MXPA01000441A - Compounds, compositions, and methods for stimulating neuronal growth and elongation - Google Patents

Abstract

Compounds that inhibit the peptidyl-prolyl isomerase (rotamase) enzyme activity of the FK-506 binding protein (FKBP) and compositions comprising these compounds are described. The FKBP-inhibiting compounds have a bicyclic [3.3.1], [4.3.1]or polycyclic azaamide nucleus. Pharmaceutical compositions containing such compounds help stimulate the outgrowth of neurites in nerve cells and augmenting nerve regeneration. Methods of treating nerve cells with such compositions are useful to promote repair of neuronal damage caused by disease and physical trauma.

Description

COMPOUNDS, COMPOSITIONS, AND METHODS TO STIMULATE GROWTH AND NEURONAL EXTENSION Field of Invention The present invention relates to methods and compounds and pharmaceutical compositions for stimulating the result of neurites and nerve cells responsible for nerve regeneration.

More particularly, the compositions comprise compounds that inhibit the activity of the peptidyl-propyl isomerase enzyme (rotamase) associated with the binding protein FK-506 (FKBP). The methods include the treatment of cells Nerve with compositions comprising the compound that inhibits the rotamase. The methods of the invention can be used to promote the repair of neuronal damage caused by disease or physical trauma. »20 Background of the Invention.

Immunophilins are a family of soluble proteins that serve as receptors for important immunosuppressive drugs such as Ref: 126239 cyclosporin A, FK-506 and rapamycin. An immunophilin of particular interest is the binding protein FK-506 (FKBP). For a review of the role of immunophilins in the nervous system, see Solomon et al., "Immunophilins and the Nervous Systems," Na t ure Med. , 1 (1), 32-37 (1995).

The binding protein FK-506 12-kiloDalton, FKBP12, binds the FK-506 with a high affinity.

Such linkage is measured directly using microcalorimage and radiolabelled FK-506, for example, [3H] dihydro-FK-506 (see Siekierka et al., Na ture, 341, 755-57 (1989); and Patent "US No. 5,696,135 for Steiner et al.), And 32- [1- 14 C] -benzoyl-FK-506 (see Harding et al., Na t ure, 341, 758-60 (1989)). The binding affinity of other compounds for FKBP can be determined directly by microcalorimay or competitive binding assays using either the FK-506 titled or 14C-labeled, as described by Siekierka et al., Or Harding et al.

The protein bound to FK-506 FKBP12 participates in a variety of significant cellular functions. FKBP12 catalyzes the cis-trans isomeration of idyl-propyl peptide bonds. This activity of the peptidyl-propyl isomerase enzyme is also referred to as the rotamase activity. Such activity is easily assayed by methods known in the art (see Fischer et al., Bi or Chim. Bi ophys.Atta 791, 87 (1984); Fisher et al., Biomed. Bi och im. Acta 43, 1101 (Fisher et al. 1984); (and Fischer et al, Na ture 337, 476-478 (1989)) US Patents Nos. 5,192,773 and 5,330,993 to Armistead et al. Report affinities of the FKBP linkage that are co-related to inhibition activities. of the rotamase for many compounds.

FK-506 and compounds that bind to FKBP competitively with FKBP stimulate the result of neurites (axons) in nerve cells (see U.S. Patent No. 5,696,135 to Steiner et al.). Lyons et al. (Proc. Na tl. Acad.Sci. USA, 91, 3191-95 (1994)) demonstrates that FK-506 acts to increase or potentiate the effectiveness of nerve growth factor (NGF) in the stimulation of the result of neurites in a rat pheochromocytoma cell line. The mechanism of stimulation of such neurite result appears to be 10 to 100 times the potentiation of the action of nerve growth factor The potency for the inhibition of the activity of. Enzyme (rotamase) of the peptidyl prolyl isomerase of FKBP by FK-506, and by compound that competitively inhibit the binding of FK-506 to FKBP, is co-related empirically with the activity for the stimulation of the result of neurites. Due to the close co-relationship between the rotamase inhibition and the neurotropic action, it has been proposed that the rotamase can be converted to a protein substrate in a manner that promotes neural growth (see U.S. Patent No. 5,696,135). For example, it has been found that FKB012 forms complex linkages with intracellular calcium ion channels-the ryanodine receptor (RyR) and the 1,4-inositol triphosphate (IP3R) receptor (Jayaraman et al., J. Bi ol. Ch em, 267, 9474-9477 (1992); Cameron et al., Proc. Na tl. Aca d. Sci, USA, 92, 1784-1788 (1995)), helping to stabilize the release of calcium. For both the RyR and the IP3R, it has been shown that FK-506 and rapamycin are able to disassociate FKBP12 from these receptors. In both cases, complete "removal" of FKBP12 leads to increased leakage of calcium channels and low intracellular calcium concentrations. It has been suggested that the flow of calcium may be associated with the stimulation of the neurite result.

In addition, the linked complexes FK-506-FKBP bind and inhibit calcineurin, a cytoplasmic phosphatase. The phosphatase activity of calcineurin is necessary for dephosphorylation and the subsequent translocation in the nuclear factor nuclei of activated T cells (NF-AT) (see Flanagan et al., Na t ure, 352, 803-807 (1991)). The NF-TA is a transcription factor that initiates the activation of the interleukin-2 gene, which again mediates the proliferation of the T cell, these steps are important in the activation of an immune response. The inhibition activity of calcinetrin is related to the immunosuppressive activity of FK-506 and related compounds.

The calcineurin inhibitors, however, are not co-related to the stimulation of the neurite result. Therefore, compounds that are potent inhibitors of rotamase are desired, but are not strong inhibitors of calcineurin, since they may be neurotrophic but not immunosuppressive.

Such neuronal agents, desirably find use in increasing the outcome of neurites, and thereby promote neuronal growth and regeneration in various pathological situations where neuronal repair can be facilitated, including peripheral nerve damage caused by injury or diseases such as diabetes, brain damage associated with infarction, and for the treatment of neurological disorders related to neurodegeneration, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). Furthermore, such use is preferably without the associated effect of immunosuppression, since long-term use of immunosuppressants is associated with side effects such as kidney poisoning, neurological deficiencies, and vascular hypertension.

Several inhibitors of the activity of the rotamase enzyme, compounds that bind the FKBP, or immunomodulatory compounds are known. See, for example, U.S. Patents Nos. 5,192,773, 5,330,993, 5,516,797, 5,612,350, 5,614,547, 5,622,970, 5,654,332, 5,665,774, 5,696,135, and 5,721,256. See also, International Publications Nos. WO 96/41609, WO 96/40633, and WO 96/40140.

In view of the variety of disorders that can be treated by the stimulation of the neurite result and the relatively potent FKBP12-binding compounds that are known to possess this property, a need for compounds that bind the rotamase, additional neurotrophs, persists. Such compounds should desirably have appropriate physical and chemical properties for use in pharmaceutical preparations, for example, biological availability, half-life, and effective release at the active site. In view of the desired properties, small organic molecules are preferred over proteins. Additionally, such compounds should desirably lack significant immunosuppressant activity.

Brief Description of the Invention It is therefore the object of the invention to provide small molecule neurotrophic agents. A further object is to make rotamase binding compounds that are not immunorepressive agents. It is a further object of the invention to provide effective processes for synthesizing such compounds, as well as useful intermediates thereof. Another object of the invention is to provide methods for the treatment in patients having neurological trauma or disorders as a result of, or associated with, conditions that include (but are not limited to) neuralgia, muscular atrophy, Bell's palsy, muscle weakness. severe, Parkinson's disease, Alzheimer's disease, multiple sclerosis, ALS, infarction and ischemia associated with infarction, neural parapathy, other neural degenerative diseases, neuron motor diseases, and nerve injuries including spinal cord injuries.

Such objects have been made by the rotamase binding agents of the present invention, which can be used to stimulate the growth and regeneration of neurons. The administration of these agents to individuals that require therapeutic stimulation of growth and neuronal regeneration, provides effective therapies in various pathological situations, where neuronal repair can be facilitated, including peripheral nerve damage caused by injury or disease such as diabetes, brain damage associated with infarction, and for the treatment of neurological disorders related to neurodegeneration, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis.

In a general embodiment, the rotamase binding agents of the invention include compounds of the general structural formula (I-a): wherein: R1 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, aryl, C3-C8 cycloalkyl, and C5-C7 cycloalkenyl groups, and C (R11) (R12) (R13), the alkyl and alkenyl groups being optionally substituted with C 1 -C alkyl, C 2 -C 4 alkenyl, C 6 cycloalkenyl, or hydroxy, the aryl group being optionally substituted with halogen, hydroxy, N 2, CF 3, C 1 -C 6 alkyl, C 2 -C 2 alkenyl, C 1 -C 4 alkyloxy, C 2 -C alkenyloxy, benzyloxy, phenoxy, amino, or phenyl, and the cycloalkyl and cycloalkenyl groups being optionally substituted with C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, or hydroxy, and R11 and R12 are each independently lower alkyl, or R11 and R12 together with the atom to which they are linked to form cycloalkyl, and R13 being H, OH, lower alkyl, aryl, or (CH2) n-0-W1, where n is 0, 1, 2, or 3, W1 is R2 or C (0) R2, and R2 is C1-C3 alkyl, optionally substituted with one or two methoxy groups; X is selected from hydrogen, cyano, C? -C2 alkoxy, dimethyl oxymethyl, and oxygen, where when X is oxygen, the CX bond (ie, the bond connecting X to the carbon ring atom) is a bond double; and Y is selected from hydrogen, alkyl, alkenyl and cycloalkyl, the alkyl, alkenyl and cycloalkyl groups being optionally substituted at one or more positions with substituents selected from the substituted and unsubstituted alkyl, aryl, alkoxy, hydroxyalkyl, aryloxy, alkenyloxy, hydroxy, (CH2) p-0-W2, and (CH2) PN-W2, where p is 0, 1, or 2, and W2 is R3 or C (0) R3, where R3 is alkyl, alkenyl, or aryl optionally substituted with alkyl, aryl, or alkoxy; or X and Y taken together with 'the nitrogen heteroatom of the ring structure to which Y is connected (shown in formula (Ia)) forms a 5 to 7 membered heterocyclic ring, saturated or unsaturated which optionally contains an additional heteroatom (i.e., a heteroatom in addition to the described nitrogen atom of the ring structure) selected from O and N, the 5- to 7-membered heterocyclic ring saturated or unsaturated being optionally substituted with one or more substituents selected from J , K, and L, which are independently oxygen, C3-C5 cycloalkyl, or C1-C5 alkyl optionally substituted with one or two substituents independently selected from C3-C5 cycloalkyl, methoxy, methoxyphenyl, or dimethoxyphenyl, or J and K taken together form a phenyl ring optionally substituted with one or more substituents selected from methoxy, trifluoromethyl, trifluoromethoxy, and suitable substituents linked to The phenyl ring through oxygen, nitrogen, carbon, or sulfur.

In a general alternative embodiment, the invention is directed to compounds of the formula (I-b): wherein: R1 is selected from hydrogen, substituted and unsubstituted alkyl groups, alkenyl, aryl, C3-C8 cycloalkyl, and C8-C7 cycloalkenyl, and C (R11) (R12) (R13), the alkyl- and alkenyl groups being optionally substituted with C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 4 -C 6 cycloalkenyl, or hydroxy, the aryl group being optionally substituted with halogen, hydroxyl, N 2, CF 3, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 alkyloxy - C4, C2-C4 alkenyloxy, benzyloxy, phenoxy, amino, or phenyl, and the cycloalkyl and cycloalkenyl groups being optionally substituted, with C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkyloxy, or hydroxy, and R11 and R12 each independently being lower alkyl, or R11 and R12 together with the atom to which they are linked to form cycloalkyl, and R13 being H, OH, lower alkyl, aryl, or (CH ^ nO-W1, where n is O, 1, 2, or 3, W1 is R2 or C (0) R2, and R2 is C1-C3 alkyl, optionally substituted with one or two methoxy groups; X1 and X2 are cad to one independently selected from hydrogen, cyano, C? -Calkyloxy, dimethoxymethyl, and oxygen, where when X1 and X2 are oxygen, the CX bond (ie, the bond connecting X1 or X2 to the carbon ring atom) ) is a double bond (that is, X1 or X2 is = 0); or X1 and X2 together form a valence bond; and Y is selected from hydrogen, alkyl, alkenyl, and cycloalkyl, the alkyl, alkenyl and cycloalkyl groups being optionally substituted at one or more positions with substituents selected from substituted and unsubstituted alkyl, aryl, alkoxy, hydroxyalkyl, aryloxy, alkenyloxy, hydroxy , (CH2) p-0-W2, and (CH2) PN-W2, where p is 0, 1, or 2., and W2 is R3 or C (0) R3, where R3 is alkyl, alkenyl, or aryl optionally substituted with alkyl, aryl or alkoxy; or one of X1 and X2 in combination with Y taken together with, the nitrogen heteroatom of the ring structure to which Y is connected (shown in formula (Ib)) forms a saturated 5-7 membered heterocyclic ring or unsaturated, optionally containing an additional heteroatom (i.e., a heteroatom in addition to the nitrogen atom described in the ring structure) selected from O and N, the 5- to 7-membered heterocyclic ring saturated or unsaturated being optionally substituted with one or more substituents selected from J, K, and L, which are independently oxygen, C3-C5 cycloalkyl, or C1-C5 alkyl, optionally substituted with one or two substituents independently selected from C3-C5 cycloalkyl, methoxy, methoxyphenyl, or dimethoxyphenyl, or J and K taken together form a phenyl ring optionally substituted with one or more substituents selected from methoxy, trifluoromethyl, trifluoromethoxy, and subst Suitable binders linked to the phenyl ring through oxygen, nitrogen, carbon, or sulfur.

The rotamase inhibitor agents of the invention also include pharmaceutically acceptable derivatives of such compounds of the formula (I-a) or (I-b).

The invention describes additional methods of treating neurological trauma or conditions as a result of, or associated with, conditions including, neuralgia, muscle atrophy, Bell's palsy, severe muscle weakness, Parkinson's disease, Alzheimer's disease, multiple sclerosis, Amyotrophic lateral sclerosis (ALS), infarction and ischemia associated with infarction, neural parapathy, other neural degenerative diseases, motor neuron diseases, and nerve injuries including spinal cord injuries. The inventive methods comprise administering a therapeutically effective amount of a compound of formula (Ia) or (Ib), or a pharmaceutically active metabolite, prodrug, or pharmaceutically acceptable salt thereof, to a patient in need thereof. of such treatment. Such additional methods comprise administering a composition comprising an effective amount of a compound of the formula (Ia) or (Ib), or a prodrug, a pharmaceutically active metabolic, or a pharmaceutically acceptable salt thereof, in combination with a carrier. or pharmaceutically acceptable diluent and / or a therapeutically effective amount of a neurotrophic factor selected from the nerve growth factor, the insulin growth factor and its truncated active derivatives, a basic and acidic fibroblast growth factor, derived growth factors of platelet, a neurotrophic factor derived from the brain, ciliary neurotrophic factors, neurotrophic factor derived from the glial cell line, neurot rofin-3, and neurotrophin 4/5, to a patient in need of such treatment.

The invention also relates to intermediates of the formulas (II), (III), and (V), which are described below, and which are useful for preparing the compounds' which modulate the FKBP of the formula (Ia) and (Ib) The invention also relates to processes for making the compounds using such intermediates.

Other features, objects, and advantages of the invention will be apparent from the following detailed description of the invention.

Detailed Description and Preferred Forms of Realization. EKBP Inhibiting Agents of the Invention As used herein, the following terms have the defined meanings, unless otherwise indicated.

The term "alkyl" means a paraffinic hydrocarbon group (saturated aliphatic group) straight or branched chain (linear) having from 1 to 10 carbon atoms, which can be generally represented by the formula CkH2k +], where k is an integer Examples of alkyls include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, n-pentyl, isopentyl, neopentyl, and hexyl and the simple aliphatic isomers thereof. The term "anterior alkyl" designates an alkyl having from 1 to 8 carbon atoms (i.e. a Ci-Cß alkyl) • The term "alkenyl" means a straight or branched chain olefinic hydrocarbon group (unsaturated aliphatic group having one or more double bonds) containing from 2 to 10 carbons. Exemplary alkenyls include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, isobutenyl, and various isomeric pentenils and hexenyls (both include cis and trans isomers).

The term "alkoxy" means -O-alkyl, where "alkyl" is as defined above. "Lower alkoxy" refers to alkoxy groups containing an alkyl portion of 1 to 4 carbon atoms.

The term "alkenyloxy" means -0-alkenyl, wherein "alkenyl" is as defined above.

The term "aryl" means a monocyclic or polycyclic aromatic ring portion, for example, phenyl, naphthyl, furyl, thienyl, pyrrolyl, pyridyl, pyridinyl., pyrazolyl, imidazolyl, pyrazinyl, triazinyl, oxadiazolyl, H-tetrazol-5-yl, indolyl, quinolinyl, benzofuranyl, benzothiophenyl (tianaphtenyl) and the like. Where indicated, such aryl portions may be optionally substituted with one or more substituents, for example, a halogen (F, Cl, I, Br), lower alkyl, -OH, -N02, -CN, -C02H, -O -lower alkyl, aryl, -O-aryl, aryl-lower alkyl, -C02CH3, -CONH2, -OCH2CONH2, -NH2, -S02NH2, -OCHF2, -CF3, -OCF3, and the like. The aryl portions can also be substituted by two substituents forming a bridge, for example -O- (CH2) z-0-, where z is an integer from 1 to 3.

The term "aryl lower alkyl" means a lower alkyl (as defined above) substituted with an aryl.

The term "aryloxy" means -O-aryl, where "aryl" is as defined above.

The term "cycloalkyl" means a structure of a monocyclic or polycyclic carbocyclic ring, wherein each ring has from five to seven carbon atoms and is saturated. Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclophenyl, and adamantyl. Where indicated, a cycloalkyl can be substituted with one or more suitable substituents, for example, halogen, alkyl, -OR, or -SR, where R is alkyl or aryl.

The term "cycloalkenyl" means a monocyclic or polycyclic carbocyclic ring structure, wherein each ring has from five to seven carbon atoms and at least one ring is partially unsaturated or has at least one double bond.

The term "heterocycle" (or the root "hetero" in reference to a ring structure) means a ring structure containing one or more heteroatoms (non-carbon ring atoms) selected from O, N, and S. In this manner , the term "heterocycloalkyl" means a cycloalkyl in which at least one atom of the carbon ring is replaced by a heteroatom selected from 0, N and S.

The rotamase inhibitor compounds of the invention are represented by the formula (I-a) and (I-b) defined above. Preferably, the rotamase inhibitor compounds inhibit the activity of the rotamase enzyme (peptidyl prolyl isomerase) of FKBP, in particular, FKBP12. In addition to the compounds of the formula (I-a) and (I-b), the rotamase inhibiting agents of the invention include pharmaceutically acceptable derivatives of such compounds, such as prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts or solvates thereof.

In preferred embodiments of compounds represented by the above formulas (I-a) and (I-b), X, X1 and X2 are hydrogen or oxygen, or X1 and X2 form a valence bond.

In preferred compounds represented by the above formulas (Ia) and (Ib), Y is alkyl having one or more substituents selected from substituted and unsubstituted alkyl, aryl, alkoxy, hydroxyalkyl, aryl-alkyl, aryloxy, alkenyloxy, hydroxy, (CH2 ) p-0-W2, and (CH2) pN-W2, wherein p is 0, 1, or 2, and W2 is R3 or C (0) R3, where R3 is alkyl, alkenyl, or aryl optionally substituted with alkyl , aryl, or alkoxy. In more preferred embodiments, Y is: In other preferred embodiments, X, or one of X1 and X2, and Y together with any of the ring atoms intervened forms a substituted or unsubstituted piperidine or piperazine ring.

For the compounds represented by the above formula (I-a), R1 is preferably selected from: 3, 4, 5-trimethoxyphenyl; where m is 1 and n is 0 or 2; and C (R11) (R12) (R13), wherein R11 and R12 are independently selected from methyl and ethyl, and R13 is selected from H, OH, lower alkyl, aryl, and (CH ^ nO-W1, where n is 0 , 1, 2, or 3. In the above formulas, W1 is R2 or C (0) R2, where R2 is preferably C1-C3 alkyl optionally substituted with one or two methoxy groups.

Especially preferred species of compounds represented by the above formula (I-a) are the following: Especially preferred species of compounds represented by the above formula (I-b) are the following: The compounds of the invention also include pharmaceutically acceptable derivatives of compounds of the formula (I-a) and (I-b). A "pharmaceutically acceptable derivative" denotes a prodrug, a pharmaceutically active metabolite, or a pharmaceutically acceptable salt, ester, salt of such ester, or hydrate of a compound of this invention. Such compounds, when administered to a patient, are capable of directly or indirectly yielding a compound of this invention, or a metabolic waste or a product thereof, and thereby inhibit the rotamase activity of FKBP or promote or increase the result of neurites. .

The compounds of the formula (I-a) and (I-b) can be used in pharmaceutical compositions in the form of pharmaceutically acceptable salts. Such salts are preferably derived from inorganic or organic bases and acids. Exemplary acid salts include acetate, adipate, alginate, aspartate benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camforate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glycoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, iodohydrate, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. Exemplary base salts 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-salt methyl-D-glucosamine, and salts with amino acids such as arginine and lysine. Also, groups containing basic nitrogen can be quaternized with agents such as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides or iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides, and iodides; and aralkyl halides, such as benzyl and phenethyl bromides. Soluble or dispersible products can be prepared in water or oil from such salts.

In addition, the compounds of the invention can be modified by adding appropriate functionalities to increase their selective biological properties. Such modifications, which are within the reach of the artisan of ordinary skill, include that increased biological penetration within a given biological system (eg blood, lymphatic system, central nervous system), increasing oral availability, increasing solubility to allow administration by injection, altered metabolism, and a range of excretion alternation.

Some of the compounds described herein contain one or more centers of asymmetry and can thus reach the enantiomers, diastereoisomers, rotamers, and other forms of stereoisomers. The present invention is intended to include all possible stereoisomers as well as their racemic and optically pure forms. The optically active (R) and (S) isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds, they are intended to include both geometric isomers of E and Z. Furthermore, the present invention is intended to include all possible rotamers, particularly those having different orientations around the bond as follow: In addition, the chemical formulas referred to herein exhibit the phenomenon of tautomerism. As the formulas drawn within this specification can only represent one of the possible tautomeric forms, it will be understood that the invention encompasses any tautomeric form that can be generated using the described tools or in a known manner, and is not limited to any of the forms tautomerics that are described by the formulas.

Synthetic Methods.

The compounds of the formula (I-a) can be prepared from the compounds of the formula (III): AND (HI) In formula (III), R31 is selected from hydrogen and optionally substituted alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl,, where q is 0 or 1, and R, 3J0U is an alkyl or aryl group substituted or unsubstituted with one or more substituents independently selected from the hydroxyl, C? -C6 alkyl, C2-C6 alkenyl, C? -C4 alkoxy , C2-C4 alkenyloxy, benzyloxy, phenoxy, and phenyl. X is hydrogen, cyano, C? -C2 alkyloxy, dimethyl oxymethyl, or oxygen, where when X is oxygen, the bond connecting X to the ring carbon atom is a double bond; and Y is hydrogen, an alkyl, alkenyl, or cycloalkyl group substituted or unsubstituted with one or more substituents independently selected from alkyl, aryl, alkoxy, hydroxyalkyl, aryloxy, alkenyloxy, and hydroxy groups substituted or unsubstituted with one or more substituents independently selected from hydroxyl, Ci-Cß alkyl, C2-C6 alkenyl, C?-C4 alkyloxy, C2-C4 alkenyloxy, benzyloxy, phenoxy, and phenyl, (CH2) p-0-W2, and (CH2) PN-W2, in where p is 0, 1, or 2, and W2 is R3 or C (0) R3, with R3 being an alkyl, alkenyl, or aryl group substituted or unsubstituted with one or more substituents independently selected from alkyl, aryl, and alkoxy . Alternatively, X and Y, together with the carbon ring atom and the nitrogen heteroatom to which they are respectively attached, form a 5 to 7 membered heterocyclic ring, saturated or unsaturated, substituted or unsubstituted with one or more substituents J , K, and L; wherein J, K, and L represent substituents independently selected from oxygen, and C3-Cs cycloalkyl, C1-C5 alkyl groups, substituted or unsubstituted with one or more substituents independently selected from C3-C5 cycloalkyl, methoxy, methoxyphenyl, and dimethoxyphenyl; or wherein J and K together form a phenyl ring substituted or unsubstituted with one or more substituents independently selected from methoxy, trifluoromethyl, trifluoromethoxy, and substituents linked to the phenyl ring through oxygen, nitrogen, carbon or sulfur and independently selected from halogen, hydroxyl, N02, CF3, C -C6 alkyl, C2-Ce alkenyl, C1-C4 alkyloxy, C2-C4 alkenyloxy, benzyloxy, phenoxy, amino, and phenyl.

In a preferred embodiment of the invention, R 31 is more preferably benzyloxycarbonyl. Especially preferred examples of the compounds of formula (III) are: where Z is benzyloxycarbonyl. Another group of preferred compounds of the formula (III) are: where Z is benzyloxycarbonyl. Another group of preferred compounds of the formula (III) are: where Z is benzyloxycarbonyl The preferred additional compounds of the formula (III) are selected from: where Z is benzyloxycarbonyl The compounds of the formula (III) include those of the formula (Ill-a), which can be converted under reduced conditions into compounds of the formula (Ill-b). (m-b) In the formulas (Ill-a), R31 is selected from optionally substituted alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, Where q is 0 or 1, and R is an alkyl or aryl group substituted or unsubstituted with one or more substituents independently selected from hydroxyl, Ci-Cß alkyl. C2-C2 alkenyl, C1-C4 alkenyl, C2-C4 alkenyloxy, benzyloxy, phenoxy, and phenyl. In the formulas (Ill-a) and (Ill-b), X and Y are as defined in the formula (I-a). To yield a compound of the formula (I-a), a compound of the formula (Ill-b) is coupled with a compound of the formula (IV): In formula (IV), R is as defined in formula (I-a).

The compounds of the formula (Ill-a) can be prepared using compounds of the formula (II): (p) O u ^ CQCGH2) QR30 «and * * -? In formula (II) is where q is 0 or 1, and R 30 is an alkyl or aryl group substituted or unsubstituted with one or more substituents independently selected from the hydroxyl, Ci-Cß alkyl. C2-Cd alkenyl, C1-C4 alkyloxy, C2-C4 alkenyloxy, benzyloxy, phenoxy, and phenyl. Preferably, Z is benzyloxycarbonyl.

The compounds of the formula (I-b) can be prepared from the compounds of the formula (V) by analogous methods to those described above.

The compounds of the formula (V) include those of the formula (V-a), which can be converted under reduced conditions into compounds of the formula (V-b): In the formulas (V), - (V-a) and (V-b): R31 and R32 are as defined by formulas (III), (Ill-a) and (Ill-b); X1 and X2 are each independently hydrogen, cyano, C? -C2 alkyloxy, dimethoxymethyl, or = 0, or X1 and X2 together form a valence bond; and Y is how it was defined by formulas (III), (Ill-a) and (Ill-b); or one of X1 and X2 in combination with Y and the carbon ring atom and the carbon heteroatom to which they are linked respectively and any of the ring atoms intervened form a 5 to 7 membered heterocyclic ring, saturated or unsaturated, substituted or unsubstituted, with one or more substituents J, K, and L, where J, K, and L are each independently selected from oxygen and C3-C5 cycloalkyl and substituted or unsubstituted C1-C5 alkyl groups, with one or more substituents independently selected from C3-C5 cycloalkyl, methoxy, methoxyphenyl, and dimethoxyphenyl, or J and K together form a substituted or unsubstituted phenyl ring, with one or more substituents independently selected from methoxy, trifluoromethyl, trifluoromethoxy, and substituents linked to the phenyl ring through oxygen, nitrogen, carbon or sulfur that are independently selected from halogen, hydroxyl, N02, CF3, Ci-Cß alkyl. C2-C6 alkenyl, C2-C alkyloxy, C2-C4 alkenyloxy, benzyloxy, phenoxy, amino, and phenyl.

Exemplary syntheses are described below to illustrate embodiments and preferred features of the invention.

The following synthesis protocols refer to intermediate compounds and final products identified in the specification and synthesis schemes. The preparation of various compounds of the present invention is described in detail using the following examples, but the artisan will readily recognize that the chemical reactions described are generally applicable for preparing other inhibitor compounds of the FKBP of the invention. When, as an artisan will recognize, a reaction for the preparation of a compound may not be applicable precisely as described for the preparation of certain compounds of the invention, the artisan can easily determine which desired synthesis can be successfully made to make appropriate modifications in the light of knowledge in the art (eg, by appropriate blocking of protective or interfering groups, substituting other conventional reagents, or by routine modifications of the reaction conditions), or that other reaction described (or analogous to those described) in the present or a conventional method will be suitable for preparing such compound. Although certain protecting groups (groups that block reaction (s) with one or more inherent functional groups) are exemplified in the syntheses described below, other suitable protecting groups will be apparent to the artisan depending on the functionality and particular chemistry employed. See, for example, Greene and Wutz, Pro tecting Groups in Chemi ca l Syn thesi s (2nd ed.) John Wiley &; Sons, NY (1991).

In all the synthetic processes described herein (unless otherwise indicated) the starting materials are known, available, or can be easily prepared from the starting materials, all temperatures are set in degrees Centigrade, and all the parts and percentages are by weight. Reagents were purchased from commercial suppliers, such as Aldrich Chemical Company or Lancaster Synthesis Ltd. Reagents and solvents had commercial levels and were used as purchased with the following exceptions: dichloromethane (CH2C12) was distilled from calcium hydride before use; Tetrahydrofuran (THF) was distilled from sodium cetyl benzophenone before use; and the methanol was dried on a 4-Angstrom molecular sieve.

Flash column chromatography was performed using silica gel 60 (Merck Art 9385). The A-NMR spectrum (300 MHz) was measured in CDC13 solutions and was determined on a Varian-300 instrument using a computer program operating a Varian UNITYpl us300. Chemical grafts were reported in parts per million (ppm) low yield of tetramethylsilane as in the internal standard, and coupling constants are given in Hertz. The following abbreviations are used for the multiplicity return: br = extension, s = singlet, d = doublet t = triplet, q = quartet, m = multiplet, and cm multiplet complex. The infrared (IR) spectrum was recorded on a Perkin-Elmer 1600 FTIR series spectrometer and reported in wave numbers (era-1). Elemental analyzes were performed by Atlantic Microlab, Inc., Norcross, G.A. The high resolution mass spectrum (HRMS) was performed by Scripps Mass Spectra Laboratory, La Jolla, CA. The melting points (pf) were determined in a Mel-Temp II apparatus and are incorrect.

Unless indicated otherwise, the reactions placed below were carried out under positive pressure with a nitrogen balloon (N2) or argon (Ar) at room temperature in anhydrous solvents, and the reaction flasks were fitted with septum rubber. by the introduction of substrates and reagents through a syringe. The glassware is dried in heat. Thin-layer analytical chromatography (TLC) was performed on silica gel plates supported on 60 F 254 glass (Analtech, 0.25 mm) and eluted at appropriate solvent ratios (v / v), which were indicated where appropriate . The reactions were assayed by TLC and terminated as judged by the consumption of the starting material. The tip plates were visualized using an ultraviolet (UV) lamp. The visualization can also be performed using a staining chamber such as ninhydrin, ammonium, ammonium molybdenum, iodide (I2A or a p-anisaldehyde atomized reagent or phosphomilibrium acid reagent (Aldrich Chemical, 20% by weight in ethanol) activated with hot.

The works are typically given by doubling the reaction volume with the reaction solvent or extraction solvent and then washing with the indicated aqueous solutions using 25% by volume of the extraction volume (unless otherwise indicated). The product solutions were dried over anhydrous Na2SO4 before filtration and evaporation of the solvents under reduced pressure in a rotary evaporator, and scored as the solvents removed in va cuo. Flash column chromatography (Still et al., J. Org. Ch., 43: 2923 (1978)) was completed using a ratio of silica gel 60 (Merck Art 9385) crude material of about 20: 1 to 50 : 1 (unless indicated otherwise). The hydrogenolysis was carried out at the pressures indicated in the examples or at ambient pressure.

The reaction schemes outlined below can be used to prepare the compounds of the invention. These schemes include the steps of (in several orders) protection (with a protective group R32) of the upper nitrogen bridge which will be the substituent R1 in the final compound of the formula (Ia) or (Ib), the formation of the nuclei of azaamide [3.3.1] or [4.3.1], and the functionalization of the piperazine or the 1,4-diazaheptane ring with substituents X, or X1 and X2, and Y to form intermediates of the formula (Ill-a ) or (Va), respectively; Such compounds of the formula (Ill-a) and (Va) are converted to compounds of the formula (Ia) and (Ib) respectively by: (1) removing the protecting group R 32 under the appropriate reducing conditions (such conditions generally being readily discernible by those skilled in the art, for example, in light of those detailed in the examples given below) to produce a compound of the formula (Ill-b) or (Vb); and (2) coupling the deprotected compound of the formula (Ill-b) or (V-b) with a reagent of the formula (IV): where R1 is as defined above, under suitable coupling conditions (such conditions generally being readily discernible by those skilled in the art, for example, in light of those detailed in the examples given below); to yield a compound of the formula (I-a) or (I-b). R32 protective groups suitable for nitrogen include those described below, as well as others generally known to practicing practitioners (see, for example, Greene and Wutz, Pro t ec t in g Gro ups in Chemi ca l Sin thesi s (2nd ed.) John Wiley &Sons, NY (1991)). In the following syntheses, R32 is preferably the benzyloxycarbonyl protecting group, but other suitable nitrogen protecting groups may be used instead.

Scheme 1: Scheme 1, which is described below, is useful for preparing Compound 7 (and other compounds by analogous methods as noted in Table 1). In Scheme 1 and in the examples below, Z is benzyloxycarbonyl. In addition to the benzyloxycarbonyl, other portions suitable for use as protecting groups for the upper nitrogen bridge (see Greene and Wutz) may be employed. 1-benzyl ester of piperidine-1,2,6-tricarboxylic acid (Compound 1) 1 2,6-pyridine of dicarboxylic acid (25 g, 0.15 mol) was dissolved in 2. OM NaOH (154 mL) and (30 mL) of H20 at room temperature, and placed in a Parr 500 L bottle. Rhodium alumina powder (5%, 1.87 g) was added and the mixture was purged with argon for 15 minutes. The reaction mixture was stirred under 55 psi of hydrogen for 48 hours. The suspension was filtered through compacted celite, and the clean filtrate was cooled to 0 ° C. Benzyl chloroformate (30.62 g, 0.18 mol) was added from the top to the cold filtrate in three portions over a period of 30 minutes, and the solution was allowed to reach room temperature and stirred for an additional 5 hours. The remaining benzyl chloroformate was extracted from the mixture with diethyl ether. The aqueous layer was acidified with 2N HCl and extracted with ethyl acetate (EtOAc). The EtAOc was passed over a short plug of Na 2 SO 4 and evaporated. The residue was triturated with (20 mL) EtAOc, and the resulting white solid was collected by vacuum filtration, washed with (3 x 20 mL) EtOAc, and air dried to give Compound 1 (38.8 g, 83 % of performance). Rf = 0.06 (10% MeOH / CHCl3); 1 H NMR: d 1.49-1.73 (m, 4H), 1.96-2.03 (m, 2H), 4.48-4.65 (m, 2H), 5.10 (s, 2H), 7.26-7.35 (m, 5H). 2,3,4-Dioxo-3-oxa-9-a-zabicyclo [3.3.1] nonane-9-carboxylic acid benzyl ester (Compound 2) The ester. 1-Benzyl of piperidine-1,2,6-tricarboxylic acid (Compound 1, 19.7 g, 64.11 mmol) was suspended in acetic anhydride (80 mL, 848 mmol) in a 250 L dry round bottom flask. The mixture was stirred at 70 ° C for 30 minutes until a clear solution formed. The resulting acetic anhydride was stirred in vacuo, to provide Compound 2 (18.5 g, 100%) as a clear oil. The material was of good enough quality to be used in the next reaction without purification. The product was sensitive to water, thus prepared by its immediate use in the next step. 1 H NMR: d 1.57-2.01 (cm, 6H), 5.14 (s, 2H), 5.17 (s, 2H), 7.32-7.37 (m, 5H). 3- (2-Benzyloxyethyl) -2, -dioxo-3, 9-diaza-bicyclo [3.3.1] nonane-9-carboxylic acid benzyl ester (Compound 3) The benzyl ester of 2,4-dioxo-3-oxa-9-aza-bicyclo [3.3.1] nonane-9-carboxylic acid (Compound 2, 1.02 g, 3.52 mmol) was dissolved in dioxane (5 mL), and 2-benzyloxyethylamine (0.50 g, 3.32 mmol) was added from the top. The mixture was stirred at room temperature for 1 hour (hr). Then, acetic anhydride (0.62 L, 6.64 mmol) was added, and the reaction went to reflux temperature for 5 hours. The dioxane was evaporated, and the flash chromatographic purification of the residue (20% EtOAc / hexanes) gave Compound 3 (1.26 g, 90%) as a pale yellow oil: Rf (50% EtOAc / hexanes): 0.80. 3- (2-Benzyloxyethyl) -2-methoxy-4-oxo-3, 9-diaza-bicyclo [3.3.1] nonane-9-carboxylic acid benzyl ester (Compound 4) The benzyl ester of 3- (2-benzyloxyethyl) -2,4-dioxo-3,9-diaza-bicyclo [3.3.1] nonane-9-carboxylic acid (Compound 3, 0.46 g, 1.11 mmol) was dissolved in (15 mL) of methanol. The mixture was cooled to 0 ° C, and NaBH 4 (0.06 g, 1.66 mmol) was added in portions from the top. The reaction was stirred for 10 minutes at 0 ° C, and then the 4N HCl in dioxane was added to obtain a pH in the range of 1 to 2, and the reaction was stirred overnight at room temperature. The methanol was evaporated, and the residue was dissolved in EtOAc and poured into the saturated aqueous solution of NaHCO 3, then extracted with EtOAc (3 x 10 mL). The combined extracts were washed with (10 mL) brine, passed over a short plug of Na 2 SO 4, and the solvents were evaporated to give Compound 4 (0.40 g, 85%, mixture of isomers) as a thick pale yellow oil, the which was of good enough quality to be advanced to the next step without further purification. Rf (40% EtOAc / hexanes): 0.45. 3- (2-Benzyloxyethyl) -2-oxo-3,9-diaza-bicyclo [3.3.1] nonane-9-carboxylic acid benzyl ester (Compound 5) The benzyl ester of 3- (2-benzyloxyethyl) -2-methoxy-4-oxo-3,9-diaza-bicyclo [3.3.1] nonane-9-carboxylic acid (Compound 4, 0.34 g, 0.76 mmol) was dissolved in (5 mL) CH2C12 in a 25 mL flask under argon. BF3OEt2 (0.18 mL, 1.52 mmol) was added dropwise to the reaction flask (the vapor was released) followed by (0.24 g, 1.52 mmol) triet-ilsilane, and the solution was stirred overnight. The CH2C12 was evaporated and the residue was dissolved in EtOAc and washed with saturated NaHCO3 (2 x 10 mL). The mixture was extracted with EtOAc (3 x 10 mL). The organic layer was dried over Na2SO4 and concentrated. Purification of the residue by flash column chromatography with 20% EtOAc / hexanes gave Compound 5 (0.27 g, 89%, 1: 1 mixture of enantiomers) as a clear oil. Rf 0.42 (50% EtOAc / hexanes); A NMR (major rotamer): d 1.62-1.72 (m, 6H), 3.25-3.50 (m, 2H), 3.68-3.90 (m, 5H), 4.49 (s, 2H), 4.75 (s, 1H), 5.14 (s, 2H), 7.26-7.34 (m, 10H). 3- (2-benzyloxy-ethyl) -3,9-diaza-bicyclo [3.3.1] nonan-2-one (Compound 6) The benzyl ester of 3- (2-benzyloxyethyl) -2-oxo-3,9-diazabicyclo [3.3.1] nonane-9-carboxylic acid (Compound 5, 0.15 g, 0.36 mmol) was dissolved in (5 mL ) MeOH, and palladium (10%) was added to activated carbon (0.03 g). The hydrogen was applied through a balloon for 1 hour. The black suspension was then filtered through compacted celite, and the methanol was removed by a high vacuum rotary evaporator to give Compound 6 (0.09 g, 90%) as a coarse oil, which was of sufficiently good quality to be advanced to the coupling reaction without further purification. 1- [3- (2-benzyloxyethyl) -2 -oxo-3, 9-diaza-bicyclo [3.3.1] non-9-yl] -2- (3,4,5-trimethoxyphenyl) et ano-1, 2- diona (Compound 7) 3- (2-Benzyloxyethyl) -3,9-diaza-bicyclo [3.3.1] nonan-2-one (Compound 6, 0.1 g, 0.36 mmol) and 2-oxo-3,4,5-trimethoxyphenylacetic acid (34.3 mg, 1.43 mmol) were dissolved in CH C12 (5 mL), and the solution was cooled to 0 ° C. Hydroxybenzotriazole hydrate (HOBt, 0.06 g, 0.43 mmol) was added, followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC., 0.08 g, 0.43 mmol), and triethylamine (TEA, 0.06 g, 0.43 mmol). The reaction was allowed to reach room temperature and the solution was stirred for 6 hours. The volatiles were removed with a high vacuum rotary evaporator. The residue was dissolved in EtOAc and washed with a 10% citric acid solution (10 mL), followed by water (10 mL), saturated NaHCO 3 (10 mL), and brine (10 mL). The combined organic layers were dried over Na2SO4, and concentrated. Flash chromatographic purification of the residue (30% EtOAc / hexanes) gave Compound 7 (0.14 g, 78%) as a pale yellow oil. Rf (50% EtOAc / hexanes) = 0.13; IR: 2941, 2870, 1646, 1583, 1499, 1451, 1416, 1323, 1239, 1166, 1127, 1007, 733 cm "1; 1H NMR (major rotamer): d 1.60-2.18 (m, 6H), 3.21- 3.29 (m, 1H), 3.50 (dd, 1H, J = 37, 12.5), 3.67-4.01 (m, 13H), 4.15 (s, lH), 4.49 (s, 2H), 5.19 (s, 1H), 7.19 (d, 2H, J = 8.7), 7.26-7.37 (m, 5H); HRMS (M + H +): expected 497.2288, observed 497.2274.

Scheme 2: Compound 12 and the analogues shown in Table 1 can be prepared generally in accordance with the method of Scheme 2. In this synthesis of the scheme, Z is benzyloxycarbonyl (for example, in Compounds 8, 9, and 10). In addition to the benzyloxycarbonyl, other portions suitable for use as protecting groups for the nitrogen overhead bridge can be employed. 3- [2- (2-Methoxyphenyl) -ethyl] -2, -dioxo-3, 9-diaza-bicyclo [3.3.1] nonane-9-carboxylic acid benzyl ester (Compound 8) The benzyl ester of 2,4-dioxo-3-oxa-aza-bicyclo [3.3. 1) nonane-9-carboxylic acid (Compound 2. 1.00 g, 3.45 mmol), which was prepared from Compound 1, dissolved in (1 mL) dioxane, and 2-met-oxifenet-ilamine (0.50 mL, 3.45 mL) was added. mmol) from the top. The mixture was stirred at room temperature for 1 hour. After this time, the acetic anhydride (0.65 mL, 6.9 mmol) was added, and the reaction was at reflux temperature for 5 hours. Flash chromatographic purification of the residue (20% EtOAc / hexanes) gave Compound 8 (1.23 g, 90% yield) as a clear oil. Rf = 0.75 (50% EtOAc / hexanes), 0.66; 1H NMR: d 1.75-2.05 (m, 6H), 2.84-2.89 (m, 2H), 3.83 (s, 3H), 4.04 ' 4. 10 (m, 2H), 4.90 (brs, 2H), 5.16 (s, 2H), 6.78-6.83 (m, 2H), 7.05 (dd, 1H, J = 7.5, 1.6), 7.13-7.20 (m, 1H) ), 7.33-7.41 (m, 5H).

Benzyl ester of 2-hydroxy-3- [2- (2-methoxy-phenyl) -et-yl] -4 -oxo-3, 9-diza-bicyclo [3.3. l] nonane-9-carboxylic acid (Compound 9) The benzyl ester of 3- [2- (2-methoxyphenyl) -ethyl] -2,4-dioxo-3,9-diaza-bicyclo [3.3.1] nonane-9-carboxylic acid (Compound 8, 0.77 g, 1.82 mmol) was dissolved in methanol (18 mL). The mixture was cooled to 0 ° C, and NaBH 4 (0.14 g, 3.64 mmol) was added in portions from the top. The reaction was stirred for 10 minutes and then carefully quenched with water. The MeOH was removed under reduced pressure, and the residue was extracted with EtOAc. The combined organic layers were washed with 10% citric acid (5 mL), water (5 mL), saturated NaHCO 3 (5 mL), and brine (5 mL), and finally passed over a short plug of Na 2 SO 4. The solvents were evaporated to give Compound 9 (0.65 g, 83%, mixture of isomers) as a clear oil, which was of sufficiently good quality to be advanced to the next step without further purification. Rf = 0.5 (50% EtOAc / hexanes).

Compound 10 The benzyl ester of 2-hydroxy-3- [2 - (2-methoxy-phenyl) -ethyl] -4 -oxo-3,9-di-zabicyclo [3.3.1] nonane-9-carboxylic acid (Compound 9, 0.65 g, 1.52 mmol) was dissolved in CH2C12 (1 mL) and cooled to 0 ° C. Trifluoroacetic acid (TFA, 0.59 mL, 7.64 mmol) was added, and the reaction was stirred at 23 ° C overnight. The solvent was removed under reduced pressure, and the residue was dissolved in EtOAc (10 mL) and washed with NaHCO 3 (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (40% EtOAc in hexanes) to afford Compound 10 (0.54 g, 87%, single diastereomer) as a clear oil. Rf = 0.30 (50% EtOAc / hexanes); * H NMR: d 1.69-2.06 (m, 6H), 2.72-3.10 (m, 3H), 3.83 (s, 3H), 4.55-5.27 (m, 6H), 6.73-6.85 (m, 2H), 7.03- 7.34 (m, 6H).

Compound 11 Adduct 10 (0.26 g, 0.64 mmol) was dissolved in (5 mL) MeOH, and palladium (10%) in active carbon (0.05 g) was added. The hydrogen was applied through a balloon for 1 hour. The black suspension was then filtered through compacted celite, and the methanol was removed by a high vacuum rotary evaporator to give compound 11 (0.13 g, 76%) as a coarse oil, which was of sufficiently good quality to be Advanced to the next step without further purification.

Compound 12 Adduct 11 (0.13 g, 0.48 mmol) and 2-oxo-3,4,5-trimethoxyphenyl acetic acid (0.14 g, 0.57 mmol) was dissolved in CH C12 (5 mL), and the solution was cooled to 0 °. C. HOBt (0.08 g) was added, 0.57 mmol), followed by EDC. HCl (0.11 g, 0.57 mmol) and TEA (0.00 mL, 0.57 mmol). The reaction was allowed to reach room temperature and the solution was stirred for 6 hours. The volatiles were removed under reduced pressure, the residue was dissolved in EtOAc and washed with a 10% citric acid solution (10 mL), followed by water (10 mL), saturated aqueous NaHCO 3 (10 mL), and brine ( 10 mL). The combined organic layers were dried over Na2SO4, and then concentrated. Instant chromatographic purification of the residue (30% EtOAc / hexanes) gave Compound 12 as a yellow oil (0.19 g, 83%). Rf = 0.42 (50% EtOAc / hexanes); IR: 2941, 2838, 1645, 1584, 1502, 1453, 1329, 1265, 1164, 1128. 1074, 1003, 734 cm "1; A NMR (major rotamer): d 1.89-2.19 (m, 6H), 2.70- 3.20 (m, 2H), 3.52 (s, 3H), 3.68-3.90 (m, 9H), 4.56-4.67 (m, 2H), 4.94-5.01 (m, 1H), 5.21 (s, 1H), 5.75 ( s, 1H), 6.23 (d, 1H, J = 7.5), 6.36-6.46 (m, 1H), 6.66 (s, 1H), 6.80 (s, 1H), 7.26-7.31 (m, 1H); HRMS ( M + Na +): expected 517.1951, observed 517.1951.

Scheme 3: Compounds such as Compound 15 and other related compounds as shown in Table 1 can be prepared by the general method of Scheme 3, where Z is a suitable protecting group for nitrogen, such as benzyloxycarbonyl. 2,4-Dioxo-3- (4-phenylbutyl) -3,9-diaza-bicyclo [3.3.1] nonane-9-carboxylic acid benzyl ester (Compound 13) 13 [3.3.1] Anhydride 2 (0.54 g, 1.89 mmol, prepared from Compound 1) was dissolved in 1 mL of dioxane. 4-Phenylbutylamine (0.28 g, 1.89 mmol) was added from the top. The mixture was stirred at room temperature for 1 hour. After this time, acetic anhydride (0.62 mL, 3.78 mmol) was added, and the reaction was at reflux temperature for 5 hours. The dioxane was evaporated, and the flash chromatographic purification of the residue (40% EtOAc / hexanes) gave Compound 13 (0.75 g, 95% yield) as a coarse, colorless oil. Rf = 0.66 (40% EtOAc / hexanes); IR: 2935, 2863, 1710, 1688, 1430, 1341, 1311, 1256, 1126, 1096, 1069, 749, 699 cm "1; Xl NMR: d 1.41-2.04 (m, 8H), 2.61 (t, 2H J = 6.9), 3.79 (t, 2H, J = 6.9), 4.96 (s, 2H), 5.14 (s, 2H), 7.14-7.37 (m, 10H). 3- (4-phenylbutyl) -3,9-diaza-bicyclo [3.3.1] nonane-2,4-dione (Compound 14) 2,4-Dioxo-3- (4-phenylbutyl) -3,9-diaza-bicyclo [3.3.1] nonane-9-carboxylic acid benzyl ester (Compound 13, 0.57 g, 1.36 mmol) was dissolved in THF ( 3 mL), and palladium on 10% activated carbon (0.12 g) was added. Hydrogen was applied through a balloon for 1 hour. The black suspension was then filtered through compacted celite, and the THF was removed by a high vacuum rotary evaporator to give Compound 14 (0.36 g, 92%) as a coarse oil, which was of sufficiently good quality to be Advanced to the next step without further purification. 9- (oxo- (3,4,5-trimethoxyphenyl) -acetyl] -3- (4-phenyl-butyl) -3,9-diaza-bicyclo [3.3.1] nonane-2,4-dione (Compound 15) 3- (4-phenylbutyl) -3,9-diaza-bicyclo [3.3.1] nonane-2,4-dione (Compound 14, 0.42 g, 1.47 mmol) and 2-oxo-3,4,5 acid were dissolved. -trimetoxyphenylacetic acid (0.35 g, 1.47 mmol) in CH2C12 (5 mL), and the solution was cooled to 0 ° C. HOBt (0.21 g, 1.54 mmol) was added, followed by EDC'HCl (0.30 g, 1.54 mmol) TEA (0.15 g, 1.47 mmol). The reaction was allowed to reach room temperature and stirred for 5 hours. The volatiles were removed using a high vacuum rotary evaporator. The residue was dissolved in EtOAc and washed with a 10% citric acid solution (10 mL), followed by water (10 mL), saturated NaHCO 3 (10 mL), and brine (10 mL). The combined organic layers were dried over Na2SO4 and concentrated. Flash chromatographic purification of the residue (30% EtOAc / hexanes) gave Compound 15 as a pale yellow solid (0.25 g, 34%, one isomer). Mp = 101-103 ° C; Rf = 0.32 (50% EtOAc / hexanes); IR: 2939, 2866, 1739, 1682, 1651, 1582, 1503, 1454, 1416, 1361, 1337, 1243, 1167, 1126 1067, 991, 914, 862 cm "1; 1 H NMR (major rotamer): d 1.56- 1.64 (m, 5H), 1.93-2.01 (m, 5H), 2.61-2.66 (m, 2H), 3.80-3.85 (m, 2H), 3.95 (s, 9H), 4.51 (brs, 1H), 5.46 ( brs, 1H), 7.14-7.29 (m, 7H) HRMS (expected M + H 509.22: observed 509. 2275; EA: calculated, C (66.13), H (6.34), N (5.51); found, C (66.00, H (6.37), N (5.50.

Scheme 4: Scheme 4 is useful for preparing the compounds of formula 18 and similar compounds as listed in Table 1 (for example, by varying the arylmethylbromide reagents used in the first step).

In formula 18, R3, R4, R5, Rs, and R7 are each independently H or any suitable substituent linked to the nucleic ring through O, N, C, or S.Z in the above formulas is a protecting group, such as benzyloxycarbonyl.

Compound 16 reacts with a substituted aryl bromomethane in the presence of sodium hydride and DMF to give Compound 17. Compound 17 then reacts with sulfuric acid to produce a compound of formula 18. Compounds of formula 18 are converted to compounds of the formula (Ia) by removing the protecting group Z and coupling the resulting product with a compound of the formula (IV).

Scheme 5: The final coupling step with a reagent of formula (IV), converts Compound 31 to the desired compound of formula (I-a). This scheme is particularly useful for producing compounds such as those identified in Table 1 below.

Scheme 6: Scheme 6 is useful for preparing Compound 159 and other related compounds as shown in Table 1.

Ester 2-methyl ester of 1-benzyl ester of piperidine-1,2,6-tricarboxylic acid (Compound 232).

The benzyl ester of 2,4-dioxo-3-oxa-9-aza-bicyclo [3.3.1] nonane-9-carboxylic acid is dissolved in methanol (50 mL) (Compound 2, 10 g, 34.51 mmol) . The reaction mixture was stirred at room temperature for 2 hours. The MeOH was evaporated to provide Compound 232 (10 g, 96%). Rf = 0.47 (10% MeOH / CH2Cl2). The material was of good enough quality to be used in the next reaction without purification. 2-methyl ester of the 1-benzyl ester of 6-methoxy-piperidine-1,2-dicarboxylic acid (Compound 233).

The 2-methyl ester of the 1-benzyl ester of 6-methoxy-piperidine-1,2-dicarboxylic acid (Compound 232, 10 g, 31.15 mmol) was dissolved in (80 mL) methanol. A solution of sodium methoxide IN in methanol (20 mL) was added. A constant current (using platinum electrodes) of 0.3 A was applied for 1.96 hours, using a total of 4.17F / mol. The methanol was evaporated. Flash chromatographic purification of the residue (1: 2 EtOAc / hexanes) gave Compound 233 (9.14 g, 95%). Rf = 0.9 (10% MeOH / CH2Cl2). 2-methyl ester of the 6-allyl-piperidine-1,2-dicarboxylic acid 1-benzyl ester (Compound 234).

The 2-methyl ester of the 1-benzyl ester of 6-methoxy-piperidine-1,2-dicarboxylic acid (Compound 233, 1.04 g, 3.39 mmol) was dissolved in (10 mL) CH2C12, and the solution was cooled to -78 ° C using a dry ice-acetone bath. An iM TiCl4 solution in (3.7 mL) CH2C12 was added dropwise over a period of 1 minute, followed by (1.61 mL, 10.14 mmol) allyltrimethylsilane. The bath was changed to water, and the reaction mixture was stirred for 2 hours. The reaction mixture was poured into (50 mL) brine and extracted with (2 x 50 mL) CHC13. The organic layers were washed with (50 mL) saturated NaHCO 3 solution and finally dried over Na 2 SO 4. The solvent was evaporated and the residue was purified by flash chromatography (1: 5 EtOAc / hexanes) to give Compound 234 (0.91 g, 84%). Rf = 0.78 (1.2 EtOAc / hexanes). 2-methyl ester of the 6- (2,3-dihydroxy-propyl) -piperidine-1,2-dicarboxylic acid 1-benzyl ester (Compound 235).

The 2-methyl ester of the 1-benzyl ester of 6-allyl-piperidine-1,2-dicarboxylic acid (Compound 234, 0.087 g, 0.2 mmol) was dissolved in (2 mL) acetone and (0.25 mL) water. N-methylmorpholinooxide (0.068 g, 0.58 mmol) was added, followed by a 25% Os04 solution in (0.14 mL) T-BuOH. The reaction mixture was stirred at room temperature for 14 hours. Sodium pyrosulfate (0.3 g) in (1 mL) water was added with stirring, and the resulting solution was filtered through celite and washed with (10 mL) ethanol. The solvents were removed and the residue was purified by flash column chromatography (100% EtOAc) to provide Compound 235 (0.86 g, 89%, as a mixture of isomers) Rf = 0.12 and 0.06 (2: 1 EtOAc / hexanes) . 2-methyl ester of the 6- (2-oxo-ethyl) -piperidine-1,2-dicarboxylic acid 1-benzyl ester (Compound 236).

The 2-methyl ester of the 6- (2,3-dihydroxy-propyl) -piperidine-1,2-dicarboxylic acid 1-benzyl ester (Compound 235, 0.614 g, 1.75 mmol) was dissolved in (20 mL) Et20 and cooled to 0 ° C. An aqueous solution of ten percent NaI0 (4 mL) was added, and the reaction was stirred for 1 hour. The reaction mixture was poured into brine (15 mL) and extracted with Et20 (3 x 20 mL). The combined organic layer was further washed with aqueous NaS203 (10 mL), saturated NaHCO3 solution (10 mL), brine (10 mL) and finally dried over MgSO4. The solvents were removed to provide Compound 236 (0.53 g, 95%) Rf = 0.67 (1: 1 EtOAc / hexanes). The material was of good enough quality to be used in the next reaction without purification. 2-methyl ester of 6- (2, 2-dimethoxy-ethyl) -piperidine-1,2-dicarboxylic acid 1-benzyl ester (Compound 237).

The 2-methyl ester of the 1-benzyl ester of 6- (2-oxo-ethyl) -piperidine-1,2-dicarboxylic acid ester (Compound 236, 0.4 g, 1.25 mmol), trimethyl orthoformate (5 mL) and monohydrate of p-toluenesul phonic acid (0.03 g) were combined, and the reaction mixture was stirred at room temperature for 12 hours. Aqueous NaHCO3 (25 mL) was added and the reaction was extracted with CHC13 (3 x 100 mL). The combined organic layer was dried over MgSO4 and concentrated. The residue was purified by flash chromatography (1: 2 EtOAc / hexanes) to provide Compound 237 (0.44 g, 96%). Rf = 0.75 (1: 1 EtOAc / hexanes). 2- (2, 2-Dimethoxy-ethyl) -6-phenethylcarbamoyl-piperidine-1-carboxylic acid benzyl ester (Compound 239) The 2-methyl ester of the 6- (2,2-dimethoxy-ethyl) -piperidine-1,2-dicarboxylic acid 1-benzyl ester (Compound 237, 0.350 g, 0.96 mmol) was dissolved in methanol (5 mL) and 2N NaOH (4 mL). The reaction was stirred at room temperature for 8 hours. The methanol was evaporated and the residue was dissolved in Et20 and washed with 5% KHS04 (10 mL), brine (10 mL), dried over Na2SO2 and concentrated to give Compound 238 (0.335 g, 0.96 mmol) , which was used in the next reaction without further purification.

The 1-benzyl ester of 6- (2,2-dimethoxy-ethyl) -piperidine-1,2-dicarboxylic acid (Compound 238, 0.335 g, 0.96 mmol) and phenethyl amine (0.14 g, 1.15 mmol) were dissolved in CH2C12 (20 mL). HOBt (0.156 g, 1.15 mmol) was added followed by EDC. HCl (0.221 g, 1.15 mmol). The reaction was stirred at room temperature for 18 hours. Saturated NaHCO3 solution (25 mL) was added and then extracted with CHCl3 (2 x 50 mL). The combined organic layers were dried over Na2SO4, and then concentrated. Flash chromatographic purification of the residue (1: 1 EtOAc / hexanes) gave Compound 239 (0.374 g, 86%). Rf = 0.47 (1: 1 EtOAC / hexanes).

Tert-butyl ester of 2-oxo-3-phenet-il-3,10 'diaza-bicyclo [4.3.1] decane-10-carboxylic acid (Compound 240).

The benzyl ester of 2- (2,2-dimethoxy-ethyl) -6-phenethylcarbamoyl-piperidine-1-carboxylic acid (Compound 239, 0.297 g, 0.65 mmol) was dissolved in (15 mL) toluene, and the flask was immersed in an oil bath at 80 ° C. The pyridinium sulfonate of p-toluene (0.0120 g, 0.05 mmol) was added and the reaction mixture was stirred at 80 ° C for 2 hours. After this time, the reaction was cooled and the formed precipitate was removed by filtration. The toluene was evaporated and the residue was dissolved in (10 mL) dioxane. The N- (tert-butoxycarbonyl anhydride (0.285 g, 1.31 mmol) and palladium on 10% activated carbon (0.1 g) was added in. Hydrogen was applied through a Parr apparatus and the reaction was stirred at 50 psi 12 hours, the black suspension was then filtered through compacted celite, and the dioxane was removed, and the flash chromatographic purification of the residue (1: 2 EtOAc / hexanes) gave Compound 240 (0.211 g, 90%). (1: 2 EtOAc / hexanes). 1- (2-Oxo-3-phenethyl-3, 10-diaza-bicyclo [4.3.1] dec-10-yl) -2- (3,4,5-trimethoxy-phenyl) -ethane-2, 2- diona (Compound 159) The tert-butyl ester of 2-oxo-3-phenethyl-3,10-diaza-bicyclo [4.3.1] decane-10-carboxylic acid (Compound 240, 0.204 g, 0.56 mmol) was dissolved in 4M HCl in dioxane ( 3 mL), and the solution was stirred at room temperature for 1 hour. The solvent was removed and the residue was dissolved in (50 mL) CHCl 3, washed with a saturated NaHCO 3 solution, dried over NaSO 4 and concentrated to give a white solid (0.142 g, 0.55 mmol), which was dissolved in (10 mL) CH2C12. 3, 3-dimethyl-2-oxo-pentanoic acid (0.131 g, 0.54 mmol), EDC. HCl (0.126 g, 0.66 mmol) and 4-DMAP (0.081 g, 0.66 mmol) were added, and the reaction was stirred at room temperature for 18 hours. The volatiles were removed in a high vacuum evaporator, and the residue was dissolved in EtOAC and washed with (10 mL) water, (20 mL) IN HCl solution, (20 mL) saturated NaHCO 3 and (20 mL) brine. The combined organic layers were dried over Na2SO4, and concentrated. The flash chromatographic purification of the residue (2: 1 EtOAc / hexanes) gave the final compound 159 (0.120 g, 45% yield). Rf = 0.4 (2: 1 EtOAC / hexanes).

Scheme 7: Compound 162 and similar compounds can be prepared as described below. 2- (2, 2-Dimethoxy-yl) -6- (4-phenyl-butylcarbamoyl) -piperidine-1-carboxylic acid ester benzyl (Compound 242).

The 1-benzyl ester of 6- (2, 2-dimethoxy-ethyl) -piperidine-1,2-dicarboxylic acid (Compound 238, 1 g, 2.85 mmol) and 4-phenylbutylamine (0.51 g, 3.42 mmol) are dissolved in CH2C12 (60 mL). Added HOBt (0.462 g, 3.42 mmol) followed by EDC-HCl (0.655 g, 3.42 mmol). The reaction was stirred at room temperature for 12 hours. Saturated aHC? 3 (25 mL) was added and the reaction was extracted with CHC13 (2 x 50 mL). The combined organic layers were dried over Na2SO4, and then concentrated. Instant chromatographic purification of the residue (1: 1 EtOAc / hexanes) gave Compound 242 (1294 g, 94% Rf 0.62 (1: 1 EtOAC / hexanes). 9-Fluoren-9-ylmethyl 2- (2,2-dimethoxy-ethyl) -6- (4-phenyl-butylcarbamoyl) -piperidine-1-carboxylic acid ester (Compound 243).

The benzyl ester of 2- (2, 2-dimethoxy-ethyl) -6- (4-phenyl-butylcarbamoyl) -piperidine-1-carboxylic acid (Compound 242, 0.887 g, 1.83 mmol) was dissolved in methanol (50 mL ). Palladium was added (10%) on activated carbon (0.09 g). Hydrogen was applied through a Parr apparatus, and the reaction was stirred at 50 psi for 15 hours. The black suspension was then filtered through compacted celite, and the methanol was removed. The residue was dissolved in dioxane (25 mL). 9-Fluorenylmethyl chloroformate (0.473 g, 1.83 mmol) was added, followed by NaHCO3 (0.307 g, 3.66 mmol) dissolved in water (7 mL). The reaction was stirred at room temperature for 10 hours, poured into ice and a 5% KHS04 solution and then extracted with CHC13 (2 x 100 L). Instant chromatographic purification of (1: 2 EtOAc / hexanes) gave Compound 243 (1050 g, 100%). Rf = 0.59 (1: 1 EtOAc / hexanes). 9-Fluoren-9-yl-methyl-2-oxo-3- (4-phenyl-butyl) -3,10-diaza-bicyclo [4.3.1] dec-4-ene-10-carboxylic acid ester (Compound 244) ) 9-Fluoren-9-ylmethyl 2- (2,2-dimethoxy-ethyl) -6- (4-phenyl-butylcarbamoyl) -piperidine-1-carboxylic acid ether (compound 243, 1 g, 1.75 mmol) is dissolved in toluene (25 ml). Pyridinium sulfonate p-toluene is added (0.02 g, 0.08 mmol) and the reaction is stirred at 100 ° C for 2 hours. After this time, the reaction is cooled, the toluene is evaporated and the residue is dissolved in EtOAc (75 mL), washed with saturated NaHCO 3 solution (25 mL) and dried over Na 2 S 4. Flash chromatographic purification of the residue (EtOAc / hexanes 1: 2) gave Compound 244 (0.770 g, 87%). Rf = 0.5 (EtOAc / hexanes 1: 2). l- [2-Oxo-3- (4-phenyl-butyl) -3,10-diaza-bicyclo [4.3.1] dec-4-en-10-yl] -2- (3,4, 5- trimet oxy-phenyl) -ethane-1,2-dione (Compound 162).

The 9-fluoren-9-ylmethyl 2-OXO-3- (4-phenyl-butyl) -3,10-diaza-bicyclo [4.3.1] dec-4-ene-10-carboxylic acid ester is dissolved (Compound 244, 0.740 g, 1.46 mmol) in methanol (15 mL), and a solution of NaOMe IN in methanol (2.5 mL) was added. The reaction was stirred at room temperature for 2 hours. The volatiles were removed and the product was extracted with CHCl3, dried over Na2SO4 and concentrated to a white precipitate, which was dissolved in CHC13 (10 mL). 3,3-Dimethyl-2-oxo-pentanoic acid (0.141 g, 0.58 mmol), HOBt (0.080 g, 0.58 mmol), EDC was added. HCl (0.113 g, 0.58 mmol), and TEA (0.082 mL, 0.58 mmol), and the reaction was stirred at room temperature for 18 hours. The volatiles were removed using a high vacuum evaporator, and the residue was dissolved in EtOAC and washed with a 10% citric acid solution (10 mL), followed by water (10 mL), saturated NaHCO 3 (10 mL) and brine (10 mL). The combined organic layers were dried over Na2SO4, and concentrated. Flash chromatographic purification of the residue (EtOAc / hexanes 1: 1) gave Compound 162 (0.122 g, 50%). Rf (EtOAC / hexanes 1: 1): 0.122.

Biochemical and Biological Tests A variety of assays and techniques can be employed to determine the activities of the compounds of the present invention. The activity of a compound of the invention for the stimulation of the neurite result is directly related to its affinity for binding FKBP12 and its ability to inhibit the activity of the FKBP12 rotamase. In order to quantify these last properties, assays known in the art can be used to measure the ligand binding and the activity of the enzyme. The tests for the stimulation of the neurite result are described below.

For example, the compounds can be tested for their neurotrophic activity using the method described by Lyons et al., Proc. Na tl. Aca d. Sci. , 91: 3191-3195 (1994). In this rat pheochromocytoma assay for neurite outgrowth, rat pheochromocytoma cells PC12 at 37 ° C and 5% C02 were maintained in Dulbeco modified Eagle's medium (DMEM) supplemented with 10% heat-inactivated horse serum and Fetal bovine serum inactivated by 5% heat. The cells are then plated, coated at 105 by 35 mm culture wells with collagen from the rat tail at 5 mg / cm2, and allowed to aggregate. The medium is then replaced with DMEM supplemented with 2% horse serum, 1% fetal bovine serum, nerve growth factor (NGF), and / or various concentrations of the test compounds. Control cultures are administered NGF without any of the test compounds.

Another exemplary method that can be used to measure the potency of the stimulation of the neurite result is the rat dorsal root ganglion assay. In this trial, the dorsal root ganglion of 16-day-old Sprague-Dawley rat embryos is dissected. The sensory ganglion is grown in 35 mm Falcon dishes coated with collagen with an N-2 medium (DMEM / Ham F12, 1: 1) at 37 ° C in a 15% C02 environment. The medium is supplemented with selenium, progesterin, insulin, putrescine, glucose, penicillin and streptomycin. The ganglion is then treated with various concentrations of NGF (0-100 ng / ml) and the test compound. The sensory ganglion is observed every two to three days under a contrast microscope phase, and the axon lengths are measured. See Lyons et al., PNAS, 91: 3191-3195 (1994).

Other appropriate assays can be used to measure the activity of the compounds of the present invention. For example, immunosuppressive activity can be estimated through measurements of the inhibition of calcineurin phosphatase activity by complexes of compounds of the invention linked to FKBP (Babine et al., Bi org Med Ch. Le tt. 6, 385-390, 1996). The phosphopeptide phosphatase activity of calcineurin is assayed at 30 ° C using a continuous coupling spectrophotometric assay (Etzkorn et al., Bi o ch emi st, 32, 2380, 1994) and the phosphorylated 19-mer peptide substrate derivative. of the regulatory subunit (Rp) of the protein kinase dependent on cAMP. The assay mixture contains 50 mM MOPS (pH 7.5), 0.1 M NaCl, 6 mM MgCl, 0.5 mg / ml bovine serum albumin, 0.5 mM dithiothreitol, 1 mM CaCl2, 1 mM MnCl2, 20 μM of phosphorylated R peptide, 20 nM recombinant human calcineurin, 40 nM calmodulin, 10 μg / mL purine ribonucleoside phosphorylase, and 200 μM methylthioguanosine as described by Etzkorn et al., Plus 1% dimethylsulfoxide ( DMSO) as a co-solvent and 100 μM of FKBP. The compounds were tested for FKBP-dependent inhibition of calcineurin at its maximum solubility. Under these conditions, the constant apparent inhibition for the inhibition of human recombinant calcineurin by FKBP-FK506 is measured to be 43 nM.

The binding of the compounds to the FKBP can be measured directly using microcalorimetry. The calorimetric titrations are carried out using the MCS-ITC instrument (MicroCal Inc., Northhampton, MA). The degrees can be conducted as follows. The dialysate protein is degassed for 15 minutes using a MicroCal equipment. A solution of stock inhibitor is added to the co-solvent (typically DMSO) and degassed dialysis, followed by brief sonication, to produce final inhibitor solutions for use in the titrations. The final inhibitor solutions are in the concentration range of 10 to 80 μM. The dialyzed protein is added to the co-solvent and the degassed dialysate to produce FKBP12 solutions in the concentration range of 200 to 1600 μM. As both solutions are prepared using degassed dialysate, there is no additional degassing of the solutions. The co-solvent is added to the protein solutions to maintain a fixed co-solvent concentration throughout the course of the titration. The protein is titrated on the inhibitor using a 125 μL injection syringe. The titrations are conducted with the ligand in the cell due to the low solubility of the inhibitors. Typically, a preliminary injection is followed by fifteen injections of 8 μL made at various injection intervals. A complete set of dilution controls are conducted for each titration. An appropriate volume of co-solvent is added to the degassed dialysate to produce the buffering co-solvent solution used to obtain heats of dilution of the reactants. After correction of the heats of dilution and withdrawal of the preliminary injection, the results of the titration are placed using the "One Set of Sites Model" in the ORIGIN computer program package. supplied with the instrument.

The binding of FKBP as measured directly by the microcalorimetre has been found to co-relate well with the potency for inhibition of the rotamase reaction, which is easily tested by methods known in the art (see, for example, Fischer. and collaborators, Bi ochim, Bi ophys, Ac 791, 87 (1984), Fischer et al, Bi omed Biomim Acta 43, 1101 (1984), Fischer et al, Na t ure 337, 476-478 (1989). ), Siekireka et al, Na t ure, 341, 755-57 '(1989), US Patent No. 5,696,135, and Harding et al, Na ture, 341, 758-60 (1989)).

In the rotamase inhibition assay, 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, FKBP12, the compound being tested, and cimot ripsin. Cimotripcin is able to insert p-nit roaniline in the trans form of the substrate, but not in the cis form. The release of p-nit roaniline is measured spectrophotometrically. Using this assay, various amounts of the rotamase inhibitor compounds FKBP of the formula (Ia) or (Ib) are added to the cis-N-succinyl-alanine-alanine-proline-phenylalanine-para-niroaniline (Bachem, 3132 Kashiwa Street , Torrance, CA 90505) in the presence of FKBP12 and cimothyrosine. The spectrophotometric measurements of the p-nitroaniline concentrations allow the estimation of the apparent Kl values, which are provided in Table 1 below.

Table 1 Pharmaceutical Compositions and Treatments: Agents that inhibit the FKBP of the invention, such as the compounds exemplified above, can be used to prepare pharmaceutical compositions, such as those described below.

The pharmaceutical compositions of this invention comprise a compound that stimulates the effective neurite result of formula (I-a) or (I-b) and a pharmaceutically acceptable, inert carrier or diluent. The pharmaceutical compositions can, additionally, comprise a neurotrophic factor. These compositions are prepared in appropriate unit dosage forms for various routes of administration.

In one embodiment, effective levels of compounds that inhibit non-peptide rotamase are provided as such to provide therapeutic benefits that involve the regulation of FKBP. By "effective levels" of compounds, they mean levels at which the FKBP bond of FKBP12 is, at a minimum, regulated. The compounds may be administered in the form of a pro-drug which, in general, is designated to increase absorption and inserted in vi to form the active component. Effective levels may also be realized by the administration of pharmaceutically active metabolites (metabolic conversion products) of the compound.

A compound of formula (Ia) or (Ib) is administered in an appropriate dosage form prepared by the combination of a therapeutically effective amount (that is, a level effectively sufficient to effect the desirable therapeutic effect during the regulation of FKBP) of a compound of formula (Ia) or (Ib) (as an active ingredient) with standard pharmaceutical carriers or diluents according to conventional procedures. These procedures may involve mixing, granulating, and compressing or dissolving the ingredients as appropriate to achieve the desired preparation.

The pharmaceutical carrier employed may be in an appropriate form, for example, either a solid or a liquid. Exemplary solid carriers include lactose, alba earth, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Exemplary liquid carriers include syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include a material that is released with time known in the art, such as glycerin monostearate or glycerin distearate, alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate or the like.

A variety of pharmaceutical forms can be employed. For example, if a solid carrier is used, the preparation may be in tablets, placed in a hard gelatin capsule, in powder or in a pelletized form, or formed into pieces or pellets. The amount of solid carrier may vary, but preferably is from about 25 mg to about 1 g. if a liquid carrier is used, the preparation will preferably be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in a small vial or vial, or a non-aqueous liquid suspension.

To obtain a stable, water-soluble dosage form, a pharmaceutically acceptable salt of a compound of formula (Ia) 'or (Ib) can be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3M solution of acid succinic, or more preferably, citric acid. If a soluble salt form is not available, the compound of formula (I-a) or (I-b) can be dissolved in an appropriate co-solvent or combination of co-solvents. Examples of suitable cosolvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0 to 60% of the total volume. In a preferred embodiment, the active compound of the formula (I-a) or (I-b) is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle, such as water or isotonic dextrose or saline.

It will be appreciated that the preferred present doses of the compounds of formula (Ia) and (Ib) used in the compositions of this invention may vary in accordance with the particular complex to be used, the particular composition formulated, the mode of administration and the particular site, and the host and the disease to be treated. The optimum doses for a set of given conditions can be guessed by those skilled in the art using conventional dose determination tests, for example, in view of the experimental data provided herein. For oral administration, the usual daily dose generally employed is from about 0.001 to about 1000 mg / kg body weight, with courses of treatment repeated at appropriate intervals. Initial pharmacokinetics for humans can be determined from the rat model described by Gold et al., Experimen ta l Neurol ogy, 147: 269-278 (1997).

Pharmaceutical compositions containing active compounds of the present invention can be manufactured in a manner that is generally known, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, separating, or lyophilizing processes. . The pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the proper formulation depends on the chosen route of administration.

For oral administration, the compounds can be formulated easily by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers allow the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, thick mixtures, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining an active compound with a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding appropriate auxiliaries, if desired, to obtain tablets or core pellets. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Core pellets are provided with appropriate coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquered solutions, and appropriate organic solvents or solvent mixtures. The dyes or pigments can be added to the coated tablets or coated tablets for identification or to characterize different combinations of active compound doses.

The pharmaceutical preparation forms that can be used orally include pressurized capsules made of gelatin, as well as sealed, soft capsules, made of gelatin and a plasticizer, such as glycerol or sorbitol. Capsules that enter under pressure may contain the active ingredients in a mixture with a filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration will be in appropriate doses for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in a conventional manner.

An example for the preparation of an oral pharmaceutical composition of this invention is as follows: 100 mg of a compound of the formula (Ia) or (Ib) is mixed with 750 mg of lactose, and the mixture is incorporated in a dosage form oral unit, such as a hard gelatin capsule, which is suitable for oral administration.

For administration by inhalation, the compounds according to the present invention are conveniently delivered in the form of an atomized spray presentation of pressurized packings or a nebulizer, with the use of an appropriate propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, dioxide of carbon and other appropriate gas. In the case of a pressurized aerosol, the unit dose can be determined by providing a valve to release a measured quantity. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mixture of the compound and an appropriate powder base such as lactose or starch.

The compounds can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Formulations for injection may be presented in unit dose form, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in aqueous or oily vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

For injection, the agents of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffer solutions such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants for the barrier to permeate are used in the formulation and can be selected from those known in the art.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water soluble form. Additionally, suspensions of the active compounds can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles for preparing such formulations include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain appropriate tabiliants or agents that increase the solubility of the compounds to enable the preparations of highly concentrated solutions.

A parenteral pharmaceutical composition of this invention, suitable for administration by injection, can be prepared as follows: 100 mg of a compound of the formula (Ia) or (Ib) is mixed with 10 ml of a lipophilic solvent such as a fatty acid, and the mixture is incorporated in a unit dosage form suitable for administration by injection as an emulsion.

Alternatively, the active ingredient may be in powder form for constitution with an appropriate vehicle, for example sterile pyrogen-free water, before use. The compounds can also be formulated in rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long activation formulations can be administered by implantation (eg, subcutaneously or intramuscularly) or by intramuscular injection. For example, the compounds can be formulated with suitable hydrophobic or polymeric materials (for example, as an emulsion in an appropriate oil) or ion exchange resins, or as poorly soluble derivatives, for example, as a poorly soluble salt.

A suitable pharmaceutical carrier for the hydrophobic compounds of the invention is a co-solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. The co-solvent system can be the VPD co-solvent system (VPD is a solution of 3% w / v of benzyl alcohol, 8% w / v of a non-polar polysorbate 80 surfactant, and 65% w / v of polyethylene glycol 300, made up to a volume of absolute methanol). The VPD co-solvent system (VPD: 5) consists of VPD diluted 1: 1 with 5% dextrose in an aqueous solution. This cosolvent system dissolves hydrophobic compounds well, and by itself produces a low toxicity during systemic administration. Naturally, the proportions of a cosolvent system can vary considerably without destroying its solubility and toxicity characteristics. Additionally, the identity of the co-solvent components may vary: for example, other non-polar low toxicity surfactants may be used in place of the polysorbate 80; the fraction size of the polyethylene glycol can vary; other biologically compatible polymers can replace polyethylene glycol, for example, polyvinylpyrrolidone; and other sugars or polysaccharides can be replaced by dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceutical compounds can be employed. Liposomes and emulsions are well known examples of vehicles or release carriers for hydrophobic drugs. Certain organic solvents such as dimethyl sulfoxide can also be used, although usually at the cost of greater toxicity. Additionally, the compounds can be released using a sustained release system, such as solid hydrophobic polymer semi-permeable matrices containing the therapeutic agents. Various sustained release materials are stable and well known to those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a period of a few weeks to up to 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for stabilization of the protein may be employed.

The pharmaceutical compositions may also comprise appropriate solids or gel phase carriers or excipients. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

Numerous neurotrophic factors have been identified in the art and any of those factors can be used in the compositions of the invention. As used herein, the term "neurotrophic factor" refers to substances that are capable of stimulating the growth or proliferation of nervous tissue (but excluding compounds that inhibit the rotamase-FKBP of the invention), for example, growth factor. nervous (NGF), insulin growth factor (IGF-1) and its active trincate derivatives (gICF-1), acid and basic fibroblast growth factor (aFGF and bFGF, respectively), platelet-derived growth factors (PDGF) , 'Brain-derived growth factors (BDNF), ciliary neurotrophilic factors (CNTF), neurotrophic factor derived from the gial cell line (GDNF), neurotrophin-3 (NY-3), and neurotrophin 4/5 (NT-4) /5) . The pharmaceutical compositions may include as active ingredients, in addition to one or more agents of the invention, one or more such neurotrophic factors. The most preferred neurotrophic factor to be used in the composition of this invention is NGF.

Other components of the acceptable pharmaceutical compositions of this invention may include benzyl alcohol and other suitable preservatives, absorption promoters to increase biological availability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

A pharmaceutical composition contains a total amount of the active ingredient (s) sufficient to perform the intended therapeutic effect. More specifically, the pharmaceutical composition contains a therapeutically effective amount (ie, an amount effective to prevent the development of or to alleviate existing symptoms of a disease or condition mediated by FKBP) of an agent that inhibits the FKBP of the invention. . The total amounts of the FKBP inhibitory agent of the invention and any optional neurotrophic factor that can be combined with the carrier materials to produce a single dose form, can vary depending on the host treated and the particular mode of administration. Preferably, the compositions of the invention each contain both an inhibitor agent of FKBP and a neurotrophic agent, with the inhibitory agent of FKBP acting to enhance the activity of the neurotrophic factor to enhance the stimulation of the neurite result. The amount . of neurotrophic factor in such compositions is advantageously less than the amount required in a monotherapy using only the factor. Preferably, the compositions are formulated so that a dose between 0.01 to 100 mg / kg of body weight / day of an inhibitor agent of FKBP12 is administered and a dose of between 0.01 to 100 mg / kg of body weight / day of a factor neurotrophic is administered to a patient receiving the compositions.

The pharmaceutical composition of the invention can be used in a method for inhibiting the rotamase enzyme activity of an FK-506 binding protein, which comprises administering the composition to the patient. The inventive compositions can also be used to stimulate neurite outcome in nerve cells, to stimulate nerve regeneration, or to promote neuronal regeneration. Preferably, the composition further comprises a neurotrophic factor.

Although the invention has been illustrated with reference to specific and preferred embodiments, those skilled in the art will recognize, for example, through the experimentation routine and the practice of the invention, that variations and modifications may be made. For example, those of ordinary skill in the art can recognize that apparent variations or substitutions can be made of the compounds of the formula (I-a) and the formula (I-b) without. adversely affect in a significant way their efficacy in the pharmaceutical compositions. In this way, the invention is not intended to be limited by the aforementioned description, but to be defined by the appended claims and their equivalents.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (29)

Claims

1. A compound of formula: characterized in that: R1 is: hydrogen; an aryl group substituted or unsubstituted with halogen, hydroxyl, N02, CF3, C ± -C alkyl, C2-C6 alkenyl, C? ~ alkyloxy, C2-C alkenyloxy, benzyloxy, phenoxy, amino, and phenyl; an alkyl or alkenyl group substituted or unsubstituted with one or more substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, and hydroxy; a C3-Cß cycloalkyl or Cs-C cycloalkenyl group substituted or unsubstituted with one or more substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, and hydroxy; or CÍR11) (R12) (R13), wherein R11 and R12 are each independently lower alkyl, or R11 and R12 together with the atom to which they are linked form cycloalkyl, and R13 is H, OH, lower alkyl, aryl, or (CH2) nO-1, where n is 0, 1, 2, or 3, W1 is R2 or C (0) R2, with R2 being C1-C3 alkyl, substituted or unsubstituted with one or two methoxy groups; X is hydrogen, cyano, C 1 -C 2 alkyloxy, dimethoxymethyl, or = 0; and Y is: hydrogen; an alkyl, alkenyl or cycloalkyl group, substituted or unsubstituted with one or more substituents independently selected from the group consisting of alkyl, aryl, alkoxy, hydroxyalkyl, aryloxy, alkenyloxy and hydroxy substituted or unsubstituted with one or more substituents independently selected from the group which consists of hydroxyl, C? -C6 alkyl, C2-C6 alkenyl. C 1 -C 4 alkyloxy, C 2 -C 4 alkenyloxy, benzyloxy, phenoxy, and phenyl; or (CH2) p-0-W2, and (CH2) pN-W2, where p is 0, 1, or 2, and W2 is R3 or C (0) R3, with R3 being an alkyl, alkenyl, or aryl group substituted or unsubstituted with one or more substituents selected from the group consisting of alkyl, aryl, or alkoxy; or X and Y, together with the atom of the carbon ring and the nitrogen heteroatom to which they are respectively linked, form a 5 to 7 membered heterocyclic ring, saturated or unsaturated with one or more substituents J, K, and L; wherein J, K and L represent substituents independently selected from the group consisting of oxygen, and C3-C5 cycloalkyl and C1-C5 alkyl groups substituted or unsubstituted with one or more substituents independently selected from the group consisting of C3-C5 cycloalkoxy, methoxy , methoxypheni, and dimethoxyphenyl; or where J and K taken together form a phenyl ring substituted or unsubstituted with one or more substituents independently selected from the group consisting of methoxy, trifluoromethyl, trifluoromethoxy, and substituents linked to the phenyl ring through oxygen, nitrogen, carbon, or sulfur and independently selected from the group consisting of halogen, hydroxyl, N02, CF3, C? -C6 alkyl. C2-C6 alkenyl, C?-C4 alkyloxy, C2-C4 alkenyloxy, benzyloxy, phenoxy, amino, and phenyl.

2. The compound or a pharmaceutically acceptable derivative according to claim 1, characterized in that R1 is aryl substituted or unsubstituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, N02, CF3, Ci-Cß alkyl. C2-C6 alkenyl, C1-C4 alkyloxy, C2-C4 alkenyloxy, benzyloxy, phenoxy, amino, and phenyl.

3. The compound or a pharmaceutically acceptable derivative according to claim 1, characterized in that R1 is selected from the group consisting of adamantyl, naphthyl, indolyl, furyl, thienyl, pyridyl, and phenyl, the phenyl having from one to three substituents independently selected from the group consisting of group consisting of halogen, hydroxyl, N02, CF3, C? -C6 alkyl, C2-C6 alkenyl, C1-C4 alkyloxy, C2-C alkenyloxy, benzyloxy, phenoxy, amino, and phenyl.

4. The compound or a pharmaceutically acceptable derivative according to claim 3, characterized in that R1 is 3, 4, 5-trimethoxyphenyl.

5. The compound or a pharmaceutically acceptable derivative according to claim 1, characterized in that R1 is where m is 1 n is 0, 1, 2. and W is as defined in claim 1.

6. The compound or a pharmaceutically acceptable derivative according to claim 1, characterized in that R1 is C (R11) (R12) (R13), wherein R11 and R12 together with the atom to which they are linked form cyclopentyl or cyclohexyl; and R13 is selected from H, OH, lower alkyl, aryl, and (CH2) n_0-1, where n is 0, 1, 2, or 3, and W1 is R2 or C (0) R2, where R2 is alkyl C -C3 substituted or unsubstituted with one or two methoxy groups.

1. . The compound or a pharmaceutically acceptable derivative according to claim 6, characterized in that R1 is selected from the group consisting of: where m is 1 or 2

8. The compound or a pharmaceutically acceptable derivative according to claim 1, characterized in that R1 is C (R11) (R12) (R13), wherein R11 and R12 are each independently methyl or ethyl; and R13 is H, OH, lower alkyl, aryl, or (CH2) n-0-1, where n is O, 1, 2, or 3, and 1 is R2 or C (0) R2, where R2 is alkyl C -C3 substituted or unsubstituted with one or two methoxy groups.

9. The compound or a pharmaceutically acceptable derivative according to claim 8, characterized in that R1 is selected from the group consisting of:

10. The compound or a pharmaceutically acceptable derivative according to claim 1, characterized in that Y is alkyl substituted with one or more substituents independently selected from the group consisting of alkyl, aryl, alkoxy, hydroxyalkyl, aryloxy, alkenyloxy, hydroxy, (CH2) p-0-W2, and (CH2) PN-W2, where p is 0, 1, or 2, and w is R 'C (O) ileon R- being alkyl, alkenyl, or aryl-alkyl, or aryl substituted or unsubstituted with one or more substituents selected from the group consisting of alkyl, aryl, and alkoxy.

11. The compound or a pharmaceutically acceptable derivative according to claim 10, characterized in that Y is selected from the group consisting of:

12. The compound or a pharmaceutically acceptable derivative according to claim 1, characterized in that X and Y, together with the carbon ring atom and the nitrogen heteroatom to which they are respectively linked, form a 5- to 7-membered heterocyclic ring, saturated or unsaturated optionally having, in addition to the nitrogen heteroatom, an additional heteroatom selected from the group consisting of 0 and N.

13. The compound or a pharmaceutically acceptable derivative according to claim 12, characterized in that the 5- to 7-membered heterocyclic ring, saturated or unsaturated, is selected from piperidine and piperazine.

14. The compound or a pharmaceutically acceptable derivative according to claim 1, characterized in that the compound is selected from the group consisting of: i ^

15. The compound or a pharmaceutically acceptable derivative according to claim 1, characterized in that the compound is selected from the group consisting of:

16. A pharmaceutical composition, characterized in that it comprises: a rotamase inhibitor agent comprising a therapeutically effective amount of at least one pharmaceutically acceptable compound or derivative of claim 1; and a pharmaceutically acceptable carrier.

17. The pharmaceutical composition according to claim 16, characterized in that, in addition, they comprise a neurotrophic factor.

18. A method for treating neuralgic disorders in a patient, characterized in that it comprises administering to the patient a therapeutically effective amount of a pharmaceutically acceptable compound or derivative of claim 1.

19. The method according to claim 18, characterized in that the neurological disorder is selected from the group consisting of peripheral neuropathies caused by physical injury or disease state, physical damage to the brain, physical damage to the spine, infarction associated with damage to the brain , and neurological disorders related to neurodegeneration.

20. The method according to claim 18, characterized in that the neurological disorder is the disease of Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis.

21. The method according to claim 18, characterized in that, further, it comprises administering to the patient a neurotrophic factor selected from the group consisting of nerve growth factor, insulin growth factor and its active truncated derivatives, basic fibroblast growth factor and acid, platelet-derived growth factors, a neurotrophic factor derived from the brain, ciliary neurotrophic factors, neurotrophic factor derived from the glial cell line, neurotrofin-3, and neurotrophin 4/5.

22. A process for making a compound or a pharmaceutically acceptable derivative according to claim 1, characterized in that it comprises: (a) converting a compound of the formula (Ill-a): (ip-a) on R i is selected from the group consisting of optionally substituted alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, where q is 0 or 1, and R, 3JoU is an alkyl or aryl group substituted or unsubstituted with one or more substituents independently selected from the group consisting of hydroxyl, Ci-Ce alkyl, C2-C al alkenyl, C alco alkoxy? ~ C4, C2-C4 alkenyloxy, benzyloxy, phenoxy, and phenyl; X is hydrogen, cyano, C 1 -C 2 alkyloxy, dimethoxymethyl, or oxygen, where when X is oxygen, the bond connecting X to the ring carbon atom is a double bond; and Y is hydrogen, an alkyl, alkenyl, or cycloalkyl group substituted or unsubstituted with one or more substituents independently selected from the group consisting of alkyl, aryl, alkoxy, hydroxyalkyl, aryloxy, alkenyloxy, and hydroxy groups substituted or unsubstituted with one or more substituents independently selected from the group consisting of hydroxyl, C _-C6 alkyl, C2-Cd alkenyl, C1-C4 alkyloxy, C2-C4 alkenyloxy, benzyloxy, phenoxy, and phenyl, (CH2) p-0-2, and (CH2) PN-W2, wherein p is 0, 1, or 2, and 2 is R3 or C (0) R3, with R3 being an alkyl, alkenyl, or aryl group substituted or unsubstituted with one or more substituents independently selected from the group consisting of alkyl, aryl, and alkoxy; or X and Y, together with the atom of the carbon ring and the nitrogen heteroatom to which they are respectively attached, form a 5 to 7 membered heterocyclic ring, saturated or unsaturated, substituted or unsubstituted with one or more substituents J, K, and L; wherein J, K, and L represent substituents independently selected from the group consisting of oxygen, and C3-C5 cycloalkyl, and C1-C5 alkyl groups, substituted or unsubstituted with one or more substituents independently selected from the group consisting of C3- cycloalkyl Cs, methoxy, methoxyphenyl, and dimethoxyphenyl; or wherein J and K together form a phenyl ring substituted or unsubstituted with one or more substituents independently selected from the group consisting of methoxy, trifluoromethyl, trifluoromethoxy, and substituents linked to the phenyl ring through oxygen, nitrogen, carbon or sulfur and independently selected from the group consisting of halogen, hydroxyl, N02, CF3, C? -C6 alkyl, C2-C6 alkenyl, Ci- C4 alkyloxy, C2-C4 alkenyloxy, benzyloxy, phenoxy, amino, and phenyl; under reduced conditions for a compound of formula (Ill-b): Y (ip-b) where X Y are as defined above; Y (b) coupling the compound of formula (III-B) with a compound of formula (IV): wherein: R1 is: hydrogen; an aryl group substituted or unsubstituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, N02, CF3, C? -C6 alkyl, C2-Ce alkenyl, CX-C4 alkyloxy, C-C4 alkenyloxy, benzyloxy, phenoxy, amino, and phenyl; an alkyl or alkenyl group substituted or unsubstituted with one or more substituents independently selected from the group consisting of C? -C alkyl, C2-C4 alkenyl, C1-C4 alkoxy, and hydroxy; a C3-C8 cycloalkyl or Cs-C7 cycloalkenyl group substituted or unsubstituted with one or more substituents independently selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, and hydroxy; or C (R11) (R12) (R13), where R11 and R12 are each independently lower alkyl, or R11 and R12 together with the atom to which they are linked form cycloalkyl, and R13 is H, OH, lower alkyl, aryl , or (CH2) n-0-1, where n is 0, 1, 2, or 3, 1 is R2 or C (0) R2, with R2 being C1-C3 alkyl, substituted or unsubstituted with one or two methoxy groups.

23. The process according to claim 22, characterized in that the compound of formula (Ill-a) is selected from the group consisting of: where Z is benzyloxycarbonyl.

24. The process according to claim 22, characterized in that the compound of formula (Ill-a) is selected from the group consisting of: wherein Z is benzyloxycarbonyl

25. The process according to claim 22, characterized in that the compound of formula (Ill-a) is: where Z is benzyloxycarbonyl.

26. The process according to claim 22, characterized in that the compound of formula (Ill-a) is selected from the group consisting of: wherein Z is benzyloxycarbonyl.

27. The process according to claim 22, characterized in that it further comprises: converting a compound of formula (II): < P > wherein Z is where q is 0 or 1, and R, 30 is an alkyl or aryl group substituted or unsubstituted with one or more substituents independently selected from the group consisting of hydroxyl, Ci-Cd alkyl, C-C6 alkenyl, alkoxy C? -C4, C2-? Alkenyloxy, benzyloxy, phenoxy, and phenyl, to the compound of formula (Ill-a)

28 A compound of formula characterized in that: R1 is: hydrogen; an aryl group substituted or unsubstituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, N02, CF3, C? -C6 alkyl, C2-Ce alkenyl, C1-C4 alkyloxy, C2-C4 alkenyloxy, benzyloxy, phenoxy, amino, and phenyl; an alkyl or alkenyl group substituted or unsubstituted with one or more substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, and hydroxy; a C3-C8 cycloalkyl or Cs-C7 cycloalkenyl group substituted or unsubstituted with one or more substituents independently selected from the group consisting of C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, and hydroxy; or C (R11) (R12) (R13), where R11 and R12 are each independently lower alkyl, or R11 and R12 together with the atom to which they are linked form cycloalkyl, and R13 is H, OH, lower alkyl, aryl , or (CH2) n-0-W1, where n is 0, 1, 2, or 3, 1 is R2 or C (0) R27 with R2 being C1-C3 alkyl, substituted or unsubstituted with one or two methoxy groups; X1 and X2 are each independently hydrogen, cyano, C3-C2 alkyloxy. dimethoxymethyl, o = 0; or X1 and X2 together form a valence bond; and Y is: hydrogen; an alkyl, alkenyl or cycloalkyl group, substituted or unsubstituted with one or more substituents independently selected from the group consisting of alkyl, aryl, alkoxy, hydroxyalkyl, aryloxy, alkenyloxy and hydroxy groups substituted or unsubstituted with one or more substituents independently selected from a group consisting of hydroxyl, Ci-Cβ alkyl, 2-Cs alkenyl, C_-C4 alkyloxy, C2-C4 alkenyloxy, benzyloxy, phenoxy, and phenyl; or (CH2) p-0-2, and (CH2) PN-2, where p is 0, 1, or 2, and W2 is R3 or C (0) R3, with R3 being an alkyl, alkenyl, or aryl group substituted or unsubstituted with one or more substituents selected from the group consisting of alkyl, aryl, or alkoxy; or one of X1 and X2 in combination with Y taken together with the nitrogen heteroatom of the ring structure to which Y is connected form a 5 to 7 membered heterocyclic ring, saturated or unsaturated, optionally containing an additional heteroatom selected from O and N, the 5 to 7 membered heterocyclic ring, saturated or unsaturated being optionally substituted with one or more substituents selected from J, K, and L, which are independently, oxygen, C3-C5 cycloalkyl, or C1-6alkyl C5 optionally substituted with one or two substituents independently selected from C3-C5 cycloalkyl, methoxy, methoxyphenyl, or dimethoxyphenyl, or J and K taken together form a phenyl ring optionally substituted with one or more substituents selected from methoxy, trifluoromethyl, trifluoromethoxy, and substituents suitable linked to the phenyl ring via oxygen, nitrogen, carbon, or sulfur; or a pharmaceutically acceptable derivative of the compound.

29. The compound or a pharmaceutically acceptable derivative according to claim 28, characterized in that the compound is selected from the group consisting of: