MXPA99002814A - Heterocyclic esters and amides - Google Patents

Abstract

This invention relates to neurotrophic low molecular weight, small molecule heterocyclic esters and amides having an affinity for FKBP-type immunophilins, and their use as inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase, enzyme activity.

Description

ESTERES AND HETEROCICLIC AMAS BACKGROUND OF THE INVENTION FIELD OF THE INVENTION This invention relates to small molecule, low molecular weight, heterocyclic heterocyclic esters and amides that have an X affinity for FKBP type immunophilins, and their uses as inhibitors of the associated enzymatic activity of immunophilin proteins. , particularly peptidyl-prolyl isomerase enzymatic activity, or rotamase.

DESCRITION OF THE PREVIOUS ICA TECHNIQUE The term immunophilin refers to a number of proteins that serve as receptors for the major immunosuppressive drugs, cyclosporin A (CsA), FK506, and rapamycin. Known classes of immunophilins are cyclophilins and FK506 binding proteins, or FKBPs. Cyclosporin A binds to cyclophilin A while FK506 and rapamycin bind to FKBP12. These drug-immunophilin complexes make superficial contact with various intracellular signal transduction systems, especially the immune and nervous systems. Immunophilins are known to have peptidyl-prolyl isomerase enzymatic activity (PPlase), or rotamase. It has been determined that the enzymatic activity of the rotamase plays a role in the catalysis of the interconversion of the cis and trans isomers of peptides and protein substrates for the immunophilin proteins.

The immunophilins were discovered and originally studied in the immune tissue. It was initially postulated by those skilled in the art that the inhibition of the rotamase activity of the immunophilins leads to the inhibition of T-cell proliferation, immunosuppressive activity exhibited by immunosuppressive drugs, such as cyclosporin A, FK506 and rapamycin. Additional studies have shown that inhibition of% activity. Rotamase, in and of itself, does not result in immunosuppressive activity. s Schreiber et al., Science, 1990, vol. 250, pp. 556-559. Instead, immunosuppression seems to be maintained against the formulation of a drug complex and immunosuppressive immunophilins. i! It has been shown that drug-immunophilin complexes interact with tertiary protein targets as their mode of action. Schreiber et al., Cell, 1991, Vol. 66, pp. 807-815. In the case of FKBP-FK506 and cyclophilin-Cs'A, the drug-immunophilin complexes bind to the calcineurin enzyme and inhibit T-cell receptor signaling which leads to T-cell proliferation. Similarly, the drug-immunophilin complex of rapamycin-FKBP interacts with the RAFT1 / FRAP protein and inhibits IL-2 receptor signaling. It has been found that immunophilins are present in high concentrations in the central nervous system. Immunophilins are enriched 1 0-50 times more in the central nervous system than in the immune system. Within neural tissues, immunophilins appear to influence the synthesis of nitric oxide, neurotransmitter release and neuronal process extension.

It has been found that picomolar concentrations of an immunosuppressant such as FK506 and rapamycin stimulate neurite outbreaks in PC12 cells and sensory neurons, namely dorsal root ganglion cells (DRGs). Lyons et al., Proc. of Nati. I I • -Acad. Sci., 1994, vol, 91, pp. 3191-3195. In complete animal experiments, FK506 has been shown to stimulate nerve regeneration following damage to the facial nerve. Surprisingly, it has been found that certain compounds with a high affinity for FKBPs are potent rotamase inhibitors and exhibit excellent neutrotrophic effects. In addition, these rotamase inhibitors are devoid of immunosuppressive activity. These findings suggest the use of rotamase inhibitors in the treatment of several peripheral neuropathies and increase neuronal re-growth in the nervous system (CNS). Studies have shown that degenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), can occur due to the loss, or decreased availability, of a neurotrophic substance specific to a particular population of affected neurons in the disorder. : Several neurotrophic factors affecting specific neuronal populations in the central nervous system have been identified. For example, the hypothesis has been proposed that Alzheimer's disease results from a decrease or loss of nerve growth factor (NG F). Thus it has been proposed to treat SDAT patients with exogenous nerve growth factor or other neurotrophic proteins, such as brain-derived growth factor, glial-derived growth factor, ciliary neurotrophic factor and neurotropin-3, to increase the survival of degenerative neuronal populations. 11 The clinical application of these proteins in various states of neurological disease is hampered by difficulties in the delivery and bioavailability of large proteins to targets in the central nervous system. In contrast, immunosuppressive drugs with neurotrophic activity are relatively small and exhibit excellent bioavailability and specificity. However, when administered chronically, immunosuppressive drugs exhibit a number of potentially serious side effects including nephrotoxicity, such as Neurological disorders, such as involuntary tremors, or non-specific cerebral angina, such as 'non-localized headaches' (De Groen et al., N Engl J J Med, 1987, 317: 861); and vascular hypertension with complications resulting therefrom (Kahan et al., N.

Engl. J. Med., 1989, 321: 1725). In order to avoid side effects associated with the use of immunosupersive compounds, the present invention provides non-immunosuppressive compounds containing rotamase inhibitors.

Small molecule FKBP to increase neurite outbreaks, and L! promote neuronal growth and regeneration in several situations:? clothing neumatics where neuronal repair can be facilitated, including peripheral nerve damage caused by physical injury or disease status such as diabetes; physical damage to the central nervous system jl (spinal cord and brain); brain damage associated with stroke; and neurological disorders related to neurodegeneration, such as Parkinson's disease, SDAT (Alzheimer's disease), and amyotrophic lateral sclerosis.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to small molecular weight, low molecular weight neurotrophic compounds that have an affinity for FKBP type immunophilins. Once bound to these proteins, the neurotrophic compounds are potent inhibitors of the associated enzymatic activity; with immunophilin proteins, particularly enzymatic activity, of peptidyl-prolyl isomerase, or rotamase. A key aspect of the compounds of the present invention is that they can not exert any significant immunosuppressive activity in addition to their neurotrophic activity. Specifically, the present invention relates to a compound of the formula I: or a pharmaceutically acceptable salt thereof, wherein: A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered saturated or unsaturated heterocyclic ring containing, in addition to the nitrogen atom ,?! I at least one additional heteroatom of O, S, SO, SO2, N H or NR! in any state of chemically stable oxidation; X is O or S; 'Z is O, N H or N R?; W and Y are independently O, S, CH2, or H2; 'I R- \ is straight or branched chain alkyl or alkenyl of C? C6, which is substituted at one or more positions with (Ar?) P, (Ar -)) connected by an alkyl or straight or branched chain alkenyl of C? -C6,; I C3-C8 cycloalkyl, C3-C8 cycloalkyl connected by a straight or branched chain alkyl or alkenyl of C-? -C6, Ar2, or a combination thereof; • N is 1 or 2; R2 is either a straight or branched chain alkyl or alkenyl of C1-C9, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, or An, wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl are either unsubstituted or substituted at one or more positions with straight or branched alkyl or alkenyl chain of C1-C4, hydroxyl, or a combination thereof; and An and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, alkyl or: alkenyl of C 1 -C 4 alkoxy chain, C 1 -C 4 alkenyloxy, enoxyl, oxoxy, ammonium, or a combination thereof; where the individual ring sizes are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, and a combination thereof. '! A preferred embodiment of this invention is a compound of the formula I I: or a pharmaceutically acceptable salt thereof, wherein: 'I! A, B and C are independently CH 2, O, S, SO, SO 2, NH, or N R-,; *? -i is straight or branched chain alkyl or alkenyl of C1-C5, which is substituted in one or more positions with (Ar?) ", (Ar?) n connected by a straight-chain alkyl or alkenyl, or branched of C? -C6, or a combination thereof; 'N is 1 or 2, R2 is any straight or branched chain alkyl or alkenyl of I-C1-C9, C3-C8 cycloalkyl, C5-cycloalkenyl C7, or An; and An is a mono-, bi-, or tricyclic, carbo or heterocyclic ring, wherein the ring is unsubstituted or substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, alkyl or alkenyl straight or branched chain of Cí-Cs, C 1 -C 4 alkenyloxy akoxy, phenoxy, benzyloxy, amino or a combination thereof, wherein the individual ring sizes are 5-6 members, and wherein the heterocyclic ring contains 1 of 1-6 heteroatoms selected from the group consisting of O, N, S, and a combination thereof • 1 Other preferred embodiment Rida is a compound of the formula l l l: 111 or a pharmaceutically acceptable salt thereof, wherein: A, B and C are independently CH2, O, S, SO, SO2, NH or NR ^ ¡1 R1 is a straight or branched chain alkyl or alkenyl of C1-C5, which is substituted in one or more positions with (An) n, (An) "connected by a straight or branched chain alkyl or alkenyl of d- C6, or a combination thereof; íl N is 1 or 2; ..

R2 is either a straight or branched chain alkyl or alkenyl fl of C1-C9, C3-C8 cycloalkyl, or An; and An is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, where the ring is unsubstituted or substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, alkyl or alkenyl of chain straight or branched C? -C6, C? -C4 alkoxy, alkenyloxy of C? -C, phenoxy, benzyl?, Amino, or a combination thereof; in i | where the sizes of individual rings are 5-6 members; and where the heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, and a combination thereof. The present invention also relates to a pharmaceutical composition comprising a neurotrophically effective amount of the! compound of formula I, I I or I, and an acceptable pharmaceutically acceptable carrier. '; The present invention also relates to a method for effecting a neuron activity! in an animal, comprising: administering to the animal a neurotrophically effective amount of the compound of formula I, I I or l l.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 (A) is a representative micrograph photo of compound 1 (1 pM) that promotes neurite outbreaks in sensory neurons. l l Figure 1 (B) is a representative micrograph photo of the compound:! 1 (10 pM) that promotes neurite outbreaks in sensory neurons.

Figure 1 (C) a representative micrograph photo of the compound (100 pM) that promotes neurite outbreaks in sensory neurons. Figure 2 (A) is a representative micrograph photo of the compound (10 pM) that promotes neurite outbreaks in sensory neurons. Figure 2 (B) is a representative micrograph photo of the compound (100 pM) that promotes neurite outbreaks in sensory neurons. Figure 2 (C) is a representative micrograph photo of the compound »i 2 (10 nM) that promotes neurite outbreaks in sensory neurons. ,! I DETAILED DESCRIPTION OF THE INVENTION • r; Definitions "Alkyl" means a branched or unbranched saturated hydrocarbon chain containing from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, n- pentyl, n-hexyl, and the like, unless otherwise indicated. "Alkoxy" means the group -OR where R is alkyl as defined herein. Preferably, R is a branched unbranched saturated p-hydrocarbon chain containing from 1 to 3 carbon atoms. I "Halo" means fluorine, chlorine, bromine or iodine, unless otherwise indicated. '* "Phenyl" includes all possible isomeric phenyl radicals, monosubstituted or optionally multi-substituted with substituents selected from the group consisting of alkyl, alkoxy, hydroxy, halo, and haloalkyl.;, The term "pharmaceutically acceptable salt" refers to salts of the subject compounds which possess desired pharmacological activity and which are not biologically or otherwise undesirable. The salts can be formed, with inorganic acids such as acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphaprosulfonate, cyclopentánpropionate, digluconate, dodecyl sulfate, ethansulfonate, fumarate, glycoheptanoate, glycerophosphate, hemisulfate heptane, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane sulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate and undecanoate.

Basic salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salt with organic bases such as dicyclohexylamine salts, N-rnethyl-D-glucamine. , and salts with amino acids such as arginine, lysine, and so on. Also, the basic groups containing nitrogen can be quaternized with agents such as lower alkyl halides, such as methyl, ethyl chlorides, bromides and iodides, propyl, and butyl; dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as chlorides, bromides, and decidium iodides, lauryl, myristyl, and stearyl, aralkyl halides such as benzyl bromides and phenethyl and II others. Thus, products soluble or dispersible in water or oil are obtained. The compounds of this invention possess asymmetric centers and thus can be produced as ezclas of stereoisomers or individual stereoisomers. Individual stereoisomers can be obtained by using an optically active starting material by resolving a racemic or non-racemic mixture of an intermediate at any appropriate stage of the synthesis, or by resolution of the compound of the formula (I). It is understood that the individual stereoisomers as well as the mixtures (racemic or non-racemic) of the stereoisomers are t? n covered in the scope of the present invention. The compounds of this invention possess at least one asymmetric center and l, thus they can be produced as mixtures of t stereoisomers or as individual R- and S-stereoisomers. The individual enantiomers can be obtained by solving a mixture "Isomers" are different compounds that have the same formula! molecular. "Stereoisomers" are isomers that differ only by the way atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of one another. "Diastereoisóméros" are stereoisomers that are not mirror images of each other. : "Racemic mixture" means a mixture containing equal parts of individual enantiomers. "Non-racemic mixture" is a mixture containing unequal portions of individual enantiomers or stereoisomers. I The term "treatment" as used herein covers any treatment of a disease and / or condition in an animal, particularly a human, and includes: (i) but that has not yet been diagnosed that has it; (ii) inhibit the disease and / or condition, that is, stop its development; or (iii) alleviating the disease and / or condition, i.e., causing regression of the disease and / or condition. The system used to name the compounds of the present invention is shown below, using a compound of the formula I I as an example. ! A compound of formula II wherein A is CH2, B is S, C is CH2, Ri is 3-phenylpropy, and R2 is 3,3-dimethylpentyl, it is named 3- (1-phenyl-1-pro-pil (2S) -1- (3, 3-dimethyl-1,2-dioxopentyl) -2 carboxylate. - (4-thiazolidine). íf! The FKBP neurotrophic inhibitor compounds of the small, low molecular weight molecule of this invention have an affinity for FKBP type immunophilins, such as FKBP12. When the neurotrophic compounds of this invention are linked to an FKBP-type immunophilin, they have been found to inhibit the cis-trans isomerase activity of prolyl-peptidyl, or rotamase, binding protein activity and unexpectedly stimulate neurite outbreak. .

I FORMULA I In particular, this invention relates to a compound of the formula or a pharmaceutically acceptable salt thereof, wherein: A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a 5-7 membered heterocyclic or unsaturated ring containing, in addition to the nitrogen atom, at least one hete =! roatomo of O, S, SO, S02, NH or N RT in any *. chemically stable oxidation state; X is O or S; »! Z is O, N H or N R,. W and Y are independently O, S, CH2, or H2; Ri is alkyl or which is substituted by a straight or branched chain alkyl or alkenyl of C? -C3, C3-C8 cycloalkyl, C3-C8 cycloalkyl connected by an alkenyl alkyl of caden Ar2, or a combination thereof; n is 1 or 2; R 2 is any straight or branched chain alkyl or alkenyl of C 1 -C 9 C 3 -C 8 cycloalkyl, C 5 -C 7 cycloalkenyl, or An, wherein said alkyl, cycloalkyl or cycloalkenyl are either unsubstituted or substituted positions with straight chain alkyl or alkenyl C1-C, hydroxyl, or a combination thereof; Y; An and Ar2 are independently a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, alkyl, or alkenyl of Straight or branched chain of Ci-Cß, heteroatoms selected from the group consisting of O, N, S, and a combination thereof. J The mono-, and bicyclic, carbo- and heterocyclic rings include without limitation naphthyl, iridolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl and phenyl.

FORMULA II A preferred embodiment of this invention is a compound of the formula I I: or a pharmaceutically acceptable salt thereof, wherein: A. B and C are independently CH2, O, S, SO, SO2, NH, or NR ^ R, is straight or branched chain alkyl or alkenyl of C1-C2, the which is substituted in one or more positions with (An) n, (An) n connected by a straight or branched chain alkyl or alkenyl of C? -C6, or »a combination thereof; n is 1 or 2; I *! R2 is either a straight or branched chain alkyl or alkenyl of C1-C3. C3-C8 cycloalkyl, C5-C7 cycloalkenyl, An; and An is a mono-, bi-, or tricyclic, carbo- or heterocyclic ring, wherein the ring is unsubstituted or substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, straight-chained alkyl or alkenyl. or branched de'jC-i- Ce, C -? - C4 alkoxy, C1-C4 alkenyloxy, phenoxy, 1 / benzyloxy, amino, or a combination thereof; wherein the sizes of individual rings are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, and a combination thereof. In a particularly preferred embodiment of compounds of the formula II:,) A is CH2; ! B is CH2 or S; C is CH2 or N HX i R-i is selected from the group consisting of 3-phenylpropi and 3- (3-pyridyl) propyl; and? 2 is selected from the group consisting of 3,3-a? met? pent? o, cyclohextlo, and tert-buti ?. Specific examples of this modality are presented in TABLE I. [Á tsLA i No. ABC i I i 1 CH2 S 'CH2 3-phenylpropyl 3,3-dimethylpentyl _ i 2 CHI5 1 CH 3- (pi ridii) propiio 3,3-dimetiipentiio 1 3 CH2 S' CH2 3- phenylpropyl cyclohexyl 4C H2s, CH2 3-phenpropyl tert-butyl 5CH2CH2'NH3-phenylpropyl 3,3-d? methylpentyl 1 i6 C H2 CH2 \ 'NH 3-phenyiopropium cyclohexyium 7CH2CH2. N H 3-phenolpropyl tert-butyl, FORMU LA l l Another preferred embodiment of this invention is a compound of the. '\ formula l l l: I u? or a pharmaceutically acceptable salt thereof, wherein: A, B, C and D are independently CH2, O, S, SO, SO2, NH or NR-i; Ri is a straight or branched chain alkyl or alkenyl of C1-C5, which is substituted at one or more positions with (An) n, (An) n connected by a straight or branched chain alkyl or alkenyl of: ! i C -? - C6, or a combination thereof; n is 1 or 2; R2 is any straight or branched chain alkyl or alkenyl of C3-C8 cycloalkyl, C5-C7 cycloalkenyl, or An; and An is a mono-, bi- or tricyclic, carbo- or heterocyclic an il, in .1 where the ring is either unsubstituted or substituted in one to three! halo, dihydroxyl, nitro, trifluoromethyl, straight or branched chain alkyl or alkenyl positions of C? -Ce, C1-C4 alkoxy, C1-C alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the sizes of individual rings are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, S, and a combination thereof. In a particularly preferred embodiment of compounds of formula ll: '! A is CH2; , X B is CH2; C is S, O or N H; 'D is CH2; t R-i is selected from the group consisting of 3-phenypropyl and (3,4,5-trimethoxy) phenylpropyl; and R2 is selected from the group consisting of 3,3-dimethylpentyl, cyclohexyl, 3,3-dimethylpropyl, phenyl, and 3,4,5-trimethoxyphenyl. Specific examples of this modality are presented in the TABLE 8 CH2 CH2 S CH2 3-phenylpropyl 3,3-dimethylpropyl CH2 CH2; O CH2 3-phenylpropyl 3,3-dimethylpropyl CH2 3-phenylpropyl cyclohexyl CH2 3-phenylpropyl cyclohexyl CH2 3-phenylpropyl phenyl CH2 3-phenylpropyl phenyl CH2 3-phenylpropyl 3,3-dimethylpropyl CH2 3-phenylpropyl phenyl The present invention exists as antimimer or diastereomeric forms. Including inventions are the enantiomedes, the diastereoisomeric form. The enantiomers, and be separated by methods known to those skilled in the art. i .1 Methods for Using the Compounds of the Invention (1) The compounds of the present invention have an affinity for the FK506 binding protein, particularly FKBP12, which is present in the brain When the compounds of the invention bind to FKBP in the brain. brain, exhibit excellent neurotrophic activity.This activity is useful in the stimulation of damaged neurons, the promotion of neuronal regeneration, the prevention of neurodegeneration, and the treatment of several neurological disorders known to be associated with neuronal degeneration and peripheral neuropathies. In addition, the present invention further relates to a method for carrying out a neuronal activity in an animal, comprising: administering a neurotrophic effective amount of a compound of the formula I, II or III to the in-imal. neuronal activity is selected from the group consisting of stimulation of ne damaged uronas, neuronal regeneration promotion, prevention of neurodegeneration and treatment of neurological disorder. The neurological disorders that can be treated include, but are not limited to: * Trigeminal neuralgia; glossopharyngeal neuralgia; Palsy de Bell; myasthenia gravis; muscular dystrophy; Amyotrophic Lateral Sclerosis; progressive muscular atrophy; progressive hereditary muscular atrophy; Syndromes of herniated invertebrate disc, fractured or prolapsed; cervical spondylosis; Plexus disorders; syndromes of thoracic outlet destruction; peripheral neuropathy such as those caused by lead, dapsone, ticks, porphyria, or Gullain-Barré syndrome; Alzheimer's disease; and Parkinson's disease. The compounds of the present invention are particularly useful for treating a neurological disorder selected from the group consisting of: peripheral neuropathy caused by physical illness or injury, physical damage to the brain, physical damage to the spinal cord, stroke associated with damage cerebral, and neurological disorder related to neurodegeneration. Examples of related neurological disorders -i with neurodegeneration are Alzheimer's disease, disease of! -I Parkinson, and amyotrophic lateral sclerosis. For these purposes the compounds of the present invention can be administered orally, parenterally, by inhalation of i? spray, topically, rectally, nasally, orally, vaginally or via a depot implanted in dosage formulations containing 1 conventional, non-toxic, acceptable carrier and carrier vehicles and pharmaceutically. The term "parenteral" as used herein includes techniques of subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection and infusion. To be therapeutically effective as targets of the central nervous system, the compounds of the present invention should rapidly penetrate the blood-brain barrier when peripherally administered I. Compounds that can not penetrate the blood-brain barrier can be effectively administered by an intraventricular route. The compounds of the present invention can be administered. in the form of sterile injectable preparations, for example, as sterile injectable aqueous or oleaginous suspensions These 11 suspensions can be formulated according to techniques known in the art using suitable dispersing agents or humectants and suspending agents. s can also be sterile injectable solutions or suspensions in diluents-I 'II or non-toxic solvents that are parenterally acceptable, for example, as solutions in 1,3-but'anodiol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, fixed, sterile oils are used,! conventionally as solvent or suspension media. For this purpose, any soft fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives, including olive oil and castor oil especially in their polyoxyethylated versions, are useful in the preparation of injectables. These solutions or suspensions of oil can also contain diluents or dispersants of long-chain alcohol. The compounds can be administered orally in the form of capsules, tablets, suspensions or aqueous solutions. The tablets may contain carriers such as lactose and corn starch, and / or lubricating agents such as magnesium stearate. The capsules may contain diluents including lactose and dried corn starch.

The aqueous suspensions may contain emulsifying and suspension agents combined with the active ingredient. The oral dosage forms 1 may further contain sweetening and / or flavoring and / or coloring agents. The compounds of this invention may be administered: i also rectally in the form of suppositories. These compositions can be prepared by mixing the drug with a non-irritating excipient which is suitable. solid at room temperature, but liquid at the rectal temperature and, therefore, it will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. The compounds of this invention can also be administered topically, especially when the conditions !! Necessary for treatment involve accessible areas or organs for topical application, including neurological disorders of the eye, skin, or lower intestinal tract. Suitable topical formulations are rapidly prepared for each of these areas. For topical application to the eye, or ophthalmic use, the compounds I can be formulated as micronized suspensions in sterile, pH adjusted, isotonic, or preferably, as solutions in sterile, pH-adjusted, isotonic salines, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses the compounds can be formulated in an ointment such as petrolatum. For topical application to the skin, the compounds can be formulated in a suitable ointment containing the suspended or dissolved compound therein, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, composed of polyoxyethylene, polyoxypropylene, emulsifying wax and water. Alternatively, the compounds may be formulated in a suitable lotion or cream containing the active compound suspended or dissolved therein; for example, a mixture of one or more of the following I: mineral oil, sorbitan monostearate, polysorbate 60, wax of cetyl esters, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Topical application for the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. II Dosage levels in the order of about 0.1 mg to about 10,000 mg of the compound of the active ingredient are useful in the treatment of the above conditions, with preferred levels of about 0.1 mg to about 1,000 mg. The amount of active ingredient that can be combined with the carrier materials to produce a single dose form will vary depending on the host treated and the particular mode of administration. It is understood, however, that a specific dose level for any patient in the , particular will depend on a variety of factors that include the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, excretion regimen, drug combination, and the severity of the disease particular that is treated and form of administration Compounds can be administered with other neurotransmitters such as neurotrophic growth factor (NGF), glial factor-derived growth, brain-derived growth factor, ciliary neurotrophic factor, and neurotropin-3. The dose level of other neurotrophic drugs will depend on the previously established factors and the neurotrophic effectiveness of the drug combination.

Pharmaceutical Compositions of the Invention The present invention also relates to a pharmaceutical composition comprising: (i) a neurotrophically effective amount of the compound of the formulas l ', I I or 11, and (ii) a pharmaceutically acceptable carrier. The above discussion regarding the utility and administration of the compounds of the present invention also applies to the pharmaceutical compositions of the present invention.

Examples • The following examples are illustrative of the present invention and are not intended to be limitations thereof. Unless otherwise specified, all percentages are based on 100% by weight of the final compound.

EJ EMPLO 1 I! Synthesis of 3-phenyl-1-propyl (2S) -1 - (3,3-dimethyl-1, 2-dioxopentyl) -2- (4-thiazolidine) carbonate (1) Carboxylate de-1 - (1,2-dioxo-2-methoxyethyl) 2- (4-thiazolidine). A solution of L-thioproline (1.51 g; 11.34 mmol) in 40 mL of dry methylene chloride was cooled to 0 ° C and treated with 3.3 mL (2.41 g, 23.81 mmol) of triethylamine. After stirring this mixture for 30 minutes, a solution of methyl oxalyl chloride (1.81 g, 14.74 mmol) was added dropwise. The resulting mixture was stirred at 0 ° C for 1.5 hours, filtered through celite to remove solids, dried and concentrated. The crude material was purified on a column of silica gel, eluted with 10% of - I MeOH in methylene chloride, to obtain 2.0 g of oxamate as a. I orange-yellow solid. 3-Phenyl-1-propyl (2S) -1 - (1,2-dioxo-2-methoxyethyl) 2- (4-thiazolidine) carboxylate. 1 - (1, 2-) carboxylate was stirred together overnight dimethylaminopyridine (95 mg, 0.75 mmol) and camphorsulfonic acid (175 mg; 0. 75 mmol) in 30 mL of methylene chloride. The mixture was filtered through Ceiite to remove solids and chromatographed (25% ethyl acetate / hexane) to obtain 690 mg of material, H1 N MR (CDCl3, 300 MHz): d 1.92-2.01 (m, '2H); 2.61 -2.69 (m, 2H); 3.34 (m, 1 H); 4.1 1 -4.25 (m, 2H); 4.73 (m, 1 H); 5 34 (m, 1 H); 7.12 (m, 3H); 7.23 (m, 2H). 3-Phenyl-1-propyl (2S) -1 - (3,3-dimethyl-1,2-dioxopentyl) -2- (4-thiazolidine) carboxylate (1). A solution of 3-phenyl-1-propyl (2S) -1 - (1, 2-dioxo-2-methyloxy?) 2- (4-thiazolidine) carboxylate (670 mg, 1.98 mmol) in tetrahydrofuran ( 10 rjnL) was cooled to -78 ° C and treated with 2.3 mL of a 1.0 M * solution of 1,1-dimethylpropylmagnesium chloride in ether. After stirring the mixture for 3 hours, it was poured into saturated ammonium chloride, extracted in ethyl acetate, and the organic phase was washed with water, dried and concentrated. The crude material was purified on a column of silica gel, eluted with 25% ethyl acetate in hexane, to obtain 380 mg of the compound of Example 1 as a yellow oil, H1 NMR (CDCl3, 300 MHz): d 0.86 (t, 3H); 1.21 (s, 3H); 1.26 (s, 3H); 1.62-1.91 (m, 3H); 2.01 (m, 2H); 2.71 (m, 2H); 3.26-3.33 (m, 2H); 4.19 (m, 2H); 4.58 (m, 1H /); 7.19 (m, 3H); 7.30 (m, 2H). Anal. Clcd. for! l C20H27NO4S: C, 63.63; '; H, 7.23; N, 3.71. Found: C, 64.29; H, 7.39; N, 3. 46. l ' . EXAMPLE 2 Synthesis of 3- (3-pyridyl) -1-propyl (2S) -1- (3,3-dimethyl-1,2-dioxopentyl) -2- (4-thiazolidine) carboxylate (2) The compound of Example 2 was prepared according to the procedure of Example 1, using 3- (3-pyridyl) -1-propanol in the final step -I, to give 3- (3-pyridyl) -1-propyl carboxylate. (2S) -1- (3,3-dimethyl-1, 2-dioxopentyl) -2- (4-thiazochrome, H 1 NMR (CDCl 3, 300 MHz): d 0.89 (t, 3H, J = 7.3); "2.03 (tt, 2H, J = 6.4, 7.5), 2.72 (t, .23 (dd, 1H, J = 7.0, 11.8), 4.23 (t, 2H, J = 8.4), 4.55 (d, 2H, J = 8.9), 5.08 (dd, 1H, J = 4.0, 7.0), 7.24 (m, 1H), 8.48 (m, 2H), Anal.Called, for C19H26N2O4S-0.5 H2O: C, 58. 89; H, 7.02; N, 7.23. Found: C, 58.83; H, 7.05; N, 7.19 As discussed above, the compounds of the present invention M have an affinity for the FK506 binding protein, particularly FKBP12. Inhibition of the prolylpeptidyl cis-trans isomerase activity of FKBP can be measured as an indicator of its affinity. : Test Procedure Ki Inhibition of peptidyl-prolyl isomerase activity (rotamase) of the compounds of the invention can be evaluated by known methods described in the literature (Harding, et al., Nature, 1989, 341: 758-760; Holt et al., J. Am. Chem. Soc., 1 15: 9923-9938). These values are obtained as apparent Ki's and are presented in Table ll l. The cis-trans isomerization of a t-alanine-proline binding in a model substrate, N-succinyl-Ala-Ala-Pro-Phe-p-nitroaniiide, is monitored spectrophotometrically in a coupled chymotrypsin assay, which releases para-nitroanilide from the trans form of the substrate. The inhibition of this reaction caused by the addition of different inhibitor concentrations is determined, and the information is analyzed as a load in constant first order relation as a function of inhibitor concentration to give the values Apparent Ki. In a plastic cuvette, 950 mL of ice-cold assay buffer (25 mM, HEPES, pH 7.8, 100 mL NaCl), 10 mL of FKBP (2.5 mM in 10 mM Tris-Cl pH 7.5, 1 00 mM NaCl, were added). 1 mM dithiothreitol), 25 mL of chymotrypsin (50 mg / ml in 1 mM HCl) and 10 mL of test compound at various concentrations in dimethyl sulfoxide. The reaction is initiated by the addition of. 5 mL of substrate (succinyl-Ala-Fe-Pro-Fe-para- - I nitroanilide, 5 mg / m L in 2.35 mM LiCl in trifluoroethanol). Absorbance at 390 nm versus time is monitored for 90 seconds using a spectrophotometer and the relationship constants are determined from the absorbance information logs versus time. tl The information for these experiments for representative compounds is presented in Table l l l under the "Ki" column.

The neurotrophic effects of the compounds of the present invention can be demonstrated in in vitro cell biology experiments, as described below.

Dorsal Root Ganglion of Chicken; I! , I Cultures and • * Buds of Neurites A dorsal root ganglia were dissected from embryos I • i chicken ten days of gestation. Total lymph node explants were cultured in Matrigel-coated 12-well thin-film plates with Liebovitz ™ t L15 plus medium high glucose supplemented with 2 mM glutamine and 10% fetal calf serum, and also containing 10 μM ti of cytosine ß-D arabinofuranoside (Ara C) at 37 ° C in an environment containing 5% C02. Twenty-four hours later, the DRGs were i! treated with several immunophilin ligands. Forty-eight hours after drug treatment, the nodes were visualized under phase contrast or Hoffman Modulation contrast with an inverted Zeiss Axiqvert microscope. Photomicrographs of the explants were made, > ? '1 and were quantified? flos shoots of neurites. Neurites longer than .1 DGR diameter were counted as positive, with total number of * 1 neurites quantified for each experimental condition. Three out of four DGLs were grown t per box, and each treatment was performed in duplicate. The information for these experiments for representative compounds is presented in column "ED50" of Table III. In the l? Fig's. , 1 (A-C) and 2 (A-C) are representative photomicrographs of compounds 1 (1 pM, 10 pM, 100 pM) and 2 (10 pM, 100 pM, 10 nM) that promote neurite outbreaks in sensory neurons respectively. .I »I TABLE l l l ^ Ensavo Results ln Vitro Compound Ki, nM ED 50, nM 1! 215 0.031 2 '! 638 2.0 All publications and patents identified above are incorporated herein by reference. The invention thus described, it will be obvious that it can be varied in many ways. Such variations are not taken into account as departing from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims.

Claims (35)

1. CLAIMS • i 1. A compound of the formula I:

   or a pharmaceutically acceptable salt thereof, wherein: A and B, together with the nitrogen and carbon atoms to which they are respectively attached, form a saturated heterocyclic ring or

   5 to 7 membered unsaturated containing, in addition to the nitrogen atom, at least one heteroatom of O, S, SO, SO2, N H or N R-t in any chemically stable oxidation state; a X is O or S; 1,

   O, S, CH2, or H2; Ri is straight or branched chain alkyl or alkylene of C?-C5, which is substituted at one or more positions with (An) n, (An) p connected by a straight or branched chain alkyl or alkenyl. of d-Ce, C3-C8 cycloalkyl, C3-C8 cycloalkyl connected by a straight or branched chain alkyl or alkenyl of Ci-Cß, Ar2, or a combination, 1 thereof; .n is 1 or 2; R2 is any straight or branched chain alkyl or alkenyl of C? -C6, C3-C8 cycloalkyl, C3-C7 cycloalkenyl, or An, wherein said alkyl, alkenyl, cycloalkyl, or cycloalkenyl is either unsubstituted or substituted? in one or more positions with straight or branched chain alkyl or alkenyl of C? -C, hydroxyl, or a combination thereof? same; and 11 Ar! and Ar2 are independently a mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring is either unsubstituted or substituted in one, three positions with halo, hydroxyl, nitro, • trifluoromethyl, alkyl or alkenyl of straight or branched chain of Ci-Cβ, C 1 -C 4 alkoxy, C 1 -C alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof; wherein the sizes of the individual rings are 5-6 members; and wherein the heterocyclic ring contains 1-6 heteroatoms selected from the group consisting of O, N, I 1 S, and a combination thereof.
2. 2. The compound of Claim 1, wherein the mono- or bicyclic, carbo- or heterocyclic ring is selected from the group consisting of "naphthyl, indolllo, furyl, thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinyl, fluorenyl and phenyl. .
3. 3. The compound of Claim 1, wherein the at least one additional heteroatom in the 5-7 membered saturated or unsaturated heterocyclic ring is N H or N R,.
4. .1 • 1 4.
5. The compound of claim 1, wherein the compound "j has an affinity for immunophilins of the FKBP type of claim 4, wherein the immunophilin of
6. 6. The compound of claim 1, wherein the The compound inhibits rotamase enzymatic activity .1
7. 7. A pharmaceutical composition comprising a neurotrophic effective amount of the compound of Claim 1 and a pharmaceutically acceptable carrier
8. 8. A method for effecting neuronal activity in an animal, comprising :. ' administering to the animal a neurotrophically effective amount of the compound of Claim 1.
9. 9. The method of Claim 8, wherein the neuronal I- 'activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, Prevention of Neurodegeneration and Neurological Disorder Treatment 1.
10. The method of Claim 9, wherein the neurological disorder is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with damage to the brain, and neurological disorder related to neurodegeneration.
11. The method of Claim 10, wherein the neurological disorder related to neurodegeneration is selected from the group consisting of of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. of formula II:
12. I or a pharmaceutically acceptable salt thereof, wherein: il A, B and C are independently CH 2, O, S, SO, SO 2, N H or N R-,; Ri is straight or branched chain alkyl or alkenyl of C1-C5, which is substituted in one or more positions with (An) n, (An) n connected II by a straight or branched chain alkyl or alkenyl of Ci Cß, or a combination thereof; n is 1 or 2; R2 is any straight or branched chain alkyl or alkenyl of C-i-Cg, C3-C8 cycloalkyl, C5-C7 cycloalkenyl, or Ar-,; and An is a mono-, bi- or tricyclic, carbo- or heterocyclic ring, where the ring is either unsubstituted or substituted in one to three positions f, with halo, hydroxyl, nitro, trifluoromethyl, alkyl or alkenyl of string > ? straight or branched from ^ C ^ Cs, C1-C alkoxy, C-C4 anynyloxy, phenoxy, I-benzyloxy, amino or a combination thereof; wherein the sizes of individual rings are 5-6 members; and wherein the heterocyclic ring contains, from 1-6 heteroatoms selected from the group consisting of O, N, S, and a combination thereof.
13. 13. The compound of Claim 12, wherein: A is CH2;; | B is CH2 or S; -l t C is CH2 or NH; Ri is selected from the group consisting of 3-phenylpropyl and 3- (3-pyridyl) propyl; Y ! 'I R2 is selected from the group consisting of 3,3-dimethylpentyl, cyclohexyl, and tert-butyl.
14. 14. The compound of Claim 13, wherein B is CH2; "" i C is N H; and "~" Ri is 3-phenylpropyl.
15. 15. The compound of Claim 13, wherein: B is S; and C is CH2. i |
16. 16. The compound of claim 12, wherein the compound fj is selected from the group consisting of: i. 3-phenyl-1-propyl (2S) -1 - (3,3-dimethyl-1,2-dioxopentyl) -2- (4-thiazolidine) carboxylate; and 'carboxylate, of 3- (3-pyridyl) -1-propyl (2S) -1 - (3,3-dimethyl-1, 2-dioxopentyl) -2- (4-thiazide)).
17. 17. The compound of Claim 12, wherein the compound ti has an affinity for immunofilins of the FKBP type.
18. 18. The compound of Claim 17, wherein the FKBP type immunophilin is FKBP12.
19. 19. The compound of Claim 12, wherein the -I compound inhibits the rotamase enzymatic activity.
20. 20. A pharmaceutical composition comprising a neurotrophic effective amount of the compound of claim 12 and a pharmaceutically acceptable carrier. ? l [
21. 21. A method for effecting a neuronal activity in an animal, comprising: administering to the animal a neurotrophically effective amount of the compound of Claim 12.
22. 22. The method of Claim 21, wherein the neuronal activity is selected from the group consisting of of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorder.
23. 23. The method of Claim 22, wherein the neurological I disorder is selected from the group consisting of peripheral neuropathy. caused by injury or illness, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and disorder! ! neurological related to neurodegeneration.
24. 24. The method of claim 23, wherein the neurological disorder related to neurodegeneration is selected from the group consisting of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.
25. 25 A compound of the formula l l l:

    or a pharmaceutically acceptable salt thereof, wherein: A, B and C are independently CH2, O, S, SO, SO2, NH or NR ^ Ri is straight or branched chain alkyl or alkynyl of C1-C5, the which is substituted e, n one or more positions with (An) n, (An) p connected • I by a straight or branched chain alkyl or alkenyl of C? -C6, or: j a combination thereof; I n is 1 or 2; R2 is any straight or branched chain alkyl or alkenyl of

    C1-C9, C3-C3 cycloalkyl, C5-C7 cycloalkenyl, or An; and - í.! , Ar! is a mono-, bi- or tricyclic, carbo- or heterocyclic ring, where the ring is unsubstituted or substituted in one to three positions with halo, hydroxyl, nitro, trifluoromethyl, straight or branched alkyl or alkenyl. of (LX-Ce, C1-C4 alkoxy, C-, C4-alkenyloxy, phenoxy, benzyloxy, amino, or a combination thereof, wherein the individual ring sizes are 5-6 members, and where the heterocyclic ring contains from 1-6 heteroatoms selected from the group consisting of O, NS, and a combination thereof.
26. 26. The compound of Claim 25, wherein: A is CH2; B is CH2; : 'f i C is S, O or N H; D is CH2; [,. Ri is selected from the group consisting of 3-phenylpropyl and (3,4,5-

    A group consisting of 3,3-dimethylpentyl, phenyl, and 3,4,5-trimethoxyphenyl.
27. 27. The compound of Claim 26, wherein: H C is N H; Y .' R2 is 3,3-dimethylpropyl or phenyl.
28. 28. The compound of claim 25, wherein compound 11 has an affinity for immunophilins of the FKBP type.
29. 29. The compound of Claim 28, wherein the immunofiiin i. of type FKBP is FKBP12.
30. 30. The compound of Claim 25, wherein the compound "A" inhibits rotamase enzymatic activity. "A pharmaceutical composition comprising a neurotrophically effective amount of the compound of Claim 25 and a The pharmaceutically acceptable carrier r 32. A method for effecting neuronal activity in an animal, comprising: • administering to an an imal a neurotrophically effective amount of the compound of Claim 25. -i go 11 33. The method of Claim 32, wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of il neurodegeneration and treatment of neurological disorder 34. The method of Claim 33, wherein the Disorder? I "neurological is selected from the group consisting of peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorder related to neurodegeneration. 35. The method of Claim 34, wherein the disorder;? Neurological-related neurodegeneration is selected from the group 'i > t which consists of Alzheimer's Disease, Parkinson's Disease, and i ', 1 amyotrophic lateral sclerosis. 11 'ii