pathology can not be identified as the cause of the age-related decrease in behavior in rodents. However, the various experimental therapeutic proposals that have been taken to improve the function of memory in aged rodents have leaned somewhat towards the cholinergic hypothesis. 15 Morris's water labyrinth is widely used to evaluate the formation and retention of spatial memory in experimental animals. The test depends on the animal's ability to use spatial visual information to locate a submerged escape platform in a water tank. It is important that the tank itself be free of specific visual characteristics as much as possible - so, it is always in a circular shape, the sides remain smooth smooth and in uniform pale colors, and the water becomes opaque with pigment coloring non-toxic water or milk powder. This is to ensure that the animal navigates only by the use of visual clues more ^^^ gj ^ g ^^ g ^ í ^ g ^^ g ^ distant, or by the use of intra-labyrinth cues specifically provided by the experimenter. The tank fills up to a level that forces the animal to actively swim. Normal mice and rats react adversely to the swim portion of the test and will rise, and remain on, on an escape platform from which they are removed to a heated resting cage. If the platform is visible (ie, above the surface), the animals located in the tank will quickly learn to go to the platform and climb on it. The test with a visible platform will also ensure that the experimental animals are not blind and show sufficient motivation and resistance to perform the task, which may be important in experiments involving aged rodents. If the platform is invisible (ie, submerged just below the surface), normal animals learn to use distant visuals in the test room to orient themselves in the test tank, and, when they are placed in the tank, they will move quickly to the approximate location of the platform and that area circulates until the platform is found. The trajectory, speed and swimming time of the animals is tracked with a roof camera for later computer analysis. During the course of several successive tests, spatial learning can therefore be defined as a fall of the swim distance, or the time elapsed, from the placement in the tank to the escape on the invisible platform. The test can be adapted to assess various aspects of spatial memory: a) acquisition of a task with 5 clues, where the ability of the animal to attach a visual clue directly to the escape platform depends on the cortical function (ie, it is suspended a ball on the escape platform and the animal learns to follow this track to find the platform); b) acquisition of a spatial task, where the The ability of the animal to learn the location of a submerged escape platform based on the combination of distant visual clues depends on the function of the hippocampus (ie, the animal learns to triangulate its position in the tank by visually aligning the paper towel dispenser with the door and the ceiling lamp); c) retention of a successfully acquired spatial task, which is predominantly dependent on cortical function (ie, the animal must remember the spatial location of the platform for several weeks); d) a reverse hippocampus-dependent task where the animal must reacquire a new space platform location (ie, the platform moves to a new location between swimming tests and the animal must abandon its previous search strategy and acquire a new one). These different modifications of the procedure of Morris water maze can be applied in sequence to the "" "fr - * - * - • - ¿fe - * - same set of experimental animals and allows a complete characterization of its memory function and its decline with normal aging.In addition, such series of sequential memory tests sheds some light on the functional integrity of specific brain systems involved in the acquisition and retention of spatial memory (for example, rats with cholinergic lesions of the hippocampus may remember the location of a platform acquired weeks earlier, but persevere on location from the old platform after the platform moves).

EXAMPLE 20 EFFECTS OF THE CHRONIC ADMINISTRATION OF GPI-1046 ON LEARNING AND SPACE MEMORY IN RODENTS 15 OLD This example shows the effects of chronic treatment with the ligand FKBP GPI-1046 systematically available in learning and spatial memory in old rodents. The procedure involves the use of male mice C57BL / 6N-Nia three months old (young) and 18-19 months old (old) used to the well-known and conventional Morris water maze during a visible platform training phase of 4 tests / day, 3 -4 days. The subsequent spatial acquisition test was conducted as follows: All mice had 4 trials / day (block) for 5 days. He - ^ n maximum swimming time was 90 seconds. The old mice were housed in a group "decreased by age" if their functioning during blocks 4 or 5 of the acquisition phase was > 1 S.D. above the average of "young" mice, and to a group 5"not decreased by age" if its functioning was < 0.5 S.D. above the average of "young" mice. The old groups were then divided into statistically similar "GPI-1046" and "vehicle" groups. Daily treatment with 10 mg / kg of GPI-1046 was initiated 3 days after the end of the training acquisition, and continued through the retention test. The retention test began after 3 weeks of dosing using the same methods as in the acquisition phase. Swimming distances (cm) were analyzed in a 7X5 ANOVA including Groups and Blocks (1-5) as factors in the analysis, treating the Blocks as a repeated measure. The results showed that planned contrasts revealed that there are significant differences between the "young" groups and those treated with "GPI-1046 and vehicle weakened by the age "at the end of the acquisition phase, F1 58 = 26.75, P = 0.0001, and F1 58 = 17.70, P = 0.0001 respectively.While there were no significant differences between the two" weakened old "groups, F1 58 = 0.67 , P = 0.42 During the retention test, however, animals treated with "vehicle weakened by age "had a significantly run LdáßifiÍÍIMlMt _ ^^^^^^ _-.._. > a ^^ __ ^ _ ^ _ ^^^^^^^^^^^^^^^^^^^ _ ^ _ ^ _ i ^ _ ^^^^ _ ^^^^^^^^^^^ ^ BA ^ ^ more deficient than "weakened old animals - GPI-1046" and "young", F1 69 = 8.11, P = 0.006, and F1 69 = 25.45, P = 0.0001 respectively. There was no longer any statistically significant difference between the groups treated "young" and "weakened old -GPI-1046" during the retention phase, F, 69 = 3.09, P = 0.08. In summary, the systemic treatment with GPI-1046 significantly improved the spatial memory of mice with age-related spatial memory impairments. The invention being thus described, it will be obvious that it can be varied in many ways. Such variations will not be considered as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims. ^^^^^^^^^^^^^ g ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^ ^ ^ ^ ^ ^

Claims (35)

1. A method for treating a vision disorder, improving vision, treating memory depletion, or increasing memory performance in an animal, which comprises administering to the animal an effective amount of an N-linked urea or carbamate of a compound heterocyclic thioester. The method according to claim 1, characterized in that the N-linked urea or carbamate of a heterocyclic thioester compound is immunosuppressive or non-immunosuppressive. 3. The method according to claim 1, characterized in that the N-linked urea or carbamate of a heterocyclic thioester compound has an affinity for an immunoglycine type FKBP. 4. The method according to claim 3, characterized in that the immunophilin type FKBP is FKBP-1

2. The method according to claim 1, characterized in that the vision disorder is selected from the group consisting of: visual decrease; orbital disorders; disorders of the lacrimal apparatus; disorders of the eyelids; disorders of the conjunctiva; disorders of the cornea; waterfalls; disorders of the uveal tract; disorders of the retina; optic nerve disorders; or visual trajectories; disorders and diseases of the eye induced by free radicals; disorders and diseases of the eye mediated immunologically; eye injuries; and symptoms and complications of eye disease, eye disorder, or eye injuries. 6. The method according to claim 1, characterized in that it is to improve the vision that naturally occurs in an animal, in the absence of any disorder, disease, or ophthalmological wound. The method according to claim 1, characterized in that the N-linked urea or carbamate of a heterocyclic thioester compound is a compound having the formula (I): or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A and B, taken 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 additional heteroatoms O, S, SO, SO2, N, NH, and NR3; X is either O or S; ife is a direct bond to Z, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any of the carbon atoms of the alkyl or alkenyl are substituted optionally 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 where any of the alkyl or alkenyl carbon atoms are optionally replaced with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C ^ Ce. straight or branched chain alkenyl or alkynyl of C3-C6, and connecting alkyl of 0, -04, wherein the connecting alkyl forms a heterocyclic ring initiating with the nitrogen of NR, and ending with one of the carbon atoms of the alkyl or alkenyl chain and wherein the heterocyclic 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 either substituted or unsubstituted with one or more substituents independently selected from the group including, but not limited to a, alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, straight or branched chain alkyl of 0, -Cg, C2-C9 alkenyloxy, straight chain alkenyl or • Branched amphibole of C2-C9, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilide, halo, haloalkyl, hydroxy, isocyano, isonitrile, nitrile, nitro , nitroso, phenoxy, sulfhydryl, sulfonyl sulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl and carboxylic and heterocyclic portions, including alicyclic and aromatic structures; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring consists of 1-6 heteroatoms independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any of the carbon atoms of the alkyl or alkenyl are 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 of the carbon atoms of the alkyl or alkenyl are optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl of C ^ Ce, or straight or branched chain alkenyl of C2-C6; wherein any of the alkyl atoms of the alkyl or alkenyl are optionally substituted at one or more positions with C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, or Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C2-C6 alkenyl alkyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, alkyl, alkylamino, aminoalkyl , sulfhydryl, thioalkyl, or sulfonyl; 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 of the carbon atoms of the alkyl or alkenyl are optionally replaced with O, NH, NR3, S, SO or SO2; W is O or S, CH2, or H2; and U is either 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, C3-C8 cycloalkyl, alkyl or straight or branched chain alkenyl and straight or branched chain C2-C6 alkyl or alkenyl substituted at one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, straight or branched chain alkyl of C1-C6, straight or branched chain alkenyl of C2-C6, carbonyl, thiocarbonyl, thioester ester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, and alkyl or alkenyl substituted on Ma ^ ^^^ taMMtfaMaH _ ^ _ ^ _ ^ jI ^^^ _ ^^^^ _. ^ _______ B ^ ¡= £ ^ where any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO2, O, or NR3; and when U is N, then R, and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl or alkenyl of C, -C6? and straight or branched C2-C6 alkyl or alkenyl substituted at one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, straight or branched chain alkyl of C1-C6, straight or branched chain alkenyl of C2-C6, carbonyl, thiocarbonyl, thioester ester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, and substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO2, O, or NR

3. or R, and R2 can be taken together to form a heterocyclic ring. The method according to claim 7, characterized in that Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl fluorenyl and phenyl. The method according to claim 1, characterized in that the N-linked urea or carbamate of a heterocyclic thioester compound is a compound having the formula (II): or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F, G and J are independently CH2, O, S, SO, SO2, NH, or NR3; X is either O or S; Y is a direct bond to Z, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any of the carbon atoms of the alkyl or alkenyl are 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 of the atoms carbon of the alkyl or alkenyl are optionally replaced with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C, -C6, alkenyl or alkynyl straight or branched chain of C3-C6, and connecting alkyl of 0, -04, wherein the alkyl of connection forms a heterocyclic ring initiating with the nitrogen of NR, and ending with one of the carbon atoms of the alkyl or alkenyl chain and wherein the heterocyclic 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 either substituted or unsubstituted with one or more substituents independently selected from the group including, but not limited to a, alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, straight or branched chain alkyl of C, -C9, C, -Cg alkoxy, C2-C9 alkenyloxy, straight or branched chain alkenyl of C2-C9, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilide, halo, haloalkyl, hydroxy, imino, isocyano, isonitrile, nitrile, nitro, nitroso, phenoxy, sulfhydryl, sulfonyl sulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl and carboxylic and heterocyclic portions, including alicyclic and aromatic structures; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring consists of 1-6 heteroatoms independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl or straight or branched chain alkenyl of C2-C6, wherein any of the carbon atoms of the alkyl or alkenyl are 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 of the carbon atoms of the alkyl or alkenyl are optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6; wherein any of the alkyl atoms of the alkyl or alkenyl are optionally substituted at one or more positions with C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, or Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, 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 at one or more positions with oxygen to form a carbonyl; or wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with O, NH, NR3, S, SO or SO2; W is O or S, CH2, or H2; and U is either 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, C3-C8 cycloalkyl, alkyl or straight or branched chain alkenyl of C, -C6 and straight or branched chain C2-C6 alkyl or alkenyl substituted at one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, straight or branched chain alkyl of C1-C6, straight or branched chain alkenyl of C2-C6, carbonyl, thiocarbonyl, thioester ester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, and substituted alkyl or alkenyl where any of the alkyl or alkenyl carbon atoms are optionally replaced with S, SO, SO2, O, or NR3; and when U is N, then R, and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl or alkenyl of C, -C6? and C2-C6 straight or branched chain alkyl or alkenyl substituted at one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, straight or branched chain alkyl of C1-C6, straight or branched chain alkenyl of C2-C6, carbonyl, thiocarbonyl, thioester ester, alkoxy, The alkenoxy, cyano, nitro, alkyl, alkylamine, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, and substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO2, O, or NR3 or R, and R2 can be taken together to form a heterocyclic ring 10. The method according to claim 9, characterized in that Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl 11. The method according to claim 1, characterized in that the N-linked urea or carbamate of a heterocyclic thioester compound is a compound having the formula (III): or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F, and G are independently CH2, O, S, SO, SO2, NH, and NR3 wherein at least 2 of E, F, and G are CH2; X is either O or S; It is a direct bond to Z, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any of the carbon atoms of the alkyl or alkenyl are 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 where any of the carbon atoms of the alkyl or alkenyl are optionally replaced with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C, -C6, alkenyl or alkynyl straight or branched chain of C3-C6, and C, -C4 connecting alkyl, wherein the alkyl of connection forms a heterocyclic ring initiating with the nitrogen of NR, and ending with one of the carbon atoms of the alkyl or alkenyl chain and wherein the heterocyclic 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 either substituted or unsubstituted with one or more substituents independently selected from the group including, but not limited to a, alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, straight or branched chain alkyl of C, -C9, C, -C9 alkoxy, C2-C9 alkenyloxy, straight chain alkenyl or ^^ branched C2-C9 gfe, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilide, halo, haloalkyl, hydroxy, imino, isocyan, isonitrile, nitrile, nitro, nitrous , phenoxy, sulfhydryl, sulfonyl sulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl and carboxylic and heterocyclic portions, including alicyclic and aromatic structures; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring consists of 1-6 heteroatoms independently selected from the group 10 consists of O, N and S; and wherein the aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any of the alkyl atoms of the alkyl or alkenyl are 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 of the carbon atoms of the alkyl or alkenyl are optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl of C, -C6, or straight chain alkenyl or 25 branched C2-C6; where any of the atoms in The carbon of the alkyl or alkenyl is optionally substituted in one or more positions with C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxyl, carbonyl oxygen, or; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, 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 a 10 or more positions with oxygen to form a carbonyl; or wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with O, NH, NR3, S, SO or SO2; W is O or S, CH2, or H2; and 15 U is either 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, C3-C8 cycloalkyl, alkyl or straight or branched chain alkenyl of C, -C6 and straight chain alkyl or alkenyl or Branched C2-C6 substituted at one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, straight or branched chain alkyl of C1-C6, straight or branched chain alkenyl of C2-C6, carbonyl, thiocarbonyl , thioester ester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, Sulfhydryl, thioalkyl, sulfonyl, and alkyl or alkenyl substituted in MtWÜMIllllriMt. wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO2, O, or NR3; and when U is N, then R, and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl or alkenyl of C, -C6, and straight chain alkyl or alkenyl. or branched C2-C6 substituted at one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, straight or branched chain alkyl of C1-C6, straight or branched chain alkenyl of C2-C6, carbonyl, thiocarbonyl , thioester ester, alkoxy, alkenoxy, cyano, nitro, amino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, and substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO2, O, or NR3; or R, and R2 can be taken together to form a heterocyclic ring. The method according to claim 11, characterized in that Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl. The method according to claim 1, characterized in that the N-linked urea or carbamate of a heterocyclic thioester compound is a compound having the formula (IV): du > BAtrtt ÜNHták. Ri or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: n is 1, 2 or 3 forming a 5-7 membered heterocyclic ring; X is either O or S; Y is a direct bond to Z, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any of the carbon atoms of the alkyl or alkenyl are 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 of the alkyl or alkenyl carbon are optionally replaced with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C, -C6, alkenyl or alkynyl straight or branched chain of C3-C6, and C, -C4 connecting alkyl, wherein the alkyl of connection forms a ring _ ¿Yzzí¡. heterocyclic starting with the nitrogen of NR, and ending with one of the carbon atoms of the alkyl or alkenyl chain and wherein the heterocyclic 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 either substituted or unsubstituted with one or more substituents independently selected from the group including, but not limited to a, alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, straight or branched chain alkyl of C, -C9, C, -C9 alkoxy, C2-C9 alkenyloxy, straight or branched chain alkenyl of C2-C9, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilide, halo, haloalkyl, hydroxy, isocyano, isonitrile, nitrile, nitro, nitroso, phenoxy, sulfhydryl, sulfonyl sulfoxy, thio , thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl and carboxylic and heterocyclic portions, including alicyclic and aromatic structures; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring consists of 1-6 heteroatoms independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any of the carbon atoms of the alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, amino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl or oxygen to form a carbonyl, or wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6; wherein any of the alkyl atoms of the alkyl or alkenyl are optionally substituted at one or more positions with C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, or Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, 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 at one or more positions with oxygen to form a carbonyl; or wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with O, NH, NR3, S, SO or SO2; W is O or S, CH2, or H2; and U is either 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, C3-C8 cycloalkyl, alkyl or straight or branched chain alkenyl of C, -C6 and straight or branched chain C2-C6 alkyl or alkenyl substituted at one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, straight or branched chain alkyl of C1-C6, straight or branched chain alkenyl of C2-C6, carbonyl, thiocarbonyl, thioester ester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, and substituted alkyl or alkenyl where any of the alkyl or alkenyl carbon atoms are optionally replaced with S, SO, SO2, O, or NR3; and when U is N, then R, and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl or alkenyl of C, -C6 and straight chain alkyl or alkenyl or branched C 2 -C 6 substituted at one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, straight or branched chain alkyl of C 1 -C 6, straight or branched chain alkenyl of C 2 -C 6, carbonyl, thiocarbonyl, ester thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, and substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO2, O, or NR3; or R, and R2 can be taken together to form a heterocyclic ring. The method according to claim 13, characterized in that Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl fluorenyl and phenyl. 15. The method according to claim 13, characterized in that n is 1 or 2: Y is (CH2) 2 or a direct bond; Z is CH; C is 3-pyridyl, 4-methoxyphenyl, phenyl, or 2-phenylethyl; D is hydrogen, phenyl or 2-phenylethyl; R, is hydrogen; and R 2 is 2-methylbutyl, 1,1-dimethylpropyl, cyclohexyl, 1-adamantyl, or phenyl. 16. The method according to claim 13, characterized in that the compound is selected from the group consisting of: 3- (3-Pi rid i I) -1 -propi I-2S-1 - [(2-methyl butyl) carbamoyl] pyrrole n-2-carboxylate; 3- (3-Pi rid i I) -1-propyl I-2S-1 - [(1 ', 1'-Dimethyl propi I) carbamoyl] pyrrole id in-2-carboxylate; 3- (3-Pi rid i I) -1-pro pil -2 S-1 - [(cyclohexyl) thiocarbamoi I] pyrrole idin-2-carboxylate; and pharmaceutically acceptable salts, esters and solvates thereof. The method according to claim 1, characterized in that the N-linked urea or carbamate of a heterocyclic thioester compound is a compound having the formula (V): 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 C, -Cg, or straight or branched chain alkenyl of C2-C6, wherein any alkyl or alkenyl carbon atom Is optionally substituted at one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, amino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or in wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; Y is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, 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 carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C, -C6, alkenyl or alkynyl of straight or branched chain of C3-C6, and alkyl of C-C4 connection, wherein a bridge is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing the heteroatom forms a ring, wherein the ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic ring, mono-, bi- or 20 tricyclic, carbo- or heterocyclic, wherein the ring is either substituted or unsubstituted with one or more substituents; wherein the individual ring size of 5-8 members; wherein the heterocyclic ring consists of 1-6 heteroatoms independently selected from the group consisting of O, N and S; and where the The aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of C | -C6, or straight or branched chain alkenyl of C2-C6, 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 replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6; wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino , alkylamino, ammoalkyl, 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 alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; A, B, R1, R2, U, W and X are as defined in another manner in claim 7 above. The method according to claim 1, characterized in that the N-linked urea or carbamate of a heterocyclic thioester compound is administered to the animal in combination with an effective amount of one or more factors useful in the treatment of the disorders of vision , improvement of the vision, treatment of the decrease of the memory, or increase of the operation of the memory in an animal. The method according to claim 18, characterized in that one or more factors are selected from the group thr consisting of immunosuppressants for treating autoimmune, inflammatory, and immunologically mediated disorders; healing agents for injuries to treat injuries resulting from injuries or surgery; antiglaucomatous medications to treat abnormally high intraocular pressure; neurotrophic factors and growth factors to treat neurodegenerative disorders or stimulate neurite growth; effective compounds to limit or prevent hemorrhage or neovascularization to treat macular degeneration; and antioxidants to treat oxidative damage to eye tissues. 20. A pharmaceutical composition for treating a ^^^ * vision disorder, improve vision, treat memory depletion, or increase memory performance in an animal characterized in that it comprises: (i) an effective amount of a linked urea or carbamate N-5 a heterocyclic thioester compound for treating a vision disorder, improving vision, treating memory depletion, or increasing memory performance in an animal; and (ii) a pharmaceutically acceptable carrier. 21. The pharmaceutical composition according to claim 20, characterized in that the N-linked urea or carbamate of a heterocyclic thioester compound is immunosuppressant or non-immunosuppressant. 22. The pharmaceutical composition according to claim 20, characterized in that the N-linked urea or carbamate of a heterocyclic thioester compound has an affinity for an immunophilin type FKBP. 23. The pharmaceutical composition according to claim 22, characterized in that the immunophilin type FKBP 20 is FKBP-12. 2

4. The pharmaceutical composition according to claim 20, characterized in that the vision disorder is selected from the group consisting of: visual decline, orbital disorders; disorders of the lacrimal apparatus; disorders 25 the eyelids; disorders of the conjunctiva; disorders of the cornea; Jump up ^ stet Hj ^ cataracts; disorders of the uveal tract; disorders of the retina; optic nerve disorders or visual trajectories, disorders and diseases of the eye induced by free radicals; disorders and diseases of the eye mediated immunologically; eye injuries; and symptoms and complications of eye diseases, eye disorders, or eye injuries. 2

5. The pharmaceutical composition according to claim 20, characterized in that the N-linked urea or carbamate of a heterocyclic thioester compound is a compound having the formula (I): or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A and B, taken together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing any combination of CH2O, S, SO, SO2, N, NH, or NR3; X is either O or S; It is a direct bond to Z, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any of the carbon atoms of the alkyl or alkenyl are optionally substituted in one or more 5 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 where any of the alkyl or alkenyl carbon atoms are optionally replaced with 10 O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C, -C6, alkenyl or alkynyl straight or branched chain of C3-C6, and C, -C4 connecting alkyl, wherein the alkyl of connection forms a ring Heterocyclic initiating with the nitrogen of NR, and ending with one of the carbon atoms of the alkyl or alkenyl chain and wherein the heterocyclic ring is optionally fused to an Ar group; Ar is an alicyclic or aromatic ring, mono-, bi- or 20 tricyclic, carbo- or heterocyclic, wherein the ring is either substituted or unsubstituted with one or more substituents independently selected from the group including, but not limited to, alkylamino, amido, amino, aminoalkyl, azo, benzyloxy , straight or branched chain alkyl of C, -C9, alkoxy 25 C, -C9, C2-C9 alkenyloxy, straight chain alkenyl or Ethyl-aluminum, branched-chain C2-C8, C3-C8-cycloalkyl, C5-C7-cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilide, halo, haloalkyl, hydroxy, isocyano, isonitrile, nitrile , nitro, nitroso, phenoxy, sulfhydryl, sulfonyl sulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl and carboxylic and heterocyclic portions, including alicyclic and aromatic structures; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring consists of 1-6 heteroatoms independently selected from the group 10 consists of O, N and S; and wherein the aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any of the alkyl atoms of the alkyl or alkenyl are 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 of the carbon atoms of the alkyl or alkenyl are optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl of C, -C6, or straight chain alkenyl or 25 branched C2-C6; where any of the atoms in alkyl or alkenyl carbon are optionally substituted at one or more positions with C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, or Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, 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 at one or more positions with oxygen to form a carbonyl; or wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with O, NH, NR3, S, SO or SO2; W is O or S, CH2, or H2; and U is either 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, C3-C8 cycloalkyl, alkyl or straight or branched chain alkenyl of C, -C6 and straight or branched chain C2-C6 alkyl or alkenyl substituted at one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, straight or branched chain alkyl of C1-C6, straight or branched chain alkenyl of C2-C6, carbonyl, thiocarbonyl, thioester ester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, and substituted alkyl or alkenyl where any of the alkyl or alkenyl carbon atoms are optionally replaced with S, SO, SO2, O, or NR3; and when U is N, then R, and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl or alkenyl of C, -C6? and C2-C6 straight or branched chain alkyl or alkenyl substituted at one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, straight or branched chain alkyl of C1-C6, straight or branched chain alkenyl of C2-C6, carbonyl, thiocarbonyl, thioester ester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, and substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO2, O, or NR3; or R, and R2 can be taken together to form a heterocyclic ring. 2

6. The pharmaceutical composition according to claim 20, characterized in that Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl fluorenyl and phenyl. The pharmaceutical composition according to claim 20, characterized in that the N-linked urea or carbamate of a heterocyclic thioester compound is a compound having the formula (II): or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F, G and J are independently CH2, O, S, SO, SO2, NH and NR3 wherein at least two of E, F, G, and J are CH2; X is either O or S; Y is a direct bond to Z, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any of the carbon atoms of the alkyl or alkenyl are 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 of the alkyl or alkenyl carbon are optionally replaced with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C, -C6, alkenyl or alkynyl straight or branched chain of C3-C6, and C, -C4 connecting alkyl, wherein the alkyl of connection forms a heterocyclic ring initiating with the nitrogen of NR, and ending with one of the carbon atoms of the alkyl or alkenyl chain and wherein the heterocyclic 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 either substituted or unsubstituted with one or more substituents 10 independently selected from the group including, but not limited to, alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, straight or branched chain alkyl of C, -C8, C, -C9 alkoxy, C2 alkenyloxy -C9, straight or branched chain alkenyl of C2-C8, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, Carbonyl, carboxy, cyano, diazo, ester, formanilide, halo, haloalkyl, hydroxy, imino, isocyano, isonitrile, nitrile, nitro, nitroso, phenoxy, sulfhydryl, sulfonyl sulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl and carboxylic and heterocyclic portions, including structures 20 alicyclic and aromatic; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring consists of 1-6 heteroatoms independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkyl amine is optionally oxidized to an N-oxide 25 corresponding; Z is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any of the carbon atoms of the alkyl or alkenyl are optionally substituted in one or more of the carbon atoms. 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 of the carbon atoms of the alkyl or alkenyl are optionally replaced with O, 10 NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6; wherein any of the carbon atoms of the alkyl or alkenyl are optionally substituted in One or more positions with C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, or Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, 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 at one or more positions with oxygen to form a carbonyl; or wherein any of the carbon atoms of the alkyl or ^ mtt ¿* «*** - * - < alkenyl are optionally replaced with O, NH, NR3, S, SO or SO2; W is O or S, CH2, or H2; and U is either 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, C3-C8 cycloalkyl, alkyl or straight or branched chain alkenyl of C, -C6 and straight or branched chain alkyl or alkenyl of C2-C6 substituted at one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, straight or branched chain alkyl of C1-C6, straight or branched chain alkenyl of C2-C6, carbonyl, thiocarbonyl, thioester ester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, and substituted alkyl or alkenyl where any of the alkyl or alkenyl carbon atoms are optionally replaced with S, SO, SO2, O, or NR3; and when U is N, then R, and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl or alkenyl of C, -C6 and straight chain alkyl or alkenyl or branched C 2 -C 6 substituted at one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, straight or branched chain alkyl of C 1 -C 6, straight or branched chain alkenyl of C 2 -C 6, carbonyl, thiocarbonyl, thioester, alkoxy, alkenoxy, cyano, nitro, alkyl, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl ester, and substituted alkyl or alkenyl wherein any of the alkyl or alkenyl carbon atoms are optionally replaced with S, SO, SO2, O, or NR3 or R, and R2 can be taken together to form a heterocyclic ring. 28. The pharmaceutical composition according to claim 27, characterized in that Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl fluorenyl and phenyl. 29. The pharmaceutical composition according to claim 20, characterized in that the N-linked urea or carbamate of a heterocyclic thioester compound is a compound having the formula (III): or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: E, F, and G are independently CH2, O, S, SO, SO2, NH, and NR3 wherein at least 2 of E, F, and G are CH2; j JkJ-3 »-. X is either O or S; Y is a direct bond to Z, straight or branched chain alkyl or straight or branched chain alkenyl of C2-C6, wherein any of the carbon atoms of the alkyl or alkenyl are 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 of the carbon atoms of the alkyl or alkenyl they are optionally replaced with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C, -C6, alkenyl or alkynyl straight or branched chain of C3-C6, and C, -C4 connecting alkyl, wherein the alkyl of connection forms a heterocyclic ring initiating with the nitrogen of NR, and ending with one of the carbon atoms of the alkyl or alkenyl chain and wherein the heterocyclic 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 either substituted or unsubstituted with one or more substituents independently selected from the group included, but is not limited to, alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, straight or branched chain alkyl of C, -C9, C, -C9 alkoxy, C2-C9 alkenyloxy, straight or branched chain alkenyl of C2-C9 , C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilide, halo, haloalkyl, hydroxy, methyl, isonitrile, nitrile, nitro, nitroso, phenoxy, sulfhydryl, sulfonyl sulfoxy , thio, thioalkyl, thiocarbonyl, thiocene, thioester, thioformamido, trifluoromethyl and carboxylic and heterocyclic portions, including alicyclic and aromatic structures; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring consists of 1-6 heteroatoms independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any of the carbon atoms of the alkyl or alkenyl are 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 of the carbon atoms of the alkyl or alkenyl are optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl of C, -C6, or straight chain alkenyl or daMHHMKIÜÉB ^^ ki branched C2-C6; wherein any of the alkyl atoms of the alkyl or alkenyl are optionally substituted at one or more positions with C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, or Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, mino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; 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 of the carbon atoms of the alkyl or alkenyl are optionally replaced with O, NH, NR3, S, SO or SO2; W is O or S, CH2, or H2; and U is either 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, C3-C8 cycloalkyl, straight or branched chain alkyl or alkenyl of C , -C6 and straight or branched C2-C6 alkyl or alkenyl substituted at one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, straight or branched chain alkyl of C1-C6, straight chain alkenyl or branched C2-C6, carbonyl, thiocarbonyl, thioester ester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, • kA HÉriUÉ ^^ - ^^ sulfhydryl, thioalkyl, sulfonyl, and substituted alkyl or alkenyl wherein any of the alkyl atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO2, O, or NR3; and when U is N, then R, and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl or alkenyl of C, -C6 and straight chain alkyl or alkenyl or branched C 2 -C 6 substituted at one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, straight or branched chain alkyl of C 1 -C 6, straight or branched chain alkenyl of C 2 -C 6, carbonyl, thiocarbonyl, ester thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, and substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO2, O, or NR3; or R, and R2 can be taken together to form a heterocyclic ring. 30. The pharmaceutical composition according to claim 29, characterized in that Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl. The pharmaceutical composition according to claim 20, characterized in that the N-linked urea or carbamate of a heterocyclic thioester compound is a compound having the formula (IV): or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: n is 1, 2 or 3 forming a 5-7 membered heterocyclic ring; X is either O or S; Y is a direct bond to Z, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any of the carbon atoms of the alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamine, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any of the alkyl or alkenyl carbon are optionally replaced with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C, -C6, alkenyl or alkynyl straight or branched chain of C3-C6, and C, -C4 connecting alkyl, wherein the alkyl of connection forms a heterocyclic ring initiating with the nitrogen of NR, and ending with one of the carbon atoms of the alkyl or alkenyl chain and wherein the heterocyclic 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 either substituted or unsubstituted with one or more substituents independently selected from the group including, but not limited to a, alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, straight or branched chain alkyl of C, -C9, C, -C9 alkoxy, C2-C9 alkenyloxy, straight or branched chain alkenyl of C2-C9, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilide, halo, haloalkyl, hydroxy, imino, isocyano, isonitrile, nitrile, nitro, nitroso, phenoxy, sulfhydryl, sulfonyl sulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl and carboxylic and heterocyclic portions, including alicyclic and aromatic structures; wherein the individual ring size is 5-8 members; wherein the heterocyclic ring consists of 1-6 heteroatoms independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, wherein any of the carbon atoms of the alkyl or alkenyl are 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 of the carbon atoms of the alkyl or alkenyl are optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6; wherein any of the carbon atoms of the alkyl or alkenyl are optionally substituted at one or more positions with C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, or Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, 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 at one or more positions with oxygen to form a carbonyl; or wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with O, NH, NR3, S, SO or SO2; W is O or S, CH2, or H2; and U is either 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, C3-C8 cycloalkyl, alkyl or straight or branched chain alkenyl of C, -C6 and straight or branched chain C2-C6 alkyl or alkenyl substituted at one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, straight or branched chain alkyl of C1-C6, straight or branched chain alkenyl of C2-C6, carbonyl, thiocarbonyl, thioester ester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, and substituted alkyl or alkenyl where any of the alkyl or alkenyl carbon atoms are optionally replaced with S, SO, SO2, O, or NR3; and when U is N, then R, and R2 are independently selected from the group consisting of hydrogen, Ar, C3-C8 cycloalkyl, straight or branched chain alkyl or alkenyl of C, -C6 and straight chain alkyl or alkenyl or branched C 2 -C 6 substituted at one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, straight or branched chain alkyl of C 1 -C 6, straight or branched chain alkenyl of C 2 -C 6, carbonyl, thiocarbonyl, ester thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, and substituted alkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO2, O, or NR3; or R, and R2 can be taken together to form a heterocyclic ring. 32. The pharmaceutical composition according to claim 31, characterized in that Ar is selected from the group consisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, and phenyl. 33. The pharmaceutical composition according to claim 31, characterized in that n is 1 or 2: Y is (CH2) 2 or a direct bond; Z is CH; C is 3-pyridyl, 4-methoxyphenyl, phenyl, or 2-phenylethyl; D is hydrogen, phenyl or 2-phenylethyl; R, is hydrogen; and R 2 is 2-methylbutyl, 1,1-dimethylpropyl, cyclohexyl, 1-adamantyl, or phenyl. 34. The pharmaceutical composition according to claim 31, characterized in that the compound is selected from the group consisting of: Hfwtoß ^ idMMBÜ- 3- (3-Pi rid i I) -1-propyl-2S-1 - [(2-methyl butyl) carba moi I] pyrrole id in-2-carboxylate; 3- (3-Pyrid i I) -1-propyI-2S-1 - [(1 ', 1' -Di methyl propyl) carbamoi I] pyrrole-n-2-carboxylate; 3- (3-Pyridyl) -1-propyl-2S-1 - [(cyclohexyl) thiocarbamoyl] pyrrolidin-2-carboxylate; and pharmaceutically acceptable salts, esters and solvates thereof. 35. The pharmaceutical composition according to claim 20, characterized in that the N-linked urea or carbamate of a heterocyclic thioester compound is a compound having the formula (V): 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 C, -C6, or straight or branched chain alkenyl of C2-C6, 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, alkylamine, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any alkyl or alkenyl carbon atom is 5 optionally replaced with O, NH, NR3, S, SO or SO2; Y is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, 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, sulfur, thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom of the alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO or SO2; R3 is selected from the group consisting of hydrogen, straight or branched chain alkyl of C, -C6, alkenyl or straight or branched chain alkynyl of C3-C6, and C, -C4 connecting alkyl, wherein a bridge it is formed between the nitrogen and a carbon atom of the alkyl or alkenyl chain containing the heteroatom forms 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 either substituted or unsubstituted with one or more substituents; wherein the 25 individual ring size of 5-8 members; where the ring ^^ ^ | ^ gj | g ^^^ ridÉÉMÉtaüi heterocyclic consists of 1-6 heteroatoms independently selected from the group consisting of O, N and S; and wherein the aromatic or tertiary alkyl amine is optionally oxidized to a corresponding N-oxide; Z is a direct bond, straight or branched chain alkyl of C, -C6, or straight or branched chain alkenyl of C2-C6, 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, alkyl, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl or oxygen to form a carbonyl, or wherein any carbon atom of the alkyl or alkenyl is optionally replaced with O, NH, NR3, S, SO or SO2; C and D are independently hydrogen, Ar, straight or branched chain alkyl or straight or branched chain alkenyl of C2-C6; wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from the group consisting of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein the alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C, -C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, 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 on One or more positions with oxygen to form a carbonyl; or wherein any alkyl or alkenyl carbon atom is optionally replaced with O, NH, NR3, S, SO or SO2; A, B, R1, R2, U, W and X are as defined otherwise in claim 25 above.