MXPA01002919A - Cyclic ester or amide derivatives - Google Patents

Abstract

This invention relates to low molecular weight, small molecule cyclic esters and amides having an affinity for FKBP-type immunophilins, pharmaceutical compositions comprising the same, and methods of using the same to effect a neuronal activity.

Description

t go *,, 1 to Z-? . , "l CYCLIC ESTER OR AMIDA DERIVATIVES Field of the Invention This invention relates to cyclic, small molecule, low molecular weight, neurotrophic ester or amide derivatives, which have affinity to FKBP type immunophilins, pharmaceutical compositions comprising the same and methods of using same to order to carry out a neuronal activity.

BACKGROUND OF THE INVENTION The term immunophilin refers to several proteins that serve as receptors for the major immunosuppressants, cyclosporin A (CsA), FK506 and rapamycin. The known classes of immunophilins are cyclophilins and binding proteins FK506 or FKBPs. Cyclosporin A binds to cyclophilin A, while FK506 and rapamycin bind to FKBP12. These immunophilin-drug complexes are interconnected with various intracellular signal transduction systems, especially in the immune and nervous systems. It is known that immunophilins have peptidyl prolyl isomerase enzyme (PPlasa) or rotamase activity. This has determined that the rotamase enzyme activity plays a role in the catalysis of the interconversion of the cis and trans isomers of the peptide and protein substrates for the immunophilin proteins. The immunophilins were discovered and originally studied in the immune tissue. He was initially nominated by those experts in the It is important that the inhibition of the rotamase activity of the immune cells leads to the inhibition of the proliferation of T cells, thus originating the. . immunosuppressive activity exhibited by immunosupre.sopes% drugs. < such as cyclosporin A, FK506, and rapamycin. Studies demonstrated that the inhibition of rotamase activity, in and of itself, does not result in immunosuppressive activity. Schreiber ei, al. , Science, 1990, Vol. 250, pp. 556-559. Instead, immunosuppression seems to come from the formation of a complex of immunosuppressive drugs with immunophilins. It has been shown that immunophilin-drug complexes interact with ternary protein targets as their mode of action. Schreiber et al., Cell, 1991, Vol. 66, pp. 807-815. In the case of FKBP-FK506 and cyclophilin-CsA, the immunophilin-drug complex binds to calcineurin enzyme and inhibits the T cell receptor signaling necessary for T cell proliferation. Similarly, the immunophilin complex - FKBP-rapamycin drug interacts with the RAFT1 / FRAP protein and inhibits IL-2 receptor signaling also necessary for T cell proliferation. In any case, T cell proliferation is inhibited. In addition to immune tissues, Immunophilins have also been found in the central nervous system. Immunophilin concentrations are 10-50 times higher in the central nervous system than in the immune system. Within neural tissues, immunophilins appear to influence the synthesis of nitric oxide, neurotransmitter release and the extension of the neuronal process. It has been found that the picomolar concentrations of immunosuppressants such > as íFK506 and rapamycin stimulate the outgrowth of neurites in PC12 cells and sensory neurons such as dorsal root ganglia cells (DRGs). Lyons ef al., Proc. of Nati. Acad. Sci., 1994, Vol. 91, pp. 3191-3195. In all animal experiments, FK506 has been shown to stimulate nerve regeneration after damage to the facial nerve. However, when administered chronically, immunosuppressive drugs exhibit several potentially serious side effects including nephrotoxicity, such as uneven glomerular filtration and irreversible interstitial fibrosis (Kopp et al., J. Am. Soc. Nephrol. ., 1991, 1: 162); neurological deficits, such as involuntary tremors or non-specific cerebral angina, such as non-localized headaches (De Groen et al., N. Engl. J. Med., 1 987 317: 861); and vascular hypertension with complications resulting therefrom (Kahan et al., N. Engl. J. Med. 1989, 321: 1725). Surprisingly, it has been found that certain compounds with high affinity to FKBPs are potent rotamase inhibitors and exhibit excellent neurotrophic effects, but lack immunosuppressive activity. These findings suggest the use of rotamase inhibitors in the treatment of various peripheral neuropathies and in the improvement of neuronal outgrowth in the central nervous system (CNS). Studies have shown that neurodegenerative disorders, such as Alzheimer's disease, Parkinson's and amyotrophic lateral sclerosis (ALS) can occur due to the loss or decreased availability of a neurotrophic substance specific 'for a particular population of affected neurons in the disorder. > > v r,, Several neurotrophic factors have been identified that affect * specific neuronal populations in the central nervous system. Ro "< For example, it is hypothesized that Alzheimer's age results in a decrease or loss of nerve growth factor (NGF). It has thus been proposed to treat SDAT patients with exogenous nerve growth factor or other neurotrophic proteins, such as brain-derived growth factor, glial-derived growth factor, ciliary neurotrophic factor and neurotropin-3, to increase the survival of the cells. degenerative neuronal populations. The present invention provides compounds containing rotamase inhibitors of small molecule FKBP to enhance the outgrowth of neurites and promote neuronal growth and regeneration in various neuropathological situations where neuronal repair can be facilitated, including: damage to the peripheral nerve caused by physical damage or disease status such as diabetes; physical damage to the central nervous system (spinal cord and brain); brain damage associated with bumps; and neurological disorders related to neurodegeneration, such as Parkinson's disease, SDAT (Alzheimer's disease) and amyotrophic lateral sclerosis. The inventive compounds are also useful for treating alopecia, promoting hair growth, treating vision disorders, improving vision, treating memory loss and improving memory performance in an animal. - 5 BRIEF DESCRIPTION OF THE INVENTION The present invention relates to small molecule, low molecular weight, f-cyclic, neurotrophic ester and amide derivatives, which < • « They have affinity with immunophilins of the FKBP type. Once bound to these proteins, the compounds are potent inhibitors of the enzyme activity associated with immunophilin proteins, particularly the activity of peptidyl prolyl isomerase enzyme or rotamase. The compounds may or may not exert immunosuppressive activity. Specifically, the present invention relates to a compound of the formula I or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: 0 A and B, taken together with the nitrogen and carbon atoms to which they are respectively attached, form a saturated or unsaturated carbocyclic or heterocyclic ring composed of 7 members, said heterocyclic ring containing one or more heteroatoms selected independently from the group consisting of 5 O, S, SO, SO2, N, NH and NR; 1 '' 1 -1 VL ^ R, R1 and R2 are independently straight or branched chain alkyl C? -C, straight or branched chain alkenyl C2-C9, C3-C9 cycloalkyl, C3-C9 cycloalkenyl, or Ar, in wherein said R, Ri and R2 are substituted or are not substituted independently with one or more substitutes; Ar is a heterocyclic, mono-, bi- or tricyclic, aromatic carbocyclic ring having an individual ring size of 5-9 members, said heterocyclic ring containing one or more heteroatoms selected independently from the group consisting of , S, SO, SO2, N, NH and NR; W and X are independently O, S, CH2 or H2; And it is O or S; and Z is O, NH or NR. A preferred embodiment of this invention is a compound of formula II or a pharmaceutically acceptable salt, ester or solvate thereof, wherein A and B, taken together with the carbon atoms to which they are respectively attached, form a heterocyclic ring saturated or not saturated, composed of ^ 5-7 members, cross-linking, heterocyclic, one or more 1 heteroatoms selected independently from the group consisting of O.-S,: SO,, SO2, N ,,; NHi j. { v NR; . ' '- *:,,'.

R and R are independently straight or branched C1-C9 alkyl, C2-C9 straight or branched chain alkenyl, C3-C9 cycloalkyl, C3-C9 cycloalkenyl, or Ar, wherein said R and Ri are substituted or unsubstituted substitute independently with one or more substitutes; R2 is C3-C9 cycloalkyl, C3-C9 cycloalkenyl or Ar, wherein said cycloalkyl or cycloalkenyl are substituted or are not substituted with one or more substitutes, or said Ar is substituted with one or more substitutes; Ar is a heterocyclic, mono-, bi- or tricyclic, aromatic, heterocyclic ring having an individual ring size of 5-9 members, said heterocyclic ring containing one or more heteroatoms selected independently from the group consisting of , S, SO, SO2, N, NH and NR; W and X are independently O, S, CH2 or H2; And it is O or S; and Z is O, NH or NR. Another preferred embodiment of this invention is a compound of the formula III or a pharmaceutically acceptable salt, ester or solvate thereof. The present invention also relates to a pharmaceutical composition comprising an effective amount of the compound of formula I, II or III and a pharmaceutically acceptable carrier. The present invention further relates to a method for effecting a neuronal activity in an animal, comprising administering to said animal an effective amount of the compound of the formula I, II or III.

DETAILED DESCRIPTION OF THE INVENTION Definitions "Alkyl" means a saturated, branched or unbranched hydrocarbon chain, containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert -butyl, n-pentyl, n-hexyl and the like, unless otherwise indicated. "Alkoxy" means the group -OR where R is alkyl as defined hereafter. Preferably, R is a saturated, branched or unbranched hydrocarbon chain containing from 1 to 3 carbon atoms. "Alopecia" refers to poor hair growth and • partial or complete loss of hair, including without limitation androgenic alopecia (male pattern baldness), toxic alopecia, senile alopecia, alopecia areata, peeling alopecia and trichotillomania.Alapecia results when the pillar cycle is disturbed. more frequent is a shortening of hair growth or anagen phase due to the cessation of cell proliferation.This results in the early onset of the catagen phase and, consequently, a large number of hair in the telogen phase during which the follicles They separate from the dermal papilla and the hair falls out Alopecia has several etiologies, including genetic factors, aging, local and systemic diseases, febrile conditions, mental tension, hormonal problems and drug side effects. "Improvement of memory performance "refers to the improvement or increase of the mental faculty by which they are recorded, retained or remembered ex past experiences, knowledge, ideas, sensations, thoughts or impressions. "Eye" refers to the anatomical structure responsible for vision in humans and other animals and covers the following anatomical structures, without limitation: lenses, vitreous body, ciliary body, posterior chamber, anterior chamber, pupil, cornea, iris, canal Schieum, Zinn zonules, limbus, conjunctiva, choroid, retina, central vessels of the retina, optic nerve, fovea centralis, macula lutea and sclera. "Halo" means fluoro, chloro, bromo or iodo, unless otherwise indicated. "Isomers" refers to different compounds that have the The same formula -molecular .. "Stereoisomers" are isomers that differ, only in the way in which atoms are installed in space. "Enantiomers" are a pair of stereoisomers that are not mirror images of overlap with each other. "Diastereoisomers" 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. "Memory disorder" refers to a mental record, retention or memory of past experiences, knowledge, ideas, sensations, thoughts or impressions, diminished. A memory disorder can affect the retention of information, ease with the spatial relationship, strategies of memory (exercise) and management and verbal production, long and short term. The common causes of memory disorders are age, severe head trauma, anoxia or cerebral ischemia, alcohol-nutritional diseases and drug poisoning. Examples of memory disorders include, without limitation, benign amnesia, amnesia, and any disorder in which memory deficiency occurs, such as Korsakoff's amnesic psychosis, dementia, and learning disorders. "Ophthalmological" refers to anything concerning the eye, without limitation and is used interchangeably as "ocular", "ophthalmic", "ophthalmologic" and other such terms without limitation. "Pharmaceutically acceptable salt, ester or solvate" refers to a salt, ester, or solvate of a subject compound that possesses the activity "ta"? - "^ (¡? - -> - - 1 1 XXi .2f > '¿' 'pharmacological desired 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, dodecylisulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, naphthylate, 2-naphthalenesulfonate, nicotinate, oxalate, sulfate, thiocyanate, tosylate and undecanoate. Examples of salts, esters or solvates base include ammonium salts; alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as calcium and magnesium salts; salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine; and salts with amino acids, such as arginine, lysine and so on. Also, groups containing basic nitrogen can be quaternized with agents such as lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides, such as chlorides, bromides and iodides of decyl, lauplo, myristyl and stellate; aralkyl halides, such as benzyl and phenethyl bromides; and others. The products dispersible or soluble in water or oil are thus obtained "Phenyl" includes all the radicals of phenyl isomeric possible, optionally monosubstituted or multisubstituted with substitutes selected from the group consisting of alkyl, alkoxy, hydroxy, halo and haloalkyl. . > < . + t > "Pillar cycle" refers to the life cycle of the hair follicles, and includes three phases: * "^ ^ (1) the anagen phase, the period of active hair growth, in terms of scalp, hard approximately three to five years; (2) the catagen phase, the period when growth stops and the follicle atrophies, which, as far as the scalp is concerned, lasts approximately one to two weeks; and (3) the telogen phase, the rest period when the hair separates progressively and finally falls, which, as far as the scalp is concerned, lasts approximately three to four months. Normally, 80 to 90 percent of the follicles are in the anagen phase, with less than 1 percent in the catagen phase and the rest in the telogen phase. In the telogen phase, the hair is of uniform diameter with a non-pigmented root, slightly bulbous. In contrast, in the anagen phase, the hair has a large bulb of color at its root. "Prevent Vision Degeneration", as used herein, includes the ability to prevent vision degeneration in patients newly diagnosed as having a degenerative disease that affects vision, or a risk of developing a new vision.

"Degenerative disease that affects vision and to prevent the subsequent degeneration of vision in patients who already suffer or have symptoms of a degenerative disease that affects vision. "Promoting hair growth" refers to maintaining, inducing, stimulating, accelerating or revitalizing hair germination. "Promoting vision regeneration" refers to maintaining, improving, stimulating or accelerating the recovery, or revitalization, of one or more components of the visual system in a manner that improves vision, whether in the presence or absence of any disorder, Ophthalmological disease or damage. "Treatment" 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 who has not yet been diagnosed as having it; (ii) inhibit the disease and / or condition, that is, decrease its development; or (iii) alleviating the disease and / or condition, i.e., causing the regression of the disease and / or condition. "Alopecia treatment" refers to: (i) preventing alopecia in an animal that may be predisposed to alopecia; and / or (ii) inhibiting, retarding or reducing alopecia; and / or (iii) promote hair growth; and / or (iv) prolonging the anagen phase of the hair cycle; and / or (v) convert hair to terminal hair growth.

The hair ends long, thick hair, .pigmented, ,, in which the bulb of the hair follicle. It sits deep in the dermis :; . On the other side, the hair is short, thin, thin, not pigmented, in which the? Hair bulb is located superficially in the dermis. As r, alopecia progresses, hair changes from terminal to hair. "Vision", as used herein, refers to the ability of humans and other animals to process images and is used interchangeably with "sight", "vision" and other such terms, without limitation. "Vision Disorder" refers to any disorder that affects or involves vision, including without limitation, visual inequality, orbital disorders, lacrimal apparatus disorders, eyelid disorders, conjunctival disorders, corneal disorders, cataracts, disorders of the uveal tract, disorders of the retina, disorders of the optic nerve or visual trajectories, disorders and eye diseases induced by free radicals, disorders and immunologically mediated eye diseases, eye damage and symptoms and complications of eye disease, eye disorder or eye damage. "Visual Inequality" refers to any vision dysfunction, including, without limitation, disturbances or decreased vision (eg, binocular, central, peripheral, scotopic), visual acuity for nearby objects and for visual field, eye mobility, perception of colors, adaptation to light and darkness, accommodation, refraction and lagpmación See Physicians' Desk Reference (PDR) for Ophthalmology, 16th Edition, 6:47 (1988). Compounds of the Invention The small molecule, low molecular weight FKBP inhibitor compounds of this invention have affinity for immunophilins. of type FKBP, such as FKBP12. When the compounds of this invention bind to an FKBP type immunophilin, they have been found to inhibit cis-trans isomerase activity of prolyl-peptidyl or rotamase, activity of the binding protein. Unexpectedly, the compounds are effective in stimulating the growth of neurites, as well as in the treatment of alopecia, the promotion of hair growth, the treatment of disorders of vision, the improvement of vision, the treatment of disorder of the memory and the improvement of memory performance in an animal. The compounds may or may not be immunosuppressive. FORMULA I The cyclic ester or amide derivative can be a compound of the formula I or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: NR; R, Ri and R2 are independently straight or branched chain alkyl C-Cg, straight or branched chain alkenyl C2-C9) C3-C9 cycloalkyl, C3-C9 cycloalkenyl, or Ar, wherein said R, R1 and R2 are substituted or are not substituted independently with one or more substitutes and the carbon atoms of said alkyl, alkenyl, cycloalkyl and cycloalkenyl are substituted or are not substituted independently with one or more heteroatoms; Ar is a carbo- or heterocyclic ring, mono-, bi- or tricyclic, aromatic, having an individual ring size of 5-9 members, said heterocyclic ring containing one or more heteroatoms selected independently from the group consisting of O, S, SO, SO2, N, NH and NR; W and X are independently O, S, CH2 or H2; 20 And it's O or S; and Z is O, NH or NR. FORMULA II In a preferred embodiment, the cyclic ester or amide derivative is a compound of formula II 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 saturated or unsaturated heterocyclic ring composed of 5-7 members, said heterocyclic ring containing one or more heteroatoms selected independently from the group consisting of O, S, SO, SO2, N, NH and NR = R and Ri are independently straight or branched chain alkyl Ci-Cg, straight or branched chain alkenyl C2-C9, C3-C9 cycloalkyl C3-C9 cycloalkenyl, or Ar, wherein said R and R, are substituted or not they are independently substituted with one or more substitutes and the carbon atoms of said alkyl, alkenyl, cycloalkyl and cycloalkenyl are substituted or are not independently substituted with one or more heteroatoms; R2 is C3-C9 cycloalkyl, C3-C9 cycloalkenyl or Ar, wherein said R2 is substituted or is not substituted with one or more substitutes and the carbon atoms of said cycloalkyl and cycloalkenyl are substituted or they are not substituted independently with one or more heteroatoms; Ar is a heterocyclic, mono-, bi- or tricyclic, aromatic, heterocyclic ring having an individual ring size of 5-9 members, said heterocyclic ring containing one or more heteroatoms selected independently from the group consisting of , S, SO, SO2, N, NH and NR; W and X are independently O, S, CH2 or H2; And it is O or S; and Z is O, NH or NR. In another preferred embodiment, R2 is substituted with (Ar) n and n is 1 - . 1 -2. FORMULA In the most preferred embodiment, the cyclic ester or amide derivative is 4,4-diphenylcyclohexyl (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -pyrrolidine-2-carboxylate, a compound of the formula III or a pharmaceutically acceptable salt, ester or solvate thereof. In the compounds of the formulas 1-11, the possible substitutes of R, Ri and R2 are straight or branched chain alkyl C? -C9 > straight or branched chain alkenyl C2-C9, C?-C8 alkoxy, C2-C9 alkenyloxy, phenoxy, benzyloxy, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxy, carboxy, carbonyl, amino. 'amido,' cyano, isocyano, nitro, nitroso, nitrilo, isonitrilo, imino, azo; diazo, sulfonyl, sulfoxy, thio, thiocarbonyl, thiocyano, formanilide, thioformamido, sulfhydryl, halo, haloalkyl, trifluoromethyl and carbocyclic and heterocyclic elements. Carbocyclic elements include alicyclic and aromatic structures. Examples of useful carbocyclic and heterocyclic elements include, without limitation, phenyl, benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, pyrrolyl. , pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl, thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl, isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, trityanil, indolizinyl , pyrazolyl, pyrazolinyl, pyrazolidinyl, thienyl, tertrahydroisoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl. All the compounds of the formulas 1-11 have asymmetric centers and can therefore be produced as mixtures of stereoisomers or as individual R- and S-stereoisomers. Individual stereoisomers can be obtained by the use of an optically active starting material, by resolution of a racemic or non-racemic mixture of an intermediate at a certain appropriate stage of the synthesis or by resolution of compounds 1-11. HE .X "''". ' . ,. - 20 - "'understands' that the compounds of the formulas l-11 - encompass, individual stereoisomers as well as mixtures of stereoisomers (racemic and non-racemic) S-., Stereoisomers are more preferred Pharmaceutical Compositions of the Invention The present invention also relates to a pharmaceutical composition comprising: (i) an effective amount of a compound of the formula I, II or III, and (ii) a pharmaceutically acceptable carrier, The preferred compounds of the formulas I and II are set forth above In a preferred embodiment of the inventive pharmaceutical composition, the amount of the compound of the formula I, II or III is effective to bind an immunophilin of the FKBP type. In another preferred embodiment, the amount of the compound of formula I, II or III is effective to effect neuronal activity in an animal. Methods of the Invention The compounds of the present invention have an affinity for the binding protein FK506, particularly FKBP12, which occurs in the brain. When the inventive compound binds to FKBP in the brain, it exhibits excellent neurotrophic activity. This activity is useful in the stimulation of damaged neurons, the promotion of neuronal regeneration, the prevention of neurodegeneration and the treatment of several "Peripherals and degeneration? EuronaL For the above reasons, the present invention relates i, in addition to a method for effecting neuronal activity in comprising the administration to said animal of an effective amount of a compound of formula I, II or III. The preferred compounds of formula I and II are set forth above. In a preferred embodiment, the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder. Neurological disorders that can be treated include, but are not limited to: trigeminal neuralgia; glossopharyngeal neuralgia; Palsy of 15 Bell; myasthenia gravis; muscular dystrophy; Amyotrophic Lateral Sclerosis; progressive muscular atrophy; Progressive bulbar inherited muscular atrophy; invertebrate disc syndromes with rupture, herniated or prolapsed; cervical spondylosis; plexus disorders; syndromes of destruction of the thoracic outlet; peripheral neuropathies such as those caused by lead, dapsone, tics, porphyria or Guillain-Barré syndrome; Alzheimer disease; and Parkinson's disease. The compounds of the present invention are particularly useful in the treatment of a neurological disorder selected from the group consisting of: peripheral neuropathy caused by a state of disease or physical damage, traumatic brain damage, physical damage to the spinal cord, blow associated with? damage, < cerebral and neurological disorders related to neurodegeneration. The, examples of ^ f »neurological disorders related to neurodegeneration, - con. { «, .and > , Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. For these purposes, the compounds of the present invention can be administered orally, parenterally, by spray inhalation, topically, rectally, nasally, buccally, vaginally or through a container implanted in dosage formulations containing vehicles, adjuvants and carriers. pharmaceutically acceptable, non-toxic, conventional. The term parenteral, as used herein, includes subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, and intracranial injection or infusion techniques. To be therapeutically effective, since it targets the central nervous system, the immunophilin-drug complex must easily penetrate the blood-brain barrier when administered peripherally. The compounds of this invention that can not penetrate the blood-brain barrier can be administered effectively by an intraventricular route. The compounds may be in the form of an injectable preparation, for example as an injectable, sterile, aqueous or oleaginous suspension. This suspension can be formulated according to techniques known in the art by the use of suitable dispersing or wetting agents or suspending agents. The (Sterile injectable prep ration can also be an injectable, sterile solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol, Among the acceptable vehicles and solvents that can be used. Water, Ringer's solution and isotonic sodium chloride solution are used, and sterile, fixed oils are conventionally used as a solvent or suspension medium.For this purpose, any fixed, soft oil that includes mono- Synthetic di-glycerides Fatty acids such as oleic acid and its glyceride derivatives find use in the preparation of injectables, olive oil or castor oil, especially in their polyoxyethylated versions.These solutions or suspensions of oil may also contain a diluent or long chain alcohol dispersant., the compounds may be administered orally in the form of capsules or tablets, for example, or as a suspension or aqueous solution. In the case of tablets for oral use, the vehicles that are commonly used contain lactose and corn starch. Lubricating agents such as magnesium stearate are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added. The compounds of this invention can also administered in the form of suppositories for the rectal administration of the drug. These compositions can be prepared by mixing! drug with a suitable, non-irritating excipient, which is solid at room temperature, but liquid at rectal temperature and will subsequently melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. The compounds of this invention can also be administered optically, especially when the conditions directed to the treatment involve easily accessible areas or organs by topical application, including neurological disorders of the eye, the skin or the lower intestinal tract. Suitable topical formulations are easily prepared for each of these areas. For ophthalmic use, the compounds can be formulated as micronized suspensions in sterile, pH-adjusted, isotonic saline or, preferably, as sterile, pH-adjusted, isotonic saline solutions, either with or without a condom such as benzyl-allyl chloride. Alternatively, for ophthalmic uses, the compounds may be formulated in an ointment such as petrol. For topical application to the skin, the compounds may be formulated in a suitable ointment containing the compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, Polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the compounds may -,? - 95 - appropriate lotion or cream containing the compound active suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Topical application to the lower intestinal tract can be done in a rectal suppository formulation (see above) or in a suitable enema formulation. The dose levels of the order of about .1 mg to about 10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels of about 0.1 mg to about 1,000 mg. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. However, it is understood that a specific dose level for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, the rate of excretion, the combination of drugs and the severity of the particular disease being treated and the manner of administration. The compounds can be administered with other neurotrophic agents such as neurotrophic growth factor (NGF), glial-derived growth factor, growth factor derived from brain, ciliary neurotrophic factor and "neurotropin-3" The dose level of other neurotrophic drugs will depend on the previously established factors and the neurotrophic efficacy of the drug combination Test Procedure K The inhibition of isomerase activity (rotamase) of petidil Prolyl of the inventive compounds can be evaluated by known methods, described in the literature (Harding, MW et al., Nature 341: 758-760 (1989); Holt et al., J. Am. Chem. Soc. 1 15: 9923- 9938) These values are obtained as apparent ki's and are presented in Table I. The cis-trans isomerization of an alanine-proline binding in a model substrate, N-succinyl-Ala-Ala-Pro-Phe- p-nitroanilide, is monitored spectrophotometrically in an assay coupled to chymotrypsin, which liberates para-nitroanilide from the trans form of the substrate. The inhibition of this reaction caused by the addition of different concentrations of inhibitor is determined and the data analyzed as a change in the first order rate constant as a function of the inhibitor concentration to produce the apparent values ki. In a plastic cuvette, 950 mL of ice 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) were added. , 1 mM dithiothreitol), 25 mL of chymotrypsin (50 mg / mL in 1 mM HCl) and 10 mL of test compound at various concentrations in dimethyl sulfoxide. The reaction is initiated by the addition of 5 mL of substrate (succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg / mL in 2.35 mM LiCl in trifluoroethanol). Absorption at 390 nM versus time is monitored during 90 sec using a spectrophotometer and, the rate constants, are determined from the data files of absorption against time. The data for these experiments are presented in Table I Table I Compound Ki (nM) 5638 In mammalian cells, FKBP-12 is complexed with the inositol triphosphate receptor (IP3R) and the ryanodine receptor (RyR). It is believed that the neurotrophic compounds of this invention dissociate the FKBP-12 from these complexes, causing the calcium channel to become "permeable" (Cameron et al., 1995). Calcium fluxes are involved in the neurite extensions so that the IP3R receptor and the ryanodine receptor can be involved in the neurotrophic effects of the drugs. Since the drugs bind to the same site as FKBP-12 as the IP3R receptor, one might assume that the drugs displace the channels from FKBP-1 2. Cultures of Dorsal Root Ganglia and Chicken Neurites Excretion The root ganglia dorsal dissect chicken embryos ten days gestation. Complete lymph node explants are cultured in 12-well plates covered with a thin layer Matrigel with Liebovitz L15 plus medium high in glucose ,. •, Z < V '- 28 -'i < . { supplemented with '2 mM glutamine and 10% unborn bovine serum and < they also contain 10 μM of ß-D arabinof uranoside of cytosine (Ara C) a 37 ° C in an environment containing 5% CO2. Twenty-four hours later, DRGs are treated with different concentrations of factor nerve growth (NGF), immunophilin ligands or combinations of NFG plus drugs. Forty-eight hours after drug treatment, the nodes are visualized under phase contrast or Hoffman Modulation contrast with an inverted Zeiss Axiovert microscope. The photomicrographs of the explants are elaborated and quantified the excrescence of neurites. Neurites longer than the diameter of DRG are counted as positive, with a total number of neurites quantified by each experimental condition. Three to four DRGs are grown per perforation, and each treatment is carried out in duplicate. The compounds of the present invention promote excrescence of neurites in sensory neurons. Sciatic Nerve Axotomy Six-week-old male Sprague-Dawley rats were anaesthetized and the sciatic nerve was exposed and fractured, at the level of the femorotibial joint, by means of forceps. The compounds or vehicle The test is administered subcutaneously just before the injury and daily for the next 18 days. The sections of the sciatic nerve are stained with Holmes silver dyeing to quantify the number of axons and Luxol strong blue to quantify the level of myelination. Eighteen days after the injury, there is a significant decrease in the number of axons (50% decrease compared to the unharmed control) and graduated the myelination f (90% decrease Jen compared to -the control; z < non-injured) in animals treated with vehicle. s. , The administration of neuroinmunophilin FKBP ligands, which are compounds related to those of the present invention, just before the injury and daily for 18 days after the injury, results in significant regeneration of both the number of axons as the degree of myelination compared to vehicle-treated animals.The significant efficacy of FKBP ligands of neuroimmunofilin is consistent with its potent activity in the inhibition of rotamase activity and the stimulation of neurite outgrowth in DRGs of Chicken MPTP Model of Parkinson's Disease in Mice The neurotrophic effects of the compounds of the present invention are further demonstrated in an animal model of neurodegenerative disease: the MPTP lesion of dopaminergic neurons in mice is used as an animal model of Parkinson's Disease .

White CD1 male mice of four weeks of age are dosed i.p. with 30 mg / kg of MPTP for 5 days. S.c. a cyclic ester or amide derivative (10-40 mg / kg) or vehicle together with the MPTP for 5 days, as well as for an additional 5 days after stopping the MPTP treatment. On day 18 after the MPTP treatment, the animals are sacrificed and the stria is dissected and homogenized. The binding of [3H] CFT, a radioligand for the dopamine transporter, to the estiatal membranes is performed to quantify the level of the dopamine transporter (DAT) after injury and drug treatment. He '' - 30 - •, w • immunostaining is carried out in the cerebral / sagittal and coronal sections by the use of anti-tyrosine Ig hydroxylase to quantify the survival and recovery of dopaminergic neurons. In animals treated with MPTP and vehicle, a loss is observed. Substantial functional dopaminergic terminals compared to unharmed animals. Injured animals receiving the cyclic ester or amide derivatives show an almost quantitative recovery of dopaminergic neurons stained with TH. These experiments demonstrate significant recovery in functional dopaminergic terminals, as tested by binding to [3 H] -CFT, relative to animals receiving MPTP but not an ester derivative or cyclic amide. Animals receiving 40 mg / kg of ester derivative or cyclic amide in addition to MPTP show a higher recovery of [3 H] -CFT binding. Immunostaining for tyrosine hydroxylase (a marker of viable dopaminergic neurons) in the striatum, nigra and medial bulk of the forebrain, shows a clear and marked recovery of functional neurons in animals receiving an ester or cyclic amide derivative, in comparison with animals that received injury but not drug agent (MPTP / Vehicle). 20 Data of the Related Compounds The Patent Application of E. U. No. 09 / 089,416, filed June 3, 1998, is incorporated herein by reference. Said application includes K-data, for various FKBP ligands of neuroimmunofilin, which are related to the compounds of the invention. present invention (see Tables IX-XVI) e E.U. No. 08 / 479,436, filed June 7, 1995 is also incorporated herein by reference. Said application includes neurite outgrowth data and MPTP recovery for various FKBP ligands of neuroimmunophilin, which are related to the compounds of the present invention (see Table II and Figures 4-8, respectively). The U.S. Patent Application. No. 08 / 719,947, filed September 25, 1996, is also incorporated herein by reference. Said application includes neurite outgrowth data for various FKBP ligands of neuroimmunofilin, which are related to the compounds of the present invention (see Table III, Figures 1 (AC) and Figures 2IA-C-)) EXAMPLES The following examples are illustrative of the present invention and do not intend to be limitations thereto. Unless indicated otherwise, all percentages are based on 100% by weight of the final compound or composition. The compounds of the present invention can be easily prepared by standard techniques of organic chemistry, using the The general synthetic trajectory illustrated below in Scheme I The precursor compounds can be prepared by methods known to those skilled in the art.

Esauema I EXAMPLE 1 Synthesis of 4,4-Diphenylcyclohexyl (2S) -1- (3,3-dimethyl-2-oxopentanoyl) -pyrrolidine-2-carboxylate (Formula III) 1. Synthesis of methyl (2S) -1 - (1,2-dioxo-2-methoxyethyl) -2-pyrrolidinecarboxylate A solution of methyl ester hydrochloride of L-proline (3.08 g, 18.60 mmol) in dry methylene chloride is cooled to 0 ° C and treated with triethylamine (3.92 g, 38.74 mmol, 2.1 eq.). After stirring the mixture formed under a nitrogen atmosphere for 15 minutes, a solution of methyl oxalyl chloride (3 20 g; The mixture was stirred at 0 ° C for 1 hr. .5 hours After filtering to remove the solids, the organic phase was rinsed with water, dried over MgSO4 and concentrated.The crude residue was purified on a column of silica gel, 5 levigating with 50% ethyl acetate. in hexane, to obtain 3.52 g (88%) of the product as a reddish oil Mixture of cis-trans amide rotamers, given data for trans rotamer 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 (ss, 1 H, J = 8.4, 3.3), 10 2. Synthesis of (2S) -1 - (1,2-dioxo-3,3-d? methylpentyl) -2-pyrrolidinecarboxylate methyl A solution of (2S) -1 - (1,2-dioxo-2-methoxyethyl) -2-pyrrolidinecarboxylate of methyl (2.35 g, 1 0.90 mmol) in 30 mL of tetrahydrofuran (THF) was cooled to -78 ° C and treated with 14.2 mL of 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 rinsed with water, dried and concentrated, and the crude material obtained after 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. 1 H NMR (CDCl 3): 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, 1 H); 3.54 (m, 2H); 3.76 (s, 3H); 4.52 (dm, 1 H, J = 8 4, 3.4) 25 3 Synthesis of (2S) -1 - (1 .2-d? Oxo-3,3-d? Met? Lpent? L) -2- 1 I - 34 - pyrrolidinecarboxylic acid *,,,,;, •,, - - «'\. X l? < A mixture of methyl 1 '' (2S) -1 - (1, 2-dioxo-3,3-dimethylpentyl) t2-pyrrolidinecarboxylate (2.10 g, 8.23 mmol), 1 N LiOH (15, mL) and ^ 'methanol (50 mL) was stirred at 0 ° C for > 30 min and at room temperature, / ^ overnight. The mixture was acidified to pH 1 with 1 N of HCl, diluted with water and extracted into 100 mL of methylene chloride. The organic extract was rinsed with saline and concentrated to give 1.73 g (87%) of white solid which does not require further purification. 1 H NMR (CDCl 3): d 0.87 (t, 3H); 1.22, 1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.17 (m, 1 H); 2.25 (m, 1 H); 3.53 (dd, 2H, J = 10.4, 7.3); 4.55 (dd, 1 H, J = 8.6, 4.1). 4. Synthesis of (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -pyrrolidine-2-carboxylate of 4,4-diphenylcyclohexyl (Formula III) A mixture of (2S) -1 - (1, 2-dioxo- 3,3-dimethylpentyl) -2-pyrrolidinecarboxylic acid (600 mg, 2.49 mmol), 4,4-diphenylcyclohexanol (942 mg, 3.73 mmol), dicyclohexylcarbodiimide (822 mg, 3.98 mmol), camphorsulfonic acid (1 90 mg, 0.8 mmol) and 4-dimethylaminopyridine (100 mg, 0.8 mmol) in methylene chloride (20 mL) was stirred overnight under a nitrogen atmosphere. The reaction mixture was filtered through Celite to remove the solids and concentrated in vacuo and the crude material was purified on a flash column (25% ethyl acetate in hexane) to obtain the compound of Formula III as a solid. white, mp 127 5-1 28.8 ° C. 1 H NMR (CDCl 3, 400MHz): d 0.84 (t, 3H, J = 7.5); 1 .26, 1 .28 (s, 3H each); 2.01 -2.56 (m, 10H); 2.15-2.28 (m, 2H); 2.48-2.67 (m, 2H), 3.42-3 68 (m, 2H); 4 48 (1 H, dd, J = 3 6, 8 5); 4.96 (m, 1 H), 7.25- 7. 34, (m, 10H) r «• Example 2 A patient suffers from damage to the peripheral nerve caused by a state of physical injury or illness such as diabetes. An ester derivative or cyclic amide as identified above, or a pharmaceutical composition comprising the same, can be administered to the patient. After treatment, improved neuronal outgrowth and neuronal growth and regeneration are expected to occur. Example 3 A patient suffers from physical damage to the central nervous system (spinal cord and brain). A cyclic ester or amide derivative as identified above, or a pharmaceutical composition comprising the same, can be administered to the patient. After treatment, improved neuronal outgrowth and neuronal growth and regeneration are expected to occur. Example 4 A patient suffers from brain damage associated with a stroke. A cyclic ester or amide derivative as identified above, or a pharmaceutical composition comprising the same, may be administered to the patient. After treatment, improved neuronal outgrowth and neuronal growth and regeneration are expected to occur. Example 5 A patient suffers from neurodegeneration resulting from Parkinson's disease. A cyclic ester or amide derivative as identified above, or a pharmaceutical composition comprising the "'' 'He was able to complete the mission. - After the, treatment, it is expected to occur, 1 'enhanced' excrescence of neurites and growth, and neuronal regeneration. . K, Example 6 A patient suffers from neurodegeneration resulting from amyotrophic lateral sclerosis. A cyclic ester or amide derivative as identified above, or a pharmaceutical composition comprising the same, can be administered to the patient. After treatment, improved neuronal outgrowth and neuronal growth and regeneration are expected to occur. Example 7 A patient suffers from neurodegeneration resulting from SDAT (Alzheimer's disease). A cyclic ester or amide derivative as identified above, or a pharmaceutical composition comprising the same, can be administered to the patient. After treatment, improved neuronal outgrowth and neuronal growth and regeneration are expected to occur. The invention being thus described, it will be obvious that it can vary in various ways. Such variations are not contemplated as a section of the spirit and scope of the invention and all such modifications attempt to be included within the scope of the following claims.

Claims (44)

1. CLAIMS 1. A compound according to formula I or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A and B, taken together with the carbon atoms to which they are attached, form a saturated or unsaturated carbocyclic or heterocyclic ring composed of 5-7 members, containing said heterocyclic ring one or more heteroatoms selected independently from the group consisting of O, S, SO, SO2, N, NH and NR; R, Ri and R2 are independently straight or branched chain C? -C8, straight or branched chain alkenyl C2-C9, C3-C9 cycloalkyl, C3-C9 cycloalkenyl, or Ar, wherein said R, Ri and R2 are they substitute or are not replaced independently with one or more substitutes and the carbon atoms of said alkyl, alkenyl, cycloalkyl and cycloalkenyl are substituted or are not independently substituted with one or more heteroatoms; Ar is a carbo- or heterocyclic, mono-, bi- or tricyclic, aromatic ring, having an individual ring size of 5-9 members, & < - '- 38 containing said heterocyclic ring one or more heteroatoms selected independently from the group consisting of O, S, SO, SO2, N, NH and NR; W and X are independently O, S, CH2 or H; And it is O or S; and Z is O, NH or NR.
2. 2. The compound according to claim 1, characterized in that said compound is immunosuppressive.
3. 3. The compound according to claim 1, characterized in that said compound is non-immunosuppressive.
4. 4. The compound according to claim 1, characterized in that said compound has an affinity with an immunophilin of the FKBP type.
5. 5. The compound according to claim 4, characterized in that the immunophilin of the FKBP type is FKBP-12.
6. 6. A compound of formula II or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A and B, taken together with the nitrogen and carbon atoms to • "-" - "-" ", which are respectively ranexan.nforman a heterocyclic rings - '?? and saturated or unsaturated integrated, by ,, fr5-7, members, containing said zz-z heterocyclic ring one or more heteroatoms selected in a manner /, independently from the group consisting of O, S, SO, SO2, N, NH, and R, R3 and R are independently straight chain alkyl or branched Ci-Cg, straight or branched chain alkenyl C2-C9, C3-C9 cycloalkyl, C3-C9 cycloalkenyl, or Ar, wherein said R and Ri are substituted or are not substituted independently with one or more substitutes and carbon atoms of said alkyl, alkenyl, cycloalkyl and cycloalkenyl are substituted or are not substituted independently with one or more heteroatoms, R2 is C3-C9 cycloalkyl, C3-C9 cycloalkenyl, or Ar, wherein said cycloalkyl or cycloalkenyl are substituted or are not replaced with one or more substitutes and the carbon atoms of said cycloalkyl and cycloalkenyl are substituted or are not substituted independently with one or more heteroatoms; or said Ar is replaced with one or more substitutes; Ar is a heterocyclic, mono-, bi- or tricyclic, aromatic, heterocyclic ring having an individual ring size of 5-9 members, said heterocyclic ring containing one or more heteroatoms selected independently from the group consisting of , S, SO, SO2, N, NH and NR; W and X are independently O, S, CH2 or H2; And it is O or S; Y Z is O, NH or NR. The compound according to claim 6, characterized in that said compound is immunosuppressive. The compound according to claim 6, characterized in that said compound is non-immunosuppressive. 9. The compound according to claim 6, characterized in that said compound has an affinity with an immunophilin of the FKBP type. 10. The compound according to claim 9, characterized in that the FKBP type immunophilin is FKBP-12. eleven . The compound according to claim 6, characterized in that: R2 is substituted with (Ar) "; and n is 1 -2. The compound according to claim 1, characterized in that said compound is (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -pyrrolidine-2-carboxylate 4,4-diphenylcyclohexyl of the formula III or a pharmaceutically acceptable salt or solvate thereof. 13. A pharmaceutical composition comprising: (i) an effective amount of a compound of the formula or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A and B, taken together with the carbon atoms to which they are attached, form a saturated or unsaturated carbocyclic or heterocyclic ring composed of 5-7 members, containing said heterocyclic ring one or more heteroatoms independently selected from the group consisting of O, S, SO, SO2) N, NH and NR; R, R, and R2 are independently straight or branched chain alkyl Ci-Cg, straight or branched chain alkenyl C2-C9, cycloalkyl C3-C9, cycloalkenyl C3-C9, or Ar, wherein said R, Ri and R2 are they substitute or are not replaced independently with one or more substitutes and the carbon atoms of said alkyl, alkenyl, cycloalkyl and cycloalkenyl are substituted or are not independently substituted with one or more heteroatoms; Ar is a heterocyclic, mono-, bi- or tricyclic, aromatic, heterocyclic ring having an individual ring size of 5-9 members, said heterocyclic ring containing one or more heteroatoms selected independently from the group consisting of , S, SO, SO2, Ni NH and NR; W and X are independently O, S, CH2 or H2; And it is O or S; and Z is O, NH or NR; and (ii) a pharmaceutically acceptable carrier. 14. The pharmaceutical composition according to claim 13, characterized in that said compound is immunosuppressive. 15. The pharmaceutical composition according to claim 13, characterized in that said compound is non-immunosuppressive. 16. The pharmaceutical composition according to claim 13, characterized in that said compound has an affinity with an immunophilin of the FKBP type. 17. The pharmaceutical composition according to claim 16, characterized in that the immunophilin of the FKBP type is FKBP-12. 18. The pharmaceutical composition according to claim 13, characterized in that it further comprises one or more neurotrophic agents. The pharmaceutical composition according to claim 18, characterized in that said one or more neurotrophic agents are selected from the group consisting of neurotrophic growth factor (NGF), glial-derived growth factor, brain-derived growth factor, factor neurotrophic cilia and neurotropin-3. 20. A pharmaceutical composition comprising: (i) an effective amount of a compound of the formula II 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 saturated or unsaturated heterocyclic ring composed of 5-7 members, said heterocyclic ring containing one or more heteroatoms selected independently from the group consisting of O, S, SO, SO2, N, NH and NR; R and R are independently straight or branched chain alkyl C? -C9, straight or branched chain alkenyl C2-C9, C3-C9 cycloalkyl, C3-C8 cycloalkenyl, or Ar, wherein said R and R, are substituted or they are not substituted independently with one or more substitutes and the carbon atoms of said alkyl, alkenyl, cycloalkyl and cycloalkenyl are substituted or are not independently substituted with one or more heteroatoms; R2 is C3-Cg cycloalkyl, C3-Cg cycloalkenyl, or Ar, wherein said cycloalkyl or cycloalkenyl are substituted or are not substituted with one or more substitutes and the carbon atoms of said cycloalkyl and cycloalkenyl are substituted or not substituted Independent ? with one or more heteroatoms; or said Ar is replaced with one or more substitutes; • Ar is a carbo- or heterocyclic, mono-, bi- or tricyclic, aromatic ring, having an individual ring size of 5-9 members, said heterocyclic ring containing one or more heteroatoms selected independently from the group consisting of O, S, SO, SO2l N, NH and NR; W and X are independently O, S, CH2 or H2; And it is O or S; and Z is O, NH or NR; and (ii) a pharmaceutically acceptable carrier. twenty-one . The pharmaceutical composition according to claim 20, characterized in that said compound is immunosuppressive. 22. The pharmaceutical composition according to claim 20, characterized in that said compound is non-immunosuppressive. 23. The pharmaceutical composition according to claim 20, characterized in that said compound has an affinity with an immunophilin of the FKBP type. 24. The pharmaceutical composition according to claim 23, characterized in that the immunophilin of the FKBP type is FKBP-12. 25. The pharmaceutical composition according to claim 20, characterized in that: R2 is substituted with (Ar) "; and n is 1 -2 26. The pharmaceutical composition according to claim 25, characterized in that said compound is (2S) -1 - (3,3-dimethyl-2-oxopentanoyl) -pyrrolidine-2-carboxylate 4,4-diphenylcyclohexyl of the formula III or a pharmaceutically acceptable salt or solvate thereof. 27. A method for effecting neuronal activity in an animal, characterized in that it comprises administering to said animal an effective amount of a compound of the formula I or a pharmaceutically acceptable salt, ester or solvate thereof, wherein: A and B, taken together with the carbon atoms to which they are attached, form a saturated or unsaturated carbocyclic or heterocyclic ring composed of 5-7 members, containing said heterocyclic ring one or more heteroatoms selected independently from the group consisting of O, S, SO, SO2, N, NH and NR; R, Ri and R2 are independently straight or branched C1-C9 alkyl, straight or branched chain alkenyl C2-Cß, C3-C9 cycloalkyl, C3-C9 cycloalkenyl, or Ar, wherein said R, Ri and R2 are substituted or are not substituted independently with one or more substitutes and the carbon atoms of said alkyl, alkenyl, cycloalkyl and cycloalkenyl are substituted or are not independently substituted with one or more heteroatoms; Ar is a heterocyclic, mono-, bi- or tricyclic, aromatic, heterocyclic ring having an individual ring size of 5-9 members, said heterocyclic ring containing one or more heteroatoms selected independently from the group consisting of , S, SO, SO2, N, NH and NR; W and X are independently O, S, CH2 or H2; And it is O or S; and Z is O, NH or NR. The method according to claim 27, characterized in that the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder. 29. The method according to claim 28, characterized in that the neurological disorder is selected from the group consisting of peripheral neuropathy caused by a state of physical injury or illness, traumatic brain damage, physical damage to the bone marrow. spinal, stroke associated with brain damage and neurological disorder related to neurodegeneration. 30. The method according to claim 29, characterized in that the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. 31 The method according to claim 27, characterized in that said compound is immunosuppressive. 32. The method according to claim 27, characterized in that said compound is non-immunosuppressive. 33. The method according to claim 27, characterized in that said compound has an affinity with an immunophilin of the FKBP type. 34. The method according to claim 33, characterized in that the FKBP type immunophilin is FKBP-1 2. 35. A method for effecting a neuronal activity in an animal, characterized in that it comprises administering to said animal an effective amount of a compound of formula II or a pharmaceutically acceptable salt, ester or solvate thereof, in "- ,, where: v - '" * •' * »&';"' "'" A and B, taken together with the nitrogen and carbon atoms to which they are attached respectively, form a heterocyclic ring saturated or unsaturated consisting of 5-7 members, said heterocyclic ring containing one or more heteroatoms selected independently from the group consisting of O, S, SO, SO2, N, NH and NR; R and R are independently straight or branched chain alkyl C? -C9, straight or branched chain alkenyl C2-C9 C3-C9 cycloalkyl, C3-C9 cycloalkenyl, or Ar, wherein said R and Ri are substituted or not they are independently substituted with one or more substitutes and the carbon atoms of said alkyl, alkenyl, cycloalkyl and cycloalkenyl are substituted or are not independently substituted with one or more heteroatoms; R2 is C3-C9 cycloalkyl, C3-C9 cycloalkenyl, or Ar, wherein said cycloalkyl or cycloalkenyl are substituted or are not substituted with one or more substitutes and the carbon atoms of said cycloalkyl and cycloalkenyl are substituted or not substituted independent with one or more heteroatoms; or said Ar is replaced with one or more substitutes; Ar is a heterocyclic, mono-, bi- or tricyclic, aromatic carbocyclic ring having an individual ring size of 5-9 members, said heterocyclic ring containing one or more heteroatoms selected independently from the group consisting of , S, SO, SO2, N, NH and NR; W and X are independently O, S, CH2 or H2; And it is O or S; and Z is O, NH or NR. 36. The method according to claim 35, characterized in that the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder. 37. The method according to claim 36, characterized in that the neurological disorder is selected from the group consisting of peripheral neuropathy caused by a state of physical injury or illness, traumatic brain damage, physical damage to the spinal cord, stroke associated with brain damage and neurological disorder related to neurodegeneration. 38. The method according to claim 37, characterized in that the neurological disorder relating to neurodegeneration is selected from the group consisting of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. 39. The method according to claim 35, characterized in that said compound is immunosuppressive. 40. The method according to claim 35, characterized in that said compound is non-immunosuppressive. 41 The method according to claim 35, characterized in that said compound has an affinity with an immunophilin of the FKBP type. 42. The method according to claim 41, characterized in that the FKBP-type immunophilin is FKBP-12. 43. The method according to claim 41, characterized in that: R2 is substituted with (Ar) "; and n is 1-2 44. The method according to claim 43, characterized in that said compound is (2S) -1- (3,3-dimethyl-2-oxopentanoyl) -pyrrolidine-2-carboxylic acid 4,4-diphenylcyclohexyl of the formula lll or a pharmaceutically acceptable salt or solvate thereof.