MXPA97009829A - Methods and compositions to stimulate the growth of neur - Google Patents

Abstract

The present invention relates to methods and pharmaceutical compositions for stimulating the growth of neurites in nerve cells. The compositions comprise a neurotrophic amount of a compound that binds to the binding protein FK-506 (FKBP) and a neurotrophic factor, for example a nerve growth factor NGF. The methods comprise treating the nerve cells with the compositions described above or with compositions comprising the FKBP binding compound without a neurotrophic factor. The methods of the invention can be used to promote the repair of neuronal damage caused by physical diseases or traumas.

Description

METHODS AND COMPOSITIONS TO STIMULATE THE GROWTH OF NEURITA TECHNICAL FIELD OF THE INVENTION The present invention relates to methods and pharmaceutical compositions for stimulating the growth of neurites in nerve cells. The compositions comprise a neurotrophic amount of a compound that binds to the binding protein FK-506 (FKBP) and a neurotrophic factor, for example, the nerve growth factor NGF. The methods comprise the treatment of nerve cells with the compositions described above, or the compositions comprising the FKBP binding compounds without a neurotrophic factor. The methods of this invention can be used to promote the repair of neuronal damage caused by diseases or physical traumas.

BACKGROUND OF THE INVENTION Immunophilins are a family of soluble proteins that mediate the actions of immunosuppressive drugs such as cyclosporin A, FK506 and rapamycin. Of particular interest is the immunofilin 1 2 kDa, the binding protein FK-506 (FKBP12). FKBP1 2 binds to FK-506 and rapamycin leading to an inhibition of T cell activation and proliferation. Interestingly, the mechanism of action of FK-506 and rapamycin are different. For review, see, S. H. Solomon et al. , Nature Med .. 1. pp. 32-37 (1995). FK-506 binds to FK BP1 2 and the resulting complex binds to calcineurin and inhibits it, a cytoplasmic phosphatase. The phosphatase activity of calcineurin is necessary for the dephosphorylation and subsequent translocation within the nucleus of the transcription factor N F-AT. NF-AT causes the activation of the interleukin-2 gene which in turn mediates the proliferation of the T cell. The rapamycin-FKBP1 2 complex, on the other hand, is associated with an unknown fusion protein called RAFT1 / FRAP. This tripartite complex is known to inhibit several kinases in the cell (ie, p70S6, p34cdc2, cdk2) that are necessary for cell cycle progression in T cells. Rapamycin is also known to be a potent antagonist of FK-506 , presumably acting as a competitive inhibitor for FKBP1 binding 2. More recently, it has been found that FKBP plays an important role in the body. It has been found that FK BP12 forms a complex with the intracellular channels of the calcium ion, the ryanodine receptor (RyR) and the inositol 1, 4,5-triphosphate receptor (I P3R) [T. Jayaraman et al. , J. Biol.

Chem. 267, pp. 9474-77 (1992); A. M. Cameron et al. , Proc. Nati, acad. Sci. U SA. 92, pp. 1784-44 (1995)], helping to stabilize the release of calcium. The ryanodine receptor has been found in skeletal muscle, cardiac muscle, brain and other excitable tissues. IP3R mediates intracellular calcium release caused by hormones and neurotransmitters that act on the cell surface to activate phospholipase C and generate inositol 1, 4,5-triphosphase (IP3). Most of the IP3R is associated with the endoplasmic reticulum, but a part can be present on the cell surface and mediate the flow of calcium into the cell. For RyR and for IP3R it has been shown that FK506 and rapamycin are able to dissociate FKBP1 2 from the receptor. In each case, the "separation" of FK BP12 leads to a greater leakage of the calcium channel and lower concentrations of intracellular calcium. Another role of FKBP1 2 is the regulation of neurite overgrowth in nerve cells, W. E. Lyons et al. rProc. Nati Acad. Sci. USA. 91, pp. 3191 -95 (1994)] demonstrated that FK506 acts synergistically with nerve growth factor (NGF) by stimulating neurite overgrowth in a rat pheochromocytoma cell line. Interestingly, rapamycin does not inhibit the effects of FK-506 on neurite overgrowth, but was itself neurotrophic, showing an additive effect with FK-506. In the sensory ganglia, FK-506 demonstrated similar neurotrophic effects, but these effects were blocked by rapamycin. These results lead the authors to speculate that FK-506 was exerting its neurotrophic effect through its complexation with FK BP12 and calcineurin and inhibition of phosphatase activity of the latter. Alternatively, the authors propose that the FK-506 was acting by a "separation" mechanism, such as that involved in FKBP1 2 from RyR and I P3R. By virtue of the wide variety of disorders that can be treated by stimulation of neurite overgrowth and the relatively few FKBP1 2 binding compounds that are known to possess this property, there is a great need for additional neurotrophic FKBP1 2 binding compounds.

BRIEF DESCRIPTION OF THE INVENTION The Applicant has solved the aforementioned problem by discovering that the genders of the novel FK BP12 binding compounds of the Applicant which had previously co-invented, also possess neurotrophic activity. The applicant has previously described a series of acylated amino acid derivatives that bind to FKPB1 2 in PCT patent publication WO 92/19593 and WO 94/07858. Another series of ligands FKBP1 2 are described in the applicant's United States patents 5,192,773 and 5,330,993 and PCT patent publication WO 92/00278. Each series of compounds stimulates neurite overgrowth in the presence of exogenous or endogenous NGF. The compositions provided comprise a compound from one of the two genera described above and a neuronal growth factor. The methods described herein employ those previously mentioned compounds and the compositions comprising them to effect the neurite overgrowth which is useful for treating nerve damage caused by various diseases and physical traumas.

DETAILED DESCRIPTION OF THE INVENTION According to one embodiment, the present invention provides pharmaceutical compositions comprising: a) a compound with affinity for FKB P1 2 having the formula (I): (i) and pharmaceutically acceptable derivatives thereof, wherein A in O, N H or N- (C 1 -C 4 alkyl); wherein B is hydrogen, CH L-Ar, straight or branched chain alkyl of (C1-C6), straight or branched chain alkenyl of (C2-C6), cycloalkyl of (C5-C7), cycloalkenyl of (C5-) C 7) or (C 1 -C 6) alkyl or (C 2 -C 6) alkenyl substituted with Ar wherein L and Q are independently hydrogen, straight or branched chain alkylene of (C1-C6) or straight or branched chain alkenyl of (C2-C6); wherein T is Ar or a cyclohexyl substituted with the substituents at positions 3 and 4 which are independently selected from the group consisting of hydrogen, hydroxyl, O-alkyl of (C1-C4) or O-alkenyl of (C2-) C4) and carbonyl; wherein Ar is selected from the group consisting of 1 -naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl having one to three substituents are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, CF3, straight or branched chain alkyl of (C1-C6) or straight or branched chain alkenyl of (C2-C6), straight chain O-alkyl or branched of (C1-C4) or O- (straight or branched chain alkylene of (C2-C4)), O-benzyl, O-phenyl, amino and phenyl; where D is U; E is either oxygen, or CH-U, with the proviso that if D is hydrogen, then E is CH-U or if E is oxygen then D is not hydrogen; wherein each U is independently selected from hydrogen, straight or branched chain O-alkyl of (C1-C4) or O- (straight or branched chain alkenyl of (C2-C4)), straight or branched chain alkenyl of (C1-C6) or straight or branched chain alkenyl of (C2-C6), cycloalkyl of (C5-C7) or cycloalkenyl of (C5-C7) substituted with straight or branched chain alkyl of (C1-C4) or alkenyl straight or branched chain of (C2-C4), 2-indolyl, 3-indolyl, [(C1-C4) alkyl or (C2-C4) alkenyl] - Ar or Ar; wherein J is hydrogen or C1 or C2 alkyl; K is straight or branched chain alkyl of (C 1 -C 4), benzyl or cyclohexylmethyl; or wherein J and K taken together form a 5- to 7-membered heterocyclic ring, which may contain an O, S, SO or SO2 substituent thereon; wherein the stereochemistry at the position of carbon 1 is R or S; b) a neurotrophic factor; and c) a pharmaceutically acceptable carrier. More preferably, in the compound with affinity for FKBP1 2 in these pharmaceutical compositions: A is oxygen; J is hydrogen or C1 or C2 alkyl; K is straight or branched chain alkyl of (C 1 -C 4), benzyl or cyclohexylmethyl; or J and K taken together form pyrrolidyl or piperidyl; and the stereochemistry at the carbon 1 position is In the above preferred compounds wherein J and K taken together form pyrrolidyl or piperidyl and E is CH-U, U is preferably dimethylaminophenyl, methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, nitrophenyl, furyl, indolyl, pyridyl or methylenedioxyphenyl. In the above preferred compounds, wherein J and K are taken together to form pyrrolidyl or piperidyl and E is oxygen: B is preferably benzyl, naphthyl, tert-butyl, hydrogen, E-3-phenyl-2-methyl-prop-2-enyl, E-3- (4-hydroxy-enyl) 2-methyl-prop-2-enyl, E -3- [trans- (4-hydroxycyclohexyl)] - 2-methyl-prop-2-enyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclopentylpropyl, E-3- (4-methoxyphenyl) -2-methyl-prop-2-enyl , E-3- (3,4-dimethoxyphenyl) -2-methyl-prop-2-enyl or E-3- [cis- (4-hydroxycyclohexyl)] - 2-methyl-prop-2-enyl; and D is preferably phenyl, methoxyphenyl, cyclohexyl, ethyl, methoxy, nitrobenzyl, thiophenyl, indolyl, furyl, pyridyl, pyridyl-N-oxide, nitrophenyl, fluorophenyl, trimethoxyphenyl or dimethoxyphenyl. The most preferred compounds of the formula (I) useful in the compositions and methods of the invention are those of the formulas la, Ib, le and Id, listed in Tables 1 a to 1 d, respectively, set forth in Example 1 below. The synthesis of the compounds of the formula (I) with affinity for FKBP12 in these compositions is described in U.S. Patents 5,192,773 and 5,330,993 and PCT patent publication WO 92/00278, the descriptions of which they are incorporated herein by reference. According to an alternative embodiment, the present invention provides pharmaceutical compositions comprising: a) a compound with affinity for FKBP12 having the formula (II): (II) and pharmaceutically acceptable derivatives thereof, wherein A 'is CH2, oxygen , NH or N- (Ci alkyl ¬ C4); wherein B 'and W are independently: (i) hydrogen, Ar', straight or branched chain alkyl of (C1-C10), alkenyl or straight or branched chain alkynyl of (C2-C10), straight chain alkyl or branched (C 1 -C 6) substituted with (C 5 -C 7) cycloalkyl, straight or branched chain alkenyl or alkynyl of (C 2 -C 6), straight or branched chain alkyl of (C 1 -C 6) substituted with cycloalkenyl of ( C5-C7), straight or branched chain alkenyl or alkynyl of (C2-C6) or straight or branched chain alkyl of (C1-C6) substituted with straight or branched chain, straight or branched Ar ', alkenyl or alkynyl ) wherein, in each case, any of the CH2 groups of the alkyl, alkenyl or alkynyl chains can be optionally replaced by a heteroatom selected from the group consisting of O, S, SO, SO2, N, and NR, wherein R is selected from the group consisting of hydrogen, straight or branched chain alkyl of (C1-C4), straight chain or branched alkenyl or alkynyl of (C2-C4), and (C1-C4) alkyl acting as a bridge, where a bridge is formed between the nitrogen and a carbon atom of the heteroatom-containing chain to form a ring, and where the ring is optionally fused with an Ar 'group; or (ii) wherein Q * is hydrogen, straight or branched chain alkyl of (C1-C6) or straight or branched chain alkenyl or alkynyl of (C2-C6); wherein T 'is Ar' or 5-7 membered cycloalkyl substituted with substituents at positions 3 and 4, which are independently selected from the group consisting of oxo, hydrogen, hydroxyl, O-(C1-C4) alkyl, and O-alkenyl-of (C2-C4), wherein Ar 'is a carbocyclic aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl and anthracene; or a heterocyclic aromatic group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl , isothiazolyl, 1,3-oxadiazolyl, 1,2,3-triazolyl, 1,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3-triazinyl, 1,3-trityanil, indolizinyl , indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, 1 H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl; wherein Ar 'may contain one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy, straight or branched chain alkyl of (C1-C6), straight-chain alkenyl or branched (C2-C6), O- [straight or branched chain alkyl of (C1-C4)], O- [straight or branched chain alkenyl of (C2-C4)], O-benzyl, O-phenyl , 1,2-methylenedioxy, amino, carboxyl, N- [straight or branched chain alkyl of (C1-C5)] or (straight or branched chain alkenyl of (C2-C5)) carboxamide, N, N-di- [straight or branched chain alkyl of (C1-C5)] or straight or branched chain alkenyl of (C2-C5)], N-morpholinocarboxamide, N-benzylcarboxamide, N-thiomorpholinocarboxamide, N-picolinoylcarboxamide, OX, CH2- ( CH2) qX, O- (CH2) -qX, (CH2) qOX, and CH = CH-X; wherein X is 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl or pyrimidyl; and q is 0-2; where G is U '; M is either oxygen or CH-U '; with the proviso that if G is hydrogen, then M is CH-U 'or if M is oxygen, then G is U'; wherein U 'is hydrogen, O- [straight or branched chain alkyl of (C1-C4)] or O- [straight or branched chain alkenyl of (C2-C4)], straight or branched chain alkyl of (C1) -C6) or straight or branched chain alkenyl of (C2-C6), (C5-C7) cycloalkyl or (C5-C7) cycloalkenyl substituted with straight or branched chain alkyl of (C1-C4) or chain alkenyl straight or branched of (C2-C4), [(C1-C4) alkyl or (C2-C4) alkenyl] - Y or Y; wherein Y is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, 2-pyrrolinyl, 3-pyrrolinyl, pi rol id in yl, 1,3-dioxolyl, 2- imidazolinyl, imidazolidinyl, 2H-pyranyl, 4H-pyranyl, piperidyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, quinuclidinyl, and heterocyclic aromatic groups as defined for Ar 'in the foregoing; wherein Y may contain one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy, straight or branched chain alkyl of (C1-C6), straight-chain alkenyl or branched chain of (C2-C6), O- [straight or branched chain alkyl of (C1-C4)], O- [straight or branched chain alkenyl of (C2-C4)], O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, and carboxyl; wherein J 'is hydrogen, alkyl or benzyl of (C1-C2); K is cyclohexylmethyl, benzyl or straight or branched chain alkyl of (C 1 -C 4), or wherein J 'and K taken together can form a 5 to 7 membered heterocyclic ring which may contain a heteroatom selected from the group consisting of O , S, SO and SO2; and where m is 0-3; b) a neurotrophic factor; and c) a pharmaceutically acceptable carrier. The compounds of the formula (I I) exclude any compound of the formula (I). More preferably, in the compound with affinity for FKBP1 2 in these pharmaceutical compositions: B 'and W are independently: (i) hydrogen, Ar', straight or branched chain alkyl of (C1-C10), straight chain alkenyl or alkynyl or branched (C2-C10), straight or branched chain alkyl of (C1-C6) substituted with (C5-C7) cycloalkyl, straight-chain or branched alkenyl or alkynyl of (C2-C6), straight-chain alkyl or branched (C 1 -C 6) substituted with (C 5 -C 7) cycloalkenyl, straight or branched chain alkenyl or alkynyl of (C 2 -C 6), or straight or branched chain alkyl of (C 1 -C 6) substituted with Ar ' , straight or branched chain alkenyl or alkynyl of (C2-C6), wherein in each case, any of the CH2 groups of the alkyl, alkenyl or alkynyl chains may be optionally replaced with a heteroatom selected from the group consisting of O, S , SO, SO2; or (ii) Ar 'may contain one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy, straight or branched chain alkyl of (C1-C6), straight-chain alkenyl or branched chain of (C2-C6), O- [straight or branched chain alkyl of (C1-C4)], O- [straight or branched chain alkenyl of (C2-C4)], O-benzyl, O-phenyl, 1,2-methylenedioxy, amino and carboxyl; and Y is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl and heterocyclic aromatic groups as defined for Ar 'above. According to other preferred embodiments, in the compound with affinity for FKBP1 2 having the formula (II): at least one of B 'or W is independently selected from the group consisting of straight or branched chain alkynyl of (C2-) C10); alkylated straight or branched chain of (C2-C6) substituted with (C5-C7) cycloalkyl; straight or branched chain alkynyl of (C2-C6) substituted with (C5-C7) cycloalkenyl; and straight or branched chain alkynyl of (C2-C6) substituted with Ar '. Alternatively, at least one of B 'or W is independently represented by the formula - (CH2) r * (Z) - (CH2) s "Ar \ where: Z is independently selected from the group consisting of CH2, O, S, SO, SO2, N and NR, r is 0-4, s is 0-1, and Ar 'and R are as defined above in formula II.Although in another embodiment of formula II, at least one of B 'or W is independently selected from the group consisting of Ar', straight or branched chain alkyl of (C1-C6), substituted with Ar ', straight or branched chain alkenyl of (C2-C6) substituted with Ar' or alkynyl; wherein Ar 'is substituted with one to three substituents which are independently selected from the group consisting of N- (C 1 -C 5 alkyl) or straight or branched chain (C 2 -C 5) alkenyl) carboxamides, N, N- di (straight or branched chain (C1-C5) alkyl or (C2-C5) alkenyl) carboxamides, N-morpholinocarboxamide, N-benzylcarboxamide, N-thiomorpholinocarboxamide, N-picolinoylcarboxamide, OX, CH-2 (CH2) qX , O- (CH2) qX, (CH2) qOX, and CH = C HX; and Ar ', X and q are as defined above. More preferably, the compounds of the formula (II) used in the pharmaceutical compositions are selected from those of the formula (I I ') listed in Table 2, as noted in Example 1. The synthesis of the compounds of the formula I I is described in detail in the PCT patent publications of the applicant WO 92/19593 and WO 94/07858, the descriptions of which are incorporated herein by reference. In the form used herein, the FKBP12 binding compounds used in the pharmaceutical compositions and methods of this invention are defined to inclpharmaceutically acceptable derivatives thereof. A "pharmaceutically acceptable derivative" means any pharmaceutically acceptable salt, ester or salt of such ester of the compound of this invention or any other compound which, when administered to a patient, is capable of providing (directly or indirectly) a compound of this invention, or a metabolite or residue thereof, characterized by the ability to promote or increase neurite overgrowth. If the pharmaceutically acceptable salts of the FKBP1 2 binding compounds are used, those salts are preferably derived from inorganic or organic bases and acids. The salts of acids inclthe following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorrate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfonate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. The base salts inclammonium salts, alkali metal salts, such as, for example, sodium and potassium salts, alkaline earth metal salts, such as, for example, calcium and magnesium salts, salts with organic bases such as, for example, dicyclohexylamine salts, N-methyl-D-glucamine and salts with amino acids such as, for example, arginine, lysine and the like. Also, the basic nitrogen containing groups can be quaternized with those agents such as the lower alkyl halides for example, methyl, ethyl, propyl and butyl chloride, bromide and iodide; dialkylsulfates, such as, for example, dimethyl, diethyl, dibutyl and diamyl sulfates, long-chain halides such as chlorides, bromides and decyl, lauryl, myristyl and stearyl iodides, aralkyl halides such as phenyls and phenethylbromides and others. In this way, products soluble in water or in oil or dispersible in them are obtained. The FKBP1 2 binding compounds used in the compositions and methods of the invention can also be modified by attaching the appropriate functionalities to improve the selective biological properties. These modifications are known in the art and inclthose that increase the biological penetration towards a particular biological system (for example blood, the lymphatic system, the central nervous system), increasing the oral solubility, increasing the solubility to allow administration by injection, altering the metabolism and altering the rate of excretion. The neurotrophic activity of the FKBP12 binding compounds of this invention is directly related to its affinity for FKBP12 and its ability to inhibit the rotomasa activity of FKBP12. In order to quantify these properties, several assays known in the art can be employed. For example, competitive binding assays of LH20 using FK506, labeled as a reporter ligand that has been described by M.W. Harding et al. Nature 341 pp. 758-60 (1989), and by J. J. Siekierka et al. , Nature. 341, pp. 755-57 (1989). Preferably, the assay measures the inhibition of the rotomasa activity of FKBP1 2. This assay has also been described by M. W. Harding et al. , supra and by J. J. Siekierka et al. , supra. In this test the isomerization of an artificial substrate, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide-, is followed spectrophotometrically. The assay includes the cis form of the substrate, FKBP1 2, the inhibitor and chymotrypsin. Chymotrypsin is able to separate p-nitroanilide from the trans form of the substrate but not from the cis form. The release of p-nitroanilide is what is measured. The second component in each of the pharmaceutical compositions described above is a neurotrophic factor. The term "neurotrophic factor" in the sense used herein refers to compounds that are capable of stimulating the growth or stimulation of nervous tissue. In the sense employed herein, the term "neurotrophic factor" excludes the inhibiting compounds FKBP1 2 described herein as well as FK-506 and rapamycin. Several neurotrophic factors have been identified in the art and any of these factors can be used in the compositions of the invention. These neurotrophic factors include, but are not limited to, nerve growth factor (NGF), insulin growth factor (IGF-1), and their active truncated derivatives such as g lGF-1, fibroblast growth factors, and basic (aFGF and bFGF, respectively), growth factors, platelet derivatives (PDGF), neurotrophic factors derived from the brain (BDNF), ciliary neurotrophic factors (CNTF), neurotrophic factors derived from the glial cell line (GDNF), neurotrophin- 3 (NT-3) and neurotrophin 4/5 (NT-4/5). The most preferred neurotrophic factors for the compositions of the invention are NGF. The third component of the pharmaceutically acceptable compositions of this invention is a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers that can be employed in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, whey proteins, such as human serum albumin, regulatory substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, sodium diacid phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, trisilicate of magnesium, polyvinylpyrrolidone, substances based on cellulose, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and wool grease. The compositions of the present invention can be administered orally, parenterally, by inhalation of spray, topically, rectally, nasally, buccally, vaginally or by means of an implanted container. The term "parenteral" in the sense used here includes injection techniques or subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intraasternal, intrathecal, intrahepatic, intralesional, and intracranial infusion. Preferably, the compositions are administered orally, intraperitoneally or intravenously. The sterile injectable forms of the compositions of the invention can be of oleaginous or aqueous suspension. These suspensions may be formulated according to techniques known in the art using suitable suspending agents and wetting or dispersing agents. Sterile injectable preparations can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable solvent or diluent., for example, as a solution in 1, 3-butandol. Among the acceptable solvents and vehicles that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, fixed sterile oils are conventionally employed as a solvent or suspending medium. For this purpose, any soft fixed oil can be employed including diglycerides or synthetic monoglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, such as natural pharmaceutically acceptable oils, for example, olive oil or castor oil, especially their polyoxyethylated versions. These suspensions or oil solutions may also contain a long chain alcohol dispersant or diluent such as, for example, Ph. Helv or similar alcohol. The pharmaceutical compositions of the invention can be administered orally, in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous solutions or suspensions. In the case of tablets for oral use, carriers that are commonly used include 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 dehydrated corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, some sweetening, flavoring or coloring agents may also be added. Alternatively, the pharmaceutical compositions of this invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature, but is liquid at rectal temperature and will therefore melt in the rectum to release the drug. These materials include cocoa butter, beeswax and polyethylene glycols. The pharmaceutical compositions of the invention can also be administered topically, especially when the purpose of the treatment includes areas or organs easily accessible by topical applications, where diseases of the eyes, skin or the large intestine tract are included. Suitable topical formulations are easily prepared for each of these areas or organs. Topical application for the large bowel tract can be done in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical transdermal patches can also be used. For topical applications, the pharmaceutical compositions can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the invention include, without limitation, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated in a suitable lotion or cream form containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, without limitation, mineral oil, sorbitan monostearate, polysorbate 60, wax cetyl esters, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. For ophthalmic use, the pharmaceutical compositions can be formulated as micronized suspensions in sterile saline adjusted for pH, isotonic, or preferably as solutions in sterile saline solution adjusted with pH, isotonic, either with or without preservatives such as benzylalkonium chloride.

Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum. The pharmaceutical compositions of this invention can also be administered by inhalation or nasal spray. These compositions are prepared according to techniques well known in the art of pharmaceutical formulations and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons and / or other dispersing agents or conventional solubilizers. The amount of the FKBP12 binding compound and the neurotrophic factor that can be combined with the carrier materials to produce a single dosage form will vary depending on the host to be treated and the particular mode of administration. The two active ingredients of the pharmaceutical compositions of this invention act synergistically to stimulate neurite overgrowth. Therefore, the amount of neurotrophic factor in these compositions will be less than that required in monotherapy using only that factor. Preferably, the compositions can be formulated so that a dose of between 0.01-100 mg / kg body weight / day of the binding protein FKBP12 and a dose of between 0.01-100 μg / kg body weight / day of the neurotrophic, to a patient who receives these compositions. It should also be understood that a specific treatment and dose regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health status, sex, diet , the time of administration, the rate of excretion, the combination of drugs and the judgment of the attending physician and the severity of the particular disease being treated. The amount of the active ingredients will also depend on the particular binding compound FKBP1 2 and the neurotrophic factor in the composition. According to another embodiment, the invention provides methods for stimulating neurite overgrowth. These methods comprise the step of treating the nerve cells with any of the FKBP12 binding compounds described above. Preferably, this method is used to stimulate neurite overgrowth in a patient and the FKBP12 binding compound is formulated in a composition further comprising a pharmaceutically acceptable carrier. The amount of the FKBP1 2 binding compound used in these methods is between about 0.01 and 1 00 mg / kg body weight / day. According to an alternative embodiment, the method for stimulating neurite overgrowth comprises the additional step of treating the nerve cells with a neurotrophic factor, such as, for example, those contained in the pharmaceutical compositions of this invention. The embodiment includes administering the FKBP1 2 binding compound and the neurotrophic agent in a single dose form or in multiple multiple dose forms. If the dosage forms are used, they may be administered concurrently or with less than 5 hours apart. Preferably, the methods of the invention are used to stimulate neurite overgrowth in a patient. The methods and compositions of the invention can be used to treat nerve damage caused by a wide variety of physical illnesses or traumas. These include, but are not limited to, Alzheimer's disease, Parkinson's disease, ALS, stroke and ischemia associated with embolisms, neural parapathia, other neural degenerative diseases, motor neuron diseases, sciatic attack, damage to the spine and attack on the facial nerve. In order that the invention described herein can be more fully understood, the following examples are pointed out. It should be understood that these examples have illustrative purposes only and should not be construed as limiting the invention in any way.

EXAMPLE 1 Joint test FKBP12 Inhibition of rotamase FKBP activity by the preferred FKBP1 2 binding compounds present in the compositions of this invention were analyzed. In this analysis various amounts of the binding compound FKBP1 2 (0.1 nM - 10 μM) were added to the cis-N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide in the presence of FKBP1 2 and chymotrypsin. FKBP12 converts the cis form of the substrate to the trans form. This allows the chymotrypsin to separate the p-nitroanilide from the substrate. The release of the p-nitroanilide was measured spectrophotometrically. This test makes it possible to measure the change in the first order velocity constant of the rotomass activity as a function of the concentration of the binding compound FKBP1 2 and yielded an estimate of apparent K i. The most preferred FKBP1 2 binding compounds used in the compositions and methods of this invention and their calculated K i are tabulated below.

TABLE 1a (formula la] TABLE 1b (formula 1b) TABLE 1c (formula him) TABLE 1d (formula 1d) TABLE 2 (formula II1 EXAMPLE 2 Neurite Overgrowth Test in Crops PC1 2 In order to directly determine the neurotrophic activity of the binding compounds of FKBP1 2 used in this invention, the assay of W. E. Lyons et al. , Proc. Nati Acad. Sci. USES. 91 pp. 3191 -95 (1994) was carried out. PC12 rat pheochromocytoma cells were maintained at 37 ° C and 5% CO2 in Dulbecco's modified Eagle's medium (OMEM) supplemented with 10% thermally inactivated horse serum (HS) and thermally inactivated fetal bovine serum. at 5% (FBS). The cells were then plated at 105 in each 35 mm culture well coated with 5 μg / cm2 of rat tail collagen and allowed to attach. Subsequently, the medium was replaced with DMEM + 2% HS and 1% FBS, NGF (1-100 ng / ml) and by varying the concentrations of the FK BP1 2 binding compound (0.1 nM -1 0 μM). The control cultures are administered with NGF without FKBP12 binding compound. The FKBP12 binding compounds used in this invention cause a significant increase in neurite overgrowth over control cultures.

EXAMPLE 3 Neurite Overgrowth Assay in a Dorsal Root Ganglion Culture Another way to directly determine the neurotrophic activity of the FKBP1 2 binding compounds used in this invention is the dorsal root ganglion culture assay, also described by W. E. Lyons et al., Proc. Nati Acad. Sci. USES. 91, pp. 3191 -95 (1994). In this trial, the dorsal root ganglia are dissected from day 1 6 of the rat embryo and cultured on 35 mm plates coated with collagen with an N2 medium at 37 ° C in an environment of 15% CO2. Sensory ganglia are then treated with a diverse concentration of NG F (0 -1 00 ng / ml) and a binding compound FKB12 (0.1 nM - 10 μM). The ganglia are observed every two days under a phase contrast microscope and the lengths of the axons are measured. Control cultures, either lacking the FKBP1 2 binding compound or lacking the binding compound FKBP12 and NGF. The FKBP12 binding compounds used in this invention, cause a considerable effect in neurite overgrowth on control cultures lacking such compounds, both in the presence and absence of NGF.

While in the foregoing, various embodiments of the invention have been presented, it will be apparent that the basic interpretation may be altered to provide other embodiments utilizing the methods of the invention. Therefore, it will be appreciated that the scope of the invention will be defined by the claims appended hereto and not by the specific embodiments that have been presented in the foregoing by way of example.

Claims (25)

1. Claims: 1. A pharmaceutically acceptable composition comprising: a) a neurotrophic amount of a compound with affinity for FKBP12 having the formula (I): (I) and pharmaceutically acceptable derivatives thereof, wherein A in O, NH or N- (C1-C4 alkyl); wherein B is hydrogen, CHL-Ar, straight or branched chain alkyl of (C1-C6), straight or branched chain alkenyl of (C2-C6), cycloalkyl of (C5-C7), cycloalkenyl of (C5-C7) ) or (C1-C6) alkyl or (C2-C6) alkenyl substituted with Ar straight or branched chain (C 1 -C 6) or straight or branched chain alkenyl (C 2 -C 6) alkylene; and T is Ar or a cyclohexyl substituted with the substituents at positions 3 and 4 which are independently selected from the group consisting of hydrogen, hydroxyl, O-alkyl of (C1-C4) or O-alkenyl of (C2-C4) and carbonyl; wherein Ar is selected from the group consisting of 1 -naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl having one to three substituents are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, CF3, straight or branched chain alkyl of (C1-C6) or straight or branched chain alkenyl of (C2-C6), straight chain O-alkyl or branched of (C1-C4) or O- (straight or branched chain alkylene of (C2-C4)), O-benzyl, O-phenyl, amino and phenyl; From his; E is either oxygen, or CH-U, with the proviso that if D is hydrogen, then E is CH-U or if E is oxygen then D is not hydrogen; wherein each U is independently selected from hydrogen, straight or branched chain O-alkylated (C1-C4) or O- (alkene straight or branched chain of (C2-C4)), straight chain alkenyl or branched (C 1 -C 6) or alkene straight or branched chain of (C 2 -C 6), (C 5 -C 7) cycloalkyl or (C 5 -C 7) cycloalkenyl substituted with straight or branched chain alkyl of (C 1 - C4) or straight or branched chain alkenyl of (C2-C4), 2-indolyl, 3-indolyl, [(C1-C4) alkyl or (C2-C4) alkenyl] - Ar or Ar; J is hydrogen or C1 or C2 alkyl; K is straight or branched chain alkyl of (C1-C4), benzyl or cyclohexylmethyl; or wherein J and K taken together form a 5- to 7-membered heterocyclic ring, which may contain an O, S, SO or SO2 substituent thereon; and the stereochemistry at the position of carbon 1 is R or S; b) a neurotrophic factor; and c) a pharmaceutically acceptable carrier.
2. 2. The composition according to claim 1, wherein: A is oxygen; J is hydrogen or C1 or C2 alkyl; K is straight or branched chain alkyl of (C 1 -C 4), benzyl or cyclohexylmethyl; or J and K taken together form pyrrolidyl or piperidyl; and the stereochemistry at the position of carbon 1 is S.
3. The composition according to claim 2, wherein: J and K are taken together to form pyrrolidyl or piperidyl; and E is CH-U; and U is preferably dimethylaminophenyl, methoxyphenyl, dimethoxyphenyl, trimethoxyphene, nitrophenyl, furyl, indolyl, pyridyl or methylenedioxyphenyl.
4. 4. The composition according to claim 2, wherein: J and K are taken together to form pyrrolidyl or piperidyl; E is oxygen: B is benzyl, naphthyl, tert-butyl, hydrogen, E-3-phenyl-2-methyl-prop-2-enyl, E-3- (4-hydroxyphenyl) 2-methyl-prop-2 -eni lo, E-3- [trans- (4-hydroxycyclohexy l)] - 2-methyl-prop-2-enyl, cyclohexylethyl, cyclohexylpropyl, cyclohexyl butyl, cyclopentylpropyl, E-3- (4-methoxyphenyl) -2- methyl-prop-2-enyl, E-3- (3,4-dimethoxyphenyl) -2-methyl-prop-2-enyl or E-3- [cis- (4-hydroxycyclohexyl)] - 2-methyl -prop-2-enyl; and D is preferably phenyl, methoxyphenyl, cyclohexyl, ethyl, methoxy, nitrobenzyl, thiophenyl, indolyl, furyl, pyridyl, pyridyl-N-oxide, nitrophenol, fl uorophenyl, trimethoxyphenyl or dimethoxyphenyl.
5. 5. A pharmaceutically acceptable composition comprising: a) a neurotrophic amount of a compound with affinity for FK B P1 2 having the formula (II): (ID and pharmaceutically acceptable derivatives thereof, wherein A * is CH2, oxygen, NH or N- (C1-C4 alkyl); B 'and W are independently: (i) hydrogen, Ar \ straight or branched chain alkyl of (C1-C10), alkenyl or alkynyl straight or branched chain of (C2-C10), straight or branched chain alkyl of ( C1-C6) substituted with (C5-C7) cycloalkyl, straight or branched chain alkenyl or alkynyl of (C2-C6), straight or branched chain alkyl of (C1-C6) substituted with cycloalkenyl of (C5-C7) , straight or branched chain alkenyl or alkynyl of (C2-C6) or straight chain or branched chain of (C1-C6) substituted with straight or branched chain or branched Ar ', alkenyl or alkynyl of (C2-C6) where, in each case, any of the CH2 groups of the alkyl, alkenyl or alkynyl chains may be optionally replaced by a heteroatom selected from the group consisting of O, S, SO, SO2, N, and NR, wherein R is selected from the group consisting of hydrogen, straight or branched chain alkyl of (C1-C4), alkenyl or straight or branched chain alkynyl of (C2-C4) , and (C 1 -C 4) alkyl acting as a bridge, wherein a bridge is formed between the nitrogen and a carbon atom of the heteroatom-containing chain to form a ring, and wherein the ring is optionally fused to a group Ar '; or (ii) wherein Q 'is hydrogen, straight or branched chain alkyl of (C1-C6) or straight or branched chain alkenyl or (C2-C6) alkynyl; and T 'is Ar' or 5-7 membered cycloalkyl substituted with substituents at positions 3 and 4, which are independently selected from the group consisting of oxo, hydrogen, hydroxyl, O-(C 1 -C 4) alkyl, and O -alkenyl-of (C2-C4), wherein Ar 'is a carbocyclic aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl; or a heterocyclic aromatic group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazole, midazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazole, 1, 2,3-triazolyl, 1,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl or, 1,3,5-triazinyl, , 3,5-trityanil, indolizinyl, idolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, 1 H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl , cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthridinyl, pteridinyl, carbazoli, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl; and wherein Ar 'may contain one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy, straight or branched chain alkyl of (C1-C6), chain alkenyl straight or branched chain of (C2-C6), O- [straight or branched chain alkyl of (C1-C4)], O- [straight or branched chain alkenyl of (C2-C4)], O-benzyl, O- phenyl, 1,2-methylenedioxy, amino, carboxyl, N- [straight or branched chain alkyl of (C1-C5)] or (alkene straight or branched chain of (C2-C5)) carboxamide, N, N-di- [straight or branched chain alkyl of (C1-C5)] or straight-chain alkenyl or branched (C2-C5)], N-morpholinocarboxamide, N-benzylcarboxamide, N-thiomorpholinocarboxamide, N-picolinoylcarboxamide, OX, CH2- (CH2) qX, O- (CH2) -qX, (CH2) q-0-X , and CH = CH-X; wherein X is 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiozoyl, thiazoyl, 2-thienyl, 3-thienyl or pyrimidyl; and q is 0-2; G is U '; M is either oxygen or CH-U '; with the proviso that if G is hydrogen, then M is CH-U 'or if M is oxygen, then G is U'; wherein U 'is hydrogen, O- [straight or branched chain alkyl of (C1-C4)] or O- [straight or branched chain alkenyl of (C2-C4)], straight or branched chain alkyl of (C1) -C6) or straight or branched chain alkenyl of (C2-C6), cycloalkyl of (C5-C7) or cycloalkenyl of (C5-C7) substituted with straight or branched chain alkyl of (C1-C4) or alkenyl of chain straight or branched of (C2-C4), [(C1-C4) alkyl or (C2-C4) alkenyl] - Y or Y; wherein Y is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrolidinyl, 1,3-dioxolyl, 2-imidazolinyl, imidazolidinyl, 2H-pyranyl, 4H-pyranyl, piperidyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, quinuclidinyl, and heterocyclic aromatic groups as defined for Ar 'in the foregoing; and wherein Y may contain one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, hydroxy methyl, nitro, trifluoromethyl, trifluoromethoxy, straight or branched chain alkyl of (C1-C6), chain alkenyl straight or branched of (C2-C6), O- [straight or branched chain alkyl of (C 1 -C 4)], O- [straight or branched chain alkynyl of (C 2 -C 4)], O-benzyl, O phenyl, 1,2-methylenedioxy, amino, and carboxyl; J 'is hydrogen, alkyl or benzyl of (C1-C2); K is cyclohexylmethyl, benzyl or straight or branched chain alkyl of (C 1 -C 4), or where J 'and K taken together can form a 5 to 7 membered heterocyclic ring which may contain a heteroatom selected from the group consists of O, S, SO, and SO2; m is 0-3; and wherein the compound is not a compound of the formula (I); b) a neurotrophic factor; and c) a pharmaceutically acceptable carrier.
6. 6. The composition according to claim 5, wherein: B 'and W are independently: (i) hydrogen, Ar', straight or branched chain alof (C1-C10), alkenyl or straight or branched chain alkynyl of ( C2-C10), straight or branched chain alof (C1-C6) substituted with (C5-C7) cycloal straight or branched chain alkenyl or alkynyl of (C2-C6), straight or branched chain alof ( C1-C6) substituted with (C5-C7) cycloalkenyl, straight or branched chain alkenyl or alkynyl of (C2-C6), or straight or branched chain alof (C1-C6) substituted with Ar ', alkenyl or alkynyl straight or branched chain of (C2-C6), wherein in each case, any of the CH2 groups of the al alkenyl or alkynyl chains may be optionally replaced with a heteroatom selected from the group consisting of O, S, SO, SO2; or (ii) Ar 'may contain one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy, straight or branched chain alkyl of (C1-C6), straight or branched chain alkenyl of (C2-C6), O- [straight or branched chain alkyl of (C1-C4)], O- [straight or branched chain alkenyl of (C2-C4)], O-benzyl, O-phenyl, 1 , 2-methylenedioxy, amino and carboxyl; and Y is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenium, anthracenyl and heterocyclic aromatic groups as defined for Ar 'above.
7. The composition according to claim 5, wherein: at least one of B 'or W is independently selected from the group consisting of straight or branched chain alkynyl of (C2-C10); straight or branched chain alkynyl of (C2-C6) substituted with (C5-C7) cycloalkyl; straight or branched chain alkynyl of (C2-C6) substituted with (C5-C7) cycloalkenyl; and straight or branched chain alkynyl of (C2-C6) substituted with Ar '.
8. The composition according to claim 5, wherein: at least one of B 'or W is independently represented by the formula * (CH2) r- (Z) - (CH2) s-Ar', wherein: Z is independently selects from the group consisting of CH2, O, S, SO, SO2, N and NR; r is 0-4; s is 0-1.
9. The composition according to claim 5, wherein: at least one of B 'or W is independently selected from the group consisting of Ar', straight or branched chain alkyl of (C 1 -C 6), substituted with Ar ', straight or branched chain alkenyl of (C2-C6) substituted with Ar 'or alkynyl; wherein Ar 'is substituted with one to three substituents which are independently selected from the group consisting of N- (C 1 -C 5 alkyl) or straight or branched chain (C 2 -C 5) alkenyl) carboxamides, N, N- di (straight or branched chain (C1-C5) alkyl or (C2-C5) alkenyl) carboxamides, N-morpholinocarboxamide, N-benzylcarboxamide, N-thiomorpholinocarboxamide, N-picolinoylcarboxamide, OX, CH-2 (CH2) qX , O- (CH2) qX, (CH2) q-0-X, and CH = CH-X.
10. 10. The composition according to claims 1 or 5, wherein the neurotrophic factor is selected from: nerve growth factor (NGF), insulin growth factor (IGF-1), and its active truncated derivatives thereof, acid fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), growth factors, platelet derivatives (PDGF), brain-derived neurotrophic factors (BDNF), ciliary neurotrophic factors (CNTF), neurotrophic factors derived from the glial cell line (GDNF), neurotrophin -3 (NT-3) and neurotrophin 4/5 (NT-4/5). eleven .
11. The composition according to claim 10, wherein the neurotrophic factor is NGF.
12. 12. A method for stimulating neurite growth in nerve cells, comprising the step of contacting the nerve cells with a composition comprising a neurotrophic amount of a compound with affinity for FKBP12 having the formula (I): (I) and pharmaceutically acceptable derivatives thereof, wherein A in O, NH or N- (C1-C4 alkyl); wherein B is hydrogen, CHL-Ar, straight or branched chain alkyl of (C1-C6), straight or branched chain alkenyl of (C2-C6), cycloalkyl of (C5-C7), cycloalkenyl of (C5-C7) ) or (C1-C6) alkyl or (C2-C6) alkenyl substituted with Ar straight or branched chain (C 1 -C 6) or straight or branched chain alkenyl (C 2 -C 6) alkylene; and T is Ar or a cyclohexyl substituted with the substituents at positions 3 and 4 which are independently selected from the group consisting of hydrogen, hydroxyl, O-alkyl of (C1-C4) or O-alqueni that of (C2-C4) ) and carbonyl; where Ar is selected from the group consisting of 1 - . 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl having one to three substituents which are independently selected from the group consisting of hydrogen, halo, hydroxyl, nitro, CF3, straight or branched chain alkyl of (C1-C6) or straight chain or branched alkenyl of (C2-C6), straight or branched chain O-alkyl of (C1-C4) ) or O- (straight or branched chain alkylene of (C2-C4)), O-benzyl, O-phenyl, amino and phenyl; From his; E is either oxygen, or CH-U, with the proviso that if D is hydrogen, then E is CH-U or if E is oxygen then D is not hydrogen; wherein each U is independently selected from hydrogen, straight or branched chain O-alkyla of (C1-C4) or O- (straight or branched chain alkenyl of (C2-C4)), straight or branched chain alkenyl of (C1-C6) or straight or branched chain alkenyl of (C2-C6), (C5-C7) cycloalkyl or (C5-C7) cycloalkenyl substituted with straight or branched chain alkyl of (C1-C4) ) or branched or straight chain alkenyl of (C2-C4), 2-indolyl, 3-i ndolyl, [(C1-C4) alkyl or (C2-C4) alkenyl] - Ar or Ar; J is hydrogen or C1 or C2 alkyl; K is straight or branched chain alkyl of (C 1 -C 4), benzyl or cyclohexymethyl; or wherein J and K taken together form a 5- to 7-membered heterocyclic ring, which may contain an O, S, SO or SO2 substituent thereon; and the stereochemistry at the position of carbon 1 is R or S.
13. The method according to claim 1 2, wherein the compound with affinity for FKBP12: A is oxygen; J is hydrogen or C1 or C2 alkyl; K is straight or branched chain alkyl of (C 1 -C 4), benzyl or cyclohexylmethyl; or J and K taken together form pyrrolidyl or piperidyl; and the stereochemistry at the position of carbon 1 is S.
14. The method according to claim 13, wherein the compound with affinity for FKBP12: J and K are taken together to form pyrrolidyl or piperidyl; and E is CH-U; and U is preferably dimethyl laminophenyl, methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, nitrophenyl, furyl, indolyl, pyridyl or methylenedioxyphenyl.
15. 15. The method according to claim 1, wherein the compound with affinity for FK BP1 2: J and K are taken together to form idyl or piperidyl pyrrole; E is oxygen: B is benzyl, naphthyl, tert-butyl, hydrogen, E-3-phenyl-2-methyl-prop-2-enyl, E-3- (4-hydroxyphenyl) 2-methyl-prop-2- enyl, E-3- [trans- (4-hydroxycyclohexyl)] - 2-methyl-prop-2-enyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cyclopentylpropyl, E-3- (4-methoxyphenyl) -2-methyl- prop-2-eni lo, E-3- (3,4-dimethoxyphenyl) -2-methyl-prop-2-enyl or E-3- [cis- (4-hydroxycyclohexyl)] - 2-methyl-prop- 2-on it; and D is preferably phenyl, methoxyphenyl, cyclohexyl, ethyl, methoxy, nitrobenzyl, thiophenyl, indolyl, furyl, pyridyl, pyridyl-N-oxide, nitrophenyl, fluorophenyl, trimethoxyphenyl or di methoxyphenyl.
16. 1 6. A method for stimulating the growth of neurite in nerve cells, comprising the step of contacting the nerve cells with a composition comprising a neurotrophic amount of a compound with affinity for FKBP12, which has the formula ( II): (II) and pharmaceutically acceptable derivatives thereof, wherein A 'is CH2, oxygen, NH or N- (C1-C4 alkyl); B 'and W are independently: (i) hydrogen, Ar', straight or branched chain alkyl of (C 1 -C 10), straight or branched chain alkenyl or alkynyl of (C 2 -C 10), straight or branched chain alkyl of (C1-C6) substituted with (C5-C7) cycloalkyl, straight or branched chain alkenyl or alkynyl of (C2-C6), straight or branched chain alkyl of (C1-C6) substituted with cycloalkenyl of (C5-C7) ), straight or branched chain alkenyl or alkynyl of (C2-C6) or straight or branched chain alkyl of (C1-C6) substituted with straight or branched chain or branched Ar ', alkenyl or alkynyl of (C2-C6) where , in each case, any of the CH2 groups of the alkyl, alkenyl or alkynyl chains may be optionally replaced by a heteroatom selected from the group consisting of O, S, SO, SO2, N, and NR, wherein R is selected from a group consisting of hydrogen, straight or branched chain alkyl of (C1-C4), alkenyl or straight or branched chain alkynyl of (C2-) C4), and (C1-C4) alkyl acting as a bridge, wherein a bridge is formed between the nitrogen and a carbon atom of the heteroatom-containing chain to form a ring, and wherein the ring is optionally fused with an Ar 'group; or (ii) wherein Q 'is hydrogen, straight or branched chain alkyl of (C1-C6) or straight or branched chain (C2-C6) alkynyl or quenyl; and T 'is Ar' or cycloalkyl of 5-7 members substituted with substituents at positions 3 and 4, which are independently selected from the group consisting of oxo, hydrogen, hydroxyl, O-(C 1 -C 4) alkyl, and O-alkenyl-of (C2-C4), where Ar 'is a carbocyclic aromatic group selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl and anthracenyl; or a heterocyclic aromatic group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl , isothiazolyl, 1,3-oxadiazolyl, 1,2,3-triazolyl, 1,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3-trityanil, indolizinyl indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo [b] furanyl, benzo [b] thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, , 8-naphthridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl; and wherein Ar 'may contain one to three substituents that are independently selected from the group consisting of hydrogen, halogen, hydroxyl, hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy, straight or branched chain alkyl of (C1-C6), chain alkenyl straight or branched of (C2-C6), O- [straight or branched chain alkyl of (C1-C4)], O- [straight or branched chain alkenyl of (C2-C4)], O-benzyl, O- phenyl, 1,2-methylenedioxy, amino, carboxyl, N- [straight or branched chain alkyl of (C1-C5)] or (straight or branched chain alkenyl of (C2-C5)) carboxamide, N, N-di - [straight or branched chain alkyl of (C1-C5)] or straight or branched chain alkenyl of (C2-C5)], N-morpholinecarboxamide, N-benzylcarboxamide, N-thiomorpholinocarboxamide, N-picolinoylcarboxamide, OX, CH2- (CH2) qX, O- (CH2) -qX, (C H2) qOX, and CH = CH-X; wherein X is 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiozoyl, thiazoyl, 2-thienyl, 3-thienyl or pyridyl; and q is 0-2; G is U '; M is either oxygen or CH-U '; with the proviso that if G is hydrogen, then M is CH-U 'or if M is oxygen, then G is U'; wherein U 'is hydrogen, O- [straight or branched chain alkyl of (C1-C4)] or O- [straight or branched chain alkenyl of (C2-C4)], straight or branched chain alkyl of (C1) -C6) or straight or branched chain alkenyl of (C2-C6), cycloalkyl of (C5-C7) or cycloalkenyl of (C5-C7) substituted with straight or branched chain alkyl of (C1-C4) or alkenyl of straight or branched chain of (C2-C4), [(C1-C4) alkyl or (C2-C4) alkenyl] - Y or Y; wherein Y is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrolidinyl, 1,3-dioxolyl, 2-imidazolinyl, imidazolidinyl, 2H-pyranyl, 4H-pyranyl, piperidyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, piperazinyl, quinuclidinyl, and heterocyclic aromatic groups as defined for Ar 'in the foregoing; and wherein Y may contain one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy, straight or branched chain alkyl of (C1-C6), straight-chain alkenyl or branched (C2-C6), O- [straight or branched chain alkyl of (C1-C4)], O- [straight or branched chain alkenyl of (C2-C4)], O-benzyl, O-phenyl , 1,2-methylenedioxy, amino, and carboxyl; J 'is hydrogen, alkyl or benzyl of (C1-C2); K is cyclohexylmethyl, benzyl or straight or branched chain alkyl of (C 1 -C 4), or where J 'and K taken together can form a 5 to 7 membered heterocyclic ring which may contain a heteroatom selected from the group consisting of O , S, SO and SO2; m is 0-3; and wherein the compound is not a compound of the formula (I).
17. 17. The method according to claim 16, wherein in the compound with affinity for FKBP12: B 'and W are independently: (i) hydrogen, Ar', straight or branched chain alkyl of (C1-C10), alkenyl or alkynyl straight or branched chain of (C2-C10), straight or branched chain alkyl of (C1-C6) substituted with (C5-C7) cycloalkyl, straight or branched chain alkenyl or alkynyl of (C2-C6), alkyl straight or branched chain of (C1-C6) substituted with straight or branched chain (C2-C6) (C5-C7) cycloalkenyl, alkenyl or alkynyl, or straight or branched chain alkyl of (C1-C6) substituted with straight or branched chain C ', aryl, alkenyl or alkynyl of (C2-C6), wherein in each case, any of the CH2 groups of the alkyl, alkenyl or alkynyl chains may be optionally replaced with a heteroatom selected from the group consisting of O, S, SO, SO2; or H (ü) Ar 'may contain one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy, straight or branched chain alkyl of (C1-C6), straight or branched chain alkenyl of (C2-C6), O- [straight or branched chain alkyl of (C1-C4)], O- [alkene straight or branched chain of (C2-C4)], O-benzyl, O-phenyl, 1,2-methylenedioxy, amino and carboxyl; and Y is selected from the group consisting of phenyl, 1 -naphthyl, 2-naphthyl or, indenyl, azulenyl, fluorenyl, anthracenyl and heterocyclic aromatic groups as defined for Ar 'above.
18. 18. The method according to claim 16, wherein in the compound with affinity for FKBP1 2: at least one of B 'or W is independently selected from the group consisting of straight or branched chain alkynyl of (C2-C1 0 ); straight or branched chain alkynyl of (C2-C6) substituted with (C5-C7) cycloalkyl; straight or branched chain alkynyl of (C2-C6) substituted with (C5-C7) cycloalkenyl; and straight or branched chain alkynyl of (C2-C6) substituted with Ar '.
19. The method according to claim 16, wherein in the compound with affinity for FKB P12: at least one of B 'or W is independently represented by the formula - (CH2) r- (Z) - (CH2) s -Ar \ where: Z is independently selected from the group consisting of CH2, O, S, SO, SO2, N and NR; r is 0-4; s is 0-1.
20. 20. The method according to claim 16, wherein in the compound with affinity for FKBP12: at least one of B 'or W is independently selected from the group consisting of Ar', straight or branched chain alkyl of (C1- C6), substituted with Ar ', alkene straight or branched chain of (C2-C6) substituted with Ar' or alkynyl; wherein Ar 'is substituted with one to three substituents which are independently selected from the group consisting of N- (C 1 -C 5 alkyl) or straight or branched chain (C 2 -C 5) alkenyl) carboxamides, N, N- di (straight or branched chain (C1-C5) alkyl or (C2-C5) alkenyl) carboxamides, N-morpholinocarboxamide, N-benzylcarboxamide, N-thiomorpholinocarboxamide, N-picolinoylcarboxamide, OX, CH-2 (CH2) qX , O- (CH2) qX, (CH2) q-0-X, and CH = CH-X. twenty-one .
21. The method according to claim 12 or 16, wherein the method comprises the additional step of contacting the nerve cells with a neurotrophic factor.
22. 22. The method according to claim 21, wherein the neurotrophic factor is selected from: nerve growth factor (NGF), insulin growth factor (I GF-1), and its active truncated derivatives thereof, factor of acid fibroblast growth (aFGF), basic fibroblast growth factor (bFGF), growth factors, platelet derivatives (PDGF), neurotrophic factors derived from the brain (B DN F), ciliary neurotrophic factors (CNTF), neurotrophic factors derivatives of the glial cell line (GD NF), neurotrofi na-3 (NT-3) and neurotrophin 4/5 (NT-4/5).
23. 23. The method according to claim 22, wherein the neurotrophic factor is NGF.
24. The method according to claims 1 2 or 1 6, wherein the method is used to treat a patient who is suffering or who has suffered from Alzheimer's disease, Parkinson's disease, ALS, stroke and ischemia associated with embolism, Neural paropathy and other neural degenerative diseases, neuromotor diseases, sciatic crushing, spinal cord damage or crushing of the facial nerve.
25. 25. The method according to claim 21, wherein the method is used to treat a patient who is suffering or has suffered the disease from: Alzheimer's, Parkinson's disease, ALS, stroke and ischemia associated with embolism, neural paropathy and other neural degenerative diseases, neuromotor diseases, sciatic crushing, damage to the spinal cord or crushing of the facial nerve.